| 1 | 2023-02-23 12:07:03 | Drug Description | <h4>What is A-Methapred and how is it used?</h4> <p>A-Methapred is a prescription medicine used to treat the symptoms of Allergic Conditions and Acute Exacerbation of Multiple <a href="/sclerosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Sclerosis</a>. A-Methapred may be used alone or with other medications.</p> <p>A-Methapred belongs to a class of drugs called Corticosteroids; Anti-Inflammatory Agents.</p> <p>It is not known if A-Methapred is safe and effective in children younger than 12 years of age.</p> <h4>What are the possible side effects of A-Methapred?</h4> <p>A-Methapred may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>blurred vision,</li> <li><a href="/tunnel_vision/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">tunnel vision</a>,</li> <li>eye pain,</li> <li>seeing halos around lights,</li> <li>shortness of breath,</li> <li>swelling,</li> <li>rapid weight gain,</li> <li>severe depression,</li> <li>changes in personality,</li> <li>unusual thoughts or behavior,</li> <li>new or unusual pain in an arm or leg or in your back,</li> <li>severe pain in your upper stomach spreading to your back,</li> <li>nausea,</li> <li>vomiting,</li> <li>bloody or tarry stools,</li> <li><a href="/coughing_up_blood/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">coughing up blood</a>,</li> <li><a href="/vomit/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">vomit</a> that looks like coffee grounds,</li> <li><a href="/seizure/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">seizure</a>,</li> <li>leg cramps,</li> <li>constipation,</li> <li>irregular heartbeats,</li> <li>fluttering in your chest,</li> <li>increased thirst,</li> <li>increased urination,</li> <li>numbness or tingling,</li> <li>muscle weakness, and</li> <li>limp feeling</li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of A-Methapred include:</p> <ul> <li>weight gain (especially in your face or your upper back and torso),</li> <li>slow wound healing,</li> <li>muscle pain or weakness,</li> <li>thinning skin,</li> <li>increased sweating,</li> <li>stomach discomfort,</li> <li>bloating,</li> <li>headache, and</li> <li>changes in your menstrual periods</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of A-Methapred. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <a name="D"></a> <h3>DESCRIPTION</h3> <p>A-Methapred (methylprednisolone sodium succinate for injection, USP) sterile powder contains methylprednisolone sodium succinate as the active ingredient. Methylprednisolone sodium succinate, USP, occurs as a white, or nearly white, odorless hygroscopic, amorphous solid. It is very soluble in water and in alcohol; it is insoluble in <a href="/script/main/art.asp?articlekey=7796">chloroform</a> and is very slightly soluble in <a href="/script/main/art.asp?articlekey=6845">acetone</a>.</p> <p>The chemical name for methylprednisolone sodium succinate is pregna-1,4-diene-3,20-dione,21-(3-carboxy-1-oxo-propoxy)-11,17-dihydroxy-6-methyl-monosodium salt, (6a, 11ß), and the molecular weight is 496.53.</p> <p>The structural formula is represented below:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="204"> <tbody> <tr> <td><img alt="A-Methapred (methylprednisolone sodium succinate) structural formula illustration" height="169" src="https://images.rxlist.com/images/rxlist/a-methapred1.gif" width="314" /></td> </tr> </tbody> </table> </center> <p></p> <p>Methylprednisolone sodium succinate is so extremely soluble in water that it may be administered in a small volume of diluent and is especially well suited for intravenous use in situations in which high blood levels of methylprednisolone are required rapidly.</p> <p>A-Methapred (methylprednisolone sodium succinate) is available in several strengths and packages for intravenous or <a href="/intramuscular_im/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">intramuscular</a> administration.</p> <p><b>40 mg Single-Dose Vial</b>- Each mL (when mixed) contains methylprednisolone sodium succinate equivalent to 40 mg methylprednisolone; also 1.6 mg monobasic sodium <a href="/script/main/art.asp?articlekey=4879">phosphate</a> anhydrous; 17.46 mg dibasic sodium phosphate anhydrous; 25 mg <a href="/script/main/art.asp?articlekey=25973">lactose</a> anhydrous; 8.8 mg benzyl alcohol added as preservative.</p> <p><b>125 mg Single-Dose Vial</b>- Each 2 mL (when mixed) contains methylprednisolone sodium succinate equivalent to 125 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; 17.4 mg dibasic sodium phosphate anhydrous; 17.6 mg benzyl alcohol added as preservative.</p> <p>When necessary, the pH of each formula was adjusted with sodium hydroxide so that the pH of the reconstituted solution is within the USP specified range of 7 to 8 and the tonicities are, for the 40 mg per mL solution, 0.50 <a href="/script/main/art.asp?articlekey=24592">osmolar</a>; for the 125 mg per 2 mL, 0.40 osmolar; (Isotonic <a href="/script/main/art.asp?articlekey=16206">saline</a> = 0.28 osmolar).</p> <p><b>IMPORTANT</b>- Use only Bacteriostatic Water For Injection with Benzyl Alcohol when reconstituting A-Methapred (methylprednisolone sodium succinate) .</p> <p><b>Use within 48 hours after mixing. </b></p> </div> <div id="667441035-1" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-1", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <h4>What is A-Methapred and how is it used?</h4> <p>A-Methapred is a prescription medicine used to treat the symptoms of Allergic Conditions and Acute Exacerbation of Multiple <a href="/sclerosis/definition.htm" ">Sclerosis</a>. A-Methapred may be used alone or with other medications.</p> <p>A-Methapred belongs to a class of drugs called Corticosteroids; Anti-Inflammatory Agents.</p> <p>It is not known if A-Methapred is safe and effective in children younger than 12 years of age.</p> <h4>What are the possible side effects of A-Methapred?</h4> <p>A-Methapred may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>blurred vision,</li> <li><a href="/tunnel_vision/definition.htm" ">tunnel vision</a>,</li> <li>eye pain,</li> <li>seeing halos around lights,</li> <li>shortness of breath,</li> <li>swelling,</li> <li>rapid weight gain,</li> <li>severe depression,</li> <li>changes in personality,</li> <li>unusual thoughts or behavior,</li> <li>new or unusual pain in an arm or leg or in your back,</li> <li>severe pain in your upper stomach spreading to your back,</li> <li>nausea,</li> <li>vomiting,</li> <li>bloody or tarry stools,</li> <li><a href="/coughing_up_blood/definition.htm" ">coughing up blood</a>,</li> <li><a href="/vomit/definition.htm" ">vomit</a> that looks like coffee grounds,</li> <li><a href="/seizure/definition.htm" ">seizure</a>,</li> <li>leg cramps,</li> <li>constipation,</li> <li>irregular heartbeats,</li> <li>fluttering in your chest,</li> <li>increased thirst,</li> <li>increased urination,</li> <li>numbness or tingling,</li> <li>muscle weakness, and</li> <li>limp feeling</li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of A-Methapred include:</p> <ul> <li>weight gain (especially in your face or your upper back and torso),</li> <li>slow wound healing,</li> <li>muscle pain or weakness,</li> <li>thinning skin,</li> <li>increased sweating,</li> <li>stomach discomfort,</li> <li>bloating,</li> <li>headache, and</li> <li>changes in your menstrual periods</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of A-Methapred. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <a name="D"></a> <h3>DESCRIPTION</h3> <p>A-Methapred (methylprednisolone sodium succinate for injection, USP) sterile powder contains methylprednisolone sodium succinate as the active ingredient. Methylprednisolone sodium succinate, USP, occurs as a white, or nearly white, odorless hygroscopic, amorphous solid. It is very soluble in water and in alcohol; it is insoluble in <a href="/script/main/art.asp?articlekey=7796">chloroform</a> and is very slightly soluble in <a href="/script/main/art.asp?articlekey=6845">acetone</a>.</p> <p>The chemical name for methylprednisolone sodium succinate is pregna-1,4-diene-3,20-dione,21-(3-carboxy-1-oxo-propoxy)-11,17-dihydroxy-6-methyl-monosodium salt, (6a, 11ß), and the molecular weight is 496.53.</p> <p>The structural formula is represented below:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="204"> <tbody> <tr> <td><img alt="A-Methapred (methylprednisolone sodium succinate) structural formula illustration" height="169" src="https://images.rxlist.com/images/rxlist/a-methapred1.gif" width="314" /></td> </tr> </tbody> </table> </center> <p></p> <p>Methylprednisolone sodium succinate is so extremely soluble in water that it may be administered in a small volume of diluent and is especially well suited for intravenous use in situations in which high blood levels of methylprednisolone are required rapidly.</p> <p>A-Methapred (methylprednisolone sodium succinate) is available in several strengths and packages for intravenous or <a href="/intramuscular_im/definition.htm" ">intramuscular</a> administration.</p> <p><b>40 mg Single-Dose Vial</b>- Each mL (when mixed) contains methylprednisolone sodium succinate equivalent to 40 mg methylprednisolone; also 1.6 mg monobasic sodium <a href="/script/main/art.asp?articlekey=4879">phosphate</a> anhydrous; 17.46 mg dibasic sodium phosphate anhydrous; 25 mg <a href="/script/main/art.asp?articlekey=25973">lactose</a> anhydrous; 8.8 mg benzyl alcohol added as preservative.</p> <p><b>125 mg Single-Dose Vial</b>- Each 2 mL (when mixed) contains methylprednisolone sodium succinate equivalent to 125 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; 17.4 mg dibasic sodium phosphate anhydrous; 17.6 mg benzyl alcohol added as preservative.</p> <p>When necessary, the pH of each formula was adjusted with sodium hydroxide so that the pH of the reconstituted solution is within the USP specified range of 7 to 8 and the tonicities are, for the 40 mg per mL solution, 0.50 <a href="/script/main/art.asp?articlekey=24592">osmolar</a>; for the 125 mg per 2 mL, 0.40 osmolar; (Isotonic <a href="/script/main/art.asp?articlekey=16206">saline</a> = 0.28 osmolar).</p> <p><b>IMPORTANT</b>- Use only Bacteriostatic Water For Injection with Benzyl Alcohol when reconstituting A-Methapred (methylprednisolone sodium succinate) .</p> <p><b>Use within 48 hours after mixing. </b></p> </div> <div id="667441035-1" class="medianet"><</div> </div> </div> | 1 | 2023-02-01 17:16:26 | A-Methapred (Methylprednisolone Sodium Succinate) | A | Corticosteroids | A-Methapred | methylprednisolone sodium succinate | A-Methapred | John P. Cunha, DO, FACOEP |
| 2 | 2023-02-23 12:07:03 | Indications | <a name="I"></a><h3>INDICATIONS</h3> <p>When oral therapy is not feasible, and the strength, dosage form and route of administration of the drug reasonably lend the preparation to the treatment of the condition, A-Methapred (methylprednisolone sodium succinate) sterile powder is indicated for intravenous or intramuscular use in the following conditions: </p> <ol> <li><b>Endocrine Disorders</b> <ul> <li> Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with <a href="/script/main/art.asp?articlekey=4390">mineralocorticoids</a> where applicable; in infancy, mineralocorticoid supplementation is of particular importance)</li> <li> Acute adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; mineralocorticoid supplementation may be necessary, particularly when synthetic analogs are used)</li> <li> Preoperatively and in the event of serious trauma or illness, in patients with known adrenal insufficiency or when adrenocortical reserve is doubtful</li> <li> <a href="/shock/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Shock</a> unresponsive to conventional therapy if adrenocortical insufficiency exists or is suspected</li> <li> <a href="/script/main/art.asp?articlekey=15599">Congenital</a> adrenal <a href="/script/main/art.asp?articlekey=3845">hyperplasia</a></li> <li> <a href="/script/main/art.asp?articlekey=3834">Hypercalcemia</a> associated with <a href="/script/main/art.asp?articlekey=2580">cancer</a></li> <li> Nonsuppurative <a href="/script/main/art.asp?articlekey=5784">thyroiditis</a></li> </ul> </li> <li><b>Rheumatic Disorders </b><br /> As adjunctive therapy for short-term administration (to tide the patient over an acute episode or <a href="/script/main/art.asp?articlekey=24661">exacerbation</a>) in: <ul> <li> Post-traumatic <a href="/script/main/art.asp?articlekey=4675">osteoarthritis</a></li> <li> <a href="/script/main/art.asp?articlekey=5688">Synovitis</a> of osteoarthritis</li> <li> <a href="/script/main/art.asp?articlekey=5354">Rheumatoid arthritis</a>, including <a href="/script/main/art.asp?articlekey=4081">juvenile rheumatoid arthritis</a> (selected cases may require low-dose <a href="/script/main/art.asp?articlekey=4248">maintenance therapy</a>)</li> <li> Acute and <a href="/script/main/art.asp?articlekey=6875">subacute</a> <a href="/script/main/art.asp?articlekey=2559">bursitis</a></li> <li> <a href="/script/main/art.asp?articlekey=64374">Epicondylitis</a></li> <li> Acute nonspecific tenosynovitis</li> <li> Acute <a href="/script/main/art.asp?articlekey=3626">gouty arthritis</a></li> <li> <a href="/script/main/art.asp?articlekey=5105">Psoriatic arthritis</a></li> <li> <a href="/script/main/art.asp?articlekey=2264">Ankylosing spondylitis</a></li> </ul> </li> <li><b>Collagen Diseases </b><br /> During an exacerbation or as maintenance therapy in selected cases of: <ul> <li> <a href="/script/main/art.asp?articlekey=8065">Systemic lupus erythematosus</a></li> <li> <a href="/script/main/art.asp?articlekey=25440">Systemic</a> <a href="/script/main/art.asp?articlekey=2955">dermatomyositis</a> (<a href="/script/main/art.asp?articlekey=4995">polymyositis</a>)</li> <li> Acute rheumatic <a href="/script/main/art.asp?articlekey=2633">carditis</a></li> </ul> </li> <li><b>Dermatologic Diseases </b> <ul> <li> <a href="/script/main/art.asp?articlekey=30710">Pemphigus</a></li> <li> Severe <a href="/script/main/art.asp?articlekey=3306">erythema</a> multi-forme (<a href="/script/main/art.asp?articlekey=14086">Stevens-Johnson syndrome</a>)</li> <li> Exfoliative <a href="/script/main/art.asp?articlekey=2951">dermatitis</a></li> <li> <a href="/script/main/art.asp?articlekey=2548">Bullous</a> <a href="/dermatitis_herpetiformis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">dermatitis herpetiformis</a></li> <li> Severe <a href="/script/main/art.asp?articlekey=31325">seborrheic dermatitis</a></li> <li> Severe <a href="/script/main/art.asp?articlekey=5104">psoriasis</a></li> <li> <a href="/script/main/art.asp?articlekey=4475">Mycosis fungoides</a></li> </ul> </li> <li><b>Allergic States </b><br /> Control of severe or incapacitating allergic conditions <a href="/script/main/art.asp?articlekey=4008">intractable</a> to adequate trials of conventional treatment in: <ul> <li> Bronchial <a href="/script/main/art.asp?articlekey=2373">asthma</a></li> <li> <a href="/script/main/art.asp?articlekey=20442">Contact dermatitis</a></li> <li> <a href="/script/main/art.asp?articlekey=9692">Atopic dermatitis</a></li> <li> <a href="/script/main/art.asp?articlekey=5470">Serum</a> sickness</li> <li> Seasonal or perennial <a href="/script/main/art.asp?articlekey=2197">allergic rhinitis</a></li> <li> Drug hypersensitivity reactions</li> <li> Urticarial <a href="/script/main/art.asp?articlekey=5836">transfusion</a> reactions</li> <li> Acute noninfectious <a href="/script/main/art.asp?articlekey=6215">laryngeal</a> <a href="/script/main/art.asp?articlekey=3192">edema</a> (<a href="/script/main/art.asp?articlekey=3286">epinephrine</a> is the drug of first choice)</li> </ul> </li> <li><b>Ophthalmic Diseases </b><br /> Severe acute and <a href="/script/main/art.asp?articlekey=2728">chronic</a> allergic and inflammatory processes involving the eye, such as: <ul> <li> <a href="/script/main/art.asp?articlekey=3734">Herpes zoster</a> ophthalmicus</li> <li> <a href="/script/main/art.asp?articlekey=4045">Iritis</a>, iridocyclitis</li> <li> Chorioretinitis</li> <li> Diffuse <a href="/script/main/art.asp?articlekey=9277">posterior</a> <a href="/script/main/art.asp?articlekey=9889">uveitis</a> and <a href="/script/main/art.asp?articlekey=11118">choroiditis</a></li> <li> <a href="/script/main/art.asp?articlekey=4651">Optic</a> <a href="/script/main/art.asp?articlekey=4549">neuritis</a></li> <li> <a href="/script/main/art.asp?articlekey=24262">Sympathetic ophthalmia</a></li> <li> <a href="/script/main/art.asp?articlekey=9248">Anterior</a> segment <a href="/script/main/art.asp?articlekey=3979">inflammation</a></li> <li> <a href="/script/main/art.asp?articlekey=2195">Allergic conjunctivitis</a></li> <li> Allergic <a href="/script/main/art.asp?articlekey=10600">corneal</a> marginal ulcers</li> <li> <a href="/script/main/art.asp?articlekey=4092">Keratitis</a></li> </ul> </li> <li><b>Gastrointestinal Diseases</b><br /> To tide the patient over a critical period of the disease in: <ul> <li>Ulcerative colitis (<a href="/script/main/art.asp?articlekey=5695">systemic therapy</a>)</li> <li> <a href="/script/main/art.asp?articlekey=5280">Regional enteritis</a> (systemic therapy)</li> </ul> </li> <li><b>Respiratory Diseases </b> <ul> <li> <a href="/script/main/art.asp?articlekey=20424">Symptomatic</a> <a href="/script/main/art.asp?articlekey=13430">sarcoidosis</a></li> <li> <a href="/script/main/art.asp?articlekey=25539">Berylliosis</a></li> <li> Fulminating or disseminated <a href="/script/main/art.asp?articlekey=23035">pulmonary tuberculosis</a> when used concurrently with appropriate antituberculous <a href="/script/main/art.asp?articlekey=2698">chemotherapy</a></li> <li> Loeffler's <a href="/script/main/art.asp?articlekey=5613">syndrome</a> not manageable by other means </li> <li> <a href="/script/main/art.asp?articlekey=2369">Aspiration</a> pneumonitis</li> </ul> </li> <li><b>Hematologic Disorders </b> <ul> <li> <a href="/script/main/art.asp?articlekey=2118">Acquired</a> (<a href="/script/main/art.asp?articlekey=19102">autoimmune</a>) <a href="/script/main/art.asp?articlekey=3695">hemolytic anemia</a></li> <li> <a href="/script/main/art.asp?articlekey=24177">Idiopathic thrombocytopenic purpura</a> in adults (IV only; IM administration is contraindicated)</li> <li> Secondary <a href="/script/main/art.asp?articlekey=97574">thrombocytopenia</a> in adults</li> <li> Erythroblastopenia (<a href="/script/main/art.asp?articlekey=9988">RBC</a> <a href="/script/main/art.asp?articlekey=15491">anemia</a>)</li> <li> Congenital (erythroid) hypoplastic anemia</li> </ul> </li> <li><b>Neoplastic Diseases </b><br /> For palliative management of: <ul> <li> Leukemias and lymphomas in adults</li> <li> <a href="/script/main/art.asp?articlekey=2135">Acute leukemia</a> of childhood</li> </ul> </li> <li><b>Edematous States </b></li> <ul> <li> To induce <a href="/script/main/art.asp?articlekey=21221">diuresis</a> or <a href="/script/main/art.asp?articlekey=5296">remission</a> of <a href="/script/main/art.asp?articlekey=5086">proteinuria</a> in the nephrotic syndrome, without <a href="/script/main/art.asp?articlekey=11854">uremia</a>, of the <a href="/script/main/art.asp?articlekey=3892">idiopathic</a> type or that due to <a href="/script/main/art.asp?articlekey=8064">lupus</a> erythematosus</li> </ul> <li><b>Nervous System </b></li> <ul> <li> Acute exacerbations of <a href="/script/main/art.asp?articlekey=4457">multiple sclerosis</a></li> </ul> <li><b>Miscellaneous</b> <ul> <li> <a href="/script/main/art.asp?articlekey=39968">Tuberculous meningitis</a> with <a href="/script/main/art.asp?articlekey=13757">subarachnoid</a> block or impending block when used concurrently with appropriate antituberculous chemotherapy</li> <li> <a href="/script/main/art.asp?articlekey=8144">Trichinosis</a> with neurologic or myocardial involvement</li> </ul> </li> </ol> </div> <a class="mediaPrmo ss" href="/kidney_stone_slideshow/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/kidney_stone_s1_crystal.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">Kidney Stones: Symptoms, Causes, and Treatment</span> <span class="btn">See Slideshow</span> </a> </div> </div> | <a name="I"></a><h3>INDICATIONS</h3> <p>When oral therapy is not feasible, and the strength, dosage form and route of administration of the drug reasonably lend the preparation to the treatment of the condition, A-Methapred (methylprednisolone sodium succinate) sterile powder is indicated for intravenous or intramuscular use in the following conditions: </p> <ol> <li><b>Endocrine Disorders</b> <ul> <li> Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with <a href="/script/main/art.asp?articlekey=4390">mineralocorticoids</a> where applicable; in infancy, mineralocorticoid supplementation is of particular importance)</li> <li> Acute adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; mineralocorticoid supplementation may be necessary, particularly when synthetic analogs are used)</li> <li> Preoperatively and in the event of serious trauma or illness, in patients with known adrenal insufficiency or when adrenocortical reserve is doubtful</li> <li> <a href="/shock/definition.htm" ">Shock</a> unresponsive to conventional therapy if adrenocortical insufficiency exists or is suspected</li> <li> <a href="/script/main/art.asp?articlekey=15599">Congenital</a> adrenal <a href="/script/main/art.asp?articlekey=3845">hyperplasia</a></li> <li> <a href="/script/main/art.asp?articlekey=3834">Hypercalcemia</a> associated with <a href="/script/main/art.asp?articlekey=2580">cancer</a></li> <li> Nonsuppurative <a href="/script/main/art.asp?articlekey=5784">thyroiditis</a></li> </ul> </li> <li><b>Rheumatic Disorders </b><br /> As adjunctive therapy for short-term administration (to tide the patient over an acute episode or <a href="/script/main/art.asp?articlekey=24661">exacerbation</a>) in: <ul> <li> Post-traumatic <a href="/script/main/art.asp?articlekey=4675">osteoarthritis</a></li> <li> <a href="/script/main/art.asp?articlekey=5688">Synovitis</a> of osteoarthritis</li> <li> <a href="/script/main/art.asp?articlekey=5354">Rheumatoid arthritis</a>, including <a href="/script/main/art.asp?articlekey=4081">juvenile rheumatoid arthritis</a> (selected cases may require low-dose <a href="/script/main/art.asp?articlekey=4248">maintenance therapy</a>)</li> <li> Acute and <a href="/script/main/art.asp?articlekey=6875">subacute</a> <a href="/script/main/art.asp?articlekey=2559">bursitis</a></li> <li> <a href="/script/main/art.asp?articlekey=64374">Epicondylitis</a></li> <li> Acute nonspecific tenosynovitis</li> <li> Acute <a href="/script/main/art.asp?articlekey=3626">gouty arthritis</a></li> <li> <a href="/script/main/art.asp?articlekey=5105">Psoriatic arthritis</a></li> <li> <a href="/script/main/art.asp?articlekey=2264">Ankylosing spondylitis</a></li> </ul> </li> <li><b>Collagen Diseases </b><br /> During an exacerbation or as maintenance therapy in selected cases of: <ul> <li> <a href="/script/main/art.asp?articlekey=8065">Systemic lupus erythematosus</a></li> <li> <a href="/script/main/art.asp?articlekey=25440">Systemic</a> <a href="/script/main/art.asp?articlekey=2955">dermatomyositis</a> (<a href="/script/main/art.asp?articlekey=4995">polymyositis</a>)</li> <li> Acute rheumatic <a href="/script/main/art.asp?articlekey=2633">carditis</a></li> </ul> </li> <li><b>Dermatologic Diseases </b> <ul> <li> <a href="/script/main/art.asp?articlekey=30710">Pemphigus</a></li> <li> Severe <a href="/script/main/art.asp?articlekey=3306">erythema</a> multi-forme (<a href="/script/main/art.asp?articlekey=14086">Stevens-Johnson syndrome</a>)</li> <li> Exfoliative <a href="/script/main/art.asp?articlekey=2951">dermatitis</a></li> <li> <a href="/script/main/art.asp?articlekey=2548">Bullous</a> <a href="/dermatitis_herpetiformis/definition.htm" ">dermatitis herpetiformis</a></li> <li> Severe <a href="/script/main/art.asp?articlekey=31325">seborrheic dermatitis</a></li> <li> Severe <a href="/script/main/art.asp?articlekey=5104">psoriasis</a></li> <li> <a href="/script/main/art.asp?articlekey=4475">Mycosis fungoides</a></li> </ul> </li> <li><b>Allergic States </b><br /> Control of severe or incapacitating allergic conditions <a href="/script/main/art.asp?articlekey=4008">intractable</a> to adequate trials of conventional treatment in: <ul> <li> Bronchial <a href="/script/main/art.asp?articlekey=2373">asthma</a></li> <li> <a href="/script/main/art.asp?articlekey=20442">Contact dermatitis</a></li> <li> <a href="/script/main/art.asp?articlekey=9692">Atopic dermatitis</a></li> <li> <a href="/script/main/art.asp?articlekey=5470">Serum</a> sickness</li> <li> Seasonal or perennial <a href="/script/main/art.asp?articlekey=2197">allergic rhinitis</a></li> <li> Drug hypersensitivity reactions</li> <li> Urticarial <a href="/script/main/art.asp?articlekey=5836">transfusion</a> reactions</li> <li> Acute noninfectious <a href="/script/main/art.asp?articlekey=6215">laryngeal</a> <a href="/script/main/art.asp?articlekey=3192">edema</a> (<a href="/script/main/art.asp?articlekey=3286">epinephrine</a> is the drug of first choice)</li> </ul> </li> <li><b>Ophthalmic Diseases </b><br /> Severe acute and <a href="/script/main/art.asp?articlekey=2728">chronic</a> allergic and inflammatory processes involving the eye, such as: <ul> <li> <a href="/script/main/art.asp?articlekey=3734">Herpes zoster</a> ophthalmicus</li> <li> <a href="/script/main/art.asp?articlekey=4045">Iritis</a>, iridocyclitis</li> <li> Chorioretinitis</li> <li> Diffuse <a href="/script/main/art.asp?articlekey=9277">posterior</a> <a href="/script/main/art.asp?articlekey=9889">uveitis</a> and <a href="/script/main/art.asp?articlekey=11118">choroiditis</a></li> <li> <a href="/script/main/art.asp?articlekey=4651">Optic</a> <a href="/script/main/art.asp?articlekey=4549">neuritis</a></li> <li> <a href="/script/main/art.asp?articlekey=24262">Sympathetic ophthalmia</a></li> <li> <a href="/script/main/art.asp?articlekey=9248">Anterior</a> segment <a href="/script/main/art.asp?articlekey=3979">inflammation</a></li> <li> <a href="/script/main/art.asp?articlekey=2195">Allergic conjunctivitis</a></li> <li> Allergic <a href="/script/main/art.asp?articlekey=10600">corneal</a> marginal ulcers</li> <li> <a href="/script/main/art.asp?articlekey=4092">Keratitis</a></li> </ul> </li> <li><b>Gastrointestinal Diseases</b><br /> To tide the patient over a critical period of the disease in: <ul> <li>Ulcerative colitis (<a href="/script/main/art.asp?articlekey=5695">systemic therapy</a>)</li> <li> <a href="/script/main/art.asp?articlekey=5280">Regional enteritis</a> (systemic therapy)</li> </ul> </li> <li><b>Respiratory Diseases </b> <ul> <li> <a href="/script/main/art.asp?articlekey=20424">Symptomatic</a> <a href="/script/main/art.asp?articlekey=13430">sarcoidosis</a></li> <li> <a href="/script/main/art.asp?articlekey=25539">Berylliosis</a></li> <li> Fulminating or disseminated <a href="/script/main/art.asp?articlekey=23035">pulmonary tuberculosis</a> when used concurrently with appropriate antituberculous <a href="/script/main/art.asp?articlekey=2698">chemotherapy</a></li> <li> Loeffler's <a href="/script/main/art.asp?articlekey=5613">syndrome</a> not manageable by other means </li> <li> <a href="/script/main/art.asp?articlekey=2369">Aspiration</a> pneumonitis</li> </ul> </li> <li><b>Hematologic Disorders </b> <ul> <li> <a href="/script/main/art.asp?articlekey=2118">Acquired</a> (<a href="/script/main/art.asp?articlekey=19102">autoimmune</a>) <a href="/script/main/art.asp?articlekey=3695">hemolytic anemia</a></li> <li> <a href="/script/main/art.asp?articlekey=24177">Idiopathic thrombocytopenic purpura</a> in adults (IV only; IM administration is contraindicated)</li> <li> Secondary <a href="/script/main/art.asp?articlekey=97574">thrombocytopenia</a> in adults</li> <li> Erythroblastopenia (<a href="/script/main/art.asp?articlekey=9988">RBC</a> <a href="/script/main/art.asp?articlekey=15491">anemia</a>)</li> <li> Congenital (erythroid) hypoplastic anemia</li> </ul> </li> <li><b>Neoplastic Diseases </b><br /> For palliative management of: <ul> <li> Leukemias and lymphomas in adults</li> <li> <a href="/script/main/art.asp?articlekey=2135">Acute leukemia</a> of childhood</li> </ul> </li> <li><b>Edematous States </b></li> <ul> <li> To induce <a href="/script/main/art.asp?articlekey=21221">diuresis</a> or <a href="/script/main/art.asp?articlekey=5296">remission</a> of <a href="/script/main/art.asp?articlekey=5086">proteinuria</a> in the nephrotic syndrome, without <a href="/script/main/art.asp?articlekey=11854">uremia</a>, of the <a href="/script/main/art.asp?articlekey=3892">idiopathic</a> type or that due to <a href="/script/main/art.asp?articlekey=8064">lupus</a> erythematosus</li> </ul> <li><b>Nervous System </b></li> <ul> <li> Acute exacerbations of <a href="/script/main/art.asp?articlekey=4457">multiple sclerosis</a></li> </ul> <li><b>Miscellaneous</b> <ul> <li> <a href="/script/main/art.asp?articlekey=39968">Tuberculous meningitis</a> with <a href="/script/main/art.asp?articlekey=13757">subarachnoid</a> block or impending block when used concurrently with appropriate antituberculous chemotherapy</li> <li> <a href="/script/main/art.asp?articlekey=8144">Trichinosis</a> with neurologic or myocardial involvement</li> </ul> </li> </ol> </div> <a class="mediaPrmo ss" href="/kidney_stone_slideshow/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/kidney_stone_s1_crystal.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">Kidney Stones: Symptoms, Causes, and Treatment</span> <span class="btn">See Slideshow</span> </a> </div> </div> | 1 | 2023-02-01 17:16:26 | A-Methapred (Methylprednisolone Sodium Succinate) | A | Corticosteroids | A-Methapred | methylprednisolone sodium succinate | A-Methapred | John P. Cunha, DO, FACOEP |
| 3 | 2023-02-23 12:07:03 | Dosage | <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3> <p>When high dose therapy is desired, the recommended dose of A-Methapred (methylprednisolone sodium succinate) sterile powder is 30 mg/kg administered intravenously over at least 30 minutes. This dose may be repeated every 4 to 6 hours for 48 hours.</p> <p> In general, high dose <a href="/script/main/art.asp?articlekey=2849">corticosteroid</a> therapy should be continued only until the patient's condition has stabilized; usually not beyond 48 to 72 hours.</p> <p> Although adverse effects associated with high dose short-term corticoid therapy are uncommon, peptic <a href="/script/main/art.asp?articlekey=11848">ulceration</a> may occur. <a href="/script/main/art.asp?articlekey=11902">Prophylactic</a> antacid therapy may be indicated. </p> <p> In other indications initial dosage will vary from 10 to 40 mg of methylprednisolone depending on the clinical problem being treated. The larger doses may be required for short-term management of severe, acute conditions. The initial dose usually should be given intravenously over a period of several minutes. Subsequent doses may be given intravenously or intramuscularly at intervals dictated by the patient's response and clinical condition. Corticoid therapy is an adjunct to, and not replacement for conventional therapy. </p> <p> Dosage may be reduced for infants and children but should be governed more by the severity of the condition and response of the patient than by age or size. It should not be less than 0.5 mg/kg every 24 hours. </p> <p> Dosage must be decreased or discontinued gradually when the drug has been administered for more than a few days. If a period of spontaneous remission occurs in a chronic condition, treatment should be discontinued. Routine <a href="/script/main/art.asp?articlekey=6463">laboratory</a> studies, such as <a href="/script/main/art.asp?articlekey=5911">urinalysis</a>, two-hour <a href="/script/main/art.asp?articlekey=12094">postprandial</a> <a href="/script/main/art.asp?articlekey=32859">blood sugar</a>, determination of <a href="/script/main/art.asp?articlekey=2486">blood pressure</a> and body weight, and a <a href="/script/main/art.asp?articlekey=2701">chest X-ray</a> should be made at regular intervals during prolonged therapy. Upper <a href="/gi/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">GI</a> X-rays are desirable in patients with an <a href="/script/main/art.asp?articlekey=11847">ulcer</a> history or significant <a href="/script/main/art.asp?articlekey=8285">dyspepsia</a>.</p> <p> A-Methapred (methylprednisolone sodium succinate) may be administered by intravenous or intramuscular injection or by intravenous infusion, the preferred method for initial emergency use being intravenous injection. To administer by intravenous (or intramuscular) injection, prepare solution as directed. The desired dose may be administered intravenously over a period of several minutes. </p> <p>To prepare solutions for intravenous infusion, first prepare the solution for injection as directed. This solution may then be added to indicated amounts of 5% <a href="/script/main/art.asp?articlekey=7040">dextrose</a> in water, isotonic <a href="/script/main/art.asp?articlekey=16206">saline</a> solution or 5% dextrose in isotonic saline solution.</p> <h4>Multiple Sclerosis</h4> <p>In treatment of acute exacerbations of multiple sclerosis, daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective (4 mg of methylprednisolone is equivalent to 5 mg of prednisolone).</p> <h4>Directions for Reconstitution </h4> <ol> <li>Remove protective cap.</li> <li>Cleanse stopper with suitable germicide.</li> <li>Aseptically add 1 mL <a href="/script/main/art.asp?articlekey=20600">Bacteriostatic</a> Water for Injection, USP (with benzyl alcohol) for the 40 mg vial or 2 mL Bacteriostatic Water for Injection, USP (with benzyl alcohol) for the 125 mg vial.</li> <li>Agitate to effect solution.</li> <li><a href="/script/main/art.asp?articlekey=17678">Invert</a> vial. Insert needle through target area of stopper until tip is just visible. Withdraw dose.</li> </ol> <h4>Storage Conditions</h4> <p>Protect from light.</p> <p> Store unreconstituted product at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]</p> <p> Store solution at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]</p> <p> Use solution within 48 hours after mixing.</p> <a name="HS"></a><h3>HOW SUPPLIED</h3> <p>A-Methapred (methylprednisolone sodium succinate) sterile powder is available in the following packages:</p> <p><center> <table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="20%">List </td> <td class="EmphTd" width="40%">Container </td> <td class="EmphTd" width="40%">Concentration </td> </tr> <tr> <td align="center">3217</td> <td align="center">Single-Dose Vial</td> <td align="center">40 mg/vial</td> </tr> <tr> <td align="center">3218 </td> <td align="center">Single-Dose Vial</td> <td align="center">125 mg/vial</td> </tr> </table></center></p> <p class="source">Rev: October, 2005. Hospira Inc., Lake Forest, IL 60045, USA. FDA rev date: 11/25/2008 </p> </div> <div id="667441035-3" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-3", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3> <p>When high dose therapy is desired, the recommended dose of A-Methapred (methylprednisolone sodium succinate) sterile powder is 30 mg/kg administered intravenously over at least 30 minutes. This dose may be repeated every 4 to 6 hours for 48 hours.</p> <p> In general, high dose <a href="/script/main/art.asp?articlekey=2849">corticosteroid</a> therapy should be continued only until the patient's condition has stabilized; usually not beyond 48 to 72 hours.</p> <p> Although adverse effects associated with high dose short-term corticoid therapy are uncommon, peptic <a href="/script/main/art.asp?articlekey=11848">ulceration</a> may occur. <a href="/script/main/art.asp?articlekey=11902">Prophylactic</a> antacid therapy may be indicated. </p> <p> In other indications initial dosage will vary from 10 to 40 mg of methylprednisolone depending on the clinical problem being treated. The larger doses may be required for short-term management of severe, acute conditions. The initial dose usually should be given intravenously over a period of several minutes. Subsequent doses may be given intravenously or intramuscularly at intervals dictated by the patient's response and clinical condition. Corticoid therapy is an adjunct to, and not replacement for conventional therapy. </p> <p> Dosage may be reduced for infants and children but should be governed more by the severity of the condition and response of the patient than by age or size. It should not be less than 0.5 mg/kg every 24 hours. </p> <p> Dosage must be decreased or discontinued gradually when the drug has been administered for more than a few days. If a period of spontaneous remission occurs in a chronic condition, treatment should be discontinued. Routine <a href="/script/main/art.asp?articlekey=6463">laboratory</a> studies, such as <a href="/script/main/art.asp?articlekey=5911">urinalysis</a>, two-hour <a href="/script/main/art.asp?articlekey=12094">postprandial</a> <a href="/script/main/art.asp?articlekey=32859">blood sugar</a>, determination of <a href="/script/main/art.asp?articlekey=2486">blood pressure</a> and body weight, and a <a href="/script/main/art.asp?articlekey=2701">chest X-ray</a> should be made at regular intervals during prolonged therapy. Upper <a href="/gi/definition.htm" ">GI</a> X-rays are desirable in patients with an <a href="/script/main/art.asp?articlekey=11847">ulcer</a> history or significant <a href="/script/main/art.asp?articlekey=8285">dyspepsia</a>.</p> <p> A-Methapred (methylprednisolone sodium succinate) may be administered by intravenous or intramuscular injection or by intravenous infusion, the preferred method for initial emergency use being intravenous injection. To administer by intravenous (or intramuscular) injection, prepare solution as directed. The desired dose may be administered intravenously over a period of several minutes. </p> <p>To prepare solutions for intravenous infusion, first prepare the solution for injection as directed. This solution may then be added to indicated amounts of 5% <a href="/script/main/art.asp?articlekey=7040">dextrose</a> in water, isotonic <a href="/script/main/art.asp?articlekey=16206">saline</a> solution or 5% dextrose in isotonic saline solution.</p> <h4>Multiple Sclerosis</h4> <p>In treatment of acute exacerbations of multiple sclerosis, daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective (4 mg of methylprednisolone is equivalent to 5 mg of prednisolone).</p> <h4>Directions for Reconstitution </h4> <ol> <li>Remove protective cap.</li> <li>Cleanse stopper with suitable germicide.</li> <li>Aseptically add 1 mL <a href="/script/main/art.asp?articlekey=20600">Bacteriostatic</a> Water for Injection, USP (with benzyl alcohol) for the 40 mg vial or 2 mL Bacteriostatic Water for Injection, USP (with benzyl alcohol) for the 125 mg vial.</li> <li>Agitate to effect solution.</li> <li><a href="/script/main/art.asp?articlekey=17678">Invert</a> vial. Insert needle through target area of stopper until tip is just visible. Withdraw dose.</li> </ol> <h4>Storage Conditions</h4> <p>Protect from light.</p> <p> Store unreconstituted product at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]</p> <p> Store solution at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.]</p> <p> Use solution within 48 hours after mixing.</p> <a name="HS"></a><h3>HOW SUPPLIED</h3> <p>A-Methapred (methylprednisolone sodium succinate) sterile powder is available in the following packages:</p> <p><center> <table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="20%">List </td> <td class="EmphTd" width="40%">Container </td> <td class="EmphTd" width="40%">Concentration </td> </tr> <tr> <td align="center">3217</td> <td align="center">Single-Dose Vial</td> <td align="center">40 mg/vial</td> </tr> <tr> <td align="center">3218 </td> <td align="center">Single-Dose Vial</td> <td align="center">125 mg/vial</td> </tr> </table></center></p> <p class="source">Rev: October, 2005. Hospira Inc., Lake Forest, IL 60045, USA. FDA rev date: 11/25/2008 </p> </div> <div id="667441035-3" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-3", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | 1 | 2023-02-01 17:16:26 | A-Methapred (Methylprednisolone Sodium Succinate) | A | Corticosteroids | A-Methapred | methylprednisolone sodium succinate | A-Methapred | John P. Cunha, DO, FACOEP |
| 4 | 2023-02-23 11:36:54 | Side Effects & Drug Interactions | <a name="AR"></a><h3>SIDE EFFECTS</h3> <h4>Fluid and Electrolyte Disturbances </h4> <p><a href="/script/main/art.asp?articlekey=9969">Sodium</a> retention, Fluid retention, <a href="/script/main/art.asp?articlekey=6972">Congestive heart failure</a> in susceptible patients, <a href="/script/main/art.asp?articlekey=9970">Potassium</a> loss, Hypokalemic <a href="/script/main/art.asp?articlekey=6852">alkalosis</a>, <a href="/script/main/art.asp?articlekey=3846">Hypertension</a></p> <h4>Musculoskeletal </h4> <p><a href="/script/main/art.asp?articlekey=4464">Muscle</a> weakness, <a href="/script/main/art.asp?articlekey=5556">Steroid</a> <a href="/script/main/art.asp?articlekey=4492">myopathy</a>, Loss of muscle mass, Severe <a href="/script/main/art.asp?articlekey=2343">arthralgia</a>, Vertebral <a href="/script/main/art.asp?articlekey=39885">compression</a> fractures, <a href="/script/main/art.asp?articlekey=2366">Aseptic necrosis</a> of <a href="/script/main/art.asp?articlekey=3406">femoral</a> and humeral heads, <a href="/script/main/art.asp?articlekey=25868">Pathologic fracture</a> of long bones, <a href="/script/main/art.asp?articlekey=4686">Osteoporosis</a></p> <h4>Gastrointestinal</h4> <p><a href="/script/main/art.asp?articlekey=4829">Peptic ulcer</a> with possible perforation and <a href="/script/main/art.asp?articlekey=14263">hemorrhage</a>, <a href="/script/main/art.asp?articlekey=4745">Pancreatitis</a>, <a href="/script/main/art.asp?articlekey=19269">Abdominal</a> <a href="/script/main/art.asp?articlekey=13145">distention</a>, and Ulcerative <a href="/script/main/art.asp?articlekey=3322">esophagitis</a></p> <h4>Dermatologic</h4> <p>Impaired wound healing, Thin fragile skin, <a href="/script/main/art.asp?articlekey=4853">Petechiae</a> and ecchymoses, Facial <a href="/script/main/art.asp?articlekey=3306">erythema</a>, Increased <a href="/script/main/art.asp?articlekey=9299">sweating</a>, May suppress reactions to skin tests</p> <h4>Neurological</h4> <p>Increased <a href="/script/main/art.asp?articlekey=13759">intracranial</a> pressure with <a href="/script/main/art.asp?articlekey=4757">papilledema</a> (pseudo-tumor cerebri) usually after treatment, Convulsions, <a href="/script/main/art.asp?articlekey=6129">Vertigo</a>, Headache</p> <h4>Endocrine</h4> <p>Development of <a href="/script/main/art.asp?articlekey=9080">Cushingoid</a> state, Suppression of growth in children, Secondary adrenocortical and <a href="/script/main/art.asp?articlekey=21320">pituitary</a> unresponsiveness, particularly in times of <a href="/script/main/art.asp?articlekey=20104">stress</a>, as in <a href="/script/main/art.asp?articlekey=8171">trauma</a>, <a href="/script/main/art.asp?articlekey=5603">surgery</a> or illness, <a href="/script/main/art.asp?articlekey=30736">Menstrual</a> irregularities, Decreased <a href="/script/main/art.asp?articlekey=6553">carbohydrate</a> tolerance, Manifestations of <a href="/script/main/art.asp?articlekey=38176">latent</a> <a href="/script/main/art.asp?articlekey=2974">diabetes mellitus</a>, Increased requirements for <a href="/script/main/art.asp?articlekey=3989">insulin</a> or oral <a href="/script/main/art.asp?articlekey=18046">hypoglycemic</a> agents in diabetics</p> <h4>Ophthalmic</h4> <p><a href="/script/main/art.asp?articlekey=9277">Posterior</a> subcapsular cataracts, Increased <a href="/script/main/art.asp?articlekey=4014">intraocular pressure</a>, <a href="/script/main/art.asp?articlekey=3596">Glaucoma</a>, <a href="/script/main/art.asp?articlekey=3355">Exophthalmos</a></p> <h4>Metabolic</h4> <p>Negative <a href="/script/main/art.asp?articlekey=32780">nitrogen</a> balance due to <a href="/script/main/art.asp?articlekey=6554">protein</a> <a href="/script/main/art.asp?articlekey=11103">catabolism</a> </p> <p>The following additional adverse reactions are related to <a href="/script/main/art.asp?articlekey=4776">parenteral</a> <a href="/script/main/art.asp?articlekey=2849">corticosteroid</a> <a href="/script/main/art.asp?articlekey=10897">therapy</a>: <a href="/script/main/art.asp?articlekey=3844">Hyperpigmentation</a> or hypopigmentation, <a href="/script/main/art.asp?articlekey=8265">Subcutaneous</a> and <a href="/script/main/art.asp?articlekey=2885">cutaneous</a> <a href="/script/main/art.asp?articlekey=2389">atrophy</a>, Sterile <a href="/script/main/art.asp?articlekey=2097">abscess</a>, Anaphylactic reaction with or without <a href="/script/main/art.asp?articlekey=2737">circulatory</a> collapse, <a href="/script/main/art.asp?articlekey=11095">cardiac arrest</a>, bronchospasm, <a href="/script/main/art.asp?articlekey=5919">Urticaria</a>, <a href="/script/main/art.asp?articlekey=4510">Nausea</a> and vomiting, <a href="/script/main/art.asp?articlekey=2628">Cardiac</a> arrhythmias; <a href="/script/main/art.asp?articlekey=3864">hypotension</a> or hypertension</p> <a name="DI"></a><h3>DRUG INTERACTIONS</h3> <p>The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of <a href="/script/main/art.asp?articlekey=4359">metabolism</a> occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin.</p> </div> <a class="mediaPrmo quiz" href="/quiz_kidney_disease/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/kidney-disease/kidney-disease-s1.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">The only purpose of the kidneys is to filter blood.</span> <span class="btn">See Answer</span> </a> </div> </div> | <a name="AR"></a><h3>SIDE EFFECTS</h3> <h4>Fluid and Electrolyte Disturbances </h4> <p><a href="/script/main/art.asp?articlekey=9969">Sodium</a> retention, Fluid retention, <a href="/script/main/art.asp?articlekey=6972">Congestive heart failure</a> in susceptible patients, <a href="/script/main/art.asp?articlekey=9970">Potassium</a> loss, Hypokalemic <a href="/script/main/art.asp?articlekey=6852">alkalosis</a>, <a href="/script/main/art.asp?articlekey=3846">Hypertension</a></p> <h4>Musculoskeletal </h4> <p><a href="/script/main/art.asp?articlekey=4464">Muscle</a> weakness, <a href="/script/main/art.asp?articlekey=5556">Steroid</a> <a href="/script/main/art.asp?articlekey=4492">myopathy</a>, Loss of muscle mass, Severe <a href="/script/main/art.asp?articlekey=2343">arthralgia</a>, Vertebral <a href="/script/main/art.asp?articlekey=39885">compression</a> fractures, <a href="/script/main/art.asp?articlekey=2366">Aseptic necrosis</a> of <a href="/script/main/art.asp?articlekey=3406">femoral</a> and humeral heads, <a href="/script/main/art.asp?articlekey=25868">Pathologic fracture</a> of long bones, <a href="/script/main/art.asp?articlekey=4686">Osteoporosis</a></p> <h4>Gastrointestinal</h4> <p><a href="/script/main/art.asp?articlekey=4829">Peptic ulcer</a> with possible perforation and <a href="/script/main/art.asp?articlekey=14263">hemorrhage</a>, <a href="/script/main/art.asp?articlekey=4745">Pancreatitis</a>, <a href="/script/main/art.asp?articlekey=19269">Abdominal</a> <a href="/script/main/art.asp?articlekey=13145">distention</a>, and Ulcerative <a href="/script/main/art.asp?articlekey=3322">esophagitis</a></p> <h4>Dermatologic</h4> <p>Impaired wound healing, Thin fragile skin, <a href="/script/main/art.asp?articlekey=4853">Petechiae</a> and ecchymoses, Facial <a href="/script/main/art.asp?articlekey=3306">erythema</a>, Increased <a href="/script/main/art.asp?articlekey=9299">sweating</a>, May suppress reactions to skin tests</p> <h4>Neurological</h4> <p>Increased <a href="/script/main/art.asp?articlekey=13759">intracranial</a> pressure with <a href="/script/main/art.asp?articlekey=4757">papilledema</a> (pseudo-tumor cerebri) usually after treatment, Convulsions, <a href="/script/main/art.asp?articlekey=6129">Vertigo</a>, Headache</p> <h4>Endocrine</h4> <p>Development of <a href="/script/main/art.asp?articlekey=9080">Cushingoid</a> state, Suppression of growth in children, Secondary adrenocortical and <a href="/script/main/art.asp?articlekey=21320">pituitary</a> unresponsiveness, particularly in times of <a href="/script/main/art.asp?articlekey=20104">stress</a>, as in <a href="/script/main/art.asp?articlekey=8171">trauma</a>, <a href="/script/main/art.asp?articlekey=5603">surgery</a> or illness, <a href="/script/main/art.asp?articlekey=30736">Menstrual</a> irregularities, Decreased <a href="/script/main/art.asp?articlekey=6553">carbohydrate</a> tolerance, Manifestations of <a href="/script/main/art.asp?articlekey=38176">latent</a> <a href="/script/main/art.asp?articlekey=2974">diabetes mellitus</a>, Increased requirements for <a href="/script/main/art.asp?articlekey=3989">insulin</a> or oral <a href="/script/main/art.asp?articlekey=18046">hypoglycemic</a> agents in diabetics</p> <h4>Ophthalmic</h4> <p><a href="/script/main/art.asp?articlekey=9277">Posterior</a> subcapsular cataracts, Increased <a href="/script/main/art.asp?articlekey=4014">intraocular pressure</a>, <a href="/script/main/art.asp?articlekey=3596">Glaucoma</a>, <a href="/script/main/art.asp?articlekey=3355">Exophthalmos</a></p> <h4>Metabolic</h4> <p>Negative <a href="/script/main/art.asp?articlekey=32780">nitrogen</a> balance due to <a href="/script/main/art.asp?articlekey=6554">protein</a> <a href="/script/main/art.asp?articlekey=11103">catabolism</a> </p> <p>The following additional adverse reactions are related to <a href="/script/main/art.asp?articlekey=4776">parenteral</a> <a href="/script/main/art.asp?articlekey=2849">corticosteroid</a> <a href="/script/main/art.asp?articlekey=10897">therapy</a>: <a href="/script/main/art.asp?articlekey=3844">Hyperpigmentation</a> or hypopigmentation, <a href="/script/main/art.asp?articlekey=8265">Subcutaneous</a> and <a href="/script/main/art.asp?articlekey=2885">cutaneous</a> <a href="/script/main/art.asp?articlekey=2389">atrophy</a>, Sterile <a href="/script/main/art.asp?articlekey=2097">abscess</a>, Anaphylactic reaction with or without <a href="/script/main/art.asp?articlekey=2737">circulatory</a> collapse, <a href="/script/main/art.asp?articlekey=11095">cardiac arrest</a>, bronchospasm, <a href="/script/main/art.asp?articlekey=5919">Urticaria</a>, <a href="/script/main/art.asp?articlekey=4510">Nausea</a> and vomiting, <a href="/script/main/art.asp?articlekey=2628">Cardiac</a> arrhythmias; <a href="/script/main/art.asp?articlekey=3864">hypotension</a> or hypertension</p> <a name="DI"></a><h3>DRUG INTERACTIONS</h3> <p>The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of <a href="/script/main/art.asp?articlekey=4359">metabolism</a> occurs with concurrent use of cyclosporin and methylprednisolone; therefore, it is possible that adverse events associated with the individual use of either drug may be more apt to occur. Convulsions have been reported with concurrent use of methylprednisolone and cyclosporin.</p> </div> <a class="mediaPrmo quiz" href="/quiz_kidney_disease/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/kidney-disease/kidney-disease-s1.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">The only purpose of the kidneys is to filter blood.</span> <span class="btn">See Answer</span> </a> </div> </div> | 1 | 2023-02-01 17:16:26 | A-Methapred (Methylprednisolone Sodium Succinate) | A | Corticosteroids | A-Methapred | methylprednisolone sodium succinate | A-Methapred | John P. Cunha, DO, FACOEP |
| 5 | 2023-02-23 12:07:03 | Warnings | <a name="W"></a><h3>WARNINGS</h3> <p><b>While on corticosteroid therapy patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response. </b></p> <p>In patients on corticosteroid therapy subjected to any unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated. </p> <p> Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used. </p> <p> A study has failed to establish the efficacy of Methylprednisolone Sodium Succinate for Injection, USP in the treatment of <a href="/sepsis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">sepsis</a> syndrome and <a href="/septic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">septic</a> shock. The study also suggests that treatment of these conditions with Methylprednisolone Sodium Succinate for Injection, USP may increase the risk of mortality in certain patients (ie, patients with elevated serum creatinine levels or patients who develop secondary infections after Methylprednisolone Sodium Succinate for Injection, USP. </p> <p> Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary <a href="/ocular/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ocular</a> infections due to <a href="/script/main/art.asp?articlekey=24858">fungi</a> or <a href="/script/main/art.asp?articlekey=6000">viruses</a>.</p> <h4>Usage in pregnancy</h4> <p> Since adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in pregnancy, nursing mothers, or women of child-bearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and <a href="/script/main/art.asp?articlekey=3225">embryo</a> or <a href="/script/main/art.asp?articlekey=3424">fetus</a>. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. </p> <p> Average and large doses of <a href="/script/main/art.asp?articlekey=6547">cortisone</a> or hydrocortisone can cause elevation of <a href="/script/main/art.asp?articlekey=2486">blood pressure</a>, salt and <a href="/script/main/art.asp?articlekey=97568">water retention</a>, and increased excretion of <a href="/script/main/art.asp?articlekey=9970">potassium</a>. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. </p> <p> While on corticosteroid therapy patients should not be vaccinated against <a href="/smallpox/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">smallpox</a>. Other <a href="/immunization/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">immunization</a> procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of <a href="/neurological/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">neurological</a> complications and a lack of antibody response.</p> <p>The use of Methylprednisolone Sodium Succinate for Injection, USP sterile powder in <a href="/script/main/art.asp?articlekey=23031">active tuberculosis</a> should be restricted to those cases of fulminatingor disseminated <a href="/tuberculosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">tuberculosis</a> in which the corticosteroid is used for the management of the disease in conjunction with appropriate antituberculous regimen. </p> <p> If corticosteroids are indicated in patients with latent tuberculosis or <a href="/tuberculin/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">tuberculin</a> reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive <a href="/script/main/art.asp?articlekey=26649">chemoprophylaxis</a>. </p> <p> Because rare instances of anaphylactic (eg, bronchospasm) reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of <a href="/allergy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">allergy</a> to any drug. </p> <p>There are reports of cardiac arrhythmias and/or circulatory collapse and/or cardiac arrest following the rapid administration of large IV doses of Methylprednisolone Sodium Succinate for Injection, USP (greater than 0.5 <a href="/gram_measure/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">gram</a> administered over a period of less than 10 minutes). <a href="/bradycardia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Bradycardia</a> has been reported during or after the administration of large doses of Methylprednisolone sodium succinate, and may be unrelated to the <a href="/speed/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">speed</a> or duration of infusion. </p> <p>Persons who are on drugs which suppress the <a href="/script/main/art.asp?articlekey=3907">immune system</a> are more susceptible to infections than healthy individuals. <a href="/script/main/art.asp?articlekey=38177">Chicken pox</a> and <a href="/script/main/art.asp?articlekey=4302">measles</a>, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, <a href="/script/main/art.asp?articlekey=12063">prophylaxis</a> with <a href="/varicella_chickenpox/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">varicella</a> zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular <a href="/immunoglobulin/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">immunoglobulin</a> (<a href="/ig/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">IG</a>) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with <a href="/antiviral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antiviral</a> agents may be considered. </p> </div> </div> </div> | <a name="W"></a><h3>WARNINGS</h3> <p><b>While on corticosteroid therapy patients should not be vaccinated against smallpox. Other immunization procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of neurological complications and a lack of antibody response. </b></p> <p>In patients on corticosteroid therapy subjected to any unusual stress, increased dosage of rapidly acting corticosteroids before, during, and after the stressful situation is indicated. </p> <p> Corticosteroids may mask some signs of infection, and new infections may appear during their use. There may be decreased resistance and inability to localize infection when corticosteroids are used. </p> <p> A study has failed to establish the efficacy of Methylprednisolone Sodium Succinate for Injection, USP in the treatment of <a href="/sepsis/definition.htm" ">sepsis</a> syndrome and <a href="/septic/definition.htm" ">septic</a> shock. The study also suggests that treatment of these conditions with Methylprednisolone Sodium Succinate for Injection, USP may increase the risk of mortality in certain patients (ie, patients with elevated serum creatinine levels or patients who develop secondary infections after Methylprednisolone Sodium Succinate for Injection, USP. </p> <p> Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary <a href="/ocular/definition.htm" ">ocular</a> infections due to <a href="/script/main/art.asp?articlekey=24858">fungi</a> or <a href="/script/main/art.asp?articlekey=6000">viruses</a>.</p> <h4>Usage in pregnancy</h4> <p> Since adequate human reproduction studies have not been done with corticosteroids, the use of these drugs in pregnancy, nursing mothers, or women of child-bearing potential requires that the possible benefits of the drug be weighed against the potential hazards to the mother and <a href="/script/main/art.asp?articlekey=3225">embryo</a> or <a href="/script/main/art.asp?articlekey=3424">fetus</a>. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. </p> <p> Average and large doses of <a href="/script/main/art.asp?articlekey=6547">cortisone</a> or hydrocortisone can cause elevation of <a href="/script/main/art.asp?articlekey=2486">blood pressure</a>, salt and <a href="/script/main/art.asp?articlekey=97568">water retention</a>, and increased excretion of <a href="/script/main/art.asp?articlekey=9970">potassium</a>. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion. </p> <p> While on corticosteroid therapy patients should not be vaccinated against <a href="/smallpox/definition.htm" ">smallpox</a>. Other <a href="/immunization/definition.htm" ">immunization</a> procedures should not be undertaken in patients who are on corticosteroids, especially on high dose, because of possible hazards of <a href="/neurological/definition.htm" ">neurological</a> complications and a lack of antibody response.</p> <p>The use of Methylprednisolone Sodium Succinate for Injection, USP sterile powder in <a href="/script/main/art.asp?articlekey=23031">active tuberculosis</a> should be restricted to those cases of fulminatingor disseminated <a href="/tuberculosis/definition.htm" ">tuberculosis</a> in which the corticosteroid is used for the management of the disease in conjunction with appropriate antituberculous regimen. </p> <p> If corticosteroids are indicated in patients with latent tuberculosis or <a href="/tuberculin/definition.htm" ">tuberculin</a> reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive <a href="/script/main/art.asp?articlekey=26649">chemoprophylaxis</a>. </p> <p> Because rare instances of anaphylactic (eg, bronchospasm) reactions have occurred in patients receiving parenteral corticosteroid therapy, appropriate precautionary measures should be taken prior to administration, especially when the patient has a history of <a href="/allergy/definition.htm" ">allergy</a> to any drug. </p> <p>There are reports of cardiac arrhythmias and/or circulatory collapse and/or cardiac arrest following the rapid administration of large IV doses of Methylprednisolone Sodium Succinate for Injection, USP (greater than 0.5 <a href="/gram_measure/definition.htm" ">gram</a> administered over a period of less than 10 minutes). <a href="/bradycardia/definition.htm" ">Bradycardia</a> has been reported during or after the administration of large doses of Methylprednisolone sodium succinate, and may be unrelated to the <a href="/speed/definition.htm" ">speed</a> or duration of infusion. </p> <p>Persons who are on drugs which suppress the <a href="/script/main/art.asp?articlekey=3907">immune system</a> are more susceptible to infections than healthy individuals. <a href="/script/main/art.asp?articlekey=38177">Chicken pox</a> and <a href="/script/main/art.asp?articlekey=4302">measles</a>, for example, can have a more serious or even fatal course in non-immune children or adults on corticosteroids. In such children or adults who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, <a href="/script/main/art.asp?articlekey=12063">prophylaxis</a> with <a href="/varicella_chickenpox/definition.htm" ">varicella</a> zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular <a href="/immunoglobulin/definition.htm" ">immunoglobulin</a> (<a href="/ig/definition.htm" ">IG</a>) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with <a href="/antiviral/definition.htm" ">antiviral</a> agents may be considered. </p> </div> </div> </div> | 1 | 2023-02-01 17:16:26 | A-Methapred (Methylprednisolone Sodium Succinate) | A | Corticosteroids | A-Methapred | methylprednisolone sodium succinate | A-Methapred | John P. Cunha, DO, FACOEP |
| 6 | 2023-02-23 12:07:03 | Precautions | <a name="P"></a><h3>PRECAUTIONS</h3> <h4>General Precautions</h4> <p>Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, <a href="/script/main/art.asp?articlekey=3798">hormone therapy</A> should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. </p> <p> There is an enhanced effect of corticosteroids on patients with <a href="/script/main/art.asp?articlekey=3868">hypothyroidism </a> and in those with <a href="/script/main/art.asp?articlekey=2740">cirrhosis</a>.</p> <p> Corticosteroids should be used cautiously in patients with ocular <a href="/herpes/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">herpes</a> simplex because of possible corneal perforation. </p> <p> The lowest possible dose of corticosteroid should be used to control the condition under treatment, and when reduction in dosage is possible, the reduction should be gradual.</p> <p> Psychic derangements may appear when corticosteroids are used, ranging from <a href="/script/main/art.asp?articlekey=11351">euphoria</a>, <a href="/script/main/art.asp?articlekey=17762">insomnia</a>, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.</p> <p>Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.</p> <p>Steroids should be used with caution in nonspecific <a href="/script/main/art.asp?articlekey=7370">ulcerative colitis</a>, if there is a probability of impending perforation, abscess or other pyogenic infection; <a href="/script/main/art.asp?articlekey=3080">diverticulitis</a>; fresh intestinal anastomoses; active or latent <a href="/script/main/art.asp?articlekey=4829">peptic ulcer</a>; renal insufficiency; <a href="/script/main/art.asp?articlekey=3846">hypertension</a>; <a href="/script/main/art.asp?articlekey=4686">osteoporosis</a>; and <a href="/script/main/art.asp?articlekey=4473">myasthenia gravis</a>. </p> <p> Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed.</p> <p> Although controlled clinical trials have shown corticosteroids to be effective in speeding the <a href="/script/main/art.asp?articlekey=5325">resolution</a> of acute exacerbations of <a href="/script/main/art.asp?articlekey=4457">multiple sclerosis</a>, they do not show that corticosteroids affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See <b><a href="/a-methapred-drug.htm#DAA">DOSAGE AND ADMINISTRATION</a></b>.)</p> <p> Since complications of treatment with glucocorticoids are dependent on the size of the dose and duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. </p> </div> </div> </div> | <a name="P"></a><h3>PRECAUTIONS</h3> <h4>General Precautions</h4> <p>Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, <a href="/script/main/art.asp?articlekey=3798">hormone therapy</A> should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. </p> <p> There is an enhanced effect of corticosteroids on patients with <a href="/script/main/art.asp?articlekey=3868">hypothyroidism </a> and in those with <a href="/script/main/art.asp?articlekey=2740">cirrhosis</a>.</p> <p> Corticosteroids should be used cautiously in patients with ocular <a href="/herpes/definition.htm" ">herpes</a> simplex because of possible corneal perforation. </p> <p> The lowest possible dose of corticosteroid should be used to control the condition under treatment, and when reduction in dosage is possible, the reduction should be gradual.</p> <p> Psychic derangements may appear when corticosteroids are used, ranging from <a href="/script/main/art.asp?articlekey=11351">euphoria</a>, <a href="/script/main/art.asp?articlekey=17762">insomnia</a>, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.</p> <p>Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia.</p> <p>Steroids should be used with caution in nonspecific <a href="/script/main/art.asp?articlekey=7370">ulcerative colitis</a>, if there is a probability of impending perforation, abscess or other pyogenic infection; <a href="/script/main/art.asp?articlekey=3080">diverticulitis</a>; fresh intestinal anastomoses; active or latent <a href="/script/main/art.asp?articlekey=4829">peptic ulcer</a>; renal insufficiency; <a href="/script/main/art.asp?articlekey=3846">hypertension</a>; <a href="/script/main/art.asp?articlekey=4686">osteoporosis</a>; and <a href="/script/main/art.asp?articlekey=4473">myasthenia gravis</a>. </p> <p> Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed.</p> <p> Although controlled clinical trials have shown corticosteroids to be effective in speeding the <a href="/script/main/art.asp?articlekey=5325">resolution</a> of acute exacerbations of <a href="/script/main/art.asp?articlekey=4457">multiple sclerosis</a>, they do not show that corticosteroids affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See <b><a href="/a-methapred-drug.htm#DAA">DOSAGE AND ADMINISTRATION</a></b>.)</p> <p> Since complications of treatment with glucocorticoids are dependent on the size of the dose and duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used. </p> </div> </div> </div> | 1 | 2023-02-01 17:16:26 | A-Methapred (Methylprednisolone Sodium Succinate) | A | Corticosteroids | A-Methapred | methylprednisolone sodium succinate | A-Methapred | John P. Cunha, DO, FACOEP |
| 7 | 2023-02-23 11:36:54 | Overdosage & Contraindications | <a name="OD"></a><h3>OVERDOSE</h3> <p>No information provided.</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3> <p>The use of A-Methapred (methylprednisolone sodium succinate) sterile powder is contraindicated in premature infants because the reconstitution diluent contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal "Gasping <a href="/script/main/art.asp?articlekey=5613">Syndrome</a>" in premature infants. A-Methapred (methylprednisolone sodium succinate) sterile powder is also contraindicated in <a href="/script/main/art.asp?articlekey=25440">systemic</a> <a href="/script/main/art.asp?articlekey=15039">fungal</a> infections and patients with known hypersensitivity to the product and its constituents. </p> </div> </div> </div> | <a name="OD"></a><h3>OVERDOSE</h3> <p>No information provided.</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3> <p>The use of A-Methapred (methylprednisolone sodium succinate) sterile powder is contraindicated in premature infants because the reconstitution diluent contains benzyl alcohol. Benzyl alcohol has been reported to be associated with a fatal "Gasping <a href="/script/main/art.asp?articlekey=5613">Syndrome</a>" in premature infants. A-Methapred (methylprednisolone sodium succinate) sterile powder is also contraindicated in <a href="/script/main/art.asp?articlekey=25440">systemic</a> <a href="/script/main/art.asp?articlekey=15039">fungal</a> infections and patients with known hypersensitivity to the product and its constituents. </p> </div> </div> </div> | 1 | 2023-02-01 17:16:26 | A-Methapred (Methylprednisolone Sodium Succinate) | A | Corticosteroids | A-Methapred | methylprednisolone sodium succinate | A-Methapred | John P. Cunha, DO, FACOEP |
| 8 | 2023-02-23 11:36:54 | Clinical Pharmacology | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3> <p>Methylprednisolone is a potent anti-inflammatory <a href="/script/main/art.asp?articlekey=5556">steroid</a> with greater anti-inflammatory potency than prednisolone and even less tendency than prednisolone to induce <a href="/script/main/art.asp?articlekey=9969">sodium</a> and <a href="/script/main/art.asp?articlekey=97568">water retention</a>. </p> <p> Methylprednisolone sodium succinate has the same <a href="/script/main/art.asp?articlekey=18074">metabolic</a> and anti-inflammatory actions as methylprednisolone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. The relative potency of A-Methapred (methylprednisolone sodium succinate) sterile powder and hydrocortisone sodium succinate, as indicated by <a href="/script/main/art.asp?articlekey=2947">depression</a> of <a href="/script/main/art.asp?articlekey=3268">eosinophil</a> count, following <a href="/script/main/art.asp?articlekey=4021">intravenous</a> administration, is at least four to one. This is in good agreement with the relative oral potency of methylprednisolone and hydrocortisone. </p> </div> </div> </div> | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3> <p>Methylprednisolone is a potent anti-inflammatory <a href="/script/main/art.asp?articlekey=5556">steroid</a> with greater anti-inflammatory potency than prednisolone and even less tendency than prednisolone to induce <a href="/script/main/art.asp?articlekey=9969">sodium</a> and <a href="/script/main/art.asp?articlekey=97568">water retention</a>. </p> <p> Methylprednisolone sodium succinate has the same <a href="/script/main/art.asp?articlekey=18074">metabolic</a> and anti-inflammatory actions as methylprednisolone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. The relative potency of A-Methapred (methylprednisolone sodium succinate) sterile powder and hydrocortisone sodium succinate, as indicated by <a href="/script/main/art.asp?articlekey=2947">depression</a> of <a href="/script/main/art.asp?articlekey=3268">eosinophil</a> count, following <a href="/script/main/art.asp?articlekey=4021">intravenous</a> administration, is at least four to one. This is in good agreement with the relative oral potency of methylprednisolone and hydrocortisone. </p> </div> </div> </div> | 1 | 2023-02-01 17:16:26 | A-Methapred (Methylprednisolone Sodium Succinate) | A | Corticosteroids | A-Methapred | methylprednisolone sodium succinate | A-Methapred | John P. Cunha, DO, FACOEP |
| 9 | 2023-02-23 11:36:54 | Medication Guide | <a name="PI"></a><h3>PATIENT INFORMATION</h3> <p>Persons who are on <a href="/script/main/art.asp?articlekey=25054">immunosuppressant</a> doses of corticosteroids should be warned to avoid exposure to <a href="/script/main/art.asp?articlekey=38177">chicken pox</a> or <a href="/script/main/art.asp?articlekey=4302">measles</a>. Patients should also be advised that if they are exposed, medical advice should be sought without delay. </p> </div> </div> </div> | <a name="PI"></a><h3>PATIENT INFORMATION</h3> <p>Persons who are on <a href="/script/main/art.asp?articlekey=25054">immunosuppressant</a> doses of corticosteroids should be warned to avoid exposure to <a href="/script/main/art.asp?articlekey=38177">chicken pox</a> or <a href="/script/main/art.asp?articlekey=4302">measles</a>. Patients should also be advised that if they are exposed, medical advice should be sought without delay. </p> </div> </div> </div> | 1 | 2023-02-01 17:16:26 | A-Methapred (Methylprednisolone Sodium Succinate) | A | Corticosteroids | A-Methapred | methylprednisolone sodium succinate | A-Methapred | John P. Cunha, DO, FACOEP |
| 10 | 2023-02-23 12:07:03 | Drug Description | <h4>What is Kivexa and how is it used?</h4> <p>Kivexa is a prescription medicine used to treat the symptoms of <a href="/hiv/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HIV</a> Infection. Kivexa may be used alone or with other medications.</p> <p>Kivexa belongs to a class of drugs called HIV, ART Combos.</p> <p>It is not known if Kivexa is safe and effective in children weighing less than 25 kilos.</p> <h4>What are the possible side effects of Kivexa?</h4> <p>Kivexa may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>dizziness,</li> <li>pale skin,</li> <li>unusual tiredness,</li> <li>weakness,</li> <li>shortness of breath,</li> <li>unusual bleeding,</li> <li>nosebleeds,</li> <li>easy bruising,</li> <li>blood in urine,</li> <li>coughing blood,</li> <li>bleeding gums,</li> <li>any bleeding that will not stop,</li> <li>poor concentration,</li> <li>changes in weight,</li> <li>decreased interest in activities,</li> <li>thoughts of self-harm,</li> <li>changes in sleep,</li> <li>fever,</li> <li>chills,</li> <li><a href="/sore_throat/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">sore throat</a>,</li> <li>cough,</li> <li>nausea,</li> <li>vomiting,</li> <li>abdominal pain (upper left side),</li> <li>diarrhea,</li> <li>black or tarry stools,</li> <li><a href="/vomit/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">vomit</a> that looks like coffee grounds,</li> <li>any rash (no matter how minor),</li> <li>a rash with blistering or peeling,</li> <li><a href="/back_pain/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">back pain</a>,</li> <li>rapid heartbeat,</li> <li>swelling of the abdomen,</li> <li>dizziness,</li> <li>rapid heart rate, and</li> <li>rapid or shallow breathing </li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Kivexa include:</p> <ul> <li>diarrhea,</li> <li>fatigue,</li> <li>fever,</li> <li>hair loss,</li> <li>headache,</li> <li>joint or muscle pain,</li> <li>lack of energy,</li> <li>loss of appetite,</li> <li>nausea,</li> <li>skin rash, and</li> <li>difficulty sleeping</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Kivexa. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p><b>Abacavir, a component of KIVEXA tablets, is associated with hypersensitivity reactions, which can be life-threatening, and in rare cases fatal. KIVEXA tablets, or any other medicinal product containing abacavir (TRIUMEQ, TRIZIVIR and ZIAGEN), MUST NEVER be restarted following a hypersensitivity reaction (see Section <b>WARNINGS AND <a href="/kivexa-drug.htm#P">PRECAUTIONS</a></b> and Section <a href="/kivexa-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>).</b></p> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <h4>List Of Excipients</h4> <h5>Tablet Core</h5> <p>magnesium stearate<br /> microcrystalline cellulose<br /> sodium starch glycollate</p> <h5>Tablet Coating</h5> <p>Opadry Orange YS-1-13065-A contains:</p> <ul> <li>hypromellose</li> <li>titanium dioxide</li> <li>macrogol 400</li> <li>polysorbate 80</li> <li>sunset yellow FCF aluminium lake.</li> </ul> <h4>Physicochemical Properties</h4> <p>The chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C<sub>14</sub>H<sub>18</sub>N<sub>6</sub>O)2•H<sub>2</sub>SO<sub>4</sub> and a molecular weight of 670.76 daltons.</p> <p>The chemical name of lamivudine is (2R,cis)-4-amino-1-[2- (hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2’,3’-dideoxy, 3’-thiacytidine. It has a molecular formula of C<sub>8</sub>H<sub>11</sub>N<sub>3</sub>O<sub>3</sub>S and a molecular weight of 229.3 daltons.</p> <h5>Chemical Structure</h5> <p>Abacavir sulfate has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="345"> <tbody> <tr> <td><img alt="Abacavir sulfate Structural Formula Illustration" height="227" src="https://images.rxlist.com/images/rxlist/kivexa1.gif" width="345" /></td> </tr> </tbody> </table> </center> <p></p> <p>Lamivudine has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="208"> <tbody> <tr> <td><img alt="Lamivudine Structural Formula Illustration" height="179" src="https://images.rxlist.com/images/rxlist/kivexa2.gif" width="208" /></td> </tr> </tbody> </table> </center> <p></p> <h5>CAS Number</h5> <p>188062-50-2 (abacavir sulfate); 134678-17-4 (lamivudine)</p> </div> <div id="667441035-1" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-1", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <h4>What is Kivexa and how is it used?</h4> <p>Kivexa is a prescription medicine used to treat the symptoms of <a href="/hiv/definition.htm" ">HIV</a> Infection. Kivexa may be used alone or with other medications.</p> <p>Kivexa belongs to a class of drugs called HIV, ART Combos.</p> <p>It is not known if Kivexa is safe and effective in children weighing less than 25 kilos.</p> <h4>What are the possible side effects of Kivexa?</h4> <p>Kivexa may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>dizziness,</li> <li>pale skin,</li> <li>unusual tiredness,</li> <li>weakness,</li> <li>shortness of breath,</li> <li>unusual bleeding,</li> <li>nosebleeds,</li> <li>easy bruising,</li> <li>blood in urine,</li> <li>coughing blood,</li> <li>bleeding gums,</li> <li>any bleeding that will not stop,</li> <li>poor concentration,</li> <li>changes in weight,</li> <li>decreased interest in activities,</li> <li>thoughts of self-harm,</li> <li>changes in sleep,</li> <li>fever,</li> <li>chills,</li> <li><a href="/sore_throat/definition.htm" ">sore throat</a>,</li> <li>cough,</li> <li>nausea,</li> <li>vomiting,</li> <li>abdominal pain (upper left side),</li> <li>diarrhea,</li> <li>black or tarry stools,</li> <li><a href="/vomit/definition.htm" ">vomit</a> that looks like coffee grounds,</li> <li>any rash (no matter how minor),</li> <li>a rash with blistering or peeling,</li> <li><a href="/back_pain/definition.htm" ">back pain</a>,</li> <li>rapid heartbeat,</li> <li>swelling of the abdomen,</li> <li>dizziness,</li> <li>rapid heart rate, and</li> <li>rapid or shallow breathing </li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Kivexa include:</p> <ul> <li>diarrhea,</li> <li>fatigue,</li> <li>fever,</li> <li>hair loss,</li> <li>headache,</li> <li>joint or muscle pain,</li> <li>lack of energy,</li> <li>loss of appetite,</li> <li>nausea,</li> <li>skin rash, and</li> <li>difficulty sleeping</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Kivexa. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p><b>Abacavir, a component of KIVEXA tablets, is associated with hypersensitivity reactions, which can be life-threatening, and in rare cases fatal. KIVEXA tablets, or any other medicinal product containing abacavir (TRIUMEQ, TRIZIVIR and ZIAGEN), MUST NEVER be restarted following a hypersensitivity reaction (see Section <b>WARNINGS AND <a href="/kivexa-drug.htm#P">PRECAUTIONS</a></b> and Section <a href="/kivexa-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>).</b></p> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <h4>List Of Excipients</h4> <h5>Tablet Core</h5> <p>magnesium stearate<br /> microcrystalline cellulose<br /> sodium starch glycollate</p> <h5>Tablet Coating</h5> <p>Opadry Orange YS-1-13065-A contains:</p> <ul> <li>hypromellose</li> <li>titanium dioxide</li> <li>macrogol 400</li> <li>polysorbate 80</li> <li>sunset yellow FCF aluminium lake.</li> </ul> <h4>Physicochemical Properties</h4> <p>The chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C<sub>14</sub>H<sub>18</sub>N<sub>6</sub>O)2•H<sub>2</sub>SO<sub>4</sub> and a molecular weight of 670.76 daltons.</p> <p>The chemical name of lamivudine is (2R,cis)-4-amino-1-[2- (hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2’,3’-dideoxy, 3’-thiacytidine. It has a molecular formula of C<sub>8</sub>H<sub>11</sub>N<sub>3</sub>O<sub>3</sub>S and a molecular weight of 229.3 daltons.</p> <h5>Chemical Structure</h5> <p>Abacavir sulfate has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="345"> <tbody> <tr> <td><img alt="Abacavir sulfate Structural Formula Illustration" height="227" src="https://images.rxlist.com/images/rxlist/kivexa1.gif" width="345" /></td> </tr> </tbody> </table> </center> <p></p> <p>Lamivudine has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="208"> <tbody> <tr> <td><img alt="Lamivudine Structural Formula Illustration" height="179" src="https://images.rxlist.com/images/rxlist/kivexa2.gif" width="208" /></td> </tr> </tbody> </table> </center> <p></p> <h5>CAS Number</h5> <p>188062-50-2 (abacavir sulfate); 134678-17-4 (lamivudine)</p> </div> <div id="667441035-1" class="medianet"><</div> </div> </div> | 2 | 2023-02-01 17:38:10 | Abacavir and Lamivudine Film-coated Tablets (Kivexa) | A | | Kivexa | abacavir and lamivudine film-coated tablets | Kivexa | John P. Cunha, DO, FACOEP |
| 11 | 2023-02-23 12:07:03 | Indications & Dosage | <a name="I"></a><h3>INDICATIONS</h3> <h4>Therapeutic</h4> <p> KIVEXA tablets are a combination of two nucleoside analogues (abacavir and lamivudine). KIVEXA is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection in adults and adolescents from 12 years of age.</p> <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3> <p>KIVEXA is supplied as film-coated tablets each containing 600 mg of abacavir as abacavir sulfate and 300 mg lamivudine.</p> <p>Abacavir sulfate is a white to off-white crystalline powder with a solubility of approximately 77 mg/mL in water at 25°C.</p> <p>Lamivudine is a white to off-white crystalline solid which is highly soluble in water.</p> <p>For the full list of excipients, see Section <a href="/kivexa-drug.htm#D"><b>DESCRIPTION</b></a>.</p> <h4>Dose And Method Of Administration</h4> <p>Therapy should be initiated by a physician experienced in the management of HIV infection.</p> <p>KIVEXA tablets should not be administered to adults or adolescents who weigh less than 40 kg because it is a fixed-dose tablet that cannot be dose reduced.</p> <p>KIVEXA tablets can be taken with or without food.</p> <p>KIVEXA tablets should not be prescribed for patients requiring dosage adjustments, such as those with creatinine clearance < 50 mL/min. Separate preparations of abacavir (ZIAGEN) or lamivudine (3TC) should be administered in cases where discontinuation or dose adjustment is indicated. In these cases the physician should refer to the individual product information for these medicinal products.</p> <h5>Adults And Adolescents</h5> <p>The recommended dose of KIVEXA tablets in adults and adolescents is one tablet once daily.</p> <h5>Elderly</h5> <p>The pharmacokinetics of abacavir and lamivudine have not been studied in patients over 65 years of age. When treating elderly patients, consideration needs to be given to the greater frequency of decreased hepatic, renal and cardiac function, concomitant medicinal products or disease.</p> <h5>Children</h5> <p>KIVEXA tablets are not recommended for treatment of children less than 12 years of age as the necessary dose adjustment cannot be made. Physicians should refer to the individual product information for lamivudine and abacavir.</p> <p>Renal impairment Whilst no dosage adjustment of abacavir is necessary in patients with renal impairment, a dose reduction of lamivudine is required due to decreased clearance. Therefore, KIVEXA tablets are not recommended for use in patients with a creatinine clearance < 50 mL/min (see Section <a href="/kivexa-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a> - <b>Special populations</b>).</p> <h5>Hepatic Impairment</h5> <p>A dose reduction of abacavir may be required for patients with mild hepatic impairment (Child-Pugh grade A). As dose reduction is not possible with KIVEXA tablets, the separate preparations of abacavir and lamivudine should be used when this is judged to be necessary. KIVEXA is not recommended in patients with moderate and severe hepatic impairment (Child-Pugh grade B or C) (see Section <a href="/kivexa-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a> - <b>Special populations</b>).</p> <a name="HS"></a><h3>HOW SUPPLIED</h3> <h4>Dosage Forms And Strengths</h4> <p>Orange, film-coated, modified capsule shaped tablets, debossed with GS FC2 on one side.</p> <h4>Incompatibilities</h4> <p>Incompatibilities were either not assessed or not identified as part of the registration of this medicine.</p> <h4>Shelf Life</h4> <p>In Australia, information on the shelf life can be found on the public summary of the ARTG. The expiry date can be found on the packaging.</p> <h4>Special Precautions For Storage</h4> <p>Store below 30°C in a dry place.</p> <h4>Nature And Contents Of Container</h4> <p><b>KIVEXA</b> tablets are supplied in opaque white, polyvinyl chloride (<a href="/pvc/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">PVC</a>)/polyvinylidene chloride (PVdC) blister packs or in opaque white, PVC/PVdC child-resistant* blister packs. Each pack type contains 30 tablets.</p> <p class="credit">*complies with European Standard <i>EN 14375:2003 Child-resistant Non-reclosable Packaging for Pharmaceutical Products - Requirements And Testing.</i></p> <p>Not all blister types may be distributed in Australia.</p> <h4>Special Precautions For Disposal</h4> <p>In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.</p> <p class="credit">Manufactured by: ViiV Healthcare Pty Ltd Level 4, 436 Johnston Street, Abbotsford, Victoria, 3067 Australia. Revised: April 2018</p> </div> <a class="mediaPrmo ss" href="/aids_retrospective_slideshow/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/aids_s1_quilt.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">A Timeline of the HIV/AIDS Pandemic</span> <span class="btn">See Slideshow</span> </a> </div> </div> | <a name="I"></a><h3>INDICATIONS</h3> <h4>Therapeutic</h4> <p> KIVEXA tablets are a combination of two nucleoside analogues (abacavir and lamivudine). KIVEXA is indicated in antiretroviral combination therapy for the treatment of Human Immunodeficiency Virus (HIV) infection in adults and adolescents from 12 years of age.</p> <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3> <p>KIVEXA is supplied as film-coated tablets each containing 600 mg of abacavir as abacavir sulfate and 300 mg lamivudine.</p> <p>Abacavir sulfate is a white to off-white crystalline powder with a solubility of approximately 77 mg/mL in water at 25°C.</p> <p>Lamivudine is a white to off-white crystalline solid which is highly soluble in water.</p> <p>For the full list of excipients, see Section <a href="/kivexa-drug.htm#D"><b>DESCRIPTION</b></a>.</p> <h4>Dose And Method Of Administration</h4> <p>Therapy should be initiated by a physician experienced in the management of HIV infection.</p> <p>KIVEXA tablets should not be administered to adults or adolescents who weigh less than 40 kg because it is a fixed-dose tablet that cannot be dose reduced.</p> <p>KIVEXA tablets can be taken with or without food.</p> <p>KIVEXA tablets should not be prescribed for patients requiring dosage adjustments, such as those with creatinine clearance < 50 mL/min. Separate preparations of abacavir (ZIAGEN) or lamivudine (3TC) should be administered in cases where discontinuation or dose adjustment is indicated. In these cases the physician should refer to the individual product information for these medicinal products.</p> <h5>Adults And Adolescents</h5> <p>The recommended dose of KIVEXA tablets in adults and adolescents is one tablet once daily.</p> <h5>Elderly</h5> <p>The pharmacokinetics of abacavir and lamivudine have not been studied in patients over 65 years of age. When treating elderly patients, consideration needs to be given to the greater frequency of decreased hepatic, renal and cardiac function, concomitant medicinal products or disease.</p> <h5>Children</h5> <p>KIVEXA tablets are not recommended for treatment of children less than 12 years of age as the necessary dose adjustment cannot be made. Physicians should refer to the individual product information for lamivudine and abacavir.</p> <p>Renal impairment Whilst no dosage adjustment of abacavir is necessary in patients with renal impairment, a dose reduction of lamivudine is required due to decreased clearance. Therefore, KIVEXA tablets are not recommended for use in patients with a creatinine clearance < 50 mL/min (see Section <a href="/kivexa-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a> - <b>Special populations</b>).</p> <h5>Hepatic Impairment</h5> <p>A dose reduction of abacavir may be required for patients with mild hepatic impairment (Child-Pugh grade A). As dose reduction is not possible with KIVEXA tablets, the separate preparations of abacavir and lamivudine should be used when this is judged to be necessary. KIVEXA is not recommended in patients with moderate and severe hepatic impairment (Child-Pugh grade B or C) (see Section <a href="/kivexa-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a> - <b>Special populations</b>).</p> <a name="HS"></a><h3>HOW SUPPLIED</h3> <h4>Dosage Forms And Strengths</h4> <p>Orange, film-coated, modified capsule shaped tablets, debossed with GS FC2 on one side.</p> <h4>Incompatibilities</h4> <p>Incompatibilities were either not assessed or not identified as part of the registration of this medicine.</p> <h4>Shelf Life</h4> <p>In Australia, information on the shelf life can be found on the public summary of the ARTG. The expiry date can be found on the packaging.</p> <h4>Special Precautions For Storage</h4> <p>Store below 30°C in a dry place.</p> <h4>Nature And Contents Of Container</h4> <p><b>KIVEXA</b> tablets are supplied in opaque white, polyvinyl chloride (<a href="/pvc/definition.htm" ">PVC</a>)/polyvinylidene chloride (PVdC) blister packs or in opaque white, PVC/PVdC child-resistant* blister packs. Each pack type contains 30 tablets.</p> <p class="credit">*complies with European Standard <i>EN 14375:2003 Child-resistant Non-reclosable Packaging for Pharmaceutical Products - Requirements And Testing.</i></p> <p>Not all blister types may be distributed in Australia.</p> <h4>Special Precautions For Disposal</h4> <p>In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.</p> <p class="credit">Manufactured by: ViiV Healthcare Pty Ltd Level 4, 436 Johnston Street, Abbotsford, Victoria, 3067 Australia. Revised: April 2018</p> </div> <a class="mediaPrmo ss" href="/aids_retrospective_slideshow/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/aids_s1_quilt.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">A Timeline of the HIV/AIDS Pandemic</span> <span class="btn">See Slideshow</span> </a> </div> </div> | 2 | 2023-02-01 17:38:10 | Abacavir and Lamivudine Film-coated Tablets (Kivexa) | A | | Kivexa | abacavir and lamivudine film-coated tablets | Kivexa | John P. Cunha, DO, FACOEP |
| 12 | 2023-02-23 12:07:03 | Side Effects | <a name="AR"></a><h3>SIDE EFFECTS</h3> <p>KIVEXA tablets contain abacavir and lamivudine, therefore adverse events would be expected to be similar to those experienced by patients on separate preparations of lamivudine and abacavir. For many of the adverse events listed it is unclear whether they are related to specific <a href="/antiretroviral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antiretroviral</a> agents, or the wide range of other medications taken by HIV-infected patients, or whether they are a result of the underlying disease process.</p> <h4>Description Of Selected Adverse Effects</h4> <p>Hypersensitivity to abacavir (see Section <b>WARNINGS AND <a href="/kivexa-drug.htm#P">PRECAUTIONS</a></b>).</p> <p>Abacavir hypersensitivity reaction (HSR) has been identified as a common adverse reaction with abacavir therapy. The signs and symptoms of this hypersensitivity reaction are listed below. These have been identified either from clinical studies or post marketing surveillance. Those reported in <b>at least 10% of patients</b> with a hypersensitivity reaction are in bold text.</p> <p>Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however, reactions have occurred without rash or fever. Other key symptoms include <a href="/gastrointestinal/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">gastrointestinal</a>, respiratory or constitutional symptoms such as <a href="/lethargy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lethargy</a> and <a href="/malaise/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">malaise</a>.</p> <p><i><b>Skin:</b></i> <b>rash</b> (usually maculopapular or urticarial)</p> <p><i><b>Gastrointestinal tract:</b></i> <b>nausea, vomiting, diarrhoea, abdominal pain,</b> mouth <a href="/ulceration/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ulceration</a></p> <p><i><b>Respiratory tract:</b></i> <b>dyspnoea, cough,</b> <a href="/sore/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">sore</a> throat, adult <a href="/respiratory_distress_syndrome_rds/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">respiratory distress syndrome</a>, <a href="/respiratory_failure/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">respiratory failure</a></p> <p><i><b>Miscellaneous:</b></i> <b>fever, fatigue, malaise,</b> oedema, <a href="/lymphadenopathy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lymphadenopathy</a>, <a href="/hypotension/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypotension</a>, <a href="/conjunctivitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">conjunctivitis</a>, <a href="/anaphylaxis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">anaphylaxis</a></p> <p><i><b>Neurological/psychiatry:</b></i> <b>headache,</b> <a href="/paraesthesia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">paraesthesia</a></p> <p><i><b>Haematological:</b></i> lymphopenia</p> <p><i><b>Liver/pancreas:</b></i> <b>elevated liver function tests,</b> hepatic failure</p> <p><i><b>Musculoskeletal:</b></i> <b>myalgia, </b>rarely myolysis, <a href="/arthralgia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">arthralgia</a>, elevated <a href="/creatine/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">creatine</a> phosphokinase</p> <p><i><b>Urology:</b></i> elevated creatinine, renal failure</p> <p>Restarting abacavir following an abacavir HSR results in a prompt return of symptoms within hours. This recurrence of the HSR is usually more severe than on initial presentation, and may include life-threatening hypotension and death. Reactions have also occurred infrequently after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior to stopping abacavir; and on very rare occasions have also been seen in patients who have restarted therapy with no preceding symptoms of a HSR (i.e., patients previously considered to be abacavir tolerant).</p> <p>For details of clinical management in the event of a suspected abacavir HSR see Section <b>WARNINGS AND <a href="/kivexa-drug.htm#P">PRECAUTIONS</a></b>.</p> <h4>Clinical Trial Data</h4> <p>Table 1 lists the most common adverse events, occurring at an incidence of 5% or more, reported in the controlled pivotal clinical trial CNA30021, irrespective of the investigator's assessment of possible relationship to the study drug:</p> <p>Many of the adverse events listed occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity reaction. If KIVEXA tablets have been discontinued in patients due to experiencing any one of these symptoms and a decision is made to restart abacavir, this must be done only under direct medical supervision (see Special considerations following an interruption of KIVEXA therapy in Section <b>WARNINGS AND <a href="/kivexa-drug.htm#P">PRECAUTIONS</a></b>).</p> <p align="center"><b>Table 1: Most Common (Greater than or equal to 5% Incidence) Grade 2 to 4 Adverse Events (Safety Population - CNA30021)</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="50%">Adverse Event</td> <td class="EmphTd" width="25%">ABC once/day<br /> N=384<br /> n (%)</td> <td class="EmphTd" width="25%">ABC twice/day<br /> N=386<br /> n (%)</td> </tr> <tr> <td>Subjects with ANY Grade 2 to 4 AE</td> <td align="center">267 (70%)</td> <td align="center">276 (72%)</td> </tr> <tr> <td>Drug hypersensitivity</td> <td align="center">35 (9%)</td> <td align="center">27 (7%)</td> </tr> <tr> <td>Insomnia</td> <td align="center">26 (7%)</td> <td align="center">36 (9%)</td> </tr> <tr> <td>Depression</td> <td align="center">25 (7%)</td> <td align="center">26 (7%)</td> </tr> <tr> <td>Diarrhea</td> <td align="center">21 (5%)</td> <td align="center">25 (6%)</td> </tr> <tr> <td>Nausea</td> <td align="center">21 (5%)</td> <td align="center">25 (6%)</td> </tr> <tr> <td>Headache</td> <td align="center">21 (5%)</td> <td align="center">21 (5%)</td> </tr> <tr> <td>Rash</td> <td align="center">21 (5%)</td> <td align="center">19 (5%)</td> </tr> <tr> <td>Fatigue</td> <td align="center">20 (5%)</td> <td align="center">29 (8%)</td> </tr> <tr> <td>Dizziness</td> <td align="center">19 (5%)</td> <td align="center">19 (5%)</td> </tr> <tr> <td>Pyrexia</td> <td align="center">19 (5%)</td> <td align="center">13 (3%)</td> </tr> <tr> <td>Abnormal dreams</td> <td align="center">15 (4%)</td> <td align="center">19 (5%)</td> </tr> <tr> <td>Anxiety</td> <td align="center">12 (3%)</td> <td align="center">20 (5%)</td> </tr> </table> </center></p> <p align="center"><b>Table 2: Grade 3 to 4 Treatment Emergent Laboratory Abnormalities (Safety Population - CNA30021)</b><br /> <center><table class="blacktbl" width="650" cellspacing="0"> <tr> <td class="EmphTd" width="28%">Grade 3 and 4 Laboratory Abnormalities</td> <td colspan="3" class="EmphTd">ABC once/day<br /> N=384<br /> N(%)</td> <td colspan="3" class="EmphTd">ABC twice/day<br /> N=386<br /> N(%)</td> </tr> <tr> <td class="EmphTd">Clinical Chemistry</td> <td class="EmphTd" width="12%">Gr 3</td> <td class="EmphTd" width="12%">Gr 4</td> <td class="EmphTd" width="12%">Gr 3-4</td> <td class="EmphTd" width="12%">Gr 3</td> <td class="EmphTd" width="12%">Gr 4</td> <td class="EmphTd" width="12%">Gr 3-4</td> </tr> <tr> <td>Elevated ALT</td> <td align="center">14 (4%)</td> <td align="center">9 (2%)</td> <td align="center">23 (6%)</td> <td align="center">18 (5%)</td> <td align="center">6 (2%)</td> <td align="center">24 (6%)</td> </tr> <tr> <td>Elevated AST</td> <td align="center">10 (3%)</td> <td align="center">13 (3%)</td> <td align="center">23 (6%)</td> <td align="center">9 (2%)</td> <td align="center">5 (1%)</td> <td align="center">14 (4%)</td> </tr> <tr> <td>Alkaline phosphatase</td> <td align="center">1 (<1%)</td> <td align="center">0</td> <td align="center">1 (<1%)</td> <td align="center">0</td> <td align="center">1 (<1%)</td> <td align="center">1 (<1%)</td> </tr> <tr> <td>Amylase</td> <td align="center">13 (3%)</td> <td align="center">2 (<1%)</td> <td align="center">15 (4%)</td> <td align="center">12 (3%)</td> <td align="center">0</td> <td align="center">12 (3%)</td> </tr> <tr> <td>Bilirubin</td> <td align="center">0</td> <td align="center">2 (<1%)</td> <td align="center">2 (<1%)</td> <td align="center">1 (<1%)</td> <td align="center">1 (<1%)</td> <td align="center">2 (<1%)</td> </tr> <tr> <td>Creatine kinase</td> <td align="center">13 (3%)</td> <td align="center">31 (8%)</td> <td align="center">44 (12%)</td> <td align="center">13 (3%)</td> <td align="center">22 (6%)</td> <td align="center">35 (9%)</td> </tr> <tr> <td>Creatinine</td> <td align="center">0</td> <td align="center">0</td> <td align="center">0</td> <td align="center">0</td> <td align="center">1 (<1%)</td> <td align="center">1 (<1%)</td> </tr> <tr> <td>Glucose</td> <td align="center">4 (1%)</td> <td align="center">1 (<1%)</td> <td align="center">5 (1%)</td> <td align="center">5 (1%)</td> <td align="center">0</td> <td align="center">5 (1%)</td> </tr> <tr> <td>Sodium</td> <td align="center">2 (<1%)</td> <td align="center">0</td> <td align="center">2 (<1%)</td> <td align="center">1 (<1%)</td> <td align="center">0</td> <td align="center">1 (<1%)</td> </tr> <tr> <td>Triglycerides</td> <td align="center">13 (3%)</td> <td align="center">5 (1%)</td> <td align="center">18 (5%)</td> <td align="center">13 (3%)</td> <td align="center">8 (2%)</td> <td align="center">21 (6%)</td> </tr> <tr> <td><b>Hematology</b></td> <td align="center"> </td> <td align="center"> </td> <td align="center"> </td> <td align="center"> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td>Hemoglobin</td> <td align="center">0</td> <td align="center">1 (<1%)</td> <td align="center">1 (<1%)</td> <td align="center">0</td> <td align="center">0</td> <td align="center">0</td> </tr> <tr> <td>Neutrophils absolute</td> <td align="center">6 (2%)</td> <td align="center">3 (<1%)</td> <td align="center">9 (2%)</td> <td align="center">4 (1%)</td> <td align="center">1 (<1%)</td> <td align="center">5 (1%)</td> </tr> <tr> <td>Platelets</td> <td align="center">2 (<1%)</td> <td align="center">0</td> <td align="center">2 (<1%)</td> <td align="center">2 (<1%)</td> <td align="center">0</td> <td align="center">2 (<1%)</td> </tr> <tr> <td>WBC</td> <td align="center">0</td> <td align="center">0</td> <td align="center">0</td> <td align="center">1 (<1%)</td> <td align="center">0</td> <td align="center">1 (<1%)</td> </tr> </table> </center></p> <h4>Postmarketing Data</h4> <p>In addition to the adverse events included from clinical trial data, the following adverse events listed in Table 3 below have been identified during post-approval use of abacavir and lamivudine. These events have been chosen for inclusion due to a potential causal connection to abacavir and/or lamivudine.</p> <p align="center"><b>Table 3: Adverse Events Identified Post Approval</b><br /> <center><table class="blacktbl" width="650" cellspacing="0"> <tr> <td class="EmphTd" width="35%">Body system</td> <td class="EmphTd" width="30%">Abacavir</td> <td class="EmphTd" width="35%">Lamivudine</td> </tr> <tr> <td>Blood and lymphatic systems disorde</td> <td> </td> <td>Very rare: pure red cell aplasia</td> </tr> <tr> <td>Metabolism and nutrition disorders</td> <td>Common: hyperlactataemia<br /> Rare: lactic acidosis<sup>1</sup></td> <td>Common: hyperlactataemia<br /> Rare: lactic acidosis<sup>1</sup></td> </tr> <tr> <td>Nervous system disorders</td> <td> </td> <td>Very rare: paraesthesiae, peripheral neuropathy has been reported although a causal relationship to treatment is uncertain</td> </tr> <tr> <td>Gastrointestinal disorders</td> <td>Rare: pancreatitis, but a causal relationship to abacavir is uncertain</td> <td>Rare: rises in serum amylase, pancreatitis, although a causal relationship to lamivudine is uncertain</td> </tr> <tr> <td>Skin and subcutaneous tissue disorders</td> <td>Common: rash (without systemic symptoms)<br /> Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis</td> <td>Common: alopecia</td> </tr> <tr> <td>Musculoskeletal and connective tissue disorders</td> <td> </td> <td>Common: arthralgia,muscle disorders<br /> Rare: rhabdomyolysis</td> </tr> <tr> <td class="credit" colspan="3"><sup>1</sup>See Section <b>WARNINGS AND <a href="/kivexa-drug.htm#P">PRECAUTIONS</a></b></td> </tr> </table> </center></p> <p>Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://<b>www.tga.gov.au/reporting-problems.</b></p> </div> </div> </div> | <a name="AR"></a><h3>SIDE EFFECTS</h3> <p>KIVEXA tablets contain abacavir and lamivudine, therefore adverse events would be expected to be similar to those experienced by patients on separate preparations of lamivudine and abacavir. For many of the adverse events listed it is unclear whether they are related to specific <a href="/antiretroviral/definition.htm" ">antiretroviral</a> agents, or the wide range of other medications taken by HIV-infected patients, or whether they are a result of the underlying disease process.</p> <h4>Description Of Selected Adverse Effects</h4> <p>Hypersensitivity to abacavir (see Section <b>WARNINGS AND <a href="/kivexa-drug.htm#P">PRECAUTIONS</a></b>).</p> <p>Abacavir hypersensitivity reaction (HSR) has been identified as a common adverse reaction with abacavir therapy. The signs and symptoms of this hypersensitivity reaction are listed below. These have been identified either from clinical studies or post marketing surveillance. Those reported in <b>at least 10% of patients</b> with a hypersensitivity reaction are in bold text.</p> <p>Almost all patients developing hypersensitivity reactions will have fever and/or rash (usually maculopapular or urticarial) as part of the syndrome, however, reactions have occurred without rash or fever. Other key symptoms include <a href="/gastrointestinal/definition.htm" ">gastrointestinal</a>, respiratory or constitutional symptoms such as <a href="/lethargy/definition.htm" ">lethargy</a> and <a href="/malaise/definition.htm" ">malaise</a>.</p> <p><i><b>Skin:</b></i> <b>rash</b> (usually maculopapular or urticarial)</p> <p><i><b>Gastrointestinal tract:</b></i> <b>nausea, vomiting, diarrhoea, abdominal pain,</b> mouth <a href="/ulceration/definition.htm" ">ulceration</a></p> <p><i><b>Respiratory tract:</b></i> <b>dyspnoea, cough,</b> <a href="/sore/definition.htm" ">sore</a> throat, adult <a href="/respiratory_distress_syndrome_rds/definition.htm" ">respiratory distress syndrome</a>, <a href="/respiratory_failure/definition.htm" ">respiratory failure</a></p> <p><i><b>Miscellaneous:</b></i> <b>fever, fatigue, malaise,</b> oedema, <a href="/lymphadenopathy/definition.htm" ">lymphadenopathy</a>, <a href="/hypotension/definition.htm" ">hypotension</a>, <a href="/conjunctivitis/definition.htm" ">conjunctivitis</a>, <a href="/anaphylaxis/definition.htm" ">anaphylaxis</a></p> <p><i><b>Neurological/psychiatry:</b></i> <b>headache,</b> <a href="/paraesthesia/definition.htm" ">paraesthesia</a></p> <p><i><b>Haematological:</b></i> lymphopenia</p> <p><i><b>Liver/pancreas:</b></i> <b>elevated liver function tests,</b> hepatic failure</p> <p><i><b>Musculoskeletal:</b></i> <b>myalgia, </b>rarely myolysis, <a href="/arthralgia/definition.htm" ">arthralgia</a>, elevated <a href="/creatine/definition.htm" ">creatine</a> phosphokinase</p> <p><i><b>Urology:</b></i> elevated creatinine, renal failure</p> <p>Restarting abacavir following an abacavir HSR results in a prompt return of symptoms within hours. This recurrence of the HSR is usually more severe than on initial presentation, and may include life-threatening hypotension and death. Reactions have also occurred infrequently after restarting abacavir in patients who had only one of the key symptoms of hypersensitivity (see above) prior to stopping abacavir; and on very rare occasions have also been seen in patients who have restarted therapy with no preceding symptoms of a HSR (i.e., patients previously considered to be abacavir tolerant).</p> <p>For details of clinical management in the event of a suspected abacavir HSR see Section <b>WARNINGS AND <a href="/kivexa-drug.htm#P">PRECAUTIONS</a></b>.</p> <h4>Clinical Trial Data</h4> <p>Table 1 lists the most common adverse events, occurring at an incidence of 5% or more, reported in the controlled pivotal clinical trial CNA30021, irrespective of the investigator's assessment of possible relationship to the study drug:</p> <p>Many of the adverse events listed occur commonly (nausea, vomiting, diarrhoea, fever, lethargy, rash) in patients with abacavir hypersensitivity. Therefore, patients with any of these symptoms should be carefully evaluated for the presence of this hypersensitivity reaction. If KIVEXA tablets have been discontinued in patients due to experiencing any one of these symptoms and a decision is made to restart abacavir, this must be done only under direct medical supervision (see Special considerations following an interruption of KIVEXA therapy in Section <b>WARNINGS AND <a href="/kivexa-drug.htm#P">PRECAUTIONS</a></b>).</p> <p align="center"><b>Table 1: Most Common (Greater than or equal to 5% Incidence) Grade 2 to 4 Adverse Events (Safety Population - CNA30021)</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="50%">Adverse Event</td> <td class="EmphTd" width="25%">ABC once/day<br /> N=384<br /> n (%)</td> <td class="EmphTd" width="25%">ABC twice/day<br /> N=386<br /> n (%)</td> </tr> <tr> <td>Subjects with ANY Grade 2 to 4 AE</td> <td align="center">267 (70%)</td> <td align="center">276 (72%)</td> </tr> <tr> <td>Drug hypersensitivity</td> <td align="center">35 (9%)</td> <td align="center">27 (7%)</td> </tr> <tr> <td>Insomnia</td> <td align="center">26 (7%)</td> <td align="center">36 (9%)</td> </tr> <tr> <td>Depression</td> <td align="center">25 (7%)</td> <td align="center">26 (7%)</td> </tr> <tr> <td>Diarrhea</td> <td align="center">21 (5%)</td> <td align="center">25 (6%)</td> </tr> <tr> <td>Nausea</td> <td align="center">21 (5%)</td> <td align="center">25 (6%)</td> </tr> <tr> <td>Headache</td> <td align="center">21 (5%)</td> <td align="center">21 (5%)</td> </tr> <tr> <td>Rash</td> <td align="center">21 (5%)</td> <td align="center">19 (5%)</td> </tr> <tr> <td>Fatigue</td> <td align="center">20 (5%)</td> <td align="center">29 (8%)</td> </tr> <tr> <td>Dizziness</td> <td align="center">19 (5%)</td> <td align="center">19 (5%)</td> </tr> <tr> <td>Pyrexia</td> <td align="center">19 (5%)</td> <td align="center">13 (3%)</td> </tr> <tr> <td>Abnormal dreams</td> <td align="center">15 (4%)</td> <td align="center">19 (5%)</td> </tr> <tr> <td>Anxiety</td> <td align="center">12 (3%)</td> <td align="center">20 (5%)</td> </tr> </table> </center></p> <p align="center"><b>Table 2: Grade 3 to 4 Treatment Emergent Laboratory Abnormalities (Safety Population - CNA30021)</b><br /> <center><table class="blacktbl" width="650" cellspacing="0"> <tr> <td class="EmphTd" width="28%">Grade 3 and 4 Laboratory Abnormalities</td> <td colspan="3" class="EmphTd">ABC once/day<br /> N=384<br /> N(%)</td> <td colspan="3" class="EmphTd">ABC twice/day<br /> N=386<br /> N(%)</td> </tr> <tr> <td class="EmphTd">Clinical Chemistry</td> <td class="EmphTd" width="12%">Gr 3</td> <td class="EmphTd" width="12%">Gr 4</td> <td class="EmphTd" width="12%">Gr 3-4</td> <td class="EmphTd" width="12%">Gr 3</td> <td class="EmphTd" width="12%">Gr 4</td> <td class="EmphTd" width="12%">Gr 3-4</td> </tr> <tr> <td>Elevated ALT</td> <td align="center">14 (4%)</td> <td align="center">9 (2%)</td> <td align="center">23 (6%)</td> <td align="center">18 (5%)</td> <td align="center">6 (2%)</td> <td align="center">24 (6%)</td> </tr> <tr> <td>Elevated AST</td> <td align="center">10 (3%)</td> <td align="center">13 (3%)</td> <td align="center">23 (6%)</td> <td align="center">9 (2%)</td> <td align="center">5 (1%)</td> <td align="center">14 (4%)</td> </tr> <tr> <td>Alkaline phosphatase</td> <td align="center">1 (<1%)</td> <td align="center">0</td> <td align="center">1 (<1%)</td> <td align="center">0</td> <td align="center">1 (<1%)</td> <td align="center">1 (<1%)</td> </tr> <tr> <td>Amylase</td> <td align="center">13 (3%)</td> <td align="center">2 (<1%)</td> <td align="center">15 (4%)</td> <td align="center">12 (3%)</td> <td align="center">0</td> <td align="center">12 (3%)</td> </tr> <tr> <td>Bilirubin</td> <td align="center">0</td> <td align="center">2 (<1%)</td> <td align="center">2 (<1%)</td> <td align="center">1 (<1%)</td> <td align="center">1 (<1%)</td> <td align="center">2 (<1%)</td> </tr> <tr> <td>Creatine kinase</td> <td align="center">13 (3%)</td> <td align="center">31 (8%)</td> <td align="center">44 (12%)</td> <td align="center">13 (3%)</td> <td align="center">22 (6%)</td> <td align="center">35 (9%)</td> </tr> <tr> <td>Creatinine</td> <td align="center">0</td> <td align="center">0</td> <td align="center">0</td> <td align="center">0</td> <td align="center">1 (<1%)</td> <td align="center">1 (<1%)</td> </tr> <tr> <td>Glucose</td> <td align="center">4 (1%)</td> <td align="center">1 (<1%)</td> <td align="center">5 (1%)</td> <td align="center">5 (1%)</td> <td align="center">0</td> <td align="center">5 (1%)</td> </tr> <tr> <td>Sodium</td> <td align="center">2 (<1%)</td> <td align="center">0</td> <td align="center">2 (<1%)</td> <td align="center">1 (<1%)</td> <td align="center">0</td> <td align="center">1 (<1%)</td> </tr> <tr> <td>Triglycerides</td> <td align="center">13 (3%)</td> <td align="center">5 (1%)</td> <td align="center">18 (5%)</td> <td align="center">13 (3%)</td> <td align="center">8 (2%)</td> <td align="center">21 (6%)</td> </tr> <tr> <td><b>Hematology</b></td> <td align="center"> </td> <td align="center"> </td> <td align="center"> </td> <td align="center"> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td>Hemoglobin</td> <td align="center">0</td> <td align="center">1 (<1%)</td> <td align="center">1 (<1%)</td> <td align="center">0</td> <td align="center">0</td> <td align="center">0</td> </tr> <tr> <td>Neutrophils absolute</td> <td align="center">6 (2%)</td> <td align="center">3 (<1%)</td> <td align="center">9 (2%)</td> <td align="center">4 (1%)</td> <td align="center">1 (<1%)</td> <td align="center">5 (1%)</td> </tr> <tr> <td>Platelets</td> <td align="center">2 (<1%)</td> <td align="center">0</td> <td align="center">2 (<1%)</td> <td align="center">2 (<1%)</td> <td align="center">0</td> <td align="center">2 (<1%)</td> </tr> <tr> <td>WBC</td> <td align="center">0</td> <td align="center">0</td> <td align="center">0</td> <td align="center">1 (<1%)</td> <td align="center">0</td> <td align="center">1 (<1%)</td> </tr> </table> </center></p> <h4>Postmarketing Data</h4> <p>In addition to the adverse events included from clinical trial data, the following adverse events listed in Table 3 below have been identified during post-approval use of abacavir and lamivudine. These events have been chosen for inclusion due to a potential causal connection to abacavir and/or lamivudine.</p> <p align="center"><b>Table 3: Adverse Events Identified Post Approval</b><br /> <center><table class="blacktbl" width="650" cellspacing="0"> <tr> <td class="EmphTd" width="35%">Body system</td> <td class="EmphTd" width="30%">Abacavir</td> <td class="EmphTd" width="35%">Lamivudine</td> </tr> <tr> <td>Blood and lymphatic systems disorde</td> <td> </td> <td>Very rare: pure red cell aplasia</td> </tr> <tr> <td>Metabolism and nutrition disorders</td> <td>Common: hyperlactataemia<br /> Rare: lactic acidosis<sup>1</sup></td> <td>Common: hyperlactataemia<br /> Rare: lactic acidosis<sup>1</sup></td> </tr> <tr> <td>Nervous system disorders</td> <td> </td> <td>Very rare: paraesthesiae, peripheral neuropathy has been reported although a causal relationship to treatment is uncertain</td> </tr> <tr> <td>Gastrointestinal disorders</td> <td>Rare: pancreatitis, but a causal relationship to abacavir is uncertain</td> <td>Rare: rises in serum amylase, pancreatitis, although a causal relationship to lamivudine is uncertain</td> </tr> <tr> <td>Skin and subcutaneous tissue disorders</td> <td>Common: rash (without systemic symptoms)<br /> Very rare: erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis</td> <td>Common: alopecia</td> </tr> <tr> <td>Musculoskeletal and connective tissue disorders</td> <td> </td> <td>Common: arthralgia,muscle disorders<br /> Rare: rhabdomyolysis</td> </tr> <tr> <td class="credit" colspan="3"><sup>1</sup>See Section <b>WARNINGS AND <a href="/kivexa-drug.htm#P">PRECAUTIONS</a></b></td> </tr> </table> </center></p> <p>Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://<b>www.tga.gov.au/reporting-problems.</b></p> </div> </div> </div> | 2 | 2023-02-01 17:38:10 | Abacavir and Lamivudine Film-coated Tablets (Kivexa) | A | | Kivexa | abacavir and lamivudine film-coated tablets | Kivexa | John P. Cunha, DO, FACOEP |
| 13 | 2023-02-23 12:07:03 | Drug Interactions | <a name="DI"></a><h3>DRUG INTERACTIONS</h3> <p>As KIVEXA tablets contain abacavir and lamivudine, any interactions that have been identified with these agents individually may occur with KIVEXA tablets. Clinical studies have shown that there are no clinically significant interactions between abacavir and lamivudine. Abacavir and lamivudine are not significantly metabolised by cytochrome P<sub>450</sub> enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6) nor do they inhibit or induce this enzyme system. Therefore, there is little potential for interactions with antiretroviral <a href="/protease/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">protease</a> inhibitors, non-nucleosides and other medicinal products metabolised by major P<sub>450</sub> enzymes.</p> <p>The likelihood of metabolic interactions with lamivudine is low due to limited <a href="/metabolism/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">metabolism</a> and plasma protein binding, and almost complete renal clearance. Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when the main route of elimination is renal.</p> <h4>Effect Of Abacavir On The Pharmacokinetics Of Other Agents</h4> <p><i>In vitro</i>, abacavir demonstrates no or weak inhibition of the drug transporters organic <a href="/anion/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">anion</a> transporter 1B1 (OATP1B1), OATP1B3, <a href="/breast_cancer/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">breast cancer</a> resistance protein (BCRP) or P-<a href="/glycoprotein/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">glycoprotein</a> (Pgp) and minimal inhibition of organic cation transporter 1 (OCT1), OCT2 and multidrug and <a href="/toxin/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">toxin</a> extrusion protein 2-K (MATE2-K). Abacavir is therefore not expected to affect the plasma concentrations of drugs that are substrates of these drug transporters.</p> <p>Abacavir is an inhibitor of MATE1 <i>in vitro</i>, however abacavir has low potential to affect the plasma concentrations of MATE1 substrates at therapeutic drug exposures (up to 600 mg).</p> <h4>Effect Of Other Agents On The Pharmacokinetics Of Abacavir</h4> <p><i>In vitro</i>, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, Multidrug resistance-associated protein 2 (MRP2) or MRP4, therefore drugs that modulate these transporters are not expected to affect abacavir plasma concentrations.</p> <p>Although abacavir is a substrate of BCRP and Pgp <i>in vitro</i>, clinical studies demonstrate no clinically significant changes in abacavir pharmacokinetics when co-administered with lopinavir/ritonavir (Pgp and BCRP inhibitors).</p> <h4>Interactions Relevant To Abacavir</h4> <h5>Ethanol</h5> <p>The metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of abacavir of about 41%. Given the safety profile of abacavir, these findings are not considered clinically significant. Abacavir has no effect on the metabolism of ethanol.</p> <h5>Methadone</h5> <p>In a pharmacokinetic study, co-administration of 600 mg abacavir twice daily with <a href="/methadone/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">methadone</a> showed a 35% reduction in abacavir Cmax and a one hour delay in tmax, but AUC was unchanged. The changes in abacavir pharmacokinetics are not considered clinically relevant. In this study, abacavir increased the mean methadone systemic clearance by 22%. This change is not considered clinically relevant for the majority of patients, however occasionally methadone dose re-titration may be required.</p> <h5>Retinoids</h5> <p><a href="/retinoid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Retinoid</a> compounds such as isotretinoin, are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible but has not been studied.</p> <h4>Effect Of Lamivudine On The Pharmacokinetics Of Other Agents</h4> <p><i>In vitro</i>, lamivudine demonstrates no or weak inhibition of the drug transporters OATP1B1, OATP1B3, BCRP or Pgp, MATE1, MATE2-K or OCT3. Lamivudine is therefore not expected to affect the plasma concentrations of drugs that are substrates of these drug transporters.</p> <p>Lamivudine is an inhibitor of OCT1 and OCT2 <i>in vitro</i> with IC50 values of 17 and 33 uM, respectively, however lamivudine has low potential to affect the plasma concentrations of OCT1 and OCT2 substrates at therapeutic drug exposures (up to 300 mg).</p> <h4>Effect Of Other Agents On The Pharmacokinetics Of Lamivudine</h4> <p>Lamivudine is a substrate of MATE1, MATE2-K and OCT2 <i>in vitro</i>. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations, however this interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.</p> <p>Lamivudine is a substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinical significance.</p> <p>Lamivudine is a substrate of Pgp and BCRP, however due to its high bioavailability it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore co-administration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.</p> <h4>Interactions Relevant To Lamivudine</h4> <h5>Sorbitol</h5> <p>Coadministration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose of lamivudine oral solution resulted in dose-dependent decreases of 14% (9 - 20%), 32% (28 - 37%), and 36% (32 - 41%) in lamivudine exposure (AUC∞) and 28% (20 - 34%), 52% (47 - 57%), and 55% (50 - 59%) in the Cmax of lamivudine in adults. When possible, avoid chronic coadministration of sorbitol-containing medicines with lamivudine. Consider more frequent monitoring of HIV-1 viral load when chronic coadministration cannot be avoided.</p> <h5>Trimethoprim</h5> <p>Administration of trimethoprim/sulphamethoxazole 160 mg/800 mg (co-trimoxazole) causes a 40% increase in lamivudine exposure because of the trimethoprim component. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary (see Section <a href="/kivexa-drug.htm#DAA"><b>Dose And Method Of Administration</b></a>). Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole. Administration of lamivudine in patients with renal impairment should be assessed carefully. The effect of co-administration of lamivudine with higher doses of co-trimoxazole used for the treatment of <i>Pneumocystis carinii</i> <a href="/pneumonia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pneumonia</a> and <a href="/toxoplasmosis_toxo/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">toxoplasmosis</a> has not been studied.</p> <h5>Emtricitabine</h5> <p>Lamivudine may inhibit the intracellular <a href="/phosphorylation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">phosphorylation</a> of emtricitabine when the two medicinal products are used concurrently. Additionally, the mechanism of viral resistance for both lamivudine and emtricitabine is mediated via mutation of the same viral <a href="/reverse_transcriptase/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">reverse transcriptase</a> gene (M184V) and therefore the therapeutic efficacy of these drugs in combination therapy may be limited. Lamivudine is not recommended for use in combination with emtricitabine or emtricitabine-containing fixed-dose combinations.</p> <h4>Effects On Ability To Drive And Use Machines</h4> <p>There have been no studies to investigate the effect of abacavir or lamivudine, on driving performance or the ability to operate machinery. Further, a detrimental effect on such activities cannot be predicted from the <a href="/pharmacology/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pharmacology</a> of these medicinal products. The clinical status of the patient and the adverse event profile of KIVEXA tablets should be borne in mind when considering the patient's ability to drive or operate machinery.</p> </div> </div> </div> | <a name="DI"></a><h3>DRUG INTERACTIONS</h3> <p>As KIVEXA tablets contain abacavir and lamivudine, any interactions that have been identified with these agents individually may occur with KIVEXA tablets. Clinical studies have shown that there are no clinically significant interactions between abacavir and lamivudine. Abacavir and lamivudine are not significantly metabolised by cytochrome P<sub>450</sub> enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6) nor do they inhibit or induce this enzyme system. Therefore, there is little potential for interactions with antiretroviral <a href="/protease/definition.htm" ">protease</a> inhibitors, non-nucleosides and other medicinal products metabolised by major P<sub>450</sub> enzymes.</p> <p>The likelihood of metabolic interactions with lamivudine is low due to limited <a href="/metabolism/definition.htm" ">metabolism</a> and plasma protein binding, and almost complete renal clearance. Lamivudine is predominantly eliminated by active organic cationic secretion. The possibility of interactions with other medicinal products administered concurrently should be considered, particularly when the main route of elimination is renal.</p> <h4>Effect Of Abacavir On The Pharmacokinetics Of Other Agents</h4> <p><i>In vitro</i>, abacavir demonstrates no or weak inhibition of the drug transporters organic <a href="/anion/definition.htm" ">anion</a> transporter 1B1 (OATP1B1), OATP1B3, <a href="/breast_cancer/definition.htm" ">breast cancer</a> resistance protein (BCRP) or P-<a href="/glycoprotein/definition.htm" ">glycoprotein</a> (Pgp) and minimal inhibition of organic cation transporter 1 (OCT1), OCT2 and multidrug and <a href="/toxin/definition.htm" ">toxin</a> extrusion protein 2-K (MATE2-K). Abacavir is therefore not expected to affect the plasma concentrations of drugs that are substrates of these drug transporters.</p> <p>Abacavir is an inhibitor of MATE1 <i>in vitro</i>, however abacavir has low potential to affect the plasma concentrations of MATE1 substrates at therapeutic drug exposures (up to 600 mg).</p> <h4>Effect Of Other Agents On The Pharmacokinetics Of Abacavir</h4> <p><i>In vitro</i>, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, Multidrug resistance-associated protein 2 (MRP2) or MRP4, therefore drugs that modulate these transporters are not expected to affect abacavir plasma concentrations.</p> <p>Although abacavir is a substrate of BCRP and Pgp <i>in vitro</i>, clinical studies demonstrate no clinically significant changes in abacavir pharmacokinetics when co-administered with lopinavir/ritonavir (Pgp and BCRP inhibitors).</p> <h4>Interactions Relevant To Abacavir</h4> <h5>Ethanol</h5> <p>The metabolism of abacavir is altered by concomitant ethanol resulting in an increase in AUC of abacavir of about 41%. Given the safety profile of abacavir, these findings are not considered clinically significant. Abacavir has no effect on the metabolism of ethanol.</p> <h5>Methadone</h5> <p>In a pharmacokinetic study, co-administration of 600 mg abacavir twice daily with <a href="/methadone/definition.htm" ">methadone</a> showed a 35% reduction in abacavir Cmax and a one hour delay in tmax, but AUC was unchanged. The changes in abacavir pharmacokinetics are not considered clinically relevant. In this study, abacavir increased the mean methadone systemic clearance by 22%. This change is not considered clinically relevant for the majority of patients, however occasionally methadone dose re-titration may be required.</p> <h5>Retinoids</h5> <p><a href="/retinoid/definition.htm" ">Retinoid</a> compounds such as isotretinoin, are eliminated via alcohol dehydrogenase. Interaction with abacavir is possible but has not been studied.</p> <h4>Effect Of Lamivudine On The Pharmacokinetics Of Other Agents</h4> <p><i>In vitro</i>, lamivudine demonstrates no or weak inhibition of the drug transporters OATP1B1, OATP1B3, BCRP or Pgp, MATE1, MATE2-K or OCT3. Lamivudine is therefore not expected to affect the plasma concentrations of drugs that are substrates of these drug transporters.</p> <p>Lamivudine is an inhibitor of OCT1 and OCT2 <i>in vitro</i> with IC50 values of 17 and 33 uM, respectively, however lamivudine has low potential to affect the plasma concentrations of OCT1 and OCT2 substrates at therapeutic drug exposures (up to 300 mg).</p> <h4>Effect Of Other Agents On The Pharmacokinetics Of Lamivudine</h4> <p>Lamivudine is a substrate of MATE1, MATE2-K and OCT2 <i>in vitro</i>. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations, however this interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.</p> <p>Lamivudine is a substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinical significance.</p> <p>Lamivudine is a substrate of Pgp and BCRP, however due to its high bioavailability it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore co-administration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.</p> <h4>Interactions Relevant To Lamivudine</h4> <h5>Sorbitol</h5> <p>Coadministration of sorbitol solution (3.2 g, 10.2 g, 13.4 g) with a single 300 mg dose of lamivudine oral solution resulted in dose-dependent decreases of 14% (9 - 20%), 32% (28 - 37%), and 36% (32 - 41%) in lamivudine exposure (AUC∞) and 28% (20 - 34%), 52% (47 - 57%), and 55% (50 - 59%) in the Cmax of lamivudine in adults. When possible, avoid chronic coadministration of sorbitol-containing medicines with lamivudine. Consider more frequent monitoring of HIV-1 viral load when chronic coadministration cannot be avoided.</p> <h5>Trimethoprim</h5> <p>Administration of trimethoprim/sulphamethoxazole 160 mg/800 mg (co-trimoxazole) causes a 40% increase in lamivudine exposure because of the trimethoprim component. However, unless the patient has renal impairment, no dosage adjustment of lamivudine is necessary (see Section <a href="/kivexa-drug.htm#DAA"><b>Dose And Method Of Administration</b></a>). Lamivudine has no effect on the pharmacokinetics of trimethoprim or sulphamethoxazole. Administration of lamivudine in patients with renal impairment should be assessed carefully. The effect of co-administration of lamivudine with higher doses of co-trimoxazole used for the treatment of <i>Pneumocystis carinii</i> <a href="/pneumonia/definition.htm" ">pneumonia</a> and <a href="/toxoplasmosis_toxo/definition.htm" ">toxoplasmosis</a> has not been studied.</p> <h5>Emtricitabine</h5> <p>Lamivudine may inhibit the intracellular <a href="/phosphorylation/definition.htm" ">phosphorylation</a> of emtricitabine when the two medicinal products are used concurrently. Additionally, the mechanism of viral resistance for both lamivudine and emtricitabine is mediated via mutation of the same viral <a href="/reverse_transcriptase/definition.htm" ">reverse transcriptase</a> gene (M184V) and therefore the therapeutic efficacy of these drugs in combination therapy may be limited. Lamivudine is not recommended for use in combination with emtricitabine or emtricitabine-containing fixed-dose combinations.</p> <h4>Effects On Ability To Drive And Use Machines</h4> <p>There have been no studies to investigate the effect of abacavir or lamivudine, on driving performance or the ability to operate machinery. Further, a detrimental effect on such activities cannot be predicted from the <a href="/pharmacology/definition.htm" ">pharmacology</a> of these medicinal products. The clinical status of the patient and the adverse event profile of KIVEXA tablets should be borne in mind when considering the patient's ability to drive or operate machinery.</p> </div> </div> </div> | 2 | 2023-02-01 17:38:10 | Abacavir and Lamivudine Film-coated Tablets (Kivexa) | A | | Kivexa | abacavir and lamivudine film-coated tablets | Kivexa | John P. Cunha, DO, FACOEP |
| 14 | 2023-02-23 12:07:03 | Warnings & Precautions | <a name="W"></a><h3>WARNINGS</h3> <p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a><h3>PRECAUTIONS</h3> <h4>Hypersensitivity</h4> <h5>Special Warning</h5> <p>The special warnings and precautions relevant to both abacavir and lamivudine are included in this section. There are no additional precautions and warnings relevant to KIVEXA tablets.</p> <p>Hypersensitivity to abacavir (see Section <a href="/kivexa-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>). Hypersensitivity to abacavir is a multi-organ clinical syndrome which can occur at any time during treatment, but most often occurs within the first 6 weeks of therapy. Signs or symptom usually present in 2 or more of the following groups although hypersensitivity following the presentation of a single sign or symptom has been reported infrequently.</p> <ul> <li>fever</li> <li>rash</li> <li>gastrointestinal, including nausea, vomiting, diarrhoea, or abdominal pain</li> <li>constitutional, including generalized malaise, fatigue, or achiness</li> <li>respiratory, including <a href="/dyspnoea/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">dyspnoea</a>, cough, or <a href="/pharyngitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pharyngitis</a>.</li> </ul> <p>Hypersensitivity reactions may present similarly to pneumonia, <a href="/bronchitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bronchitis</a> or pharyngitis, <a href="/influenza/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">influenza</a>-like illness or <a href="/gastroenteritis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">gastroenteritis</a>.</p> <ul> <li><b>Discontinue KIVEXA as soon as a hypersensitivity reaction is suspected.</b></li> <li><b>If hypersensitivity reaction cannot be ruled out, KIVEXA or any other medicinal product containing abacavir must not be restarted.</b></li> <li>The risk is significantly increased for patients who test positive for the <a href="/hla/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HLA</a>-B*5701 <a href="/allele/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">allele</a>. However, abacavir hypersensitivity reactions have been reported at a lower frequency in patients who do not carry this allele.</li> <li><b>KIVEXA is not recommended for use in patients with the HLA-B*5701 allele or in patients who have had a suspected abacavir HSR while taking any medicinal product containing abacavir.</b></li> <li>Testing for HLA-B*5701 status is recommended before initiating abacavir treatment and also before re-starting abacavir treatment in patients of unknown HLA-B*5701 status who have previously tolerated abacavir.</li> <li>The diagnosis of hypersensitivity reaction is based on clinical judgment. <b>If a hypersensitivity reaction is suspected, KIVEXA must be stopped without delay, even in the absence of the HLA-B*5701 allele.</b> Delay in stopping treatment with abacavir after the onset of hypersensitivity may result in a life-threatening hypotension and death.</li> <li>Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity reaction have also experienced life-threatening reactions within hours of re-initiating abacavir therapy. Therefore, if a hypersensitivity reaction is ruled out, the reintroduction of KIVEXA or any other abacavir-containing product is recommended only if medical care can be readily accessed.</li> <li>Each patient should be reminded to read the Consumer Medicine Information. They should be reminded of the importance of removing the Alert Card included in the pack, and keeping it with them at all times.</li> <li>Patients who have experienced a hypersensitivity reaction should be instructed to dispose of their remaining KIVEXA tablets in order to avoid restarting abacavir.</li> </ul> <h4>Lactic Acidosis/Severe Hepatomegaly With Steatosis</h4> <p><a href="/lactic_acidosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Lactic acidosis</a> and severe <a href="/hepatomegaly/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hepatomegaly</a> with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including abacavir and lamivudine in the treatment of HIV infection. A majority of these cases have been in women. Clinical features which may be indicative of the development of lactic <a href="/acidosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">acidosis</a> include generalised weakness, <a href="/anorexia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">anorexia</a> and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnoea and tachypnoea). Caution should be exercised when administering KIVEXA tablets, particularly to those with known risk factors for <a href="/liver_disease/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">liver disease</a>. Treatment with KIVEXA tablets should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis with or without <a href="/hepatitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hepatitis</a> (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).</p> <h4>Fat Loss Or Fat Gain</h4> <p>Fat loss or fat gain has been reported during combination <a href="/antiretroviral_therapy_art/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antiretroviral therapy</a>. The long term consequences of these events are currently unknown. A causal relationship has not been established.</p> <h4>Serum Lipids And Blood Glucose</h4> <p>Serum <a href="/lipid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lipid</a> and <a href="/blood_glucose/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">blood glucose</a> levels may increase during antiretroviral therapy. Disease control and life style changes may also be contributing factors. Consideration should be given to the measurement of serum <a href="/lipids/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lipids</a> and blood glucose. Lipid disorders should be managed as clinically appropriate.</p> <h4>Immune Reconstitution Syndrome</h4> <p>In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviral therapy (ART), an inflammatory reaction to <a href="/asymptomatic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">asymptomatic</a> or <a href="/residual/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">residual</a> opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples are <a href="/cytomegalovirus_cmv/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cytomegalovirus</a> retinitis, generalised and/or <a href="/focal/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">focal</a> mycobacterial infections and <i>Pneumocystis jiroveci</i> pneumonia (often referred to as <a href="/pcp/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">PCP</a>). Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. <a href="/autoimmune/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Autoimmune</a> disorders (such as Graves’ disease, <a href="/polymyositis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">polymyositis</a> and <a href="/guillain-barre_syndrome/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Guillain-Barre syndrome</a>) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be an <a href="/atypical/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">atypical</a> presentation.</p> <h4>Post-Treatment Exacerbations Of Hepatitis B</h4> <p>Clinical study and marketed use of lamivudine, have shown that some patients with chronic <a href="/hepatitis_b/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hepatitis B</a> virus (<a href="/hbv/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HBV</a>) disease may experience clinical or laboratory evidence of <a href="/recurrent/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">recurrent</a> hepatitis upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. If KIVEXA tablets are discontinued in patients co-infected with hepatitis <a href="/b_virus/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">B virus</a>, periodic monitoring of both liver function tests and markers of HBV replication should be considered.</p> <h4>Opportunistic Infections</h4> <p>Patients receiving KIVEXA tablets or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.</p> <h4>Transmission Of Infection</h4> <p>Patients should be advised that current antiretroviral therapy, including KIVEXA tablets, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.</p> <h4>Mitochondrial Dysfunction</h4> <p>Nucleoside and <a href="/nucleotide/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">nucleotide</a> analogues have been demonstrated <i>in vitro</i> and <i>in vivo</i> to cause a variable degree of <a href="/mitochondrial/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">mitochondrial</a> damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed <i>in utero</i> and/or post-natally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, <a href="/neutropenia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">neutropenia</a>), metabolic disorders (hyperlactatemia, hyperlipasemia). These events are often transitory. Some late-onset <a href="/neurological/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">neurological</a> disorders have been reported (<a href="/hypertonia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypertonia</a>, <a href="/convulsion/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">convulsion</a>, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed <i>in utero</i> to nucleoside and nucleotide analogues, even HIV-negative children should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent <a href="/vertical_transmission/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">vertical transmission</a> of HIV.</p> <h4>Myocardial Infarction</h4> <p>Several observational, epidemiological studies have reported an association with abacavir use and the risk of <a href="/myocardial_infarction/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">myocardial infarction</a>. Meta-analyses of randomised controlled trials have observed no excess risk of myocardial <a href="/infarction/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">infarction</a> with abacavir use. To date there is no established biological mechanism to explain a potential increase in risk. In totality the available data from observational studies and from controlled clinical trials show inconsistency and therefore the evidence for a causal relationship between abacavir treatment and the risk of myocardial infarction is inconclusive.</p> <p>As a precaution the underlying risk of coronary <a href="/heart_disease/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">heart disease</a> should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g. <a href="/hypertension/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypertension</a>, hyperlipidaemia, <a href="/diabetes_mellitus/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">diabetes mellitus</a> and smoking).</p> <h4>General</h4> <p>KIVEXA should not be taken with any other abacavir or lamivudine containing product (3TC, COMBIVIR, TRIUMEQ, TRIZIVIR, ZEFFIX, ZIAGEN).</p> <p>As part of a triple drug-regimen, KIVEXA is generally recommended for use with antiretroviral agents from different pharmacological classes and not solely with other nucleoside/nucleotide reverse transcriptase inhibitors. This is based on results from randomised, double-blind, controlled studies in which the proportion of subjects with early virological failure (for example tenofovir, lamivudine and abacavir or tenofovir, lamivudine and didanosine) was higher in the triple nucleoside groups than in groups who received regimens involving two nucleosides in combination with an agent from a different pharmacological class. However, consideration needs to be given to a number of factors, including compliance, safety, toxicity and preservation of future treatment options, which also remain important when selecting an appropriate antiretroviral combination for a patient.</p> <h4>Therapy Experienced Patients</h4> <p>In clinical trials patients with prolonged prior NRTI exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir or lamivudine and other NRTIs should be considered when choosing new therapeutic regimens in therapy-experienced patients with prolonged prior NRTI exposure, or who have HIV-1 isolates containing multiple mutations conferring resistance to NRTIs (see Section <a href="/kivexa-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a> - <b>Cross-resistance</b>).</p> <h4>Use In Hepatic Impairment</h4> <p>See Section <b>Dose And Method Of Administration</b> and Section <a href="/kivexa-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a> - <b>Special populations</b>.</p> <h4>Use In Renal Impairment</h4> <p>See Section <b>Dose And Method Of Administration</b> and Section <a href="/kivexa-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a> - <b>Special populations</b>.</p> <h4>Use In The Elderly</h4> <p>See Section <b><a href="/kivexa-drug.htm#DAA">Dose And Method Of Administration</a></b>.</p> <h4>Paediatric Use</h4> <p>KIVEXA is a fixed combination product not suitable for use in children aged <12 years who weigh less than 40 kg, for whom dosage recommendations vary based on body weight.</p> <h4>Effects On Laboratory Tests</h4> <p>See Section <a href="/kivexa-drug.htm#AR"><b>ADVERSE REACTIONS</b></a> - Table 2.</p> <a name="USP"></a><h4>Use In Specific Populations</h4> <h4>Therapeutic Indications</h4> <p>KIVEXA tablets are a combination of two nucleoside analogues (abacavir and lamivudine).</p> <p>KIVEXA is indicated in antiretroviral combination therapy for the treatment of <a href="/human_immunodeficiency_virus/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Human Immunodeficiency Virus</a> (HIV) infection in adults and adolescents from 12 years of age.</p> <h4>Fertility, Pregnancy And Lactation</h4> <h5>Effects On Fertility</h5> <p>Abacavir had no adverse effects on the mating performance or fertility of male and female rats at oral doses of up to 427 mg/kg per day, a dose expected to produce exposures approximately 30-fold higher than that in humans at the therapeutic dose based on AUC. Orally administered lamivudine (up to 70 times anticipated clinical exposure based on Cmax) have shown evidence of impairment of fertility in male and female rats.</p> <p>There are no data on the affect of abacavir or lamivudine on human female fertility.</p> <h5>Use In Pregnancy (Category B3)</h5> <p>There are no adequate and well-controlled studies in pregnant women and the safe use of abacavir, lamivudine or KIVEXA in human pregnancy has not been established. Therefore, administration of KIVEXA in pregnancy should be considered only if the benefit to the mother outweighs the possible risk to the foetus.</p> <p>Abacavir has been evaluated in the Antiretroviral Pregnancy Registry. Available human data from the Antiretroviral Pregnancy Registry do not show an increased risk of major birth defects for abacavir compared to the background rate. The Antiretroviral Pregnancy Registry has received <a href="/prospective/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">prospective</a> reports of over 2,000 exposures to abacavir during pregnancy resulting in live birth. These consist of over 800 exposures during the first trimester, over 1,100 exposures during the second/third trimester and included 27 and 32 birth defects respectively. The <a href="/prevalence/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">prevalence</a> (95% CI) of defects in the first trimester was 3.1% (2.0, 4.4%) and in the second/third trimester, 2.7% (1.9, 3.9%). Among pregnant women in the reference population, the background rate of birth defects is 2.7%. There was no association between abacavir and overall birth defects observed in the Antiretroviral Pregnancy Registry.</p> <p>Lamivudine has been evaluated in the Antiretroviral Pregnancy Registry. Available human data from the Antiretroviral Pregnancy Registry do not show an increased risk of major birth defects for lamivudine compared to the background rate. The Antiretroviral Pregnancy Registry has received reports of over 11,000 exposures to lamivudine during pregnancy resulting in live birth. These consist of over 4,200 exposures during the first trimester, over 6,900 exposures during the second/third trimester and included 135 and 198 birth defects respectively. The prevalence (95% CI) of defects in the first trimester was 3.2% (2.6, 3.7%) and in the second/third trimester, 2.8% (2.4, 3.2%). Among pregnant women in the reference population, the background rate of birth defects is 2.7%. The Antiretroviral Pregnancy Registry does not show an increased risk of major birth defects for lamivudine compared to the background rate.</p> <p>There is no data available on the treatment with a combination of abacavir, and lamivudine in animals. In reproductive studies in animals, abacavir and lamivudine were shown to cross the placenta.</p> <p>Studies in pregnant rats showed that abacavir is transferred to the foetus through the placenta. Developmental toxicity (depressed foetal body weight and reduced <a href="/crown/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">crown</a>-rump length) and increased incidences of foetal <a href="/anasarca/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">anasarca</a> and skeletal malformations were observed when rats were treated with abacavir at doses of 648 mg/kg during organogenesis (approximately 35 times the human exposure at the recommended dose, based on AUC). In a fertility study, evidence of toxicity to the developing embryo and foetuses (increased resorptions, decreased foetal body weights) occurred only at 427 mg/kg per day. The offspring of female rats treated with abacavir at 427 mg/kg (beginning at embryo <a href="/implantation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">implantation</a> and ending at weaning) showed increased incidence of stillbirth and lower body weights throughout life. In the rabbit, there was no evidence of drug-related developmental toxicity and no increases in foetal malformations at doses up to 453 mg/kg (8.5 times the human exposure at the recommended dose, based on AUC).</p> <p>Lamivudine caused an increase in early embryonic deaths in the rabbit at exposures (based on Cmax and AUC) less than the maximum anticipated clinical exposure. Lamivudine was not <a href="/teratogenic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">teratogenic</a> in rats and rabbits with exposure (based on Cmax) up to 40 and 36 times respectively those observed in humans at the clinical dosage.</p> <p>There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed <i>in utero</i> or <a href="/peri-/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">peri-</a>partum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of <a href="/developmental_delay/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">developmental delay</a>, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure <i>in utero</i> or peri-partum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent <a href="/vertical/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">vertical</a> transmission of HIV.</p> <h5>Use In Lactation</h5> <p>No studies have been carried out to determine the effects of the combination of abacavir and lamivudine in lactating animals.</p> <p>Abacavir and its metabolites are excreted into the milk of lactating rats. A study in lactating rats showed that the concentration of lamivudine in milk was more than four times higher than that in maternal plasma.</p> <p>Excretion of abacavir and lamivudine in breast milk has been reported in clinical studies, resulting in <a href="/sub-/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">sub-</a>therapeutic infant plasma levels.</p> <p>There is no data available on the safety of abacavir and/or lamivudine administered to babies less than three months old.</p> <p><a href="/breast_feeding/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Breast feeding</a> is not advised because of the potential for HIV transmission from mother to child, and the potential risk of adverse events due to antiretroviral drug excretion in breast milk.</p> <p>In settings where <a href="/formula_feeding/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">formula feeding</a> is unsafe or unavailable, the World Health Organisation has provided Guidelines.</p> <h4>Preclinical Safety Data</h4> <h5>Genotoxicity</h5> <p>Abacavir was inactive in <i>in vitro</i> tests for gene mutation in bacteria but it showed clastogenic activity against human lymphocytes <i>in vitro</i> and in an <i>in vivo</i> mouse micronucleus test. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse <a href="/lymphoma/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lymphoma</a> assay. Abacavir was not mutagenic in bacterial mutagenicity assays.</p> <p>Lamivudine was not active in a microbial mutagenicity screen but did induce mutations at the thymidine kinase <a href="/locus/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">locus</a> of mouse lymphoma L5178Y cells without metabolic activation. Lamivudine was clastogenic in human peripheral blood lymphocytes <i>in vitro</i>, with or without metabolic activation. In rats, lamivudine did not cause chromosomal damage in <a href="/bone_marrow/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bone marrow</a> cells <i>in vivo</i> or cause DNA damage in primary hepatocytes.</p> <h5>Carcinogenicity</h5> <p>There are no data available on the effects of the combination of abacavir and lamivudine in animals.</p> <p>Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the incidence of <a href="/malignant/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">malignant</a> and non-malignant tumours. Malignant tumours occurred in the preputial <a href="/gland/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">gland</a> of males and the <a href="/clitoral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">clitoral</a> gland of females of both species, and in the liver, urinary <a href="/bladder/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bladder</a>, lymph nodes and the subcutis of female rats. Nonmalignant tumours occurred in the liver of mice and rats, Harderian gland of female mice, and <a href="/thyroid_gland/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">thyroid gland</a> of rats. In rats, there were also increased incidences of urothelial <a href="/hyperplasia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hyperplasia</a> and urinary bladder tumours, associated with increased urinary <a href="/calculi/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">calculi</a>.</p> <p>The majority of these tumours occurred at the highest abacavir dose of 330 mg/kg/day in mice and 600 mg/kg/day in rats. These dose levels were equivalent to 24 to 33 times the expected systemic exposure in humans. The exception was the preputial gland tumour which occurred at a dose of 110 mg/kg. This is equivalent to six times the expected human systemic exposure.</p> <p>Mild myocardial degeneration in the heart of mice and rats was observed following administration of abacavir for two years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.</p> <p>When lamivudine was administered orally to separate groups of rodents at doses up to 2000 times (mice and male rats) and 3000 (female rats) mg/kg/day, there was no evidence of a <a href="/carcinogenic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">carcinogenic</a> effect due to lamivudine in the mouse study. In the rat study there was an increased incidence of endometrial tumours at the highest dose (approximately 70 times the estimated human exposure at the recommended therapeutic dose of one tablet twice daily, based on AUC). However, the relationship of this increase to treatment is uncertain.</p> </div> </div> </div> | <a name="W"></a><h3>WARNINGS</h3> <p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a><h3>PRECAUTIONS</h3> <h4>Hypersensitivity</h4> <h5>Special Warning</h5> <p>The special warnings and precautions relevant to both abacavir and lamivudine are included in this section. There are no additional precautions and warnings relevant to KIVEXA tablets.</p> <p>Hypersensitivity to abacavir (see Section <a href="/kivexa-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>). Hypersensitivity to abacavir is a multi-organ clinical syndrome which can occur at any time during treatment, but most often occurs within the first 6 weeks of therapy. Signs or symptom usually present in 2 or more of the following groups although hypersensitivity following the presentation of a single sign or symptom has been reported infrequently.</p> <ul> <li>fever</li> <li>rash</li> <li>gastrointestinal, including nausea, vomiting, diarrhoea, or abdominal pain</li> <li>constitutional, including generalized malaise, fatigue, or achiness</li> <li>respiratory, including <a href="/dyspnoea/definition.htm" ">dyspnoea</a>, cough, or <a href="/pharyngitis/definition.htm" ">pharyngitis</a>.</li> </ul> <p>Hypersensitivity reactions may present similarly to pneumonia, <a href="/bronchitis/definition.htm" ">bronchitis</a> or pharyngitis, <a href="/influenza/definition.htm" ">influenza</a>-like illness or <a href="/gastroenteritis/definition.htm" ">gastroenteritis</a>.</p> <ul> <li><b>Discontinue KIVEXA as soon as a hypersensitivity reaction is suspected.</b></li> <li><b>If hypersensitivity reaction cannot be ruled out, KIVEXA or any other medicinal product containing abacavir must not be restarted.</b></li> <li>The risk is significantly increased for patients who test positive for the <a href="/hla/definition.htm" ">HLA</a>-B*5701 <a href="/allele/definition.htm" ">allele</a>. However, abacavir hypersensitivity reactions have been reported at a lower frequency in patients who do not carry this allele.</li> <li><b>KIVEXA is not recommended for use in patients with the HLA-B*5701 allele or in patients who have had a suspected abacavir HSR while taking any medicinal product containing abacavir.</b></li> <li>Testing for HLA-B*5701 status is recommended before initiating abacavir treatment and also before re-starting abacavir treatment in patients of unknown HLA-B*5701 status who have previously tolerated abacavir.</li> <li>The diagnosis of hypersensitivity reaction is based on clinical judgment. <b>If a hypersensitivity reaction is suspected, KIVEXA must be stopped without delay, even in the absence of the HLA-B*5701 allele.</b> Delay in stopping treatment with abacavir after the onset of hypersensitivity may result in a life-threatening hypotension and death.</li> <li>Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity reaction have also experienced life-threatening reactions within hours of re-initiating abacavir therapy. Therefore, if a hypersensitivity reaction is ruled out, the reintroduction of KIVEXA or any other abacavir-containing product is recommended only if medical care can be readily accessed.</li> <li>Each patient should be reminded to read the Consumer Medicine Information. They should be reminded of the importance of removing the Alert Card included in the pack, and keeping it with them at all times.</li> <li>Patients who have experienced a hypersensitivity reaction should be instructed to dispose of their remaining KIVEXA tablets in order to avoid restarting abacavir.</li> </ul> <h4>Lactic Acidosis/Severe Hepatomegaly With Steatosis</h4> <p><a href="/lactic_acidosis/definition.htm" ">Lactic acidosis</a> and severe <a href="/hepatomegaly/definition.htm" ">hepatomegaly</a> with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogues alone or in combination, including abacavir and lamivudine in the treatment of HIV infection. A majority of these cases have been in women. Clinical features which may be indicative of the development of lactic <a href="/acidosis/definition.htm" ">acidosis</a> include generalised weakness, <a href="/anorexia/definition.htm" ">anorexia</a> and sudden unexplained weight loss, gastrointestinal symptoms and respiratory symptoms (dyspnoea and tachypnoea). Caution should be exercised when administering KIVEXA tablets, particularly to those with known risk factors for <a href="/liver_disease/definition.htm" ">liver disease</a>. Treatment with KIVEXA tablets should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis with or without <a href="/hepatitis/definition.htm" ">hepatitis</a> (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).</p> <h4>Fat Loss Or Fat Gain</h4> <p>Fat loss or fat gain has been reported during combination <a href="/antiretroviral_therapy_art/definition.htm" ">antiretroviral therapy</a>. The long term consequences of these events are currently unknown. A causal relationship has not been established.</p> <h4>Serum Lipids And Blood Glucose</h4> <p>Serum <a href="/lipid/definition.htm" ">lipid</a> and <a href="/blood_glucose/definition.htm" ">blood glucose</a> levels may increase during antiretroviral therapy. Disease control and life style changes may also be contributing factors. Consideration should be given to the measurement of serum <a href="/lipids/definition.htm" ">lipids</a> and blood glucose. Lipid disorders should be managed as clinically appropriate.</p> <h4>Immune Reconstitution Syndrome</h4> <p>In HIV-infected patients with severe immune deficiency at the time of initiation of anti-retroviral therapy (ART), an inflammatory reaction to <a href="/asymptomatic/definition.htm" ">asymptomatic</a> or <a href="/residual/definition.htm" ">residual</a> opportunistic infections may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of ART. Relevant examples are <a href="/cytomegalovirus_cmv/definition.htm" ">cytomegalovirus</a> retinitis, generalised and/or <a href="/focal/definition.htm" ">focal</a> mycobacterial infections and <i>Pneumocystis jiroveci</i> pneumonia (often referred to as <a href="/pcp/definition.htm" ">PCP</a>). Any inflammatory symptoms must be evaluated without delay and treatment initiated when necessary. <a href="/autoimmune/definition.htm" ">Autoimmune</a> disorders (such as Graves’ disease, <a href="/polymyositis/definition.htm" ">polymyositis</a> and <a href="/guillain-barre_syndrome/definition.htm" ">Guillain-Barre syndrome</a>) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment and sometimes can be an <a href="/atypical/definition.htm" ">atypical</a> presentation.</p> <h4>Post-Treatment Exacerbations Of Hepatitis B</h4> <p>Clinical study and marketed use of lamivudine, have shown that some patients with chronic <a href="/hepatitis_b/definition.htm" ">hepatitis B</a> virus (<a href="/hbv/definition.htm" ">HBV</a>) disease may experience clinical or laboratory evidence of <a href="/recurrent/definition.htm" ">recurrent</a> hepatitis upon discontinuation of lamivudine, which may have more severe consequences in patients with decompensated liver disease. If KIVEXA tablets are discontinued in patients co-infected with hepatitis <a href="/b_virus/definition.htm" ">B virus</a>, periodic monitoring of both liver function tests and markers of HBV replication should be considered.</p> <h4>Opportunistic Infections</h4> <p>Patients receiving KIVEXA tablets or any other antiretroviral therapy may still develop opportunistic infections and other complications of HIV infection. Therefore, patients should remain under close clinical observation by physicians experienced in the treatment of these associated HIV diseases.</p> <h4>Transmission Of Infection</h4> <p>Patients should be advised that current antiretroviral therapy, including KIVEXA tablets, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be taken.</p> <h4>Mitochondrial Dysfunction</h4> <p>Nucleoside and <a href="/nucleotide/definition.htm" ">nucleotide</a> analogues have been demonstrated <i>in vitro</i> and <i>in vivo</i> to cause a variable degree of <a href="/mitochondrial/definition.htm" ">mitochondrial</a> damage. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed <i>in utero</i> and/or post-natally to nucleoside analogues. The main adverse events reported are haematological disorders (anaemia, <a href="/neutropenia/definition.htm" ">neutropenia</a>), metabolic disorders (hyperlactatemia, hyperlipasemia). These events are often transitory. Some late-onset <a href="/neurological/definition.htm" ">neurological</a> disorders have been reported (<a href="/hypertonia/definition.htm" ">hypertonia</a>, <a href="/convulsion/definition.htm" ">convulsion</a>, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed <i>in utero</i> to nucleoside and nucleotide analogues, even HIV-negative children should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent <a href="/vertical_transmission/definition.htm" ">vertical transmission</a> of HIV.</p> <h4>Myocardial Infarction</h4> <p>Several observational, epidemiological studies have reported an association with abacavir use and the risk of <a href="/myocardial_infarction/definition.htm" ">myocardial infarction</a>. Meta-analyses of randomised controlled trials have observed no excess risk of myocardial <a href="/infarction/definition.htm" ">infarction</a> with abacavir use. To date there is no established biological mechanism to explain a potential increase in risk. In totality the available data from observational studies and from controlled clinical trials show inconsistency and therefore the evidence for a causal relationship between abacavir treatment and the risk of myocardial infarction is inconclusive.</p> <p>As a precaution the underlying risk of coronary <a href="/heart_disease/definition.htm" ">heart disease</a> should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g. <a href="/hypertension/definition.htm" ">hypertension</a>, hyperlipidaemia, <a href="/diabetes_mellitus/definition.htm" ">diabetes mellitus</a> and smoking).</p> <h4>General</h4> <p>KIVEXA should not be taken with any other abacavir or lamivudine containing product (3TC, COMBIVIR, TRIUMEQ, TRIZIVIR, ZEFFIX, ZIAGEN).</p> <p>As part of a triple drug-regimen, KIVEXA is generally recommended for use with antiretroviral agents from different pharmacological classes and not solely with other nucleoside/nucleotide reverse transcriptase inhibitors. This is based on results from randomised, double-blind, controlled studies in which the proportion of subjects with early virological failure (for example tenofovir, lamivudine and abacavir or tenofovir, lamivudine and didanosine) was higher in the triple nucleoside groups than in groups who received regimens involving two nucleosides in combination with an agent from a different pharmacological class. However, consideration needs to be given to a number of factors, including compliance, safety, toxicity and preservation of future treatment options, which also remain important when selecting an appropriate antiretroviral combination for a patient.</p> <h4>Therapy Experienced Patients</h4> <p>In clinical trials patients with prolonged prior NRTI exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir or lamivudine and other NRTIs should be considered when choosing new therapeutic regimens in therapy-experienced patients with prolonged prior NRTI exposure, or who have HIV-1 isolates containing multiple mutations conferring resistance to NRTIs (see Section <a href="/kivexa-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a> - <b>Cross-resistance</b>).</p> <h4>Use In Hepatic Impairment</h4> <p>See Section <b>Dose And Method Of Administration</b> and Section <a href="/kivexa-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a> - <b>Special populations</b>.</p> <h4>Use In Renal Impairment</h4> <p>See Section <b>Dose And Method Of Administration</b> and Section <a href="/kivexa-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a> - <b>Special populations</b>.</p> <h4>Use In The Elderly</h4> <p>See Section <b><a href="/kivexa-drug.htm#DAA">Dose And Method Of Administration</a></b>.</p> <h4>Paediatric Use</h4> <p>KIVEXA is a fixed combination product not suitable for use in children aged <12 years who weigh less than 40 kg, for whom dosage recommendations vary based on body weight.</p> <h4>Effects On Laboratory Tests</h4> <p>See Section <a href="/kivexa-drug.htm#AR"><b>ADVERSE REACTIONS</b></a> - Table 2.</p> <a name="USP"></a><h4>Use In Specific Populations</h4> <h4>Therapeutic Indications</h4> <p>KIVEXA tablets are a combination of two nucleoside analogues (abacavir and lamivudine).</p> <p>KIVEXA is indicated in antiretroviral combination therapy for the treatment of <a href="/human_immunodeficiency_virus/definition.htm" ">Human Immunodeficiency Virus</a> (HIV) infection in adults and adolescents from 12 years of age.</p> <h4>Fertility, Pregnancy And Lactation</h4> <h5>Effects On Fertility</h5> <p>Abacavir had no adverse effects on the mating performance or fertility of male and female rats at oral doses of up to 427 mg/kg per day, a dose expected to produce exposures approximately 30-fold higher than that in humans at the therapeutic dose based on AUC. Orally administered lamivudine (up to 70 times anticipated clinical exposure based on Cmax) have shown evidence of impairment of fertility in male and female rats.</p> <p>There are no data on the affect of abacavir or lamivudine on human female fertility.</p> <h5>Use In Pregnancy (Category B3)</h5> <p>There are no adequate and well-controlled studies in pregnant women and the safe use of abacavir, lamivudine or KIVEXA in human pregnancy has not been established. Therefore, administration of KIVEXA in pregnancy should be considered only if the benefit to the mother outweighs the possible risk to the foetus.</p> <p>Abacavir has been evaluated in the Antiretroviral Pregnancy Registry. Available human data from the Antiretroviral Pregnancy Registry do not show an increased risk of major birth defects for abacavir compared to the background rate. The Antiretroviral Pregnancy Registry has received <a href="/prospective/definition.htm" ">prospective</a> reports of over 2,000 exposures to abacavir during pregnancy resulting in live birth. These consist of over 800 exposures during the first trimester, over 1,100 exposures during the second/third trimester and included 27 and 32 birth defects respectively. The <a href="/prevalence/definition.htm" ">prevalence</a> (95% CI) of defects in the first trimester was 3.1% (2.0, 4.4%) and in the second/third trimester, 2.7% (1.9, 3.9%). Among pregnant women in the reference population, the background rate of birth defects is 2.7%. There was no association between abacavir and overall birth defects observed in the Antiretroviral Pregnancy Registry.</p> <p>Lamivudine has been evaluated in the Antiretroviral Pregnancy Registry. Available human data from the Antiretroviral Pregnancy Registry do not show an increased risk of major birth defects for lamivudine compared to the background rate. The Antiretroviral Pregnancy Registry has received reports of over 11,000 exposures to lamivudine during pregnancy resulting in live birth. These consist of over 4,200 exposures during the first trimester, over 6,900 exposures during the second/third trimester and included 135 and 198 birth defects respectively. The prevalence (95% CI) of defects in the first trimester was 3.2% (2.6, 3.7%) and in the second/third trimester, 2.8% (2.4, 3.2%). Among pregnant women in the reference population, the background rate of birth defects is 2.7%. The Antiretroviral Pregnancy Registry does not show an increased risk of major birth defects for lamivudine compared to the background rate.</p> <p>There is no data available on the treatment with a combination of abacavir, and lamivudine in animals. In reproductive studies in animals, abacavir and lamivudine were shown to cross the placenta.</p> <p>Studies in pregnant rats showed that abacavir is transferred to the foetus through the placenta. Developmental toxicity (depressed foetal body weight and reduced <a href="/crown/definition.htm" ">crown</a>-rump length) and increased incidences of foetal <a href="/anasarca/definition.htm" ">anasarca</a> and skeletal malformations were observed when rats were treated with abacavir at doses of 648 mg/kg during organogenesis (approximately 35 times the human exposure at the recommended dose, based on AUC). In a fertility study, evidence of toxicity to the developing embryo and foetuses (increased resorptions, decreased foetal body weights) occurred only at 427 mg/kg per day. The offspring of female rats treated with abacavir at 427 mg/kg (beginning at embryo <a href="/implantation/definition.htm" ">implantation</a> and ending at weaning) showed increased incidence of stillbirth and lower body weights throughout life. In the rabbit, there was no evidence of drug-related developmental toxicity and no increases in foetal malformations at doses up to 453 mg/kg (8.5 times the human exposure at the recommended dose, based on AUC).</p> <p>Lamivudine caused an increase in early embryonic deaths in the rabbit at exposures (based on Cmax and AUC) less than the maximum anticipated clinical exposure. Lamivudine was not <a href="/teratogenic/definition.htm" ">teratogenic</a> in rats and rabbits with exposure (based on Cmax) up to 40 and 36 times respectively those observed in humans at the clinical dosage.</p> <p>There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed <i>in utero</i> or <a href="/peri-/definition.htm" ">peri-</a>partum to nucleoside reverse transcriptase inhibitors (NRTIs). The clinical relevance of transient elevations in serum lactate is unknown. There have also been very rare reports of <a href="/developmental_delay/definition.htm" ">developmental delay</a>, seizures and other neurological disease. However, a causal relationship between these events and NRTI exposure <i>in utero</i> or peri-partum has not been established. These findings do not affect current recommendations to use antiretroviral therapy in pregnant women to prevent <a href="/vertical/definition.htm" ">vertical</a> transmission of HIV.</p> <h5>Use In Lactation</h5> <p>No studies have been carried out to determine the effects of the combination of abacavir and lamivudine in lactating animals.</p> <p>Abacavir and its metabolites are excreted into the milk of lactating rats. A study in lactating rats showed that the concentration of lamivudine in milk was more than four times higher than that in maternal plasma.</p> <p>Excretion of abacavir and lamivudine in breast milk has been reported in clinical studies, resulting in <a href="/sub-/definition.htm" ">sub-</a>therapeutic infant plasma levels.</p> <p>There is no data available on the safety of abacavir and/or lamivudine administered to babies less than three months old.</p> <p><a href="/breast_feeding/definition.htm" ">Breast feeding</a> is not advised because of the potential for HIV transmission from mother to child, and the potential risk of adverse events due to antiretroviral drug excretion in breast milk.</p> <p>In settings where <a href="/formula_feeding/definition.htm" ">formula feeding</a> is unsafe or unavailable, the World Health Organisation has provided Guidelines.</p> <h4>Preclinical Safety Data</h4> <h5>Genotoxicity</h5> <p>Abacavir was inactive in <i>in vitro</i> tests for gene mutation in bacteria but it showed clastogenic activity against human lymphocytes <i>in vitro</i> and in an <i>in vivo</i> mouse micronucleus test. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse <a href="/lymphoma/definition.htm" ">lymphoma</a> assay. Abacavir was not mutagenic in bacterial mutagenicity assays.</p> <p>Lamivudine was not active in a microbial mutagenicity screen but did induce mutations at the thymidine kinase <a href="/locus/definition.htm" ">locus</a> of mouse lymphoma L5178Y cells without metabolic activation. Lamivudine was clastogenic in human peripheral blood lymphocytes <i>in vitro</i>, with or without metabolic activation. In rats, lamivudine did not cause chromosomal damage in <a href="/bone_marrow/definition.htm" ">bone marrow</a> cells <i>in vivo</i> or cause DNA damage in primary hepatocytes.</p> <h5>Carcinogenicity</h5> <p>There are no data available on the effects of the combination of abacavir and lamivudine in animals.</p> <p>Carcinogenicity studies with orally administered abacavir in mice and rats showed an increase in the incidence of <a href="/malignant/definition.htm" ">malignant</a> and non-malignant tumours. Malignant tumours occurred in the preputial <a href="/gland/definition.htm" ">gland</a> of males and the <a href="/clitoral/definition.htm" ">clitoral</a> gland of females of both species, and in the liver, urinary <a href="/bladder/definition.htm" ">bladder</a>, lymph nodes and the subcutis of female rats. Nonmalignant tumours occurred in the liver of mice and rats, Harderian gland of female mice, and <a href="/thyroid_gland/definition.htm" ">thyroid gland</a> of rats. In rats, there were also increased incidences of urothelial <a href="/hyperplasia/definition.htm" ">hyperplasia</a> and urinary bladder tumours, associated with increased urinary <a href="/calculi/definition.htm" ">calculi</a>.</p> <p>The majority of these tumours occurred at the highest abacavir dose of 330 mg/kg/day in mice and 600 mg/kg/day in rats. These dose levels were equivalent to 24 to 33 times the expected systemic exposure in humans. The exception was the preputial gland tumour which occurred at a dose of 110 mg/kg. This is equivalent to six times the expected human systemic exposure.</p> <p>Mild myocardial degeneration in the heart of mice and rats was observed following administration of abacavir for two years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans. The clinical relevance of this finding has not been determined.</p> <p>When lamivudine was administered orally to separate groups of rodents at doses up to 2000 times (mice and male rats) and 3000 (female rats) mg/kg/day, there was no evidence of a <a href="/carcinogenic/definition.htm" ">carcinogenic</a> effect due to lamivudine in the mouse study. In the rat study there was an increased incidence of endometrial tumours at the highest dose (approximately 70 times the estimated human exposure at the recommended therapeutic dose of one tablet twice daily, based on AUC). However, the relationship of this increase to treatment is uncertain.</p> </div> </div> </div> | 2 | 2023-02-01 17:38:10 | Abacavir and Lamivudine Film-coated Tablets (Kivexa) | A | | Kivexa | abacavir and lamivudine film-coated tablets | Kivexa | John P. Cunha, DO, FACOEP |
| 15 | 2023-02-23 12:07:03 | Overdosage & Contraindications | <a name="OD"></a><h3>OVERDOSE</h3> <h4>Symptoms And Signs</h4> <p>No specific symptoms or signs have been identified following acute overdose with abacavir or lamivudine, apart from those listed as Adverse Effects.</p> <h4>Treatment</h4> <p>If overdose occurs the patient should be monitored for evidence of toxicity and standard supportive treatment applied as necessary. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied. It is not known whether abacavir can be removed by <a href="/peritoneal_dialysis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">peritoneal dialysis</a> or haemodialysis.</p> <p>For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3> <p>KIVEXA tablets are contra-indicated in patients with known hypersensitivity to abacavir or lamivudine, or to any of the excipients.</p> </div> </div> </div> | <a name="OD"></a><h3>OVERDOSE</h3> <h4>Symptoms And Signs</h4> <p>No specific symptoms or signs have been identified following acute overdose with abacavir or lamivudine, apart from those listed as Adverse Effects.</p> <h4>Treatment</h4> <p>If overdose occurs the patient should be monitored for evidence of toxicity and standard supportive treatment applied as necessary. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdose, although this has not been studied. It is not known whether abacavir can be removed by <a href="/peritoneal_dialysis/definition.htm" ">peritoneal dialysis</a> or haemodialysis.</p> <p>For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3> <p>KIVEXA tablets are contra-indicated in patients with known hypersensitivity to abacavir or lamivudine, or to any of the excipients.</p> </div> </div> </div> | 2 | 2023-02-01 17:38:10 | Abacavir and Lamivudine Film-coated Tablets (Kivexa) | A | | Kivexa | abacavir and lamivudine film-coated tablets | Kivexa | John P. Cunha, DO, FACOEP |
| 16 | 2023-02-23 12:07:03 | Clinical Pharmacology | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3> <h4>Pharmacodynamic Properties</h4> <h5>Mechanism Of Action</h5> <p>Abacavir and lamivudine are NRTIs, and are potent, selective inhibitors of HIV-1 and HIV-2. Both abacavir and lamivudine are metabolised sequentially by intracellular kinases to the respective triphosphate (TP) which are the active moieties. Lamivudine-TP and carbovir-TP (the active triphosphate form of abacavir) are substrates for and competitive inhibitors of HIV reverse transcriptase (<a href="/rt/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">RT</a>). However, their main <a href="/antiviral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antiviral</a> activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Abacavir and lamivudine triphosphates show significantly less <a href="/affinity/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">affinity</a> for host cell DNA polymerases.</p> <p>In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg dose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life in this study of 2.6 hours. Similar intracellular <a href="/kinetics/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">kinetics</a> are expected from abacavir 600 mg once daily. For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was prolonged to 16 to 19 hours, compared to the plasma lamivudine half-life of 5 to 7 hours. These data support the use of lamivudine 300 mg and abacavir 600 mg once daily for the treatment of HIV-infected patients. Additionally, the efficacy of this combination given once daily has been demonstrated in a pivotal clinical study (CNA30021 - See Section <b> </b> <b>Clinical Trials</b>).</p> <p>The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the <a href="/protease_inhibitor/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">protease inhibitor</a> (PI) amprenavir. No antagonistic effects <i>in vitro</i> were seen with lamivudine and other antiretrovirals (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine).</p> <h5>Resistance</h5> <p>HIV-1 resistance to lamivudine involves the development of a M184V <a href="/amino_acid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">amino acid</a> change close to the active site of the viral RT. This variant arises both <i>in vitro</i> and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity <i>in vitro</i>. Studies <i>in vitro</i> indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings remains, however, not well defined.</p> <p>Genetic analysis of isolates from patients failing an abacavir-containing regimen demonstrated that reverse transcriptase amino acid residue 184 was consistently the most frequent position for NRTI resistance-associated mutations (M184V or M184I). The second most frequent mutation was L74V. Mutations Y115F and K65R were uncommon. Viral resistance to abacavir develops relatively slowly <i>in vitro</i> and <i>in vivo</i>, requiring multiple mutations to reach an eight-fold increase in IC50 over wild-type virus, which may be a clinically relevant level.</p> <p>In a study of therapy-naive adults receiving abacavir 600 mg once daily (n = 384) or 300 mg twice daily (n = 386) in a background regimen of lamivudine 300 mg and efavirenz 600 mg once daily (Study CNA30021), there was a low overall incidence of virologic failure at 48 weeks in both the once and twice daily treatment groups (10% and 8% respectively). Additionally, for technical reasons genotyping was restricted to samples with plasma HIV-1 RNA > 500 copies/mL. This resulted in a small sample size. Therefore, no firm conclusions could be drawn regarding differences in treatment emergent mutations between the two treatment groups. Genotypic (n = 38) and phenotypic analyses (n = 35) of virologic failure isolates from this study showed that the abacavir- and lamivudine-associated resistance mutation M184V/I was the most commonly observed mutation in virologic failure isolates from patients receiving abacavir/lamivudine once daily (56%, 10/18) and twice daily (40%, 8/20). L74V, Y115F and K65R were the other RT mutations observed in the study.</p> <p>Thirty-nine percent (7/18) of the isolates from patients who experienced virologic failure in the abacavir once-daily arm had a > 2.5-fold decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range 0.5 to 11) compared with 29% (5/17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range 0.7 to 13). Fifty-six percent (10/18) of the virologic failure isolates in the once-daily abacavir group compared to 41% (7/17) of the failure isolates in the twice-daily abacavir group had a > 2.5-fold decrease in lamivudine susceptibility with median-fold changes of 81 (range 0.79 to > 116) and 1.1 (range 0.68 to > 116) in the once-daily and twice-daily abacavir arms, respectively.</p> <h5>Cross-Resistance</h5> <p>Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors. <a href="/viruses/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Viruses</a> containing abacavir and lamivudine resistance-associated mutations, namely, M184V, L74V, Y115F and K65R, exhibit cross-resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine <i>in vitro</i> and in patients. The M184V mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine; the L74V mutation can confer resistance to abacavir, didanosine, and zalcitabine and the K65R mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with the L74V plus the M184V/I mutation, viruses with K65R with or without the M184V/I mutation, and viruses with thymidine <a href="/analog/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">analog</a> mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.</p> <a name="CS"></a><h4>Clinical Trials</h4> <p>Abacavir and lamivudine have been used as components of antiretroviral combination therapy in naïve and experienced patients. Combination therapy has included other antiretroviral agents of the same class or different classes, such as PIs and NNRTIs. Abacavir and lamivudine from KIVEXA tablets have been shown to be bioequivalent to abacavir and lamivudine when given separately (see Section <b>CLINICAL PHARMACOLOGY</b>). The clinical efficacy of antiretroviral combination therapy containing abacavir plus lamivudine, administered once or twice daily has been confirmed in the studies described below.</p> <p>A once daily regimen of abacavir and lamivudine was investigated in a multicentre, double-blind, controlled study (CNA30021) of 770 HIV-infected, therapy-naïve adults. They were randomised to receive either abacavir 600 mg once daily or 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. Patients were stratified at baseline based on plasma HIV-1 RNA ≤ 100,000 copies/mL or > 100,000 copies/mL. The duration of double-blind treatment was at least 48 weeks. The results are summarised in the Table 4.</p> <p align="center"><b>Table 4: Virological Response Based on Plasma HIV-1 RNA <50 copies/mL at Week 48 ITT-Exposed Population</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="40%">Populations</td> <td class="EmphTd" width="15%">ABC once/day + 3TC + EFV<br /> (N = 384)</td> <td class="EmphTd" width="15%">ABC twice/day + 3TC + EFV<br /> (N = 386)</td> <td class="EmphTd" width="15%">Point Estimate</td> <td class="EmphTd" width="15%">95% CI*</td> </tr> <tr> <td><b>Stratified</b></td> <td align="center"> </td> <td align="center"> </td> <td align="center">-1.7</td> <td align="center">-8.4, 4.9</td> </tr> <tr> <td colspan="5"><b>Sub-group by baseline RNA</b></td> </tr> <tr> <td>≤100,000 copies/mL</td> <td align="center">141/217 (65%)</td> <td align="center">145/217 (67%)</td> <td align="center">-1.8</td> <td align="center">-10.8, 7.1</td> </tr> <tr> <td>>100,000 copies/mL</td> <td align="center">112/167 (67%)</td> <td align="center">116/169 (69%)</td> <td align="center">-1.6</td> <td align="center">-11.6, 8.4</td> </tr> <tr> <td><b>Total population</b></td> <td align="center">253/384 (66%)</td> <td align="center">261/386 (68%)</td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td class="credit" colspan="5">* Confidence interval</td> </tr> </table> </center></p> <p>The abacavir once daily group was demonstrated to be non-<a href="/inferior/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">inferior</a> when compared to the twice daily group in the overall and base-line viral load sub-groups. The incidence of adverse events reported were similar in the two treatment groups.</p> <p>In a multicentre, double-blind, controlled study (CNA30024), 654 HIV-infected, antiretroviral therapy-naïve patients were randomised to receive either abacavir 300 mg twice daily or zidovudine 300 mg twice daily, both in combination with lamivudine 150 mg twice daily and efavirenz 600 mg once daily. The duration of double-blind treatment was at least 48 weeks.</p> <p>In the intent-to-treat (ITT) population, 70% of patients in the abacavir group, compared to 69% of patients in the zidovudine group, achieved a virologic response of plasma HIV-1</p> <p>RNA ≤ 50 copies/mL by Week 48. Patients were stratified at baseline based on plasma HIV-1 RNA ≤ 100,000 copies/mL or > 100,000 copies/mL. The abacavir group was demonstrated to be non-inferior when compared to the zidovudine group in the overall and base-line viral load sub-groups. This study confirms the non-inferiority of a regimen containing abacavir plus lamivudine, compared to a more widely used regimen of zidovudine plus lamivudine.</p> <h4>Pharmacokinetic Properties</h4> <p>KIVEXA tablets have been shown to be bioequivalent to abacavir and lamivudine administered separately. This was demonstrated in a single dose, 3-way crossover bioequivalence study (CAL10001) of KIVEXA tablets (fasted) versus 2 x 300 mg abacavir tablets plus 2 x 150 mg lamivudine tablets (fasted) versus KIVEXA tablets administered with a high fat meal, in healthy volunteers (n = 30).</p> <p>In the fasted state there was no significant difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of each component. Food did not alter the extent of systemic exposure to abacavir based on AUC, but Cmax was decreased by approximately 24% compared to fasted conditions. These results indicate that KIVEXA tablets can be taken with or without food.</p> <p>The pharmacokinetic properties of lamivudine and abacavir are described below.</p> <h5>Absorption</h5> <p>Abacavir and lamivudine are rapidly and well absorbed following oral administration. The absolute bioavailability of oral abacavir and lamivudine in adults is 83% and 80-85% respectively. The mean time to maximal serum concentrations (tmax) is about 1.5 hours and 1.0 hour for abacavir and lamivudine respectively. Following a single oral dose of 600 mg of abacavir, the mean Cmax is 4.26 μg/mL and the mean AUC∞ is 11.95 μg.h/mL. Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days the mean steady-state Cmax is 2.04 μg/mL and the mean AUC24 is 8.87 μg.h/mL.</p> <h5>Distribution</h5> <p>Intravenous studies with abacavir and lamivudine showed that the mean apparent volume of distribution is 0.8 and 1.3 L/kg respectively. Plasma protein binding studies <i>in vitro</i> indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (< 36%). This indicates a low likelihood for interactions with other medicinal products through plasma protein binding displacement.</p> <p>Data show that abacavir and lamivudine penetrate the <a href="/central_nervous_system_cns/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">central nervous system</a> (CNS) and reach the <a href="/cerebrospinal_fluid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cerebrospinal fluid</a> (<a href="/csf_colony-stimulating_factor/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">CSF</a>). Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44%. The observed values of the peak concentrations are 9-fold greater than the IC50 of abacavir of 0.08 μg/mL or 0.26 μM when abacavir is given at 600 mg twice daily. The mean ratio of CSF/serum lamivudine concentrations 2-4 hours after oral administration was approximately 12%. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.</p> <h5>Metabolism</h5> <p>Abacavir is primarily metabolised by the liver with less than 2% of the administered dose being renally excreted as unchanged compound. The primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation to produce the 5’-carboxylic acid and 5’-glucuronide which account for about 66% of the administered dose. These metabolites are excreted in the urine.</p> <p>Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic interactions with lamivudine is low due to the small extent of hepatic metabolism (< 10%).</p> <h5>Excretion</h5> <p>The mean plasma half-life of abacavir is about 1.5 hours. Following multiple oral doses of abacavir 300 mg twice a day, there is no significant accumulation of abacavir. Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine. The remainder is eliminated in the faeces.</p> <p>The observed lamivudine half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, predominantly by renal clearance (> 70%) via the organic cationic transport system.</p> <h4>Special Populations</h4> <h5>Impaired Hepatic Function</h5> <p>Pharmacokinetic data has been obtained for abacavir and lamivudine separately. Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5-6). The results showed that there was a mean increase of 1.89 fold in the abacavir AUC and 1.58 fold in the half-life of abacavir. The AUCs of the metabolites were not modified by the liver disease. However, the rates of formation and elimination of these were decreased.</p> <p>Dosage reduction of abacavir is likely to be required in patients with mild hepatic impairment. The separate preparation of abacavir (ZIAGEN) should therefore be used to treat these patients. The pharmacokinetics of abacavir have not been studied in patients with moderate or severe hepatic impairment. Plasma concentrations of abacavir are expected to be variable and substantially increased in these patients. Abacavir is therefore not recommended in patients with moderate to severe impairment of hepatic function and KIVEXA tablets are therefore also not recommended in such patients.</p> <p>Data obtained for lamivudine in patients with moderate to severe hepatic impairment show that the pharmacokinetics are not significantly affected by hepatic dysfunction.</p> <h5>Impaired Renal Function</h5> <p>Pharmacokinetic data have been obtained for abacavir and lamivudine separately. Abacavir is primarily metabolised by the liver, with approximately 2% of abacavir excreted unchanged in the urine. The pharmacokinetics of abacavir in patients with <a href="/end-stage_renal_disease/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">end-stage renal disease</a> is similar to patients with normal renal function. Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance. Lamivudine requires dose adjustment in patients with creatinine clearance of < 50 mL/min; as KIVEXA cannot be dose adjusted it is not recommended in these patients and the separate preparation of lamivudine (3TC) should be used.</p> </div> </div> </div> | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3> <h4>Pharmacodynamic Properties</h4> <h5>Mechanism Of Action</h5> <p>Abacavir and lamivudine are NRTIs, and are potent, selective inhibitors of HIV-1 and HIV-2. Both abacavir and lamivudine are metabolised sequentially by intracellular kinases to the respective triphosphate (TP) which are the active moieties. Lamivudine-TP and carbovir-TP (the active triphosphate form of abacavir) are substrates for and competitive inhibitors of HIV reverse transcriptase (<a href="/rt/definition.htm" ">RT</a>). However, their main <a href="/antiviral/definition.htm" ">antiviral</a> activity is through incorporation of the monophosphate form into the viral DNA chain, resulting in chain termination. Abacavir and lamivudine triphosphates show significantly less <a href="/affinity/definition.htm" ">affinity</a> for host cell DNA polymerases.</p> <p>In a study of 20 HIV-infected patients receiving abacavir 300 mg twice daily, with only one 300 mg dose taken prior to the 24 hour sampling period, the geometric mean terminal carbovir-TP intracellular half-life at steady-state was 20.6 hours, compared to the geometric mean abacavir plasma half-life in this study of 2.6 hours. Similar intracellular <a href="/kinetics/definition.htm" ">kinetics</a> are expected from abacavir 600 mg once daily. For patients receiving lamivudine 300 mg once daily, the terminal intracellular half-life of lamivudine-TP was prolonged to 16 to 19 hours, compared to the plasma lamivudine half-life of 5 to 7 hours. These data support the use of lamivudine 300 mg and abacavir 600 mg once daily for the treatment of HIV-infected patients. Additionally, the efficacy of this combination given once daily has been demonstrated in a pivotal clinical study (CNA30021 - See Section <b> </b> <b>Clinical Trials</b>).</p> <p>The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the <a href="/protease_inhibitor/definition.htm" ">protease inhibitor</a> (PI) amprenavir. No antagonistic effects <i>in vitro</i> were seen with lamivudine and other antiretrovirals (tested agents: abacavir, didanosine, nevirapine, zalcitabine, and zidovudine).</p> <h5>Resistance</h5> <p>HIV-1 resistance to lamivudine involves the development of a M184V <a href="/amino_acid/definition.htm" ">amino acid</a> change close to the active site of the viral RT. This variant arises both <i>in vitro</i> and in HIV-1 infected patients treated with lamivudine-containing antiretroviral therapy. M184V mutants display greatly reduced susceptibility to lamivudine and show diminished viral replicative capacity <i>in vitro</i>. Studies <i>in vitro</i> indicate that zidovudine-resistant virus isolates can become zidovudine sensitive when they simultaneously acquire resistance to lamivudine. The clinical relevance of such findings remains, however, not well defined.</p> <p>Genetic analysis of isolates from patients failing an abacavir-containing regimen demonstrated that reverse transcriptase amino acid residue 184 was consistently the most frequent position for NRTI resistance-associated mutations (M184V or M184I). The second most frequent mutation was L74V. Mutations Y115F and K65R were uncommon. Viral resistance to abacavir develops relatively slowly <i>in vitro</i> and <i>in vivo</i>, requiring multiple mutations to reach an eight-fold increase in IC50 over wild-type virus, which may be a clinically relevant level.</p> <p>In a study of therapy-naive adults receiving abacavir 600 mg once daily (n = 384) or 300 mg twice daily (n = 386) in a background regimen of lamivudine 300 mg and efavirenz 600 mg once daily (Study CNA30021), there was a low overall incidence of virologic failure at 48 weeks in both the once and twice daily treatment groups (10% and 8% respectively). Additionally, for technical reasons genotyping was restricted to samples with plasma HIV-1 RNA > 500 copies/mL. This resulted in a small sample size. Therefore, no firm conclusions could be drawn regarding differences in treatment emergent mutations between the two treatment groups. Genotypic (n = 38) and phenotypic analyses (n = 35) of virologic failure isolates from this study showed that the abacavir- and lamivudine-associated resistance mutation M184V/I was the most commonly observed mutation in virologic failure isolates from patients receiving abacavir/lamivudine once daily (56%, 10/18) and twice daily (40%, 8/20). L74V, Y115F and K65R were the other RT mutations observed in the study.</p> <p>Thirty-nine percent (7/18) of the isolates from patients who experienced virologic failure in the abacavir once-daily arm had a > 2.5-fold decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range 0.5 to 11) compared with 29% (5/17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range 0.7 to 13). Fifty-six percent (10/18) of the virologic failure isolates in the once-daily abacavir group compared to 41% (7/17) of the failure isolates in the twice-daily abacavir group had a > 2.5-fold decrease in lamivudine susceptibility with median-fold changes of 81 (range 0.79 to > 116) and 1.1 (range 0.68 to > 116) in the once-daily and twice-daily abacavir arms, respectively.</p> <h5>Cross-Resistance</h5> <p>Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors. <a href="/viruses/definition.htm" ">Viruses</a> containing abacavir and lamivudine resistance-associated mutations, namely, M184V, L74V, Y115F and K65R, exhibit cross-resistance to didanosine, emtricitabine, lamivudine, tenofovir, and zalcitabine <i>in vitro</i> and in patients. The M184V mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, and zalcitabine; the L74V mutation can confer resistance to abacavir, didanosine, and zalcitabine and the K65R mutation can confer resistance to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with the L74V plus the M184V/I mutation, viruses with K65R with or without the M184V/I mutation, and viruses with thymidine <a href="/analog/definition.htm" ">analog</a> mutations (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.</p> <a name="CS"></a><h4>Clinical Trials</h4> <p>Abacavir and lamivudine have been used as components of antiretroviral combination therapy in naïve and experienced patients. Combination therapy has included other antiretroviral agents of the same class or different classes, such as PIs and NNRTIs. Abacavir and lamivudine from KIVEXA tablets have been shown to be bioequivalent to abacavir and lamivudine when given separately (see Section <b>CLINICAL PHARMACOLOGY</b>). The clinical efficacy of antiretroviral combination therapy containing abacavir plus lamivudine, administered once or twice daily has been confirmed in the studies described below.</p> <p>A once daily regimen of abacavir and lamivudine was investigated in a multicentre, double-blind, controlled study (CNA30021) of 770 HIV-infected, therapy-naïve adults. They were randomised to receive either abacavir 600 mg once daily or 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. Patients were stratified at baseline based on plasma HIV-1 RNA ≤ 100,000 copies/mL or > 100,000 copies/mL. The duration of double-blind treatment was at least 48 weeks. The results are summarised in the Table 4.</p> <p align="center"><b>Table 4: Virological Response Based on Plasma HIV-1 RNA <50 copies/mL at Week 48 ITT-Exposed Population</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="40%">Populations</td> <td class="EmphTd" width="15%">ABC once/day + 3TC + EFV<br /> (N = 384)</td> <td class="EmphTd" width="15%">ABC twice/day + 3TC + EFV<br /> (N = 386)</td> <td class="EmphTd" width="15%">Point Estimate</td> <td class="EmphTd" width="15%">95% CI*</td> </tr> <tr> <td><b>Stratified</b></td> <td align="center"> </td> <td align="center"> </td> <td align="center">-1.7</td> <td align="center">-8.4, 4.9</td> </tr> <tr> <td colspan="5"><b>Sub-group by baseline RNA</b></td> </tr> <tr> <td>≤100,000 copies/mL</td> <td align="center">141/217 (65%)</td> <td align="center">145/217 (67%)</td> <td align="center">-1.8</td> <td align="center">-10.8, 7.1</td> </tr> <tr> <td>>100,000 copies/mL</td> <td align="center">112/167 (67%)</td> <td align="center">116/169 (69%)</td> <td align="center">-1.6</td> <td align="center">-11.6, 8.4</td> </tr> <tr> <td><b>Total population</b></td> <td align="center">253/384 (66%)</td> <td align="center">261/386 (68%)</td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td class="credit" colspan="5">* Confidence interval</td> </tr> </table> </center></p> <p>The abacavir once daily group was demonstrated to be non-<a href="/inferior/definition.htm" ">inferior</a> when compared to the twice daily group in the overall and base-line viral load sub-groups. The incidence of adverse events reported were similar in the two treatment groups.</p> <p>In a multicentre, double-blind, controlled study (CNA30024), 654 HIV-infected, antiretroviral therapy-naïve patients were randomised to receive either abacavir 300 mg twice daily or zidovudine 300 mg twice daily, both in combination with lamivudine 150 mg twice daily and efavirenz 600 mg once daily. The duration of double-blind treatment was at least 48 weeks.</p> <p>In the intent-to-treat (ITT) population, 70% of patients in the abacavir group, compared to 69% of patients in the zidovudine group, achieved a virologic response of plasma HIV-1</p> <p>RNA ≤ 50 copies/mL by Week 48. Patients were stratified at baseline based on plasma HIV-1 RNA ≤ 100,000 copies/mL or > 100,000 copies/mL. The abacavir group was demonstrated to be non-inferior when compared to the zidovudine group in the overall and base-line viral load sub-groups. This study confirms the non-inferiority of a regimen containing abacavir plus lamivudine, compared to a more widely used regimen of zidovudine plus lamivudine.</p> <h4>Pharmacokinetic Properties</h4> <p>KIVEXA tablets have been shown to be bioequivalent to abacavir and lamivudine administered separately. This was demonstrated in a single dose, 3-way crossover bioequivalence study (CAL10001) of KIVEXA tablets (fasted) versus 2 x 300 mg abacavir tablets plus 2 x 150 mg lamivudine tablets (fasted) versus KIVEXA tablets administered with a high fat meal, in healthy volunteers (n = 30).</p> <p>In the fasted state there was no significant difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of each component. Food did not alter the extent of systemic exposure to abacavir based on AUC, but Cmax was decreased by approximately 24% compared to fasted conditions. These results indicate that KIVEXA tablets can be taken with or without food.</p> <p>The pharmacokinetic properties of lamivudine and abacavir are described below.</p> <h5>Absorption</h5> <p>Abacavir and lamivudine are rapidly and well absorbed following oral administration. The absolute bioavailability of oral abacavir and lamivudine in adults is 83% and 80-85% respectively. The mean time to maximal serum concentrations (tmax) is about 1.5 hours and 1.0 hour for abacavir and lamivudine respectively. Following a single oral dose of 600 mg of abacavir, the mean Cmax is 4.26 μg/mL and the mean AUC∞ is 11.95 μg.h/mL. Following multiple-dose oral administration of lamivudine 300 mg once daily for seven days the mean steady-state Cmax is 2.04 μg/mL and the mean AUC24 is 8.87 μg.h/mL.</p> <h5>Distribution</h5> <p>Intravenous studies with abacavir and lamivudine showed that the mean apparent volume of distribution is 0.8 and 1.3 L/kg respectively. Plasma protein binding studies <i>in vitro</i> indicate that abacavir binds only low to moderately (~49%) to human plasma proteins at therapeutic concentrations. Lamivudine exhibits linear pharmacokinetics over the therapeutic dose range and displays low plasma protein binding (< 36%). This indicates a low likelihood for interactions with other medicinal products through plasma protein binding displacement.</p> <p>Data show that abacavir and lamivudine penetrate the <a href="/central_nervous_system_cns/definition.htm" ">central nervous system</a> (CNS) and reach the <a href="/cerebrospinal_fluid/definition.htm" ">cerebrospinal fluid</a> (<a href="/csf_colony-stimulating_factor/definition.htm" ">CSF</a>). Studies with abacavir demonstrate a CSF to plasma AUC ratio of between 30 to 44%. The observed values of the peak concentrations are 9-fold greater than the IC50 of abacavir of 0.08 μg/mL or 0.26 μM when abacavir is given at 600 mg twice daily. The mean ratio of CSF/serum lamivudine concentrations 2-4 hours after oral administration was approximately 12%. The true extent of CNS penetration of lamivudine and its relationship with any clinical efficacy is unknown.</p> <h5>Metabolism</h5> <p>Abacavir is primarily metabolised by the liver with less than 2% of the administered dose being renally excreted as unchanged compound. The primary pathways of metabolism in man are by alcohol dehydrogenase and by glucuronidation to produce the 5’-carboxylic acid and 5’-glucuronide which account for about 66% of the administered dose. These metabolites are excreted in the urine.</p> <p>Metabolism of lamivudine is a minor route of elimination. Lamivudine is predominately cleared unchanged by renal excretion. The likelihood of metabolic interactions with lamivudine is low due to the small extent of hepatic metabolism (< 10%).</p> <h5>Excretion</h5> <p>The mean plasma half-life of abacavir is about 1.5 hours. Following multiple oral doses of abacavir 300 mg twice a day, there is no significant accumulation of abacavir. Elimination of abacavir is via hepatic metabolism with subsequent excretion of metabolites primarily in the urine. The metabolites and unchanged abacavir account for about 83% of the administered abacavir dose in the urine. The remainder is eliminated in the faeces.</p> <p>The observed lamivudine half-life of elimination is 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/h/kg, predominantly by renal clearance (> 70%) via the organic cationic transport system.</p> <h4>Special Populations</h4> <h5>Impaired Hepatic Function</h5> <p>Pharmacokinetic data has been obtained for abacavir and lamivudine separately. Abacavir is metabolised primarily by the liver. The pharmacokinetics of abacavir have been studied in patients with mild hepatic impairment (Child-Pugh score 5-6). The results showed that there was a mean increase of 1.89 fold in the abacavir AUC and 1.58 fold in the half-life of abacavir. The AUCs of the metabolites were not modified by the liver disease. However, the rates of formation and elimination of these were decreased.</p> <p>Dosage reduction of abacavir is likely to be required in patients with mild hepatic impairment. The separate preparation of abacavir (ZIAGEN) should therefore be used to treat these patients. The pharmacokinetics of abacavir have not been studied in patients with moderate or severe hepatic impairment. Plasma concentrations of abacavir are expected to be variable and substantially increased in these patients. Abacavir is therefore not recommended in patients with moderate to severe impairment of hepatic function and KIVEXA tablets are therefore also not recommended in such patients.</p> <p>Data obtained for lamivudine in patients with moderate to severe hepatic impairment show that the pharmacokinetics are not significantly affected by hepatic dysfunction.</p> <h5>Impaired Renal Function</h5> <p>Pharmacokinetic data have been obtained for abacavir and lamivudine separately. Abacavir is primarily metabolised by the liver, with approximately 2% of abacavir excreted unchanged in the urine. The pharmacokinetics of abacavir in patients with <a href="/end-stage_renal_disease/definition.htm" ">end-stage renal disease</a> is similar to patients with normal renal function. Studies with lamivudine show that plasma concentrations (AUC) are increased in patients with renal dysfunction due to decreased clearance. Lamivudine requires dose adjustment in patients with creatinine clearance of < 50 mL/min; as KIVEXA cannot be dose adjusted it is not recommended in these patients and the separate preparation of lamivudine (3TC) should be used.</p> </div> </div> </div> | 2 | 2023-02-01 17:38:10 | Abacavir and Lamivudine Film-coated Tablets (Kivexa) | A | | Kivexa | abacavir and lamivudine film-coated tablets | Kivexa | John P. Cunha, DO, FACOEP |
| 17 | 2023-02-23 11:36:54 | Medication Guide | <a name="PI"></a><h3>PATIENT INFORMATION</h3> <p>No information provided. Please refer to the <b><a href="/kivexa-drug.htm#W">WARNINGS</a></b> and <a href="/kivexa-drug.htm#P"><b>PRECAUTIONS</b></a> sections.</p> </div> </div> </div> | <a name="PI"></a><h3>PATIENT INFORMATION</h3> <p>No information provided. Please refer to the <b><a href="/kivexa-drug.htm#W">WARNINGS</a></b> and <a href="/kivexa-drug.htm#P"><b>PRECAUTIONS</b></a> sections.</p> </div> </div> </div> | 2 | 2023-02-01 17:38:10 | Abacavir and Lamivudine Film-coated Tablets (Kivexa) | A | | Kivexa | abacavir and lamivudine film-coated tablets | Kivexa | John P. Cunha, DO, FACOEP |
| 18 | 2023-02-23 12:07:03 | Drug Description | <div class="webmdrx"> <a href="https://www.webmd.com/rx/drug-prices/abacavir?ecd=oo_webmdrx_rx-mono_rx/drug-prices/abacavir_dsktp_rxlist.com//rx/drug-prices/abacavir" target="_blank" onclick="wmdPageLink('webmdrx');"><p class="webmdrx_p">Find Lowest Prices on <span class="webmdrx_img"></span></p></a> </div> <h4>What is Ziagen and how is it used?</h4> <p>Ziagen is a prescription medicine used to treat the symptoms of HIV Infection. Ziagen may be used alone or with other medications.</p> <p>Ziagen belongs to a class of drugs called HIV, NRTIs; <a href="/antiretroviral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Antiretroviral</a> Agents.</p> <p>It is not known if Ziagen is safe and effective in children younger than 3 months of age.</p> <h4>What are the possible side effects of Ziagen?</h4> <p>Ziagen may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>fever,</li> <li>rash,</li> <li>nausea,</li> <li>vomiting,</li> <li>diarrhea,</li> <li>stomach pain,</li> <li>general ill feeling,</li> <li>extreme tiredness,</li> <li>body aches,</li> <li>shortness of breath,</li> <li>cough,</li> <li><a href="/sore_throat_pharyngitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">sore throat</a>,</li> <li>severe upper stomach pain,</li> <li>loss of appetite,</li> <li>swelling around your midsection,</li> <li>dark urine,</li> <li><a href="/clay/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">clay</a>-colored stools,</li> <li>yellowing of <a href="/skin_anatomy_picture_definition_function/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">the skin</a> or eyes (<a href="/kernicterus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">jaundice</a>),</li> <li>unusual tiredness,</li> <li>chest pain or pressure,</li> <li>pain spreading to your jaw or <a href="/shoulder/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">shoulder</a>,</li> <li>unusual <a href="/muscle_pain/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">muscle pain</a>,</li> <li>stomach pain,</li> <li>irregular heart rate,</li> <li>dizziness,</li> <li>feeling cold,</li> <li>weakness,</li> <li>tiredness,</li> <li><a href="/night_sweats/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">night sweats</a>,</li> <li>swollen glands,</li> <li><a href="/herpes_simplex_infections_non-genital/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">cold sores</a>,</li> <li>cough,</li> <li><a href="/wheezing/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">wheezing</a>,</li> <li>diarrhea,</li> <li>weight loss,</li> <li>trouble speaking or swallowing,</li> <li>problems with balance or eye movement,</li> <li>weakness or prickly feeling,</li> <li>swelling in your neck or throat (<a href="/enlarged_thyroid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">enlarged thyroid</a>),</li> <li>menstrual changes, and</li> <li><a href="/impotence/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">impotence</a></li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Ziagen include:</p> <ul> <li>sleep problems,</li> <li>strange <a href="/dreams/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">dreams</a>,</li> <li>headache,</li> <li>tiredness,</li> <li>fever,</li> <li>chills,</li> <li>general ill feeling,</li> <li>nausea,</li> <li>vomiting,</li> <li>rash,</li> <li><a href="/stuffy_nose/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">stuffy nose</a>,</li> <li>sneezing,</li> <li><a href="/sore/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">sore</a> throat, and</li> <li>ear pain</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Ziagen. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p align="center"><b>HYPERSENSITIVITY REACTIONS, and LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS</b></p> <h4>Hypersensitivity Reactions</h4> <p><b>Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with ZIAGEN (abacavir).</b></p> <p><b>Patients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele [see WARNINGS AND <a href="/ziagen-drug.htm#P">PRECAUTIONS</a>].</b></p> <p><b>ZIAGEN is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see <a href="/ziagen-drug.htm#CI">CONTRAINDICATIONS</a>, WARNINGS AND <a href="/ziagen-drug.htm#P">PRECAUTIONS</a>]. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN or reinitiation of therapy with ZIAGEN, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue ZIAGEN immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see <a href="/ziagen-drug.htm#CI">CONTRAINDICATIONS</a>, WARNINGS AND <a href="/ziagen-drug.htm#P">PRECAUTIONS</a>].</b></p> <p><b>Following a hypersensitivity reaction to ZIAGEN, NEVER restart ZIAGEN or any other abacavir-containing product because more severe symptoms, including death can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see WARNINGS AND <a href="/ziagen-drug.htm#P">PRECAUTIONS</a>].</b></p> <h4>Lactic Acidosis and Severe Hepatomegaly with Steatosis</h4> <p><b>Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue ZIAGEN if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see WARNINGS AND <a href="/ziagen-drug.htm#P">PRECAUTIONS</a>].</b></p> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <p>ZIAGEN is the brand name for abacavir sulfate, a synthetic carbocyclic nucleoside analogue with inhibitory activity against <a href="/script/main/art.asp?articlekey=3769" onclick="wmdTrack('embd-lnk');" rel="dict">HIV</a>-1. The chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C<sub>14</sub>H<sub>18</sub>N<sub>6</sub>O)<sub>2</sub>•H<sub>2</sub>SO<sub>4</sub> and a molecular weight of 670.76 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="379"> <tbody> <tr> <td><img alt="ZIAGEN® (abacavir)Structural Formula Illustration" height="307" src="https://images.rxlist.com/images/rxlist/abavir1.gif" width="379" /></td> </tr> </tbody> </table> </center> <p></p> <p>Abacavir sulfate is a white to off-white solid and is soluble in water.</p> <p>ZIAGEN tablets are for oral administration. Each tablet contains abacavir sulfate equivalent to 300 mg of abacavir as active ingredient and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film that is made of hypromellose, polysorbate 80, synthetic yellow iron oxide, titanium dioxide, and triacetin.</p> <p>ZIAGEN oral solution is for oral administration. Each milliliter (1 mL) of ZIAGEN oral solution contains abacavir sulfate equivalent to 20 mg of abacavir (i.e., 20 mg per mL) as active ingredient and the following inactive ingredients: artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben and propylparaben (added as preservatives), propylene glycol, <a href="/script/main/art.asp?articlekey=13208" onclick="wmdTrack('embd-lnk');" rel="dict">saccharin</a> sodium, sodium citrate (dihydrate), sorbitol solution, and water.</p> <p>In vivo, abacavir sulfate dissociates to its free base, abacavir. Dosages are expressed in terms of abacavir.</p> </div> <div id="667441035-1" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-1", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <div class="webmdrx"> <a href="https://www.webmd.com/rx/drug-prices/abacavir?ecd=oo_webmdrx_rx-mono_rx/drug-prices/abacavir_dsktp_rxlist.com//rx/drug-prices/abacavir" target="_blank" onclick="wmdPageLink('webmdrx');"><p class="webmdrx_p">Find Lowest Prices on <span class="webmdrx_img"></span></p></a> </div> <h4>What is Ziagen and how is it used?</h4> <p>Ziagen is a prescription medicine used to treat the symptoms of HIV Infection. Ziagen may be used alone or with other medications.</p> <p>Ziagen belongs to a class of drugs called HIV, NRTIs; <a href="/antiretroviral/definition.htm" ">Antiretroviral</a> Agents.</p> <p>It is not known if Ziagen is safe and effective in children younger than 3 months of age.</p> <h4>What are the possible side effects of Ziagen?</h4> <p>Ziagen may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>fever,</li> <li>rash,</li> <li>nausea,</li> <li>vomiting,</li> <li>diarrhea,</li> <li>stomach pain,</li> <li>general ill feeling,</li> <li>extreme tiredness,</li> <li>body aches,</li> <li>shortness of breath,</li> <li>cough,</li> <li><a href="/sore_throat_pharyngitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">sore throat</a>,</li> <li>severe upper stomach pain,</li> <li>loss of appetite,</li> <li>swelling around your midsection,</li> <li>dark urine,</li> <li><a href="/clay/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">clay</a>-colored stools,</li> <li>yellowing of <a href="/skin_anatomy_picture_definition_function/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">the skin</a> or eyes (<a href="/kernicterus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">jaundice</a>),</li> <li>unusual tiredness,</li> <li>chest pain or pressure,</li> <li>pain spreading to your jaw or <a href="/shoulder/definition.htm" ">shoulder</a>,</li> <li>unusual <a href="/muscle_pain/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">muscle pain</a>,</li> <li>stomach pain,</li> <li>irregular heart rate,</li> <li>dizziness,</li> <li>feeling cold,</li> <li>weakness,</li> <li>tiredness,</li> <li><a href="/night_sweats/definition.htm" ">night sweats</a>,</li> <li>swollen glands,</li> <li><a href="/herpes_simplex_infections_non-genital/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">cold sores</a>,</li> <li>cough,</li> <li><a href="/wheezing/definition.htm" ">wheezing</a>,</li> <li>diarrhea,</li> <li>weight loss,</li> <li>trouble speaking or swallowing,</li> <li>problems with balance or eye movement,</li> <li>weakness or prickly feeling,</li> <li>swelling in your neck or throat (<a href="/enlarged_thyroid/definition.htm" ">enlarged thyroid</a>),</li> <li>menstrual changes, and</li> <li><a href="/impotence/definition.htm" ">impotence</a></li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Ziagen include:</p> <ul> <li>sleep problems,</li> <li>strange <a href="/dreams/definition.htm" ">dreams</a>,</li> <li>headache,</li> <li>tiredness,</li> <li>fever,</li> <li>chills,</li> <li>general ill feeling,</li> <li>nausea,</li> <li>vomiting,</li> <li>rash,</li> <li><a href="/stuffy_nose/definition.htm" ">stuffy nose</a>,</li> <li>sneezing,</li> <li><a href="/sore/definition.htm" ">sore</a> throat, and</li> <li>ear pain</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Ziagen. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p align="center"><b>HYPERSENSITIVITY REACTIONS, and LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS</b></p> <h4>Hypersensitivity Reactions</h4> <p><b>Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with ZIAGEN (abacavir).</b></p> <p><b>Patients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele [see WARNINGS AND <a href="/ziagen-drug.htm#P">PRECAUTIONS</a>].</b></p> <p><b>ZIAGEN is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see <a href="/ziagen-drug.htm#CI">CONTRAINDICATIONS</a>, WARNINGS AND <a href="/ziagen-drug.htm#P">PRECAUTIONS</a>]. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN or reinitiation of therapy with ZIAGEN, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue ZIAGEN immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see <a href="/ziagen-drug.htm#CI">CONTRAINDICATIONS</a>, WARNINGS AND <a href="/ziagen-drug.htm#P">PRECAUTIONS</a>].</b></p> <p><b>Following a hypersensitivity reaction to ZIAGEN, NEVER restart ZIAGEN or any other abacavir-containing product because more severe symptoms, including death can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see WARNINGS AND <a href="/ziagen-drug.htm#P">PRECAUTIONS</a>].</b></p> <h4>Lactic Acidosis and Severe Hepatomegaly with Steatosis</h4> <p><b>Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue ZIAGEN if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see WARNINGS AND <a href="/ziagen-drug.htm#P">PRECAUTIONS</a>].</b></p> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <p>ZIAGEN is the brand name for abacavir sulfate, a synthetic carbocyclic nucleoside analogue with inhibitory activity against <a href="/script/main/art.asp?articlekey=3769" onclick="wmdTrack('embd-lnk');" rel="dict">HIV</a>-1. The chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C<sub>14</sub>H<sub>18</sub>N<sub>6</sub>O)<sub>2</sub>•H<sub>2</sub>SO<sub>4</sub> and a molecular weight of 670.76 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="379"> <tbody> <tr> <td><img alt="ZIAGEN® (abacavir)Structural Formula Illustration" height="307" src="https://images.rxlist.com/images/rxlist/abavir1.gif" width="379" /></td> </tr> </tbody> </table> </center> <p></p> <p>Abacavir sulfate is a white to off-white solid and is soluble in water.</p> <p>ZIAGEN tablets are for oral administration. Each tablet contains abacavir sulfate equivalent to 300 mg of abacavir as active ingredient and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film that is made of hypromellose, polysorbate 80, synthetic yellow iron oxide, titanium dioxide, and triacetin.</p> <p>ZIAGEN oral solution is for oral administration. Each milliliter (1 mL) of ZIAGEN oral solution contains abacavir sulfate equivalent to 20 mg of abacavir (i.e., 20 mg per mL) as active ingredient and the following inactive ingredients: artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben and propylparaben (added as preservatives), propylene glycol, <a href="/script/main/art.asp?articlekey=13208" onclick="wmdTrack('embd-lnk');" rel="dict">saccharin</a> sodium, sodium citrate (dihydrate), sorbitol solution, and water.</p> <p>In vivo, abacavir sulfate dissociates to its free base, abacavir. Dosages are expressed in terms of abacavir.</p> </div> <div id="667441035-1" class="medianet"><</div> </div> </div> | 3 | 2023-02-01 17:38:21 | Abacavir Sulfate (Ziagen) | A | HIV, NNRTIs, Antiretroviral Agents | Ziagen | abacavir sulfate | Ziagen | John P. Cunha, DO, FACOEP |
| 19 | 2023-02-23 11:36:54 | Indications & Dosage | <div class="webmdrx_coup"> </div> <a name="I"></a><h3>INDICATIONS</h3><p>ZIAGEN tablets and oral solution, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV-1) infection.</p> <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3><h4>Screening For HLA-B*5701 Allele Prior To Starting ZIAGEN</h4><p>Screen for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</p><h4>Recommended Dosage For Adult Patients</h4><p>The recommended dosage of ZIAGEN for adults is 600 mg daily, administered orally as either 300 mg twice daily or 600 mg once daily, in combination with other antiretroviral agents.</p><h4>Recommended Dosage For Pediatric Patients</h4><p>The recommended dosage of ZIAGEN oral solution in HIV-1–infected pediatric patients aged 3 months and older is 8 mg per kg orally twice daily or 16 mg per kg orally once daily (up to a maximum of 600 mg daily) in combination with other antiretroviral agents.</p><p>ZIAGEN is also available as a scored tablet for HIV-1–infected pediatric patients weighing greater than or equal to 14 kg for whom a solid dosage form is appropriate. Before prescribing ZIAGEN tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow ZIAGEN tablets, the oral solution formulation should be prescribed. The recommended oral dosage of ZIAGEN tablets for HIV-1–infected pediatric patients is presented in Table 1.</p><p align="center"><b>Table 1. Dosing Recommendations for ZIAGEN Scored Tablets in Pediatric Patients</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" rowspan="2" width="20%">Weight(kg)</td><td class="EmphTd" rowspan="2" width="20%">Once-Daily Dosing Regimen<sup>a</sup></td><td class="EmphTd" colspan="3">Twice-Daily Dosing Regimen</td></tr><tr><td class="EmphTd" width="20%">AM Dose</td><td class="EmphTd" width="20%">PM Dose</td><td class="EmphTd" width="20%">Total Daily Dose</td></tr><tr><td>14 to <20</td><td align="center">1 tablet<br />(300 mg)</td><td align="center">½ tablet<br />(150 mg)</td><td align="center">½ tablet<br />(150 mg)</td><td align="center">300 mg</td></tr><tr><td>≥20 to <25</td><td align="center">1½ tablets<br />(450 mg)</td><td align="center">½ tablet<br />(150 mg)</td><td align="center">1 tablet<br />(300 mg)</td><td align="center">450 mg</td></tr><tr><td>≥25</td><td align="center">2 tablets<br />(600 mg)</td><td align="center">1 tablet<br />(300 mg)</td><td align="center">1 tablet<br />(300 mg)</td><td align="center">600 mg</td></tr><tr><td class="credit" colspan="5"><sup>a</sup> Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment [see <b>Clinical Studies</b>].</td></tr></tbody></table></center><p></p><h4>Recommended Dosage For Patients With Hepatic Impairment</h4><p>The recommended dose of ZIAGEN in patients with mild hepatic impairment (Child-Pugh Class A) is 200 mg twice daily. To enable dose reduction, ZIAGEN oral solution (10 mL twice daily) should be used for the treatment of these patients. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate to severe hepatic impairment; therefore, ZIAGEN is contraindicated in these patients.</p> <a name="HS"></a><h3>HOW SUPPLIED</h3><h4>Dosage Forms And Strengths</h4><p>ZIAGEN tablets contain 300 mg of abacavir as abacavir sulfate. The tablets are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with “GX 623” on both sides.</p><p>ZIAGEN oral solution contains 20 mg per mL of abacavir as abacavir sulfate. The solution is a clear to opalescent, yellowish, strawberry-banana-flavored liquid, which may turn brown over time.</p><h4>Storage And Handling</h4><p><b>ZIAGEN tablets</b>, containing abacavir sulfate equivalent to 300 mg abacavir are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with “GX 623” on both sides. They are packaged as follows:</p><p class="EmphText">Bottles of 60 tablets (<b>NDC</b> 49702-221-18).</p><p><b>Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see USP).</b></p><p><b>ZIAGEN oral solution</b> is a clear to opalescent, yellowish, strawberry-banana-flavored liquid, which may turn brown over time. Each mL of the solution contains abacavir sulfate equivalent to 20 mg of abacavir. It is packaged in plastic bottles as follows:</p><p class="EmphText">Bottles of 240 mL (<b>NDC</b> 49702-222-48) with child-resistant closure. This product does not require reconstitution.</p><p><b>Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see USP). DO NOT FREEZE. May be refrigerated.</b></p><p class="credit">Manufactured by: GlaxoSmithKline Research Triangle Park, NC 27709. Revised: Nov 2020</p> </div> <a class="mediaPrmo ss" href="/aids_retrospective_slideshow/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/aids_s1_quilt.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">A Timeline of the HIV/AIDS Pandemic</span> <span class="btn">See Slideshow</span> </a> </div> </div> | <div class="webmdrx_coup"> </div> <a name="I"></a><h3>INDICATIONS</h3><p>ZIAGEN tablets and oral solution, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV-1) infection.</p> <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3><h4>Screening For HLA-B*5701 Allele Prior To Starting ZIAGEN</h4><p>Screen for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</p><h4>Recommended Dosage For Adult Patients</h4><p>The recommended dosage of ZIAGEN for adults is 600 mg daily, administered orally as either 300 mg twice daily or 600 mg once daily, in combination with other antiretroviral agents.</p><h4>Recommended Dosage For Pediatric Patients</h4><p>The recommended dosage of ZIAGEN oral solution in HIV-1–infected pediatric patients aged 3 months and older is 8 mg per kg orally twice daily or 16 mg per kg orally once daily (up to a maximum of 600 mg daily) in combination with other antiretroviral agents.</p><p>ZIAGEN is also available as a scored tablet for HIV-1–infected pediatric patients weighing greater than or equal to 14 kg for whom a solid dosage form is appropriate. Before prescribing ZIAGEN tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow ZIAGEN tablets, the oral solution formulation should be prescribed. The recommended oral dosage of ZIAGEN tablets for HIV-1–infected pediatric patients is presented in Table 1.</p><p align="center"><b>Table 1. Dosing Recommendations for ZIAGEN Scored Tablets in Pediatric Patients</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" rowspan="2" width="20%">Weight(kg)</td><td class="EmphTd" rowspan="2" width="20%">Once-Daily Dosing Regimen<sup>a</sup></td><td class="EmphTd" colspan="3">Twice-Daily Dosing Regimen</td></tr><tr><td class="EmphTd" width="20%">AM Dose</td><td class="EmphTd" width="20%">PM Dose</td><td class="EmphTd" width="20%">Total Daily Dose</td></tr><tr><td>14 to <20</td><td align="center">1 tablet<br />(300 mg)</td><td align="center">½ tablet<br />(150 mg)</td><td align="center">½ tablet<br />(150 mg)</td><td align="center">300 mg</td></tr><tr><td>≥20 to <25</td><td align="center">1½ tablets<br />(450 mg)</td><td align="center">½ tablet<br />(150 mg)</td><td align="center">1 tablet<br />(300 mg)</td><td align="center">450 mg</td></tr><tr><td>≥25</td><td align="center">2 tablets<br />(600 mg)</td><td align="center">1 tablet<br />(300 mg)</td><td align="center">1 tablet<br />(300 mg)</td><td align="center">600 mg</td></tr><tr><td class="credit" colspan="5"><sup>a</sup> Data regarding the efficacy of once-daily dosing is limited to subjects who transitioned from twice-daily dosing to once-daily dosing after 36 weeks of treatment [see <b>Clinical Studies</b>].</td></tr></tbody></table></center><p></p><h4>Recommended Dosage For Patients With Hepatic Impairment</h4><p>The recommended dose of ZIAGEN in patients with mild hepatic impairment (Child-Pugh Class A) is 200 mg twice daily. To enable dose reduction, ZIAGEN oral solution (10 mL twice daily) should be used for the treatment of these patients. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate to severe hepatic impairment; therefore, ZIAGEN is contraindicated in these patients.</p> <a name="HS"></a><h3>HOW SUPPLIED</h3><h4>Dosage Forms And Strengths</h4><p>ZIAGEN tablets contain 300 mg of abacavir as abacavir sulfate. The tablets are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with “GX 623” on both sides.</p><p>ZIAGEN oral solution contains 20 mg per mL of abacavir as abacavir sulfate. The solution is a clear to opalescent, yellowish, strawberry-banana-flavored liquid, which may turn brown over time.</p><h4>Storage And Handling</h4><p><b>ZIAGEN tablets</b>, containing abacavir sulfate equivalent to 300 mg abacavir are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with “GX 623” on both sides. They are packaged as follows:</p><p class="EmphText">Bottles of 60 tablets (<b>NDC</b> 49702-221-18).</p><p><b>Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see USP).</b></p><p><b>ZIAGEN oral solution</b> is a clear to opalescent, yellowish, strawberry-banana-flavored liquid, which may turn brown over time. Each mL of the solution contains abacavir sulfate equivalent to 20 mg of abacavir. It is packaged in plastic bottles as follows:</p><p class="EmphText">Bottles of 240 mL (<b>NDC</b> 49702-222-48) with child-resistant closure. This product does not require reconstitution.</p><p><b>Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see USP). DO NOT FREEZE. May be refrigerated.</b></p><p class="credit">Manufactured by: GlaxoSmithKline Research Triangle Park, NC 27709. Revised: Nov 2020</p> </div> <a class="mediaPrmo ss" href="/aids_retrospective_slideshow/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/aids_s1_quilt.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">A Timeline of the HIV/AIDS Pandemic</span> <span class="btn">See Slideshow</span> </a> </div> </div> | 3 | 2023-02-01 17:38:21 | Abacavir Sulfate (Ziagen) | A | HIV, NNRTIs, Antiretroviral Agents | Ziagen | abacavir sulfate | Ziagen | John P. Cunha, DO, FACOEP |
| 20 | 2023-02-23 11:36:54 | Side Effects & Drug Interactions | <a name="AR"></a><h3>SIDE EFFECTS</h3><p>The following adverse reactions are discussed in other sections of the labeling:</p><ul><li>Serious and sometimes fatal hypersensitivity reactions [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Lactic acidosis and severe hepatomegaly with steatosis [see <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Immune reconstitution syndrome [see <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Myocardial infarction [see <b>WARNINGS AND PRECAUTIONS</b>].</li></ul><h4>Clinical Trials Experience In Adult Subjects</h4><p>Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.</p><h4>Serious And Fatal Abacavir-Associated Hypersensitivity Reactions</h4><p>In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.</p><p>Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized).</p><h4>Additional Adverse Reactions With Use Of ZIAGEN</h4><h5>Therapy-Naive Adults</h5><p>Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 2.</p><p align="center"><b>Table 2. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30024<sup>a</sup>) through 48 Weeks of Treatment</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="40%">Adverse Reaction</td><td class="EmphTd" width="30%">ZIAGEN plus Lamivudine plus Efavirenz<br />(n = 324)</td><td class="EmphTd" width="30%">Zidovudine plus Lamivudine plus Efavirenz<br />(n = 325)</td></tr><tr><td>Dreams/sleep disorders</td><td align="center">10%</td><td align="center">10%</td></tr><tr><td>Drug hypersensitivity</td><td align="center">9%</td><td align="center"><1%<sup>b</sup></td></tr><tr><td>Headaches/migraine</td><td align="center">7%</td><td align="center">11%</td></tr><tr><td>Nausea</td><td align="center">7%</td><td align="center">11%</td></tr><tr><td>Fatigue/malaise</td><td align="center">7%</td><td align="center">10%</td></tr><tr><td>Diarrhea</td><td align="center">7%</td><td align="center">6%</td></tr><tr><td>Rashes</td><td align="center">6%</td><td align="center">12%</td></tr><tr><td>Abdominal pain/gastritis/gastrointestinal signs and symptoms</td><td align="center">6%</td><td align="center">8%</td></tr><tr><td>Depressive disorders</td><td align="center">6%</td><td align="center">6%</td></tr><tr><td>Dizziness</td><td align="center">6%</td><td align="center">6%</td></tr><tr><td>Musculoskeletal pain</td><td align="center">6%</td><td align="center">5%</td></tr><tr><td>Bronchitis</td><td align="center">4%</td><td align="center">5%</td></tr><tr><td>Vomiting</td><td align="center">2%</td><td align="center">9%</td></tr><tr><td class="credit" colspan="3"><sup>a</sup> This trial used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group.<br /><sup>b </sup>Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding.</td></tr></tbody></table></center><p></p><p>Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 3.</p><p align="center"><b>Table 3. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of Treatment</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="30%">Adverse Reaction</td><td class="EmphTd" width="35%">ZIAGEN plus Lamivudine/Zidovudine<br />(n = 262)</td><td class="EmphTd" width="35%">Indinavir plus Lamivudine/Zidovudine<br />(n = 264)</td></tr><tr><td>Nausea</td><td align="center">19%</td><td align="center">17%</td></tr><tr><td>Headache</td><td align="center">13%</td><td align="center">9%</td></tr><tr><td>Malaise and fatigue</td><td align="center">12%</td><td align="center">12%</td></tr><tr><td>Nausea and vomiting</td><td align="center">10%</td><td align="center">10%</td></tr><tr><td>Hypersensitivity reaction</td><td align="center">8%</td><td align="center">2%</td></tr><tr><td>Diarrhea</td><td align="center">7%</td><td align="center">5%</td></tr><tr><td>Fever and/or chills</td><td align="center">6%</td><td align="center">3%</td></tr><tr><td>Depressive disorders</td><td align="center">6%</td><td align="center">4%</td></tr><tr><td>Musculoskeletal pain</td><td align="center">5%</td><td align="center">7%</td></tr><tr><td>Skin rashes</td><td align="center">5%</td><td align="center">4%</td></tr><tr><td>Ear/nose/throat infections</td><td align="center">5%</td><td align="center">4%</td></tr><tr><td>Viral respiratory infections</td><td align="center">5%</td><td align="center">5%</td></tr><tr><td>Anxiety</td><td align="center">5%</td><td align="center">3%</td></tr><tr><td>Renal signs/symptoms</td><td align="center"><1%</td><td align="center">5%</td></tr><tr><td>Pain (non-site-specific)</td><td align="center"><1%</td><td align="center">5%</td></tr></tbody></table></center><p></p><p>Five subjects receiving ZIAGEN in CNA3005 experienced worsening of pre-existing depression compared with none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.</p><h5>ZIAGEN Once Daily versus ZIAGEN Twice Daily (CNA30021)</h5><p>Treatment-emergent clinical adverse reactions (rated by the investigator as at least moderate) with a greater than or equal to 5% frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily from CNA30021, were similar. For hypersensitivity reactions, subjects receiving ZIAGEN once daily showed a rate of 9% in comparison with a rate of 7% for subjects receiving ZIAGEN twice daily. However, subjects receiving ZIAGEN 600 mg once daily experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN 300 mg twice daily. Five percent (5%) of subjects receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving ZIAGEN 300 mg twice daily. Two percent (2%) of subjects receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN 300 mg twice daily had this event.</p><h5>Laboratory Abnormalities</h5><p>Laboratory abnormalities (Grades 3-4) in therapy-naive adults during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 4.</p><p align="center"><b>Table 4. Laboratory Abnormalities (Grades 3-4) in Therapy-Naive Adults (CNA30024) through 48 Weeks of Treatment</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="40%">Grade 3/4 Laboratory Abnormalities</td><td class="EmphTd" width="30%">ZIAGEN plus Lamivudine plus Efavirenz<br />(n = 324)</td><td class="EmphTd" width="30%">Zidovudine plus Lamivudine plus Efavirenz<br />(n = 325)</td></tr><tr><td>Elevated CPK (>4 X ULN)</td><td align="center">8%</td><td align="center">8%</td></tr><tr><td>Elevated ALT (>5 X ULN)</td><td align="center">6%</td><td align="center">6%</td></tr><tr><td>Elevated AST (>5 X ULN)</td><td align="center">6%</td><td align="center">5%</td></tr><tr><td>Hypertriglyceridemia (>750 mg/dL)</td><td align="center">6%</td><td align="center">5%</td></tr><tr><td>Hyperamylasemia (>2 X ULN)</td><td align="center">4%</td><td align="center">5%</td></tr><tr><td>Neutropenia (ANC <750/mm<sup>3</sup>)</td><td align="center">2%</td><td align="center">4%</td></tr><tr><td>Anemia (Hgb ≤6.9 gm/dL)</td><td align="center"><1%</td><td align="center">2%</td></tr><tr><td>Thrombocytopenia (Platelets <50,000/mm<sup>3</sup>)</td><td align="center">1%</td><td align="center"><1%</td></tr><tr><td>Leukopenia (WBC ≤1,500/mm<sup>3</sup>)</td><td align="center"><1%</td><td align="center">2%</td></tr><tr><td class="credit" colspan="3">ULN = Upper limit of normal.<br />n = Number of subjects assessed.</td></tr></tbody></table></center><p></p><p>Laboratory abnormalities in CNA3005 are listed in Table 5.</p><p align="center"><b>Table 5. Treatment-Emergent Laboratory Abnormalities (Grades 3-4) in CNA3005</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="40%">Grade 3/4 Laboratory Abnormalities</td><td class="EmphTd" width="30%">ZIAGEN plus Lamivudine/Zidovudine<br />(n = 262)</td><td class="EmphTd" width="30%">Indinavir plus Lamivudine/Zidovudine<br />(n = 264)</td></tr><tr><td>Elevated CPK (>4 x ULN)</td><td align="center">18 (7%)</td><td align="center">18 (7%)</td></tr><tr><td>ALT (>5.0 x ULN)</td><td align="center">16 (6%)</td><td align="center">16 (6%)</td></tr><tr><td>Neutropenia (<750/mm<sup>3</sup>)</td><td align="center">13 (5%)</td><td align="center">13 (5%)</td></tr><tr><td>Hypertriglyceridemia (>750 mg/dL)</td><td align="center">5 (2%)</td><td align="center">3 (1%)</td></tr><tr><td>Hyperamylasemia (>2.0 x ULN)</td><td align="center">5 (2%)</td><td align="center">1 (<1%)</td></tr><tr><td>Hyperglycemia (>13.9 mmol/L)</td><td align="center">2 (<1%)</td><td align="center">2 (<1%)</td></tr><tr><td>Anemia (Hgb ≤6.9 g/dL)</td><td align="center">0 (0%)</td><td align="center">3 (1%)</td></tr><tr><td class="credit" colspan="3">ULN = Upper limit of normal.<br />n = Number of subjects assessed.</td></tr></tbody></table></center><p></p><p>The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021.</p><h4>Clinical Trials Experience In Pediatric Subjects</h4><h5>Therapy-Experienced Pediatric Subjects (Twice-Daily Dosing)</h5><p>Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 8 mg per kg twice daily, lamivudine 4 mg per kg twice daily, and zidovudine 180 mg per m<sup>2</sup> twice daily compared with lamivudine 4 mg per kg twice daily and zidovudine 180 mg per m<sup>2</sup> twice daily from CNA3006 are listed in Table 6.</p><p align="center"><b>Table 6. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Experienced Pediatric Subjects (CNA3006) through 16 Weeks of Treatment</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="40%">Adverse Reaction</td><td class="EmphTd" width="30%">ZIAGEN plus Lamivudine plus Zidovudine<br />(n = 102)</td><td class="EmphTd" width="30%">Lamivudine plus Zidovudine<br />(n = 103)</td></tr><tr><td>Fever and/or chills</td><td align="center">9%</td><td align="center">7%</td></tr><tr><td>Nausea and vomiting</td><td align="center">9%</td><td align="center">2%</td></tr><tr><td>Skin rashes</td><td align="center">7%</td><td align="center">1%</td></tr><tr><td>Ear/nose/throat infections</td><td align="center">5%</td><td align="center">1%</td></tr><tr><td>Pneumonia</td><td align="center">4%</td><td align="center">5%</td></tr><tr><td>Headache</td><td align="center">1%</td><td align="center">5%</td></tr></tbody></table></center><p></p><h5>Laboratory Abnormalities</h5><p>In CNA3006, laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequencies as in a trial of therapy-naive adults (CNA30024). Mild elevations of blood glucose were more frequent in pediatric subjects receiving ZIAGEN (CNA3006) as compared with adult subjects (CNA30024).</p><h4>Other Adverse Events</h4><p>In addition to adverse reactions and laboratory abnormalities reported in Tables 2, 3, 4, 5, and 6, other adverse reactions observed in the expanded access program were pancreatitis and increased GGT.</p><h5>Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677)</h5><p>The safety of once-daily compared with twice-daily dosing of ZIAGEN was assessed in the ARROW trial. Primary safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator.</p><h4>Postmarketing Experience</h4><p>The following adverse reactions have been identified during postmarketing use of ZIAGEN. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposures.</p><h5>Body As A Whole</h5><p>Redistribution/accumulation of body fat.</p><h5>Cardiovascular</h5><p>Myocardial infarction.</p><h5>Hepatic</h5><p>Lactic acidosis and hepatic steatosis [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Skin</h5><p>Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases.</p><p>There have also been reports of erythema multiforme with abacavir use [see <b>Clinical Trials Experience In Adult Subjects</b>].</p> <a name="DI"></a><h3>DRUG INTERACTIONS</h3><h4>Methadone</h4><p>In a trial of 11 HIV-1–infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see <b>CLINICAL PHARMACOLOGY</b>]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.</p><h4>Riociguat</h4><p>Coadministration with fixed-dose abacavir/dolutegravir/lamivudine resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [see <b>CLINICAL PHARMACOLOGY</b>]. The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).</p> </div> </div> </div> | <a name="AR"></a><h3>SIDE EFFECTS</h3><p>The following adverse reactions are discussed in other sections of the labeling:</p><ul><li>Serious and sometimes fatal hypersensitivity reactions [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Lactic acidosis and severe hepatomegaly with steatosis [see <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Immune reconstitution syndrome [see <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Myocardial infarction [see <b>WARNINGS AND PRECAUTIONS</b>].</li></ul><h4>Clinical Trials Experience In Adult Subjects</h4><p>Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.</p><h4>Serious And Fatal Abacavir-Associated Hypersensitivity Reactions</h4><p>In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.</p><p>Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized).</p><h4>Additional Adverse Reactions With Use Of ZIAGEN</h4><h5>Therapy-Naive Adults</h5><p>Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 2.</p><p align="center"><b>Table 2. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30024<sup>a</sup>) through 48 Weeks of Treatment</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="40%">Adverse Reaction</td><td class="EmphTd" width="30%">ZIAGEN plus Lamivudine plus Efavirenz<br />(n = 324)</td><td class="EmphTd" width="30%">Zidovudine plus Lamivudine plus Efavirenz<br />(n = 325)</td></tr><tr><td>Dreams/sleep disorders</td><td align="center">10%</td><td align="center">10%</td></tr><tr><td>Drug hypersensitivity</td><td align="center">9%</td><td align="center"><1%<sup>b</sup></td></tr><tr><td>Headaches/migraine</td><td align="center">7%</td><td align="center">11%</td></tr><tr><td>Nausea</td><td align="center">7%</td><td align="center">11%</td></tr><tr><td>Fatigue/malaise</td><td align="center">7%</td><td align="center">10%</td></tr><tr><td>Diarrhea</td><td align="center">7%</td><td align="center">6%</td></tr><tr><td>Rashes</td><td align="center">6%</td><td align="center">12%</td></tr><tr><td>Abdominal pain/gastritis/gastrointestinal signs and symptoms</td><td align="center">6%</td><td align="center">8%</td></tr><tr><td>Depressive disorders</td><td align="center">6%</td><td align="center">6%</td></tr><tr><td>Dizziness</td><td align="center">6%</td><td align="center">6%</td></tr><tr><td>Musculoskeletal pain</td><td align="center">6%</td><td align="center">5%</td></tr><tr><td>Bronchitis</td><td align="center">4%</td><td align="center">5%</td></tr><tr><td>Vomiting</td><td align="center">2%</td><td align="center">9%</td></tr><tr><td class="credit" colspan="3"><sup>a</sup> This trial used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group.<br /><sup>b </sup>Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding.</td></tr></tbody></table></center><p></p><p>Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 3.</p><p align="center"><b>Table 3. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of Treatment</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="30%">Adverse Reaction</td><td class="EmphTd" width="35%">ZIAGEN plus Lamivudine/Zidovudine<br />(n = 262)</td><td class="EmphTd" width="35%">Indinavir plus Lamivudine/Zidovudine<br />(n = 264)</td></tr><tr><td>Nausea</td><td align="center">19%</td><td align="center">17%</td></tr><tr><td>Headache</td><td align="center">13%</td><td align="center">9%</td></tr><tr><td>Malaise and fatigue</td><td align="center">12%</td><td align="center">12%</td></tr><tr><td>Nausea and vomiting</td><td align="center">10%</td><td align="center">10%</td></tr><tr><td>Hypersensitivity reaction</td><td align="center">8%</td><td align="center">2%</td></tr><tr><td>Diarrhea</td><td align="center">7%</td><td align="center">5%</td></tr><tr><td>Fever and/or chills</td><td align="center">6%</td><td align="center">3%</td></tr><tr><td>Depressive disorders</td><td align="center">6%</td><td align="center">4%</td></tr><tr><td>Musculoskeletal pain</td><td align="center">5%</td><td align="center">7%</td></tr><tr><td>Skin rashes</td><td align="center">5%</td><td align="center">4%</td></tr><tr><td>Ear/nose/throat infections</td><td align="center">5%</td><td align="center">4%</td></tr><tr><td>Viral respiratory infections</td><td align="center">5%</td><td align="center">5%</td></tr><tr><td>Anxiety</td><td align="center">5%</td><td align="center">3%</td></tr><tr><td>Renal signs/symptoms</td><td align="center"><1%</td><td align="center">5%</td></tr><tr><td>Pain (non-site-specific)</td><td align="center"><1%</td><td align="center">5%</td></tr></tbody></table></center><p></p><p>Five subjects receiving ZIAGEN in CNA3005 experienced worsening of pre-existing depression compared with none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.</p><h5>ZIAGEN Once Daily versus ZIAGEN Twice Daily (CNA30021)</h5><p>Treatment-emergent clinical adverse reactions (rated by the investigator as at least moderate) with a greater than or equal to 5% frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily from CNA30021, were similar. For hypersensitivity reactions, subjects receiving ZIAGEN once daily showed a rate of 9% in comparison with a rate of 7% for subjects receiving ZIAGEN twice daily. However, subjects receiving ZIAGEN 600 mg once daily experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN 300 mg twice daily. Five percent (5%) of subjects receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving ZIAGEN 300 mg twice daily. Two percent (2%) of subjects receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN 300 mg twice daily had this event.</p><h5>Laboratory Abnormalities</h5><p>Laboratory abnormalities (Grades 3-4) in therapy-naive adults during therapy with ZIAGEN 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily compared with zidovudine 300 mg twice daily, lamivudine 150 mg twice daily, and efavirenz 600 mg daily from CNA30024 are listed in Table 4.</p><p align="center"><b>Table 4. Laboratory Abnormalities (Grades 3-4) in Therapy-Naive Adults (CNA30024) through 48 Weeks of Treatment</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="40%">Grade 3/4 Laboratory Abnormalities</td><td class="EmphTd" width="30%">ZIAGEN plus Lamivudine plus Efavirenz<br />(n = 324)</td><td class="EmphTd" width="30%">Zidovudine plus Lamivudine plus Efavirenz<br />(n = 325)</td></tr><tr><td>Elevated CPK (>4 X ULN)</td><td align="center">8%</td><td align="center">8%</td></tr><tr><td>Elevated ALT (>5 X ULN)</td><td align="center">6%</td><td align="center">6%</td></tr><tr><td>Elevated AST (>5 X ULN)</td><td align="center">6%</td><td align="center">5%</td></tr><tr><td>Hypertriglyceridemia (>750 mg/dL)</td><td align="center">6%</td><td align="center">5%</td></tr><tr><td>Hyperamylasemia (>2 X ULN)</td><td align="center">4%</td><td align="center">5%</td></tr><tr><td>Neutropenia (ANC <750/mm<sup>3</sup>)</td><td align="center">2%</td><td align="center">4%</td></tr><tr><td>Anemia (Hgb ≤6.9 gm/dL)</td><td align="center"><1%</td><td align="center">2%</td></tr><tr><td>Thrombocytopenia (Platelets <50,000/mm<sup>3</sup>)</td><td align="center">1%</td><td align="center"><1%</td></tr><tr><td>Leukopenia (WBC ≤1,500/mm<sup>3</sup>)</td><td align="center"><1%</td><td align="center">2%</td></tr><tr><td class="credit" colspan="3">ULN = Upper limit of normal.<br />n = Number of subjects assessed.</td></tr></tbody></table></center><p></p><p>Laboratory abnormalities in CNA3005 are listed in Table 5.</p><p align="center"><b>Table 5. Treatment-Emergent Laboratory Abnormalities (Grades 3-4) in CNA3005</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="40%">Grade 3/4 Laboratory Abnormalities</td><td class="EmphTd" width="30%">ZIAGEN plus Lamivudine/Zidovudine<br />(n = 262)</td><td class="EmphTd" width="30%">Indinavir plus Lamivudine/Zidovudine<br />(n = 264)</td></tr><tr><td>Elevated CPK (>4 x ULN)</td><td align="center">18 (7%)</td><td align="center">18 (7%)</td></tr><tr><td>ALT (>5.0 x ULN)</td><td align="center">16 (6%)</td><td align="center">16 (6%)</td></tr><tr><td>Neutropenia (<750/mm<sup>3</sup>)</td><td align="center">13 (5%)</td><td align="center">13 (5%)</td></tr><tr><td>Hypertriglyceridemia (>750 mg/dL)</td><td align="center">5 (2%)</td><td align="center">3 (1%)</td></tr><tr><td>Hyperamylasemia (>2.0 x ULN)</td><td align="center">5 (2%)</td><td align="center">1 (<1%)</td></tr><tr><td>Hyperglycemia (>13.9 mmol/L)</td><td align="center">2 (<1%)</td><td align="center">2 (<1%)</td></tr><tr><td>Anemia (Hgb ≤6.9 g/dL)</td><td align="center">0 (0%)</td><td align="center">3 (1%)</td></tr><tr><td class="credit" colspan="3">ULN = Upper limit of normal.<br />n = Number of subjects assessed.</td></tr></tbody></table></center><p></p><p>The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021.</p><h4>Clinical Trials Experience In Pediatric Subjects</h4><h5>Therapy-Experienced Pediatric Subjects (Twice-Daily Dosing)</h5><p>Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a greater than or equal to 5% frequency during therapy with ZIAGEN 8 mg per kg twice daily, lamivudine 4 mg per kg twice daily, and zidovudine 180 mg per m<sup>2</sup> twice daily compared with lamivudine 4 mg per kg twice daily and zidovudine 180 mg per m<sup>2</sup> twice daily from CNA3006 are listed in Table 6.</p><p align="center"><b>Table 6. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Experienced Pediatric Subjects (CNA3006) through 16 Weeks of Treatment</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="40%">Adverse Reaction</td><td class="EmphTd" width="30%">ZIAGEN plus Lamivudine plus Zidovudine<br />(n = 102)</td><td class="EmphTd" width="30%">Lamivudine plus Zidovudine<br />(n = 103)</td></tr><tr><td>Fever and/or chills</td><td align="center">9%</td><td align="center">7%</td></tr><tr><td>Nausea and vomiting</td><td align="center">9%</td><td align="center">2%</td></tr><tr><td>Skin rashes</td><td align="center">7%</td><td align="center">1%</td></tr><tr><td>Ear/nose/throat infections</td><td align="center">5%</td><td align="center">1%</td></tr><tr><td>Pneumonia</td><td align="center">4%</td><td align="center">5%</td></tr><tr><td>Headache</td><td align="center">1%</td><td align="center">5%</td></tr></tbody></table></center><p></p><h5>Laboratory Abnormalities</h5><p>In CNA3006, laboratory abnormalities (anemia, neutropenia, liver function test abnormalities, and CPK elevations) were observed with similar frequencies as in a trial of therapy-naive adults (CNA30024). Mild elevations of blood glucose were more frequent in pediatric subjects receiving ZIAGEN (CNA3006) as compared with adult subjects (CNA30024).</p><h4>Other Adverse Events</h4><p>In addition to adverse reactions and laboratory abnormalities reported in Tables 2, 3, 4, 5, and 6, other adverse reactions observed in the expanded access program were pancreatitis and increased GGT.</p><h5>Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677)</h5><p>The safety of once-daily compared with twice-daily dosing of ZIAGEN was assessed in the ARROW trial. Primary safety assessment in the ARROW trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator.</p><h4>Postmarketing Experience</h4><p>The following adverse reactions have been identified during postmarketing use of ZIAGEN. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposures.</p><h5>Body As A Whole</h5><p>Redistribution/accumulation of body fat.</p><h5>Cardiovascular</h5><p>Myocardial infarction.</p><h5>Hepatic</h5><p>Lactic acidosis and hepatic steatosis [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Skin</h5><p>Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases.</p><p>There have also been reports of erythema multiforme with abacavir use [see <b>Clinical Trials Experience In Adult Subjects</b>].</p> <a name="DI"></a><h3>DRUG INTERACTIONS</h3><h4>Methadone</h4><p>In a trial of 11 HIV-1–infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see <b>CLINICAL PHARMACOLOGY</b>]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.</p><h4>Riociguat</h4><p>Coadministration with fixed-dose abacavir/dolutegravir/lamivudine resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [see <b>CLINICAL PHARMACOLOGY</b>]. The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).</p> </div> </div> </div> | 3 | 2023-02-01 17:38:21 | Abacavir Sulfate (Ziagen) | A | HIV, NNRTIs, Antiretroviral Agents | Ziagen | abacavir sulfate | Ziagen | John P. Cunha, DO, FACOEP |
| 21 | 2023-02-23 11:36:54 | Warnings & Precautions | <a name="W"></a><h3>WARNINGS</h3><p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a><h3>PRECAUTIONS</h3><h4>Hypersensitivity Reactions</h4><p>Serious and sometimes fatal hypersensitivity reactions have occurred with ZIAGEN (abacavir). These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with ZIAGEN (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see <b>ADVERSE REACTIONS</b>]. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.</p><p>Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with ZIAGEN:</p><ul><li>All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN or reinitiation of therapy with ZIAGEN, unless patients have a previously documented HLA-B*5701 allele assessment.</li><li>ZIAGEN is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.</li><li>Before starting ZIAGEN, review medical history for prior exposure to any abacavircontaining product. NEVER restart ZIAGEN or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.</li><li>To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue ZIAGEN immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).</li><li>If a hypersensitivity reaction cannot be ruled out, do not restart ZIAGEN or any other abacavir-containing products because more severe symptoms which may include life-threatening hypotension and death, can occur within hours.</li><li>If a hypersensitivity reaction is ruled out, patients may restart ZIAGEN. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of ZIAGEN or any other abacavir-containing product is recommended only if medical care can be readily accessed.</li><li>A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.</li></ul><h4>Lactic Acidosis And Severe Hepatomegaly With Steatosis</h4><p>Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including ZIAGEN. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment with ZIAGEN should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.</p><h4>Immune Reconstitution Syndrome</h4><p>Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ZIAGEN. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as <i>Mycobacterium avium</i> infection, cytomegalovirus, <i>Pneumocystis jirovecii</i> pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.</p><p>Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.</p><h4>Myocardial Infarction</h4><p>Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled, clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir treatment and the risk of MI is inconclusive.</p><p>As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).</p><h4>Patient Counseling Information</h4><p>Advise the patient to read the FDA-approved patient labeling (<b>PATIENT INFORMATION</b>).</p><h5>Hypersensitivity Reactions</h5><p>Inform patients:</p><ul><li>that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of ZIAGEN and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about ZIAGEN. The complete text of the Medication Guide is reprinted at the end of this document.</li><li>to carry the Warning Card with them.</li><li>how to identify a hypersensitivity reaction [see <b>WARNINGS AND PRECAUTIONS</b>, <b>PATIENT INFORMATION</b>].</li><li>that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking ZIAGEN.</li><li>that a hypersensitivity reaction can worsen and lead to hospitalization or death if ZIAGEN is not immediately discontinued.</li><li>to not restart ZIAGEN or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.</li><li>that if they have a hypersensitivity reaction, they should dispose of any unused ZIAGEN to avoid restarting abacavir.</li><li>that a hypersensitivity reaction is usually reversible if it is detected promptly and ZIAGEN is stopped right away.</li><li>that if they have interrupted ZIAGEN for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.</li><li>to not restart ZIAGEN or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.</li></ul><h5>Lactic Acidosis/Hepatomegaly With Steatosis</h5><p>dvise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking ZIAGEN if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Immune Reconstitution Syndrome</h5><p>Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when ZIAGEN is started [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Pregnancy Registry</h5><p>Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZIAGEN during pregnancy [see <b>Use In Specific Populations</b>].</p><h5>Lactation</h5><p>Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see <b>Use In Specific Populations</b>].</p><h5>Missed Dose</h5><p>Instruct patients that if they miss a dose of ZIAGEN, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see <b>DOSAGE AND ADMINISTRATION</b>].</p><h5>Availability Of Medication Guide</h5><p>Instruct patients to read the Medication Guide before starting ZIAGEN and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.</p><p>COMBIVIR, EPIVIR, TRIUMEQ, and ZIAGEN are trademarks owned by or licensed to the ViiV Healthcare group of companies.</p><p>The other brands listed are owned by or licensed to their respective owner and are not owned by or licensed to the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.</p><h4>Nonclinical Toxicology</h4><h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4><h5>Carcinogenicity</h5><p>Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg.</p><h5>Mutagenicity</h5><p>Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an <i>in vitro</i> cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an <i>in vivo</i> mouse bone marrow micronucleus assay.</p><p>Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.</p><h5>Impairment Of Fertility</h5><p>Abacavir did not affect male or female fertility in rats at a dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.</p> <a name="USP"></a><h4>Use In Specific Populations</h4><h4>Pregnancy</h4><h5>Pregnancy Exposure Registry</h5><p>There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZIAGEN during pregnancy. Healthcare Providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.</p><h5>Risk Summary</h5><p>Available data from the APR show no difference in the overall risk of birth defects for abacavir compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see <b>Data</b>). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.</p><p>In animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose. However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately 9 times the human exposure (AUC) at the recommended clinical dose (see <b>Data</b>).</p><h5>Data</h5><p><i>Human Data</i></p><p>Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4.0%) following second/third trimester exposure to abacavir-containing regimens.</p><p>Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see <b>CLINICAL PHARMACOLOGY</b>].</p><p><i>Animal Data</i></p><p>Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on Gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately 4 times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the recommended dose.</p><h4>Lactation</h4><h5>Risk Summary</h5><p>The Centers for Disease Control and Prevention recommends that HIV-1–infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir is present in human milk. There is no information on the effects of abacavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving ZIAGEN.</p><h4>Pediatric Use</h4><p>The safety and effectiveness of ZIAGEN have been established in pediatric patients aged 3 months and older. Use of ZIAGEN is supported by pharmacokinetic trials and evidence from adequate and well-controlled trials of ZIAGEN in adults and pediatric subjects [see <b>DOSAGE AND ADMINISTRATION</b>, <b>ADVERSE REACTIONS</b>, <b>CLINICAL PHARMACOLOGY</b>, <b>Clinical Studies</b>].</p><h4>Geriatric Use</h4><p>Clinical trials of ZIAGEN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of ZIAGEN in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.</p><h4>Patients With Impaired Hepatic Function</h4><p>A dose reduction is required for patients with mild hepatic impairment (Child-Pugh Class A) [see <b>DOSAGE AND ADMINISTRATION</b>]. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate or severe hepatic impairment; therefore, ZIAGEN is contraindicated in these patients [see <b>CONTRAINDICATIONS</b>, <b>CLINICAL PHARMACOLOGY</b>].</p> </div> </div> </div> | <a name="W"></a><h3>WARNINGS</h3><p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a><h3>PRECAUTIONS</h3><h4>Hypersensitivity Reactions</h4><p>Serious and sometimes fatal hypersensitivity reactions have occurred with ZIAGEN (abacavir). These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with ZIAGEN (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see <b>ADVERSE REACTIONS</b>]. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.</p><p>Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with ZIAGEN:</p><ul><li>All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN or reinitiation of therapy with ZIAGEN, unless patients have a previously documented HLA-B*5701 allele assessment.</li><li>ZIAGEN is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.</li><li>Before starting ZIAGEN, review medical history for prior exposure to any abacavircontaining product. NEVER restart ZIAGEN or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.</li><li>To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue ZIAGEN immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).</li><li>If a hypersensitivity reaction cannot be ruled out, do not restart ZIAGEN or any other abacavir-containing products because more severe symptoms which may include life-threatening hypotension and death, can occur within hours.</li><li>If a hypersensitivity reaction is ruled out, patients may restart ZIAGEN. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of ZIAGEN or any other abacavir-containing product is recommended only if medical care can be readily accessed.</li><li>A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.</li></ul><h4>Lactic Acidosis And Severe Hepatomegaly With Steatosis</h4><p>Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including ZIAGEN. A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment with ZIAGEN should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.</p><h4>Immune Reconstitution Syndrome</h4><p>Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ZIAGEN. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as <i>Mycobacterium avium</i> infection, cytomegalovirus, <i>Pneumocystis jirovecii</i> pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.</p><p>Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.</p><h4>Myocardial Infarction</h4><p>Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled, clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir treatment and the risk of MI is inconclusive.</p><p>As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).</p><h4>Patient Counseling Information</h4><p>Advise the patient to read the FDA-approved patient labeling (<b>PATIENT INFORMATION</b>).</p><h5>Hypersensitivity Reactions</h5><p>Inform patients:</p><ul><li>that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of ZIAGEN and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about ZIAGEN. The complete text of the Medication Guide is reprinted at the end of this document.</li><li>to carry the Warning Card with them.</li><li>how to identify a hypersensitivity reaction [see <b>WARNINGS AND PRECAUTIONS</b>, <b>PATIENT INFORMATION</b>].</li><li>that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking ZIAGEN.</li><li>that a hypersensitivity reaction can worsen and lead to hospitalization or death if ZIAGEN is not immediately discontinued.</li><li>to not restart ZIAGEN or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.</li><li>that if they have a hypersensitivity reaction, they should dispose of any unused ZIAGEN to avoid restarting abacavir.</li><li>that a hypersensitivity reaction is usually reversible if it is detected promptly and ZIAGEN is stopped right away.</li><li>that if they have interrupted ZIAGEN for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.</li><li>to not restart ZIAGEN or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.</li></ul><h5>Lactic Acidosis/Hepatomegaly With Steatosis</h5><p>dvise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking ZIAGEN if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Immune Reconstitution Syndrome</h5><p>Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when ZIAGEN is started [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Pregnancy Registry</h5><p>Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZIAGEN during pregnancy [see <b>Use In Specific Populations</b>].</p><h5>Lactation</h5><p>Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see <b>Use In Specific Populations</b>].</p><h5>Missed Dose</h5><p>Instruct patients that if they miss a dose of ZIAGEN, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see <b>DOSAGE AND ADMINISTRATION</b>].</p><h5>Availability Of Medication Guide</h5><p>Instruct patients to read the Medication Guide before starting ZIAGEN and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.</p><p>COMBIVIR, EPIVIR, TRIUMEQ, and ZIAGEN are trademarks owned by or licensed to the ViiV Healthcare group of companies.</p><p>The other brands listed are owned by or licensed to their respective owner and are not owned by or licensed to the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.</p><h4>Nonclinical Toxicology</h4><h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4><h5>Carcinogenicity</h5><p>Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg.</p><h5>Mutagenicity</h5><p>Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an <i>in vitro</i> cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an <i>in vivo</i> mouse bone marrow micronucleus assay.</p><p>Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.</p><h5>Impairment Of Fertility</h5><p>Abacavir did not affect male or female fertility in rats at a dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.</p> <a name="USP"></a><h4>Use In Specific Populations</h4><h4>Pregnancy</h4><h5>Pregnancy Exposure Registry</h5><p>There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZIAGEN during pregnancy. Healthcare Providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.</p><h5>Risk Summary</h5><p>Available data from the APR show no difference in the overall risk of birth defects for abacavir compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see <b>Data</b>). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.</p><p>In animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose. However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately 9 times the human exposure (AUC) at the recommended clinical dose (see <b>Data</b>).</p><h5>Data</h5><p><i>Human Data</i></p><p>Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4.0%) following second/third trimester exposure to abacavir-containing regimens.</p><p>Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see <b>CLINICAL PHARMACOLOGY</b>].</p><p><i>Animal Data</i></p><p>Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on Gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately 4 times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the recommended dose.</p><h4>Lactation</h4><h5>Risk Summary</h5><p>The Centers for Disease Control and Prevention recommends that HIV-1–infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir is present in human milk. There is no information on the effects of abacavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving ZIAGEN.</p><h4>Pediatric Use</h4><p>The safety and effectiveness of ZIAGEN have been established in pediatric patients aged 3 months and older. Use of ZIAGEN is supported by pharmacokinetic trials and evidence from adequate and well-controlled trials of ZIAGEN in adults and pediatric subjects [see <b>DOSAGE AND ADMINISTRATION</b>, <b>ADVERSE REACTIONS</b>, <b>CLINICAL PHARMACOLOGY</b>, <b>Clinical Studies</b>].</p><h4>Geriatric Use</h4><p>Clinical trials of ZIAGEN did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of ZIAGEN in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.</p><h4>Patients With Impaired Hepatic Function</h4><p>A dose reduction is required for patients with mild hepatic impairment (Child-Pugh Class A) [see <b>DOSAGE AND ADMINISTRATION</b>]. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate or severe hepatic impairment; therefore, ZIAGEN is contraindicated in these patients [see <b>CONTRAINDICATIONS</b>, <b>CLINICAL PHARMACOLOGY</b>].</p> </div> </div> </div> | 3 | 2023-02-01 17:38:21 | Abacavir Sulfate (Ziagen) | A | HIV, NNRTIs, Antiretroviral Agents | Ziagen | abacavir sulfate | Ziagen | John P. Cunha, DO, FACOEP |
| 22 | 2023-02-23 11:36:54 | Overdose & Contraindications | <a name="OD"></a><h3>OVERDOSE</h3><p>There is no known specific treatment for overdose with ZIAGEN. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3><p>ZIAGEN is contraindicated in patients:</p><ul><li>who have the HLA-B*5701 allele [see <b>WARNINGS AND PRECAUTIONS</b>].</li><li>with prior hypersensitivity reaction to abacavir [see <b>WARNINGS AND PRECAUTIONS</b>].</li><li>with moderate or severe hepatic impairment [see <b>Use In Specific Populations</b>].</li></ul> </div> </div> </div> | <a name="OD"></a><h3>OVERDOSE</h3><p>There is no known specific treatment for overdose with ZIAGEN. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3><p>ZIAGEN is contraindicated in patients:</p><ul><li>who have the HLA-B*5701 allele [see <b>WARNINGS AND PRECAUTIONS</b>].</li><li>with prior hypersensitivity reaction to abacavir [see <b>WARNINGS AND PRECAUTIONS</b>].</li><li>with moderate or severe hepatic impairment [see <b>Use In Specific Populations</b>].</li></ul> </div> </div> </div> | 3 | 2023-02-01 17:38:21 | Abacavir Sulfate (Ziagen) | A | HIV, NNRTIs, Antiretroviral Agents | Ziagen | abacavir sulfate | Ziagen | John P. Cunha, DO, FACOEP |
| 23 | 2023-02-23 11:36:54 | Clinical Pharmacology | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3><h4>Mechanism Of Action</h4><p>Abacavir is an antiretroviral agent [see <b>Microbiology</b>].</p><h4>Pharmacokinetics</h4><h5>Pharmacokinetics In Adults</h5><p>The pharmacokinetic properties of abacavir were independent of dose over the range of 300 to 1,200 mg per day.</p><p><i>Absorption</i></p><p>Following oral administration, abacavir is rapidly absorbed and extensively distributed. The geometric mean absolute bioavailability of the tablet was 83%. Plasma abacavir AUC was similar following administration of the oral solution or tablets. After oral administration of 300 mg twice daily in 20 subjects, the steady-state peak serum abacavir concentration (Cmax) was 3.0 ± 0.89 mcg per mL (mean ± SD) and AUC(0-12 h) was 6.02 ± 1.73 mcg•hour per mL. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 ± 1.19 mcg per mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg•hour per mL.</p><p><i>Effect of Food</i></p><p>Bioavailability of abacavir tablets was assessed in the fasting and fed states with no significant difference in systemic exposure (AUC∞); therefore, ZIAGEN tablets may be administered with or without food. Systemic exposure to abacavir was comparable after administration of ZIAGEN oral solution and ZIAGEN tablets. Therefore, these products may be used interchangeably.</p><p><i>Distribution</i></p><p>The apparent volume of distribution after IV administration of abacavir was 0.86 ± 0.15 L per kg, suggesting that abacavir distributes into extravascular space. In 3 subjects, the CSF AUC(0-6 h) to plasma abacavir AUC(0-6 h) ratio ranged from 27% to 33%.</p><p>Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes.</p><p><i>Elimination</i></p><p>In single-dose trials, the observed elimination half-life (t<sub>½</sub>) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ± 0.24 L per hour per kg (mean ± SD).</p><p><i>Metabolism</i></p><p>In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and glucuronyl transferase to form the 5'-glucuronide. The metabolites do not have antiviral activity. <i>In vitro</i> experiments reveal that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations.</p><p><i>Excretion</i></p><p>Elimination of abacavir was quantified in a mass balance trial following administration of a 600-mg dose of <sup>14</sup>C-abacavir: 99% of the radioactivity was recovered, 1.2% was excreted in the urine as abacavir, 30% as the 5′-carboxylic acid metabolite, 36% as the 5′-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine. Fecal elimination accounted for 16% of the dose.</p><h4>Specific Populations</h4><h5>Patients With Renal Impairment</h5><p>The pharmacokinetic properties of ZIAGEN have not been determined in patients with impaired renal function. Renal excretion of unchanged abacavir is a minor route of elimination in humans.</p><h5>Patients With Hepatic Impairment</h5><p>The pharmacokinetics of abacavir have been studied in subjects with mild hepatic impairment (Child-Pugh Class A). Results showed that there was a mean increase of 89% in the abacavir AUC and an increase of 58% in the half-life of abacavir after a single dose of 600 mg of abacavir. The AUCs of the metabolites were not modified by mild liver disease; however, the rates of formation and elimination of the metabolites were decreased [see <b>CONTRAINDICATIONS</b>, <b>Use In Specific Populations</b>].</p><h5>Pregnant Women</h5><p>Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery.</p><h5>Pediatric Patients</h5><p>The pharmacokinetics of abacavir have been studied after either single or repeat doses of ZIAGEN in 169 pediatric subjects. Subjects receiving abacavir oral solution according to the recommended dosage regimen achieved plasma concentrations of abacavir similar to adults. Subjects receiving abacavir oral tablets achieved higher plasma concentrations of abacavir than subjects receiving oral solution.</p><p>The pharmacokinetics of abacavir dosed once daily in HIV-1–infected pediatric subjects aged 3 months through 12 years was evaluated in 3 trials (PENTA 13 [n = 14], PENTA 15 [n = 18], and ARROW [n = 36]). All 3 trials were 2-period, crossover, open-label pharmacokinetic trials of twice-versus once-daily dosing of abacavir and lamivudine. For the oral solution as well as the tablet formulation, these 3 trials demonstrated that once-daily dosing provides comparable AUC0-24 to twice-daily dosing of abacavir at the same total daily dose. The mean Cmax was approximately 1.6-to 2.3-fold higher with abacavir once-daily dosing compared with twice-daily dosing.</p><h5>Geriatric Patients</h5><p>The pharmacokinetics of ZIAGEN have not been studied in subjects older than 65 years.</p><h5>Male And Female Patients</h5><p>A population pharmacokinetic analysis in HIV-1–infected male (n = 304) and female (n = 67) subjects showed no gender differences in abacavir AUC normalized for lean body weight.</p><h5>Racial Groups</h5><p>There are no significant or clinically relevant racial differences between blacks and whites in abacavir pharmacokinetics.</p><h4>Drug Interaction Studies</h4><h5>Effect Of Abacavir On The Pharmacokinetics Of Other Agents</h5><p><i>In vitro</i> studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4. Abacavir did not inhibit or induce other CYP enzymes (such as CYP2C9, or CYP2D6).</p><p>Based on <i>in vitro</i> study results, abacavir at therapeutic drug exposures is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide (OATP)1B1/3, breast cancer resistance protein (BCRP) or Pglycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.</p><h5>Riociguat</h5><p>Coadministration of a single dose of riociguat (0.5 mg) to HIV-1–infected subjects receiving fixed-dose abacavir/dolutegravir/lamivudine is reported to increase riociguat AUC(∞) compared with riociguat AUC(∞) reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see <b>DRUG INTERACTIONS</b>].</p><h5>Effect Of Other Agents On The Pharmacokinetics Of Abacavir</h5><p><i>In vitro</i>, abacavir is not a substrate of OATP1B1, OAP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein (MRP)2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is a substrate of BCRP and P-gp <i>in vitro</i>; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations.</p><h5>Lamivudine And/Or Zidovudine</h5><p>Fifteen HIV-1–infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.</p><h5>Ethanol</h5><p>Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure. Due to the common metabolic pathways of abacavir and ethanol via alcohol dehydrogenase, the pharmacokinetic interaction between abacavir and ethanol was studied in 24 HIV-1–infected male subjects. Each subject received the following treatments on separate occasions: a single 600-mg dose of abacavir, 0.7 g per kg ethanol (equivalent to 5 alcoholic drinks), and abacavir 600 mg plus 0.7 g per kg ethanol. Coadministration of ethanol and abacavir resulted in a 41% increase in abacavir AUC∞ and a 26% increase in abacavir t<sub>½</sub>. Abacavir had no effect on the pharmacokinetic properties of ethanol, so no clinically significant interaction is expected in men. This interaction has not been studied in females.</p><h5>Methadone</h5><p>In a trial of 11 HIV-1–infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients [see <b>DRUG INTERACTIONS</b>]. The addition of methadone had no clinically significant effect on the pharmacokinetic properties of abacavir.</p><h4>Microbiology</h4><p>Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5'-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.</p><h5>Antiviral Activity</h5><p>The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC<sub>50</sub> values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC<sub>50</sub> value was 0.26 ± 0.18 microM against 8 clinical isolates. The median EC<sub>50</sub> values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC<sub>50</sub> values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM. The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir. Ribavirin (50 microM) used in the treatment of chronic HCV infection had no effect on the anti–HIV-1 activity of abacavir in cell culture.</p><h5>Resistance</h5><p>HIV-1 isolates with reduced susceptibility to abacavir have been selected in cell culture. Genotypic analysis of isolates selected in cell culture and recovered from abacavir-treated subjects demonstrated that amino acid substitutions K65R, L74V, Y115F, and M184V/I emerged in HIV-1 RT. M184V or I substitutions resulted in an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.</p><p>Thirty-nine percent (7 of 18) of the isolates from subjects who experienced virologic failure in the abacavir once-daily arm had a greater than 2.5-fold mean decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range: 0.5 to 11) compared with 29% (5 of 17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range: 0.7 to 13).</p><h5>Cross-Resistance</h5><p>Cross-resistance has been observed among NRTIs. Isolates containing abacavir resistance-associated substitutions, namely, K65R, L74V, Y115F, and M184V, exhibited cross-resistance to didanosine, emtricitabine, lamivudine, and tenofovir in cell culture and in subjects. An increasing number of thymidine analogue mutation substitutions (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) is associated with a progressive reduction in abacavir susceptibility.</p> <a name="AP"></a><h4>Animal Toxicology And/Or Pharmacology</h4><p>Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.</p> <a name="CS"></a><h4>Clinical Studies</h4><h4>Adult Trials</h4><h5>Therapy-Naive Adults</h5><p>CNA30024 was a multicenter, double-blind, controlled trial in which 649 HIV-1–infected, therapy-naive adults were randomized and received either ZIAGEN (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily). The duration of double-blind treatment was at least 48 weeks. Trial participants were male (81%), white (51%), black (21%), and Hispanic (26%). The median age was 35 years; the median pretreatment CD4+ cell count was 264 cells per mm<sup>3</sup>, and median plasma HIV-1 RNA was 4.79 log<sub>10</sub> copies per mL. The outcomes of randomized treatment are provided in Table 7.</p><p align="center"><b>Table 7. Outcomes of Randomized Treatment through Week 48 (CNA30024)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Outcome</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine plus Efavirenz<br />(n = 324)</td><td class="EmphTd" width="25%">Zidovudine plus Lamivudine plus Efavirenz<br />(n = 325)</td></tr><tr><td>Responder<sup>a</sup></td><td align="center">69% (73%)</td><td align="center">69% (71%)</td></tr><tr><td>Virologic failures<sup>b</sup></td><td align="center">6%</td><td align="center">4%</td></tr><tr><td>Discontinued due to adverse reactions</td><td align="center">14%</td><td align="center">16%</td></tr><tr><td>Discontinued due to other reasons<sup>c</sup></td><td align="center">10%</td><td align="center">11%</td></tr><tr><td class="credit" colspan="3"><sup>a</sup> Subjects achieved and maintained confirmed HIV-1 RNA less than or equal to 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test 1.0 PCR).<br /><sup>b</sup> Includes viral rebound, insufficient viral response according to the investigator, and failure to achieve confirmed less than or equal to 50 copies per mL by Week 48.<br /><sup>c</sup> Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, clinical progression, and other.</td></tr></tbody></table></center><p></p><p>After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 209 cells per mm<sup>3</sup> in the group receiving ZIAGEN and 155 cells per mm<sup>3</sup> in the zidovudine group. Through Week 48, 8 subjects (2%) in the group receiving ZIAGEN (5 CDC classification C events and 3 deaths) and 5 subjects (2%) on the zidovudine arm (3 CDC classification C events and 2 deaths) experienced clinical disease progression.</p><p>CNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV-1–infected, therapy-naive adults were randomized to receive either ZIAGEN (300 mg twice daily) plus COMBIVIR (lamivudine 150 mg/zidovudine 300 mg twice daily), or indinavir (800 mg 3 times a day) plus COMBIVIR twice daily. The trial was stratified at randomization by pre-entry plasma HIV-1 RNA 10,000 to 100,000 copies per mL and plasma HIV-1 RNA greater than 100,000 copies per mL. Trial participants were male (87%), white (73%), black (15%), and Hispanic (9%). At baseline the median age was 36 years; the median baseline CD4+ cell count was 360 cells per mm<sup>3</sup>, and median baseline plasma HIV-1 RNA was 4.8 log<sub>10</sub> copies per mL. Proportions of subjects with plasma HIV-1 RNA less than 400 copies per mL (using Roche AMPLICOR HIV-1 MONITOR Test) through 48 weeks of treatment are summarized in Table 8.</p><p align="center"><b>Table 8. Outcomes of Randomized Treatment through Week 48 (CNA3005)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Outcome</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine/ Zidovudine<br />(n = 262)</td><td class="EmphTd" width="25%">Indinavir plus Lamivudine/ Zidovudine<br />(n = 265)</td></tr><tr><td>Responder<sup>a</sup></td><td align="center">49%</td><td align="center">50%</td></tr><tr><td>Virologic failure<sup>b</sup></td><td align="center">31%</td><td align="center">28%</td></tr><tr><td>Discontinued due to adverse reactions</td><td align="center">10%</td><td align="center">12%</td></tr><tr><td>Discontinued due to other reasons<sup>c</sup></td><td align="center">11%</td><td align="center">10%</td></tr><tr><td class="credit" colspan="3"><sup>a</sup> Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL.<br /><sup>b</sup> Includes viral rebound and failure to achieve confirmed less than 400 copies per mL by Week 48.<br /><sup>c</sup> Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, clinical progression, and other.</td></tr></tbody></table></center><p></p><p>Treatment response by plasma HIV-1 RNA strata is shown in Table 9.</p><p align="center"><b>Table 9. Proportions of Responders through Week 48 by Screening Plasma HIV-1 RNA Levels (CNA3005)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" rowspan="2" width="40%">Screening HIV-1 RNA (copies/mL)</td><td class="EmphTd" colspan="2">ZIAGEN plus Lamivudine /Zidovudine<br />(n = 262)</td><td class="EmphTd" colspan="2">Indinavir plus Lamivudine /Zidovudine<br />(n = 265)</td></tr><tr><td class="EmphTd" width="20%"><400 copies/mL</td><td class="EmphTd" width="10%">n</td><td class="EmphTd" width="20%"><400 copies/mL</td><td class="EmphTd" width="10%">n</td></tr><tr><td>≥10,000 -≤100,000</td><td align="center">50%</td><td align="center">166</td><td align="center">48%</td><td align="center">165</td></tr><tr><td>>100,000</td><td align="center">48%</td><td align="center">96</td><td align="center">52%</td><td align="center">100</td></tr></tbody></table></center><p></p><p>In subjects with baseline viral load greater than 100,000 copies per mL, percentages of subjects with HIV-1 RNA levels less than 50 copies per mL were 31% in the group receiving abacavir versus 45% in the group receiving indinavir.</p><p>Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells per mm<sup>3</sup> was observed in both treatment arms. Through Week 48, 9 subjects (3.4%) in the group receiving abacavir (6 CDC classification C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir (2 CDC classification C events and 1 death) experienced clinical disease progression.</p><p>CNA30021 was an international, multicenter, double-blind, controlled trial in which 770 HIV-1– infected, therapy-naive adults were randomized and received either abacavir 600 mg once daily or abacavir 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had a mean age of 37 years; were male (81%), white (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells per mm<sup>3</sup> (range: 21 to 918 cells per mm<sup>3</sup>) and the median baseline plasma HIV-1 RNA was 4.89 log<sub>10</sub> copies per mL (range: 2.60 to 6.99 log<sub>10</sub> copies per mL).</p><p>The outcomes of randomized treatment are provided in Table 10.</p><p align="center"><b>Table 10. Outcomes of Randomized Treatment through Week 48 (CNA30021)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="40%">Outcome</td><td class="EmphTd" width="30%">ZIAGEN 600 mg q.d. plus EPIVIR plus Efavirenz<br />(n = 384)</td><td class="EmphTd" width="30%">ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz<br />(n = 386)</td></tr><tr><td>Responder<sup>a</sup></td><td align="center">64% (71%)</td><td align="center">65% (72%)</td></tr><tr><td>Virologic failure<sup>b</sup></td><td align="center">11% (5%)</td><td align="center">11% (5%)</td></tr><tr><td>Discontinued due to adverse reactions</td><td align="center">13%</td><td align="center">11%</td></tr><tr><td>Discontinued due to other reasons<sup>c</sup></td><td align="center">11%</td><td align="center">13%</td></tr><tr><td class="credit" colspan="3"><p><sup>a</sup> Subjects achieved and maintained confirmed HIV-1 RNA less than 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test version 1.0).<br /><sup>b</sup> Includes viral rebound, failure to achieve confirmed less than 50 copies per mL (less than 400 copies per mL) by Week 48, and insufficient viral load response.<br /><sup>c</sup> Includes consent withdrawn, lost to follow up, protocol violations, clinical progression, and other.</p></td></tr></tbody></table></center><p></p><p>After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells per mm<sup>3</sup> in the group receiving abacavir 600 mg once daily and 200 cells per mm<sup>3</sup> in the group receiving abacavir 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications.</p><h4>Pediatric Trials</h4><h5>Therapy-Experienced Pediatric Subjects</h5><p>CNA3006 was a randomized, double-blind trial comparing ZIAGEN 8 mg per kg twice daily plus lamivudine 4 mg per kg twice daily plus zidovudine 180 mg per m<sup>2</sup> twice daily versus lamivudine 4 mg per kg twice daily plus zidovudine 180 mg per m<sup>2</sup> twice daily. Two hundred and five therapy-experienced pediatric subjects were enrolled: female (56%), white (17%), black (50%), Hispanic (30%), median age of 5.4 years, baseline CD4+ cell percent greater than 15% (median = 27%), and median baseline plasma HIV-1 RNA of 4.6 log<sub>10</sub> copies per mL. Eighty percent and 55% of subjects had prior therapy with zidovudine and lamivudine, respectively, most often in combination. The median duration of prior nucleoside analogue therapy was 2 years. At 16 weeks, the proportion of subjects responding based on plasma HIV-1 RNA less than or equal to 400 copies per mL was significantly higher in subjects receiving ZIAGEN plus lamivudine plus zidovudine compared with subjects receiving lamivudine plus zidovudine, 13% versus 2%, respectively. Median plasma HIV-1 RNA changes from baseline were -0.53 log<sub>10</sub> copies per mL in the group receiving ZIAGEN plus lamivudine plus zidovudine compared with -0.21 log<sub>10</sub> copies per mL in the group receiving lamivudine plus zidovudine. Median CD4+ cell count increases from baseline were 69 cells per mm<sup>3</sup> in the group receiving ZIAGEN plus lamivudine plus zidovudine and 9 cells per mm<sup>3</sup> in the group receiving lamivudine plus zidovudine.</p><h5>Once-Daily Dosing</h5><p>ARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1–infected, treatment-naive subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing ZIAGEN and lamivudine, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks of treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of ZIAGEN and lamivudine, in combination with a third antiretroviral drug, for an additional 96 weeks. Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Virologic suppression was not a requirement for participation at baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed compared with 71% of subjects in the once-daily cohort.</p><p>The proportions of subjects with HIV-1 RNA less than 80 copies per mL through 96 weeks are shown in Table 11. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.</p><p align="center"><b>Table 11. Virologic Outcome of Randomized Treatment at Week 96<sup>a</sup> (ARROW Randomization 3)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Outcome</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine Twice-Daily Dosing<br />(n = 333)</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine Once-Daily Dosing<br />(n = 336)</td></tr><tr><td><b>HIV-1 RNA <80 copies/mL<sup>b</sup></b></td><td align="center">70%</td><td align="center">67%</td></tr><tr><td><b>HIV-1 RNA ≥80 copies/mL<sup>c</sup></b></td><td align="center">28%</td><td align="center">31%</td></tr><tr><td colspan="3"><b>No virologic data</b></td></tr><tr><td> Discontinued due to adverse event or death</td><td align="center">1%</td><td align="center"><1%</td></tr><tr><td> Discontinued study for other reasons<sup>d</sup></td><td align="center">0%</td><td align="center"><1%</td></tr><tr><td> Missing data during window but on study</td><td align="center">1%</td><td align="center">1%</td></tr><tr><td class="credit" colspan="3"><sup>a</sup> Analyses were based on the last observed viral load data within the Week 96 window.<br /><sup>b</sup> Predicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96.<br /><sup>c</sup> Includes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and who had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol.<br /><sup>d</sup> Other includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing).</td></tr></tbody></table></center><p></p> </div> </div> </div> | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3><h4>Mechanism Of Action</h4><p>Abacavir is an antiretroviral agent [see <b>Microbiology</b>].</p><h4>Pharmacokinetics</h4><h5>Pharmacokinetics In Adults</h5><p>The pharmacokinetic properties of abacavir were independent of dose over the range of 300 to 1,200 mg per day.</p><p><i>Absorption</i></p><p>Following oral administration, abacavir is rapidly absorbed and extensively distributed. The geometric mean absolute bioavailability of the tablet was 83%. Plasma abacavir AUC was similar following administration of the oral solution or tablets. After oral administration of 300 mg twice daily in 20 subjects, the steady-state peak serum abacavir concentration (Cmax) was 3.0 ± 0.89 mcg per mL (mean ± SD) and AUC(0-12 h) was 6.02 ± 1.73 mcg•hour per mL. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 ± 1.19 mcg per mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg•hour per mL.</p><p><i>Effect of Food</i></p><p>Bioavailability of abacavir tablets was assessed in the fasting and fed states with no significant difference in systemic exposure (AUC∞); therefore, ZIAGEN tablets may be administered with or without food. Systemic exposure to abacavir was comparable after administration of ZIAGEN oral solution and ZIAGEN tablets. Therefore, these products may be used interchangeably.</p><p><i>Distribution</i></p><p>The apparent volume of distribution after IV administration of abacavir was 0.86 ± 0.15 L per kg, suggesting that abacavir distributes into extravascular space. In 3 subjects, the CSF AUC(0-6 h) to plasma abacavir AUC(0-6 h) ratio ranged from 27% to 33%.</p><p>Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes.</p><p><i>Elimination</i></p><p>In single-dose trials, the observed elimination half-life (t<sub>½</sub>) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ± 0.24 L per hour per kg (mean ± SD).</p><p><i>Metabolism</i></p><p>In humans, abacavir is not significantly metabolized by cytochrome P450 enzymes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and glucuronyl transferase to form the 5'-glucuronide. The metabolites do not have antiviral activity. <i>In vitro</i> experiments reveal that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations.</p><p><i>Excretion</i></p><p>Elimination of abacavir was quantified in a mass balance trial following administration of a 600-mg dose of <sup>14</sup>C-abacavir: 99% of the radioactivity was recovered, 1.2% was excreted in the urine as abacavir, 30% as the 5′-carboxylic acid metabolite, 36% as the 5′-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine. Fecal elimination accounted for 16% of the dose.</p><h4>Specific Populations</h4><h5>Patients With Renal Impairment</h5><p>The pharmacokinetic properties of ZIAGEN have not been determined in patients with impaired renal function. Renal excretion of unchanged abacavir is a minor route of elimination in humans.</p><h5>Patients With Hepatic Impairment</h5><p>The pharmacokinetics of abacavir have been studied in subjects with mild hepatic impairment (Child-Pugh Class A). Results showed that there was a mean increase of 89% in the abacavir AUC and an increase of 58% in the half-life of abacavir after a single dose of 600 mg of abacavir. The AUCs of the metabolites were not modified by mild liver disease; however, the rates of formation and elimination of the metabolites were decreased [see <b>CONTRAINDICATIONS</b>, <b>Use In Specific Populations</b>].</p><h5>Pregnant Women</h5><p>Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in postpartum and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in neonatal plasma cord samples at birth were essentially equal to those in maternal plasma at delivery.</p><h5>Pediatric Patients</h5><p>The pharmacokinetics of abacavir have been studied after either single or repeat doses of ZIAGEN in 169 pediatric subjects. Subjects receiving abacavir oral solution according to the recommended dosage regimen achieved plasma concentrations of abacavir similar to adults. Subjects receiving abacavir oral tablets achieved higher plasma concentrations of abacavir than subjects receiving oral solution.</p><p>The pharmacokinetics of abacavir dosed once daily in HIV-1–infected pediatric subjects aged 3 months through 12 years was evaluated in 3 trials (PENTA 13 [n = 14], PENTA 15 [n = 18], and ARROW [n = 36]). All 3 trials were 2-period, crossover, open-label pharmacokinetic trials of twice-versus once-daily dosing of abacavir and lamivudine. For the oral solution as well as the tablet formulation, these 3 trials demonstrated that once-daily dosing provides comparable AUC0-24 to twice-daily dosing of abacavir at the same total daily dose. The mean Cmax was approximately 1.6-to 2.3-fold higher with abacavir once-daily dosing compared with twice-daily dosing.</p><h5>Geriatric Patients</h5><p>The pharmacokinetics of ZIAGEN have not been studied in subjects older than 65 years.</p><h5>Male And Female Patients</h5><p>A population pharmacokinetic analysis in HIV-1–infected male (n = 304) and female (n = 67) subjects showed no gender differences in abacavir AUC normalized for lean body weight.</p><h5>Racial Groups</h5><p>There are no significant or clinically relevant racial differences between blacks and whites in abacavir pharmacokinetics.</p><h4>Drug Interaction Studies</h4><h5>Effect Of Abacavir On The Pharmacokinetics Of Other Agents</h5><p><i>In vitro</i> studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4. Abacavir did not inhibit or induce other CYP enzymes (such as CYP2C9, or CYP2D6).</p><p>Based on <i>in vitro</i> study results, abacavir at therapeutic drug exposures is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide (OATP)1B1/3, breast cancer resistance protein (BCRP) or Pglycoprotein (P-gp), organic cation transporter (OCT)1, OCT2, or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.</p><h5>Riociguat</h5><p>Coadministration of a single dose of riociguat (0.5 mg) to HIV-1–infected subjects receiving fixed-dose abacavir/dolutegravir/lamivudine is reported to increase riociguat AUC(∞) compared with riociguat AUC(∞) reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see <b>DRUG INTERACTIONS</b>].</p><h5>Effect Of Other Agents On The Pharmacokinetics Of Abacavir</h5><p><i>In vitro</i>, abacavir is not a substrate of OATP1B1, OAP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein (MRP)2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is a substrate of BCRP and P-gp <i>in vitro</i>; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations.</p><h5>Lamivudine And/Or Zidovudine</h5><p>Fifteen HIV-1–infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.</p><h5>Ethanol</h5><p>Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure. Due to the common metabolic pathways of abacavir and ethanol via alcohol dehydrogenase, the pharmacokinetic interaction between abacavir and ethanol was studied in 24 HIV-1–infected male subjects. Each subject received the following treatments on separate occasions: a single 600-mg dose of abacavir, 0.7 g per kg ethanol (equivalent to 5 alcoholic drinks), and abacavir 600 mg plus 0.7 g per kg ethanol. Coadministration of ethanol and abacavir resulted in a 41% increase in abacavir AUC∞ and a 26% increase in abacavir t<sub>½</sub>. Abacavir had no effect on the pharmacokinetic properties of ethanol, so no clinically significant interaction is expected in men. This interaction has not been studied in females.</p><h5>Methadone</h5><p>In a trial of 11 HIV-1–infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%). This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients [see <b>DRUG INTERACTIONS</b>]. The addition of methadone had no clinically significant effect on the pharmacokinetic properties of abacavir.</p><h4>Microbiology</h4><p>Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5'-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.</p><h5>Antiviral Activity</h5><p>The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC<sub>50</sub> values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC<sub>50</sub> value was 0.26 ± 0.18 microM against 8 clinical isolates. The median EC<sub>50</sub> values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC<sub>50</sub> values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM. The antiviral activity of abacavir in cell culture was not antagonized when combined with the nucleoside reverse transcriptase inhibitors (NRTIs) didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine or zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, or the protease inhibitor (PI) amprenavir. Ribavirin (50 microM) used in the treatment of chronic HCV infection had no effect on the anti–HIV-1 activity of abacavir in cell culture.</p><h5>Resistance</h5><p>HIV-1 isolates with reduced susceptibility to abacavir have been selected in cell culture. Genotypic analysis of isolates selected in cell culture and recovered from abacavir-treated subjects demonstrated that amino acid substitutions K65R, L74V, Y115F, and M184V/I emerged in HIV-1 RT. M184V or I substitutions resulted in an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.</p><p>Thirty-nine percent (7 of 18) of the isolates from subjects who experienced virologic failure in the abacavir once-daily arm had a greater than 2.5-fold mean decrease in abacavir susceptibility with a median-fold decrease of 1.3 (range: 0.5 to 11) compared with 29% (5 of 17) of the failure isolates in the twice-daily arm with a median-fold decrease of 0.92 (range: 0.7 to 13).</p><h5>Cross-Resistance</h5><p>Cross-resistance has been observed among NRTIs. Isolates containing abacavir resistance-associated substitutions, namely, K65R, L74V, Y115F, and M184V, exhibited cross-resistance to didanosine, emtricitabine, lamivudine, and tenofovir in cell culture and in subjects. An increasing number of thymidine analogue mutation substitutions (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) is associated with a progressive reduction in abacavir susceptibility.</p> <a name="AP"></a><h4>Animal Toxicology And/Or Pharmacology</h4><p>Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.</p> <a name="CS"></a><h4>Clinical Studies</h4><h4>Adult Trials</h4><h5>Therapy-Naive Adults</h5><p>CNA30024 was a multicenter, double-blind, controlled trial in which 649 HIV-1–infected, therapy-naive adults were randomized and received either ZIAGEN (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and efavirenz (600 mg once daily). The duration of double-blind treatment was at least 48 weeks. Trial participants were male (81%), white (51%), black (21%), and Hispanic (26%). The median age was 35 years; the median pretreatment CD4+ cell count was 264 cells per mm<sup>3</sup>, and median plasma HIV-1 RNA was 4.79 log<sub>10</sub> copies per mL. The outcomes of randomized treatment are provided in Table 7.</p><p align="center"><b>Table 7. Outcomes of Randomized Treatment through Week 48 (CNA30024)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Outcome</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine plus Efavirenz<br />(n = 324)</td><td class="EmphTd" width="25%">Zidovudine plus Lamivudine plus Efavirenz<br />(n = 325)</td></tr><tr><td>Responder<sup>a</sup></td><td align="center">69% (73%)</td><td align="center">69% (71%)</td></tr><tr><td>Virologic failures<sup>b</sup></td><td align="center">6%</td><td align="center">4%</td></tr><tr><td>Discontinued due to adverse reactions</td><td align="center">14%</td><td align="center">16%</td></tr><tr><td>Discontinued due to other reasons<sup>c</sup></td><td align="center">10%</td><td align="center">11%</td></tr><tr><td class="credit" colspan="3"><sup>a</sup> Subjects achieved and maintained confirmed HIV-1 RNA less than or equal to 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test 1.0 PCR).<br /><sup>b</sup> Includes viral rebound, insufficient viral response according to the investigator, and failure to achieve confirmed less than or equal to 50 copies per mL by Week 48.<br /><sup>c</sup> Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, clinical progression, and other.</td></tr></tbody></table></center><p></p><p>After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 209 cells per mm<sup>3</sup> in the group receiving ZIAGEN and 155 cells per mm<sup>3</sup> in the zidovudine group. Through Week 48, 8 subjects (2%) in the group receiving ZIAGEN (5 CDC classification C events and 3 deaths) and 5 subjects (2%) on the zidovudine arm (3 CDC classification C events and 2 deaths) experienced clinical disease progression.</p><p>CNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV-1–infected, therapy-naive adults were randomized to receive either ZIAGEN (300 mg twice daily) plus COMBIVIR (lamivudine 150 mg/zidovudine 300 mg twice daily), or indinavir (800 mg 3 times a day) plus COMBIVIR twice daily. The trial was stratified at randomization by pre-entry plasma HIV-1 RNA 10,000 to 100,000 copies per mL and plasma HIV-1 RNA greater than 100,000 copies per mL. Trial participants were male (87%), white (73%), black (15%), and Hispanic (9%). At baseline the median age was 36 years; the median baseline CD4+ cell count was 360 cells per mm<sup>3</sup>, and median baseline plasma HIV-1 RNA was 4.8 log<sub>10</sub> copies per mL. Proportions of subjects with plasma HIV-1 RNA less than 400 copies per mL (using Roche AMPLICOR HIV-1 MONITOR Test) through 48 weeks of treatment are summarized in Table 8.</p><p align="center"><b>Table 8. Outcomes of Randomized Treatment through Week 48 (CNA3005)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Outcome</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine/ Zidovudine<br />(n = 262)</td><td class="EmphTd" width="25%">Indinavir plus Lamivudine/ Zidovudine<br />(n = 265)</td></tr><tr><td>Responder<sup>a</sup></td><td align="center">49%</td><td align="center">50%</td></tr><tr><td>Virologic failure<sup>b</sup></td><td align="center">31%</td><td align="center">28%</td></tr><tr><td>Discontinued due to adverse reactions</td><td align="center">10%</td><td align="center">12%</td></tr><tr><td>Discontinued due to other reasons<sup>c</sup></td><td align="center">11%</td><td align="center">10%</td></tr><tr><td class="credit" colspan="3"><sup>a</sup> Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL.<br /><sup>b</sup> Includes viral rebound and failure to achieve confirmed less than 400 copies per mL by Week 48.<br /><sup>c</sup> Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, clinical progression, and other.</td></tr></tbody></table></center><p></p><p>Treatment response by plasma HIV-1 RNA strata is shown in Table 9.</p><p align="center"><b>Table 9. Proportions of Responders through Week 48 by Screening Plasma HIV-1 RNA Levels (CNA3005)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" rowspan="2" width="40%">Screening HIV-1 RNA (copies/mL)</td><td class="EmphTd" colspan="2">ZIAGEN plus Lamivudine /Zidovudine<br />(n = 262)</td><td class="EmphTd" colspan="2">Indinavir plus Lamivudine /Zidovudine<br />(n = 265)</td></tr><tr><td class="EmphTd" width="20%"><400 copies/mL</td><td class="EmphTd" width="10%">n</td><td class="EmphTd" width="20%"><400 copies/mL</td><td class="EmphTd" width="10%">n</td></tr><tr><td>≥10,000 -≤100,000</td><td align="center">50%</td><td align="center">166</td><td align="center">48%</td><td align="center">165</td></tr><tr><td>>100,000</td><td align="center">48%</td><td align="center">96</td><td align="center">52%</td><td align="center">100</td></tr></tbody></table></center><p></p><p>In subjects with baseline viral load greater than 100,000 copies per mL, percentages of subjects with HIV-1 RNA levels less than 50 copies per mL were 31% in the group receiving abacavir versus 45% in the group receiving indinavir.</p><p>Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells per mm<sup>3</sup> was observed in both treatment arms. Through Week 48, 9 subjects (3.4%) in the group receiving abacavir (6 CDC classification C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir (2 CDC classification C events and 1 death) experienced clinical disease progression.</p><p>CNA30021 was an international, multicenter, double-blind, controlled trial in which 770 HIV-1– infected, therapy-naive adults were randomized and received either abacavir 600 mg once daily or abacavir 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had a mean age of 37 years; were male (81%), white (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells per mm<sup>3</sup> (range: 21 to 918 cells per mm<sup>3</sup>) and the median baseline plasma HIV-1 RNA was 4.89 log<sub>10</sub> copies per mL (range: 2.60 to 6.99 log<sub>10</sub> copies per mL).</p><p>The outcomes of randomized treatment are provided in Table 10.</p><p align="center"><b>Table 10. Outcomes of Randomized Treatment through Week 48 (CNA30021)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="40%">Outcome</td><td class="EmphTd" width="30%">ZIAGEN 600 mg q.d. plus EPIVIR plus Efavirenz<br />(n = 384)</td><td class="EmphTd" width="30%">ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz<br />(n = 386)</td></tr><tr><td>Responder<sup>a</sup></td><td align="center">64% (71%)</td><td align="center">65% (72%)</td></tr><tr><td>Virologic failure<sup>b</sup></td><td align="center">11% (5%)</td><td align="center">11% (5%)</td></tr><tr><td>Discontinued due to adverse reactions</td><td align="center">13%</td><td align="center">11%</td></tr><tr><td>Discontinued due to other reasons<sup>c</sup></td><td align="center">11%</td><td align="center">13%</td></tr><tr><td class="credit" colspan="3"><p><sup>a</sup> Subjects achieved and maintained confirmed HIV-1 RNA less than 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test version 1.0).<br /><sup>b</sup> Includes viral rebound, failure to achieve confirmed less than 50 copies per mL (less than 400 copies per mL) by Week 48, and insufficient viral load response.<br /><sup>c</sup> Includes consent withdrawn, lost to follow up, protocol violations, clinical progression, and other.</p></td></tr></tbody></table></center><p></p><p>After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells per mm<sup>3</sup> in the group receiving abacavir 600 mg once daily and 200 cells per mm<sup>3</sup> in the group receiving abacavir 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications.</p><h4>Pediatric Trials</h4><h5>Therapy-Experienced Pediatric Subjects</h5><p>CNA3006 was a randomized, double-blind trial comparing ZIAGEN 8 mg per kg twice daily plus lamivudine 4 mg per kg twice daily plus zidovudine 180 mg per m<sup>2</sup> twice daily versus lamivudine 4 mg per kg twice daily plus zidovudine 180 mg per m<sup>2</sup> twice daily. Two hundred and five therapy-experienced pediatric subjects were enrolled: female (56%), white (17%), black (50%), Hispanic (30%), median age of 5.4 years, baseline CD4+ cell percent greater than 15% (median = 27%), and median baseline plasma HIV-1 RNA of 4.6 log<sub>10</sub> copies per mL. Eighty percent and 55% of subjects had prior therapy with zidovudine and lamivudine, respectively, most often in combination. The median duration of prior nucleoside analogue therapy was 2 years. At 16 weeks, the proportion of subjects responding based on plasma HIV-1 RNA less than or equal to 400 copies per mL was significantly higher in subjects receiving ZIAGEN plus lamivudine plus zidovudine compared with subjects receiving lamivudine plus zidovudine, 13% versus 2%, respectively. Median plasma HIV-1 RNA changes from baseline were -0.53 log<sub>10</sub> copies per mL in the group receiving ZIAGEN plus lamivudine plus zidovudine compared with -0.21 log<sub>10</sub> copies per mL in the group receiving lamivudine plus zidovudine. Median CD4+ cell count increases from baseline were 69 cells per mm<sup>3</sup> in the group receiving ZIAGEN plus lamivudine plus zidovudine and 9 cells per mm<sup>3</sup> in the group receiving lamivudine plus zidovudine.</p><h5>Once-Daily Dosing</h5><p>ARROW (COL105677) was a 5-year randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1–infected, treatment-naive subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing ZIAGEN and lamivudine, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks of treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of ZIAGEN and lamivudine, in combination with a third antiretroviral drug, for an additional 96 weeks. Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Virologic suppression was not a requirement for participation at baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed compared with 71% of subjects in the once-daily cohort.</p><p>The proportions of subjects with HIV-1 RNA less than 80 copies per mL through 96 weeks are shown in Table 11. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.</p><p align="center"><b>Table 11. Virologic Outcome of Randomized Treatment at Week 96<sup>a</sup> (ARROW Randomization 3)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Outcome</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine Twice-Daily Dosing<br />(n = 333)</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine Once-Daily Dosing<br />(n = 336)</td></tr><tr><td><b>HIV-1 RNA <80 copies/mL<sup>b</sup></b></td><td align="center">70%</td><td align="center">67%</td></tr><tr><td><b>HIV-1 RNA ≥80 copies/mL<sup>c</sup></b></td><td align="center">28%</td><td align="center">31%</td></tr><tr><td colspan="3"><b>No virologic data</b></td></tr><tr><td> Discontinued due to adverse event or death</td><td align="center">1%</td><td align="center"><1%</td></tr><tr><td> Discontinued study for other reasons<sup>d</sup></td><td align="center">0%</td><td align="center"><1%</td></tr><tr><td> Missing data during window but on study</td><td align="center">1%</td><td align="center">1%</td></tr><tr><td class="credit" colspan="3"><sup>a</sup> Analyses were based on the last observed viral load data within the Week 96 window.<br /><sup>b</sup> Predicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96.<br /><sup>c</sup> Includes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and who had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol.<br /><sup>d</sup> Other includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing).</td></tr></tbody></table></center><p></p> </div> </div> </div> | 3 | 2023-02-01 17:38:21 | Abacavir Sulfate (Ziagen) | A | HIV, NNRTIs, Antiretroviral Agents | Ziagen | abacavir sulfate | Ziagen | John P. Cunha, DO, FACOEP |
| 24 | 2023-02-23 12:07:03 | Medication Guide | <a name="PI"></a><h3>PATIENT INFORMATION</h3><p><b>ZIAGEN</b><br />(ZY-uh-jen)<br />(abacavir) tablets, for oral use</p><p><b>ZIAGEN</b><br />(ZY-uh-jen)<br />(abacavir) oral solution</p><p><b>What is the most important information I should know about ZIAGEN?</b></p><p><b>ZIAGEN can cause serious side effects, including:</b></p><p><b>If you get a symptom from 2 or more of the following groups while taking ZIAGEN, call your healthcare provider right away to find out if you should stop taking ZIAGEN.</b></p><p></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="15%"></td><td class="EmphTd" width="85%">Symptom(s)</td></tr><tr><td><b>Group 1</b></td><td><b>Fever</b></td></tr><tr><td><b>Group 2 </b></td><td><b>Rash</b></td></tr><tr><td><b>Group 3 </b></td><td><b>Nausea, vomiting, diarrhea, abdominal (stomach area) pain</b></td></tr><tr><td><b>Group 4 </b></td><td><b>Generally ill feeling, extreme tiredness, or achiness</b></td></tr><tr><td><b>Group 5 </b></td><td><b>Shortness of breath, cough, sore throat</b></td></tr></tbody></table></center><p>A list of these symptoms is on the Warning Card your pharmacist gives you. <b>Carry this Warning Card with you at all times.</b></p><p><b>If you stop ZIAGEN because of an allergic reaction, never take ZIAGEN (abacavir) or any other abacavir-containing medicine (EPZICOM, TRIUMEQ, or TRIZIVIR) again.</b></p><ul><li><b>Serious allergic reactions (hypersensitivity reaction)</b> that can cause death have happened with ZIAGEN and other abacavir-containing products. Your risk of this allergic reaction is much higher if you have a gene variation called <a href="/hla/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HLA</a>-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.<ul><li>If you have an allergic reaction, dispose of any unused ZIAGEN. Ask your pharmacist how to properly dispose of medicines.</li><li>If you take ZIAGEN or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get <b>life-threatening symptoms</b> that may include <b>very low blood pressure or death.</b></li><li>If you stop ZIAGEN for any other reason, even for a few days, and you are not allergic to ZIAGEN, talk with your healthcare provider before taking it again. Taking ZIAGEN again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.</li></ul></li></ul><p><b>If your healthcare provider tells you that you can take ZIAGEN again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.</b></p><p><b>What is ZIAGEN?</b></p><p>ZIAGEN is a prescription HIV-1 (<a href="/human_immunodeficiency_virus_hiv/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Human Immunodeficiency Virus</a> type 1) medicine used with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes <a href="/acquired/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Acquired</a> Immune Deficiency Syndrome (<a href="/acquired_immunodeficiency_syndrome_aids/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">AIDS</a>).</p><p>The safety and effectiveness of ZIAGEN has not been established in children under 3 months of age.</p><p><b>When used with other antiretroviral medicines to treat HIV-1 infection, ZIAGEN may help:</b></p><ul><li>reduce the amount of HIV-1 in your blood. This is called “viral load”.</li><li>increase the number of CD4+ (T) cells in your blood, that help fight off other infections.</li></ul><p>Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your <a href="/immune_system/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">immune system</a>. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).</p><p><b>ZIAGEN does not cure HIV-1 infection or AIDS.</b> You must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses.</p><p><b>Who should not take ZIAGEN?</b></p><p><b>Do not take ZIAGEN if you:</b></p><ul><li>have a certain type of gene variation called the HLA-B*5701 <a href="/allele/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">allele</a>. Your healthcare provider will test you for this before prescribing treatment with ZIAGEN.</li><li>are allergic to abacavir or any of the ingredients in ZIAGEN. See the end of this Medication Guide for a complete list of ingredients in ZIAGEN.</li><li>have liver problems.</li></ul><p><b>What should I tell my healthcare provider before taking ZIAGEN?</b></p><p><b>Before you take ZIAGEN, tell your healthcare provider if you:</b></p><p><b>Pregnancy Registry.</b> There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.</p><ul><li>have been tested and know whether or not you have a particular gene variation called HLA-B*5701.</li><li>have or have had liver problems, including <a href="/viral_hepatitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis</a> B or C virus infection.</li><li>have heart problems, smoke, or have diseases that increase your risk of <a href="/heart_disease/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">heart disease</a> such as <a href="/high_blood_pressure_hypertension_medications/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">high blood pressure</a>, high <a href="/cholesterol/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cholesterol</a>, or <a href="/diabetes_mellitus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">diabetes</a>.</li><li>drink alcohol or take medicines that contain alcohol.</li><li>are pregnant or plan to become pregnant. Talk to your healthcare provider if you are pregnant or plan to become pregnant.</li><li>are breastfeeding or plan to breastfeed. <b>Do not breastfeed if you take ZIAGEN.</b><ul><li>You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.</li></ul></li></ul><p><b>Tell your healthcare provider about all the medicines you take,</b> including prescription and over-thecounter medicines, vitamins, and herbal supplements.</p><p><b>Some medicines interact with ZIAGEN. <b>Keep a list of your medicines to show your healthcare provider and pharmacist.</b> You can ask your healthcare provider or pharmacist for a list of medicines that interact with ZIAGEN. <b>Do not start taking a new medicine without telling your healthcare provider.</b> Your healthcare provider can tell you if it is safe to take ZIAGEN with other medicines.</b></p><p><b>Tell your healthcare provider if you take:</b></p><ul><li>any other medicine to treat HIV-1</li><li><a href="/methadone/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">methadone</a></li><li>riociguat</li></ul><p><b>How should I take ZIAGEN?</b></p><ul><li><b>Take ZIAGEN exactly as your healthcare provider tells you.</b></li><li>Do not change your dose or stop taking ZIAGEN without talking with your healthcare provider. If you miss a dose of ZIAGEN, take it as soon as you remember. Do not take 2 doses at the same time. If you are not sure about your dosing, call your healthcare provider.</li><li>Stay under the care of a healthcare provider while taking ZIAGEN.</li><li>ZIAGEN may be taken with or without food.</li><li>For children aged 3 months and older, your healthcare provider will prescribe a dose of ZIAGEN based on your child’s body weight.</li><li>Tell your healthcare provider if you or your child has trouble swallowing tablets. ZIAGEN comes as a tablet or as a liquid (oral solution).</li><li>Do not run out of ZIAGEN. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run out, get more from your healthcare provider or pharmacy.</li><li>If you take too much ZIAGEN, call your healthcare provider or go to the nearest hospital emergency room right away.</li></ul><p><b>What are the possible side effects of ZIAGEN?</b></p><p><b>You may be more likely to get lactic acidosis or serious liver problems if you are female or very overweight (obese).</b></p><ul><li><b>ZIAGEN can cause serious side effects including:</b></li><li><b>See “What is the most important information I should know about ZIAGEN?”</b></li><li><b>Build-up of acid in your blood (lactic acidosis).</b> <a href="/lactic_acidosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Lactic acidosis</a> can happen in some people who take ZIAGEN. Lactic <a href="/acidosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">acidosis</a> is a serious medical emergency that can cause death. <b>Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:</b><ul><li>feel very weak or tired</li><li>feel cold, especially in your arms and legs</li><li>unusual (not normal) muscle pain</li><li>feel dizzy or light-headed</li><li>trouble breathing</li><li>have a fast or irregular heartbeat</li><li>stomach pain with <a href="/nausea_and_vomiting/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">nausea and vomiting</a></li></ul></li><li><b>Serious liver problems</b> can happen in people who take ZIAGEN. In some cases, these serious liver problems can lead to death. Your liver may become large (<a href="/hepatomegaly/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hepatomegaly</a>) and you may develop fat in your liver (steatosis) when you take ZIAGEN. <b>Call your healthcare provider right away if you have any of the following signs of liver problems:</b><ul><li>your skin or the white part of your eyes turns yellow (jaundice)</li><li>loss of appetite for several days or longer</li><li>nausea</li><li>dark or “tea-colored” urine</li><li>pain, aching, or tenderness on the right side of your stomach area</li><li>light-colored stools (bowel movements)</li></ul></li><li><b>Changes in your immune system (Immune Reconstitution Syndrome)</b> can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking ZIAGEN.</li><li><b>Heart attack (myocardial infarction).</b> Some HIV-1 medicines including ZIAGEN may increase your risk of <a href="/heart_attack/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">heart attack</a>.</li></ul><p><b>The most common side effects of ZIAGEN in adults include:</b></p><ul><li>nausea</li><li>tiredness</li><li>headache</li><li>vomiting</li><li>generally not feeling well</li><li>bad dreams or sleep problems</li></ul><p><b>The most common side effects of ZIAGEN in children include:</b></p><ul><li>fever and chills</li><li>rash</li><li>nausea</li><li>ear, nose, or throat infections</li><li>vomiting</li></ul><p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p><p>These are not all the possible side effects of ZIAGEN. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p><p><b>How should I store ZIAGEN?</b></p><ul><li>Store ZIAGEN at room temperature, between 68°F to 77°F (20°C to 25°C).</li><li>Do not freeze ZIAGEN oral solution. You may store ZIAGEN oral solution in a refrigerator.</li></ul><p><b>Keep ZIAGEN and all medicines out of the reach of children.</b></p><p><b>General information for safe and effective use of ZIAGEN</b></p><p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ZIAGEN for a condition for which it was not prescribed. Do not give ZIAGEN to other people, even if they have the same symptoms that you have. It may harm them.</p><p>If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for the information about ZIAGEN that is written for health professionals.</p><p>For more information go to www.ZIAGEN.com or call 1-877-844-8872.</p><p><b>What are the ingredients in ZIAGEN?</b></p><p>Active ingredient: abacavir</p><p>Inactive ingredients:</p><p>Tablets: Colloidal <a href="/silicon/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">silicon</a> dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.</p><p>Tablet film-coating contains: hypromellose, polysorbate 80, synthetic yellow iron oxide, titanium dioxide, and triacetin.</p><p>Oral Solution: Artificial <a href="/strawberry/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">strawberry</a> and banana flavors, citric acid (anhydrous), methylparaben and propylparaben (added as preservatives), propylene glycol, saccharin sodium, sodium citrate (dihydrate), sorbitol solution, and water.</p><p class="credit">This Medication Guide has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | <a name="PI"></a><h3>PATIENT INFORMATION</h3><p><b>ZIAGEN</b><br />(ZY-uh-jen)<br />(abacavir) tablets, for oral use</p><p><b>ZIAGEN</b><br />(ZY-uh-jen)<br />(abacavir) oral solution</p><p><b>What is the most important information I should know about ZIAGEN?</b></p><p><b>ZIAGEN can cause serious side effects, including:</b></p><p><b>If you get a symptom from 2 or more of the following groups while taking ZIAGEN, call your healthcare provider right away to find out if you should stop taking ZIAGEN.</b></p><p></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="15%"></td><td class="EmphTd" width="85%">Symptom(s)</td></tr><tr><td><b>Group 1</b></td><td><b>Fever</b></td></tr><tr><td><b>Group 2 </b></td><td><b>Rash</b></td></tr><tr><td><b>Group 3 </b></td><td><b>Nausea, vomiting, diarrhea, abdominal (stomach area) pain</b></td></tr><tr><td><b>Group 4 </b></td><td><b>Generally ill feeling, extreme tiredness, or achiness</b></td></tr><tr><td><b>Group 5 </b></td><td><b>Shortness of breath, cough, sore throat</b></td></tr></tbody></table></center><p>A list of these symptoms is on the Warning Card your pharmacist gives you. <b>Carry this Warning Card with you at all times.</b></p><p><b>If you stop ZIAGEN because of an allergic reaction, never take ZIAGEN (abacavir) or any other abacavir-containing medicine (EPZICOM, TRIUMEQ, or TRIZIVIR) again.</b></p><ul><li><b>Serious allergic reactions (hypersensitivity reaction)</b> that can cause death have happened with ZIAGEN and other abacavir-containing products. Your risk of this allergic reaction is much higher if you have a gene variation called <a href="/hla/definition.htm" ">HLA</a>-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.<ul><li>If you have an allergic reaction, dispose of any unused ZIAGEN. Ask your pharmacist how to properly dispose of medicines.</li><li>If you take ZIAGEN or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get <b>life-threatening symptoms</b> that may include <b>very low blood pressure or death.</b></li><li>If you stop ZIAGEN for any other reason, even for a few days, and you are not allergic to ZIAGEN, talk with your healthcare provider before taking it again. Taking ZIAGEN again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.</li></ul></li></ul><p><b>If your healthcare provider tells you that you can take ZIAGEN again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.</b></p><p><b>What is ZIAGEN?</b></p><p>ZIAGEN is a prescription HIV-1 (<a href="/human_immunodeficiency_virus_hiv/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Human Immunodeficiency Virus</a> type 1) medicine used with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes <a href="/acquired/definition.htm" ">Acquired</a> Immune Deficiency Syndrome (<a href="/acquired_immunodeficiency_syndrome_aids/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">AIDS</a>).</p><p>The safety and effectiveness of ZIAGEN has not been established in children under 3 months of age.</p><p><b>When used with other antiretroviral medicines to treat HIV-1 infection, ZIAGEN may help:</b></p><ul><li>reduce the amount of HIV-1 in your blood. This is called “viral load”.</li><li>increase the number of CD4+ (T) cells in your blood, that help fight off other infections.</li></ul><p>Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your <a href="/immune_system/definition.htm" ">immune system</a>. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).</p><p><b>ZIAGEN does not cure HIV-1 infection or AIDS.</b> You must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses.</p><p><b>Who should not take ZIAGEN?</b></p><p><b>Do not take ZIAGEN if you:</b></p><ul><li>have a certain type of gene variation called the HLA-B*5701 <a href="/allele/definition.htm" ">allele</a>. Your healthcare provider will test you for this before prescribing treatment with ZIAGEN.</li><li>are allergic to abacavir or any of the ingredients in ZIAGEN. See the end of this Medication Guide for a complete list of ingredients in ZIAGEN.</li><li>have liver problems.</li></ul><p><b>What should I tell my healthcare provider before taking ZIAGEN?</b></p><p><b>Before you take ZIAGEN, tell your healthcare provider if you:</b></p><p><b>Pregnancy Registry.</b> There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.</p><ul><li>have been tested and know whether or not you have a particular gene variation called HLA-B*5701.</li><li>have or have had liver problems, including <a href="/viral_hepatitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis</a> B or C virus infection.</li><li>have heart problems, smoke, or have diseases that increase your risk of <a href="/heart_disease/definition.htm" ">heart disease</a> such as <a href="/high_blood_pressure_hypertension_medications/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">high blood pressure</a>, high <a href="/cholesterol/definition.htm" ">cholesterol</a>, or <a href="/diabetes_mellitus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">diabetes</a>.</li><li>drink alcohol or take medicines that contain alcohol.</li><li>are pregnant or plan to become pregnant. Talk to your healthcare provider if you are pregnant or plan to become pregnant.</li><li>are breastfeeding or plan to breastfeed. <b>Do not breastfeed if you take ZIAGEN.</b><ul><li>You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.</li></ul></li></ul><p><b>Tell your healthcare provider about all the medicines you take,</b> including prescription and over-thecounter medicines, vitamins, and herbal supplements.</p><p><b>Some medicines interact with ZIAGEN. <b>Keep a list of your medicines to show your healthcare provider and pharmacist.</b> You can ask your healthcare provider or pharmacist for a list of medicines that interact with ZIAGEN. <b>Do not start taking a new medicine without telling your healthcare provider.</b> Your healthcare provider can tell you if it is safe to take ZIAGEN with other medicines.</b></p><p><b>Tell your healthcare provider if you take:</b></p><ul><li>any other medicine to treat HIV-1</li><li><a href="/methadone/definition.htm" ">methadone</a></li><li>riociguat</li></ul><p><b>How should I take ZIAGEN?</b></p><ul><li><b>Take ZIAGEN exactly as your healthcare provider tells you.</b></li><li>Do not change your dose or stop taking ZIAGEN without talking with your healthcare provider. If you miss a dose of ZIAGEN, take it as soon as you remember. Do not take 2 doses at the same time. If you are not sure about your dosing, call your healthcare provider.</li><li>Stay under the care of a healthcare provider while taking ZIAGEN.</li><li>ZIAGEN may be taken with or without food.</li><li>For children aged 3 months and older, your healthcare provider will prescribe a dose of ZIAGEN based on your child’s body weight.</li><li>Tell your healthcare provider if you or your child has trouble swallowing tablets. ZIAGEN comes as a tablet or as a liquid (oral solution).</li><li>Do not run out of ZIAGEN. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run out, get more from your healthcare provider or pharmacy.</li><li>If you take too much ZIAGEN, call your healthcare provider or go to the nearest hospital emergency room right away.</li></ul><p><b>What are the possible side effects of ZIAGEN?</b></p><p><b>You may be more likely to get lactic acidosis or serious liver problems if you are female or very overweight (obese).</b></p><ul><li><b>ZIAGEN can cause serious side effects including:</b></li><li><b>See “What is the most important information I should know about ZIAGEN?”</b></li><li><b>Build-up of acid in your blood (lactic acidosis).</b> <a href="/lactic_acidosis/definition.htm" ">Lactic acidosis</a> can happen in some people who take ZIAGEN. Lactic <a href="/acidosis/definition.htm" ">acidosis</a> is a serious medical emergency that can cause death. <b>Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:</b><ul><li>feel very weak or tired</li><li>feel cold, especially in your arms and legs</li><li>unusual (not normal) muscle pain</li><li>feel dizzy or light-headed</li><li>trouble breathing</li><li>have a fast or irregular heartbeat</li><li>stomach pain with <a href="/nausea_and_vomiting/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">nausea and vomiting</a></li></ul></li><li><b>Serious liver problems</b> can happen in people who take ZIAGEN. In some cases, these serious liver problems can lead to death. Your liver may become large (<a href="/hepatomegaly/definition.htm" ">hepatomegaly</a>) and you may develop fat in your liver (steatosis) when you take ZIAGEN. <b>Call your healthcare provider right away if you have any of the following signs of liver problems:</b><ul><li>your skin or the white part of your eyes turns yellow (jaundice)</li><li>loss of appetite for several days or longer</li><li>nausea</li><li>dark or “tea-colored” urine</li><li>pain, aching, or tenderness on the right side of your stomach area</li><li>light-colored stools (bowel movements)</li></ul></li><li><b>Changes in your immune system (Immune Reconstitution Syndrome)</b> can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking ZIAGEN.</li><li><b>Heart attack (myocardial infarction).</b> Some HIV-1 medicines including ZIAGEN may increase your risk of <a href="/heart_attack/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">heart attack</a>.</li></ul><p><b>The most common side effects of ZIAGEN in adults include:</b></p><ul><li>nausea</li><li>tiredness</li><li>headache</li><li>vomiting</li><li>generally not feeling well</li><li>bad dreams or sleep problems</li></ul><p><b>The most common side effects of ZIAGEN in children include:</b></p><ul><li>fever and chills</li><li>rash</li><li>nausea</li><li>ear, nose, or throat infections</li><li>vomiting</li></ul><p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p><p>These are not all the possible side effects of ZIAGEN. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p><p><b>How should I store ZIAGEN?</b></p><ul><li>Store ZIAGEN at room temperature, between 68°F to 77°F (20°C to 25°C).</li><li>Do not freeze ZIAGEN oral solution. You may store ZIAGEN oral solution in a refrigerator.</li></ul><p><b>Keep ZIAGEN and all medicines out of the reach of children.</b></p><p><b>General information for safe and effective use of ZIAGEN</b></p><p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ZIAGEN for a condition for which it was not prescribed. Do not give ZIAGEN to other people, even if they have the same symptoms that you have. It may harm them.</p><p>If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for the information about ZIAGEN that is written for health professionals.</p><p>For more information go to www.ZIAGEN.com or call 1-877-844-8872.</p><p><b>What are the ingredients in ZIAGEN?</b></p><p>Active ingredient: abacavir</p><p>Inactive ingredients:</p><p>Tablets: Colloidal <a href="/silicon/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">silicon</a> dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.</p><p>Tablet film-coating contains: hypromellose, polysorbate 80, synthetic yellow iron oxide, titanium dioxide, and triacetin.</p><p>Oral Solution: Artificial <a href="/strawberry/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">strawberry</a> and banana flavors, citric acid (anhydrous), methylparaben and propylparaben (added as preservatives), propylene glycol, saccharin sodium, sodium citrate (dihydrate), sorbitol solution, and water.</p><p class="credit">This Medication Guide has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | 3 | 2023-02-01 17:38:21 | Abacavir Sulfate (Ziagen) | A | HIV, NNRTIs, Antiretroviral Agents | Ziagen | abacavir sulfate | Ziagen | John P. Cunha, DO, FACOEP |
| 25 | 2023-02-23 12:07:03 | Drug Description | <div class="webmdrx"> <a href="https://www.webmd.com/rx/drug-prices/epzicom?ecd=oo_webmdrx_rx-mono_rx/drug-prices/epzicom_dsktp_rxlist.com//rx/drug-prices/epzicom" target="_blank" onclick="wmdPageLink('webmdrx');"><p class="webmdrx_p">Find Lowest Prices on <span class="webmdrx_img"></span></p></a> </div> <h4>What is Epzicom and how is it used?</h4> <p>Epzicom is a prescription medicine used to treat the symptoms of <a href="/hiv/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HIV</a> Infection. Epzicom may be used alone or with other medications.</p> <p>Epzicom belongs to a class of drugs called HIV, ART Combos.</p> <p>It is not known if Epzicom is safe and effective in children weighing less than 55 lbs (25 kgs).</p> <h4>What are the possible side effects of Epzicom?</h4> <p>Epzicom may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>unexplained weight loss,</li> <li>severe tiredness,</li> <li>muscle aches,</li> <li>weakness,</li> <li>severe headaches,</li> <li>joint pain,</li> <li>numbness or tingling of the hands, feet, arms, legs,</li> <li>vision changes,</li> <li>fever,</li> <li>chills,</li> <li><a href="/swollen_lymph_nodes/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">swollen lymph nodes</a>,</li> <li>cough,</li> <li>non-healing skin sores,</li> <li>irritability,</li> <li>nervousness,</li> <li>heat intolerance,</li> <li>fast, pounding, or irregular heartbeat,</li> <li><a href="/bulging/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bulging</a> eyes,</li> <li>unusual growth in the neck or <a href="/thyroid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">thyroid</a> (<a href="/goiter/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">goiter</a>),</li> <li>trouble swallowing,</li> <li>difficulty moving your eyes,</li> <li>drooping face,</li> <li><a href="/paralysis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">paralysis</a>,</li> <li>difficulty speaking,</li> <li>mental or mood changes,</li> <li>depression,</li> <li>anxiety,</li> <li>easy bruising,</li> <li>unusual bleeding,</li> <li>unusual tiredness,</li> <li>fast breathing,</li> <li>pale skin,</li> <li>nausea,</li> <li>vomiting,</li> <li>stomach pain,</li> <li><a href="/back_pain/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">back pain</a>,</li> <li>fever,</li> <li>loss of appetite,</li> <li>yellowing of the eyes and skin (<a href="/kernicterus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">jaundice</a>),</li> <li>dark urine,</li> <li>deep or rapid breathing, and</li> <li>drowsiness</li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Epzicom include:</p> <ul> <li>headache,</li> <li>nausea,</li> <li>diarrhea,</li> <li>dizziness,</li> <li>tiredness, and</li> <li>trouble sleeping</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Epzicom. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p align="center"><b>HYPERSENSITIVITY REACTIONS AND EXACERBATIONS OF HEPATITIS B</b></p> <h4>Hypersensitivity Reactions</h4> <p><b>Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of EPZICOM (abacavir and lamivudine). Patients who carry the HLA B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA B*5701 allele [see <b>WARNINGS AND <a href="/epzicom-drug.htm#P">PRECAUTIONS</a></b>].</b></p> <p><b>EPZICOM is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA B*5701-positive patients [see <a href="/epzicom-drug.htm#CI"><b>CONTRAINDICATIONS</b></a>, <b>WARNINGS AND <a href="/epzicom-drug.htm#P">PRECAUTIONS</a></b>]. All patients should be screened for the <a href="/hla/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HLA</a> B*5701 <a href="/allele/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">allele</a> prior to initiating therapy with EPZICOM or reinitiation of therapy with EPZICOM, unless patients have a previously documented HLA B*5701 allele assessment. Discontinue EPZICOM immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see <a href="/epzicom-drug.htm#CI"><b>CONTRAINDICATIONS</b></a>, <b>WARNINGS AND <a href="/epzicom-drug.htm#P">PRECAUTIONS</a></b>].</b></p> <p><b>Following a hypersensitivity reaction to EPZICOM, NEVER restart EPZICOM or any other abacavir containing product because more severe symptoms, including death, can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see WARNINGS AND <a href="/epzicom-drug.htm#P">PRECAUTIONS</a>].</b></p> <h4>Exacerbations of Hepatitis B</h4> <p><b>Severe acute exacerbations of <a href="/viral_hepatitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis</a> B have been reported in patients who are co infected with <a href="/hepatitis_b/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis B</a> virus (<a href="/hbv/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HBV</a>) and <a href="/human_immunodeficiency_virus_hiv/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">human immunodeficiency virus</a> (HIV 1) and have discontinued lamivudine, which is a component of EPZICOM. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue EPZICOM and are co-infected with HIV 1 and HBV. If appropriate, initiation of anti hepatitis B therapy may be warranted [see <b>WARNINGS AND <a href="/epzicom-drug.htm#P">PRECAUTIONS</a></b>].</b></p> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <h4>Epzicom</h4> <p>EPZICOM tablets contain the following 2 synthetic nucleoside analogues: abacavir (ZIAGEN, also a component of TRIZIVIR) and lamivudine (also known as EPIVIR or 3TC) with inhibitory activity against HIV 1.</p> <p>EPZICOM tablets are for oral administration. Each orange, film coated tablet contains the active ingredients 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine, and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film (OPADRY orange YS-1-13065-A) that is made of FD&C Yellow No. 6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide.</p> <h4>Abacavir Sulfate</h4> <p>The chemical name of abacavir sulfate is (1<i>S</i>,<i>cis</i>)-4-[2-amino-6-(cyclopropylamino)-9<i>H</i>-purin-9-yl]-2- cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with <i>1S</i>, <i>4R</i> absolute configuration on the cyclopentene ring. It has a molecular formula of (C<sub>14</sub>H<sub>18</sub>N<sub>6</sub>O)<sub>2</sub>•H<sub>2</sub>SO<sub>4</sub> and a molecular weight of 670.76 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="375"> <tbody> <tr> <td><img alt="Abacavir Sulfate - Structural Formula Illustration" height="311" src="https://images.rxlist.com/images/rxlist/epzicom1.gif" width="375" /></td> </tr> </tbody> </table> </center> <p></p> <p>Abacavir sulfate is a white to off white solid and is soluble in water.</p> <p><i>In vivo</i>, abacavir sulfate dissociates to its free base, abacavir. Dosages are expressed in terms of abacavir.</p> <h4>Lamivudine</h4> <p>The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)- pyrimidin-2-one. Lamivudine is the ( )enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as ( )2',3'-dideoxy, 3'-thiacytidine. It has a molecular formula of C<sub>8</sub>H<sub>11</sub>N<sub>3</sub>O<sub>3</sub>S and a molecular weight of 229.3 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic"> <tbody> <tr> <td><img alt="Lamivudine - Structural Formula Illustration" height="203" src="https://images.rxlist.com/images/rxlist/epzicom2.gif" width="247" /></td> </tr> </tbody> </table> </center> <p></p> <p>Lamivudine is a white to off white crystalline solid and is soluble in water.</p> </div> <div id="667441035-1" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-1", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <div class="webmdrx"> <a href="https://www.webmd.com/rx/drug-prices/epzicom?ecd=oo_webmdrx_rx-mono_rx/drug-prices/epzicom_dsktp_rxlist.com//rx/drug-prices/epzicom" target="_blank" onclick="wmdPageLink('webmdrx');"><p class="webmdrx_p">Find Lowest Prices on <span class="webmdrx_img"></span></p></a> </div> <h4>What is Epzicom and how is it used?</h4> <p>Epzicom is a prescription medicine used to treat the symptoms of <a href="/hiv/definition.htm" ">HIV</a> Infection. Epzicom may be used alone or with other medications.</p> <p>Epzicom belongs to a class of drugs called HIV, ART Combos.</p> <p>It is not known if Epzicom is safe and effective in children weighing less than 55 lbs (25 kgs).</p> <h4>What are the possible side effects of Epzicom?</h4> <p>Epzicom may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>unexplained weight loss,</li> <li>severe tiredness,</li> <li>muscle aches,</li> <li>weakness,</li> <li>severe headaches,</li> <li>joint pain,</li> <li>numbness or tingling of the hands, feet, arms, legs,</li> <li>vision changes,</li> <li>fever,</li> <li>chills,</li> <li><a href="/swollen_lymph_nodes/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">swollen lymph nodes</a>,</li> <li>cough,</li> <li>non-healing skin sores,</li> <li>irritability,</li> <li>nervousness,</li> <li>heat intolerance,</li> <li>fast, pounding, or irregular heartbeat,</li> <li><a href="/bulging/definition.htm" ">bulging</a> eyes,</li> <li>unusual growth in the neck or <a href="/thyroid/definition.htm" ">thyroid</a> (<a href="/goiter/definition.htm" ">goiter</a>),</li> <li>trouble swallowing,</li> <li>difficulty moving your eyes,</li> <li>drooping face,</li> <li><a href="/paralysis/definition.htm" ">paralysis</a>,</li> <li>difficulty speaking,</li> <li>mental or mood changes,</li> <li>depression,</li> <li>anxiety,</li> <li>easy bruising,</li> <li>unusual bleeding,</li> <li>unusual tiredness,</li> <li>fast breathing,</li> <li>pale skin,</li> <li>nausea,</li> <li>vomiting,</li> <li>stomach pain,</li> <li><a href="/back_pain/definition.htm" ">back pain</a>,</li> <li>fever,</li> <li>loss of appetite,</li> <li>yellowing of the eyes and skin (<a href="/kernicterus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">jaundice</a>),</li> <li>dark urine,</li> <li>deep or rapid breathing, and</li> <li>drowsiness</li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Epzicom include:</p> <ul> <li>headache,</li> <li>nausea,</li> <li>diarrhea,</li> <li>dizziness,</li> <li>tiredness, and</li> <li>trouble sleeping</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Epzicom. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p align="center"><b>HYPERSENSITIVITY REACTIONS AND EXACERBATIONS OF HEPATITIS B</b></p> <h4>Hypersensitivity Reactions</h4> <p><b>Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of EPZICOM (abacavir and lamivudine). Patients who carry the HLA B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA B*5701 allele [see <b>WARNINGS AND <a href="/epzicom-drug.htm#P">PRECAUTIONS</a></b>].</b></p> <p><b>EPZICOM is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA B*5701-positive patients [see <a href="/epzicom-drug.htm#CI"><b>CONTRAINDICATIONS</b></a>, <b>WARNINGS AND <a href="/epzicom-drug.htm#P">PRECAUTIONS</a></b>]. All patients should be screened for the <a href="/hla/definition.htm" ">HLA</a> B*5701 <a href="/allele/definition.htm" ">allele</a> prior to initiating therapy with EPZICOM or reinitiation of therapy with EPZICOM, unless patients have a previously documented HLA B*5701 allele assessment. Discontinue EPZICOM immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see <a href="/epzicom-drug.htm#CI"><b>CONTRAINDICATIONS</b></a>, <b>WARNINGS AND <a href="/epzicom-drug.htm#P">PRECAUTIONS</a></b>].</b></p> <p><b>Following a hypersensitivity reaction to EPZICOM, NEVER restart EPZICOM or any other abacavir containing product because more severe symptoms, including death, can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see WARNINGS AND <a href="/epzicom-drug.htm#P">PRECAUTIONS</a>].</b></p> <h4>Exacerbations of Hepatitis B</h4> <p><b>Severe acute exacerbations of <a href="/viral_hepatitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis</a> B have been reported in patients who are co infected with <a href="/hepatitis_b/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis B</a> virus (<a href="/hbv/definition.htm" ">HBV</a>) and <a href="/human_immunodeficiency_virus_hiv/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">human immunodeficiency virus</a> (HIV 1) and have discontinued lamivudine, which is a component of EPZICOM. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue EPZICOM and are co-infected with HIV 1 and HBV. If appropriate, initiation of anti hepatitis B therapy may be warranted [see <b>WARNINGS AND <a href="/epzicom-drug.htm#P">PRECAUTIONS</a></b>].</b></p> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <h4>Epzicom</h4> <p>EPZICOM tablets contain the following 2 synthetic nucleoside analogues: abacavir (ZIAGEN, also a component of TRIZIVIR) and lamivudine (also known as EPIVIR or 3TC) with inhibitory activity against HIV 1.</p> <p>EPZICOM tablets are for oral administration. Each orange, film coated tablet contains the active ingredients 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine, and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film (OPADRY orange YS-1-13065-A) that is made of FD&C Yellow No. 6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide.</p> <h4>Abacavir Sulfate</h4> <p>The chemical name of abacavir sulfate is (1<i>S</i>,<i>cis</i>)-4-[2-amino-6-(cyclopropylamino)-9<i>H</i>-purin-9-yl]-2- cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with <i>1S</i>, <i>4R</i> absolute configuration on the cyclopentene ring. It has a molecular formula of (C<sub>14</sub>H<sub>18</sub>N<sub>6</sub>O)<sub>2</sub>•H<sub>2</sub>SO<sub>4</sub> and a molecular weight of 670.76 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="375"> <tbody> <tr> <td><img alt="Abacavir Sulfate - Structural Formula Illustration" height="311" src="https://images.rxlist.com/images/rxlist/epzicom1.gif" width="375" /></td> </tr> </tbody> </table> </center> <p></p> <p>Abacavir sulfate is a white to off white solid and is soluble in water.</p> <p><i>In vivo</i>, abacavir sulfate dissociates to its free base, abacavir. Dosages are expressed in terms of abacavir.</p> <h4>Lamivudine</h4> <p>The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)- pyrimidin-2-one. Lamivudine is the ( )enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as ( )2',3'-dideoxy, 3'-thiacytidine. It has a molecular formula of C<sub>8</sub>H<sub>11</sub>N<sub>3</sub>O<sub>3</sub>S and a molecular weight of 229.3 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic"> <tbody> <tr> <td><img alt="Lamivudine - Structural Formula Illustration" height="203" src="https://images.rxlist.com/images/rxlist/epzicom2.gif" width="247" /></td> </tr> </tbody> </table> </center> <p></p> <p>Lamivudine is a white to off white crystalline solid and is soluble in water.</p> </div> <div id="667441035-1" class="medianet"><</div> </div> </div> | 4 | 2023-02-01 17:38:24 | Abacavir Sulfate and Lamivudine Tablets (Epzicom) | A | HIV, NNRTIs | Epzicom | abacavir sulfate and lamivudine tablets | Epzicom | John P. Cunha, DO, FACOEP |
| 26 | 2023-02-23 11:36:54 | Indications & Dosage | <div class="webmdrx_coup"> </div> <a name="I"></a> <h3>INDICATIONS</h3> <p>EPZICOM, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.</p> <a name="D"></a> <h3>DOSAGE AND ADMINISTRATION</h3> <h4>Screening For HLA-B*5701 Allele Prior To Starting EPZICOM</h4> <p>Screen for the HLA-B*5701 allele prior to initiating therapy with EPZICOM [see <b>BOX WARNING</b> , <b>WARNINGS AND PRECAUTIONS</b>].</p> <h4>Recommended Dosage For Adult Patients</h4> <p>The recommended dosage of EPZICOM for adults is one tablet taken orally once daily, in combination with other antiretroviral agents, with or without food.</p> <h4>Recommended Dosage For Pediatric Patients</h4> <p>The recommended oral dose of EPZICOM for pediatric patients weighing at least 25 kg is one tablet daily in combination with other antiretroviral agents [see <b>Clinical Studies</b>]. Before prescribing EPZICOM tablets, pediatric patients should be assessed for the ability to swallow tablets.</p> <h4>Not Recommended Due To Lack Of Dosage Adjustment</h4> <p>Because EPZICOM is a fixed-dose tablet and cannot be dose adjusted, EPZICOM is not recommended for:</p> <ul> <li>patients with creatinine clearance less than 30 mL per minute [see <b>Use In Specific Populations</b>].</li> <li>patients with mild hepatic impairment. EPZICOM is contraindicated in patients with moderate or severe hepatic impairment [see <b>CONTRAINDICATIONS</b>, <b>Use In Specific Populations</b>].</li> </ul> <p>Use of EPIVIR (lamivudine) oral solution or tablets and ZIAGEN (abacavir) oral solution may be considered.</p> <a name="HS"></a> <h3>HOW SUPPLIED</h3> <h4>Dosage Forms And Strengths</h4> <p>EPZICOM tablets contain 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine. The tablets are modified capsule-shaped, orange, film-coated, and debossed with “GS FC2” on one side with no markings on the reverse side.</p> <h4>Storage And Handling</h4> <p><b>EPZICOM</b> is available as tablets. Each tablet contains 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine. The tablets are orange, film-coated, modified capsule-shaped, and debossed with GS FC2 on one side with no markings on the reverse side. They are packaged as follows:</p> <p class="EmphText">Bottles of 30 tablets (<b>NDC</b> 49702-206-13).</p> <p>Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature).</p> <p class="credit">Manufactured for: ViiV Healthcare, Research Triangle Park, NC 27709. Revised: Dec 2021</p> </div> <a class="mediaPrmo quiz" href="/quiz_hiv-aids/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/hivaids/hivaids-s1.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">What is HIV?</span> <span class="btn">See Answer</span> </a> </div> </div> | <div class="webmdrx_coup"> </div> <a name="I"></a> <h3>INDICATIONS</h3> <p>EPZICOM, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.</p> <a name="D"></a> <h3>DOSAGE AND ADMINISTRATION</h3> <h4>Screening For HLA-B*5701 Allele Prior To Starting EPZICOM</h4> <p>Screen for the HLA-B*5701 allele prior to initiating therapy with EPZICOM [see <b>BOX WARNING</b> , <b>WARNINGS AND PRECAUTIONS</b>].</p> <h4>Recommended Dosage For Adult Patients</h4> <p>The recommended dosage of EPZICOM for adults is one tablet taken orally once daily, in combination with other antiretroviral agents, with or without food.</p> <h4>Recommended Dosage For Pediatric Patients</h4> <p>The recommended oral dose of EPZICOM for pediatric patients weighing at least 25 kg is one tablet daily in combination with other antiretroviral agents [see <b>Clinical Studies</b>]. Before prescribing EPZICOM tablets, pediatric patients should be assessed for the ability to swallow tablets.</p> <h4>Not Recommended Due To Lack Of Dosage Adjustment</h4> <p>Because EPZICOM is a fixed-dose tablet and cannot be dose adjusted, EPZICOM is not recommended for:</p> <ul> <li>patients with creatinine clearance less than 30 mL per minute [see <b>Use In Specific Populations</b>].</li> <li>patients with mild hepatic impairment. EPZICOM is contraindicated in patients with moderate or severe hepatic impairment [see <b>CONTRAINDICATIONS</b>, <b>Use In Specific Populations</b>].</li> </ul> <p>Use of EPIVIR (lamivudine) oral solution or tablets and ZIAGEN (abacavir) oral solution may be considered.</p> <a name="HS"></a> <h3>HOW SUPPLIED</h3> <h4>Dosage Forms And Strengths</h4> <p>EPZICOM tablets contain 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine. The tablets are modified capsule-shaped, orange, film-coated, and debossed with “GS FC2” on one side with no markings on the reverse side.</p> <h4>Storage And Handling</h4> <p><b>EPZICOM</b> is available as tablets. Each tablet contains 600 mg of abacavir as abacavir sulfate and 300 mg of lamivudine. The tablets are orange, film-coated, modified capsule-shaped, and debossed with GS FC2 on one side with no markings on the reverse side. They are packaged as follows:</p> <p class="EmphText">Bottles of 30 tablets (<b>NDC</b> 49702-206-13).</p> <p>Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature).</p> <p class="credit">Manufactured for: ViiV Healthcare, Research Triangle Park, NC 27709. Revised: Dec 2021</p> </div> <a class="mediaPrmo quiz" href="/quiz_hiv-aids/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/hivaids/hivaids-s1.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">What is HIV?</span> <span class="btn">See Answer</span> </a> </div> </div> | 4 | 2023-02-01 17:38:24 | Abacavir Sulfate and Lamivudine Tablets (Epzicom) | A | HIV, NNRTIs | Epzicom | abacavir sulfate and lamivudine tablets | Epzicom | John P. Cunha, DO, FACOEP |
| 27 | 2023-02-23 11:36:54 | Side Effects | <a name="AR"></a> <h3>SIDE EFFECTS</h3> <p>The following adverse reactions are discussed in other sections of the labeling:</p> <ul> <li>Serious and sometimes fatal hypersensitivity reactions [see <b>BOX WARNING</b> ,<b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Exacerbations of hepatitis B [see <b>BOX WARNING</b> , <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Lactic acidosis and severe hepatomegaly with steatosis [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Immune reconstitution syndrome [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Myocardial infarction [see <b>WARNINGS AND PRECAUTIONS</b>].</li> </ul> <h4>Clinical Trials Experience In Adult Subjects</h4> <p>Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.</p> <h4>Serious And Fatal Abacavir-Associated Hypersensitivity Reactions</h4> <p>In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of EPZICOM [see <b>BOX WARNING</b> , <b>WARNINGS AND PRECAUTIONS</b>]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.</p> <p>Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia and abnormal chest x-ray findings (predominantly infiltrates, which were localized).</p> <h4>Additional Adverse Reactions With Use Of EPZICOM</h4> <h5>Therapy-Naive Adults</h5> <p>Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with greater than or equal to 5% frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily, are listed in Table 1.</p> <p align="center"><b>Table 1. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30021) through 48 Weeks of Treatment</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Adverse Event</td> <td class="EmphTd" width="25%">ZIAGEN 600 mg q.d.<br /> plus EPIVIR plus<br /> Efavirenz<br /> (n = 384)</td> <td class="EmphTd" width="25%">ZIAGEN 300 mg b.i.d.<br /> plus EPIVIR plus<br /> Efavirenz<br /> (n = 386)</td> </tr> <tr> <td><b>Drug hypersensitivity<sup>a,b</sup></b></td> <td align="center">9%</td> <td align="center">7%</td> </tr> <tr> <td>Insomnia</td> <td align="center">7%</td> <td align="center">9%</td> </tr> <tr> <td>Depression/Depressed mood</td> <td align="center">7%</td> <td align="center">7%</td> </tr> <tr> <td>Headache/Migraine</td> <td align="center">7%</td> <td align="center">6%</td> </tr> <tr> <td>Fatigue/Malaise</td> <td align="center">6%</td> <td align="center">8%</td> </tr> <tr> <td>Dizziness/Vertigo</td> <td align="center">6%</td> <td align="center">6%</td> </tr> <tr> <td>Nausea</td> <td align="center">5%</td> <td align="center">6%</td> </tr> <tr> <td>Diarrhea<sup>a</sup></td> <td align="center">5%</td> <td align="center">6%</td> </tr> <tr> <td>Rash</td> <td align="center">5%</td> <td align="center">5%</td> </tr> <tr> <td>Pyrexia</td> <td align="center">5%</td> <td align="center">3%</td> </tr> <tr> <td>Abdominal pain/gastritis</td> <td align="center">4%</td> <td align="center">5%</td> </tr> <tr> <td>Abnormal dreams</td> <td align="center">4%</td> <td align="center">5%</td> </tr> <tr> <td>Anxiety</td> <td align="center">3%</td> <td align="center">5%</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Subjects receiving ZIAGEN 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN 300 mg twice daily. Five percent (5%) of subjects receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving ZIAGEN 300 mg twice daily. Two percent (2%) of subjects receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN 300 mg twice daily had this event. <sup>b</sup> CNA30024 was a multi-center, double-blind, controlled trial in which 649 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN (300 mg twice daily), EPIVIR (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), EPIVIR (150 mg twice daily), and efavirenz (600 mg once daily). CNA30024 used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group.</td> </tr> </tbody> </table> </center> <p></p> <h5>Laboratory Abnormalities</h5> <p>Laboratory abnormalities observed in clinical trials of ZIAGEN were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase.</p> <p>The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021.</p> <h5>Other Adverse Events</h5> <p>In addition to adverse reactions listed above, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT.</p> <h4>Clinical Trials Experience In Pediatric Subjects</h4> <p>The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as EPZICOM, was assessed in the ARROW trial (n = 336). Primary safety assessment in the ARROW (COL105677) trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. No additional safety issues were identified in pediatric subjects receiving abacavir and lamivudine once-daily compared with historical data in adults [see <b>Clinical Trials Experience In Adult Subjects</b>].</p> <h4>Postmarketing Experience</h4> <p>The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.</p> <h4>Abacavir</h4> <h5>Cardiovascular</h5> <p>Myocardial infarction.</p> <h5>Skin</h5> <p>Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use [see <b>Clinical Trials Experience In Adult Subjects</b>].</p> <h4>Abacavir And Lamivudine</h4> <p><b><i>Body as a Whole:</i></b> Redistribution/accumulation of body fat.</p> <p><b><i>Digestive:</i></b> Stomatitis.</p> <p><b><i>Endocrine and Metabolic:</i></b> Hyperglycemia.</p> <p><b><i>General:</i></b> Weakness.</p> <p><b><i>Hemic and Lymphatic:</i></b> Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly.</p> <p><b><i>Hepatic:</i></b> Lactic acidosis and hepatic steatosis [see <b>WARNINGS AND PRECAUTIONS</b>], posttreatment exacerbations of hepatitis B [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p><b><i>Hypersensitivity:</i></b> Sensitization reactions (including anaphylaxis), urticaria.</p> <p><b><i>Musculoskeletal:</i></b> Muscle weakness, creatinine phosphokinase (CPK) elevation, rhabdomyolysis.</p> <p><b><i>Nervous:</i></b> Paresthesia, peripheral neuropathy, seizures.</p> <p><b><i>Respiratory:</i></b> Abnormal breath sounds/wheezing.</p> <p><b><i>Skin:</i></b> Alopecia, erythema multiforme, Stevens-Johnson syndrome.</p> </div> </div> </div> | <a name="AR"></a> <h3>SIDE EFFECTS</h3> <p>The following adverse reactions are discussed in other sections of the labeling:</p> <ul> <li>Serious and sometimes fatal hypersensitivity reactions [see <b>BOX WARNING</b> ,<b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Exacerbations of hepatitis B [see <b>BOX WARNING</b> , <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Lactic acidosis and severe hepatomegaly with steatosis [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Immune reconstitution syndrome [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Myocardial infarction [see <b>WARNINGS AND PRECAUTIONS</b>].</li> </ul> <h4>Clinical Trials Experience In Adult Subjects</h4> <p>Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.</p> <h4>Serious And Fatal Abacavir-Associated Hypersensitivity Reactions</h4> <p>In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of EPZICOM [see <b>BOX WARNING</b> , <b>WARNINGS AND PRECAUTIONS</b>]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.</p> <p>Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia and abnormal chest x-ray findings (predominantly infiltrates, which were localized).</p> <h4>Additional Adverse Reactions With Use Of EPZICOM</h4> <h5>Therapy-Naive Adults</h5> <p>Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with greater than or equal to 5% frequency during therapy with ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with lamivudine 300 mg once daily and efavirenz 600 mg once daily, are listed in Table 1.</p> <p align="center"><b>Table 1. Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA30021) through 48 Weeks of Treatment</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Adverse Event</td> <td class="EmphTd" width="25%">ZIAGEN 600 mg q.d.<br /> plus EPIVIR plus<br /> Efavirenz<br /> (n = 384)</td> <td class="EmphTd" width="25%">ZIAGEN 300 mg b.i.d.<br /> plus EPIVIR plus<br /> Efavirenz<br /> (n = 386)</td> </tr> <tr> <td><b>Drug hypersensitivity<sup>a,b</sup></b></td> <td align="center">9%</td> <td align="center">7%</td> </tr> <tr> <td>Insomnia</td> <td align="center">7%</td> <td align="center">9%</td> </tr> <tr> <td>Depression/Depressed mood</td> <td align="center">7%</td> <td align="center">7%</td> </tr> <tr> <td>Headache/Migraine</td> <td align="center">7%</td> <td align="center">6%</td> </tr> <tr> <td>Fatigue/Malaise</td> <td align="center">6%</td> <td align="center">8%</td> </tr> <tr> <td>Dizziness/Vertigo</td> <td align="center">6%</td> <td align="center">6%</td> </tr> <tr> <td>Nausea</td> <td align="center">5%</td> <td align="center">6%</td> </tr> <tr> <td>Diarrhea<sup>a</sup></td> <td align="center">5%</td> <td align="center">6%</td> </tr> <tr> <td>Rash</td> <td align="center">5%</td> <td align="center">5%</td> </tr> <tr> <td>Pyrexia</td> <td align="center">5%</td> <td align="center">3%</td> </tr> <tr> <td>Abdominal pain/gastritis</td> <td align="center">4%</td> <td align="center">5%</td> </tr> <tr> <td>Abnormal dreams</td> <td align="center">4%</td> <td align="center">5%</td> </tr> <tr> <td>Anxiety</td> <td align="center">3%</td> <td align="center">5%</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Subjects receiving ZIAGEN 600 mg once daily, experienced a significantly higher incidence of severe drug hypersensitivity reactions and severe diarrhea compared with subjects who received ZIAGEN 300 mg twice daily. Five percent (5%) of subjects receiving ZIAGEN 600 mg once daily had severe drug hypersensitivity reactions compared with 2% of subjects receiving ZIAGEN 300 mg twice daily. Two percent (2%) of subjects receiving ZIAGEN 600 mg once daily had severe diarrhea while none of the subjects receiving ZIAGEN 300 mg twice daily had this event. <sup>b</sup> CNA30024 was a multi-center, double-blind, controlled trial in which 649 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN (300 mg twice daily), EPIVIR (150 mg twice daily), and efavirenz (600 mg once daily); or zidovudine (300 mg twice daily), EPIVIR (150 mg twice daily), and efavirenz (600 mg once daily). CNA30024 used double-blind ascertainment of suspected hypersensitivity reactions. During the blinded portion of the trial, suspected hypersensitivity to abacavir was reported by investigators in 9% of 324 subjects in the abacavir group and 3% of 325 subjects in the zidovudine group.</td> </tr> </tbody> </table> </center> <p></p> <h5>Laboratory Abnormalities</h5> <p>Laboratory abnormalities observed in clinical trials of ZIAGEN were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase.</p> <p>The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021.</p> <h5>Other Adverse Events</h5> <p>In addition to adverse reactions listed above, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT.</p> <h4>Clinical Trials Experience In Pediatric Subjects</h4> <p>The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as EPZICOM, was assessed in the ARROW trial (n = 336). Primary safety assessment in the ARROW (COL105677) trial was based on Grade 3 and Grade 4 adverse events. The frequency of Grade 3 and 4 adverse events was similar among subjects randomized to once-daily dosing compared with subjects randomized to twice-daily dosing. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. No additional safety issues were identified in pediatric subjects receiving abacavir and lamivudine once-daily compared with historical data in adults [see <b>Clinical Trials Experience In Adult Subjects</b>].</p> <h4>Postmarketing Experience</h4> <p>The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.</p> <h4>Abacavir</h4> <h5>Cardiovascular</h5> <p>Myocardial infarction.</p> <h5>Skin</h5> <p>Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use [see <b>Clinical Trials Experience In Adult Subjects</b>].</p> <h4>Abacavir And Lamivudine</h4> <p><b><i>Body as a Whole:</i></b> Redistribution/accumulation of body fat.</p> <p><b><i>Digestive:</i></b> Stomatitis.</p> <p><b><i>Endocrine and Metabolic:</i></b> Hyperglycemia.</p> <p><b><i>General:</i></b> Weakness.</p> <p><b><i>Hemic and Lymphatic:</i></b> Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly.</p> <p><b><i>Hepatic:</i></b> Lactic acidosis and hepatic steatosis [see <b>WARNINGS AND PRECAUTIONS</b>], posttreatment exacerbations of hepatitis B [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p><b><i>Hypersensitivity:</i></b> Sensitization reactions (including anaphylaxis), urticaria.</p> <p><b><i>Musculoskeletal:</i></b> Muscle weakness, creatinine phosphokinase (CPK) elevation, rhabdomyolysis.</p> <p><b><i>Nervous:</i></b> Paresthesia, peripheral neuropathy, seizures.</p> <p><b><i>Respiratory:</i></b> Abnormal breath sounds/wheezing.</p> <p><b><i>Skin:</i></b> Alopecia, erythema multiforme, Stevens-Johnson syndrome.</p> </div> </div> </div> | 4 | 2023-02-01 17:38:24 | Abacavir Sulfate and Lamivudine Tablets (Epzicom) | A | HIV, NNRTIs | Epzicom | abacavir sulfate and lamivudine tablets | Epzicom | John P. Cunha, DO, FACOEP |
| 28 | 2023-02-23 11:36:54 | Drug Interactions | <a name="DI"></a> <h3>DRUG INTERACTIONS</h3> <h4>Methadone</h4> <p>In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see <b>CLINICAL PHARMACOLOGY</b>]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.</p> <h4>Sorbitol</h4> <p>Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see <b>CLINICAL PHARMACOLOGY</b>].</p> <h4>Riociguat</h4> <p>Coadministration with fixed-dose abacavir/dolutegravir/lamivudine resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [see <b>CLINICAL PHARMACOLOGY</b>]. The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).</p> </div> </div> </div> | <a name="DI"></a> <h3>DRUG INTERACTIONS</h3> <h4>Methadone</h4> <p>In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see <b>CLINICAL PHARMACOLOGY</b>]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.</p> <h4>Sorbitol</h4> <p>Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see <b>CLINICAL PHARMACOLOGY</b>].</p> <h4>Riociguat</h4> <p>Coadministration with fixed-dose abacavir/dolutegravir/lamivudine resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [see <b>CLINICAL PHARMACOLOGY</b>]. The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).</p> </div> </div> </div> | 4 | 2023-02-01 17:38:24 | Abacavir Sulfate and Lamivudine Tablets (Epzicom) | A | HIV, NNRTIs | Epzicom | abacavir sulfate and lamivudine tablets | Epzicom | John P. Cunha, DO, FACOEP |
| 29 | 2023-02-23 11:36:54 | Warnings & Precautions | <a name="W"></a> <h3>WARNINGS</h3> <p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a> <h3>PRECAUTIONS</h3> <h4>Hypersensitivity Reactions</h4> <p>Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of EPZICOM. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see <b>ADVERSE REACTIONS</b>]. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.</p> <p>Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:</p> <ul> <li>All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with EPZICOM or reinitiation of therapy with EPZICOM, unless patients have a previously documented HLA-B*5701 allele assessment.</li> <li>EPZICOM is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.</li> <li>Before starting EPZICOM, review medical history for prior exposure to any abacavircontaining product. NEVER restart EPZICOM or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.</li> <li>To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue EPZICOM immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).</li> <li>If a hypersensitivity reaction cannot be ruled out, do not restart EPZICOM or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours.</li> <li>If a hypersensitivity reaction is ruled out, patients may restart EPZICOM. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of EPZICOM or any other abacavir-containing product is recommended only if medical care can be readily accessed.</li> <li>A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.</li> </ul> <h4>Patients With Hepatitis B Virus Co-Infection</h4> <h5>Posttreatment Exacerbations Of Hepatitis</h5> <p>Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.</p> <h5>Emergence Of Lamivudine-Resistant HBV</h5> <p>Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine).</p> <h4>Lactic Acidosis And Severe Hepatomegaly With Steatosis</h4> <p>Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir and lamivudine (components of EPZICOM). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Treatment with EPZICOM should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.</p> <h4>Immune Reconstitution Syndrome</h4> <p>Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EPZICOM. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as <i>Mycobacterium avium</i> infection, cytomegalovirus, <i>Pneumocystis jirovecii</i> pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.</p> <p>Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.</p> <h4>Myocardial Infarction</h4> <p>Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain the potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir treatment and the risk of MI is inconclusive.</p> <p>As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).</p> <h4>Patient Counseling Information</h4> <p>Advise the patient to read the FDA-approved patient labeling (<b>Medication Guide</b>).</p> <h5>Hypersensitivity Reactions Inform Patients</h5> <ul> <li>that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of EPZICOM and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about EPZICOM. The complete text of the Medication Guide is reprinted at the end of this document.</li> <li>to carry the Warning Card with them.</li> <li>how to identify a hypersensitivity reaction [see <b>WARNINGS AND PRECAUTIONS</b>, <b>PATIENT INFORMATION</b>].</li> <li>that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking EPZICOM.</li> <li>that a hypersensitivity reaction can worsen and lead to hospitalization or death if EPZICOM is not immediately discontinued.</li> <li>to not restart EPZICOM or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.</li> <li>that if they have a hypersensitivity reaction, they should dispose of any unused EPZICOM to avoid restarting abacavir.</li> <li>that a hypersensitivity reaction is usually reversible if it is detected promptly and EPZICOM is stopped right away.</li> <li>that if they have interrupted EPZICOM for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.</li> <li>to not restart EPZICOM or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.</li> </ul> <h5>Patients With Hepatitis B Or C Co-Infection</h5> <p>Advise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their physician [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Lactic Acidosis/Hepatomegaly With Steatosis</h5> <p>Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking EPZICOM if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Immune Reconstitution Syndrome</h5> <p>Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when EPZICOM is started [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Pregnancy Registry</h5> <p>Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EPZICOM during pregnancy [see <b>Use In Specific Populations</b>].</p> <h5>Lactation</h5> <p>Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see <b>Use In Specific Populations</b>].</p> <h5>Missed Dose</h5> <p>Instruct patients that if they miss a dose of EPZICOM, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <h5>Availability Of Medication Guide</h5> <p>Instruct patients to read the Medication Guide before starting EPZICOM and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.</p> <p>EPIVIR, EPZICOM, TRIZIVIR, and ZIAGEN are trademarks owned by or licensed to the ViiV Healthcare group of companies.</p> <p>The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.</p> <h4>Nonclinical Toxicology</h4> <h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4> <h5>Carcinogenicity</h5> <p><i>Abacavir</i></p> <p>Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg.</p> <p><i>Lamivudine</i></p> <p>Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.</p> <h5>Mutagenicity</h5> <p><i>Abacavir</i></p> <p>Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an <i>in vitro</i> cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an <i>in vivo</i> mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.</p> <p><i>Lamivudine</i></p> <p>Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an <i>in vitro</i> cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.</p> <h5>Impairment Of Fertility</h5> <p><i>Abacavir</i></p> <p>Abacavir did not affect male or female fertility in rats at a dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.</p> <p><i>Lamivudine</i></p> <p>Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (Cmax) in humans at the dose of 300 mg.</p> <a name="USP"></a> <h4>Use In Specific Populations</h4> <h4>Pregnancy</h4> <h5>Pregnancy Exposure Registry</h5> <p>There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EPZICOM during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.</p> <h5>Risk Summary</h5> <p>Available data from the APR show no difference in the overall risk of birth defects for abacavir or lamivudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see <b>Data</b>). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.</p> <p>In animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose. However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately 9 times the human exposure (AUC) at the recommended clinical dose. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the recommended clinical dose (see <b>Data</b>).</p> <h5>Data</h5> <p><i>Human Data</i></p> <p><i>Abacavir</i></p> <p>Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the</p> <p>U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4.0%) following second/third trimester exposure to abacavir-containing regimens.</p> <p>Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p><i>Lamivudine</i></p> <p>Based on prospective reports to the APR of exposures to lamivudine during pregnancy resulting in live births (including over 5,300 exposed in the first trimester and over 7,400 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5%, 3.3%) following second/third trimester exposure to lamivudinecontaining regimens.</p> <p>Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8).</p> <p><i>Animal Data</i></p> <p><i>Abacavir</i></p> <p>Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on Gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately 4 times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the recommended dose.</p> <p><i>Lamivudine</i></p> <p>Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300 and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, were not affected by the maternal administration of lamivudine.</p> <h4>Lactation</h4> <h5>Risk Summary</h5> <p>The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir and lamivudine are present in human milk. There is no information on the effects of abacavir and lamivudine on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving EPZICOM.</p> <h4>Pediatric Use</h4> <p>The dosing recommendations in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or EPZICOM [see <b>DOSAGE AND ADMINISTRATION</b>, <b>ADVERSE REACTIONS</b>, <b>Clinical Studies</b>].</p> <p>In pediatric patients weighing less than 25 kg, use of abacavir and lamivudine as single products is recommended to achieve appropriate dosing.</p> <h4>Geriatric Use</h4> <p>Clinical trials of abacavir and lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of EPZICOM in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see <b>DOSAGE AND ADMINISTRATION</b>, <b>Patients With Impaired Renal Function, Patients With Impaired Hepatic Function</b>].</p> <h4>Patients With Impaired Renal Function</h4> <p>EPZICOM is not recommended for patients with creatinine clearance less than 30 mL per min because EPZICOM is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of EPZICOM, is required for patients with creatinine clearance less than 30 mL per min, then the individual components should be used [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p>Patients with a creatinine clearance between 30 and 49 mL per min receiving EPZICOM may experience a 1.6-to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL per min. There are no safety data from randomized, controlled trials comparing EPZICOM to the individual components in patients with a creatinine clearance between 30 and 49 mL per min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of hematologic toxicities (neutropenia and anemia), although discontinuations due to neutropenia or anemia each occurred in <1% of subjects. Patients with a sustained creatinine clearance between 30 and 49 mL per min who receive EPZICOM should be monitored for hematologic toxicities. If new or worsening neutropenia or anemia develop, dose adjustment of lamivudine, per lamivudine prescribing information, is recommended. If lamivudine dose adjustment is indicated, EPZICOM should be discontinued and the individual components should be used to construct the treatment regimen.</p> <h4>Patients With Impaired Hepatic Function</h4> <p>EPZICOM is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of EPZICOM, is required for patients with mild hepatic impairment (Child-Pugh Class A), then the individual components should be used [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p>The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment; therefore, EPZICOM is contraindicated in these patients [see <b>CONTRAINDICATIONS</b>].</p> </div> </div> </div> | <a name="W"></a> <h3>WARNINGS</h3> <p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a> <h3>PRECAUTIONS</h3> <h4>Hypersensitivity Reactions</h4> <p>Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of EPZICOM. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see <b>ADVERSE REACTIONS</b>]. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.</p> <p>Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:</p> <ul> <li>All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with EPZICOM or reinitiation of therapy with EPZICOM, unless patients have a previously documented HLA-B*5701 allele assessment.</li> <li>EPZICOM is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.</li> <li>Before starting EPZICOM, review medical history for prior exposure to any abacavircontaining product. NEVER restart EPZICOM or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.</li> <li>To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue EPZICOM immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).</li> <li>If a hypersensitivity reaction cannot be ruled out, do not restart EPZICOM or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours.</li> <li>If a hypersensitivity reaction is ruled out, patients may restart EPZICOM. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of EPZICOM or any other abacavir-containing product is recommended only if medical care can be readily accessed.</li> <li>A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill.</li> </ul> <h4>Patients With Hepatitis B Virus Co-Infection</h4> <h5>Posttreatment Exacerbations Of Hepatitis</h5> <p>Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.</p> <h5>Emergence Of Lamivudine-Resistant HBV</h5> <p>Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine).</p> <h4>Lactic Acidosis And Severe Hepatomegaly With Steatosis</h4> <p>Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir and lamivudine (components of EPZICOM). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Treatment with EPZICOM should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.</p> <h4>Immune Reconstitution Syndrome</h4> <p>Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EPZICOM. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as <i>Mycobacterium avium</i> infection, cytomegalovirus, <i>Pneumocystis jirovecii</i> pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.</p> <p>Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.</p> <h4>Myocardial Infarction</h4> <p>Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain the potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir treatment and the risk of MI is inconclusive.</p> <p>As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).</p> <h4>Patient Counseling Information</h4> <p>Advise the patient to read the FDA-approved patient labeling (<b>Medication Guide</b>).</p> <h5>Hypersensitivity Reactions Inform Patients</h5> <ul> <li>that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of EPZICOM and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about EPZICOM. The complete text of the Medication Guide is reprinted at the end of this document.</li> <li>to carry the Warning Card with them.</li> <li>how to identify a hypersensitivity reaction [see <b>WARNINGS AND PRECAUTIONS</b>, <b>PATIENT INFORMATION</b>].</li> <li>that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking EPZICOM.</li> <li>that a hypersensitivity reaction can worsen and lead to hospitalization or death if EPZICOM is not immediately discontinued.</li> <li>to not restart EPZICOM or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.</li> <li>that if they have a hypersensitivity reaction, they should dispose of any unused EPZICOM to avoid restarting abacavir.</li> <li>that a hypersensitivity reaction is usually reversible if it is detected promptly and EPZICOM is stopped right away.</li> <li>that if they have interrupted EPZICOM for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.</li> <li>to not restart EPZICOM or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.</li> </ul> <h5>Patients With Hepatitis B Or C Co-Infection</h5> <p>Advise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their physician [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Lactic Acidosis/Hepatomegaly With Steatosis</h5> <p>Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking EPZICOM if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Immune Reconstitution Syndrome</h5> <p>Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when EPZICOM is started [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Pregnancy Registry</h5> <p>Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EPZICOM during pregnancy [see <b>Use In Specific Populations</b>].</p> <h5>Lactation</h5> <p>Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see <b>Use In Specific Populations</b>].</p> <h5>Missed Dose</h5> <p>Instruct patients that if they miss a dose of EPZICOM, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <h5>Availability Of Medication Guide</h5> <p>Instruct patients to read the Medication Guide before starting EPZICOM and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.</p> <p>EPIVIR, EPZICOM, TRIZIVIR, and ZIAGEN are trademarks owned by or licensed to the ViiV Healthcare group of companies.</p> <p>The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.</p> <h4>Nonclinical Toxicology</h4> <h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4> <h5>Carcinogenicity</h5> <p><i>Abacavir</i></p> <p>Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg.</p> <p><i>Lamivudine</i></p> <p>Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.</p> <h5>Mutagenicity</h5> <p><i>Abacavir</i></p> <p>Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an <i>in vitro</i> cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an <i>in vivo</i> mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.</p> <p><i>Lamivudine</i></p> <p>Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an <i>in vitro</i> cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.</p> <h5>Impairment Of Fertility</h5> <p><i>Abacavir</i></p> <p>Abacavir did not affect male or female fertility in rats at a dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.</p> <p><i>Lamivudine</i></p> <p>Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (Cmax) in humans at the dose of 300 mg.</p> <a name="USP"></a> <h4>Use In Specific Populations</h4> <h4>Pregnancy</h4> <h5>Pregnancy Exposure Registry</h5> <p>There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EPZICOM during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.</p> <h5>Risk Summary</h5> <p>Available data from the APR show no difference in the overall risk of birth defects for abacavir or lamivudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see <b>Data</b>). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.</p> <p>In animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose. However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately 9 times the human exposure (AUC) at the recommended clinical dose. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the recommended clinical dose (see <b>Data</b>).</p> <h5>Data</h5> <p><i>Human Data</i></p> <p><i>Abacavir</i></p> <p>Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the</p> <p>U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4.0%) following second/third trimester exposure to abacavir-containing regimens.</p> <p>Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p><i>Lamivudine</i></p> <p>Based on prospective reports to the APR of exposures to lamivudine during pregnancy resulting in live births (including over 5,300 exposed in the first trimester and over 7,400 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5%, 3.3%) following second/third trimester exposure to lamivudinecontaining regimens.</p> <p>Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8).</p> <p><i>Animal Data</i></p> <p><i>Abacavir</i></p> <p>Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on Gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately 4 times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the recommended dose.</p> <p><i>Lamivudine</i></p> <p>Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300 and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, were not affected by the maternal administration of lamivudine.</p> <h4>Lactation</h4> <h5>Risk Summary</h5> <p>The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir and lamivudine are present in human milk. There is no information on the effects of abacavir and lamivudine on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving EPZICOM.</p> <h4>Pediatric Use</h4> <p>The dosing recommendations in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or EPZICOM [see <b>DOSAGE AND ADMINISTRATION</b>, <b>ADVERSE REACTIONS</b>, <b>Clinical Studies</b>].</p> <p>In pediatric patients weighing less than 25 kg, use of abacavir and lamivudine as single products is recommended to achieve appropriate dosing.</p> <h4>Geriatric Use</h4> <p>Clinical trials of abacavir and lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of EPZICOM in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see <b>DOSAGE AND ADMINISTRATION</b>, <b>Patients With Impaired Renal Function, Patients With Impaired Hepatic Function</b>].</p> <h4>Patients With Impaired Renal Function</h4> <p>EPZICOM is not recommended for patients with creatinine clearance less than 30 mL per min because EPZICOM is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of EPZICOM, is required for patients with creatinine clearance less than 30 mL per min, then the individual components should be used [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p>Patients with a creatinine clearance between 30 and 49 mL per min receiving EPZICOM may experience a 1.6-to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL per min. There are no safety data from randomized, controlled trials comparing EPZICOM to the individual components in patients with a creatinine clearance between 30 and 49 mL per min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of hematologic toxicities (neutropenia and anemia), although discontinuations due to neutropenia or anemia each occurred in <1% of subjects. Patients with a sustained creatinine clearance between 30 and 49 mL per min who receive EPZICOM should be monitored for hematologic toxicities. If new or worsening neutropenia or anemia develop, dose adjustment of lamivudine, per lamivudine prescribing information, is recommended. If lamivudine dose adjustment is indicated, EPZICOM should be discontinued and the individual components should be used to construct the treatment regimen.</p> <h4>Patients With Impaired Hepatic Function</h4> <p>EPZICOM is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of EPZICOM, is required for patients with mild hepatic impairment (Child-Pugh Class A), then the individual components should be used [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p>The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment; therefore, EPZICOM is contraindicated in these patients [see <b>CONTRAINDICATIONS</b>].</p> </div> </div> </div> | 4 | 2023-02-01 17:38:24 | Abacavir Sulfate and Lamivudine Tablets (Epzicom) | A | HIV, NNRTIs | Epzicom | abacavir sulfate and lamivudine tablets | Epzicom | John P. Cunha, DO, FACOEP |
| 30 | 2023-02-23 11:36:54 | Overdose & Contraindications | <a name="OD"></a> <h3>OVERDOSE</h3> <p>There is no known specific treatment for overdose with EPZICOM. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.</p> <h4>Abacavir</h4> <p>It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.</p> <h4>Lamivudine</h4> <p>Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.</p> <a name="CI"></a> <h3>CONTRAINDICATIONS</h3> <p>EPZICOM is contraindicated in patients:</p> <ul> <li>who have the HLA-B*5701 allele [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>with prior hypersensitivity reaction to abacavir [see <b>WARNINGS AND PRECAUTIONS</b>] or lamivudine.</li> <li>with moderate or severe hepatic impairment [see <b>Use In Specific Populations</b>].</li> </ul> </div> </div> </div> | <a name="OD"></a> <h3>OVERDOSE</h3> <p>There is no known specific treatment for overdose with EPZICOM. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.</p> <h4>Abacavir</h4> <p>It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.</p> <h4>Lamivudine</h4> <p>Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.</p> <a name="CI"></a> <h3>CONTRAINDICATIONS</h3> <p>EPZICOM is contraindicated in patients:</p> <ul> <li>who have the HLA-B*5701 allele [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>with prior hypersensitivity reaction to abacavir [see <b>WARNINGS AND PRECAUTIONS</b>] or lamivudine.</li> <li>with moderate or severe hepatic impairment [see <b>Use In Specific Populations</b>].</li> </ul> </div> </div> </div> | 4 | 2023-02-01 17:38:24 | Abacavir Sulfate and Lamivudine Tablets (Epzicom) | A | HIV, NNRTIs | Epzicom | abacavir sulfate and lamivudine tablets | Epzicom | John P. Cunha, DO, FACOEP |
| 31 | 2023-02-23 12:07:03 | Clinical Pharmacology | <a name="CP"></a> <h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism Of Action</h4> <p>EPZICOM is an antiretroviral agent with activity against HIV-1 [see <b>Microbiology</b>].</p> <h4>Pharmacokinetics</h4> <h5>Pharmacokinetics In Adults</h5> <p>In a single-dose, 3-way crossover bioavailability trial of 1 EPZICOM tablet versus 2 ZIAGEN tablets (2 x 300 mg) and 2 EPIVIR tablets (2 x 150 mg) administered simultaneously in healthy subjects (n = 25), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of each component.</p> <p><i>Abacavir</i></p> <p>Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 ± 1.19 mcg per mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg•hour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5′-carboxylic acid and glucuronyl transferase to form the 5′-glucuronide.</p> <p><i>Lamivudine</i></p> <p>Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state Cmax (Cmax,ss) was 2.04 ± 0.54 mcg per mL (mean ± SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 ± 1.83 mcg•hour per mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).</p> <p>In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 (CYP) enzymes.</p> <p>The pharmacokinetic properties of abacavir and lamivudine in fasting subjects are summarized in Table 2.</p> <p align="center"><b>Table 2. Pharmacokinetic Parameters<sup>a</sup> for Abacavir and Lamivudine in Adults</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="40%">Parameter</td> <td class="EmphTd" colspan="2">Abacavir</td> <td class="EmphTd" colspan="2">Lamivudine</td> </tr> <tr> <td>Oral bioavailability (%)</td> <td align="center" width="20%">86 ± 25</td> <td align="center" width="10%">n = 6</td> <td align="center" width="20%">86 ± 16</td> <td align="center" width="10%">n = 12</td> </tr> <tr> <td>Apparent volume of distribution (L/kg)</td> <td align="center">0.86 ± 0.15</td> <td align="center">n = 6</td> <td align="center">1.3 ± 0.4</td> <td align="center">n = 20</td> </tr> <tr> <td>Systemic clearance (L/h/kg)</td> <td align="center">0.80 ± 0.24</td> <td align="center">n = 6</td> <td align="center">0.33 ± 0.06</td> <td align="center">n = 20</td> </tr> <tr> <td>Renal clearance (L/h/kg)</td> <td align="center">0.007 ± 0.008</td> <td align="center">n = 6</td> <td align="center">0.22 ± 0.06</td> <td align="center">n = 20</td> </tr> <tr> <td>Elimination half-life (h)</td> <td align="center">1.45 ± 0.32</td> <td align="center">n = 20</td> <td align="center" colspan="2">13 to 19<sup>b</sup></td> </tr> <tr> <td class="credit" colspan="5"><sup>a</sup> Data presented as mean ± standard deviation except where noted.<br /> <sup>b</sup> Approximate range.</td> </tr> </tbody> </table> </center> <p></p> <h5>Effect Of Food On Absorption Of EPZICOM</h5> <p>EPZICOM may be administered with or without food. Administration with a high-fat meal in a single-dose bioavailability trial resulted in no change in AUClast, AUC∞, and Cmax for lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC∞), but the rate of absorption (Cmax) was decreased approximately 24% compared with fasted conditions (n = 25). These results are similar to those from previous trials of the effect of food on abacavir and lamivudine tablets administered separately.</p> <h4>Specific Populations</h4> <h5>Patients With Renal Impairment</h5> <p>The pharmacokinetics for the individual lamivudine component of EPZICOM has been evaluated in patients with renal impairment (see the U.S. prescribing information for the individual lamivudine component).</p> <h5>Patients With Hepatic Impairment</h5> <p>The pharmacokinetics for the individual components of EPZICOM have been evaluated in patients with varying degrees of hepatic impairment (see the U.S. prescribing information for the individual abacavir and lamivudine components).</p> <h5>Pregnant Women</h5> <p><i>Abacavir</i></p> <p>Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in <a href="/postpartum/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">postpartum</a> and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in <a href="/neonatal/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">neonatal</a> plasma <a href="/cord/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cord</a> samples at birth were essentially equal to those in maternal plasma at delivery.</p> <p><i>Lamivudine</i></p> <p>Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and <a href="/umbilical_cord/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">umbilical cord</a> serum samples.</p> <h5>Pediatric Patients</h5> <p><i>Abacavir and Lamivudine</i></p> <p>The pharmacokinetic data for abacavir and lamivudine following administration of EPZICOM in pediatric subjects weighing 25 kg and above are limited. The dosing recommendations in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or EPZICOM. Refer to the EPIVIR and ZIAGEN USPI for pharmacokinetic information on the individual products in pediatric patients [see <b>DOSAGE AND ADMINISTRATION</b>, <b>ADVERSE REACTIONS</b>, <b>Clinical Studies</b>].</p> <p><i>Geriatric Patients</i></p> <p>The pharmacokinetics of abacavir and lamivudine have not been studied in subjects over 65 years of age.</p> <p><i>Male and Female Patients</i></p> <p>There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components.</p> <p><i>Racial Groups</i></p> <p>There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components.</p> <h4>Drug Interaction Studies</h4> <p>The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities; no drug interaction trials have been conducted with EPZICOM.</p> <h5>Effect of Abacavir and Lamivudine on the Pharmacokinetics of Other Agents:</h5> <p><i>In vitro</i> studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit <a href="/metabolism/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">metabolism</a> mediated by CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6). Based on <i>in vitro</i> study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic <a href="/anion/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">anion</a> transporter <a href="/polypeptide/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">polypeptide</a> (OATP)1B1/3, <a href="/breast_cancer_facts_stages/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">breast cancer</a> resistance protein (BCRP) or P-<a href="/glycoprotein/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">glycoprotein</a> (P-gp), organic cation transporter (OCT)1, OCT2, OCT3 (lamivudine only), or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.</p> <h5>Riociguat</h5> <p>Coadministration of a single dose of riociguat (0.5 mg) to HIV-1–infected subjects receiving fixed-dose abacavir/dolutegravir/lamivudine is reported to increase riociguat AUC(∞) compared with riociguat AUC(∞) reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see <b>DRUG INTERACTIONS</b> ].</p> <h5>Effect of Other Agents on the Pharmacokinetics of Abacavir or Lamivudine</h5> <p>Abacavir and lamivudine are not significantly metabolized by CYP enzymes; therefore, CYP enzyme inhibitors or inducers are not expected to affect their concentrations. <i>In vitro</i>, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein 2 (MRP2) or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is a substrate of BCRP and P-gp <i>in vitro</i>; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations.</p> <p>Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 <i>in vitro</i>. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.</p> <p>Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.</p> <h5>Abacavir</h5> <p><i>Lamivudine and/or Zidovudine</i></p> <p>Fifteen HIV-1-infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.</p> <h5>Lamivudine</h5> <p><i>Zidovudine</i></p> <p>No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 <a href="/asymptomatic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">asymptomatic</a> HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 h).</p> <h5>Other Interactions</h5> <p><i>Ethanol</i></p> <p>Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.</p> <p><i>Interferon Alfa</i></p> <p>There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.</p> <p><i>Methadone</i></p> <p>In a trial of 11 HIV-1-infected subjects receiving <a href="/methadone/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">methadone</a>-<a href="/maintenance_therapy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">maintenance therapy</a> (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see <b>DRUG INTERACTIONS</b> ]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.</p> <p><i>Ribavirin</i></p> <p><i>In vitro</i> data indicate ribavirin reduces <a href="/phosphorylation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">phosphorylation</a> of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.</p> <p><i>Sorbitol (Excipient)</i></p> <p>Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24); 14%, 32%, and 36% in the AUC(∞); and 28%, 52%, and 55% in the Cmax; of lamivudine, respectively.</p> <p>The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 3.</p> <p align="center"><b>Table 3. Effect of Coadministered Drugs on Abacavir or Lamivudine</b></p> <center> <table cellspacing="0" class="blacktbl" width="550"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="20%">Coadministered Drug and Dose</td> <td class="EmphTd" rowspan="2" width="20%">Drug and Dose</td> <td class="EmphTd" rowspan="2" width="10%">n</td> <td class="EmphTd" colspan="2">Concentrations of Abacavir or Lamivudine</td> <td class="EmphTd" rowspan="2" width="20%">Concentration of Coadministered Drug</td> </tr> <tr> <td class="EmphTd" width="10%">AUC</td> <td class="EmphTd" width="20%">Variability</td> </tr> <tr> <td>Ethanol 0.7 g/kg</td> <td align="center">Abacavir Single 600 mg</td> <td align="center">24</td> <td align="center">↑41%</td> <td align="center">90% CI:<br /> 35% to 48%</td> <td align="center">↔<sup>a</sup></td> </tr> <tr> <td>Nelfinavir 750 mg every 8 h x 7 to 10 days</td> <td align="center">Lamivudine Single 150 mg</td> <td align="center">11</td> <td align="center">↑10%</td> <td align="center">95% CI:<br /> 1% to 20%</td> <td align="center">↔</td> </tr> <tr> <td>Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days</td> <td align="center">Lamivudine Single 300 mg</td> <td align="center">14</td> <td align="center">↑43%</td> <td align="center">90% CI:<br /> 32% to 55%</td> <td align="center">↔</td> </tr> <tr> <td class="credit" colspan="6">↑ = Increase; ↔ = No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval.<br /> <sup>a</sup> The drug-drug interaction was only evaluated in males.</td> </tr> </tbody> </table> </center> <p></p> <h4>Microbiology</h4> <h5>Mechanism Of Action</h5> <p><i>Abacavir</i></p> <p>Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.</p> <p><i>Lamivudine</i></p> <p>Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.</p> <h5>Antiviral Activity</h5> <p><i>Abacavir</i></p> <p>The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC<sub>50</sub> values ranged from 3,700 to 5,800 nM (1 nM = 0.28 ng per mL) and 70 to 1,000 nM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC<sub>50</sub> value was 260 ± 180 nM against 8 clinical isolates. The median EC<sub>50</sub> values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC<sub>50</sub> values against HIV-2 isolates (n = 4) ranged from 24 to 490 nM.</p> <p><i>Lamivudine</i></p> <p>The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC<sub>50</sub> values were in the range of 3 to 15,000 nM (1 nM = 0.23 ng per mL). The median EC<sub>50</sub> values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC<sub>50</sub> values against HIV-2 isolates (n = 4) ranged from 3 to 120 nM in PBMCs. Ribavirin (50,000 nM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.</p> <p>The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture against non-subtype B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates. Neither abacavir, nor lamivudine, were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Ribavirin, used in the treatment of HCV infection, decreased the anti-HIV-1 potency of abacavir/lamivudine reproducibly by 2-to 6-fold in cell culture.</p> <h5>Resistance</h5> <p>HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions K65R, L74V, Y115F, and M184V/I emerging in HIV-1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7-to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.</p> <h5>Cross-Resistance</h5> <p>Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors (NRTIs). The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with thymidine analog mutation substitutions (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.</p> <a name="AP"></a> <h4>Animal Toxicology And/Or Pharmacology</h4> <p>Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.</p> <a name="CS"></a> <h4>Clinical Studies</h4> <h4>Adults</h4> <p>One EPZICOM tablet given once daily is an alternative regimen to EPIVIR tablets 300 mg once daily plus ZIAGEN tablets 2 x 300 mg once daily as a component of antiretroviral therapy.</p> <p>The following trial was conducted with the individual components of EPZICOM.</p> <h5>Therapy-Naive Adults</h5> <p>CNA30021 was an international, multicenter, double-blind, controlled trial in which 770 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with EPIVIR 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had a mean age of 37 years; were male (81%), white (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells per mm<sup>3</sup> (range: 21 to 918 cells per mm<sup>3</sup>) and the median baseline plasma HIV-1 RNA was 4.89 log10 copies per mL (range: 2.60 to 6.99 log10 copies per mL).</p> <p>The outcomes of randomized treatment are provided in Table 4.</p> <p align="center"><b>Table 4. Outcomes of Randomized Treatment through Week 48 (CNA30021)</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Outcome</td> <td class="EmphTd" width="25%">ZIAGEN 600 mg q.d. plus EPIVIR plus<br /> Efavirenz<br /> (n = 384)</td> <td class="EmphTd" width="25%">ZIAGEN 300 mg b.i.d. plus EPIVIR plus<br /> Efavirenz<br /> (n = 386)</td> </tr> <tr> <td>Responder<sup>a</sup></td> <td align="center">64% (71%)</td> <td align="center">65% (72%)</td> </tr> <tr> <td>Virologic failure<sup>b</sup></td> <td align="center">11% (5%)</td> <td align="center">11% (5%)</td> </tr> <tr> <td>Discontinued due to adverse reactions</td> <td align="center">13%</td> <td align="center">11%</td> </tr> <tr> <td>Discontinued due to other reasons<sup>c</sup></td> <td align="center">11%</td> <td align="center">11%</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Subjects achieved and maintained confirmed HIV-1 RNA less than 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test version 1.0).<br /> <sup>b</sup> Includes viral rebound, failure to achieve confirmed less than 50 copies per mL (less than 400 copies per mL) by Week 48, and insufficient viral load response.<br /> <sup>c</sup> Includes consent withdrawn, lost to follow-up, protocol violations, clinical progression, and other.</td> </tr> </tbody> </table> </center> <p></p> <p>After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells per mm<sup>3</sup> in the group receiving ZIAGEN 600 mg once daily and 200 cells per mm<sup>3</sup> in the group receiving ZIAGEN 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications.</p> <h4>Pediatric Subjects</h4> <p>ARROW (COL105677) was a 5-year, randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1–infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing abacavir and lamivudine, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks of treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of abacavir and lamivudine, in combination with a third antiretroviral drug, for an additional 96 weeks. Virologic suppression was not a requirement for participation at baseline for Randomization 3. At baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared with 71% of subjects in the once-daily cohort.</p> <p>Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Subjects randomized to receive once-daily dosing (n = 336) and who weighed at least 25 kg received abacavir 600 mg and lamivudine 300 mg, as either the single entities or as EPZICOM.</p> <p>The proportions of subjects with HIV-1 RNA less than 80 copies per mL through 96 weeks are shown in Table 5. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.</p> <p align="center"><b>Table 5. Virologic Outcome of Randomized Treatment at Week 96<sup>a</sup> (ARROW Randomization 3)</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Outcome</td> <td class="EmphTd" width="25%">Abacavir plus Lamivudine Twice-Daily Dosing<br /> (n = 333)</td> <td class="EmphTd" width="25%">Abacavir plus Lamivudine Once-Daily Dosing<br /> (n = 336)</td> </tr> <tr> <td><b>HIV-1 RNA <80 copies/mL<sup>b</sup></b></td> <td align="center">70%</td> <td align="center">67%</td> </tr> <tr> <td><b>HIV-1 RNA ≥80 copies/mL<sup>c</sup></b></td> <td align="center">28%</td> <td align="center">31%</td> </tr> <tr> <td><b>No virologic data</b></td> <td align="center">28%</td> <td align="center">31%</td> </tr> <tr> <td> Discontinued due to adverse event or death</td> <td align="center">1%</td> <td align="center"><1%</td> </tr> <tr> <td> Discontinued study for other reasons<sup>d</sup></td> <td align="center">0%</td> <td align="center"><1%</td> </tr> <tr> <td> Missing data during window but on study</td> <td align="center">1%</td> <td align="center">1%</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Analyses were based on the last observed viral load data within the Week 96 window.<br /> <sup>b</sup> Risk difference (95% CI) of response rate is -2.4% (-9% to 5%) at Week 96.<br /> <sup>c</sup> Includes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol.<br /> <sup>d</sup> Other includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing).</td> </tr> </tbody> </table> </center> <p></p> </div> </div> </div> | <a name="CP"></a> <h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism Of Action</h4> <p>EPZICOM is an antiretroviral agent with activity against HIV-1 [see <b>Microbiology</b>].</p> <h4>Pharmacokinetics</h4> <h5>Pharmacokinetics In Adults</h5> <p>In a single-dose, 3-way crossover bioavailability trial of 1 EPZICOM tablet versus 2 ZIAGEN tablets (2 x 300 mg) and 2 EPIVIR tablets (2 x 150 mg) administered simultaneously in healthy subjects (n = 25), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of each component.</p> <p><i>Abacavir</i></p> <p>Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 ± 1.19 mcg per mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg•hour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5′-carboxylic acid and glucuronyl transferase to form the 5′-glucuronide.</p> <p><i>Lamivudine</i></p> <p>Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state Cmax (Cmax,ss) was 2.04 ± 0.54 mcg per mL (mean ± SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 ± 1.83 mcg•hour per mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).</p> <p>In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 (CYP) enzymes.</p> <p>The pharmacokinetic properties of abacavir and lamivudine in fasting subjects are summarized in Table 2.</p> <p align="center"><b>Table 2. Pharmacokinetic Parameters<sup>a</sup> for Abacavir and Lamivudine in Adults</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="40%">Parameter</td> <td class="EmphTd" colspan="2">Abacavir</td> <td class="EmphTd" colspan="2">Lamivudine</td> </tr> <tr> <td>Oral bioavailability (%)</td> <td align="center" width="20%">86 ± 25</td> <td align="center" width="10%">n = 6</td> <td align="center" width="20%">86 ± 16</td> <td align="center" width="10%">n = 12</td> </tr> <tr> <td>Apparent volume of distribution (L/kg)</td> <td align="center">0.86 ± 0.15</td> <td align="center">n = 6</td> <td align="center">1.3 ± 0.4</td> <td align="center">n = 20</td> </tr> <tr> <td>Systemic clearance (L/h/kg)</td> <td align="center">0.80 ± 0.24</td> <td align="center">n = 6</td> <td align="center">0.33 ± 0.06</td> <td align="center">n = 20</td> </tr> <tr> <td>Renal clearance (L/h/kg)</td> <td align="center">0.007 ± 0.008</td> <td align="center">n = 6</td> <td align="center">0.22 ± 0.06</td> <td align="center">n = 20</td> </tr> <tr> <td>Elimination half-life (h)</td> <td align="center">1.45 ± 0.32</td> <td align="center">n = 20</td> <td align="center" colspan="2">13 to 19<sup>b</sup></td> </tr> <tr> <td class="credit" colspan="5"><sup>a</sup> Data presented as mean ± standard deviation except where noted.<br /> <sup>b</sup> Approximate range.</td> </tr> </tbody> </table> </center> <p></p> <h5>Effect Of Food On Absorption Of EPZICOM</h5> <p>EPZICOM may be administered with or without food. Administration with a high-fat meal in a single-dose bioavailability trial resulted in no change in AUClast, AUC∞, and Cmax for lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC∞), but the rate of absorption (Cmax) was decreased approximately 24% compared with fasted conditions (n = 25). These results are similar to those from previous trials of the effect of food on abacavir and lamivudine tablets administered separately.</p> <h4>Specific Populations</h4> <h5>Patients With Renal Impairment</h5> <p>The pharmacokinetics for the individual lamivudine component of EPZICOM has been evaluated in patients with renal impairment (see the U.S. prescribing information for the individual lamivudine component).</p> <h5>Patients With Hepatic Impairment</h5> <p>The pharmacokinetics for the individual components of EPZICOM have been evaluated in patients with varying degrees of hepatic impairment (see the U.S. prescribing information for the individual abacavir and lamivudine components).</p> <h5>Pregnant Women</h5> <p><i>Abacavir</i></p> <p>Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in <a href="/postpartum/definition.htm" ">postpartum</a> and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in <a href="/neonatal/definition.htm" ">neonatal</a> plasma <a href="/cord/definition.htm" ">cord</a> samples at birth were essentially equal to those in maternal plasma at delivery.</p> <p><i>Lamivudine</i></p> <p>Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and <a href="/umbilical_cord/definition.htm" ">umbilical cord</a> serum samples.</p> <h5>Pediatric Patients</h5> <p><i>Abacavir and Lamivudine</i></p> <p>The pharmacokinetic data for abacavir and lamivudine following administration of EPZICOM in pediatric subjects weighing 25 kg and above are limited. The dosing recommendations in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or EPZICOM. Refer to the EPIVIR and ZIAGEN USPI for pharmacokinetic information on the individual products in pediatric patients [see <b>DOSAGE AND ADMINISTRATION</b>, <b>ADVERSE REACTIONS</b>, <b>Clinical Studies</b>].</p> <p><i>Geriatric Patients</i></p> <p>The pharmacokinetics of abacavir and lamivudine have not been studied in subjects over 65 years of age.</p> <p><i>Male and Female Patients</i></p> <p>There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components.</p> <p><i>Racial Groups</i></p> <p>There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (abacavir or lamivudine) based on the available information that was analyzed for each of the individual components.</p> <h4>Drug Interaction Studies</h4> <p>The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities; no drug interaction trials have been conducted with EPZICOM.</p> <h5>Effect of Abacavir and Lamivudine on the Pharmacokinetics of Other Agents:</h5> <p><i>In vitro</i> studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit <a href="/metabolism/definition.htm" ">metabolism</a> mediated by CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6). Based on <i>in vitro</i> study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic <a href="/anion/definition.htm" ">anion</a> transporter <a href="/polypeptide/definition.htm" ">polypeptide</a> (OATP)1B1/3, <a href="/breast_cancer_facts_stages/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">breast cancer</a> resistance protein (BCRP) or P-<a href="/glycoprotein/definition.htm" ">glycoprotein</a> (P-gp), organic cation transporter (OCT)1, OCT2, OCT3 (lamivudine only), or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.</p> <h5>Riociguat</h5> <p>Coadministration of a single dose of riociguat (0.5 mg) to HIV-1–infected subjects receiving fixed-dose abacavir/dolutegravir/lamivudine is reported to increase riociguat AUC(∞) compared with riociguat AUC(∞) reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see <b>DRUG INTERACTIONS</b> ].</p> <h5>Effect of Other Agents on the Pharmacokinetics of Abacavir or Lamivudine</h5> <p>Abacavir and lamivudine are not significantly metabolized by CYP enzymes; therefore, CYP enzyme inhibitors or inducers are not expected to affect their concentrations. <i>In vitro</i>, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein 2 (MRP2) or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is a substrate of BCRP and P-gp <i>in vitro</i>; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations.</p> <p>Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 <i>in vitro</i>. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.</p> <p>Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.</p> <h5>Abacavir</h5> <p><i>Lamivudine and/or Zidovudine</i></p> <p>Fifteen HIV-1-infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.</p> <h5>Lamivudine</h5> <p><i>Zidovudine</i></p> <p>No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 <a href="/asymptomatic/definition.htm" ">asymptomatic</a> HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 h).</p> <h5>Other Interactions</h5> <p><i>Ethanol</i></p> <p>Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.</p> <p><i>Interferon Alfa</i></p> <p>There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.</p> <p><i>Methadone</i></p> <p>In a trial of 11 HIV-1-infected subjects receiving <a href="/methadone/definition.htm" ">methadone</a>-<a href="/maintenance_therapy/definition.htm" ">maintenance therapy</a> (40 mg and 90 mg daily), with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see <b>DRUG INTERACTIONS</b> ]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.</p> <p><i>Ribavirin</i></p> <p><i>In vitro</i> data indicate ribavirin reduces <a href="/phosphorylation/definition.htm" ">phosphorylation</a> of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.</p> <p><i>Sorbitol (Excipient)</i></p> <p>Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24); 14%, 32%, and 36% in the AUC(∞); and 28%, 52%, and 55% in the Cmax; of lamivudine, respectively.</p> <p>The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 3.</p> <p align="center"><b>Table 3. Effect of Coadministered Drugs on Abacavir or Lamivudine</b></p> <center> <table cellspacing="0" class="blacktbl" width="550"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="20%">Coadministered Drug and Dose</td> <td class="EmphTd" rowspan="2" width="20%">Drug and Dose</td> <td class="EmphTd" rowspan="2" width="10%">n</td> <td class="EmphTd" colspan="2">Concentrations of Abacavir or Lamivudine</td> <td class="EmphTd" rowspan="2" width="20%">Concentration of Coadministered Drug</td> </tr> <tr> <td class="EmphTd" width="10%">AUC</td> <td class="EmphTd" width="20%">Variability</td> </tr> <tr> <td>Ethanol 0.7 g/kg</td> <td align="center">Abacavir Single 600 mg</td> <td align="center">24</td> <td align="center">↑41%</td> <td align="center">90% CI:<br /> 35% to 48%</td> <td align="center">↔<sup>a</sup></td> </tr> <tr> <td>Nelfinavir 750 mg every 8 h x 7 to 10 days</td> <td align="center">Lamivudine Single 150 mg</td> <td align="center">11</td> <td align="center">↑10%</td> <td align="center">95% CI:<br /> 1% to 20%</td> <td align="center">↔</td> </tr> <tr> <td>Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days</td> <td align="center">Lamivudine Single 300 mg</td> <td align="center">14</td> <td align="center">↑43%</td> <td align="center">90% CI:<br /> 32% to 55%</td> <td align="center">↔</td> </tr> <tr> <td class="credit" colspan="6">↑ = Increase; ↔ = No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval.<br /> <sup>a</sup> The drug-drug interaction was only evaluated in males.</td> </tr> </tbody> </table> </center> <p></p> <h4>Microbiology</h4> <h5>Mechanism Of Action</h5> <p><i>Abacavir</i></p> <p>Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.</p> <p><i>Lamivudine</i></p> <p>Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.</p> <h5>Antiviral Activity</h5> <p><i>Abacavir</i></p> <p>The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC<sub>50</sub> values ranged from 3,700 to 5,800 nM (1 nM = 0.28 ng per mL) and 70 to 1,000 nM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC<sub>50</sub> value was 260 ± 180 nM against 8 clinical isolates. The median EC<sub>50</sub> values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC<sub>50</sub> values against HIV-2 isolates (n = 4) ranged from 24 to 490 nM.</p> <p><i>Lamivudine</i></p> <p>The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC<sub>50</sub> values were in the range of 3 to 15,000 nM (1 nM = 0.23 ng per mL). The median EC<sub>50</sub> values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC<sub>50</sub> values against HIV-2 isolates (n = 4) ranged from 3 to 120 nM in PBMCs. Ribavirin (50,000 nM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.</p> <p>The combination of abacavir and lamivudine has demonstrated antiviral activity in cell culture against non-subtype B isolates and HIV-2 isolates with equivalent antiviral activity as for subtype B isolates. Neither abacavir, nor lamivudine, were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Ribavirin, used in the treatment of HCV infection, decreased the anti-HIV-1 potency of abacavir/lamivudine reproducibly by 2-to 6-fold in cell culture.</p> <h5>Resistance</h5> <p>HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions K65R, L74V, Y115F, and M184V/I emerging in HIV-1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7-to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.</p> <h5>Cross-Resistance</h5> <p>Cross-resistance has been observed among nucleoside reverse transcriptase inhibitors (NRTIs). The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with thymidine analog mutation substitutions (TAMs: M41L, D67N, K70R, L210W, T215Y/F, K219E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.</p> <a name="AP"></a> <h4>Animal Toxicology And/Or Pharmacology</h4> <p>Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.</p> <a name="CS"></a> <h4>Clinical Studies</h4> <h4>Adults</h4> <p>One EPZICOM tablet given once daily is an alternative regimen to EPIVIR tablets 300 mg once daily plus ZIAGEN tablets 2 x 300 mg once daily as a component of antiretroviral therapy.</p> <p>The following trial was conducted with the individual components of EPZICOM.</p> <h5>Therapy-Naive Adults</h5> <p>CNA30021 was an international, multicenter, double-blind, controlled trial in which 770 HIV-1-infected, therapy-naive adults were randomized and received either ZIAGEN 600 mg once daily or ZIAGEN 300 mg twice daily, both in combination with EPIVIR 300 mg once daily and efavirenz 600 mg once daily. The double-blind treatment duration was at least 48 weeks. Trial participants had a mean age of 37 years; were male (81%), white (54%), black (27%), and American Hispanic (15%). The median baseline CD4+ cell count was 262 cells per mm<sup>3</sup> (range: 21 to 918 cells per mm<sup>3</sup>) and the median baseline plasma HIV-1 RNA was 4.89 log10 copies per mL (range: 2.60 to 6.99 log10 copies per mL).</p> <p>The outcomes of randomized treatment are provided in Table 4.</p> <p align="center"><b>Table 4. Outcomes of Randomized Treatment through Week 48 (CNA30021)</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Outcome</td> <td class="EmphTd" width="25%">ZIAGEN 600 mg q.d. plus EPIVIR plus<br /> Efavirenz<br /> (n = 384)</td> <td class="EmphTd" width="25%">ZIAGEN 300 mg b.i.d. plus EPIVIR plus<br /> Efavirenz<br /> (n = 386)</td> </tr> <tr> <td>Responder<sup>a</sup></td> <td align="center">64% (71%)</td> <td align="center">65% (72%)</td> </tr> <tr> <td>Virologic failure<sup>b</sup></td> <td align="center">11% (5%)</td> <td align="center">11% (5%)</td> </tr> <tr> <td>Discontinued due to adverse reactions</td> <td align="center">13%</td> <td align="center">11%</td> </tr> <tr> <td>Discontinued due to other reasons<sup>c</sup></td> <td align="center">11%</td> <td align="center">11%</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Subjects achieved and maintained confirmed HIV-1 RNA less than 50 copies per mL (less than 400 copies per mL) through Week 48 (Roche AMPLICOR Ultrasensitive HIV-1 MONITOR standard test version 1.0).<br /> <sup>b</sup> Includes viral rebound, failure to achieve confirmed less than 50 copies per mL (less than 400 copies per mL) by Week 48, and insufficient viral load response.<br /> <sup>c</sup> Includes consent withdrawn, lost to follow-up, protocol violations, clinical progression, and other.</td> </tr> </tbody> </table> </center> <p></p> <p>After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells per mm<sup>3</sup> in the group receiving ZIAGEN 600 mg once daily and 200 cells per mm<sup>3</sup> in the group receiving ZIAGEN 300 mg twice daily. Through Week 48, 6 subjects (2%) in the group receiving ZIAGEN 600 mg once daily (4 CDC classification C events and 2 deaths) and 10 subjects (3%) in the group receiving ZIAGEN 300 mg twice daily (7 CDC classification C events and 3 deaths) experienced clinical disease progression. None of the deaths were attributed to trial medications.</p> <h4>Pediatric Subjects</h4> <p>ARROW (COL105677) was a 5-year, randomized, multicenter trial which evaluated multiple aspects of clinical management of HIV-1 infection in pediatric subjects. HIV-1–infected, treatment-naïve subjects aged 3 months to 17 years were enrolled and treated with a first-line regimen containing abacavir and lamivudine, dosed twice daily according to World Health Organization recommendations. After a minimum of 36 weeks of treatment, subjects were given the option to participate in Randomization 3 of the ARROW trial, comparing the safety and efficacy of once-daily dosing with twice-daily dosing of abacavir and lamivudine, in combination with a third antiretroviral drug, for an additional 96 weeks. Virologic suppression was not a requirement for participation at baseline for Randomization 3. At baseline for Randomization 3 (following a minimum of 36 weeks of twice-daily treatment), 75% of subjects in the twice-daily cohort were virologically suppressed, compared with 71% of subjects in the once-daily cohort.</p> <p>Of the 1,206 original ARROW subjects, 669 participated in Randomization 3. Subjects randomized to receive once-daily dosing (n = 336) and who weighed at least 25 kg received abacavir 600 mg and lamivudine 300 mg, as either the single entities or as EPZICOM.</p> <p>The proportions of subjects with HIV-1 RNA less than 80 copies per mL through 96 weeks are shown in Table 5. The differences between virologic responses in the two treatment arms were comparable across baseline characteristics for gender and age.</p> <p align="center"><b>Table 5. Virologic Outcome of Randomized Treatment at Week 96<sup>a</sup> (ARROW Randomization 3)</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Outcome</td> <td class="EmphTd" width="25%">Abacavir plus Lamivudine Twice-Daily Dosing<br /> (n = 333)</td> <td class="EmphTd" width="25%">Abacavir plus Lamivudine Once-Daily Dosing<br /> (n = 336)</td> </tr> <tr> <td><b>HIV-1 RNA <80 copies/mL<sup>b</sup></b></td> <td align="center">70%</td> <td align="center">67%</td> </tr> <tr> <td><b>HIV-1 RNA ≥80 copies/mL<sup>c</sup></b></td> <td align="center">28%</td> <td align="center">31%</td> </tr> <tr> <td><b>No virologic data</b></td> <td align="center">28%</td> <td align="center">31%</td> </tr> <tr> <td> Discontinued due to adverse event or death</td> <td align="center">1%</td> <td align="center"><1%</td> </tr> <tr> <td> Discontinued study for other reasons<sup>d</sup></td> <td align="center">0%</td> <td align="center"><1%</td> </tr> <tr> <td> Missing data during window but on study</td> <td align="center">1%</td> <td align="center">1%</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Analyses were based on the last observed viral load data within the Week 96 window.<br /> <sup>b</sup> Risk difference (95% CI) of response rate is -2.4% (-9% to 5%) at Week 96.<br /> <sup>c</sup> Includes subjects who discontinued due to lack or loss of efficacy or for reasons other than an adverse event or death, and had a viral load value of greater than or equal to 80 copies per mL, or subjects who had a switch in background regimen that was not permitted by the protocol.<br /> <sup>d</sup> Other includes reasons such as withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA less than 80 copies per mL (or missing).</td> </tr> </tbody> </table> </center> <p></p> </div> </div> </div> | 4 | 2023-02-01 17:38:24 | Abacavir Sulfate and Lamivudine Tablets (Epzicom) | A | HIV, NNRTIs | Epzicom | abacavir sulfate and lamivudine tablets | Epzicom | John P. Cunha, DO, FACOEP |
| 32 | 2023-02-23 12:07:03 | Medication Guide | <a name="PI"></a> <h3>PATIENT INFORMATION</h3> <p><b>EPZICOM</b><br /> (ep' zih com)<br /> (abacavir and lamivudine tablets)</p> <p><b>What is the most important information I should know about EPZICOM?</b></p> <p><b>EPZICOM can cause serious side effects, including:</b></p> <ul> <li><b>Serious allergic reactions (hypersensitivity reaction)</b> that can cause death have happened with EPZICOM and other abacavir-containing products. Your risk of this allergic reaction is much higher if you have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.</li> </ul> <p><b>If you get a symptom from 2 or more of the following groups while taking EPZICOM, call your healthcare provider right away to find out if you should stop taking EPZICOM.</b></p> <p></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="30%"></td> <td class="EmphTd" width="70%">Symptom(s)</td> </tr> <tr> <td>Group 1</td> <td>Fever</td> </tr> <tr> <td>Group 2</td> <td>Rash</td> </tr> <tr> <td>Group 3</td> <td>Nausea, vomiting, diarrhea, abdominal (stomach area) pain</td> </tr> <tr> <td>Group 4</td> <td>Generally ill feeling, extreme tiredness, or achiness</td> </tr> <tr> <td>Group 5</td> <td>Shortness of breath, cough, sore throat</td> </tr> </tbody> </table> </center> <p></p> <p>A list of these symptoms is on the Warning Card your pharmacist gives you. <b>Carry this Warning Card with you at all times.</b></p> <p><b>If you stop EPZICOM because of an allergic reaction, never take EPZICOM (abacavir and lamivudine) or any other abacavir-containing medicine (TRIUMEQ, TRIZIVIR, or ZIAGEN) again.</b></p> <ul> <li> <ul> <li>If you have an allergic reaction, dispose of any unused EPZICOM. Ask your pharmacist how to properly dispose of medicines.</li> <li>If you take EPZICOM or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get life-threatening symptoms that may include very <a href="/low_blood_pressure_hypotension_causes/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">low blood pressure</a> or death.</li> <li>If you stop EPZICOM for any other reason, even for a few days, and you are not allergic to EPZICOM, talk with your healthcare provider before taking it again. Taking EPZICOM again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.</li> </ul> </li> </ul> <p><b>If your healthcare provider tells you that you can take EPZICOM again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.</b></p> <ul> <li><b>Worsening of hepatitis B virus (HBV) infection.</b> If you have HBV infection and take EPZICOM, your HBV may get worse (flare-up) if you stop taking EPZICOM. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. <ul> <li>Do not run out of EPZICOM. Refill your prescription or talk to your healthcare provider before your EPZICOM is all gone.</li> <li>Do not stop EPZICOM without first talking to your healthcare provider.</li> <li>If you stop taking EPZICOM, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you a medicine to treat HBV. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking EPZICOM.</li> </ul> </li> <li><b>Resistant HBV.</b> If you have human <a href="/immunodeficiency/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">immunodeficiency</a> virus-1 (HIV-1) and HBV, the HBV can change (mutate) during your treatment with EPZICOM and become harder to treat (resistant).</li> <li><b>For more information about side effects, see “What are the possible side effects of EPZICOM?”</b></li> </ul> <p><b>What is EPZICOM?</b></p> <p>EPZICOM is a prescription medicine used with other HIV-1 medicines to treat HIV-1 infection.</p> <p>HIV-1 is the virus that causes <a href="/acquired/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Acquired</a> Immune Deficiency Syndrome (<a href="/acquired_immunodeficiency_syndrome_aids/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">AIDS</a>).</p> <p>EPZICOM contains the prescription medicines abacavir and lamivudine .</p> <p>EPZICOM should not be used in children weighing less than 55 pounds (25 kg).</p> <p><b>Do not take EPZICOM if you:</b></p> <ul> <li>have a certain type of gene variation called the HLA-B*5701 allele. Your healthcare provider will test you for this before prescribing treatment with EPZICOM.</li> <li>are allergic to abacavir, lamivudine, or any of the ingredients in EPZICOM. See the end of this Medication Guide for a complete list of ingredients in EPZICOM.</li> <li>have certain liver problems.</li> </ul> <p><b>Before you take EPZICOM tell your healthcare provider about all of your medical conditions, including if you:</b></p> <ul> <li>have been tested and know whether or not you have a particular gene variation called HLA-B*5701.</li> <li>have or have had liver problems, including hepatitis B or C virus infection.</li> <li>have kidney problems.</li> <li>have heart problems, smoke, or have diseases that increase your risk of <a href="/heart_disease/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">heart disease</a> such as <a href="/high_blood_pressure_hypertension_medications/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">high blood pressure</a>, high <a href="/cholesterol/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cholesterol</a>, or <a href="/diabetes_mellitus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">diabetes</a>.</li> <li>are pregnant or plan to become pregnant.</li> </ul> <p><b>Pregnancy Registry.</b> There is a pregnancy registry for women who take HIV-1 medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.</p> <ul> <li>are breastfeeding or plan to breastfeed. <b>Do not breastfeed if you take EPZICOM</b>. <ul> <li>You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.</li> </ul> </li> </ul> <p><b>Tell your healthcare provider about all the medicines you take,</b> including prescription and over-thecounter medicines, vitamins, and herbal supplements.</p> <p>Some medicines interact with EPZICOM. <b>Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.</b></p> <ul> <li>You can ask your healthcare provider or pharmacist for a list of medicines that interact with EPZICOM.</li> <li><b>Do not start taking a new medicine without telling your healthcare provider.</b> Your healthcare provider can tell you if it is safe to take EPZICOM with other medicines.</li> </ul> <p><b>How should I take EPZICOM?</b></p> <ul> <li><b>Take EPZICOM exactly as your healthcare provider tells you to take it.</b></li> <li>Do not change your dose or stop taking EPZICOM without talking with your healthcare provider.</li> <li>If you miss a dose of EPZICOM, take it as soon as you remember. Do not take 2 doses at the same time or take more than your healthcare provider tells you to take.</li> <li>Stay under the care of a healthcare provider during treatment with EPZICOM.</li> <li>EPZICOM may be taken with or without food.</li> <li>Tell your healthcare provider if your child has trouble swallowing EPZICOM tablets.</li> <li>Do not run out of EPZICOM. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy</li> <li>If you take too much EPZICOM, call your healthcare provider or go to the nearest hospital emergency room right away.</li> </ul> <p><b>What are the possible side effects of EPZICOM?</b></p> <ul> <li><b>EPZICOM can cause serious side effects including:</b></li> <li><b>See “What is the most important information I should know about EPZICOM?”</b></li> <li><b>Too much lactic acid in your blood (lactic acidosis).</b><b> Lactic acidosis is a serious medical emergency that can cause death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:</b> <ul> <li>feel very weak or tired</li> <li>unusual (not normal) <a href="/muscle_pain/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">muscle pain</a></li> <li>trouble breathing</li> <li>stomach pain with <a href="/nausea_and_vomiting/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">nausea and vomiting</a></li> <li>feel cold, especially in your arms and legs</li> <li>feel dizzy or light-headed</li> <li>have a fast or irregular heartbeat</li> </ul> </li> <li><b>Severe liver problems.</b> In some cases, severe liver problems can lead to death. Your liver may become large (<a href="/hepatomegaly/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hepatomegaly</a>) and you may develop fat in your liver (steatosis).<b>Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:</b> <ul> <li>your skin or the white part of your eyes turns yellow (jaundice)</li> <li>dark or “tea-colored” urine</li> <li>light-colored stools (bowel movements)</li> <li>loss of appetite for several days or longer</li> <li>nausea</li> <li>pain, aching, or tenderness on the right side of your stomach area</li> </ul> </li> </ul> <p><b>You may be more likely to get lactic acidosis or serious liver problems if you are female or very overweight (obese).</b></p> <ul> <li><b>Changes in your immune system (Immune Reconstitution Syndrome)</b> can happen when you start taking HIV-1 medicines. Your <a href="/immune_system/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">immune system</a> may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking EPZICOM.</li> <li><b>Heart attack .</b> Some HIV-1 medicines including EPZICOM may increase your risk of <a href="/heart_attack/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">heart attack</a>.</li> </ul> <p><b>The most common side effects of EPZICOM include:</b></p> <ul> <li>allergic reactions</li> <li>trouble sleeping</li> <li>depression</li> <li>headache or <a href="/migraine/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">migraine</a></li> <li>tiredness or weakness</li> <li>dizziness</li> <li>nausea</li> <li>diarrhea</li> </ul> <p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of EPZICOM. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <p><b>How should I store EPZICOM?</b></p> <ul> <li>Store EPZICOM at room temperature.</li> </ul> <p><b>Keep EPZICOM and all medicines out of the reach of children.</b></p> <p><b>General information for safe and effective use of EPZICOM.</b></p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EPZICOM for a condition for which it was not prescribed. Do not give EPZICOM to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for the information about EPZICOM that is written for health professionals.</p> <p><b>What are the ingredients in EPZICOM?</b></p> <p>Active ingredients: abacavir and lamivudine</p> <p>Inactive ingredients: magnesium stearate, microcrystalline cellulose, sodium starch glycolate.</p> <p>Tablet film coating contains: OPADRY orange YS-1-13065-A made of FD&C Yellow No. 6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide.</p> <p class="credit">This Medication Guide has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | <a name="PI"></a> <h3>PATIENT INFORMATION</h3> <p><b>EPZICOM</b><br /> (ep' zih com)<br /> (abacavir and lamivudine tablets)</p> <p><b>What is the most important information I should know about EPZICOM?</b></p> <p><b>EPZICOM can cause serious side effects, including:</b></p> <ul> <li><b>Serious allergic reactions (hypersensitivity reaction)</b> that can cause death have happened with EPZICOM and other abacavir-containing products. Your risk of this allergic reaction is much higher if you have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.</li> </ul> <p><b>If you get a symptom from 2 or more of the following groups while taking EPZICOM, call your healthcare provider right away to find out if you should stop taking EPZICOM.</b></p> <p></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="30%"></td> <td class="EmphTd" width="70%">Symptom(s)</td> </tr> <tr> <td>Group 1</td> <td>Fever</td> </tr> <tr> <td>Group 2</td> <td>Rash</td> </tr> <tr> <td>Group 3</td> <td>Nausea, vomiting, diarrhea, abdominal (stomach area) pain</td> </tr> <tr> <td>Group 4</td> <td>Generally ill feeling, extreme tiredness, or achiness</td> </tr> <tr> <td>Group 5</td> <td>Shortness of breath, cough, sore throat</td> </tr> </tbody> </table> </center> <p></p> <p>A list of these symptoms is on the Warning Card your pharmacist gives you. <b>Carry this Warning Card with you at all times.</b></p> <p><b>If you stop EPZICOM because of an allergic reaction, never take EPZICOM (abacavir and lamivudine) or any other abacavir-containing medicine (TRIUMEQ, TRIZIVIR, or ZIAGEN) again.</b></p> <ul> <li> <ul> <li>If you have an allergic reaction, dispose of any unused EPZICOM. Ask your pharmacist how to properly dispose of medicines.</li> <li>If you take EPZICOM or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get life-threatening symptoms that may include very <a href="/low_blood_pressure_hypotension_causes/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">low blood pressure</a> or death.</li> <li>If you stop EPZICOM for any other reason, even for a few days, and you are not allergic to EPZICOM, talk with your healthcare provider before taking it again. Taking EPZICOM again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.</li> </ul> </li> </ul> <p><b>If your healthcare provider tells you that you can take EPZICOM again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.</b></p> <ul> <li><b>Worsening of hepatitis B virus (HBV) infection.</b> If you have HBV infection and take EPZICOM, your HBV may get worse (flare-up) if you stop taking EPZICOM. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. <ul> <li>Do not run out of EPZICOM. Refill your prescription or talk to your healthcare provider before your EPZICOM is all gone.</li> <li>Do not stop EPZICOM without first talking to your healthcare provider.</li> <li>If you stop taking EPZICOM, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you a medicine to treat HBV. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking EPZICOM.</li> </ul> </li> <li><b>Resistant HBV.</b> If you have human <a href="/immunodeficiency/definition.htm" ">immunodeficiency</a> virus-1 (HIV-1) and HBV, the HBV can change (mutate) during your treatment with EPZICOM and become harder to treat (resistant).</li> <li><b>For more information about side effects, see “What are the possible side effects of EPZICOM?”</b></li> </ul> <p><b>What is EPZICOM?</b></p> <p>EPZICOM is a prescription medicine used with other HIV-1 medicines to treat HIV-1 infection.</p> <p>HIV-1 is the virus that causes <a href="/acquired/definition.htm" ">Acquired</a> Immune Deficiency Syndrome (<a href="/acquired_immunodeficiency_syndrome_aids/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">AIDS</a>).</p> <p>EPZICOM contains the prescription medicines abacavir and lamivudine .</p> <p>EPZICOM should not be used in children weighing less than 55 pounds (25 kg).</p> <p><b>Do not take EPZICOM if you:</b></p> <ul> <li>have a certain type of gene variation called the HLA-B*5701 allele. Your healthcare provider will test you for this before prescribing treatment with EPZICOM.</li> <li>are allergic to abacavir, lamivudine, or any of the ingredients in EPZICOM. See the end of this Medication Guide for a complete list of ingredients in EPZICOM.</li> <li>have certain liver problems.</li> </ul> <p><b>Before you take EPZICOM tell your healthcare provider about all of your medical conditions, including if you:</b></p> <ul> <li>have been tested and know whether or not you have a particular gene variation called HLA-B*5701.</li> <li>have or have had liver problems, including hepatitis B or C virus infection.</li> <li>have kidney problems.</li> <li>have heart problems, smoke, or have diseases that increase your risk of <a href="/heart_disease/definition.htm" ">heart disease</a> such as <a href="/high_blood_pressure_hypertension_medications/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">high blood pressure</a>, high <a href="/cholesterol/definition.htm" ">cholesterol</a>, or <a href="/diabetes_mellitus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">diabetes</a>.</li> <li>are pregnant or plan to become pregnant.</li> </ul> <p><b>Pregnancy Registry.</b> There is a pregnancy registry for women who take HIV-1 medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.</p> <ul> <li>are breastfeeding or plan to breastfeed. <b>Do not breastfeed if you take EPZICOM</b>. <ul> <li>You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.</li> </ul> </li> </ul> <p><b>Tell your healthcare provider about all the medicines you take,</b> including prescription and over-thecounter medicines, vitamins, and herbal supplements.</p> <p>Some medicines interact with EPZICOM. <b>Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.</b></p> <ul> <li>You can ask your healthcare provider or pharmacist for a list of medicines that interact with EPZICOM.</li> <li><b>Do not start taking a new medicine without telling your healthcare provider.</b> Your healthcare provider can tell you if it is safe to take EPZICOM with other medicines.</li> </ul> <p><b>How should I take EPZICOM?</b></p> <ul> <li><b>Take EPZICOM exactly as your healthcare provider tells you to take it.</b></li> <li>Do not change your dose or stop taking EPZICOM without talking with your healthcare provider.</li> <li>If you miss a dose of EPZICOM, take it as soon as you remember. Do not take 2 doses at the same time or take more than your healthcare provider tells you to take.</li> <li>Stay under the care of a healthcare provider during treatment with EPZICOM.</li> <li>EPZICOM may be taken with or without food.</li> <li>Tell your healthcare provider if your child has trouble swallowing EPZICOM tablets.</li> <li>Do not run out of EPZICOM. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy</li> <li>If you take too much EPZICOM, call your healthcare provider or go to the nearest hospital emergency room right away.</li> </ul> <p><b>What are the possible side effects of EPZICOM?</b></p> <ul> <li><b>EPZICOM can cause serious side effects including:</b></li> <li><b>See “What is the most important information I should know about EPZICOM?”</b></li> <li><b>Too much lactic acid in your blood (lactic acidosis).</b><b> Lactic acidosis is a serious medical emergency that can cause death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:</b> <ul> <li>feel very weak or tired</li> <li>unusual (not normal) <a href="/muscle_pain/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">muscle pain</a></li> <li>trouble breathing</li> <li>stomach pain with <a href="/nausea_and_vomiting/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">nausea and vomiting</a></li> <li>feel cold, especially in your arms and legs</li> <li>feel dizzy or light-headed</li> <li>have a fast or irregular heartbeat</li> </ul> </li> <li><b>Severe liver problems.</b> In some cases, severe liver problems can lead to death. Your liver may become large (<a href="/hepatomegaly/definition.htm" ">hepatomegaly</a>) and you may develop fat in your liver (steatosis).<b>Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:</b> <ul> <li>your skin or the white part of your eyes turns yellow (jaundice)</li> <li>dark or “tea-colored” urine</li> <li>light-colored stools (bowel movements)</li> <li>loss of appetite for several days or longer</li> <li>nausea</li> <li>pain, aching, or tenderness on the right side of your stomach area</li> </ul> </li> </ul> <p><b>You may be more likely to get lactic acidosis or serious liver problems if you are female or very overweight (obese).</b></p> <ul> <li><b>Changes in your immune system (Immune Reconstitution Syndrome)</b> can happen when you start taking HIV-1 medicines. Your <a href="/immune_system/definition.htm" ">immune system</a> may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking EPZICOM.</li> <li><b>Heart attack .</b> Some HIV-1 medicines including EPZICOM may increase your risk of <a href="/heart_attack/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">heart attack</a>.</li> </ul> <p><b>The most common side effects of EPZICOM include:</b></p> <ul> <li>allergic reactions</li> <li>trouble sleeping</li> <li>depression</li> <li>headache or <a href="/migraine/definition.htm" ">migraine</a></li> <li>tiredness or weakness</li> <li>dizziness</li> <li>nausea</li> <li>diarrhea</li> </ul> <p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of EPZICOM. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <p><b>How should I store EPZICOM?</b></p> <ul> <li>Store EPZICOM at room temperature.</li> </ul> <p><b>Keep EPZICOM and all medicines out of the reach of children.</b></p> <p><b>General information for safe and effective use of EPZICOM.</b></p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use EPZICOM for a condition for which it was not prescribed. Do not give EPZICOM to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for the information about EPZICOM that is written for health professionals.</p> <p><b>What are the ingredients in EPZICOM?</b></p> <p>Active ingredients: abacavir and lamivudine</p> <p>Inactive ingredients: magnesium stearate, microcrystalline cellulose, sodium starch glycolate.</p> <p>Tablet film coating contains: OPADRY orange YS-1-13065-A made of FD&C Yellow No. 6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide.</p> <p class="credit">This Medication Guide has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | 4 | 2023-02-01 17:38:24 | Abacavir Sulfate and Lamivudine Tablets (Epzicom) | A | HIV, NNRTIs | Epzicom | abacavir sulfate and lamivudine tablets | Epzicom | John P. Cunha, DO, FACOEP |
| 33 | 2023-02-23 12:07:03 | Drug Description | <div class="webmdrx"> <a href="https://www.webmd.com/rx/drug-prices/abacavir-lamivudine-zidovudine?ecd=oo_webmdrx_rx-mono_rx/drug-prices/abacavir-lamivudine-zidovudine_dsktp_rxlist.com//rx/drug-prices/abacavir-lamivudine-zidovudine" target="_blank" onclick="wmdPageLink('webmdrx');"><p class="webmdrx_p">Find Lowest Prices on <span class="webmdrx_img"></span></p></a> </div> <h4>What is Trizivir and how is it used?</h4> <p>Trizivir is a prescription medicine used to treat the symptoms of <a href="/hiv/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HIV</a> Infection. Trizivir may be used alone or with other medications.</p> <p>Trizivir belongs to a class of drugs called HIV, ART Combos.</p> <p>It is not known if Trizivir is safe and effective in children weighing less than 88 pounds (40 kilos).</p> <h4>What are the possible side effects of Trizivir?</h4> <p>Trizivir may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>fever,</li> <li>rash,</li> <li>nausea,</li> <li>vomiting,</li> <li>stomach pain,</li> <li>feeling <a href="/unwell/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">unwell</a>,</li> <li>extreme tiredness,</li> <li>body aches,</li> <li>shortness of breath,</li> <li><a href="/sore_throat_pharyngitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">sore throat</a>,</li> <li><a href="/night_sweats/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">night sweats</a>,</li> <li>swollen glands,</li> <li><a href="/herpes_simplex_infections_non-genital/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">cold sores</a>,</li> <li>cough,</li> <li><a href="/wheezing/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">wheezing</a>,</li> <li>diarrhea,</li> <li>weight loss,</li> <li>trouble speaking or swallowing,</li> <li>problems with balance or eye movement,</li> <li>weakness or prickly feeling,</li> <li>swelling in your neck or throat (<a href="/enlarged_thyroid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">enlarged thyroid</a>),</li> <li>menstrual changes, and</li> <li><a href="/impotence/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">impotence</a></li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Trizivir include:</p> <ul> <li>headache,</li> <li>weakness,</li> <li>tiredness,</li> <li>nausea,</li> <li>vomiting, and</li> <li>changes in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and waist)</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Trizivir. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p align="center"><b>HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B</b></p> <h4>Hypersensitivity Reactions</h4> <p><b>Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of TRIZIVIR (abacavir, lamivudine, and zidovudine). Patients who carry the HLA B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA B*5701 allele [see <b>WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a></b>].</b></p> <p><b>TRIZIVIR is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA B*5701-positive patients [see <a href="/trizivir-drug.htm#CI"><b>CONTRAINDICATIONS</b></a>, <b>WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a></b>]. All patients should be screened for the <a href="/hla/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HLA</a>�B*5701 <a href="/allele/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">allele</a> prior to initiating therapy with TRIZIVIR or reinitiation of therapy with TRIZIVIR, unless patients have a previously documented HLA B*5701 allele assessment. Discontinue TRIZIVIR immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see <a href="/trizivir-drug.htm#CI"><b>CONTRAINDICATIONS</b></a>, <b>WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a></b>].</b></p> <p><b>Following a hypersensitivity reaction to TRIZIVIR, NEVER restart TRIZIVIR or any other abacavircontaining product because more severe symptoms, including death, can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a>].</b></p> <h4>Hematologic Toxicity</h4> <p><b>Zidovudine, a component of TRIZIVIR, has been associated with hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV1) disease [see WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a></b>].</p> <h4>Myopathy</h4> <p><b>Prolonged use of zidovudine has been associated with symptomatic <a href="/myopathy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">myopathy</a> [see <b>WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a></b>].</b></p> <h4>Lactic Acidosis and Severe Hepatomegaly with Steatosis</h4> <p><b><a href="/lactic_acidosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Lactic acidosis</a> and severe <a href="/hepatomegaly/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hepatomegaly</a> with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidos is or pronounced hepatotoxicity occur [see <b>WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a></b>].</b></p> <h4>Exacerbations of Hepatitis B</h4> <p><b>Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with hepatitis B virus (HBV) and HIV1 and have discontinued lamivudine, a component of TRIZIVIR. Hepatic function should be monitored closely with both clinical and laboratory follow-up for atleast several months in patients who discontinue TRIZIVIR and are co-infected with HIV1 and HBV. If appropriate, initiation of antihepatitis B therapy may be warranted [see WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a>]</b>.</p> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <p>TRIZIVIR tablets contain the following 3 synthetic nucleoside analogues: abacavir (ZIAGEN), lamivudine (also known as EPIVIR or 3TC), and zidovudine (also known as RETROVIR, azidothymidine, or ZDV) with inhibitory activity against HIV-1.</p> <p>TRIZIVIR tablets are for oral administration. Each film-coated tablet contains the active ingredients 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine, and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film (OPADRY green 03B11434) that is made of FD&C Blue No. 2, hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide.</p> <h4>Abacavir Sulfate</h4> <p>The chemical name of abacavir sulfate is (1<i>S</i>,<i>cis</i>)-4-[2-amino-6-(cyclopropylamino)- 9<i>H</i>-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with <i>1S</i>, <i>4R</i> absolute configuration on the cyclopentene ring. It has a molecular formula of (C<sub>14</sub>H<sub>18</sub>N<sub>6</sub>O)<sub>2</sub>•H<sub>2</sub>SO<sub>4</sub> and a molecular weight of 670.76 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="352"> <tbody> <tr> <td><img alt="Abacavir - Structural Formula Illustration" height="280" src="https://images.rxlist.com/images/rxlist/trizivir1.gif" width="352" /></td> </tr> </tbody> </table> </center> <p></p> <p>Abacavir sulfate is a white to off-white solid and soluble in water. Dosages are expressed in terms of abacavir.</p> <h4>Lamivudine</h4> <p>The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3- oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2',3'-dideoxy, 3'-thiacytidine. It has a molecular formula of C<sub>8</sub>H<sub>11</sub>N<sub>3</sub>O<sub>3</sub>S and a molecular weight of 229.3 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="243"> <tbody> <tr> <td><img alt="Lamivudine - Structural Formula Illustration" height="215" src="https://images.rxlist.com/images/rxlist/trizivir2.gif" width="243" /></td> </tr> </tbody> </table> </center> <p></p> <p>Lamivudine is a white to off-white crystalline solid and is soluble in water.</p> <h4>Zidovudine</h4> <p>The chemical name of zidovudine is 3'-azido-3'-deoxythymidine. It has a molecular formula of C<sub>10</sub>H<sub>13</sub>N<sub>5</sub>O<sub>4</sub> and a molecular weight of 267.24 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="159"> <tbody> <tr> <td><img alt="Zidovudine - Structural Formula Illustration" height="206" src="https://images.rxlist.com/images/rxlist/trizivir3.gif" width="159" /></td> </tr> </tbody> </table> </center> <p></p> <p>Zidovudine is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg per mL in water at 25°C.</p> </div> <div id="667441035-1" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-1", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <div class="webmdrx"> <a href="https://www.webmd.com/rx/drug-prices/abacavir-lamivudine-zidovudine?ecd=oo_webmdrx_rx-mono_rx/drug-prices/abacavir-lamivudine-zidovudine_dsktp_rxlist.com//rx/drug-prices/abacavir-lamivudine-zidovudine" target="_blank" onclick="wmdPageLink('webmdrx');"><p class="webmdrx_p">Find Lowest Prices on <span class="webmdrx_img"></span></p></a> </div> <h4>What is Trizivir and how is it used?</h4> <p>Trizivir is a prescription medicine used to treat the symptoms of <a href="/hiv/definition.htm" ">HIV</a> Infection. Trizivir may be used alone or with other medications.</p> <p>Trizivir belongs to a class of drugs called HIV, ART Combos.</p> <p>It is not known if Trizivir is safe and effective in children weighing less than 88 pounds (40 kilos).</p> <h4>What are the possible side effects of Trizivir?</h4> <p>Trizivir may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>fever,</li> <li>rash,</li> <li>nausea,</li> <li>vomiting,</li> <li>stomach pain,</li> <li>feeling <a href="/unwell/definition.htm" ">unwell</a>,</li> <li>extreme tiredness,</li> <li>body aches,</li> <li>shortness of breath,</li> <li><a href="/sore_throat_pharyngitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">sore throat</a>,</li> <li><a href="/night_sweats/definition.htm" ">night sweats</a>,</li> <li>swollen glands,</li> <li><a href="/herpes_simplex_infections_non-genital/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">cold sores</a>,</li> <li>cough,</li> <li><a href="/wheezing/definition.htm" ">wheezing</a>,</li> <li>diarrhea,</li> <li>weight loss,</li> <li>trouble speaking or swallowing,</li> <li>problems with balance or eye movement,</li> <li>weakness or prickly feeling,</li> <li>swelling in your neck or throat (<a href="/enlarged_thyroid/definition.htm" ">enlarged thyroid</a>),</li> <li>menstrual changes, and</li> <li><a href="/impotence/definition.htm" ">impotence</a></li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Trizivir include:</p> <ul> <li>headache,</li> <li>weakness,</li> <li>tiredness,</li> <li>nausea,</li> <li>vomiting, and</li> <li>changes in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and waist)</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Trizivir. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p align="center"><b>HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B</b></p> <h4>Hypersensitivity Reactions</h4> <p><b>Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of TRIZIVIR (abacavir, lamivudine, and zidovudine). Patients who carry the HLA B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA B*5701 allele [see <b>WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a></b>].</b></p> <p><b>TRIZIVIR is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA B*5701-positive patients [see <a href="/trizivir-drug.htm#CI"><b>CONTRAINDICATIONS</b></a>, <b>WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a></b>]. All patients should be screened for the <a href="/hla/definition.htm" ">HLA</a>�B*5701 <a href="/allele/definition.htm" ">allele</a> prior to initiating therapy with TRIZIVIR or reinitiation of therapy with TRIZIVIR, unless patients have a previously documented HLA B*5701 allele assessment. Discontinue TRIZIVIR immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see <a href="/trizivir-drug.htm#CI"><b>CONTRAINDICATIONS</b></a>, <b>WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a></b>].</b></p> <p><b>Following a hypersensitivity reaction to TRIZIVIR, NEVER restart TRIZIVIR or any other abacavircontaining product because more severe symptoms, including death, can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a>].</b></p> <h4>Hematologic Toxicity</h4> <p><b>Zidovudine, a component of TRIZIVIR, has been associated with hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV1) disease [see WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a></b>].</p> <h4>Myopathy</h4> <p><b>Prolonged use of zidovudine has been associated with symptomatic <a href="/myopathy/definition.htm" ">myopathy</a> [see <b>WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a></b>].</b></p> <h4>Lactic Acidosis and Severe Hepatomegaly with Steatosis</h4> <p><b><a href="/lactic_acidosis/definition.htm" ">Lactic acidosis</a> and severe <a href="/hepatomegaly/definition.htm" ">hepatomegaly</a> with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine, and zidovudine (components of TRIZIVIR). Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidos is or pronounced hepatotoxicity occur [see <b>WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a></b>].</b></p> <h4>Exacerbations of Hepatitis B</h4> <p><b>Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with hepatitis B virus (HBV) and HIV1 and have discontinued lamivudine, a component of TRIZIVIR. Hepatic function should be monitored closely with both clinical and laboratory follow-up for atleast several months in patients who discontinue TRIZIVIR and are co-infected with HIV1 and HBV. If appropriate, initiation of antihepatitis B therapy may be warranted [see WARNINGS AND <a href="/trizivir-drug.htm#P">PRECAUTIONS</a>]</b>.</p> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <p>TRIZIVIR tablets contain the following 3 synthetic nucleoside analogues: abacavir (ZIAGEN), lamivudine (also known as EPIVIR or 3TC), and zidovudine (also known as RETROVIR, azidothymidine, or ZDV) with inhibitory activity against HIV-1.</p> <p>TRIZIVIR tablets are for oral administration. Each film-coated tablet contains the active ingredients 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine, and the inactive ingredients magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablets are coated with a film (OPADRY green 03B11434) that is made of FD&C Blue No. 2, hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide.</p> <h4>Abacavir Sulfate</h4> <p>The chemical name of abacavir sulfate is (1<i>S</i>,<i>cis</i>)-4-[2-amino-6-(cyclopropylamino)- 9<i>H</i>-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate is the enantiomer with <i>1S</i>, <i>4R</i> absolute configuration on the cyclopentene ring. It has a molecular formula of (C<sub>14</sub>H<sub>18</sub>N<sub>6</sub>O)<sub>2</sub>•H<sub>2</sub>SO<sub>4</sub> and a molecular weight of 670.76 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="352"> <tbody> <tr> <td><img alt="Abacavir - Structural Formula Illustration" height="280" src="https://images.rxlist.com/images/rxlist/trizivir1.gif" width="352" /></td> </tr> </tbody> </table> </center> <p></p> <p>Abacavir sulfate is a white to off-white solid and soluble in water. Dosages are expressed in terms of abacavir.</p> <h4>Lamivudine</h4> <p>The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3- oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2',3'-dideoxy, 3'-thiacytidine. It has a molecular formula of C<sub>8</sub>H<sub>11</sub>N<sub>3</sub>O<sub>3</sub>S and a molecular weight of 229.3 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="243"> <tbody> <tr> <td><img alt="Lamivudine - Structural Formula Illustration" height="215" src="https://images.rxlist.com/images/rxlist/trizivir2.gif" width="243" /></td> </tr> </tbody> </table> </center> <p></p> <p>Lamivudine is a white to off-white crystalline solid and is soluble in water.</p> <h4>Zidovudine</h4> <p>The chemical name of zidovudine is 3'-azido-3'-deoxythymidine. It has a molecular formula of C<sub>10</sub>H<sub>13</sub>N<sub>5</sub>O<sub>4</sub> and a molecular weight of 267.24 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="159"> <tbody> <tr> <td><img alt="Zidovudine - Structural Formula Illustration" height="206" src="https://images.rxlist.com/images/rxlist/trizivir3.gif" width="159" /></td> </tr> </tbody> </table> </center> <p></p> <p>Zidovudine is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg per mL in water at 25°C.</p> </div> <div id="667441035-1" class="medianet"><</div> </div> </div> | 5 | 2023-02-01 17:38:34 | Abacavir Sulfate, Lamivudine, and Zidovudine (Trizivir) | A | HIV, NNRTIs | Trizivir | abacavir sulfate, lamivudine, and zidovudine | Trizivir | John P. Cunha, DO, FACOEP |
| 34 | 2023-02-23 11:36:54 | Indications & Dosage | <div class="webmdrx_coup"> </div> <a name="I"></a><h3>INDICATIONS</h3><p>TRIZIVIR is indicated in combination with other antiretrovirals or alone for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.</p><h4>Limitations Of Use</h4><ul><li>Limited data exist on the use of TRIZIVIR alone in patients with higher baseline viral load levels (greater than 100,000 copies per mL) [see<b> Clinical Studies</b>].</li></ul> <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3><h4>Screening For HLA-B*5701 Allele Prior To Starting TRIZIVIR</h4><p>Screen for the HLA-B*5701 allele prior to initiating therapy with TRIZIVIR [see<b> BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</p><h4>Recommended Dosage For Adults and Pediatric Patients Weighing At Least 40 kg</h4><p>The recommended dosage of TRIZIVIR is one tablet taken orally twice daily with or without food.</p><h4>Not Recommended Due To Lack Of Dosage Adjustment</h4><p>Because TRIZIVIR is a fixed-dose tablet and cannot be dose adjusted, TRIZIVIR is not recommended for:</p><ul><li>pediatric patients who weigh less than 40 kg [see<b> Use In Specific Populations</b>].</li><li>patients with creatinine clearance less than 50 mL per minute [see <b>Use In Specific Populations</b>].</li><li>patients with mild hepatic impairment. TRIZIVIR is contraindicated in patients with moderate or severe hepatic impairment [see<b> CONTRAINDICATIONS</b>, <b>Use In Specific Populations</b>].</li></ul> <a name="HS"></a><h3>HOW SUPPLIED</h3><h4>Dosage Forms And Strengths</h4><p>TRIZIVIR tablets contain 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine. The tablets are blue-green, capsule-shaped, film-coated, and imprinted with “GX LL1” on one side with no markings on the reverse side.</p><h4>Storage And Handling</h4><p><b>TRIZIVIR</b> is available as tablets. Each tablet contains 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine. The tablets are blue-green capsule-shaped, film-coated, and imprinted with GX LL1 on one side with no markings on the reverse side. They are packaged as follows:</p><p class="EmphText">Bottles of 60 tablets (<b>NDC</b> 49702-217-18).</p><p>Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see <b>USP Controlled Room Temperature</b>).</p><p class="credit">Manufactured for: ViiV Healthcare, Research Triangle Park, NC 27709. Revised: Feb 2021</p> </div> <a class="mediaPrmo quiz" href="/quiz_hiv-aids/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/hivaids/hivaids-s1.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">What is HIV?</span> <span class="btn">See Answer</span> </a> </div> </div> | <div class="webmdrx_coup"> </div> <a name="I"></a><h3>INDICATIONS</h3><p>TRIZIVIR is indicated in combination with other antiretrovirals or alone for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.</p><h4>Limitations Of Use</h4><ul><li>Limited data exist on the use of TRIZIVIR alone in patients with higher baseline viral load levels (greater than 100,000 copies per mL) [see<b> Clinical Studies</b>].</li></ul> <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3><h4>Screening For HLA-B*5701 Allele Prior To Starting TRIZIVIR</h4><p>Screen for the HLA-B*5701 allele prior to initiating therapy with TRIZIVIR [see<b> BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</p><h4>Recommended Dosage For Adults and Pediatric Patients Weighing At Least 40 kg</h4><p>The recommended dosage of TRIZIVIR is one tablet taken orally twice daily with or without food.</p><h4>Not Recommended Due To Lack Of Dosage Adjustment</h4><p>Because TRIZIVIR is a fixed-dose tablet and cannot be dose adjusted, TRIZIVIR is not recommended for:</p><ul><li>pediatric patients who weigh less than 40 kg [see<b> Use In Specific Populations</b>].</li><li>patients with creatinine clearance less than 50 mL per minute [see <b>Use In Specific Populations</b>].</li><li>patients with mild hepatic impairment. TRIZIVIR is contraindicated in patients with moderate or severe hepatic impairment [see<b> CONTRAINDICATIONS</b>, <b>Use In Specific Populations</b>].</li></ul> <a name="HS"></a><h3>HOW SUPPLIED</h3><h4>Dosage Forms And Strengths</h4><p>TRIZIVIR tablets contain 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine. The tablets are blue-green, capsule-shaped, film-coated, and imprinted with “GX LL1” on one side with no markings on the reverse side.</p><h4>Storage And Handling</h4><p><b>TRIZIVIR</b> is available as tablets. Each tablet contains 300 mg of abacavir as abacavir sulfate, 150 mg of lamivudine, and 300 mg of zidovudine. The tablets are blue-green capsule-shaped, film-coated, and imprinted with GX LL1 on one side with no markings on the reverse side. They are packaged as follows:</p><p class="EmphText">Bottles of 60 tablets (<b>NDC</b> 49702-217-18).</p><p>Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see <b>USP Controlled Room Temperature</b>).</p><p class="credit">Manufactured for: ViiV Healthcare, Research Triangle Park, NC 27709. Revised: Feb 2021</p> </div> <a class="mediaPrmo quiz" href="/quiz_hiv-aids/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/hivaids/hivaids-s1.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">What is HIV?</span> <span class="btn">See Answer</span> </a> </div> </div> | 5 | 2023-02-01 17:38:34 | Abacavir Sulfate, Lamivudine, and Zidovudine (Trizivir) | A | HIV, NNRTIs | Trizivir | abacavir sulfate, lamivudine, and zidovudine | Trizivir | John P. Cunha, DO, FACOEP |
| 35 | 2023-02-23 11:36:54 | Side Effects | <a name="AR"></a><h3>SIDE EFFECTS</h3><p>The following adverse reactions are discussed in other sections of the labeling:</p><ul><li>Serious and sometimes fatal hypersensitivity reactions [see<b> BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Hematologic toxicity, including neutropenia and anemia [see <b>BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Symptomatic myopathy [see <b>BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Lactic acidosis and severe hepatomegaly with steatosis [see<b> BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Exacerbations of hepatitis B [see <b>BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see<b> WARNINGS AND PRECAUTIONS</b>].</li><li>Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see<b> WARNINGS AND PRECAUTIONS</b>].</li><li>Immune reconstitution syndrome [see<b> WARNINGS AND PRECAUTIONS</b>].</li><li>Lipoatrophy [see<b> WARNINGS AND PRECAUTIONS</b>].</li><li>Myocardial infarction [see<b> WARNINGS AND PRECAUTIONS</b>].</li></ul><h4>Clinical Trials Experience</h4><p>Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.</p><h5>Serious And Fatal Abacavir-Associated Hypersensitivity Reactions</h5><p>In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIZIVIR [see <b>BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.</p><p>Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized).</p><h5>Additional Adverse Reactions With Use Of TRIZIVIR</h5><p>Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a frequency greater than or equal to 5% during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 1.</p><p align="center"><b>Table 1: Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of Treatment</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Adverse Reaction</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine/ Zidovudine<br />(n = 262)</td><td class="EmphTd" width="25%">Indinavir plus Lamivudine /Zidovudine<br />(n = 264)</td></tr><tr><td>Nausea</td><td align="center">19%</td><td align="center">17%</td></tr><tr><td>Headache</td><td align="center">13%</td><td align="center">9%</td></tr><tr><td>Malaise and fatigue</td><td align="center">12%</td><td align="center">12%</td></tr><tr><td>Nausea and vomiting</td><td align="center">10%</td><td align="center">10%</td></tr><tr><td>Hypersensitivity reaction</td><td align="center">8%</td><td align="center">2%</td></tr><tr><td>Diarrhea</td><td align="center">7%</td><td align="center">5%</td></tr><tr><td>Fever and/or chills</td><td align="center">6%</td><td align="center">3%</td></tr><tr><td>Depressive disorders</td><td align="center">6%</td><td align="center">4%</td></tr><tr><td>Musculoskeletal pain</td><td align="center">5%</td><td align="center">7%</td></tr><tr><td>Skin rashes</td><td align="center">5%</td><td align="center">4%</td></tr><tr><td>Ear/nose/throat infections</td><td align="center">5%</td><td align="center">4%</td></tr><tr><td>Viral respiratory infections</td><td align="center">5%</td><td align="center">5%</td></tr><tr><td>Anxiety</td><td align="center">5%</td><td align="center">3%</td></tr><tr><td>Renal signs/symptoms</td><td align="center"><1%</td><td align="center">5%</td></tr><tr><td>Pain (non-site-specific)</td><td align="center"><1%</td><td align="center">5%</td></tr></tbody></table></center><p></p><p>Five subjects receiving abacavir in CNA3005 experienced worsening of pre-existing depression compared to none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.</p><h5>Laboratory Abnormalities</h5><p>Laboratory abnormalities in CNA3005 are listed in Table 2.</p><p align="center"><b>Table 2: Treatment-Emergent Laboratory Abnormalities (Grades 3/4) in CNA3005</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Laboratory Parameter</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine/ Zidovudine<br />(n = 262)</td><td class="EmphTd" width="25%">Indinavir plus Lamivudine/ Zidovudine<br />(n = 264)</td></tr><tr><td>Elevated CPK (>4 x ULN)</td><td align="center">18 (7%)</td><td align="center">18 (7%)</td></tr><tr><td>ALT (>5.0 x ULN)</td><td align="center">16 (6%)</td><td align="center">16 (6%)</td></tr><tr><td>Neutropenia (<750/mm³)</td><td align="center">13 (5%)</td><td align="center">13 (5%)</td></tr><tr><td>Hypertriglyceridemia (>750 mg/dL)</td><td align="center">5 (2%)</td><td align="center">3 (1%)</td></tr><tr><td>Hyperamylasemia (>2.0 x ULN)</td><td align="center">5 (2%)</td><td align="center">1 (<1%)</td></tr><tr><td>Hyperglycemia (>13.9 mmol/L)</td><td align="center">2 (<1%)</td><td align="center">2 (<1%)</td></tr><tr><td>Anemia (Hgb ≤6.9 g/dL)</td><td align="center">0 (0%)</td><td align="center">3 (1%)</td></tr><tr><td class="credit" colspan="3">ULN = Upper limit of normal.<br />n = Number of subjects assessed.</td></tr></tbody></table></center><p></p><h5>Other Adverse Events</h5><p>In addition to adverse reactions in Tables 1 and 2, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT.</p><h4>Postmarketing Experience</h4><p>The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.</p><h5>Abacavir</h5><p><b>Cardiovascular:</b> Myocardial infarction.</p><p><b>Skin:</b> Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use [see <b>ADVERSE REACTIONS</b>].</p><h5>Abacavir, Lamivudine, And/Or Zidovudine</h5><p><b>Body as a Whole:</b> Redistribution/accumulation of body fat.</p><p><b>Cardiovascular:</b> Cardiomyopathy.</p><p><b>Digestive:</b> Stomatitis.</p><p><b>Endocrine and Metabolic:</b> Gynecomastia.</p><p><b>Gastrointestinal:</b> Anorexia and/or decreased appetite, abdominal pain, dyspepsia, oral mucosal pigmentation.</p><p><b>General:</b> Vasculitis, weakness.</p><p><b>Hemic and Lymphatic:</b> Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly, thrombocytopenia.</p><p><b>Hepatic:</b> Lactic acidosis and hepatic steatosis [see<b> WARNINGS AND PRECAUTIONS</b>], elevated bilirubin, elevated transaminases, posttreatment exacerbations of hepatitis B [see <b>WARNINGS AND PRECAUTIONS</b>].</p><p><b>Hypersensitivity:</b> Sensitization reactions (including anaphylaxis), urticaria.</p><p><b>Musculoskeletal:</b> Arthralgia, myalgia, muscle weakness, rhabdomyolysis.</p><p><b>Nervous:</b> Dizziness, paresthesia, peripheral neuropathy, seizures.</p><p><b>Psychiatric:</b> Insomnia and other sleep disorders.</p><p><b>Respiratory:</b> Abnormal breath sounds/wheezing.</p><p><b>Skin:</b> Alopecia, erythema multiforme, Stevens-Johnson syndrome.</p> </div> </div> </div> | <a name="AR"></a><h3>SIDE EFFECTS</h3><p>The following adverse reactions are discussed in other sections of the labeling:</p><ul><li>Serious and sometimes fatal hypersensitivity reactions [see<b> BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Hematologic toxicity, including neutropenia and anemia [see <b>BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Symptomatic myopathy [see <b>BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Lactic acidosis and severe hepatomegaly with steatosis [see<b> BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Exacerbations of hepatitis B [see <b>BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li><li>Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C [see<b> WARNINGS AND PRECAUTIONS</b>].</li><li>Exacerbation of anemia in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine [see<b> WARNINGS AND PRECAUTIONS</b>].</li><li>Immune reconstitution syndrome [see<b> WARNINGS AND PRECAUTIONS</b>].</li><li>Lipoatrophy [see<b> WARNINGS AND PRECAUTIONS</b>].</li><li>Myocardial infarction [see<b> WARNINGS AND PRECAUTIONS</b>].</li></ul><h4>Clinical Trials Experience</h4><p>Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.</p><h5>Serious And Fatal Abacavir-Associated Hypersensitivity Reactions</h5><p>In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIZIVIR [see <b>BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.</p><p>Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia, and abnormal chest x-ray findings (predominantly infiltrates, which were localized).</p><h5>Additional Adverse Reactions With Use Of TRIZIVIR</h5><p>Treatment-emergent clinical adverse reactions (rated by the investigator as moderate or severe) with a frequency greater than or equal to 5% during therapy with abacavir 300 mg twice daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily compared with indinavir 800 mg 3 times daily, lamivudine 150 mg twice daily, and zidovudine 300 mg twice daily from CNA3005 are listed in Table 1.</p><p align="center"><b>Table 1: Treatment-Emergent (All Causality) Adverse Reactions of at Least Moderate Intensity (Grades 2-4, Greater than or Equal to 5% Frequency) in Therapy-Naive Adults (CNA3005) through 48 Weeks of Treatment</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Adverse Reaction</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine/ Zidovudine<br />(n = 262)</td><td class="EmphTd" width="25%">Indinavir plus Lamivudine /Zidovudine<br />(n = 264)</td></tr><tr><td>Nausea</td><td align="center">19%</td><td align="center">17%</td></tr><tr><td>Headache</td><td align="center">13%</td><td align="center">9%</td></tr><tr><td>Malaise and fatigue</td><td align="center">12%</td><td align="center">12%</td></tr><tr><td>Nausea and vomiting</td><td align="center">10%</td><td align="center">10%</td></tr><tr><td>Hypersensitivity reaction</td><td align="center">8%</td><td align="center">2%</td></tr><tr><td>Diarrhea</td><td align="center">7%</td><td align="center">5%</td></tr><tr><td>Fever and/or chills</td><td align="center">6%</td><td align="center">3%</td></tr><tr><td>Depressive disorders</td><td align="center">6%</td><td align="center">4%</td></tr><tr><td>Musculoskeletal pain</td><td align="center">5%</td><td align="center">7%</td></tr><tr><td>Skin rashes</td><td align="center">5%</td><td align="center">4%</td></tr><tr><td>Ear/nose/throat infections</td><td align="center">5%</td><td align="center">4%</td></tr><tr><td>Viral respiratory infections</td><td align="center">5%</td><td align="center">5%</td></tr><tr><td>Anxiety</td><td align="center">5%</td><td align="center">3%</td></tr><tr><td>Renal signs/symptoms</td><td align="center"><1%</td><td align="center">5%</td></tr><tr><td>Pain (non-site-specific)</td><td align="center"><1%</td><td align="center">5%</td></tr></tbody></table></center><p></p><p>Five subjects receiving abacavir in CNA3005 experienced worsening of pre-existing depression compared to none in the indinavir arm. The background rates of pre-existing depression were similar in the 2 treatment arms.</p><h5>Laboratory Abnormalities</h5><p>Laboratory abnormalities in CNA3005 are listed in Table 2.</p><p align="center"><b>Table 2: Treatment-Emergent Laboratory Abnormalities (Grades 3/4) in CNA3005</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Laboratory Parameter</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine/ Zidovudine<br />(n = 262)</td><td class="EmphTd" width="25%">Indinavir plus Lamivudine/ Zidovudine<br />(n = 264)</td></tr><tr><td>Elevated CPK (>4 x ULN)</td><td align="center">18 (7%)</td><td align="center">18 (7%)</td></tr><tr><td>ALT (>5.0 x ULN)</td><td align="center">16 (6%)</td><td align="center">16 (6%)</td></tr><tr><td>Neutropenia (<750/mm³)</td><td align="center">13 (5%)</td><td align="center">13 (5%)</td></tr><tr><td>Hypertriglyceridemia (>750 mg/dL)</td><td align="center">5 (2%)</td><td align="center">3 (1%)</td></tr><tr><td>Hyperamylasemia (>2.0 x ULN)</td><td align="center">5 (2%)</td><td align="center">1 (<1%)</td></tr><tr><td>Hyperglycemia (>13.9 mmol/L)</td><td align="center">2 (<1%)</td><td align="center">2 (<1%)</td></tr><tr><td>Anemia (Hgb ≤6.9 g/dL)</td><td align="center">0 (0%)</td><td align="center">3 (1%)</td></tr><tr><td class="credit" colspan="3">ULN = Upper limit of normal.<br />n = Number of subjects assessed.</td></tr></tbody></table></center><p></p><h5>Other Adverse Events</h5><p>In addition to adverse reactions in Tables 1 and 2, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT.</p><h4>Postmarketing Experience</h4><p>The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.</p><h5>Abacavir</h5><p><b>Cardiovascular:</b> Myocardial infarction.</p><p><b>Skin:</b> Suspected Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases. There have also been reports of erythema multiforme with abacavir use [see <b>ADVERSE REACTIONS</b>].</p><h5>Abacavir, Lamivudine, And/Or Zidovudine</h5><p><b>Body as a Whole:</b> Redistribution/accumulation of body fat.</p><p><b>Cardiovascular:</b> Cardiomyopathy.</p><p><b>Digestive:</b> Stomatitis.</p><p><b>Endocrine and Metabolic:</b> Gynecomastia.</p><p><b>Gastrointestinal:</b> Anorexia and/or decreased appetite, abdominal pain, dyspepsia, oral mucosal pigmentation.</p><p><b>General:</b> Vasculitis, weakness.</p><p><b>Hemic and Lymphatic:</b> Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly, thrombocytopenia.</p><p><b>Hepatic:</b> Lactic acidosis and hepatic steatosis [see<b> WARNINGS AND PRECAUTIONS</b>], elevated bilirubin, elevated transaminases, posttreatment exacerbations of hepatitis B [see <b>WARNINGS AND PRECAUTIONS</b>].</p><p><b>Hypersensitivity:</b> Sensitization reactions (including anaphylaxis), urticaria.</p><p><b>Musculoskeletal:</b> Arthralgia, myalgia, muscle weakness, rhabdomyolysis.</p><p><b>Nervous:</b> Dizziness, paresthesia, peripheral neuropathy, seizures.</p><p><b>Psychiatric:</b> Insomnia and other sleep disorders.</p><p><b>Respiratory:</b> Abnormal breath sounds/wheezing.</p><p><b>Skin:</b> Alopecia, erythema multiforme, Stevens-Johnson syndrome.</p> </div> </div> </div> | 5 | 2023-02-01 17:38:34 | Abacavir Sulfate, Lamivudine, and Zidovudine (Trizivir) | A | HIV, NNRTIs | Trizivir | abacavir sulfate, lamivudine, and zidovudine | Trizivir | John P. Cunha, DO, FACOEP |
| 36 | 2023-02-23 11:36:54 | Drug Interactions | <a name="DI"></a><h3>DRUG INTERACTIONS</h3><h4>Abacavir</h4><h5>Methadone</h5><p>In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see <b>CLINICAL PHARMACOLOGY</b>]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.</p><h5>Riociguat</h5><p>Coadministration with fixed-dose abacavir/dolutegravir/lamivudine resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [see<b> CLINICAL PHARMACOLOGY</b>]. The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).</p><h4>Lamivudine</h4><h5>Sorbitol</h5><p>Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see <b>CLINICAL PHARMACOLOGY</b>].</p><h4>Zidovudine</h4><h5>Agents Antagonistic With Zidovudine</h5><p>Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro:</p><ul><li>Stavudine</li><li>Doxorubicin</li><li>Nucleoside analogues, e.g., ribavirin</li></ul><h5>Hematologic/Bone Marrow Suppressive/Cytotoxic Agents</h5><p>Coadministration with the following drugs may increase the hematologic toxicity of zidovudine:</p><ul><li>Ganciclovir</li><li>Interferon alfa</li><li>Ribavirin</li><li>Other bone marrow suppressive or cytotoxic agents</li></ul> </div> </div> </div> | <a name="DI"></a><h3>DRUG INTERACTIONS</h3><h4>Abacavir</h4><h5>Methadone</h5><p>In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of ZIAGEN twice daily (twice the currently recommended dose), oral methadone clearance increased [see <b>CLINICAL PHARMACOLOGY</b>]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.</p><h5>Riociguat</h5><p>Coadministration with fixed-dose abacavir/dolutegravir/lamivudine resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [see<b> CLINICAL PHARMACOLOGY</b>]. The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).</p><h4>Lamivudine</h4><h5>Sorbitol</h5><p>Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see <b>CLINICAL PHARMACOLOGY</b>].</p><h4>Zidovudine</h4><h5>Agents Antagonistic With Zidovudine</h5><p>Concomitant use of zidovudine with the following drugs should be avoided since an antagonistic relationship has been demonstrated in vitro:</p><ul><li>Stavudine</li><li>Doxorubicin</li><li>Nucleoside analogues, e.g., ribavirin</li></ul><h5>Hematologic/Bone Marrow Suppressive/Cytotoxic Agents</h5><p>Coadministration with the following drugs may increase the hematologic toxicity of zidovudine:</p><ul><li>Ganciclovir</li><li>Interferon alfa</li><li>Ribavirin</li><li>Other bone marrow suppressive or cytotoxic agents</li></ul> </div> </div> </div> | 5 | 2023-02-01 17:38:34 | Abacavir Sulfate, Lamivudine, and Zidovudine (Trizivir) | A | HIV, NNRTIs | Trizivir | abacavir sulfate, lamivudine, and zidovudine | Trizivir | John P. Cunha, DO, FACOEP |
| 37 | 2023-02-23 11:36:54 | Warnings & Precautions | <a name="W"></a><h3>WARNINGS</h3><p>Included as part of the <b>PRECAUTIONS</b> section.</p> <a name="P"></a><h3>PRECAUTIONS</h3><h4>Hypersensitivity Reactions</h4><p>Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIZIVIR. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see<b> ADVERSE REACTIONS</b>]. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.</p><p>Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:</p><ul><li>All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with TRIZIVIR or reinitiation of therapy with TRIZIVIR, unless patients have a previously documented HLA-B*5701 allele assessment.</li><li>TRIZIVIR is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.</li><li>Before starting TRIZIVIR, review medical history for prior exposure to any abacavircontaining product. NEVER restart TRIZIVIR or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.</li><li>To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue TRIZIVIR immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).</li><li>If a hypersensitivity reaction cannot be ruled out, do not restart TRIZIVIR or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours.</li><li>If a hypersensitivity reaction is ruled out, patients may restart TRIZIVIR. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of TRIZIVIR or any other abacavir-containing product is recommended only if medical care can be readily accessed.</li><li>A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill.</li></ul><h4>Hematologic Toxicity/Bone Marrow Suppression</h4><p>Zidovudine, a component of TRIZIVIR, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. TRIZIVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm³ or hemoglobin less than 9.5 grams per dL [see<b> ADVERSE REACTIONS</b>].</p><p>Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with TRIZIVIR. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed.</p><h4>Myopathy</h4><p>Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with TRIZIVIR.</p><h4>Lactic Acidosis And Severe Hepatomegaly With Steatosis</h4><p>Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine and zidovudine (components of TRIZIVIR). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for ZIAGEN (abacavir), EPIVIR (lamivudine), and RETROVIR (zidovudine). Treatment with TRIZIVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).</p><h4>Patients With Hepatitis B Virus Co-infection</h4><h5>Posttreatment Exacerbations Of Hepatitis</h5><p>Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.</p><h5>Emergence Of Lamivudine-Resistant HBV</h5><p>Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV–1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine).</p><h4>Use With Interferon-And Ribavirin-Based Regimens</h4><p>Patients receiving interferon alfa with or without ribavirin and TRIZIVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for RETROVIR (zidovudine). Discontinuation of TRIZIVIR should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see full prescribing information for interferon and ribavirin).</p><p>Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and TRIZIVIR is not advised.</p><h4>Immune Reconstitution Syndrome</h4><p>Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRIZIVIR. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, <i>Pneumocystis jirovecii</i> pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.</p><p>Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.</p><h4>Lipoatrophy</h4><p>Treatment with zidovudine, a component of TRIZIVIR, has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs, and buttocks, may be only partially reversible and improvement may take months to years after switching to a non-zidovudinecontaining regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine-containing products, and if feasible, therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy.</p><h4>Myocardial Infarction</h4><p>Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir treatment and the risk of MI is inconclusive.</p><p>As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).</p><h4>Therapy-Experienced Patients</h4><p>In clinical trials, subjects with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir and other NRTIs should be considered when choosing new therapeutic regimens in therapy-experienced patients [see <b>Microbiology</b>].</p><h4>Patient Counseling Information</h4><p>Advise the patient to read the FDA-approved patient labeling (<b>Medication Guide</b>).</p><h5>Hypersensitivity Reaction</h5><p><i>Inform Patients</i></p><ul><li>that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of TRIZIVIR, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about TRIZIVIR. The complete text of the Medication Guide is reprinted at the end of this document.</li><li>to carry the Warning Card with them.</li><li>how to identify a hypersensitivity reaction [see <b>WARNINGS AND PRECAUTIONS</b>, <b>Medication Guide</b>].</li><li>that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking TRIZIVIR.</li><li>that a hypersensitivity reaction can worsen and lead to hospitalization or death if TRIZIVIR is not immediately discontinued.</li><li>to not restart TRIZIVIR or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.</li><li>that if they have a hypersensitivity reaction, they should dispose of any unused TRIZIVIR to avoid restarting abacavir.</li><li>that a hypersensitivity reaction is usually reversible if it is detected promptly and TRIZIVIR is stopped right away.</li><li>that if they have interrupted TRIZIVIR for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.</li><li>to not restart TRIZIVIR or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.</li></ul><h5>Neutropenia And Anemia</h5><p>Inform patients that the important toxicities associated with zidovudine are neutropenia and/or anemia. Inform them of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced HIV-1 disease [see <b>BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Myopathy</h5><p>Inform patients that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine [see<b> WARNINGS AND PRECAUTIONS</b>].</p><h5>Lactic Acidosis/Hepatomegaly With Steatosis</h5><p>Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking TRIZIVIR if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see<b> WARNINGS AND PRECAUTIONS</b>].</p><h5>Patients With Hepatitis B Or C Co-infection</h5><p>Advise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their healthcare provider [see <b>WARNINGS AND PRECAUTIONS</b>].</p><p>Inform patients with HIV-1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Drug Interactions</h5><p>Advise patients that other medications may interact with TRIZIVIR and certain medications, including ganciclovir, interferon alfa, and ribavirin, may exacerbate the toxicity of zidovudine, a component of TRIZIVIR [see <b>DRUG INTERACTIONS</b>].</p><h5>Immune Reconstitution Syndrome</h5><p>Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when TRIZIVIR is started [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Lipoatrophy</h5><p>Advise patients that loss of subcutaneous fat may occur in patients receiving TRIZIVIR and that they will be regularly assessed during therapy [see<b> WARNINGS AND PRECAUTIONS</b>].</p><h5>Pregnancy Registry</h5><p>Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRIZIVIR during pregnancy [see <b>Use In Specific Populations</b>].</p><h5>Lactation</h5><p>Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see <b>Use In Specific Populations</b>].</p><h5>Missed Dose</h5><p>Instruct patients that if they miss a dose of TRIZIVIR, to take it as soon as they remember.</p><p>Advise patients not to double their next dose or take more than the prescribed dose [see<b> DOSAGE AND ADMINISTRATION</b>].</p><h5>Availability Of Medication Guide</h5><p>Instruct patients to read the Medication Guide before starting TRIZIVIR and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.</p><p>Other brands listed are trademarks owned by or licensed to their respective owners and are not trademarks owned by or licensed to the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.</p><h4>Nonclinical Toxicology</h4><h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4><h5>Carcinogenicity</h5><p><i>Abacavir</i></p><p>Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg.</p><p><i>Lamivudine</i></p><p>Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.</p><p><i>Zidovudine</i></p><p>Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after Day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg per day on Day 279.</p><p>In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 non-metastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.</p><p>In rats, 2 late-appearing (after 20 months), non-metastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.</p><p>At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.</p><p>It is not known how predictive the results of rodent carcinogenicity studies may be for humans.</p><p>Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg per kg per day or 40 mg per kg per day from Gestation Day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. At these doses, exposures were approximately 3 times the estimated human exposure at the recommended doses. After 24 months at the 40-mg-per-kg-per-day dose, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1,000 mg per kg nonpregnant body weight or approximately 450 mg per kg of term body weight) to pregnant mice from Days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.</p><h5>Mutagenicity</h5><p><i>Abacavir</i></p><p>Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.</p><p><i>Lamivudine</i></p><p>Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.</p><p><i>Zidovudine</i></p><p>Zidovudine was mutagenic in an L5178Y mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.</p><h5>Impairment Of Fertility</h5><p><i>Abacavir</i></p><p>Abacavir did not affect male or female fertility in rats at a dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.</p><p><i>Lamivudine</i></p><p>Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (Cmax) in humans at the dose of 300 mg.</p><p><i>Zidovudine</i></p><p>Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is 7 times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates.</p> <a name="USP"></a><h4>Use In Specific Populations</h4><h4>Pregnancy</h4><h5>Pregnancy Exposure Registry</h5><p>There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRIZIVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.</p><h5>Risk Summary</h5><p>Available data from the APR show no difference in the overall risk of birth defects for abacavir, lamivudine, or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see<b> Data</b>). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.</p><p>Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established (see<b> Data</b>).</p><p>In animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose. However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately 9 times the human exposure (AUC) at the recommended clinical dose. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the recommended clinical dose. Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose (see<b> Data</b>).</p><h5>Data</h5><p><i>Human Data</i></p><p>Abacavir: Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4.0%) following second/third trimester exposure to abacavir-containing regimens.</p><p>Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see <b>CLINICAL PHARMACOLOGY</b>].</p><p>Lamivudine: Based on prospective reports to the APR of exposures to lamivudine during pregnancy resulting in live births (including over 5,300 exposed in the first trimester and over 7,400 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudinecontaining regimens.</p><p>Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8).</p><p>Zidovudine: Based on prospective reports to the APR of exposures to zidovudine during pregnancy resulting in live births (including over 4,200 exposed in the first trimester and over 9,700 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.1%) following second/third trimester exposure to zidovudinecontaining regimens.</p><p>A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of trial drug. See full prescribing information for RETROVIR (zidovudine) and COMBIVIR (lamivudine and zidovudine).</p><p>Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see<b> CLINICAL PHARMACOLOGY</b>]. There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to zidovudine-containing products. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established. The clinical relevance of transient elevations in serum lactate is unknown.</p><p><i>Animal Data</i></p><p>Abacavir: Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on Gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately 4 times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the recommended dose.</p><p>Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine.</p><p>Zidovudine: A study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on Gestation Days 6 through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on Gestation Days 6 through 18) showed increased fetal resorptions at the 500-mg-per-kg-per-day dose which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days 6 through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.</p><h4>Lactation</h4><h5>Risk Summary</h5><p>The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir, lamivudine and zidovudine are present in human milk. There is no information on the effects of abacavir, lamivudine and zidovudine on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving TRIZIVIR.</p><h4>Pediatric Use</h4><p>TRIZIVIR is not recommended in children who weigh less than 40 kg because it is a fixed-dose tablet that cannot be adjusted for these patient populations [see <b>DOSAGE AND ADMINISTRATION</b>].</p><h5>Therapy-Experienced Pediatric Trial</h5><p>A randomized, double-blind trial, CNA3006, compared ZIAGEN plus lamivudine and zidovudine versus lamivudine and zidovudine in pediatric subjects, most of whom were extensively pretreated with nucleoside analogue antiretroviral agents. Subjects in this trial had a limited response to abacavir.</p><h4>Geriatric Use</h4><p>Clinical trials of abacavir, lamivudine, and zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TRIZIVIR in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see<b> CLINICAL PHARMACOLOGY</b>].</p><h4>Patients With Impaired Renal Function</h4><p>TRIZIVIR is not recommended for patients with creatinine clearance less than 50 mL per min because TRIZIVIR is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of the lamivudine or zidovudine components of TRIZIVIR is required for patients with renal impairment then the individual components should be used [see<b> DOSAGE AND ADMINISTRATION</b>, <b>CLINICAL PHARMACOLOGY</b>].</p><h4>Patients With Impaired Hepatic Function</h4><p>TRIZIVIR is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of TRIZIVIR, is required for patients with mild hepatic impairment (Child-Pugh Class A), then the individual components should be used [see<b> CLINICAL PHARMACOLOGY</b>].</p><p>The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment; therefore, TRIZIVIR is contraindicated in these patients [see<b> CONTRAINDICATIONS</b>].</p><p>Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations are increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised.</p> </div> </div> </div> | <a name="W"></a><h3>WARNINGS</h3><p>Included as part of the <b>PRECAUTIONS</b> section.</p> <a name="P"></a><h3>PRECAUTIONS</h3><h4>Hypersensitivity Reactions</h4><p>Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIZIVIR. These hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see<b> ADVERSE REACTIONS</b>]. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.</p><p>Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:</p><ul><li>All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with TRIZIVIR or reinitiation of therapy with TRIZIVIR, unless patients have a previously documented HLA-B*5701 allele assessment.</li><li>TRIZIVIR is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.</li><li>Before starting TRIZIVIR, review medical history for prior exposure to any abacavircontaining product. NEVER restart TRIZIVIR or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.</li><li>To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue TRIZIVIR immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications).</li><li>If a hypersensitivity reaction cannot be ruled out, do not restart TRIZIVIR or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours.</li><li>If a hypersensitivity reaction is ruled out, patients may restart TRIZIVIR. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of TRIZIVIR or any other abacavir-containing product is recommended only if medical care can be readily accessed.</li><li>A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill.</li></ul><h4>Hematologic Toxicity/Bone Marrow Suppression</h4><p>Zidovudine, a component of TRIZIVIR, has been associated with hematologic toxicity including neutropenia and anemia, particularly in patients with advanced HIV-1 disease. TRIZIVIR should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells per mm³ or hemoglobin less than 9.5 grams per dL [see<b> ADVERSE REACTIONS</b>].</p><p>Frequent blood counts are strongly recommended in patients with advanced HIV-1 disease who are treated with TRIZIVIR. Periodic blood counts are recommended for other HIV-1-infected patients. If anemia or neutropenia develops, dosage interruption may be needed.</p><h4>Myopathy</h4><p>Myopathy and myositis, with pathological changes similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine, and therefore may occur with therapy with TRIZIVIR.</p><h4>Lactic Acidosis And Severe Hepatomegaly With Steatosis</h4><p>Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir, lamivudine and zidovudine (components of TRIZIVIR). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for ZIAGEN (abacavir), EPIVIR (lamivudine), and RETROVIR (zidovudine). Treatment with TRIZIVIR should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).</p><h4>Patients With Hepatitis B Virus Co-infection</h4><h5>Posttreatment Exacerbations Of Hepatitis</h5><p>Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.</p><h5>Emergence Of Lamivudine-Resistant HBV</h5><p>Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV–1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR (lamivudine).</p><h4>Use With Interferon-And Ribavirin-Based Regimens</h4><p>Patients receiving interferon alfa with or without ribavirin and TRIZIVIR should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia, and anemia. See full prescribing information for RETROVIR (zidovudine). Discontinuation of TRIZIVIR should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6) (see full prescribing information for interferon and ribavirin).</p><p>Exacerbation of anemia has been reported in HIV-1/HCV co-infected patients receiving ribavirin and zidovudine. Coadministration of ribavirin and TRIZIVIR is not advised.</p><h4>Immune Reconstitution Syndrome</h4><p>Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRIZIVIR. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, <i>Pneumocystis jirovecii</i> pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.</p><p>Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.</p><h4>Lipoatrophy</h4><p>Treatment with zidovudine, a component of TRIZIVIR, has been associated with loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to cumulative exposure. This fat loss, which is most evident in the face, limbs, and buttocks, may be only partially reversible and improvement may take months to years after switching to a non-zidovudinecontaining regimen. Patients should be regularly assessed for signs of lipoatrophy during therapy with zidovudine-containing products, and if feasible, therapy should be switched to an alternative regimen if there is suspicion of lipoatrophy.</p><h4>Myocardial Infarction</h4><p>Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir treatment and the risk of MI is inconclusive.</p><p>As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).</p><h4>Therapy-Experienced Patients</h4><p>In clinical trials, subjects with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who had HIV-1 isolates that contained multiple mutations conferring resistance to NRTIs had limited response to abacavir. The potential for cross-resistance between abacavir and other NRTIs should be considered when choosing new therapeutic regimens in therapy-experienced patients [see <b>Microbiology</b>].</p><h4>Patient Counseling Information</h4><p>Advise the patient to read the FDA-approved patient labeling (<b>Medication Guide</b>).</p><h5>Hypersensitivity Reaction</h5><p><i>Inform Patients</i></p><ul><li>that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of TRIZIVIR, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about TRIZIVIR. The complete text of the Medication Guide is reprinted at the end of this document.</li><li>to carry the Warning Card with them.</li><li>how to identify a hypersensitivity reaction [see <b>WARNINGS AND PRECAUTIONS</b>, <b>Medication Guide</b>].</li><li>that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking TRIZIVIR.</li><li>that a hypersensitivity reaction can worsen and lead to hospitalization or death if TRIZIVIR is not immediately discontinued.</li><li>to not restart TRIZIVIR or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.</li><li>that if they have a hypersensitivity reaction, they should dispose of any unused TRIZIVIR to avoid restarting abacavir.</li><li>that a hypersensitivity reaction is usually reversible if it is detected promptly and TRIZIVIR is stopped right away.</li><li>that if they have interrupted TRIZIVIR for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.</li><li>to not restart TRIZIVIR or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.</li></ul><h5>Neutropenia And Anemia</h5><p>Inform patients that the important toxicities associated with zidovudine are neutropenia and/or anemia. Inform them of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced HIV-1 disease [see <b>BOXED WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Myopathy</h5><p>Inform patients that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine [see<b> WARNINGS AND PRECAUTIONS</b>].</p><h5>Lactic Acidosis/Hepatomegaly With Steatosis</h5><p>Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogues and other antiretrovirals. Advise patients to stop taking TRIZIVIR if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see<b> WARNINGS AND PRECAUTIONS</b>].</p><h5>Patients With Hepatitis B Or C Co-infection</h5><p>Advise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their healthcare provider [see <b>WARNINGS AND PRECAUTIONS</b>].</p><p>Inform patients with HIV-1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Drug Interactions</h5><p>Advise patients that other medications may interact with TRIZIVIR and certain medications, including ganciclovir, interferon alfa, and ribavirin, may exacerbate the toxicity of zidovudine, a component of TRIZIVIR [see <b>DRUG INTERACTIONS</b>].</p><h5>Immune Reconstitution Syndrome</h5><p>Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when TRIZIVIR is started [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Lipoatrophy</h5><p>Advise patients that loss of subcutaneous fat may occur in patients receiving TRIZIVIR and that they will be regularly assessed during therapy [see<b> WARNINGS AND PRECAUTIONS</b>].</p><h5>Pregnancy Registry</h5><p>Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRIZIVIR during pregnancy [see <b>Use In Specific Populations</b>].</p><h5>Lactation</h5><p>Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see <b>Use In Specific Populations</b>].</p><h5>Missed Dose</h5><p>Instruct patients that if they miss a dose of TRIZIVIR, to take it as soon as they remember.</p><p>Advise patients not to double their next dose or take more than the prescribed dose [see<b> DOSAGE AND ADMINISTRATION</b>].</p><h5>Availability Of Medication Guide</h5><p>Instruct patients to read the Medication Guide before starting TRIZIVIR and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.</p><p>Other brands listed are trademarks owned by or licensed to their respective owners and are not trademarks owned by or licensed to the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.</p><h4>Nonclinical Toxicology</h4><h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4><h5>Carcinogenicity</h5><p><i>Abacavir</i></p><p>Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of 6 to 32 times the human exposure at the recommended dose of 600 mg.</p><p><i>Lamivudine</i></p><p>Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) the human exposures at the recommended dose of 300 mg.</p><p><i>Zidovudine</i></p><p>Zidovudine was administered orally at 3 dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60, and 120 mg per kg per day in mice and 80, 220, and 600 mg per kg per day in rats. The doses in mice were reduced to 20, 30, and 40 mg per kg per day after Day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg per kg per day on Day 91 and then to 300 mg per kg per day on Day 279.</p><p>In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 non-metastasizing squamous cell carcinomas, 1 squamous cell papilloma, and 1 squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.</p><p>In rats, 2 late-appearing (after 20 months), non-metastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.</p><p>At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.</p><p>It is not known how predictive the results of rodent carcinogenicity studies may be for humans.</p><p>Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg per kg per day or 40 mg per kg per day from Gestation Day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. At these doses, exposures were approximately 3 times the estimated human exposure at the recommended doses. After 24 months at the 40-mg-per-kg-per-day dose, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg per day or 25 mg per day (approximately 1,000 mg per kg nonpregnant body weight or approximately 450 mg per kg of term body weight) to pregnant mice from Days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver, and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.</p><h5>Mutagenicity</h5><p><i>Abacavir</i></p><p>Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.</p><p><i>Lamivudine</i></p><p>Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.</p><p><i>Zidovudine</i></p><p>Zidovudine was mutagenic in an L5178Y mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.</p><h5>Impairment Of Fertility</h5><p><i>Abacavir</i></p><p>Abacavir did not affect male or female fertility in rats at a dose associated with exposures (AUC) approximately 3.3 times (male) or 4.1 times (female) those in humans at the clinically recommended dose.</p><p><i>Lamivudine</i></p><p>Lamivudine did not affect male or female fertility in rats at doses up to 4,000 mg per kg per day, associated with concentrations approximately 42 times (male) or 63 times (female) higher than the concentrations (Cmax) in humans at the dose of 300 mg.</p><p><i>Zidovudine</i></p><p>Zidovudine, administered to male and female rats at doses up to 450 mg per kg per day, which is 7 times the recommended adult dose (300 mg twice daily) based on body surface area, had no effect on fertility based on conception rates.</p> <a name="USP"></a><h4>Use In Specific Populations</h4><h4>Pregnancy</h4><h5>Pregnancy Exposure Registry</h5><p>There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRIZIVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.</p><h5>Risk Summary</h5><p>Available data from the APR show no difference in the overall risk of birth defects for abacavir, lamivudine, or zidovudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see<b> Data</b>). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown.</p><p>Hyperlactatemia, which may be due to mitochondrial dysfunction, has been reported in infants with in utero exposure to zidovudine-containing products. These events were transient and asymptomatic in most cases. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established (see<b> Data</b>).</p><p>In animal reproduction studies, oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the recommended clinical daily dose. However, no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis, at exposures approximately 9 times the human exposure (AUC) at the recommended clinical dose. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the recommended clinical dose; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the recommended clinical dose. Administration of oral zidovudine to female rats prior to mating and throughout gestation resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 33 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed after oral administration of zidovudine to pregnant rats during organogenesis at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended clinical dose. Administration of oral zidovudine to pregnant rabbits during organogenesis resulted in embryotoxicity at doses that produced systemic exposure (AUC) approximately 108 times higher than exposure at the recommended clinical dose. However, no embryotoxicity was observed at doses that produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended clinical dose (see<b> Data</b>).</p><h5>Data</h5><p><i>Human Data</i></p><p>Abacavir: Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4.0%) following second/third trimester exposure to abacavir-containing regimens.</p><p>Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see <b>CLINICAL PHARMACOLOGY</b>].</p><p>Lamivudine: Based on prospective reports to the APR of exposures to lamivudine during pregnancy resulting in live births (including over 5,300 exposed in the first trimester and over 7,400 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudinecontaining regimens.</p><p>Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8).</p><p>Zidovudine: Based on prospective reports to the APR of exposures to zidovudine during pregnancy resulting in live births (including over 4,200 exposed in the first trimester and over 9,700 exposed in the second/third trimester), there was no difference between the overall risk of birth defects for zidovudine compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.2% (95% CI: 2.7% to 3.8%) following first trimester exposure to zidovudine-containing regimens and 2.8% (95% CI: 2.5% to 3.1%) following second/third trimester exposure to zidovudinecontaining regimens.</p><p>A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission. Zidovudine treatment during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Of the 363 neonates that were evaluated, congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of trial drug. See full prescribing information for RETROVIR (zidovudine) and COMBIVIR (lamivudine and zidovudine).</p><p>Zidovudine has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see<b> CLINICAL PHARMACOLOGY</b>]. There have been reports of mild, transient elevations in serum lactate levels, which may be due to mitochondrial dysfunction, in neonates and infants exposed in utero or peri-partum to zidovudine-containing products. There have been few reports of developmental delay, seizures, and other neurological disease. However, a causal relationship between these events and exposure to zidovudine-containing products in utero or peri-partum has not been established. The clinical relevance of transient elevations in serum lactate is unknown.</p><p><i>Animal Data</i></p><p>Abacavir: Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on Gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown-rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the recommended daily dose. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately 4 times the human exposure at the recommended daily dose. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the recommended dose.</p><p>Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300, and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre-and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by maternal administration of lamivudine.</p><p>Zidovudine: A study in pregnant rats (at 50, 150, or 450 mg per kg per day starting 26 days prior to mating through gestation to postnatal Day 21) showed increased fetal resorptions at doses that produced systemic exposures (AUC) approximately 33 times higher than exposure at the recommended daily human dose (300 mg twice daily). However, in an oral embryo-fetal development study in rats (at 125, 250, or 500 mg per kg per day on Gestation Days 6 through 15), no fetal resorptions were observed at doses that produced systemic exposure (AUC) approximately 117 times higher than exposures at the recommended daily human dose. An oral embryo-fetal development study in rabbits (at 75, 150, or 500 mg per kg per day on Gestation Days 6 through 18) showed increased fetal resorptions at the 500-mg-per-kg-per-day dose which produced systemic exposures (AUC) approximately 108 times higher than exposure at the recommended daily human dose; however, no fetal resorptions were noted at doses up to 150 mg per kg per day, which produced systemic exposure (AUC) approximately 23 times higher than exposures at the recommended daily human dose. These oral embryo-fetal development studies in the rat and rabbit revealed no evidence of fetal malformations with zidovudine. In another developmental toxicity study, pregnant rats (dosed at 3,000 mg per kg per day from Days 6 through 15 of gestation) showed marked maternal toxicity and an increased incidence of fetal malformations at exposures greater than 300 times the recommended daily human dose based on AUC. However, there were no signs of fetal malformations at doses up to 600 mg per kg per day.</p><h4>Lactation</h4><h5>Risk Summary</h5><p>The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Abacavir, lamivudine and zidovudine are present in human milk. There is no information on the effects of abacavir, lamivudine and zidovudine on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving TRIZIVIR.</p><h4>Pediatric Use</h4><p>TRIZIVIR is not recommended in children who weigh less than 40 kg because it is a fixed-dose tablet that cannot be adjusted for these patient populations [see <b>DOSAGE AND ADMINISTRATION</b>].</p><h5>Therapy-Experienced Pediatric Trial</h5><p>A randomized, double-blind trial, CNA3006, compared ZIAGEN plus lamivudine and zidovudine versus lamivudine and zidovudine in pediatric subjects, most of whom were extensively pretreated with nucleoside analogue antiretroviral agents. Subjects in this trial had a limited response to abacavir.</p><h4>Geriatric Use</h4><p>Clinical trials of abacavir, lamivudine, and zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TRIZIVIR in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see<b> CLINICAL PHARMACOLOGY</b>].</p><h4>Patients With Impaired Renal Function</h4><p>TRIZIVIR is not recommended for patients with creatinine clearance less than 50 mL per min because TRIZIVIR is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of the lamivudine or zidovudine components of TRIZIVIR is required for patients with renal impairment then the individual components should be used [see<b> DOSAGE AND ADMINISTRATION</b>, <b>CLINICAL PHARMACOLOGY</b>].</p><h4>Patients With Impaired Hepatic Function</h4><p>TRIZIVIR is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of TRIZIVIR, is required for patients with mild hepatic impairment (Child-Pugh Class A), then the individual components should be used [see<b> CLINICAL PHARMACOLOGY</b>].</p><p>The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment; therefore, TRIZIVIR is contraindicated in these patients [see<b> CONTRAINDICATIONS</b>].</p><p>Zidovudine is primarily eliminated by hepatic metabolism and zidovudine concentrations are increased in patients with impaired hepatic function, which may increase the risk of hematologic toxicity. Frequent monitoring of hematologic toxicities is advised.</p> </div> </div> </div> | 5 | 2023-02-01 17:38:34 | Abacavir Sulfate, Lamivudine, and Zidovudine (Trizivir) | A | HIV, NNRTIs | Trizivir | abacavir sulfate, lamivudine, and zidovudine | Trizivir | John P. Cunha, DO, FACOEP |
| 38 | 2023-02-23 11:36:54 | Overdose & Contraindications | <a name="OD"></a><h3>OVERDOSE</h3><p>There is no known specific treatment for overdose with TRIZIVIR. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.</p><h4>Abacavir</h4><p>It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.</p><h4>Lamivudine</h4><p>Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.</p><h4>Zidovudine</h4><p>Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite, 3'azido-3'-deoxy-5'-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3><p>TRIZIVIR is contraindicated in patients:</p><ul><li>who have the HLA-B*5701 allele [see<b> WARNINGS AND PRECAUTIONS</b>].</li><li>with prior hypersensitivity reaction to abacavir [see <b>WARNINGS AND PRECAUTIONS</b>], lamivudine, or zidovudine.</li><li>with moderate or severe hepatic impairment [see <b>Use In Specific Populations</b>].</li></ul> </div> </div> </div> | <a name="OD"></a><h3>OVERDOSE</h3><p>There is no known specific treatment for overdose with TRIZIVIR. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.</p><h4>Abacavir</h4><p>It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.</p><h4>Lamivudine</h4><p>Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.</p><h4>Zidovudine</h4><p>Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting, and occasional reports of hematological disturbances. Patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine, while elimination of its primary metabolite, 3'azido-3'-deoxy-5'-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3><p>TRIZIVIR is contraindicated in patients:</p><ul><li>who have the HLA-B*5701 allele [see<b> WARNINGS AND PRECAUTIONS</b>].</li><li>with prior hypersensitivity reaction to abacavir [see <b>WARNINGS AND PRECAUTIONS</b>], lamivudine, or zidovudine.</li><li>with moderate or severe hepatic impairment [see <b>Use In Specific Populations</b>].</li></ul> </div> </div> </div> | 5 | 2023-02-01 17:38:34 | Abacavir Sulfate, Lamivudine, and Zidovudine (Trizivir) | A | HIV, NNRTIs | Trizivir | abacavir sulfate, lamivudine, and zidovudine | Trizivir | John P. Cunha, DO, FACOEP |
| 39 | 2023-02-23 12:07:03 | Clinical Pharmacology | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3><h4>Mechanism Of Action</h4><p>TRIZIVIR is an antiretroviral agent [see <b>Microbiology</b>].</p><h4>Pharmacokinetics</h4><h5>Pharmacokinetics In Adults</h5><p>In a single-dose, 3-way crossover bioavailability trial of 1 TRIZIVIR tablet versus 1 ZIAGEN tablet (300 mg), 1 EPIVIR tablet (150 mg), plus 1 RETROVIR tablet (300 mg) administered simultaneously in healthy subjects (n = 24), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of all 3 components. One TRIZIVIR tablet was bioequivalent to 1 ZIAGEN tablet (300 mg), 1 EPIVIR tablet (150 mg), plus 1 RETROVIR tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24).</p><p><i>Abacavir</i></p><p>Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of 300 mg of abacavir twice daily in 20 subjects, Cmax was 3.0 ± 0.89 mcg per mL (mean ± SD) and AUC(0-12 h) was 6.02 ± 1.73 mcg•hour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and glucuronyl transferase to form the 5'-glucuronide.</p><p><i>Lamivudine</i></p><p>Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).</p><p><i>Zidovudine</i></p><p>Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3'-amino-3'deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.</p><p>In humans, abacavir, lamivudine, and zidovudine are not significantly metabolized by CYP enzymes.</p><p>The pharmacokinetic properties of abacavir, lamivudine, and zidovudine in fasting subjects are summarized in Table 3.</p><p align="center"><b>Table 3: Pharmacokinetic Parameters<sup>a</sup> for Abacavir, Lamivudine, and Zidovudine in Adults</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="28%">Parameter</td><td class="EmphTd" colspan="2">Abacavir</td><td class="EmphTd" colspan="2">Lamivudine</td><td class="EmphTd" colspan="2">Zidovudine</td></tr><tr><td>Oral bioavailability (%)</td><td align="center" width="16%">86 ± 25</td><td align="center" width="8%">n = 6</td><td align="center" width="16%">86 ± 16</td><td align="center" width="8%">n = 12</td><td align="center" width="16%">64 ± 10</td><td align="center" width="8%">n = 5</td></tr><tr><td>Apparent volume of distribution (L/kg)</td><td align="center">0.86 ± 0.15</td><td align="center">n = 6</td><td align="center">1.3 ± 0.4</td><td align="center">n = 20</td><td align="center">1.6 ± 0.6</td><td align="center">n = 8</td></tr><tr><td>Systemic clearance (L/h/kg)</td><td align="center">0.80 ± 0.24</td><td align="center">n = 6</td><td align="center">0.33 ± 0.06</td><td align="center">n = 20</td><td align="center">1.6 ± 0.6</td><td align="center">n = 6</td></tr><tr><td>Renal clearance (L/h/kg)</td><td align="center">0.007 ± 0.008</td><td align="center">n = 6</td><td align="center">0.22 ± 0.06</td><td align="center">n = 20</td><td align="center">0.34 ± 0.05</td><td align="center">n = 9</td></tr><tr><td>Elimination half-life (h)</td><td align="center">1.45 ± 0.32</td><td align="center">n = 20</td><td align="center" colspan="2">13 to 19<sup>b</sup></td><td align="center" colspan="2">0.5 to 3<sup>b</sup></td></tr><tr><td class="credit" colspan="7"><sup>a</sup> Data presented as mean ±standard deviation except where noted.<br /><sup>b</sup> Approximate range.</td></tr></tbody></table></center><p></p><h5>Effect Of Food On Absorption Of TRIZIVIR</h5><p>Administration with food in a single-dose bioavailability trial resulted in lower Cmax, similar to results observed previously for the reference formulations. The average [90% CI] decrease in abacavir, lamivudine, and zidovudine Cmax was 32% [24% to 38%], 18% [10% to 25%], and 28% [13% to 40%], respectively, when administered with a high-fat meal, compared with administration under fasted conditions. Administration of TRIZIVIR with food did not alter the extent of abacavir, lamivudine, and zidovudine absorption (AUC), as compared with administration under fasted conditions (n = 24) [see <b>DOSAGE AND ADMINISTRATION</b>].</p><h4>Specific Populations</h4><h5>Patients With Renal Impairment</h5><p><i>TRIZIVIR</i></p><p>The effect of renal impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components).</p><h5>Patients With Hepatic Impairment</h5><p><i>TRIZIVIR</i></p><p>The effect of hepatic impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components).</p><h5>Pregnant Women</h5><p><i>Abacavir</i></p><p>Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in <a href="/postpartum/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">postpartum</a> and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in <a href="/neonatal/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">neonatal</a> plasma <a href="/cord/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cord</a> samples at birth were essentially equal to those in maternal plasma at delivery.</p><p><i>Lamivudine</i></p><p>Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and <a href="/umbilical_cord/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">umbilical cord</a> serum samples.</p><p><i>Zidovudine</i></p><p>Zidovudine pharmacokinetics have been studied in a Phase 1 trial of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.</p><p>Although data are limited, <a href="/methadone/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">methadone</a> <a href="/maintenance_therapy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">maintenance therapy</a> in 5 pregnant women did not appear to alter zidovudine pharmacokinetics.</p><h5>Geriatric Patients</h5><p>The pharmacokinetics of abacavir, lamivudine, and zidovudine have not been studied in subjects over 65 years of age.</p><h5>Male And Female Patients</h5><p>There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir, lamivudine, or zidovudine) based on the available information that was analyzed for each of the individual components.</p><h5>Racial Groups</h5><p>Abacavir and Lamivudine: There are no significant or clinically relevant racial differences in pharmacokinetics of abacavir or lamivudine based on the available information that was analyzed for each of the individual components.</p><p><i>Zidovudine</i></p><p>The pharmacokinetics of zidovudine with respect to race have not been determined.</p><h4>Drug Interaction Studies</h4><p>The drug interaction trials described were conducted with abacavir, lamivudine or zidovudine as single entities; no drug interaction trials have been conducted using TRIZIVIR. No clinically significant drug interactions are expected between abacavir, lamivudine, and zidovudine.</p><h5>Effect Of Abacavir And Lamivudine On The Pharmacokinetics Of Other Agents</h5><p>In vitro studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit <a href="/metabolism/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">metabolism</a> mediated by CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6). Based on in vitro study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic <a href="/anion/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">anion</a> transporter <a href="/polypeptide/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">polypeptide</a> (OATP)1B1/3, <a href="/breast_cancer_facts_stages/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">breast cancer</a> resistance protein (BCRP) or P-<a href="/glycoprotein/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">glycoprotein</a> (P-gp), organic cation transporter (OCT)1, OCT2, OCT3 (lamivudine only), or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.</p><h5>Riociguat</h5><p>Coadministration of a single dose of riociguat (0.5 mg) to HIV-1–infected subjects receiving fixed-dose abacavir/dolutegravir/lamivudine is reported to increase riociguat AUC(∞) compared with riociguat AUC(∞) reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see <b>DRUG INTERACTIONS</b>].</p><h5>Effect Of Other Agents On The Pharmacokinetics Of Abacavir, Lamivudine, Or Zidovudine</h5><p>Abacavir, lamivudine, and zidovudine are not significantly metabolized by CYP enzymes; therefore, CYP enzyme inhibitors or inducers are not expected to affect their concentrations. In vitro, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein (MRP)2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is a substrate of BCRP and P-gp in vitro; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations.</p><p>Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.</p><p>Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.</p><h5>Glucuronyl Transferase</h5><p>Due to the common metabolic pathways of abacavir and zidovudine via glucuronyl transferase, 15 HIV-1-infected subjects were enrolled in a crossover trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.</p><h5>Ethanol</h5><p>Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.</p><h5>Interferon Alfa</h5><p>There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.</p><h5>Methadone</h5><p>In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see <b>DRUG INTERACTIONS</b>]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.</p><h5>Ribavirin</h5><p>In vitro data indicate ribavirin reduces <a href="/phosphorylation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">phosphorylation</a> of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Sorbitol (Excipient)</h5><p>Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24); 14%, 32%, and 36% in the AUC(∞); and 28%, 52%, and 55% in the Cmax; of lamivudine, respectively.</p><p>The effects of other coadministered drugs on abacavir, lamivudine, or zidovudine are provided in Table 4.</p><p align="center"><b>Table 4: Effect of Coadministered Drugs on Abacavir, Lamivudine, and Zidovudine AUC<sup>a</sup></b></p><center><table cellspacing="0" class="blacktbl" width="650"><tbody><tr><td class="EmphTd" rowspan="2" width="25%">Coadministered Drug and Dose</td><td class="EmphTd" rowspan="2" width="20%">Drug and Dose</td><td class="EmphTd" rowspan="2" width="10%">n</td><td class="EmphTd" colspan="2">Concentrations of Abacavir, Lamivudine, or Zidovudine</td><td class="EmphTd" rowspan="2" width="15%">Concentration of Coadministered Drug</td></tr><tr><td class="EmphTd" width="15%">AUC</td><td class="EmphTd" width="15%">Variability</td></tr><tr><td>Ethanol 0.7 g/kg</td><td>Abacavir single 600 mg</td><td align="center">24</td><td align="center">↑41%</td><td align="center">90% CI: 35% to 48%</td><td align="center">↔<sup>b</sup></td></tr><tr><td>Nelfinavir 750 mg every 8 h x 7 to 10 days</td><td>Lamivudine single 150 mg</td><td align="center">11</td><td align="center">↑10%</td><td align="center">95% CI: 1% to 20%</td><td align="center">↔</td></tr><tr><td>Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days</td><td>Lamivudine single 300 mg</td><td align="center">14</td><td align="center">↑43%</td><td align="center">90% CI: 32% to 55%</td><td align="center">↔</td></tr><tr><td>Atovaquone 750 mg every 12 h with food</td><td>Zidovudine 200 mg every 8 h</td><td align="center">14</td><td align="center">↑31%</td><td align="center">Range: 23% to 78%<sup>c</sup></td><td align="center">↔</td></tr><tr><td>Clarithromycin 500 mg twice daily</td><td>Zidovudine 100 mg every 4 h x 7 days</td><td align="center">4</td><td align="center">↓12%</td><td align="center">Range: ↓34% to ↑14%</td><td align="center">Not Reported</td></tr><tr><td>Fluconazole 400 mg daily</td><td>Zidovudine 200 mg every 8 h</td><td align="center">12</td><td align="center">↑74%</td><td align="center">95% CI: 54% to 98%</td><td align="center">Not Reported</td></tr><tr><td>Methadone 30 to 90 mg daily</td><td>Zidovudine 200 mg every 4 h</td><td align="center">9</td><td align="center">↑43%</td><td align="center">Range: 16% to 64%<sup>c</sup></td><td align="center">↔</td></tr><tr><td>Nelfinavir 750 mg every 8 h x 7 to 10 days</td><td>Zidovudine single 200 mg</td><td align="center">11</td><td align="center">↓35%</td><td align="center">Range: 28% to 41%</td><td align="center">↔</td></tr><tr><td>Probenecid 500 mg every 6 h x 2 days</td><td>Zidovudine 2 mg/kg every 8 h x 3 days</td><td align="center">3</td><td align="center">↑106%</td><td align="center">Range: 100% to 170%<sup>c</sup></td><td align="center">Not Assessed</td></tr><tr><td>Rifampin 600 mg daily x 14 days</td><td>Zidovudine 200 mg every 8 h x 14 days</td><td align="center">8</td><td align="center">↓47%</td><td align="center">90% CI: 41% to 53%</td><td align="center">Not Assessed</td></tr><tr><td>Ritonavir 300 mg every 6 h x 4 days</td><td>Zidovudine 200 mg every 8 h x 4 days</td><td align="center">9</td><td align="center">↓25%</td><td align="center">95% CI: 15% to 34%</td><td align="center">↔</td></tr><tr><td>Valproic acid 250 mg or 500 mg every 8 h x 4 days</td><td>Zidovudine 100 mg every 8 h x 4 days</td><td align="center">6</td><td align="center">↑80%</td><td align="center">Range: 64% to 130%<sup>c</sup></td><td align="center">Not Assessed</td></tr><tr><td class="credit" colspan="6">↑ = Increase; ↓ = Decrease; ↔ = No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval.<br /><sup>a</sup> See <b>DRUG INTERACTIONS</b> for additional information on drug interactions.<br /><sup>b</sup> The drug-drug interaction was only evaluated in males.<br /><sup>c</sup> Estimated range of percent difference.</td></tr></tbody></table></center><p></p><h4>Microbiology</h4><h5>Mechanism Of Action</h5><p><i>Abacavir</i></p><p>Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5'-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 <a href="/reverse_transcriptase/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">reverse transcriptase</a> (<a href="/rt/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">RT</a>) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.</p><p><i>Lamivudine</i></p><p>Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the <a href="/nucleotide/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">nucleotide</a> analogue.</p><p><i>Zidovudine</i></p><p>Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5'-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.</p><h5>Antiviral Activity</h5><p><i>Abacavir</i></p><p>The <a href="/antiviral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antiviral</a> activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC50 values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC50 value was 0.26 ± 0.18 microM against 8 clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O <a href="/viruses/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">viruses</a> (n = 3 except n = 2 for <a href="/clade/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">clade</a> B), respectively. The EC50 values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM.</p><p><i>Lamivudine</i></p><p>The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4) ranged from 0.003 to 0.120 microM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.</p><p><i>Zidovudine</i></p><p>The antiviral activity of zidovudine against HIV-1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes. The EC50 and EC90 values for zidovudine were 0.01 to 0.49 microM (1 microM = 0.27 mcg per mL) and 0.1 to 9 microM, respectively. HIV-1 from therapy-naive subjects with no <a href="/amino_acid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">amino acid</a> substitutions associated with resistance gave median EC50 values of 0.011 microM (range: 0.005 to 0.110 microM) from Virco (n = 92 baseline samples) and 0.0017 microM (range: 0.006 to 0.0340 microM) from Monogram Biosciences (n = 135 baseline samples). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 microM, and against HIV-2 isolates from 0.00049 to 0.004 microM. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.</p><p>Neither abacavir, lamivudine, nor zidovudine was antagonistic to tested anti-HIV agents, with the exception of stavudine where an antagonistic relationship with zidovudine has been demonstrated in cell culture. See full prescribing information for ZIAGEN (abacavir), EPIVIR (lamivudine), RETROVIR (zidovudine).</p><h5>Resistance</h5><p>HIV-1 isolates with reduced susceptibility to abacavir, lamivudine, or zidovudine have been selected in cell culture and were also recovered from subjects treated with abacavir, lamivudine, and zidovudine, or the combinations of the individual components.</p><p><i>Abacavir And Lamivudine</i></p><p>HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions, K65R, L74V, Y115F, and M184V/I emerging in HIV-1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7-to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.</p><p><i>Zidovudine</i></p><p>Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated subjects showed thymidine analogue mutation (TAM) substitutions in HIV-1 RT (M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N) that confer zidovudine resistance. In general, higher levels of resistance were associated with a greater number of substitutions. In some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine.</p><h5>Cross-Resistance</h5><p>Cross-resistance has been observed among NRTIs. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with TAM substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.</p><p>TAMs are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, and tenofovir. Cross-resistance between lamivudine and zidovudine has not been reported.</p> <a name="AP"></a><h4>Animal Toxicology And/Or Pharmacology</h4><p>Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.</p> <a name="CS"></a><h4>Clinical Studies</h4><p>The following trial was conducted with the individual components of TRIZIVIR [see <b>CLINICAL PHARMACOLOGY</b>].</p><p>CNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV-1-infected, therapy-naive adults were randomized to receive either ZIAGEN (300 mg twice daily) plus COMBIVIR (lamivudine 150 mg/zidovudine 300 mg twice daily), or indinavir (800 mg 3 times a day) plus COMBIVIR twice daily. The trial was stratified at <a href="/randomization/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">randomization</a> by pre-entry plasma HIV-1 RNA 10,000 to 100,000 copies per mL and plasma HIV-1 RNA greater than 100,000 copies per mL. Trial participants were male (87%), Caucasian (73%), black (15%), and Hispanic (9%). At baseline the median age was 36 years; the median pretreatment CD4+ cell count was 360 cells per mm³, and median plasma HIV-1 RNA was 4.8 log<sub>10</sub> copies per mL. Proportions of subjects with plasma HIV-1 RNA less than 400 copies per mL (using Roche AMPLICOR HIV-1 MONITOR Test) through 48 weeks of treatment are summarized in Table 5.</p><p align="center"><b>Table 5: Outcomes of Randomized Treatment through Week 48 (CNA3005)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Outcome</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine/ Zidovudine<br />(n = 262)</td><td class="EmphTd" width="25%">Indinavir plus Lamivudine/ Zidovudine<br />(n = 265)</td></tr><tr><td>Responder<sup>a</sup></td><td align="center">49%</td><td align="center">50%</td></tr><tr><td>Virologic failure<sup>b</sup></td><td align="center">31%</td><td align="center">28%</td></tr><tr><td>Discontinued due to adverse reactions</td><td align="center">10%</td><td align="center">12%</td></tr><tr><td>Discontinued due to other reasons<sup>c</sup></td><td align="center">11%</td><td align="center">10%</td></tr><tr><td class="credit" colspan="3"><sup>a</sup> Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL.<br /><sup>b</sup> Includes viral rebound and failure to achieve confirmed less than 400 copies per mL by Week 48.<br /><sup>c</sup> Includes consent withdrawn, lost to follow-up, protocol violations, those with missing data, clinical progression, and other.</td></tr></tbody></table></center><p></p><p>Treatment response by plasma HIV-1 RNA strata is shown in Table 6.</p><p align="center"><b>Table 6: Proportions of Responders through Week 48 by Screening Plasma HIV-1 RNA Levels (CNA3005)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" rowspan="2" width="20%">Screening HIV-1 RNA (copies/mL)</td><td class="EmphTd" colspan="2">ZIAGEN plus Lamivudine/ Zidovudine<br />(n = 262)</td><td class="EmphTd" colspan="2">Indinavir plus Lamivudine /Zidovudine<br />(n = 265)</td></tr><tr><td class="EmphTd" width="20%"><400 copies/mL</td><td class="EmphTd" width="20%">n</td><td class="EmphTd" width="20%"><400 copies/mL</td><td class="EmphTd" width="20%">n</td></tr><tr><td>≥10,000 - ≤100,000</td><td align="center">50%</td><td align="center">166</td><td align="center">48%</td><td align="center">165</td></tr><tr><td>>100,000</td><td align="center">48%</td><td align="center">96</td><td align="center">52%</td><td align="center">100</td></tr></tbody></table></center><p></p><p>In subjects with baseline viral load greater than 100,000 copies per mL, percentages of subjects with HIV-1 RNA levels less than 50 copies per mL were 31% in the group receiving abacavir vs. 45% in the group receiving indinavir.</p><p>Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells per mm³ was observed in both treatment arms. Through Week 48, 9 subjects (3.4%) in the group receiving abacavir (6 CDC classification C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir (2 CDC classification C events and 1 death) experienced <a href="/clinical_disease/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">clinical disease</a> progression.</p> </div> </div> </div> | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3><h4>Mechanism Of Action</h4><p>TRIZIVIR is an antiretroviral agent [see <b>Microbiology</b>].</p><h4>Pharmacokinetics</h4><h5>Pharmacokinetics In Adults</h5><p>In a single-dose, 3-way crossover bioavailability trial of 1 TRIZIVIR tablet versus 1 ZIAGEN tablet (300 mg), 1 EPIVIR tablet (150 mg), plus 1 RETROVIR tablet (300 mg) administered simultaneously in healthy subjects (n = 24), there was no difference in the extent of absorption, as measured by the area under the plasma concentration-time curve (AUC) and maximal peak concentration (Cmax), of all 3 components. One TRIZIVIR tablet was bioequivalent to 1 ZIAGEN tablet (300 mg), 1 EPIVIR tablet (150 mg), plus 1 RETROVIR tablet (300 mg) following single-dose administration to fasting healthy subjects (n = 24).</p><p><i>Abacavir</i></p><p>Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of 300 mg of abacavir twice daily in 20 subjects, Cmax was 3.0 ± 0.89 mcg per mL (mean ± SD) and AUC(0-12 h) was 6.02 ± 1.73 mcg•hour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and glucuronyl transferase to form the 5'-glucuronide.</p><p><i>Lamivudine</i></p><p>Following oral administration, lamivudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).</p><p><i>Zidovudine</i></p><p>Following oral administration, zidovudine is rapidly absorbed and extensively distributed. Binding to plasma protein is low. Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74% of the dose following oral administration, respectively. A second metabolite, 3'-amino-3'deoxythymidine (AMT), has been identified in plasma. The AMT AUC was one-fifth of the zidovudine AUC.</p><p>In humans, abacavir, lamivudine, and zidovudine are not significantly metabolized by CYP enzymes.</p><p>The pharmacokinetic properties of abacavir, lamivudine, and zidovudine in fasting subjects are summarized in Table 3.</p><p align="center"><b>Table 3: Pharmacokinetic Parameters<sup>a</sup> for Abacavir, Lamivudine, and Zidovudine in Adults</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="28%">Parameter</td><td class="EmphTd" colspan="2">Abacavir</td><td class="EmphTd" colspan="2">Lamivudine</td><td class="EmphTd" colspan="2">Zidovudine</td></tr><tr><td>Oral bioavailability (%)</td><td align="center" width="16%">86 ± 25</td><td align="center" width="8%">n = 6</td><td align="center" width="16%">86 ± 16</td><td align="center" width="8%">n = 12</td><td align="center" width="16%">64 ± 10</td><td align="center" width="8%">n = 5</td></tr><tr><td>Apparent volume of distribution (L/kg)</td><td align="center">0.86 ± 0.15</td><td align="center">n = 6</td><td align="center">1.3 ± 0.4</td><td align="center">n = 20</td><td align="center">1.6 ± 0.6</td><td align="center">n = 8</td></tr><tr><td>Systemic clearance (L/h/kg)</td><td align="center">0.80 ± 0.24</td><td align="center">n = 6</td><td align="center">0.33 ± 0.06</td><td align="center">n = 20</td><td align="center">1.6 ± 0.6</td><td align="center">n = 6</td></tr><tr><td>Renal clearance (L/h/kg)</td><td align="center">0.007 ± 0.008</td><td align="center">n = 6</td><td align="center">0.22 ± 0.06</td><td align="center">n = 20</td><td align="center">0.34 ± 0.05</td><td align="center">n = 9</td></tr><tr><td>Elimination half-life (h)</td><td align="center">1.45 ± 0.32</td><td align="center">n = 20</td><td align="center" colspan="2">13 to 19<sup>b</sup></td><td align="center" colspan="2">0.5 to 3<sup>b</sup></td></tr><tr><td class="credit" colspan="7"><sup>a</sup> Data presented as mean ±standard deviation except where noted.<br /><sup>b</sup> Approximate range.</td></tr></tbody></table></center><p></p><h5>Effect Of Food On Absorption Of TRIZIVIR</h5><p>Administration with food in a single-dose bioavailability trial resulted in lower Cmax, similar to results observed previously for the reference formulations. The average [90% CI] decrease in abacavir, lamivudine, and zidovudine Cmax was 32% [24% to 38%], 18% [10% to 25%], and 28% [13% to 40%], respectively, when administered with a high-fat meal, compared with administration under fasted conditions. Administration of TRIZIVIR with food did not alter the extent of abacavir, lamivudine, and zidovudine absorption (AUC), as compared with administration under fasted conditions (n = 24) [see <b>DOSAGE AND ADMINISTRATION</b>].</p><h4>Specific Populations</h4><h5>Patients With Renal Impairment</h5><p><i>TRIZIVIR</i></p><p>The effect of renal impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components).</p><h5>Patients With Hepatic Impairment</h5><p><i>TRIZIVIR</i></p><p>The effect of hepatic impairment on the combination of abacavir, lamivudine, and zidovudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, lamivudine, and zidovudine components).</p><h5>Pregnant Women</h5><p><i>Abacavir</i></p><p>Abacavir pharmacokinetics were studied in 25 pregnant women during the last trimester of pregnancy receiving abacavir 300 mg twice daily. Abacavir exposure (AUC) during pregnancy was similar to those in <a href="/postpartum/definition.htm" ">postpartum</a> and in HIV-infected non-pregnant historical controls. Consistent with passive diffusion of abacavir across the placenta, abacavir concentrations in <a href="/neonatal/definition.htm" ">neonatal</a> plasma <a href="/cord/definition.htm" ">cord</a> samples at birth were essentially equal to those in maternal plasma at delivery.</p><p><i>Lamivudine</i></p><p>Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and <a href="/umbilical_cord/definition.htm" ">umbilical cord</a> serum samples.</p><p><i>Zidovudine</i></p><p>Zidovudine pharmacokinetics have been studied in a Phase 1 trial of 8 women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.</p><p>Although data are limited, <a href="/methadone/definition.htm" ">methadone</a> <a href="/maintenance_therapy/definition.htm" ">maintenance therapy</a> in 5 pregnant women did not appear to alter zidovudine pharmacokinetics.</p><h5>Geriatric Patients</h5><p>The pharmacokinetics of abacavir, lamivudine, and zidovudine have not been studied in subjects over 65 years of age.</p><h5>Male And Female Patients</h5><p>There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (abacavir, lamivudine, or zidovudine) based on the available information that was analyzed for each of the individual components.</p><h5>Racial Groups</h5><p>Abacavir and Lamivudine: There are no significant or clinically relevant racial differences in pharmacokinetics of abacavir or lamivudine based on the available information that was analyzed for each of the individual components.</p><p><i>Zidovudine</i></p><p>The pharmacokinetics of zidovudine with respect to race have not been determined.</p><h4>Drug Interaction Studies</h4><p>The drug interaction trials described were conducted with abacavir, lamivudine or zidovudine as single entities; no drug interaction trials have been conducted using TRIZIVIR. No clinically significant drug interactions are expected between abacavir, lamivudine, and zidovudine.</p><h5>Effect Of Abacavir And Lamivudine On The Pharmacokinetics Of Other Agents</h5><p>In vitro studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit <a href="/metabolism/definition.htm" ">metabolism</a> mediated by CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6). Based on in vitro study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic <a href="/anion/definition.htm" ">anion</a> transporter <a href="/polypeptide/definition.htm" ">polypeptide</a> (OATP)1B1/3, <a href="/breast_cancer_facts_stages/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">breast cancer</a> resistance protein (BCRP) or P-<a href="/glycoprotein/definition.htm" ">glycoprotein</a> (P-gp), organic cation transporter (OCT)1, OCT2, OCT3 (lamivudine only), or multidrug and toxic extrusion protein (MATE)1 and MATE2-K.</p><h5>Riociguat</h5><p>Coadministration of a single dose of riociguat (0.5 mg) to HIV-1–infected subjects receiving fixed-dose abacavir/dolutegravir/lamivudine is reported to increase riociguat AUC(∞) compared with riociguat AUC(∞) reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see <b>DRUG INTERACTIONS</b>].</p><h5>Effect Of Other Agents On The Pharmacokinetics Of Abacavir, Lamivudine, Or Zidovudine</h5><p>Abacavir, lamivudine, and zidovudine are not significantly metabolized by CYP enzymes; therefore, CYP enzyme inhibitors or inducers are not expected to affect their concentrations. In vitro, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, multidrug resistance-associated protein (MRP)2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is a substrate of BCRP and P-gp in vitro; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations.</p><p>Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.</p><p>Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.</p><h5>Glucuronyl Transferase</h5><p>Due to the common metabolic pathways of abacavir and zidovudine via glucuronyl transferase, 15 HIV-1-infected subjects were enrolled in a crossover trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.</p><h5>Ethanol</h5><p>Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.</p><h5>Interferon Alfa</h5><p>There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.</p><h5>Methadone</h5><p>In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see <b>DRUG INTERACTIONS</b>]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.</p><h5>Ribavirin</h5><p>In vitro data indicate ribavirin reduces <a href="/phosphorylation/definition.htm" ">phosphorylation</a> of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h5>Sorbitol (Excipient)</h5><p>Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24); 14%, 32%, and 36% in the AUC(∞); and 28%, 52%, and 55% in the Cmax; of lamivudine, respectively.</p><p>The effects of other coadministered drugs on abacavir, lamivudine, or zidovudine are provided in Table 4.</p><p align="center"><b>Table 4: Effect of Coadministered Drugs on Abacavir, Lamivudine, and Zidovudine AUC<sup>a</sup></b></p><center><table cellspacing="0" class="blacktbl" width="650"><tbody><tr><td class="EmphTd" rowspan="2" width="25%">Coadministered Drug and Dose</td><td class="EmphTd" rowspan="2" width="20%">Drug and Dose</td><td class="EmphTd" rowspan="2" width="10%">n</td><td class="EmphTd" colspan="2">Concentrations of Abacavir, Lamivudine, or Zidovudine</td><td class="EmphTd" rowspan="2" width="15%">Concentration of Coadministered Drug</td></tr><tr><td class="EmphTd" width="15%">AUC</td><td class="EmphTd" width="15%">Variability</td></tr><tr><td>Ethanol 0.7 g/kg</td><td>Abacavir single 600 mg</td><td align="center">24</td><td align="center">↑41%</td><td align="center">90% CI: 35% to 48%</td><td align="center">↔<sup>b</sup></td></tr><tr><td>Nelfinavir 750 mg every 8 h x 7 to 10 days</td><td>Lamivudine single 150 mg</td><td align="center">11</td><td align="center">↑10%</td><td align="center">95% CI: 1% to 20%</td><td align="center">↔</td></tr><tr><td>Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days</td><td>Lamivudine single 300 mg</td><td align="center">14</td><td align="center">↑43%</td><td align="center">90% CI: 32% to 55%</td><td align="center">↔</td></tr><tr><td>Atovaquone 750 mg every 12 h with food</td><td>Zidovudine 200 mg every 8 h</td><td align="center">14</td><td align="center">↑31%</td><td align="center">Range: 23% to 78%<sup>c</sup></td><td align="center">↔</td></tr><tr><td>Clarithromycin 500 mg twice daily</td><td>Zidovudine 100 mg every 4 h x 7 days</td><td align="center">4</td><td align="center">↓12%</td><td align="center">Range: ↓34% to ↑14%</td><td align="center">Not Reported</td></tr><tr><td>Fluconazole 400 mg daily</td><td>Zidovudine 200 mg every 8 h</td><td align="center">12</td><td align="center">↑74%</td><td align="center">95% CI: 54% to 98%</td><td align="center">Not Reported</td></tr><tr><td>Methadone 30 to 90 mg daily</td><td>Zidovudine 200 mg every 4 h</td><td align="center">9</td><td align="center">↑43%</td><td align="center">Range: 16% to 64%<sup>c</sup></td><td align="center">↔</td></tr><tr><td>Nelfinavir 750 mg every 8 h x 7 to 10 days</td><td>Zidovudine single 200 mg</td><td align="center">11</td><td align="center">↓35%</td><td align="center">Range: 28% to 41%</td><td align="center">↔</td></tr><tr><td>Probenecid 500 mg every 6 h x 2 days</td><td>Zidovudine 2 mg/kg every 8 h x 3 days</td><td align="center">3</td><td align="center">↑106%</td><td align="center">Range: 100% to 170%<sup>c</sup></td><td align="center">Not Assessed</td></tr><tr><td>Rifampin 600 mg daily x 14 days</td><td>Zidovudine 200 mg every 8 h x 14 days</td><td align="center">8</td><td align="center">↓47%</td><td align="center">90% CI: 41% to 53%</td><td align="center">Not Assessed</td></tr><tr><td>Ritonavir 300 mg every 6 h x 4 days</td><td>Zidovudine 200 mg every 8 h x 4 days</td><td align="center">9</td><td align="center">↓25%</td><td align="center">95% CI: 15% to 34%</td><td align="center">↔</td></tr><tr><td>Valproic acid 250 mg or 500 mg every 8 h x 4 days</td><td>Zidovudine 100 mg every 8 h x 4 days</td><td align="center">6</td><td align="center">↑80%</td><td align="center">Range: 64% to 130%<sup>c</sup></td><td align="center">Not Assessed</td></tr><tr><td class="credit" colspan="6">↑ = Increase; ↓ = Decrease; ↔ = No significant change; AUC = Area under the concentration versus time curve; CI = Confidence interval.<br /><sup>a</sup> See <b>DRUG INTERACTIONS</b> for additional information on drug interactions.<br /><sup>b</sup> The drug-drug interaction was only evaluated in males.<br /><sup>c</sup> Estimated range of percent difference.</td></tr></tbody></table></center><p></p><h4>Microbiology</h4><h5>Mechanism Of Action</h5><p><i>Abacavir</i></p><p>Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5'-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 <a href="/reverse_transcriptase/definition.htm" ">reverse transcriptase</a> (<a href="/rt/definition.htm" ">RT</a>) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.</p><p><i>Lamivudine</i></p><p>Lamivudine is a synthetic nucleoside analogue. Intracellularly, lamivudine is phosphorylated to its active 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the <a href="/nucleotide/definition.htm" ">nucleotide</a> analogue.</p><p><i>Zidovudine</i></p><p>Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5'-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.</p><h5>Antiviral Activity</h5><p><i>Abacavir</i></p><p>The <a href="/antiviral/definition.htm" ">antiviral</a> activity of abacavir against HIV-1 was assessed in a number of cell lines including primary monocytes/macrophages and peripheral blood mononuclear cells (PBMCs). EC50 values ranged from 3.7 to 5.8 microM (1 microM = 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC50 value was 0.26 ± 0.18 microM against 8 clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O <a href="/viruses/definition.htm" ">viruses</a> (n = 3 except n = 2 for <a href="/clade/definition.htm" ">clade</a> B), respectively. The EC50 values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM.</p><p><i>Lamivudine</i></p><p>The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM = 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4) ranged from 0.003 to 0.120 microM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.</p><p><i>Zidovudine</i></p><p>The antiviral activity of zidovudine against HIV-1 was assessed in a number of cell lines including monocytes and fresh human peripheral blood lymphocytes. The EC50 and EC90 values for zidovudine were 0.01 to 0.49 microM (1 microM = 0.27 mcg per mL) and 0.1 to 9 microM, respectively. HIV-1 from therapy-naive subjects with no <a href="/amino_acid/definition.htm" ">amino acid</a> substitutions associated with resistance gave median EC50 values of 0.011 microM (range: 0.005 to 0.110 microM) from Virco (n = 92 baseline samples) and 0.0017 microM (range: 0.006 to 0.0340 microM) from Monogram Biosciences (n = 135 baseline samples). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 microM, and against HIV-2 isolates from 0.00049 to 0.004 microM. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.</p><p>Neither abacavir, lamivudine, nor zidovudine was antagonistic to tested anti-HIV agents, with the exception of stavudine where an antagonistic relationship with zidovudine has been demonstrated in cell culture. See full prescribing information for ZIAGEN (abacavir), EPIVIR (lamivudine), RETROVIR (zidovudine).</p><h5>Resistance</h5><p>HIV-1 isolates with reduced susceptibility to abacavir, lamivudine, or zidovudine have been selected in cell culture and were also recovered from subjects treated with abacavir, lamivudine, and zidovudine, or the combinations of the individual components.</p><p><i>Abacavir And Lamivudine</i></p><p>HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions, K65R, L74V, Y115F, and M184V/I emerging in HIV-1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and an approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74M, or Y115F with M184V or I conferred a 7-to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.</p><p><i>Zidovudine</i></p><p>Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated subjects showed thymidine analogue mutation (TAM) substitutions in HIV-1 RT (M41L, D67N, K70R, L210W, T215Y or F, and K219E/R/H/Q/N) that confer zidovudine resistance. In general, higher levels of resistance were associated with a greater number of substitutions. In some subjects harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine.</p><h5>Cross-Resistance</h5><p>Cross-resistance has been observed among NRTIs. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with TAM substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.</p><p>TAMs are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, and tenofovir. Cross-resistance between lamivudine and zidovudine has not been reported.</p> <a name="AP"></a><h4>Animal Toxicology And/Or Pharmacology</h4><p>Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 24 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.</p> <a name="CS"></a><h4>Clinical Studies</h4><p>The following trial was conducted with the individual components of TRIZIVIR [see <b>CLINICAL PHARMACOLOGY</b>].</p><p>CNA3005 was a multicenter, double-blind, controlled trial in which 562 HIV-1-infected, therapy-naive adults were randomized to receive either ZIAGEN (300 mg twice daily) plus COMBIVIR (lamivudine 150 mg/zidovudine 300 mg twice daily), or indinavir (800 mg 3 times a day) plus COMBIVIR twice daily. The trial was stratified at <a href="/randomization/definition.htm" ">randomization</a> by pre-entry plasma HIV-1 RNA 10,000 to 100,000 copies per mL and plasma HIV-1 RNA greater than 100,000 copies per mL. Trial participants were male (87%), Caucasian (73%), black (15%), and Hispanic (9%). At baseline the median age was 36 years; the median pretreatment CD4+ cell count was 360 cells per mm³, and median plasma HIV-1 RNA was 4.8 log<sub>10</sub> copies per mL. Proportions of subjects with plasma HIV-1 RNA less than 400 copies per mL (using Roche AMPLICOR HIV-1 MONITOR Test) through 48 weeks of treatment are summarized in Table 5.</p><p align="center"><b>Table 5: Outcomes of Randomized Treatment through Week 48 (CNA3005)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Outcome</td><td class="EmphTd" width="25%">ZIAGEN plus Lamivudine/ Zidovudine<br />(n = 262)</td><td class="EmphTd" width="25%">Indinavir plus Lamivudine/ Zidovudine<br />(n = 265)</td></tr><tr><td>Responder<sup>a</sup></td><td align="center">49%</td><td align="center">50%</td></tr><tr><td>Virologic failure<sup>b</sup></td><td align="center">31%</td><td align="center">28%</td></tr><tr><td>Discontinued due to adverse reactions</td><td align="center">10%</td><td align="center">12%</td></tr><tr><td>Discontinued due to other reasons<sup>c</sup></td><td align="center">11%</td><td align="center">10%</td></tr><tr><td class="credit" colspan="3"><sup>a</sup> Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL.<br /><sup>b</sup> Includes viral rebound and failure to achieve confirmed less than 400 copies per mL by Week 48.<br /><sup>c</sup> Includes consent withdrawn, lost to follow-up, protocol violations, those with missing data, clinical progression, and other.</td></tr></tbody></table></center><p></p><p>Treatment response by plasma HIV-1 RNA strata is shown in Table 6.</p><p align="center"><b>Table 6: Proportions of Responders through Week 48 by Screening Plasma HIV-1 RNA Levels (CNA3005)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" rowspan="2" width="20%">Screening HIV-1 RNA (copies/mL)</td><td class="EmphTd" colspan="2">ZIAGEN plus Lamivudine/ Zidovudine<br />(n = 262)</td><td class="EmphTd" colspan="2">Indinavir plus Lamivudine /Zidovudine<br />(n = 265)</td></tr><tr><td class="EmphTd" width="20%"><400 copies/mL</td><td class="EmphTd" width="20%">n</td><td class="EmphTd" width="20%"><400 copies/mL</td><td class="EmphTd" width="20%">n</td></tr><tr><td>≥10,000 - ≤100,000</td><td align="center">50%</td><td align="center">166</td><td align="center">48%</td><td align="center">165</td></tr><tr><td>>100,000</td><td align="center">48%</td><td align="center">96</td><td align="center">52%</td><td align="center">100</td></tr></tbody></table></center><p></p><p>In subjects with baseline viral load greater than 100,000 copies per mL, percentages of subjects with HIV-1 RNA levels less than 50 copies per mL were 31% in the group receiving abacavir vs. 45% in the group receiving indinavir.</p><p>Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells per mm³ was observed in both treatment arms. Through Week 48, 9 subjects (3.4%) in the group receiving abacavir (6 CDC classification C events and 3 deaths) and 3 subjects (1.5%) in the group receiving indinavir (2 CDC classification C events and 1 death) experienced <a href="/clinical_disease/definition.htm" ">clinical disease</a> progression.</p> </div> </div> </div> | 5 | 2023-02-01 17:38:34 | Abacavir Sulfate, Lamivudine, and Zidovudine (Trizivir) | A | HIV, NNRTIs | Trizivir | abacavir sulfate, lamivudine, and zidovudine | Trizivir | John P. Cunha, DO, FACOEP |
| 40 | 2023-02-23 12:07:03 | Medication Guide | <a name="PI"></a><h3>PATIENT INFORMATION</h3><p><b>TRIZIVIR</b><br />(TRY-zih-veer)<br />(abacavir, lamivudine, and zidovudine tablets)</p><p><b>What is the most important information I should know about TRIZIVIR?</b></p><p><b>TRIZIVIR can cause serious side effects, including:</b></p><ul><li><b>Serious allergic reactions (hypersensitivity reaction)</b> that can cause death have happened with TRIZIVIR and other abacavir-containing products. Your risk of this allergic reaction is much higher if you have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.</li></ul><p><b>If you get a symptom from 2 or more of the following groups while taking TRIZIVIR, call your healthcare provider right away to find out if you should stop taking TRIZIVIR.</b></p><p></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="30%"></td><td class="EmphTd" width="70%">Symptom(s)</td></tr><tr><td>Group 1</td><td>Fever</td></tr><tr><td>Group 2</td><td>Rash</td></tr><tr><td>Group 3</td><td>Nausea, vomiting, diarrhea, abdominal (stomach area) pain</td></tr><tr><td>Group 4</td><td>Generally ill feeling, extreme tiredness, or achiness</td></tr><tr><td>Group 5</td><td>Shortness of breath, cough, sore throat</td></tr></tbody></table></center><p></p><p>A list of these symptoms is on the Warning Card your pharmacist gives you. <b>Carry this Warning Card with you at all times.</b></p><p><b>If you stop TRIZIVIR because of an allergic reaction, never take TRIZIVIR (abacavir, lamivudine and zidovudine) or any other abacavir-containing medicine (EPZICOM, TRIUMEQ, or ZIAGEN) again.</b></p><ul><li>If you have an allergic reaction, dispose of any unused TRIZIVIR. Ask your pharmacist how to properly dispose of medicines.</li><li>If you take TRIZIVIR or any other abacavir-containing medicine again after you have had an allergic reaction, <b>within hours</b> you may get life-threatening symptoms that may include <b>very low blood pressure or death.</b></li><li>If you stop TRIZIVIR for any other reason, even for a few days, and you are not allergic to TRIZIVIR, talk with your healthcare provider before taking it again. Taking TRIZIVIR again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.</li></ul><p><b>If your healthcare provider tells you that you can take TRIZIVIR again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.</b></p><ul><li><b>Blood problems.</b> Zidovudine, one of the medicines in TRIZIVIR, can cause serious blood cell problems. These include reduced numbers of white blood cells (<a href="/neutropenia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">neutropenia</a>) and extremely reduced numbers of <a href="/red_blood_cells/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">red blood cells</a> (<a href="/anemia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anemia</a>). These blood cell problems are especially likely to happen in people with advanced <a href="/human_immunodeficiency_virus_hiv/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">human immunodeficiency virus</a>-1 (HIV-1) infection or <a href="/acquired/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Acquired</a> Immune Deficiency Syndrome (<a href="/acquired_immunodeficiency_syndrome_aids/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">AIDS</a>). Your healthcare provider should check your blood cell counts regularly during treatment with TRIZIVIR.</li><li><b>Muscle pain or weakness</b> can happen during treatment with TRIZIVIR. Zidovudine, one of the medicines in TRIZIVIR, can cause <a href="/muscle_pain/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">muscle pain</a> or weakness when used for a long time.</li><li><b>Too much lactic acid in your blood (lactic acidosis).</b> Lactic <a href="/acidosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">acidosis</a> is a serious medical emergency that can lead to death. <b>Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:</b><ul><li>feel very weak or tired</li><li>feel cold, especially in your arms and legs</li><li>unusual (not normal) muscle pain</li><li>feel dizzy or light-headed</li><li>trouble breathing</li><li>have a fast or irregular heartbeat</li><li>stomach pain with <a href="/nausea_and_vomiting/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">nausea and vomiting</a></li></ul></li><li><b>Severe liver problems.</b> In some cases, severe liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). <b>Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:</b><ul><li>your skin or the white part of your eyes turns yellow (<a href="/kernicterus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">jaundice</a>)</li><li>loss of appetite for several days or longer</li><li>dark or “tea-colored” urine</li><li>nausea</li><li>light colored stools (bowel movements)</li><li>pain, aching, or tenderness on the right side of your stomach area</li></ul></li></ul><p><b>You may be more likely to get lactic acidosis or serious liver problems if you are female or very overweight (obese).</b></p><ul><li><b>Worsening of hepatitis B virus (HBV) infection.</b> If you have <a href="/hbv/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HBV</a> infection and take TRIZIVIR, your HBV may get worse (flare-up) if you stop taking TRIZIVIR. A “flare-up” is when your HBV infection suddenly returns in a worse way than before.<ul><li>Do not run out of TRIZIVIR. Refill your prescription or talk to your healthcare provider before your TRIZIVIR is all gone.</li><li>Do not stop TRIZIVIR without first talking to your healthcare provider.</li><li>If you stop taking TRIZIVIR, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you a medicine to treat HBV. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking TRIZIVIR.</li></ul></li><li><b>Resistant HBV.</b> If you have HIV-1 and HBV, the HBV can change (mutate) during your treatment with TRIZIVIR and become harder to treat (resistant).</li><li><b>Use with interferon and ribavirin-based regimens.</b> Worsening of <a href="/liver_disease/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">liver disease</a> that has caused death has happened in people infected with both HIV-1 and <a href="/viral_hepatitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis</a> C virus who are taking HIV-1 medicines and are also being treated for <a href="/hepatitis_c/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis C</a> with interferon alfa with or without ribavirin. If you are taking TRIZIVIR and interferon alfa with or without ribavirin, tell your healthcare provider if you have any new symptoms.</li><li><b>For more information about side effects, see “What are the possible side effects of TRIZIVIR?”</b></li></ul><p><b>What is TRIZIVIR?</b></p><p>TRIZIVIR is a prescription medicine used alone or with other HIV-1 medicines to treat HIV-1 infection.</p><p>HIV-1 is the virus that causes AIDS.</p><p>TRIZIVIR contains the prescription medicines abacavir, lamivudine, and zidovudine.</p><p>TRIZIVIR should not be used in children weighing less than 88 pounds (40 kg).</p><p><b>Do not take TRIZIVIR if you:</b></p><ul><li>have a certain type of gene variation called the HLA-B*5701 allele. Your healthcare provider will test you for this before prescribing treatment with TRIZIVIR.</li><li>are allergic to abacavir, lamivudine, zidovudine, or any of the ingredients in TRIZIVIR. See the end of this Medication Guide for a complete list of ingredients in TRIZIVIR.</li><li>have certain liver problems.</li></ul><p><b>Before you take TRIZIVIR, tell your healthcare provider about all of your medical conditions, including if you:</b></p><ul><li>have been tested and know whether or not you have a particular gene variation called HLA-B*5701.</li><li>have or have had liver problems, including <a href="/hepatitis_b/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis B</a> or C virus infection.</li><li>have kidney problems.</li><li>have low blood cell counts (<a href="/bone_marrow/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bone marrow</a> problem). Ask your healthcare provider if you are not sure.</li><li>have heart problems, smoke, or have diseases that increase your risk of <a href="/heart_disease/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">heart disease</a> such as <a href="/high_blood_pressure_hypertension_medications/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">high blood pressure</a>, high <a href="/cholesterol/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cholesterol</a>, or <a href="/diabetes_mellitus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">diabetes</a>.</li><li>are pregnant or plan to become pregnant.<ul><li><b>Pregnancy Registry.</b> There is a pregnancy registry for women who take HIV-1 medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.</li></ul></li><li>are breastfeeding or plan to breastfeed. <b>Do not breastfeed if you take TRIZIVIR.</b><ul><li>You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.</li></ul></li></ul><p><b>Tell your healthcare provider about all the medicines you take,</b> including prescription and over-thecounter medicines, vitamins, and herbal supplements.</p><p>Some medicines interact with TRIZIVIR. <b>Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.</b></p><ul><li>You can ask your healthcare provider or pharmacist for a list of medicines that interact with TRIZIVIR.</li><li><b>Do not start taking a new medicine without telling your healthcare provider.</b> Your healthcare provider can tell you if it is safe to take TRIZIVIR with other medicines.</li></ul><p><b>How should I take TRIZIVIR?</b></p><ul><li><b>Take TRIZIVIR exactly as your healthcare provider tells you to take it.</b></li><li>Do not change your dose or stop taking TRIZIVIR without talking with your healthcare provider.</li><li>If you miss a dose of TRIZIVIR, take it as soon as you remember. Do not take 2 doses at the same time or take more than your healthcare provider tells you to take.</li><li>Stay under the care of a healthcare provider during treatment with TRIZIVIR.</li><li>TRIZIVIR may be taken with or without food.</li><li>Do not run out of TRIZIVIR. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.</li><li>If you take too much TRIZIVIR, call your healthcare provider or go to the nearest hospital emergency room right away.</li></ul><p><b>What are the possible side effects of TRIZIVIR?</b></p><ul><li><b>TRIZIVIR can cause serious side effects including:</b></li><li><b>See “What is the most important information I should know about TRIZIVIR?”</b></li><li><b>Changes in your immune system (Immune Reconstitution Syndrome)</b> can happen when you start taking HIV-1 medicines. Your <a href="/immune_system/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">immune system</a> may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking TRIZIVIR.</li><li><b>Loss of body fat</b> can happen in people who take HIV-1 medicines that contain zidovudine. This loss of fat may occur in the legs, arms, buttocks, and face. The loss of fat may be permanent and long-term health effects are not known.</li><li><b>Heart attack.</b> Some HIV-1 medicines including TRIZIVIR may increase your risk of <a href="/heart_attack/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">heart attack</a>.</li></ul><p><b>The most common side effects of TRIZIVIR include:</b></p><ul><li>nausea</li><li>headache</li><li>weakness or tiredness</li><li>vomiting</li></ul><p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p><p>These are not all the possible side effects of TRIZIVIR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p><p><b>How should I store TRIZIVIR?</b></p><ul><li>Store TRIZIVIR at room temperature.</li></ul><p><b>Keep TRIZIVIR and all medicines out of the reach of children.</b></p><p><b>General information for safe and effective use of TRIZIVIR.</b></p><p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRIZIVIR for a condition for which it was not prescribed. Do not give TRIZIVIR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for the information about TRIZIVIR that is written for health professionals.</p><p><b>What are the ingredients in TRIZIVIR?</b></p><p><b>Active ingredients:</b> abacavir, lamivudine, and zidovudine</p><p><b>Inactive ingredients:</b> magnesium stearate, microcrystalline cellulose, sodium starch glycolate</p><p>Tablet film coating contains: OPADRY green 03B11434 made of FD&C Blue No. 2, hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide.</p><p><b>WARNING CARD</b></p><p><b>TRIZIVIR®</b><br />(abacavir, lamivudine, and zidovudine) tablets</p><p><b>Patients taking TRIZIVIR may have a serious allergic reaction (hypersensitivityreaction) that can cause death. If you get a symptom from 2 or more of the following groups while taking TRIZIVIR, call your healthcare provider right away to find out if you should stop taking this medicine.</b></p><p></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="30%"></td><td class="EmphTd" width="70%">Symptom(s)</td></tr><tr><td>Group 1</td><td>Fever</td></tr><tr><td>Group 2</td><td>Rash</td></tr><tr><td>Group 3</td><td>Nausea, vomiting, diarrhea, or abdominal (stomach area) pain</td></tr><tr><td>Group 4</td><td>Generally ill feeling, extreme tiredness, or achiness</td></tr><tr><td>Group 5</td><td>Shortness of breath, cough, or sore throat</td></tr></tbody></table></center><p></p><p>Always carry this Warning Card with you to help recognize symptoms of this allergic reaction.</p><p>(Back of Card)</p><p><b>WARNING CARD</b></p><p><b>TRIZIVIR® (abacavir, lamivudine, and zidovudine) tablets</b></p><p>If you must stop treatment with TRIZIVIR because you have had an allergic reaction to abacavir, NEVER take TRIZIVIR or any other abacavir-containing medicine (ZIAGEN® , EPZICOM®, or TRIUMEQ®) again. If you have an allergic reaction, dispose of any unused TRIZIVIR. Ask your pharmacist how to properly dispose of medicines. If you take TRIZIVIR or another abacavir-containing medicine again after you have had an allergic reaction, WITHIN HOURS you may get life-threatening symptoms that may include very <a href="/low_blood_pressure_hypotension_causes/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">low blood pressure</a> or death.</p><p>Please read the Medication Guide for additional information on TRIZIVIR.</p><p class="credit">This Medication Guide has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | <a name="PI"></a><h3>PATIENT INFORMATION</h3><p><b>TRIZIVIR</b><br />(TRY-zih-veer)<br />(abacavir, lamivudine, and zidovudine tablets)</p><p><b>What is the most important information I should know about TRIZIVIR?</b></p><p><b>TRIZIVIR can cause serious side effects, including:</b></p><ul><li><b>Serious allergic reactions (hypersensitivity reaction)</b> that can cause death have happened with TRIZIVIR and other abacavir-containing products. Your risk of this allergic reaction is much higher if you have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.</li></ul><p><b>If you get a symptom from 2 or more of the following groups while taking TRIZIVIR, call your healthcare provider right away to find out if you should stop taking TRIZIVIR.</b></p><p></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="30%"></td><td class="EmphTd" width="70%">Symptom(s)</td></tr><tr><td>Group 1</td><td>Fever</td></tr><tr><td>Group 2</td><td>Rash</td></tr><tr><td>Group 3</td><td>Nausea, vomiting, diarrhea, abdominal (stomach area) pain</td></tr><tr><td>Group 4</td><td>Generally ill feeling, extreme tiredness, or achiness</td></tr><tr><td>Group 5</td><td>Shortness of breath, cough, sore throat</td></tr></tbody></table></center><p></p><p>A list of these symptoms is on the Warning Card your pharmacist gives you. <b>Carry this Warning Card with you at all times.</b></p><p><b>If you stop TRIZIVIR because of an allergic reaction, never take TRIZIVIR (abacavir, lamivudine and zidovudine) or any other abacavir-containing medicine (EPZICOM, TRIUMEQ, or ZIAGEN) again.</b></p><ul><li>If you have an allergic reaction, dispose of any unused TRIZIVIR. Ask your pharmacist how to properly dispose of medicines.</li><li>If you take TRIZIVIR or any other abacavir-containing medicine again after you have had an allergic reaction, <b>within hours</b> you may get life-threatening symptoms that may include <b>very low blood pressure or death.</b></li><li>If you stop TRIZIVIR for any other reason, even for a few days, and you are not allergic to TRIZIVIR, talk with your healthcare provider before taking it again. Taking TRIZIVIR again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.</li></ul><p><b>If your healthcare provider tells you that you can take TRIZIVIR again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.</b></p><ul><li><b>Blood problems.</b> Zidovudine, one of the medicines in TRIZIVIR, can cause serious blood cell problems. These include reduced numbers of white blood cells (<a href="/neutropenia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">neutropenia</a>) and extremely reduced numbers of <a href="/red_blood_cells/definition.htm" ">red blood cells</a> (<a href="/anemia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anemia</a>). These blood cell problems are especially likely to happen in people with advanced <a href="/human_immunodeficiency_virus_hiv/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">human immunodeficiency virus</a>-1 (HIV-1) infection or <a href="/acquired/definition.htm" ">Acquired</a> Immune Deficiency Syndrome (<a href="/acquired_immunodeficiency_syndrome_aids/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">AIDS</a>). Your healthcare provider should check your blood cell counts regularly during treatment with TRIZIVIR.</li><li><b>Muscle pain or weakness</b> can happen during treatment with TRIZIVIR. Zidovudine, one of the medicines in TRIZIVIR, can cause <a href="/muscle_pain/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">muscle pain</a> or weakness when used for a long time.</li><li><b>Too much lactic acid in your blood (lactic acidosis).</b> Lactic <a href="/acidosis/definition.htm" ">acidosis</a> is a serious medical emergency that can lead to death. <b>Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:</b><ul><li>feel very weak or tired</li><li>feel cold, especially in your arms and legs</li><li>unusual (not normal) muscle pain</li><li>feel dizzy or light-headed</li><li>trouble breathing</li><li>have a fast or irregular heartbeat</li><li>stomach pain with <a href="/nausea_and_vomiting/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">nausea and vomiting</a></li></ul></li><li><b>Severe liver problems.</b> In some cases, severe liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). <b>Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems:</b><ul><li>your skin or the white part of your eyes turns yellow (<a href="/kernicterus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">jaundice</a>)</li><li>loss of appetite for several days or longer</li><li>dark or “tea-colored” urine</li><li>nausea</li><li>light colored stools (bowel movements)</li><li>pain, aching, or tenderness on the right side of your stomach area</li></ul></li></ul><p><b>You may be more likely to get lactic acidosis or serious liver problems if you are female or very overweight (obese).</b></p><ul><li><b>Worsening of hepatitis B virus (HBV) infection.</b> If you have <a href="/hbv/definition.htm" ">HBV</a> infection and take TRIZIVIR, your HBV may get worse (flare-up) if you stop taking TRIZIVIR. A “flare-up” is when your HBV infection suddenly returns in a worse way than before.<ul><li>Do not run out of TRIZIVIR. Refill your prescription or talk to your healthcare provider before your TRIZIVIR is all gone.</li><li>Do not stop TRIZIVIR without first talking to your healthcare provider.</li><li>If you stop taking TRIZIVIR, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you a medicine to treat HBV. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking TRIZIVIR.</li></ul></li><li><b>Resistant HBV.</b> If you have HIV-1 and HBV, the HBV can change (mutate) during your treatment with TRIZIVIR and become harder to treat (resistant).</li><li><b>Use with interferon and ribavirin-based regimens.</b> Worsening of <a href="/liver_disease/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">liver disease</a> that has caused death has happened in people infected with both HIV-1 and <a href="/viral_hepatitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis</a> C virus who are taking HIV-1 medicines and are also being treated for <a href="/hepatitis_c/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis C</a> with interferon alfa with or without ribavirin. If you are taking TRIZIVIR and interferon alfa with or without ribavirin, tell your healthcare provider if you have any new symptoms.</li><li><b>For more information about side effects, see “What are the possible side effects of TRIZIVIR?”</b></li></ul><p><b>What is TRIZIVIR?</b></p><p>TRIZIVIR is a prescription medicine used alone or with other HIV-1 medicines to treat HIV-1 infection.</p><p>HIV-1 is the virus that causes AIDS.</p><p>TRIZIVIR contains the prescription medicines abacavir, lamivudine, and zidovudine.</p><p>TRIZIVIR should not be used in children weighing less than 88 pounds (40 kg).</p><p><b>Do not take TRIZIVIR if you:</b></p><ul><li>have a certain type of gene variation called the HLA-B*5701 allele. Your healthcare provider will test you for this before prescribing treatment with TRIZIVIR.</li><li>are allergic to abacavir, lamivudine, zidovudine, or any of the ingredients in TRIZIVIR. See the end of this Medication Guide for a complete list of ingredients in TRIZIVIR.</li><li>have certain liver problems.</li></ul><p><b>Before you take TRIZIVIR, tell your healthcare provider about all of your medical conditions, including if you:</b></p><ul><li>have been tested and know whether or not you have a particular gene variation called HLA-B*5701.</li><li>have or have had liver problems, including <a href="/hepatitis_b/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis B</a> or C virus infection.</li><li>have kidney problems.</li><li>have low blood cell counts (<a href="/bone_marrow/definition.htm" ">bone marrow</a> problem). Ask your healthcare provider if you are not sure.</li><li>have heart problems, smoke, or have diseases that increase your risk of <a href="/heart_disease/definition.htm" ">heart disease</a> such as <a href="/high_blood_pressure_hypertension_medications/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">high blood pressure</a>, high <a href="/cholesterol/definition.htm" ">cholesterol</a>, or <a href="/diabetes_mellitus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">diabetes</a>.</li><li>are pregnant or plan to become pregnant.<ul><li><b>Pregnancy Registry.</b> There is a pregnancy registry for women who take HIV-1 medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.</li></ul></li><li>are breastfeeding or plan to breastfeed. <b>Do not breastfeed if you take TRIZIVIR.</b><ul><li>You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.</li></ul></li></ul><p><b>Tell your healthcare provider about all the medicines you take,</b> including prescription and over-thecounter medicines, vitamins, and herbal supplements.</p><p>Some medicines interact with TRIZIVIR. <b>Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.</b></p><ul><li>You can ask your healthcare provider or pharmacist for a list of medicines that interact with TRIZIVIR.</li><li><b>Do not start taking a new medicine without telling your healthcare provider.</b> Your healthcare provider can tell you if it is safe to take TRIZIVIR with other medicines.</li></ul><p><b>How should I take TRIZIVIR?</b></p><ul><li><b>Take TRIZIVIR exactly as your healthcare provider tells you to take it.</b></li><li>Do not change your dose or stop taking TRIZIVIR without talking with your healthcare provider.</li><li>If you miss a dose of TRIZIVIR, take it as soon as you remember. Do not take 2 doses at the same time or take more than your healthcare provider tells you to take.</li><li>Stay under the care of a healthcare provider during treatment with TRIZIVIR.</li><li>TRIZIVIR may be taken with or without food.</li><li>Do not run out of TRIZIVIR. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.</li><li>If you take too much TRIZIVIR, call your healthcare provider or go to the nearest hospital emergency room right away.</li></ul><p><b>What are the possible side effects of TRIZIVIR?</b></p><ul><li><b>TRIZIVIR can cause serious side effects including:</b></li><li><b>See “What is the most important information I should know about TRIZIVIR?”</b></li><li><b>Changes in your immune system (Immune Reconstitution Syndrome)</b> can happen when you start taking HIV-1 medicines. Your <a href="/immune_system/definition.htm" ">immune system</a> may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking TRIZIVIR.</li><li><b>Loss of body fat</b> can happen in people who take HIV-1 medicines that contain zidovudine. This loss of fat may occur in the legs, arms, buttocks, and face. The loss of fat may be permanent and long-term health effects are not known.</li><li><b>Heart attack.</b> Some HIV-1 medicines including TRIZIVIR may increase your risk of <a href="/heart_attack/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">heart attack</a>.</li></ul><p><b>The most common side effects of TRIZIVIR include:</b></p><ul><li>nausea</li><li>headache</li><li>weakness or tiredness</li><li>vomiting</li></ul><p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p><p>These are not all the possible side effects of TRIZIVIR. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p><p><b>How should I store TRIZIVIR?</b></p><ul><li>Store TRIZIVIR at room temperature.</li></ul><p><b>Keep TRIZIVIR and all medicines out of the reach of children.</b></p><p><b>General information for safe and effective use of TRIZIVIR.</b></p><p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRIZIVIR for a condition for which it was not prescribed. Do not give TRIZIVIR to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for the information about TRIZIVIR that is written for health professionals.</p><p><b>What are the ingredients in TRIZIVIR?</b></p><p><b>Active ingredients:</b> abacavir, lamivudine, and zidovudine</p><p><b>Inactive ingredients:</b> magnesium stearate, microcrystalline cellulose, sodium starch glycolate</p><p>Tablet film coating contains: OPADRY green 03B11434 made of FD&C Blue No. 2, hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide.</p><p><b>WARNING CARD</b></p><p><b>TRIZIVIR®</b><br />(abacavir, lamivudine, and zidovudine) tablets</p><p><b>Patients taking TRIZIVIR may have a serious allergic reaction (hypersensitivityreaction) that can cause death. If you get a symptom from 2 or more of the following groups while taking TRIZIVIR, call your healthcare provider right away to find out if you should stop taking this medicine.</b></p><p></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="30%"></td><td class="EmphTd" width="70%">Symptom(s)</td></tr><tr><td>Group 1</td><td>Fever</td></tr><tr><td>Group 2</td><td>Rash</td></tr><tr><td>Group 3</td><td>Nausea, vomiting, diarrhea, or abdominal (stomach area) pain</td></tr><tr><td>Group 4</td><td>Generally ill feeling, extreme tiredness, or achiness</td></tr><tr><td>Group 5</td><td>Shortness of breath, cough, or sore throat</td></tr></tbody></table></center><p></p><p>Always carry this Warning Card with you to help recognize symptoms of this allergic reaction.</p><p>(Back of Card)</p><p><b>WARNING CARD</b></p><p><b>TRIZIVIR® (abacavir, lamivudine, and zidovudine) tablets</b></p><p>If you must stop treatment with TRIZIVIR because you have had an allergic reaction to abacavir, NEVER take TRIZIVIR or any other abacavir-containing medicine (ZIAGEN® , EPZICOM®, or TRIUMEQ®) again. If you have an allergic reaction, dispose of any unused TRIZIVIR. Ask your pharmacist how to properly dispose of medicines. If you take TRIZIVIR or another abacavir-containing medicine again after you have had an allergic reaction, WITHIN HOURS you may get life-threatening symptoms that may include very <a href="/low_blood_pressure_hypotension_causes/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">low blood pressure</a> or death.</p><p>Please read the Medication Guide for additional information on TRIZIVIR.</p><p class="credit">This Medication Guide has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | 5 | 2023-02-01 17:38:34 | Abacavir Sulfate, Lamivudine, and Zidovudine (Trizivir) | A | HIV, NNRTIs | Trizivir | abacavir sulfate, lamivudine, and zidovudine | Trizivir | John P. Cunha, DO, FACOEP |
| 41 | 2023-02-23 12:07:03 | Drug Description | <div class="webmdrx"> <a href="https://www.webmd.com/rx/drug-prices/triumeq?ecd=oo_webmdrx_rx-mono_rx/drug-prices/triumeq_dsktp_rxlist.com//rx/drug-prices/triumeq" target="_blank" onclick="wmdPageLink('webmdrx');"><p class="webmdrx_p">Find Lowest Prices on <span class="webmdrx_img"></span></p></a> </div> <h4>What is Triumeq and how is it used?</h4> <p>Triumeq is a prescription medicine used to treat the symptoms of HIV-1 Infection. Triumeq may be used alone or with other medications.</p> <p>Triumeq belongs to a class of drugs called HIV, ART Combos.</p> <p>It is not known if Triumeq is safe and effective in children weigh less than 88 lbs (40 kg).</p> <h4>What are the possible side effects of Triumeq?</h4> <p>Triumeq may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>fever,</li> <li>rash,</li> <li>nausea,</li> <li>vomiting,</li> <li>diarrhea,</li> <li>stomach pain,</li> <li>general ill feeling,</li> <li>extreme tiredness,</li> <li>body aches,</li> <li>shortness of breath,</li> <li>cough,</li> <li><a href="/sore_throat_pharyngitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">sore throat</a>,</li> <li>unusual <a href="/muscle_pain/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">muscle pain</a>,</li> <li>trouble breathing,</li> <li>stomach pain,</li> <li>irregular heart rate,</li> <li>dizziness,</li> <li>feeling cold,</li> <li>weakness,</li> <li>tiredness,</li> <li>swelling around your midsection,</li> <li>right-sided upper stomach pain,</li> <li>loss of appetite,</li> <li>dark urine,</li> <li><a href="/clay/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">clay</a>-colored stools,</li> <li>yellowing of <a href="/skin_anatomy_picture_definition_function/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">the skin</a> or eyes (<a href="/kernicterus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">jaundice</a>),</li> <li>chest pain or pressure,</li> <li>pain spreading to your jaw or <a href="/shoulder/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">shoulder</a>, and</li> <li>sweating</li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Triumeq include:</p> <ul> <li>headache,</li> <li>tiredness, and</li> <li>trouble sleeping</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Triumeq. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p align="center"><b>HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS B</b></p> <h4>Hypersensitivity Reactions</h4> <p><b>Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of TRIUMEQ (abacavir, dolutegravir, and lamivudine). Patients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele [see WARNINGS AND <a href="/triumeq-drug.htm#P">PRECAUTIONS</a>].</b></p> <p><b>TRIUMEQ is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see <a href="/triumeq-drug.htm#CI">CONTRAINDICATIONS</a>, WARNINGS AND <a href="/triumeq-drug.htm#P">PRECAUTIONS</a>]. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with TRIUMEQ or reinitiation of therapy with TRIUMEQ, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue TRIUMEQ immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see <a href="/triumeq-drug.htm#CI">CONTRAINDICATIONS</a>, WARNINGS AND <a href="/triumeq-drug.htm#P">PRECAUTIONS</a>].</b></p> <p><b>Following a hypersensitivity reaction to TRIUMEQ, NEVER restart TRIUMEQ or any other abacavir-containing product because more severe symptoms, including death can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see WARNINGS AND <a href="/triumeq-drug.htm#P">PRECAUTIONS</a>].</b></p> <h4>Lactic Acidosis and Severe Hepatomegaly with Steatosis</h4> <p><b>Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir, lamivudine, and other antiretrovirals. Discontinue TRIUMEQ if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see WARNINGS AND <a href="/triumeq-drug.htm#P">PRECAUTIONS</a>].</b></p> <h4>Exacerbations of Hepatitis B</h4> <p><b>Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of TRIUMEQ. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue TRIUMEQ and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see WARNINGS AND <a href="/triumeq-drug.htm#P">PRECAUTIONS</a>].</b></p> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <h4>TRIUMEQ</h4> <p>TRIUMEQ contains an INSTI (dolutegravir) and 2 nucleoside analogues (abacavir and lamivudine) with inhibitory activity against <a href="/script/main/art.asp?articlekey=3769" onclick="wmdTrack('embd-lnk');" rel="dict">HIV</a>.</p> <p>Each film-coated tablet contains abacavir sulfate equivalent to 600 mg of abacavir, dolutegravir sodium equivalent to 50 mg of dolutegravir, and 300 mg of lamivudine. TRIUMEQ tablets are purple, biconvex, oval, debossed with “572 Tr1” on one side and contain the inactive ingredients D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. The tablet film-coating (OPADRY® II Purple 85F90057) contains the inactive ingredients iron oxide black, iron oxide red, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium oxide.</p> <h4>Abacavir Sulfate</h4> <p>The chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). It has a molecular formula of (C<sub>14</sub>H<sub>18</sub>N<sub>6</sub>O)<sub>2</sub>•H<sub>2</sub>SO<sub>4</sub> and a molecular weight of 670.76 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="371"> <tbody> <tr> <td><img alt="Abacavir Sulfate - Structural Formula Illustration" height="308" src="https://images.rxlist.com/images/rxlist/triumeq1.gif" width="371" /></td> </tr> </tbody> </table> </center> <p></p> <p>Abacavir sulfate is a white to off-white solid and is soluble in water.</p> <h4>Dolutegravir</h4> <p>The chemical name of dolutegravir sodium is sodium (4R,12aS)-9-{[(2,4difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2Hpyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate. The empirical formula is C<sub>20</sub>H<sub>18</sub>F<sub>2</sub>N<sub>3</sub>NaO<sub>5</sub> and the molecular weight is 441.36 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="339"> <tbody> <tr> <td><img alt="Dolutegravir - Structural Formula Illustration" height="135" src="https://images.rxlist.com/images/rxlist/triumeq2.gif" width="339" /></td> </tr> </tbody> </table> </center> <p></p> <p>Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water.</p> <h4>Lamivudine</h4> <p>The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2',3'-dideoxy, 3'-thiacytidine. It has a molecular formula of C<sub>8</sub>H<sub>11</sub>N<sub>3</sub>O<sub>3</sub>S and a molecular weight of 229.3 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="243"> <tbody> <tr> <td><img alt="Lamivudine - Structural Formula Illustration" height="215" src="https://images.rxlist.com/images/rxlist/triumeq3.gif" width="243" /></td> </tr> </tbody> </table> </center> <p></p> <p>Lamivudine is a white to off-white crystalline solid and is soluble in water.</p> </div> <div id="667441035-1" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-1", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <div class="webmdrx"> <a href="https://www.webmd.com/rx/drug-prices/triumeq?ecd=oo_webmdrx_rx-mono_rx/drug-prices/triumeq_dsktp_rxlist.com//rx/drug-prices/triumeq" target="_blank" onclick="wmdPageLink('webmdrx');"><p class="webmdrx_p">Find Lowest Prices on <span class="webmdrx_img"></span></p></a> </div> <h4>What is Triumeq and how is it used?</h4> <p>Triumeq is a prescription medicine used to treat the symptoms of HIV-1 Infection. Triumeq may be used alone or with other medications.</p> <p>Triumeq belongs to a class of drugs called HIV, ART Combos.</p> <p>It is not known if Triumeq is safe and effective in children weigh less than 88 lbs (40 kg).</p> <h4>What are the possible side effects of Triumeq?</h4> <p>Triumeq may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>fever,</li> <li>rash,</li> <li>nausea,</li> <li>vomiting,</li> <li>diarrhea,</li> <li>stomach pain,</li> <li>general ill feeling,</li> <li>extreme tiredness,</li> <li>body aches,</li> <li>shortness of breath,</li> <li>cough,</li> <li><a href="/sore_throat_pharyngitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">sore throat</a>,</li> <li>unusual <a href="/muscle_pain/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">muscle pain</a>,</li> <li>trouble breathing,</li> <li>stomach pain,</li> <li>irregular heart rate,</li> <li>dizziness,</li> <li>feeling cold,</li> <li>weakness,</li> <li>tiredness,</li> <li>swelling around your midsection,</li> <li>right-sided upper stomach pain,</li> <li>loss of appetite,</li> <li>dark urine,</li> <li><a href="/clay/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">clay</a>-colored stools,</li> <li>yellowing of <a href="/skin_anatomy_picture_definition_function/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">the skin</a> or eyes (<a href="/kernicterus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">jaundice</a>),</li> <li>chest pain or pressure,</li> <li>pain spreading to your jaw or <a href="/shoulder/definition.htm" ">shoulder</a>, and</li> <li>sweating</li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Triumeq include:</p> <ul> <li>headache,</li> <li>tiredness, and</li> <li>trouble sleeping</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Triumeq. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p align="center"><b>HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS B</b></p> <h4>Hypersensitivity Reactions</h4> <p><b>Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of TRIUMEQ (abacavir, dolutegravir, and lamivudine). Patients who carry the HLA-B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele [see WARNINGS AND <a href="/triumeq-drug.htm#P">PRECAUTIONS</a>].</b></p> <p><b>TRIUMEQ is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see <a href="/triumeq-drug.htm#CI">CONTRAINDICATIONS</a>, WARNINGS AND <a href="/triumeq-drug.htm#P">PRECAUTIONS</a>]. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with TRIUMEQ or reinitiation of therapy with TRIUMEQ, unless patients have a previously documented HLA-B*5701 allele assessment. Discontinue TRIUMEQ immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see <a href="/triumeq-drug.htm#CI">CONTRAINDICATIONS</a>, WARNINGS AND <a href="/triumeq-drug.htm#P">PRECAUTIONS</a>].</b></p> <p><b>Following a hypersensitivity reaction to TRIUMEQ, NEVER restart TRIUMEQ or any other abacavir-containing product because more severe symptoms, including death can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see WARNINGS AND <a href="/triumeq-drug.htm#P">PRECAUTIONS</a>].</b></p> <h4>Lactic Acidosis and Severe Hepatomegaly with Steatosis</h4> <p><b>Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir, lamivudine, and other antiretrovirals. Discontinue TRIUMEQ if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see WARNINGS AND <a href="/triumeq-drug.htm#P">PRECAUTIONS</a>].</b></p> <h4>Exacerbations of Hepatitis B</h4> <p><b>Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of TRIUMEQ. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue TRIUMEQ and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see WARNINGS AND <a href="/triumeq-drug.htm#P">PRECAUTIONS</a>].</b></p> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <h4>TRIUMEQ</h4> <p>TRIUMEQ contains an INSTI (dolutegravir) and 2 nucleoside analogues (abacavir and lamivudine) with inhibitory activity against <a href="/script/main/art.asp?articlekey=3769" onclick="wmdTrack('embd-lnk');" rel="dict">HIV</a>.</p> <p>Each film-coated tablet contains abacavir sulfate equivalent to 600 mg of abacavir, dolutegravir sodium equivalent to 50 mg of dolutegravir, and 300 mg of lamivudine. TRIUMEQ tablets are purple, biconvex, oval, debossed with “572 Tr1” on one side and contain the inactive ingredients D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. The tablet film-coating (OPADRY® II Purple 85F90057) contains the inactive ingredients iron oxide black, iron oxide red, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium oxide.</p> <h4>Abacavir Sulfate</h4> <p>The chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). It has a molecular formula of (C<sub>14</sub>H<sub>18</sub>N<sub>6</sub>O)<sub>2</sub>•H<sub>2</sub>SO<sub>4</sub> and a molecular weight of 670.76 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="371"> <tbody> <tr> <td><img alt="Abacavir Sulfate - Structural Formula Illustration" height="308" src="https://images.rxlist.com/images/rxlist/triumeq1.gif" width="371" /></td> </tr> </tbody> </table> </center> <p></p> <p>Abacavir sulfate is a white to off-white solid and is soluble in water.</p> <h4>Dolutegravir</h4> <p>The chemical name of dolutegravir sodium is sodium (4R,12aS)-9-{[(2,4difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2Hpyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate. The empirical formula is C<sub>20</sub>H<sub>18</sub>F<sub>2</sub>N<sub>3</sub>NaO<sub>5</sub> and the molecular weight is 441.36 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="339"> <tbody> <tr> <td><img alt="Dolutegravir - Structural Formula Illustration" height="135" src="https://images.rxlist.com/images/rxlist/triumeq2.gif" width="339" /></td> </tr> </tbody> </table> </center> <p></p> <p>Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water.</p> <h4>Lamivudine</h4> <p>The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2',3'-dideoxy, 3'-thiacytidine. It has a molecular formula of C<sub>8</sub>H<sub>11</sub>N<sub>3</sub>O<sub>3</sub>S and a molecular weight of 229.3 g per mol. It has the following structural formula:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="243"> <tbody> <tr> <td><img alt="Lamivudine - Structural Formula Illustration" height="215" src="https://images.rxlist.com/images/rxlist/triumeq3.gif" width="243" /></td> </tr> </tbody> </table> </center> <p></p> <p>Lamivudine is a white to off-white crystalline solid and is soluble in water.</p> </div> <div id="667441035-1" class="medianet"><</div> </div> </div> | 6 | 2023-02-01 17:38:35 | Abacavir, Dolutegravir, and Lamivudine Film-coated Tablets (Triumeq) | A | HIV, ART Combos | Triumeq | abacavir, dolutegravir, and lamivudine film-coated tablets | Triumeq | John P. Cunha, DO, FACOEP |
| 42 | 2023-02-23 11:36:54 | Indications & Dosage | <div class="webmdrx_coup"> </div> <a name="I"></a> <h3>INDICATIONS</h3> <p>TRIUMEQ and TRIUMEQ PD are indicated for the treatment of HIV-1 infection in adults and in pediatric patients weighing at least 10 kg.</p> <h4>Limitations Of Use</h4> <ul> <li>TRIUMEQ and TRIUMEQ PD alone are not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor (INSTI) resistance because the dose of dolutegravir in TRIUMEQ and TRIUMEQ PD is insufficient in these subpopulations. See full prescribing information for TIVICAY(dolutegravir).</li> </ul> <a name="D"></a> <h3>DOSAGE AND ADMINISTRATION</h3> <h4>Screening For HLA-B*5701 Allele Prior To Initiating TRIUMEQ</h4> <p>Screen for the HLA-B*5701 allele prior to initiating therapy with TRIUMEQ or TRIUMEQ PD [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</p> <h4>Testing Prior To Or When Initiating Treatment With TRIUMEQ</h4> <p>Prior to or when initiating TRIUMEQ or TRIUMEQ PD, test patients for HBV infection [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>Pregnancy testing is recommended before initiation of TRIUMEQ in adolescents and adults of childbearing potential [see <b>WARNINGS AND PRECAUTIONS</b>, <b>Use In Specific Populations</b>].</p> <h4>Overview Of TRIUMEQ Dosage Forms</h4> <p>TRIUMEQ is available in two dosage forms. <b>Do not interchange TRIUMEQ tablets and TRIUMEQ PD tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles for the dolutegravir component</b> [see <b>WARNINGS AND PRECAUTIONS</b>, <b>CLINICAL PHARMACOLOGY</b>].</p> <ul> <li>TRIUMEQ tablets: 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine. TRIUMEQ is recommended in adults and pediatric patients weighing at least 25 kg [see <b>Recommended Dosage In Adults, Recommended Dosage And Administration Instructions For Pediatric Patients Weighing At Least 10 kg</b>].</li> <li>TRIUMEQ PD tablets for oral suspension: 60 mg of abacavir, 5 mg of dolutegravir, and 30 mg of lamivudine. TRIUMEQ PD is recommended in pediatric patients weighing 10 kg to less than 25 kg. [see <b>Recommended Dosage And Administration Instructions For Pediatric Patients Weighing At Least 10 kg</b>].</li> <li>Because TRIUMEQ PD is a fixed-dose tablet and the dosage of individual components cannot be adjusted, it may lead to a suboptimal dosing for patients weighing ≥25 kg. TRIUMEQ PD is not recommended in patients weighing 25 kg or more [see <b>Recommended Dosage In Adults, Recommended Dosage And Administration Instructions For Pediatric Patients Weighing At Least 10 kg</b>].</li> </ul> <h4>Recommended Dosage In Adults</h4> <p>TRIUMEQ is a fixed-dose combination product containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine. The recommended dosage regimen of TRIUMEQ in adults is one tablet once daily orally with or without food. Do not use TRIUMEQ PD in adults.</p> <h4>Recommended Dosage And Administration Instructions For Pediatric Patients Weighing At Least 10 kg</h4> <p>The dosage and dosage form recommended for pediatric patients varies by weight as shown in Table 1 below.</p> <p align="center"><b>Table 1. Recommended Dosage of TRIUMEQ Tablets and TRIUMEQ PD Tablets for Oral Suspension in Pediatric Patients </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="20%">Body Weight</td> <td class="EmphTd" width="20%">TRIUMEQ Tablets<sup>a</sup></td> <td class="EmphTd" width="25%">TRIUMEQ PD<sup>b</sup> Number of Tablets</td> <td class="EmphTd" width="35%">Total Daily Dose</td> </tr> <tr> <td><b>10 kg to <14 kg</b></td> <td>Not recommended</td> <td>4 tablets once daily</td> <td>240 mg abacavir, 20 mg dolutegravir, and 120 mg lamivudine once daily</td> </tr> <tr> <td><b>14 kg to <20 kg</b></td> <td>Not recommended</td> <td>5 tablets once daily</td> <td>300 mg abacavir, 25 mg dolutegravir, and 150 mg lamivudine once daily</td> </tr> <tr> <td><b>20 kg to <25 kg</b></td> <td>Not recommended</td> <td>6 tablets once daily</td> <td>360 mg abacavir, 30 mg dolutegravir, and 180 mg lamivudine once daily</td> </tr> <tr> <td><b>≥25 kg</b></td> <td>1 tablet once daily</td> <td>Not recommended</td> <td>600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine</td> </tr> <tr> <td class="credit" colspan="4"><sup>a</sup> TRIUMEQ is a fixed-dose combination product containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine.<br /> <sup>b</sup>TRIUMEQ PD is a fixed-dose combination product containing 60 mg of abacavir, 5 mg of dolutegravir, and 30 mg of lamivudine.</td> </tr> </tbody> </table> </center> <p></p> <p>Administer <b>TRIUMEQ PD</b> tablets for oral suspension with or without food. Instruct patients (or instruct caregivers) <b>to fully disperse the tablets for oral suspension in 20 mL of drinking water</b> in the supplied cup; swirl the suspension so that no lumps remain. After full dispersion, administer the oral suspension within 30 minutes of mixing [see <b>INSTRUCTIONS FOR USE</b>]. Do not chew, cut, or crush the tablets.</p> <p>Administer TRIUMEQ tablet with or without food. Do not chew, cut, or crush the tablet.</p> <h4>Dosage Recommendation With Certain Concomitant Medications</h4> <p>The dolutegravir dose in TRIUMEQ (50 mg) and TRIUMEQ PD (5 mg) is insufficient when coadministered with medications listed in Table 2 that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended.</p> <p align="center"><b>Table 2. Dosing Recommendations for TRIUMEQ and TRIUMEQ PD with Coadministered Medications </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="30%">Coadministered Drug</td> <td class="EmphTd" width="70%">Dosing Recommendation</td> </tr> <tr> <td>Efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin</td> <td>In adults and in pediatric patients <b>weighing at least 25 kg</b>, the recommended dolutegravir dosage regimen is 50 mg twice daily. Thus, an additional TIVICAY 50-mg tablet, separated by 12 hours from TRIUMEQ, should be taken. In pediatric patients <b>weighing 10 kg to <25 kg</b>, an additional weight-based dose of dolutegravir should be given separated by 12 hours from TRIUMEQ PD. <ul> <li>10 to <14 kg: administer an additional 20-mg dose of dolutegravir (4 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>14 to <20 kg: administer an additional 25-mg dose of dolutegravir (5 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>20 to <25 kg: administer an additional 30-mg dose of dolutegravir (6 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.</li> </ul> </td> </tr> </tbody> </table> </center> <p></p> <h4>Not Recommended Due To Lack Of Dosage Adjustment</h4> <p>Because TRIUMEQ and TRIUMEQ PD are fixed-dose tablets and cannot be dose adjusted, TRIUMEQ and TRIUMEQ PD are not recommended in:</p> <ul> <li>patients with creatinine clearance <30 mL/min [see <b>Use In Specific Populations</b>].</li> <li>patients with mild hepatic impairment. TRIUMEQ and TRIUMEQ PD are contraindicated in patients with moderate or severe hepatic impairment [see <b>CONTRAINDICATIONS</b>, <b>Use In Specific Populations</b>].</li> </ul> <a name="HS"></a> <h3>HOW SUPPLIED</h3> <h4>Dosage Forms And Strengths</h4> <p>TRIUMEQ tablets are purple, biconvex, oval, and debossed with “572 Tri” on one side. Each film-coated tablet contains 600 mg of abacavir (as abacavir sulfate), 50 mg of dolutegravir (as dolutegravir sodium), and 300 mg of lamivudine [see <b>DESCRIPTION</b>].</p> <p>TRIUMEQ PD tablets for oral suspension are yellow, capsule-shaped, strawberry cream flavored, biconvex, film-coated tablets debossed with “SV WTU” on one side. Each film-coated tablet contains 60 mg of abacavir (as abacavir sulfate), 5 mg of dolutegravir (as dolutegravir sodium), and 30 mg of lamivudine [see <b>DESCRIPTION</b>].</p> <h4>Storage And Handling</h4> <h5>TRIUMEQ tablets</h5> <p><b>TRIUMEQ tablets</b> are purple, oval, film-coated, biconvex tablets debossed with “572 Tri” on one side and contain 600 mg of abacavir (as abacavir sulfate), 50 mg of dolutegravir (as dolutegravir sodium), and 300 mg lamivudine.</p> <p class="EmphText">Bottle of 30 tablets with desiccant and child-resistant closure. <b>NDC</b> 49702-231-13. Store and dispense in the original package, protect from moisture, and keep the bottle tightly closed. Do not remove desiccant.</p> <p>Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F). [See USP Controlled Room Temperature].</p> <h5>TRIUMEQ PD Tablets For Oral Suspension</h5> <p><b>TRIUMEQ PD tablets for oral suspension</b>, are yellow, capsule-shaped, strawberry cream flavored, film-coated, biconvex tablets debossed with “SV WTU” on one side and contain 60 mg of abacavir (as abacavir sulfate), 5 mg of dolutegravir (as dolutegravir sodium), and 30 mg lamivudine.</p> <p class="EmphText">Bottle of 90 tablets (<b>NDC</b> 49702-272-59) with desiccant and child-resistant closure. Each bottle is packaged as a kit (<b>NDC</b> 49702-258-37) with one 40-mL dosing cup.</p> <p>Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F). [See USP Controlled Room Temperature]. Store and dispense in the original bottle, protect from moisture, and keep the bottle tightly closed. Do not remove desiccant.</p> <p class="credit">Manufactured by: GlaxoSmithKline Research Triangle Park, NC 27709. Revised Mar 2022.</p> </div> <a class="mediaPrmo quiz" href="/quiz_hiv-aids/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/hivaids/hivaids-s1.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">What is HIV?</span> <span class="btn">See Answer</span> </a> </div> </div> | <div class="webmdrx_coup"> </div> <a name="I"></a> <h3>INDICATIONS</h3> <p>TRIUMEQ and TRIUMEQ PD are indicated for the treatment of HIV-1 infection in adults and in pediatric patients weighing at least 10 kg.</p> <h4>Limitations Of Use</h4> <ul> <li>TRIUMEQ and TRIUMEQ PD alone are not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor (INSTI) resistance because the dose of dolutegravir in TRIUMEQ and TRIUMEQ PD is insufficient in these subpopulations. See full prescribing information for TIVICAY(dolutegravir).</li> </ul> <a name="D"></a> <h3>DOSAGE AND ADMINISTRATION</h3> <h4>Screening For HLA-B*5701 Allele Prior To Initiating TRIUMEQ</h4> <p>Screen for the HLA-B*5701 allele prior to initiating therapy with TRIUMEQ or TRIUMEQ PD [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</p> <h4>Testing Prior To Or When Initiating Treatment With TRIUMEQ</h4> <p>Prior to or when initiating TRIUMEQ or TRIUMEQ PD, test patients for HBV infection [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>Pregnancy testing is recommended before initiation of TRIUMEQ in adolescents and adults of childbearing potential [see <b>WARNINGS AND PRECAUTIONS</b>, <b>Use In Specific Populations</b>].</p> <h4>Overview Of TRIUMEQ Dosage Forms</h4> <p>TRIUMEQ is available in two dosage forms. <b>Do not interchange TRIUMEQ tablets and TRIUMEQ PD tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles for the dolutegravir component</b> [see <b>WARNINGS AND PRECAUTIONS</b>, <b>CLINICAL PHARMACOLOGY</b>].</p> <ul> <li>TRIUMEQ tablets: 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine. TRIUMEQ is recommended in adults and pediatric patients weighing at least 25 kg [see <b>Recommended Dosage In Adults, Recommended Dosage And Administration Instructions For Pediatric Patients Weighing At Least 10 kg</b>].</li> <li>TRIUMEQ PD tablets for oral suspension: 60 mg of abacavir, 5 mg of dolutegravir, and 30 mg of lamivudine. TRIUMEQ PD is recommended in pediatric patients weighing 10 kg to less than 25 kg. [see <b>Recommended Dosage And Administration Instructions For Pediatric Patients Weighing At Least 10 kg</b>].</li> <li>Because TRIUMEQ PD is a fixed-dose tablet and the dosage of individual components cannot be adjusted, it may lead to a suboptimal dosing for patients weighing ≥25 kg. TRIUMEQ PD is not recommended in patients weighing 25 kg or more [see <b>Recommended Dosage In Adults, Recommended Dosage And Administration Instructions For Pediatric Patients Weighing At Least 10 kg</b>].</li> </ul> <h4>Recommended Dosage In Adults</h4> <p>TRIUMEQ is a fixed-dose combination product containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine. The recommended dosage regimen of TRIUMEQ in adults is one tablet once daily orally with or without food. Do not use TRIUMEQ PD in adults.</p> <h4>Recommended Dosage And Administration Instructions For Pediatric Patients Weighing At Least 10 kg</h4> <p>The dosage and dosage form recommended for pediatric patients varies by weight as shown in Table 1 below.</p> <p align="center"><b>Table 1. Recommended Dosage of TRIUMEQ Tablets and TRIUMEQ PD Tablets for Oral Suspension in Pediatric Patients </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="20%">Body Weight</td> <td class="EmphTd" width="20%">TRIUMEQ Tablets<sup>a</sup></td> <td class="EmphTd" width="25%">TRIUMEQ PD<sup>b</sup> Number of Tablets</td> <td class="EmphTd" width="35%">Total Daily Dose</td> </tr> <tr> <td><b>10 kg to <14 kg</b></td> <td>Not recommended</td> <td>4 tablets once daily</td> <td>240 mg abacavir, 20 mg dolutegravir, and 120 mg lamivudine once daily</td> </tr> <tr> <td><b>14 kg to <20 kg</b></td> <td>Not recommended</td> <td>5 tablets once daily</td> <td>300 mg abacavir, 25 mg dolutegravir, and 150 mg lamivudine once daily</td> </tr> <tr> <td><b>20 kg to <25 kg</b></td> <td>Not recommended</td> <td>6 tablets once daily</td> <td>360 mg abacavir, 30 mg dolutegravir, and 180 mg lamivudine once daily</td> </tr> <tr> <td><b>≥25 kg</b></td> <td>1 tablet once daily</td> <td>Not recommended</td> <td>600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine</td> </tr> <tr> <td class="credit" colspan="4"><sup>a</sup> TRIUMEQ is a fixed-dose combination product containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine.<br /> <sup>b</sup>TRIUMEQ PD is a fixed-dose combination product containing 60 mg of abacavir, 5 mg of dolutegravir, and 30 mg of lamivudine.</td> </tr> </tbody> </table> </center> <p></p> <p>Administer <b>TRIUMEQ PD</b> tablets for oral suspension with or without food. Instruct patients (or instruct caregivers) <b>to fully disperse the tablets for oral suspension in 20 mL of drinking water</b> in the supplied cup; swirl the suspension so that no lumps remain. After full dispersion, administer the oral suspension within 30 minutes of mixing [see <b>INSTRUCTIONS FOR USE</b>]. Do not chew, cut, or crush the tablets.</p> <p>Administer TRIUMEQ tablet with or without food. Do not chew, cut, or crush the tablet.</p> <h4>Dosage Recommendation With Certain Concomitant Medications</h4> <p>The dolutegravir dose in TRIUMEQ (50 mg) and TRIUMEQ PD (5 mg) is insufficient when coadministered with medications listed in Table 2 that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended.</p> <p align="center"><b>Table 2. Dosing Recommendations for TRIUMEQ and TRIUMEQ PD with Coadministered Medications </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="30%">Coadministered Drug</td> <td class="EmphTd" width="70%">Dosing Recommendation</td> </tr> <tr> <td>Efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin</td> <td>In adults and in pediatric patients <b>weighing at least 25 kg</b>, the recommended dolutegravir dosage regimen is 50 mg twice daily. Thus, an additional TIVICAY 50-mg tablet, separated by 12 hours from TRIUMEQ, should be taken. In pediatric patients <b>weighing 10 kg to <25 kg</b>, an additional weight-based dose of dolutegravir should be given separated by 12 hours from TRIUMEQ PD. <ul> <li>10 to <14 kg: administer an additional 20-mg dose of dolutegravir (4 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>14 to <20 kg: administer an additional 25-mg dose of dolutegravir (5 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>20 to <25 kg: administer an additional 30-mg dose of dolutegravir (6 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.</li> </ul> </td> </tr> </tbody> </table> </center> <p></p> <h4>Not Recommended Due To Lack Of Dosage Adjustment</h4> <p>Because TRIUMEQ and TRIUMEQ PD are fixed-dose tablets and cannot be dose adjusted, TRIUMEQ and TRIUMEQ PD are not recommended in:</p> <ul> <li>patients with creatinine clearance <30 mL/min [see <b>Use In Specific Populations</b>].</li> <li>patients with mild hepatic impairment. TRIUMEQ and TRIUMEQ PD are contraindicated in patients with moderate or severe hepatic impairment [see <b>CONTRAINDICATIONS</b>, <b>Use In Specific Populations</b>].</li> </ul> <a name="HS"></a> <h3>HOW SUPPLIED</h3> <h4>Dosage Forms And Strengths</h4> <p>TRIUMEQ tablets are purple, biconvex, oval, and debossed with “572 Tri” on one side. Each film-coated tablet contains 600 mg of abacavir (as abacavir sulfate), 50 mg of dolutegravir (as dolutegravir sodium), and 300 mg of lamivudine [see <b>DESCRIPTION</b>].</p> <p>TRIUMEQ PD tablets for oral suspension are yellow, capsule-shaped, strawberry cream flavored, biconvex, film-coated tablets debossed with “SV WTU” on one side. Each film-coated tablet contains 60 mg of abacavir (as abacavir sulfate), 5 mg of dolutegravir (as dolutegravir sodium), and 30 mg of lamivudine [see <b>DESCRIPTION</b>].</p> <h4>Storage And Handling</h4> <h5>TRIUMEQ tablets</h5> <p><b>TRIUMEQ tablets</b> are purple, oval, film-coated, biconvex tablets debossed with “572 Tri” on one side and contain 600 mg of abacavir (as abacavir sulfate), 50 mg of dolutegravir (as dolutegravir sodium), and 300 mg lamivudine.</p> <p class="EmphText">Bottle of 30 tablets with desiccant and child-resistant closure. <b>NDC</b> 49702-231-13. Store and dispense in the original package, protect from moisture, and keep the bottle tightly closed. Do not remove desiccant.</p> <p>Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F). [See USP Controlled Room Temperature].</p> <h5>TRIUMEQ PD Tablets For Oral Suspension</h5> <p><b>TRIUMEQ PD tablets for oral suspension</b>, are yellow, capsule-shaped, strawberry cream flavored, film-coated, biconvex tablets debossed with “SV WTU” on one side and contain 60 mg of abacavir (as abacavir sulfate), 5 mg of dolutegravir (as dolutegravir sodium), and 30 mg lamivudine.</p> <p class="EmphText">Bottle of 90 tablets (<b>NDC</b> 49702-272-59) with desiccant and child-resistant closure. Each bottle is packaged as a kit (<b>NDC</b> 49702-258-37) with one 40-mL dosing cup.</p> <p>Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F). [See USP Controlled Room Temperature]. Store and dispense in the original bottle, protect from moisture, and keep the bottle tightly closed. Do not remove desiccant.</p> <p class="credit">Manufactured by: GlaxoSmithKline Research Triangle Park, NC 27709. Revised Mar 2022.</p> </div> <a class="mediaPrmo quiz" href="/quiz_hiv-aids/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/hivaids/hivaids-s1.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">What is HIV?</span> <span class="btn">See Answer</span> </a> </div> </div> | 6 | 2023-02-01 17:38:35 | Abacavir, Dolutegravir, and Lamivudine Film-coated Tablets (Triumeq) | A | HIV, ART Combos | Triumeq | abacavir, dolutegravir, and lamivudine film-coated tablets | Triumeq | John P. Cunha, DO, FACOEP |
| 43 | 2023-02-23 12:07:03 | Side Effects | <a name="AR"></a> <h3>SIDE EFFECTS</h3> <p>The following adverse reactions are discussed in other sections of the labeling:</p> <ul> <li>Serious and sometimes fatal hypersensitivity reaction [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Exacerbations of hepatitis B [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Hepatotoxicity [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Lactic acidosis and severe hepatomegaly with steatosis [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Immune reconstitution syndrome [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Myocardial infarction [see <b>WARNINGS AND PRECAUTIONS</b>].</li> </ul> <h4>Clinical Trials Experience</h4> <p>Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.</p> <h4>Clinical Trials In Adults</h4> <h5>Serious and Fatal Abacavir-Associated Hypersensitivity Reactions</h5> <p>In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIUMEQ and TRIUMEQ PD [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.</p> <p>Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia and abnormal chest x-ray findings (predominantly infiltrates, which were localized).</p> <h5>Serious Dolutegravir Hypersensitivity Reactions</h5> <p>In clinical trials, hypersensitivity reactions have occurred with dolutegravir, a component of TRIUMEQ and TRIUMEQ PD [see <b>WARNINGS AND PRECAUTIONS</b>]. These hypersensitivity reactions have been characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury.</p> <h5>Additional Treatment-Emergent Adverse Drug Reactions (ADRs) with Use of TRIUMEQ</h5> <p>The safety assessment of TRIUMEQ is primarily based on the analyses of data from a randomized, international, multicenter, double-blind, active-controlled trial, SINGLE (ING114467) and supported by data in treatment-experienced, INSTI-naive subjects from SAILING (ING111762) and by data from other treatment-naive trials. See full prescribing information for TIVICAY.</p> <h5>Treatment-Naive Subjects</h5> <p>In SINGLE, 833 adult subjects were randomized and received at least one dose of either dolutegravir (TIVICAY) 50 mg with fixed-dose abacavir and lamivudine (EPZICOM) once daily (n = 414) or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA) once daily (n = 419) (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, the rate of adverse events leading to discontinuation was 4% in subjects receiving TIVICAY + EPZICOM and 14% in subjects receiving ATRIPLA once daily.</p> <p>Treatment-emergent ADRs of moderate to severe intensity observed in at least 2% of subjects in either treatment arm of SINGLE are provided in Table 3.</p> <p align="center"><b>Table 3. Treatment-Emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in Treatment-Naive Subjects in SINGLE (Week 144 Analysis) </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Adverse Reaction</td> <td class="EmphTd" width="25%">TIVICAY + EPZICOM<br /> Once Daily<br /> (n = 414)</td> <td class="EmphTd" width="25%">ATRIPLA<br /> Once Daily<br /> (n = 419)</td> </tr> <tr> <td colspan="3"><b>Psychiatric</b></td> </tr> <tr> <td> Insomnia</td> <td align="center">3%</td> <td align="center">3%</td> </tr> <tr> <td> Depression</td> <td align="center">1%</td> <td align="center">2%</td> </tr> <tr> <td> Abnormal dreams</td> <td align="center"><1%</td> <td align="center">2%</td> </tr> <tr> <td colspan="3"><b>Nervous System</b></td> </tr> <tr> <td> Dizziness</td> <td align="center"><1%</td> <td align="center">5%</td> </tr> <tr> <td> Headache</td> <td align="center">2%</td> <td align="center">2%</td> </tr> <tr> <td colspan="3"><b>Gastrointestinal</b></td> </tr> <tr> <td> Nausea</td> <td align="center"><1%</td> <td align="center">3%</td> </tr> <tr> <td> Diarrhea</td> <td align="center"><1%</td> <td align="center">2%</td> </tr> <tr> <td colspan="3"><b>General Disorders</b></td> </tr> <tr> <td> Fatigue</td> <td align="center">2%</td> <td align="center">2%</td> </tr> <tr> <td colspan="3"><b>Skin and Subcutaneous Tissue</b></td> </tr> <tr> <td> Rash<sup>a</sup></td> <td align="center"><1%</td> <td align="center">6%</td> </tr> <tr> <td colspan="3"><b> Ear and Labyrinth</b></td> </tr> <tr> <td> Vertigo</td> <td align="center">0</td> <td align="center">2%</td> </tr> <tr> <td class="credit" colspan="3"><sup>a </sup>Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption.</td> </tr> </tbody> </table> </center> <p></p> <h5>Treatment-Experienced Subjects</h5> <p>SAILING is an international, double-blind trial in INSTI-naive, antiretroviral treatment-experienced adult subjects. Subjects were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator- selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rate of adverse events leading to discontinuation was consistent with that seen in the overall treatment-naive patient population. See full prescribing information for TIVICAY.</p> <p>The ADRs observed in the subset of subjects who received TIVICAY + EPZICOM were generally consistent with those seen in the overall treatment- naive patient population.</p> <h5>Less Common Adverse Reactions Observed in Clinical Trials</h5> <p>The following adverse reactions occurred in <2% of treatment- naive or treatment-experienced subjects in any one trial. These events have been included because of their seriousness and/or assessment of potential causal relationship.</p> <p><i><b>Gastrointestinal Disorders: </b></i> Abdominal pain, abdominal distention, abdominal discomfort, dyspepsia, flatulence, gastroesophageal reflux disease, upper abdominal pain, vomiting.</p> <p><i><b>General Disorders: </b></i>Fever, lethargy.</p> <p><i><b>Hepatobiliary Disorders: </b></i>Hepatitis.</p> <p><i><b>Metabolism and Nutrition Disorders: </b></i> Anorexia, hypertriglyceridemia.</p> <p><i><b>Musculoskeletal Disorders: </b></i> Arthralgia, myositis.</p> <p><i><b>Nervous System Disorders: </b></i>Somnolence.</p> <p><i><b>Psychiatric Disorders: </b></i>Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Nightmare and sleep disorder.</p> <p><i><b>Renal and Urinary Disorders: </b></i>Renal impairment.</p> <p><i><b>Skin and Subcutaneous Tissue Disorders: </b></i>Pruritus.</p> <h5>Laboratory Abnormalities</h5> <p><b><i>Treatment-Naive Subjects: </i></b> Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects in SINGLE are presented in Table 4. The mean change from baseline observed for selected lipid values is presented in Table 5.</p> <p align="center"><b>Table 4. Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Naive Subjects in SINGLE (Week 144 Analysis) </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Laboratory Abnormality</td> <td class="EmphTd" width="25%">TIVICAY + EPZICOM<br /> Once Daily<br /> (n = 414)</td> <td class="EmphTd" width="25%">ATRIPLA<br /> Once Daily<br /> (n = 419)</td> </tr> <tr> <td colspan="3">ALT</td> </tr> <tr> <td> Grade 2 (>2.5-5.0 x ULN)</td> <td align="center">3%</td> <td align="center">5%</td> </tr> <tr> <td> Grade 3 to 4 (>5.0 x ULN)</td> <td align="center">1%</td> <td align="center"><1%</td> </tr> <tr> <td colspan="3">AST</td> </tr> <tr> <td> Grade 2 (>2.5-5.0 x ULN)</td> <td align="center">3%</td> <td align="center">4%</td> </tr> <tr> <td> Grade 3 to 4 (>5.0 x ULN)</td> <td align="center">1%</td> <td align="center">3%</td> </tr> <tr> <td colspan="3">Creatine kinase</td> </tr> <tr> <td> Grade 2 (6.0-9.9 x ULN)</td> <td align="center">5%</td> <td align="center">3%</td> </tr> <tr> <td> Grade 3 to 4 (≥10.0 x ULN)</td> <td align="center">7%</td> <td align="center">8%</td> </tr> <tr> <td colspan="3">Hyperglycemia</td> </tr> <tr> <td> Grade 2 (126-250 mg/dL)</td> <td align="center">9%</td> <td align="center">6%</td> </tr> <tr> <td> Grade 3 (>250 mg/dL)</td> <td align="center">2%</td> <td align="center"><1%</td> </tr> <tr> <td>Lipase</td> <td align="center"></td> <td align="center"></td> </tr> <tr> <td> Grade 2 (>1.5-3.0 x ULN)</td> <td align="center">11%</td> <td align="center">11%</td> </tr> <tr> <td> Grade 3 to 4 (>3.0 ULN)</td> <td align="center">5%</td> <td align="center">4%</td> </tr> <tr> <td colspan="3">Total neutrophils</td> </tr> <tr> <td> Grade 2 (0.75-0.99 x 10<sup>9</sup>)</td> <td align="center">4%</td> <td align="center">5%</td> </tr> <tr> <td> Grade 3 to 4 (<0.75 x 10<sup>9</sup>)</td> <td align="center">3%</td> <td align="center">3%</td> </tr> <tr> <td class="credit" colspan="3">ALT = Alanine aminotransferase, AST = Aspartate aminotransferase, ULN = upper limit of normal.</td> </tr> </tbody> </table> </center> <p></p> <p align="center"><b>Table 5. Mean Change from Baseline in Fasted Lipid Values in Treatment-Naive Subjects in SINGLE (Week 144 Analysis<sup>a</sup>) </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Lipid</td> <td class="EmphTd" width="25%">TIVICAY + EPZICOM<br /> Once Daily<br /> (n = 414)</td> <td class="EmphTd" width="25%">ATRIPLA<br /> Once Daily<br /> (n = 419)</td> </tr> <tr> <td>Cholesterol (mg/dL)</td> <td align="center">24.0</td> <td align="center">26.7</td> </tr> <tr> <td>HDL cholesterol (mg/dL)</td> <td align="center">5.4</td> <td align="center">7.2</td> </tr> <tr> <td>LDL cholesterol (mg/dL)</td> <td align="center">16.0</td> <td align="center">14.6</td> </tr> <tr> <td>Triglycerides (mg/dL)</td> <td align="center">13.6</td> <td align="center">31.9</td> </tr> <tr> <td class="credit" colspan="3">HDL = High-density lipoprotein, LDL = Low-density lipoprotein.<br /> <sup>a</sup> Subjects on lipid-lowering agents at baseline were excluded from these analyses (TIVICAY + EPZICOM: n = 30 and ATRIPLA: n = 27). Seventy-two subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless if they discontinued the agent (TIVICAY + EPZICOM: n = 36 and ATRIPLA: n = 36).</td> </tr> </tbody> </table> </center> <p></p> <p><i>Treatment-Experienced Subjects</i></p> <p>Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment- naive trials.</p> <p><i>Hepatitis C Virus Co-infection</i></p> <p>In SINGLE, the pivotal Phase 3 trial, subjects with <a href="/viral_hepatitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis</a> C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal; subjects with <a href="/hepatitis_b/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis B</a> co-infection were excluded. Overall, the safety profile in subjects with <a href="/hepatitis_c/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis C</a> virus co-infection was similar to that observed in subjects without hepatitis C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with <a href="/hepatitis_c_virus/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hepatitis C virus</a> co-infection for both treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis C co-infected compared with HIV monoinfected subjects receiving TRIUMEQ were observed in 15% and 2% (vs. 24% and 4% of subjects treated with ATRIPLA) (Week 96 analysis), respectively [see <b>WARNINGS AND PRECAUTIONS</b>]. See also full prescribing information for TIVICAY.</p> <p><i>Changes in Serum Creatinine</i></p> <p>Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal <a href="/glomerular/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">glomerular</a> function [see <b>CLINICAL PHARMACOLOGY</b>]. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 144 weeks. In SINGLE, a mean change from baseline of 0.14 mg per dL (range: -0.25 mg per dL to 0.81 mg per dL) was observed after 144 weeks of treatment. Creatinine increases were similar in treatment-experienced subjects.</p> <p><i>Abacavir and Lamivudine</i></p> <p>Laboratory abnormalities observed in clinical trials of ZIAGEN (in combination with other <a href="/antiretroviral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antiretroviral</a> treatment) were <a href="/anemia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anemia</a>, <a href="/neutropenia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">neutropenia</a>, liver function test abnormalities, and elevations of CPK, <a href="/blood_glucose/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">blood glucose</a>, and <a href="/triglyceride_test/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">triglycerides</a>. Additional laboratory abnormalities observed in clinical trials of EPIVIR (in combination with other antiretroviral treatment) were <a href="/thrombocytopenia_low_platelet_count/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">thrombocytopenia</a> and elevated levels of bilirubin, <a href="/amylase/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">amylase</a>, and <a href="/lipase/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">lipase</a>.</p> <h4>Clinical Trials Experience In Pediatric Subjects</h4> <h5>Abacavir and Lamivudine</h5> <p>The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as EPZICOM, was assessed in the ARROW trial (n = 336). Primary safety assessment in the ARROW (COL105677) trial was based on Grade 3 and Grade 4 adverse events. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. No additional safety issues were identified in pediatric subjects compared with historical data in adults.</p> <h5>Dolutegravir</h5> <p>The safety of dolutegravir in pediatric subjects with HIV-1 infection weighing at least 10 kg was evaluated in the IMPAACT P1093 trial [see <b>Use In Specific Populations</b>, <b>CLINICAL PHARMACOLOGY</b>]. Overall, the safety data in this pediatric study was similar to that seen in adults. IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of pediatric subjects with HIV-1 infection, aged <18 years. One hundred and five subjects weighing at least 10 kg were enrolled in this trial [see <b>Use In Specific Populations</b>, <b>CLINICAL PHARMACOLOGY</b>, <b>Clinical Studies</b>].</p> <p>The safety analysis through Week 24 included 40 subjects from Cohorts I (n = 19), IIA (n = 5), III-<a href="/dt/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">DT</a> (n = 15), and IV-DT (n=1) weighing at least 10 kg at enrollment who received the recommended dose (determined by weight and age) and formulation. This analysis showed that 6 subjects (all from Cohort I) experienced drug-related clinical adverse reactions. There were no Grade 3 or 4 drug-related adverse reactions reported. No adverse reactions led to discontinuation.</p> <p>All laboratory abnormalities considered to be drug-related in subjects weighing at least 10 kg at enrollment were Grade 1 or 2 in severity. Only one grade 3 laboratory abnormality was reported in more than 1 subject (decreased blood <a href="/bicarbonate/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bicarbonate</a>, n = 2). Changes in median serum creatinine were similar to those observed in adults.</p> <h4>Postmarketing Experience</h4> <p>In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use with one or more of the components of TRIUMEQ and TRIUMEQ PD. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.</p> <h5>Blood And Lymphatic Systems</h5> <p><a href="/aplastic_anemia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Aplastic anemia</a>, anemia (including pure red cell <a href="/aplasia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">aplasia</a> and severe anemias progressing on therapy), <a href="/lymphadenopathy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lymphadenopathy</a>, <a href="/splenomegaly/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">splenomegaly</a>.</p> <h5>Digestive</h5> <p>Stomatitis.</p> <h5>Gastrointestinal</h5> <p><a href="/pancreatitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Pancreatitis</a>.</p> <h5>General</h5> <p>Weakness.</p> <h5>Hepatobiliary Disorders</h5> <p>Acute <a href="/liver_failure/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">liver failure</a>, <a href="/liver_transplant/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">liver transplant</a> [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Hypersensitivity</h5> <p>Sensitization reactions (including <a href="/anaphylaxis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anaphylaxis</a>), <a href="/urticaria/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">urticaria</a> [see <b>WARNINGS AND PRECAUTIONS</b>, <b>Clinical Trials Experience</b>].</p> <h5>Investigations</h5> <p>Weight increased.</p> <h5>Metabolism And Nutrition Disorders</h5> <p>Hyperlactemia.</p> <h5>Musculoskeletal</h5> <p>CPK elevation, muscle weakness, <a href="/myalgia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">myalgia</a>, <a href="/rhabdomyolysis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">rhabdomyolysis</a>.</p> <h5>Nervous</h5> <p><a href="/paresthesia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Paresthesia</a>, <a href="/peripheral_neuropathy/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">peripheral neuropathy</a>, seizures.</p> <h5>Psychiatric</h5> <p>Anxiety.</p> <h5>Respiratory</h5> <p>Abnormal breath sounds/<a href="/wheezing/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">wheezing</a>.</p> <h5>Skin</h5> <p><a href="/alopecia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Alopecia</a>, <a href="/erythema_multiforme/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">erythema multiforme</a>. Suspected <a href="/stevens-johnson_syndrome/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Stevens-Johnson syndrome</a> (<a href="/sjs/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">SJS</a>) and <a href="/toxic_epidermal_necrolysis_ten/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">toxic epidermal necrolysis</a> (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases [see <b>Clinical Trials Experience</b>].</p> </div> </div> </div> | <a name="AR"></a> <h3>SIDE EFFECTS</h3> <p>The following adverse reactions are discussed in other sections of the labeling:</p> <ul> <li>Serious and sometimes fatal hypersensitivity reaction [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Exacerbations of hepatitis B [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Hepatotoxicity [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Lactic acidosis and severe hepatomegaly with steatosis [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Immune reconstitution syndrome [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Myocardial infarction [see <b>WARNINGS AND PRECAUTIONS</b>].</li> </ul> <h4>Clinical Trials Experience</h4> <p>Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.</p> <h4>Clinical Trials In Adults</h4> <h5>Serious and Fatal Abacavir-Associated Hypersensitivity Reactions</h5> <p>In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIUMEQ and TRIUMEQ PD [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.</p> <p>Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia and abnormal chest x-ray findings (predominantly infiltrates, which were localized).</p> <h5>Serious Dolutegravir Hypersensitivity Reactions</h5> <p>In clinical trials, hypersensitivity reactions have occurred with dolutegravir, a component of TRIUMEQ and TRIUMEQ PD [see <b>WARNINGS AND PRECAUTIONS</b>]. These hypersensitivity reactions have been characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury.</p> <h5>Additional Treatment-Emergent Adverse Drug Reactions (ADRs) with Use of TRIUMEQ</h5> <p>The safety assessment of TRIUMEQ is primarily based on the analyses of data from a randomized, international, multicenter, double-blind, active-controlled trial, SINGLE (ING114467) and supported by data in treatment-experienced, INSTI-naive subjects from SAILING (ING111762) and by data from other treatment-naive trials. See full prescribing information for TIVICAY.</p> <h5>Treatment-Naive Subjects</h5> <p>In SINGLE, 833 adult subjects were randomized and received at least one dose of either dolutegravir (TIVICAY) 50 mg with fixed-dose abacavir and lamivudine (EPZICOM) once daily (n = 414) or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA) once daily (n = 419) (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, the rate of adverse events leading to discontinuation was 4% in subjects receiving TIVICAY + EPZICOM and 14% in subjects receiving ATRIPLA once daily.</p> <p>Treatment-emergent ADRs of moderate to severe intensity observed in at least 2% of subjects in either treatment arm of SINGLE are provided in Table 3.</p> <p align="center"><b>Table 3. Treatment-Emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in Treatment-Naive Subjects in SINGLE (Week 144 Analysis) </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Adverse Reaction</td> <td class="EmphTd" width="25%">TIVICAY + EPZICOM<br /> Once Daily<br /> (n = 414)</td> <td class="EmphTd" width="25%">ATRIPLA<br /> Once Daily<br /> (n = 419)</td> </tr> <tr> <td colspan="3"><b>Psychiatric</b></td> </tr> <tr> <td> Insomnia</td> <td align="center">3%</td> <td align="center">3%</td> </tr> <tr> <td> Depression</td> <td align="center">1%</td> <td align="center">2%</td> </tr> <tr> <td> Abnormal dreams</td> <td align="center"><1%</td> <td align="center">2%</td> </tr> <tr> <td colspan="3"><b>Nervous System</b></td> </tr> <tr> <td> Dizziness</td> <td align="center"><1%</td> <td align="center">5%</td> </tr> <tr> <td> Headache</td> <td align="center">2%</td> <td align="center">2%</td> </tr> <tr> <td colspan="3"><b>Gastrointestinal</b></td> </tr> <tr> <td> Nausea</td> <td align="center"><1%</td> <td align="center">3%</td> </tr> <tr> <td> Diarrhea</td> <td align="center"><1%</td> <td align="center">2%</td> </tr> <tr> <td colspan="3"><b>General Disorders</b></td> </tr> <tr> <td> Fatigue</td> <td align="center">2%</td> <td align="center">2%</td> </tr> <tr> <td colspan="3"><b>Skin and Subcutaneous Tissue</b></td> </tr> <tr> <td> Rash<sup>a</sup></td> <td align="center"><1%</td> <td align="center">6%</td> </tr> <tr> <td colspan="3"><b> Ear and Labyrinth</b></td> </tr> <tr> <td> Vertigo</td> <td align="center">0</td> <td align="center">2%</td> </tr> <tr> <td class="credit" colspan="3"><sup>a </sup>Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption.</td> </tr> </tbody> </table> </center> <p></p> <h5>Treatment-Experienced Subjects</h5> <p>SAILING is an international, double-blind trial in INSTI-naive, antiretroviral treatment-experienced adult subjects. Subjects were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator- selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rate of adverse events leading to discontinuation was consistent with that seen in the overall treatment-naive patient population. See full prescribing information for TIVICAY.</p> <p>The ADRs observed in the subset of subjects who received TIVICAY + EPZICOM were generally consistent with those seen in the overall treatment- naive patient population.</p> <h5>Less Common Adverse Reactions Observed in Clinical Trials</h5> <p>The following adverse reactions occurred in <2% of treatment- naive or treatment-experienced subjects in any one trial. These events have been included because of their seriousness and/or assessment of potential causal relationship.</p> <p><i><b>Gastrointestinal Disorders: </b></i> Abdominal pain, abdominal distention, abdominal discomfort, dyspepsia, flatulence, gastroesophageal reflux disease, upper abdominal pain, vomiting.</p> <p><i><b>General Disorders: </b></i>Fever, lethargy.</p> <p><i><b>Hepatobiliary Disorders: </b></i>Hepatitis.</p> <p><i><b>Metabolism and Nutrition Disorders: </b></i> Anorexia, hypertriglyceridemia.</p> <p><i><b>Musculoskeletal Disorders: </b></i> Arthralgia, myositis.</p> <p><i><b>Nervous System Disorders: </b></i>Somnolence.</p> <p><i><b>Psychiatric Disorders: </b></i>Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Nightmare and sleep disorder.</p> <p><i><b>Renal and Urinary Disorders: </b></i>Renal impairment.</p> <p><i><b>Skin and Subcutaneous Tissue Disorders: </b></i>Pruritus.</p> <h5>Laboratory Abnormalities</h5> <p><b><i>Treatment-Naive Subjects: </i></b> Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects in SINGLE are presented in Table 4. The mean change from baseline observed for selected lipid values is presented in Table 5.</p> <p align="center"><b>Table 4. Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Naive Subjects in SINGLE (Week 144 Analysis) </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Laboratory Abnormality</td> <td class="EmphTd" width="25%">TIVICAY + EPZICOM<br /> Once Daily<br /> (n = 414)</td> <td class="EmphTd" width="25%">ATRIPLA<br /> Once Daily<br /> (n = 419)</td> </tr> <tr> <td colspan="3">ALT</td> </tr> <tr> <td> Grade 2 (>2.5-5.0 x ULN)</td> <td align="center">3%</td> <td align="center">5%</td> </tr> <tr> <td> Grade 3 to 4 (>5.0 x ULN)</td> <td align="center">1%</td> <td align="center"><1%</td> </tr> <tr> <td colspan="3">AST</td> </tr> <tr> <td> Grade 2 (>2.5-5.0 x ULN)</td> <td align="center">3%</td> <td align="center">4%</td> </tr> <tr> <td> Grade 3 to 4 (>5.0 x ULN)</td> <td align="center">1%</td> <td align="center">3%</td> </tr> <tr> <td colspan="3">Creatine kinase</td> </tr> <tr> <td> Grade 2 (6.0-9.9 x ULN)</td> <td align="center">5%</td> <td align="center">3%</td> </tr> <tr> <td> Grade 3 to 4 (≥10.0 x ULN)</td> <td align="center">7%</td> <td align="center">8%</td> </tr> <tr> <td colspan="3">Hyperglycemia</td> </tr> <tr> <td> Grade 2 (126-250 mg/dL)</td> <td align="center">9%</td> <td align="center">6%</td> </tr> <tr> <td> Grade 3 (>250 mg/dL)</td> <td align="center">2%</td> <td align="center"><1%</td> </tr> <tr> <td>Lipase</td> <td align="center"></td> <td align="center"></td> </tr> <tr> <td> Grade 2 (>1.5-3.0 x ULN)</td> <td align="center">11%</td> <td align="center">11%</td> </tr> <tr> <td> Grade 3 to 4 (>3.0 ULN)</td> <td align="center">5%</td> <td align="center">4%</td> </tr> <tr> <td colspan="3">Total neutrophils</td> </tr> <tr> <td> Grade 2 (0.75-0.99 x 10<sup>9</sup>)</td> <td align="center">4%</td> <td align="center">5%</td> </tr> <tr> <td> Grade 3 to 4 (<0.75 x 10<sup>9</sup>)</td> <td align="center">3%</td> <td align="center">3%</td> </tr> <tr> <td class="credit" colspan="3">ALT = Alanine aminotransferase, AST = Aspartate aminotransferase, ULN = upper limit of normal.</td> </tr> </tbody> </table> </center> <p></p> <p align="center"><b>Table 5. Mean Change from Baseline in Fasted Lipid Values in Treatment-Naive Subjects in SINGLE (Week 144 Analysis<sup>a</sup>) </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Lipid</td> <td class="EmphTd" width="25%">TIVICAY + EPZICOM<br /> Once Daily<br /> (n = 414)</td> <td class="EmphTd" width="25%">ATRIPLA<br /> Once Daily<br /> (n = 419)</td> </tr> <tr> <td>Cholesterol (mg/dL)</td> <td align="center">24.0</td> <td align="center">26.7</td> </tr> <tr> <td>HDL cholesterol (mg/dL)</td> <td align="center">5.4</td> <td align="center">7.2</td> </tr> <tr> <td>LDL cholesterol (mg/dL)</td> <td align="center">16.0</td> <td align="center">14.6</td> </tr> <tr> <td>Triglycerides (mg/dL)</td> <td align="center">13.6</td> <td align="center">31.9</td> </tr> <tr> <td class="credit" colspan="3">HDL = High-density lipoprotein, LDL = Low-density lipoprotein.<br /> <sup>a</sup> Subjects on lipid-lowering agents at baseline were excluded from these analyses (TIVICAY + EPZICOM: n = 30 and ATRIPLA: n = 27). Seventy-two subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless if they discontinued the agent (TIVICAY + EPZICOM: n = 36 and ATRIPLA: n = 36).</td> </tr> </tbody> </table> </center> <p></p> <p><i>Treatment-Experienced Subjects</i></p> <p>Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment- naive trials.</p> <p><i>Hepatitis C Virus Co-infection</i></p> <p>In SINGLE, the pivotal Phase 3 trial, subjects with <a href="/viral_hepatitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis</a> C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal; subjects with <a href="/hepatitis_b/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis B</a> co-infection were excluded. Overall, the safety profile in subjects with <a href="/hepatitis_c/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis C</a> virus co-infection was similar to that observed in subjects without hepatitis C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with <a href="/hepatitis_c_virus/definition.htm" ">hepatitis C virus</a> co-infection for both treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis C co-infected compared with HIV monoinfected subjects receiving TRIUMEQ were observed in 15% and 2% (vs. 24% and 4% of subjects treated with ATRIPLA) (Week 96 analysis), respectively [see <b>WARNINGS AND PRECAUTIONS</b>]. See also full prescribing information for TIVICAY.</p> <p><i>Changes in Serum Creatinine</i></p> <p>Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal <a href="/glomerular/definition.htm" ">glomerular</a> function [see <b>CLINICAL PHARMACOLOGY</b>]. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 144 weeks. In SINGLE, a mean change from baseline of 0.14 mg per dL (range: -0.25 mg per dL to 0.81 mg per dL) was observed after 144 weeks of treatment. Creatinine increases were similar in treatment-experienced subjects.</p> <p><i>Abacavir and Lamivudine</i></p> <p>Laboratory abnormalities observed in clinical trials of ZIAGEN (in combination with other <a href="/antiretroviral/definition.htm" ">antiretroviral</a> treatment) were <a href="/anemia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anemia</a>, <a href="/neutropenia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">neutropenia</a>, liver function test abnormalities, and elevations of CPK, <a href="/blood_glucose/definition.htm" ">blood glucose</a>, and <a href="/triglyceride_test/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">triglycerides</a>. Additional laboratory abnormalities observed in clinical trials of EPIVIR (in combination with other antiretroviral treatment) were <a href="/thrombocytopenia_low_platelet_count/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">thrombocytopenia</a> and elevated levels of bilirubin, <a href="/amylase/definition.htm" ">amylase</a>, and <a href="/lipase/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">lipase</a>.</p> <h4>Clinical Trials Experience In Pediatric Subjects</h4> <h5>Abacavir and Lamivudine</h5> <p>The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as EPZICOM, was assessed in the ARROW trial (n = 336). Primary safety assessment in the ARROW (COL105677) trial was based on Grade 3 and Grade 4 adverse events. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. No additional safety issues were identified in pediatric subjects compared with historical data in adults.</p> <h5>Dolutegravir</h5> <p>The safety of dolutegravir in pediatric subjects with HIV-1 infection weighing at least 10 kg was evaluated in the IMPAACT P1093 trial [see <b>Use In Specific Populations</b>, <b>CLINICAL PHARMACOLOGY</b>]. Overall, the safety data in this pediatric study was similar to that seen in adults. IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of pediatric subjects with HIV-1 infection, aged <18 years. One hundred and five subjects weighing at least 10 kg were enrolled in this trial [see <b>Use In Specific Populations</b>, <b>CLINICAL PHARMACOLOGY</b>, <b>Clinical Studies</b>].</p> <p>The safety analysis through Week 24 included 40 subjects from Cohorts I (n = 19), IIA (n = 5), III-<a href="/dt/definition.htm" ">DT</a> (n = 15), and IV-DT (n=1) weighing at least 10 kg at enrollment who received the recommended dose (determined by weight and age) and formulation. This analysis showed that 6 subjects (all from Cohort I) experienced drug-related clinical adverse reactions. There were no Grade 3 or 4 drug-related adverse reactions reported. No adverse reactions led to discontinuation.</p> <p>All laboratory abnormalities considered to be drug-related in subjects weighing at least 10 kg at enrollment were Grade 1 or 2 in severity. Only one grade 3 laboratory abnormality was reported in more than 1 subject (decreased blood <a href="/bicarbonate/definition.htm" ">bicarbonate</a>, n = 2). Changes in median serum creatinine were similar to those observed in adults.</p> <h4>Postmarketing Experience</h4> <p>In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use with one or more of the components of TRIUMEQ and TRIUMEQ PD. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.</p> <h5>Blood And Lymphatic Systems</h5> <p><a href="/aplastic_anemia/definition.htm" ">Aplastic anemia</a>, anemia (including pure red cell <a href="/aplasia/definition.htm" ">aplasia</a> and severe anemias progressing on therapy), <a href="/lymphadenopathy/definition.htm" ">lymphadenopathy</a>, <a href="/splenomegaly/definition.htm" ">splenomegaly</a>.</p> <h5>Digestive</h5> <p>Stomatitis.</p> <h5>Gastrointestinal</h5> <p><a href="/pancreatitis/definition.htm" ">Pancreatitis</a>.</p> <h5>General</h5> <p>Weakness.</p> <h5>Hepatobiliary Disorders</h5> <p>Acute <a href="/liver_failure/definition.htm" ">liver failure</a>, <a href="/liver_transplant/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">liver transplant</a> [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Hypersensitivity</h5> <p>Sensitization reactions (including <a href="/anaphylaxis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anaphylaxis</a>), <a href="/urticaria/definition.htm" ">urticaria</a> [see <b>WARNINGS AND PRECAUTIONS</b>, <b>Clinical Trials Experience</b>].</p> <h5>Investigations</h5> <p>Weight increased.</p> <h5>Metabolism And Nutrition Disorders</h5> <p>Hyperlactemia.</p> <h5>Musculoskeletal</h5> <p>CPK elevation, muscle weakness, <a href="/myalgia/definition.htm" ">myalgia</a>, <a href="/rhabdomyolysis/definition.htm" ">rhabdomyolysis</a>.</p> <h5>Nervous</h5> <p><a href="/paresthesia/definition.htm" ">Paresthesia</a>, <a href="/peripheral_neuropathy/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">peripheral neuropathy</a>, seizures.</p> <h5>Psychiatric</h5> <p>Anxiety.</p> <h5>Respiratory</h5> <p>Abnormal breath sounds/<a href="/wheezing/definition.htm" ">wheezing</a>.</p> <h5>Skin</h5> <p><a href="/alopecia/definition.htm" ">Alopecia</a>, <a href="/erythema_multiforme/definition.htm" ">erythema multiforme</a>. Suspected <a href="/stevens-johnson_syndrome/definition.htm" ">Stevens-Johnson syndrome</a> (<a href="/sjs/definition.htm" ">SJS</a>) and <a href="/toxic_epidermal_necrolysis_ten/definition.htm" ">toxic epidermal necrolysis</a> (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases [see <b>Clinical Trials Experience</b>].</p> </div> </div> </div> | 6 | 2023-02-01 17:38:35 | Abacavir, Dolutegravir, and Lamivudine Film-coated Tablets (Triumeq) | A | HIV, ART Combos | Triumeq | abacavir, dolutegravir, and lamivudine film-coated tablets | Triumeq | John P. Cunha, DO, FACOEP |
| 44 | 2023-02-23 12:07:03 | Drug Interactions | <a name="DI"></a> <h3>DRUG INTERACTIONS</h3> <h4>Effect Of Dolutegravir On The Pharmacokinetics Of Other Agents</h4> <p><i>In vitro</i>, dolutegravir inhibited the renal organic cation transporters (OCT)2 (IC<sub>50</sub> = 1.93 microM) and multidrug and <a href="/toxin/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">toxin</a> extrusion transporter (MATE)1 (IC<sub>50</sub> = 6.34 microM). <i>In vivo</i>, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide, dalfampridine, and metformin) [see <b>CONTRAINDICATIONS</b>, <b>Established And Other Potentially Significant Drug Interactions</b>].</p> <p><i>In vitro</i>, dolutegravir inhibited the basolateral renal transporters, organic <a href="/anion/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">anion</a> transporter (OAT) 1 (IC<sub>50</sub> = 2.12 microM) and OAT3 (IC<sub>50</sub> = 1.97 microM). However, <i>in vivo</i>, dolutegravir did not alter the plasma concentrations of tenofovir or <a href="/para-_prefix/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">para-</a>amino hippurate, substrates of OAT1 and OAT3.</p> <p><i>In vitro</i>, dolutegravir did not inhibit (IC<sub>50</sub> >50 microM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1, UGT2B7, P-<a href="/glycoprotein/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">glycoprotein</a> (P-gp), <a href="/breast_cancer_facts_stages/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">breast cancer</a> resistance protein (BCRP), <a href="/bile/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bile</a> salt export pump (BSEP), organic anion transporter <a href="/polypeptide/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">polypeptide</a> (OATP)1B1, OATP1B3, OCT1, or multidrug resistance protein (MRP)2, or MRP4. <i>In vitro</i>, dolutegravir did not induce CYP1A2, CYP2B6, CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters.</p> <p>In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs: daclatasvir, tenofovir, <a href="/methadone/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">methadone</a>, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol. Using crossstudy comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, and boceprevir.</p> <h4>Effect Of Other Agents On The Pharmacokinetics Of Dolutegravir</h4> <p>Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp <i>in vitro</i>. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir.</p> <p>Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations.</p> <p>Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir and is expected to be mitigated by atazanavir/ritonavir (Table 6) [see <b>Established And Other Potentially Significant Drug Interactions</b>, <b>CLINICAL PHARMACOLOGY</b>].</p> <p><i>In vitro</i>, dolutegravir was not a substrate of OATP1B1 or OATP1B3. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, daclatasvir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir.</p> <h4>Established And Other Potentially Significant Drug Interactions</h4> <p>There were no drug-drug interaction trials conducted with the abacavir, dolutegravir, and lamivudine fixed-dose combination tablets.</p> <p>Information regarding potential drug interactions with the individual components of TRIUMEQ and TRIUMEQ PD are provided below. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. [see <b>CONTRAINDICATIONS</b>, <b>CLINICAL PHARMACOLOGY</b>]</p> <p align="center"><b>Table 6. Established and Other Potentially Significant Drug Interactions for Dolutegravir: Alterations in Dose May Be Recommended Based on Drug Interaction Trials or Predicted Interactions </b></p> <center> <table cellspacing="0" class="blacktbl" width="650"> <tbody> <tr> <td class="EmphTd" width="25%">Concomitant Drug Class:<br /> Drug Name</td> <td class="EmphTd" width="30%">Effect on Concentration</td> <td class="EmphTd" width="45%">Clinical Comment</td> </tr> <tr> <td align="center" colspan="3"><b>HIV-1 Antiviral Agents</b></td> </tr> <tr> <td><b>Non-nucleoside reverse transcriptase inhibitor: </b><br /> Etravirine<sup>a</sup></td> <td>↓Dolutegravir</td> <td>Use of TRIUMEQ or TRIUMEQ PD with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.</td> </tr> <tr> <td><b>Non-nucleoside reverse transcriptase inhibitor:<br /> </b>Efavirenz<sup>a</sup></td> <td>↓Dolutegravir</td> <td>In adults and in pediatric patients <b>weighing at least 25 kg</b>, adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of TIVICAY should be taken, separated by 12 hours from TRIUMEQ.<br /> In pediatric patients <b>weighing 10 to <25 kg</b>, an additional weight-based dose of dolutegravir should be given separated by 12 hours from TRIUMEQ PD. <ul> <li>10 to <14 kg: administer an additional 20-mg dose of dolutegravir (4 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>14 to <20 kg: administer an additional 25-mg dose of dolutegravir (5 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>20 to <25 kg: administer an additional 30-mg dose of dolutegravir (6 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.</li> </ul> </td> </tr> <tr> <td><b>Non-nucleoside reverse transcriptase inhibitor:<br /> </b>Nevirapine</td> <td>↓Dolutegravir</td> <td>Avoid coadministration with TRIUMEQ or TRIUMEQ PD becausethere are insufficient data to make dosing recommendations.</td> </tr> <tr> <td><b>Protease inhibitor: </b> Fosamprenavir/ ritonavir<sup>a</sup><br /> Tipranavir/ritonavir<sup>a</sup></td> <td>↓Dolutegravir</td> <td>In adults and in pediatric patients <b>weighing at least 25 kg</b>, adjust dolutegravir dose to 50 mg twice daily. An additional TIVICAY 50-mg dose should be taken, separated by 12 hours from TRIUMEQ.<br /> In pediatric patients <b>weighing 10 to <25 kg</b>, an additional weight-based dose of dolutegravir should be given separated by 12 hours from TRIUMEQ PD. <ul> <li>10 to <14 kg: administer an additional 20-mg dose of dolutegravir (4 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>14 to <20 kg: administer an additional 25-mg dose of dolutegravir (5 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>20 to <25 kg: administer an additional 30-mg dose of dolutegravir (6 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.</li> </ul> </td> </tr> <tr> <td align="center" colspan="3"><i><b>Other Agents</b></i></td> </tr> <tr> <td><b>Antiarrhythmic: </b> Dofetilide</td> <td>↑Dofetilide</td> <td>Coadministration is contraindicated with TRIUMEQ and TRIUMEQ PD [see <b>CONTRAINDICATIONS</b>].</td> </tr> <tr> <td><b>Potassium channel blocker: </b><br /> Dalfampridine</td> <td>↑Dalfampridine</td> <td>Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with TRIUMEQ or TRIUMEQ PD should be considered against the risk of seizures in these patients.</td> </tr> <tr> <td> Carbamazepine<sup>a</sup></td> <td>↓Dolutegravir</td> <td>In adults and in pediatric patients <b>weighing at least 25 kg</b>, adjust dolutegravir dose to 50 mg twice daily. An additional TIVICAY 50-mg dose should be taken, separated by 12 hours from TRIUMEQ.<br /> In pediatric patients <b>weighing 10 to < 25 kg</b>, an additional weight-based dose of dolutegravir should be given separated by 12 hours from TRIUMEQ PD. <ul> <li>10 to <14 kg: administer an additional 20-mg dose of dolutegravir (4 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD, 14 to <20 kg: administer an additional 25-mg dose of dolutegravir (5 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>20 to <25 kg: administer an additional 30-mg dose of dolutegravir (6 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.</li> </ul> </td> </tr> <tr> <td>Oxcarbazepine Phenytoin Phenobarbital St. John’s wort (<i>Hypericum perforatum</i>)</td> <td>↓Dolutegravir</td> <td>Avoid coadministration with TRIUMEQ or TRIUMEQ PD because there are insufficient data to make dosing recommendations.</td> </tr> <tr> <td><b>Medications containing polyvalent cations (e.g., Mg or Al): </b><br /> Cation-containing antacids<sup>a</sup> or laxatives Sucralfate Buffered medications</td> <td>↓Dolutegravir</td> <td>Administer TRIUMEQ or TRIUMEQ PD 2 hours before or 6 hours after taking medications containing polyvalent cations.</td> </tr> <tr> <td><b>Oral calcium and iron supplements, including multivitamins containing calcium or iron<sup>a</sup></b></td> <td>↓Dolutegravir</td> <td>When taken with food, TRIUMEQ or TRIUMEQ PD and supplements or multivitamins containing calcium or iron can be taken at the same time. Under fasting conditions, TRIUMEQ or TRIUMEQ PD should be taken 2 hours before or 6 hours after taking supplements containing calcium or iron.</td> </tr> <tr> <td> Metformin<sup>a</sup></td> <td>↑Metformin</td> <td>Refer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of TRIUMEQ or TRIUMEQ PD and metformin.</td> </tr> <tr> <td> Rifampin<sup>a</sup></td> <td>↓Dolutegravir</td> <td>In adults and in pediatric patients <b>weighing at least 25 kg</b>, adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of TIVICAY should be taken, separated by 12 hours from TRIUMEQ.<br /> In pediatric patients <b>weighing 10 to < 25 kg</b>, an additional weight-based dose of dolutegravir should be given separated by 12 hours from TRIUMEQ PD. <ul> <li>10 to <14 kg: administer an additional 20-mg dose of dolutegravir (4 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>14 to <20 kg: administer an additional 25-mg dose of dolutegravir (5 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>20 to <25 kg: administer an additional 30-mg dose of dolutegravir (6 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.</li> </ul> </td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> See <b>CLINICAL PHARMACOLOGY</b> Table 8 or Table 9 for magnitude of interaction.</td> </tr> </tbody> </table> </center> <p></p> <h5>Methadone</h5> <p><i>Abacavir</i></p> <p>In a trial of 11 HIV-1–infected subjects receiving methadone-<a href="/maintenance_therapy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">maintenance therapy</a> with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased [see <b>CLINICAL PHARMACOLOGY</b>]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.</p> <h5>Sorbitol</h5> <p><i>Lamivudine</i></p> <p>Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitolcontaining medicines with lamivudine-containing medicines [see <b>CLINICAL PHARMACOLOGY</b>].</p> <h5>Riociguat</h5> <p><i>Abacavir</i></p> <p>Coadministration with TRIUMEQ resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [see <b>CLINICAL PHARMACOLOGY</b>]. The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).</p> </div> </div> </div> | <a name="DI"></a> <h3>DRUG INTERACTIONS</h3> <h4>Effect Of Dolutegravir On The Pharmacokinetics Of Other Agents</h4> <p><i>In vitro</i>, dolutegravir inhibited the renal organic cation transporters (OCT)2 (IC<sub>50</sub> = 1.93 microM) and multidrug and <a href="/toxin/definition.htm" ">toxin</a> extrusion transporter (MATE)1 (IC<sub>50</sub> = 6.34 microM). <i>In vivo</i>, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide, dalfampridine, and metformin) [see <b>CONTRAINDICATIONS</b>, <b>Established And Other Potentially Significant Drug Interactions</b>].</p> <p><i>In vitro</i>, dolutegravir inhibited the basolateral renal transporters, organic <a href="/anion/definition.htm" ">anion</a> transporter (OAT) 1 (IC<sub>50</sub> = 2.12 microM) and OAT3 (IC<sub>50</sub> = 1.97 microM). However, <i>in vivo</i>, dolutegravir did not alter the plasma concentrations of tenofovir or <a href="/para-_prefix/definition.htm" ">para-</a>amino hippurate, substrates of OAT1 and OAT3.</p> <p><i>In vitro</i>, dolutegravir did not inhibit (IC<sub>50</sub> >50 microM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1, UGT2B7, P-<a href="/glycoprotein/definition.htm" ">glycoprotein</a> (P-gp), <a href="/breast_cancer_facts_stages/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">breast cancer</a> resistance protein (BCRP), <a href="/bile/definition.htm" ">bile</a> salt export pump (BSEP), organic anion transporter <a href="/polypeptide/definition.htm" ">polypeptide</a> (OATP)1B1, OATP1B3, OCT1, or multidrug resistance protein (MRP)2, or MRP4. <i>In vitro</i>, dolutegravir did not induce CYP1A2, CYP2B6, CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters.</p> <p>In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs: daclatasvir, tenofovir, <a href="/methadone/definition.htm" ">methadone</a>, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol. Using crossstudy comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, and boceprevir.</p> <h4>Effect Of Other Agents On The Pharmacokinetics Of Dolutegravir</h4> <p>Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp <i>in vitro</i>. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir.</p> <p>Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations.</p> <p>Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir and is expected to be mitigated by atazanavir/ritonavir (Table 6) [see <b>Established And Other Potentially Significant Drug Interactions</b>, <b>CLINICAL PHARMACOLOGY</b>].</p> <p><i>In vitro</i>, dolutegravir was not a substrate of OATP1B1 or OATP1B3. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, daclatasvir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir.</p> <h4>Established And Other Potentially Significant Drug Interactions</h4> <p>There were no drug-drug interaction trials conducted with the abacavir, dolutegravir, and lamivudine fixed-dose combination tablets.</p> <p>Information regarding potential drug interactions with the individual components of TRIUMEQ and TRIUMEQ PD are provided below. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. [see <b>CONTRAINDICATIONS</b>, <b>CLINICAL PHARMACOLOGY</b>]</p> <p align="center"><b>Table 6. Established and Other Potentially Significant Drug Interactions for Dolutegravir: Alterations in Dose May Be Recommended Based on Drug Interaction Trials or Predicted Interactions </b></p> <center> <table cellspacing="0" class="blacktbl" width="650"> <tbody> <tr> <td class="EmphTd" width="25%">Concomitant Drug Class:<br /> Drug Name</td> <td class="EmphTd" width="30%">Effect on Concentration</td> <td class="EmphTd" width="45%">Clinical Comment</td> </tr> <tr> <td align="center" colspan="3"><b>HIV-1 Antiviral Agents</b></td> </tr> <tr> <td><b>Non-nucleoside reverse transcriptase inhibitor: </b><br /> Etravirine<sup>a</sup></td> <td>↓Dolutegravir</td> <td>Use of TRIUMEQ or TRIUMEQ PD with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.</td> </tr> <tr> <td><b>Non-nucleoside reverse transcriptase inhibitor:<br /> </b>Efavirenz<sup>a</sup></td> <td>↓Dolutegravir</td> <td>In adults and in pediatric patients <b>weighing at least 25 kg</b>, adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of TIVICAY should be taken, separated by 12 hours from TRIUMEQ.<br /> In pediatric patients <b>weighing 10 to <25 kg</b>, an additional weight-based dose of dolutegravir should be given separated by 12 hours from TRIUMEQ PD. <ul> <li>10 to <14 kg: administer an additional 20-mg dose of dolutegravir (4 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>14 to <20 kg: administer an additional 25-mg dose of dolutegravir (5 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>20 to <25 kg: administer an additional 30-mg dose of dolutegravir (6 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.</li> </ul> </td> </tr> <tr> <td><b>Non-nucleoside reverse transcriptase inhibitor:<br /> </b>Nevirapine</td> <td>↓Dolutegravir</td> <td>Avoid coadministration with TRIUMEQ or TRIUMEQ PD becausethere are insufficient data to make dosing recommendations.</td> </tr> <tr> <td><b>Protease inhibitor: </b> Fosamprenavir/ ritonavir<sup>a</sup><br /> Tipranavir/ritonavir<sup>a</sup></td> <td>↓Dolutegravir</td> <td>In adults and in pediatric patients <b>weighing at least 25 kg</b>, adjust dolutegravir dose to 50 mg twice daily. An additional TIVICAY 50-mg dose should be taken, separated by 12 hours from TRIUMEQ.<br /> In pediatric patients <b>weighing 10 to <25 kg</b>, an additional weight-based dose of dolutegravir should be given separated by 12 hours from TRIUMEQ PD. <ul> <li>10 to <14 kg: administer an additional 20-mg dose of dolutegravir (4 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>14 to <20 kg: administer an additional 25-mg dose of dolutegravir (5 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>20 to <25 kg: administer an additional 30-mg dose of dolutegravir (6 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.</li> </ul> </td> </tr> <tr> <td align="center" colspan="3"><i><b>Other Agents</b></i></td> </tr> <tr> <td><b>Antiarrhythmic: </b> Dofetilide</td> <td>↑Dofetilide</td> <td>Coadministration is contraindicated with TRIUMEQ and TRIUMEQ PD [see <b>CONTRAINDICATIONS</b>].</td> </tr> <tr> <td><b>Potassium channel blocker: </b><br /> Dalfampridine</td> <td>↑Dalfampridine</td> <td>Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with TRIUMEQ or TRIUMEQ PD should be considered against the risk of seizures in these patients.</td> </tr> <tr> <td> Carbamazepine<sup>a</sup></td> <td>↓Dolutegravir</td> <td>In adults and in pediatric patients <b>weighing at least 25 kg</b>, adjust dolutegravir dose to 50 mg twice daily. An additional TIVICAY 50-mg dose should be taken, separated by 12 hours from TRIUMEQ.<br /> In pediatric patients <b>weighing 10 to < 25 kg</b>, an additional weight-based dose of dolutegravir should be given separated by 12 hours from TRIUMEQ PD. <ul> <li>10 to <14 kg: administer an additional 20-mg dose of dolutegravir (4 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD, 14 to <20 kg: administer an additional 25-mg dose of dolutegravir (5 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>20 to <25 kg: administer an additional 30-mg dose of dolutegravir (6 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.</li> </ul> </td> </tr> <tr> <td>Oxcarbazepine Phenytoin Phenobarbital St. John’s wort (<i>Hypericum perforatum</i>)</td> <td>↓Dolutegravir</td> <td>Avoid coadministration with TRIUMEQ or TRIUMEQ PD because there are insufficient data to make dosing recommendations.</td> </tr> <tr> <td><b>Medications containing polyvalent cations (e.g., Mg or Al): </b><br /> Cation-containing antacids<sup>a</sup> or laxatives Sucralfate Buffered medications</td> <td>↓Dolutegravir</td> <td>Administer TRIUMEQ or TRIUMEQ PD 2 hours before or 6 hours after taking medications containing polyvalent cations.</td> </tr> <tr> <td><b>Oral calcium and iron supplements, including multivitamins containing calcium or iron<sup>a</sup></b></td> <td>↓Dolutegravir</td> <td>When taken with food, TRIUMEQ or TRIUMEQ PD and supplements or multivitamins containing calcium or iron can be taken at the same time. Under fasting conditions, TRIUMEQ or TRIUMEQ PD should be taken 2 hours before or 6 hours after taking supplements containing calcium or iron.</td> </tr> <tr> <td> Metformin<sup>a</sup></td> <td>↑Metformin</td> <td>Refer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of TRIUMEQ or TRIUMEQ PD and metformin.</td> </tr> <tr> <td> Rifampin<sup>a</sup></td> <td>↓Dolutegravir</td> <td>In adults and in pediatric patients <b>weighing at least 25 kg</b>, adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of TIVICAY should be taken, separated by 12 hours from TRIUMEQ.<br /> In pediatric patients <b>weighing 10 to < 25 kg</b>, an additional weight-based dose of dolutegravir should be given separated by 12 hours from TRIUMEQ PD. <ul> <li>10 to <14 kg: administer an additional 20-mg dose of dolutegravir (4 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>14 to <20 kg: administer an additional 25-mg dose of dolutegravir (5 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD,</li> <li>20 to <25 kg: administer an additional 30-mg dose of dolutegravir (6 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.</li> </ul> </td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> See <b>CLINICAL PHARMACOLOGY</b> Table 8 or Table 9 for magnitude of interaction.</td> </tr> </tbody> </table> </center> <p></p> <h5>Methadone</h5> <p><i>Abacavir</i></p> <p>In a trial of 11 HIV-1–infected subjects receiving methadone-<a href="/maintenance_therapy/definition.htm" ">maintenance therapy</a> with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased [see <b>CLINICAL PHARMACOLOGY</b>]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients.</p> <h5>Sorbitol</h5> <p><i>Lamivudine</i></p> <p>Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitolcontaining medicines with lamivudine-containing medicines [see <b>CLINICAL PHARMACOLOGY</b>].</p> <h5>Riociguat</h5> <p><i>Abacavir</i></p> <p>Coadministration with TRIUMEQ resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [see <b>CLINICAL PHARMACOLOGY</b>]. The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).</p> </div> </div> </div> | 6 | 2023-02-01 17:38:35 | Abacavir, Dolutegravir, and Lamivudine Film-coated Tablets (Triumeq) | A | HIV, ART Combos | Triumeq | abacavir, dolutegravir, and lamivudine film-coated tablets | Triumeq | John P. Cunha, DO, FACOEP |
| 45 | 2023-02-23 12:07:03 | Warnings & Precautions | <a name="W"></a> <h3>WARNINGS</h3> <p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a> <h3>PRECAUTIONS</h3> <h4>Hypersensitivity Reactions</h4> <p>Hypersensitivity reactions have been reported with the use of abacavir or dolutegravir, components of TRIUMEQ and TRIUMEQ PD.</p> <h5>Abacavir</h5> <p>Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing regimens. See full prescribing information for ZIAGEN (abacavir).</p> <p>Abacavir hypersensitivity reactions have included multi-<a href="/organ_failure/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">organ failure</a> and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see <b>ADVERSE REACTIONS</b>]. Patients who carry the <a href="/hla/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HLA</a>-B*5701 <a href="/allele/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">allele</a> are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.</p> <p>Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:</p> <ul> <li>All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with TRIUMEQ or TRIUMEQ PD or reinitiation of therapy with TRIUMEQ or TRIUMEQ PD, unless patients have a previously documented HLA-B*5701 allele assessment.</li> <li>TRIUMEQ and TRIUMEQ PD are contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.</li> <li>Before starting TRIUMEQ or TRIUMEQ PD, review <a href="/medical_history/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">medical history</a> for prior exposure to any abacavir-containing product. NEVER restart TRIUMEQ or TRIUMEQ PD or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.</li> <li>To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue TRIUMEQ or TRIUMEQ PD immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as <a href="/pneumonia_facts/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">pneumonia</a>, <a href="/bronchitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bronchitis</a>, <a href="/pharyngitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pharyngitis</a>, or <a href="/influenza/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">influenza</a>; <a href="/gastroenteritis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">gastroenteritis</a>; or reactions to other medications). Clinical status, including liver chemistries, should be monitored and appropriate therapy initiated.</li> <li>If a hypersensitivity reaction cannot be ruled out, do not restart TRIUMEQ or TRIUMEQ PD or any other abacavir-containing products because more severe symptoms, which may include life-threatening <a href="/hypotension/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypotension</a> and death, can occur within hours.</li> <li>Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ or TRIUMEQ PD would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or TRIUMEQ PD or any other abacavir- or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ or TRIUMEQ PD due to a hypersensitivity reaction.</li> <li>If a hypersensitivity reaction is ruled out, patients may restart TRIUMEQ or TRIUMEQ PD. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of TRIUMEQ or TRIUMEQ PD, or any other abacavir-containing product, is recommended only if medical care can be readily accessed.</li> <li>A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill.</li> </ul> <h5>Dolutegravir</h5> <p>Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in <1% of subjects receiving TIVICAY in Phase 3 clinical trials. Discontinue TRIUMEQ or TRIUMEQ PD and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general <a href="/malaise/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">malaise</a>, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, <a href="/conjunctivitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">conjunctivitis</a>, facial edema, hepatitis, <a href="/eosinophilia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">eosinophilia</a>, <a href="/angioedema/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">angioedema</a>, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with TRIUMEQ or TRIUMEQ PD or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction.</p> <p>Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ or TRIUMEQ PD would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or TRIUMEQ PD or any other abacavir- or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ or TRIUMEQ PD due to a hypersensitivity reaction.</p> <h4>Patients Co-Infected With HIV-1 And HBV: Emergence Of Lamivudine-Resistant HBV And The Risk Of Posttreatment Exacerbations Of HBV</h4> <p>All patients with HIV-1 should be tested for the presence of <a href="/hbv/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HBV</a> prior to or when initiating TRIUMEQ or TRIUMEQ PD.</p> <h5>Emergence Of Lamivudine Resistant HBV</h5> <p>Safety and efficacy of lamivudine have not been established for treatment of chronic HBV in subjects dually infected with HIV-1 and HBV. Emergence of HBV variants associated with resistance to lamivudine has been reported in HIV-1−infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with HBV. If a decision is made to administer TRIUMEQ or TRIUMEQ PD to patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen.</p> <h5>Severe Acute Exacerbations Of HBV In Patients Co-Infected With HIV-1 And HBV</h5> <p>Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued products containing lamivudine, and may occur with discontinuation of TRIUMEQ or TRIUMEQ PD. Patients who are co-infected with HIV-1 and HBV who discontinue TRIUMEQ or TRIUMEQ PD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with TRIUMEQ or TRIUMEQ PD. If appropriate, initiation of anti-HBV therapy may be warranted, especially in patients with advanced <a href="/liver_disease/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">liver disease</a> or <a href="/cirrhosis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">cirrhosis</a>, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.</p> <h4>Hepatotoxicity</h4> <p>Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen [see <b>ADVERSE REACTIONS</b>]. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TRIUMEQ or TRIUMEQ PD [see <b>ADVERSE REACTIONS</b>]. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure, have also been reported in patients, including pediatric patients receiving a dolutegravir-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ. Monitoring for hepatotoxicity is recommended.</p> <h4>Lactic Acidosis And Severe Hepatomegaly With Steatosis</h4> <p><a href="/lactic_acidosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Lactic acidosis</a> and severe <a href="/hepatomegaly/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hepatomegaly</a> with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir and lamivudine (components of TRIUMEQ and TRIUMEQ PD). A majority of these cases have been in women. Female sex and <a href="/obesity/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">obesity</a> may be risk factors for the development of lactic <a href="/acidosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">acidosis</a> and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Treatment with TRIUMEQ or TRIUMEQ PD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.</p> <h4>Embryo-Fetal Toxicity</h4> <p>An ongoing observational study showed an association between dolutegravir and an increased risk of <a href="/neural/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">neural</a> tube defects when dolutegravir was administered at the time of <a href="/conception/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">conception</a> and in early pregnancy. As there is limited understanding of the association of reported types of neural tube defects with dolutegravir use, inform adolescents and adults of childbearing potential, including those actively trying to become pregnant, about the potential increased risk of neural tube defects with TRIUMEQ. Assess the risks and benefits of TRIUMEQ and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester [see <b>Use In Specific Populations</b>].</p> <p>Pregnancy testing is recommended before initiation of TRIUMEQ in adolescents and adults of childbearing potential [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>Adolescents and adults of childbearing potential should be counseled on the consistent use of effective contraception [see <b>Use In Specific Populations</b>].</p> <p>TRIUMEQ may be considered during the second and third trimesters of pregnancy if the expected benefit justifies the potential risk to the pregnant woman and the fetus.</p> <h4>Risk Of Adverse Reactions Or Loss Of Virologic Response Due To Drug Interactions</h4> <p>The concomitant use of TRIUMEQ or TRIUMEQ PD and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see <b>CONTRAINDICATIONS</b>, <b>DRUG INTERACTIONS</b>]:</p> <ul> <li>Loss of therapeutic effect of TRIUMEQ or TRIUMEQ PD and possible development of resistance.</li> <li>Possible clinically significant adverse reactions from greater exposures of concomitant drugs.</li> </ul> <p>See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TRIUMEQ or TRIUMEQ PD, review concomitant medications during therapy with TRIUMEQ or TRIUMEQ PD, and monitor for the adverse reactions associated with the concomitant drugs.</p> <h4>Immune Reconstitution Syndrome</h4> <p>Immune reconstitution syndrome has been reported in patients treated with combination <a href="/antiretroviral_therapy_art/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antiretroviral therapy</a>, including TRIUMEQ or TRIUMEQ PD. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an <a href="/inflammatory_response/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">inflammatory response</a> to indolent or <a href="/residual/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">residual</a> opportunistic infections (such as <i>Mycobacterium avium</i> infection, <a href="/cytomegalovirus_cmv/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cytomegalovirus</a>, <i>Pneumocystis jirovecii</i> pneumonia [<a href="/pcp/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">PCP</a>], or <a href="/tuberculosis_tb_facts/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">tuberculosis</a>), which may necessitate further evaluation and treatment.</p> <p><a href="/autoimmune/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Autoimmune</a> disorders (such as Graves’ disease, <a href="/polymyositis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">polymyositis</a>, Guillain-Barré syndrome, <a href="/autoimmune_hepatitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">autoimmune hepatitis</a>) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.</p> <h4>Different Formulations Are Not Interchangeable</h4> <p>TRIUMEQ and TRIUMEQ PD are not bioequivalent and are not interchangeable on a <a href="/milligram/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">milligram</a>-per-milligram basis [see <b>CLINICAL PHARMACOLOGY</b>]. If a pediatric patient switches from the tablets for oral suspension to the tablets, the dosage must be adjusted [see <b>DOSAGE AND ADMINISTRATION</b>]. Incorrect dosing of a given formulation may result in underdosing and loss of therapeutic effect and possible development of resistance or possible clinically significant adverse reactions from greater exposure to the individual components.</p> <h4>Myocardial Infarction</h4> <p>Several <a href="/prospective/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">prospective</a>, observational, epidemiological studies have reported an association with the use of abacavir and the risk of <a href="/myocardial_infarction/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">myocardial infarction</a> (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir and the risk of MI is inconclusive.</p> <p>As a precaution, the underlying risk of coronary <a href="/heart_disease/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">heart disease</a> should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., <a href="/hypertension/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypertension</a>, <a href="/hyperlipidemia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hyperlipidemia</a>, <a href="/diabetes_mellitus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">diabetes</a> mellitus, <a href="/smoking_and_quitting_smoking/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">smoking</a>).</p> <h4>Patient Counseling Information</h4> <p>Advise the patient to read the FDA-approved patient labeling (<b>PATIENT INFORMATION</b> and <b>Instructions for Use</b>).</p> <h5>Drug Interactions</h5> <p>TRIUMEQ or TRIUMEQ PD may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort [see <b>CONTRAINDICATIONS</b>, <b>WARNINGS AND PRECAUTIONS</b>, <b>DRUG INTERACTIONS</b>].</p> <h5>Hypersensitivity Reaction</h5> <p><i>Inform Patients</i></p> <ul> <li>that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of TRIUMEQ or TRIUMEQ PD, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about TRIUMEQ or TRIUMEQ PD. The complete text of the <b>Medication Guide</b> is reprinted at the end of this document.</li> <li>to carry the Warning Card with them.</li> <li>how to identify a hypersensitivity reaction [see <b>WARNINGS AND PRECAUTIONS</b>,<b>PATIENT INFORMATION</b>].</li> <li>that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking TRIUMEQ or TRIUMEQ PD.</li> <li>that a hypersensitivity reaction can worsen and lead to hospitalization or death if TRIUMEQ or TRIUMEQ PD is not immediately discontinued.</li> <li>to not restart TRIUMEQ or TRIUMEQ PD or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.</li> <li>that if they have a hypersensitivity reaction, they should dispose of any unused TRIUMEQ or TRIUMEQ PD to avoid restarting abacavir.</li> <li>that a hypersensitivity reaction is usually reversible if it is detected promptly and TRIUMEQ or TRIUMEQ PD is stopped right away.</li> <li>that if they have interrupted TRIUMEQ or TRIUMEQ PD for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.</li> <li>to not restart TRIUMEQ or TRIUMEQ PD or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.</li> <li>to not restart TRIUMEQ or TRIUMEQ PD or any other dolutegravir-containing product following a hypersensitivity reaction to TRIUMEQ or TRIUMEQ PD.</li> </ul> <h5>Hepatotoxicity</h5> <p>Inform patients that hepatotoxicity has been reported with dolutegravir, a component of TRIUMEQ and TRIUMEQ PD [see <b>WARNINGS AND PRECAUTIONS</b>, <b>ADVERSE REACTIONS</b>]. Inform patients that monitoring for hepatotoxicity during therapy with TRIUMEQ or TRIUMEQ PD is recommended.</p> <h5>Severe Acute Exacerbations Of Hepatitis In Patients With HBV Co-Infection</h5> <p>Advise all patients with HIV-1 to be tested for the presence of HBV prior to or when initiating TRIUMEQ or TRIUMEQ PD. Advise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their physician [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Lactic Acidosis/Hepatomegaly</h5> <p>Inform patients that some HIV medicines, including TRIUMEQ and TRIUMEQ PD, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Embryo-Fetal Toxicity</h5> <p>Advise adolescents and adults of childbearing potential, including those actively trying to become pregnant, to discuss the risks and benefits of TRIUMEQ with their healthcare provider to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy. If pregnancy is confirmed in the first trimester, advise patients to contact their healthcare provider [see <b>WARNINGS AND PRECAUTIONS</b> and <b>Use In Specific Populations</b>].</p> <p>Adolescents and adults of childbearing potential taking TRIUMEQ should be counseled on the consistent use of effective contraception [see <b>WARNINGS AND PRECAUTIONS</b>, <b>Use In Specific Populations</b>].</p> <h5>Immune Reconstitution Syndrome</h5> <p>Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when TRIUMEQ or TRIUMEQ PD is started [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>TRIUMEQ Tablets and TRIUMEQ PD Tablets for Oral Suspension <u>Are Not Bioequivalent</u> Advise patients that TRIUMEQ and TRIUMEQ PD are not bioequivalent and are not interchangeable on a milligram-per-milligram basis. Advise patients or their care provider that patients switching from the tablets for oral suspension to the tablets must adjust the dose [see <b>DOSAGE AND ADMINISTRATION</b> and <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Pregnancy Registry</h5> <p>Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to TRIUMEQ during pregnancy [see <b>Use In Specific Populations</b>].</p> <h5>Lactation</h5> <p>Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see <b>Use In Specific Populations</b>].</p> <h5>Administration Instructions</h5> <p>To avoid a dosing error from using the wrong formulation of TRIUMEQ, strongly advise patients and caregivers to visually inspect the tablets to verify the correct formulation each time the prescription is filled [see <b>DOSAGE AND ADMINISTRATION</b>, <b>WARNINGS AND PRECAUTIONS</b>, <b>HOW SUPPLIED</b>].</p> <p>Inform patients and caregivers that TRIUMEQ PD tablets for oral suspension should be dispersed in drinking water and should not be chewed, cut or crushed [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>Instruct patients and caregivers that if a dose of TRIUMEQ or TRIUMEQ PD is missed, to take it as soon as they remember. Advise patients and caregivers not to double the next dose or take more than the prescribed dose [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <h5>Availability Of Medication Guide</h5> <p>Instruct patients and caregivers to read the Medication Guide before starting TRIUMEQ or TRIUMEQ PD and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.</p> <h5>Storage</h5> <p>Instruct patients and caregivers to store TRIUMEQ and TRIUMEQ PD tablets for oral suspension in the original package, protect from moisture, and keep the bottle tightly closed. Do not remove desiccant.</p> <p>EPIVIR, EPZICOM, TIVICAY, TIVICAY PD, TRIUMEQ, TRIUMEQ PD, and ZIAGEN are trademarks owned by or licensed to the ViiV Healthcare group of companies.</p> <p>EPIVIR-HBV is a trademark owned by or licensed to the GSK group of companies.</p> <p>The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.</p> <h4>Nonclinical Toxicology</h4> <h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4> <h5>Carcinogenicity</h5> <p><i>Dolutegravir</i></p> <p>Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg/kg, and rats were administered doses of up to 50 mg/kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 26-fold higher than those in humans at the recommended dose of 50 mg once daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 17-fold and 30-fold higher in males and females, respectively, than those in humans at the recommended dose of 50 mg once daily. Abacavir: Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of <a href="/malignant/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">malignant</a> and non-malignant tumors. Malignant tumors occurred in the preputial <a href="/gland/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">gland</a> of males and the <a href="/clitoral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">clitoral</a> gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and <a href="/thyroid_gland/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">thyroid gland</a> of female rats. These observations were made at systemic exposures in the range of 7 to 28 times the human exposure at the recommended dose of 600 mg.</p> <p><i>Lamivudine</i></p> <p>Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of <a href="/carcinogenic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">carcinogenic</a> potential at exposures up to 12 times (mice) and 57 times (rats) the human exposures at the recommended dose of 300 mg.</p> <h5>Mutagenicity</h5> <p><i>Dolutegravir</i></p> <p>Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse <a href="/lymphoma/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lymphoma</a> assay, or in the <i>in vivo</i> rodent micronucleus assay.</p> <p><i>Abacavir</i></p> <p>Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an <i>in vitro</i> cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an <i>in vivo</i> mouse <a href="/bone_marrow/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bone marrow</a> micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.</p> <p><i>Lamivudine</i></p> <p>Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an <i>in vitro</i> cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.</p> <h5>Impairment Of Fertility</h5> <p>Dolutegravir, abacavir, or lamivudine did not affect male or female fertility in rats at doses associated with exposures approximately 44, 9, or 112 times (respectively) higher than the exposures in humans at the doses of 50 mg, 600 mg, and 300 mg (respectively).</p> <a name="USP"></a> <h4>Use In Specific Populations</h4> <h4>Pregnancy</h4> <h5>Pregnancy Exposure Registry</h5> <p>There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TRIUMEQ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.</p> <h5>Risk Summary</h5> <p>Data from an ongoing birth outcome surveillance study has identified an increased risk of neural tube defects when dolutegravir, a component of TRIUMEQ, is administered at the time of conception. As defects related to closure of the neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of gestation are at potential risk.</p> <p>Advise adolescents and adults of childbearing potential, including those actively trying to become pregnant, of the potential risk of neural tube defects with use of TRIUMEQ. Assess the risks and benefits of TRIUMEQ and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester. A benefit-risk assessment should consider factors such as feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in utero dolutegravir exposure during critical periods of fetal development [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>There are insufficient human data on the use of TRIUMEQ during pregnancy to definitively assess a drug-associated risk for <a href="/birth_defects/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">birth defects</a> and <a href="/miscarriage_causes_and_symptoms/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">miscarriage</a>. The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.</p> <p>In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and approximately 50 times (rats) the exposure in humans at the recommended human dose (RHD) (see <b>Data</b>). Oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the RHD. No adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis at exposures approximately 9 times the human exposure (AUC) at the RHD. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at a human exposure (AUC) similar to the RHD; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the RHD (see <b>Data</b>).</p> <h5>Data</h5> <p><i>Human Data</i></p> <p><i>Dolutegravir</i></p> <p>In a birth outcome surveillance study in Botswana, there were 7 cases of neural tube defects reported out of 3,591 deliveries (0.19%) to women who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the <a href="/neural_tube_defect/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">neural tube defect</a> <a href="/prevalence/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">prevalence</a> rates were 0.11% (21/19,361 deliveries) in the non-dolutegravir arm and 0.07% (87/119,630 deliveries) in the HIV-uninfected arm. Seven cases reported with dolutegravir included 3 cases of myelomeningocele, 2 cases of encephalocele, and one case each of <a href="/anencephaly/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anencephaly</a> and <a href="/iniencephaly/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">iniencephaly</a>. In the same study, no increased risk of neural tube defects was identified in women who started dolutegravir during pregnancy. Two infants out of 4,448 (0.04%) deliveries to women who started dolutegravir during pregnancy had a neural tube defect, compared with 5 infants out of 6,748 (0.07%) deliveries to women who started non-dolutegravircontaining regimens during pregnancy. The reported risks of neural tube defects by treatment groups were based on interim analyses from the ongoing surveillance study in Botswana. It is unknown if baseline characteristics were balanced between the study treatment groups. The observed trends of association could change as data accumulate.</p> <p>Data analyzed to date from other sources including the APR, clinical trials, and postmarketing data are insufficient to definitively address the risk of neural tube defects with dolutegravir. Data from the birth outcome surveillance study described above and postmarketing sources with more than 1,000 pregnancy outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes.</p> <p>Based on prospective reports to the APR of over 1,000 exposures to dolutegravir during pregnancy resulting in live births (including 634 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 2.1% to 5.0%) following first-trimester exposure to dolutegravir-containing regimens and 5.1% (95% CI: 3.2% to 7.7%) following second-/thirdtrimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta <a href="/congenital/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Congenital</a> Defects Program (MACDP), the background <a href="/birth_defect/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">birth defect</a> rate was 2.7%.</p> <p><i>Abacavir</i></p> <p>Based on prospective reports to the APR of over 2,700 exposures to abacavir during pregnancy resulting in live births (including 1,391 exposed in the first trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.2%) following first trimester exposure to abacavir-containing regimens and 3.0% (95% CI: 2.1% to 4.0%) following second/third trimester exposure to abacavir-containing regimens.</p> <p>Abacavir has been shown to cross the placenta and concentrations in <a href="/neonatal/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">neonatal</a> plasma at birth were essentially equal to those in maternal plasma at delivery [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p><i>Lamivudine</i></p> <p>Based on prospective reports to the APR of over 12,900 exposures to lamivudine during pregnancy resulting in live births (including 5,472 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5%, 3.3%) following second/third trimester exposure to lamivudine-containing regimens.</p> <p>Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and <a href="/umbilical_cord/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">umbilical cord</a> serum samples. In a subset of subjects, <a href="/amniotic_fluid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">amniotic fluid</a> specimens were collected following natural <a href="/rupture/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">rupture</a> of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9-fold (1.2- to 12.8-fold) greater compared with paired maternal serum concentration (n = 8).</p> <p><i>Animal Data</i></p> <p><i>Dolutegravir</i></p> <p>Dolutegravir was administered orally to pregnant rats and rabbits (up to 1,000 mg/kg/day) on Gestation Days 6 to 17 and 6 to 18, respectively, and to rats on Gestation Day 6 to lactation/post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed up to the highest dose tested. During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the RHD and in rats were approximately 50 times the exposure in humans at the RHD. In the rat pre/post-natal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 50 times human exposure at the RHD).</p> <p><i>Abacavir</i></p> <p>Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg/kg/day) and rabbits (at 125, 350, or 700 mg/kg/day) during organogenesis (on Gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal <a href="/anasarca/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">anasarca</a> and skeletal malformations) or developmental toxicity (decreased fetal body weight and <a href="/crown/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">crown</a>-rump length) were observed in rats at doses up to 1,000 mg/kg/day, resulting in exposures approximately 35 times the human exposure (AUC) at the RHD. No developmental effects were observed in rats at 100 mg/kg/day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryofetal development study conducted in rats (at 60, 160, or 500 mg/kg/day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg/kg/day. No developmental effects were observed in rats at 60 mg/kg/day, resulting in exposures (AUC) approximately 4 times the human exposure at the RHD. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the RHD.</p> <p><i>Lamivudine</i></p> <p>Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg/kg/day) and rabbits (at 90, 300 and 1,000 mg/kg/day and at 15, 40, and 90 mg/kg/day) during organogenesis (on Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre- and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg/kg/day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, were not affected by the maternal administration of lamivudine.</p> <h4>Lactation</h4> <h5>Risk Summary</h5> <p>The <a href="/centers_for_disease_control_and_prevention/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Centers for Disease Control and Prevention</a> recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.</p> <p>Abacavir and lamivudine are present in human milk. When administered to lactating rats, dolutegravir was present in milk (see <b>Data</b>). There is no information on the effects of TRIUMEQ or its components on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving TRIUMEQ.</p> <h5>Data</h5> <p><i>Animal Data</i></p> <p>Dolutegravir was the primary drug-related component excreted into the milk of lactating rats following a single oral dose of 50 mg/kg/day on Lactation Day 10, with milk concentrations of up to approximately 1.3 times that of maternal plasma concentrations observed 8 hours postdose.</p> <h4>Females And Males Of Reproductive Potential</h4> <p>In adolescents and adults of childbearing potential currently on TRIUMEQ who are actively trying to become pregnant or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing TRIUMEQ and discuss with the patient if an alternative treatment should be considered [see <b>WARNINGS AND PRECAUTIONS</b>, <b>Pregnancy</b>].</p> <h5>Pregnancy Testing</h5> <p>Pregnancy testing is recommended in adolescents and adults of childbearing potential before initiation of TRIUMEQ [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <h5>Contraception</h5> <p>Adolescents and adults of childbearing potential who are taking TRIUMEQ should be counseled on the consistent use of effective contraception.</p> <h4>Pediatric Use</h4> <p>The clinical data supporting use of TRIUMEQ and TRIUMEQ PD in pediatric patients with HIV-1 infection weighing at least 10 kg is derived from the following previously conducted pediatric trials using the individual components of TRIUMEQ and TRIUMEQ PD:</p> <ul> <li>The safety and efficacy of once-daily abacavir and lamivudine were established with a randomized, multicenter trial (ARROW [COL105677]) in HIV-1–infected, treatment- naive subjects aged 3 months to 17 years with a first-line regimen containing abacavir and lamivudine, using either the combination of EPIVIR and ZIAGEN or EPZICOM [see <b>ADVERSE REACTIONS</b>, <b>Clinical Studies</b>].</li> <li>The safety, pharmacokinetics, and <a href="/antiviral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antiviral</a> activity (efficacy) of TIVICAY and TIVICAY PD were established through an ongoing, open-label, multicenter, dose-finding clinical trial (IMPAACT P1093), in which HIV-1–infected, treatment-naive or treatment-experienced, INSTI-naive, pediatric and adolescent subjects aged 4 weeks to <18 years and weighing at least 3 kg were treated with TIVICAY or TIVICAY PD plus optimized background therapy [see <b>ADVERSE REACTIONS</b>, <b>CLINICAL PHARMACOLOGY</b>, <b>Clinical Studies</b>].</li> <li>Additional pharmacokinetics data were evaluated in 2 pharmacokinetic substudies in ODYSSEY, an ongoing open-label, randomized, non-inferiority trial to evaluate the safety, efficacy, and pharmacokinetic parameters of TIVICAY or TIVICAY PD plus two NRTIs (mainly abacavir and lamivudine) compared with <a href="/standard_of_care/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">standard of care</a> in HIV-1–infected pediatric subjects younger than 18 years [see <b>CLINICAL PHARMACOLOGY</b>].</li> </ul> <p>Overall, the safety, and efficacy profile of TRIUMEQ and TRIUMEQ PD in pediatric patients is comparable to that observed in adults. There are no data available on the use of lamivudine in pediatric patients with renal impairment [see <b>WARNINGS AND PRECAUTIONS</b>, <b>ADVERSE REACTIONS</b>, <b>Patients With Impaired Renal Function</b>, <b>CLINICAL PHARMACOLOGY</b>, <b>Clinical Studies</b>].</p> <p>Safety and effectiveness of TRIUMEQ PD have not been established in pediatric patients weighing <10 kg.</p> <h4>Geriatric Use</h4> <p>Clinical trials of abacavir, dolutegravir, or lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TRIUMEQ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see <b>CLINICAL PHARMACOLOGY</b>].</p> <h4>Patients With Impaired Renal Function</h4> <p>TRIUMEQ and TRIUMEQ PD are not recommended for patients with creatinine clearance <30 mL/min because TRIUMEQ and TRIUMEQ PD are fixed-dose combinations and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of TRIUMEQ and TRIUMEQ PD, is required for patients with creatinine clearance <30 mL/min, then the individual components should be used [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p>Patients with a creatinine clearance between 30 and 49 mL/min receiving TRIUMEQ may experience a 1.6- to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL/min. There are no safety data from randomized, controlled trials comparing TRIUMEQ to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. Additionally, there are no data available on the use of lamivudine in pediatric patients with renal impairment. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of hematologic toxicities (neutropenia and anemia), although discontinuations due to neutropenia or anemia each occurred in <1% of subjects.</p> <p>Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive TRIUMEQ or TRIUMEQ PD should be monitored for hematologic toxicities. If new or worsening neutropenia or anemia develop, dose adjustment of lamivudine, per lamivudine prescribing information, is recommended. If lamivudine dose adjustment is indicated, TRIUMEQ or TRIUMEQ PD should be discontinued and the individual components should be used to construct the treatment regimen.</p> <h4>Patients With Impaired Hepatic Function</h4> <p>TRIUMEQ and TRIUMEQ PD are fixed-dose combinations and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of TRIUMEQ and TRIUMEQ PD, is required for patients with mild hepatic impairment (Child-Pugh Score A), then the individual components should be used [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p>The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Score B) or severe (Child-Pugh Score C) hepatic impairment; therefore, TRIUMEQ and TRIUMEQ PD are contraindicated in these patients [see <b>CONTRAINDICATIONS</b>].</p> </div> </div> </div> | <a name="W"></a> <h3>WARNINGS</h3> <p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a> <h3>PRECAUTIONS</h3> <h4>Hypersensitivity Reactions</h4> <p>Hypersensitivity reactions have been reported with the use of abacavir or dolutegravir, components of TRIUMEQ and TRIUMEQ PD.</p> <h5>Abacavir</h5> <p>Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing regimens. See full prescribing information for ZIAGEN (abacavir).</p> <p>Abacavir hypersensitivity reactions have included multi-<a href="/organ_failure/definition.htm" ">organ failure</a> and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see <b>ADVERSE REACTIONS</b>]. Patients who carry the <a href="/hla/definition.htm" ">HLA</a>-B*5701 <a href="/allele/definition.htm" ">allele</a> are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA-B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.</p> <p>Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir:</p> <ul> <li>All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with TRIUMEQ or TRIUMEQ PD or reinitiation of therapy with TRIUMEQ or TRIUMEQ PD, unless patients have a previously documented HLA-B*5701 allele assessment.</li> <li>TRIUMEQ and TRIUMEQ PD are contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients.</li> <li>Before starting TRIUMEQ or TRIUMEQ PD, review <a href="/medical_history/definition.htm" ">medical history</a> for prior exposure to any abacavir-containing product. NEVER restart TRIUMEQ or TRIUMEQ PD or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status.</li> <li>To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue TRIUMEQ or TRIUMEQ PD immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as <a href="/pneumonia_facts/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">pneumonia</a>, <a href="/bronchitis/definition.htm" ">bronchitis</a>, <a href="/pharyngitis/definition.htm" ">pharyngitis</a>, or <a href="/influenza/definition.htm" ">influenza</a>; <a href="/gastroenteritis/definition.htm" ">gastroenteritis</a>; or reactions to other medications). Clinical status, including liver chemistries, should be monitored and appropriate therapy initiated.</li> <li>If a hypersensitivity reaction cannot be ruled out, do not restart TRIUMEQ or TRIUMEQ PD or any other abacavir-containing products because more severe symptoms, which may include life-threatening <a href="/hypotension/definition.htm" ">hypotension</a> and death, can occur within hours.</li> <li>Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ or TRIUMEQ PD would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or TRIUMEQ PD or any other abacavir- or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ or TRIUMEQ PD due to a hypersensitivity reaction.</li> <li>If a hypersensitivity reaction is ruled out, patients may restart TRIUMEQ or TRIUMEQ PD. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of TRIUMEQ or TRIUMEQ PD, or any other abacavir-containing product, is recommended only if medical care can be readily accessed.</li> <li>A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill.</li> </ul> <h5>Dolutegravir</h5> <p>Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in <1% of subjects receiving TIVICAY in Phase 3 clinical trials. Discontinue TRIUMEQ or TRIUMEQ PD and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general <a href="/malaise/definition.htm" ">malaise</a>, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, <a href="/conjunctivitis/definition.htm" ">conjunctivitis</a>, facial edema, hepatitis, <a href="/eosinophilia/definition.htm" ">eosinophilia</a>, <a href="/angioedema/definition.htm" ">angioedema</a>, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with TRIUMEQ or TRIUMEQ PD or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction.</p> <p>Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ or TRIUMEQ PD would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or TRIUMEQ PD or any other abacavir- or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ or TRIUMEQ PD due to a hypersensitivity reaction.</p> <h4>Patients Co-Infected With HIV-1 And HBV: Emergence Of Lamivudine-Resistant HBV And The Risk Of Posttreatment Exacerbations Of HBV</h4> <p>All patients with HIV-1 should be tested for the presence of <a href="/hbv/definition.htm" ">HBV</a> prior to or when initiating TRIUMEQ or TRIUMEQ PD.</p> <h5>Emergence Of Lamivudine Resistant HBV</h5> <p>Safety and efficacy of lamivudine have not been established for treatment of chronic HBV in subjects dually infected with HIV-1 and HBV. Emergence of HBV variants associated with resistance to lamivudine has been reported in HIV-1−infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with HBV. If a decision is made to administer TRIUMEQ or TRIUMEQ PD to patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen.</p> <h5>Severe Acute Exacerbations Of HBV In Patients Co-Infected With HIV-1 And HBV</h5> <p>Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued products containing lamivudine, and may occur with discontinuation of TRIUMEQ or TRIUMEQ PD. Patients who are co-infected with HIV-1 and HBV who discontinue TRIUMEQ or TRIUMEQ PD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with TRIUMEQ or TRIUMEQ PD. If appropriate, initiation of anti-HBV therapy may be warranted, especially in patients with advanced <a href="/liver_disease/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">liver disease</a> or <a href="/cirrhosis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">cirrhosis</a>, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.</p> <h4>Hepatotoxicity</h4> <p>Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen [see <b>ADVERSE REACTIONS</b>]. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TRIUMEQ or TRIUMEQ PD [see <b>ADVERSE REACTIONS</b>]. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure, have also been reported in patients, including pediatric patients receiving a dolutegravir-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ. Monitoring for hepatotoxicity is recommended.</p> <h4>Lactic Acidosis And Severe Hepatomegaly With Steatosis</h4> <p><a href="/lactic_acidosis/definition.htm" ">Lactic acidosis</a> and severe <a href="/hepatomegaly/definition.htm" ">hepatomegaly</a> with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir and lamivudine (components of TRIUMEQ and TRIUMEQ PD). A majority of these cases have been in women. Female sex and <a href="/obesity/definition.htm" ">obesity</a> may be risk factors for the development of lactic <a href="/acidosis/definition.htm" ">acidosis</a> and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Treatment with TRIUMEQ or TRIUMEQ PD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.</p> <h4>Embryo-Fetal Toxicity</h4> <p>An ongoing observational study showed an association between dolutegravir and an increased risk of <a href="/neural/definition.htm" ">neural</a> tube defects when dolutegravir was administered at the time of <a href="/conception/definition.htm" ">conception</a> and in early pregnancy. As there is limited understanding of the association of reported types of neural tube defects with dolutegravir use, inform adolescents and adults of childbearing potential, including those actively trying to become pregnant, about the potential increased risk of neural tube defects with TRIUMEQ. Assess the risks and benefits of TRIUMEQ and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester [see <b>Use In Specific Populations</b>].</p> <p>Pregnancy testing is recommended before initiation of TRIUMEQ in adolescents and adults of childbearing potential [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>Adolescents and adults of childbearing potential should be counseled on the consistent use of effective contraception [see <b>Use In Specific Populations</b>].</p> <p>TRIUMEQ may be considered during the second and third trimesters of pregnancy if the expected benefit justifies the potential risk to the pregnant woman and the fetus.</p> <h4>Risk Of Adverse Reactions Or Loss Of Virologic Response Due To Drug Interactions</h4> <p>The concomitant use of TRIUMEQ or TRIUMEQ PD and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see <b>CONTRAINDICATIONS</b>, <b>DRUG INTERACTIONS</b>]:</p> <ul> <li>Loss of therapeutic effect of TRIUMEQ or TRIUMEQ PD and possible development of resistance.</li> <li>Possible clinically significant adverse reactions from greater exposures of concomitant drugs.</li> </ul> <p>See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TRIUMEQ or TRIUMEQ PD, review concomitant medications during therapy with TRIUMEQ or TRIUMEQ PD, and monitor for the adverse reactions associated with the concomitant drugs.</p> <h4>Immune Reconstitution Syndrome</h4> <p>Immune reconstitution syndrome has been reported in patients treated with combination <a href="/antiretroviral_therapy_art/definition.htm" ">antiretroviral therapy</a>, including TRIUMEQ or TRIUMEQ PD. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an <a href="/inflammatory_response/definition.htm" ">inflammatory response</a> to indolent or <a href="/residual/definition.htm" ">residual</a> opportunistic infections (such as <i>Mycobacterium avium</i> infection, <a href="/cytomegalovirus_cmv/definition.htm" ">cytomegalovirus</a>, <i>Pneumocystis jirovecii</i> pneumonia [<a href="/pcp/definition.htm" ">PCP</a>], or <a href="/tuberculosis_tb_facts/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">tuberculosis</a>), which may necessitate further evaluation and treatment.</p> <p><a href="/autoimmune/definition.htm" ">Autoimmune</a> disorders (such as Graves’ disease, <a href="/polymyositis/definition.htm" ">polymyositis</a>, Guillain-Barré syndrome, <a href="/autoimmune_hepatitis/definition.htm" ">autoimmune hepatitis</a>) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.</p> <h4>Different Formulations Are Not Interchangeable</h4> <p>TRIUMEQ and TRIUMEQ PD are not bioequivalent and are not interchangeable on a <a href="/milligram/definition.htm" ">milligram</a>-per-milligram basis [see <b>CLINICAL PHARMACOLOGY</b>]. If a pediatric patient switches from the tablets for oral suspension to the tablets, the dosage must be adjusted [see <b>DOSAGE AND ADMINISTRATION</b>]. Incorrect dosing of a given formulation may result in underdosing and loss of therapeutic effect and possible development of resistance or possible clinically significant adverse reactions from greater exposure to the individual components.</p> <h4>Myocardial Infarction</h4> <p>Several <a href="/prospective/definition.htm" ">prospective</a>, observational, epidemiological studies have reported an association with the use of abacavir and the risk of <a href="/myocardial_infarction/definition.htm" ">myocardial infarction</a> (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir-treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir and the risk of MI is inconclusive.</p> <p>As a precaution, the underlying risk of coronary <a href="/heart_disease/definition.htm" ">heart disease</a> should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., <a href="/hypertension/definition.htm" ">hypertension</a>, <a href="/hyperlipidemia/definition.htm" ">hyperlipidemia</a>, <a href="/diabetes_mellitus/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">diabetes</a> mellitus, <a href="/smoking_and_quitting_smoking/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">smoking</a>).</p> <h4>Patient Counseling Information</h4> <p>Advise the patient to read the FDA-approved patient labeling (<b>PATIENT INFORMATION</b> and <b>Instructions for Use</b>).</p> <h5>Drug Interactions</h5> <p>TRIUMEQ or TRIUMEQ PD may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John’s wort [see <b>CONTRAINDICATIONS</b>, <b>WARNINGS AND PRECAUTIONS</b>, <b>DRUG INTERACTIONS</b>].</p> <h5>Hypersensitivity Reaction</h5> <p><i>Inform Patients</i></p> <ul> <li>that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of TRIUMEQ or TRIUMEQ PD, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about TRIUMEQ or TRIUMEQ PD. The complete text of the <b>Medication Guide</b> is reprinted at the end of this document.</li> <li>to carry the Warning Card with them.</li> <li>how to identify a hypersensitivity reaction [see <b>WARNINGS AND PRECAUTIONS</b>,<b>PATIENT INFORMATION</b>].</li> <li>that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking TRIUMEQ or TRIUMEQ PD.</li> <li>that a hypersensitivity reaction can worsen and lead to hospitalization or death if TRIUMEQ or TRIUMEQ PD is not immediately discontinued.</li> <li>to not restart TRIUMEQ or TRIUMEQ PD or any other abacavir-containing product following a hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.</li> <li>that if they have a hypersensitivity reaction, they should dispose of any unused TRIUMEQ or TRIUMEQ PD to avoid restarting abacavir.</li> <li>that a hypersensitivity reaction is usually reversible if it is detected promptly and TRIUMEQ or TRIUMEQ PD is stopped right away.</li> <li>that if they have interrupted TRIUMEQ or TRIUMEQ PD for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), a serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.</li> <li>to not restart TRIUMEQ or TRIUMEQ PD or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.</li> <li>to not restart TRIUMEQ or TRIUMEQ PD or any other dolutegravir-containing product following a hypersensitivity reaction to TRIUMEQ or TRIUMEQ PD.</li> </ul> <h5>Hepatotoxicity</h5> <p>Inform patients that hepatotoxicity has been reported with dolutegravir, a component of TRIUMEQ and TRIUMEQ PD [see <b>WARNINGS AND PRECAUTIONS</b>, <b>ADVERSE REACTIONS</b>]. Inform patients that monitoring for hepatotoxicity during therapy with TRIUMEQ or TRIUMEQ PD is recommended.</p> <h5>Severe Acute Exacerbations Of Hepatitis In Patients With HBV Co-Infection</h5> <p>Advise all patients with HIV-1 to be tested for the presence of HBV prior to or when initiating TRIUMEQ or TRIUMEQ PD. Advise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their physician [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Lactic Acidosis/Hepatomegaly</h5> <p>Inform patients that some HIV medicines, including TRIUMEQ and TRIUMEQ PD, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see <b>BOX WARNING</b>, <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Embryo-Fetal Toxicity</h5> <p>Advise adolescents and adults of childbearing potential, including those actively trying to become pregnant, to discuss the risks and benefits of TRIUMEQ with their healthcare provider to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy. If pregnancy is confirmed in the first trimester, advise patients to contact their healthcare provider [see <b>WARNINGS AND PRECAUTIONS</b> and <b>Use In Specific Populations</b>].</p> <p>Adolescents and adults of childbearing potential taking TRIUMEQ should be counseled on the consistent use of effective contraception [see <b>WARNINGS AND PRECAUTIONS</b>, <b>Use In Specific Populations</b>].</p> <h5>Immune Reconstitution Syndrome</h5> <p>Advise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when TRIUMEQ or TRIUMEQ PD is started [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>TRIUMEQ Tablets and TRIUMEQ PD Tablets for Oral Suspension <u>Are Not Bioequivalent</u> Advise patients that TRIUMEQ and TRIUMEQ PD are not bioequivalent and are not interchangeable on a milligram-per-milligram basis. Advise patients or their care provider that patients switching from the tablets for oral suspension to the tablets must adjust the dose [see <b>DOSAGE AND ADMINISTRATION</b> and <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Pregnancy Registry</h5> <p>Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to TRIUMEQ during pregnancy [see <b>Use In Specific Populations</b>].</p> <h5>Lactation</h5> <p>Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see <b>Use In Specific Populations</b>].</p> <h5>Administration Instructions</h5> <p>To avoid a dosing error from using the wrong formulation of TRIUMEQ, strongly advise patients and caregivers to visually inspect the tablets to verify the correct formulation each time the prescription is filled [see <b>DOSAGE AND ADMINISTRATION</b>, <b>WARNINGS AND PRECAUTIONS</b>, <b>HOW SUPPLIED</b>].</p> <p>Inform patients and caregivers that TRIUMEQ PD tablets for oral suspension should be dispersed in drinking water and should not be chewed, cut or crushed [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>Instruct patients and caregivers that if a dose of TRIUMEQ or TRIUMEQ PD is missed, to take it as soon as they remember. Advise patients and caregivers not to double the next dose or take more than the prescribed dose [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <h5>Availability Of Medication Guide</h5> <p>Instruct patients and caregivers to read the Medication Guide before starting TRIUMEQ or TRIUMEQ PD and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.</p> <h5>Storage</h5> <p>Instruct patients and caregivers to store TRIUMEQ and TRIUMEQ PD tablets for oral suspension in the original package, protect from moisture, and keep the bottle tightly closed. Do not remove desiccant.</p> <p>EPIVIR, EPZICOM, TIVICAY, TIVICAY PD, TRIUMEQ, TRIUMEQ PD, and ZIAGEN are trademarks owned by or licensed to the ViiV Healthcare group of companies.</p> <p>EPIVIR-HBV is a trademark owned by or licensed to the GSK group of companies.</p> <p>The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.</p> <h4>Nonclinical Toxicology</h4> <h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4> <h5>Carcinogenicity</h5> <p><i>Dolutegravir</i></p> <p>Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg/kg, and rats were administered doses of up to 50 mg/kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 26-fold higher than those in humans at the recommended dose of 50 mg once daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 17-fold and 30-fold higher in males and females, respectively, than those in humans at the recommended dose of 50 mg once daily. Abacavir: Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of <a href="/malignant/definition.htm" ">malignant</a> and non-malignant tumors. Malignant tumors occurred in the preputial <a href="/gland/definition.htm" ">gland</a> of males and the <a href="/clitoral/definition.htm" ">clitoral</a> gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and <a href="/thyroid_gland/definition.htm" ">thyroid gland</a> of female rats. These observations were made at systemic exposures in the range of 7 to 28 times the human exposure at the recommended dose of 600 mg.</p> <p><i>Lamivudine</i></p> <p>Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of <a href="/carcinogenic/definition.htm" ">carcinogenic</a> potential at exposures up to 12 times (mice) and 57 times (rats) the human exposures at the recommended dose of 300 mg.</p> <h5>Mutagenicity</h5> <p><i>Dolutegravir</i></p> <p>Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse <a href="/lymphoma/definition.htm" ">lymphoma</a> assay, or in the <i>in vivo</i> rodent micronucleus assay.</p> <p><i>Abacavir</i></p> <p>Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an <i>in vitro</i> cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an <i>in vivo</i> mouse <a href="/bone_marrow/definition.htm" ">bone marrow</a> micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.</p> <p><i>Lamivudine</i></p> <p>Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an <i>in vitro</i> cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.</p> <h5>Impairment Of Fertility</h5> <p>Dolutegravir, abacavir, or lamivudine did not affect male or female fertility in rats at doses associated with exposures approximately 44, 9, or 112 times (respectively) higher than the exposures in humans at the doses of 50 mg, 600 mg, and 300 mg (respectively).</p> <a name="USP"></a> <h4>Use In Specific Populations</h4> <h4>Pregnancy</h4> <h5>Pregnancy Exposure Registry</h5> <p>There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TRIUMEQ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.</p> <h5>Risk Summary</h5> <p>Data from an ongoing birth outcome surveillance study has identified an increased risk of neural tube defects when dolutegravir, a component of TRIUMEQ, is administered at the time of conception. As defects related to closure of the neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of gestation are at potential risk.</p> <p>Advise adolescents and adults of childbearing potential, including those actively trying to become pregnant, of the potential risk of neural tube defects with use of TRIUMEQ. Assess the risks and benefits of TRIUMEQ and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester. A benefit-risk assessment should consider factors such as feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in utero dolutegravir exposure during critical periods of fetal development [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>There are insufficient human data on the use of TRIUMEQ during pregnancy to definitively assess a drug-associated risk for <a href="/birth_defects/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">birth defects</a> and <a href="/miscarriage_causes_and_symptoms/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">miscarriage</a>. The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.</p> <p>In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and approximately 50 times (rats) the exposure in humans at the recommended human dose (RHD) (see <b>Data</b>). Oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the RHD. No adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis at exposures approximately 9 times the human exposure (AUC) at the RHD. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at a human exposure (AUC) similar to the RHD; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the RHD (see <b>Data</b>).</p> <h5>Data</h5> <p><i>Human Data</i></p> <p><i>Dolutegravir</i></p> <p>In a birth outcome surveillance study in Botswana, there were 7 cases of neural tube defects reported out of 3,591 deliveries (0.19%) to women who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the <a href="/neural_tube_defect/definition.htm" ">neural tube defect</a> <a href="/prevalence/definition.htm" ">prevalence</a> rates were 0.11% (21/19,361 deliveries) in the non-dolutegravir arm and 0.07% (87/119,630 deliveries) in the HIV-uninfected arm. Seven cases reported with dolutegravir included 3 cases of myelomeningocele, 2 cases of encephalocele, and one case each of <a href="/anencephaly/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anencephaly</a> and <a href="/iniencephaly/definition.htm" ">iniencephaly</a>. In the same study, no increased risk of neural tube defects was identified in women who started dolutegravir during pregnancy. Two infants out of 4,448 (0.04%) deliveries to women who started dolutegravir during pregnancy had a neural tube defect, compared with 5 infants out of 6,748 (0.07%) deliveries to women who started non-dolutegravircontaining regimens during pregnancy. The reported risks of neural tube defects by treatment groups were based on interim analyses from the ongoing surveillance study in Botswana. It is unknown if baseline characteristics were balanced between the study treatment groups. The observed trends of association could change as data accumulate.</p> <p>Data analyzed to date from other sources including the APR, clinical trials, and postmarketing data are insufficient to definitively address the risk of neural tube defects with dolutegravir. Data from the birth outcome surveillance study described above and postmarketing sources with more than 1,000 pregnancy outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes.</p> <p>Based on prospective reports to the APR of over 1,000 exposures to dolutegravir during pregnancy resulting in live births (including 634 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 2.1% to 5.0%) following first-trimester exposure to dolutegravir-containing regimens and 5.1% (95% CI: 3.2% to 7.7%) following second-/thirdtrimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta <a href="/congenital/definition.htm" ">Congenital</a> Defects Program (MACDP), the background <a href="/birth_defect/definition.htm" ">birth defect</a> rate was 2.7%.</p> <p><i>Abacavir</i></p> <p>Based on prospective reports to the APR of over 2,700 exposures to abacavir during pregnancy resulting in live births (including 1,391 exposed in the first trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.3% to 4.2%) following first trimester exposure to abacavir-containing regimens and 3.0% (95% CI: 2.1% to 4.0%) following second/third trimester exposure to abacavir-containing regimens.</p> <p>Abacavir has been shown to cross the placenta and concentrations in <a href="/neonatal/definition.htm" ">neonatal</a> plasma at birth were essentially equal to those in maternal plasma at delivery [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p><i>Lamivudine</i></p> <p>Based on prospective reports to the APR of over 12,900 exposures to lamivudine during pregnancy resulting in live births (including 5,472 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5%, 3.3%) following second/third trimester exposure to lamivudine-containing regimens.</p> <p>Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and <a href="/umbilical_cord/definition.htm" ">umbilical cord</a> serum samples. In a subset of subjects, <a href="/amniotic_fluid/definition.htm" ">amniotic fluid</a> specimens were collected following natural <a href="/rupture/definition.htm" ">rupture</a> of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9-fold (1.2- to 12.8-fold) greater compared with paired maternal serum concentration (n = 8).</p> <p><i>Animal Data</i></p> <p><i>Dolutegravir</i></p> <p>Dolutegravir was administered orally to pregnant rats and rabbits (up to 1,000 mg/kg/day) on Gestation Days 6 to 17 and 6 to 18, respectively, and to rats on Gestation Day 6 to lactation/post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed up to the highest dose tested. During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the RHD and in rats were approximately 50 times the exposure in humans at the RHD. In the rat pre/post-natal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 50 times human exposure at the RHD).</p> <p><i>Abacavir</i></p> <p>Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg/kg/day) and rabbits (at 125, 350, or 700 mg/kg/day) during organogenesis (on Gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal <a href="/anasarca/definition.htm" ">anasarca</a> and skeletal malformations) or developmental toxicity (decreased fetal body weight and <a href="/crown/definition.htm" ">crown</a>-rump length) were observed in rats at doses up to 1,000 mg/kg/day, resulting in exposures approximately 35 times the human exposure (AUC) at the RHD. No developmental effects were observed in rats at 100 mg/kg/day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryofetal development study conducted in rats (at 60, 160, or 500 mg/kg/day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg/kg/day. No developmental effects were observed in rats at 60 mg/kg/day, resulting in exposures (AUC) approximately 4 times the human exposure at the RHD. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the RHD.</p> <p><i>Lamivudine</i></p> <p>Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg/kg/day) and rabbits (at 90, 300 and 1,000 mg/kg/day and at 15, 40, and 90 mg/kg/day) during organogenesis (on Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre- and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg/kg/day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, were not affected by the maternal administration of lamivudine.</p> <h4>Lactation</h4> <h5>Risk Summary</h5> <p>The <a href="/centers_for_disease_control_and_prevention/definition.htm" ">Centers for Disease Control and Prevention</a> recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.</p> <p>Abacavir and lamivudine are present in human milk. When administered to lactating rats, dolutegravir was present in milk (see <b>Data</b>). There is no information on the effects of TRIUMEQ or its components on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving TRIUMEQ.</p> <h5>Data</h5> <p><i>Animal Data</i></p> <p>Dolutegravir was the primary drug-related component excreted into the milk of lactating rats following a single oral dose of 50 mg/kg/day on Lactation Day 10, with milk concentrations of up to approximately 1.3 times that of maternal plasma concentrations observed 8 hours postdose.</p> <h4>Females And Males Of Reproductive Potential</h4> <p>In adolescents and adults of childbearing potential currently on TRIUMEQ who are actively trying to become pregnant or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing TRIUMEQ and discuss with the patient if an alternative treatment should be considered [see <b>WARNINGS AND PRECAUTIONS</b>, <b>Pregnancy</b>].</p> <h5>Pregnancy Testing</h5> <p>Pregnancy testing is recommended in adolescents and adults of childbearing potential before initiation of TRIUMEQ [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <h5>Contraception</h5> <p>Adolescents and adults of childbearing potential who are taking TRIUMEQ should be counseled on the consistent use of effective contraception.</p> <h4>Pediatric Use</h4> <p>The clinical data supporting use of TRIUMEQ and TRIUMEQ PD in pediatric patients with HIV-1 infection weighing at least 10 kg is derived from the following previously conducted pediatric trials using the individual components of TRIUMEQ and TRIUMEQ PD:</p> <ul> <li>The safety and efficacy of once-daily abacavir and lamivudine were established with a randomized, multicenter trial (ARROW [COL105677]) in HIV-1–infected, treatment- naive subjects aged 3 months to 17 years with a first-line regimen containing abacavir and lamivudine, using either the combination of EPIVIR and ZIAGEN or EPZICOM [see <b>ADVERSE REACTIONS</b>, <b>Clinical Studies</b>].</li> <li>The safety, pharmacokinetics, and <a href="/antiviral/definition.htm" ">antiviral</a> activity (efficacy) of TIVICAY and TIVICAY PD were established through an ongoing, open-label, multicenter, dose-finding clinical trial (IMPAACT P1093), in which HIV-1–infected, treatment-naive or treatment-experienced, INSTI-naive, pediatric and adolescent subjects aged 4 weeks to <18 years and weighing at least 3 kg were treated with TIVICAY or TIVICAY PD plus optimized background therapy [see <b>ADVERSE REACTIONS</b>, <b>CLINICAL PHARMACOLOGY</b>, <b>Clinical Studies</b>].</li> <li>Additional pharmacokinetics data were evaluated in 2 pharmacokinetic substudies in ODYSSEY, an ongoing open-label, randomized, non-inferiority trial to evaluate the safety, efficacy, and pharmacokinetic parameters of TIVICAY or TIVICAY PD plus two NRTIs (mainly abacavir and lamivudine) compared with <a href="/standard_of_care/definition.htm" ">standard of care</a> in HIV-1–infected pediatric subjects younger than 18 years [see <b>CLINICAL PHARMACOLOGY</b>].</li> </ul> <p>Overall, the safety, and efficacy profile of TRIUMEQ and TRIUMEQ PD in pediatric patients is comparable to that observed in adults. There are no data available on the use of lamivudine in pediatric patients with renal impairment [see <b>WARNINGS AND PRECAUTIONS</b>, <b>ADVERSE REACTIONS</b>, <b>Patients With Impaired Renal Function</b>, <b>CLINICAL PHARMACOLOGY</b>, <b>Clinical Studies</b>].</p> <p>Safety and effectiveness of TRIUMEQ PD have not been established in pediatric patients weighing <10 kg.</p> <h4>Geriatric Use</h4> <p>Clinical trials of abacavir, dolutegravir, or lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TRIUMEQ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see <b>CLINICAL PHARMACOLOGY</b>].</p> <h4>Patients With Impaired Renal Function</h4> <p>TRIUMEQ and TRIUMEQ PD are not recommended for patients with creatinine clearance <30 mL/min because TRIUMEQ and TRIUMEQ PD are fixed-dose combinations and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of TRIUMEQ and TRIUMEQ PD, is required for patients with creatinine clearance <30 mL/min, then the individual components should be used [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p>Patients with a creatinine clearance between 30 and 49 mL/min receiving TRIUMEQ may experience a 1.6- to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL/min. There are no safety data from randomized, controlled trials comparing TRIUMEQ to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. Additionally, there are no data available on the use of lamivudine in pediatric patients with renal impairment. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of hematologic toxicities (neutropenia and anemia), although discontinuations due to neutropenia or anemia each occurred in <1% of subjects.</p> <p>Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive TRIUMEQ or TRIUMEQ PD should be monitored for hematologic toxicities. If new or worsening neutropenia or anemia develop, dose adjustment of lamivudine, per lamivudine prescribing information, is recommended. If lamivudine dose adjustment is indicated, TRIUMEQ or TRIUMEQ PD should be discontinued and the individual components should be used to construct the treatment regimen.</p> <h4>Patients With Impaired Hepatic Function</h4> <p>TRIUMEQ and TRIUMEQ PD are fixed-dose combinations and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of TRIUMEQ and TRIUMEQ PD, is required for patients with mild hepatic impairment (Child-Pugh Score A), then the individual components should be used [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p>The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Score B) or severe (Child-Pugh Score C) hepatic impairment; therefore, TRIUMEQ and TRIUMEQ PD are contraindicated in these patients [see <b>CONTRAINDICATIONS</b>].</p> </div> </div> </div> | 6 | 2023-02-01 17:38:35 | Abacavir, Dolutegravir, and Lamivudine Film-coated Tablets (Triumeq) | A | HIV, ART Combos | Triumeq | abacavir, dolutegravir, and lamivudine film-coated tablets | Triumeq | John P. Cunha, DO, FACOEP |
| 46 | 2023-02-23 12:07:03 | Overdose & Contraindications | <a name="OD"></a> <h3>OVERDOSE</h3> <p>There is no known specific treatment for overdose with TRIUMEQ or TRIUMEQ PD. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.</p> <h4>Dolutegravir</h4> <p>As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by <a href="/dialysis/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">dialysis</a>.</p> <h4>Abacavir</h4> <p>It is not known whether abacavir can be removed by <a href="/peritoneal_dialysis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">peritoneal dialysis</a> or <a href="/hemodialysis/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">hemodialysis</a>.</p> <h4>Lamivudine</h4> <p>Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory <a href="/peritoneal/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">peritoneal</a> dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.</p> <a name="CI"></a> <h3>CONTRAINDICATIONS</h3> <p>TRIUMEQ and TRIUMEQ PD are contraindicated in patients:</p> <ul> <li>who have the HLA-B*5701 allele [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>with prior hypersensitivity reaction to abacavir, dolutegravir [see <b>WARNINGS AND PRECAUTIONS</b>], or lamivudine.</li> <li>receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events with concomitant use of dolutegravir [see <b>DRUG INTERACTIONS</b>].</li> <li>with moderate or severe hepatic impairment [see <b>Use In Specific Populations</b>].</li> </ul> </div> </div> </div> | <a name="OD"></a> <h3>OVERDOSE</h3> <p>There is no known specific treatment for overdose with TRIUMEQ or TRIUMEQ PD. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required.</p> <h4>Dolutegravir</h4> <p>As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by <a href="/dialysis/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">dialysis</a>.</p> <h4>Abacavir</h4> <p>It is not known whether abacavir can be removed by <a href="/peritoneal_dialysis/definition.htm" ">peritoneal dialysis</a> or <a href="/hemodialysis/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">hemodialysis</a>.</p> <h4>Lamivudine</h4> <p>Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory <a href="/peritoneal/definition.htm" ">peritoneal</a> dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.</p> <a name="CI"></a> <h3>CONTRAINDICATIONS</h3> <p>TRIUMEQ and TRIUMEQ PD are contraindicated in patients:</p> <ul> <li>who have the HLA-B*5701 allele [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>with prior hypersensitivity reaction to abacavir, dolutegravir [see <b>WARNINGS AND PRECAUTIONS</b>], or lamivudine.</li> <li>receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events with concomitant use of dolutegravir [see <b>DRUG INTERACTIONS</b>].</li> <li>with moderate or severe hepatic impairment [see <b>Use In Specific Populations</b>].</li> </ul> </div> </div> </div> | 6 | 2023-02-01 17:38:35 | Abacavir, Dolutegravir, and Lamivudine Film-coated Tablets (Triumeq) | A | HIV, ART Combos | Triumeq | abacavir, dolutegravir, and lamivudine film-coated tablets | Triumeq | John P. Cunha, DO, FACOEP |
| 47 | 2023-02-23 12:07:03 | Clinical Pharmacology | <a name="CP"></a> <h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism Of Action</h4> <p>TRIUMEQ and TRIUMEQ PD are a fixed-dose combination of the HIV-1 antiretroviral agents abacavir, dolutegravir, and lamivudine [see <b>Microbiology</b>].</p> <h4>Pharmacodynamics</h4> <h5>Effects On Electrocardiogram</h5> <p>A thorough QT trial has been conducted for dolutegravir. Neither the effects of abacavir nor lamivudine as single entities or the combination of abacavir, dolutegravir, and lamivudine on the QT interval have been evaluated.</p> <p>In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3– fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours postdose.</p> <h5>Effects On Renal Function</h5> <p>The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of <a href="/probe/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">probe</a> drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, <a href="/para/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">para</a>-amino hippurate) compared with the placebo.</p> <h4>Pharmacokinetics</h4> <h5>Pharmacokinetics In Adults</h5> <p>One TRIUMEQ tablet was bioequivalent to one dolutegravir (TIVICAY) tablet (50 mg) plus one abacavir and lamivudine fixed-dose combination tablet (EPZICOM) under fasted conditions in healthy subjects (n = 62).</p> <p>TRIUMEQ tablets and TRIUMEQ PD tablets for oral suspension are bioequivalent for the abacavir and lamivudine components, but not for the dolutegravir component. The relative dolutegravir bioavailability of TRIUMEQ PD is approximately 1.7-fold higher than TRIUMEQ; therefore, the 2 dosage forms are not interchangeable on a milligram-per-milligram basis [see <b>DOSAGE AND ADMINISTRATION</b>, <b>WARNINGS AND PRECAUTIONS</b>]. The relative dolutegravir bioavailability is expected to be similar between TRIUMEQ PD and TIVICAY PD.</p> <p><i>Abacavir</i></p> <p>Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 ± 1.19 mcg/mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg•hour/mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration.</p> <p>Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are <a href="/metabolism/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">metabolism</a> by alcohol dehydrogenase to form the 5′-carboxylic acid and glucuronyl transferase to form the 5′-glucuronide. In single-dose trials, the observed elimination half-life (t<sub>½</sub>) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ± 0.24 L/h/kg (mean ± SD).</p> <p><i>Dolutegravir</i></p> <p>Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C<sub>24</sub> h ranging from 1.2 to 1.5. Dolutegravir is a P-gp substrate <i>in vitro</i>. The absolute bioavailability of dolutegravir has not been established. Dolutegravir is highly bound (≥98.9%) to human plasma proteins based on <i>in vivo</i> data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis.</p> <p>Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After a single oral dose of [<sup>14</sup>C] dolutegravir, 53% of the total oral dose is excreted unchanged in the feces. Thirty-one percent of the total oral dose is excreted in the urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was <1% of the dose. Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L/h based on population pharmacokinetic analyses.</p> <p>The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV-1–infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV-1–infected subjects.</p> <p align="center"><b>Table 7. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1- Infected Adults </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Parameter</td> <td class="EmphTd" width="50%">50 mg Once Daily<br /> Geometric Mean (%CV)</td> </tr> <tr> <td>AUC(0-24) (mcg•h/mL)</td> <td align="center">53.6 (27)</td> </tr> <tr> <td>Cmax (mcg/mL)</td> <td align="center">3.67 (20)</td> </tr> <tr> <td>Cmin (mcg/mL)</td> <td align="center">1.11 (46)</td> </tr> </tbody> </table> </center> <p></p> <p><i>Cerebrospinal Fluid (CSF)</i></p> <p>In 11 treatment- naive subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in <a href="/csf_colony-stimulating_factor/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">CSF</a> was 18 ng/mL (range: 4 ng/mL to 23.2 ng/mL) 2 to 6 hours postdose after 2 weeks of treatment. The clinical relevance of this finding has not been established.</p> <p><i>Lamivudine</i></p> <p>Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state Cmax (Cmax,ss) was 2.04 ± 0.54 mcg/mL (mean ± SD) and the 24-hour steady-state AUC (AUC24, ss) was 8.87 ± 1.83 mcg•hour/mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the <a href="/trans-_prefix/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">trans-</a>sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). In most single-dose trials with plasma sampling up to 48 or 72 hours after dosing, the observed mean elimination half-life (t<sub>½</sub>) ranged from 13 to 19 hours. In HIV-1–infected subjects, total clearance was 398.5 ± 69.1 mL per min (mean ± SD).</p> <h5>Effect Of Food On Oral Absorption</h5> <p>TRIUMEQ or TRIUMEQ PD may be taken with or without food. Overall, when compared with fasted conditions, administration of TRIUMEQ to healthy adult subjects with a high-fat meal (53% fat, 869 calories) resulted in decreased Cmax for abacavir and increased Cmax and AUC for dolutegravir. Lamivudine exposures were not affected by food. With a high-fat meal, the Cmax of abacavir decreased 23% and the Cmax and AUC of dolutegravir increased 37% and 48%, respectively. When compared with fasted conditions, administration of TRIUMEQ PD to healthy adult subjects with a high-fat meal (50% fat, 917 calories) resulted in decreased Cmax for abacavir (55%), dolutegravir (29%) and lamivudine (36%). AUCs for all 3 components were not affected by food.</p> <h4>Specific Populations</h4> <h5>Patients With Renal Impairment</h5> <p>The pharmacokinetics for the individual components of TRIUMEQ and TRIUMEQ PD have been evaluated in patients with renal impairment (see the U.S. prescribing information for the individual abacavir, dolutegravir, and lamivudine components).</p> <h5>Patients With Hepatic Impairment</h5> <p>The pharmacokinetics for the individual components of TRIUMEQ and TRIUMEQ PD have been evaluated in patients with varying degrees of hepatic impairment (see the U.S. prescribing information for the individual abacavir, dolutegravir, and lamivudine components).</p> <h5>Pediatric Patients</h5> <p>The pharmacokinetics for the individual components of TRIUMEQ and TRIUMEQ PD (abacavir, dolutegravir, and lamivudine) have been evaluated in pediatric subjects.</p> <h5>Dolutegravir</h5> <p>The pharmacokinetics of dolutegravir were evaluated in the IMPAACT P1093 trial and in 2 weight-band–based pharmacokinetic substudies from the ODYSSEY trial [see <b>Use In Specific Populations</b>, <b>Clinical Studies</b>].</p> <p>Mean dolutegravir AUC0-24h and C<sub>24</sub>h in HIV-1–infected pediatric subjects weighing at least 10 kg were comparable to those in adults after 50 mg once daily or 50 mg twice daily. Mean Cmax is higher in <a href="/pediatrics/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pediatrics</a>, but the increase is not considered clinically significant as the safety profiles were similar in pediatric and adult subjects [see <b>ADVERSE REACTIONS</b>]. Refer to the prescribing information for TIVICAY for pharmacokinetic information on dolutegravir in pediatric patients.</p> <h5>Abacavir And Lamivudine</h5> <p>In pediatric patients weighing 25 kg and above, the dosing recommendations for TRIUMEQ in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or EPZICOM.</p> <p>In pediatric patients weighing 10 to <25 kg, predicted exposures (AUC0-24h) of abacavir and lamivudine at the recommended doses for TRIUMEQ PD are within the observed exposure ranges at the recommended doses of individual products in adults and pediatrics.</p> <p>Refer to the prescribing information for EPIVIR and ZIAGEN for pharmacokinetic information on the individual products in pediatric patients [see <b>DOSAGE AND ADMINISTRATION</b>, <b>Clinical Studies</b>].</p> <h5>Geriatric Patients</h5> <p>Population analyses using pooled pharmacokinetic data from adult trials indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir. The pharmacokinetics of abacavir or lamivudine have not been studied in subjects older than 65 years.</p> <h5>Male And Female Patients</h5> <p>There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components.</p> <h5>Racial Groups</h5> <p>There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components.</p> <h4>Drug Interaction Studies</h4> <p>The drug interaction trials described were conducted with dolutegravir, abacavir, and/or lamivudine as single entities; no drug interaction trials have been conducted using the combination of abacavir, dolutegravir, and lamivudine. No clinically significant drug interactions are expected between dolutegravir, abacavir, and lamivudine.</p> <p>Dosing recommendations as a result of established and other potentially significant drug-drug interactions with the individual components of TRIUMEQ and TRIUMEQ PD are provided in Section 7.3 [see <b>DRUG INTERACTIONS</b>].</p> <p align="center"><b>Table 8. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs </b></p> <center> <table cellspacing="0" class="blacktbl" width="650"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="20%">Coadministered Drug(s) and Dose(s)</td> <td class="EmphTd" rowspan="2" width="20%">Dose of Dolutegravir</td> <td class="EmphTd" rowspan="2" width="9%">n</td> <td class="EmphTd" colspan="3" height="119">Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir<br /> No Effect = 1.00</td> </tr> <tr> <td class="EmphTd" width="17%">Cmax</td> <td class="EmphTd" width="17%">AUC</td> <td class="EmphTd" width="17%">Cτ or C24</td> </tr> <tr> <td>Daclatasvir<br /> 60 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">12</td> <td align="center" width="20%">1.03<br /> (0.84 to 1.25)</td> <td align="center" width="20%">0.98<br /> (0.83 to 1.15)</td> <td align="center" width="20%">1.06<br /> (0.88 to 1.29)</td> </tr> <tr> <td>Ethinyl estradiol<br /> 0.035 mg</td> <td align="center">50 mg twice daily</td> <td align="center">15</td> <td align="center" width="20%">0.99<br /> (0.91 to 1.08)</td> <td align="center" width="20%">1.03<br /> (0.96 to 1.11)</td> <td align="center" width="20%">1.02<br /> (0.93 to 1.11)</td> </tr> <tr> <td>Metformin<br /> 500 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">15<sup>a</sup></td> <td align="center" width="20%">1.66<br /> (1.53 to 1.81)</td> <td align="center" width="20%">1.79<br /> (1.65 to 1.93)</td> <td align="center" width="20%">_</td> </tr> <tr> <td>Metformin<br /> 500 mg twice daily</td> <td align="center">50 mg twice daily</td> <td align="center">15<sup>a</sup></td> <td align="center" width="20%">2.11<br /> (1.91 to 2.33)</td> <td align="center" width="20%">2.45<br /> (2.25 to 2.66)</td> <td align="center" width="20%">_</td> </tr> <tr> <td>Methadone<br /> 16 to 150 mg</td> <td align="center">50 mg twice daily</td> <td align="center">11</td> <td align="center" width="20%">1.00<br /> (0.94 to 1.06)</td> <td align="center" width="20%">0.98<br /> (0.91 to 1.06)</td> <td align="center" width="20%">0.99<br /> (0.91 to 1.07)</td> </tr> <tr> <td>Midazolam<br /> 3 mg</td> <td align="center">25 mg once daily</td> <td align="center">10</td> <td align="center" width="20%">_</td> <td align="center" width="20%">0.95<br /> (0.79 to 1.15)</td> <td align="center" width="20%">_</td> </tr> <tr> <td>Norelgestromin<br /> 0.25 mg</td> <td align="center">50 mg twice daily</td> <td align="center">15</td> <td align="center" width="20%">0.89<br /> (0.82 to 0.97)</td> <td align="center" width="20%">0.98<br /> (0.91 to 1.04)</td> <td align="center" width="20%">0.93<br /> (0.85 to 1.03)</td> </tr> <tr> <td>Rilpivirine<br /> 25 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">16</td> <td align="center">1.10<br /> (0.99 to 1.22)</td> <td align="center">1.06<br /> (0.98 to 1.16)</td> <td align="center">1.21<br /> (1.07 to 1.38)</td> </tr> <tr> <td>Tenofovir disoproxil fumarate<br /> 300 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">15</td> <td align="center">1.09<br /> (0.97 to 1.23)</td> <td align="center">1.12<br /> (1.01 to 1.24)</td> <td align="center">1.19<br /> (1.04 to 1.35)</td> </tr> <tr> <td class="credit" colspan="6"><sup>a </sup>The number of subjects represents the maximum number of subjects that were evaluated.</td> </tr> </tbody> </table> </center> <p></p> <p align="center"><b>Table 9. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir </b></p> <center> <table cellspacing="0" class="blacktbl" width="650"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="20%">Coadministered Drug(s) and Dose(s)</td> <td class="EmphTd" rowspan="2" width="19%">Dose of Dolutegravir</td> <td class="EmphTd" rowspan="2" width="10%">n</td> <td class="EmphTd" colspan="3">Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir<br /> No Effect = 1.00</td> </tr> <tr> <td class="EmphTd" width="17%">Cmax</td> <td class="EmphTd" width="17%">AUC</td> <td class="EmphTd" width="17%">Cτ or C<sub>24</sub></td> </tr> <tr> <td>Atazanavir<br /> 400 mg once daily</td> <td align="center">30 mg once daily</td> <td align="center">12</td> <td align="center">1.50<br /> (1.40 to 1.59)</td> <td align="center">1.91<br /> (1.80 to 2.03)</td> <td align="center">2.80<br /> (2.52 to 3.11)</td> </tr> <tr> <td>Atazanavir/ritonavir<br /> 300/100 mg once daily</td> <td align="center">30 mg once daily</td> <td align="center">12</td> <td align="center">1.34<br /> (1.25 to 1.42)</td> <td align="center">1.62<br /> (1.50 to 1.74)</td> <td align="center">2.21<br /> (1.97 to 2.47)</td> </tr> <tr> <td>Darunavir/ritonavir<br /> 600/100 mg twice daily</td> <td align="center">30 mg once daily</td> <td align="center">15</td> <td align="center">0.89<br /> (0.83 to 0.97)</td> <td align="center">0.78<br /> (0.72 to 0.85)</td> <td align="center">0.62<br /> (0.56 to 0.69)</td> </tr> <tr> <td>Efavirenz<br /> 600 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">12</td> <td align="center">0.61<br /> (0.51 to 0.73)</td> <td align="center">0.43<br /> (0.35 to 0.54)</td> <td align="center">0.25<br /> (0.18 to 0.34)</td> </tr> <tr> <td>Etravirine<br /> 200 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">16</td> <td align="center">0.48<br /> (0.43 to 0.54)</td> <td align="center">0.29<br /> (0.26 to 0.34)</td> <td align="center">0.12<br /> (0.09 to 0.16)</td> </tr> <tr> <td>Etravirine + darunavir/ritonavir<br /> 200 mg +600/100 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">9</td> <td align="center">0.88<br /> (0.78 to 1.00)</td> <td align="center">0.75<br /> (0.69 to 0.81)</td> <td align="center">0.63<br /> (0.52 to 0.76)</td> </tr> <tr> <td>Etravirine + lopinavir/ritonavir<br /> 200 mg + 400/100 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">8</td> <td align="center">1.07<br /> (1.02 to 1.13)</td> <td align="center">1.11<br /> (1.02 to 1.20)</td> <td align="center">1.28<br /> (1.13 to 1.45)</td> </tr> <tr> <td>Fosamprenavir/ritonavir<br /> 700 mg/100 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">12</td> <td align="center">0.76<br /> (0.63 to 0.92)</td> <td align="center">0.65<br /> (0.54 to 0.78)</td> <td align="center">0.51<br /> (0.41 to 0.63)</td> </tr> <tr> <td>Lopinavir/ritonavir<br /> 400/100 mg twice daily</td> <td align="center">30 mg once daily</td> <td align="center">15</td> <td align="center">1.00<br /> (0.94 to 1.07)</td> <td align="center">0.97<br /> (0.91 to 1.04)</td> <td align="center">0.94<br /> (0.85 to 1.05)</td> </tr> <tr> <td>Rilpivirine<br /> 25 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">16</td> <td align="center">1.13<br /> (1.06 to 1.21)</td> <td align="center">1.12<br /> (1.05 to 1.19)</td> <td align="center">1.22<br /> (1.15 to 1.30)</td> </tr> <tr> <td>Tenofovir<br /> 300 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">15</td> <td align="center">0.97<br /> (0.87 to 1.08)</td> <td align="center">1.01<br /> (0.91 to 1.11)</td> <td align="center">0.92<br /> (0.82 to 1.04)</td> </tr> <tr> <td>Tipranavir/ritonavir<br /> 500/200 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">14</td> <td align="center">0.54<br /> (0.50 to 0.57)</td> <td align="center">0.41<br /> (0.38 to 0.44)</td> <td align="center">0.24<br /> (0.21 to 0.27)</td> </tr> <tr> <td>Antacid (MAALOX)<br /> simultaneous administration</td> <td align="center">50 mg single dose</td> <td align="center">16</td> <td align="center">0.28<br /> (0.23 to 0.33)</td> <td align="center">0.26<br /> (0.22 to 0.32)</td> <td align="center">0.26<br /> (0.21 to 0.31)</td> </tr> <tr> <td>Antacid (MAALOX)<br /> 2 h after dolutegravir</td> <td align="center">50 mg single dose</td> <td align="center">16</td> <td align="center">0.82<br /> (0.69 to 0.98)</td> <td align="center">0.74<br /> (0.62 to 0.90)</td> <td align="center">0.70<br /> (0.58 to 0.85)</td> </tr> <tr> <td>Boceprevir<br /> 800 mg every 8 h</td> <td align="center">50 mg once daily</td> <td align="center">13</td> <td align="center">1.05<br /> (0.96 to 1.15)</td> <td align="center">1.07<br /> (0.95 to 1.20)</td> <td align="center">1.08<br /> (0.91 to 1.28)</td> </tr> <tr> <td>Calcium carbonate 1,200 mg<br /> simultaneous administration (fasted)</td> <td align="center">50 mg single dose</td> <td align="center">12</td> <td align="center">0.63<br /> (0.50 to 0.81)</td> <td align="center">0.61<br /> (0.47 to 0.80)</td> <td align="center">0.61<br /> (0.47 to 0.80)</td> </tr> <tr> <td>Calcium carbonate 1,200 mg<br /> simultaneous administration (fed)</td> <td align="center">50 mg single dose</td> <td align="center">11</td> <td align="center">1.07<br /> (0.83 to 1.38)</td> <td align="center">1.09<br /> (0.84 to 1.43)</td> <td align="center">1.08<br /> (0.81 to 1.42)</td> </tr> <tr> <td>Calcium carbonate 1,200 mg<br /> 2 h after dolutegravir</td> <td align="center">50 mg single dose</td> <td align="center">11</td> <td align="center">1.00<br /> (0.78 to 1.29)</td> <td align="center">0.94<br /> (0.72 to 1.23)</td> <td align="center">0.90<br /> (0.68 to 1.19)</td> </tr> <tr> <td>Carbamazepine<br /> 300 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">16<sup>c</sup></td> <td align="center">0.67<br /> (0.61 to 0.73)</td> <td align="center">0.51<br /> (0.48 to 0.55)</td> <td align="center">0.27<br /> (0.24 to 0.31)</td> </tr> <tr> <td>Daclatasvir<br /> 60 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">12</td> <td align="center">1.29<br /> (1.07 to 1.57)</td> <td align="center">1.33<br /> (1.11 to 1.59)</td> <td align="center">1.45<br /> (1.25 to 1.68)</td> </tr> <tr> <td>Ferrous fumarate 324 mg<br /> simultaneous administration (fasted)</td> <td align="center">50 mg single dose</td> <td align="center">11</td> <td align="center">0.43<br /> (0.35 to 0.52)</td> <td align="center">0.46<br /> (0.38 to 0.56)</td> <td align="center">0.44<br /> (0.36 to 0.54)</td> </tr> <tr> <td>Ferrous fumarate 324 mg<br /> simultaneous administration (fed)</td> <td align="center">50 mg single dose</td> <td align="center">11</td> <td align="center">1.03<br /> (0.84 to 1.26)</td> <td align="center">0.98<br /> (0.81 to 1.20)</td> <td align="center">1.00<br /> (0.81 to 1.23)</td> </tr> <tr> <td>Ferrous fumarate 324 mg<br /> 2 h after dolutegravir</td> <td align="center">50 mg single dose</td> <td align="center">10</td> <td align="center">0.99<br /> (0.81 to 1.21)</td> <td align="center">0.95<br /> (0.77 to 1.15)</td> <td align="center">0.92<br /> (0.74 to 1.13)</td> </tr> <tr> <td>Multivitamin (One-A-Day)<br /> simultaneous administration</td> <td align="center">50 mg single dose</td> <td align="center">16</td> <td align="center">0.65<br /> (0.54 to 0.77)</td> <td align="center">0.67<br /> (0.55 to 0.81)</td> <td align="center">0.68<br /> (0.56 to 0.82)</td> </tr> <tr> <td>Omeprazole<br /> 40 mg once daily</td> <td align="center">50 mg single dose</td> <td align="center">12</td> <td align="center">0.92<br /> (0.75 to 1.11)</td> <td align="center">0.97<br /> (0.78 to 1.20)</td> <td align="center">0.95<br /> (0.75 to 1.21)</td> </tr> <tr> <td>Prednisone<br /> 60 mg once daily with taper</td> <td align="center">50 mg once daily</td> <td align="center">12</td> <td align="center">1.06<br /> (0.99 to 1.14)</td> <td align="center">1.11<br /> (1.03 to 1.20)</td> <td align="center">1.17<br /> (1.06 to 1.28)</td> </tr> <tr> <td>Rifampin<sup>a</sup><br /> 600 mg once daily</td> <td align="center">50 mg twice daily</td> <td align="center">11</td> <td align="center">0.57<br /> (0.49 to 0.65)</td> <td align="center">0.46<br /> (0.38 to 0.55)</td> <td align="center">0.28<br /> (0.23 to 0.34)</td> </tr> <tr> <td>Rifampin<sup>b</sup><br /> 600 mg once daily</td> <td align="center">50 mg twice daily</td> <td align="center">11</td> <td align="center">1.18<br /> (1.03 to 1.37)</td> <td align="center">1.33<br /> (1.15 to 1.53)</td> <td align="center">1.22<br /> (1.01 to 1.48)</td> </tr> <tr> <td>Rifabutin<br /> 300 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">9</td> <td align="center">1.16<br /> (0.98 to 1.37)</td> <td align="center">0.95<br /> (0.82 to 1.10)</td> <td align="center">0.70<br /> (0.57 to 0.87)</td> </tr> <tr> <td class="credit" colspan="6"><sup>a</sup> Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily.<br /> <sup>b</sup> Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily.<br /> <sup>c</sup> The number of subjects represents the maximum number of subjects that were evaluated.</td> </tr> </tbody> </table> </center> <p></p> <h5>Abacavir Or Lamivudine</h5> <p>The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities.</p> <h5>Effect Of Abacavir And Lamivudine On The Pharmacokinetics Of Other Agents</h5> <p><i>In vitro</i> studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6). Based on <i>in vitro</i> study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: OATP1B1/3, BCRP or P-gp, OCT1, OCT2, OCT3 (lamivudine only), or MATE1 and MATE2-K.</p> <h5>Abacavir, Dolutegravir, And Lamivudine</h5> <p>Coadministration of a single dose of riociguat (0.5 mg) to HIV-1–infected subjects receiving TRIUMEQ is reported to increase riociguat AUC(∞) compared with riociguat AUC(∞) reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see <b>DRUG INTERACTIONS</b>].</p> <h5>Effect Of Other Agents On The Pharmacokinetics Of Abacavir Or Lamivudine</h5> <p><i>In vitro</i>, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, MRP2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is a substrate of BCRP and P-gp <i>in vitro</i>; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations.</p> <p>Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 <i>in vitro</i>. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed. Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.</p> <h5>Ethanol</h5> <p>Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.</p> <h5>Interferon Alfa</h5> <p>There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.</p> <h5>Methadone</h5> <p>In a trial of 11 HIV-1–infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see <b>DRUG INTERACTIONS</b>]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.</p> <h5>Ribavirin</h5> <p><i>In vitro</i> data indicate ribavirin reduces <a href="/phosphorylation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">phosphorylation</a> of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.</p> <h5>Sorbitol (Excipient)</h5> <p>Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 g, 10.2 g, or 13.4 g of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24); 14%, 32%, and 36% in the AUC(∞); and 28%, 52%, and 55% in the Cmax; of lamivudine, respectively.</p> <h5>Abacavir, Lamivudine, Zidovudine</h5> <p>Fifteen HIV-1–infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.</p> <h5>Lamivudine And Zidovudine</h5> <p>No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 <a href="/asymptomatic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">asymptomatic</a> HIV-1–infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).</p> <p>The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 10.</p> <p align="center"><b>Table 10. Effect of Coadministered Drugs on Abacavir or Lamivudine </b></p> <center> <table cellspacing="0" class="blacktbl" width="650"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="30%">Coadministered Drug and Dose</td> <td class="EmphTd" rowspan="2" width="15%">Drug and Dose</td> <td class="EmphTd" rowspan="2" width="5%">n</td> <td class="EmphTd" colspan="2">Concentrations of Abacavir or Lamivudine</td> <td class="EmphTd" rowspan="2" width="20%">Concentration of CoadministeredDrug</td> </tr> <tr> <td class="EmphTd" width="15%">AUC</td> <td class="EmphTd" width="15%">Variability</td> </tr> <tr> <td>Ethanol<br /> 0.7 g/kg</td> <td align="center">Abacavir Single 600 mg</td> <td align="center">24</td> <td align="center">↑41%</td> <td align="center">90% CI:<br /> 35% to 48%</td> <td align="center">↔<sup>a</sup></td> </tr> <tr> <td>Nelfinavir<br /> 750 mg every 8 h x 7 to 10 days</td> <td align="center">Lamivudine Single 150 mg</td> <td align="center">11</td> <td align="center">↑10%</td> <td align="center">95% CI:<br /> 1% to 20%</td> <td align="center">↔</td> </tr> <tr> <td>Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days</td> <td align="center">Lamivudine Single 300 mg</td> <td align="center">14</td> <td align="center">↑43%</td> <td align="center">90% CI:<br /> 32% to 55%</td> <td align="center">↔</td> </tr> <tr> <td class="credit" colspan="6">↑ = Increase; ↔ = No significant change.<br /> <sup>a</sup> The drug-drug interaction was only evaluated in males.</td> </tr> </tbody> </table> </center> <p></p> <h4>Microbiology</h4> <h5>Mechanism Of Action</h5> <p><i>Dolutegravir</i></p> <p>Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified recombinant HIV-1 integrase and pre-processed substrate DNA resulted in IC<sub>50</sub> values of 2.7 nM and 12.6 nM.</p> <p><i>Abacavir</i></p> <p>Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.</p> <p><i>Lamivudine</i></p> <p>Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.</p> <h5>Antiviral Activity In Cell Culture</h5> <p><i>Dolutegravir</i></p> <p>Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean concentration of drug necessary to affect viral replication by 50% (EC<sub>50</sub>) values of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a median EC<sub>50</sub> value of 0.54 nM (range: 0.41 to 0.60 nM) in a viral susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV-1 clinical isolates with median EC<sub>50</sub> values of 0.18 nM (n = 3, range: 0.09 to 0.5 nM), 0.08 nM (n = 5, range: 0.05 to 2.14 nM), 0.12 nM (n = 4, range: 0.05 to 0.51 nM), 0.17 nM (n = 3, range: 0.16 to 0.35 nM), 0.24 nM (n = 3, range: 0.09 to 0.32 nM), 0.17 nM (n = 4, range: 0.07 to 0.44 nM), 0.2 nM (n = 3, range: 0.02 to 0.87 nM), and 0.42 nM (n = 3, range: 0.41 to 1.79 nM) for clades A, B, C, D, E, F, and G, and group O viruses, respectively. Dolutegravir EC<sub>50</sub> values against three HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM.</p> <p><i>Abacavir</i></p> <p>The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including in primary monocytes/macrophages and PBMCs. EC<sub>50</sub> values ranged from 3,700 to 5,800 nM (1 nM = 0.28 ng/mL) and 70 to 1,000 nM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC<sub>50</sub> value was 260 ± 180 nM against 8 clinical isolates. The median EC<sub>50</sub> values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC<sub>50</sub> values against HIV-2 isolates (n = 4), ranged from 24 to 490 nM.</p> <p><i>Lamivudine</i></p> <p>The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC<sub>50</sub> values were in the range of 3 to 15,000 nM (1 nM = 0.23 ng/mL). The median EC<sub>50</sub> values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC<sub>50</sub> values against HIV-2 isolates (n = 4) from 3 to 120 nM in PBMCs. Ribavirin (50,000 nM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.</p> <h5>Antiviral Activity In Combination With Other Antiviral Agents</h5> <p>Neither dolutegravir, abacavir, nor lamivudine were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir), TIVICAY (dolutegravir), and EPIVIR (lamivudine).</p> <h5>Resistance In Cell Culture</h5> <p><i>Dolutegravir</i></p> <p>Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold.</p> <p><i>Abacavir and Lamivudine</i></p> <p>HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions K65R, L74V, Y115F, and M184V/I in HIV-1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74V, or Y115F with M184V or I conferred a 7- to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.</p> <h5>Resistance In Clinical Subjects</h5> <p>No subjects in the treatment arm receiving dolutegravir + EPZICOM in SINGLE (treatmentnaive trial) had a detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n = 11 with HIV-1 RNA >400 copies/mL at failure or last visit and having resistance data). Two virologic failure subjects in SINGLE had treatment-emergent G/D/E193D and G193G/E integrase substitutions at Week 84 and Week 108, respectively, and 1 subject with 275 copies/mL HIV-1 RNA had a treatment-emergent Q157Q/P integrase substitution detected at Week 24. None of these subjects had a corresponding decrease in dolutegravir susceptibility. No treatment-emergent genotypic resistance to abacavir and lamivudine, components of TRIUMEQ and TRIUMEQ PD, was observed in the arm receiving dolutegravir + EPZICOM in the SINGLE trial through Week 144.</p> <h5>Cross-Resistance</h5> <p><i>Dolutegravir</i></p> <p>Cross-resistance has been observed among INSTIs. The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a >2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, R or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a >2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference). In HIV-2 mutants, combinations of substitutions A153G/N155H/S163G and E92Q/T97A/N155H/S163D conferred 4-fold decreases in dolutegravir susceptibility, and E92Q/N155H and G140S/Q148R showed 8.5-fold and 17-fold decreases in dolutegravir susceptibility, respectively.</p> <p><i>Abacavir and Lamivudine</i></p> <p>Cross-resistance has been observed among NRTIs. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with thymidine analog mutation (TAM) substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.</p> <a name="AP"></a> <h4>Animal Toxicology And/Or Pharmacology</h4> <p>Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 21 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.</p> <a name="CS"></a> <h4>Clinical Studies</h4> <h4>Adult Subjects</h4> <p>The efficacy of TRIUMEQ is supported by data from a randomized, controlled trial (doubleblind through 96 weeks and open-label phase from 96 to 144 weeks) in antiretroviral treatmentnaive subjects, SINGLE (ING114467, NCT01263015) and other trials in treatment- naive subjects. See full prescribing information for TIVICAY. The efficacy of dolutegravir, in combination with at least two active background regimens in treatment-experienced, INSTInaive subjects is supported by data from SAILING (ING111762, NCT01231516) (refer to the prescribing information for TIVICAY).</p> <h5>Treatment-Naive Subjects</h5> <p>In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily with fixed-dose abacavir and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir disoproxil fumarate (ATRIPLA). At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis C co-infection (hepatitis B virus co-infection was excluded), 4% were CDC Class C (AIDS), 32% had HIV-1 RNA >100,000 copies/mL, and 53% had CD4+ cell count <350 cells/mm<sup>3</sup>; these characteristics were similar between treatment groups.</p> <p>Week 144 (open-label-phase analysis which followed the Week 96 double-blind phase) outcomes for SINGLE are provided in Table 11.</p> <p align="center"><b>Table 11. Virologic Outcomes of Randomized Treatment in SINGLE at 144 Weeks (Snapshot Algorithm) </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%"></td> <td class="EmphTd" width="25%">TIVICAY + EPZICOM<br /> Once Daily<br /> (n = 414)</td> <td class="EmphTd" width="25%">ATRIPLA<br /> Once Daily<br /> (n = 419)</td> </tr> <tr> <td><b>HIV-1 RNA <50 copies/mL</b></td> <td align="center">71%</td> <td align="center">63%</td> </tr> <tr> <td> Treatment difference<sup>a</sup></td> <td align="center" colspan="2">8.3% (95% CI: 2.0%, 14.6%)<sup>d</sup></td> </tr> <tr> <td><b>Virologic nonresponse</b></td> <td align="center">10%</td> <td align="center">7%</td> </tr> <tr> <td> Data in window not <50 copies/mL</td> <td align="center">4%</td> <td align="center"><1%</td> </tr> <tr> <td> Discontinued for lack of efficacy</td> <td align="center">3%</td> <td align="center">3%</td> </tr> <tr> <td> Discontinued for other reasons while not suppressed</td> <td align="center">3%</td> <td align="center">4%</td> </tr> <tr> <td><b>No virologic data</b></td> <td align="center">18%</td> <td align="center">30%</td> </tr> <tr> <td colspan="3">Reasons</td> </tr> <tr> <td> Discontinued study/study drug due to adverse event or death<sup>b</sup></td> <td align="center">4%</td> <td align="center">14%</td> </tr> <tr> <td> Discontinued study/study drug for other reasons<sup>c</sup></td> <td align="center">12%</td> <td align="center">13%</td> </tr> <tr> <td> Missing data during window but on study</td> <td align="center">2%</td> <td align="center">3%</td> </tr> <tr> <td align="center" colspan="3"><b>Proportion (%) of Subjects with HIV-1 RNA <50 copies/mL by Baseline Category</b></td> </tr> <tr> <td colspan="3"><b>Plasma viral load (copies/mL)</b></td> </tr> <tr> <td> ≤100,000</td> <td align="center">73%</td> <td align="center">64%</td> </tr> <tr> <td> ≥100,000</td> <td align="center">69%</td> <td align="center">61%</td> </tr> <tr> <td colspan="3"><b>Gender</b></td> </tr> <tr> <td> Male</td> <td align="center">72%</td> <td align="center">66%</td> </tr> <tr> <td> Female</td> <td align="center">69%</td> <td align="center">48%</td> </tr> <tr> <td colspan="3"><b>Race</b></td> </tr> <tr> <td> White</td> <td align="center">72%</td> <td align="center">71%</td> </tr> <tr> <td> African American/African Heritage/Other</td> <td align="center">71%</td> <td align="center">47%</td> </tr> <tr> <td class="credit" colspan="3"><sup>a </sup>Adjusted for pre-specified stratification factors.<br /> <sup>b</sup> Includes subjects who discontinued due to an adverse event or death at any time point if this resulted in no virologic data on treatment during the analysis window.<br /> <sup>c</sup> Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.<br /> <sup>d</sup> The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 81% in the ATRIPLA group, with a treatment difference of 7.4% and 95% CI of (2.5%, 12.3%).</td> </tr> </tbody> </table> </center> <p></p> <p>Treatment differences were maintained across baseline characteristics including baseline viral load, CD4+ cell count, age, gender, and race. The adjusted mean changes in CD4+ cell counts from baseline were 378 cells per mm<sup>3</sup> in the group receiving TIVICAY + EPZICOM and 332 cells per mm<sup>3</sup> for the ATRIPLA group at 144 weeks. The adjusted difference between treatment arms and 95% CI was 46.9 cells per mm<sup>3</sup> (15.6 cells per mm<sup>3</sup>, 78.2 cells per mm<sup>3</sup>) (adjusted for pre-specified stratification factors: baseline HIV-1 RNA, and baseline CD4+ cell count).</p> <h5>Treatment-Experienced</h5> <p>In SAILING, there were 715 subjects included in the efficacy and safety analyses (see full prescribing information for TIVICAY). At Week 48, 71% of subjects randomized to TIVICAY plus background regimen versus 64% of subjects randomized to raltegravir plus background regimen had HIV-1 RNA <50 copies/mL (treatment difference and 95% CI: 7.4% [0.7%, 14.2%]).</p> <h4>Pediatric Subjects</h4> <p>The efficacy of the individual components of TRIUMEQ and TRIUMEQ PD for the treatment of HIV-1 infection was evaluated in pediatric patients enrolled in the ARROW trial (NCT02028676) and IMPAACT P1093 trial (NCT01302847), as summarized below.</p> <ul> <li>Abacavir and lamivudine once daily, in combination with a third antiretroviral drug, were evaluated in a randomized, multicenter trial (ARROW) in treatment- naive pediatric subjects with HIV-1 infection. Subjects randomized to once-daily dosing (n = 336) and who weighed at least 25 kg received abacavir 600 mg and lamivudine 300 mg, as either the single entities or as EPZICOM. At Week 96, 67% of subjects receiving abacavir and lamivudine once-daily in combination with a third antiretroviral drug, had HIV-1 RNA <80 copies/mL.</li> <li>Dolutegravir (TIVICAY or TIVICAY PD), in combination with other antiretroviral drugs was evaluated in treatment naive or treatment-experienced, INSTI- naive, HIV-1–infected subjects aged at least 4 weeks to 18 years in an ongoing open-label, multicenter, dose-finding clinical trial, IMPAACT P1093. Subjects were stratified by age cohort; subjects aged 12 to <18 years were enrolled in Cohort I, subjects aged 6 to <12 years were enrolled in Cohort IIA, and subjects aged 2 to <6 years were enrolled in Cohort III-DT. Subjects weighing at least 10 kg from Cohorts I (n = 19), IIA (n = 5), and III-DT (n = 3) who received the recommended dose (determined by weight and age) and formulation contributed to the efficacy analysis at Week 48. Across all 3 cohorts, 67% (18/27) of subjects weighing at least 10 kg achieved HIV-1 RNA <50 copies/mL at Week 48 (Snapshot algorithm).</li> </ul> </div> </div> </div> | <a name="CP"></a> <h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism Of Action</h4> <p>TRIUMEQ and TRIUMEQ PD are a fixed-dose combination of the HIV-1 antiretroviral agents abacavir, dolutegravir, and lamivudine [see <b>Microbiology</b>].</p> <h4>Pharmacodynamics</h4> <h5>Effects On Electrocardiogram</h5> <p>A thorough QT trial has been conducted for dolutegravir. Neither the effects of abacavir nor lamivudine as single entities or the combination of abacavir, dolutegravir, and lamivudine on the QT interval have been evaluated.</p> <p>In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3– fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours postdose.</p> <h5>Effects On Renal Function</h5> <p>The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of <a href="/probe/definition.htm" ">probe</a> drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, <a href="/para/definition.htm" ">para</a>-amino hippurate) compared with the placebo.</p> <h4>Pharmacokinetics</h4> <h5>Pharmacokinetics In Adults</h5> <p>One TRIUMEQ tablet was bioequivalent to one dolutegravir (TIVICAY) tablet (50 mg) plus one abacavir and lamivudine fixed-dose combination tablet (EPZICOM) under fasted conditions in healthy subjects (n = 62).</p> <p>TRIUMEQ tablets and TRIUMEQ PD tablets for oral suspension are bioequivalent for the abacavir and lamivudine components, but not for the dolutegravir component. The relative dolutegravir bioavailability of TRIUMEQ PD is approximately 1.7-fold higher than TRIUMEQ; therefore, the 2 dosage forms are not interchangeable on a milligram-per-milligram basis [see <b>DOSAGE AND ADMINISTRATION</b>, <b>WARNINGS AND PRECAUTIONS</b>]. The relative dolutegravir bioavailability is expected to be similar between TRIUMEQ PD and TIVICAY PD.</p> <p><i>Abacavir</i></p> <p>Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 ± 1.19 mcg/mL (mean ± SD) and AUC∞ was 11.95 ± 2.51 mcg•hour/mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration.</p> <p>Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are <a href="/metabolism/definition.htm" ">metabolism</a> by alcohol dehydrogenase to form the 5′-carboxylic acid and glucuronyl transferase to form the 5′-glucuronide. In single-dose trials, the observed elimination half-life (t<sub>½</sub>) was 1.54 ± 0.63 hours. After intravenous administration, total clearance was 0.80 ± 0.24 L/h/kg (mean ± SD).</p> <p><i>Dolutegravir</i></p> <p>Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C<sub>24</sub> h ranging from 1.2 to 1.5. Dolutegravir is a P-gp substrate <i>in vitro</i>. The absolute bioavailability of dolutegravir has not been established. Dolutegravir is highly bound (≥98.9%) to human plasma proteins based on <i>in vivo</i> data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis.</p> <p>Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After a single oral dose of [<sup>14</sup>C] dolutegravir, 53% of the total oral dose is excreted unchanged in the feces. Thirty-one percent of the total oral dose is excreted in the urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was <1% of the dose. Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L/h based on population pharmacokinetic analyses.</p> <p>The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV-1–infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV-1–infected subjects.</p> <p align="center"><b>Table 7. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1- Infected Adults </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Parameter</td> <td class="EmphTd" width="50%">50 mg Once Daily<br /> Geometric Mean (%CV)</td> </tr> <tr> <td>AUC(0-24) (mcg•h/mL)</td> <td align="center">53.6 (27)</td> </tr> <tr> <td>Cmax (mcg/mL)</td> <td align="center">3.67 (20)</td> </tr> <tr> <td>Cmin (mcg/mL)</td> <td align="center">1.11 (46)</td> </tr> </tbody> </table> </center> <p></p> <p><i>Cerebrospinal Fluid (CSF)</i></p> <p>In 11 treatment- naive subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in <a href="/csf_colony-stimulating_factor/definition.htm" ">CSF</a> was 18 ng/mL (range: 4 ng/mL to 23.2 ng/mL) 2 to 6 hours postdose after 2 weeks of treatment. The clinical relevance of this finding has not been established.</p> <p><i>Lamivudine</i></p> <p>Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state Cmax (Cmax,ss) was 2.04 ± 0.54 mcg/mL (mean ± SD) and the 24-hour steady-state AUC (AUC24, ss) was 8.87 ± 1.83 mcg•hour/mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the <a href="/trans-_prefix/definition.htm" ">trans-</a>sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). In most single-dose trials with plasma sampling up to 48 or 72 hours after dosing, the observed mean elimination half-life (t<sub>½</sub>) ranged from 13 to 19 hours. In HIV-1–infected subjects, total clearance was 398.5 ± 69.1 mL per min (mean ± SD).</p> <h5>Effect Of Food On Oral Absorption</h5> <p>TRIUMEQ or TRIUMEQ PD may be taken with or without food. Overall, when compared with fasted conditions, administration of TRIUMEQ to healthy adult subjects with a high-fat meal (53% fat, 869 calories) resulted in decreased Cmax for abacavir and increased Cmax and AUC for dolutegravir. Lamivudine exposures were not affected by food. With a high-fat meal, the Cmax of abacavir decreased 23% and the Cmax and AUC of dolutegravir increased 37% and 48%, respectively. When compared with fasted conditions, administration of TRIUMEQ PD to healthy adult subjects with a high-fat meal (50% fat, 917 calories) resulted in decreased Cmax for abacavir (55%), dolutegravir (29%) and lamivudine (36%). AUCs for all 3 components were not affected by food.</p> <h4>Specific Populations</h4> <h5>Patients With Renal Impairment</h5> <p>The pharmacokinetics for the individual components of TRIUMEQ and TRIUMEQ PD have been evaluated in patients with renal impairment (see the U.S. prescribing information for the individual abacavir, dolutegravir, and lamivudine components).</p> <h5>Patients With Hepatic Impairment</h5> <p>The pharmacokinetics for the individual components of TRIUMEQ and TRIUMEQ PD have been evaluated in patients with varying degrees of hepatic impairment (see the U.S. prescribing information for the individual abacavir, dolutegravir, and lamivudine components).</p> <h5>Pediatric Patients</h5> <p>The pharmacokinetics for the individual components of TRIUMEQ and TRIUMEQ PD (abacavir, dolutegravir, and lamivudine) have been evaluated in pediatric subjects.</p> <h5>Dolutegravir</h5> <p>The pharmacokinetics of dolutegravir were evaluated in the IMPAACT P1093 trial and in 2 weight-band–based pharmacokinetic substudies from the ODYSSEY trial [see <b>Use In Specific Populations</b>, <b>Clinical Studies</b>].</p> <p>Mean dolutegravir AUC0-24h and C<sub>24</sub>h in HIV-1–infected pediatric subjects weighing at least 10 kg were comparable to those in adults after 50 mg once daily or 50 mg twice daily. Mean Cmax is higher in <a href="/pediatrics/definition.htm" ">pediatrics</a>, but the increase is not considered clinically significant as the safety profiles were similar in pediatric and adult subjects [see <b>ADVERSE REACTIONS</b>]. Refer to the prescribing information for TIVICAY for pharmacokinetic information on dolutegravir in pediatric patients.</p> <h5>Abacavir And Lamivudine</h5> <p>In pediatric patients weighing 25 kg and above, the dosing recommendations for TRIUMEQ in this population are based on the safety and efficacy established in a controlled trial conducted using either the combination of EPIVIR and ZIAGEN or EPZICOM.</p> <p>In pediatric patients weighing 10 to <25 kg, predicted exposures (AUC0-24h) of abacavir and lamivudine at the recommended doses for TRIUMEQ PD are within the observed exposure ranges at the recommended doses of individual products in adults and pediatrics.</p> <p>Refer to the prescribing information for EPIVIR and ZIAGEN for pharmacokinetic information on the individual products in pediatric patients [see <b>DOSAGE AND ADMINISTRATION</b>, <b>Clinical Studies</b>].</p> <h5>Geriatric Patients</h5> <p>Population analyses using pooled pharmacokinetic data from adult trials indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir. The pharmacokinetics of abacavir or lamivudine have not been studied in subjects older than 65 years.</p> <h5>Male And Female Patients</h5> <p>There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components.</p> <h5>Racial Groups</h5> <p>There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components.</p> <h4>Drug Interaction Studies</h4> <p>The drug interaction trials described were conducted with dolutegravir, abacavir, and/or lamivudine as single entities; no drug interaction trials have been conducted using the combination of abacavir, dolutegravir, and lamivudine. No clinically significant drug interactions are expected between dolutegravir, abacavir, and lamivudine.</p> <p>Dosing recommendations as a result of established and other potentially significant drug-drug interactions with the individual components of TRIUMEQ and TRIUMEQ PD are provided in Section 7.3 [see <b>DRUG INTERACTIONS</b>].</p> <p align="center"><b>Table 8. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs </b></p> <center> <table cellspacing="0" class="blacktbl" width="650"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="20%">Coadministered Drug(s) and Dose(s)</td> <td class="EmphTd" rowspan="2" width="20%">Dose of Dolutegravir</td> <td class="EmphTd" rowspan="2" width="9%">n</td> <td class="EmphTd" colspan="3" height="119">Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir<br /> No Effect = 1.00</td> </tr> <tr> <td class="EmphTd" width="17%">Cmax</td> <td class="EmphTd" width="17%">AUC</td> <td class="EmphTd" width="17%">Cτ or C24</td> </tr> <tr> <td>Daclatasvir<br /> 60 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">12</td> <td align="center" width="20%">1.03<br /> (0.84 to 1.25)</td> <td align="center" width="20%">0.98<br /> (0.83 to 1.15)</td> <td align="center" width="20%">1.06<br /> (0.88 to 1.29)</td> </tr> <tr> <td>Ethinyl estradiol<br /> 0.035 mg</td> <td align="center">50 mg twice daily</td> <td align="center">15</td> <td align="center" width="20%">0.99<br /> (0.91 to 1.08)</td> <td align="center" width="20%">1.03<br /> (0.96 to 1.11)</td> <td align="center" width="20%">1.02<br /> (0.93 to 1.11)</td> </tr> <tr> <td>Metformin<br /> 500 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">15<sup>a</sup></td> <td align="center" width="20%">1.66<br /> (1.53 to 1.81)</td> <td align="center" width="20%">1.79<br /> (1.65 to 1.93)</td> <td align="center" width="20%">_</td> </tr> <tr> <td>Metformin<br /> 500 mg twice daily</td> <td align="center">50 mg twice daily</td> <td align="center">15<sup>a</sup></td> <td align="center" width="20%">2.11<br /> (1.91 to 2.33)</td> <td align="center" width="20%">2.45<br /> (2.25 to 2.66)</td> <td align="center" width="20%">_</td> </tr> <tr> <td>Methadone<br /> 16 to 150 mg</td> <td align="center">50 mg twice daily</td> <td align="center">11</td> <td align="center" width="20%">1.00<br /> (0.94 to 1.06)</td> <td align="center" width="20%">0.98<br /> (0.91 to 1.06)</td> <td align="center" width="20%">0.99<br /> (0.91 to 1.07)</td> </tr> <tr> <td>Midazolam<br /> 3 mg</td> <td align="center">25 mg once daily</td> <td align="center">10</td> <td align="center" width="20%">_</td> <td align="center" width="20%">0.95<br /> (0.79 to 1.15)</td> <td align="center" width="20%">_</td> </tr> <tr> <td>Norelgestromin<br /> 0.25 mg</td> <td align="center">50 mg twice daily</td> <td align="center">15</td> <td align="center" width="20%">0.89<br /> (0.82 to 0.97)</td> <td align="center" width="20%">0.98<br /> (0.91 to 1.04)</td> <td align="center" width="20%">0.93<br /> (0.85 to 1.03)</td> </tr> <tr> <td>Rilpivirine<br /> 25 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">16</td> <td align="center">1.10<br /> (0.99 to 1.22)</td> <td align="center">1.06<br /> (0.98 to 1.16)</td> <td align="center">1.21<br /> (1.07 to 1.38)</td> </tr> <tr> <td>Tenofovir disoproxil fumarate<br /> 300 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">15</td> <td align="center">1.09<br /> (0.97 to 1.23)</td> <td align="center">1.12<br /> (1.01 to 1.24)</td> <td align="center">1.19<br /> (1.04 to 1.35)</td> </tr> <tr> <td class="credit" colspan="6"><sup>a </sup>The number of subjects represents the maximum number of subjects that were evaluated.</td> </tr> </tbody> </table> </center> <p></p> <p align="center"><b>Table 9. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir </b></p> <center> <table cellspacing="0" class="blacktbl" width="650"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="20%">Coadministered Drug(s) and Dose(s)</td> <td class="EmphTd" rowspan="2" width="19%">Dose of Dolutegravir</td> <td class="EmphTd" rowspan="2" width="10%">n</td> <td class="EmphTd" colspan="3">Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir<br /> No Effect = 1.00</td> </tr> <tr> <td class="EmphTd" width="17%">Cmax</td> <td class="EmphTd" width="17%">AUC</td> <td class="EmphTd" width="17%">Cτ or C<sub>24</sub></td> </tr> <tr> <td>Atazanavir<br /> 400 mg once daily</td> <td align="center">30 mg once daily</td> <td align="center">12</td> <td align="center">1.50<br /> (1.40 to 1.59)</td> <td align="center">1.91<br /> (1.80 to 2.03)</td> <td align="center">2.80<br /> (2.52 to 3.11)</td> </tr> <tr> <td>Atazanavir/ritonavir<br /> 300/100 mg once daily</td> <td align="center">30 mg once daily</td> <td align="center">12</td> <td align="center">1.34<br /> (1.25 to 1.42)</td> <td align="center">1.62<br /> (1.50 to 1.74)</td> <td align="center">2.21<br /> (1.97 to 2.47)</td> </tr> <tr> <td>Darunavir/ritonavir<br /> 600/100 mg twice daily</td> <td align="center">30 mg once daily</td> <td align="center">15</td> <td align="center">0.89<br /> (0.83 to 0.97)</td> <td align="center">0.78<br /> (0.72 to 0.85)</td> <td align="center">0.62<br /> (0.56 to 0.69)</td> </tr> <tr> <td>Efavirenz<br /> 600 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">12</td> <td align="center">0.61<br /> (0.51 to 0.73)</td> <td align="center">0.43<br /> (0.35 to 0.54)</td> <td align="center">0.25<br /> (0.18 to 0.34)</td> </tr> <tr> <td>Etravirine<br /> 200 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">16</td> <td align="center">0.48<br /> (0.43 to 0.54)</td> <td align="center">0.29<br /> (0.26 to 0.34)</td> <td align="center">0.12<br /> (0.09 to 0.16)</td> </tr> <tr> <td>Etravirine + darunavir/ritonavir<br /> 200 mg +600/100 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">9</td> <td align="center">0.88<br /> (0.78 to 1.00)</td> <td align="center">0.75<br /> (0.69 to 0.81)</td> <td align="center">0.63<br /> (0.52 to 0.76)</td> </tr> <tr> <td>Etravirine + lopinavir/ritonavir<br /> 200 mg + 400/100 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">8</td> <td align="center">1.07<br /> (1.02 to 1.13)</td> <td align="center">1.11<br /> (1.02 to 1.20)</td> <td align="center">1.28<br /> (1.13 to 1.45)</td> </tr> <tr> <td>Fosamprenavir/ritonavir<br /> 700 mg/100 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">12</td> <td align="center">0.76<br /> (0.63 to 0.92)</td> <td align="center">0.65<br /> (0.54 to 0.78)</td> <td align="center">0.51<br /> (0.41 to 0.63)</td> </tr> <tr> <td>Lopinavir/ritonavir<br /> 400/100 mg twice daily</td> <td align="center">30 mg once daily</td> <td align="center">15</td> <td align="center">1.00<br /> (0.94 to 1.07)</td> <td align="center">0.97<br /> (0.91 to 1.04)</td> <td align="center">0.94<br /> (0.85 to 1.05)</td> </tr> <tr> <td>Rilpivirine<br /> 25 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">16</td> <td align="center">1.13<br /> (1.06 to 1.21)</td> <td align="center">1.12<br /> (1.05 to 1.19)</td> <td align="center">1.22<br /> (1.15 to 1.30)</td> </tr> <tr> <td>Tenofovir<br /> 300 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">15</td> <td align="center">0.97<br /> (0.87 to 1.08)</td> <td align="center">1.01<br /> (0.91 to 1.11)</td> <td align="center">0.92<br /> (0.82 to 1.04)</td> </tr> <tr> <td>Tipranavir/ritonavir<br /> 500/200 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">14</td> <td align="center">0.54<br /> (0.50 to 0.57)</td> <td align="center">0.41<br /> (0.38 to 0.44)</td> <td align="center">0.24<br /> (0.21 to 0.27)</td> </tr> <tr> <td>Antacid (MAALOX)<br /> simultaneous administration</td> <td align="center">50 mg single dose</td> <td align="center">16</td> <td align="center">0.28<br /> (0.23 to 0.33)</td> <td align="center">0.26<br /> (0.22 to 0.32)</td> <td align="center">0.26<br /> (0.21 to 0.31)</td> </tr> <tr> <td>Antacid (MAALOX)<br /> 2 h after dolutegravir</td> <td align="center">50 mg single dose</td> <td align="center">16</td> <td align="center">0.82<br /> (0.69 to 0.98)</td> <td align="center">0.74<br /> (0.62 to 0.90)</td> <td align="center">0.70<br /> (0.58 to 0.85)</td> </tr> <tr> <td>Boceprevir<br /> 800 mg every 8 h</td> <td align="center">50 mg once daily</td> <td align="center">13</td> <td align="center">1.05<br /> (0.96 to 1.15)</td> <td align="center">1.07<br /> (0.95 to 1.20)</td> <td align="center">1.08<br /> (0.91 to 1.28)</td> </tr> <tr> <td>Calcium carbonate 1,200 mg<br /> simultaneous administration (fasted)</td> <td align="center">50 mg single dose</td> <td align="center">12</td> <td align="center">0.63<br /> (0.50 to 0.81)</td> <td align="center">0.61<br /> (0.47 to 0.80)</td> <td align="center">0.61<br /> (0.47 to 0.80)</td> </tr> <tr> <td>Calcium carbonate 1,200 mg<br /> simultaneous administration (fed)</td> <td align="center">50 mg single dose</td> <td align="center">11</td> <td align="center">1.07<br /> (0.83 to 1.38)</td> <td align="center">1.09<br /> (0.84 to 1.43)</td> <td align="center">1.08<br /> (0.81 to 1.42)</td> </tr> <tr> <td>Calcium carbonate 1,200 mg<br /> 2 h after dolutegravir</td> <td align="center">50 mg single dose</td> <td align="center">11</td> <td align="center">1.00<br /> (0.78 to 1.29)</td> <td align="center">0.94<br /> (0.72 to 1.23)</td> <td align="center">0.90<br /> (0.68 to 1.19)</td> </tr> <tr> <td>Carbamazepine<br /> 300 mg twice daily</td> <td align="center">50 mg once daily</td> <td align="center">16<sup>c</sup></td> <td align="center">0.67<br /> (0.61 to 0.73)</td> <td align="center">0.51<br /> (0.48 to 0.55)</td> <td align="center">0.27<br /> (0.24 to 0.31)</td> </tr> <tr> <td>Daclatasvir<br /> 60 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">12</td> <td align="center">1.29<br /> (1.07 to 1.57)</td> <td align="center">1.33<br /> (1.11 to 1.59)</td> <td align="center">1.45<br /> (1.25 to 1.68)</td> </tr> <tr> <td>Ferrous fumarate 324 mg<br /> simultaneous administration (fasted)</td> <td align="center">50 mg single dose</td> <td align="center">11</td> <td align="center">0.43<br /> (0.35 to 0.52)</td> <td align="center">0.46<br /> (0.38 to 0.56)</td> <td align="center">0.44<br /> (0.36 to 0.54)</td> </tr> <tr> <td>Ferrous fumarate 324 mg<br /> simultaneous administration (fed)</td> <td align="center">50 mg single dose</td> <td align="center">11</td> <td align="center">1.03<br /> (0.84 to 1.26)</td> <td align="center">0.98<br /> (0.81 to 1.20)</td> <td align="center">1.00<br /> (0.81 to 1.23)</td> </tr> <tr> <td>Ferrous fumarate 324 mg<br /> 2 h after dolutegravir</td> <td align="center">50 mg single dose</td> <td align="center">10</td> <td align="center">0.99<br /> (0.81 to 1.21)</td> <td align="center">0.95<br /> (0.77 to 1.15)</td> <td align="center">0.92<br /> (0.74 to 1.13)</td> </tr> <tr> <td>Multivitamin (One-A-Day)<br /> simultaneous administration</td> <td align="center">50 mg single dose</td> <td align="center">16</td> <td align="center">0.65<br /> (0.54 to 0.77)</td> <td align="center">0.67<br /> (0.55 to 0.81)</td> <td align="center">0.68<br /> (0.56 to 0.82)</td> </tr> <tr> <td>Omeprazole<br /> 40 mg once daily</td> <td align="center">50 mg single dose</td> <td align="center">12</td> <td align="center">0.92<br /> (0.75 to 1.11)</td> <td align="center">0.97<br /> (0.78 to 1.20)</td> <td align="center">0.95<br /> (0.75 to 1.21)</td> </tr> <tr> <td>Prednisone<br /> 60 mg once daily with taper</td> <td align="center">50 mg once daily</td> <td align="center">12</td> <td align="center">1.06<br /> (0.99 to 1.14)</td> <td align="center">1.11<br /> (1.03 to 1.20)</td> <td align="center">1.17<br /> (1.06 to 1.28)</td> </tr> <tr> <td>Rifampin<sup>a</sup><br /> 600 mg once daily</td> <td align="center">50 mg twice daily</td> <td align="center">11</td> <td align="center">0.57<br /> (0.49 to 0.65)</td> <td align="center">0.46<br /> (0.38 to 0.55)</td> <td align="center">0.28<br /> (0.23 to 0.34)</td> </tr> <tr> <td>Rifampin<sup>b</sup><br /> 600 mg once daily</td> <td align="center">50 mg twice daily</td> <td align="center">11</td> <td align="center">1.18<br /> (1.03 to 1.37)</td> <td align="center">1.33<br /> (1.15 to 1.53)</td> <td align="center">1.22<br /> (1.01 to 1.48)</td> </tr> <tr> <td>Rifabutin<br /> 300 mg once daily</td> <td align="center">50 mg once daily</td> <td align="center">9</td> <td align="center">1.16<br /> (0.98 to 1.37)</td> <td align="center">0.95<br /> (0.82 to 1.10)</td> <td align="center">0.70<br /> (0.57 to 0.87)</td> </tr> <tr> <td class="credit" colspan="6"><sup>a</sup> Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily.<br /> <sup>b</sup> Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily.<br /> <sup>c</sup> The number of subjects represents the maximum number of subjects that were evaluated.</td> </tr> </tbody> </table> </center> <p></p> <h5>Abacavir Or Lamivudine</h5> <p>The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities.</p> <h5>Effect Of Abacavir And Lamivudine On The Pharmacokinetics Of Other Agents</h5> <p><i>In vitro</i> studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6). Based on <i>in vitro</i> study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: OATP1B1/3, BCRP or P-gp, OCT1, OCT2, OCT3 (lamivudine only), or MATE1 and MATE2-K.</p> <h5>Abacavir, Dolutegravir, And Lamivudine</h5> <p>Coadministration of a single dose of riociguat (0.5 mg) to HIV-1–infected subjects receiving TRIUMEQ is reported to increase riociguat AUC(∞) compared with riociguat AUC(∞) reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see <b>DRUG INTERACTIONS</b>].</p> <h5>Effect Of Other Agents On The Pharmacokinetics Of Abacavir Or Lamivudine</h5> <p><i>In vitro</i>, abacavir is not a substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, MRP2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is a substrate of BCRP and P-gp <i>in vitro</i>; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in a clinically relevant impact on abacavir concentrations.</p> <p>Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 <i>in vitro</i>. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed. Lamivudine is a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.</p> <h5>Ethanol</h5> <p>Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure.</p> <h5>Interferon Alfa</h5> <p>There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects.</p> <h5>Methadone</h5> <p>In a trial of 11 HIV-1–infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see <b>DRUG INTERACTIONS</b>]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir.</p> <h5>Ribavirin</h5> <p><i>In vitro</i> data indicate ribavirin reduces <a href="/phosphorylation/definition.htm" ">phosphorylation</a> of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects.</p> <h5>Sorbitol (Excipient)</h5> <p>Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received a single 300-mg dose of lamivudine oral solution alone or coadministered with a single dose of 3.2 g, 10.2 g, or 13.4 g of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24); 14%, 32%, and 36% in the AUC(∞); and 28%, 52%, and 55% in the Cmax; of lamivudine, respectively.</p> <h5>Abacavir, Lamivudine, Zidovudine</h5> <p>Fifteen HIV-1–infected subjects were enrolled in a crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.</p> <h5>Lamivudine And Zidovudine</h5> <p>No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 <a href="/asymptomatic/definition.htm" ">asymptomatic</a> HIV-1–infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).</p> <p>The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 10.</p> <p align="center"><b>Table 10. Effect of Coadministered Drugs on Abacavir or Lamivudine </b></p> <center> <table cellspacing="0" class="blacktbl" width="650"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="30%">Coadministered Drug and Dose</td> <td class="EmphTd" rowspan="2" width="15%">Drug and Dose</td> <td class="EmphTd" rowspan="2" width="5%">n</td> <td class="EmphTd" colspan="2">Concentrations of Abacavir or Lamivudine</td> <td class="EmphTd" rowspan="2" width="20%">Concentration of CoadministeredDrug</td> </tr> <tr> <td class="EmphTd" width="15%">AUC</td> <td class="EmphTd" width="15%">Variability</td> </tr> <tr> <td>Ethanol<br /> 0.7 g/kg</td> <td align="center">Abacavir Single 600 mg</td> <td align="center">24</td> <td align="center">↑41%</td> <td align="center">90% CI:<br /> 35% to 48%</td> <td align="center">↔<sup>a</sup></td> </tr> <tr> <td>Nelfinavir<br /> 750 mg every 8 h x 7 to 10 days</td> <td align="center">Lamivudine Single 150 mg</td> <td align="center">11</td> <td align="center">↑10%</td> <td align="center">95% CI:<br /> 1% to 20%</td> <td align="center">↔</td> </tr> <tr> <td>Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days</td> <td align="center">Lamivudine Single 300 mg</td> <td align="center">14</td> <td align="center">↑43%</td> <td align="center">90% CI:<br /> 32% to 55%</td> <td align="center">↔</td> </tr> <tr> <td class="credit" colspan="6">↑ = Increase; ↔ = No significant change.<br /> <sup>a</sup> The drug-drug interaction was only evaluated in males.</td> </tr> </tbody> </table> </center> <p></p> <h4>Microbiology</h4> <h5>Mechanism Of Action</h5> <p><i>Dolutegravir</i></p> <p>Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified recombinant HIV-1 integrase and pre-processed substrate DNA resulted in IC<sub>50</sub> values of 2.7 nM and 12.6 nM.</p> <p><i>Abacavir</i></p> <p>Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.</p> <p><i>Lamivudine</i></p> <p>Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.</p> <h5>Antiviral Activity In Cell Culture</h5> <p><i>Dolutegravir</i></p> <p>Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean concentration of drug necessary to affect viral replication by 50% (EC<sub>50</sub>) values of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a median EC<sub>50</sub> value of 0.54 nM (range: 0.41 to 0.60 nM) in a viral susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV-1 clinical isolates with median EC<sub>50</sub> values of 0.18 nM (n = 3, range: 0.09 to 0.5 nM), 0.08 nM (n = 5, range: 0.05 to 2.14 nM), 0.12 nM (n = 4, range: 0.05 to 0.51 nM), 0.17 nM (n = 3, range: 0.16 to 0.35 nM), 0.24 nM (n = 3, range: 0.09 to 0.32 nM), 0.17 nM (n = 4, range: 0.07 to 0.44 nM), 0.2 nM (n = 3, range: 0.02 to 0.87 nM), and 0.42 nM (n = 3, range: 0.41 to 1.79 nM) for clades A, B, C, D, E, F, and G, and group O viruses, respectively. Dolutegravir EC<sub>50</sub> values against three HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM.</p> <p><i>Abacavir</i></p> <p>The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including in primary monocytes/macrophages and PBMCs. EC<sub>50</sub> values ranged from 3,700 to 5,800 nM (1 nM = 0.28 ng/mL) and 70 to 1,000 nM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC<sub>50</sub> value was 260 ± 180 nM against 8 clinical isolates. The median EC<sub>50</sub> values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B), respectively. The EC<sub>50</sub> values against HIV-2 isolates (n = 4), ranged from 24 to 490 nM.</p> <p><i>Lamivudine</i></p> <p>The antiviral activity of lamivudine against HIV-1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC<sub>50</sub> values were in the range of 3 to 15,000 nM (1 nM = 0.23 ng/mL). The median EC<sub>50</sub> values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: 3 to 40 nM), 30 nM (range: 1 to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: 3 to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group O viruses (n = 3 except n = 2 for clade B) respectively. The EC<sub>50</sub> values against HIV-2 isolates (n = 4) from 3 to 120 nM in PBMCs. Ribavirin (50,000 nM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.</p> <h5>Antiviral Activity In Combination With Other Antiviral Agents</h5> <p>Neither dolutegravir, abacavir, nor lamivudine were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir), TIVICAY (dolutegravir), and EPIVIR (lamivudine).</p> <h5>Resistance In Cell Culture</h5> <p><i>Dolutegravir</i></p> <p>Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold.</p> <p><i>Abacavir and Lamivudine</i></p> <p>HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions K65R, L74V, Y115F, and M184V/I in HIV-1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74V, or Y115F with M184V or I conferred a 7- to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.</p> <h5>Resistance In Clinical Subjects</h5> <p>No subjects in the treatment arm receiving dolutegravir + EPZICOM in SINGLE (treatmentnaive trial) had a detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n = 11 with HIV-1 RNA >400 copies/mL at failure or last visit and having resistance data). Two virologic failure subjects in SINGLE had treatment-emergent G/D/E193D and G193G/E integrase substitutions at Week 84 and Week 108, respectively, and 1 subject with 275 copies/mL HIV-1 RNA had a treatment-emergent Q157Q/P integrase substitution detected at Week 24. None of these subjects had a corresponding decrease in dolutegravir susceptibility. No treatment-emergent genotypic resistance to abacavir and lamivudine, components of TRIUMEQ and TRIUMEQ PD, was observed in the arm receiving dolutegravir + EPZICOM in the SINGLE trial through Week 144.</p> <h5>Cross-Resistance</h5> <p><i>Dolutegravir</i></p> <p>Cross-resistance has been observed among INSTIs. The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a >2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, R or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a >2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference). In HIV-2 mutants, combinations of substitutions A153G/N155H/S163G and E92Q/T97A/N155H/S163D conferred 4-fold decreases in dolutegravir susceptibility, and E92Q/N155H and G140S/Q148R showed 8.5-fold and 17-fold decreases in dolutegravir susceptibility, respectively.</p> <p><i>Abacavir and Lamivudine</i></p> <p>Cross-resistance has been observed among NRTIs. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with thymidine analog mutation (TAM) substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility.</p> <a name="AP"></a> <h4>Animal Toxicology And/Or Pharmacology</h4> <p>Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 21 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined.</p> <a name="CS"></a> <h4>Clinical Studies</h4> <h4>Adult Subjects</h4> <p>The efficacy of TRIUMEQ is supported by data from a randomized, controlled trial (doubleblind through 96 weeks and open-label phase from 96 to 144 weeks) in antiretroviral treatmentnaive subjects, SINGLE (ING114467, NCT01263015) and other trials in treatment- naive subjects. See full prescribing information for TIVICAY. The efficacy of dolutegravir, in combination with at least two active background regimens in treatment-experienced, INSTInaive subjects is supported by data from SAILING (ING111762, NCT01231516) (refer to the prescribing information for TIVICAY).</p> <h5>Treatment-Naive Subjects</h5> <p>In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily with fixed-dose abacavir and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir disoproxil fumarate (ATRIPLA). At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis C co-infection (hepatitis B virus co-infection was excluded), 4% were CDC Class C (AIDS), 32% had HIV-1 RNA >100,000 copies/mL, and 53% had CD4+ cell count <350 cells/mm<sup>3</sup>; these characteristics were similar between treatment groups.</p> <p>Week 144 (open-label-phase analysis which followed the Week 96 double-blind phase) outcomes for SINGLE are provided in Table 11.</p> <p align="center"><b>Table 11. Virologic Outcomes of Randomized Treatment in SINGLE at 144 Weeks (Snapshot Algorithm) </b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%"></td> <td class="EmphTd" width="25%">TIVICAY + EPZICOM<br /> Once Daily<br /> (n = 414)</td> <td class="EmphTd" width="25%">ATRIPLA<br /> Once Daily<br /> (n = 419)</td> </tr> <tr> <td><b>HIV-1 RNA <50 copies/mL</b></td> <td align="center">71%</td> <td align="center">63%</td> </tr> <tr> <td> Treatment difference<sup>a</sup></td> <td align="center" colspan="2">8.3% (95% CI: 2.0%, 14.6%)<sup>d</sup></td> </tr> <tr> <td><b>Virologic nonresponse</b></td> <td align="center">10%</td> <td align="center">7%</td> </tr> <tr> <td> Data in window not <50 copies/mL</td> <td align="center">4%</td> <td align="center"><1%</td> </tr> <tr> <td> Discontinued for lack of efficacy</td> <td align="center">3%</td> <td align="center">3%</td> </tr> <tr> <td> Discontinued for other reasons while not suppressed</td> <td align="center">3%</td> <td align="center">4%</td> </tr> <tr> <td><b>No virologic data</b></td> <td align="center">18%</td> <td align="center">30%</td> </tr> <tr> <td colspan="3">Reasons</td> </tr> <tr> <td> Discontinued study/study drug due to adverse event or death<sup>b</sup></td> <td align="center">4%</td> <td align="center">14%</td> </tr> <tr> <td> Discontinued study/study drug for other reasons<sup>c</sup></td> <td align="center">12%</td> <td align="center">13%</td> </tr> <tr> <td> Missing data during window but on study</td> <td align="center">2%</td> <td align="center">3%</td> </tr> <tr> <td align="center" colspan="3"><b>Proportion (%) of Subjects with HIV-1 RNA <50 copies/mL by Baseline Category</b></td> </tr> <tr> <td colspan="3"><b>Plasma viral load (copies/mL)</b></td> </tr> <tr> <td> ≤100,000</td> <td align="center">73%</td> <td align="center">64%</td> </tr> <tr> <td> ≥100,000</td> <td align="center">69%</td> <td align="center">61%</td> </tr> <tr> <td colspan="3"><b>Gender</b></td> </tr> <tr> <td> Male</td> <td align="center">72%</td> <td align="center">66%</td> </tr> <tr> <td> Female</td> <td align="center">69%</td> <td align="center">48%</td> </tr> <tr> <td colspan="3"><b>Race</b></td> </tr> <tr> <td> White</td> <td align="center">72%</td> <td align="center">71%</td> </tr> <tr> <td> African American/African Heritage/Other</td> <td align="center">71%</td> <td align="center">47%</td> </tr> <tr> <td class="credit" colspan="3"><sup>a </sup>Adjusted for pre-specified stratification factors.<br /> <sup>b</sup> Includes subjects who discontinued due to an adverse event or death at any time point if this resulted in no virologic data on treatment during the analysis window.<br /> <sup>c</sup> Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.<br /> <sup>d</sup> The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 81% in the ATRIPLA group, with a treatment difference of 7.4% and 95% CI of (2.5%, 12.3%).</td> </tr> </tbody> </table> </center> <p></p> <p>Treatment differences were maintained across baseline characteristics including baseline viral load, CD4+ cell count, age, gender, and race. The adjusted mean changes in CD4+ cell counts from baseline were 378 cells per mm<sup>3</sup> in the group receiving TIVICAY + EPZICOM and 332 cells per mm<sup>3</sup> for the ATRIPLA group at 144 weeks. The adjusted difference between treatment arms and 95% CI was 46.9 cells per mm<sup>3</sup> (15.6 cells per mm<sup>3</sup>, 78.2 cells per mm<sup>3</sup>) (adjusted for pre-specified stratification factors: baseline HIV-1 RNA, and baseline CD4+ cell count).</p> <h5>Treatment-Experienced</h5> <p>In SAILING, there were 715 subjects included in the efficacy and safety analyses (see full prescribing information for TIVICAY). At Week 48, 71% of subjects randomized to TIVICAY plus background regimen versus 64% of subjects randomized to raltegravir plus background regimen had HIV-1 RNA <50 copies/mL (treatment difference and 95% CI: 7.4% [0.7%, 14.2%]).</p> <h4>Pediatric Subjects</h4> <p>The efficacy of the individual components of TRIUMEQ and TRIUMEQ PD for the treatment of HIV-1 infection was evaluated in pediatric patients enrolled in the ARROW trial (NCT02028676) and IMPAACT P1093 trial (NCT01302847), as summarized below.</p> <ul> <li>Abacavir and lamivudine once daily, in combination with a third antiretroviral drug, were evaluated in a randomized, multicenter trial (ARROW) in treatment- naive pediatric subjects with HIV-1 infection. Subjects randomized to once-daily dosing (n = 336) and who weighed at least 25 kg received abacavir 600 mg and lamivudine 300 mg, as either the single entities or as EPZICOM. At Week 96, 67% of subjects receiving abacavir and lamivudine once-daily in combination with a third antiretroviral drug, had HIV-1 RNA <80 copies/mL.</li> <li>Dolutegravir (TIVICAY or TIVICAY PD), in combination with other antiretroviral drugs was evaluated in treatment naive or treatment-experienced, INSTI- naive, HIV-1–infected subjects aged at least 4 weeks to 18 years in an ongoing open-label, multicenter, dose-finding clinical trial, IMPAACT P1093. Subjects were stratified by age cohort; subjects aged 12 to <18 years were enrolled in Cohort I, subjects aged 6 to <12 years were enrolled in Cohort IIA, and subjects aged 2 to <6 years were enrolled in Cohort III-DT. Subjects weighing at least 10 kg from Cohorts I (n = 19), IIA (n = 5), and III-DT (n = 3) who received the recommended dose (determined by weight and age) and formulation contributed to the efficacy analysis at Week 48. Across all 3 cohorts, 67% (18/27) of subjects weighing at least 10 kg achieved HIV-1 RNA <50 copies/mL at Week 48 (Snapshot algorithm).</li> </ul> </div> </div> </div> | 6 | 2023-02-01 17:38:35 | Abacavir, Dolutegravir, and Lamivudine Film-coated Tablets (Triumeq) | A | HIV, ART Combos | Triumeq | abacavir, dolutegravir, and lamivudine film-coated tablets | Triumeq | John P. Cunha, DO, FACOEP |
| 48 | 2023-02-23 12:07:03 | Medication Guide | <a name="PI"></a> <h3>PATIENT INFORMATION</h3> <p><b>TRIUMEQ</b><br /> (TRI-u-meck)<br /> (abacavir, dolutegravir, and lamivudine) tablets</p> <p><b>TRIUMEQ PD</b><br /> (TRI-u-meck Pe De)<br /> (abacavir, dolutegravir, and lamivudine) tablets for oral suspension</p> <p><b>What is the most important information I should know about TRIUMEQ and TRIUMEQ PD?</b></p> <p><b>TRIUMEQ and TRIUMEQ PD can cause serious side effects, including:</b></p> <p><b>Serious allergic reactions (hypersensitivity reaction)</b>that can cause death have happened with TRIUMEQ or TRIUMEQ PD and other abacavir-containing products. Your risk of this allergic reaction to abacavir is much higher if you have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.</p> <p><b>If you get a symptom from 2 or more of the following groups while taking TRIUMEQ or TRIUMEQ PD, call your healthcare provider right away to find out if you should stop taking TRIUMEQ or TRIUMEQ PD.</b></p> <p></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="30%"></td> <td class="EmphTd" width="70%">Symptom(s)</td> </tr> <tr> <td><b>Group 1</b></td> <td><b>Fever</b></td> </tr> <tr> <td><b>Group 2</b></td> <td><b>Rash</b></td> </tr> <tr> <td><b>Group 3</b></td> <td><b>Nausea, vomiting, diarrhea, abdominal (stomach area) pain</b></td> </tr> <tr> <td><b>Group 4</b></td> <td><b>Generally ill feeling, extreme tiredness, or achiness</b></td> </tr> <tr> <td><b>Group 5</b></td> <td><b>Shortness of breath, cough, sore throat</b></td> </tr> </tbody> </table> </center> <p></p> <p>A list of these symptoms is on the Warning Card your pharmacist gives you. <b>Carry this Warning Card with you at all times.</b></p> <p><b>If you stop TRIUMEQ or TRIUMEQ PD because of an allergic reaction, never take TRIUMEQ, TRIUMEQ PD (abacavir, dolutegravir and lamivudine), or any other medicine that contains abacavir or dolutegravir (DOVATO, EPZICOM, JULUCA, TIVICAY, TIVICAY PD, TRIZIVIR, or ZIAGEN) again.</b></p> <ul> <li>If you have an allergic reaction, dispose of any unused TRIUMEQ or TRIUMEQ PD. Ask your pharmacist how to properly dispose of medicines.</li> <li>If you take TRIUMEQ, TRIUMEQ PD or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get life-threatening symptoms that may include very <a href="/low_blood_pressure_hypotension_causes/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">low blood pressure</a> or death.</li> <li>If you stop TRIUMEQ or TRIUMEQ PD for any other reason, even for a few days, and you are not allergic to TRIUMEQ or TRIUMEQ PD, talk with your healthcare provider before taking it again. Taking TRIUMEQ or TRIUMEQ PD again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.</li> </ul> <p><b>If your healthcare provider tells you that you can take TRIUMEQ or TRIUMEQ PD again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.</b></p> <ul> <li><b>Worsening of Hepatitis B virus (HBV) infection.</b> Your healthcare provider will test you for HBV infection before you start treatment with TRIUMEQ or TRIUMEQ PD.<br /> If you have HBV infection and take TRIUMEQ or TRIUMEQ PD, your HBV may get worse (flare-up) if you stop taking TRIUMEQ or TRIUMEQ PD. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. <ul> <li>Do not run out of TRIUMEQ or TRIUMEQ PD. Refill your prescription or talk to your healthcare provider before your TRIUMEQ or TRIUMEQ PD is all gone.</li> <li>Do not stop TRIUMEQ or TRIUMEQ PD without first talking to your healthcare provider.</li> <li>If you stop taking TRIUMEQ or TRIUMEQ PD, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you a medicine to treat hepatitis B. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking TRIUMEQ or TRIUMEQ PD.</li> </ul> </li> <li><b>Resistant HBV.</b> If you have <a href="/human_immunodeficiency_virus_hiv/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">human immunodeficiency virus</a>-1 (HIV-1) and HBV, the HBV can change (mutate) during your treatment with TRIUMEQ or TRIUMEQ PD and become harder to treat (resistant). Your healthcare provider may give you other medicines to treat HBV infection if you have HIV-1 and HBV infections and take TRIUMEQ or TRIUMEQ PD.</li> <li><b>For more information about side effects, see “What are the possible side effects of TRIUMEQ or TRIUMEQ PD?”</b></li> </ul> <p><b>What is TRIUMEQ and TRIUMEQ PD?</b></p> <p>TRIUMEQ and TRIUMEQ PD are prescription medicines used to treat HIV-1 infection in adults and children who weigh at least 22 pounds (10 kg).</p> <p>HIV-1 is the virus that causes <a href="/acquired/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Acquired</a> Immune Deficiency Syndrome (<a href="/acquired_immunodeficiency_syndrome_aids/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">AIDS</a>). TRIUMEQ and TRIUMEQ PD contain the prescription medicines abacavir, dolutegravir, and lamivudine.</p> <ul> <li>TRIUMEQ or TRIUMEQ PD should not be used by itself in people who have resistance to certain types of medicines.</li> </ul> <p>It is not known if TRIUMEQ PD is safe and effective in children who weigh less than 22 pounds (10 kg).</p> <p><b>Do not take TRIUMEQ or TRIUMEQ PD if you:</b></p> <ul> <li>have a certain type of gene variation called the HLA-B*5701 allele. Your healthcare provider will test you for this before prescribing treatment with TRIUMEQ or TRIUMEQ PD.</li> <li>are allergic to abacavir, dolutegravir, lamivudine, or any of the ingredients in TRIUMEQ or TRIUMEQ PD. See the end of this Medication Guide for a complete list of ingredients in TRIUMEQ and TRIUMEQ PD.</li> <li>take dofetilide. Taking TRIUMEQ or TRIUMEQ PD and dofetilide can cause side effects that may be serious or life-threatening.</li> <li>have certain liver problems.</li> </ul> <p><b>Before you take TRIUMEQ or TRIUMEQ PD, tell your healthcare provider about all of your medical conditions, including if you:</b></p> <ul> <li>have been tested and know whether or not you have a particular gene variation called HLA-B*5701.</li> <li>have or have had liver problems, including hepatitis B or C virus infection.</li> <li>have kidney problems.</li> <li>have heart problems, smoke, or have diseases that increase your risk of heart disease such as <a href="/high_blood_pressure_hypertension_medications/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">high blood pressure</a>, high <a href="/cholesterol/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cholesterol</a>, or diabetes.</li> <li>drink alcohol or take medicines that contain alcohol.</li> <li>are pregnant or plan to become pregnant. One of the medicines in TRIUMEQ and TRIUMEQ PD called dolutegravir may harm your unborn baby. <ul> <li>Your healthcare provider may prescribe a different medicine than TRIUMEQ if you are planning to become pregnant or if pregnancy is confirmed during the first 12 weeks of pregnancy.</li> <li>If you can become pregnant, your healthcare provider may perform a <a href="/pregnancy_test/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">pregnancy test</a> before you start treatment with TRIUMEQ.</li> <li>If you can become pregnant, you and your healthcare provider should talk about the use of effective birth control (contraception) during treatment with TRIUMEQ.</li> <li>Tell your healthcare provider right away if you are planning to become pregnant, you become pregnant, or think you may be pregnant during treatment with TRIUMEQ.</li> </ul> </li> </ul> <p><b>Pregnancy Registry.</b> There is a pregnancy registry for individuals who take TRIUMEQ and TRIUMEQ PD during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.</p> <ul> <li>are breastfeeding or plan to breastfeed. <b>Do not breastfeed if you take TRIUMEQ.</b> <ul> <li>You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.</li> <li>Two of the medicines in TRIUMEQ and TRIUMEQ PD (abacavir and lamivudine) pass into your breastmilk.</li> </ul> </li> </ul> <p><b>Tell your healthcare provider about all the medicines you take</b>, including prescription and over-thecounter medicines, vitamins, and herbal supplements.</p> <p>Some medicines interact with TRIUMEQ or TRIUMEQ PD. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.</p> <ul> <li>You can ask your healthcare provider or pharmacist for a list of medicines that interact with TRIUMEQ or TRIUMEQ PD.</li> <li><b>Do not start taking a new medicine without telling your healthcare provider.</b>Your healthcare provider can tell you if it is safe to take TRIUMEQ or TRIUMEQ PD with other medicines.</li> </ul> <p><b>How should I take TRIUMEQ or TRIUMEQ PD?</b></p> <p><b>Read the Instructions for Use at the end of this Medication Guide for detailed instructions on how to prepare a dose of TRIUMEQ PD tablets for oral suspension.</b></p> <ul> <li><b>Take TRIUMEQ or TRIUMEQ PD exactly as your healthcare provider tells you to take it.</b></li> <li>Do not change your dose, switch medicines or stop taking TRIUMEQ or TRIUMEQ PD without talking with your healthcare provider first.</li> <li><b>TRIUMEQ tablets are not the same as TRIUMEQ PD tablets for oral suspension and cannot be substituted for each other. Check to make sure you receive the correct dosage form each time you or your child’s prescription is filled to avoid using the wrong medicine.</b></li> <li>Your child’s healthcare provider will prescribe TRIUMEQ or TRIUMEQ PD based on your child’s weight.</li> <li>TRIUMEQ PD tablets for oral suspension should be dispersed in drinking water.</li> <li>Do <b>not</b> chew, cut, or crush TRIUMEQ tablets or TRIUMEQ PD tablets for oral suspension.</li> <li>TRIUMEQ or TRIUMEQ PD may be taken with or without food.</li> <li>If you take antacids, laxatives, or other medicines that contain aluminum, magnesium, or buffered medicines, TRIUMEQ or TRIUMEQ PD should be taken at least 2 hours before or 6 hours after you take these medicines.</li> <li>If you need to take iron or calcium supplements by mouth during treatment with TRIUMEQ or TRIUMEQ PD: <ul> <li>If you take TRIUMEQ or TRIUMEQ PD with food, you may take these supplements at the same time that you take TRIUMEQ or TRIUMEQ PD.</li> <li>If you do not take TRIUMEQ or TRIUMEQ PD with food, take TRIUMEQ or TRIUMEQ PD at least 2 hours before or 6 hours after you take these supplements.</li> </ul> </li> <li>If you miss a dose of TRIUMEQ or TRIUMEQ PD, take it as soon as you remember. Do not take 2 doses at the same time or take more than your healthcare provider tells you to take.</li> <li>Stay under the care of a healthcare provider during treatment with TRIUMEQ or TRIUMEQ PD.</li> <li>Do not run out of TRIUMEQ or TRIUMEQ PD. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.</li> <li>If you take too much TRIUMEQ or TRIUMEQ PD, call your healthcare provider or go to the nearest hospital emergency room right away.</li> </ul> <p><b>What are the possible side effects of TRIUMEQ or TRIUMEQ PD?</b></p> <p><b>TRIUMEQ or TRIUMEQ PD can cause serious side effects, including:</b></p> <p><b>See “What is the most important information I should know about TRIUMEQ and TRIUMEQ PD?”</b></p> <ul> <li><b>Liver problems.</b>People with a history of hepatitis B or C virus may have an increased risk of developing new or worsening changes in certain liver function tests during treatment with TRIUMEQ or TRIUMEQ PD. Liver problems including liver failure have also happened with TRIUMEQ or TRIUMEQ PD in people without a history of liver disease or other risk factors. Liver failure resulting in liver transplant has also been reported with TRIUMEQ. Your healthcare provider may do blood tests to check your liver.<b>Call your healthcare provider right away if you develop any of the signs or symptoms of liver problems listed below.</b> <ul> <li>your skin or the white part of your eyes turns yellow (jaundice)</li> <li>dark or “tea-colored” urine</li> <li>light colored stools (bowel movements)</li> <li>loss of appetite</li> <li>nausea or vomiting</li> <li>pain, aching, or tenderness on the right side of your stomach area</li> </ul> </li> <li><b>Too much lactic acid in your blood (lactic acidosis).</b> Too much lactic acid is a serious medical emergency that can lead to death. <b>Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:</b> <ul> <li>feel very weak or tired</li> <li>unusual (not normal) muscle pain</li> <li>trouble breathing</li> <li>stomach pain with <a href="/nausea_and_vomiting/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">nausea and vomiting</a></li> <li>feel cold, especially in your arms and legs</li> <li>feel dizzy or lightheaded</li> <li>have a fast or irregular heartbeat</li> </ul> </li> <li><b>Lactic acidosis can also lead to severe liver problems,</b>which can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). <b>Call your healthcare provider right away if you get any of the signs or symptoms of liver problems which are listed above under “Liver problems”.</b></li> <li><b>You may be more likely to get lactic acidosis or severe liver problems if you are female or very overweight (obese).</b></li> <li><b>Changes in your immune system (Immune Reconstitution Syndrome)</b> can happen when you start taking HIV-1 medicines. Your <a href="/immune_system/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">immune system</a> may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking TRIUMEQ or TRIUMEQ PD.</li> <li><b>Heart attack.</b>Some HIV-1 medicines including TRIUMEQ or TRIUMEQ PD may increase your risk of <a href="/heart_attack/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">heart attack</a>.</li> <li><b>The most common side effects of TRIUMEQ include:</b> <ul> <li>trouble sleeping</li> <li>headache</li> <li>tiredness</li> </ul> </li> </ul> <p>These are not all the possible side effects of TRIUMEQ or TRIUMEQ PD.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <p><b>How should I store TRIUMEQ or TRIUMEQ PD?</b></p> <ul> <li>Store TRIUMEQ and TRIUMEQ PD at room temperature between 68°F to 77°F (20°C to 25°C) in the original bottle. Keep the bottle tightly closed and protect it from moisture.</li> <li>The bottle of TRIUMEQ and TRIUMEQ PD contains a desiccant packet to help keep your medicine dry (protect it from moisture). Do not remove the desiccant packet from the bottle.</li> </ul> <p><b>Keep TRIUMEQ, TRIUMEQ PD, and all medicines out of the reach of children.</b></p> <p><b>General information about the safe and effective use of TRIUMEQ or TRIUMEQ PD.</b></p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRIUMEQ or TRIUMEQ PD for a condition for which it was not prescribed. Do not give TRIUMEQ or TRIUMEQ PD to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TRIUMEQ or TRIUMEQ PD that is written for health professionals.</p> <p><b>What are the ingredients in TRIUMEQ and TRIUMEQ PD?</b></p> <p><b>Active ingredients:</b> abacavir, dolutegravir, and lamivudine</p> <p><b>Inactive ingredients:</b></p> <p>TRIUMEQ tablets: D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Tablet film-coating contains: iron oxide black, iron oxide red, macrogol/PEG, polyvinyl alcohol–part hydrolyzed, talc, and titanium oxide.</p> <p>TRIUMEQ PD tablets for oral suspension: acesulfame <a href="/potassium/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">potassium</a>, crospovidone, mannitol, microcrystalline cellulose, povidone K29/32, silicified microcrystalline cellulose, sodium starch glycolate, sodium stearyl fumarate, <a href="/strawberry/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">strawberry</a> cream flavor, and sucralose.</p> <p>Tablet film-coating contains: ferric oxide yellow, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.</p> <p class="credit">This Medication Guide has been approved by the U.S. Food and Drug Administration.</p> <p><b>INSTRUCTIONS FOR USE</b></p> <p><b>TRIUMEQ PD</b><br /> (TRI-u-meck Pe De)<br /> (abacavir, dolutegravir, and lamivudine)<br /> tablets for oral suspension</p> <p>This Instructions for Use contains information on how to take TRIUMEQ PD. Read this Instructions for Use before your child starts taking TRIUMEQ PD for the first time and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your child’s medical condition or treatment. Talk to your healthcare provider or pharmacist if you have any questions on how to prepare or give the prescribed dose of TRIUMEQ PD.</p> <p><b>Important information</b></p> <ul> <li>Give TRIUMEQ PD exactly as your healthcare provider tells you.</li> <li><b>Each time you receive your child’s prescription, check the bottle to make sure that you received the correct dosage form of TRIUMEQ PD. Contact your pharmacist or healthcare provider if you did not receive the correct dosage form.</b></li> <li><b>Do not</b> chew, cut, or crush the tablets for oral suspension.</li> <li>If you forget to give a dose of TRIUMEQ PD, give it as soon as you remember. Do not give 2 doses at the same time or give more than your healthcare provider has prescribed.</li> <li>If your child does not or cannot take the full dose, call your healthcare provider.</li> <li>If you give too much TRIUMEQ PD, get emergency medical help right away.</li> <li>For more information about TRIUMEQ PD, read the Medication Guide.</li> </ul> <p><b>Your pack contains:</b></p> <ul> <li>A bottle containing 90 <b>TRIUMEQ PD</b> tablets for oral suspension</li> <li>Dosing cup</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="239"> <tbody> <tr> <td><img alt="A bottle containing 90 TRIUMEQ PD tablets for oral suspension, Dosing cup - Illustration" height="239" src="https://images.rxlist.com/images/rxlist/triumeq4.gif" width="239" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>You will also need:</b></p> <ul> <li>Clean drinking water.</li> </ul> <p><b>Getting Ready</b></p> <p><b>Step 1. Pour water</b></p> <ul> <li>Pour 20 mL of clean drinking water into the cup.</li> </ul> <p><b>See Figure A.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="296"> <tbody> <tr> <td><img alt="Pour 20 mL of clean drinking water into the cup - Illustration" height="195" src="https://images.rxlist.com/images/rxlist/triumeq5.gif" width="296" /></td> </tr> </tbody> </table> <br /> <b>Figure A</b></center> <p></p> <p><b>Use drinking water only.</b></p> <p><b>Do not</b> use any other drink or food to prepare the dose.</p> <p><b>Step 2. Prepare the medicine</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="163"> <tbody> <tr> <td><img alt="Add the prescribed number of tablet(s) to the water - Illustration" height="195" src="https://images.rxlist.com/images/rxlist/triumeq6.gif" width="163" /></td> </tr> </tbody> </table> <br /> <b>Figure B</b></center> <p></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="127"> <tbody> <tr> <td><img alt="Swirl the cup gently for 1 to 2 minutes to disperse the tablet(s). The medicine will become cloudy - Illustration" height="193" src="https://images.rxlist.com/images/rxlist/triumeq7.gif" width="127" /></td> </tr> </tbody> </table> <br /> <b>Figure C</b></center> <p></p> <ul> <li>Add the prescribed number of tablet(s) to the water.<b>See Figure B.</b></li> <li>Swirl the cup gently for 1 to 2 minutes to disperse the tablet(s). The medicine will become cloudy. Take care not to spill any of the medicine. <b>See Figure C.</b></li> <li>Check that the medicine is ready. If there are any lumps of tablet, swirl the cup until they are gone.</li> </ul> <p>If you spill any medicine, clean up the spill.</p> <p>Throw away the rest of the prepared medicine and make a new dose.</p> <p><b>You must give the dose of medicine within 30 minutes of preparing the dose.</b> If it has been more than 30 minutes, wash away all the dose in the cup using water and prepare a new dose of medicine.</p> <p><b>Giving the medicine</b></p> <p><b>Step 3. Give the medicine</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="288"> <tbody> <tr> <td><img alt="Make sure that the child is upright. Give all the prepared medicine to the child - Illustration" height="183" src="https://images.rxlist.com/images/rxlist/triumeq8.gif" width="288" /></td> </tr> </tbody> </table> <br /> <b>Figure D</b></center> <p></p> <ul> <li>Make sure that the child is upright. Give all the prepared medicine to the child. <b>See Figure D.</b></li> <li>Add another 15 mL of drinking water to the cup, swirl, and give it all to the child.</li> <li><b>Repeat if any medicine remains in the cup to make sure the child gets the full dose.</b></li> </ul> <p><b>Clean</b></p> <p><b>Step 4. Clean the dosing cup</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="257"> <tbody> <tr> <td><img alt="Wash the cup with water - Illustration" height="165" src="https://images.rxlist.com/images/rxlist/triumeq9.gif" width="257" /></td> </tr> </tbody> </table> <br /> <b>Figure E</b></center> <p></p> <ul> <li>Wash the cup with water. <b>See Figure E.</b></li> <li>The cup will need to be clean before preparing the next dose.</li> </ul> <p><b>Storage Information</b></p> <ul> <li>Store TRIUMEQ PD tablets for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C) in the original bottle. Keep the bottle tightly closed and protect from moisture.</li> <li>The TRIUMEQ PD bottle contains a desiccant packet to help keep your medicine dry (protect it from moisture). Do not remove the desiccant packet from the bottle.</li> </ul> <p><b>Keep TRIUMEQ PD and all medicines out of the reach of children.</b></p> <p><b>Disposal Information</b></p> <p><b>When all the tablets in the bottle have been taken or are no longer needed, throw away the bottle and cup. Dispose of them using your local household waste guidelines.</b></p> <p>You will get a new cup in your next pack.</p> <p class="credit">This Instructions for Use has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | <a name="PI"></a> <h3>PATIENT INFORMATION</h3> <p><b>TRIUMEQ</b><br /> (TRI-u-meck)<br /> (abacavir, dolutegravir, and lamivudine) tablets</p> <p><b>TRIUMEQ PD</b><br /> (TRI-u-meck Pe De)<br /> (abacavir, dolutegravir, and lamivudine) tablets for oral suspension</p> <p><b>What is the most important information I should know about TRIUMEQ and TRIUMEQ PD?</b></p> <p><b>TRIUMEQ and TRIUMEQ PD can cause serious side effects, including:</b></p> <p><b>Serious allergic reactions (hypersensitivity reaction)</b>that can cause death have happened with TRIUMEQ or TRIUMEQ PD and other abacavir-containing products. Your risk of this allergic reaction to abacavir is much higher if you have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation.</p> <p><b>If you get a symptom from 2 or more of the following groups while taking TRIUMEQ or TRIUMEQ PD, call your healthcare provider right away to find out if you should stop taking TRIUMEQ or TRIUMEQ PD.</b></p> <p></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="30%"></td> <td class="EmphTd" width="70%">Symptom(s)</td> </tr> <tr> <td><b>Group 1</b></td> <td><b>Fever</b></td> </tr> <tr> <td><b>Group 2</b></td> <td><b>Rash</b></td> </tr> <tr> <td><b>Group 3</b></td> <td><b>Nausea, vomiting, diarrhea, abdominal (stomach area) pain</b></td> </tr> <tr> <td><b>Group 4</b></td> <td><b>Generally ill feeling, extreme tiredness, or achiness</b></td> </tr> <tr> <td><b>Group 5</b></td> <td><b>Shortness of breath, cough, sore throat</b></td> </tr> </tbody> </table> </center> <p></p> <p>A list of these symptoms is on the Warning Card your pharmacist gives you. <b>Carry this Warning Card with you at all times.</b></p> <p><b>If you stop TRIUMEQ or TRIUMEQ PD because of an allergic reaction, never take TRIUMEQ, TRIUMEQ PD (abacavir, dolutegravir and lamivudine), or any other medicine that contains abacavir or dolutegravir (DOVATO, EPZICOM, JULUCA, TIVICAY, TIVICAY PD, TRIZIVIR, or ZIAGEN) again.</b></p> <ul> <li>If you have an allergic reaction, dispose of any unused TRIUMEQ or TRIUMEQ PD. Ask your pharmacist how to properly dispose of medicines.</li> <li>If you take TRIUMEQ, TRIUMEQ PD or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get life-threatening symptoms that may include very <a href="/low_blood_pressure_hypotension_causes/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">low blood pressure</a> or death.</li> <li>If you stop TRIUMEQ or TRIUMEQ PD for any other reason, even for a few days, and you are not allergic to TRIUMEQ or TRIUMEQ PD, talk with your healthcare provider before taking it again. Taking TRIUMEQ or TRIUMEQ PD again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.</li> </ul> <p><b>If your healthcare provider tells you that you can take TRIUMEQ or TRIUMEQ PD again, start taking it when you are around medical help or people who can call a healthcare provider if you need one.</b></p> <ul> <li><b>Worsening of Hepatitis B virus (HBV) infection.</b> Your healthcare provider will test you for HBV infection before you start treatment with TRIUMEQ or TRIUMEQ PD.<br /> If you have HBV infection and take TRIUMEQ or TRIUMEQ PD, your HBV may get worse (flare-up) if you stop taking TRIUMEQ or TRIUMEQ PD. A “flare-up” is when your HBV infection suddenly returns in a worse way than before. <ul> <li>Do not run out of TRIUMEQ or TRIUMEQ PD. Refill your prescription or talk to your healthcare provider before your TRIUMEQ or TRIUMEQ PD is all gone.</li> <li>Do not stop TRIUMEQ or TRIUMEQ PD without first talking to your healthcare provider.</li> <li>If you stop taking TRIUMEQ or TRIUMEQ PD, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you a medicine to treat hepatitis B. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking TRIUMEQ or TRIUMEQ PD.</li> </ul> </li> <li><b>Resistant HBV.</b> If you have <a href="/human_immunodeficiency_virus_hiv/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">human immunodeficiency virus</a>-1 (HIV-1) and HBV, the HBV can change (mutate) during your treatment with TRIUMEQ or TRIUMEQ PD and become harder to treat (resistant). Your healthcare provider may give you other medicines to treat HBV infection if you have HIV-1 and HBV infections and take TRIUMEQ or TRIUMEQ PD.</li> <li><b>For more information about side effects, see “What are the possible side effects of TRIUMEQ or TRIUMEQ PD?”</b></li> </ul> <p><b>What is TRIUMEQ and TRIUMEQ PD?</b></p> <p>TRIUMEQ and TRIUMEQ PD are prescription medicines used to treat HIV-1 infection in adults and children who weigh at least 22 pounds (10 kg).</p> <p>HIV-1 is the virus that causes <a href="/acquired/definition.htm" ">Acquired</a> Immune Deficiency Syndrome (<a href="/acquired_immunodeficiency_syndrome_aids/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">AIDS</a>). TRIUMEQ and TRIUMEQ PD contain the prescription medicines abacavir, dolutegravir, and lamivudine.</p> <ul> <li>TRIUMEQ or TRIUMEQ PD should not be used by itself in people who have resistance to certain types of medicines.</li> </ul> <p>It is not known if TRIUMEQ PD is safe and effective in children who weigh less than 22 pounds (10 kg).</p> <p><b>Do not take TRIUMEQ or TRIUMEQ PD if you:</b></p> <ul> <li>have a certain type of gene variation called the HLA-B*5701 allele. Your healthcare provider will test you for this before prescribing treatment with TRIUMEQ or TRIUMEQ PD.</li> <li>are allergic to abacavir, dolutegravir, lamivudine, or any of the ingredients in TRIUMEQ or TRIUMEQ PD. See the end of this Medication Guide for a complete list of ingredients in TRIUMEQ and TRIUMEQ PD.</li> <li>take dofetilide. Taking TRIUMEQ or TRIUMEQ PD and dofetilide can cause side effects that may be serious or life-threatening.</li> <li>have certain liver problems.</li> </ul> <p><b>Before you take TRIUMEQ or TRIUMEQ PD, tell your healthcare provider about all of your medical conditions, including if you:</b></p> <ul> <li>have been tested and know whether or not you have a particular gene variation called HLA-B*5701.</li> <li>have or have had liver problems, including hepatitis B or C virus infection.</li> <li>have kidney problems.</li> <li>have heart problems, smoke, or have diseases that increase your risk of heart disease such as <a href="/high_blood_pressure_hypertension_medications/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">high blood pressure</a>, high <a href="/cholesterol/definition.htm" ">cholesterol</a>, or diabetes.</li> <li>drink alcohol or take medicines that contain alcohol.</li> <li>are pregnant or plan to become pregnant. One of the medicines in TRIUMEQ and TRIUMEQ PD called dolutegravir may harm your unborn baby. <ul> <li>Your healthcare provider may prescribe a different medicine than TRIUMEQ if you are planning to become pregnant or if pregnancy is confirmed during the first 12 weeks of pregnancy.</li> <li>If you can become pregnant, your healthcare provider may perform a <a href="/pregnancy_test/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">pregnancy test</a> before you start treatment with TRIUMEQ.</li> <li>If you can become pregnant, you and your healthcare provider should talk about the use of effective birth control (contraception) during treatment with TRIUMEQ.</li> <li>Tell your healthcare provider right away if you are planning to become pregnant, you become pregnant, or think you may be pregnant during treatment with TRIUMEQ.</li> </ul> </li> </ul> <p><b>Pregnancy Registry.</b> There is a pregnancy registry for individuals who take TRIUMEQ and TRIUMEQ PD during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.</p> <ul> <li>are breastfeeding or plan to breastfeed. <b>Do not breastfeed if you take TRIUMEQ.</b> <ul> <li>You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.</li> <li>Two of the medicines in TRIUMEQ and TRIUMEQ PD (abacavir and lamivudine) pass into your breastmilk.</li> </ul> </li> </ul> <p><b>Tell your healthcare provider about all the medicines you take</b>, including prescription and over-thecounter medicines, vitamins, and herbal supplements.</p> <p>Some medicines interact with TRIUMEQ or TRIUMEQ PD. Keep a list of your medicines to show your healthcare provider and pharmacist when you get a new medicine.</p> <ul> <li>You can ask your healthcare provider or pharmacist for a list of medicines that interact with TRIUMEQ or TRIUMEQ PD.</li> <li><b>Do not start taking a new medicine without telling your healthcare provider.</b>Your healthcare provider can tell you if it is safe to take TRIUMEQ or TRIUMEQ PD with other medicines.</li> </ul> <p><b>How should I take TRIUMEQ or TRIUMEQ PD?</b></p> <p><b>Read the Instructions for Use at the end of this Medication Guide for detailed instructions on how to prepare a dose of TRIUMEQ PD tablets for oral suspension.</b></p> <ul> <li><b>Take TRIUMEQ or TRIUMEQ PD exactly as your healthcare provider tells you to take it.</b></li> <li>Do not change your dose, switch medicines or stop taking TRIUMEQ or TRIUMEQ PD without talking with your healthcare provider first.</li> <li><b>TRIUMEQ tablets are not the same as TRIUMEQ PD tablets for oral suspension and cannot be substituted for each other. Check to make sure you receive the correct dosage form each time you or your child’s prescription is filled to avoid using the wrong medicine.</b></li> <li>Your child’s healthcare provider will prescribe TRIUMEQ or TRIUMEQ PD based on your child’s weight.</li> <li>TRIUMEQ PD tablets for oral suspension should be dispersed in drinking water.</li> <li>Do <b>not</b> chew, cut, or crush TRIUMEQ tablets or TRIUMEQ PD tablets for oral suspension.</li> <li>TRIUMEQ or TRIUMEQ PD may be taken with or without food.</li> <li>If you take antacids, laxatives, or other medicines that contain aluminum, magnesium, or buffered medicines, TRIUMEQ or TRIUMEQ PD should be taken at least 2 hours before or 6 hours after you take these medicines.</li> <li>If you need to take iron or calcium supplements by mouth during treatment with TRIUMEQ or TRIUMEQ PD: <ul> <li>If you take TRIUMEQ or TRIUMEQ PD with food, you may take these supplements at the same time that you take TRIUMEQ or TRIUMEQ PD.</li> <li>If you do not take TRIUMEQ or TRIUMEQ PD with food, take TRIUMEQ or TRIUMEQ PD at least 2 hours before or 6 hours after you take these supplements.</li> </ul> </li> <li>If you miss a dose of TRIUMEQ or TRIUMEQ PD, take it as soon as you remember. Do not take 2 doses at the same time or take more than your healthcare provider tells you to take.</li> <li>Stay under the care of a healthcare provider during treatment with TRIUMEQ or TRIUMEQ PD.</li> <li>Do not run out of TRIUMEQ or TRIUMEQ PD. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.</li> <li>If you take too much TRIUMEQ or TRIUMEQ PD, call your healthcare provider or go to the nearest hospital emergency room right away.</li> </ul> <p><b>What are the possible side effects of TRIUMEQ or TRIUMEQ PD?</b></p> <p><b>TRIUMEQ or TRIUMEQ PD can cause serious side effects, including:</b></p> <p><b>See “What is the most important information I should know about TRIUMEQ and TRIUMEQ PD?”</b></p> <ul> <li><b>Liver problems.</b>People with a history of hepatitis B or C virus may have an increased risk of developing new or worsening changes in certain liver function tests during treatment with TRIUMEQ or TRIUMEQ PD. Liver problems including liver failure have also happened with TRIUMEQ or TRIUMEQ PD in people without a history of liver disease or other risk factors. Liver failure resulting in liver transplant has also been reported with TRIUMEQ. Your healthcare provider may do blood tests to check your liver.<b>Call your healthcare provider right away if you develop any of the signs or symptoms of liver problems listed below.</b> <ul> <li>your skin or the white part of your eyes turns yellow (jaundice)</li> <li>dark or “tea-colored” urine</li> <li>light colored stools (bowel movements)</li> <li>loss of appetite</li> <li>nausea or vomiting</li> <li>pain, aching, or tenderness on the right side of your stomach area</li> </ul> </li> <li><b>Too much lactic acid in your blood (lactic acidosis).</b> Too much lactic acid is a serious medical emergency that can lead to death. <b>Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:</b> <ul> <li>feel very weak or tired</li> <li>unusual (not normal) muscle pain</li> <li>trouble breathing</li> <li>stomach pain with <a href="/nausea_and_vomiting/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">nausea and vomiting</a></li> <li>feel cold, especially in your arms and legs</li> <li>feel dizzy or lightheaded</li> <li>have a fast or irregular heartbeat</li> </ul> </li> <li><b>Lactic acidosis can also lead to severe liver problems,</b>which can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). <b>Call your healthcare provider right away if you get any of the signs or symptoms of liver problems which are listed above under “Liver problems”.</b></li> <li><b>You may be more likely to get lactic acidosis or severe liver problems if you are female or very overweight (obese).</b></li> <li><b>Changes in your immune system (Immune Reconstitution Syndrome)</b> can happen when you start taking HIV-1 medicines. Your <a href="/immune_system/definition.htm" ">immune system</a> may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking TRIUMEQ or TRIUMEQ PD.</li> <li><b>Heart attack.</b>Some HIV-1 medicines including TRIUMEQ or TRIUMEQ PD may increase your risk of <a href="/heart_attack/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">heart attack</a>.</li> <li><b>The most common side effects of TRIUMEQ include:</b> <ul> <li>trouble sleeping</li> <li>headache</li> <li>tiredness</li> </ul> </li> </ul> <p>These are not all the possible side effects of TRIUMEQ or TRIUMEQ PD.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <p><b>How should I store TRIUMEQ or TRIUMEQ PD?</b></p> <ul> <li>Store TRIUMEQ and TRIUMEQ PD at room temperature between 68°F to 77°F (20°C to 25°C) in the original bottle. Keep the bottle tightly closed and protect it from moisture.</li> <li>The bottle of TRIUMEQ and TRIUMEQ PD contains a desiccant packet to help keep your medicine dry (protect it from moisture). Do not remove the desiccant packet from the bottle.</li> </ul> <p><b>Keep TRIUMEQ, TRIUMEQ PD, and all medicines out of the reach of children.</b></p> <p><b>General information about the safe and effective use of TRIUMEQ or TRIUMEQ PD.</b></p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRIUMEQ or TRIUMEQ PD for a condition for which it was not prescribed. Do not give TRIUMEQ or TRIUMEQ PD to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TRIUMEQ or TRIUMEQ PD that is written for health professionals.</p> <p><b>What are the ingredients in TRIUMEQ and TRIUMEQ PD?</b></p> <p><b>Active ingredients:</b> abacavir, dolutegravir, and lamivudine</p> <p><b>Inactive ingredients:</b></p> <p>TRIUMEQ tablets: D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Tablet film-coating contains: iron oxide black, iron oxide red, macrogol/PEG, polyvinyl alcohol–part hydrolyzed, talc, and titanium oxide.</p> <p>TRIUMEQ PD tablets for oral suspension: acesulfame <a href="/potassium/definition.htm" ">potassium</a>, crospovidone, mannitol, microcrystalline cellulose, povidone K29/32, silicified microcrystalline cellulose, sodium starch glycolate, sodium stearyl fumarate, <a href="/strawberry/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">strawberry</a> cream flavor, and sucralose.</p> <p>Tablet film-coating contains: ferric oxide yellow, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.</p> <p class="credit">This Medication Guide has been approved by the U.S. Food and Drug Administration.</p> <p><b>INSTRUCTIONS FOR USE</b></p> <p><b>TRIUMEQ PD</b><br /> (TRI-u-meck Pe De)<br /> (abacavir, dolutegravir, and lamivudine)<br /> tablets for oral suspension</p> <p>This Instructions for Use contains information on how to take TRIUMEQ PD. Read this Instructions for Use before your child starts taking TRIUMEQ PD for the first time and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your child’s medical condition or treatment. Talk to your healthcare provider or pharmacist if you have any questions on how to prepare or give the prescribed dose of TRIUMEQ PD.</p> <p><b>Important information</b></p> <ul> <li>Give TRIUMEQ PD exactly as your healthcare provider tells you.</li> <li><b>Each time you receive your child’s prescription, check the bottle to make sure that you received the correct dosage form of TRIUMEQ PD. Contact your pharmacist or healthcare provider if you did not receive the correct dosage form.</b></li> <li><b>Do not</b> chew, cut, or crush the tablets for oral suspension.</li> <li>If you forget to give a dose of TRIUMEQ PD, give it as soon as you remember. Do not give 2 doses at the same time or give more than your healthcare provider has prescribed.</li> <li>If your child does not or cannot take the full dose, call your healthcare provider.</li> <li>If you give too much TRIUMEQ PD, get emergency medical help right away.</li> <li>For more information about TRIUMEQ PD, read the Medication Guide.</li> </ul> <p><b>Your pack contains:</b></p> <ul> <li>A bottle containing 90 <b>TRIUMEQ PD</b> tablets for oral suspension</li> <li>Dosing cup</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="239"> <tbody> <tr> <td><img alt="A bottle containing 90 TRIUMEQ PD tablets for oral suspension, Dosing cup - Illustration" height="239" src="https://images.rxlist.com/images/rxlist/triumeq4.gif" width="239" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>You will also need:</b></p> <ul> <li>Clean drinking water.</li> </ul> <p><b>Getting Ready</b></p> <p><b>Step 1. Pour water</b></p> <ul> <li>Pour 20 mL of clean drinking water into the cup.</li> </ul> <p><b>See Figure A.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="296"> <tbody> <tr> <td><img alt="Pour 20 mL of clean drinking water into the cup - Illustration" height="195" src="https://images.rxlist.com/images/rxlist/triumeq5.gif" width="296" /></td> </tr> </tbody> </table> <br /> <b>Figure A</b></center> <p></p> <p><b>Use drinking water only.</b></p> <p><b>Do not</b> use any other drink or food to prepare the dose.</p> <p><b>Step 2. Prepare the medicine</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="163"> <tbody> <tr> <td><img alt="Add the prescribed number of tablet(s) to the water - Illustration" height="195" src="https://images.rxlist.com/images/rxlist/triumeq6.gif" width="163" /></td> </tr> </tbody> </table> <br /> <b>Figure B</b></center> <p></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="127"> <tbody> <tr> <td><img alt="Swirl the cup gently for 1 to 2 minutes to disperse the tablet(s). The medicine will become cloudy - Illustration" height="193" src="https://images.rxlist.com/images/rxlist/triumeq7.gif" width="127" /></td> </tr> </tbody> </table> <br /> <b>Figure C</b></center> <p></p> <ul> <li>Add the prescribed number of tablet(s) to the water.<b>See Figure B.</b></li> <li>Swirl the cup gently for 1 to 2 minutes to disperse the tablet(s). The medicine will become cloudy. Take care not to spill any of the medicine. <b>See Figure C.</b></li> <li>Check that the medicine is ready. If there are any lumps of tablet, swirl the cup until they are gone.</li> </ul> <p>If you spill any medicine, clean up the spill.</p> <p>Throw away the rest of the prepared medicine and make a new dose.</p> <p><b>You must give the dose of medicine within 30 minutes of preparing the dose.</b> If it has been more than 30 minutes, wash away all the dose in the cup using water and prepare a new dose of medicine.</p> <p><b>Giving the medicine</b></p> <p><b>Step 3. Give the medicine</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="288"> <tbody> <tr> <td><img alt="Make sure that the child is upright. Give all the prepared medicine to the child - Illustration" height="183" src="https://images.rxlist.com/images/rxlist/triumeq8.gif" width="288" /></td> </tr> </tbody> </table> <br /> <b>Figure D</b></center> <p></p> <ul> <li>Make sure that the child is upright. Give all the prepared medicine to the child. <b>See Figure D.</b></li> <li>Add another 15 mL of drinking water to the cup, swirl, and give it all to the child.</li> <li><b>Repeat if any medicine remains in the cup to make sure the child gets the full dose.</b></li> </ul> <p><b>Clean</b></p> <p><b>Step 4. Clean the dosing cup</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="257"> <tbody> <tr> <td><img alt="Wash the cup with water - Illustration" height="165" src="https://images.rxlist.com/images/rxlist/triumeq9.gif" width="257" /></td> </tr> </tbody> </table> <br /> <b>Figure E</b></center> <p></p> <ul> <li>Wash the cup with water. <b>See Figure E.</b></li> <li>The cup will need to be clean before preparing the next dose.</li> </ul> <p><b>Storage Information</b></p> <ul> <li>Store TRIUMEQ PD tablets for oral suspension at room temperature between 68°F to 77°F (20°C to 25°C) in the original bottle. Keep the bottle tightly closed and protect from moisture.</li> <li>The TRIUMEQ PD bottle contains a desiccant packet to help keep your medicine dry (protect it from moisture). Do not remove the desiccant packet from the bottle.</li> </ul> <p><b>Keep TRIUMEQ PD and all medicines out of the reach of children.</b></p> <p><b>Disposal Information</b></p> <p><b>When all the tablets in the bottle have been taken or are no longer needed, throw away the bottle and cup. Dispose of them using your local household waste guidelines.</b></p> <p>You will get a new cup in your next pack.</p> <p class="credit">This Instructions for Use has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | 6 | 2023-02-01 17:38:35 | Abacavir, Dolutegravir, and Lamivudine Film-coated Tablets (Triumeq) | A | HIV, ART Combos | Triumeq | abacavir, dolutegravir, and lamivudine film-coated tablets | Triumeq | John P. Cunha, DO, FACOEP |
| 49 | 2023-02-23 12:07:03 | Drug Description | <div class="webmdrx"> <a href="https://www.webmd.com/rx/drug-prices/tymlos?ecd=oo_webmdrx_rx-mono_rx/drug-prices/tymlos_dsktp_rxlist.com//rx/drug-prices/tymlos" target="_blank" onclick="wmdPageLink('webmdrx');"><p class="webmdrx_p">Find Lowest Prices on <span class="webmdrx_img"></span></p></a> </div> <h4>What is Tymlos and how is it used?</h4> <p>Tymlos is a prescription medicine used to treat the symptoms of <a href="/osteoporosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Osteoporosis</a> in <a href="/postmenopausal/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Postmenopausal</a> women at risk for <a href="/fracture/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">fracture</a>. Tymlos may be used alone or with other medications.</p> <p>Tymlos belongs to a class of drugs called <a href="/parathyroid_hormone/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Parathyroid Hormone</a> Analogs.</p> <p>It is not known if Tymlos is safe and effective in children.</p> <h4>What are the possible side effects of Tymlos?</h4> <p>Tymlos may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>nausea, and</li> <li><a href="/palpitations/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">palpitations</a></li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Tymlos include:</p> <ul> <li>high calcium levels in the urine (<a href="/hypercalciuria/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypercalciuria</a>),</li> <li>dizziness,</li> <li>headache,</li> <li>fatigue,</li> <li>upper abdominal pain, and</li> <li>spinning sensation (<a href="/vertigo/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">vertigo</a>)</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Tymlos. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p align="center"><b>RISK OF OSTEOSARCOMA</b></p> <ul> <li><b>Abaloparatide caused a dos e-dependent increase in the incidence of osteosarcoma (a malignant bone tumor) in male and female rats. The effect was observed at systemic exposures to abaloparatide ranging from 4 to 28 times the exposure in humans receiving the 80 mcg dos e. It is unknown if TYMLOS will cause osteosarcomain humans [see WARNINGS AND <a href="/tymlos-drug.htm#P">PRECAUTIONS</a> and Nonclinical Toxicology].</b></li> <li><b>The use of TYMLOS is not recommended in patients at increased risk of osteosarcoma including those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, open epiphyses, bone metastases or skeletal malignancies , hereditary disorders predisposing to osteosarcoma, or prior external beam or implant radiation therapy involving the skeleton [see WARNINGS AND <a href="/tymlos-drug.htm#P">PRECAUTIONS</a>].</b></li> <li><b>Cumulative us e of TYMLOS and parathyroid hormone analogs (e.g., teriparatide) for more than 2 years during a patient’s lifetime is not recommended [see WARNINGS AND <a href="/tymlos-drug.htm#P">PRECAUTIONS</a>].</b></li> </ul> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <p>TYMLOS injection for subcutaneous administration contains abaloparatide, a synthetic 34 <a href="/amino_acid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">amino acid</a> <a href="/peptide/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">peptide</a>. Abaloparatide is an <a href="/analog/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">analog</a> of human parathyroid hormone related peptide, PTHrP(1-34). It has 41% homology to hPTH(1-34) (human parathyroid hormone 1-34) and 76% homology to hPTHrP(1-34) (human parathyroid hormone-related peptide 1-34).</p> <p>Abaloparatide has a molecular formula of C<sub>174</sub>H<sub>300</sub>N<sub>56</sub>O<sub>49</sub> and a molecular weight of 3961 daltons with the amino acid sequence shown below:</p> <p>Ala-<a href="/val/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Val</a>-<a href="/ser/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Ser</a>-<a href="/glu/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Glu</a>-His-<a href="/gln/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Gln</a>-<a href="/leu/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Leu</a>-Leu-His-<a href="/asp/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Asp</a>-Lys-<a href="/gly/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Gly</a>-Lys-Ser-<a href="/ile/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Ile</a>-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-<a href="/thr/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Thr</a>-Ala-NH<sub>2</sub></p> <p>TYMLOS injection is supplied as a sterile, colorless, clear solution in a glass cartridge which is preassembled into a disposable single-patient-use pen. The pen is intended to deliver 30 once daily abaloparatide doses of 80 mcg in 40 mcL. Each cartridge contains 1.56 mL of TYMLOS solution. Each mL contains 2000 mcg abaloparatide and the following inactive ingredients: 5 mg <a href="/phenol/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">phenol</a>, 5.08 mg sodium acetate trihydrate, 6.38 mg <a href="/acetic_acid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">acetic acid</a>, and water for injection.</p> </div> <div id="667441035-1" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-1", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <div class="webmdrx"> <a href="https://www.webmd.com/rx/drug-prices/tymlos?ecd=oo_webmdrx_rx-mono_rx/drug-prices/tymlos_dsktp_rxlist.com//rx/drug-prices/tymlos" target="_blank" onclick="wmdPageLink('webmdrx');"><p class="webmdrx_p">Find Lowest Prices on <span class="webmdrx_img"></span></p></a> </div> <h4>What is Tymlos and how is it used?</h4> <p>Tymlos is a prescription medicine used to treat the symptoms of <a href="/osteoporosis/definition.htm" ">Osteoporosis</a> in <a href="/postmenopausal/definition.htm" ">Postmenopausal</a> women at risk for <a href="/fracture/definition.htm" ">fracture</a>. Tymlos may be used alone or with other medications.</p> <p>Tymlos belongs to a class of drugs called <a href="/parathyroid_hormone/definition.htm" ">Parathyroid Hormone</a> Analogs.</p> <p>It is not known if Tymlos is safe and effective in children.</p> <h4>What are the possible side effects of Tymlos?</h4> <p>Tymlos may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>nausea, and</li> <li><a href="/palpitations/definition.htm" ">palpitations</a></li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Tymlos include:</p> <ul> <li>high calcium levels in the urine (<a href="/hypercalciuria/definition.htm" ">hypercalciuria</a>),</li> <li>dizziness,</li> <li>headache,</li> <li>fatigue,</li> <li>upper abdominal pain, and</li> <li>spinning sensation (<a href="/vertigo/definition.htm" ">vertigo</a>)</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Tymlos. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p align="center"><b>RISK OF OSTEOSARCOMA</b></p> <ul> <li><b>Abaloparatide caused a dos e-dependent increase in the incidence of osteosarcoma (a malignant bone tumor) in male and female rats. The effect was observed at systemic exposures to abaloparatide ranging from 4 to 28 times the exposure in humans receiving the 80 mcg dos e. It is unknown if TYMLOS will cause osteosarcomain humans [see WARNINGS AND <a href="/tymlos-drug.htm#P">PRECAUTIONS</a> and Nonclinical Toxicology].</b></li> <li><b>The use of TYMLOS is not recommended in patients at increased risk of osteosarcoma including those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, open epiphyses, bone metastases or skeletal malignancies , hereditary disorders predisposing to osteosarcoma, or prior external beam or implant radiation therapy involving the skeleton [see WARNINGS AND <a href="/tymlos-drug.htm#P">PRECAUTIONS</a>].</b></li> <li><b>Cumulative us e of TYMLOS and parathyroid hormone analogs (e.g., teriparatide) for more than 2 years during a patient’s lifetime is not recommended [see WARNINGS AND <a href="/tymlos-drug.htm#P">PRECAUTIONS</a>].</b></li> </ul> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <p>TYMLOS injection for subcutaneous administration contains abaloparatide, a synthetic 34 <a href="/amino_acid/definition.htm" ">amino acid</a> <a href="/peptide/definition.htm" ">peptide</a>. Abaloparatide is an <a href="/analog/definition.htm" ">analog</a> of human parathyroid hormone related peptide, PTHrP(1-34). It has 41% homology to hPTH(1-34) (human parathyroid hormone 1-34) and 76% homology to hPTHrP(1-34) (human parathyroid hormone-related peptide 1-34).</p> <p>Abaloparatide has a molecular formula of C<sub>174</sub>H<sub>300</sub>N<sub>56</sub>O<sub>49</sub> and a molecular weight of 3961 daltons with the amino acid sequence shown below:</p> <p>Ala-<a href="/val/definition.htm" ">Val</a>-<a href="/ser/definition.htm" ">Ser</a>-<a href="/glu/definition.htm" ">Glu</a>-His-<a href="/gln/definition.htm" ">Gln</a>-<a href="/leu/definition.htm" ">Leu</a>-Leu-His-<a href="/asp/definition.htm" ">Asp</a>-Lys-<a href="/gly/definition.htm" ">Gly</a>-Lys-Ser-<a href="/ile/definition.htm" ">Ile</a>-Gln-Asp-Leu-Arg-Arg-Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-<a href="/thr/definition.htm" ">Thr</a>-Ala-NH<sub>2</sub></p> <p>TYMLOS injection is supplied as a sterile, colorless, clear solution in a glass cartridge which is preassembled into a disposable single-patient-use pen. The pen is intended to deliver 30 once daily abaloparatide doses of 80 mcg in 40 mcL. Each cartridge contains 1.56 mL of TYMLOS solution. Each mL contains 2000 mcg abaloparatide and the following inactive ingredients: 5 mg <a href="/phenol/definition.htm" ">phenol</a>, 5.08 mg sodium acetate trihydrate, 6.38 mg <a href="/acetic_acid/definition.htm" ">acetic acid</a>, and water for injection.</p> </div> <div id="667441035-1" class="medianet"><</div> </div> </div> | 7 | 2023-02-01 17:38:38 | Abaloparatide Injection (Tymlos) | A | Parathyroid Hormone Analogs | Tymlos | abaloparatide injection | Tymlos | John P. Cunha, DO, FACOEP |
| 50 | 2023-02-23 12:07:03 | Indications & Dosage | <div class="webmdrx_coup"> </div> <a name="I"></a> <h3>INDICATIONS</h3> <h4>Treatment Of Postmenopausal Women With Osteoporosis At High Risk For Fracture</h4> <p>TYMLOS is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture), or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, TYMLOS reduces the risk of vertebral fractures and nonvertebral fractures.</p> <h4>Treatment To Increase Bone Density In Men With Osteoporosis At High Risk For Fracture</h4> <p>TYMLOS is indicated to increase <a href="/bone_density/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bone density</a> in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture), or patients who have failed or are intolerant to other available osteoporosis therapy.</p> <a name="D"></a> <h3>DOSAGE AND ADMINISTRATION</h3> <h4>Recommended Dosage</h4> <ul> <li>The recommended dosage of TYMLOS is 80 mcg administered subcutaneously once daily.</li> <li>Patients should receive supplemental calcium and <a href="/vitamin_d/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">vitamin D</a> if dietary intake is inadequate.</li> </ul> <h4>Administration Instructions</h4> <ul> <li>Administer TYMLOS as a subcutaneous injection into the periumbilical region of the abdomen. Rotate the site of the injection every day and administer at approximately the same time every day. Do not administer intravenously or intramuscularly.</li> <li>Administer the first several doses where the patient can sit or lie down if necessary, in case symptoms of <a href="/orthostatic_hypotension/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">orthostatic hypotension</a> occur [see <b>WARNINGS AND PRECAUTIONS</b> and <b>ADVERSE REACTIONS</b>].</li> <li>Visually inspect TYMLOS for particulate matter and discoloration prior to administration. TYMLOS is a clear and colorless solution. Do not use if solid particles appear or if the solution is cloudy or colored.</li> <li>Provide appropriate training and instruction to patients and caregivers on the proper use of the TYMLOS pen.</li> </ul> <h4>Treatment Duration</h4> <p>The safety and efficacy of TYMLOS have not been evaluated beyond 2 years of treatment. Use of the drug for more than 2 years during a patient’s lifetime is not recommended.</p> <a name="HS"></a> <h3>HOW SUPPLIED</h3> <h4>Dosage Forms And Strengths</h4> <p>Injection: 3120 mcg/1.56 mL (2000 mcg/mL) of abaloparatide in clear, colorless solution in a single-patient-use prefilled pen. The prefilled pen delivers 30 doses of TYMLOS, each containing 80 mcg of abaloparatide in 40 mcL.</p> <p><b>TYMLOS</b> (abaloparatide injection) is a clear and colorless solution, available as a pre-assembled single-patient-use disposable pen (<b>NDC</b> 70539-001-01) packaged in a cardboard carton (<b>NDC</b> 70539-001-02) with the <b>Instructions for Use</b> and <b>Medication Guide</b>. Each disposable pen embodies a glass cartridge that contains 3120 mcg of abaloparatide in 1.56 mL (2000 mcg/mL). Each pen provides a 30-day supply for once daily injection of 80 mcg abaloparatide in 40 mcL. Sterile needles are not included.</p> <h4>Storage And Handling</h4> <ul> <li>Before first use, store TYMLOS under refrigeration between 2°C to 8°C (36°F to 46°F).</li> <li>After first use, store for up to 30 days at 20°C to 25°C (68°F to 77°F).</li> <li>Do not freeze or subject to heat.</li> </ul> <p class="credit">Manufactured in Germany for: <a href="/radius/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Radius</a> Health, Inc. 22 Boston Wharf Road, 7th Floor Boston, MA 02210 TYMLOS is a registered trademark of Radius Health, Inc. Revised: Dec 2022</p> </div> <a class="mediaPrmo quiz" href="/quiz_osteoporosis/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/osteoporosis/s1.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">What is another medical term for osteoporosis?</span> <span class="btn">See Answer</span> </a> </div> </div> | <div class="webmdrx_coup"> </div> <a name="I"></a> <h3>INDICATIONS</h3> <h4>Treatment Of Postmenopausal Women With Osteoporosis At High Risk For Fracture</h4> <p>TYMLOS is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture), or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, TYMLOS reduces the risk of vertebral fractures and nonvertebral fractures.</p> <h4>Treatment To Increase Bone Density In Men With Osteoporosis At High Risk For Fracture</h4> <p>TYMLOS is indicated to increase <a href="/bone_density/definition.htm" ">bone density</a> in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture), or patients who have failed or are intolerant to other available osteoporosis therapy.</p> <a name="D"></a> <h3>DOSAGE AND ADMINISTRATION</h3> <h4>Recommended Dosage</h4> <ul> <li>The recommended dosage of TYMLOS is 80 mcg administered subcutaneously once daily.</li> <li>Patients should receive supplemental calcium and <a href="/vitamin_d/definition.htm" ">vitamin D</a> if dietary intake is inadequate.</li> </ul> <h4>Administration Instructions</h4> <ul> <li>Administer TYMLOS as a subcutaneous injection into the periumbilical region of the abdomen. Rotate the site of the injection every day and administer at approximately the same time every day. Do not administer intravenously or intramuscularly.</li> <li>Administer the first several doses where the patient can sit or lie down if necessary, in case symptoms of <a href="/orthostatic_hypotension/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">orthostatic hypotension</a> occur [see <b>WARNINGS AND PRECAUTIONS</b> and <b>ADVERSE REACTIONS</b>].</li> <li>Visually inspect TYMLOS for particulate matter and discoloration prior to administration. TYMLOS is a clear and colorless solution. Do not use if solid particles appear or if the solution is cloudy or colored.</li> <li>Provide appropriate training and instruction to patients and caregivers on the proper use of the TYMLOS pen.</li> </ul> <h4>Treatment Duration</h4> <p>The safety and efficacy of TYMLOS have not been evaluated beyond 2 years of treatment. Use of the drug for more than 2 years during a patient’s lifetime is not recommended.</p> <a name="HS"></a> <h3>HOW SUPPLIED</h3> <h4>Dosage Forms And Strengths</h4> <p>Injection: 3120 mcg/1.56 mL (2000 mcg/mL) of abaloparatide in clear, colorless solution in a single-patient-use prefilled pen. The prefilled pen delivers 30 doses of TYMLOS, each containing 80 mcg of abaloparatide in 40 mcL.</p> <p><b>TYMLOS</b> (abaloparatide injection) is a clear and colorless solution, available as a pre-assembled single-patient-use disposable pen (<b>NDC</b> 70539-001-01) packaged in a cardboard carton (<b>NDC</b> 70539-001-02) with the <b>Instructions for Use</b> and <b>Medication Guide</b>. Each disposable pen embodies a glass cartridge that contains 3120 mcg of abaloparatide in 1.56 mL (2000 mcg/mL). Each pen provides a 30-day supply for once daily injection of 80 mcg abaloparatide in 40 mcL. Sterile needles are not included.</p> <h4>Storage And Handling</h4> <ul> <li>Before first use, store TYMLOS under refrigeration between 2°C to 8°C (36°F to 46°F).</li> <li>After first use, store for up to 30 days at 20°C to 25°C (68°F to 77°F).</li> <li>Do not freeze or subject to heat.</li> </ul> <p class="credit">Manufactured in Germany for: <a href="/radius/definition.htm" ">Radius</a> Health, Inc. 22 Boston Wharf Road, 7th Floor Boston, MA 02210 TYMLOS is a registered trademark of Radius Health, Inc. Revised: Dec 2022</p> </div> <a class="mediaPrmo quiz" href="/quiz_osteoporosis/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/osteoporosis/s1.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">What is another medical term for osteoporosis?</span> <span class="btn">See Answer</span> </a> </div> </div> | 7 | 2023-02-01 17:38:38 | Abaloparatide Injection (Tymlos) | A | Parathyroid Hormone Analogs | Tymlos | abaloparatide injection | Tymlos | John P. Cunha, DO, FACOEP |
| 51 | 2023-02-23 12:07:03 | Side Effects & Drug Interactions | <a name="AR"></a> <h3>SIDE EFFECTS</h3> <p>The following adverse reactions are described in greater detail in other sections:</p> <ul> <li>Orthostatic <a href="/hypotension/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Hypotension</a> [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li><a href="/hypercalcemia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Hypercalcemia</a> [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Hypercalciuria and <a href="/urolithiasis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Urolithiasis</a> [see<b> WARNINGS AND PRECAUTIONS</b>]</li> </ul> <h4>Clinical Trials Experience</h4> <p>Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.</p> <h4>Adverse Reactions From Clinical Trial In Postmenopausal Women With Osteoporosis</h4> <p>The safety of TYMLOS was evaluated in a randomized, multicenter, double-blind, placebocontrolled clinical trial in postmenopausal women with osteoporosis aged 49 to 86 years (mean age 69 years) who were randomized to receive 80 mcg of TYMLOS (N = 824) or placebo (N = 821), given subcutaneously once daily for 18 months [see<b> Clinical Studies</b>].</p> <p>In this study, the incidence of all-cause mortality was 0.4% in the TYMLOS group and 0.6% in the placebo group. The incidence of serious adverse events was 10% in the TYMLOS group and 11% in the placebo group. The percentage of patients who discontinued study drug due to adverse events was 10% in the TYMLOS group and 6% in the placebo group. The most common adverse reactions leading to study drug discontinuation in the TYMLOS group were nausea (2%), dizziness (1%), headache (1%), and palpitations (1%).</p> <p>Table 1 shows the most common adverse reactions in the trial. These adverse reactions were generally not present at baseline, occurred more commonly with TYMLOS than with placebo, and occurred in at least 2% of the patients treated with TYMLOS.</p> <p align="center"><b>Table 1: Common Adverse Reactions Reported in Postmenopausal Women with Osteoporosis*</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Preferred term</td> <td class="EmphTd" width="25%">TYMLOS<br /> (N=822) (%)</td> <td class="EmphTd" width="25%">Placebo<br /> (N=820) (%)</td> </tr> <tr> <td>Hypercalciuria</td> <td align="center">11</td> <td align="center">9</td> </tr> <tr> <td>Dizziness</td> <td align="center">10</td> <td align="center">6</td> </tr> <tr> <td>Nausea</td> <td align="center">8</td> <td align="center">3</td> </tr> <tr> <td>Headache</td> <td align="center">8</td> <td align="center">6</td> </tr> <tr> <td>Palpitations</td> <td align="center">5</td> <td align="center">0.4</td> </tr> <tr> <td>Fatigue</td> <td align="center">3</td> <td align="center">2</td> </tr> <tr> <td>Abdominal pain upper</td> <td align="center">3</td> <td align="center">2</td> </tr> <tr> <td>Vertigo</td> <td align="center">2</td> <td align="center">2</td> </tr> <tr> <td class="credit" colspan="3">* Adverse reactions reported in ≥2% of TYMLOS-treated patients.</td> </tr> </tbody> </table> </center> <p></p> <h4>Orthostatic Hypotension</h4> <p>In the clinical trial of women with postmenopausal osteoporosis, the incidence of orthostatic blood pressure decline ≥20 mmHg <a href="/systolic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">systolic</a> or ≥10 mmHg <a href="/diastolic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">diastolic</a> at 1 hour after the first injection was 4% in the TYMLOS group and 3% in the placebo group. At later time points the incidence was generally similar between the treatment groups. Adverse reactions of orthostatic hypotension were reported in 1% of patients receiving TYMLOS and 0.5% of patients receiving placebo. Dizziness was reported by more TYMLOS-treated patients (10%) compared to placebo (6%) [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h4>Tachycardia</h4> <p>In women with postmenopausal osteoporosis, adverse reactions of <a href="/tachycardia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">tachycardia</a>, including <a href="/sinus_tachycardia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">sinus tachycardia</a>, were reported in 2% of patients receiving TYMLOS and 1% of patients in the placebo group. In 5 of the 13 patients receiving TYMLOS who experienced tachycardia, symptoms occurred within 1 hour of administration. TYMLOS has been associated with a dosedependent increase in heart rate which developed within 15 minutes after injection and resolved in about 6 hours [see <b>CLINICAL PHARMACOLOGY</b>].</p> <h4>Injection Site Reactions</h4> <p>During the first month of the trial, injection site reactions were assessed daily one-hour after injection. TYMLOS had a higher incidence than placebo of injection site redness (58% vs. 28%), edema (11% vs. 3%), and pain (10% vs. 7%). Severe redness, severe edema, and severe pain were reported among 2.9%, 0.4%, and 0.4% of the TYMLOS-treated patients.</p> <h4>Laboratory Abnormalities</h4> <h5>Hypercalcemia</h5> <p>In the clinical trial of women with postmenopausal osteoporosis, TYMLOS caused increases in serum calcium concentrations [see<b> WARNINGS AND PRECAUTIONS</b>]. The incidence of hypercalcemia, defined as <a href="/albumin/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">albumin</a>-corrected serum calcium ≥10.7 mg/dL at 4 hours following injection at any visit, was 3% in TYMLOS-treated patients and 0.1% with placebo. Pre-dose serum calcium was similar to baseline in both groups. There were 2 (0.2%) TYMLOS-treated patients and no placebo-treated patients who discontinued from the study due to hypercalcemia. The incidence of hypercalcemia with TYMLOS was higher in patients with mild or moderate renal impairment (4%) compared to patients with normal renal function (1%).</p> <h5>Increases In Serum Uric Acid</h5> <p>TYMLOS increased serum <a href="/uric_acid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">uric acid</a> concentrations. In the postmenopausal osteoporosis trial, among patients with normal baseline uric acid concentrations, 25% of patients in the TYMLOS group and 6% of patients in the placebo group had at least one post-baseline concentration above the <a href="/normal_range/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">normal range</a>. The <a href="/hyperuricemia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hyperuricemia</a> observed in TYMLOS-treated patients was not associated with an increase in adverse reactions of <a href="/gout/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">gout</a> or <a href="/arthralgia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">arthralgia</a> over that observed with placebo.</p> <h5>Hypercalciuria And Urolithiasis</h5> <p>In the clinical trial of women with postmenopausal osteoporosis, the overall incidence of urine calcium:creatinine ratio >400 mg/g was higher with TYMLOS than with placebo (20% vs 15%, respectively). Urolithiases were reported in 2.1% of TYMLOS-treated patients and 1.7% of placebo-treated patients.</p> <h4>Adverse Reactions From The Extension Study In Postmenopausal Women With Osteoporosis</h4> <p>Following 18 months of treatment with TYMLOS or placebo, 1139 women transitioned to treatment with alendronate 70 mg administered orally once weekly. The incidence of adverse events occurring during alendronate treatment was similar in patients with prior placebo or TYMLOS therapy [see <b>Clinical Studies</b>].</p> <h4>Adverse Reactions From Clinical Trial In Men With Osteoporosis</h4> <p>The safety of TYMLOS was evaluated in a randomized, multicenter, double-blind, placebocontrolled clinical trial in men with osteoporosis aged 42 to 85 years (mean age 68 years) who were randomized to receive 80 mcg of TYMLOS (N = 149) or placebo (N = 79), given subcutaneously once daily for 12 months [see<b> Clinical Studies</b>].</p> <p>In this study, no patient from either treatment group had an adverse reaction with a fatal outcome during the trial. Serious adverse reactions were reported by 5.4% of subjects treated with TYMLOS and 5.1% of subjects in the placebo group. Adverse reactions leading to study drug discontinuation were reported for 6.7% of patients treated with TYMLOS and 5.1% of patients receiving placebo. The most common adverse reaction leading to study drug discontinuation in the TYMLOS group was dizziness (2%).</p> <p>Table 2 shows the most common adverse reactions in the trial. These adverse reactions were generally not present at baseline, occurred more commonly with TYMLOS than with placebo and occurred in at least 2% of the patients treated with TYMLOS.</p> <p align="center"><b>Table 2: Common Adverse Reactions Reported in Men with Osteoporosis*</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Preferred Term</td> <td class="EmphTd" width="25%">TYMLOS<br /> (N=149)(%)</td> <td class="EmphTd" width="25%">Placebo<br /> (N=79)(%)</td> </tr> <tr> <td>Injection site erythema</td> <td align="center">13</td> <td align="center">5</td> </tr> <tr> <td>Dizziness</td> <td align="center">9</td> <td align="center">1</td> </tr> <tr> <td>Arthralgia</td> <td align="center">7</td> <td align="center">1</td> </tr> <tr> <td>Injection site swelling</td> <td align="center">7</td> <td align="center">0</td> </tr> <tr> <td>Injection site pain</td> <td align="center">6</td> <td align="center">0</td> </tr> <tr> <td>Contusion</td> <td align="center">3</td> <td align="center">0</td> </tr> <tr> <td>Abdominal distention</td> <td align="center">3</td> <td align="center">0</td> </tr> <tr> <td>Diarrhea</td> <td align="center">3</td> <td align="center">0</td> </tr> <tr> <td>Nausea</td> <td align="center">3</td> <td align="center">0</td> </tr> <tr> <td>Abdominal Pain</td> <td align="center">2</td> <td align="center">0</td> </tr> <tr> <td>Bone Pain</td> <td align="center">2</td> <td align="center">0</td> </tr> <tr> <td class="credit" colspan="3">* Adverse reactions reported in ≥2% of TYMLOS-treated patients.</td> </tr> </tbody> </table> </center> <p></p> <h4>Orthostatic Hypotension</h4> <p>In the clinical trial of men with osteoporosis, the incidence of orthostatic blood pressure declines of ≥20 mmHg systolic or ≥10 mmHg diastolic at 1 hour after the first injection was 6% in the TYMLOS group and 3% in the placebo group. Adverse reactions of orthostatic hypotension were reported in 1% of patients receiving TYMLOS and 0 patients receiving placebo. Dizziness was reported by more TYMLOS-treated patients (9%) compared to placebo (1%) [see<b> WARNINGS AND PRECAUTIONS</b>].</p> <h4>Laboratory Abnormalities</h4> <h5>Hypercalcemia</h5> <p>In the clinical trial of men with osteoporosis, TYMLOS caused increases in serum calcium concentrations [see <b>WARNINGS AND PRECAUTIONS</b>]. The incidence of hypercalcemia, defined as albumin-corrected serum calcium ≥10.8 mg/dL at 4 hours following injection at any visit, was 3% in TYMLOS-treated patients and 0% with placebo. Pre-dose serum calcium was similar to baseline in both groups. The incidence of hypercalcemia, defined as albumin-corrected serum calcium ≥10.8 mg/dL at 4 hours following injection, with TYMLOS was higher in patients with mild or moderate renal impairment (4%) compared to patients with normal renal function (0%).</p> <h5>Increases In Serum Uric Acid</h5> <p>TYMLOS increased serum uric acid concentrations. In the male osteoporosis trial, among patients with normal baseline uric acid concentrations, 7% of patients in the TYMLOS group and 6% of patients in the placebo group had at least one post-baseline concentration above the normal range. The hyperuricemia observed in TYMLOS-treated patients was not associated with an increase in adverse reactions of gout or arthralgia over that observed with placebo.</p> <h5>Hypercalciuria And Urolithiasis</h5> <p>In the clinical trial of men with osteoporosis, the overall incidence of urine calcium: creatinine ratio >400 mg/g was not greater with TYMLOS than with placebo. Urolithiases were reported in 2% of TYMLOS-treated patients and 1% of placebo-treated patients.</p> <h4>Postmarketing Experience</h4> <p>The following adverse reactions have been identified during the post-approval use of TYMLOS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.</p> <ul> <li>Abdominal distension, abdominal pain</li> <li>Constipation, diarrhea, vomiting</li> <li><a href="/asthenia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Asthenia</a>, <a href="/lethargy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lethargy</a>, <a href="/malaise/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">malaise</a></li> <li>Insomnia</li> <li>Hypersensitivity and anaphylactic reactions, <a href="/dyspnea/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">dyspnea</a> (in the context of allergic reactions)</li> <li><a href="/pruritus/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Pruritus</a>, rash</li> <li>Generalized pain and pain in bone, joint, back, and extremity</li> <li><a href="/muscle_spasms/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Muscle spasms</a> of the leg and back</li> <li>Injection site reactions including bruising, <a href="/hemorrhage/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hemorrhage</a>, pruritus, and rash</li> </ul> <a name="DI"></a> <h3>DRUG INTERACTIONS</h3> <p>No specific drug-drug interaction studies have been performed [see <b>CLINICAL PHARMACOLOGY</b>].</p> </div> </div> </div> | <a name="AR"></a> <h3>SIDE EFFECTS</h3> <p>The following adverse reactions are described in greater detail in other sections:</p> <ul> <li>Orthostatic <a href="/hypotension/definition.htm" ">Hypotension</a> [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li><a href="/hypercalcemia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Hypercalcemia</a> [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Hypercalciuria and <a href="/urolithiasis/definition.htm" ">Urolithiasis</a> [see<b> WARNINGS AND PRECAUTIONS</b>]</li> </ul> <h4>Clinical Trials Experience</h4> <p>Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.</p> <h4>Adverse Reactions From Clinical Trial In Postmenopausal Women With Osteoporosis</h4> <p>The safety of TYMLOS was evaluated in a randomized, multicenter, double-blind, placebocontrolled clinical trial in postmenopausal women with osteoporosis aged 49 to 86 years (mean age 69 years) who were randomized to receive 80 mcg of TYMLOS (N = 824) or placebo (N = 821), given subcutaneously once daily for 18 months [see<b> Clinical Studies</b>].</p> <p>In this study, the incidence of all-cause mortality was 0.4% in the TYMLOS group and 0.6% in the placebo group. The incidence of serious adverse events was 10% in the TYMLOS group and 11% in the placebo group. The percentage of patients who discontinued study drug due to adverse events was 10% in the TYMLOS group and 6% in the placebo group. The most common adverse reactions leading to study drug discontinuation in the TYMLOS group were nausea (2%), dizziness (1%), headache (1%), and palpitations (1%).</p> <p>Table 1 shows the most common adverse reactions in the trial. These adverse reactions were generally not present at baseline, occurred more commonly with TYMLOS than with placebo, and occurred in at least 2% of the patients treated with TYMLOS.</p> <p align="center"><b>Table 1: Common Adverse Reactions Reported in Postmenopausal Women with Osteoporosis*</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Preferred term</td> <td class="EmphTd" width="25%">TYMLOS<br /> (N=822) (%)</td> <td class="EmphTd" width="25%">Placebo<br /> (N=820) (%)</td> </tr> <tr> <td>Hypercalciuria</td> <td align="center">11</td> <td align="center">9</td> </tr> <tr> <td>Dizziness</td> <td align="center">10</td> <td align="center">6</td> </tr> <tr> <td>Nausea</td> <td align="center">8</td> <td align="center">3</td> </tr> <tr> <td>Headache</td> <td align="center">8</td> <td align="center">6</td> </tr> <tr> <td>Palpitations</td> <td align="center">5</td> <td align="center">0.4</td> </tr> <tr> <td>Fatigue</td> <td align="center">3</td> <td align="center">2</td> </tr> <tr> <td>Abdominal pain upper</td> <td align="center">3</td> <td align="center">2</td> </tr> <tr> <td>Vertigo</td> <td align="center">2</td> <td align="center">2</td> </tr> <tr> <td class="credit" colspan="3">* Adverse reactions reported in ≥2% of TYMLOS-treated patients.</td> </tr> </tbody> </table> </center> <p></p> <h4>Orthostatic Hypotension</h4> <p>In the clinical trial of women with postmenopausal osteoporosis, the incidence of orthostatic blood pressure decline ≥20 mmHg <a href="/systolic/definition.htm" ">systolic</a> or ≥10 mmHg <a href="/diastolic/definition.htm" ">diastolic</a> at 1 hour after the first injection was 4% in the TYMLOS group and 3% in the placebo group. At later time points the incidence was generally similar between the treatment groups. Adverse reactions of orthostatic hypotension were reported in 1% of patients receiving TYMLOS and 0.5% of patients receiving placebo. Dizziness was reported by more TYMLOS-treated patients (10%) compared to placebo (6%) [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h4>Tachycardia</h4> <p>In women with postmenopausal osteoporosis, adverse reactions of <a href="/tachycardia/definition.htm" ">tachycardia</a>, including <a href="/sinus_tachycardia/definition.htm" ">sinus tachycardia</a>, were reported in 2% of patients receiving TYMLOS and 1% of patients in the placebo group. In 5 of the 13 patients receiving TYMLOS who experienced tachycardia, symptoms occurred within 1 hour of administration. TYMLOS has been associated with a dosedependent increase in heart rate which developed within 15 minutes after injection and resolved in about 6 hours [see <b>CLINICAL PHARMACOLOGY</b>].</p> <h4>Injection Site Reactions</h4> <p>During the first month of the trial, injection site reactions were assessed daily one-hour after injection. TYMLOS had a higher incidence than placebo of injection site redness (58% vs. 28%), edema (11% vs. 3%), and pain (10% vs. 7%). Severe redness, severe edema, and severe pain were reported among 2.9%, 0.4%, and 0.4% of the TYMLOS-treated patients.</p> <h4>Laboratory Abnormalities</h4> <h5>Hypercalcemia</h5> <p>In the clinical trial of women with postmenopausal osteoporosis, TYMLOS caused increases in serum calcium concentrations [see<b> WARNINGS AND PRECAUTIONS</b>]. The incidence of hypercalcemia, defined as <a href="/albumin/definition.htm" ">albumin</a>-corrected serum calcium ≥10.7 mg/dL at 4 hours following injection at any visit, was 3% in TYMLOS-treated patients and 0.1% with placebo. Pre-dose serum calcium was similar to baseline in both groups. There were 2 (0.2%) TYMLOS-treated patients and no placebo-treated patients who discontinued from the study due to hypercalcemia. The incidence of hypercalcemia with TYMLOS was higher in patients with mild or moderate renal impairment (4%) compared to patients with normal renal function (1%).</p> <h5>Increases In Serum Uric Acid</h5> <p>TYMLOS increased serum <a href="/uric_acid/definition.htm" ">uric acid</a> concentrations. In the postmenopausal osteoporosis trial, among patients with normal baseline uric acid concentrations, 25% of patients in the TYMLOS group and 6% of patients in the placebo group had at least one post-baseline concentration above the <a href="/normal_range/definition.htm" ">normal range</a>. The <a href="/hyperuricemia/definition.htm" ">hyperuricemia</a> observed in TYMLOS-treated patients was not associated with an increase in adverse reactions of <a href="/gout/definition.htm" ">gout</a> or <a href="/arthralgia/definition.htm" ">arthralgia</a> over that observed with placebo.</p> <h5>Hypercalciuria And Urolithiasis</h5> <p>In the clinical trial of women with postmenopausal osteoporosis, the overall incidence of urine calcium:creatinine ratio >400 mg/g was higher with TYMLOS than with placebo (20% vs 15%, respectively). Urolithiases were reported in 2.1% of TYMLOS-treated patients and 1.7% of placebo-treated patients.</p> <h4>Adverse Reactions From The Extension Study In Postmenopausal Women With Osteoporosis</h4> <p>Following 18 months of treatment with TYMLOS or placebo, 1139 women transitioned to treatment with alendronate 70 mg administered orally once weekly. The incidence of adverse events occurring during alendronate treatment was similar in patients with prior placebo or TYMLOS therapy [see <b>Clinical Studies</b>].</p> <h4>Adverse Reactions From Clinical Trial In Men With Osteoporosis</h4> <p>The safety of TYMLOS was evaluated in a randomized, multicenter, double-blind, placebocontrolled clinical trial in men with osteoporosis aged 42 to 85 years (mean age 68 years) who were randomized to receive 80 mcg of TYMLOS (N = 149) or placebo (N = 79), given subcutaneously once daily for 12 months [see<b> Clinical Studies</b>].</p> <p>In this study, no patient from either treatment group had an adverse reaction with a fatal outcome during the trial. Serious adverse reactions were reported by 5.4% of subjects treated with TYMLOS and 5.1% of subjects in the placebo group. Adverse reactions leading to study drug discontinuation were reported for 6.7% of patients treated with TYMLOS and 5.1% of patients receiving placebo. The most common adverse reaction leading to study drug discontinuation in the TYMLOS group was dizziness (2%).</p> <p>Table 2 shows the most common adverse reactions in the trial. These adverse reactions were generally not present at baseline, occurred more commonly with TYMLOS than with placebo and occurred in at least 2% of the patients treated with TYMLOS.</p> <p align="center"><b>Table 2: Common Adverse Reactions Reported in Men with Osteoporosis*</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Preferred Term</td> <td class="EmphTd" width="25%">TYMLOS<br /> (N=149)(%)</td> <td class="EmphTd" width="25%">Placebo<br /> (N=79)(%)</td> </tr> <tr> <td>Injection site erythema</td> <td align="center">13</td> <td align="center">5</td> </tr> <tr> <td>Dizziness</td> <td align="center">9</td> <td align="center">1</td> </tr> <tr> <td>Arthralgia</td> <td align="center">7</td> <td align="center">1</td> </tr> <tr> <td>Injection site swelling</td> <td align="center">7</td> <td align="center">0</td> </tr> <tr> <td>Injection site pain</td> <td align="center">6</td> <td align="center">0</td> </tr> <tr> <td>Contusion</td> <td align="center">3</td> <td align="center">0</td> </tr> <tr> <td>Abdominal distention</td> <td align="center">3</td> <td align="center">0</td> </tr> <tr> <td>Diarrhea</td> <td align="center">3</td> <td align="center">0</td> </tr> <tr> <td>Nausea</td> <td align="center">3</td> <td align="center">0</td> </tr> <tr> <td>Abdominal Pain</td> <td align="center">2</td> <td align="center">0</td> </tr> <tr> <td>Bone Pain</td> <td align="center">2</td> <td align="center">0</td> </tr> <tr> <td class="credit" colspan="3">* Adverse reactions reported in ≥2% of TYMLOS-treated patients.</td> </tr> </tbody> </table> </center> <p></p> <h4>Orthostatic Hypotension</h4> <p>In the clinical trial of men with osteoporosis, the incidence of orthostatic blood pressure declines of ≥20 mmHg systolic or ≥10 mmHg diastolic at 1 hour after the first injection was 6% in the TYMLOS group and 3% in the placebo group. Adverse reactions of orthostatic hypotension were reported in 1% of patients receiving TYMLOS and 0 patients receiving placebo. Dizziness was reported by more TYMLOS-treated patients (9%) compared to placebo (1%) [see<b> WARNINGS AND PRECAUTIONS</b>].</p> <h4>Laboratory Abnormalities</h4> <h5>Hypercalcemia</h5> <p>In the clinical trial of men with osteoporosis, TYMLOS caused increases in serum calcium concentrations [see <b>WARNINGS AND PRECAUTIONS</b>]. The incidence of hypercalcemia, defined as albumin-corrected serum calcium ≥10.8 mg/dL at 4 hours following injection at any visit, was 3% in TYMLOS-treated patients and 0% with placebo. Pre-dose serum calcium was similar to baseline in both groups. The incidence of hypercalcemia, defined as albumin-corrected serum calcium ≥10.8 mg/dL at 4 hours following injection, with TYMLOS was higher in patients with mild or moderate renal impairment (4%) compared to patients with normal renal function (0%).</p> <h5>Increases In Serum Uric Acid</h5> <p>TYMLOS increased serum uric acid concentrations. In the male osteoporosis trial, among patients with normal baseline uric acid concentrations, 7% of patients in the TYMLOS group and 6% of patients in the placebo group had at least one post-baseline concentration above the normal range. The hyperuricemia observed in TYMLOS-treated patients was not associated with an increase in adverse reactions of gout or arthralgia over that observed with placebo.</p> <h5>Hypercalciuria And Urolithiasis</h5> <p>In the clinical trial of men with osteoporosis, the overall incidence of urine calcium: creatinine ratio >400 mg/g was not greater with TYMLOS than with placebo. Urolithiases were reported in 2% of TYMLOS-treated patients and 1% of placebo-treated patients.</p> <h4>Postmarketing Experience</h4> <p>The following adverse reactions have been identified during the post-approval use of TYMLOS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.</p> <ul> <li>Abdominal distension, abdominal pain</li> <li>Constipation, diarrhea, vomiting</li> <li><a href="/asthenia/definition.htm" ">Asthenia</a>, <a href="/lethargy/definition.htm" ">lethargy</a>, <a href="/malaise/definition.htm" ">malaise</a></li> <li>Insomnia</li> <li>Hypersensitivity and anaphylactic reactions, <a href="/dyspnea/definition.htm" ">dyspnea</a> (in the context of allergic reactions)</li> <li><a href="/pruritus/definition.htm" ">Pruritus</a>, rash</li> <li>Generalized pain and pain in bone, joint, back, and extremity</li> <li><a href="/muscle_spasms/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Muscle spasms</a> of the leg and back</li> <li>Injection site reactions including bruising, <a href="/hemorrhage/definition.htm" ">hemorrhage</a>, pruritus, and rash</li> </ul> <a name="DI"></a> <h3>DRUG INTERACTIONS</h3> <p>No specific drug-drug interaction studies have been performed [see <b>CLINICAL PHARMACOLOGY</b>].</p> </div> </div> </div> | 7 | 2023-02-01 17:38:38 | Abaloparatide Injection (Tymlos) | A | Parathyroid Hormone Analogs | Tymlos | abaloparatide injection | Tymlos | John P. Cunha, DO, FACOEP |
| 52 | 2023-02-23 12:07:03 | Warnings & Precautions | <a name="W"></a> <h3>WARNINGS</h3> <p>Included as part of the <b>PRECAUTIONS</b> section.</p> <a name="P"></a> <h3>PRECAUTIONS</h3> <h4>Risk Of Osteosarcoma</h4> <p>Abaloparatide caused a dose-dependent increase in the incidence of <a href="/osteosarcoma/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">osteosarcoma</a> in male and female rats after subcutaneous administration at exposures 4 to 28 times the human exposure at the clinical dose of 80 mcg [see <b>Nonclinical Toxicology</b>]. It is unknown whether TYMLOS will cause osteosarcoma in humans.</p> <p>Osteosarcoma has been reported in patients treated with a PTH-analog in the post marketing setting; however, an increased risk of osteosarcoma has not been observed in observational studies in humans. There are limited data assessing the risk of osteosarcoma beyond 2 years of TYMLOS and/or use of a PTH-analog [see<b> DOSAGE AND ADMINISTRATION</b> and <b>Nonclinical Toxicology</b>].</p> <p>Avoid TYMLOS use in patients with (these patients are at increased baseline risk of osteosarcoma):</p> <ul> <li>Open epiphyses (pediatric and young adult patients) (TYMLOS is not approved in pediatric patients) [see<b> Use In Specific Populations</b>].</li> <li>Metabolic bone diseases other than osteoporosis, including Paget’s disease of the bone.</li> <li>Bone metastases or a history of skeletal malignancies.</li> <li>Prior external beam or <a href="/implant/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">implant</a> <a href="/radiation_therapy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">radiation therapy</a> involving the <a href="/skeleton/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">skeleton</a>.</li> <li>Hereditary disorders predisposing to osteosarcoma.</li> </ul> <h4>Orthostatic Hypotension</h4> <p>Orthostatic hypotension may occur with TYMLOS, typically within 4 hours of injection. Associated symptoms may include dizziness, palpitations, tachycardia, or nausea, and may resolve by having the patient lie down. For the first several doses, TYMLOS should be administered where the patient can sit or lie down if necessary [see <b>ADVERSE REACTIONS</b>].</p> <h4>Hypercalcemia</h4> <p>TYMLOS may cause hypercalcemia. TYMLOS is not recommended in patients with preexisting hypercalcemia or in patients who have an underlying hypercalcemic disorder, such as primary <a href="/hyperparathyroidism/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hyperparathyroidism</a>, because of the possibility of exacerbating hypercalcemia [see<b> ADVERSE REACTIONS</b>].</p> <h4>Hypercalciuria And Urolithiasis</h4> <p>TYMLOS may cause hypercalciuria. It is unknown whether TYMLOS may exacerbate urolithiasis in patients with active or a history of urolithiasis. If active urolithiasis or pre-existing hypercalciuria is suspected, measurement of urinary calcium excretion should be considered [see<b> ADVERSE REACTIONS</b>].</p> <h4>Patient Counseling Information</h4> <p>Advise the patient to read the FDA-approved patient labeling (<b>Medication Guide and Instructions for Use</b>).</p> <h5>Risk Of Osteosarcoma</h5> <p>Advise patients that the active ingredient in TYMLOS, abaloparatide, caused a dose-dependent increase in the incidence of osteosarcoma in male and female rats and that it is unknown whether TYMLOS will cause osteosarcoma in humans [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>Instruct patients to promptly report signs and symptoms of possible osteosarcoma such as persistent localized pain or occurrence of a new soft tissue mass that is tender to palpation.</p> <h5>Hypercalcemia</h5> <p>Advise patients that TYMLOS may cause hypercalcemia and discuss the symptoms of hypercalcemia (e.g., nausea, vomiting, constipation, lethargy, muscle weakness) [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>Instruct patients to promptly report signs and symptoms of hypercalcemia.</p> <h5>Orthostatic Hypotension</h5> <p>Advise patients to sit or lie down if they feel lightheaded or have palpitations after the injection until their symptoms resolve. If these symptoms persist or worsen, advise patients to consult their healthcare provider before continuing treatment [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <h5>Hypersensitivity Reactions</h5> <p>Advise patients to seek immediate medical attention if they experience signs or symptoms of a hypersensitivity reaction including <a href="/anaphylaxis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anaphylaxis</a>, dyspnea, or <a href="/urticaria/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">urticaria</a> [see <b>CONTRAINDICATIONS</b> and <b>ADVERSE REACTIONS</b>].</p> <h5>Use Of TYMLOS Pen</h5> <p>Instruct patients and caregivers who administer TYMLOS on how to properly use the TYMLOS pen and to follow sharps disposal recommendations [see<b> DOSAGE AND ADMINISTRATION</b>]. Advise patients not to share their TYMLOS pen or needles with other patients and not to transfer the contents of the pen to a syringe.</p> <p>Advise patients that each TYMLOS pen can be used for up to 30 days, and after the 30-day use period, to discard the TYMLOS pen, even if it still contains unused solution [see<b> HOW SUPPLIED</b>/<b>Storage And Handling</b>].</p> <h4>Nonclinical Toxicology</h4> <h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4> <h5>Carcinogenesis</h5> <p>In a 2-year carcinogenicity study, abaloparatide was administered once daily to male and female Fischer rats by subcutaneous injection at doses of 10, 25, and 50 mcg/kg. These doses resulted in systemic exposures to abaloparatide that were 4, 16, and 28 times, respectively, the systemic exposure observed in humans following the recommended subcutaneous dose of 80 mcg (based on AUC comparisons). <a href="/neoplastic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Neoplastic</a> changes related to treatment with abaloparatide consisted of marked dose-dependent increases in osteosarcoma and <a href="/osteoblastoma/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">osteoblastoma</a> incidence in all male and female dose groups. The incidence of osteosarcoma was 0-2% in untreated controls and reached 87% and 62% in male and female high-dose groups, respectively. The bone neoplasms were accompanied by marked increases in bone mass.</p> <p>The relevance of the rat findings to humans is uncertain. The use of TYMLOS is not recommended in patients at increased risk of osteosarcoma [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Mutagenesis</h5> <p>Abaloparatide was not genotoxic or mutagenic in a standard battery of tests including the <a href="/ames_test/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Ames test</a> for bacterial <a href="/mutagenesis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">mutagenesis</a>, the chromosome aberration test using human peripheral lymphocytes, and the mouse micronucleus test.</p> <h5>Impairment Of Fertility</h5> <p>Abaloparatide effects on female fertility have not been assessed nonclinically. No adverse effects of abaloparatide on male fertility were observed in male rats. In a male rat fertility study, abaloparatide was administered via subcutaneous injection 2 weeks prior to mating, through the mating period and for approximately 2 weeks after the mating period (for total of 6 weeks) at doses of 10, 25 and 70 μg/kg/day. Abaloparatide did not cause <a href="/adverse_effect/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">adverse effect</a> on mating, fertility indices, <a href="/conception/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">conception</a> rate, reproductive organ weights or <a href="/sperm/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">sperm</a> parameters up to 70 μg/kg/day (28-fold the systemic exposure observed in humans following the recommended subcutaneous dose of 80 mcg (based on AUC comparisons).</p> <a name="USP"></a> <h4>Use In Specific Populations</h4> <h4>Pregnancy</h4> <h5>Risk Summary</h5> <p>TYMLOS is not indicated for use in females of reproductive potential. There are no human data with TYMLOS use in pregnant women to inform any drug associated risks. Animal reproduction studies with abaloparatide have not been conducted.</p> <h4>Lactation</h4> <h5>Risk Summary</h5> <p>TYMLOS is not indicated for use in females of reproductive potential. There is no information on the presence of abaloparatide in human milk, the effects on the breastfed infant, or the effects on milk production.</p> <h4>Pediatric Use</h4> <p>Safety and effectiveness of TYMLOS have not been established in pediatric patients. TYMLOS is not recommended for use in pediatric patients with open epiphyses or hereditary disorders predisposing to osteosarcoma because of an increased baseline risk of osteosarcoma [see<b> WARNINGS AND PRECAUTIONS</b>].</p> <h4>Geriatric Use</h4> <p>Of the total number of patients in the postmenopausal osteoporosis clinical studies of TYMLOS, 82% were age 65 years and over, and 19% were age 75 years and over. In the male osteoporosis study, 74% were age 65 years and over and 23% were age 75 years or over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.</p> <h4>Renal Impairment</h4> <p>No dosage adjustment is required for patients with mild, moderate, or severe renal impairment. A study of a single dose of TYMLOS 80 mcg given subcutaneously was conducted in subjects with normal renal function or mild, moderate, or severe renal impairment. The maximal concentration (Cmax) and area under the concentration-time curve (AUC) of abaloparatide increased 1.4- and 2.1-fold, respectively, in subjects with severe renal impairment, compared to subjects with normal renal function. Patients with severe renal impairment may have increased abaloparatide exposure that may increase the risk of adverse reactions; therefore, monitor for adverse reactions [see <b>CLINICAL PHARMACOLOGY</b>].</p> </div> </div> </div> | <a name="W"></a> <h3>WARNINGS</h3> <p>Included as part of the <b>PRECAUTIONS</b> section.</p> <a name="P"></a> <h3>PRECAUTIONS</h3> <h4>Risk Of Osteosarcoma</h4> <p>Abaloparatide caused a dose-dependent increase in the incidence of <a href="/osteosarcoma/definition.htm" ">osteosarcoma</a> in male and female rats after subcutaneous administration at exposures 4 to 28 times the human exposure at the clinical dose of 80 mcg [see <b>Nonclinical Toxicology</b>]. It is unknown whether TYMLOS will cause osteosarcoma in humans.</p> <p>Osteosarcoma has been reported in patients treated with a PTH-analog in the post marketing setting; however, an increased risk of osteosarcoma has not been observed in observational studies in humans. There are limited data assessing the risk of osteosarcoma beyond 2 years of TYMLOS and/or use of a PTH-analog [see<b> DOSAGE AND ADMINISTRATION</b> and <b>Nonclinical Toxicology</b>].</p> <p>Avoid TYMLOS use in patients with (these patients are at increased baseline risk of osteosarcoma):</p> <ul> <li>Open epiphyses (pediatric and young adult patients) (TYMLOS is not approved in pediatric patients) [see<b> Use In Specific Populations</b>].</li> <li>Metabolic bone diseases other than osteoporosis, including Paget’s disease of the bone.</li> <li>Bone metastases or a history of skeletal malignancies.</li> <li>Prior external beam or <a href="/implant/definition.htm" ">implant</a> <a href="/radiation_therapy/definition.htm" ">radiation therapy</a> involving the <a href="/skeleton/definition.htm" ">skeleton</a>.</li> <li>Hereditary disorders predisposing to osteosarcoma.</li> </ul> <h4>Orthostatic Hypotension</h4> <p>Orthostatic hypotension may occur with TYMLOS, typically within 4 hours of injection. Associated symptoms may include dizziness, palpitations, tachycardia, or nausea, and may resolve by having the patient lie down. For the first several doses, TYMLOS should be administered where the patient can sit or lie down if necessary [see <b>ADVERSE REACTIONS</b>].</p> <h4>Hypercalcemia</h4> <p>TYMLOS may cause hypercalcemia. TYMLOS is not recommended in patients with preexisting hypercalcemia or in patients who have an underlying hypercalcemic disorder, such as primary <a href="/hyperparathyroidism/definition.htm" ">hyperparathyroidism</a>, because of the possibility of exacerbating hypercalcemia [see<b> ADVERSE REACTIONS</b>].</p> <h4>Hypercalciuria And Urolithiasis</h4> <p>TYMLOS may cause hypercalciuria. It is unknown whether TYMLOS may exacerbate urolithiasis in patients with active or a history of urolithiasis. If active urolithiasis or pre-existing hypercalciuria is suspected, measurement of urinary calcium excretion should be considered [see<b> ADVERSE REACTIONS</b>].</p> <h4>Patient Counseling Information</h4> <p>Advise the patient to read the FDA-approved patient labeling (<b>Medication Guide and Instructions for Use</b>).</p> <h5>Risk Of Osteosarcoma</h5> <p>Advise patients that the active ingredient in TYMLOS, abaloparatide, caused a dose-dependent increase in the incidence of osteosarcoma in male and female rats and that it is unknown whether TYMLOS will cause osteosarcoma in humans [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>Instruct patients to promptly report signs and symptoms of possible osteosarcoma such as persistent localized pain or occurrence of a new soft tissue mass that is tender to palpation.</p> <h5>Hypercalcemia</h5> <p>Advise patients that TYMLOS may cause hypercalcemia and discuss the symptoms of hypercalcemia (e.g., nausea, vomiting, constipation, lethargy, muscle weakness) [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>Instruct patients to promptly report signs and symptoms of hypercalcemia.</p> <h5>Orthostatic Hypotension</h5> <p>Advise patients to sit or lie down if they feel lightheaded or have palpitations after the injection until their symptoms resolve. If these symptoms persist or worsen, advise patients to consult their healthcare provider before continuing treatment [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <h5>Hypersensitivity Reactions</h5> <p>Advise patients to seek immediate medical attention if they experience signs or symptoms of a hypersensitivity reaction including <a href="/anaphylaxis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anaphylaxis</a>, dyspnea, or <a href="/urticaria/definition.htm" ">urticaria</a> [see <b>CONTRAINDICATIONS</b> and <b>ADVERSE REACTIONS</b>].</p> <h5>Use Of TYMLOS Pen</h5> <p>Instruct patients and caregivers who administer TYMLOS on how to properly use the TYMLOS pen and to follow sharps disposal recommendations [see<b> DOSAGE AND ADMINISTRATION</b>]. Advise patients not to share their TYMLOS pen or needles with other patients and not to transfer the contents of the pen to a syringe.</p> <p>Advise patients that each TYMLOS pen can be used for up to 30 days, and after the 30-day use period, to discard the TYMLOS pen, even if it still contains unused solution [see<b> HOW SUPPLIED</b>/<b>Storage And Handling</b>].</p> <h4>Nonclinical Toxicology</h4> <h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4> <h5>Carcinogenesis</h5> <p>In a 2-year carcinogenicity study, abaloparatide was administered once daily to male and female Fischer rats by subcutaneous injection at doses of 10, 25, and 50 mcg/kg. These doses resulted in systemic exposures to abaloparatide that were 4, 16, and 28 times, respectively, the systemic exposure observed in humans following the recommended subcutaneous dose of 80 mcg (based on AUC comparisons). <a href="/neoplastic/definition.htm" ">Neoplastic</a> changes related to treatment with abaloparatide consisted of marked dose-dependent increases in osteosarcoma and <a href="/osteoblastoma/definition.htm" ">osteoblastoma</a> incidence in all male and female dose groups. The incidence of osteosarcoma was 0-2% in untreated controls and reached 87% and 62% in male and female high-dose groups, respectively. The bone neoplasms were accompanied by marked increases in bone mass.</p> <p>The relevance of the rat findings to humans is uncertain. The use of TYMLOS is not recommended in patients at increased risk of osteosarcoma [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Mutagenesis</h5> <p>Abaloparatide was not genotoxic or mutagenic in a standard battery of tests including the <a href="/ames_test/definition.htm" ">Ames test</a> for bacterial <a href="/mutagenesis/definition.htm" ">mutagenesis</a>, the chromosome aberration test using human peripheral lymphocytes, and the mouse micronucleus test.</p> <h5>Impairment Of Fertility</h5> <p>Abaloparatide effects on female fertility have not been assessed nonclinically. No adverse effects of abaloparatide on male fertility were observed in male rats. In a male rat fertility study, abaloparatide was administered via subcutaneous injection 2 weeks prior to mating, through the mating period and for approximately 2 weeks after the mating period (for total of 6 weeks) at doses of 10, 25 and 70 μg/kg/day. Abaloparatide did not cause <a href="/adverse_effect/definition.htm" ">adverse effect</a> on mating, fertility indices, <a href="/conception/definition.htm" ">conception</a> rate, reproductive organ weights or <a href="/sperm/definition.htm" ">sperm</a> parameters up to 70 μg/kg/day (28-fold the systemic exposure observed in humans following the recommended subcutaneous dose of 80 mcg (based on AUC comparisons).</p> <a name="USP"></a> <h4>Use In Specific Populations</h4> <h4>Pregnancy</h4> <h5>Risk Summary</h5> <p>TYMLOS is not indicated for use in females of reproductive potential. There are no human data with TYMLOS use in pregnant women to inform any drug associated risks. Animal reproduction studies with abaloparatide have not been conducted.</p> <h4>Lactation</h4> <h5>Risk Summary</h5> <p>TYMLOS is not indicated for use in females of reproductive potential. There is no information on the presence of abaloparatide in human milk, the effects on the breastfed infant, or the effects on milk production.</p> <h4>Pediatric Use</h4> <p>Safety and effectiveness of TYMLOS have not been established in pediatric patients. TYMLOS is not recommended for use in pediatric patients with open epiphyses or hereditary disorders predisposing to osteosarcoma because of an increased baseline risk of osteosarcoma [see<b> WARNINGS AND PRECAUTIONS</b>].</p> <h4>Geriatric Use</h4> <p>Of the total number of patients in the postmenopausal osteoporosis clinical studies of TYMLOS, 82% were age 65 years and over, and 19% were age 75 years and over. In the male osteoporosis study, 74% were age 65 years and over and 23% were age 75 years or over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.</p> <h4>Renal Impairment</h4> <p>No dosage adjustment is required for patients with mild, moderate, or severe renal impairment. A study of a single dose of TYMLOS 80 mcg given subcutaneously was conducted in subjects with normal renal function or mild, moderate, or severe renal impairment. The maximal concentration (Cmax) and area under the concentration-time curve (AUC) of abaloparatide increased 1.4- and 2.1-fold, respectively, in subjects with severe renal impairment, compared to subjects with normal renal function. Patients with severe renal impairment may have increased abaloparatide exposure that may increase the risk of adverse reactions; therefore, monitor for adverse reactions [see <b>CLINICAL PHARMACOLOGY</b>].</p> </div> </div> </div> | 7 | 2023-02-01 17:38:38 | Abaloparatide Injection (Tymlos) | A | Parathyroid Hormone Analogs | Tymlos | abaloparatide injection | Tymlos | John P. Cunha, DO, FACOEP |
| 53 | 2023-02-23 12:07:03 | Overdose & Contraindications | <a name="OD"></a> <h3>OVERDOSE</h3> <p>In a clinical study, accidental overdose was reported in a patient who received 400 mcg in one day (5 times the recommended clinical dose); dosing was temporarily interrupted. The patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day the patient’s serum calcium was within the normal range. The effects of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache.</p> <h4>Overdosage Management</h4> <p>There is no specific <a href="/antidote/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antidote</a> for TYMLOS. Treatment of suspected overdose should include discontinuation of TYMLOS, monitoring of serum calcium and <a href="/phosphorus/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">phosphorus</a>, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable.</p> <a name="CI"></a> <h3>CONTRAINDICATIONS</h3> <p>TYMLOS is contraindicated in patients with a history of systemic hypersensitivity to abaloparatide or to any component of the product formulation. Reactions have included anaphylaxis, dyspnea, and urticaria [see<b> ADVERSE REACTIONS</b>].</p> </div> </div> </div> | <a name="OD"></a> <h3>OVERDOSE</h3> <p>In a clinical study, accidental overdose was reported in a patient who received 400 mcg in one day (5 times the recommended clinical dose); dosing was temporarily interrupted. The patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day the patient’s serum calcium was within the normal range. The effects of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache.</p> <h4>Overdosage Management</h4> <p>There is no specific <a href="/antidote/definition.htm" ">antidote</a> for TYMLOS. Treatment of suspected overdose should include discontinuation of TYMLOS, monitoring of serum calcium and <a href="/phosphorus/definition.htm" ">phosphorus</a>, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable.</p> <a name="CI"></a> <h3>CONTRAINDICATIONS</h3> <p>TYMLOS is contraindicated in patients with a history of systemic hypersensitivity to abaloparatide or to any component of the product formulation. Reactions have included anaphylaxis, dyspnea, and urticaria [see<b> ADVERSE REACTIONS</b>].</p> </div> </div> </div> | 7 | 2023-02-01 17:38:38 | Abaloparatide Injection (Tymlos) | A | Parathyroid Hormone Analogs | Tymlos | abaloparatide injection | Tymlos | John P. Cunha, DO, FACOEP |
| 54 | 2023-02-23 12:07:03 | Clinical Pharmacology | <a name="CP"></a> <h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism Of Action</h4> <p>Abaloparatide is a PTHrP(1-34) analog which acts as an <a href="/agonist/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">agonist</a> at the PTH1 receptor (PTH1R). This results in activation of the cAMP signaling pathway in target cells. Once-daily administration of abaloparatide stimulates new bone formation on trabecular and <a href="/cortical/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cortical</a> bone surfaces by stimulation of osteoblastic activity. In rats and monkeys, abaloparatide had an anabolic effect on bone, demonstrated by increases in BMD and bone mineral content (BMC) that correlated with increases in bone strength at vertebral and/or nonvertebral sites [see<b> Nonclinical Toxicology</b>].</p> <h4>Pharmacodynamics</h4> <h5>Effects On Markers Of Bone Turnover</h5> <p>A dose-finding study of abaloparatide administered once daily for 24 weeks in postmenopausal women with osteoporosis demonstrated a dose-response relationship for BMD and bone formation markers.</p> <p>Daily administration of TYMLOS to postmenopausal women with osteoporosis for 18 months increased the bone formation marker serum <a href="/procollagen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">procollagen</a> type I N-propeptide (sPINP) and the bone <a href="/resorption/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">resorption</a> marker serum <a href="/collagen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">collagen</a> type I cross-linked C-telopeptide (sCTX). The increase in geometric mean sPINP levels peaked at Month 1 at 93% above baseline in postmenopausal women then decreased slowly over time to 45% above baseline at Month 18. The increase in geometric mean sCTX levels in postmenopausal women peaked at Month 3 at 26% above baseline then decreased to baseline levels by Month 18.</p> <p>Daily administration of TYMLOS to men with osteoporosis for 12 months increased the bone formation marker sPINP and the bone resorption marker sCTX. The increase in geometric mean sPINP levels peaked at Month 1 at 133% above baseline in men then decreased slowly over time to 84% above baseline at Month 12. The increase in geometric mean sCTX levels in men peaked at Month 6 at 46% above baseline and was 35% above baseline by Month 12.</p> <h5>Cardiac Electrophysiology</h5> <p>A 4-way cross-over thorough QT/QTc study was conducted in 55 healthy subjects who received single doses of placebo, subcutaneous doses of abaloparatide at 80 mcg and 240 mcg (three times the recommended dose), and moxifloxacin 400 mg orally. Abaloparatide increased heart rate, with a mean peak increase of 15 beats per minute (bpm) and 20 bpm at the first time point (15 minutes) after dosing with 80 mcg and 240 mcg, respectively. There were no clinically meaningful effects of abaloparatide on QTcI (individually corrected QT intervals) or cardiac <a href="/electrophysiology/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">electrophysiology</a>.</p> <h4>Pharmacokinetics</h4> <p>Following seven days of subcutaneous administration of abaloparatide 80 mcg, the mean (SD) abaloparatide exposure was 812 (118) pg/mL for Cmax and 1622 (641) pg·hr/mL for AUC0-24 in postmenopausal women with osteoporosis.</p> <h5>Absorption</h5> <p>The median (range) time to peak concentration of abaloparatide 80 mcg was 0.51 hr (0.25 to 0.52 hr) following subcutaneous administration. The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%.</p> <h5>Distribution</h5> <p>The in vitro plasma protein binding of abaloparatide was approximately 70%. The volume of distribution was approximately 50 L.</p> <h5>Elimination</h5> <p><i>Excretion</i></p> <p>The mean (SD) half-life of abaloparatide is approximately 1 h. The peptide fragments are primarily eliminated through renal excretion.</p> <p><i>Metabolism</i></p> <p>No specific <a href="/metabolism/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">metabolism</a> or excretion studies have been performed with TYMLOS. The metabolism of abaloparatide is consistent with non-specific proteolytic degradation into smaller peptide fragments, followed by elimination by renal clearance.</p> <h4>Specific Populations</h4> <h5>Male And Female Subjects</h5> <p>Mean serum abaloparatide concentration-time profiles observed in a study conducted in healthy men with a mean (±SD) age of 53.1 (±6.9) years were comparable to those observed in the healthy women with a mean (±SD) age of 53.7 (±7.1) years using the same dosing regimen.</p> <h5>Geriatric Patients</h5> <p>No age-related differences in abaloparatide pharmacokinetics were observed in men and postmenopausal women ranging from 18 to 85 years of age.</p> <h5>Race</h5> <p>No differences in abaloparatide pharmacokinetics based on race were observed in clinical trials.</p> <h5>Patients With Renal Impairment</h5> <p>A single 80 mcg subcutaneous dose of abaloparatide was administered to male and female patients with renal impairment: 8 patients with mild renal impairment (CLCr 60 to 89 mL/min), patients with moderate renal impairment (CLCr 30 to 59 mL/min), 8 patients with severe renal impairment (CLCr 15 to 29 mL/min), and 8 healthy subjects with normal renal function (CLCr 90 or greater mL/min) matched by sex, age, and <a href="/body_mass_index/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">body mass index</a> (<a href="/bmi/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">BMI</a>). Abaloparatide Cmax increased 1.0-, 1.3-, and 1.4-fold in patients with mild, moderate, and severe renal impairment, compared to the healthy subjects with normal renal function. Abaloparatide AUC increased 1.2-, 1.7-, and 2.1-fold in patients with mild, moderate, and severe renal impairment, compared to the healthy subjects with normal renal function. Patients undergoing <a href="/dialysis/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">dialysis</a> were not included in the study.</p> <h4>Drug Interactions</h4> <p>In vitro studies showed that abaloparatide, at therapeutic concentrations, does not inhibit or induce Cytochrome P450 enzymes. Abaloparatide is not a substrate of the renal transporters OAT1, OAT3, OCT2, MATE1, or MATE2K.</p> <h4>Immunogenicity</h4> <p>The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of abaloparatide or of other abaloparatide products.</p> <h5>Postmenopausal Women With Osteoporosis</h5> <p>Of the patients receiving TYMLOS for 18 months, 41% (318/773) developed anti-abaloparatide antibodies, and 26% (204/773) developed neutralizing antibodies to abaloparatide. Of the patients with anti-abaloparatide antibodies tested for cross-reactivity, 2.4% (7/297) developed cross-reactivity to PTHrP, of which 3 of the 7 patients developed neutralizing antibodies to PTHrP. Only 0.3% (1/297) developed cross-reactive antibodies to PTH, which were not neutralizing to PTH. Antibody formation did not appear to have any clinically significant impact on safety or efficacy endpoints, including <a href="/bone_mineral_density/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bone mineral density</a> (BMD) response, fracture reduction, or adverse events.</p> <p>Most of the patients with anti-abaloparatide antibodies during treatment with TYMLOS, 86% (275/318), had follow-up antibody measurements every six months after completion of TYMLOS therapy until seroconverting to antibody negative or lost to follow-up. Among these patients, 127 remained antibody positive at 1 year after discontinuing treatment, 55 remained antibody positive at 2 years, and 6 remained antibody positive at 3 years.</p> <h5>Men With Osteoporosis</h5> <p>Of the male patients receiving TYMLOS for 12 months, 25% (36/142) developed anti-abaloparatide antibodies and 1.4% (2/142) developed neutralizing antibodies to abaloparatide. Of the patients with anti-abaloparatide antibodies tested for cross-reactivity, none developed cross-reactivity to PTHrP or PTH. Antibody formation did not appear to have any clinically significant impact on safety or efficacy endpoints, including bone mineral density (BMD) response or adverse events.</p> <a name="AP"></a> <h4>Animal Toxicology And Pharmacology</h4> <p>In toxicity studies in rats and monkeys of up to 26-week and 39-week duration, respectively, findings included <a href="/vasodilation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">vasodilation</a>, increases in serum calcium, decreases in serum phosphorus, and soft tissue mineralization at doses ≥10 mcg/kg/day. The 10 mcg/kg/day dose resulted in systemic exposures to abaloparatide in rats and monkeys that were 2 and 3 times, respectively, the exposure in humans at daily subcutaneous doses of 80 mcg.</p> <p>Pharmacologic effects of abaloparatide on the skeleton were assessed in 12- and 16-month studies in ovariectomized (OVX) rats and monkeys, at doses up to 11- and 1-times human exposure at the recommended subcutaneous dose of 80 mcg, respectively (based on AUC comparisons). In these animal models of postmenopausal osteoporosis, treatment with abaloparatide resulted in dosedependent increases in bone mass at vertebral and/or nonvertebral sites, correlating with increases in bone strength. The anabolic effect of abaloparatide was due to the predominant increase in osteoblastic bone formation and was evidenced by increases in trabecular thickness and/or cortical thickness due to endosteal bone <a href="/apposition/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">apposition</a>. Abaloparatide maintained or improved bone quality at all skeletal sites evaluated and did not cause any mineralization defects.</p> <p>In an 8-week study in <a href="/androgen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">androgen</a>-deficient orchiectomized (ORX) male rats, a male osteoporosis model, the effects of 5 and 25 mcg/kg/day abaloparatide (≥47-fold clinical exposures by AUC) were examined on bone formation, bone mass, and bone strength. Abaloparatide induced bone formation and improved cortical and trabecular BMD, geometry, and architecture without increasing parameters of bone resorption.</p> <a name="CS"></a> <h4>Clinical Studies</h4> <h4>Efficacy Study In Women With Postmenopausal Osteoporosis</h4> <p>The efficacy of TYMLOS for the treatment of postmenopausal osteoporosis was evaluated in Study 003 (NCT 01343004), an 18-month, randomized, multicenter, double-blind, placebocontrolled clinical trial in postmenopausal women aged 49 to 86 years (mean age of 69) who were randomized to receive TYMLOS 80 mcg (N = 824) or placebo (N = 821) given subcutaneously once daily. Approximately 80% of patients were Caucasian, 16% were Asian, and 3% were Black; 24% were Hispanic. At baseline, the mean T-scores were -2.9 at the <a href="/lumbar/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lumbar</a> spine, -2.1 at the <a href="/femoral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">femoral</a> neck, and -1.9 at the total hip. At baseline, 24% of patients had at least one prevalent vertebral fracture and 48% had at least one prior nonvertebral fracture. Patients took daily supplemental calcium (500 to 1000 mg) and vitamin D (400 to 800 IU).</p> <p>The efficacy study was extended as Study 005 (NCT 01657162), an open-label study where patients were no longer receiving TYMLOS or placebo but were maintained in their original randomized treatment group and received 70 mg alendronate weekly, with calcium and vitamin D supplements for 6 months. Study 005 enrolled 1139 patients, representing 92% of patients who completed Study 003. This included 558 patients who had previously received TYMLOS and 581 patients who had previously received placebo. The cumulative 25-month efficacy dataset included 18 months of exposure to TYMLOS or placebo in Study 003, 1 month of no treatment, followed by 6 months of alendronate therapy in Study 005. Study 005 was then continued to complete 18 months of additional alendronate exposure during which time patients were no longer blinded to their original Study 003 treatment group.</p> <h5>Effect On New Vertebral Fractures</h5> <p>The primary endpoint was the incidence of new vertebral fractures in patients treated with TYMLOS compared to placebo. TYMLOS resulted in a significant reduction in the incidence of new vertebral fractures compared to placebo at 18 months (0.6% TYMLOS compared to 4.2% placebo, p <0.0001). The absolute risk reduction in new vertebral fractures was 3.6% at 18 months and the relative risk reduction was 86% for TYMLOS compared to placebo (Table 3). The incidence of new vertebral fractures at 25 months was 0.6% in patients treated with TYMLOS then alendronate, compared to 4.4% in patients treated with placebo then alendronate (p <0.0001). The relative risk reduction in new vertebral fractures at 25 months was 87% for patients treated with TYMLOS then alendronate, compared to patients treated with placebo then alendronate, and the absolute risk reduction was 3.9% (Table 3). After 24 months of open-label alendronate therapy, the vertebral fracture risk reduction achieved with TYMLOS therapy was maintained.</p> <p align="center"><b>Table 3: Percentage of Postmenopausal Women with Osteoporosis with New Vertebral Fractures (modified Intent to Treat Population)*†</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="25%"></td> <td class="EmphTd" colspan="2">Percentage of Postmenopausal Women With Fractures</td> <td class="EmphTd" rowspan="2" width="25%">Absolute Risk Reduction (%) (95% CI‡)</td> <td class="EmphTd" rowspan="2" width="25%">Relative Risk Reduction (%) (95% CI‡)</td> </tr> <tr> <td class="EmphTd" width="25%">TYMLOS<br /> (N=690*) (%)</td> <td class="EmphTd" width="25%">Placebo<br /> (N=711*) (%)</td> </tr> <tr> <td>0-18 months</td> <td align="center">0.6</td> <td align="center">4.2</td> <td align="center">3.6 (2.1, 5.4)</td> <td align="center">86 (61, 95)</td> </tr> <tr> <td class="EmphTd"></td> <td class="EmphTd">TYMLOS/ Alendronate (N=544†) (%)</td> <td class="EmphTd">Placebo/ Alendronate (N=568†) (%)</td> <td class="EmphTd"></td> <td class="EmphTd"></td> </tr> <tr> <td>0-25 months</td> <td align="center">0.6</td> <td align="center">4.4</td> <td align="center">3.9 (2.1, 5.9)</td> <td align="center">87 (59, 96)</td> </tr> <tr> <td class="credit" colspan="5">* Includes patients who had both pre- and post-treatment spine radiographs in Study 003<br /> † Includes patients who had both pre- and post-treatment spine radiographs in Study 005<br /> ‡ Confidence Interval</td> </tr> </tbody> </table> </center> <p></p> <h5>Effect On Nonvertebral Fractures</h5> <p>TYMLOS resulted in a significant reduction in the incidence of nonvertebral fractures at the end of the 18 months of treatment plus 1 month follow-up where no drug was administered (2.7% for TYMLOS-treated patients compared to 4.7% for placebo-treated patients). The relative risk reduction in nonvertebral fractures for TYMLOS compared to placebo was 43% (logrank test p = 0.049) and the absolute risk reduction was 2.0%.</p> <p>Following 6 months of alendronate treatment in Study 005, the cumulative incidence of nonvertebral fractures at 25 months was 2.7% for women in the prior TYMLOS group compared to 5.6% for women in the prior placebo group (Figure 1). At 25 months, the relative risk reduction in nonvertebral fractures was 52% (logrank test p = 0.017) and the absolute risk reduction was 2.9%.</p> <p align="center"><b>Figure 1: Cumulative Incidence of Nonvertebral Fractures* over 25 Months (Intent to Treat Population)†</b></p> <center> <table cellspacing="0" class="blackpic" width="573"> <tbody> <tr> <td><img alt="Cumulative Incidence of Nonvertebral Fractures* over 25 Months (Intent to Treat Population)† - Illustration" height="542" src="https://images.rxlist.com/images/rxlist/tymlos1.gif" width="573" /></td> </tr> </tbody> </table> </center> <p></p> <p>* Excludes fractures of the <a href="/sternum/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">sternum</a>, <a href="/patella/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">patella</a>, toes, fingers, skull and face and those associated with high <a href="/trauma/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">trauma</a>.</p> <p>† Includes patients randomized in Study 003</p> <p>TYMLOS demonstrated consistent reductions in the risk of vertebral and nonvertebral fractures regardless of age, years since <a href="/menopause/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">menopause</a>, presence or absence of prior fracture (vertebral, nonvertebral), and BMD at baseline.</p> <h5>Effect On Bone Mineral Density (BMD)</h5> <p>Treatment with TYMLOS for 18 months in Study 003 resulted in significant increases in BMD compared to placebo at the lumbar spine, total hip, and femoral neck, each with p<0.0001 (Table 4). Similar findings were seen following 6 months of alendronate treatment in Study 005 (Table 4).</p> <p align="center"><b>Table 4: Mean Percent Changes in Bone Mineral Density (BMD) From Baseline to Endpoint in Postmenopausal Women with Osteoporosis (Intent to Treat Population)*† ‡</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="25%"></td> <td class="EmphTd" width="25%">TYMLOS<br /> (N=824*) (%)</td> <td class="EmphTd" width="25%">Placebo<br /> (N=821*) (%)</td> <td class="EmphTd" width="25%">Treatment Difference (%) (95% CI§)</td> </tr> <tr> <td colspan="4"><b>18 Months</b></td> </tr> <tr> <td>Lumbar Spine</td> <td align="center">9.2</td> <td align="center">0.5</td> <td align="center">8.8 (8.2, 9.3)</td> </tr> <tr> <td>Total Hip</td> <td align="center">3.4</td> <td align="center">-0.1</td> <td align="center">3.5 (3.3, 3.8)</td> </tr> <tr> <td>Femoral Neck</td> <td align="center">2.9</td> <td align="center">-0.4</td> <td align="center">3.3 (3.0, 3.7)</td> </tr> <tr> <td class="EmphTd"></td> <td class="EmphTd">TYMLOS/ Alendronate<br /> (N=558†) (%)</td> <td class="EmphTd">Placebo/ Alendronate<br /> (N=581†) (%)</td> <td class="EmphTd"></td> </tr> <tr> <td colspan="4"><b>25 Months</b></td> </tr> <tr> <td>Lumbar Spine</td> <td align="center">12.8</td> <td align="center">3.5</td> <td align="center">9.3 (8.6, 10.1)</td> </tr> <tr> <td>Total Hip</td> <td align="center">5.5</td> <td align="center">1.4</td> <td align="center">4.1 (3.7, 4.5)</td> </tr> <tr> <td>Femoral Neck</td> <td align="center">4.5</td> <td align="center">0.5</td> <td align="center">4.1 (3.6, 4.6)</td> </tr> <tr> <td class="credit" colspan="4">* Includes patients randomized in Study 003<br /> † Includes patients enrolled in Study 005<br /> ‡ Last-observation-carried-forward<br /> § Confidence Interval</td> </tr> </tbody> </table> </center> <p></p> <p>There was no evidence of differences in the effects of TYMLOS on BMD across subgroups defined by age, years since menopause, race, ethnicity, geographic region, presence or absence of prior fracture (vertebral, nonvertebral), and BMD at baseline.</p> <h5>Effect On Bone Histology</h5> <p>Bone biopsy specimens were obtained from 71 patients with osteoporosis after 12 – 18 months of treatment (36 in the TYMLOS group and 35 in the placebo group). Of the biopsies obtained, 55 were adequate for quantitative histomorphometry assessment (27 in the TYMLOS group and 28 in the placebo group). Qualitative and quantitative histology assessment showed normal bone architecture and no evidence of woven bone, marrow fibrosis, or mineralization defects.</p> <h4>Men With Osteoporosis</h4> <p>The efficacy of TYMLOS for the treatment of men with osteoporosis was evaluated in Study 019 (NCT 03512262), a 12-month, randomized, multicenter, double-blind, placebo-controlled clinical trial in men aged 42 to 85 years (mean age of 68) who were randomized to receive TYMLOS 80 mcg (N = 149) or placebo (N = 79) given subcutaneously once daily. Approximately 95% of patients were Caucasian, 4% were Asian, and <1% (0.4%) were Black; 16% were Hispanic. At baseline, the mean T-scores were -2.1 at the lumbar spine, -2.1 at the femoral neck, and -1.7 at the total hip. Patients took daily supplemental calcium (500 to 1000 mg) and vitamin D (400 to 800 IU).</p> <h5>Effect On Bone Mineral Density (BMD)</h5> <p>The primary endpoint was the percent change from baseline in lumbar spine BMD at 12 months in patients treated with TYMLOS compared to placebo. Treatment with TYMLOS for 12 months in Study 019 resulted in significant increases in BMD compared to placebo at the lumbar spine, total hip, and femoral neck, each with p<0.0001 (Table 5).</p> <p align="center"><b>Table 5: Mean Percent Changes in Bone Mineral Density (BMD) From Baseline to 12 Months in Men with Osteoporosis (Intent to Treat Population)</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="25%"></td> <td class="EmphTd" width="25%">TYMLOS (N=149*) (%)</td> <td class="EmphTd" width="25%">Placebo (N=79*) (%)</td> <td class="EmphTd" width="25%">Treatment Difference (%) (99% CI†)</td> </tr> <tr> <td colspan="4"><b>12 Months</b></td> </tr> <tr> <td>Lumbar Spine</td> <td align="center">8.5</td> <td align="center">1.2</td> <td align="center">7.3 (5.1, 9.6)</td> </tr> <tr> <td>Total Hip</td> <td align="center">2.1</td> <td align="center"><0.1</td> <td align="center">2.1 (1.0, 3.2)</td> </tr> <tr> <td>Femoral Neck</td> <td align="center">3.0</td> <td align="center">0.2</td> <td align="center">2.8 (1.4, 4.2)</td> </tr> <tr> <td class="credit" colspan="4">* Includes patients randomized in Study 019<br /> † Confidence Interval</td> </tr> </tbody> </table> </center> <p></p> <p>There was no evidence of differences in the effects of TYMLOS on BMD at Month 12 across subgroups defined by age, race, ethnicity, geographic region, presence or absence of prior fracture, and BMD at baseline.</p> </div> </div> </div> | <a name="CP"></a> <h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism Of Action</h4> <p>Abaloparatide is a PTHrP(1-34) analog which acts as an <a href="/agonist/definition.htm" ">agonist</a> at the PTH1 receptor (PTH1R). This results in activation of the cAMP signaling pathway in target cells. Once-daily administration of abaloparatide stimulates new bone formation on trabecular and <a href="/cortical/definition.htm" ">cortical</a> bone surfaces by stimulation of osteoblastic activity. In rats and monkeys, abaloparatide had an anabolic effect on bone, demonstrated by increases in BMD and bone mineral content (BMC) that correlated with increases in bone strength at vertebral and/or nonvertebral sites [see<b> Nonclinical Toxicology</b>].</p> <h4>Pharmacodynamics</h4> <h5>Effects On Markers Of Bone Turnover</h5> <p>A dose-finding study of abaloparatide administered once daily for 24 weeks in postmenopausal women with osteoporosis demonstrated a dose-response relationship for BMD and bone formation markers.</p> <p>Daily administration of TYMLOS to postmenopausal women with osteoporosis for 18 months increased the bone formation marker serum <a href="/procollagen/definition.htm" ">procollagen</a> type I N-propeptide (sPINP) and the bone <a href="/resorption/definition.htm" ">resorption</a> marker serum <a href="/collagen/definition.htm" ">collagen</a> type I cross-linked C-telopeptide (sCTX). The increase in geometric mean sPINP levels peaked at Month 1 at 93% above baseline in postmenopausal women then decreased slowly over time to 45% above baseline at Month 18. The increase in geometric mean sCTX levels in postmenopausal women peaked at Month 3 at 26% above baseline then decreased to baseline levels by Month 18.</p> <p>Daily administration of TYMLOS to men with osteoporosis for 12 months increased the bone formation marker sPINP and the bone resorption marker sCTX. The increase in geometric mean sPINP levels peaked at Month 1 at 133% above baseline in men then decreased slowly over time to 84% above baseline at Month 12. The increase in geometric mean sCTX levels in men peaked at Month 6 at 46% above baseline and was 35% above baseline by Month 12.</p> <h5>Cardiac Electrophysiology</h5> <p>A 4-way cross-over thorough QT/QTc study was conducted in 55 healthy subjects who received single doses of placebo, subcutaneous doses of abaloparatide at 80 mcg and 240 mcg (three times the recommended dose), and moxifloxacin 400 mg orally. Abaloparatide increased heart rate, with a mean peak increase of 15 beats per minute (bpm) and 20 bpm at the first time point (15 minutes) after dosing with 80 mcg and 240 mcg, respectively. There were no clinically meaningful effects of abaloparatide on QTcI (individually corrected QT intervals) or cardiac <a href="/electrophysiology/definition.htm" ">electrophysiology</a>.</p> <h4>Pharmacokinetics</h4> <p>Following seven days of subcutaneous administration of abaloparatide 80 mcg, the mean (SD) abaloparatide exposure was 812 (118) pg/mL for Cmax and 1622 (641) pg·hr/mL for AUC0-24 in postmenopausal women with osteoporosis.</p> <h5>Absorption</h5> <p>The median (range) time to peak concentration of abaloparatide 80 mcg was 0.51 hr (0.25 to 0.52 hr) following subcutaneous administration. The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%.</p> <h5>Distribution</h5> <p>The in vitro plasma protein binding of abaloparatide was approximately 70%. The volume of distribution was approximately 50 L.</p> <h5>Elimination</h5> <p><i>Excretion</i></p> <p>The mean (SD) half-life of abaloparatide is approximately 1 h. The peptide fragments are primarily eliminated through renal excretion.</p> <p><i>Metabolism</i></p> <p>No specific <a href="/metabolism/definition.htm" ">metabolism</a> or excretion studies have been performed with TYMLOS. The metabolism of abaloparatide is consistent with non-specific proteolytic degradation into smaller peptide fragments, followed by elimination by renal clearance.</p> <h4>Specific Populations</h4> <h5>Male And Female Subjects</h5> <p>Mean serum abaloparatide concentration-time profiles observed in a study conducted in healthy men with a mean (±SD) age of 53.1 (±6.9) years were comparable to those observed in the healthy women with a mean (±SD) age of 53.7 (±7.1) years using the same dosing regimen.</p> <h5>Geriatric Patients</h5> <p>No age-related differences in abaloparatide pharmacokinetics were observed in men and postmenopausal women ranging from 18 to 85 years of age.</p> <h5>Race</h5> <p>No differences in abaloparatide pharmacokinetics based on race were observed in clinical trials.</p> <h5>Patients With Renal Impairment</h5> <p>A single 80 mcg subcutaneous dose of abaloparatide was administered to male and female patients with renal impairment: 8 patients with mild renal impairment (CLCr 60 to 89 mL/min), patients with moderate renal impairment (CLCr 30 to 59 mL/min), 8 patients with severe renal impairment (CLCr 15 to 29 mL/min), and 8 healthy subjects with normal renal function (CLCr 90 or greater mL/min) matched by sex, age, and <a href="/body_mass_index/definition.htm" ">body mass index</a> (<a href="/bmi/definition.htm" ">BMI</a>). Abaloparatide Cmax increased 1.0-, 1.3-, and 1.4-fold in patients with mild, moderate, and severe renal impairment, compared to the healthy subjects with normal renal function. Abaloparatide AUC increased 1.2-, 1.7-, and 2.1-fold in patients with mild, moderate, and severe renal impairment, compared to the healthy subjects with normal renal function. Patients undergoing <a href="/dialysis/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">dialysis</a> were not included in the study.</p> <h4>Drug Interactions</h4> <p>In vitro studies showed that abaloparatide, at therapeutic concentrations, does not inhibit or induce Cytochrome P450 enzymes. Abaloparatide is not a substrate of the renal transporters OAT1, OAT3, OCT2, MATE1, or MATE2K.</p> <h4>Immunogenicity</h4> <p>The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of abaloparatide or of other abaloparatide products.</p> <h5>Postmenopausal Women With Osteoporosis</h5> <p>Of the patients receiving TYMLOS for 18 months, 41% (318/773) developed anti-abaloparatide antibodies, and 26% (204/773) developed neutralizing antibodies to abaloparatide. Of the patients with anti-abaloparatide antibodies tested for cross-reactivity, 2.4% (7/297) developed cross-reactivity to PTHrP, of which 3 of the 7 patients developed neutralizing antibodies to PTHrP. Only 0.3% (1/297) developed cross-reactive antibodies to PTH, which were not neutralizing to PTH. Antibody formation did not appear to have any clinically significant impact on safety or efficacy endpoints, including <a href="/bone_mineral_density/definition.htm" ">bone mineral density</a> (BMD) response, fracture reduction, or adverse events.</p> <p>Most of the patients with anti-abaloparatide antibodies during treatment with TYMLOS, 86% (275/318), had follow-up antibody measurements every six months after completion of TYMLOS therapy until seroconverting to antibody negative or lost to follow-up. Among these patients, 127 remained antibody positive at 1 year after discontinuing treatment, 55 remained antibody positive at 2 years, and 6 remained antibody positive at 3 years.</p> <h5>Men With Osteoporosis</h5> <p>Of the male patients receiving TYMLOS for 12 months, 25% (36/142) developed anti-abaloparatide antibodies and 1.4% (2/142) developed neutralizing antibodies to abaloparatide. Of the patients with anti-abaloparatide antibodies tested for cross-reactivity, none developed cross-reactivity to PTHrP or PTH. Antibody formation did not appear to have any clinically significant impact on safety or efficacy endpoints, including bone mineral density (BMD) response or adverse events.</p> <a name="AP"></a> <h4>Animal Toxicology And Pharmacology</h4> <p>In toxicity studies in rats and monkeys of up to 26-week and 39-week duration, respectively, findings included <a href="/vasodilation/definition.htm" ">vasodilation</a>, increases in serum calcium, decreases in serum phosphorus, and soft tissue mineralization at doses ≥10 mcg/kg/day. The 10 mcg/kg/day dose resulted in systemic exposures to abaloparatide in rats and monkeys that were 2 and 3 times, respectively, the exposure in humans at daily subcutaneous doses of 80 mcg.</p> <p>Pharmacologic effects of abaloparatide on the skeleton were assessed in 12- and 16-month studies in ovariectomized (OVX) rats and monkeys, at doses up to 11- and 1-times human exposure at the recommended subcutaneous dose of 80 mcg, respectively (based on AUC comparisons). In these animal models of postmenopausal osteoporosis, treatment with abaloparatide resulted in dosedependent increases in bone mass at vertebral and/or nonvertebral sites, correlating with increases in bone strength. The anabolic effect of abaloparatide was due to the predominant increase in osteoblastic bone formation and was evidenced by increases in trabecular thickness and/or cortical thickness due to endosteal bone <a href="/apposition/definition.htm" ">apposition</a>. Abaloparatide maintained or improved bone quality at all skeletal sites evaluated and did not cause any mineralization defects.</p> <p>In an 8-week study in <a href="/androgen/definition.htm" ">androgen</a>-deficient orchiectomized (ORX) male rats, a male osteoporosis model, the effects of 5 and 25 mcg/kg/day abaloparatide (≥47-fold clinical exposures by AUC) were examined on bone formation, bone mass, and bone strength. Abaloparatide induced bone formation and improved cortical and trabecular BMD, geometry, and architecture without increasing parameters of bone resorption.</p> <a name="CS"></a> <h4>Clinical Studies</h4> <h4>Efficacy Study In Women With Postmenopausal Osteoporosis</h4> <p>The efficacy of TYMLOS for the treatment of postmenopausal osteoporosis was evaluated in Study 003 (NCT 01343004), an 18-month, randomized, multicenter, double-blind, placebocontrolled clinical trial in postmenopausal women aged 49 to 86 years (mean age of 69) who were randomized to receive TYMLOS 80 mcg (N = 824) or placebo (N = 821) given subcutaneously once daily. Approximately 80% of patients were Caucasian, 16% were Asian, and 3% were Black; 24% were Hispanic. At baseline, the mean T-scores were -2.9 at the <a href="/lumbar/definition.htm" ">lumbar</a> spine, -2.1 at the <a href="/femoral/definition.htm" ">femoral</a> neck, and -1.9 at the total hip. At baseline, 24% of patients had at least one prevalent vertebral fracture and 48% had at least one prior nonvertebral fracture. Patients took daily supplemental calcium (500 to 1000 mg) and vitamin D (400 to 800 IU).</p> <p>The efficacy study was extended as Study 005 (NCT 01657162), an open-label study where patients were no longer receiving TYMLOS or placebo but were maintained in their original randomized treatment group and received 70 mg alendronate weekly, with calcium and vitamin D supplements for 6 months. Study 005 enrolled 1139 patients, representing 92% of patients who completed Study 003. This included 558 patients who had previously received TYMLOS and 581 patients who had previously received placebo. The cumulative 25-month efficacy dataset included 18 months of exposure to TYMLOS or placebo in Study 003, 1 month of no treatment, followed by 6 months of alendronate therapy in Study 005. Study 005 was then continued to complete 18 months of additional alendronate exposure during which time patients were no longer blinded to their original Study 003 treatment group.</p> <h5>Effect On New Vertebral Fractures</h5> <p>The primary endpoint was the incidence of new vertebral fractures in patients treated with TYMLOS compared to placebo. TYMLOS resulted in a significant reduction in the incidence of new vertebral fractures compared to placebo at 18 months (0.6% TYMLOS compared to 4.2% placebo, p <0.0001). The absolute risk reduction in new vertebral fractures was 3.6% at 18 months and the relative risk reduction was 86% for TYMLOS compared to placebo (Table 3). The incidence of new vertebral fractures at 25 months was 0.6% in patients treated with TYMLOS then alendronate, compared to 4.4% in patients treated with placebo then alendronate (p <0.0001). The relative risk reduction in new vertebral fractures at 25 months was 87% for patients treated with TYMLOS then alendronate, compared to patients treated with placebo then alendronate, and the absolute risk reduction was 3.9% (Table 3). After 24 months of open-label alendronate therapy, the vertebral fracture risk reduction achieved with TYMLOS therapy was maintained.</p> <p align="center"><b>Table 3: Percentage of Postmenopausal Women with Osteoporosis with New Vertebral Fractures (modified Intent to Treat Population)*†</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="25%"></td> <td class="EmphTd" colspan="2">Percentage of Postmenopausal Women With Fractures</td> <td class="EmphTd" rowspan="2" width="25%">Absolute Risk Reduction (%) (95% CI‡)</td> <td class="EmphTd" rowspan="2" width="25%">Relative Risk Reduction (%) (95% CI‡)</td> </tr> <tr> <td class="EmphTd" width="25%">TYMLOS<br /> (N=690*) (%)</td> <td class="EmphTd" width="25%">Placebo<br /> (N=711*) (%)</td> </tr> <tr> <td>0-18 months</td> <td align="center">0.6</td> <td align="center">4.2</td> <td align="center">3.6 (2.1, 5.4)</td> <td align="center">86 (61, 95)</td> </tr> <tr> <td class="EmphTd"></td> <td class="EmphTd">TYMLOS/ Alendronate (N=544†) (%)</td> <td class="EmphTd">Placebo/ Alendronate (N=568†) (%)</td> <td class="EmphTd"></td> <td class="EmphTd"></td> </tr> <tr> <td>0-25 months</td> <td align="center">0.6</td> <td align="center">4.4</td> <td align="center">3.9 (2.1, 5.9)</td> <td align="center">87 (59, 96)</td> </tr> <tr> <td class="credit" colspan="5">* Includes patients who had both pre- and post-treatment spine radiographs in Study 003<br /> † Includes patients who had both pre- and post-treatment spine radiographs in Study 005<br /> ‡ Confidence Interval</td> </tr> </tbody> </table> </center> <p></p> <h5>Effect On Nonvertebral Fractures</h5> <p>TYMLOS resulted in a significant reduction in the incidence of nonvertebral fractures at the end of the 18 months of treatment plus 1 month follow-up where no drug was administered (2.7% for TYMLOS-treated patients compared to 4.7% for placebo-treated patients). The relative risk reduction in nonvertebral fractures for TYMLOS compared to placebo was 43% (logrank test p = 0.049) and the absolute risk reduction was 2.0%.</p> <p>Following 6 months of alendronate treatment in Study 005, the cumulative incidence of nonvertebral fractures at 25 months was 2.7% for women in the prior TYMLOS group compared to 5.6% for women in the prior placebo group (Figure 1). At 25 months, the relative risk reduction in nonvertebral fractures was 52% (logrank test p = 0.017) and the absolute risk reduction was 2.9%.</p> <p align="center"><b>Figure 1: Cumulative Incidence of Nonvertebral Fractures* over 25 Months (Intent to Treat Population)†</b></p> <center> <table cellspacing="0" class="blackpic" width="573"> <tbody> <tr> <td><img alt="Cumulative Incidence of Nonvertebral Fractures* over 25 Months (Intent to Treat Population)† - Illustration" height="542" src="https://images.rxlist.com/images/rxlist/tymlos1.gif" width="573" /></td> </tr> </tbody> </table> </center> <p></p> <p>* Excludes fractures of the <a href="/sternum/definition.htm" ">sternum</a>, <a href="/patella/definition.htm" ">patella</a>, toes, fingers, skull and face and those associated with high <a href="/trauma/definition.htm" ">trauma</a>.</p> <p>† Includes patients randomized in Study 003</p> <p>TYMLOS demonstrated consistent reductions in the risk of vertebral and nonvertebral fractures regardless of age, years since <a href="/menopause/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">menopause</a>, presence or absence of prior fracture (vertebral, nonvertebral), and BMD at baseline.</p> <h5>Effect On Bone Mineral Density (BMD)</h5> <p>Treatment with TYMLOS for 18 months in Study 003 resulted in significant increases in BMD compared to placebo at the lumbar spine, total hip, and femoral neck, each with p<0.0001 (Table 4). Similar findings were seen following 6 months of alendronate treatment in Study 005 (Table 4).</p> <p align="center"><b>Table 4: Mean Percent Changes in Bone Mineral Density (BMD) From Baseline to Endpoint in Postmenopausal Women with Osteoporosis (Intent to Treat Population)*† ‡</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="25%"></td> <td class="EmphTd" width="25%">TYMLOS<br /> (N=824*) (%)</td> <td class="EmphTd" width="25%">Placebo<br /> (N=821*) (%)</td> <td class="EmphTd" width="25%">Treatment Difference (%) (95% CI§)</td> </tr> <tr> <td colspan="4"><b>18 Months</b></td> </tr> <tr> <td>Lumbar Spine</td> <td align="center">9.2</td> <td align="center">0.5</td> <td align="center">8.8 (8.2, 9.3)</td> </tr> <tr> <td>Total Hip</td> <td align="center">3.4</td> <td align="center">-0.1</td> <td align="center">3.5 (3.3, 3.8)</td> </tr> <tr> <td>Femoral Neck</td> <td align="center">2.9</td> <td align="center">-0.4</td> <td align="center">3.3 (3.0, 3.7)</td> </tr> <tr> <td class="EmphTd"></td> <td class="EmphTd">TYMLOS/ Alendronate<br /> (N=558†) (%)</td> <td class="EmphTd">Placebo/ Alendronate<br /> (N=581†) (%)</td> <td class="EmphTd"></td> </tr> <tr> <td colspan="4"><b>25 Months</b></td> </tr> <tr> <td>Lumbar Spine</td> <td align="center">12.8</td> <td align="center">3.5</td> <td align="center">9.3 (8.6, 10.1)</td> </tr> <tr> <td>Total Hip</td> <td align="center">5.5</td> <td align="center">1.4</td> <td align="center">4.1 (3.7, 4.5)</td> </tr> <tr> <td>Femoral Neck</td> <td align="center">4.5</td> <td align="center">0.5</td> <td align="center">4.1 (3.6, 4.6)</td> </tr> <tr> <td class="credit" colspan="4">* Includes patients randomized in Study 003<br /> † Includes patients enrolled in Study 005<br /> ‡ Last-observation-carried-forward<br /> § Confidence Interval</td> </tr> </tbody> </table> </center> <p></p> <p>There was no evidence of differences in the effects of TYMLOS on BMD across subgroups defined by age, years since menopause, race, ethnicity, geographic region, presence or absence of prior fracture (vertebral, nonvertebral), and BMD at baseline.</p> <h5>Effect On Bone Histology</h5> <p>Bone biopsy specimens were obtained from 71 patients with osteoporosis after 12 – 18 months of treatment (36 in the TYMLOS group and 35 in the placebo group). Of the biopsies obtained, 55 were adequate for quantitative histomorphometry assessment (27 in the TYMLOS group and 28 in the placebo group). Qualitative and quantitative histology assessment showed normal bone architecture and no evidence of woven bone, marrow fibrosis, or mineralization defects.</p> <h4>Men With Osteoporosis</h4> <p>The efficacy of TYMLOS for the treatment of men with osteoporosis was evaluated in Study 019 (NCT 03512262), a 12-month, randomized, multicenter, double-blind, placebo-controlled clinical trial in men aged 42 to 85 years (mean age of 68) who were randomized to receive TYMLOS 80 mcg (N = 149) or placebo (N = 79) given subcutaneously once daily. Approximately 95% of patients were Caucasian, 4% were Asian, and <1% (0.4%) were Black; 16% were Hispanic. At baseline, the mean T-scores were -2.1 at the lumbar spine, -2.1 at the femoral neck, and -1.7 at the total hip. Patients took daily supplemental calcium (500 to 1000 mg) and vitamin D (400 to 800 IU).</p> <h5>Effect On Bone Mineral Density (BMD)</h5> <p>The primary endpoint was the percent change from baseline in lumbar spine BMD at 12 months in patients treated with TYMLOS compared to placebo. Treatment with TYMLOS for 12 months in Study 019 resulted in significant increases in BMD compared to placebo at the lumbar spine, total hip, and femoral neck, each with p<0.0001 (Table 5).</p> <p align="center"><b>Table 5: Mean Percent Changes in Bone Mineral Density (BMD) From Baseline to 12 Months in Men with Osteoporosis (Intent to Treat Population)</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="25%"></td> <td class="EmphTd" width="25%">TYMLOS (N=149*) (%)</td> <td class="EmphTd" width="25%">Placebo (N=79*) (%)</td> <td class="EmphTd" width="25%">Treatment Difference (%) (99% CI†)</td> </tr> <tr> <td colspan="4"><b>12 Months</b></td> </tr> <tr> <td>Lumbar Spine</td> <td align="center">8.5</td> <td align="center">1.2</td> <td align="center">7.3 (5.1, 9.6)</td> </tr> <tr> <td>Total Hip</td> <td align="center">2.1</td> <td align="center"><0.1</td> <td align="center">2.1 (1.0, 3.2)</td> </tr> <tr> <td>Femoral Neck</td> <td align="center">3.0</td> <td align="center">0.2</td> <td align="center">2.8 (1.4, 4.2)</td> </tr> <tr> <td class="credit" colspan="4">* Includes patients randomized in Study 019<br /> † Confidence Interval</td> </tr> </tbody> </table> </center> <p></p> <p>There was no evidence of differences in the effects of TYMLOS on BMD at Month 12 across subgroups defined by age, race, ethnicity, geographic region, presence or absence of prior fracture, and BMD at baseline.</p> </div> </div> </div> | 7 | 2023-02-01 17:38:38 | Abaloparatide Injection (Tymlos) | A | Parathyroid Hormone Analogs | Tymlos | abaloparatide injection | Tymlos | John P. Cunha, DO, FACOEP |
| 55 | 2023-02-23 12:07:03 | Medication Guide | <a name="PI"></a> <h3>PATIENT INFORMATION</h3> <p><b>TYMLOS®</b><br /> (tim lows’)<br /> (abaloparatide) injection, for subcutaneous use</p> <p><b>What is the most important information I should know about TYMLOS?</b></p> <p><b>TYMLOS may cause serious side effects including:</b></p> <ul> <li><b>Possible bone cancer (osteosarcoma).</b> During animal drug testing, the medicine in TYMLOS caused some rats to develop a bone cancer called osteosarcoma. It is not known if people who take TYMLOS will have a higher chance of getting osteosarcoma. <ul> <li>Tell your healthcare provider right away if you have pain in your bones, pain in any areas of your body that does not go away, or any new or unusual lumps or swelling under your skin that is tender to touch.</li> </ul> </li> </ul> <p><b>What is TYMLOS?</b></p> <p>TYMLOS is a prescription medicine used to:</p> <ul> <li>treat osteoporosis in postmenopausal women who are at high risk for bone fracture, or who cannot use another osteoporosis treatment or other osteoporosis treatments did not work well. TYMLOS can decrease the chance of having a fracture of the spine and other bones in postmenopausal women with thinning and weakening bones (osteoporosis)</li> <li>increase bone density in men with osteoporosis who are at high risk for bone fracture, or who cannot use another osteoporosis treatment or other osteoporosis treatments did not work well</li> </ul> <p>It is not known if TYMLOS is safe and effective for children 18 years and younger. TYMLOS should not be used in children and young adults whose bones are still growing.</p> <p>It is not recommended that people use TYMLOS for more than 2 years during their lifetime.</p> <p><b>Do not take TYMLOS:</b></p> <ul> <li>if you had an allergic reaction to abaloparatide, or any of the other ingredients in TYMLOS. See the end of this Medication Guide for a complete list of ingredients in TYMLOS.</li> </ul> <p><b>Before you take TYMLOS, tell your healthcare provider about all of your medical conditions, including if you:</b></p> <ul> <li>have Paget’s disease of the bone or other bone disease.</li> <li>have or have had cancer in your bones.</li> <li>have or have had radiation therapy involving your bones.</li> <li>have or have had too much calcium in your blood.</li> <li>have or have had an increase in your parathyroid hormone (hyperparathyroidism).</li> <li>will have trouble injecting yourself with the TYMLOS pen and do not have someone who can help you.</li> <li>are pregnant or plan to become pregnant. TYMLOS is not for pregnant women.</li> <li>are breastfeeding or plan to breastfeed. It is not known if TYMLOS passes into your breast milk. You and your healthcare provider should decide if you will take TYMLOS or breastfeed. You should not do both.</li> </ul> <p><b>Tell your healthcare provider about all the medicines you take,</b> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p> <p>Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist each time you get a new medicine.</p> <p><b>How should I use TYMLOS?</b></p> <ul> <li>Read the detailed Instructions for Use provided with your medicine.</li> <li>Use TYMLOS exactly as your healthcare provider tells you to use it.</li> <li>Do not try to inject TYMLOS yourself until you or your caregiver receive training from a healthcare provider on the right way to use the TYMLOS pen.</li> <li>You should receive your first several injections of TYMLOS where you can sit or lie down, if necessary, until you know how it affects you.</li> <li>Inject TYMLOS 1 time each day into your lower stomach area (abdomen) just under your skin (subcutaneous). Avoid giving your injection within the 2-inch area around your belly button (navel).</li> <li>Talk to your healthcare provider about how to change (rotate) your injection site for each injection. Do not give TYMLOS in your veins (intravenously) or deep into your muscles (intramuscularly).</li> <li>You can take TYMLOS with or without food or drink.</li> <li>Take TYMLOS at about the same time each day.</li> <li>If you forget or cannot take TYMLOS at your usual time, take it as soon as you can on that day.</li> <li>The TYMLOS pen has enough medicine for 30 days. It is set to give 1 dose of medicine with each injection. Do not take more than 1 injection in the same day.</li> <li>Do not transfer the medicine from the TYMLOS pen to a syringe. This can cause you to use the wrong dose of TYMLOS. If you do not have pen needles to use with your TYMLOS pen, talk with your healthcare provider.</li> <li>Do not share your TYMLOS pen or pen needles with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them.</li> <li>TYMLOS should look clear and colorless. Do not use TYMLOS if it has particles in it, or if it is cloudy or colored.</li> <li>Your healthcare provider may do blood and urine tests during your treatment with TYMLOS.</li> <li>Your healthcare provider may ask you to have a bone mineral density test after your treatment with TYMLOS.</li> <li>If you take more TYMLOS than prescribed you may have symptoms such as muscle weakness, low energy, headache, nausea, dizziness (especially when getting up after sitting for a while), and a faster heartbeat. Stop taking TYMLOS and call your healthcare provider right away.</li> <li>You should not use TYMLOS for more than 2 years over your lifetime.</li> <li>If your healthcare provider recommends calcium and vitamin D supplements, you can take them while using TYMLOS.</li> </ul> <p><b>What are the possible side effects of TYMLOS?</b></p> <p><b>TYMLOS may cause serious side effects including:</b></p> <ul> <li>See <b>“What is the most important information I should know about TYMLOS?”</b></li> <li><b>Decrease in blood pressure when you change positions.</b> Some people may feel dizzy, have a faster heartbeat, or feel lightheaded soon after the TYMLOS injection is given. These symptoms generally go away within a few hours. Take your injections of TYMLOS in a place where you can sit or lie down right away if you get these symptoms. If your symptoms get worse or do not go away, stop taking TYMLOS and call your healthcare provider.</li> <li><b>Increased blood calcium (hypercalcemia).</b> TYMLOS can cause some people to have a higher blood calcium level than normal. Your healthcare provider may check your blood calcium before you start and during your treatment with TYMLOS. Tell your healthcare provider if you have nausea, vomiting, constipation, low energy, or muscle weakness. These may be signs there is too much calcium in your blood.</li> <li><b>Increased urine calcium (hypercalciuria).</b> TYMLOS can cause some people to have higher levels of calcium in their urine than normal. Increased calcium may also cause you to develop kidney stones (urolithiasis) in your kidneys, bladder, or urinary tract. Tell your healthcare provider right away if you get any symptoms of kidney stones which may include pain in your lower back or lower stomach area, pain when you urinate, or blood in your urine.</li> </ul> <p><b>The most common side effects of TYMLOS in women with postmenopausal osteoporosis include:</b></p> <ul> <li>dizziness</li> <li>fast heartbeat</li> <li>upper stomach pain</li> <li>nausea</li> <li>feeling tired (fatigue)</li> <li>spinning feeling (vertigo)</li> <li>headache</li> </ul> <p><b>The most common side effects of TYMLOS in men with osteoporosis include:</b></p> <ul> <li>redness at injection site</li> <li>pain at injection site</li> <li>nausea</li> <li>dizziness</li> <li>bruising</li> <li>abdominal pain</li> <li>joint pain</li> <li>abdominal bloating</li> <li>bone pain</li> <li>swelling at injection site</li> <li>diarrhea</li> </ul> <p>These are not all the possible side effects of TYMLOS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <p><b>How should I store TYMLOS?</b></p> <ul> <li><b>Before first use,</b> store TYMLOS pens in the refrigerator between 36°F to 46°F (2°C to 8°C).</li> <li><b>After first use,</b> store your TYMLOS pen for up to 30 days at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li><b>Do not freeze</b> the TYMLOS pen or expose it to heat.</li> <li>Do not use TYMLOS after the expiration date printed on the pen and packaging.</li> <li>Throw away the TYMLOS pen after 30 days even if some medicine is left in the pen (see “Instructions for Use”). <b>Keep TYMLOS and all medicines out of the reach of children.</b></li> </ul> <p><b>General information about the safe and effective use of TYMLOS.</b></p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TYMLOS for a condition for which it was not prescribed. Do not give TYMLOS to other people, even if they have the same condition you have. It may harm them.</p> <p>You can ask your pharmacist or healthcare provider for information about TYMLOS that is written for health professionals.</p> <p><b>What are the ingredients in TYMLOS?</b></p> <p><b>Active ingredient:</b> abaloparatide</p> <p><b>Inactive ingredients:</b> phenol, sodium acetate trihydrate, acetic acid, and water for injection.</p> <p><b>INSTRUCTIONS FOR USE</b></p> <p><b>TYMLOS™</b><br /> (tim lows’) (abaloparatide) injection, for subcutaneous use</p> <p><b>Instructions for Use</b></p> <p>Read and follow this Instructions for Use so that you inject TYMLOS pen the right way. Call your healthcare provider if you have any questions about the right way to inject the TYMLOS pen.</p> <p><b>Important information about your TYMLOS pen</b></p> <ul> <li>Do not try to inject TYMLOS yourself until you or your caregiver receive training from a healthcare provider on the right way to use TYMLOS pen.</li> <li>Do not share your TYMLOS pen or pen needles with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.</li> <li>Each TYMLOS pen is a prefilled pen containing 30 doses of TYMLOS. Each dose will contain 80 mcg of TYMLOS. You do not have to measure your dose. The pen measures each dose of TYMLOS for you.</li> <li>Use a new pen needle for each injection. Keep the cap on the TYMLOS pen when not using the pen.</li> <li>Before using the pen always check the label to be sure it is your TYMLOS pen.</li> <li>Do not use your TYMLOS pen if it looks damaged. If you drop your TYMLOS pen or it becomes damaged, call your healthcare provider or pharmacist or call 1-855-672-3487.</li> <li>To clean your TYMLOS pen, wipe the outside of the pen with a clean, damp cloth, if needed.</li> <li>The TYMLOS pen is not recommended for use by the blind or visually impaired without the help of a person trained in the right way to use the pen.</li> </ul> <p><b>Pen needles to use with your TYMLOS pen</b></p> <ul> <li>Pen needles are not included with your TYMLOS pen. You will need a prescription from your healthcare provider to get pen needles from your pharmacy.</li> <li>The correct needles to use with your TYMLOS pen are 5 to 8 mm, 31-gauge needles. Compatible needles include Clickfine®, BD Ultra-Fine™, MedtFine®, Easy Comfort, Clever Choice™ Comfort EZ™, and SureComfort™. If you are not sure what type of needle to use, ask your healthcare provider or pharmacist.</li> </ul> <p><b>Supplies you will need for each injection using your TYMLOS pen</b></p> <ul> <li>1 TYMLOS pen</li> <li>1 pen needle</li> <li>1 alcohol swab</li> <li>1 cotton ball or gauze pad</li> <li>1 sharps disposal container for pen needles and TYMLOS pens. See “How should I throw away (dispose) of the pen needles and TYMLOS pens?” in the far right column.</li> </ul> <p><b>How should I store the TYMLOS pen?</b></p> <ul> <li><b>Before first use,</b> store TYMLOS pens in the refrigerator between 36°F to 46°F (2°C to 8°C).</li> <li>Do not store pens with the needle attached.</li> <li>Do not freeze the TYMLOS pen <b>or expose it to heat.</b></li> </ul> <p><b>During 30 days of use:</b></p> <ul> <li><b>After first use,</b> store the TYMLOS pen for up to 30 days at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li>Keep the pen cap on your TYMLOS pen when storing. Do not store the TYMLOS pen with needle attached.</li> <li>Use your TYMLOS pen for only 30 days.</li> <li>Write down the date of your first use of TYMLOS here: _______/_______/_______. Throw away your TYMLOS pen 30 days after first opening it even if it still contains unused medicine.</li> </ul> <p><b>Keep the TYMLOS pen, pen needles and all medicines out of the reach of children.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="658"> <tbody> <tr> <td><img alt="Parts of the TYMLOS pen - Illustration" height="692" src="https://images.rxlist.com/images/rxlist/tymlos2.gif" width="658" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>How should I throw away (dispose) of the pen needles and TYMLOS pens?</b></p> <ul> <li>Throw away (dispose of) your TYMLOS pen, in a FDA-cleared sharps disposal container or puncture resistant container, 30 days after first opening it even if it still contains unused medicine.</li> <li>Put your used pen needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) your used sharps disposal container in your household trash.</li> <li>If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: <ul> <li>made of a heavy-duty <a href="/plastic/article.htm" rel="sub" onclick="wmdTrack('embd-lnk');">plastic</a>,</li> <li>can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,</li> <li>upright and stable during use,</li> <li>leak-resistant, and properly labeled to warn of hazardous waste inside the container.</li> </ul> </li> <li>When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles, syringes, and prefilled syringes.</li> <li>For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to FDA’s website at: https://www.fda.gov/safesharpsdisposal.</li> <li>Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.</li> </ul> <p><b>For more information about the TYMLOS pen</b></p> <p>For more information, go to www.TYMLOS.com or call 1-855-672-3487.</p> <p><b>Begin the injection.</b></p> <p><b>Check the TYMLOS™ pen</b></p> <p><b>Step 1.</b> Wash and dry your hands.</p> <p><b>Step 2.</b> Check the expiration date (Exp.) on the TYMLOS pen.</p> <ul> <li>Do not use the pen if the expiration date has passed.</li> <li>Call your healthcare provider or pharmacist if the expiration date has passed.</li> </ul> <p><b>Attach pen needle to your TYMLOS pen</b></p> <p><b>Step 3.</b> Pull off the pen cap from your TYMLOS pen. (See Figure D.)</p> <ul> <li>Check the TYMLOS cartridge. The liquid should be clear, colorless, and free of particles; if not, do not use.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="516"> <tbody> <tr> <td><img alt="Pull off the pen cap from your TYMLOS pen - Illustration" height="282" src="https://images.rxlist.com/images/rxlist/tymlos3.gif" width="516" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 4.</b> Pull off the protective paper from the outer needle cap of your pen needle. (See Figure E.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="566"> <tbody> <tr> <td><img alt="Pull off the protective paper from the outer needle cap of your pen needle - Illustration" height="282" src="https://images.rxlist.com/images/rxlist/tymlos4.gif" width="566" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 5.</b> Keep the needle straight and screw it onto the pen until fixed; a secure fit is ensured even if there is no noticeable stop. Do not over-tighten. (See Figure F.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="585"> <tbody> <tr> <td><img alt=" Keep the needle straight and screw it onto the pen until fixed; a secure fit is ensured even if there is no noticeable stop - Illustration" height="428" src="https://images.rxlist.com/images/rxlist/tymlos5.gif" width="585" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 6.</b> Pull off the outer pen needle cap from the pen needle and keep it to use after your injection. (See Figure G.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="600"> <tbody> <tr> <td><img alt="Pull off the outer pen needle cap from the pen needle and keep it to use after your injection - Illustration" height="292" src="https://images.rxlist.com/images/rxlist/tymlos6.gif" width="600" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 7.</b> Carefully pull off the inner pen needle cap and dispose of it. (See Figure H.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="563"> <tbody> <tr> <td><img alt="Carefully pull off the inner pen needle cap and dispose of it - Illustration" height="287" src="https://images.rxlist.com/images/rxlist/tymlos7.gif" width="563" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 8.</b> If you are using this pen for the first time, go to the “New pen setup -Day 1 Only” section to prime your pen.</p> <ul> <li>If you have already used this pen before, go to Step 13 for Days 2 through 30.</li> </ul> <p><b>New pen setup – Day 1 Only (Priming your TYMLOS pen)</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="237"> <tbody> <tr> <td><img alt="If you have already used this pen before, go to Step 13 for Days 2 through 30 - Illustration" height="77" src="https://images.rxlist.com/images/rxlist/tymlos8.gif" width="237" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Do not repeat new pen setup on Days 2 through 30.</b></p> <p><b>Step 9.</b> The “New pen setup” removes air bubbles (primes your pen). You only need to prime your pen on Day 1 for each new pen. Otherwise, you will waste medicine.</p> <ul> <li><b>Skip Steps 10 through 12 on Days 2 through 30.</b></li> </ul> <p><b>Step 10.</b> Turn the dose knob on your TYMLOS pen away from you (clockwise) until it stops. (See Figure I.)</p> <p>Note: You will see “ • 80 ” lined up in the dose display window.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="520"> <tbody> <tr> <td><img alt="Turn the dose knob on your TYMLOS pen away from you - Illustration" height="464" src="https://images.rxlist.com/images/rxlist/tymlos9.gif" width="520" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 11.</b> Hold the TYMLOS pen with the pen needle pointing up. Tap lightly with your finger on the cartridge holder to move any air bubbles in the cartridge to the top of the cartridge. (See Figure J.)</p> <p><b>Note: Do Step 11 even if you do not see air bubbles.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="515"> <tbody> <tr> <td><img alt="Hold the TYMLOS pen with the pen needle pointing up - Illustration" height="500" src="https://images.rxlist.com/images/rxlist/tymlos10.gif" width="515" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 12.</b> Press the green injection button until it will not go any further. (See Figure K).</p> <p><b>Note:</b> You should see liquid come out of the needle tip.</p> <p><b>Note:</b> You will see “•0” lined up in the dose display window.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="459"> <tbody> <tr> <td><img alt="Press the green injection button until it will not go any further - Illustration" height="482" src="https://images.rxlist.com/images/rxlist/tymlos11.gif" width="459" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>What should I do if liquid does not come out of the needle tip?</b></p> <ul> <li>If you do not see a drop of TYMLOS, repeat Steps 10 through 12. A drop of liquid should come out of the needle tip.</li> <li>If you still do not see a drop of liquid call your healthcare provider or pharmacist and use a new TYMLOS pen.</li> <li>When you are ready to use your new TYMLOS pen for the first time, remember to repeat all Steps 9 through 12 to prime your new TYMLOS pen.</li> </ul> <p><b>Set the dose on your TYMLOS pen</b></p> <p><b>Do not push the green injection button while setting your dose.</b></p> <p><b>Step 13.</b> Turn the dose knob on your pen away from you (clockwise) until the dose knob stops and “•80”</p> <p>is lined up in the dose display window. (See Figure L.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="481"> <tbody> <tr> <td><img alt="Turn the dose knob on your pen away from you (clockwise) until the dose knob stops and “•80” - Illustration" height="443" src="https://images.rxlist.com/images/rxlist/tymlos12.gif" width="481" /></td> </tr> </tbody> </table> </center> <p></p> <p>If you set the dose before you are ready to give your injection, turn the dose knob toward you (counter clockwise) until “•0” is in the dose display window.</p> <p><b>If you are not able to set the TYMLOS pen to “•80”,</b> dispose of the pen and use a new TYMLOS pen for your injection, repeating Steps 1 through 13.</p> <ul> <li>If the pen cannot be set to “•80”, there is not enough medicine in the TYMLOS pen for your full dose. See <b>“How should I throw away (dispose) of the pen needles and TYMLOS pens?”</b> on the other side.</li> </ul> <p><b>Choose and clean your injection site</b></p> <p><b>Step 14.</b> Injections should be given in the lower stomach area (abdomen). (See Figure M.) Avoid the 2Âinch area around your <a href="/belly_button/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">belly button</a> (navel).</p> <p>For each injection, change (rotate) your injection site around your abdomen. Talk to your healthcare provider about how to change (rotate) your injection site for each injection. Do not use the same injection area for each injection. Do not inject into areas where <a href="/skin_anatomy_picture_definition_function/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">the skin</a> is tender, bruised, red, scaly, or hard. Avoid areas with <a href="/scars/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">scars</a> or <a href="/stretch_marks/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">stretch marks</a>.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="393"> <tbody> <tr> <td><img alt="Injections should be given in the lower stomach area (abdomen) - Illustration" height="466" src="https://images.rxlist.com/images/rxlist/tymlos13.gif" width="393" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 15.</b> Wipe the injection site with an alcohol swab and allow it to dry. Do not touch, fan, or blow on the injection site after you have cleaned it.</p> <p><b>Giving your TYMLOS pen injection</b></p> <p><b>Read Step 16 and Step 17 before you give your injection.</b></p> <p>Inject your TYMLOS pen the way your healthcare provider has shown you.</p> <p><b>Step 16.</b> (See Figure N.)</p> <ul> <li>Hold the pen so you can see the dose display window during the injection.</li> <li>Insert the pen needle straight into your skin.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="442"> <tbody> <tr> <td><img alt="Hold the pen so you can see the dose display window during the injection - Illustration" height="292" src="https://images.rxlist.com/images/rxlist/tymlos14.gif" width="442" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 17.</b> (See Figure O.)</p> <ul> <li>Press the green injection button until it cannot go any further and “•0” is in the dose display window. Do not move the TYMLOS pen after inserting the needle.</li> <li>Continue to press the green injection button while counting to 10. Counting to 10 will allow the full dose of TYMLOS to be given.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="518"> <tbody> <tr> <td><img alt="Press the green injection button until it cannot go any further and “•0” is in the dose display window. Do not move the TYMLOS pen after inserting the needle - Illustration" height="398" src="https://images.rxlist.com/images/rxlist/tymlos15.gif" width="518" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 18.</b> After counting to 10, release your finger from the green injection button and slowly remove the TYMLOS pen from the injection site by pulling the pen needle straight out.</p> <p><b>Remove the pen needle</b></p> <p><b>Step 19.</b> Carefully place the outer needle cap back on the pen needle. Press on the outer needle cap until it snaps into place and is secure. (See Figure P.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="470"> <tbody> <tr> <td><img alt="Carefully place the outer needle cap back on the pen needle - Illustration" height="308" src="https://images.rxlist.com/images/rxlist/tymlos16.gif" width="470" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Caution: To prevent needle stick injury, carefully follow Step 20.</b></p> <p><b>Step 20.</b> Unscrew the capped needle (like unscrewing a cap from a bottle). To unscrew the capped needle you may need to turn it 8 or more turns and then gently pull until the capped needle comes off. (See Figure Q.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="470"> <tbody> <tr> <td><img alt="Unscrew the capped needle (like unscrewing a cap from a bottle) - Illustration" height="378" src="https://images.rxlist.com/images/rxlist/tymlos17.gif" width="470" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Note:</b> Do not push on the outer needle cap while unscrewing the needle. You should see a gap widening between the outer needle cap and the pen as you unscrew the needle. (See Figure R.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="452"> <tbody> <tr> <td><img alt="Do not push on the outer needle cap while unscrewing the needle - Illustration" height="296" src="https://images.rxlist.com/images/rxlist/tymlos18.gif" width="452" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Replace pen cap</b></p> <p><b>Step 21.</b> Firmly replace the pen cap onto the TYMLOS pen. (See Figure S.)</p> <p>Keep the pen cap on your TYMLOS pen between injections.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="432"> <tbody> <tr> <td><img alt="Firmly replace the pen cap onto the TYMLOS pen - Illustration" height="251" src="https://images.rxlist.com/images/rxlist/tymlos19.gif" width="432" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>After your injection</b></p> <p><b>Step 22.</b> Press a <a href="/cotton/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">cotton</a> ball or gauze pad over the injection site and hold for 10 seconds. Do not rub the injection site. You may have slight bleeding. This is normal.</p> <p>You may cover the injection site with a small adhesive bandage, if needed.</p> <ul> <li><b>Dispose of the pen needle. See “How should I throw away (dispose) of the pen needles and TYMLOS pens?” .</b></li> </ul> <p class="credit">This Instructions for Use has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | <a name="PI"></a> <h3>PATIENT INFORMATION</h3> <p><b>TYMLOS®</b><br /> (tim lows’)<br /> (abaloparatide) injection, for subcutaneous use</p> <p><b>What is the most important information I should know about TYMLOS?</b></p> <p><b>TYMLOS may cause serious side effects including:</b></p> <ul> <li><b>Possible bone cancer (osteosarcoma).</b> During animal drug testing, the medicine in TYMLOS caused some rats to develop a bone cancer called osteosarcoma. It is not known if people who take TYMLOS will have a higher chance of getting osteosarcoma. <ul> <li>Tell your healthcare provider right away if you have pain in your bones, pain in any areas of your body that does not go away, or any new or unusual lumps or swelling under your skin that is tender to touch.</li> </ul> </li> </ul> <p><b>What is TYMLOS?</b></p> <p>TYMLOS is a prescription medicine used to:</p> <ul> <li>treat osteoporosis in postmenopausal women who are at high risk for bone fracture, or who cannot use another osteoporosis treatment or other osteoporosis treatments did not work well. TYMLOS can decrease the chance of having a fracture of the spine and other bones in postmenopausal women with thinning and weakening bones (osteoporosis)</li> <li>increase bone density in men with osteoporosis who are at high risk for bone fracture, or who cannot use another osteoporosis treatment or other osteoporosis treatments did not work well</li> </ul> <p>It is not known if TYMLOS is safe and effective for children 18 years and younger. TYMLOS should not be used in children and young adults whose bones are still growing.</p> <p>It is not recommended that people use TYMLOS for more than 2 years during their lifetime.</p> <p><b>Do not take TYMLOS:</b></p> <ul> <li>if you had an allergic reaction to abaloparatide, or any of the other ingredients in TYMLOS. See the end of this Medication Guide for a complete list of ingredients in TYMLOS.</li> </ul> <p><b>Before you take TYMLOS, tell your healthcare provider about all of your medical conditions, including if you:</b></p> <ul> <li>have Paget’s disease of the bone or other bone disease.</li> <li>have or have had cancer in your bones.</li> <li>have or have had radiation therapy involving your bones.</li> <li>have or have had too much calcium in your blood.</li> <li>have or have had an increase in your parathyroid hormone (hyperparathyroidism).</li> <li>will have trouble injecting yourself with the TYMLOS pen and do not have someone who can help you.</li> <li>are pregnant or plan to become pregnant. TYMLOS is not for pregnant women.</li> <li>are breastfeeding or plan to breastfeed. It is not known if TYMLOS passes into your breast milk. You and your healthcare provider should decide if you will take TYMLOS or breastfeed. You should not do both.</li> </ul> <p><b>Tell your healthcare provider about all the medicines you take,</b> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</p> <p>Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist each time you get a new medicine.</p> <p><b>How should I use TYMLOS?</b></p> <ul> <li>Read the detailed Instructions for Use provided with your medicine.</li> <li>Use TYMLOS exactly as your healthcare provider tells you to use it.</li> <li>Do not try to inject TYMLOS yourself until you or your caregiver receive training from a healthcare provider on the right way to use the TYMLOS pen.</li> <li>You should receive your first several injections of TYMLOS where you can sit or lie down, if necessary, until you know how it affects you.</li> <li>Inject TYMLOS 1 time each day into your lower stomach area (abdomen) just under your skin (subcutaneous). Avoid giving your injection within the 2-inch area around your belly button (navel).</li> <li>Talk to your healthcare provider about how to change (rotate) your injection site for each injection. Do not give TYMLOS in your veins (intravenously) or deep into your muscles (intramuscularly).</li> <li>You can take TYMLOS with or without food or drink.</li> <li>Take TYMLOS at about the same time each day.</li> <li>If you forget or cannot take TYMLOS at your usual time, take it as soon as you can on that day.</li> <li>The TYMLOS pen has enough medicine for 30 days. It is set to give 1 dose of medicine with each injection. Do not take more than 1 injection in the same day.</li> <li>Do not transfer the medicine from the TYMLOS pen to a syringe. This can cause you to use the wrong dose of TYMLOS. If you do not have pen needles to use with your TYMLOS pen, talk with your healthcare provider.</li> <li>Do not share your TYMLOS pen or pen needles with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them.</li> <li>TYMLOS should look clear and colorless. Do not use TYMLOS if it has particles in it, or if it is cloudy or colored.</li> <li>Your healthcare provider may do blood and urine tests during your treatment with TYMLOS.</li> <li>Your healthcare provider may ask you to have a bone mineral density test after your treatment with TYMLOS.</li> <li>If you take more TYMLOS than prescribed you may have symptoms such as muscle weakness, low energy, headache, nausea, dizziness (especially when getting up after sitting for a while), and a faster heartbeat. Stop taking TYMLOS and call your healthcare provider right away.</li> <li>You should not use TYMLOS for more than 2 years over your lifetime.</li> <li>If your healthcare provider recommends calcium and vitamin D supplements, you can take them while using TYMLOS.</li> </ul> <p><b>What are the possible side effects of TYMLOS?</b></p> <p><b>TYMLOS may cause serious side effects including:</b></p> <ul> <li>See <b>“What is the most important information I should know about TYMLOS?”</b></li> <li><b>Decrease in blood pressure when you change positions.</b> Some people may feel dizzy, have a faster heartbeat, or feel lightheaded soon after the TYMLOS injection is given. These symptoms generally go away within a few hours. Take your injections of TYMLOS in a place where you can sit or lie down right away if you get these symptoms. If your symptoms get worse or do not go away, stop taking TYMLOS and call your healthcare provider.</li> <li><b>Increased blood calcium (hypercalcemia).</b> TYMLOS can cause some people to have a higher blood calcium level than normal. Your healthcare provider may check your blood calcium before you start and during your treatment with TYMLOS. Tell your healthcare provider if you have nausea, vomiting, constipation, low energy, or muscle weakness. These may be signs there is too much calcium in your blood.</li> <li><b>Increased urine calcium (hypercalciuria).</b> TYMLOS can cause some people to have higher levels of calcium in their urine than normal. Increased calcium may also cause you to develop kidney stones (urolithiasis) in your kidneys, bladder, or urinary tract. Tell your healthcare provider right away if you get any symptoms of kidney stones which may include pain in your lower back or lower stomach area, pain when you urinate, or blood in your urine.</li> </ul> <p><b>The most common side effects of TYMLOS in women with postmenopausal osteoporosis include:</b></p> <ul> <li>dizziness</li> <li>fast heartbeat</li> <li>upper stomach pain</li> <li>nausea</li> <li>feeling tired (fatigue)</li> <li>spinning feeling (vertigo)</li> <li>headache</li> </ul> <p><b>The most common side effects of TYMLOS in men with osteoporosis include:</b></p> <ul> <li>redness at injection site</li> <li>pain at injection site</li> <li>nausea</li> <li>dizziness</li> <li>bruising</li> <li>abdominal pain</li> <li>joint pain</li> <li>abdominal bloating</li> <li>bone pain</li> <li>swelling at injection site</li> <li>diarrhea</li> </ul> <p>These are not all the possible side effects of TYMLOS. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <p><b>How should I store TYMLOS?</b></p> <ul> <li><b>Before first use,</b> store TYMLOS pens in the refrigerator between 36°F to 46°F (2°C to 8°C).</li> <li><b>After first use,</b> store your TYMLOS pen for up to 30 days at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li><b>Do not freeze</b> the TYMLOS pen or expose it to heat.</li> <li>Do not use TYMLOS after the expiration date printed on the pen and packaging.</li> <li>Throw away the TYMLOS pen after 30 days even if some medicine is left in the pen (see “Instructions for Use”). <b>Keep TYMLOS and all medicines out of the reach of children.</b></li> </ul> <p><b>General information about the safe and effective use of TYMLOS.</b></p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TYMLOS for a condition for which it was not prescribed. Do not give TYMLOS to other people, even if they have the same condition you have. It may harm them.</p> <p>You can ask your pharmacist or healthcare provider for information about TYMLOS that is written for health professionals.</p> <p><b>What are the ingredients in TYMLOS?</b></p> <p><b>Active ingredient:</b> abaloparatide</p> <p><b>Inactive ingredients:</b> phenol, sodium acetate trihydrate, acetic acid, and water for injection.</p> <p><b>INSTRUCTIONS FOR USE</b></p> <p><b>TYMLOS™</b><br /> (tim lows’) (abaloparatide) injection, for subcutaneous use</p> <p><b>Instructions for Use</b></p> <p>Read and follow this Instructions for Use so that you inject TYMLOS pen the right way. Call your healthcare provider if you have any questions about the right way to inject the TYMLOS pen.</p> <p><b>Important information about your TYMLOS pen</b></p> <ul> <li>Do not try to inject TYMLOS yourself until you or your caregiver receive training from a healthcare provider on the right way to use TYMLOS pen.</li> <li>Do not share your TYMLOS pen or pen needles with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.</li> <li>Each TYMLOS pen is a prefilled pen containing 30 doses of TYMLOS. Each dose will contain 80 mcg of TYMLOS. You do not have to measure your dose. The pen measures each dose of TYMLOS for you.</li> <li>Use a new pen needle for each injection. Keep the cap on the TYMLOS pen when not using the pen.</li> <li>Before using the pen always check the label to be sure it is your TYMLOS pen.</li> <li>Do not use your TYMLOS pen if it looks damaged. If you drop your TYMLOS pen or it becomes damaged, call your healthcare provider or pharmacist or call 1-855-672-3487.</li> <li>To clean your TYMLOS pen, wipe the outside of the pen with a clean, damp cloth, if needed.</li> <li>The TYMLOS pen is not recommended for use by the blind or visually impaired without the help of a person trained in the right way to use the pen.</li> </ul> <p><b>Pen needles to use with your TYMLOS pen</b></p> <ul> <li>Pen needles are not included with your TYMLOS pen. You will need a prescription from your healthcare provider to get pen needles from your pharmacy.</li> <li>The correct needles to use with your TYMLOS pen are 5 to 8 mm, 31-gauge needles. Compatible needles include Clickfine®, BD Ultra-Fine™, MedtFine®, Easy Comfort, Clever Choice™ Comfort EZ™, and SureComfort™. If you are not sure what type of needle to use, ask your healthcare provider or pharmacist.</li> </ul> <p><b>Supplies you will need for each injection using your TYMLOS pen</b></p> <ul> <li>1 TYMLOS pen</li> <li>1 pen needle</li> <li>1 alcohol swab</li> <li>1 cotton ball or gauze pad</li> <li>1 sharps disposal container for pen needles and TYMLOS pens. See “How should I throw away (dispose) of the pen needles and TYMLOS pens?” in the far right column.</li> </ul> <p><b>How should I store the TYMLOS pen?</b></p> <ul> <li><b>Before first use,</b> store TYMLOS pens in the refrigerator between 36°F to 46°F (2°C to 8°C).</li> <li>Do not store pens with the needle attached.</li> <li>Do not freeze the TYMLOS pen <b>or expose it to heat.</b></li> </ul> <p><b>During 30 days of use:</b></p> <ul> <li><b>After first use,</b> store the TYMLOS pen for up to 30 days at room temperature between 68°F to 77°F (20°C to 25°C).</li> <li>Keep the pen cap on your TYMLOS pen when storing. Do not store the TYMLOS pen with needle attached.</li> <li>Use your TYMLOS pen for only 30 days.</li> <li>Write down the date of your first use of TYMLOS here: _______/_______/_______. Throw away your TYMLOS pen 30 days after first opening it even if it still contains unused medicine.</li> </ul> <p><b>Keep the TYMLOS pen, pen needles and all medicines out of the reach of children.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="658"> <tbody> <tr> <td><img alt="Parts of the TYMLOS pen - Illustration" height="692" src="https://images.rxlist.com/images/rxlist/tymlos2.gif" width="658" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>How should I throw away (dispose) of the pen needles and TYMLOS pens?</b></p> <ul> <li>Throw away (dispose of) your TYMLOS pen, in a FDA-cleared sharps disposal container or puncture resistant container, 30 days after first opening it even if it still contains unused medicine.</li> <li>Put your used pen needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) your used sharps disposal container in your household trash.</li> <li>If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: <ul> <li>made of a heavy-duty <a href="/plastic/article.htm" rel="sub" onclick="wmdTrack('embd-lnk');">plastic</a>,</li> <li>can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,</li> <li>upright and stable during use,</li> <li>leak-resistant, and properly labeled to warn of hazardous waste inside the container.</li> </ul> </li> <li>When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles, syringes, and prefilled syringes.</li> <li>For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to FDA’s website at: https://www.fda.gov/safesharpsdisposal.</li> <li>Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.</li> </ul> <p><b>For more information about the TYMLOS pen</b></p> <p>For more information, go to www.TYMLOS.com or call 1-855-672-3487.</p> <p><b>Begin the injection.</b></p> <p><b>Check the TYMLOS™ pen</b></p> <p><b>Step 1.</b> Wash and dry your hands.</p> <p><b>Step 2.</b> Check the expiration date (Exp.) on the TYMLOS pen.</p> <ul> <li>Do not use the pen if the expiration date has passed.</li> <li>Call your healthcare provider or pharmacist if the expiration date has passed.</li> </ul> <p><b>Attach pen needle to your TYMLOS pen</b></p> <p><b>Step 3.</b> Pull off the pen cap from your TYMLOS pen. (See Figure D.)</p> <ul> <li>Check the TYMLOS cartridge. The liquid should be clear, colorless, and free of particles; if not, do not use.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="516"> <tbody> <tr> <td><img alt="Pull off the pen cap from your TYMLOS pen - Illustration" height="282" src="https://images.rxlist.com/images/rxlist/tymlos3.gif" width="516" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 4.</b> Pull off the protective paper from the outer needle cap of your pen needle. (See Figure E.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="566"> <tbody> <tr> <td><img alt="Pull off the protective paper from the outer needle cap of your pen needle - Illustration" height="282" src="https://images.rxlist.com/images/rxlist/tymlos4.gif" width="566" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 5.</b> Keep the needle straight and screw it onto the pen until fixed; a secure fit is ensured even if there is no noticeable stop. Do not over-tighten. (See Figure F.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="585"> <tbody> <tr> <td><img alt=" Keep the needle straight and screw it onto the pen until fixed; a secure fit is ensured even if there is no noticeable stop - Illustration" height="428" src="https://images.rxlist.com/images/rxlist/tymlos5.gif" width="585" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 6.</b> Pull off the outer pen needle cap from the pen needle and keep it to use after your injection. (See Figure G.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="600"> <tbody> <tr> <td><img alt="Pull off the outer pen needle cap from the pen needle and keep it to use after your injection - Illustration" height="292" src="https://images.rxlist.com/images/rxlist/tymlos6.gif" width="600" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 7.</b> Carefully pull off the inner pen needle cap and dispose of it. (See Figure H.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="563"> <tbody> <tr> <td><img alt="Carefully pull off the inner pen needle cap and dispose of it - Illustration" height="287" src="https://images.rxlist.com/images/rxlist/tymlos7.gif" width="563" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 8.</b> If you are using this pen for the first time, go to the “New pen setup -Day 1 Only” section to prime your pen.</p> <ul> <li>If you have already used this pen before, go to Step 13 for Days 2 through 30.</li> </ul> <p><b>New pen setup – Day 1 Only (Priming your TYMLOS pen)</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="237"> <tbody> <tr> <td><img alt="If you have already used this pen before, go to Step 13 for Days 2 through 30 - Illustration" height="77" src="https://images.rxlist.com/images/rxlist/tymlos8.gif" width="237" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Do not repeat new pen setup on Days 2 through 30.</b></p> <p><b>Step 9.</b> The “New pen setup” removes air bubbles (primes your pen). You only need to prime your pen on Day 1 for each new pen. Otherwise, you will waste medicine.</p> <ul> <li><b>Skip Steps 10 through 12 on Days 2 through 30.</b></li> </ul> <p><b>Step 10.</b> Turn the dose knob on your TYMLOS pen away from you (clockwise) until it stops. (See Figure I.)</p> <p>Note: You will see “ • 80 ” lined up in the dose display window.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="520"> <tbody> <tr> <td><img alt="Turn the dose knob on your TYMLOS pen away from you - Illustration" height="464" src="https://images.rxlist.com/images/rxlist/tymlos9.gif" width="520" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 11.</b> Hold the TYMLOS pen with the pen needle pointing up. Tap lightly with your finger on the cartridge holder to move any air bubbles in the cartridge to the top of the cartridge. (See Figure J.)</p> <p><b>Note: Do Step 11 even if you do not see air bubbles.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="515"> <tbody> <tr> <td><img alt="Hold the TYMLOS pen with the pen needle pointing up - Illustration" height="500" src="https://images.rxlist.com/images/rxlist/tymlos10.gif" width="515" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 12.</b> Press the green injection button until it will not go any further. (See Figure K).</p> <p><b>Note:</b> You should see liquid come out of the needle tip.</p> <p><b>Note:</b> You will see “•0” lined up in the dose display window.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="459"> <tbody> <tr> <td><img alt="Press the green injection button until it will not go any further - Illustration" height="482" src="https://images.rxlist.com/images/rxlist/tymlos11.gif" width="459" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>What should I do if liquid does not come out of the needle tip?</b></p> <ul> <li>If you do not see a drop of TYMLOS, repeat Steps 10 through 12. A drop of liquid should come out of the needle tip.</li> <li>If you still do not see a drop of liquid call your healthcare provider or pharmacist and use a new TYMLOS pen.</li> <li>When you are ready to use your new TYMLOS pen for the first time, remember to repeat all Steps 9 through 12 to prime your new TYMLOS pen.</li> </ul> <p><b>Set the dose on your TYMLOS pen</b></p> <p><b>Do not push the green injection button while setting your dose.</b></p> <p><b>Step 13.</b> Turn the dose knob on your pen away from you (clockwise) until the dose knob stops and “•80”</p> <p>is lined up in the dose display window. (See Figure L.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="481"> <tbody> <tr> <td><img alt="Turn the dose knob on your pen away from you (clockwise) until the dose knob stops and “•80” - Illustration" height="443" src="https://images.rxlist.com/images/rxlist/tymlos12.gif" width="481" /></td> </tr> </tbody> </table> </center> <p></p> <p>If you set the dose before you are ready to give your injection, turn the dose knob toward you (counter clockwise) until “•0” is in the dose display window.</p> <p><b>If you are not able to set the TYMLOS pen to “•80”,</b> dispose of the pen and use a new TYMLOS pen for your injection, repeating Steps 1 through 13.</p> <ul> <li>If the pen cannot be set to “•80”, there is not enough medicine in the TYMLOS pen for your full dose. See <b>“How should I throw away (dispose) of the pen needles and TYMLOS pens?”</b> on the other side.</li> </ul> <p><b>Choose and clean your injection site</b></p> <p><b>Step 14.</b> Injections should be given in the lower stomach area (abdomen). (See Figure M.) Avoid the 2Âinch area around your <a href="/belly_button/definition.htm" ">belly button</a> (navel).</p> <p>For each injection, change (rotate) your injection site around your abdomen. Talk to your healthcare provider about how to change (rotate) your injection site for each injection. Do not use the same injection area for each injection. Do not inject into areas where <a href="/skin_anatomy_picture_definition_function/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">the skin</a> is tender, bruised, red, scaly, or hard. Avoid areas with <a href="/scars/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">scars</a> or <a href="/stretch_marks/definition.htm" ">stretch marks</a>.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="393"> <tbody> <tr> <td><img alt="Injections should be given in the lower stomach area (abdomen) - Illustration" height="466" src="https://images.rxlist.com/images/rxlist/tymlos13.gif" width="393" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 15.</b> Wipe the injection site with an alcohol swab and allow it to dry. Do not touch, fan, or blow on the injection site after you have cleaned it.</p> <p><b>Giving your TYMLOS pen injection</b></p> <p><b>Read Step 16 and Step 17 before you give your injection.</b></p> <p>Inject your TYMLOS pen the way your healthcare provider has shown you.</p> <p><b>Step 16.</b> (See Figure N.)</p> <ul> <li>Hold the pen so you can see the dose display window during the injection.</li> <li>Insert the pen needle straight into your skin.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="442"> <tbody> <tr> <td><img alt="Hold the pen so you can see the dose display window during the injection - Illustration" height="292" src="https://images.rxlist.com/images/rxlist/tymlos14.gif" width="442" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 17.</b> (See Figure O.)</p> <ul> <li>Press the green injection button until it cannot go any further and “•0” is in the dose display window. Do not move the TYMLOS pen after inserting the needle.</li> <li>Continue to press the green injection button while counting to 10. Counting to 10 will allow the full dose of TYMLOS to be given.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="518"> <tbody> <tr> <td><img alt="Press the green injection button until it cannot go any further and “•0” is in the dose display window. Do not move the TYMLOS pen after inserting the needle - Illustration" height="398" src="https://images.rxlist.com/images/rxlist/tymlos15.gif" width="518" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 18.</b> After counting to 10, release your finger from the green injection button and slowly remove the TYMLOS pen from the injection site by pulling the pen needle straight out.</p> <p><b>Remove the pen needle</b></p> <p><b>Step 19.</b> Carefully place the outer needle cap back on the pen needle. Press on the outer needle cap until it snaps into place and is secure. (See Figure P.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="470"> <tbody> <tr> <td><img alt="Carefully place the outer needle cap back on the pen needle - Illustration" height="308" src="https://images.rxlist.com/images/rxlist/tymlos16.gif" width="470" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Caution: To prevent needle stick injury, carefully follow Step 20.</b></p> <p><b>Step 20.</b> Unscrew the capped needle (like unscrewing a cap from a bottle). To unscrew the capped needle you may need to turn it 8 or more turns and then gently pull until the capped needle comes off. (See Figure Q.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="470"> <tbody> <tr> <td><img alt="Unscrew the capped needle (like unscrewing a cap from a bottle) - Illustration" height="378" src="https://images.rxlist.com/images/rxlist/tymlos17.gif" width="470" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Note:</b> Do not push on the outer needle cap while unscrewing the needle. You should see a gap widening between the outer needle cap and the pen as you unscrew the needle. (See Figure R.)</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="452"> <tbody> <tr> <td><img alt="Do not push on the outer needle cap while unscrewing the needle - Illustration" height="296" src="https://images.rxlist.com/images/rxlist/tymlos18.gif" width="452" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Replace pen cap</b></p> <p><b>Step 21.</b> Firmly replace the pen cap onto the TYMLOS pen. (See Figure S.)</p> <p>Keep the pen cap on your TYMLOS pen between injections.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="432"> <tbody> <tr> <td><img alt="Firmly replace the pen cap onto the TYMLOS pen - Illustration" height="251" src="https://images.rxlist.com/images/rxlist/tymlos19.gif" width="432" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>After your injection</b></p> <p><b>Step 22.</b> Press a <a href="/cotton/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">cotton</a> ball or gauze pad over the injection site and hold for 10 seconds. Do not rub the injection site. You may have slight bleeding. This is normal.</p> <p>You may cover the injection site with a small adhesive bandage, if needed.</p> <ul> <li><b>Dispose of the pen needle. See “How should I throw away (dispose) of the pen needles and TYMLOS pens?” .</b></li> </ul> <p class="credit">This Instructions for Use has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | 7 | 2023-02-01 17:38:38 | Abaloparatide Injection (Tymlos) | A | Parathyroid Hormone Analogs | Tymlos | abaloparatide injection | Tymlos | John P. Cunha, DO, FACOEP |
| 56 | 2023-02-23 12:07:03 | Drug Description | <p><b>What is XEGLYZE and how is it used?</b></p> <p>XEGLYZE is a prescription medicine used to get rid of <a href="/head_lice/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">head lice</a> in people 6 months of age and older.</p> <p>After XEGLYZE is rinsed off, a fine-tooth comb may be used to remove dead lice and nits from the hair and scalp. All personal items exposed to the hair or lice should be washed in hot water or dry-cleaned. See <b>“How do I stop the spread of lice?”</b> at the end of the XEGLYZE Instructions for Use.</p> <p>It is not known if XEGLYZE is safe and effective in children under 6 months of age.</p> <p><b>What are the possible side effects of XEGLYZE?</b></p> <p>The most common side effects of XEGLYZE include:</p> <ul> <li>Redness of <a href="/skin_anatomy_picture_definition_function/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">the skin</a> or scalp</li> <li>Rash</li> <li>Burning sensation of the skin</li> <li>Skin irritation</li> <li>Vomiting</li> <li>Eye irritation</li> <li>Itchy scalp</li> <li>Changes in your hair color</li> </ul> <p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of XEGLYZE. For more information, ask your healthcare provider or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.</p> <a name="D"></a> <h3>DESCRIPTION</h3> <p>The active pharmacological ingredient in XEGLYZE (abametapir) Lotion is the <a href="/pediculicide/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pediculicide</a>, abametapir, which is a dipyridyl compound. The chemical name of abametapir is 5,5'-dimethyl2,2'-bipyridinyl.</p> <p>The structural formula is:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="227"> <tbody> <tr> <td><img alt="XEGLYZE (abametapir) Structrual Formula Illustration" height="81" src="https://images.rxlist.com/images/rxlist/xelgyze1.gif" width="227" /></td> </tr> </tbody> </table> </center> <p></p> <p>The empirical formula is C<sub>12</sub>H<sub>12</sub>N<sub>2</sub> and the molecular weight is 184.24.</p> <p>XEGLYZE is a white to off-white oil in water emulsion, containing 0.74% [weight by weight] of abametapir, intended for topical administration. XEGLYZE contains the following inactive ingredients: benzyl alcohol, butylated hydroxytoluene, carbomer 980, light mineral oil, polysorbate 20, trolamine and water.</p> </div> <div id="667441035-1" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-1", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <p><b>What is XEGLYZE and how is it used?</b></p> <p>XEGLYZE is a prescription medicine used to get rid of <a href="/head_lice/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">head lice</a> in people 6 months of age and older.</p> <p>After XEGLYZE is rinsed off, a fine-tooth comb may be used to remove dead lice and nits from the hair and scalp. All personal items exposed to the hair or lice should be washed in hot water or dry-cleaned. See <b>“How do I stop the spread of lice?”</b> at the end of the XEGLYZE Instructions for Use.</p> <p>It is not known if XEGLYZE is safe and effective in children under 6 months of age.</p> <p><b>What are the possible side effects of XEGLYZE?</b></p> <p>The most common side effects of XEGLYZE include:</p> <ul> <li>Redness of <a href="/skin_anatomy_picture_definition_function/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">the skin</a> or scalp</li> <li>Rash</li> <li>Burning sensation of the skin</li> <li>Skin irritation</li> <li>Vomiting</li> <li>Eye irritation</li> <li>Itchy scalp</li> <li>Changes in your hair color</li> </ul> <p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of XEGLYZE. For more information, ask your healthcare provider or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.</p> <a name="D"></a> <h3>DESCRIPTION</h3> <p>The active pharmacological ingredient in XEGLYZE (abametapir) Lotion is the <a href="/pediculicide/definition.htm" ">pediculicide</a>, abametapir, which is a dipyridyl compound. The chemical name of abametapir is 5,5'-dimethyl2,2'-bipyridinyl.</p> <p>The structural formula is:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="227"> <tbody> <tr> <td><img alt="XEGLYZE (abametapir) Structrual Formula Illustration" height="81" src="https://images.rxlist.com/images/rxlist/xelgyze1.gif" width="227" /></td> </tr> </tbody> </table> </center> <p></p> <p>The empirical formula is C<sub>12</sub>H<sub>12</sub>N<sub>2</sub> and the molecular weight is 184.24.</p> <p>XEGLYZE is a white to off-white oil in water emulsion, containing 0.74% [weight by weight] of abametapir, intended for topical administration. XEGLYZE contains the following inactive ingredients: benzyl alcohol, butylated hydroxytoluene, carbomer 980, light mineral oil, polysorbate 20, trolamine and water.</p> </div> <div id="667441035-1" class="medianet"><</div> </div> </div> | 8 | 2023-02-01 17:39:00 | Abametapir Lotion (Xeglyze) | A | Topical Pediculicide | Xeglyze | abametapir lotion | Xeglyze | John P. Cunha, DO, FACOEP |
| 57 | 2023-02-23 11:36:54 | Indications & Dosage | <a name="I"></a><h3>INDICATIONS</h3><p>XEGLYZE is indicated for the topical treatment of head lice infestation in patients 6 months of age and older.</p><p>XEGLYZE should be used in the context of an overall lice management program:</p><ul><li>Wash (with hot water) or dry-clean all recently worn clothing, hats, used bedding and towels</li><li>Wash personal care items such as combs, brushes, and hair clips in hot water</li></ul><p>Use a fine-tooth comb or special nit comb to remove dead lice and nits</p> <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3><p>For topical use only. XEGLYZE is not for oral, ophthalmic, or intravaginal use. Treatment with XEGLYZE involves a single application.</p><p>Shake well before use. Apply XEGLYZE to dry hair in an amount (up to the full content of one bottle) sufficient to thoroughly coat the hair and scalp. Massage XEGLYZE into the scalp and throughout the hair. Avoid contact with eyes. Leave on the hair and scalp for 10 minutes and then rinse off with warm water. Wash hands after application. Hair may be shampooed any time after the treatment.</p><p>Discard any unused product. Do not flush contents down sink or toilet.</p> <a name="HS"></a><h3>HOW SUPPLIED</h3><h4>Dosage Forms And Strengths</h4><p>Lotion, 0.74% [weight by weight], a viscous white to off-white oil in water emulsion, containing abametapir.</p><h4>Storage And Handling</h4><p class="EmphText"><b>XEGLYZE</b> is a white to off-white oil in water emulsion containing 0.74% [weight by weight] abametapir and supplied in a polyvinyl chloride (PVC) safety-coated single-use round amber glass bottle affixed with a polypropylene child resistant cap (<b>NDC</b> # 43598-921-11) featuring a tri-foil inner liner. The container is filled to a nominal 200 g (approximately 7 oz. or 210 mL) of the lotion.</p><p>Store upright at room temperature, 20°C to 25°C (68°F to 77°F), with allowable excursions between 15°C and 30°C (59°F and 86°F).</p><p>Do not refrigerate or freeze.</p><p class="credit">Manufactured by Groupe Parima, Inc., for Dr. Reddy’s Laboratories, S.A. Elisabethenanlage 11, 4051 Basel, Switzerland. Revised: Jun 2020</p> </div> <a class="mediaPrmo ss" href="/adult_skin_problems_slideshow/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/common-adult-skin-problems-s1-photo-of-freckled-young-woman.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">Rosacea, Acne, Shingles, Covid-19 Rashes: Common Adult Skin Diseases</span> <span class="btn">See Slideshow</span> </a> </div> </div> | <a name="I"></a><h3>INDICATIONS</h3><p>XEGLYZE is indicated for the topical treatment of head lice infestation in patients 6 months of age and older.</p><p>XEGLYZE should be used in the context of an overall lice management program:</p><ul><li>Wash (with hot water) or dry-clean all recently worn clothing, hats, used bedding and towels</li><li>Wash personal care items such as combs, brushes, and hair clips in hot water</li></ul><p>Use a fine-tooth comb or special nit comb to remove dead lice and nits</p> <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3><p>For topical use only. XEGLYZE is not for oral, ophthalmic, or intravaginal use. Treatment with XEGLYZE involves a single application.</p><p>Shake well before use. Apply XEGLYZE to dry hair in an amount (up to the full content of one bottle) sufficient to thoroughly coat the hair and scalp. Massage XEGLYZE into the scalp and throughout the hair. Avoid contact with eyes. Leave on the hair and scalp for 10 minutes and then rinse off with warm water. Wash hands after application. Hair may be shampooed any time after the treatment.</p><p>Discard any unused product. Do not flush contents down sink or toilet.</p> <a name="HS"></a><h3>HOW SUPPLIED</h3><h4>Dosage Forms And Strengths</h4><p>Lotion, 0.74% [weight by weight], a viscous white to off-white oil in water emulsion, containing abametapir.</p><h4>Storage And Handling</h4><p class="EmphText"><b>XEGLYZE</b> is a white to off-white oil in water emulsion containing 0.74% [weight by weight] abametapir and supplied in a polyvinyl chloride (PVC) safety-coated single-use round amber glass bottle affixed with a polypropylene child resistant cap (<b>NDC</b> # 43598-921-11) featuring a tri-foil inner liner. The container is filled to a nominal 200 g (approximately 7 oz. or 210 mL) of the lotion.</p><p>Store upright at room temperature, 20°C to 25°C (68°F to 77°F), with allowable excursions between 15°C and 30°C (59°F and 86°F).</p><p>Do not refrigerate or freeze.</p><p class="credit">Manufactured by Groupe Parima, Inc., for Dr. Reddy’s Laboratories, S.A. Elisabethenanlage 11, 4051 Basel, Switzerland. Revised: Jun 2020</p> </div> <a class="mediaPrmo ss" href="/adult_skin_problems_slideshow/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/common-adult-skin-problems-s1-photo-of-freckled-young-woman.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">Rosacea, Acne, Shingles, Covid-19 Rashes: Common Adult Skin Diseases</span> <span class="btn">See Slideshow</span> </a> </div> </div> | 8 | 2023-02-01 17:39:00 | Abametapir Lotion (Xeglyze) | A | Topical Pediculicide | Xeglyze | abametapir lotion | Xeglyze | John P. Cunha, DO, FACOEP |
| 58 | 2023-02-23 11:36:54 | Side Effects & Drug Interactions | <a name="AR"></a><h3>SIDE EFFECTS</h3><h4>Clinical Trials Experience</h4><p>Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug, and may not reflect the rates observed in practice.</p><p>The data described below reflect exposure to a single 10-minute treatment of XEGLYZE in 349 subjects (6 months of age and older) with head lice infestation in randomized, double-blind, vehicle-controlled trials (Trials 1 and 2). Of these subjects, 21 were 6 months to 4 years of age, 166 subjects were 4 to 12 years of age, 57 subjects were 12 to 18 years of age, and 105 subjects were 18 years of age or older.</p><p>Table 1 provides adverse reactions that occurred in at least 1% of subjects in the XEGLYZE group and at a greater frequency than in the vehicle group.</p><p align="center"><b>Table 1: Adverse Reactions Occurring in ≥ 1% of the XEGLYZE Group and at a Greater Frequency than in the Vehicle Group (Trials 1 and 2)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Adverse Reactions</td><td class="EmphTd" width="25%">XEGLYZE<br />N=349<br />Subjects (%)</td><td class="EmphTd" width="25%">Vehicle<br />N=350<br />Subjects (%)</td></tr><tr><td>Erythema</td><td align="center">14 (4.0)</td><td align="center">6 (2)</td></tr><tr><td>Rash</td><td align="center">11 (3.2)</td><td align="center">8 (2.3)</td></tr><tr><td>Skin burning sensation</td><td align="center">9 (2.6)</td><td align="center">0 (0.0)</td></tr><tr><td>Contact dermatitis</td><td align="center">6 (1.7)</td><td align="center">4 (1.1)</td></tr><tr><td>Vomiting</td><td align="center">6 (1.7)</td><td align="center">2 (0.6)</td></tr><tr><td>Eye irritation</td><td align="center">4 (1.2)</td><td align="center">2 (0.6)</td></tr><tr><td>Hair color changes</td><td align="center">3 (1)</td><td align="center">0 (0.0)</td></tr></tbody></table></center><p></p><p>During the trials, subjects were monitored for new onset of scalp erythema/edema, scalp pruritus, and eye irritation. The number and percentage of subjects who developed these local adverse reactions after treatment are presented in Table 2.</p><p align="center"><b>Table 2: Monitored Local Adverse Reactions with New Onset on Day 1 Post-Treatment (Trials 1 and 2)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Adverse Reactions</td><td class="EmphTd" width="25%">XEGLYZE<br />Subjects (%)*</td><td class="EmphTd" width="25%">Vehicle<br />Subjects (%)*</td></tr><tr><td>Scalp Erythema/Edema</td><td align="center">11 (3.2)</td><td align="center">5 (1.4)</td></tr><tr><td>Scalp Pruritus</td><td align="center">2 (1.4)</td><td align="center">1 (0.7)</td></tr><tr><td>Eye Irritation</td><td align="center">6 (1.7)</td><td align="center">5 (1.4)</td></tr><tr><td class="credit" colspan="3">* For the calculation of the percentages, the denominators are the number of subjects who did not have the monitored local adverse reaction at baseline.</td></tr></tbody></table></center><p></p> <a name="DI"></a><h3>DRUG INTERACTIONS</h3><p><i>In vitro</i> studies suggest there is a potential for inhibition of cytochrome P450 (CYP) 3A4, 2B6 and 1A2 enzymes following a single application of XEGLYZE. Use of XEGLYZE with drugs that are substrates of these enzymes may lead to increased systemic concentrations of the interacting drugs. Avoid administration of drugs that are substrates of CYP3A4, CYP2B6, or CYP1A2 within 2 weeks after application of XEGLYZE. If this is not feasible, avoid use of XEGLYZE [see <b>CLINICAL PHARMACOLOGY</b>].</p> </div> </div> </div> | <a name="AR"></a><h3>SIDE EFFECTS</h3><h4>Clinical Trials Experience</h4><p>Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug, and may not reflect the rates observed in practice.</p><p>The data described below reflect exposure to a single 10-minute treatment of XEGLYZE in 349 subjects (6 months of age and older) with head lice infestation in randomized, double-blind, vehicle-controlled trials (Trials 1 and 2). Of these subjects, 21 were 6 months to 4 years of age, 166 subjects were 4 to 12 years of age, 57 subjects were 12 to 18 years of age, and 105 subjects were 18 years of age or older.</p><p>Table 1 provides adverse reactions that occurred in at least 1% of subjects in the XEGLYZE group and at a greater frequency than in the vehicle group.</p><p align="center"><b>Table 1: Adverse Reactions Occurring in ≥ 1% of the XEGLYZE Group and at a Greater Frequency than in the Vehicle Group (Trials 1 and 2)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Adverse Reactions</td><td class="EmphTd" width="25%">XEGLYZE<br />N=349<br />Subjects (%)</td><td class="EmphTd" width="25%">Vehicle<br />N=350<br />Subjects (%)</td></tr><tr><td>Erythema</td><td align="center">14 (4.0)</td><td align="center">6 (2)</td></tr><tr><td>Rash</td><td align="center">11 (3.2)</td><td align="center">8 (2.3)</td></tr><tr><td>Skin burning sensation</td><td align="center">9 (2.6)</td><td align="center">0 (0.0)</td></tr><tr><td>Contact dermatitis</td><td align="center">6 (1.7)</td><td align="center">4 (1.1)</td></tr><tr><td>Vomiting</td><td align="center">6 (1.7)</td><td align="center">2 (0.6)</td></tr><tr><td>Eye irritation</td><td align="center">4 (1.2)</td><td align="center">2 (0.6)</td></tr><tr><td>Hair color changes</td><td align="center">3 (1)</td><td align="center">0 (0.0)</td></tr></tbody></table></center><p></p><p>During the trials, subjects were monitored for new onset of scalp erythema/edema, scalp pruritus, and eye irritation. The number and percentage of subjects who developed these local adverse reactions after treatment are presented in Table 2.</p><p align="center"><b>Table 2: Monitored Local Adverse Reactions with New Onset on Day 1 Post-Treatment (Trials 1 and 2)</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="50%">Adverse Reactions</td><td class="EmphTd" width="25%">XEGLYZE<br />Subjects (%)*</td><td class="EmphTd" width="25%">Vehicle<br />Subjects (%)*</td></tr><tr><td>Scalp Erythema/Edema</td><td align="center">11 (3.2)</td><td align="center">5 (1.4)</td></tr><tr><td>Scalp Pruritus</td><td align="center">2 (1.4)</td><td align="center">1 (0.7)</td></tr><tr><td>Eye Irritation</td><td align="center">6 (1.7)</td><td align="center">5 (1.4)</td></tr><tr><td class="credit" colspan="3">* For the calculation of the percentages, the denominators are the number of subjects who did not have the monitored local adverse reaction at baseline.</td></tr></tbody></table></center><p></p> <a name="DI"></a><h3>DRUG INTERACTIONS</h3><p><i>In vitro</i> studies suggest there is a potential for inhibition of cytochrome P450 (CYP) 3A4, 2B6 and 1A2 enzymes following a single application of XEGLYZE. Use of XEGLYZE with drugs that are substrates of these enzymes may lead to increased systemic concentrations of the interacting drugs. Avoid administration of drugs that are substrates of CYP3A4, CYP2B6, or CYP1A2 within 2 weeks after application of XEGLYZE. If this is not feasible, avoid use of XEGLYZE [see <b>CLINICAL PHARMACOLOGY</b>].</p> </div> </div> </div> | 8 | 2023-02-01 17:39:00 | Abametapir Lotion (Xeglyze) | A | Topical Pediculicide | Xeglyze | abametapir lotion | Xeglyze | John P. Cunha, DO, FACOEP |
| 59 | 2023-02-23 11:36:54 | Warnings & Precautions | <a name="W"></a><h3>WARNINGS</h3><p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a><h3>PRECAUTIONS</h3><h4>Risk Of Neonatal Benzyl Alcohol Toxicity</h4><p>XEGLYZE contains benzyl alcohol. Systemic exposure to benzyl alcohol has been associated with serious and fatal adverse reactions including “gasping syndrome” in neonates and low birth weight infants. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants may be more likely to develop toxicity [see <b>Use In Specific Populations</b>].</p><p>The safety and effectiveness of XEGLYZE have not been established in pediatric patients below the age of 6 months. Use is not recommended in pediatric patients under 6 months of age because of the potential for increased systemic absorption.</p><h4>Risk Of Benzyl Alcohol Toxicity From Accidental Ingestion</h4><p>In order to prevent accidental ingestion in pediatric patients, XEGLYZE should only be administered under direct supervision of an adult.</p><p>Ingestion of benzyl alcohol in large quantities may result in gastrointestinal (nausea, vomiting, diarrhea) and central nervous system (headache, ataxia, convulsions, coma) adverse reactions. Serious adverse reactions may include respiratory depression and death. If accidentally swallowed, advise the patient or the caregiver to call their Poison Control Center at 1-800-2221222.</p><h4>Patient Counseling Information</h4><p>Advise the patient or caregiver to read the FDA-approved patient labeling (<b>PATIENT INFORMATION and Instructions for Use</b>).</p><p>Inform the patient and caregiver of the following instructions:</p><ul><li>Do not ingest XEGLYZE.</li><li>Keep out of reach of children. Use on children should be under the direct supervision of an adult because of the risk of benzyl alcohol toxicity [see <b>WARNINGS AND PRECAUTIONS</b> and <b>Use In Specific Populations</b>].</li><li>Avoid contact with eyes.</li><li>Wash hands after application.</li><li>Hair may be shampooed any time after the treatment.</li><li>Treatment with XEGLYZE involves a single application. Do not re-treat.</li><li>Discard any unused portion. Do not flush contents down sink or toilet.</li></ul><h4>Nonclinical Toxicology</h4><h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4><p>Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of XEGLYZE or abametapir.</p><p>Abametapir was not mutagenic or clastogenic based on the results of two <i>in vitro</i> genotoxicity tests (Ames test and human lymphocyte chromosomal aberration assay) and one <i>in vivo</i> genotoxicity test (rat micronucleus assay).</p><p>No effects on fertility have been observed in rats following repeated oral doses of up to 75 mg/kg/day abametapir (50 times the MRHD based on Cmax comparisons).</p> <a name="USP"></a><h4>Use In Specific Populations</h4><h4>Pregnancy</h4><h5>Risk Summary</h5><p>There are no available data on XEGLYZE use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In embryofetal development studies conducted with oral administration of abametapir during organogenesis, no evidence of fetal harm or malformations, independent of maternal toxicity were observed in pregnant rats and rabbits at doses that produced exposures up to 50 times and equivalent to the maximum recommended human dose (MRHD) in rats and rabbits, respectively. The highest dose evaluated in rabbits was limited due to maternal toxicity associated with the vehicle used in the study (see <b>Data</b>).</p><p>The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.</p><h5>Data</h5><p><i>Animal Data</i></p><p>Systemic embryofetal development studies were performed in rats and rabbits. Oral doses of 10, 25 and 75 mg/kg/day abametapir were administered during the period of organogenesis (gestational days 6 – 17) to pregnant rats. In the presence of maternal toxicity, embryofetal toxicity (lower fetal body weights and delayed ossification) was noted at 75 mg/kg/day. No treatment related effects on malformations were noted at 75 mg/kg/day (50 times the MRHD based on Cmax comparisons).</p><p>Oral doses of 4, 16 and 40 mg/kg/day abametapir were administered during the period of organogenesis (gestational days 6 – 19) to pregnant rabbits. No treatment related effects on embryofetal toxicity or malformations were noted at 40 mg/kg/day (~1 time the MRHD based on Cmax comparisons). Maternal toxicity related to the vehicle limited the maximum dose in pregnant rabbits.</p><p>In a perinatal and postnatal development study in rats, oral doses of 10, 25 and 75 mg/kg/day were administered from the beginning of organogenesis (gestational day 6) through the end of lactation (lactation day 20). In the presence of maternal toxicity, embryofetal lethality, and decreased fetal body weight gain were noted at 75 mg/kg/day. No treatment related effects on postnatal development were noted at 75 mg/kg/day (47 times the MRHD based on Cmax comparisons).</p><h4>Lactation</h4><h5>Risk Summary</h5><p>No data are available regarding the presence of abametapir in human milk or the effects of abametapir on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XEGLYZE and any potential adverse effects on the breastfed child from XEGLYZE or from the underlying maternal condition.</p><h4>Pediatric Use</h4><p>The safety and effectiveness of XEGLYZE have been established in pediatric patients 6 months of age and older [see <b>CLINICAL PHARMACOLOGY</b> and <b>Clinical Studies</b>].</p><p>The safety and effectiveness of XEGLYZE have not been established in pediatric patients below the age of 6 months. XEGLYZE is not recommended in pediatric patients under 6 months of age because of the potential for increased systemic absorption due to a high ratio of skin surface to body mass and the potential for an immature skin barrier.</p><p>XEGLYZE contains benzyl alcohol. Benzyl alcohol has been associated with serious adverse reactions and death in neonates and low birth-weight infants. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with intravenously administered benzyl alcohol dosages >99 mg/kg/day in neonates and low birthweight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.</p><p>The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity [see <b>WARNINGS AND PRECAUTIONS</b>].</p><p>Because of the risk of accidental ingestion, XEGLYZE should be administered to pediatric patients only under direct adult supervision [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h4>Geriatric Use</h4><p>Clinical studies of XEGLYZE did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger subjects.</p> </div> </div> </div> | <a name="W"></a><h3>WARNINGS</h3><p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a><h3>PRECAUTIONS</h3><h4>Risk Of Neonatal Benzyl Alcohol Toxicity</h4><p>XEGLYZE contains benzyl alcohol. Systemic exposure to benzyl alcohol has been associated with serious and fatal adverse reactions including “gasping syndrome” in neonates and low birth weight infants. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth weight infants may be more likely to develop toxicity [see <b>Use In Specific Populations</b>].</p><p>The safety and effectiveness of XEGLYZE have not been established in pediatric patients below the age of 6 months. Use is not recommended in pediatric patients under 6 months of age because of the potential for increased systemic absorption.</p><h4>Risk Of Benzyl Alcohol Toxicity From Accidental Ingestion</h4><p>In order to prevent accidental ingestion in pediatric patients, XEGLYZE should only be administered under direct supervision of an adult.</p><p>Ingestion of benzyl alcohol in large quantities may result in gastrointestinal (nausea, vomiting, diarrhea) and central nervous system (headache, ataxia, convulsions, coma) adverse reactions. Serious adverse reactions may include respiratory depression and death. If accidentally swallowed, advise the patient or the caregiver to call their Poison Control Center at 1-800-2221222.</p><h4>Patient Counseling Information</h4><p>Advise the patient or caregiver to read the FDA-approved patient labeling (<b>PATIENT INFORMATION and Instructions for Use</b>).</p><p>Inform the patient and caregiver of the following instructions:</p><ul><li>Do not ingest XEGLYZE.</li><li>Keep out of reach of children. Use on children should be under the direct supervision of an adult because of the risk of benzyl alcohol toxicity [see <b>WARNINGS AND PRECAUTIONS</b> and <b>Use In Specific Populations</b>].</li><li>Avoid contact with eyes.</li><li>Wash hands after application.</li><li>Hair may be shampooed any time after the treatment.</li><li>Treatment with XEGLYZE involves a single application. Do not re-treat.</li><li>Discard any unused portion. Do not flush contents down sink or toilet.</li></ul><h4>Nonclinical Toxicology</h4><h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4><p>Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of XEGLYZE or abametapir.</p><p>Abametapir was not mutagenic or clastogenic based on the results of two <i>in vitro</i> genotoxicity tests (Ames test and human lymphocyte chromosomal aberration assay) and one <i>in vivo</i> genotoxicity test (rat micronucleus assay).</p><p>No effects on fertility have been observed in rats following repeated oral doses of up to 75 mg/kg/day abametapir (50 times the MRHD based on Cmax comparisons).</p> <a name="USP"></a><h4>Use In Specific Populations</h4><h4>Pregnancy</h4><h5>Risk Summary</h5><p>There are no available data on XEGLYZE use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In embryofetal development studies conducted with oral administration of abametapir during organogenesis, no evidence of fetal harm or malformations, independent of maternal toxicity were observed in pregnant rats and rabbits at doses that produced exposures up to 50 times and equivalent to the maximum recommended human dose (MRHD) in rats and rabbits, respectively. The highest dose evaluated in rabbits was limited due to maternal toxicity associated with the vehicle used in the study (see <b>Data</b>).</p><p>The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.</p><h5>Data</h5><p><i>Animal Data</i></p><p>Systemic embryofetal development studies were performed in rats and rabbits. Oral doses of 10, 25 and 75 mg/kg/day abametapir were administered during the period of organogenesis (gestational days 6 – 17) to pregnant rats. In the presence of maternal toxicity, embryofetal toxicity (lower fetal body weights and delayed ossification) was noted at 75 mg/kg/day. No treatment related effects on malformations were noted at 75 mg/kg/day (50 times the MRHD based on Cmax comparisons).</p><p>Oral doses of 4, 16 and 40 mg/kg/day abametapir were administered during the period of organogenesis (gestational days 6 – 19) to pregnant rabbits. No treatment related effects on embryofetal toxicity or malformations were noted at 40 mg/kg/day (~1 time the MRHD based on Cmax comparisons). Maternal toxicity related to the vehicle limited the maximum dose in pregnant rabbits.</p><p>In a perinatal and postnatal development study in rats, oral doses of 10, 25 and 75 mg/kg/day were administered from the beginning of organogenesis (gestational day 6) through the end of lactation (lactation day 20). In the presence of maternal toxicity, embryofetal lethality, and decreased fetal body weight gain were noted at 75 mg/kg/day. No treatment related effects on postnatal development were noted at 75 mg/kg/day (47 times the MRHD based on Cmax comparisons).</p><h4>Lactation</h4><h5>Risk Summary</h5><p>No data are available regarding the presence of abametapir in human milk or the effects of abametapir on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XEGLYZE and any potential adverse effects on the breastfed child from XEGLYZE or from the underlying maternal condition.</p><h4>Pediatric Use</h4><p>The safety and effectiveness of XEGLYZE have been established in pediatric patients 6 months of age and older [see <b>CLINICAL PHARMACOLOGY</b> and <b>Clinical Studies</b>].</p><p>The safety and effectiveness of XEGLYZE have not been established in pediatric patients below the age of 6 months. XEGLYZE is not recommended in pediatric patients under 6 months of age because of the potential for increased systemic absorption due to a high ratio of skin surface to body mass and the potential for an immature skin barrier.</p><p>XEGLYZE contains benzyl alcohol. Benzyl alcohol has been associated with serious adverse reactions and death in neonates and low birth-weight infants. The “gasping syndrome” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with intravenously administered benzyl alcohol dosages >99 mg/kg/day in neonates and low birthweight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.</p><p>The minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity [see <b>WARNINGS AND PRECAUTIONS</b>].</p><p>Because of the risk of accidental ingestion, XEGLYZE should be administered to pediatric patients only under direct adult supervision [see <b>WARNINGS AND PRECAUTIONS</b>].</p><h4>Geriatric Use</h4><p>Clinical studies of XEGLYZE did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger subjects.</p> </div> </div> </div> | 8 | 2023-02-01 17:39:00 | Abametapir Lotion (Xeglyze) | A | Topical Pediculicide | Xeglyze | abametapir lotion | Xeglyze | John P. Cunha, DO, FACOEP |
| 60 | 2023-02-23 11:36:54 | Overdose & Contraindications | <a name="OD"></a><h3>OVERDOSE</h3><p>If accidentally swallowed, advise patients to seek medical advice immediately and to call their local Poison Control Center at 1-800-222-1222.</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3><p>None.</p> </div> </div> </div> | <a name="OD"></a><h3>OVERDOSE</h3><p>If accidentally swallowed, advise patients to seek medical advice immediately and to call their local Poison Control Center at 1-800-222-1222.</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3><p>None.</p> </div> </div> </div> | 8 | 2023-02-01 17:39:00 | Abametapir Lotion (Xeglyze) | A | Topical Pediculicide | Xeglyze | abametapir lotion | Xeglyze | John P. Cunha, DO, FACOEP |
| 61 | 2023-02-23 12:07:03 | Clinical Pharmacology | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3><h4>Mechanism Of Action</h4><p>Abametapir (5,5’-dimethyl 2,2’-bipyridinyl) is a metalloproteinase inhibitor. Metalloproteinases have a role in physiological processes critical to egg development and survival of lice.</p><h4>Pharmacokinetics</h4><h5>Absorption</h5><p>The pharmacokinetics of XEGLYZE were evaluated in 3 trials, Trials A, B, and C. Each trial enrolled lice infested subjects who received a single 10-minute application of XEGLYZE. Pharmacokinetic samplings were carried out to 72 hours post-dose in adults and 8 hours post-dose in pediatric subjects in all trials.</p><p>Trial A evaluated pharmacokinetics in 6 adult and 12 pediatric subjects 3 to 12 years of age. The mean (%CV) abametapir plasma maximum concentration (Cmax) and area under the concentration time curve from 0 to 8 hours post-dose (AUC0-8h) in the adult group were 41 (66%) ng/mL and 121 (50%) ng*h/mL, respectively. The mean (%CV) Cmax and AUC0-8h in the pediatric group were 73 (57%) ng/mL and 264 (62%) ng*h/mL, respectively. The mean (%CV) terminal half-life in adults was 21 (11%) hours.</p><p>Trials B and C evaluated pharmacokinetics in 50 pediatric subjects 6 months to 17 years old. The pharmacokinetic results for plasma abametapir are shown in Table 3. Even though the values varied between the 2 trials, abametapir exposure increased as the age of the subject decreased. Abametapir absorption was rapid with a median Tmax of 0.57 to 1.54 hours.</p><p align="center"><b>Table 3 Abametapir Pharmacokinetic Parameters in Subjects with Head Lice Infestation</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="10%">Study</td><td class="EmphTd" width="30%">Age Group</td><td class="EmphTd" width="10%">n</td><td class="EmphTd" width="20%">Cmax (ng/mL)<br />Mean (%CV)</td><td class="EmphTd" width="30%">AUC0-8h<br />(ng*h/mL) Mean (%CV)</td></tr><tr><td align="center">B</td><td align="center" rowspan="2">6 months to <1 year</td><td align="center">1</td><td align="center">418</td><td align="center">1057</td></tr><tr><td align="center">C</td><td align="center">5</td><td align="center">228 (50%)</td><td align="center">688 (43%)</td></tr><tr><td align="center">B</td><td align="center" rowspan="2">1 year to <2 years</td><td align="center">3</td><td align="center">209 (62%)</td><td align="center">446 (65%)</td></tr><tr><td align="center">C</td><td align="center">8</td><td align="center">147 (49%)</td><td align="center">406 (37%)</td></tr><tr><td align="center">B</td><td align="center" rowspan="2">2 years to <3 years</td><td align="center">6</td><td align="center">206 (66%)</td><td align="center">633 (57%)</td></tr><tr><td align="center">C</td><td align="center">8</td><td align="center">160 (48%)</td><td align="center">602 (51%)</td></tr><tr><td align="center">B</td><td align="center" rowspan="2">3 years to 17 years</td><td align="center">12</td><td align="center">121 (60%)</td><td align="center">330 (49%)</td></tr><tr><td align="center">C</td><td align="center">7</td><td align="center">52 (45%)</td><td align="center">194 (39%)</td></tr></tbody></table></center><p></p><p>Serum concentration of benzyl alcohol, an excipient in the formulation of XEGLYZE, was assessed in Trials B and C. Benzyl alcohol in serum was measurable (limit of quantitation = 0.5 μg/mL) in 7 subjects out of 39 evaluable subjects. The Cmax of benzyl alcohol in these 7 subjects ranged from 0.52 to 3.57 μg/mL [see <b>WARNINGS AND PRECAUTIONS</b> and <b>Use In Specific Populations</b>].</p><h5>Distribution</h5><p>Abametapir and its primary human metabolite, abametapir carboxyl, are highly bound to proteins in plasma. Abametapir is 91.3 – 92.3% bound to plasma proteins, and abametapir carboxyl is 96.0% – 97.5% bound to plasma proteins.</p><h5>Elimination</h5><p><i>Metabolism</i></p><p>Abametapir is extensively metabolized, primarily by the cytochrome P450 enzyme CYP1A2 to a mono-hydroxylated metabolite (abametapir hydroxyl) and further to a mono-carboxylated metabolite (abametapir carboxyl). Abametapir carboxyl is cleared slowly from the systemic <a href="/circulation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">circulation</a> resulting in plasma concentration higher than that of abametapir. Based on data in adults in Trial A above, where sampling was carried out to 72 hours, the ratios of Cmax and AUC0-72h between abametapir carboxyl and abametapir were about 30 and 250, respectively. The elimination half-life of abametapir carboxyl has not been well characterized but is estimated to be approximately (mean ± SD) 71 ± 40 hours or longer in adults.</p><p><i>Excretion</i></p><p>Excretion of abametapir and its human metabolites was not examined in patients.</p><h4>Drug Interaction Studies</h4><p><i>In vitro</i> studies suggest that there is a potential for inhibition of cytochrome P450 3A4, 2B6, and 1A2 enzymes following application of XEGLYZE due to high and prolonged systemic exposure of the metabolite abametapir carboxyl [see <b>DRUG INTERACTIONS</b>].</p> <a name="CS"></a><h4>Clinical Studies</h4><p>Two identical multi-center, randomized, double-blind, vehicle-controlled trials (Trials 1 and 2) were conducted in 704 subjects 6 months of age and older with head lice infestation. All subjects received a single application of either XEGLYZE or vehicle control. For the evaluation of efficacy, the youngest subject from each household was considered to be the index subject of the household (N=216). Other enrolled infested household members received the same treatment as the youngest subject and were evaluated for all efficacy and safety parameters. Index subjects ranged from 6 months to 49 years of age (mean 7 years), and approximately 85% of the index subjects were female, and 95% of the index subjects were Caucasian.</p><p>Efficacy was assessed as the proportion of index subjects who were treated with a single 10minute application and were free of live lice at all follow-up visits on Days 1, 7, and 14. Subjects with live lice at any time up to the final evaluation were considered treatment failures. Table 4 presents the proportion of subjects who were free of live lice at all visits Day 1 through Day 14 in Trials 1 and 2.</p><p align="center"><b>Table 4: Proportion of Index Subjects Free of Live Lice at All Visits Days 1 Through 14 After Treatment</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" rowspan="2" width="28%"></td><td class="EmphTd" colspan="2">Trial 1</td><td class="EmphTd" colspan="2">Trial 2</td></tr><tr><td class="EmphTd" width="18%">XEGLYZE<br />(N=53)</td><td class="EmphTd" width="18%">Vehicle<br />(N=55)</td><td class="EmphTd" width="18%">XEGLYZE<br />(N=55)</td><td class="EmphTd" width="18%">Vehicle<br />(N=53)</td></tr><tr><td>Treatment Success</td><td align="center">43 (81.1%)</td><td align="center">28 (50.9%)</td><td align="center">45 (81.8%)</td><td align="center">25 (47.2%)</td></tr></tbody></table></center><p></p> </div> </div> </div> | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3><h4>Mechanism Of Action</h4><p>Abametapir (5,5’-dimethyl 2,2’-bipyridinyl) is a metalloproteinase inhibitor. Metalloproteinases have a role in physiological processes critical to egg development and survival of lice.</p><h4>Pharmacokinetics</h4><h5>Absorption</h5><p>The pharmacokinetics of XEGLYZE were evaluated in 3 trials, Trials A, B, and C. Each trial enrolled lice infested subjects who received a single 10-minute application of XEGLYZE. Pharmacokinetic samplings were carried out to 72 hours post-dose in adults and 8 hours post-dose in pediatric subjects in all trials.</p><p>Trial A evaluated pharmacokinetics in 6 adult and 12 pediatric subjects 3 to 12 years of age. The mean (%CV) abametapir plasma maximum concentration (Cmax) and area under the concentration time curve from 0 to 8 hours post-dose (AUC0-8h) in the adult group were 41 (66%) ng/mL and 121 (50%) ng*h/mL, respectively. The mean (%CV) Cmax and AUC0-8h in the pediatric group were 73 (57%) ng/mL and 264 (62%) ng*h/mL, respectively. The mean (%CV) terminal half-life in adults was 21 (11%) hours.</p><p>Trials B and C evaluated pharmacokinetics in 50 pediatric subjects 6 months to 17 years old. The pharmacokinetic results for plasma abametapir are shown in Table 3. Even though the values varied between the 2 trials, abametapir exposure increased as the age of the subject decreased. Abametapir absorption was rapid with a median Tmax of 0.57 to 1.54 hours.</p><p align="center"><b>Table 3 Abametapir Pharmacokinetic Parameters in Subjects with Head Lice Infestation</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" width="10%">Study</td><td class="EmphTd" width="30%">Age Group</td><td class="EmphTd" width="10%">n</td><td class="EmphTd" width="20%">Cmax (ng/mL)<br />Mean (%CV)</td><td class="EmphTd" width="30%">AUC0-8h<br />(ng*h/mL) Mean (%CV)</td></tr><tr><td align="center">B</td><td align="center" rowspan="2">6 months to <1 year</td><td align="center">1</td><td align="center">418</td><td align="center">1057</td></tr><tr><td align="center">C</td><td align="center">5</td><td align="center">228 (50%)</td><td align="center">688 (43%)</td></tr><tr><td align="center">B</td><td align="center" rowspan="2">1 year to <2 years</td><td align="center">3</td><td align="center">209 (62%)</td><td align="center">446 (65%)</td></tr><tr><td align="center">C</td><td align="center">8</td><td align="center">147 (49%)</td><td align="center">406 (37%)</td></tr><tr><td align="center">B</td><td align="center" rowspan="2">2 years to <3 years</td><td align="center">6</td><td align="center">206 (66%)</td><td align="center">633 (57%)</td></tr><tr><td align="center">C</td><td align="center">8</td><td align="center">160 (48%)</td><td align="center">602 (51%)</td></tr><tr><td align="center">B</td><td align="center" rowspan="2">3 years to 17 years</td><td align="center">12</td><td align="center">121 (60%)</td><td align="center">330 (49%)</td></tr><tr><td align="center">C</td><td align="center">7</td><td align="center">52 (45%)</td><td align="center">194 (39%)</td></tr></tbody></table></center><p></p><p>Serum concentration of benzyl alcohol, an excipient in the formulation of XEGLYZE, was assessed in Trials B and C. Benzyl alcohol in serum was measurable (limit of quantitation = 0.5 μg/mL) in 7 subjects out of 39 evaluable subjects. The Cmax of benzyl alcohol in these 7 subjects ranged from 0.52 to 3.57 μg/mL [see <b>WARNINGS AND PRECAUTIONS</b> and <b>Use In Specific Populations</b>].</p><h5>Distribution</h5><p>Abametapir and its primary human metabolite, abametapir carboxyl, are highly bound to proteins in plasma. Abametapir is 91.3 – 92.3% bound to plasma proteins, and abametapir carboxyl is 96.0% – 97.5% bound to plasma proteins.</p><h5>Elimination</h5><p><i>Metabolism</i></p><p>Abametapir is extensively metabolized, primarily by the cytochrome P450 enzyme CYP1A2 to a mono-hydroxylated metabolite (abametapir hydroxyl) and further to a mono-carboxylated metabolite (abametapir carboxyl). Abametapir carboxyl is cleared slowly from the systemic <a href="/circulation/definition.htm" ">circulation</a> resulting in plasma concentration higher than that of abametapir. Based on data in adults in Trial A above, where sampling was carried out to 72 hours, the ratios of Cmax and AUC0-72h between abametapir carboxyl and abametapir were about 30 and 250, respectively. The elimination half-life of abametapir carboxyl has not been well characterized but is estimated to be approximately (mean ± SD) 71 ± 40 hours or longer in adults.</p><p><i>Excretion</i></p><p>Excretion of abametapir and its human metabolites was not examined in patients.</p><h4>Drug Interaction Studies</h4><p><i>In vitro</i> studies suggest that there is a potential for inhibition of cytochrome P450 3A4, 2B6, and 1A2 enzymes following application of XEGLYZE due to high and prolonged systemic exposure of the metabolite abametapir carboxyl [see <b>DRUG INTERACTIONS</b>].</p> <a name="CS"></a><h4>Clinical Studies</h4><p>Two identical multi-center, randomized, double-blind, vehicle-controlled trials (Trials 1 and 2) were conducted in 704 subjects 6 months of age and older with head lice infestation. All subjects received a single application of either XEGLYZE or vehicle control. For the evaluation of efficacy, the youngest subject from each household was considered to be the index subject of the household (N=216). Other enrolled infested household members received the same treatment as the youngest subject and were evaluated for all efficacy and safety parameters. Index subjects ranged from 6 months to 49 years of age (mean 7 years), and approximately 85% of the index subjects were female, and 95% of the index subjects were Caucasian.</p><p>Efficacy was assessed as the proportion of index subjects who were treated with a single 10minute application and were free of live lice at all follow-up visits on Days 1, 7, and 14. Subjects with live lice at any time up to the final evaluation were considered treatment failures. Table 4 presents the proportion of subjects who were free of live lice at all visits Day 1 through Day 14 in Trials 1 and 2.</p><p align="center"><b>Table 4: Proportion of Index Subjects Free of Live Lice at All Visits Days 1 Through 14 After Treatment</b></p><center><table cellspacing="0" class="blacktbl" width="450"><tbody><tr><td class="EmphTd" rowspan="2" width="28%"></td><td class="EmphTd" colspan="2">Trial 1</td><td class="EmphTd" colspan="2">Trial 2</td></tr><tr><td class="EmphTd" width="18%">XEGLYZE<br />(N=53)</td><td class="EmphTd" width="18%">Vehicle<br />(N=55)</td><td class="EmphTd" width="18%">XEGLYZE<br />(N=55)</td><td class="EmphTd" width="18%">Vehicle<br />(N=53)</td></tr><tr><td>Treatment Success</td><td align="center">43 (81.1%)</td><td align="center">28 (50.9%)</td><td align="center">45 (81.8%)</td><td align="center">25 (47.2%)</td></tr></tbody></table></center><p></p> </div> </div> </div> | 8 | 2023-02-01 17:39:00 | Abametapir Lotion (Xeglyze) | A | Topical Pediculicide | Xeglyze | abametapir lotion | Xeglyze | John P. Cunha, DO, FACOEP |
| 62 | 2023-02-23 12:07:03 | Medication Guide | <a name="PI"></a><h3>PATIENT INFORMATION</h3><p><b>XEGLYZE</b><br />(zeg’ lyze)<br />(abametapir) Lotion</p><p><b>Important:</b> XEGLYZE is for use on scalp hair and scalp only. Do not use XEGLYZE in your mouth, eyes, or <a href="/vagina/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">vagina</a>.</p><p><b>What is XEGLYZE?</b></p><p>XEGLYZE is a prescription medicine used to get rid of head lice in people 6 months of age and older.</p><p>After XEGLYZE is rinsed off, a fine-tooth comb may be used to remove dead lice and nits from the hair and scalp. All personal items exposed to the hair or lice should be washed in hot water or dry-cleaned. See <b>“How do I stop the spread of lice?”</b> at the end of the XEGLYZE Instructions for Use.</p><p>It is not known if XEGLYZE is safe and effective in children under 6 months of age.</p><p><b>Before you use XEGLYZE, tell your healthcare provider if you or your child:</b></p><ul><li>have any skin conditions or sensitivities</li><li>have any other medical conditions</li><li>are pregnant or plan to become pregnant. It is not known if XEGLYZE can harm your unborn baby</li><li>are breastfeeding or plan to breastfeed. It is not known if XEGLYZE passes into your breast milk.</li></ul><p><b>How should I use XEGLYZE?</b></p><p><b>See the “Instructions for Use” for detailed information about the right way to apply XEGLYZE.</b></p><ul><li>Use XEGLYZE exactly as your healthcare provider tells you to use it. Your healthcare provider will prescribe the treatment that is right for you. Do not change your treatment without talking to your healthcare provider.</li><li>Use XEGLYZE on dry hair.</li><li>Completely cover all of your hair and scalp with XEGLYZE.</li><li>Children will need an adult to apply XEGLYZE for them.</li><li><b>Do not</b> swallow XEGLYZE. If swallowed, call your Poison Control Center at 1-800-222-1222.</li><li><b>Do not</b> get XEGLYZE into your eyes. If XEGLYZE gets in your eye, gently flush with water. Wash your hands after you apply XEGLYZE.</li><li>You may shampoo your hair any time after the treatment.</li><li><b>When you complete your dose of XEGLYZE, do not</b> use XEGLYZE again. Throw away any unused XEGLYZE. Do not flush XEGLYZE down sink or toilet.</li></ul><p><b>What are the possible side effects of XEGLYZE?</b></p><p>The most common side effects of XEGLYZE include:</p><ul><li>Redness of the skin or scalp</li><li>Rash</li><li>Burning sensation of the skin</li><li>Skin irritation</li><li>Vomiting</li><li>Eye irritation</li><li>Itchy scalp</li><li>Changes in your hair color</li></ul><p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p><p>These are not all the possible side effects of XEGLYZE. For more information, ask your healthcare provider or pharmacist.</p><p>Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.</p><p><b>How should I store XEGLYZE?</b></p><ul><li>Store XEGLYZE upright at room temperature between 20°C to 25°C (68°F to 77°F), with allowable excursions between 15°C and 30°C (59°F and 86°F).</li><li>Do not refrigerate or freeze XEGLYZE.</li><li>Discard (throw away) any unused product.</li></ul><p><b>Keep XEGLYZE and all medicines out of reach of children.</b></p><p><b>General information about the safe and effective use of XEGLYZE</b></p><p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use XEGLYZE for a condition for which it was not prescribed. Do not give XEGLYZE to other people, even if they have the same symptoms you have. It may harm them. You can also ask your pharmacist or healthcare provider for information about XEGLYZE that is written for health professionals.</p><p><b>What are the ingredients in XEGLYZE?</b></p><p><b>Active ingredient:</b> abametapir</p><p><b>Inactive ingredients:</b> benzyl alcohol, <a href="/butylated_hydroxytoluene/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">butylated hydroxytoluene</a>, carbomer 980, light mineral oil, polysorbate 20, trolamine and water.</p><p><b>Instructions for Use</b></p><p><b>XEGLYZE</b><br />(zeg’ lyze)<br />(abametapir) Lotion</p><p><b>Important:</b> XEGLYZE is for use on scalp hair and scalp only. Do not use XEGLYZE in your mouth, eyes, or vagina.</p><p>Before you use XEGLYZE, it is important that you read the Patient Information and Instructions for Use. Be sure that you read, understand, and follow these Instructions for Use so that you use XEGLYZE the right way. Ask your healthcare provider or pharmacist if you have questions about the right way to use XEGLYZE.</p><p><b>Step 1:</b> Your hair and scalp must be dry before you apply XEGLYZE. Shake XEGLYZE bottle well right before use.</p><p></p><center><table cellspacing="0" class="blackpic" width="137"><tbody><tr><td><img alt="Shake XEGLYZE bottle well right before use - Illustration" height="138" src="https://images.rxlist.com/images/rxlist/xelgyze2.gif" width="137" /></td></tr></tbody></table></center><p></p><p><b>Step 2:</b> Remove the cap and apply XEGLYZE directly to dry hair and scalp.</p><p></p><center><table cellspacing="0" class="blackpic" width="138"><tbody><tr><td><img alt="Remove the cap and apply XEGLYZE directly to dry hair and scalp - Illustration" height="136" src="https://images.rxlist.com/images/rxlist/xelgyze3.gif" width="138" /></td></tr></tbody></table></center><p></p><p><b>Step 3:</b> Completely cover your scalp and hair closest to the scalp first, and then apply outwards towards the ends of your hair.</p><p></p><center><table cellspacing="0" class="blackpic" width="135"><tbody><tr><td><img alt="Completely cover your scalp and hair closest to the scalp first, and then apply outwards towards the ends of your hair - Illustration" height="133" src="https://images.rxlist.com/images/rxlist/xelgyze4.gif" width="135" /></td></tr></tbody></table></center><p></p><p><b>Step 4:</b> Rub XEGLYZE throughout your hair and scalp.</p><p>Use enough XEGLYZE to completely cover your entire scalp and all of your hair so that all lice and eggs are exposed to the lotion. You may need to use the full bottle. Be sure that each hair is coated from the scalp to the tip.</p><p></p><center><table cellspacing="0" class="blackpic" width="136"><tbody><tr><td><img alt="Rub XEGLYZE throughout your hair and scalp - Illustration" height="134" src="https://images.rxlist.com/images/rxlist/xelgyze5.gif" width="136" /></td></tr></tbody></table></center><p></p><p><b>Step 5:</b> Leave XEGLYZE on your hair and scalp for 10 minutes after it has been applied. Use a timer or clock. Start timing after you have completely covered your hair and scalp with XEGLYZE.</p><p>You or anyone who helps you apply XEGLYZE should wash their hands after application.</p><p></p><center><table cellspacing="0" class="blackpic" width="138"><tbody><tr><td><img alt="Leave XEGLYZE on your hair and scalp for 10 minutes after it has been applied - Illustration" height="137" src="https://images.rxlist.com/images/rxlist/xelgyze6.gif" width="138" /></td></tr></tbody></table></center><p></p><p><b>Step 6:</b> After 10 minutes, rinse XEGLYZE from your hair and scalp with warm water.</p><p>A fine-tooth comb or special <a href="/nit/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">nit</a> comb may be used to remove dead lice and nits.</p><p>You may shampoo your hair any time after the treatment.</p><p></p><center><table cellspacing="0" class="blackpic" width="136"><tbody><tr><td><img alt="After 10 minutes, rinse XEGLYZE from your hair and scalp with warm water - Illustration" height="137" src="https://images.rxlist.com/images/rxlist/xelgyze7.gif" width="136" /></td></tr></tbody></table></center><p></p><p><b>How do I stop the spread of lice?</b></p><p>To help prevent the spread of lice from one person to another, here are some steps you can take:</p><ul><li>Avoid direct head-to-head contact with anyone known to have live, crawling lice.</li><li>Do not share combs, brushes, hats, scarves, bandannas, ribbons, barrettes, hair bands, towels, helmets, or other hair-related personal items with anyone else, whether they have lice or not.</li><li>Disinfect combs and brushes used by an infected person by soaking them in hot water (at least 130°F) for 5 to 10 minutes.</li><li>Avoid sleepovers and slumber parties during lice outbreaks. Lice can live in bedding, pillows, and carpets that have recently been used by someone with lice.</li><li>Machine wash and dry clothing, bed linens, and other items used by anyone having lice. Machine wash at high temperatures (130°F) and the high heat drying cycle. Clothing and items that are not washable can be dry-cleaned OR sealed in a <a href="/plastic/article.htm" rel="sub" onclick="wmdTrack('embd-lnk');">plastic</a> bag and stored for 2 weeks.</li></ul><p class="credit">These Instructions for Use have been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | <a name="PI"></a><h3>PATIENT INFORMATION</h3><p><b>XEGLYZE</b><br />(zeg’ lyze)<br />(abametapir) Lotion</p><p><b>Important:</b> XEGLYZE is for use on scalp hair and scalp only. Do not use XEGLYZE in your mouth, eyes, or <a href="/vagina/definition.htm" ">vagina</a>.</p><p><b>What is XEGLYZE?</b></p><p>XEGLYZE is a prescription medicine used to get rid of head lice in people 6 months of age and older.</p><p>After XEGLYZE is rinsed off, a fine-tooth comb may be used to remove dead lice and nits from the hair and scalp. All personal items exposed to the hair or lice should be washed in hot water or dry-cleaned. See <b>“How do I stop the spread of lice?”</b> at the end of the XEGLYZE Instructions for Use.</p><p>It is not known if XEGLYZE is safe and effective in children under 6 months of age.</p><p><b>Before you use XEGLYZE, tell your healthcare provider if you or your child:</b></p><ul><li>have any skin conditions or sensitivities</li><li>have any other medical conditions</li><li>are pregnant or plan to become pregnant. It is not known if XEGLYZE can harm your unborn baby</li><li>are breastfeeding or plan to breastfeed. It is not known if XEGLYZE passes into your breast milk.</li></ul><p><b>How should I use XEGLYZE?</b></p><p><b>See the “Instructions for Use” for detailed information about the right way to apply XEGLYZE.</b></p><ul><li>Use XEGLYZE exactly as your healthcare provider tells you to use it. Your healthcare provider will prescribe the treatment that is right for you. Do not change your treatment without talking to your healthcare provider.</li><li>Use XEGLYZE on dry hair.</li><li>Completely cover all of your hair and scalp with XEGLYZE.</li><li>Children will need an adult to apply XEGLYZE for them.</li><li><b>Do not</b> swallow XEGLYZE. If swallowed, call your Poison Control Center at 1-800-222-1222.</li><li><b>Do not</b> get XEGLYZE into your eyes. If XEGLYZE gets in your eye, gently flush with water. Wash your hands after you apply XEGLYZE.</li><li>You may shampoo your hair any time after the treatment.</li><li><b>When you complete your dose of XEGLYZE, do not</b> use XEGLYZE again. Throw away any unused XEGLYZE. Do not flush XEGLYZE down sink or toilet.</li></ul><p><b>What are the possible side effects of XEGLYZE?</b></p><p>The most common side effects of XEGLYZE include:</p><ul><li>Redness of the skin or scalp</li><li>Rash</li><li>Burning sensation of the skin</li><li>Skin irritation</li><li>Vomiting</li><li>Eye irritation</li><li>Itchy scalp</li><li>Changes in your hair color</li></ul><p>Tell your healthcare provider if you have any side effect that bothers you or that does not go away.</p><p>These are not all the possible side effects of XEGLYZE. For more information, ask your healthcare provider or pharmacist.</p><p>Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.</p><p><b>How should I store XEGLYZE?</b></p><ul><li>Store XEGLYZE upright at room temperature between 20°C to 25°C (68°F to 77°F), with allowable excursions between 15°C and 30°C (59°F and 86°F).</li><li>Do not refrigerate or freeze XEGLYZE.</li><li>Discard (throw away) any unused product.</li></ul><p><b>Keep XEGLYZE and all medicines out of reach of children.</b></p><p><b>General information about the safe and effective use of XEGLYZE</b></p><p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use XEGLYZE for a condition for which it was not prescribed. Do not give XEGLYZE to other people, even if they have the same symptoms you have. It may harm them. You can also ask your pharmacist or healthcare provider for information about XEGLYZE that is written for health professionals.</p><p><b>What are the ingredients in XEGLYZE?</b></p><p><b>Active ingredient:</b> abametapir</p><p><b>Inactive ingredients:</b> benzyl alcohol, <a href="/butylated_hydroxytoluene/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">butylated hydroxytoluene</a>, carbomer 980, light mineral oil, polysorbate 20, trolamine and water.</p><p><b>Instructions for Use</b></p><p><b>XEGLYZE</b><br />(zeg’ lyze)<br />(abametapir) Lotion</p><p><b>Important:</b> XEGLYZE is for use on scalp hair and scalp only. Do not use XEGLYZE in your mouth, eyes, or vagina.</p><p>Before you use XEGLYZE, it is important that you read the Patient Information and Instructions for Use. Be sure that you read, understand, and follow these Instructions for Use so that you use XEGLYZE the right way. Ask your healthcare provider or pharmacist if you have questions about the right way to use XEGLYZE.</p><p><b>Step 1:</b> Your hair and scalp must be dry before you apply XEGLYZE. Shake XEGLYZE bottle well right before use.</p><p></p><center><table cellspacing="0" class="blackpic" width="137"><tbody><tr><td><img alt="Shake XEGLYZE bottle well right before use - Illustration" height="138" src="https://images.rxlist.com/images/rxlist/xelgyze2.gif" width="137" /></td></tr></tbody></table></center><p></p><p><b>Step 2:</b> Remove the cap and apply XEGLYZE directly to dry hair and scalp.</p><p></p><center><table cellspacing="0" class="blackpic" width="138"><tbody><tr><td><img alt="Remove the cap and apply XEGLYZE directly to dry hair and scalp - Illustration" height="136" src="https://images.rxlist.com/images/rxlist/xelgyze3.gif" width="138" /></td></tr></tbody></table></center><p></p><p><b>Step 3:</b> Completely cover your scalp and hair closest to the scalp first, and then apply outwards towards the ends of your hair.</p><p></p><center><table cellspacing="0" class="blackpic" width="135"><tbody><tr><td><img alt="Completely cover your scalp and hair closest to the scalp first, and then apply outwards towards the ends of your hair - Illustration" height="133" src="https://images.rxlist.com/images/rxlist/xelgyze4.gif" width="135" /></td></tr></tbody></table></center><p></p><p><b>Step 4:</b> Rub XEGLYZE throughout your hair and scalp.</p><p>Use enough XEGLYZE to completely cover your entire scalp and all of your hair so that all lice and eggs are exposed to the lotion. You may need to use the full bottle. Be sure that each hair is coated from the scalp to the tip.</p><p></p><center><table cellspacing="0" class="blackpic" width="136"><tbody><tr><td><img alt="Rub XEGLYZE throughout your hair and scalp - Illustration" height="134" src="https://images.rxlist.com/images/rxlist/xelgyze5.gif" width="136" /></td></tr></tbody></table></center><p></p><p><b>Step 5:</b> Leave XEGLYZE on your hair and scalp for 10 minutes after it has been applied. Use a timer or clock. Start timing after you have completely covered your hair and scalp with XEGLYZE.</p><p>You or anyone who helps you apply XEGLYZE should wash their hands after application.</p><p></p><center><table cellspacing="0" class="blackpic" width="138"><tbody><tr><td><img alt="Leave XEGLYZE on your hair and scalp for 10 minutes after it has been applied - Illustration" height="137" src="https://images.rxlist.com/images/rxlist/xelgyze6.gif" width="138" /></td></tr></tbody></table></center><p></p><p><b>Step 6:</b> After 10 minutes, rinse XEGLYZE from your hair and scalp with warm water.</p><p>A fine-tooth comb or special <a href="/nit/definition.htm" ">nit</a> comb may be used to remove dead lice and nits.</p><p>You may shampoo your hair any time after the treatment.</p><p></p><center><table cellspacing="0" class="blackpic" width="136"><tbody><tr><td><img alt="After 10 minutes, rinse XEGLYZE from your hair and scalp with warm water - Illustration" height="137" src="https://images.rxlist.com/images/rxlist/xelgyze7.gif" width="136" /></td></tr></tbody></table></center><p></p><p><b>How do I stop the spread of lice?</b></p><p>To help prevent the spread of lice from one person to another, here are some steps you can take:</p><ul><li>Avoid direct head-to-head contact with anyone known to have live, crawling lice.</li><li>Do not share combs, brushes, hats, scarves, bandannas, ribbons, barrettes, hair bands, towels, helmets, or other hair-related personal items with anyone else, whether they have lice or not.</li><li>Disinfect combs and brushes used by an infected person by soaking them in hot water (at least 130°F) for 5 to 10 minutes.</li><li>Avoid sleepovers and slumber parties during lice outbreaks. Lice can live in bedding, pillows, and carpets that have recently been used by someone with lice.</li><li>Machine wash and dry clothing, bed linens, and other items used by anyone having lice. Machine wash at high temperatures (130°F) and the high heat drying cycle. Clothing and items that are not washable can be dry-cleaned OR sealed in a <a href="/plastic/article.htm" rel="sub" onclick="wmdTrack('embd-lnk');">plastic</a> bag and stored for 2 weeks.</li></ul><p class="credit">These Instructions for Use have been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | 8 | 2023-02-01 17:39:00 | Abametapir Lotion (Xeglyze) | A | Topical Pediculicide | Xeglyze | abametapir lotion | Xeglyze | John P. Cunha, DO, FACOEP |
| 63 | 2023-02-23 12:07:03 | Drug Description | <h4>What is Plenaxis and how is it used?</h4> <p>Plenaxis is a prescription medicine used to treat the symptoms of <a href="/prostate/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Prostate</a> Cancer. Plenaxis may be used alone or with other medications.</p> <p>Plenaxis belongs to a class of drugs called GnRH Analogue; GnRH <a href="/antagonist/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Antagonist</a>; Antigonadotropin.</p> <p>It is not known if Plenaxis is safe and effective in children.</p> <h4>What are the possible side effects of Plenaxis?</h4> <p>Plenaxis may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat, and</li> <li>dizziness</li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Plenaxis include:</p> <ul> <li>hot flashes,</li> <li>sleep disturbances,</li> <li>breast enlargement or pain,</li> <li><a href="/nipple/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">nipple</a> tenderness,</li> <li>diarrhea,</li> <li>constipation,</li> <li>swelling of the extremities,</li> <li>nausea,</li> <li>dizziness,</li> <li>headache,</li> <li>fatigue,</li> <li>changes with or difficulty urinating,</li> <li><a href="/urinary_tract/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">urinary tract</a> infection, and</li> <li>upper respiratory tract infection</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Plenaxis. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p><b>Immediate-onset systemic allergic reactions, some resulting in hypotension and syncope, have occurred after administration of Plenaxis™ . These immediate-onset reactions have been reported to occur following any administration of Plenaxis™ , including after the initial dose. The cumulative risk of such a reaction increases with the duration of treatment (see <a href="/plenaxis-drug.htm#W">WARNINGS</a>). Following each injection of Plenaxis™ , patients should be observed for at least 30 minutes in the office and in the event of an allergic reaction, managed appropriately.</b></p> <ul> <li><b>Only physicians who have enrolled in the Plenaxis™ PLUS Program (Plenaxis™ User Safety Program), based on their attestation of qualifications and acceptance of prescribing responsibilities, may prescribe Plenaxis™ (See <a href="/plenaxis-drug.htm#DAA">DOSAGE AND ADMINISTRATION</a> and <a href="/plenaxis-drug.htm#HS">HOW SUPPLIED</a>).</b></li> <li><b>Plenaxis™ is indicated for the palliative treatment of men with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and have one or more of the following: (1) risk of neurological compromise due to metastases, (2) ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, or (3) severe bone pain from skeletal metastases persisting on narcotic analgesia.</b></li> <li><b>The effectiveness of Plenaxis™ in suppressing serum testosterone to castrate levels decreases with continued dosing in some patients (see <a href="/plenaxis-drug.htm#CP">CLINICAL PHARMACOLOGY</a>, Pharmacodynamics). Effectiveness beyond 12 months has not been established. Treatment failure can be detected by measuring serum total testosterone concentrations just prior to administration on Day 29 and every 8 weeks thereafter (see <a href="/plenaxis-drug.htm#W">WARNINGS</a>).</b></li> </ul> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <p>Abarelix for injectable suspension (Plenaxis™ ) is a synthetic decapeptide with potent antagonistic activity against naturally occurring <a href="/gonadotropin/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">gonadotropin</a> releasing-hormone (GnRH). Plenaxis™ inhibits gonadotropin and related <a href="/androgen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">androgen</a> production by directly and competitively blocking GnRH receptors in the <a href="/pituitary/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pituitary</a>.</p> <p>Abarelix is chemically described as acetyl-D-β-naphthylalanyl-D-4-chlorophenylalanyl- D-3-pyridylalanyl-L-seryl-L-N-methyl-tyrosyl-D-asparagyl-L-leucyl-L-N(ε)-isopropyllysyl- L-prolyl-D-alanyl-amide. It is initially manufactured as an acetate water complex and converted to a carboxymethylcellulose (CMC) water complex in manufacturing the drug product. The molecular weight for abarelix anhydrous free base is 1416.06.</p> <p>The structural formula for abarelix <a href="/peptide/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">peptide</a> is:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="563"> <tbody> <tr> <td><img alt="Plenaxis™ (abarelix) Structural Formula Illustration" height="251" src="https://images.rxlist.com/images/rxlist/plenaxis1.gif" width="563" /></td> </tr> </tbody> </table> </center> <p></p> <p>Abarelix for injectable suspension is supplied as a white to off-white sterile dry powder which, when mixed with the diluent, 0.9% Sodium Chloride Injection, USP, becomes a depot suspension intended for intramuscular (IM) injection. The single-dose vial contains 113 mg of anhydrous free base abarelix peptide (net) supplied in an abarelix CMC complex. This complex also contains 19.1 to 31 mg of CMC. After the vial is reconstituted with 2.2 mL of 0.9% sodium chloride injection, 2 mL is administered to deliver a dose of 100 mg of abarelix (net) as the abarelix CMC complex at a pH of 5±1.</p> </div> <div id="667441035-1" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-1", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <h4>What is Plenaxis and how is it used?</h4> <p>Plenaxis is a prescription medicine used to treat the symptoms of <a href="/prostate/definition.htm" ">Prostate</a> Cancer. Plenaxis may be used alone or with other medications.</p> <p>Plenaxis belongs to a class of drugs called GnRH Analogue; GnRH <a href="/antagonist/definition.htm" ">Antagonist</a>; Antigonadotropin.</p> <p>It is not known if Plenaxis is safe and effective in children.</p> <h4>What are the possible side effects of Plenaxis?</h4> <p>Plenaxis may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat, and</li> <li>dizziness</li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Plenaxis include:</p> <ul> <li>hot flashes,</li> <li>sleep disturbances,</li> <li>breast enlargement or pain,</li> <li><a href="/nipple/definition.htm" ">nipple</a> tenderness,</li> <li>diarrhea,</li> <li>constipation,</li> <li>swelling of the extremities,</li> <li>nausea,</li> <li>dizziness,</li> <li>headache,</li> <li>fatigue,</li> <li>changes with or difficulty urinating,</li> <li><a href="/urinary_tract/definition.htm" ">urinary tract</a> infection, and</li> <li>upper respiratory tract infection</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Plenaxis. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p><b>Immediate-onset systemic allergic reactions, some resulting in hypotension and syncope, have occurred after administration of Plenaxis™ . These immediate-onset reactions have been reported to occur following any administration of Plenaxis™ , including after the initial dose. The cumulative risk of such a reaction increases with the duration of treatment (see <a href="/plenaxis-drug.htm#W">WARNINGS</a>). Following each injection of Plenaxis™ , patients should be observed for at least 30 minutes in the office and in the event of an allergic reaction, managed appropriately.</b></p> <ul> <li><b>Only physicians who have enrolled in the Plenaxis™ PLUS Program (Plenaxis™ User Safety Program), based on their attestation of qualifications and acceptance of prescribing responsibilities, may prescribe Plenaxis™ (See <a href="/plenaxis-drug.htm#DAA">DOSAGE AND ADMINISTRATION</a> and <a href="/plenaxis-drug.htm#HS">HOW SUPPLIED</a>).</b></li> <li><b>Plenaxis™ is indicated for the palliative treatment of men with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and have one or more of the following: (1) risk of neurological compromise due to metastases, (2) ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, or (3) severe bone pain from skeletal metastases persisting on narcotic analgesia.</b></li> <li><b>The effectiveness of Plenaxis™ in suppressing serum testosterone to castrate levels decreases with continued dosing in some patients (see <a href="/plenaxis-drug.htm#CP">CLINICAL PHARMACOLOGY</a>, Pharmacodynamics). Effectiveness beyond 12 months has not been established. Treatment failure can be detected by measuring serum total testosterone concentrations just prior to administration on Day 29 and every 8 weeks thereafter (see <a href="/plenaxis-drug.htm#W">WARNINGS</a>).</b></li> </ul> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <p>Abarelix for injectable suspension (Plenaxis™ ) is a synthetic decapeptide with potent antagonistic activity against naturally occurring <a href="/gonadotropin/definition.htm" ">gonadotropin</a> releasing-hormone (GnRH). Plenaxis™ inhibits gonadotropin and related <a href="/androgen/definition.htm" ">androgen</a> production by directly and competitively blocking GnRH receptors in the <a href="/pituitary/definition.htm" ">pituitary</a>.</p> <p>Abarelix is chemically described as acetyl-D-β-naphthylalanyl-D-4-chlorophenylalanyl- D-3-pyridylalanyl-L-seryl-L-N-methyl-tyrosyl-D-asparagyl-L-leucyl-L-N(ε)-isopropyllysyl- L-prolyl-D-alanyl-amide. It is initially manufactured as an acetate water complex and converted to a carboxymethylcellulose (CMC) water complex in manufacturing the drug product. The molecular weight for abarelix anhydrous free base is 1416.06.</p> <p>The structural formula for abarelix <a href="/peptide/definition.htm" ">peptide</a> is:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="563"> <tbody> <tr> <td><img alt="Plenaxis™ (abarelix) Structural Formula Illustration" height="251" src="https://images.rxlist.com/images/rxlist/plenaxis1.gif" width="563" /></td> </tr> </tbody> </table> </center> <p></p> <p>Abarelix for injectable suspension is supplied as a white to off-white sterile dry powder which, when mixed with the diluent, 0.9% Sodium Chloride Injection, USP, becomes a depot suspension intended for intramuscular (IM) injection. The single-dose vial contains 113 mg of anhydrous free base abarelix peptide (net) supplied in an abarelix CMC complex. This complex also contains 19.1 to 31 mg of CMC. After the vial is reconstituted with 2.2 mL of 0.9% sodium chloride injection, 2 mL is administered to deliver a dose of 100 mg of abarelix (net) as the abarelix CMC complex at a pH of 5±1.</p> </div> <div id="667441035-1" class="medianet"><</div> </div> </div> | 9 | 2023-02-01 17:39:09 | Abarelix (Plenaxis) | A | Gonadotropin Releasing Hormone Antagonists | Plenaxis | abarelix | Plenaxis | John P. Cunha, DO, FACOEP |
| 64 | 2023-02-23 11:36:54 | Indications & Dosage | <a name="I"></a><h3>INDICATIONS</h3> <p>Plenaxis™ is indicated for the <a href="/script/main/art.asp?articlekey=10703">palliative treatment</a> of men with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and have one or more of the following: (1) risk of <a href="/script/main/art.asp?articlekey=11748">neurological</a> compromise due to metastases, (2) ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, or (3) severe bone pain from skeletal metastases persisting on narcotic analgesia.</p> <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3> <p><b>For safety reasons, Plenaxis™ is approved with marketing restrictions.</b> Only physicians who attest to the following qualifications and accept the following responsibilities, and on that basis enroll in PRAECIS PHARMACEUTICALS INCORPORATED's Plenaxis™ PLUS Program should prescribe Plenaxis™ . PRAECIS PHARMACEUTICALS INCORPORATED and its agents will provide Plenaxis™ to physicians enrolled in the Plenaxis™ PLUS Program.</p> <p>To enroll, physicians must attest that they are able and willing to:</p> <ul> <li>diagnose and manage advanced symptomatic prostate cancer.</li> <li>diagnose and treat allergic reactions, including <a href="/script/main/art.asp?articlekey=10935">anaphylaxis</a>.</li> <li>have access to medication and equipment necessary to treat allergic reactions, including anaphylaxis.</li> <li>have patients observed for development of allergic reactions for 30 minutes following each administration of Plenaxis™ .</li> <li>understand the risks and benefits of palliative treatment with Plenaxis™ , including information from the Package Insert, Patient Information, and the Physician Attestation.</li> <li>educate the patients on the risks and benefits of treatment with Plenaxis™ and obtain the patient's signature on the Patient Information signature page, sign it, and place the original signed form in the patient's medical record, and give a copy of the Patient Information leaflet with the signed page to the patient.</li> <li>report serious adverse events, such as any immediate-onset systemic allergic event (including anaphylaxis, <a href="/script/main/art.asp?articlekey=3864">hypotension</a>, and <a href="/script/main/art.asp?articlekey=5612">syncope</a>) as soon as possible to PRAECIS PHARMACEUTICALS INCORPORATED at 1-866-PLENAXIS (1-866-753-6294) or to the Food and Drug Administration's MedWatch Program at 1-800-FDA-1088.</li> <li>understand that they may withdraw their enrollment in the Plenaxis™ Prescribing Program by a written statement submitted to PRAECIS PHARMACEUTICALS INCORPORATED (contact information below) or that PRAECIS PHARMACEUTICALS INCORPORATED may withdraw physicians from the Plenaxis™ PLUS Program if they do not meet the agreed upon responsibilities.</li> </ul> <p>To enroll in the Plenaxis™ Prescribing Program call 1-866-PLENAXIS (1-866-753-6294) or visit www.plenaxisplus.com.</p> <p><b>Dose:</b> The recommended dose of Plenaxis™ is 100 mg administered intramuscularly to the buttock on Day 1, 15, 29 (week 4) and every 4 weeks thereafter. Treatment failure can be detected by measuring serum testosterone concentrations just prior to Plenaxis™ administration, beginning on Day 29 and every 8 weeks thereafter.</p> <h4>Directions for Reconstituting and Administering Plenaxis™ </h4> <p><b>Read the instructions completely before performing reconstitution.</b></p> <p>The sterile powder for suspension is to be reconstituted in accordance with the following directions:</p> <h4>Reconstitution Instructions for 1 Vial of Plenaxis™ to Provide a 100 mg (50 mg/mL) Dose as a Single IM Injection</h4> <p>Use aseptic technique throughout.</p> <p>Prior to reconstitution, gently shake the vial of Plenaxis™ (abarelix for injectable suspension). Hold the vial at an angle (45 degrees) and tap lightly on table to break up any caking.</p> <p>Withdraw 2.2 mL of 0.9% Sodium Chloride Inj., USP using the enclosed 18 G x 1 ½” needle and a 3 cc syringe. Discard the remaining diluent.</p> <p align="center"><b>Picture 1</b><br /> <center> <table width="107" cellspacing="0" class="blackpic"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/plenaxis2.gif" width="107" height="131" alt="Hold the vial at an angle (45 degrees) and tap lightly - Illustration" /></td> </tr> </table> </center></p> <p>Keeping the vial <b>upright</b>, insert the needle all the way into the vial and inject the diluent <b>quickly</b>.</p> <p>Before withdrawing the needle, remove 2.2 mL of air. Shake immediately.</p> <p align="center"><b>Picture 2</b><br /> <center> <table width="67" cellspacing="0" class="blackpic"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/plenaxis3.gif" width="67" height="139" alt="Remove 2.2 mL of air - Illustration" /></td> </tr> </table> </center></p> <p><b>Shake</b> for approximately 15 seconds. Allow the vial to stand for approximately 2 minutes. Tap the vial to <b>reduce foaming</b> and swirl the vial occasionally.</p> <p>Again, <b>shake</b> for approximately 15 seconds. Allow the vial to stand for approximately 2 minutes. Tap the vial to <b>reduce foaming</b> and swirl the vial occasionally.</p> <p align="center"><b>Picture 3</b><br /> <center> <table width="111" cellspacing="0" class="blackpic"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/plenaxis4.gif" width="111" height="135" alt="Tap the vial to reduce foaming - Illustration" /></td> </tr> </table> </center></p> <p><b>Do not reinject the air into the vial. Locate a second injection spot</b> on the stopper, and then insert the 18 G needle. Invert the vial and draw up some of the suspension into the syringe and <b>without removing the needle from the vial reinject it at any remaining solids in the vial. Repeat the process until all solids are dispersed.</b></p> <p>Swirl the vial before withdrawal and withdraw the entire contents (at least 2 mL) by positioning the needle at a 45 degree angle as shown in the picture.</p> <p align="center"><b>Picture 4</b><br /> <center> <table width="103" cellspacing="0" class="blackpic"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/plenaxis5.gif" width="103" height="114" alt="Position the needle at a 45 degree angle - Illustration" /></td> </tr> </table> </center></p> <p>Pull the plunger back to recover the residual suspension in the 18 G x1½” needle.</p> <p>Exchange the 18 G x 1 ½” needle with the enclosed 22 G x 1½” Safety Glide™ injection needle.</p> <p align="center"><b>Picture 5</b><br /> <center> <table width="95" cellspacing="0" class="blackpic"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/plenaxis6.gif" width="95" height="122" alt="Safety Glide™ injection needle - Illustration" /></td> </tr> </table> </center></p> <p>Insert the needle at the desired injection site, pull the plunger back to check for back-flow of blood. If blood flows into the syringe, do not inject at this site. Select another injection site.</p> <p>Deliver the entire reconstituted suspension intramuscularly <b>immediately.</b></p> <p align="center"><b>Picture 6</b><br /> <center> <table width="103" cellspacing="0" class="blackpic"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/plenaxis7.gif" width="103" height="122" alt="Deliver the entire reconstituted suspension intramuscularly - Illustration" /></td> </tr> </table> </center></p> <p><b>Observe the patient after injection for 30 minutes for any sign of an allergic-type response.</b></p> <p>Plenaxis™ does not contain a preservative and should be administered within 1 hour following reconstitution.</p> <h4>Storage</h4> <p>Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F), USP Controlled Room Temperature.</p> <a name="HS"></a><h3>HOW SUPPLIED</h3> <p>The physician must attest to meeting the qualifications and accepting the responsibilities in the <b>DOSAGE AND ADMINISTRATION</b> section of this package insert by submitting the Physician's Attestation form to PRAECIS PHARMACEUTICALS INCORPORATED to be enrolled in the Plenaxis™ PLUS Program. PRAECIS PHARMACEUTICALS INCORPORATED and its agents will only provide Plenaxis™ to physicians enrolled in the Plenaxis™ Prescribing Program. Plenaxis™ vials are not to be resold or redistributed.</p> <p>Plenaxis™ (abarelix for injectable suspension) is supplied as a single-dose, preservativefree vial containing 113 mg of abarelix (anhydrous free base peptide) as an abarelix CMC complex, a sterile powder (NDC 68158-149-01) which, when reconstituted with 2.2 mL of 0.9% sodium chloride solution, yields a 2 mL delivered dose of 100 mg (50 mg/mL). Each single use dispensing pack also contains: a single-use 10 mL diluent vial of 0.9% Sodium Chloride Injection, USP, one 3 cc syringe with an 18 gauge 1½ inch needle and one 22 gauge 1½ inch Safety Glide™ injection needle.</p> <p class="source">Praecis Pharmaceuticals Incorporated, 830 Winter Street, Waltham, MA 02451-1420. 02-01</p> </div> <a class="mediaPrmo img" href="/collection-of-images/prostate_picture/pictures.htm" onclick="wmdTrack('imgprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/image_collection/webmd_anatomy/prostate-anatomy.jpg"> <span class="skew"></span> <span class="icon-image"></span> <h4 class="label">IMAGES</h4> <span class="caption"></span> <span class="desc"></span> <span class="btn">See Images</span> </a> </div> </div> | <a name="I"></a><h3>INDICATIONS</h3> <p>Plenaxis™ is indicated for the <a href="/script/main/art.asp?articlekey=10703">palliative treatment</a> of men with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and have one or more of the following: (1) risk of <a href="/script/main/art.asp?articlekey=11748">neurological</a> compromise due to metastases, (2) ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, or (3) severe bone pain from skeletal metastases persisting on narcotic analgesia.</p> <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3> <p><b>For safety reasons, Plenaxis™ is approved with marketing restrictions.</b> Only physicians who attest to the following qualifications and accept the following responsibilities, and on that basis enroll in PRAECIS PHARMACEUTICALS INCORPORATED's Plenaxis™ PLUS Program should prescribe Plenaxis™ . PRAECIS PHARMACEUTICALS INCORPORATED and its agents will provide Plenaxis™ to physicians enrolled in the Plenaxis™ PLUS Program.</p> <p>To enroll, physicians must attest that they are able and willing to:</p> <ul> <li>diagnose and manage advanced symptomatic prostate cancer.</li> <li>diagnose and treat allergic reactions, including <a href="/script/main/art.asp?articlekey=10935">anaphylaxis</a>.</li> <li>have access to medication and equipment necessary to treat allergic reactions, including anaphylaxis.</li> <li>have patients observed for development of allergic reactions for 30 minutes following each administration of Plenaxis™ .</li> <li>understand the risks and benefits of palliative treatment with Plenaxis™ , including information from the Package Insert, Patient Information, and the Physician Attestation.</li> <li>educate the patients on the risks and benefits of treatment with Plenaxis™ and obtain the patient's signature on the Patient Information signature page, sign it, and place the original signed form in the patient's medical record, and give a copy of the Patient Information leaflet with the signed page to the patient.</li> <li>report serious adverse events, such as any immediate-onset systemic allergic event (including anaphylaxis, <a href="/script/main/art.asp?articlekey=3864">hypotension</a>, and <a href="/script/main/art.asp?articlekey=5612">syncope</a>) as soon as possible to PRAECIS PHARMACEUTICALS INCORPORATED at 1-866-PLENAXIS (1-866-753-6294) or to the Food and Drug Administration's MedWatch Program at 1-800-FDA-1088.</li> <li>understand that they may withdraw their enrollment in the Plenaxis™ Prescribing Program by a written statement submitted to PRAECIS PHARMACEUTICALS INCORPORATED (contact information below) or that PRAECIS PHARMACEUTICALS INCORPORATED may withdraw physicians from the Plenaxis™ PLUS Program if they do not meet the agreed upon responsibilities.</li> </ul> <p>To enroll in the Plenaxis™ Prescribing Program call 1-866-PLENAXIS (1-866-753-6294) or visit www.plenaxisplus.com.</p> <p><b>Dose:</b> The recommended dose of Plenaxis™ is 100 mg administered intramuscularly to the buttock on Day 1, 15, 29 (week 4) and every 4 weeks thereafter. Treatment failure can be detected by measuring serum testosterone concentrations just prior to Plenaxis™ administration, beginning on Day 29 and every 8 weeks thereafter.</p> <h4>Directions for Reconstituting and Administering Plenaxis™ </h4> <p><b>Read the instructions completely before performing reconstitution.</b></p> <p>The sterile powder for suspension is to be reconstituted in accordance with the following directions:</p> <h4>Reconstitution Instructions for 1 Vial of Plenaxis™ to Provide a 100 mg (50 mg/mL) Dose as a Single IM Injection</h4> <p>Use aseptic technique throughout.</p> <p>Prior to reconstitution, gently shake the vial of Plenaxis™ (abarelix for injectable suspension). Hold the vial at an angle (45 degrees) and tap lightly on table to break up any caking.</p> <p>Withdraw 2.2 mL of 0.9% Sodium Chloride Inj., USP using the enclosed 18 G x 1 ½” needle and a 3 cc syringe. Discard the remaining diluent.</p> <p align="center"><b>Picture 1</b><br /> <center> <table width="107" cellspacing="0" class="blackpic"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/plenaxis2.gif" width="107" height="131" alt="Hold the vial at an angle (45 degrees) and tap lightly - Illustration" /></td> </tr> </table> </center></p> <p>Keeping the vial <b>upright</b>, insert the needle all the way into the vial and inject the diluent <b>quickly</b>.</p> <p>Before withdrawing the needle, remove 2.2 mL of air. Shake immediately.</p> <p align="center"><b>Picture 2</b><br /> <center> <table width="67" cellspacing="0" class="blackpic"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/plenaxis3.gif" width="67" height="139" alt="Remove 2.2 mL of air - Illustration" /></td> </tr> </table> </center></p> <p><b>Shake</b> for approximately 15 seconds. Allow the vial to stand for approximately 2 minutes. Tap the vial to <b>reduce foaming</b> and swirl the vial occasionally.</p> <p>Again, <b>shake</b> for approximately 15 seconds. Allow the vial to stand for approximately 2 minutes. Tap the vial to <b>reduce foaming</b> and swirl the vial occasionally.</p> <p align="center"><b>Picture 3</b><br /> <center> <table width="111" cellspacing="0" class="blackpic"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/plenaxis4.gif" width="111" height="135" alt="Tap the vial to reduce foaming - Illustration" /></td> </tr> </table> </center></p> <p><b>Do not reinject the air into the vial. Locate a second injection spot</b> on the stopper, and then insert the 18 G needle. Invert the vial and draw up some of the suspension into the syringe and <b>without removing the needle from the vial reinject it at any remaining solids in the vial. Repeat the process until all solids are dispersed.</b></p> <p>Swirl the vial before withdrawal and withdraw the entire contents (at least 2 mL) by positioning the needle at a 45 degree angle as shown in the picture.</p> <p align="center"><b>Picture 4</b><br /> <center> <table width="103" cellspacing="0" class="blackpic"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/plenaxis5.gif" width="103" height="114" alt="Position the needle at a 45 degree angle - Illustration" /></td> </tr> </table> </center></p> <p>Pull the plunger back to recover the residual suspension in the 18 G x1½” needle.</p> <p>Exchange the 18 G x 1 ½” needle with the enclosed 22 G x 1½” Safety Glide™ injection needle.</p> <p align="center"><b>Picture 5</b><br /> <center> <table width="95" cellspacing="0" class="blackpic"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/plenaxis6.gif" width="95" height="122" alt="Safety Glide™ injection needle - Illustration" /></td> </tr> </table> </center></p> <p>Insert the needle at the desired injection site, pull the plunger back to check for back-flow of blood. If blood flows into the syringe, do not inject at this site. Select another injection site.</p> <p>Deliver the entire reconstituted suspension intramuscularly <b>immediately.</b></p> <p align="center"><b>Picture 6</b><br /> <center> <table width="103" cellspacing="0" class="blackpic"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/plenaxis7.gif" width="103" height="122" alt="Deliver the entire reconstituted suspension intramuscularly - Illustration" /></td> </tr> </table> </center></p> <p><b>Observe the patient after injection for 30 minutes for any sign of an allergic-type response.</b></p> <p>Plenaxis™ does not contain a preservative and should be administered within 1 hour following reconstitution.</p> <h4>Storage</h4> <p>Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F), USP Controlled Room Temperature.</p> <a name="HS"></a><h3>HOW SUPPLIED</h3> <p>The physician must attest to meeting the qualifications and accepting the responsibilities in the <b>DOSAGE AND ADMINISTRATION</b> section of this package insert by submitting the Physician's Attestation form to PRAECIS PHARMACEUTICALS INCORPORATED to be enrolled in the Plenaxis™ PLUS Program. PRAECIS PHARMACEUTICALS INCORPORATED and its agents will only provide Plenaxis™ to physicians enrolled in the Plenaxis™ Prescribing Program. Plenaxis™ vials are not to be resold or redistributed.</p> <p>Plenaxis™ (abarelix for injectable suspension) is supplied as a single-dose, preservativefree vial containing 113 mg of abarelix (anhydrous free base peptide) as an abarelix CMC complex, a sterile powder (NDC 68158-149-01) which, when reconstituted with 2.2 mL of 0.9% sodium chloride solution, yields a 2 mL delivered dose of 100 mg (50 mg/mL). Each single use dispensing pack also contains: a single-use 10 mL diluent vial of 0.9% Sodium Chloride Injection, USP, one 3 cc syringe with an 18 gauge 1½ inch needle and one 22 gauge 1½ inch Safety Glide™ injection needle.</p> <p class="source">Praecis Pharmaceuticals Incorporated, 830 Winter Street, Waltham, MA 02451-1420. 02-01</p> </div> <a class="mediaPrmo img" href="/collection-of-images/prostate_picture/pictures.htm" onclick="wmdTrack('imgprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/image_collection/webmd_anatomy/prostate-anatomy.jpg"> <span class="skew"></span> <span class="icon-image"></span> <h4 class="label">IMAGES</h4> <span class="caption"></span> <span class="desc"></span> <span class="btn">See Images</span> </a> </div> </div> | 9 | 2023-02-01 17:39:09 | Abarelix (Plenaxis) | A | Gonadotropin Releasing Hormone Antagonists | Plenaxis | abarelix | Plenaxis | John P. Cunha, DO, FACOEP |
| 65 | 2023-02-23 11:36:54 | Side Effects & Drug Interactions | <a name="AR"></a><h3>SIDE EFFECTS</h3> <p><b>Immediate-Onset Systemic Allergic Reactions: See <a href="/plenaxis-drug.htm#BW">BOXED WARNINGS</a> and <a href="/plenaxis-drug.htm#W">WARNINGS</a></b></p> <p>In the single study of Plenaxis™ conducted in men with advanced <a href="/script/main/art.asp?articlekey=20424">symptomatic </a> <a href="/script/main/art.asp?articlekey=5072">prostate cancer</a>, adverse events reported by ≥ 10% of patients are listed in Table 4. Adverse events are listed without regard to causality. Causality is often difficult to assess in elderly patients with multiple co-morbidities and prostate cancer.</p> <p align="center"><b>Table 4: Adverse Events in ≥ 10% of Patients in the Advanced Symptomatic Prostate Cancer Study (without regard for causality).</b><br /> <center> <table width="450" cellspacing="0" class="blacktbl"> <tr> <td class="EmphTd" width="70%">Preferred Term</td> <td class="EmphTd" width="30%">Plenaxis™ <br /> N=81<br /> n (%)</td> </tr> <tr> <td>Hot flushes*</td> <td align="center">64 (79)</td> </tr> <tr> <td>Sleep disturbance*</td> <td align="center">36 (44)</td> </tr> <tr> <td>Pain</td> <td align="center">25 (31)</td> </tr> <tr> <td>Breast enlargement*</td> <td align="center">24 (30)</td> </tr> <tr> <td>Breast pain/nipple tenderness*</td> <td align="center">16 (20)</td> </tr> <tr> <td>Back pain</td> <td align="center">14 (17)</td> </tr> <tr> <td>Constipation</td> <td align="center">12 (15)</td> </tr> <tr> <td>Peripheral edema</td> <td align="center">12 (15)</td> </tr> <tr> <td>Dizziness</td> <td align="center">10 (12)</td> </tr> <tr> <td>Headache</td> <td align="center">10 (12)</td> </tr> <tr> <td>Upper respiratory tract infection</td> <td align="center">10 (12)</td> </tr> <tr> <td>Diarrhea</td> <td align="center">9 (11)</td> </tr> <tr> <td>Dysuria</td> <td align="center">8 (10)</td> </tr> <tr> <td>Fatigue</td> <td align="center">8 (10)</td> </tr> <tr> <td>Micturition frequency</td> <td align="center">8 (10)</td> </tr> <tr> <td>Nausea</td> <td align="center">8 (10)</td> </tr> <tr> <td>Urinary retention</td> <td align="center">8 (10)</td> </tr> <tr> <td><a href="/urine_infection/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Urinary tract infection</a></td> <td align="center">8 (10)</td> </tr> <tr> <td class="source" colspan="2">* Pharmacological consequence of androgen deprivation</td> </tr> </table> </center></p> <h4>Changes in Laboratory Values</h4> <p>Clinically meaningful increases in serum transaminases were seen in a small percentage of patients in both treatment groups in each active-controlled Plenaxis™ study. In Study 1 and Study 2 combined, the percentage of Plenaxis™ patients reporting serum ALT > 2.5 times upper limit of normal or > 200 U./L was 8.2% and 1.8%, respectively. The percentage reporting serum AST > 2.5 times upper limit of normal or > 200 U/L was 3.1% and 0.8%, respectively. Similar results were reported for active comparators.</p> <p>Slight decrease in hemoglobin, a pharmacological consequence of <a href="/script/main/art.asp?articlekey=11102">castration</a>, were observed in patients receiving Plenaxis™ and active comparator. Mean increases in serum triglycerides of approximately 10% were seen in Plenaxis™ -treated patients.</p> <a name="DI"></a><h3>DRUG INTERACTIONS</h3> <p>No formal drug/drug interaction studies with Plenaxis™ were performed. Cytochrome P-450 is not known to be involved in the metabolism of Plenaxis™ . Plenaxis™ is highly bound to plasma proteins (96 to 99%).</p> <h4>Laboratory Tests</h4> <p>Response to Plenaxis™ should be monitored by measuring serum total testosterone concentrations just prior to administration on Day 29 and every 8 weeks thereafter (see <a href="/plenaxis-drug.htm#W"><b>WARNINGS</b></a>). Serum transaminase levels should be obtained before starting treatment with Plenaxis™ and periodically during treatment. Periodic measurement of serum PSA levels may also be considered.</p> </div> </div> </div> | <a name="AR"></a><h3>SIDE EFFECTS</h3> <p><b>Immediate-Onset Systemic Allergic Reactions: See <a href="/plenaxis-drug.htm#BW">BOXED WARNINGS</a> and <a href="/plenaxis-drug.htm#W">WARNINGS</a></b></p> <p>In the single study of Plenaxis™ conducted in men with advanced <a href="/script/main/art.asp?articlekey=20424">symptomatic </a> <a href="/script/main/art.asp?articlekey=5072">prostate cancer</a>, adverse events reported by ≥ 10% of patients are listed in Table 4. Adverse events are listed without regard to causality. Causality is often difficult to assess in elderly patients with multiple co-morbidities and prostate cancer.</p> <p align="center"><b>Table 4: Adverse Events in ≥ 10% of Patients in the Advanced Symptomatic Prostate Cancer Study (without regard for causality).</b><br /> <center> <table width="450" cellspacing="0" class="blacktbl"> <tr> <td class="EmphTd" width="70%">Preferred Term</td> <td class="EmphTd" width="30%">Plenaxis™ <br /> N=81<br /> n (%)</td> </tr> <tr> <td>Hot flushes*</td> <td align="center">64 (79)</td> </tr> <tr> <td>Sleep disturbance*</td> <td align="center">36 (44)</td> </tr> <tr> <td>Pain</td> <td align="center">25 (31)</td> </tr> <tr> <td>Breast enlargement*</td> <td align="center">24 (30)</td> </tr> <tr> <td>Breast pain/nipple tenderness*</td> <td align="center">16 (20)</td> </tr> <tr> <td>Back pain</td> <td align="center">14 (17)</td> </tr> <tr> <td>Constipation</td> <td align="center">12 (15)</td> </tr> <tr> <td>Peripheral edema</td> <td align="center">12 (15)</td> </tr> <tr> <td>Dizziness</td> <td align="center">10 (12)</td> </tr> <tr> <td>Headache</td> <td align="center">10 (12)</td> </tr> <tr> <td>Upper respiratory tract infection</td> <td align="center">10 (12)</td> </tr> <tr> <td>Diarrhea</td> <td align="center">9 (11)</td> </tr> <tr> <td>Dysuria</td> <td align="center">8 (10)</td> </tr> <tr> <td>Fatigue</td> <td align="center">8 (10)</td> </tr> <tr> <td>Micturition frequency</td> <td align="center">8 (10)</td> </tr> <tr> <td>Nausea</td> <td align="center">8 (10)</td> </tr> <tr> <td>Urinary retention</td> <td align="center">8 (10)</td> </tr> <tr> <td><a href="/urine_infection/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Urinary tract infection</a></td> <td align="center">8 (10)</td> </tr> <tr> <td class="source" colspan="2">* Pharmacological consequence of androgen deprivation</td> </tr> </table> </center></p> <h4>Changes in Laboratory Values</h4> <p>Clinically meaningful increases in serum transaminases were seen in a small percentage of patients in both treatment groups in each active-controlled Plenaxis™ study. In Study 1 and Study 2 combined, the percentage of Plenaxis™ patients reporting serum ALT > 2.5 times upper limit of normal or > 200 U./L was 8.2% and 1.8%, respectively. The percentage reporting serum AST > 2.5 times upper limit of normal or > 200 U/L was 3.1% and 0.8%, respectively. Similar results were reported for active comparators.</p> <p>Slight decrease in hemoglobin, a pharmacological consequence of <a href="/script/main/art.asp?articlekey=11102">castration</a>, were observed in patients receiving Plenaxis™ and active comparator. Mean increases in serum triglycerides of approximately 10% were seen in Plenaxis™ -treated patients.</p> <a name="DI"></a><h3>DRUG INTERACTIONS</h3> <p>No formal drug/drug interaction studies with Plenaxis™ were performed. Cytochrome P-450 is not known to be involved in the metabolism of Plenaxis™ . Plenaxis™ is highly bound to plasma proteins (96 to 99%).</p> <h4>Laboratory Tests</h4> <p>Response to Plenaxis™ should be monitored by measuring serum total testosterone concentrations just prior to administration on Day 29 and every 8 weeks thereafter (see <a href="/plenaxis-drug.htm#W"><b>WARNINGS</b></a>). Serum transaminase levels should be obtained before starting treatment with Plenaxis™ and periodically during treatment. Periodic measurement of serum PSA levels may also be considered.</p> </div> </div> </div> | 9 | 2023-02-01 17:39:09 | Abarelix (Plenaxis) | A | Gonadotropin Releasing Hormone Antagonists | Plenaxis | abarelix | Plenaxis | John P. Cunha, DO, FACOEP |
| 66 | 2023-02-23 11:36:54 | Warnings | <a name="W"></a><h3>WARNINGS</h3> <h4>Immediate-Onset Systemic Allergic Reactions (See <a href="/plenaxis-drug.htm#BW">BOXED WARNINGS</a>)</h4> <p><b> In the clinical trial of patients with advanced, symptomatic prostate cancer, 3 of 81 (3.7%) patients experienced an immediate-onset systemic allergic reaction within minutes of receiving Plenaxis™ . The allergic reactions were urticaria (Day 15), urticaria and pruritis (Day 29), and hypotension and syncope (Day 141). </b>Patients should be monitored for at least 30 minutes after each injection of Plenaxis™ . In the event of an allergic reaction associated with hypotension and/or syncope, appropriate supportive measures such as leg elevation, oxygen, IV fluids, antihistamines, corticosteroids, and epinephrine (alone or in combination) should be employed. From all the prostate cancer clinical trials with Plenaxis™ (mostly in men without advanced, symptomatic disease), immediate-onset systemic allergic reactions (occurring within 30 minutes of dosing), were observed in 1.1% (15/1397) of patients dosed with Plenaxis™ . In 14/15 patients who experienced an allergic reaction, each developed symptoms within 8 minutes of injection. The cumulative risk of such a reaction increased with duration of treatment. The cumulative rates (and 95% confidence intervals) on Days 56, 141, 365 and 676 were 0.51%, (0.13%, 0.88%) 0.80% (0.30%, 1.29%), 1.24% (0.43%, 2.04%) and 2.91% (0.87, 4.95%), respectively. Seven patients experienced hypotension or syncope as part of their allergic reaction, representing 0.5% of all patients. The cumulative rates (and 95% confidence intervals) for these types of reactions on Days 56, 141, 365, and 617 after the initial dose were 0.22% (0.0%, 0.46%), 0.32% (0.0%, 0.64%), 0.61% (0.0%, 1.24%) and 1.67% (0.07, 3.28%), respectively.</p> <h4>Decrease in Effectiveness With Continued Dosing</h4> <p>A decrease in overall effectiveness with increased duration of treatment, as measured by failure to maintain suppression of serum testosterone below 50 ng/dL, was noted (see <a href="/plenaxis-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a>, <b>Pharmacodynamics</b>). Treatment failure can be detected by measuring serum total testosterone concentrations just prior to administration on Day 29 after the initial dose and every 8 weeks thereafter.</p> <h4>Prolongation of the QT Interval</h4> <p>Because Plenaxis™ may prolong the QT interval (see <a href="/plenaxis-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a>, <b>Pharmacodynamics</b>), physicians should carefully consider whether the risks of Plenaxis™ outweigh the benefits in patients with baseline QTc values > 450 msec (e.g. congenital QT prolongation) and in patients taking Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications.</p> </div> </div> </div> | <a name="W"></a><h3>WARNINGS</h3> <h4>Immediate-Onset Systemic Allergic Reactions (See <a href="/plenaxis-drug.htm#BW">BOXED WARNINGS</a>)</h4> <p><b> In the clinical trial of patients with advanced, symptomatic prostate cancer, 3 of 81 (3.7%) patients experienced an immediate-onset systemic allergic reaction within minutes of receiving Plenaxis™ . The allergic reactions were urticaria (Day 15), urticaria and pruritis (Day 29), and hypotension and syncope (Day 141). </b>Patients should be monitored for at least 30 minutes after each injection of Plenaxis™ . In the event of an allergic reaction associated with hypotension and/or syncope, appropriate supportive measures such as leg elevation, oxygen, IV fluids, antihistamines, corticosteroids, and epinephrine (alone or in combination) should be employed. From all the prostate cancer clinical trials with Plenaxis™ (mostly in men without advanced, symptomatic disease), immediate-onset systemic allergic reactions (occurring within 30 minutes of dosing), were observed in 1.1% (15/1397) of patients dosed with Plenaxis™ . In 14/15 patients who experienced an allergic reaction, each developed symptoms within 8 minutes of injection. The cumulative risk of such a reaction increased with duration of treatment. The cumulative rates (and 95% confidence intervals) on Days 56, 141, 365 and 676 were 0.51%, (0.13%, 0.88%) 0.80% (0.30%, 1.29%), 1.24% (0.43%, 2.04%) and 2.91% (0.87, 4.95%), respectively. Seven patients experienced hypotension or syncope as part of their allergic reaction, representing 0.5% of all patients. The cumulative rates (and 95% confidence intervals) for these types of reactions on Days 56, 141, 365, and 617 after the initial dose were 0.22% (0.0%, 0.46%), 0.32% (0.0%, 0.64%), 0.61% (0.0%, 1.24%) and 1.67% (0.07, 3.28%), respectively.</p> <h4>Decrease in Effectiveness With Continued Dosing</h4> <p>A decrease in overall effectiveness with increased duration of treatment, as measured by failure to maintain suppression of serum testosterone below 50 ng/dL, was noted (see <a href="/plenaxis-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a>, <b>Pharmacodynamics</b>). Treatment failure can be detected by measuring serum total testosterone concentrations just prior to administration on Day 29 after the initial dose and every 8 weeks thereafter.</p> <h4>Prolongation of the QT Interval</h4> <p>Because Plenaxis™ may prolong the QT interval (see <a href="/plenaxis-drug.htm#CP"><b>CLINICAL PHARMACOLOGY</b></a>, <b>Pharmacodynamics</b>), physicians should carefully consider whether the risks of Plenaxis™ outweigh the benefits in patients with baseline QTc values > 450 msec (e.g. congenital QT prolongation) and in patients taking Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications.</p> </div> </div> </div> | 9 | 2023-02-01 17:39:09 | Abarelix (Plenaxis) | A | Gonadotropin Releasing Hormone Antagonists | Plenaxis | abarelix | Plenaxis | John P. Cunha, DO, FACOEP |
| 67 | 2023-02-23 12:07:03 | Precautions | <a name="P"></a><h3>PRECAUTIONS</h3> <h4>General</h4> <p><b><i>Decreased effectiveness in patients > 225 pounds</i>:</b> The decrease in overall effectiveness of Plenaxis™ with increased duration of treatment is greater in patients who weigh more than 225 pounds. Strict monitoring of serum testosterone in these patients is warranted. Monitoring of liver function: Clinically meaningful transaminase elevations were observed in some patients who received Plenaxis™ or comparator drugs. Serum transaminase levels should be obtained before starting treatment with Plenaxis™ and periodically during treatment (see <a href="/plenaxis-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>).</p> <p><b><i>Decrease in bone mineral density</i>:</b> Extended treatment with GnRH antagonists and LHRH agonists may result in a decrease in bone mineral density.</p> <h4>Geriatric Use</h4> <p>Prostate cancer occurs primarily in an older patient population. Clinical studies with Plenaxis™ have been conducted primarily in patients ≥ 65 years of age. No difference in the safety profile, when examined as a function of age, was apparent.</p> <h4>Pediatric Use</h4> <p>The safety and effectiveness of Plenaxis™ in pediatric patients have not been studied. Plenaxis™ is not indicated for use in pediatric patients.</p> <h4>Carcinogenesis, Mutagenesis, Impairment of Fertility</h4> <p>Plenaxis™ was not carcinogenic to mice or rats when administered as a subcutaneous depot every 28 days for 2 years at doses up to 300 mg/kg in mice and 100 mg/kg in rats. Systemic drug exposures, as measured by mean Cmax, were approximately 210-278-fold for mice and 21-32-fold for rats the human exposure following subcutaneous depot administration of 100 mg.</p> <p>Plenaxis™ was not mutagenic in the <i>in vitro </i>bacterial Ames assay or forward mutation assay in mouse <a href="/script/main/art.asp?articlekey=4225">lymphoma</a>, or clastogenic in the in vivo mouse micronucleus assay.</p> <p>No effects on mating or fertility in male and female rats given 1 mg/kg subcutaneous Plenaxis™ , a dose 0.114-fold the human therapeutic dose of 100 mg based on <a href="/script/main/art.asp?articlekey=39851">body surface area</a>. Mating and fertility were significantly decreased at doses of 3 and 10 mg/kg (0.34-fold and 1.135-fold, respectively, the human therapeutic dose of 100 mg based on body surface area), but the effects were reversible.</p> <h4>Pregnancy Category X</h4> <p>(see <a href="/plenaxis-drug.htm#CI"><b>CONTRAINDICATIONS</b></a>)</p> <p>Embryolethality occurred in pregnant rats administered a single subcutaneous dose of Plenaxis™ up to 3 mg/kg (0.228-fold the human therapeutic dose of 100 mg based on body surface area). In rabbits a dose-related increase in fetal resorptions and reduced viability was observed at doses up to 30 mg/kg (6.81-fold the human therapeutic dose of 100 mg based on body surface area). No <a href="/teratogenic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">teratogenic</a> effects were observed in rats or rabbits up to doses of 3 mg/kg or 30 mg/kg, respectively. A no-observable-<a href="/adverse_effect/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">adverse effect</a>- level (NOAEL) dose was 0.3 mg/kg (approximately 0.034-fold the human therapeutic dose of 100 mg based on body surface area) in rats and < 0.01 mg/kg ( < 0.0023-fold the human therapeutic dose of 100 mg based on body surface area) in rabbits.</p> <h4>Nursing Mothers</h4> <p>It is not known whether Plenaxis™ is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of Plenaxis™ on lactation and/or the breastfed child have not been determined, Plenaxis™ should not be used by nursing mothers.</p> </div> </div> </div> | <a name="P"></a><h3>PRECAUTIONS</h3> <h4>General</h4> <p><b><i>Decreased effectiveness in patients > 225 pounds</i>:</b> The decrease in overall effectiveness of Plenaxis™ with increased duration of treatment is greater in patients who weigh more than 225 pounds. Strict monitoring of serum testosterone in these patients is warranted. Monitoring of liver function: Clinically meaningful transaminase elevations were observed in some patients who received Plenaxis™ or comparator drugs. Serum transaminase levels should be obtained before starting treatment with Plenaxis™ and periodically during treatment (see <a href="/plenaxis-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>).</p> <p><b><i>Decrease in bone mineral density</i>:</b> Extended treatment with GnRH antagonists and LHRH agonists may result in a decrease in bone mineral density.</p> <h4>Geriatric Use</h4> <p>Prostate cancer occurs primarily in an older patient population. Clinical studies with Plenaxis™ have been conducted primarily in patients ≥ 65 years of age. No difference in the safety profile, when examined as a function of age, was apparent.</p> <h4>Pediatric Use</h4> <p>The safety and effectiveness of Plenaxis™ in pediatric patients have not been studied. Plenaxis™ is not indicated for use in pediatric patients.</p> <h4>Carcinogenesis, Mutagenesis, Impairment of Fertility</h4> <p>Plenaxis™ was not carcinogenic to mice or rats when administered as a subcutaneous depot every 28 days for 2 years at doses up to 300 mg/kg in mice and 100 mg/kg in rats. Systemic drug exposures, as measured by mean Cmax, were approximately 210-278-fold for mice and 21-32-fold for rats the human exposure following subcutaneous depot administration of 100 mg.</p> <p>Plenaxis™ was not mutagenic in the <i>in vitro </i>bacterial Ames assay or forward mutation assay in mouse <a href="/script/main/art.asp?articlekey=4225">lymphoma</a>, or clastogenic in the in vivo mouse micronucleus assay.</p> <p>No effects on mating or fertility in male and female rats given 1 mg/kg subcutaneous Plenaxis™ , a dose 0.114-fold the human therapeutic dose of 100 mg based on <a href="/script/main/art.asp?articlekey=39851">body surface area</a>. Mating and fertility were significantly decreased at doses of 3 and 10 mg/kg (0.34-fold and 1.135-fold, respectively, the human therapeutic dose of 100 mg based on body surface area), but the effects were reversible.</p> <h4>Pregnancy Category X</h4> <p>(see <a href="/plenaxis-drug.htm#CI"><b>CONTRAINDICATIONS</b></a>)</p> <p>Embryolethality occurred in pregnant rats administered a single subcutaneous dose of Plenaxis™ up to 3 mg/kg (0.228-fold the human therapeutic dose of 100 mg based on body surface area). In rabbits a dose-related increase in fetal resorptions and reduced viability was observed at doses up to 30 mg/kg (6.81-fold the human therapeutic dose of 100 mg based on body surface area). No <a href="/teratogenic/definition.htm" ">teratogenic</a> effects were observed in rats or rabbits up to doses of 3 mg/kg or 30 mg/kg, respectively. A no-observable-<a href="/adverse_effect/definition.htm" ">adverse effect</a>- level (NOAEL) dose was 0.3 mg/kg (approximately 0.034-fold the human therapeutic dose of 100 mg based on body surface area) in rats and < 0.01 mg/kg ( < 0.0023-fold the human therapeutic dose of 100 mg based on body surface area) in rabbits.</p> <h4>Nursing Mothers</h4> <p>It is not known whether Plenaxis™ is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of Plenaxis™ on lactation and/or the breastfed child have not been determined, Plenaxis™ should not be used by nursing mothers.</p> </div> </div> </div> | 9 | 2023-02-01 17:39:09 | Abarelix (Plenaxis) | A | Gonadotropin Releasing Hormone Antagonists | Plenaxis | abarelix | Plenaxis | John P. Cunha, DO, FACOEP |
| 68 | 2023-02-23 11:36:54 | Overdose & Contraindications | <a name="OD"></a><h3>OVERDOSE</h3> <p>The maximum tolerated dose of Plenaxis™ has not been determined. The maximum dose used in clinical studies was 150 mg. There have been no reports of accidental overdose with Plenaxis™ .</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3> <p>Plenaxis™ is contraindicated in those patients with a known hypersensitivity to any of the components in abarelix for injectable suspension.</p> <p>Plenaxis™ is not indicated in women or pediatric patients. In addition, Plenaxis™ may cause fetal harm if administered to a pregnant woman.</p> </div> </div> </div> | <a name="OD"></a><h3>OVERDOSE</h3> <p>The maximum tolerated dose of Plenaxis™ has not been determined. The maximum dose used in clinical studies was 150 mg. There have been no reports of accidental overdose with Plenaxis™ .</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3> <p>Plenaxis™ is contraindicated in those patients with a known hypersensitivity to any of the components in abarelix for injectable suspension.</p> <p>Plenaxis™ is not indicated in women or pediatric patients. In addition, Plenaxis™ may cause fetal harm if administered to a pregnant woman.</p> </div> </div> </div> | 9 | 2023-02-01 17:39:09 | Abarelix (Plenaxis) | A | Gonadotropin Releasing Hormone Antagonists | Plenaxis | abarelix | Plenaxis | John P. Cunha, DO, FACOEP |
| 69 | 2023-02-23 12:07:03 | Clinical Pharmacology | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism of Action</h4> <p>Abarelix exerts its pharmacological action by directly suppressing <a href="/luteinizing_hormone/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">luteinizing hormone</a> (LH) and follicle stimulating hormone (FSH) secretion and thereby reducing the secretion of <a href="/testosterone/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">testosterone</a> by the <a href="/script/main/art.asp?articlekey=8974">testes</a>. Due to the direct inhibition of the secretion of LH by abarelix, there is no initial increase in serum testosterone concentrations. Saturation binding studies revealed that [<sup>125</sup>I]-abarelix has a very high <a href="/affinity/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">affinity</a> (KD = 0.1 nM) for the rat pituitary LHRH receptor.</p> <h4>Pharmacokinetics</h4> <p>A single dose (100 mg IM) of Plenaxis™ was given to 14 healthy male volunteers 52 to 75 years of age, with body weight of 61.6 to 110.5 kg, and the pharmacokinetic information is provided in Table 1</p> <p align="center"><b>Table 1: Mean ± SD Pharmacokinetic Parameter Values of 100 mg of Plenaxis™ Following a Single IM Injection (n = 14)</b><br /> <center> <table width="450" cellspacing="0" class="blacktbl"> <tr> <td class="EmphTd" width="20%">Cmax (ng/mL)</td> <td class="EmphTd" width="20%">Tmax (days)</td> <td class="EmphTd" width="20%">AUC0-∞ (ng •day/mL)</td> <td class="EmphTd" width="20%">CL/F (L/day)</td> <td class="EmphTd" width="20%">t½ (days)</td> </tr> <tr> <td align="center">43.4 ± 32.3</td> <td align="center">3.0 ± 2.9</td> <td align="center">500 ± 96</td> <td align="center">208 ± 48</td> <td align="center">13.2 ± 3.2</td> </tr> </table> </center></p> <h5>Absorption</h5> <p>Following IM administration of 100 mg of Plenaxis™ , abarelix is absorbed slowly with a mean peak concentration of 43.4 ng/mL observed approximately 3 days after the injection.</p> <h5>Distribution</h5> <p>The apparent volume of distribution during the terminal phase determined after IM administration of Plenaxis™ was 4040 ± 1607 liters, implying that abarelix probably distributes extensively within the body.</p> <h5>Metabolism</h5> <p><i>In vitro</i> hepatocyte (rat, monkey, human) studies and in vivo studies in rats and monkeys showed that the major metabolites of abarelix were formed via hydrolysis of peptide bonds. No significant oxidative or conjugated metabolites of abarelix were found either <i>in vitro </i>or in vivo. There is no evidence of cytochrome P-450 involvement in the metabolism of abarelix.</p> <h5>Excretion</h5> <p>In humans, approximately 13% of unchanged abarelix was recovered in <a href="/script/main/art.asp?articlekey=5915">urine</a> after a 15 μg/kg IM injection; there were no detectable metabolites in urine. Renal clearance of abarelix was 14.4 L/day (or 10 mL/min) after administration of 100 mg Plenaxis™ .</p> <h4>Pharmacodynamics</h4> <p><b><i>Effects of Plenaxis™ on Serum Testosterone</i>: </b>The effectiveness of Plenaxis™ in suppressing serum testosterone was studied in two randomized, open-label, activecomparator trials. Patients were not those with advanced symptomatic <a href="/script/main/art.asp?articlekey=5072">prostate cancer</a>. They were randomized in a 2:1 ratio to Plenaxis™ 100 mg IM versus <a href="/lhrh_agonist/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">LHRH agonist</a> (Study 1) or to Plenaxis™ versus LHRH <a href="/agonist/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">agonist</a> + nonsteroidal <a href="/antiandrogen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antiandrogen</a> (Study 2). Plenaxis™ was administered IM on Days 1, 15, 29 (Week 4), then every 4 weeks thereafter for at least 6 months (24 weeks). LHRH agonist and nonsteroidal antiandrogen were administered in standard fashion. After completing 6 months of treatment, patients could continue randomized treatment for an additional 6 months.</p> <p><b><i>Avoidance of testosterone surge</i>:</b> In both studies combined, 100% (348/348) of Plenaxis™ patients and 16% (28/172) of comparator patients avoided a testosterone surge.</p> <p><b><i>Attainment of medical castration</i>:</b> The percentage of patients who attained serum testosterone concentration ≤ 50 ng/dL on Study Days 2, 8, 15 and 29 are summarized in the table below:</p> <p align="center"><b>Table 2: Percentage of patients who attained medical castration (serum testosterone concentration ≤ 50 ng/dL) in Studies 1 and 2.</b><br /> <center> <table width="450" cellspacing="0" class="blacktbl"> <tr> <td class="EmphTd" rowspan="2" width="40%">Day</td> <td class="EmphTd" colspan="2">Plenaxis™ </td> </tr> <tr> <td class="EmphTd" width="30%">Total N</td> <td class="EmphTd" width="30%">% Castrate</td> </tr> <tr> <td align="center">2</td> <td align="center">339</td> <td align="center">24</td> </tr> <tr> <td align="center">4</td> <td align="center">333</td> <td align="center">56</td> </tr> <tr> <td align="center">8</td> <td align="center">348</td> <td align="center">70</td> </tr> <tr> <td align="center">15</td> <td align="center">347</td> <td align="center">73</td> </tr> <tr> <td align="center">29</td> <td align="center">347</td> <td align="center">94</td> </tr> </table> </center></p> <p><b><i>Attainment and maintenance of medical castration</i>:</b> Successful response was defined as attainment of medical castration on Day 29 and maintenance through Day 85 (where no two consecutive serum testosterone concentrations between Days 29 and 85 were greater than 50 ng/dL). In Study 1, 92% on Plenaxis™ patients responded and 96% of LHRH agonist patients responded. In Study 2, 93% of Plenaxis™ patients and 95% of LHRH agonist + nonsteroidal antiandrogen patients responded.</p> <p>However, when failure was defined as any observed serum testosterone > 50 ng/Dl (including transient elevations) just prior to dosing on Day 29 and every 28 days thereafter, effectiveness of testosterone suppression decreased over time. Results of this analysis are summarized in Table 3.</p> <p align="center"><b>Table 3: Percentage of patients who attained and maintained medical castration; [no serum testosterone > 50 ng/dL just prior to dosing on Day 29 and every 28 days thereafter]</b><br /> <center> <table width="450" cellspacing="0" class="blacktbl"> <tr> <td class="EmphTd" width="20%">Day</td> <td class="EmphTd" width="20%">Study 1 Plenaxis™ </td> <td class="EmphTd" width="20%">N</td> <td class="EmphTd" width="20%">Study 2 Plenaxis™ </td> <td class="EmphTd" width="20%">N</td> </tr> <tr> <td align="center">85</td> <td align="center">84%</td> <td align="center">176</td> <td align="center">92%</td> <td align="center">164</td> </tr> <tr> <td align="center">169</td> <td align="center">75%</td> <td align="center">166</td> <td align="center">87%</td> <td align="center">155</td> </tr> <tr> <td align="center">365</td> <td align="center">62%</td> <td align="center">93</td> <td align="center">71%</td> <td align="center">86</td> </tr> </table> </center></p> <p><b><i>Effects of Plenaxis™ on Cardiac Electrophysiology</i></b>: In a single, active-controlled, clinical study comparing Plenaxis™ to LHRH agonist + nonsteroidal antiandrogen, periodic electrocardiograms were performed. Both therapies prolonged the mean Fridericia-corrected QT interval by > 10 msec from baseline. In approximately 20% of patients in both groups, there were either changes from baseline QTc of > 30 msec, or end-of-treatment QTc values exceeding 450 msec. Similar results were observed in 2 other Phase 3 studies with Plenaxis™ and the active-control treatments. It is unclear whether these changes were directly related to study drugs, to androgen deprivation therapy, or to other variables.</p> <h4>Special Populations</h4> <h5>Race</h5> <p>Data from Hispanics, Blacks and Caucasians demonstrated that race appeared to have no influence on the pharmacokinetics of Plenaxis™ .</p> <h5>Renal and Hepatic Insufficiency</h5> <p>The pharmacokinetics of Plenaxis™ in hepatically and/or renally impaired patients have not been determined.</p> <h5>Pediatric Use</h5> <p>There have been no studies of Plenaxis™ in pediatric patients.</p> <a name="CS"></a><h4>Clinical Studies</h4> <p>One study of Plenaxis™ was conducted in 81 men with advanced symptomatic prostate cancer who were at risk for clinical exacerbation (“clinical flare”) if treated with an LHRH agonist. The <a href="/objective/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">objective</a> of this open-label, multicenter, uncontrolled, single-arm study was to demonstrate that such patients could avoid <a href="/script/main/art.asp?articlekey=4661">orchiectomy</a> through at least 12 weeks of treatment. In this trial, treatment was to be given for at least 6 months with the option to continue treatment in an <a href="/extension/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">extension</a> trial.</p> <p>Of the 81 patients who enrolled, 9 patients from one site were excluded from the efficacy analysis due to inadequate documentation by the study investigator. The specific reasons given for enrollment of the 72 patients were: bone pain from prostate cancer skeletal metastases (n = 31); an enlarged <a href="/script/main/art.asp?articlekey=5073">prostate gland </a> or <a href="/pelvic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pelvic</a> mass causing <a href="/bladder/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bladder</a> neck <a href="/outlet/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">outlet</a> obstruction (n = 25); <a href="/bilateral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bilateral</a> retroperitoneal <a href="/adenopathy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">adenopathy</a> with ureteral obstruction (n = 9); impending neurological compromise from spinal, <a href="/script/main/art.asp?articlekey=17889">spinal cord</a>, or <a href="/epidural/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">epidural</a> metastases (n = 6); or other (n = 1). The median age was 73 years, range 40 to 94 years. There were 62 Caucasians, 6 African Americans and 4 Hispanics.</p> <p>Plenaxis™ 100 mg was administered via IM injection on Days 1, 15 and 29, then every 4 weeks thereafter. Twelve patients discontinued prior to Day 169 for the following reasons: adverse event (n=2), <a href="/voluntary/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">voluntary</a> withdrawal (n=3), death (n=4), and “other” (n=3). Sixty patients were treated for at least 24 weeks; in the extension phase, 33 patients for at least 48 weeks and 15 patients for at least 96 weeks. None (0%) of the 72 patients required orchiectomy while being treated with Plenaxis™ , including the extension phase (median combined duration of therapy was 40 weeks). However, 2 patients were withdrawn before week 12 for treatment-related adverse events (immediate-onset systemic allergic reactions consisting of <a href="/urticaria/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">urticaria</a>, and urticaria and pruritis, respectively) and received alternate therapy. In this trial, medical castration (defined as serum total testosterone concentration ≤ 50 ng/dL) was achieved in 57 of the 72 patients (79%) by Day 8, and by 68 of 71 patients (96%) by Week 4. Although the study was not designed to assess specific clinical outcomes, the following were observed:</p> <ul> <li>None (0) of 8 patients with vertebral or epidural metastases and without neurological symptoms developed neurological symptoms.</li> <li>Ten of 13 patients with <a href="/bladder_outlet_obstruction_boo/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bladder outlet obstruction</a> and a bladder drainage catheter had the <a href="/script/main/art.asp?articlekey=2646">catheter</a> removed by 12 weeks.</li> <li>Eleven of 15 patients with pain due to skeletal metastases were able to reduce the potency, dose and/or frequency of narcotic <a href="/analgesia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">analgesia</a> at 12 weeks.</li> </ul> </div> </div> </div> | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism of Action</h4> <p>Abarelix exerts its pharmacological action by directly suppressing <a href="/luteinizing_hormone/definition.htm" ">luteinizing hormone</a> (LH) and follicle stimulating hormone (FSH) secretion and thereby reducing the secretion of <a href="/testosterone/definition.htm" ">testosterone</a> by the <a href="/script/main/art.asp?articlekey=8974">testes</a>. Due to the direct inhibition of the secretion of LH by abarelix, there is no initial increase in serum testosterone concentrations. Saturation binding studies revealed that [<sup>125</sup>I]-abarelix has a very high <a href="/affinity/definition.htm" ">affinity</a> (KD = 0.1 nM) for the rat pituitary LHRH receptor.</p> <h4>Pharmacokinetics</h4> <p>A single dose (100 mg IM) of Plenaxis™ was given to 14 healthy male volunteers 52 to 75 years of age, with body weight of 61.6 to 110.5 kg, and the pharmacokinetic information is provided in Table 1</p> <p align="center"><b>Table 1: Mean ± SD Pharmacokinetic Parameter Values of 100 mg of Plenaxis™ Following a Single IM Injection (n = 14)</b><br /> <center> <table width="450" cellspacing="0" class="blacktbl"> <tr> <td class="EmphTd" width="20%">Cmax (ng/mL)</td> <td class="EmphTd" width="20%">Tmax (days)</td> <td class="EmphTd" width="20%">AUC0-∞ (ng •day/mL)</td> <td class="EmphTd" width="20%">CL/F (L/day)</td> <td class="EmphTd" width="20%">t½ (days)</td> </tr> <tr> <td align="center">43.4 ± 32.3</td> <td align="center">3.0 ± 2.9</td> <td align="center">500 ± 96</td> <td align="center">208 ± 48</td> <td align="center">13.2 ± 3.2</td> </tr> </table> </center></p> <h5>Absorption</h5> <p>Following IM administration of 100 mg of Plenaxis™ , abarelix is absorbed slowly with a mean peak concentration of 43.4 ng/mL observed approximately 3 days after the injection.</p> <h5>Distribution</h5> <p>The apparent volume of distribution during the terminal phase determined after IM administration of Plenaxis™ was 4040 ± 1607 liters, implying that abarelix probably distributes extensively within the body.</p> <h5>Metabolism</h5> <p><i>In vitro</i> hepatocyte (rat, monkey, human) studies and in vivo studies in rats and monkeys showed that the major metabolites of abarelix were formed via hydrolysis of peptide bonds. No significant oxidative or conjugated metabolites of abarelix were found either <i>in vitro </i>or in vivo. There is no evidence of cytochrome P-450 involvement in the metabolism of abarelix.</p> <h5>Excretion</h5> <p>In humans, approximately 13% of unchanged abarelix was recovered in <a href="/script/main/art.asp?articlekey=5915">urine</a> after a 15 μg/kg IM injection; there were no detectable metabolites in urine. Renal clearance of abarelix was 14.4 L/day (or 10 mL/min) after administration of 100 mg Plenaxis™ .</p> <h4>Pharmacodynamics</h4> <p><b><i>Effects of Plenaxis™ on Serum Testosterone</i>: </b>The effectiveness of Plenaxis™ in suppressing serum testosterone was studied in two randomized, open-label, activecomparator trials. Patients were not those with advanced symptomatic <a href="/script/main/art.asp?articlekey=5072">prostate cancer</a>. They were randomized in a 2:1 ratio to Plenaxis™ 100 mg IM versus <a href="/lhrh_agonist/definition.htm" ">LHRH agonist</a> (Study 1) or to Plenaxis™ versus LHRH <a href="/agonist/definition.htm" ">agonist</a> + nonsteroidal <a href="/antiandrogen/definition.htm" ">antiandrogen</a> (Study 2). Plenaxis™ was administered IM on Days 1, 15, 29 (Week 4), then every 4 weeks thereafter for at least 6 months (24 weeks). LHRH agonist and nonsteroidal antiandrogen were administered in standard fashion. After completing 6 months of treatment, patients could continue randomized treatment for an additional 6 months.</p> <p><b><i>Avoidance of testosterone surge</i>:</b> In both studies combined, 100% (348/348) of Plenaxis™ patients and 16% (28/172) of comparator patients avoided a testosterone surge.</p> <p><b><i>Attainment of medical castration</i>:</b> The percentage of patients who attained serum testosterone concentration ≤ 50 ng/dL on Study Days 2, 8, 15 and 29 are summarized in the table below:</p> <p align="center"><b>Table 2: Percentage of patients who attained medical castration (serum testosterone concentration ≤ 50 ng/dL) in Studies 1 and 2.</b><br /> <center> <table width="450" cellspacing="0" class="blacktbl"> <tr> <td class="EmphTd" rowspan="2" width="40%">Day</td> <td class="EmphTd" colspan="2">Plenaxis™ </td> </tr> <tr> <td class="EmphTd" width="30%">Total N</td> <td class="EmphTd" width="30%">% Castrate</td> </tr> <tr> <td align="center">2</td> <td align="center">339</td> <td align="center">24</td> </tr> <tr> <td align="center">4</td> <td align="center">333</td> <td align="center">56</td> </tr> <tr> <td align="center">8</td> <td align="center">348</td> <td align="center">70</td> </tr> <tr> <td align="center">15</td> <td align="center">347</td> <td align="center">73</td> </tr> <tr> <td align="center">29</td> <td align="center">347</td> <td align="center">94</td> </tr> </table> </center></p> <p><b><i>Attainment and maintenance of medical castration</i>:</b> Successful response was defined as attainment of medical castration on Day 29 and maintenance through Day 85 (where no two consecutive serum testosterone concentrations between Days 29 and 85 were greater than 50 ng/dL). In Study 1, 92% on Plenaxis™ patients responded and 96% of LHRH agonist patients responded. In Study 2, 93% of Plenaxis™ patients and 95% of LHRH agonist + nonsteroidal antiandrogen patients responded.</p> <p>However, when failure was defined as any observed serum testosterone > 50 ng/Dl (including transient elevations) just prior to dosing on Day 29 and every 28 days thereafter, effectiveness of testosterone suppression decreased over time. Results of this analysis are summarized in Table 3.</p> <p align="center"><b>Table 3: Percentage of patients who attained and maintained medical castration; [no serum testosterone > 50 ng/dL just prior to dosing on Day 29 and every 28 days thereafter]</b><br /> <center> <table width="450" cellspacing="0" class="blacktbl"> <tr> <td class="EmphTd" width="20%">Day</td> <td class="EmphTd" width="20%">Study 1 Plenaxis™ </td> <td class="EmphTd" width="20%">N</td> <td class="EmphTd" width="20%">Study 2 Plenaxis™ </td> <td class="EmphTd" width="20%">N</td> </tr> <tr> <td align="center">85</td> <td align="center">84%</td> <td align="center">176</td> <td align="center">92%</td> <td align="center">164</td> </tr> <tr> <td align="center">169</td> <td align="center">75%</td> <td align="center">166</td> <td align="center">87%</td> <td align="center">155</td> </tr> <tr> <td align="center">365</td> <td align="center">62%</td> <td align="center">93</td> <td align="center">71%</td> <td align="center">86</td> </tr> </table> </center></p> <p><b><i>Effects of Plenaxis™ on Cardiac Electrophysiology</i></b>: In a single, active-controlled, clinical study comparing Plenaxis™ to LHRH agonist + nonsteroidal antiandrogen, periodic electrocardiograms were performed. Both therapies prolonged the mean Fridericia-corrected QT interval by > 10 msec from baseline. In approximately 20% of patients in both groups, there were either changes from baseline QTc of > 30 msec, or end-of-treatment QTc values exceeding 450 msec. Similar results were observed in 2 other Phase 3 studies with Plenaxis™ and the active-control treatments. It is unclear whether these changes were directly related to study drugs, to androgen deprivation therapy, or to other variables.</p> <h4>Special Populations</h4> <h5>Race</h5> <p>Data from Hispanics, Blacks and Caucasians demonstrated that race appeared to have no influence on the pharmacokinetics of Plenaxis™ .</p> <h5>Renal and Hepatic Insufficiency</h5> <p>The pharmacokinetics of Plenaxis™ in hepatically and/or renally impaired patients have not been determined.</p> <h5>Pediatric Use</h5> <p>There have been no studies of Plenaxis™ in pediatric patients.</p> <a name="CS"></a><h4>Clinical Studies</h4> <p>One study of Plenaxis™ was conducted in 81 men with advanced symptomatic prostate cancer who were at risk for clinical exacerbation (“clinical flare”) if treated with an LHRH agonist. The <a href="/objective/definition.htm" ">objective</a> of this open-label, multicenter, uncontrolled, single-arm study was to demonstrate that such patients could avoid <a href="/script/main/art.asp?articlekey=4661">orchiectomy</a> through at least 12 weeks of treatment. In this trial, treatment was to be given for at least 6 months with the option to continue treatment in an <a href="/extension/definition.htm" ">extension</a> trial.</p> <p>Of the 81 patients who enrolled, 9 patients from one site were excluded from the efficacy analysis due to inadequate documentation by the study investigator. The specific reasons given for enrollment of the 72 patients were: bone pain from prostate cancer skeletal metastases (n = 31); an enlarged <a href="/script/main/art.asp?articlekey=5073">prostate gland </a> or <a href="/pelvic/definition.htm" ">pelvic</a> mass causing <a href="/bladder/definition.htm" ">bladder</a> neck <a href="/outlet/definition.htm" ">outlet</a> obstruction (n = 25); <a href="/bilateral/definition.htm" ">bilateral</a> retroperitoneal <a href="/adenopathy/definition.htm" ">adenopathy</a> with ureteral obstruction (n = 9); impending neurological compromise from spinal, <a href="/script/main/art.asp?articlekey=17889">spinal cord</a>, or <a href="/epidural/definition.htm" ">epidural</a> metastases (n = 6); or other (n = 1). The median age was 73 years, range 40 to 94 years. There were 62 Caucasians, 6 African Americans and 4 Hispanics.</p> <p>Plenaxis™ 100 mg was administered via IM injection on Days 1, 15 and 29, then every 4 weeks thereafter. Twelve patients discontinued prior to Day 169 for the following reasons: adverse event (n=2), <a href="/voluntary/definition.htm" ">voluntary</a> withdrawal (n=3), death (n=4), and “other” (n=3). Sixty patients were treated for at least 24 weeks; in the extension phase, 33 patients for at least 48 weeks and 15 patients for at least 96 weeks. None (0%) of the 72 patients required orchiectomy while being treated with Plenaxis™ , including the extension phase (median combined duration of therapy was 40 weeks). However, 2 patients were withdrawn before week 12 for treatment-related adverse events (immediate-onset systemic allergic reactions consisting of <a href="/urticaria/definition.htm" ">urticaria</a>, and urticaria and pruritis, respectively) and received alternate therapy. In this trial, medical castration (defined as serum total testosterone concentration ≤ 50 ng/dL) was achieved in 57 of the 72 patients (79%) by Day 8, and by 68 of 71 patients (96%) by Week 4. Although the study was not designed to assess specific clinical outcomes, the following were observed:</p> <ul> <li>None (0) of 8 patients with vertebral or epidural metastases and without neurological symptoms developed neurological symptoms.</li> <li>Ten of 13 patients with <a href="/bladder_outlet_obstruction_boo/definition.htm" ">bladder outlet obstruction</a> and a bladder drainage catheter had the <a href="/script/main/art.asp?articlekey=2646">catheter</a> removed by 12 weeks.</li> <li>Eleven of 15 patients with pain due to skeletal metastases were able to reduce the potency, dose and/or frequency of narcotic <a href="/analgesia/definition.htm" ">analgesia</a> at 12 weeks.</li> </ul> </div> </div> </div> | 9 | 2023-02-01 17:39:09 | Abarelix (Plenaxis) | A | Gonadotropin Releasing Hormone Antagonists | Plenaxis | abarelix | Plenaxis | John P. Cunha, DO, FACOEP |
| 70 | 2023-02-23 12:07:03 | Medication Guide | <a name="PI"></a><h3>PATIENT INFORMATION</h3> <p><b>Plenaxis™ </b><br /> (plen·AK·sis)<br /> (abarelix for injectable suspension)</p> <p>Read the Patient Information that comes with PlenaxisTM before you start getting injections. Sign the last page if you agree with treatment with Plenaxis™ . (Your signature will be required to start treatment.)</p> <p><b>What is the most important information I should know about Plenaxis™ ?</b></p> <ul> <li><b>Plenaxis™ can cause serious or life threatening allergic reactions that may need emergency medical treatment right away. </b>These serious reactions may include: <ul> <li><a href="/script/main/art.asp?articlekey=7670">low blood pressure</a> and <a href="/script/main/art.asp?articlekey=7661">fainting</a> (<a href="/script/main/art.asp?articlekey=5477">shock</a>)</li> <li>swelling of your face, eyelids, <a href="/script/main/art.asp?articlekey=9075">tongue</a>, or <a href="/script/main/art.asp?articlekey=53392">throat</a></li> <li><a href="/script/main/art.asp?articlekey=2373">asthma</a>, <a href="/script/main/art.asp?articlekey=9401">wheezing</a>, or other <a href="/script/main/art.asp?articlekey=11056">breathing</a> problems such as chest tightness or <a href="/script/main/art.asp?articlekey=97560">shortness of breath</a></li> </ul> </li> </ul> <p>Your chances of getting a serious or life threatening <a href="/script/main/art.asp?articlekey=2196">allergic reaction</a> may increase with each Plenaxis™ injection that you get.</p> <p>If a serious or life threatening allergic reaction happens, it is usually soon after getting a Plenaxis™ injection. <b>Therefore, you must wait in your doctor's office or health care facility for 30 minutes after each Plenaxis™ injection.</b> Tell your doctor right away if you feel any warmth, redness, light-headedness, swelling or thickness in your throat. This could mean you are having a serious allergic reaction.</p> <ul> <li><b>Only doctors signed up with PRAECIS PHARMACEUTICALS INCORPORATED can prescribe PlenaxisTM because they know about treating prostate cancer and allergic reactions from Plenaxis™ .</b></li> <li><b>Plenaxis™ is only for treating advanced prostate cancer when a patient cannot have or refuses other treatments for prostate cancer, such as other hormone treatments or surgery to remove the testicles, and there are serious symptoms from the prostate cancer such as the cancer is near or pressing on the spinal cord, causing problems urinating or blockage of urine from the kidneys or bladder, or there is very bad bone pain even when taking narcotic pain medicines.</b></li> <li><b>Plenaxis™ may not keep working for everyone over time, so doctors should do blood tests about every 8 weeks to make sure Plenaxis™ is working by keeping your testosterone hormone level low.</b></li> </ul> <p><b>What is Plenaxis™ ?</b></p> <p>Plenaxis™ is a type of medicine called a gonadotropin-releasing hormone (GnRH) antagonist that lowers the male hormone testosterone in your blood. Testosterone makes most prostate cancers grow. Other ways to treat your prostate cancer are taking other hormone medicines to lower testosterone or surgery to remove your <a href="/testicles/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">testicles</a>. Plenaxis™ is used when these other ways to treat prostate cancer cannot be used or are refused.</p> <p><b>Who should not take Plenaxis™ ?</b></p> <p><b>Do not take Plenaxis™ </b> if you are:</p> <ul> <li><b>a woman.</b> There is no approved use of Plenaxis™ in women. Plenaxis™ can cause serious allergic reactions. Plenaxis™ can cause the death of an unborn child in a pregnant woman. Plenaxis™ may also pass into breast milk.</li> <li><b>a child under the age of 18 years.</b> There are no studies that show that Plenaxis™ is safe or effective for use in children for any condition.</li> <li><b>allergic to any of the ingredients in Plenaxis™ .</b> The ingredients include abarelix and carboxymethylcellulose. The mixing solution contains sodium chloride.</li> </ul> <p><b>Tell your doctor before taking a Plenaxis™ injection:</b></p> <ul> <li>if you or any family members have a rare heart condition known as prolongation of the QTc interval</li> <li>about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Plenaxis™ has not been studied with other medicines. Plenaxis™ and some of your other medicines may affect each other and could cause side effects.</li> </ul> <p><b>How do I take Plenaxis™ ?</b></p> <p>Plenaxis™ is only prescribed by doctors who are part of the Plenaxis™ PLUS Program (Plenaxis™ User Safety Program) run by PRAECIS PHARMACEUTICALS INCORPORATED.</p> <ul> <li>Plenaxis™ is given as an injection in your buttocks. Your doctor or nurse gives a Plenaxis™ injection every two weeks for the first month, and then every four weeks (every 28 days). It is important that you keep your appointment with your doctor's office for the times when your injection is due.</li> </ul> <p>Always wait in your doctor's office for <b>30 minutes</b> after getting each Plenaxis™ injection. (See “What is the most important information I should know about Plenaxis™ ?”)</p> <p>Your doctor should do regular blood tests about every 8 weeks to check your testosterone level to see if Plenaxis™ is working for you. If you weigh more than 225 pounds, there may be a greater chance that Plenaxis™ may stop working. Your doctor should also do blood tests to check on your liver because Plenaxis™ may cause changes in your liver tests.</p> <p><b>What are the possible side effects of Plenaxis™ ?</b></p> <p><b>Plenaxis™ can cause:</b></p> <ul> <li><b>serious allergic or life threatening reactions.</b> (See “What is the most important information I should know about Plenaxis™ ?”)</li> <li><b>allergic skin reactions</b> such as a <a href="/script/main/art.asp?articlekey=5209">rash</a>, <a href="/script/main/art.asp?articlekey=3770">hives</a>, <a href="/script/main/art.asp?articlekey=4060">itching</a>, tingling, and redness (flushing). A skin reaction may happen right away after injection with Plenaxis™ or several days later. Tell your doctor right away if you get an allergic skin reaction or rash after a Plenaxis™ injection.</li> <li><b>a change in heart rhythm called prolongation of the QTc interval.</b> This condition may change the way your heart beats, cause fainting and even death in some patients.</li> <li><b>changes in liver function, which usually go away after you stop taking Plenaxis™ .</b> Your doctor should do blood tests to check your liver function before you start getting Plenaxis™ and during your treatment with it.</li> <li><b>loss in bone mineral density with extended treatment.</b> Low bone mineral density can lead to thinning of the bones (<a href="/script/main/art.asp?articlekey=4686">osteoporosis</a>).</li> </ul> <p>The most common side effects of Plenaxis™ are:</p> <ul> <li><a href="/script/main/art.asp?articlekey=7322">hot flashes</a></li> <li>problems sleeping</li> <li>pain, including <a href="/script/main/art.asp?articlekey=25125">back pain</a></li> <li>breast enlargement or <a href="/script/main/art.asp?articlekey=9886">breast pain</a></li> <li>constipation</li> </ul> <p>Talk to your doctor if you get a side effect that bothers you.</p> <p>These are not all the possible side effects of Plenaxis™ . For more information ask your doctor.</p> <p><b>General Information about Plenaxis™ </b></p> <p>This leaflet summarizes the most important information about Plenaxis™ . If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Plenaxis™ that is written for health professionals.</p> <p><b>Patient Signature for Treatment with Plenaxis™ </b></p> <ul> <li>I have read and understood the Patient Information leaflet. My doctor has answered my questions about treatment with Plenaxis™ for treating advanced prostate cancer.</li> <li>I cannot have or refuse treatments for my prostate cancer, such as other hormone treatments or surgery to remove my testicles, and my doctor has told me I have serious signs and/or symptoms from my prostate cancer such as the cancer is near or pressing on the spinal <a href="/cord/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cord</a>, or it is causing problems urinating or blockage of urine from the kidneys or bladder, or I have very bad bone pain even when taking <a href="/script/main/art.asp?articlekey=23586">narcotic</a> pain medicines.</li> <li>Plenaxis™ can cause serious allergic reactions right after an injection. Therefore, after each injection I will wait in my doctor's office or health care facility for 30 minutes so if I have a serious allergic reaction, I can be treated.</li> <li>I know that my doctor should be getting blood tests to check my testosterone level about every 8 weeks to check if Plenaxis™ is working for me.</li> <li>I understand that I can only get Plenaxis™ from doctors who have signed up with the company that makes Plenaxis™ .</li> </ul> <p>My <a href="/signature/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">signature</a> shows that I have read, understood and agree with all the statements above. I allow my doctor to begin treatment with Plenaxis™ . I only need to sign this page one time to start my treatment.</p> <p>Name of Patient (Print):________________________________________________</p> <p>Signature of Patient:________________________________Date:_______________</p> <p>Name of Physician (Print):_______________________________________________</p> <p>Signature of Physician ____________________________Date:_________________</p> <p><b>Instructions to Physician:</b></p> <p>As part of beginning Plenaxis™ treatment, give the patient a copy of the entire leaflet with the signed page, and put the original patient signature page in the patient's medical chart.</p> <p class="source">This information leaflet has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | <a name="PI"></a><h3>PATIENT INFORMATION</h3> <p><b>Plenaxis™ </b><br /> (plen·AK·sis)<br /> (abarelix for injectable suspension)</p> <p>Read the Patient Information that comes with PlenaxisTM before you start getting injections. Sign the last page if you agree with treatment with Plenaxis™ . (Your signature will be required to start treatment.)</p> <p><b>What is the most important information I should know about Plenaxis™ ?</b></p> <ul> <li><b>Plenaxis™ can cause serious or life threatening allergic reactions that may need emergency medical treatment right away. </b>These serious reactions may include: <ul> <li><a href="/script/main/art.asp?articlekey=7670">low blood pressure</a> and <a href="/script/main/art.asp?articlekey=7661">fainting</a> (<a href="/script/main/art.asp?articlekey=5477">shock</a>)</li> <li>swelling of your face, eyelids, <a href="/script/main/art.asp?articlekey=9075">tongue</a>, or <a href="/script/main/art.asp?articlekey=53392">throat</a></li> <li><a href="/script/main/art.asp?articlekey=2373">asthma</a>, <a href="/script/main/art.asp?articlekey=9401">wheezing</a>, or other <a href="/script/main/art.asp?articlekey=11056">breathing</a> problems such as chest tightness or <a href="/script/main/art.asp?articlekey=97560">shortness of breath</a></li> </ul> </li> </ul> <p>Your chances of getting a serious or life threatening <a href="/script/main/art.asp?articlekey=2196">allergic reaction</a> may increase with each Plenaxis™ injection that you get.</p> <p>If a serious or life threatening allergic reaction happens, it is usually soon after getting a Plenaxis™ injection. <b>Therefore, you must wait in your doctor's office or health care facility for 30 minutes after each Plenaxis™ injection.</b> Tell your doctor right away if you feel any warmth, redness, light-headedness, swelling or thickness in your throat. This could mean you are having a serious allergic reaction.</p> <ul> <li><b>Only doctors signed up with PRAECIS PHARMACEUTICALS INCORPORATED can prescribe PlenaxisTM because they know about treating prostate cancer and allergic reactions from Plenaxis™ .</b></li> <li><b>Plenaxis™ is only for treating advanced prostate cancer when a patient cannot have or refuses other treatments for prostate cancer, such as other hormone treatments or surgery to remove the testicles, and there are serious symptoms from the prostate cancer such as the cancer is near or pressing on the spinal cord, causing problems urinating or blockage of urine from the kidneys or bladder, or there is very bad bone pain even when taking narcotic pain medicines.</b></li> <li><b>Plenaxis™ may not keep working for everyone over time, so doctors should do blood tests about every 8 weeks to make sure Plenaxis™ is working by keeping your testosterone hormone level low.</b></li> </ul> <p><b>What is Plenaxis™ ?</b></p> <p>Plenaxis™ is a type of medicine called a gonadotropin-releasing hormone (GnRH) antagonist that lowers the male hormone testosterone in your blood. Testosterone makes most prostate cancers grow. Other ways to treat your prostate cancer are taking other hormone medicines to lower testosterone or surgery to remove your <a href="/testicles/definition.htm" ">testicles</a>. Plenaxis™ is used when these other ways to treat prostate cancer cannot be used or are refused.</p> <p><b>Who should not take Plenaxis™ ?</b></p> <p><b>Do not take Plenaxis™ </b> if you are:</p> <ul> <li><b>a woman.</b> There is no approved use of Plenaxis™ in women. Plenaxis™ can cause serious allergic reactions. Plenaxis™ can cause the death of an unborn child in a pregnant woman. Plenaxis™ may also pass into breast milk.</li> <li><b>a child under the age of 18 years.</b> There are no studies that show that Plenaxis™ is safe or effective for use in children for any condition.</li> <li><b>allergic to any of the ingredients in Plenaxis™ .</b> The ingredients include abarelix and carboxymethylcellulose. The mixing solution contains sodium chloride.</li> </ul> <p><b>Tell your doctor before taking a Plenaxis™ injection:</b></p> <ul> <li>if you or any family members have a rare heart condition known as prolongation of the QTc interval</li> <li>about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Plenaxis™ has not been studied with other medicines. Plenaxis™ and some of your other medicines may affect each other and could cause side effects.</li> </ul> <p><b>How do I take Plenaxis™ ?</b></p> <p>Plenaxis™ is only prescribed by doctors who are part of the Plenaxis™ PLUS Program (Plenaxis™ User Safety Program) run by PRAECIS PHARMACEUTICALS INCORPORATED.</p> <ul> <li>Plenaxis™ is given as an injection in your buttocks. Your doctor or nurse gives a Plenaxis™ injection every two weeks for the first month, and then every four weeks (every 28 days). It is important that you keep your appointment with your doctor's office for the times when your injection is due.</li> </ul> <p>Always wait in your doctor's office for <b>30 minutes</b> after getting each Plenaxis™ injection. (See “What is the most important information I should know about Plenaxis™ ?”)</p> <p>Your doctor should do regular blood tests about every 8 weeks to check your testosterone level to see if Plenaxis™ is working for you. If you weigh more than 225 pounds, there may be a greater chance that Plenaxis™ may stop working. Your doctor should also do blood tests to check on your liver because Plenaxis™ may cause changes in your liver tests.</p> <p><b>What are the possible side effects of Plenaxis™ ?</b></p> <p><b>Plenaxis™ can cause:</b></p> <ul> <li><b>serious allergic or life threatening reactions.</b> (See “What is the most important information I should know about Plenaxis™ ?”)</li> <li><b>allergic skin reactions</b> such as a <a href="/script/main/art.asp?articlekey=5209">rash</a>, <a href="/script/main/art.asp?articlekey=3770">hives</a>, <a href="/script/main/art.asp?articlekey=4060">itching</a>, tingling, and redness (flushing). A skin reaction may happen right away after injection with Plenaxis™ or several days later. Tell your doctor right away if you get an allergic skin reaction or rash after a Plenaxis™ injection.</li> <li><b>a change in heart rhythm called prolongation of the QTc interval.</b> This condition may change the way your heart beats, cause fainting and even death in some patients.</li> <li><b>changes in liver function, which usually go away after you stop taking Plenaxis™ .</b> Your doctor should do blood tests to check your liver function before you start getting Plenaxis™ and during your treatment with it.</li> <li><b>loss in bone mineral density with extended treatment.</b> Low bone mineral density can lead to thinning of the bones (<a href="/script/main/art.asp?articlekey=4686">osteoporosis</a>).</li> </ul> <p>The most common side effects of Plenaxis™ are:</p> <ul> <li><a href="/script/main/art.asp?articlekey=7322">hot flashes</a></li> <li>problems sleeping</li> <li>pain, including <a href="/script/main/art.asp?articlekey=25125">back pain</a></li> <li>breast enlargement or <a href="/script/main/art.asp?articlekey=9886">breast pain</a></li> <li>constipation</li> </ul> <p>Talk to your doctor if you get a side effect that bothers you.</p> <p>These are not all the possible side effects of Plenaxis™ . For more information ask your doctor.</p> <p><b>General Information about Plenaxis™ </b></p> <p>This leaflet summarizes the most important information about Plenaxis™ . If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Plenaxis™ that is written for health professionals.</p> <p><b>Patient Signature for Treatment with Plenaxis™ </b></p> <ul> <li>I have read and understood the Patient Information leaflet. My doctor has answered my questions about treatment with Plenaxis™ for treating advanced prostate cancer.</li> <li>I cannot have or refuse treatments for my prostate cancer, such as other hormone treatments or surgery to remove my testicles, and my doctor has told me I have serious signs and/or symptoms from my prostate cancer such as the cancer is near or pressing on the spinal <a href="/cord/definition.htm" ">cord</a>, or it is causing problems urinating or blockage of urine from the kidneys or bladder, or I have very bad bone pain even when taking <a href="/script/main/art.asp?articlekey=23586">narcotic</a> pain medicines.</li> <li>Plenaxis™ can cause serious allergic reactions right after an injection. Therefore, after each injection I will wait in my doctor's office or health care facility for 30 minutes so if I have a serious allergic reaction, I can be treated.</li> <li>I know that my doctor should be getting blood tests to check my testosterone level about every 8 weeks to check if Plenaxis™ is working for me.</li> <li>I understand that I can only get Plenaxis™ from doctors who have signed up with the company that makes Plenaxis™ .</li> </ul> <p>My <a href="/signature/definition.htm" ">signature</a> shows that I have read, understood and agree with all the statements above. I allow my doctor to begin treatment with Plenaxis™ . I only need to sign this page one time to start my treatment.</p> <p>Name of Patient (Print):________________________________________________</p> <p>Signature of Patient:________________________________Date:_______________</p> <p>Name of Physician (Print):_______________________________________________</p> <p>Signature of Physician ____________________________Date:_________________</p> <p><b>Instructions to Physician:</b></p> <p>As part of beginning Plenaxis™ treatment, give the patient a copy of the entire leaflet with the signed page, and put the original patient signature page in the patient's medical chart.</p> <p class="source">This information leaflet has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | 9 | 2023-02-01 17:39:09 | Abarelix (Plenaxis) | A | Gonadotropin Releasing Hormone Antagonists | Plenaxis | abarelix | Plenaxis | John P. Cunha, DO, FACOEP |
| 71 | 2023-02-23 12:07:03 | Drug Description | <h4>What is Orencia and how is it used?</h4> <p>Orencia is a prescription medicine used to treat the symptoms of Moderate-to-Severe <a href="/rheumatoid_arthritis_ra_medications/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">Rheumatoid Arthritis</a> and Psoriatic <a href="/arthritis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Arthritis</a>. Orencia may be used alone or with other medications.</p> <p>Orencia belongs to a class of drugs called DMARDs, Immunomodulators; Immunosuppressants.</p> <p>It is not known if Orencia is safe and effective in children younger than 2 years of age.</p> <h4>What are the possible side effects of Orencia?</h4> <p>Orencia may cause serious side effects including:</p> <ul> <li>fever,</li> <li>chills,</li> <li><a href="/night_sweats/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">night sweats</a>,</li> <li>flu symptoms,</li> <li>weight loss,</li> <li>feeling very tired,</li> <li>dry cough,</li> <li><a href="/sore_throat_pharyngitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">sore throat</a>,</li> <li>warmth, pain or redness of your skin</li> <li>trouble breathing,</li> <li>stabbing chest pain,</li> <li><a href="/wheezing/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">wheezing</a>,</li> <li>cough with yellow or green mucus,</li> <li>pain or burning when you urinate, and</li> <li>signs of skin infection such as itching, swelling, warmth, redness, or oozing</li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Orencia include:</p> <ul> <li>fever,</li> <li>nausea,</li> <li>diarrhea,</li> <li>stomach pain,</li> <li>headache, and</li> <li>cold symptoms (<a href="/stuffy_nose/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">stuffy nose</a>, sneezing, <a href="/sore/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">sore</a> throat, cough)</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Orencia. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <p><a name="D"></a></p> <h3>DESCRIPTION</h3> <p>ORENCIA® (abatacept) is a selective <a href="/script/main/art.asp?articlekey=11300" onclick="wmdTrack('embd-lnk');" rel="dict">T cell</a> costimulation modulator. ORENCIA is a soluble fusion protein that consists of the <a href="/script/main/art.asp?articlekey=24384" onclick="wmdTrack('embd-lnk');" rel="dict">extracellular</a> <a href="/script/main/art.asp?articlekey=3104" onclick="wmdTrack('embd-lnk');" rel="dict">domain</a> of human <a href="/script/main/art.asp?articlekey=19883" onclick="wmdTrack('embd-lnk');" rel="dict">cytotoxic</a> T-lymphocyteassociated <a href="/script/main/art.asp?articlekey=2282" onclick="wmdTrack('embd-lnk');" rel="dict">antigen</a> 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human <a href="/script/main/art.asp?articlekey=12077" onclick="wmdTrack('embd-lnk');" rel="dict">immunoglobulin</a> G1 (IgG1). Abatacept is produced by <a href="/script/main/art.asp?articlekey=5247" onclick="wmdTrack('embd-lnk');" rel="dict">recombinant DNA technology</a> in a mammalian cell expression system. The apparent molecular weight of abatacept is 92 kilodaltons.</p> <p>ORENCIA for Injection is a lyophilized powder for intravenous infusion. ORENCIA for Injection is supplied as a sterile, white, preservative-free, lyophilized powder for reconstitution and dilution prior to intravenous administration. Following reconstitution of the lyophilized powder with 10 mL of Sterile Water for Injection, USP, the solution of ORENCIA is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial of ORENCIA for Injection provides 250 mg abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and sodium chloride (14.6 mg) for administration.</p> <p>ORENCIA Injection is a sterile, preservative-free, clear to slightly opalescent, colorless to paleyellow solution with a pH range of 6.8 to 7.4 for subcutaneous administration. ORENCIA Injection is supplied as a single-dose prefilled syringe or as a single-dose ClickJect autoinjector (see Table 4).</p> <p align="center"><b>Table 4: Contents of ORENCIA Subcutaneous Injection</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="25%">Presentation</td> <td class="EmphTd" width="25%">Active Ingredient Quantity and Label Volume</td> <td class="EmphTd" width="50%">Inactive Ingredient Content</td> </tr> <tr> <td>ORENCIA Injection 50 mg/0.4 mL Prefilled Syringe</td> <td align="center">50 mg of abatacept in 0.4 mL of solution</td> <td align="center">dibasic sodium phosphate anhydrous (0.335 mg) monobasic sodium phosphate monohydrate (0.114 mg) poloxamer 188 (3.2 mg) sucrose (68 mg) qs to 0.4 mL water for injection</td> </tr> <tr> <td>ORENCIA Injection 87.5 mg/0.7 mL Prefilled Syringe</td> <td align="center">87.5 mg of abatacept in 0.7 mL of solution</td> <td align="center">dibasic sodium phosphate anhydrous (0.587 mg) monobasic sodium phosphate monohydrate (0.200 mg) poloxamer 188 (5.6 mg) sucrose (119 mg) qs to 0.7 mL water for injection</td> </tr> </tbody> </table> </center> <p></p> <p>Unlike the lyophilized formulation for intravenous use, the ORENCIA solutions for subcutaneous administration contain no maltose.</p> </div> <div id="667441035-1" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-1", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <h4>What is Orencia and how is it used?</h4> <p>Orencia is a prescription medicine used to treat the symptoms of Moderate-to-Severe <a href="/rheumatoid_arthritis_ra_medications/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">Rheumatoid Arthritis</a> and Psoriatic <a href="/arthritis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Arthritis</a>. Orencia may be used alone or with other medications.</p> <p>Orencia belongs to a class of drugs called DMARDs, Immunomodulators; Immunosuppressants.</p> <p>It is not known if Orencia is safe and effective in children younger than 2 years of age.</p> <h4>What are the possible side effects of Orencia?</h4> <p>Orencia may cause serious side effects including:</p> <ul> <li>fever,</li> <li>chills,</li> <li><a href="/night_sweats/definition.htm" ">night sweats</a>,</li> <li>flu symptoms,</li> <li>weight loss,</li> <li>feeling very tired,</li> <li>dry cough,</li> <li><a href="/sore_throat_pharyngitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">sore throat</a>,</li> <li>warmth, pain or redness of your skin</li> <li>trouble breathing,</li> <li>stabbing chest pain,</li> <li><a href="/wheezing/definition.htm" ">wheezing</a>,</li> <li>cough with yellow or green mucus,</li> <li>pain or burning when you urinate, and</li> <li>signs of skin infection such as itching, swelling, warmth, redness, or oozing</li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Orencia include:</p> <ul> <li>fever,</li> <li>nausea,</li> <li>diarrhea,</li> <li>stomach pain,</li> <li>headache, and</li> <li>cold symptoms (<a href="/stuffy_nose/definition.htm" ">stuffy nose</a>, sneezing, <a href="/sore/definition.htm" ">sore</a> throat, cough)</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Orencia. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <p><a name="D"></a></p> <h3>DESCRIPTION</h3> <p>ORENCIA® (abatacept) is a selective <a href="/script/main/art.asp?articlekey=11300" onclick="wmdTrack('embd-lnk');" rel="dict">T cell</a> costimulation modulator. ORENCIA is a soluble fusion protein that consists of the <a href="/script/main/art.asp?articlekey=24384" onclick="wmdTrack('embd-lnk');" rel="dict">extracellular</a> <a href="/script/main/art.asp?articlekey=3104" onclick="wmdTrack('embd-lnk');" rel="dict">domain</a> of human <a href="/script/main/art.asp?articlekey=19883" onclick="wmdTrack('embd-lnk');" rel="dict">cytotoxic</a> T-lymphocyteassociated <a href="/script/main/art.asp?articlekey=2282" onclick="wmdTrack('embd-lnk');" rel="dict">antigen</a> 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human <a href="/script/main/art.asp?articlekey=12077" onclick="wmdTrack('embd-lnk');" rel="dict">immunoglobulin</a> G1 (IgG1). Abatacept is produced by <a href="/script/main/art.asp?articlekey=5247" onclick="wmdTrack('embd-lnk');" rel="dict">recombinant DNA technology</a> in a mammalian cell expression system. The apparent molecular weight of abatacept is 92 kilodaltons.</p> <p>ORENCIA for Injection is a lyophilized powder for intravenous infusion. ORENCIA for Injection is supplied as a sterile, white, preservative-free, lyophilized powder for reconstitution and dilution prior to intravenous administration. Following reconstitution of the lyophilized powder with 10 mL of Sterile Water for Injection, USP, the solution of ORENCIA is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial of ORENCIA for Injection provides 250 mg abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and sodium chloride (14.6 mg) for administration.</p> <p>ORENCIA Injection is a sterile, preservative-free, clear to slightly opalescent, colorless to paleyellow solution with a pH range of 6.8 to 7.4 for subcutaneous administration. ORENCIA Injection is supplied as a single-dose prefilled syringe or as a single-dose ClickJect autoinjector (see Table 4).</p> <p align="center"><b>Table 4: Contents of ORENCIA Subcutaneous Injection</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="25%">Presentation</td> <td class="EmphTd" width="25%">Active Ingredient Quantity and Label Volume</td> <td class="EmphTd" width="50%">Inactive Ingredient Content</td> </tr> <tr> <td>ORENCIA Injection 50 mg/0.4 mL Prefilled Syringe</td> <td align="center">50 mg of abatacept in 0.4 mL of solution</td> <td align="center">dibasic sodium phosphate anhydrous (0.335 mg) monobasic sodium phosphate monohydrate (0.114 mg) poloxamer 188 (3.2 mg) sucrose (68 mg) qs to 0.4 mL water for injection</td> </tr> <tr> <td>ORENCIA Injection 87.5 mg/0.7 mL Prefilled Syringe</td> <td align="center">87.5 mg of abatacept in 0.7 mL of solution</td> <td align="center">dibasic sodium phosphate anhydrous (0.587 mg) monobasic sodium phosphate monohydrate (0.200 mg) poloxamer 188 (5.6 mg) sucrose (119 mg) qs to 0.7 mL water for injection</td> </tr> </tbody> </table> </center> <p></p> <p>Unlike the lyophilized formulation for intravenous use, the ORENCIA solutions for subcutaneous administration contain no maltose.</p> </div> <div id="667441035-1" class="medianet"><</div> </div> </div> | 10 | 2023-02-01 17:39:31 | Abatacept (Orencia) | A | DMARDs, Immunomodulators | Orencia | abatacept | Orencia | |
| 72 | 2023-02-23 12:07:03 | Indications | <a name="I"></a> <h3>INDICATIONS</h3> <h4>Adult Rheumatoid Arthritis</h4> <p>ORENCIA® is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis.</p> <h4>Polyarticular Juvenile Idiopathic Arthritis</h4> <p>ORENCIA is indicated for the treatment of patients 2 years of age and older with moderately to severely active <a href="/polyarticular/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">polyarticular</a> juvenile <a href="/idiopathic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">idiopathic</a> arthritis.</p> <h4>Adult Psoriatic Arthritis</h4> <p>ORENCIA is indicated for the treatment of adult patients with active <a href="/psoriatic_arthritis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">psoriatic arthritis</a> (PsA).</p> <h4>Prophylaxis For Acute Graft Versus Host Disease</h4> <p>ORENCIA is indicated for the <a href="/prophylaxis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">prophylaxis</a> of acute <a href="/graft_versus_host_disease_gvhd/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">graft versus host disease</a> (aGVHD), in combination with a calcineurin inhibitor and methotrexate, in adults and pediatric patients 2 years of age and older undergoing <a href="/hematopoietic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hematopoietic</a> <a href="/stem_cell_transplantation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">stem cell transplantation</a> (HSCT) from a matched or 1 <a href="/allele/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">allele</a>-mismatched unrelated-<a href="/donor/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">donor</a>.</p> <h4>Limitations Of Use</h4> <p>The concomitant use of ORENCIA with other potent immunosuppressants [e.g., biologic disease-modifying antirheumatic drugs (bDMARDS), Janus kinase (JAK) inhibitors] is not recommended.</p> </div> <a class="mediaPrmo ss" href="/rheumatoid_arthritis_slideshow/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/rheumatoid_arthritis_s1_what_is_ra.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">What Is Rheumatoid Arthritis (RA)? Symptoms, Treatment, Diagnosis</span> <span class="btn">See Slideshow</span> </a> </div> </div> | <a name="I"></a> <h3>INDICATIONS</h3> <h4>Adult Rheumatoid Arthritis</h4> <p>ORENCIA® is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis.</p> <h4>Polyarticular Juvenile Idiopathic Arthritis</h4> <p>ORENCIA is indicated for the treatment of patients 2 years of age and older with moderately to severely active <a href="/polyarticular/definition.htm" ">polyarticular</a> juvenile <a href="/idiopathic/definition.htm" ">idiopathic</a> arthritis.</p> <h4>Adult Psoriatic Arthritis</h4> <p>ORENCIA is indicated for the treatment of adult patients with active <a href="/psoriatic_arthritis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">psoriatic arthritis</a> (PsA).</p> <h4>Prophylaxis For Acute Graft Versus Host Disease</h4> <p>ORENCIA is indicated for the <a href="/prophylaxis/definition.htm" ">prophylaxis</a> of acute <a href="/graft_versus_host_disease_gvhd/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">graft versus host disease</a> (aGVHD), in combination with a calcineurin inhibitor and methotrexate, in adults and pediatric patients 2 years of age and older undergoing <a href="/hematopoietic/definition.htm" ">hematopoietic</a> <a href="/stem_cell_transplantation/definition.htm" ">stem cell transplantation</a> (HSCT) from a matched or 1 <a href="/allele/definition.htm" ">allele</a>-mismatched unrelated-<a href="/donor/definition.htm" ">donor</a>.</p> <h4>Limitations Of Use</h4> <p>The concomitant use of ORENCIA with other potent immunosuppressants [e.g., biologic disease-modifying antirheumatic drugs (bDMARDS), Janus kinase (JAK) inhibitors] is not recommended.</p> </div> <a class="mediaPrmo ss" href="/rheumatoid_arthritis_slideshow/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/rheumatoid_arthritis_s1_what_is_ra.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">What Is Rheumatoid Arthritis (RA)? Symptoms, Treatment, Diagnosis</span> <span class="btn">See Slideshow</span> </a> </div> </div> | 10 | 2023-02-01 17:39:31 | Abatacept (Orencia) | A | DMARDs, Immunomodulators | Orencia | abatacept | Orencia | |
| 73 | 2023-02-23 12:07:03 | Dosage | <a name="D"></a> <h3>DOSAGE AND ADMINISTRATION</h3> <h4>Dosage In Adult Rheumatoid Arthritis</h4> <p>For adult patients with <a href="/ra/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">RA</a>, administer as an intravenous infusion or as a subcutaneous injection. ORENCIA may be used as monotherapy or concomitantly with disease-modifying antirheumatic drugs (DMARDs) other than JAK inhibitors or bDMARDs (e.g., <a href="/tnf/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">TNF</a> antagonists).</p> <h5>Intravenous Dosing Regimen</h5> <p>Reconstitute ORENCIA lyophilized powder and administer after dilution [see <b>DOSAGE AND ADMINISTRATION</b>] as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous infusion, administer as an intravenous infusion at 2 and 4 weeks and every 4 weeks thereafter.</p> <p align="center"><b>Table 1: Dose of ORENCIA for Intravenous Infusion in Adult RA Patients</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Body Weight of Adult Patient</td> <td class="EmphTd" width="25%">Dose</td> <td class="EmphTd" width="25%">Number of Vials<sup>a</sup></td> </tr> <tr> <td>Less than 60 kg</td> <td align="center">500 mg</td> <td align="center">2</td> </tr> <tr> <td>60 to 100 kg</td> <td align="center">750 mg</td> <td align="center">3</td> </tr> <tr> <td>More than 100 kg</td> <td align="center">1,000 mg</td> <td align="center">4</td> </tr> <tr> <td class="credit" colspan="3"><sup>a </sup>Each vial provides 250 mg of abatacept for administration.</td> </tr> </tbody> </table> </center> <p></p> <h5>Subcutaneous Dosing Regimen</h5> <p>Prior to the first subcutaneous dose, may administer an optional loading dose as a single intravenous infusion (as per body weight categories in Table 1). If an intravenous loading dose is used, administer the first subcutaneous injection within one day of the infusion. Administer ORENCIA 125 mg in prefilled syringes or in ORENCIA ClickJect™ autoinjector by subcutaneous injection once weekly [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>For patients switching from ORENCIA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.</p> <h4>Dosage In Polyarticular Juvenile Idiopathic Arthritis</h4> <p>For patients with polyarticular juvenile idiopathic arthritis (pJIA), may administer ORENCIA as an intravenous infusion (only patients 6 years of age and older) or a subcutaneous injection (only patients 2 years of age and older) [see <b>Use In Specific Populations</b>]. ORENCIA may be used as monotherapy or concomitantly with methotrexate.</p> <h5>Intravenous Dosing Regimen</h5> <p>Administer ORENCIA as a 30-minute intravenous infusion based on body weight [see <b>DOSAGE AND ADMINISTRATION</b>]:</p> <ul> <li>If less than 75 kg, administer a dose of 10 mg/kg.</li> <li>If 75 kg or greater, administer as per the recommendations in Table 1 (follow the adult intravenous dosing regimen), not to exceed a maximum dose of 1,000 mg.</li> </ul> <p>Following the initial intravenous infusion, administer infusions at 2 and 4 weeks and every 4 weeks thereafter. Immediately discard any unused portion in the vials.</p> <h5>Subcutaneous Dosing Regimen</h5> <p>Administer ORENCIA for subcutaneous injection, without an intravenous loading dose, utilizing the weight range-based dosing as specified in Table 2 [see <b>DOSAGE AND ADMINISTRATION</b>]. Subsequently administer once weekly.</p> <p align="center"><b>Table 2: Dose of ORENCIA for Subcutaneous Administration in Patients 2 Years of Age and Older with JIA</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Body Weight of Pediatric Patient</td> <td class="EmphTd" width="50%">Dose (once weekly)</td> </tr> <tr> <td>10 to less than 25 kg</td> <td align="center">50 mg</td> </tr> <tr> <td>25 to less than 50 kg</td> <td align="center">87.5 mg</td> </tr> <tr> <td>50 kg or more</td> <td align="center">125 mg</td> </tr> </tbody> </table> </center> <p></p> <p>PJIA patients may self-inject with ORENCIA or the patient’s caregiver may administer ORENCIA if both the healthcare practitioner and the parent/legal guardian determines it is appropriate. The ability of pediatric patients to self-inject with the autoinjector has not been tested.</p> <h4>Dosage In Adult Psoriatic Arthritis</h4> <p>For adult patients with psoriatic arthritis, administer as an intravenous infusion or a subcutaneous injection. ORENCIA may be used with or without non-biologic DMARDs.</p> <h5>Intravenous Dosing Regimen</h5> <p>Administer ORENCIA as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous administration, administer an intravenous infusion at 2 and 4 weeks and every 4 weeks thereafter.</p> <h5>Subcutaneous Dosing Regimen</h5> <p>Administer 125 mg of ORENCIA subcutaneously once weekly (no intravenous loading dose is needed) [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>For patients switching from ORENCIA intravenous infusions to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.</p> <h4>Dosage In Prophylaxis Of Acute Graft Versus Host Disease In Adults And Pediatric Patients Aged 2 Years And Older</h4> <h5>Antiviral Prophylactic Treatment</h5> <p>Before administering ORENCIA, administer recommended <a href="/antiviral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antiviral</a> <a href="/prophylactic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">prophylactic</a> treatment for <a href="/epstein-barr_virus_ebv/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Epstein-Barr Virus</a> (<a href="/ebv/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">EBV</a>) reactivation, and continue for six months following HSCT. In addition, consider prophylactic antivirals for <a href="/cytomegalovirus_cmv/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Cytomegalovirus</a> (<a href="/cmv_cytomegalovirus/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">CMV</a>) infection/reactivation during treatment and for six months following HSCT [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Intravenous Dosing Regimen</h5> <p>For patients 6 years and older, administer ORENCIA 10 mg/kg (maximum dose of 1,000 mg) as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation.</p> <p>For patients 2 to less than 6 years old, administer ORENCIA 15 mg/kg as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by 12 mg/kg as an intravenous infusion over 60 minutes on Days 5, 14, and 28 after transplantation.</p> <h4>Preparation And Administration Instructions For Intravenous Infusion</h4> <p>Calculate the ORENCIA dose, the total volume of reconstituted solution required, and the number of ORENCIA vials needed. For a full dose, less than the full contents of one vial or more than one vial may be needed. Using <a href="/aseptic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">aseptic</a> technique, reconstitute, dilute, and then administer ORENCIA as follows:</p> <blockquote> <h5>Reconstitution</h5> </blockquote> <h5>Dilution</h5> <h5>Administration</h5> <ol> <li>Use the vial only if the vacuum is present.</li> <li>Reconstitute each vial of supplied ORENCIA lyophilized powder (each vial supplies 250 mg of abatacept) with 10 mL of Sterile Water for Injection, USP (direct the stream toward the inside wall of the vial) to obtain a concentration of 25 mg/mL. Use only the provided silicone-free syringe with an 18-to 21-gauge needle: <ol type="a"> <li>If the ORENCIA lyophilized powder is accidently reconstituted using a siliconized syringe, the solution may develop a few translucent particles (discard any solutions prepared using siliconized syringes).</li> <li>If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe. To obtain new silicone-free syringes, contact Bristol-Myers Squibb at 1-800-ORENCIA.</li> </ol> </li> <li>Gently swirl the vial to minimize foam formation, until the contents are completely dissolved. Do not shake. Avoid prolonged or vigorous agitation.</li> <li>Upon complete dissolution of the lyophilized powder, vent the vial with a needle to dissipate any foam that may be present.</li> <li>Visually inspect the reconstituted solution (the solution should be clear and colorless to pale yellow). Do not use if opaque particles, discoloration, or other foreign particles are present.</li> <li>Repeat steps 2) through 5) if two, three, or four vials are needed for a dose (see Table 1).</li> <li>Must further dilute the reconstituted ORENCIA solution to 100 mL as follows: <ol type="a"> <li>From a 100 mL infusion bag or bottle of 0.9% Sodium Chloride Injection, USP, withdraw a volume equal to the volume of the reconstituted ORENCIA solution required for the patient’s dose.</li> <li>Slowly add the reconstituted ORENCIA solution(s) into the infusion bag or bottle using the silicone-free disposable syringe provided with each vial.</li> <li>Gently mix. Do not shake the bag or bottle. The final concentration of abatacept in the bag or bottle will depend upon the amount of abatacept added, but will be no more than 10 mg/mL. Immediately discard any unused portion in the ORENCIA vial.</li> </ol> </li> <li>Prior to administration, visually inspect the ORENCIA diluted solution for particulate matter and discoloration. Discard the diluted solution if any particulate matter or discoloration is observed.</li> <li>Using an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 μm to 1.2 μm), administer the entire diluted ORENCIA solution over: <ol type="a"> <li>30 minutes for RA, pJIA, and PsA</li> <li>60 minutes for aGVHD prophylaxis</li> </ol> </li> <li>Must complete the infusion of the diluted ORENCIA solution within 24 hours of reconstitution of the ORENCIA vials.</li> </ol> <p>Do not <a href="/infuse/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">infuse</a> ORENCIA concomitantly in the same intravenous line with other agents. No physical or <a href="/biochemical/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">biochemical</a> compatibility studies have been conducted to evaluate the coadministration of ORENCIA with other drugs.</p> <h5>Storage Of Diluted ORENCIA Solution</h5> <p>May store the diluted ORENCIA solution at room temperature or refrigerate at 2°C to 8°C (36°F to 46°F) up to 24 hours before use. Discard the diluted solution if not administered within 24 hours.</p> <h4>Recommendations For Subcutaneous Administration</h4> <p>ORENCIA prefilled syringes and ORENCIA ClickJect autoinjectors are intended for:</p> <ul> <li>subcutaneous use only and are not intended for intravenous infusion</li> <li>use under the guidance of a healthcare practitioner.</li> </ul> <p>After proper training in subcutaneous injection technique, a patient or the patient’s caregiver may administer a subcutaneous injection of ORENCIA (ClickJect autoinjector or prefilled syringe) if a healthcare practitioner determines that it is appropriate. Instruct patients and/or caregivers to follow the directions provided in the Instructions for Use for additional details on administration. Specifically instruct them to inject the full amount (which provides the proper dose of ORENCIA), rotate injection sites, and to avoid injections into areas where <a href="/skin_anatomy_picture_definition_function/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">the skin</a> is tender, bruised, red, or hard.</p> <p>Visually inspect for particulate matter and discoloration prior to administration. Do not use ORENCIA prefilled syringes or ORENCIA ClickJect autoinjectors exhibiting particulate matter or discoloration. ORENCIA should be clear to slightly opalescent and colorless to pale yellow.</p> <a name="HS"></a> <h3>HOW SUPPLIED</h3> <h4>Dosage Forms And Strengths</h4> <h5>Intravenous Infusion</h5> <p>For injection: 250 mg white lyophilized powder in a single-dose vial (one may use less than the full contents of the vial or use more than one vial) [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <h5>Subcutaneous Use</h5> <p><b>Injection</b>: 50 mg/0.4 mL, 87.5 mg/0.7 mL, and 125 mg/mL of a clear to slightly opalescent, colorless to pale-yellow solution in a single-dose prefilled glass syringe.</p> <p><b>Injection</b>: 125 mg/mL of a clear to slightly opalescent, colorless to pale-yellow solution in a single-dose prefilled ClickJect autoinjector.</p> <h4>Storage And Handling</h4> <h5>For Intravenous Infusion</h5> <p><b>ORENCIA® (abatacept) for injection</b> is a white lyophilized powder for intravenous infusion after reconstitution and dilution. It is supplied as an individually packaged, single-dose vial (one may use less than the full contents of the vial or use more than one vial) with a silicone-free disposable syringe, providing 250 mg of abatacept:</p> <p class="EmphText"><b>NDC</b> 0003-2187-10: in a clamshell presentation<br /> <b>NDC</b> 0003-2187-13: in a carton presentation</p> <h5>For Subcutaneous Use</h5> <p><b>ORENCIA® (abatacept) injection and ORENCIA® ClickJect (abatacept) injection</b> are clear to slightly opalescent, colorless to pale yellow solutions for subcutaneous administration.</p> <p><i>Prefilled Syringe</i></p> <p><b>ORENCIA (abatacept) injection</b>, 50 mg/0.4 mL, 87.5 mg/0.7 mL, and 125 mg/mL, is supplied as single-dose disposable prefilled glass syringes with BD UltraSafe Passive™ needle guard and flange extenders.</p> <p>The Type I glass syringe has a coated stopper and fixed stainless steel needle (5 bevel, 29-gauge thin wall, ½-inch needle) covered with a rigid needle shield. The prefilled syringe provides ORENCIA in the following packages:</p> <p class="EmphText"><b>NDC</b> 0003-2814-11 (50 mg/0.4 mL): pack of 4 syringes with a passive needle safety guard<br /> <b>NDC</b> 0003-2818-11 (87.5 mg/0.7 mL): pack of 4 syringes with a passive needle safety guard<br /> <b>NDC</b> 0003-2188-11 (125 mg/mL): pack of 4 syringes with a passive needle safety guard</p> <p><i>ClickJect Autoinjector</i></p> <p><b>ORENCIA (abatacept) ClickJect</b>, 125 mg/mL, is supplied as a single-dose disposable prefilled autoinjector. The Type I glass syringe contained in the autoinjector has a coated stopper and fixed stainless steel needle (5 bevel, 27-gauge special thin wall, ½-inch needle) covered with a rigid needle shield. The autoinjector provides 125 mg of abatacept in 1 mL and is provided in the following package:</p> <p class="EmphText"><b>NDC</b> 0003-2188-51: pack of 4 autoinjectors</p> <h5>Storage</h5> <p>Refrigerate ORENCIA lyophilized powder supplied in a vial at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date on the vial. Protect the vials from light by storing in the original package until time of use.</p> <p>Refrigerate ORENCIA solution supplied in a prefilled syringe or ClickJect autoinjector at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date on the prefilled syringe or autoinjector. Protect from light by storing in the original package until time of use. Do not allow the prefilled syringe or autoinjector to freeze.</p> <p class="credit">Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA. Revised: Dec 2021</p> </div> <div id="667441035-3" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-3", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <a name="D"></a> <h3>DOSAGE AND ADMINISTRATION</h3> <h4>Dosage In Adult Rheumatoid Arthritis</h4> <p>For adult patients with <a href="/ra/definition.htm" ">RA</a>, administer as an intravenous infusion or as a subcutaneous injection. ORENCIA may be used as monotherapy or concomitantly with disease-modifying antirheumatic drugs (DMARDs) other than JAK inhibitors or bDMARDs (e.g., <a href="/tnf/definition.htm" ">TNF</a> antagonists).</p> <h5>Intravenous Dosing Regimen</h5> <p>Reconstitute ORENCIA lyophilized powder and administer after dilution [see <b>DOSAGE AND ADMINISTRATION</b>] as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous infusion, administer as an intravenous infusion at 2 and 4 weeks and every 4 weeks thereafter.</p> <p align="center"><b>Table 1: Dose of ORENCIA for Intravenous Infusion in Adult RA Patients</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Body Weight of Adult Patient</td> <td class="EmphTd" width="25%">Dose</td> <td class="EmphTd" width="25%">Number of Vials<sup>a</sup></td> </tr> <tr> <td>Less than 60 kg</td> <td align="center">500 mg</td> <td align="center">2</td> </tr> <tr> <td>60 to 100 kg</td> <td align="center">750 mg</td> <td align="center">3</td> </tr> <tr> <td>More than 100 kg</td> <td align="center">1,000 mg</td> <td align="center">4</td> </tr> <tr> <td class="credit" colspan="3"><sup>a </sup>Each vial provides 250 mg of abatacept for administration.</td> </tr> </tbody> </table> </center> <p></p> <h5>Subcutaneous Dosing Regimen</h5> <p>Prior to the first subcutaneous dose, may administer an optional loading dose as a single intravenous infusion (as per body weight categories in Table 1). If an intravenous loading dose is used, administer the first subcutaneous injection within one day of the infusion. Administer ORENCIA 125 mg in prefilled syringes or in ORENCIA ClickJect™ autoinjector by subcutaneous injection once weekly [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>For patients switching from ORENCIA intravenous therapy to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.</p> <h4>Dosage In Polyarticular Juvenile Idiopathic Arthritis</h4> <p>For patients with polyarticular juvenile idiopathic arthritis (pJIA), may administer ORENCIA as an intravenous infusion (only patients 6 years of age and older) or a subcutaneous injection (only patients 2 years of age and older) [see <b>Use In Specific Populations</b>]. ORENCIA may be used as monotherapy or concomitantly with methotrexate.</p> <h5>Intravenous Dosing Regimen</h5> <p>Administer ORENCIA as a 30-minute intravenous infusion based on body weight [see <b>DOSAGE AND ADMINISTRATION</b>]:</p> <ul> <li>If less than 75 kg, administer a dose of 10 mg/kg.</li> <li>If 75 kg or greater, administer as per the recommendations in Table 1 (follow the adult intravenous dosing regimen), not to exceed a maximum dose of 1,000 mg.</li> </ul> <p>Following the initial intravenous infusion, administer infusions at 2 and 4 weeks and every 4 weeks thereafter. Immediately discard any unused portion in the vials.</p> <h5>Subcutaneous Dosing Regimen</h5> <p>Administer ORENCIA for subcutaneous injection, without an intravenous loading dose, utilizing the weight range-based dosing as specified in Table 2 [see <b>DOSAGE AND ADMINISTRATION</b>]. Subsequently administer once weekly.</p> <p align="center"><b>Table 2: Dose of ORENCIA for Subcutaneous Administration in Patients 2 Years of Age and Older with JIA</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Body Weight of Pediatric Patient</td> <td class="EmphTd" width="50%">Dose (once weekly)</td> </tr> <tr> <td>10 to less than 25 kg</td> <td align="center">50 mg</td> </tr> <tr> <td>25 to less than 50 kg</td> <td align="center">87.5 mg</td> </tr> <tr> <td>50 kg or more</td> <td align="center">125 mg</td> </tr> </tbody> </table> </center> <p></p> <p>PJIA patients may self-inject with ORENCIA or the patient’s caregiver may administer ORENCIA if both the healthcare practitioner and the parent/legal guardian determines it is appropriate. The ability of pediatric patients to self-inject with the autoinjector has not been tested.</p> <h4>Dosage In Adult Psoriatic Arthritis</h4> <p>For adult patients with psoriatic arthritis, administer as an intravenous infusion or a subcutaneous injection. ORENCIA may be used with or without non-biologic DMARDs.</p> <h5>Intravenous Dosing Regimen</h5> <p>Administer ORENCIA as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous administration, administer an intravenous infusion at 2 and 4 weeks and every 4 weeks thereafter.</p> <h5>Subcutaneous Dosing Regimen</h5> <p>Administer 125 mg of ORENCIA subcutaneously once weekly (no intravenous loading dose is needed) [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>For patients switching from ORENCIA intravenous infusions to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled intravenous dose.</p> <h4>Dosage In Prophylaxis Of Acute Graft Versus Host Disease In Adults And Pediatric Patients Aged 2 Years And Older</h4> <h5>Antiviral Prophylactic Treatment</h5> <p>Before administering ORENCIA, administer recommended <a href="/antiviral/definition.htm" ">antiviral</a> <a href="/prophylactic/definition.htm" ">prophylactic</a> treatment for <a href="/epstein-barr_virus_ebv/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Epstein-Barr Virus</a> (<a href="/ebv/definition.htm" ">EBV</a>) reactivation, and continue for six months following HSCT. In addition, consider prophylactic antivirals for <a href="/cytomegalovirus_cmv/definition.htm" ">Cytomegalovirus</a> (<a href="/cmv_cytomegalovirus/definition.htm" ">CMV</a>) infection/reactivation during treatment and for six months following HSCT [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Intravenous Dosing Regimen</h5> <p>For patients 6 years and older, administer ORENCIA 10 mg/kg (maximum dose of 1,000 mg) as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation.</p> <p>For patients 2 to less than 6 years old, administer ORENCIA 15 mg/kg as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by 12 mg/kg as an intravenous infusion over 60 minutes on Days 5, 14, and 28 after transplantation.</p> <h4>Preparation And Administration Instructions For Intravenous Infusion</h4> <p>Calculate the ORENCIA dose, the total volume of reconstituted solution required, and the number of ORENCIA vials needed. For a full dose, less than the full contents of one vial or more than one vial may be needed. Using <a href="/aseptic/definition.htm" ">aseptic</a> technique, reconstitute, dilute, and then administer ORENCIA as follows:</p> <blockquote> <h5>Reconstitution</h5> </blockquote> <h5>Dilution</h5> <h5>Administration</h5> <ol> <li>Use the vial only if the vacuum is present.</li> <li>Reconstitute each vial of supplied ORENCIA lyophilized powder (each vial supplies 250 mg of abatacept) with 10 mL of Sterile Water for Injection, USP (direct the stream toward the inside wall of the vial) to obtain a concentration of 25 mg/mL. Use only the provided silicone-free syringe with an 18-to 21-gauge needle: <ol type="a"> <li>If the ORENCIA lyophilized powder is accidently reconstituted using a siliconized syringe, the solution may develop a few translucent particles (discard any solutions prepared using siliconized syringes).</li> <li>If the silicone-free disposable syringe is dropped or becomes contaminated, use a new silicone-free disposable syringe. To obtain new silicone-free syringes, contact Bristol-Myers Squibb at 1-800-ORENCIA.</li> </ol> </li> <li>Gently swirl the vial to minimize foam formation, until the contents are completely dissolved. Do not shake. Avoid prolonged or vigorous agitation.</li> <li>Upon complete dissolution of the lyophilized powder, vent the vial with a needle to dissipate any foam that may be present.</li> <li>Visually inspect the reconstituted solution (the solution should be clear and colorless to pale yellow). Do not use if opaque particles, discoloration, or other foreign particles are present.</li> <li>Repeat steps 2) through 5) if two, three, or four vials are needed for a dose (see Table 1).</li> <li>Must further dilute the reconstituted ORENCIA solution to 100 mL as follows: <ol type="a"> <li>From a 100 mL infusion bag or bottle of 0.9% Sodium Chloride Injection, USP, withdraw a volume equal to the volume of the reconstituted ORENCIA solution required for the patient’s dose.</li> <li>Slowly add the reconstituted ORENCIA solution(s) into the infusion bag or bottle using the silicone-free disposable syringe provided with each vial.</li> <li>Gently mix. Do not shake the bag or bottle. The final concentration of abatacept in the bag or bottle will depend upon the amount of abatacept added, but will be no more than 10 mg/mL. Immediately discard any unused portion in the ORENCIA vial.</li> </ol> </li> <li>Prior to administration, visually inspect the ORENCIA diluted solution for particulate matter and discoloration. Discard the diluted solution if any particulate matter or discoloration is observed.</li> <li>Using an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 μm to 1.2 μm), administer the entire diluted ORENCIA solution over: <ol type="a"> <li>30 minutes for RA, pJIA, and PsA</li> <li>60 minutes for aGVHD prophylaxis</li> </ol> </li> <li>Must complete the infusion of the diluted ORENCIA solution within 24 hours of reconstitution of the ORENCIA vials.</li> </ol> <p>Do not <a href="/infuse/definition.htm" ">infuse</a> ORENCIA concomitantly in the same intravenous line with other agents. No physical or <a href="/biochemical/definition.htm" ">biochemical</a> compatibility studies have been conducted to evaluate the coadministration of ORENCIA with other drugs.</p> <h5>Storage Of Diluted ORENCIA Solution</h5> <p>May store the diluted ORENCIA solution at room temperature or refrigerate at 2°C to 8°C (36°F to 46°F) up to 24 hours before use. Discard the diluted solution if not administered within 24 hours.</p> <h4>Recommendations For Subcutaneous Administration</h4> <p>ORENCIA prefilled syringes and ORENCIA ClickJect autoinjectors are intended for:</p> <ul> <li>subcutaneous use only and are not intended for intravenous infusion</li> <li>use under the guidance of a healthcare practitioner.</li> </ul> <p>After proper training in subcutaneous injection technique, a patient or the patient’s caregiver may administer a subcutaneous injection of ORENCIA (ClickJect autoinjector or prefilled syringe) if a healthcare practitioner determines that it is appropriate. Instruct patients and/or caregivers to follow the directions provided in the Instructions for Use for additional details on administration. Specifically instruct them to inject the full amount (which provides the proper dose of ORENCIA), rotate injection sites, and to avoid injections into areas where <a href="/skin_anatomy_picture_definition_function/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">the skin</a> is tender, bruised, red, or hard.</p> <p>Visually inspect for particulate matter and discoloration prior to administration. Do not use ORENCIA prefilled syringes or ORENCIA ClickJect autoinjectors exhibiting particulate matter or discoloration. ORENCIA should be clear to slightly opalescent and colorless to pale yellow.</p> <a name="HS"></a> <h3>HOW SUPPLIED</h3> <h4>Dosage Forms And Strengths</h4> <h5>Intravenous Infusion</h5> <p>For injection: 250 mg white lyophilized powder in a single-dose vial (one may use less than the full contents of the vial or use more than one vial) [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <h5>Subcutaneous Use</h5> <p><b>Injection</b>: 50 mg/0.4 mL, 87.5 mg/0.7 mL, and 125 mg/mL of a clear to slightly opalescent, colorless to pale-yellow solution in a single-dose prefilled glass syringe.</p> <p><b>Injection</b>: 125 mg/mL of a clear to slightly opalescent, colorless to pale-yellow solution in a single-dose prefilled ClickJect autoinjector.</p> <h4>Storage And Handling</h4> <h5>For Intravenous Infusion</h5> <p><b>ORENCIA® (abatacept) for injection</b> is a white lyophilized powder for intravenous infusion after reconstitution and dilution. It is supplied as an individually packaged, single-dose vial (one may use less than the full contents of the vial or use more than one vial) with a silicone-free disposable syringe, providing 250 mg of abatacept:</p> <p class="EmphText"><b>NDC</b> 0003-2187-10: in a clamshell presentation<br /> <b>NDC</b> 0003-2187-13: in a carton presentation</p> <h5>For Subcutaneous Use</h5> <p><b>ORENCIA® (abatacept) injection and ORENCIA® ClickJect (abatacept) injection</b> are clear to slightly opalescent, colorless to pale yellow solutions for subcutaneous administration.</p> <p><i>Prefilled Syringe</i></p> <p><b>ORENCIA (abatacept) injection</b>, 50 mg/0.4 mL, 87.5 mg/0.7 mL, and 125 mg/mL, is supplied as single-dose disposable prefilled glass syringes with BD UltraSafe Passive™ needle guard and flange extenders.</p> <p>The Type I glass syringe has a coated stopper and fixed stainless steel needle (5 bevel, 29-gauge thin wall, ½-inch needle) covered with a rigid needle shield. The prefilled syringe provides ORENCIA in the following packages:</p> <p class="EmphText"><b>NDC</b> 0003-2814-11 (50 mg/0.4 mL): pack of 4 syringes with a passive needle safety guard<br /> <b>NDC</b> 0003-2818-11 (87.5 mg/0.7 mL): pack of 4 syringes with a passive needle safety guard<br /> <b>NDC</b> 0003-2188-11 (125 mg/mL): pack of 4 syringes with a passive needle safety guard</p> <p><i>ClickJect Autoinjector</i></p> <p><b>ORENCIA (abatacept) ClickJect</b>, 125 mg/mL, is supplied as a single-dose disposable prefilled autoinjector. The Type I glass syringe contained in the autoinjector has a coated stopper and fixed stainless steel needle (5 bevel, 27-gauge special thin wall, ½-inch needle) covered with a rigid needle shield. The autoinjector provides 125 mg of abatacept in 1 mL and is provided in the following package:</p> <p class="EmphText"><b>NDC</b> 0003-2188-51: pack of 4 autoinjectors</p> <h5>Storage</h5> <p>Refrigerate ORENCIA lyophilized powder supplied in a vial at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date on the vial. Protect the vials from light by storing in the original package until time of use.</p> <p>Refrigerate ORENCIA solution supplied in a prefilled syringe or ClickJect autoinjector at 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date on the prefilled syringe or autoinjector. Protect from light by storing in the original package until time of use. Do not allow the prefilled syringe or autoinjector to freeze.</p> <p class="credit">Bristol-Myers Squibb Company Princeton, New Jersey 08543 USA. Revised: Dec 2021</p> </div> <div id="667441035-3" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-3", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | 10 | 2023-02-01 17:39:31 | Abatacept (Orencia) | A | DMARDs, Immunomodulators | Orencia | abatacept | Orencia | |
| 74 | 2023-02-23 12:07:03 | Side Effects | <a name="AR"></a> <h3>SIDE EFFECTS</h3> <p>The following clinically significant adverse reactions are described elsewhere in the labeling:</p> <ul> <li>Increased Risk of Infection with Concomitant Use with TNF Antagonists, Other Biologic RA/PsA Therapy, or JAK Inhibitors [see <b>WARNINGS AND PRECAUTIONS</b>]</li> <li>Hypersensitivity [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Infections [see <b>WARNINGS AND PRECAUTIONS</b>]</li> <li>Increased Risk of Adverse Reactions When Used in Patients with <a href="/chronic_obstructive_pulmonary_disease/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Chronic Obstructive Pulmonary Disease</a> (<a href="/copd_chronic_obstructive_pulmonary_disease/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">COPD</a>) [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li><a href="/immunosuppression/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Immunosuppression</a> [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Reactivation in aGVHD Prophylaxis after Hematopoietic <a href="/stem_cell/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Stem Cell</a> Transplant (HSCT) [see <b>WARNINGS AND PRECAUTIONS</b>]</li> </ul> <h4>Clinical Trials Experience</h4> <p>Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice.</p> <h4>Adverse Reactions In Adult Patients With RA</h4> <h5>Adverse Reactions In Adult Patients With RA Treated With Intravenous ORENCIA</h5> <p>The data from placebo-controlled studies described herein reflect exposure to ORENCIA administered intravenously in patients with active RA (1955 patients with ORENCIA, 989 with placebo) (Studies I through VI) [see <b>Clinical Studies</b>]. The studies had either a double-blind, placebo-controlled period of 6 months (258 patients with ORENCIA, 133 with placebo) or 1 year (1697 patients with ORENCIA, 856 with placebo). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF <a href="/antagonist/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antagonist</a> (204 patients with ORENCIA, 134 with placebo). The concomitant use of ORENCIA with a TNF antagonist is not recommended [see <b>INDICATIONS AND USAGE</b>]. The majority of patients in RA clinical studies received one or more of the following concomitant medications with ORENCIA: methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, TNF antagonist, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra.</p> <p>The most serious adverse reactions were serious infections and malignancies. The most commonly reported adverse events (occurring in ≥10% of patients treated with ORENCIA) were headache, upper respiratory tract infection, nasopharyngitis, and nausea.</p> <p>The adverse reactions most frequently resulting in clinical intervention (interruption or discontinuation of ORENCIA) were due to infection. The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1%), <a href="/bronchitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bronchitis</a> (0.7%), and <a href="/herpes_zoster/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">herpes zoster</a> (0.7%). The most frequent infections resulting in discontinuation were <a href="/pneumonia_facts/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">pneumonia</a> (0.2%), localized infection (0.2%), and bronchitis (0.1%).</p> <h5>Most Common Adverse Reactions In Adult Patients With RA Treated With Intravenous ORENCIA</h5> <p>Adverse reactions occurring in 3% or more of patients and at least 1% more frequently in ORENCIA-treated patients (intravenous) during placebo-controlled RA studies are summarized in Table 3.</p> <p align="center"><b>Table 3: Most Common Adverse Reactions* During Placebo-Controlled RA Studies of Intravenous ORENCIA</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%"></td> <td class="EmphTd" width="25%">Intravenous ORENCIA<br /> (n=1955)<sup>a</sup></td> <td class="EmphTd" width="25%">Placebo<br /> (n=989)<sup>b</sup></td> </tr> <tr> <td>Headache</td> <td align="center">18%</td> <td align="center">13%</td> </tr> <tr> <td>Nasopharyngitis</td> <td align="center">12%</td> <td align="center">9%</td> </tr> <tr> <td>Dizziness</td> <td align="center">9%</td> <td align="center">7%</td> </tr> <tr> <td>Cough</td> <td align="center">8%</td> <td align="center">7%</td> </tr> <tr> <td>Back pain</td> <td align="center">7%</td> <td align="center">6%</td> </tr> <tr> <td>Hypertension</td> <td align="center">7%</td> <td align="center">4%</td> </tr> <tr> <td>Dyspepsia</td> <td align="center">6%</td> <td align="center">4%</td> </tr> <tr> <td>Urinary tract infection</td> <td align="center">6%</td> <td align="center">5%</td> </tr> <tr> <td>Rash</td> <td align="center">4%</td> <td align="center">3%</td> </tr> <tr> <td>Pain in extremity</td> <td align="center">3%</td> <td align="center">2%</td> </tr> <tr> <td class="credit" colspan="3">* Occurred in ≥3% patients and >1% more frequently in ORENCIA-treated patients.<br /> <sup>a</sup> Includes 204 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab).<br /> <sup>b</sup> Includes 134 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab).</td> </tr> </tbody> </table> </center> <p></p> <h4>Infections In Adult Patients With RA Treated With Intravenous ORENCIA</h4> <p>In the placebo-controlled trials in patients with RA, infections were reported in 54% of intravenous ORENCIA-treated patients and 48% of placebo-treated patients. The most commonly reported infections (reported in 5%-13% of patients) were upper respiratory tract infection, nasopharyngitis, <a href="/sinusitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">sinusitis</a>, <a href="/uti_and_bladder_infection_medications/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">urinary tract infection</a>, <a href="/influenza/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">influenza</a>, and bronchitis. Other infections reported in fewer than 5% of patients at a higher frequency (>0.5%) with ORENCIA compared to placebo, were <a href="/rhinitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">rhinitis</a>, <a href="/herpes/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">herpes</a> simplex, and pneumonia [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>Serious infections were reported in 3% of patients treated with ORENCIA and 1.9% of patients treated with placebo. The most common (0.2%-0.5%) serious infections reported with ORENCIA were pneumonia, <a href="/cellulitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">cellulitis</a>, <a href="/urinary_tract/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">urinary tract</a> infection, bronchitis, <a href="/diverticulosis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">diverticulitis</a>, and acute <a href="/pyelonephritis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pyelonephritis</a> [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h4>Malignancies In Adult Patients With RA Treated With Intravenous ORENCIA</h4> <p>In the placebo-controlled portions of the clinical trials (1955 patients treated for RA with ORENCIA for a median of 12 months), the overall frequencies of malignancies were similar in the ORENCIA-and placebo-treated patients (1.3% and 1.1%, respectively). However, more cases of <a href="/lung_cancer/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">lung cancer</a> were observed in ORENCIA-treated patients (4 cases, 0.2%) than placebo-treated patients (0 cases, 0%). In the cumulative intravenous ORENCIA clinical trials in patients with RA (placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years) were observed in 2688 patients (3827 patient-years). The rate observed for <a href="/lymphoma/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lymphoma</a> is approximately 3.5-fold higher than expected in an age-and gender-matched general population based on the <a href="/national_cancer_institute_nci/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">National Cancer Institute</a>'s Surveillance, Epidemiology, and End Results Database. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. Other malignancies included skin, breast, <a href="/bile/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bile</a> <a href="/duct/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">duct</a>, <a href="/bladder/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bladder</a>, <a href="/cervical/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cervical</a>, endometrial, lymphoma, <a href="/melanoma/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">melanoma</a>, <a href="/myelodysplastic_syndrome/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">myelodysplastic syndrome</a>, <a href="/ovarian/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ovarian</a>, <a href="/prostate/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">prostate</a>, renal, <a href="/thyroid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">thyroid</a>, and uterine cancers [see <b>WARNINGS AND PRECAUTIONS</b>]. The potential role of ORENCIA in the development of malignancies in humans is unknown.</p> <h4>Infusion-Related Reactions And Hypersensitivity Reactions In Adult Patients With RA Treated With Intravenous ORENCIA</h4> <p>Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, IV, and V [see <b>Clinical Studies</b>] were more common in the ORENCIA-treated patients than the placebo patients (9% for ORENCIA, 6% for placebo). The most frequently reported events (1%-2%) were dizziness, headache, and <a href="/hypertension/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypertension</a>.</p> <p>Acute infusion-related events that were reported in >0.1% and ≤1% of patients treated with ORENCIA included <a href="/cardiopulmonary/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cardiopulmonary</a> symptoms, such as <a href="/hypotension/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypotension</a>, increased blood pressure, and <a href="/dyspnea/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">dyspnea</a>; other symptoms included nausea, flushing, <a href="/urticaria/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">urticaria</a>, cough, hypersensitivity, <a href="/pruritus/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pruritus</a>, rash, and wheezing. Most of these reactions were mild (68%) to moderate (28%). Fewer than 1% of ORENCIA-treated patients discontinued due to an acute infusion-related event. In controlled trials, 6 ORENCIA-treated patients compared to 2 placebo-treated patients discontinued study treatment due to acute infusion-related events.</p> <p>In clinical trials of 2688 adult RA patients treated with intravenous ORENCIA, there were two cases (<0.1%) of <a href="/anaphylaxis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anaphylaxis</a>. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients and generally occurred within 24 hours of ORENCIA infusion. Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see<b> WARNINGS AND PRECAUTIONS</b>].</p> <h4>Adverse Reactions In Patients With COPD Treated For RA With Intravenous ORENCIA</h4> <p>In Study V [see <b>Clinical Studies</b>], there were 37 and 17 patients with chronic obstructive pulmonary disease (COPD) who were treated for RA with ORENCIA and placebo, respectively. The COPD patients treated with ORENCIA for RA developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in ORENCIA-treated patients compared to placebo-treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of ORENCIA-treated patients developed a serious adverse event compared to placebo-treated patients (27% vs 6%), including COPD exacerbation [3 of 37 patients (8%)] and pneumonia [1 of 37 patients (3%)] [see<b> WARNINGS AND PRECAUTIONS</b>].</p> <h4>Adverse Reactions In Methotrexate-Naive Patients With RA Treated With Intravenous ORENCIA</h4> <p>Study VI was an active-controlled clinical trial in methotrexate-naive patients [see <b>Clinical Studies</b>]. The safety experience in these patients was consistent with the patients in Studies I-V.</p> <h4>Adverse Reactions In Adult Patients With RA Treated With Subcutaneous Or Intravenous ORENCIA</h4> <p>The data described below are derived from Study SC-1. Study SC-1 was a randomized, double-blind, double-dummy, non-inferiority study that compared the safety of ORENCIA administered subcutaneously or intravenously in 1457 patients with RA, who received background methotrexate, and experienced an inadequate response to methotrexate (<a href="/mtx/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">MTX</a>-IR) [see<b> Clinical Studies</b>]. The adverse reaction profile in patients treated with subcutaneous ORENCIA was similar to the adverse reaction profile in patients treated with intravenous ORENCIA and consistent with intravenous ORENCIA administered in Studies I-VI.</p> <h4>Injection Site Reactions In Adult RA Patients Treated With Subcutaneous ORENCIA</h4> <p>The overall frequency of injection site reactions in Study SC-1 was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous ORENCIA group and the subcutaneous placebo group (given intravenous ORENCIA), respectively [see<b> Clinical Studies</b>]. All these injection site reactions (including <a href="/hematoma/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hematoma</a>, pruritus, and <a href="/erythema/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">erythema</a>) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation.</p> <h4>Adverse Reactions In Adult Patients With PsA</h4> <h5>Adverse Reactions In Adult Patients With PsA Treated With Intravenous Or Subcutaneous ORENCIA</h5> <p>The safety of ORENCIA was evaluated in 594 patients with PsA (341 patients on ORENCIA and 253 patients on placebo), in two randomized, double-blind, placebo-controlled trials [see<b> Clinical Studies</b>]. Of the 341 patients who received ORENCIA, 128 patients received intravenous ORENCIA (PsA-I) and 213 patients received subcutaneous ORENCIA (PsA-II). The safety profile was comparable between ORENCIA given intravenously in Study PsA-I and ORENCIA given subcutaneously in Study PsA-II and also consistent with the safety profile of ORENCIA in patients with RA [see <b>WARNINGS AND PRECAUTIONS</b>, <b>ADVERSE REACTIONS</b>].</p> <h4>Adverse Reactions In Patients With pJIA</h4> <h5>Adverse Reactions In Patients With pJIA Treated With Intravenous ORENCIA</h5> <p>In general, the adverse events in pediatric patients with polyarticular JIA (pJIA) treated with intravenous ORENCIA were similar in frequency and type to those seen in adult patients with RA treated with intravenous ORENCIA [see<b> WARNINGS AND PRECAUTIONS</b> and <b>ADVERSE REACTIONS</b>].</p> <p>Study JIA-1 was a three-part study including an open-label <a href="/extension/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">extension</a> that assessed the safety of intravenous ORENCIA in 190 pediatric patients, 6 to 17 years of age, with pJIA. Overall frequency of adverse events in the 4-month, lead-in, open-label period of the study was 70%; infections occurred at a frequency of 36% [see<b> Clinical Studies</b>]. The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without <a href="/sequelae/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">sequelae</a>, and the types of infections were consistent with those commonly seen in <a href="/outpatient/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">outpatient</a> pediatric populations. Other events that occurred at a <a href="/prevalence/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">prevalence</a> of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain.</p> <p>A total of 6 serious adverse events [<a href="/acute_lymphocytic_leukemia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">acute lymphocytic leukemia</a>, <a href="/ovarian_cyst/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ovarian cyst</a>, <a href="/varicella_chickenpox/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">varicella</a> infection, disease flare (2), and joint wear] were reported during the initial 4 months of treatment with intravenous ORENCIA.</p> <p>Of the 190 pediatric patients with pJIA treated with intravenous ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of events reported in adults.</p> <p>Upon continued treatment in the open-label extension period, the types of adverse events were similar in frequency and type to those seen in adult patients, except for a single patient diagnosed with <a href="/multiple_sclerosis_ms_early_signs_and_types/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">multiple sclerosis</a> while on open-label treatment.</p> <h5>Adverse Reactions In Patients With pJIA Treated With Subcutaneous ORENCIA</h5> <p>Study JIA-2 was an open-label study with a 4-month short-term period and a long-term extension period that assessed the safety of subcutaneous ORENCIA in 205 pediatric patients, 2 to 17 years of age with pJIA. The adverse reaction profile in patients with pJIA treated with ORENCIA administered subcutaneously in Study JIA-2 were consistent with the adverse reaction profile in patients with pJIA treated with intravenous Study JIA-1.</p> <p>There were no reported cases of hypersensitivity reactions. Local injection-site reactions occurred at a frequency of 4.4%.</p> <h4>Adverse Reactions In Patients Undergoing Unrelated-Donor Hematopoietic Stem Cell Transplantation (HSCT) With Intravenous ORENCIA</h4> <p>The data described herein were from one clinical study of ORENCIA (<a href="/gvhd/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">GVHD</a>-1) for aGVHD prophylaxis in patients 6 years and older with hematologic malignancies who were undergoing unrelated HSCT wherein all patients were receiving calcineurin inhibitor and methotrexate as the <a href="/standard_of_care/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">standard of care</a> for aGVHD prophylaxis [see <b>Clinical Studies</b>]. Two cohorts were studied at 10 mg/kg (maximum dose of 1,000 mg) as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation:</p> <ol> <li>A single-arm cohort of ORENCIA-treated patients (n=43) who underwent 7 of 8 Human leukocyte antigen (<a href="/hla/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HLA</a>)-matched HSCT from unrelated donors (7 of 8 cohort) and</li> <li>A randomized cohort comprised of ORENCIA-treated patients (n=73) and placebo-treated patients (n=69) who underwent 8 of 8 HLA-matched HSCT from unrelated donors (8 of 8 cohort).</li> </ol> <p>Of the 116 patients who received ORENCIA, 27 (23%) were 6 to less than 17 years of age [see <b>Use In Specific Populations</b>].</p> <p>The safety information from the date of first dose of ORENCIA up to Day 225 post-transplantation from this study is presented below. The incidence of adverse reactions was determined based on pooled data of ORENCIA-treated patients from the 2 study cohorts (n=116).</p> <p>Serious adverse reactions reported in > 5% of patients who received ORENCIA in combination with a calcineurin inhibitor and methotrexate included pyrexia (20%), pneumonia (8%), acute kidney injury (7%), diarrhea (6%), <a href="/hypoxia_and_hypoxemia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hypoxia</a> (5%), and nausea (5%).</p> <p>Permanent discontinuation of ORENCIA due to an adverse reaction occurred in two patients (1.7%) due to one case each of pneumonia and allergic reaction.</p> <p>The most common (≥10%) adverse reactions in the ORENCIA treated patients were <a href="/anemia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anemia</a>, hypertension, CMV reactivation/CMV infection, pyrexia, pneumonia, <a href="/epistaxis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">epistaxis</a>, CD4 lymphocytes decreased, <a href="/hypermagnesemia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypermagnesemia</a>, and acute kidney injury.</p> <p>Table 4 summarizes the frequency of adverse reactions reported in the study of ORENCIA in GVHD-1.</p> <p align="center"><b>Table 4: Adverse Reactions (≥10%) in Patients with aGVHD Who Received ORENCIA with a Difference Between Arms of >2% Compared to Placebo in GVHD-1</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="3" width="28%">Adverse Reaction</td> <td class="EmphTd" colspan="2">7 of 8 Cohort</td> <td class="EmphTd" colspan="4">8 of 8 Cohort</td> </tr> <tr> <td class="EmphTd" colspan="2">ORENCIA (+CNI and MTX)<br /> (N=43)</td> <td class="EmphTd" colspan="2">ORENCIA (+CNI and MTX)<br /> (N=73)</td> <td class="EmphTd" colspan="2">Placebo (+CNI and MTX)<br /> (N=69)</td> </tr> <tr> <td class="EmphTd" width="12%">All Grades (%)</td> <td class="EmphTd" width="12%">Grade 3 or 4 (%)</td> <td class="EmphTd" width="12%">All Grades (%)</td> <td class="EmphTd" width="12%">Grade 3 or 4 (%)</td> <td class="EmphTd" width="12%">All Grades (%)</td> <td class="EmphTd" width="12%">Grade 3 or 4 (%)</td> </tr> <tr> <td colspan="7"><b>Blood and Lymphatic System Disorders</b></td> </tr> <tr> <td>Anemia</td> <td align="center">56</td> <td align="center">56</td> <td align="center">69</td> <td align="center">69</td> <td align="center">57</td> <td align="center">57</td> </tr> <tr> <td>CD4 lymphocytes decreased</td> <td align="center">14</td> <td align="center">14</td> <td align="center">14</td> <td align="center">14</td> <td align="center">9</td> <td align="center">9</td> </tr> <tr> <td colspan="7"><b>Vascular Disorders</b></td> </tr> <tr> <td>Hypertension</td> <td align="center">49</td> <td align="center">49</td> <td align="center">43</td> <td align="center">43</td> <td align="center">38</td> <td align="center">38</td> </tr> <tr> <td colspan="7"><b>General Disorders and Administrative Site Conditions</b></td> </tr> <tr> <td>Pyrexia</td> <td align="center">28</td> <td align="center">9</td> <td align="center">19</td> <td align="center">10</td> <td align="center">20</td> <td align="center">4</td> </tr> <tr> <td colspan="7"><b>Infections and Infestations</b></td> </tr> <tr> <td>CMV Reactivati on/CMV Infection</td> <td align="center">26</td> <td align="center">26</td> <td align="center">32</td> <td align="center">32</td> <td align="center">22</td> <td align="center">22</td> </tr> <tr> <td>Pneumonia</td> <td align="center">19</td> <td align="center">19</td> <td align="center">12</td> <td align="center">12</td> <td align="center">10</td> <td align="center">9</td> </tr> <tr> <td colspan="7"><b>Respiratory and Mediastinal Disorders</b></td> </tr> <tr> <td>Epistaxis</td> <td align="center">12</td> <td align="center">12</td> <td align="center">16</td> <td align="center">16</td> <td align="center">10</td> <td align="center">10</td> </tr> <tr> <td colspan="7"><b>Renal and Urinary Disorders</b></td> </tr> <tr> <td>Acute kidney injury</td> <td align="center">9</td> <td align="center">7</td> <td align="center">15</td> <td align="center">15</td> <td align="center">10</td> <td align="center">10</td> </tr> <tr> <td colspan="7"><b>Metabolism and Nutrition Disorders</b></td> </tr> <tr> <td>Hypermagnesemia</td> <td align="center">5</td> <td align="center">5</td> <td align="center">18</td> <td align="center">18</td> <td align="center">10</td> <td align="center">10</td> </tr> </tbody> </table> </center> <p></p> <p>Clinically relevant adverse reactions in <10% of patients who received ORENCIA in combination with calcineurin inhibitor and methotrexate in Study GVHD-1 included EBV reactivation.</p> <h4>Immunogenicity</h4> <p>As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other abatacept products may be misleading.</p> <h4>Immunogenicity In Adult Patients With RA Treated With Intravenous ORENCIA</h4> <p>Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by <a href="/elisa/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ELISA</a> assays in RA patients for up to 2 years following repeated treatment with intravenous ORENCIA. Thirty-four of 1993 (2%) patients developed binding antibodies to the entire abatacept molecule or to the CTLA-4 portion of abatacept. Because trough levels of abatacept can interfere with assay results, a subset analysis was performed. In the subset analysis, 9 of 154 (6%) patients that had discontinued intravenous ORENCIA treatment for over 56 days developed antibodies. Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies in a cell-based luciferase reporter assay. Six of 9 (67%) evaluable patients were shown to possess neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.</p> <p>No correlation of anti-abatacept antibody development to clinical response or adverse events was observed.</p> <h4>Immunogenicity In Adult RA Patients Treated With Subcutaneous Or Intravenous ORENCIA</h4> <p>Study SC-1 compared the immunogenicity to abatacept following subcutaneous or intravenous ORENCIA administration. The overall immunogenicity frequency to abatacept was 1% (8/725) and 2% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy.</p> <h4>Immunogenicity In Adult RA Patients Treated With Subcutaneous ORENCIA Monotherapy</h4> <p>Study SC-2 was conducted to determine the effect of subcutaneous monotherapy use of ORENCIA on immunogenicity (without an intravenous loading dose) in 100 RA patients, who had not previously received ORENCIA or other CTLA4Ig. Patients in this study received either subcutaneous ORENCIA plus methotrexate (n=51) or subcutaneous ORENCIA monotherapy (n=49). No patients in either group developed anti-abatacept antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies.</p> <h4>Immunogenicity In Adult RA Patients After Treatment, Withdrawal, And Then Restart Of Subcutaneous ORENCIA</h4> <p>Study SC-3 was conducted to investigate the immunogenicity in adult RA patients after treatment, withdrawal (three months), and restart of ORENCIA subcutaneous treatment (patients were treated concomitantly with methotrexate). One hundred sixty-seven patients were enrolled in the first 3-month treatment period and responders (n=120) were randomized to either subcutaneous ORENCIA or placebo for the second 3-month period (withdrawal period). Patients from this period then received open-label ORENCIA treatment in the final 3-month period of the study (period 3). At the end of the withdrawal period, 0/38 (0%) patients who continued to receive subcutaneous ORENCIA developed anti-abatacept antibodies compared to 7/73 (10%) of patients who had subcutaneous ORENCIA withdrawn during this period. Half of the patients who received subcutaneous placebo during the withdrawal period received a single intravenous infusion of ORENCIA at the start of period 3 and half received intravenous placebo. At the end of period 3, when all patients again received subcutaneous ORENCIA, the immunogenicity rates were 1/38 (3%) in the group who received subcutaneous ORENCIA throughout, and 2/73 (3%) in the group that had received placebo during the withdrawal period. Upon reinitiating therapy, there were no injection reactions and no differences in response to therapy in patients who were withdrawn from subcutaneous therapy for up to 3 months compared to those who remained on subcutaneous therapy (these results occurred in those who received or did not receive an intravenous loading dose). The safety observed in this study was consistent with that observed in the other studies.</p> <h4>Immunogenicity In Patients With pJIA Treated With Intravenous ORENCIA</h4> <p>Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with pJIA following repeated treatment with intravenous ORENCIA throughout the open-label period. For patients who were withdrawn from therapy for up to 6 months during the double-blind period, the rate of antibody formation to the CTLA-4 portion of the molecule was 41% (22/54), while for those who remained on therapy the rate was 13% (7/54). Twenty of these patients had samples that could be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies.</p> <p>The presence of antibodies was generally transient, and titers were low. The presence of antibodies was not associated with adverse events, changes in efficacy, or an effect on serum concentrations of abatacept. For patients who were withdrawn from ORENCIA during the double-blind period for up to 6 months, no serious acute infusion-related events were observed upon re-initiation of ORENCIA therapy.</p> <h4>Immunogenicity In Patients Treated For Prophylaxis Of aGVHD With Intravenous</h4> <p>ORENCIA Immunogenicity was assessed in patients undergoing HSCT. Overall, immunogenicity incidence and associated antibody titers were low from the 4-dose intravenous ORENCIA regimen used in this study. Of the 114 immunogenicity evaluable subjects in the ORENCIA groups, none were positive during the ORENCIA treatment period (Day -1 to Day 28 following transplant). During the off-treatment period (Day 29 and up to Day 180 following transplant); 6 of 91 immunogenicity evaluable subjects (6.6%) were positive for CTLA4 and possibly <a href="/ig/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Ig</a>; 4 of the 6 positive subjects were found to have at least one positive sample with neutralization activity. In this study, immunogenicity positive subjects only had <a href="/ada_american_diabetes_association/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ADA</a> positive samples on Day 180 (off-treatment period) and thus due to the timing of the response, the impact on PK, safety, or efficacy could not be determined.</p> <h4>Postmarketing Experience</h4> <p>Adverse reactions have been reported during the postapproval use of ORENCIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ORENCIA. Based on the postmarketing experience with ORENCIA, the following adverse reactions have been identified:</p> <ul> <li><a href="/vasculitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Vasculitis</a> (including <a href="/cutaneous/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cutaneous</a> vasculitis and leukocytoclastic vasculitis)</li> <li>New or worsening <a href="/psoriasis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">psoriasis</a></li> <li>Non-melanoma skin cancers (<a href="/basal_cell_carcinoma/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">basal cell carcinoma</a> and <a href="/squamous_cell_carcinoma/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">squamous cell carcinoma</a>)</li> <li><a href="/angioedema/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Angioedema</a> reactions [see <b>WARNINGS AND PRECAUTIONS</b>]</li> </ul> <p>During postmarketing experience with intravenous ORENCIA, systemic infusion reactions were similar to that seen in the clinical trial experience with intravenous ORENCIA with the exception of one case of fatal anaphylaxis [see <b>WARNINGS AND PRECAUTIONS</b>]. Postmarketing reports of systemic injection reactions (e.g., pruritus, throat tightness, dyspnea) have occurred following the use of subcutaneous ORENCIA.</p> </div> <a class="mediaPrmo quiz" href="/quiz_rheumatoid_arthritis/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/rheumatoid-arthritis/s1.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">The term <i>arthritis</i> refers to stiffness in the joints.</span> <span class="btn">See Answer</span> </a> </div> </div> | <a name="AR"></a> <h3>SIDE EFFECTS</h3> <p>The following clinically significant adverse reactions are described elsewhere in the labeling:</p> <ul> <li>Increased Risk of Infection with Concomitant Use with TNF Antagonists, Other Biologic RA/PsA Therapy, or JAK Inhibitors [see <b>WARNINGS AND PRECAUTIONS</b>]</li> <li>Hypersensitivity [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Infections [see <b>WARNINGS AND PRECAUTIONS</b>]</li> <li>Increased Risk of Adverse Reactions When Used in Patients with <a href="/chronic_obstructive_pulmonary_disease/definition.htm" ">Chronic Obstructive Pulmonary Disease</a> (<a href="/copd_chronic_obstructive_pulmonary_disease/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">COPD</a>) [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li><a href="/immunosuppression/definition.htm" ">Immunosuppression</a> [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Reactivation in aGVHD Prophylaxis after Hematopoietic <a href="/stem_cell/definition.htm" ">Stem Cell</a> Transplant (HSCT) [see <b>WARNINGS AND PRECAUTIONS</b>]</li> </ul> <h4>Clinical Trials Experience</h4> <p>Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice.</p> <h4>Adverse Reactions In Adult Patients With RA</h4> <h5>Adverse Reactions In Adult Patients With RA Treated With Intravenous ORENCIA</h5> <p>The data from placebo-controlled studies described herein reflect exposure to ORENCIA administered intravenously in patients with active RA (1955 patients with ORENCIA, 989 with placebo) (Studies I through VI) [see <b>Clinical Studies</b>]. The studies had either a double-blind, placebo-controlled period of 6 months (258 patients with ORENCIA, 133 with placebo) or 1 year (1697 patients with ORENCIA, 856 with placebo). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF <a href="/antagonist/definition.htm" ">antagonist</a> (204 patients with ORENCIA, 134 with placebo). The concomitant use of ORENCIA with a TNF antagonist is not recommended [see <b>INDICATIONS AND USAGE</b>]. The majority of patients in RA clinical studies received one or more of the following concomitant medications with ORENCIA: methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, TNF antagonist, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra.</p> <p>The most serious adverse reactions were serious infections and malignancies. The most commonly reported adverse events (occurring in ≥10% of patients treated with ORENCIA) were headache, upper respiratory tract infection, nasopharyngitis, and nausea.</p> <p>The adverse reactions most frequently resulting in clinical intervention (interruption or discontinuation of ORENCIA) were due to infection. The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1%), <a href="/bronchitis/definition.htm" ">bronchitis</a> (0.7%), and <a href="/herpes_zoster/definition.htm" ">herpes zoster</a> (0.7%). The most frequent infections resulting in discontinuation were <a href="/pneumonia_facts/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">pneumonia</a> (0.2%), localized infection (0.2%), and bronchitis (0.1%).</p> <h5>Most Common Adverse Reactions In Adult Patients With RA Treated With Intravenous ORENCIA</h5> <p>Adverse reactions occurring in 3% or more of patients and at least 1% more frequently in ORENCIA-treated patients (intravenous) during placebo-controlled RA studies are summarized in Table 3.</p> <p align="center"><b>Table 3: Most Common Adverse Reactions* During Placebo-Controlled RA Studies of Intravenous ORENCIA</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%"></td> <td class="EmphTd" width="25%">Intravenous ORENCIA<br /> (n=1955)<sup>a</sup></td> <td class="EmphTd" width="25%">Placebo<br /> (n=989)<sup>b</sup></td> </tr> <tr> <td>Headache</td> <td align="center">18%</td> <td align="center">13%</td> </tr> <tr> <td>Nasopharyngitis</td> <td align="center">12%</td> <td align="center">9%</td> </tr> <tr> <td>Dizziness</td> <td align="center">9%</td> <td align="center">7%</td> </tr> <tr> <td>Cough</td> <td align="center">8%</td> <td align="center">7%</td> </tr> <tr> <td>Back pain</td> <td align="center">7%</td> <td align="center">6%</td> </tr> <tr> <td>Hypertension</td> <td align="center">7%</td> <td align="center">4%</td> </tr> <tr> <td>Dyspepsia</td> <td align="center">6%</td> <td align="center">4%</td> </tr> <tr> <td>Urinary tract infection</td> <td align="center">6%</td> <td align="center">5%</td> </tr> <tr> <td>Rash</td> <td align="center">4%</td> <td align="center">3%</td> </tr> <tr> <td>Pain in extremity</td> <td align="center">3%</td> <td align="center">2%</td> </tr> <tr> <td class="credit" colspan="3">* Occurred in ≥3% patients and >1% more frequently in ORENCIA-treated patients.<br /> <sup>a</sup> Includes 204 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab).<br /> <sup>b</sup> Includes 134 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab).</td> </tr> </tbody> </table> </center> <p></p> <h4>Infections In Adult Patients With RA Treated With Intravenous ORENCIA</h4> <p>In the placebo-controlled trials in patients with RA, infections were reported in 54% of intravenous ORENCIA-treated patients and 48% of placebo-treated patients. The most commonly reported infections (reported in 5%-13% of patients) were upper respiratory tract infection, nasopharyngitis, <a href="/sinusitis/definition.htm" ">sinusitis</a>, <a href="/uti_and_bladder_infection_medications/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">urinary tract infection</a>, <a href="/influenza/definition.htm" ">influenza</a>, and bronchitis. Other infections reported in fewer than 5% of patients at a higher frequency (>0.5%) with ORENCIA compared to placebo, were <a href="/rhinitis/definition.htm" ">rhinitis</a>, <a href="/herpes/definition.htm" ">herpes</a> simplex, and pneumonia [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>Serious infections were reported in 3% of patients treated with ORENCIA and 1.9% of patients treated with placebo. The most common (0.2%-0.5%) serious infections reported with ORENCIA were pneumonia, <a href="/cellulitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">cellulitis</a>, <a href="/urinary_tract/definition.htm" ">urinary tract</a> infection, bronchitis, <a href="/diverticulosis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">diverticulitis</a>, and acute <a href="/pyelonephritis/definition.htm" ">pyelonephritis</a> [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h4>Malignancies In Adult Patients With RA Treated With Intravenous ORENCIA</h4> <p>In the placebo-controlled portions of the clinical trials (1955 patients treated for RA with ORENCIA for a median of 12 months), the overall frequencies of malignancies were similar in the ORENCIA-and placebo-treated patients (1.3% and 1.1%, respectively). However, more cases of <a href="/lung_cancer/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">lung cancer</a> were observed in ORENCIA-treated patients (4 cases, 0.2%) than placebo-treated patients (0 cases, 0%). In the cumulative intravenous ORENCIA clinical trials in patients with RA (placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years) were observed in 2688 patients (3827 patient-years). The rate observed for <a href="/lymphoma/definition.htm" ">lymphoma</a> is approximately 3.5-fold higher than expected in an age-and gender-matched general population based on the <a href="/national_cancer_institute_nci/definition.htm" ">National Cancer Institute</a>'s Surveillance, Epidemiology, and End Results Database. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. Other malignancies included skin, breast, <a href="/bile/definition.htm" ">bile</a> <a href="/duct/definition.htm" ">duct</a>, <a href="/bladder/definition.htm" ">bladder</a>, <a href="/cervical/definition.htm" ">cervical</a>, endometrial, lymphoma, <a href="/melanoma/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">melanoma</a>, <a href="/myelodysplastic_syndrome/definition.htm" ">myelodysplastic syndrome</a>, <a href="/ovarian/definition.htm" ">ovarian</a>, <a href="/prostate/definition.htm" ">prostate</a>, renal, <a href="/thyroid/definition.htm" ">thyroid</a>, and uterine cancers [see <b>WARNINGS AND PRECAUTIONS</b>]. The potential role of ORENCIA in the development of malignancies in humans is unknown.</p> <h4>Infusion-Related Reactions And Hypersensitivity Reactions In Adult Patients With RA Treated With Intravenous ORENCIA</h4> <p>Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, IV, and V [see <b>Clinical Studies</b>] were more common in the ORENCIA-treated patients than the placebo patients (9% for ORENCIA, 6% for placebo). The most frequently reported events (1%-2%) were dizziness, headache, and <a href="/hypertension/definition.htm" ">hypertension</a>.</p> <p>Acute infusion-related events that were reported in >0.1% and ≤1% of patients treated with ORENCIA included <a href="/cardiopulmonary/definition.htm" ">cardiopulmonary</a> symptoms, such as <a href="/hypotension/definition.htm" ">hypotension</a>, increased blood pressure, and <a href="/dyspnea/definition.htm" ">dyspnea</a>; other symptoms included nausea, flushing, <a href="/urticaria/definition.htm" ">urticaria</a>, cough, hypersensitivity, <a href="/pruritus/definition.htm" ">pruritus</a>, rash, and wheezing. Most of these reactions were mild (68%) to moderate (28%). Fewer than 1% of ORENCIA-treated patients discontinued due to an acute infusion-related event. In controlled trials, 6 ORENCIA-treated patients compared to 2 placebo-treated patients discontinued study treatment due to acute infusion-related events.</p> <p>In clinical trials of 2688 adult RA patients treated with intravenous ORENCIA, there were two cases (<0.1%) of <a href="/anaphylaxis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anaphylaxis</a>. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients and generally occurred within 24 hours of ORENCIA infusion. Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see<b> WARNINGS AND PRECAUTIONS</b>].</p> <h4>Adverse Reactions In Patients With COPD Treated For RA With Intravenous ORENCIA</h4> <p>In Study V [see <b>Clinical Studies</b>], there were 37 and 17 patients with chronic obstructive pulmonary disease (COPD) who were treated for RA with ORENCIA and placebo, respectively. The COPD patients treated with ORENCIA for RA developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in ORENCIA-treated patients compared to placebo-treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of ORENCIA-treated patients developed a serious adverse event compared to placebo-treated patients (27% vs 6%), including COPD exacerbation [3 of 37 patients (8%)] and pneumonia [1 of 37 patients (3%)] [see<b> WARNINGS AND PRECAUTIONS</b>].</p> <h4>Adverse Reactions In Methotrexate-Naive Patients With RA Treated With Intravenous ORENCIA</h4> <p>Study VI was an active-controlled clinical trial in methotrexate-naive patients [see <b>Clinical Studies</b>]. The safety experience in these patients was consistent with the patients in Studies I-V.</p> <h4>Adverse Reactions In Adult Patients With RA Treated With Subcutaneous Or Intravenous ORENCIA</h4> <p>The data described below are derived from Study SC-1. Study SC-1 was a randomized, double-blind, double-dummy, non-inferiority study that compared the safety of ORENCIA administered subcutaneously or intravenously in 1457 patients with RA, who received background methotrexate, and experienced an inadequate response to methotrexate (<a href="/mtx/definition.htm" ">MTX</a>-IR) [see<b> Clinical Studies</b>]. The adverse reaction profile in patients treated with subcutaneous ORENCIA was similar to the adverse reaction profile in patients treated with intravenous ORENCIA and consistent with intravenous ORENCIA administered in Studies I-VI.</p> <h4>Injection Site Reactions In Adult RA Patients Treated With Subcutaneous ORENCIA</h4> <p>The overall frequency of injection site reactions in Study SC-1 was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous ORENCIA group and the subcutaneous placebo group (given intravenous ORENCIA), respectively [see<b> Clinical Studies</b>]. All these injection site reactions (including <a href="/hematoma/definition.htm" ">hematoma</a>, pruritus, and <a href="/erythema/definition.htm" ">erythema</a>) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation.</p> <h4>Adverse Reactions In Adult Patients With PsA</h4> <h5>Adverse Reactions In Adult Patients With PsA Treated With Intravenous Or Subcutaneous ORENCIA</h5> <p>The safety of ORENCIA was evaluated in 594 patients with PsA (341 patients on ORENCIA and 253 patients on placebo), in two randomized, double-blind, placebo-controlled trials [see<b> Clinical Studies</b>]. Of the 341 patients who received ORENCIA, 128 patients received intravenous ORENCIA (PsA-I) and 213 patients received subcutaneous ORENCIA (PsA-II). The safety profile was comparable between ORENCIA given intravenously in Study PsA-I and ORENCIA given subcutaneously in Study PsA-II and also consistent with the safety profile of ORENCIA in patients with RA [see <b>WARNINGS AND PRECAUTIONS</b>, <b>ADVERSE REACTIONS</b>].</p> <h4>Adverse Reactions In Patients With pJIA</h4> <h5>Adverse Reactions In Patients With pJIA Treated With Intravenous ORENCIA</h5> <p>In general, the adverse events in pediatric patients with polyarticular JIA (pJIA) treated with intravenous ORENCIA were similar in frequency and type to those seen in adult patients with RA treated with intravenous ORENCIA [see<b> WARNINGS AND PRECAUTIONS</b> and <b>ADVERSE REACTIONS</b>].</p> <p>Study JIA-1 was a three-part study including an open-label <a href="/extension/definition.htm" ">extension</a> that assessed the safety of intravenous ORENCIA in 190 pediatric patients, 6 to 17 years of age, with pJIA. Overall frequency of adverse events in the 4-month, lead-in, open-label period of the study was 70%; infections occurred at a frequency of 36% [see<b> Clinical Studies</b>]. The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without <a href="/sequelae/definition.htm" ">sequelae</a>, and the types of infections were consistent with those commonly seen in <a href="/outpatient/definition.htm" ">outpatient</a> pediatric populations. Other events that occurred at a <a href="/prevalence/definition.htm" ">prevalence</a> of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain.</p> <p>A total of 6 serious adverse events [<a href="/acute_lymphocytic_leukemia/definition.htm" ">acute lymphocytic leukemia</a>, <a href="/ovarian_cyst/definition.htm" ">ovarian cyst</a>, <a href="/varicella_chickenpox/definition.htm" ">varicella</a> infection, disease flare (2), and joint wear] were reported during the initial 4 months of treatment with intravenous ORENCIA.</p> <p>Of the 190 pediatric patients with pJIA treated with intravenous ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of events reported in adults.</p> <p>Upon continued treatment in the open-label extension period, the types of adverse events were similar in frequency and type to those seen in adult patients, except for a single patient diagnosed with <a href="/multiple_sclerosis_ms_early_signs_and_types/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">multiple sclerosis</a> while on open-label treatment.</p> <h5>Adverse Reactions In Patients With pJIA Treated With Subcutaneous ORENCIA</h5> <p>Study JIA-2 was an open-label study with a 4-month short-term period and a long-term extension period that assessed the safety of subcutaneous ORENCIA in 205 pediatric patients, 2 to 17 years of age with pJIA. The adverse reaction profile in patients with pJIA treated with ORENCIA administered subcutaneously in Study JIA-2 were consistent with the adverse reaction profile in patients with pJIA treated with intravenous Study JIA-1.</p> <p>There were no reported cases of hypersensitivity reactions. Local injection-site reactions occurred at a frequency of 4.4%.</p> <h4>Adverse Reactions In Patients Undergoing Unrelated-Donor Hematopoietic Stem Cell Transplantation (HSCT) With Intravenous ORENCIA</h4> <p>The data described herein were from one clinical study of ORENCIA (<a href="/gvhd/definition.htm" ">GVHD</a>-1) for aGVHD prophylaxis in patients 6 years and older with hematologic malignancies who were undergoing unrelated HSCT wherein all patients were receiving calcineurin inhibitor and methotrexate as the <a href="/standard_of_care/definition.htm" ">standard of care</a> for aGVHD prophylaxis [see <b>Clinical Studies</b>]. Two cohorts were studied at 10 mg/kg (maximum dose of 1,000 mg) as an intravenous infusion over 60 minutes on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation:</p> <ol> <li>A single-arm cohort of ORENCIA-treated patients (n=43) who underwent 7 of 8 Human leukocyte antigen (<a href="/hla/definition.htm" ">HLA</a>)-matched HSCT from unrelated donors (7 of 8 cohort) and</li> <li>A randomized cohort comprised of ORENCIA-treated patients (n=73) and placebo-treated patients (n=69) who underwent 8 of 8 HLA-matched HSCT from unrelated donors (8 of 8 cohort).</li> </ol> <p>Of the 116 patients who received ORENCIA, 27 (23%) were 6 to less than 17 years of age [see <b>Use In Specific Populations</b>].</p> <p>The safety information from the date of first dose of ORENCIA up to Day 225 post-transplantation from this study is presented below. The incidence of adverse reactions was determined based on pooled data of ORENCIA-treated patients from the 2 study cohorts (n=116).</p> <p>Serious adverse reactions reported in > 5% of patients who received ORENCIA in combination with a calcineurin inhibitor and methotrexate included pyrexia (20%), pneumonia (8%), acute kidney injury (7%), diarrhea (6%), <a href="/hypoxia_and_hypoxemia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hypoxia</a> (5%), and nausea (5%).</p> <p>Permanent discontinuation of ORENCIA due to an adverse reaction occurred in two patients (1.7%) due to one case each of pneumonia and allergic reaction.</p> <p>The most common (≥10%) adverse reactions in the ORENCIA treated patients were <a href="/anemia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anemia</a>, hypertension, CMV reactivation/CMV infection, pyrexia, pneumonia, <a href="/epistaxis/definition.htm" ">epistaxis</a>, CD4 lymphocytes decreased, <a href="/hypermagnesemia/definition.htm" ">hypermagnesemia</a>, and acute kidney injury.</p> <p>Table 4 summarizes the frequency of adverse reactions reported in the study of ORENCIA in GVHD-1.</p> <p align="center"><b>Table 4: Adverse Reactions (≥10%) in Patients with aGVHD Who Received ORENCIA with a Difference Between Arms of >2% Compared to Placebo in GVHD-1</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="3" width="28%">Adverse Reaction</td> <td class="EmphTd" colspan="2">7 of 8 Cohort</td> <td class="EmphTd" colspan="4">8 of 8 Cohort</td> </tr> <tr> <td class="EmphTd" colspan="2">ORENCIA (+CNI and MTX)<br /> (N=43)</td> <td class="EmphTd" colspan="2">ORENCIA (+CNI and MTX)<br /> (N=73)</td> <td class="EmphTd" colspan="2">Placebo (+CNI and MTX)<br /> (N=69)</td> </tr> <tr> <td class="EmphTd" width="12%">All Grades (%)</td> <td class="EmphTd" width="12%">Grade 3 or 4 (%)</td> <td class="EmphTd" width="12%">All Grades (%)</td> <td class="EmphTd" width="12%">Grade 3 or 4 (%)</td> <td class="EmphTd" width="12%">All Grades (%)</td> <td class="EmphTd" width="12%">Grade 3 or 4 (%)</td> </tr> <tr> <td colspan="7"><b>Blood and Lymphatic System Disorders</b></td> </tr> <tr> <td>Anemia</td> <td align="center">56</td> <td align="center">56</td> <td align="center">69</td> <td align="center">69</td> <td align="center">57</td> <td align="center">57</td> </tr> <tr> <td>CD4 lymphocytes decreased</td> <td align="center">14</td> <td align="center">14</td> <td align="center">14</td> <td align="center">14</td> <td align="center">9</td> <td align="center">9</td> </tr> <tr> <td colspan="7"><b>Vascular Disorders</b></td> </tr> <tr> <td>Hypertension</td> <td align="center">49</td> <td align="center">49</td> <td align="center">43</td> <td align="center">43</td> <td align="center">38</td> <td align="center">38</td> </tr> <tr> <td colspan="7"><b>General Disorders and Administrative Site Conditions</b></td> </tr> <tr> <td>Pyrexia</td> <td align="center">28</td> <td align="center">9</td> <td align="center">19</td> <td align="center">10</td> <td align="center">20</td> <td align="center">4</td> </tr> <tr> <td colspan="7"><b>Infections and Infestations</b></td> </tr> <tr> <td>CMV Reactivati on/CMV Infection</td> <td align="center">26</td> <td align="center">26</td> <td align="center">32</td> <td align="center">32</td> <td align="center">22</td> <td align="center">22</td> </tr> <tr> <td>Pneumonia</td> <td align="center">19</td> <td align="center">19</td> <td align="center">12</td> <td align="center">12</td> <td align="center">10</td> <td align="center">9</td> </tr> <tr> <td colspan="7"><b>Respiratory and Mediastinal Disorders</b></td> </tr> <tr> <td>Epistaxis</td> <td align="center">12</td> <td align="center">12</td> <td align="center">16</td> <td align="center">16</td> <td align="center">10</td> <td align="center">10</td> </tr> <tr> <td colspan="7"><b>Renal and Urinary Disorders</b></td> </tr> <tr> <td>Acute kidney injury</td> <td align="center">9</td> <td align="center">7</td> <td align="center">15</td> <td align="center">15</td> <td align="center">10</td> <td align="center">10</td> </tr> <tr> <td colspan="7"><b>Metabolism and Nutrition Disorders</b></td> </tr> <tr> <td>Hypermagnesemia</td> <td align="center">5</td> <td align="center">5</td> <td align="center">18</td> <td align="center">18</td> <td align="center">10</td> <td align="center">10</td> </tr> </tbody> </table> </center> <p></p> <p>Clinically relevant adverse reactions in <10% of patients who received ORENCIA in combination with calcineurin inhibitor and methotrexate in Study GVHD-1 included EBV reactivation.</p> <h4>Immunogenicity</h4> <p>As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other abatacept products may be misleading.</p> <h4>Immunogenicity In Adult Patients With RA Treated With Intravenous ORENCIA</h4> <p>Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by <a href="/elisa/definition.htm" ">ELISA</a> assays in RA patients for up to 2 years following repeated treatment with intravenous ORENCIA. Thirty-four of 1993 (2%) patients developed binding antibodies to the entire abatacept molecule or to the CTLA-4 portion of abatacept. Because trough levels of abatacept can interfere with assay results, a subset analysis was performed. In the subset analysis, 9 of 154 (6%) patients that had discontinued intravenous ORENCIA treatment for over 56 days developed antibodies. Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies in a cell-based luciferase reporter assay. Six of 9 (67%) evaluable patients were shown to possess neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.</p> <p>No correlation of anti-abatacept antibody development to clinical response or adverse events was observed.</p> <h4>Immunogenicity In Adult RA Patients Treated With Subcutaneous Or Intravenous ORENCIA</h4> <p>Study SC-1 compared the immunogenicity to abatacept following subcutaneous or intravenous ORENCIA administration. The overall immunogenicity frequency to abatacept was 1% (8/725) and 2% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy.</p> <h4>Immunogenicity In Adult RA Patients Treated With Subcutaneous ORENCIA Monotherapy</h4> <p>Study SC-2 was conducted to determine the effect of subcutaneous monotherapy use of ORENCIA on immunogenicity (without an intravenous loading dose) in 100 RA patients, who had not previously received ORENCIA or other CTLA4Ig. Patients in this study received either subcutaneous ORENCIA plus methotrexate (n=51) or subcutaneous ORENCIA monotherapy (n=49). No patients in either group developed anti-abatacept antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies.</p> <h4>Immunogenicity In Adult RA Patients After Treatment, Withdrawal, And Then Restart Of Subcutaneous ORENCIA</h4> <p>Study SC-3 was conducted to investigate the immunogenicity in adult RA patients after treatment, withdrawal (three months), and restart of ORENCIA subcutaneous treatment (patients were treated concomitantly with methotrexate). One hundred sixty-seven patients were enrolled in the first 3-month treatment period and responders (n=120) were randomized to either subcutaneous ORENCIA or placebo for the second 3-month period (withdrawal period). Patients from this period then received open-label ORENCIA treatment in the final 3-month period of the study (period 3). At the end of the withdrawal period, 0/38 (0%) patients who continued to receive subcutaneous ORENCIA developed anti-abatacept antibodies compared to 7/73 (10%) of patients who had subcutaneous ORENCIA withdrawn during this period. Half of the patients who received subcutaneous placebo during the withdrawal period received a single intravenous infusion of ORENCIA at the start of period 3 and half received intravenous placebo. At the end of period 3, when all patients again received subcutaneous ORENCIA, the immunogenicity rates were 1/38 (3%) in the group who received subcutaneous ORENCIA throughout, and 2/73 (3%) in the group that had received placebo during the withdrawal period. Upon reinitiating therapy, there were no injection reactions and no differences in response to therapy in patients who were withdrawn from subcutaneous therapy for up to 3 months compared to those who remained on subcutaneous therapy (these results occurred in those who received or did not receive an intravenous loading dose). The safety observed in this study was consistent with that observed in the other studies.</p> <h4>Immunogenicity In Patients With pJIA Treated With Intravenous ORENCIA</h4> <p>Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with pJIA following repeated treatment with intravenous ORENCIA throughout the open-label period. For patients who were withdrawn from therapy for up to 6 months during the double-blind period, the rate of antibody formation to the CTLA-4 portion of the molecule was 41% (22/54), while for those who remained on therapy the rate was 13% (7/54). Twenty of these patients had samples that could be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies.</p> <p>The presence of antibodies was generally transient, and titers were low. The presence of antibodies was not associated with adverse events, changes in efficacy, or an effect on serum concentrations of abatacept. For patients who were withdrawn from ORENCIA during the double-blind period for up to 6 months, no serious acute infusion-related events were observed upon re-initiation of ORENCIA therapy.</p> <h4>Immunogenicity In Patients Treated For Prophylaxis Of aGVHD With Intravenous</h4> <p>ORENCIA Immunogenicity was assessed in patients undergoing HSCT. Overall, immunogenicity incidence and associated antibody titers were low from the 4-dose intravenous ORENCIA regimen used in this study. Of the 114 immunogenicity evaluable subjects in the ORENCIA groups, none were positive during the ORENCIA treatment period (Day -1 to Day 28 following transplant). During the off-treatment period (Day 29 and up to Day 180 following transplant); 6 of 91 immunogenicity evaluable subjects (6.6%) were positive for CTLA4 and possibly <a href="/ig/definition.htm" ">Ig</a>; 4 of the 6 positive subjects were found to have at least one positive sample with neutralization activity. In this study, immunogenicity positive subjects only had <a href="/ada_american_diabetes_association/definition.htm" ">ADA</a> positive samples on Day 180 (off-treatment period) and thus due to the timing of the response, the impact on PK, safety, or efficacy could not be determined.</p> <h4>Postmarketing Experience</h4> <p>Adverse reactions have been reported during the postapproval use of ORENCIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ORENCIA. Based on the postmarketing experience with ORENCIA, the following adverse reactions have been identified:</p> <ul> <li><a href="/vasculitis/definition.htm" ">Vasculitis</a> (including <a href="/cutaneous/definition.htm" ">cutaneous</a> vasculitis and leukocytoclastic vasculitis)</li> <li>New or worsening <a href="/psoriasis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">psoriasis</a></li> <li>Non-melanoma skin cancers (<a href="/basal_cell_carcinoma/definition.htm" ">basal cell carcinoma</a> and <a href="/squamous_cell_carcinoma/definition.htm" ">squamous cell carcinoma</a>)</li> <li><a href="/angioedema/definition.htm" ">Angioedema</a> reactions [see <b>WARNINGS AND PRECAUTIONS</b>]</li> </ul> <p>During postmarketing experience with intravenous ORENCIA, systemic infusion reactions were similar to that seen in the clinical trial experience with intravenous ORENCIA with the exception of one case of fatal anaphylaxis [see <b>WARNINGS AND PRECAUTIONS</b>]. Postmarketing reports of systemic injection reactions (e.g., pruritus, throat tightness, dyspnea) have occurred following the use of subcutaneous ORENCIA.</p> </div> <a class="mediaPrmo quiz" href="/quiz_rheumatoid_arthritis/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/rheumatoid-arthritis/s1.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">The term <i>arthritis</i> refers to stiffness in the joints.</span> <span class="btn">See Answer</span> </a> </div> </div> | 10 | 2023-02-01 17:39:31 | Abatacept (Orencia) | A | DMARDs, Immunomodulators | Orencia | abatacept | Orencia | |
| 75 | 2023-02-23 12:07:03 | Drug Interactions | <a name="DI"></a> <h3>DRUG INTERACTIONS</h3> <h4>Immunosuppressants</h4> <p>Concomitant administration of a TNF antagonist with ORENCIA has been associated with an increased risk of serious infections and no significant additional efficacy over use of the TNF antagonists alone. Concurrent therapy with ORENCIA and TNF antagonists is not recommended [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>There is insufficient experience to assess the safety and efficacy of ORENCIA administered concurrently with other biologic RA therapy, such as anakinra, or other biologic PsA therapy, and JAK inhibitors and therefore such use is not recommended. [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h4>Blood Glucose Testing</h4> <p><a href="/parenteral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Parenteral</a> drug products containing maltose can interfere with the readings of <a href="/blood_glucose/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">blood glucose</a> monitors that use test strips with glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA for intravenous administration, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving intravenous ORENCIA, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase <a href="/nicotine/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">nicotine</a> <a href="/adenine_a/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">adenine</a> <a href="/dinucleotide/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">dinucleotide</a> (GDH-NAD), glucose oxidase, or glucose hexokinase test methods.</p> <p>ORENCIA for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.</p> </div> <div id="667441035-5" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-5", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <a name="DI"></a> <h3>DRUG INTERACTIONS</h3> <h4>Immunosuppressants</h4> <p>Concomitant administration of a TNF antagonist with ORENCIA has been associated with an increased risk of serious infections and no significant additional efficacy over use of the TNF antagonists alone. Concurrent therapy with ORENCIA and TNF antagonists is not recommended [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>There is insufficient experience to assess the safety and efficacy of ORENCIA administered concurrently with other biologic RA therapy, such as anakinra, or other biologic PsA therapy, and JAK inhibitors and therefore such use is not recommended. [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h4>Blood Glucose Testing</h4> <p><a href="/parenteral/definition.htm" ">Parenteral</a> drug products containing maltose can interfere with the readings of <a href="/blood_glucose/definition.htm" ">blood glucose</a> monitors that use test strips with glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA for intravenous administration, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving intravenous ORENCIA, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase <a href="/nicotine/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">nicotine</a> <a href="/adenine_a/definition.htm" ">adenine</a> <a href="/dinucleotide/definition.htm" ">dinucleotide</a> (GDH-NAD), glucose oxidase, or glucose hexokinase test methods.</p> <p>ORENCIA for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.</p> </div> <div id="667441035-5" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-5", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | 10 | 2023-02-01 17:39:31 | Abatacept (Orencia) | A | DMARDs, Immunomodulators | Orencia | abatacept | Orencia | |
| 76 | 2023-02-23 12:07:03 | Warnings & Precautions | <a name="W"></a> <h3>WARNINGS</h3> <p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a> <h3>PRECAUTIONS</h3> <h4>Concomitant Use With TNF Antagonists, Other Biologic RA/PsA Therapy, Or JAK Inhibitors</h4> <p>In controlled clinical trials in patients with adult RA, patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63% vs. 43%) and serious infections (4.4% vs. 0.8%) compared to patients treated with only TNF antagonists [see <b>ADVERSE REACTIONS</b>]. These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of ORENCIA with TNF antagonists; therefore, concurrent therapy with ORENCIA and a TNF antagonist is not recommended. While transitioning from TNF antagonist therapy to ORENCIA therapy, patients should be monitored for signs of infection. Additionally, concomitant use of ORENCIA with other biologic RA/PsA therapy or JAK inhibitors is not recommended.</p> <h4>Hypersensitivity</h4> <p>In clinical trials of 2688 adult RA patients treated with intravenous ORENCIA, there were two cases (<0.1%) of anaphylaxis reactions. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients. Of the 190 ORENCIA-treated patients in pJIA clinical trials, there was one case of a hypersensitivity reaction (0.5%) [see <b>ADVERSE REACTIONS</b>].</p> <p>In postmarketing experience, fatal anaphylaxis following the first infusion of ORENCIA and life-threatening cases of angioedema have been reported. Angioedema has occurred as early as after the first dose of ORENCIA, but also has occurred with subsequent doses. Angioedema reactions have occurred within hours of administration and in some instances had a delayed onset (i.e., days).</p> <p>Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction. If an anaphylactic or other serious allergic reaction occurs, administration of intravenous or subcutaneous ORENCIA should be stopped immediately with appropriate therapy instituted, and the use of ORENCIA should be permanently discontinued.</p> <h4>Infections</h4> <p>Serious infections, including <a href="/sepsis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">sepsis</a> and pneumonia, have been reported in patients receiving ORENCIA (serious infections were reported in 3% and 1.9% of RA patients treated with intravenous ORENCIA and placebo, respectively) [see <b>ADVERSE REACTIONS</b>]. Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant <a href="/immunosuppressive/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">immunosuppressive</a> therapy which in addition to their underlying disease, could further <a href="/predispose/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">predispose</a> them to infection. A higher rate of serious infections has been observed in adult RA patients treated with concurrent TNF antagonists and ORENCIA compared to those treated with ORENCIA alone [see <b>Concomitant Use With TNF Antagonists, Other Biologic RA/PsA Therapy, Or JAK Inhibitors</b>].</p> <p>Healthcare providers should <a href="/exercise/article.htm" rel="sub" onclick="wmdTrack('embd-lnk');">exercise</a> caution when considering the use of ORENCIA in patients with a history of <a href="/recurrent/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">recurrent</a> infections, underlying conditions which may predispose them to infections, or chronic, <a href="/latent/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">latent</a>, or localized infections. Patients who develop a new infection while undergoing treatment with ORENCIA should be monitored closely. Administration of ORENCIA should be discontinued if a patient develops a serious infection.</p> <p>Prior to initiating ORENCIA, patients should be screened for latent <a href="/tuberculosis_tb_facts/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">tuberculosis</a> (<a href="/tb/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">TB</a>) infection with a <a href="/tuberculin/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">tuberculin</a> skin test. ORENCIA has not been studied in patients with a positive TB screen, and the safety of ORENCIA in individuals with latent TB infection is unknown. Patients testing positive in TB screening should be treated by standard medical practice prior to therapy with ORENCIA.</p> <p>Antirheumatic therapies have been associated with <a href="/viral_hepatitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis</a> B reactivation. Therefore, screening for <a href="/viral_hepatitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">viral hepatitis</a> should be performed in accordance with published guidelines before starting therapy with ORENCIA. In clinical studies with ORENCIA, patients who screened positive for hepatitis were excluded from study.</p> <h4>Immunizations</h4> <p>Prior to initiating ORENCIA in pediatric and adult patients, update vaccinations in accordance with current <a href="/vaccination/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">vaccination</a> guidelines. ORENCIA-treated patients may receive current non-live <a href="/vaccines/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">vaccines</a>. Live vaccines should not be given concurrently with ORENCIA or within 3 months after discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. Based on its mechanism of action, ORENCIA may blunt the effectiveness of some immunizations.</p> <h4>Use In Patients With Chronic Obstructive Pulmonary Disease (COPD)</h4> <p>In Study V, adult COPD patients treated with ORENCIA for RA developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. A greater percentage of patients treated with ORENCIA developed a serious adverse event compared to patients treated with placebo (27% vs 6%) [see <b>Clinical Studies</b> and <b>ADVERSE REACTIONS</b>]. Use of ORENCIA in patients with COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status.</p> <h4>Immunosuppression</h4> <p>The possibility exists for drugs inhibiting T cell activation, including ORENCIA, to affect host defenses against infections and malignancies since T cells mediate cellular immune responses. In clinical trials in patients with adult RA, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo-treated patients [see <b>Infections</b> and <b>ADVERSE REACTIONS</b>]. The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood [see <b>ADVERSE REACTIONS</b>]. There have been reports of malignancies, including <a href="/skin_cancer/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">skin cancer</a> in patients receiving ORENCIA [see <b>ADVERSE REACTIONS</b>]. Periodic skin examinations are recommended for all ORENCIA-treated patients, particularly those with risk factors for skin cancer.</p> <h4>Patient Counseling Information</h4> <p>Advise the patient to read the FDA-approved patient labeling (<b>PATIENT INFORMATION and Instructions for Use</b>).</p> <h5>Concomitant Use With Immunosuppressants For RA</h5> <p>Inform patients that the concomitant use with other immunosuppressives (e.g., biologic DMARDs, JAK inhibitors) is not recommended [see <b>WARNINGS AND PRECAUTIONS</b> and <b>DRUG INTERACTIONS</b>].</p> <h5>Hypersensitivity</h5> <p>Instruct patients to immediately tell their healthcare professional if they experience symptoms of an allergic reaction on the day of administration or the day after ORENCIA administration [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Infections</h5> <p>Inform patients that serious infections have been reported in patients receiving ORENCIA [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Immunizations</h5> <p>Inform patients that live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Pregnancy</h5> <p>Inform patients that there is a Pregnancy Exposure Registry [see <b>Use In Specific Populations</b>.</p> <h5>Blood Glucose Testing</h5> <p>Maltose is contained in ORENCIA for intravenous administration and can give falsely elevated blood glucose readings with certain blood glucose monitors on the day of ORENCIA infusion. Advise patients treated with intravenous ORENCIA who are using GDH-PQQ-based monitoring systems for glucose (e.g., diabetics) to consider using other methods for glucose monitoring. This recommendation is not applicable to patients treated with subcutaneous ORENCIA [see <b>DRUG INTERACTIONS</b>].</p> <h5>Disposal Of Prefilled Syringes And ClickJect Autoinjectors</h5> <p>Advise patients to follow disposal instructions in the Instructions for Use. A puncture-resistant container for disposal of needles and syringes should be used. Instruct patients that they will need to follow their community guidelines for the correct way to dispose of their sharps disposal container. Instruct patients not to recycle their used sharps disposal container.</p> <h4>Nonclinical Toxicology</h4> <h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4> <p>In a mouse carcinogenicity study, weekly subcutaneous injections of 20, 65, or 200 mg/kg of abatacept administered for up to 84 weeks in males and 88 weeks in females were associated with increases in the incidence of <a href="/malignant/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">malignant</a> lymphomas (all doses) and <a href="/mammary_gland/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">mammary gland</a> tumors (intermediate- and high-dose in females). The mice from this study were infected with murine <a href="/leukemia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">leukemia</a> virus and mouse mammary tumor virus. These <a href="/viruses/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">viruses</a> are associated with an increased incidence of lymphomas and mammary <a href="/gland/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">gland</a> tumors, respectively, in immunosuppressed mice. The doses used in these studies produced exposures 0.8, 2.0, and 3.0 times higher, respectively, than the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve). The relevance of these findings to the clinical use of ORENCIA is unknown.</p> <p>In a one-year toxicity study in cynomolgus monkeys, abatacept was administered intravenously once weekly at doses up to 50 mg/kg (producing 9 times the MRHD exposure based on AUC). Abatacept was not associated with any significant drug-related toxicity. Reversible pharmacological effects consisted of minimal transient decreases in serum <a href="/igg/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">IgG</a> and minimal to severe <a href="/lymphoid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lymphoid</a> depletion of germinal centers in the <a href="/spleen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">spleen</a> and/or lymph nodes. No evidence of lymphomas or preneoplastic morphologic changes was observed, despite the presence of a virus (lymphocryptovirus) known to cause these lesions in immunosuppressed monkeys within the time frame of this study. The relevance of these findings to the clinical use of ORENCIA is unknown.</p> <p>No mutagenic potential of abatacept was observed in the <i>in vitro</i> bacterial reverse mutation (Ames) or Chinese hamster ovary/hypoxanthine <a href="/guanine/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">guanine</a> phosphoribosyl-transferase (CHO/HGPRT) forward <a href="/point_mutation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">point mutation</a> assays with or without metabolic activation, and no chromosomal aberrations were observed in human lymphocytes treated with abatacept with or without metabolic activation.</p> <p>Abatacept had no adverse effects on male or female fertility in rats at doses up to 200 mg/kg every three days (11 times the MRHD exposure based on AUC).</p> <a name="USP"></a> <h4>Use In Specific Populations</h4> <h4>Pregnancy</h4> <h5>Pregnancy Exposure Registry</h5> <p>There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ORENCIA during pregnancy. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-311-8972.</p> <h5>Risk Summary</h5> <p>The data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk. In reproductive <a href="/toxicology/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">toxicology</a> studies in rats and rabbits, no fetal malformations were observed with intravenous administration of ORENCIA during organogenesis at doses that produced exposures approximately 29 times the exposure at the maximum recommended human dose (MRHD) of 10 mg/kg/month on an AUC basis. However, in a pre- and postnatal development study in rats, ORENCIA altered immune function in female rats at 11 times the MRHD on an AUC basis.</p> <h5>Data</h5> <p><i>Human Data</i></p> <p>There are no adequate and well-controlled studies of ORENCIA use in pregnant women. The data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk.</p> <p><i>Animal Data</i></p> <p>Intravenous administration of abatacept during organogenesis to mice (10, 55, or 300 mg/kg/day), rats (10, 45, or 200 mg/kg/day), and rabbits (10, 45, or 200 mg/kg every 3 days) produced exposures in rats and rabbits that were approximately 29 times the MRHD on an AUC basis (at maternal doses of 200 mg/kg/day in rats and rabbits), and no embryotoxicity or fetal malformations were observed in any species.</p> <p>In a study of pre- and postnatal development in rats (10, 45, or 200 mg/kg every 3 days from gestation day 6 through lactation day 21), alterations in immune function in female offspring, consisting of a 9-fold increase in T-cell-dependent antibody response relative to controls on postnatal day (PND) 56 and <a href="/thyroiditis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">thyroiditis</a> in a single female pup on PND 112, occurred at approximately 11 times the MRHD on an AUC basis (at a maternal dose of 200 mg/kg). No adverse effects were observed at approximately 3 times the MRHD (a maternal dose of 45 mg/kg). It is not known if immunologic perturbations in rats are relevant indicators of a risk for development of <a href="/autoimmune/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">autoimmune</a> diseases in humans exposed <i>in utero</i> to abatacept. Exposure to abatacept in the juvenile rat, which may be more representative of the fetal <a href="/immune_system/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">immune system</a> state in the human, resulted in immune system abnormalities including inflammation of the thyroid and pancreas [see <b>Nonclinical Toxicology</b>].</p> <h4>Lactation</h4> <h5>Risk Summary</h5> <p>There is no information regarding the presence of abatacept in human milk, the effects on the breastfed infant, or the effects on milk production. However, abatacept was present in the milk of lactating rats dosed with abatacept.</p> <h4>Pediatric Use</h4> <p>The safety and effectiveness of ORENCIA for reducing signs and symptoms in patients 2 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA) have been established (ORENCIA may be used as monotherapy or concomitantly with methotrexate). Use of ORENCIA for this indication is supported by evidence from the following studies:</p> <h5>Intravenous Use</h5> <p>A randomized withdrawal efficacy, safety, and pharmacokinetic study of intravenous ORENCIA in 190 pediatric patients 6 to 17 years of age with pJIA [see <b>CLINICAL PHARMACOLOGY</b> and <b>Clinical Studies</b>]. Given that population pharmacokinetic (PK) analyses (after intravenous ORENCIA administration) showed that clearance of abatacept increased with baseline body weight, intravenous ORENCIA is administered either weight-based or weight ranged based [see <b>DOSAGE AND ADMINISTRATION</b>]. Intravenous ORENCIA administration has not been studied in patients younger than 6 years of age.</p> <h5>Subcutaneous Use</h5> <p>An open-label PK and safety study of subcutaneous ORENCIA in 205 pediatric patients aged 2 to 17 years old with pJIA, extrapolation of effectiveness of intravenous ORENCIA in patients with pJIA and subcutaneous ORENCIA in patients with RA [see <b>CLINICAL PHARMACOLOGY</b> and <b>Clinical Studies</b>]. Given that population PK analyses (after subcutaneous ORENCIA injection) in pJIA patients showed that there was a trend toward higher clearance of abatacept with increasing body weight, subcutaneous ORENCIA dosage is weight range-based [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>The safety and efficacy of ORENCIA in pediatric patients for uses other than pJIA have not been established. The safety and effectiveness of ORENCIA in pediatric patients less than two years old has not be established.</p> <p>It is unknown if abatacept can cross the placenta into the fetus when a woman is treated with ORENCIA during pregnancy. Since abatacept is an immunomodulatory agent, the safety of administering live vaccines in infants exposed <i>in utero</i> to abatacept is unknown. Risk and benefits should be considered prior to vaccinating such infants.</p> <h5>Juvenile Animal Toxicity Data</h5> <p>A juvenile animal study conducted in rats dosed with abatacept from 4 to 94 days of age (prior to immune system maturity) showed an increase in the incidence of infections leading to death at all doses compared with controls. Altered T-cell subsets including increased T-helper cells and reduced T-regulatory cells were observed. In addition, inhibition of T-cell-dependent antibody responses (TDAR) was observed. Upon following these animals into adulthood, <a href="/lymphocytic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lymphocytic</a> inflammation of the thyroid and pancreatic islets was observed. In contrast, studies in adult mice and monkeys have not demonstrated similar findings. As the immune system of the rat is undeveloped in the first few weeks after birth, the relevance of these results to humans is unknown.</p> <h4>Geriatric Use</h4> <p>A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received ORENCIA in clinical studies. No overall differences in safety or effectiveness were observed between geriatric patients (patients aged 65 years of age and older) and younger adults, and other reported clinical experience has not identified differences in responses between geriatric patients and younger adults, but greater sensitivity of some geriatric patients cannot be ruled out. The frequency of serious infection and <a href="/malignancy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">malignancy</a> among ORENCIA-treated patients over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies in the geriatric population in general, caution should be used when treating geriatric patients.</p> </div> </div> </div> | <a name="W"></a> <h3>WARNINGS</h3> <p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a> <h3>PRECAUTIONS</h3> <h4>Concomitant Use With TNF Antagonists, Other Biologic RA/PsA Therapy, Or JAK Inhibitors</h4> <p>In controlled clinical trials in patients with adult RA, patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63% vs. 43%) and serious infections (4.4% vs. 0.8%) compared to patients treated with only TNF antagonists [see <b>ADVERSE REACTIONS</b>]. These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of ORENCIA with TNF antagonists; therefore, concurrent therapy with ORENCIA and a TNF antagonist is not recommended. While transitioning from TNF antagonist therapy to ORENCIA therapy, patients should be monitored for signs of infection. Additionally, concomitant use of ORENCIA with other biologic RA/PsA therapy or JAK inhibitors is not recommended.</p> <h4>Hypersensitivity</h4> <p>In clinical trials of 2688 adult RA patients treated with intravenous ORENCIA, there were two cases (<0.1%) of anaphylaxis reactions. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients. Of the 190 ORENCIA-treated patients in pJIA clinical trials, there was one case of a hypersensitivity reaction (0.5%) [see <b>ADVERSE REACTIONS</b>].</p> <p>In postmarketing experience, fatal anaphylaxis following the first infusion of ORENCIA and life-threatening cases of angioedema have been reported. Angioedema has occurred as early as after the first dose of ORENCIA, but also has occurred with subsequent doses. Angioedema reactions have occurred within hours of administration and in some instances had a delayed onset (i.e., days).</p> <p>Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction. If an anaphylactic or other serious allergic reaction occurs, administration of intravenous or subcutaneous ORENCIA should be stopped immediately with appropriate therapy instituted, and the use of ORENCIA should be permanently discontinued.</p> <h4>Infections</h4> <p>Serious infections, including <a href="/sepsis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">sepsis</a> and pneumonia, have been reported in patients receiving ORENCIA (serious infections were reported in 3% and 1.9% of RA patients treated with intravenous ORENCIA and placebo, respectively) [see <b>ADVERSE REACTIONS</b>]. Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant <a href="/immunosuppressive/definition.htm" ">immunosuppressive</a> therapy which in addition to their underlying disease, could further <a href="/predispose/definition.htm" ">predispose</a> them to infection. A higher rate of serious infections has been observed in adult RA patients treated with concurrent TNF antagonists and ORENCIA compared to those treated with ORENCIA alone [see <b>Concomitant Use With TNF Antagonists, Other Biologic RA/PsA Therapy, Or JAK Inhibitors</b>].</p> <p>Healthcare providers should <a href="/exercise/article.htm" rel="sub" onclick="wmdTrack('embd-lnk');">exercise</a> caution when considering the use of ORENCIA in patients with a history of <a href="/recurrent/definition.htm" ">recurrent</a> infections, underlying conditions which may predispose them to infections, or chronic, <a href="/latent/definition.htm" ">latent</a>, or localized infections. Patients who develop a new infection while undergoing treatment with ORENCIA should be monitored closely. Administration of ORENCIA should be discontinued if a patient develops a serious infection.</p> <p>Prior to initiating ORENCIA, patients should be screened for latent <a href="/tuberculosis_tb_facts/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">tuberculosis</a> (<a href="/tb/definition.htm" ">TB</a>) infection with a <a href="/tuberculin/definition.htm" ">tuberculin</a> skin test. ORENCIA has not been studied in patients with a positive TB screen, and the safety of ORENCIA in individuals with latent TB infection is unknown. Patients testing positive in TB screening should be treated by standard medical practice prior to therapy with ORENCIA.</p> <p>Antirheumatic therapies have been associated with <a href="/viral_hepatitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">hepatitis</a> B reactivation. Therefore, screening for <a href="/viral_hepatitis/definition.htm" ">viral hepatitis</a> should be performed in accordance with published guidelines before starting therapy with ORENCIA. In clinical studies with ORENCIA, patients who screened positive for hepatitis were excluded from study.</p> <h4>Immunizations</h4> <p>Prior to initiating ORENCIA in pediatric and adult patients, update vaccinations in accordance with current <a href="/vaccination/definition.htm" ">vaccination</a> guidelines. ORENCIA-treated patients may receive current non-live <a href="/vaccines/definition.htm" ">vaccines</a>. Live vaccines should not be given concurrently with ORENCIA or within 3 months after discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. Based on its mechanism of action, ORENCIA may blunt the effectiveness of some immunizations.</p> <h4>Use In Patients With Chronic Obstructive Pulmonary Disease (COPD)</h4> <p>In Study V, adult COPD patients treated with ORENCIA for RA developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. A greater percentage of patients treated with ORENCIA developed a serious adverse event compared to patients treated with placebo (27% vs 6%) [see <b>Clinical Studies</b> and <b>ADVERSE REACTIONS</b>]. Use of ORENCIA in patients with COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status.</p> <h4>Immunosuppression</h4> <p>The possibility exists for drugs inhibiting T cell activation, including ORENCIA, to affect host defenses against infections and malignancies since T cells mediate cellular immune responses. In clinical trials in patients with adult RA, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo-treated patients [see <b>Infections</b> and <b>ADVERSE REACTIONS</b>]. The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood [see <b>ADVERSE REACTIONS</b>]. There have been reports of malignancies, including <a href="/skin_cancer/definition.htm" ">skin cancer</a> in patients receiving ORENCIA [see <b>ADVERSE REACTIONS</b>]. Periodic skin examinations are recommended for all ORENCIA-treated patients, particularly those with risk factors for skin cancer.</p> <h4>Patient Counseling Information</h4> <p>Advise the patient to read the FDA-approved patient labeling (<b>PATIENT INFORMATION and Instructions for Use</b>).</p> <h5>Concomitant Use With Immunosuppressants For RA</h5> <p>Inform patients that the concomitant use with other immunosuppressives (e.g., biologic DMARDs, JAK inhibitors) is not recommended [see <b>WARNINGS AND PRECAUTIONS</b> and <b>DRUG INTERACTIONS</b>].</p> <h5>Hypersensitivity</h5> <p>Instruct patients to immediately tell their healthcare professional if they experience symptoms of an allergic reaction on the day of administration or the day after ORENCIA administration [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Infections</h5> <p>Inform patients that serious infections have been reported in patients receiving ORENCIA [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Immunizations</h5> <p>Inform patients that live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <h5>Pregnancy</h5> <p>Inform patients that there is a Pregnancy Exposure Registry [see <b>Use In Specific Populations</b>.</p> <h5>Blood Glucose Testing</h5> <p>Maltose is contained in ORENCIA for intravenous administration and can give falsely elevated blood glucose readings with certain blood glucose monitors on the day of ORENCIA infusion. Advise patients treated with intravenous ORENCIA who are using GDH-PQQ-based monitoring systems for glucose (e.g., diabetics) to consider using other methods for glucose monitoring. This recommendation is not applicable to patients treated with subcutaneous ORENCIA [see <b>DRUG INTERACTIONS</b>].</p> <h5>Disposal Of Prefilled Syringes And ClickJect Autoinjectors</h5> <p>Advise patients to follow disposal instructions in the Instructions for Use. A puncture-resistant container for disposal of needles and syringes should be used. Instruct patients that they will need to follow their community guidelines for the correct way to dispose of their sharps disposal container. Instruct patients not to recycle their used sharps disposal container.</p> <h4>Nonclinical Toxicology</h4> <h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4> <p>In a mouse carcinogenicity study, weekly subcutaneous injections of 20, 65, or 200 mg/kg of abatacept administered for up to 84 weeks in males and 88 weeks in females were associated with increases in the incidence of <a href="/malignant/definition.htm" ">malignant</a> lymphomas (all doses) and <a href="/mammary_gland/definition.htm" ">mammary gland</a> tumors (intermediate- and high-dose in females). The mice from this study were infected with murine <a href="/leukemia/definition.htm" ">leukemia</a> virus and mouse mammary tumor virus. These <a href="/viruses/definition.htm" ">viruses</a> are associated with an increased incidence of lymphomas and mammary <a href="/gland/definition.htm" ">gland</a> tumors, respectively, in immunosuppressed mice. The doses used in these studies produced exposures 0.8, 2.0, and 3.0 times higher, respectively, than the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve). The relevance of these findings to the clinical use of ORENCIA is unknown.</p> <p>In a one-year toxicity study in cynomolgus monkeys, abatacept was administered intravenously once weekly at doses up to 50 mg/kg (producing 9 times the MRHD exposure based on AUC). Abatacept was not associated with any significant drug-related toxicity. Reversible pharmacological effects consisted of minimal transient decreases in serum <a href="/igg/definition.htm" ">IgG</a> and minimal to severe <a href="/lymphoid/definition.htm" ">lymphoid</a> depletion of germinal centers in the <a href="/spleen/definition.htm" ">spleen</a> and/or lymph nodes. No evidence of lymphomas or preneoplastic morphologic changes was observed, despite the presence of a virus (lymphocryptovirus) known to cause these lesions in immunosuppressed monkeys within the time frame of this study. The relevance of these findings to the clinical use of ORENCIA is unknown.</p> <p>No mutagenic potential of abatacept was observed in the <i>in vitro</i> bacterial reverse mutation (Ames) or Chinese hamster ovary/hypoxanthine <a href="/guanine/definition.htm" ">guanine</a> phosphoribosyl-transferase (CHO/HGPRT) forward <a href="/point_mutation/definition.htm" ">point mutation</a> assays with or without metabolic activation, and no chromosomal aberrations were observed in human lymphocytes treated with abatacept with or without metabolic activation.</p> <p>Abatacept had no adverse effects on male or female fertility in rats at doses up to 200 mg/kg every three days (11 times the MRHD exposure based on AUC).</p> <a name="USP"></a> <h4>Use In Specific Populations</h4> <h4>Pregnancy</h4> <h5>Pregnancy Exposure Registry</h5> <p>There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ORENCIA during pregnancy. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-311-8972.</p> <h5>Risk Summary</h5> <p>The data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk. In reproductive <a href="/toxicology/definition.htm" ">toxicology</a> studies in rats and rabbits, no fetal malformations were observed with intravenous administration of ORENCIA during organogenesis at doses that produced exposures approximately 29 times the exposure at the maximum recommended human dose (MRHD) of 10 mg/kg/month on an AUC basis. However, in a pre- and postnatal development study in rats, ORENCIA altered immune function in female rats at 11 times the MRHD on an AUC basis.</p> <h5>Data</h5> <p><i>Human Data</i></p> <p>There are no adequate and well-controlled studies of ORENCIA use in pregnant women. The data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk.</p> <p><i>Animal Data</i></p> <p>Intravenous administration of abatacept during organogenesis to mice (10, 55, or 300 mg/kg/day), rats (10, 45, or 200 mg/kg/day), and rabbits (10, 45, or 200 mg/kg every 3 days) produced exposures in rats and rabbits that were approximately 29 times the MRHD on an AUC basis (at maternal doses of 200 mg/kg/day in rats and rabbits), and no embryotoxicity or fetal malformations were observed in any species.</p> <p>In a study of pre- and postnatal development in rats (10, 45, or 200 mg/kg every 3 days from gestation day 6 through lactation day 21), alterations in immune function in female offspring, consisting of a 9-fold increase in T-cell-dependent antibody response relative to controls on postnatal day (PND) 56 and <a href="/thyroiditis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">thyroiditis</a> in a single female pup on PND 112, occurred at approximately 11 times the MRHD on an AUC basis (at a maternal dose of 200 mg/kg). No adverse effects were observed at approximately 3 times the MRHD (a maternal dose of 45 mg/kg). It is not known if immunologic perturbations in rats are relevant indicators of a risk for development of <a href="/autoimmune/definition.htm" ">autoimmune</a> diseases in humans exposed <i>in utero</i> to abatacept. Exposure to abatacept in the juvenile rat, which may be more representative of the fetal <a href="/immune_system/definition.htm" ">immune system</a> state in the human, resulted in immune system abnormalities including inflammation of the thyroid and pancreas [see <b>Nonclinical Toxicology</b>].</p> <h4>Lactation</h4> <h5>Risk Summary</h5> <p>There is no information regarding the presence of abatacept in human milk, the effects on the breastfed infant, or the effects on milk production. However, abatacept was present in the milk of lactating rats dosed with abatacept.</p> <h4>Pediatric Use</h4> <p>The safety and effectiveness of ORENCIA for reducing signs and symptoms in patients 2 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis (pJIA) have been established (ORENCIA may be used as monotherapy or concomitantly with methotrexate). Use of ORENCIA for this indication is supported by evidence from the following studies:</p> <h5>Intravenous Use</h5> <p>A randomized withdrawal efficacy, safety, and pharmacokinetic study of intravenous ORENCIA in 190 pediatric patients 6 to 17 years of age with pJIA [see <b>CLINICAL PHARMACOLOGY</b> and <b>Clinical Studies</b>]. Given that population pharmacokinetic (PK) analyses (after intravenous ORENCIA administration) showed that clearance of abatacept increased with baseline body weight, intravenous ORENCIA is administered either weight-based or weight ranged based [see <b>DOSAGE AND ADMINISTRATION</b>]. Intravenous ORENCIA administration has not been studied in patients younger than 6 years of age.</p> <h5>Subcutaneous Use</h5> <p>An open-label PK and safety study of subcutaneous ORENCIA in 205 pediatric patients aged 2 to 17 years old with pJIA, extrapolation of effectiveness of intravenous ORENCIA in patients with pJIA and subcutaneous ORENCIA in patients with RA [see <b>CLINICAL PHARMACOLOGY</b> and <b>Clinical Studies</b>]. Given that population PK analyses (after subcutaneous ORENCIA injection) in pJIA patients showed that there was a trend toward higher clearance of abatacept with increasing body weight, subcutaneous ORENCIA dosage is weight range-based [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>The safety and efficacy of ORENCIA in pediatric patients for uses other than pJIA have not been established. The safety and effectiveness of ORENCIA in pediatric patients less than two years old has not be established.</p> <p>It is unknown if abatacept can cross the placenta into the fetus when a woman is treated with ORENCIA during pregnancy. Since abatacept is an immunomodulatory agent, the safety of administering live vaccines in infants exposed <i>in utero</i> to abatacept is unknown. Risk and benefits should be considered prior to vaccinating such infants.</p> <h5>Juvenile Animal Toxicity Data</h5> <p>A juvenile animal study conducted in rats dosed with abatacept from 4 to 94 days of age (prior to immune system maturity) showed an increase in the incidence of infections leading to death at all doses compared with controls. Altered T-cell subsets including increased T-helper cells and reduced T-regulatory cells were observed. In addition, inhibition of T-cell-dependent antibody responses (TDAR) was observed. Upon following these animals into adulthood, <a href="/lymphocytic/definition.htm" ">lymphocytic</a> inflammation of the thyroid and pancreatic islets was observed. In contrast, studies in adult mice and monkeys have not demonstrated similar findings. As the immune system of the rat is undeveloped in the first few weeks after birth, the relevance of these results to humans is unknown.</p> <h4>Geriatric Use</h4> <p>A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received ORENCIA in clinical studies. No overall differences in safety or effectiveness were observed between geriatric patients (patients aged 65 years of age and older) and younger adults, and other reported clinical experience has not identified differences in responses between geriatric patients and younger adults, but greater sensitivity of some geriatric patients cannot be ruled out. The frequency of serious infection and <a href="/malignancy/definition.htm" ">malignancy</a> among ORENCIA-treated patients over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies in the geriatric population in general, caution should be used when treating geriatric patients.</p> </div> </div> </div> | 10 | 2023-02-01 17:39:31 | Abatacept (Orencia) | A | DMARDs, Immunomodulators | Orencia | abatacept | Orencia | |
| 77 | 2023-02-23 12:07:03 | Overdose & Contraindications | <a name="OD"></a> <h3>OVERDOSE</h3> <p>ORENCIA doses up to 50 mg/kg (5 times the maximum recommended dose in patients aged 6 years and older and 3.3 times the maximum recommended dose in patients aged 2 to less than 6 years) have been administered intravenously without apparent toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate <a href="/symptomatic_treatment/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">symptomatic treatment</a> instituted.</p> <a name="CI"></a> <h3>CONTRAINDICATIONS</h3> <p>None.</p> </div> </div> </div> | <a name="OD"></a> <h3>OVERDOSE</h3> <p>ORENCIA doses up to 50 mg/kg (5 times the maximum recommended dose in patients aged 6 years and older and 3.3 times the maximum recommended dose in patients aged 2 to less than 6 years) have been administered intravenously without apparent toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate <a href="/symptomatic_treatment/definition.htm" ">symptomatic treatment</a> instituted.</p> <a name="CI"></a> <h3>CONTRAINDICATIONS</h3> <p>None.</p> </div> </div> </div> | 10 | 2023-02-01 17:39:31 | Abatacept (Orencia) | A | DMARDs, Immunomodulators | Orencia | abatacept | Orencia | |
| 78 | 2023-02-23 12:07:03 | Clinical Pharmacology | <a name="CP"></a> <h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism Of Action</h4> <p>Abatacept, a selective costimulation modulator, inhibits T cell (T <a href="/lymphocyte/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lymphocyte</a>) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. Activated T lymphocytes are implicated in the <a href="/pathogenesis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pathogenesis</a> of RA, pJIA and PsA and are found in the synovium of patients with RA, pJIA and PsA.</p> <p>In vitro, abatacept decreases T cell proliferation and inhibits the production of the cytokines TNF alpha (TNFα), interferon-γ, and <a href="/interleukin-2/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">interleukin-2</a>. In a rat <a href="/collagen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">collagen</a>-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production, and reduces antigen specific production of interferon-γ. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its clinical effects is unknown.</p> <h4>Pharmacodynamics</h4> <p>In clinical trials with ORENCIA at doses approximating 10 mg/kg, decreases were observed in serum levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), <a href="/rheumatoid_factor/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">rheumatoid factor</a> (<a href="/rf/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">RF</a>), <a href="/c-reactive_protein_test_crp/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">C-reactive protein</a> (<a href="/crp/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">CRP</a>), matrix metalloproteinase-3 (MMP3), and TNFα. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its clinical effects is unknown.</p> <p>No formal pharmacodynamic analyses of biologic response markers have been performed in patients exposed to ORENCIA as prophylaxis for aGVHD.</p> <h4>Pharmacokinetics</h4> <h5>Healthy Adults And Adult RA -Intravenous Administration</h5> <p>The pharmacokinetics of abatacept were studied in healthy adult subjects after a single 10 mg/kg intravenous infusion and in RA patients after multiple 10 mg/kg intravenous infusions of ORENCIA (see Table 6).</p> <p align="center"><b>Table 6: Pharmacokinetic Parameters (Mean, Range) in Healthy Subjects and RA Patients After 10 mg/kg ORENCIA Intravenous Infusion(s)</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">PK Parameter</td> <td class="EmphTd" width="25%">Healthy Subjects (After 10 mg/kg Single Dose)<br /> n=13</td> <td class="EmphTd" width="25%">RA Patients (After 10 mg/kg Multiple Doses<sup>a</sup>)<br /> n=14</td> </tr> <tr> <td>Peak Concentration (Cmax) [mcg/mL]</td> <td align="center">292 (175-427)</td> <td align="center">295 (171-398)</td> </tr> <tr> <td>Terminal half-life (t½) [days]</td> <td align="center">16.7 (12-23)</td> <td align="center">13.1 (8-25)</td> </tr> <tr> <td>Systemic clearance (CL) [mL/h/kg]</td> <td align="center">0.23 (0.16-0.30)</td> <td align="center">0.22 (0.13-0.47)</td> </tr> <tr> <td>Volume of distribution (Vss) [L/kg]</td> <td align="center">0.09 (0.06-0.13)</td> <td align="center">0.07 (0.02-0.13)</td> </tr> <tr> <td class="credit" colspan="3"><sup>a </sup>Multiple intravenous infusions of ORENCIA were administered at days 1, 15, 30, and monthly thereafter.</td> </tr> </tbody> </table> </center> <p></p> <p>The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be comparable. In RA patients, after multiple intravenous infusions, the pharmacokinetics of abatacept showed proportional increases of Cmax and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady state by day 60 with a mean (range) trough concentration of 24 mcg/mL (1 to 66 mcg/mL). No systemic accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at monthly intervals in RA patients.</p> <p>Population pharmacokinetic analyses in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect clearance. Concomitant methotrexate, NSAIDs, corticosteroids, and TNF antagonists did not influence abatacept clearance.</p> <p>No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of abatacept.</p> <h5>Adult RA -Subcutaneous Administration</h5> <p>Abatacept exhibited linear pharmacokinetics following subcutaneous administration. The mean (range) for Cmin and Cmax at steady state observed after 85 days of treatment was 32.5 mcg/mL (6.6 to 113.8 mcg/mL) and 48.1 mcg/mL (9.8 to 132.4 mcg/mL), respectively. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration was 79%. Mean estimates for systemic clearance (0.28 mL/h/kg), volume of distribution (0.11 L/kg), and terminal half-life (14.3 days) were comparable between subcutaneous and intravenous administration.</p> <p>Study SC-2 was conducted to determine the effect of subcutaneous monotherapy use of ORENCIA on immunogenicity (without an intravenous loading dose) in 100 RA patients [see <b>ADVERSE REACTIONS</b>]. In this study, a mean trough concentration of 12.6 mcg/mL was achieved after 2 weeks of dosing.</p> <p>Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous ORENCIA in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight [see<b> DOSAGE AND ADMINISTRATION</b>]. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent clearance.</p> <h5>Polyarticular Juvenile Idiopathic Arthritis -Intravenous Administration</h5> <p>In Study JIA-1 among patients 6 to 17 years of age, the mean (range) steady state serum peak and trough concentrations of abatacept were 217 mcg/mL (57 to 700 mcg/mL) and 11.9 mcg/mL (0.15 to 44.6 mcg/mL) [see <b>Clinical Studies</b>]. Population pharmacokinetic analyses of the serum concentration data showed that clearance of abatacept increased with baseline body weight [see<b> DOSAGE AND ADMINISTRATION</b>]. The estimated mean (range) clearance of abatacept in the juvenile idiopathic arthritis patients was 0.4 mL/h/kg (0.20 to 1.12 mL/h/kg). After accounting for the effect of body weight, the clearance of abatacept was not related to age and gender. Concomitant methotrexate, corticosteroids, and NSAIDs were also shown not to influence abatacept clearance.</p> <h5>Polyarticular Juvenile Idiopathic Arthritis -Subcutaneous Administration</h5> <p>In Study JIA-2 among patients 2 to 17 years of age, steady state of abatacept was achieved by Day 85 following the weekly body-weight–tiered subcutaneous ORENCIA dosing [see <b>Clinical Studies</b>]. Comparable trough concentrations across weight tiers and age groups were achieved by the body-weight–tiered subcutaneous dosing regimen. The mean (range) trough concentration of abatacept at Day 113 was 44.4 mcg/mL (13.4 to 88.1 mcg/mL), 46.6 mcg/mL (22.4 to 97.0 mcg/mL), and 38.5 mcg/mL (9.3 to 73.2 mcg/mL) in pediatric JIA patients weighing 10 to <25 kg, 25 to <50 kg, and ≥50 kg, respectively.</p> <p>Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous ORENCIA in JIA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight [see <b>DOSAGE AND ADMINISTRATION</b>]. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent clearance.</p> <h5>Adult Psoriatic Arthritis -Intravenous And Subcutaneous Administration</h5> <p>In Study PsA-I, a dose ranging study, intravenous ORENCIA was administered at 3 mg/kg, weight range-based dosing: 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg, or doses of 30 mg/kg on Days 1 and 15 followed by weight-range-based dosing [see <b>Clinical Studies</b>]. Following monthly intravenous ORENCIA administration, abatacept showed linear PK over the dose range in this study. At the weight-range-based dosing (see above), the steady state of abatacept was reached by Day 57 and the geometric mean (CV%) trough concentration (Cmin) was 24.3 mcg/mL (40.8%) at Day 169. In Study PsA-II following weekly subcutaneous administration of ORENCIA at 125 mg, the steady state of abatacept was reached at Day 57 and the geometric mean (CV%) Cmin was 25.6 mcg/mL (47.7%) at Day 169.</p> <p>Consistent with the RA results, population pharmacokinetic analyses for abatacept in PsA patients revealed that there was a trend toward higher clearance (L/h) of abatacept with increasing body weight [see <b>DOSAGE AND ADMINISTRATION</b>]. In addition, relative to the RA patients with the same body weight, abatacept clearance in PsA patients was approximately 8% lower, resulting in higher abatacept exposures in patients with PsA. This slight difference in exposures, however, is not considered to be clinically meaningful.</p> <h5>Prophylaxis Of Acute Graft versus Host Disease – Intravenous Administration</h5> <p align="center"><b>Table 7: Pharmacokinetic Parameters (Mean, Range) in Subjects Undergoing HSCT from a Matched or 1 Allele-Mismatched Unrelated Donor in Study GVHD-1</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">PK Parameter</td> <td class="EmphTd" width="25%">7 of 8 Cohort<br /> n=42</td> <td class="EmphTd" width="25%">8 of 8 Cohort<br /> n=73</td> </tr> <tr> <td>Minimum Concentration (Cmin) <sup>a</sup> [mcg/mL]</td> <td align="center">59 (26-112)</td> <td align="center">43 (25-73)</td> </tr> <tr> <td>Peak Concentration (Cmax) [mcg/mL]</td> <td align="center">221 (163-292)</td> <td align="center">172 (107-254)</td> </tr> <tr> <td>Terminal half-life (t½) [days]</td> <td align="center">20.6 (6-43)</td> <td align="center">20.8 (12-38)</td> </tr> <tr> <td>Systemic clearance (CL) [mL/h/kg]</td> <td align="center">0.26 (0.15-0.65)</td> <td align="center">0.32 (0.18-0.56)</td> </tr> <tr> <td>Volume of distribution (Vss) [L/kg]</td> <td align="center">0.13 (0.08-0.27)</td> <td align="center">0.17 (0.11-0.26)</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Cmin observed on Day 5 of the treatment period; n = 18 for the 7/8 Cohort; n = 32 for the 8/8 Cohort. Cmax, t½, CL, and Vss are model predicted after first 10 mg/kg ORENCIA intravenous infusion.</td> </tr> </tbody> </table> </center> <p></p> <p>In a study of patients who received ORENCIA for prophylaxis of acute Graft Versus Host Disease (aGVHD) aged 6 years and older, the geometric mean (%CV) trough concentrations (Cmin) of abatacept on Day 63 after transplant after 4 doses utilizing weight-based dosing of 10 mg/kg (maximum dose of 1,000 mg) administered on the day before transplantation (Day -1), followed by a dose on Day 5, 14, and 28 after transplant, were 22.5 mcg/mL (243.9 %CV) for recipients of 8 of 8 Human leukocyte antigen (HLA)-matched HSCTs from unrelated donors (URD), and 31.1 mcg/mL (114.4 %CV) for recipients of 7 of 8 HLA-matched HSCTs from unrelated donors (URD), respectively.</p> <p>Population pharmacokinetic analyses in patients with aGVHD demonstrated that 7 of 8 HLA-matched HSCT recipients had 29% lower clearance compared to 8 of 8 HLA-matched HSCT recipients. Consistent with previous data, increasing body weight was associated with higher clearance of abatacept, while age (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate and calcineurin inhibitors (e.g., cyclosporine and tacrolimus), did not influence abatacept clearance.</p> <p>Based on population PK modeling and simulation with data from patients aged 6 and older, simulated exposures of abatacept following the first and last dose in pediatric subjects 2 to less than 6 years of age who received 15 mg/kg of ORENCIA via 60-minute intravenous infusion on Day -1, followed by 12 mg/kg via 60-minute intravenous infusion on Day 5, 14, and 28 are comparable to those in pediatric patients 6 to less than 17 years of age and adults patients who received 10 mg/kg via 60-minute intravenous infusion on Day -1, 5, 14, and 28.</p> <a name="AP"></a> <h4>Animal Toxicology And/Or Pharmacology</h4> <p>In studies of adult mice and monkeys, inhibition of TDAR was apparent. However, infection and mortality, altered T-helper cells, and inflammation of thyroid and pancreas were not observed.</p> <a name="CS"></a> <h4>Clinical Studies</h4> <h4>Adult Rheumatoid Arthritis</h4> <h5>Description Of Clinical Studies Of Intravenous ORENCIA For The Treatment Of Patients With RA</h5> <p>The efficacy and safety of ORENCIA for intravenous administration were assessed in six randomized, double-blind, controlled studies (five placebo-controlled and one active-controlled) in patients ≥18 years of age with active RA diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, IV, and VI required patients to have at least 12 tender and 10 swollen joints at randomization, and Study V did not require any specific number of tender or swollen joints. ORENCIA or placebo treatment was given intravenously at weeks 0, 2, and 4 and then every 4 weeks thereafter in Studies I, II, III, IV, and VI.</p> <ul> <li>Study I evaluated ORENCIA as monotherapy in 122 patients with active RA who had failed at least one non-biologic DMARD or etanercept.</li> <li>In Study II and Study III, the efficacy of ORENCIA were assessed in patients with an inadequate response to MTX and who were continued on their stable dose of MTX.</li> <li>In Study IV, the efficacy of ORENCIA was assessed in patients with an inadequate response to a TNF antagonist, with the TNF antagonist discontinued prior to randomization; other DMARDs were permitted.</li> <li>Study V primarily assessed safety in patients with active RA requiring additional intervention in spite of current therapy with DMARDs; all DMARDs used at enrollment were continued. Patients in Study V were not excluded for comorbid medical conditions.</li> <li>In Study VI, the efficacy and safety of ORENCIA were assessed in methotrexate-naive patients with RA of less than 2 years disease duration. In Study VI, patients previously naive to methotrexate were randomized to receive ORENCIA plus methotrexate or methotrexate plus placebo.</li> </ul> <p>Study I patients were randomized to receive one of three doses of ORENCIA (0.5, 2, or 10 mg/kg) or placebo ending at week 8. Study II patients were randomized to receive ORENCIA 2 or 10 mg/kg or placebo for 12 months. Study III, IV, V, and VI patients were randomized to receive a dose of ORENCIA based on weight range or placebo for 12 months (Studies III, V, and VI) or 6 months (Study IV). The dose of ORENCIA was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg.</p> <p><i>Description Of Clinical Studies Of Subcutaneous Or Intravenous ORENCIA For The Treatment Of Patients With Adult RA</i></p> <p>The efficacy of ORENCIA for subcutaneous administration were assessed in Study SC-1, which was a randomized, double-blind, double-dummy, non-inferiority study that compared ORENCIA administered subcutaneously to ORENCIA administered intravenously in 1457 patients with moderate to severely active RA, receiving background methotrexate (MTX), and experiencing an inadequate response to methotrexate (MTX-IR). In Study SC-1, patients were randomized with stratification by body weight (<60 kg, 60 to 100 kg, >100 kg) to receive (1) ORENCIA 125 mg subcutaneous injections weekly, after a single intravenous loading dose of ORENCIA based on body weight or (2) ORENCIA intravenously on Days 1, 15, 29, and every four weeks thereafter. Subjects continued taking their current dose of MTX from the day of randomization.</p> <h5>Clinical Response In Adult RA Patients</h5> <p>The percent of ORENCIA-treated patients achieving ACR 20, 50, and 70 responses and major clinical response in Studies I, III, IV, and VI are shown in Table 8. ORENCIA-treated patients had higher ACR 20, 50, and 70 response rates at 6 months compared to placebo-treated patients. Month 6 ACR response rates in Study II for the 10 mg/kg group were similar to the ORENCIA group in Study III.</p> <p>In Studies III and IV, improvement in the ACR 20 response rate versus placebo was observed within 15 days in some patients and within 29 days versus MTX in Study VI. In Studies II, III, and VI, ACR response rates were maintained to 12 months in ORENCIA-treated patients. ACR responses were maintained up to three years in the open-label extension of Study II. In Study III, ORENCIA-treated patients experienced greater improvement than placebo-treated patients in morning stiffness.</p> <p>In Study VI, a greater proportion of patients treated with ORENCIA plus MTX achieved a low level of disease activity as measured by a DAS28-CRP less than 2.6 at 12 months compared to those treated with MTX plus placebo (Table 8). Of patients treated with ORENCIA plus MTX who achieved DAS28-CRP less than 2.6, 54% had no active joints, 17% had one active joint, 7% had two active joints, and 22% had three or more active joints, where an active joint was a joint that was rated as tender or swollen or both.</p> <p>In Study SC-1, the main outcome measure was ACR 20 at 6 months. The pre-specified non-inferiority margin was a treatment difference of -7.5%. As shown in Table 9, the study demonstrated non-inferiority of ORENCIA administered subcutaneously to intravenous infusions of ORENCIA with respect to ACR 20 responses up to 6 months of treatment. ACR 50 and 70 responses are also shown in Table 8. No major differences in ACR responses were observed between intravenous and subcutaneous treatment groups in subgroups based on weight categories (less than 60 kg, 60 to 100 kg, and more than 100 kg; data not shown).</p> <p align="center"><b>Table 8: Clinical Responses in Controlled Trials in Patients with RA</b></p> <center> <table cellspacing="0" class="blacktbl" width="750"> <tbody> <tr> <td class="EmphTd" rowspan="5" width="20%">Response Rate</td> <td class="EmphTd" colspan="8">Percent of Patients</td> <td class="EmphTd" colspan="2" rowspan="2">Subcutaneous or Intravenous Administration</td> </tr> <tr> <td class="EmphTd" colspan="8">Intravenous Administration</td> </tr> <tr> <td class="EmphTd" colspan="2">Inadequate Response to DMARDs</td> <td class="EmphTd" colspan="2">Inadequate Response to Methotrexate (MTX)</td> <td class="EmphTd" colspan="2">Inadequate Response to TNF Antagonists</td> <td class="EmphTd" colspan="2">MTX-Naive</td> <td class="EmphTd" colspan="2">Inadequate Response to MTX</td> </tr> <tr> <td class="EmphTd" colspan="2">Study 1</td> <td class="EmphTd" colspan="2">Study III</td> <td class="EmphTd" colspan="2">Study IV</td> <td class="EmphTd" colspan="2">Study VI</td> <td class="EmphTd" colspan="2">Study SC-1</td> </tr> <tr> <td class="EmphTd" width="8%">ORN<sup>a</sup><br /> n=32</td> <td class="EmphTd" width="8%">PBO<br /> n=32</td> <td class="EmphTd" width="8%">ORN<sup>b</sup> +MTX<br /> n=424</td> <td class="EmphTd" width="8%">PBO +MTX<br /> n=214</td> <td class="EmphTd" width="8%">ORN<sup>b</sup> + DMARDs<br /> n=256</td> <td class="EmphTd" width="8%">PBO + DMARDs<br /> n=133</td> <td class="EmphTd" width="8%">ORN<sup>b</sup> +MTX<br /> n=256</td> <td class="EmphTd" width="8%">PBO +MTX<br /> n=253</td> <td class="EmphTd" width="8%">ORN<sup>e</sup> SC +MTX<br /> n=693</td> <td class="EmphTd" width="8%">ORN<sup>e</sup> IV +MTX<br /> n=678</td> </tr> <tr> <td colspan="11"><b>ACR 20</b></td> </tr> <tr> <td>Month 3</td> <td align="center">53%</td> <td align="center">31%</td> <td align="center">62%‡</td> <td align="center">37%</td> <td align="center">46%‡</td> <td align="center">18%</td> <td align="center">64%*</td> <td align="center">53%</td> <td align="center">68%</td> <td align="center">69%</td> </tr> <tr> <td>Month 6</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">68%‡</td> <td align="center">40%</td> <td align="center">50%‡</td> <td align="center">20%</td> <td align="center">75%†</td> <td align="center">62%</td> <td align="center">76%§</td> <td align="center">76%</td> </tr> <tr> <td>Month 12</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">73%‡</td> <td align="center">40%</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">76%‡</td> <td align="center">62%</td> <td align="center">NA</td> <td align="center">NA</td> </tr> <tr> <td colspan="11"><b>ACR 50</b></td> </tr> <tr> <td>Month 3</td> <td align="center">16%</td> <td align="center">6%</td> <td align="center">32%‡</td> <td align="center">8%</td> <td align="center">18%†</td> <td align="center">6%</td> <td align="center">40%‡</td> <td align="center">23%</td> <td align="center">33%</td> <td align="center">39%</td> </tr> <tr> <td>Month 6</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">40%‡</td> <td align="center">17%</td> <td align="center">20%‡</td> <td align="center">4%</td> <td align="center">53%‡</td> <td align="center">38%</td> <td align="center">52%</td> <td align="center">50%</td> </tr> <tr> <td>Month 12</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">48%‡</td> <td align="center">18%</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">57%‡</td> <td align="center">42%</td> <td align="center">NA</td> <td align="center">NA</td> </tr> <tr> <td colspan="11"><b>ACR 70</b></td> </tr> <tr> <td>Month 3</td> <td align="center">6%</td> <td align="center">0</td> <td align="center">13%‡</td> <td align="center">3%</td> <td align="center">6%*</td> <td align="center">1%</td> <td align="center">19%†</td> <td align="center">10%</td> <td align="center">13%</td> <td align="center">16%</td> </tr> <tr> <td>Month 6</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">20%‡</td> <td align="center">7%</td> <td align="center">10%†</td> <td align="center">2%</td> <td align="center">32%†</td> <td align="center">20%</td> <td align="center">26%</td> <td align="center">25%</td> </tr> <tr> <td>Month 12</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">29%‡</td> <td align="center">6%</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">43%‡</td> <td align="center">27%</td> <td align="center">NA</td> <td align="center">NA</td> </tr> <tr> <td><b>Major Clinical Response <sup>c</sup></b></td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">14%‡</td> <td align="center">2%</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">27%‡</td> <td align="center">12%</td> <td align="center">NA</td> <td align="center">NA</td> </tr> <tr> <td colspan="11"><b>DAS28- CRP <2.6<sup>d</sup></b></td> </tr> <tr> <td>Month 12</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">41%‡</td> <td align="center">23%</td> <td align="center">NA</td> <td align="center">NA</td> </tr> <tr> <td class="credit" colspan="11">* p<0.05, ORENCIA (ORN) vs placebo (PBO) or MTX.<br /> † p<0.01, ORENCIA vs placebo or MTX.<br /> ‡ p<0.001, ORENCIA vs placebo or MTX. § 95% CI: -4.2, 4.8 (based on prespecified margin for non-inferiority of -7.5%).<br /> <sup>a</sup> 10 mg/kg.<br /> <sup>b</sup> Dosing based on weight range [see <b>DOSAGE AND ADMINISTRATION</b>].<br /> <sup>c</sup> Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period.<br /> <sup>d</sup> Refer to text for additional description of remaining joint activity.<br /> <sup>e</sup> Per protocol data is presented in table. For ITT; n=736, 721 for SC and IV ORENCIA, respectively.</td> </tr> </tbody> </table> </center> <p></p> <p>The results of the components of the ACR response criteria for Studies III, IV, and SC-1 are shown in Table 9 (results at Baseline [BL] and 6 months [6 M]). In ORENCIA-treated patients, greater improvement was seen in all ACR response criteria components through 6 and 12 months than in placebo-treated patients.</p> <p align="center"><b>Table 9: Components of ACR Responses at 6 Months in Adult Patients with RA</b></p> <center> <table cellspacing="0" class="blacktbl" width="750"> <tbody> <tr> <td class="EmphTd" rowspan="5" width="16%">Component (median)</td> <td class="EmphTd" colspan="8">Intravenous Administration</td> <td class="EmphTd" colspan="4">Subcutaneous or Intravenous Administration</td> </tr> <tr> <td class="EmphTd" colspan="4">Inadequate Response to MTX</td> <td class="EmphTd" colspan="4">Inadequate Response to TNF Antagonists</td> <td class="EmphTd" colspan="4">Inadequate Response to MTX</td> </tr> <tr> <td class="EmphTd" colspan="4">Study III</td> <td class="EmphTd" colspan="4">Study IV</td> <td class="EmphTd" colspan="4">Study SC-1<sup>c</sup></td> </tr> <tr> <td class="EmphTd" colspan="2">ORN +MTX<br /> n=424</td> <td class="EmphTd" colspan="2">PBO +MTX<br /> n=214</td> <td class="EmphTd" colspan="2">ORN +DMARDs<br /> n=256</td> <td class="EmphTd" colspan="2">PBO +DMARDs<br /> n=133</td> <td class="EmphTd" colspan="2">ORN SC +MTX<br /> n=693</td> <td class="EmphTd" colspan="2">ORN IV +MTX<br /> n=678</td> </tr> <tr> <td class="EmphTd" width="7%">BL</td> <td class="EmphTd" width="7%">6 M</td> <td class="EmphTd" width="7%">BL</td> <td class="EmphTd" width="7%">6 M</td> <td class="EmphTd" width="7%">BL</td> <td class="EmphTd" width="7%">6 M</td> <td class="EmphTd" width="7%">BL</td> <td class="EmphTd" width="7%">6 M</td> <td class="EmphTd" width="7%">BL</td> <td class="EmphTd" width="7%">6 M</td> <td class="EmphTd" width="7%">BL</td> <td class="EmphTd" width="7%">6 M</td> </tr> <tr> <td>Number of tender joints (0-68)</td> <td align="center">28</td> <td align="center">7‡</td> <td align="center">31</td> <td align="center">14</td> <td align="center">30</td> <td align="center">13‡</td> <td align="center">31</td> <td align="center">24</td> <td align="center">27</td> <td align="center">5</td> <td align="center">27</td> <td align="center">6</td> </tr> <tr> <td>Number of swollen joints (0-66)</td> <td align="center">19</td> <td align="center">5‡</td> <td align="center">20</td> <td align="center">11</td> <td align="center">21</td> <td align="center">10‡</td> <td align="center">20</td> <td align="center">14</td> <td align="center">18</td> <td align="center">4</td> <td align="center">18</td> <td align="center">3</td> </tr> <tr> <td>Pain<sup>a</sup></td> <td align="center">67</td> <td align="center">27‡</td> <td align="center">70</td> <td align="center">50</td> <td align="center">73</td> <td align="center">43†</td> <td align="center">74</td> <td align="center">64</td> <td align="center">71</td> <td align="center">25</td> <td align="center">70</td> <td align="center">28</td> </tr> <tr> <td>Patient global assessment<sup>a</sup></td> <td align="center">66</td> <td align="center">29‡</td> <td align="center">64</td> <td align="center">48</td> <td align="center">71</td> <td align="center">44‡</td> <td align="center">73</td> <td align="center">63</td> <td align="center">70</td> <td align="center">26</td> <td align="center">68</td> <td align="center">27</td> </tr> <tr> <td>Disability index<sup>b</sup></td> <td align="center">1.75</td> <td align="center">1.13‡</td> <td align="center">1.75</td> <td align="center">1.38</td> <td align="center">1.88</td> <td align="center">1.38‡</td> <td align="center">2.00</td> <td align="center">1.75</td> <td align="center">1.88</td> <td align="center">1.00</td> <td align="center">1.75</td> <td align="center">1.00</td> </tr> <tr> <td>Physician global assessment<sup>a</sup></td> <td align="center">69</td> <td align="center">21‡</td> <td align="center">68</td> <td align="center">40</td> <td align="center">71</td> <td align="center">32‡</td> <td align="center">69</td> <td align="center">54</td> <td align="center">65</td> <td align="center">16</td> <td align="center">65</td> <td align="center">15</td> </tr> <tr> <td>CRP (mg/dL)</td> <td align="center">2.2</td> <td align="center">0.9‡</td> <td align="center">2.1</td> <td align="center">1.8</td> <td align="center">3.4</td> <td align="center">1.3‡</td> <td align="center">2.8</td> <td align="center">2.3</td> <td align="center">1.6</td> <td align="center">0.7</td> <td align="center">1.8</td> <td align="center">0.7</td> </tr> <tr> <td class="credit" colspan="13">† p<0.01, ORENCIA (ORN) vs placebo (PBO), based on mean percent change from baseline.<br /> ‡ p<0.001, ORENCIA vs placebo, based on mean percent change from baseline.<br /> <sup>a</sup> Visual analog scale: 0 = best, 100 = worst.<br /> <sup>b</sup> Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, alking, hygiene, reach, grip, and activities.<br /> <sup>c</sup> SC-1 is a non-inferiority study. Per protocol data is presented in table.</td> </tr> </tbody> </table> </center> <p></p> <p>The percent of patients achieving the ACR 50 response for Study III by visit is shown in Figure 1. The time course for the ORENCIA group in Study VI was similar to that in Study III.</p> <p align="center"><b>Figure 1: Percent of Patients Achieving ACR 50 Response by Visit* (Study III)</b></p> <center> <table cellspacing="0" class="blackpic" width="432"> <tbody> <tr> <td><img alt="Percent of Patients Achieving ACR 50 Response by Visit* - Illustration" height="393" src="https://images.rxlist.com/images/rxlist/orencia1.gif" width="432" /></td> </tr> </tbody> </table> </center> <p></p> <p>The percent of patients achieving the ACR 50 response for Study SC-1 in the ORENCIA subcutaneous (SC) and intravenous (IV) treatment arms at each treatment visit was as follows: Day 15—SC 3%, IV 5%; Day 29—SC 11%, IV 14%; Day 57—SC 24%, IV 30%; Day 85— SC 33%, IV 38%; Day 113—SC 39%, IV 41%; Day 141—SC 46%, IV 47%; Day 169—SC 51%, IV 50%.</p> <h5>Radiographic Response In Adult RA Patients</h5> <p>In Study III and Study VI, structural joint damage was assessed radiographically and expressed as change from baseline in the Genant-modified Total Sharp Score (TSS) and its components, the <a href="/erosion/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Erosion</a> Score (ES) and Joint Space Narrowing (JSN) score. ORENCIA/MTX slowed the progression of structural damage compared to placebo/MTX after 12 months of treatment as shown in Table 10.</p> <p align="center"><b>Table 10: Mean Radiographic Changes in Study III<sup>a</sup> and Study VI<sup>b</sup></b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="20%">Parameter</td> <td class="EmphTd" width="20%">ORENCIA/ MTX</td> <td class="EmphTd" width="20%">Placebo/ MTX</td> <td class="EmphTd" width="20%">Differences</td> <td class="EmphTd" width="20%">P-value<sup>d</sup></td> </tr> <tr> <td colspan="5"><b>Study III</b></td> </tr> <tr> <td colspan="5"><b>First Year</b></td> </tr> <tr> <td>TSS</td> <td align="center">1.07</td> <td align="center">2.43</td> <td align="center">1.36</td> <td align="center"><0.01</td> </tr> <tr> <td>ES</td> <td align="center">0.61</td> <td align="center">1.47</td> <td align="center">0.86</td> <td align="center"><0.01</td> </tr> <tr> <td>JSN score</td> <td align="center">0.46</td> <td align="center">0.97</td> <td align="center">0.51</td> <td align="center"><0.01</td> </tr> <tr> <td colspan="5"><b>Second Year</b></td> </tr> <tr> <td>TSS</td> <td align="center">0.48</td> <td align="center">0.74<sup>c</sup></td> <td align="center">-</td> <td align="center">-</td> </tr> <tr> <td>ES</td> <td align="center">0.23</td> <td align="center">0.22<sup>c</sup></td> <td align="center">-</td> <td align="center">-</td> </tr> <tr> <td>JSN score</td> <td align="center">0.25</td> <td align="center">0.51<sup>c</sup></td> <td align="center">-</td> <td align="center">-</td> </tr> <tr> <td colspan="5"><b>Study VI</b></td> </tr> <tr> <td colspan="5"><b>First Year</b></td> </tr> <tr> <td>TSS</td> <td align="center">0.6</td> <td align="center">1.1</td> <td align="center">0.5</td> <td align="center">0.04</td> </tr> <tr> <td class="credit" colspan="5"><sup>a </sup>Patients with an inadequate response to MTX.<br /> <sup>b</sup> MTX-naive patients.<br /> <sup>c</sup> Patients received 1 year of placebo/MTX followed by 1 year of ORENCIA/MTX.<br /> <sup>d</sup> Based on a nonparametric ANCOVA model.</td> </tr> </tbody> </table> </center> <p></p> <p>In the open-label extension of Study III, 75% of patients initially randomized to ORENCIA/MTX and 65% of patients initially randomized to placebo/MTX were evaluated radiographically at Year 2. As shown in Table 10, progression of structural damage in ORENCIA/MTX-treated patients was further reduced in the second year of treatment.</p> <p>Following 2 years of treatment with ORENCIA/MTX, 51% of patients had no progression of structural damage as defined by a change in the TSS of zero or less compared with baseline. Fifty-six percent (56%) of ORENCIA/MTX-treated patients had no progression during the first year compared to 45% of placebo/MTX-treated patients. In their second year of treatment with ORENCIA/MTX, more patients had no progression than in the first year (65% vs 56%).</p> <h5>Physical Function Response And Health-Related Outcomes In Adult RA Patients</h5> <p>Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). In the HAQ-DI, ORENCIA demonstrated greater improvement from baseline versus placebo in Studies II-V and versus MTX in Study VI. In Study SC-1, improvement from baseline as measured by HAQ-DI at 6 months and over time was similar between subcutaneous and intravenous ORENCIA administration. The results from Studies II and III are shown in Table 11. Similar results were observed in Study V compared to placebo and in Study VI compared to MTX. During the open-label period of Study II, the improvement in physical function has been maintained for up to 3 years.</p> <p align="center"><b>Table 11: Mean Improvement from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) in Adult Patients with RA</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="3" width="40%">HAQ Disability Index</td> <td class="EmphTd" colspan="4">Inadequate Response to Methotrexate</td> </tr> <tr> <td class="EmphTd" colspan="2">Study II</td> <td class="EmphTd" colspan="2">Study III</td> </tr> <tr> <td class="EmphTd" width="15%">ORENCIA<sup>a</sup>+MTX<br /> (n=115)</td> <td class="EmphTd" width="15%">Placebo+ MTX<br /> (n=119)</td> <td class="EmphTd" width="15%">ORENCIA<sup>b</sup>+ MTX<br /> (n=422)</td> <td class="EmphTd" width="15%">Placebo+ MTX<br /> (n=212)</td> </tr> <tr> <td>Baseline (Mean)</td> <td align="center">0.98<sup>c</sup></td> <td align="center">0.97<sup>c</sup></td> <td align="center">1.69<sup>d</sup></td> <td align="center">1.69<sup>d</sup></td> </tr> <tr> <td colspan="5">Mean Improvement</td> </tr> <tr> <td>Year 1</td> <td align="center">0 40<sup>c</sup>,***</td> <td align="center">0.15<sup>c</sup></td> <td align="center">0.66<sup>d</sup>,***</td> <td align="center">0.37<sup>d</sup></td> </tr> <tr> <td class="credit" colspan="5">*** p<0.001, ORENCIA vs placebo.<br /> <sup>a</sup> 10 mg/kg.<br /> <sup>b</sup> Dosing based on weight range [see <b>DOSAGE AND ADMINISTRATION</b>].<br /> <sup>c</sup> Modified Health Assessment Questionnaire: 0 = best, 3 = worst; 8 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.<br /> <sup>d</sup> Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.</td> </tr> </tbody> </table> </center> <p></p> <p>Health-related <a href="/quality_of_life/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">quality of life</a> was assessed by the SF-36 questionnaire at 6 months in Studies II, III, and IV and at 12 months in Studies II and III. In these studies, improvement was observed in the ORENCIA group as compared with the placebo group in all 8 domains of the SF-36 as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS).</p> <h4>Polyarticular Juvenile Idiopathic Arthritis</h4> <h5>Polyarticular Juvenile Idiopathic Arthritis -Intravenous Administration</h5> <p>The safety and efficacy of ORENCIA with intravenous administration were assessed in Study JIA-1, a three-part study including an open-label extension in pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA). Patients 6 to 17 years of age (n=190) with moderately to severely active pJIA who had an inadequate response to one or more DMARDs, such as MTX or TNF antagonists, were treated. Patients had a disease duration of approximately 4 years with moderately to severely active disease at study entry, as determined by baseline counts of active joints (mean, 16) and joints with loss of motion (mean, 16); patients had elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dL) and <a href="/esr/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ESR</a> (mean, 32 mm/h). The patients enrolled had JIA subtypes that at disease onset included oligoarticular (16%), polyarticular (64%; 20% were rheumatoid factor positive), and systemic JIA without systemic manifestations (20%). At study entry, 74% of patients were receiving MTX (mean dose, 13.2 mg/m² per week) and remained on a stable dose of MTX (those not receiving MTX did not initiate MTX treatment during the study).</p> <p>In Period A (open-label, lead-in), patients received 10 mg/kg (maximum 1,000 mg per dose) intravenously on days 1, 15, 29, and monthly thereafter. Response was assessed utilizing the ACR Pediatric 30 definition of improvement, defined as ≥30% improvement in at least 3 of the 6 JIA core set variables and ≥30% worsening in not more than 1 of the 6 JIA core set variables. Patients demonstrating an ACR Pedi 30 response at the end of Period A were randomized into the double-blind phase (Period B) and received either ORENCIA or placebo for 6 months or until disease flare. Disease flare was defined as a ≥30% worsening in at least 3 of the 6 JIA core set variables with ≥30% improvement in not more than 1 of the 6 JIA core set variables; ≥2 cm of worsening of the Physician or Parent Global Assessment was necessary if used as 1 of the 3 JIA core set variables used to define flare, and worsening in ≥2 joints was necessary if the number of active joints or joints with limitation of motion was used as 1 of the 3 JIA core set variables used to define flare.</p> <p>At the conclusion of Period A, pediatric ACR 30/50/70 responses were 65%, 50%, and 28%, respectively. Pediatric ACR 30 responses were similar in all subtypes of JIA studied.</p> <p>During the double-blind randomized withdrawal phase (Period B), ORENCIA-treated patients (intravenous) experienced significantly fewer disease flares compared to placebo-treated patients (20% vs 53%); 95% CI of the difference (15%, 52%). The risk of disease flare among patients continuing on intravenous ORENCIA was less than one-third than that for patients withdrawn from intravenous ORENCIA treatment (hazard ratio=0.31, 95% CI [0.16, 0.59]). Among patients who received intravenous ORENCIA throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR 30/50/70 responders has remained consistent for 1 year.</p> <h5>Polyarticular Juvenile Idiopathic Arthritis -Subcutaneous Administration</h5> <p>ORENCIA for subcutaneous administration without an intravenous loading dose was assessed in Study JIA-2, a 2-period, open-label study that included pediatric patients 2 to 17 years of age (n=205). Patients had active polyarticular disease at the time of the study and had inadequate response to at least one nonbiologic or biologic DMARD. The JIA patient subtypes at study entry included polyarticular (79%; 22% were rheumatoid factor positive), extended and persistent oligoarticular (14%), enthesitis-related arthritis (1%), and systemic JIA without systemic manifestations (2%). Patients had a mean disease duration of 2.5 years with active joints (mean, 11.9), joints with loss of motion (mean, 10.4), and elevated C-reactive protein (CRP) levels (mean, 1.2 mg/dL). At study entry, 80% of patients were receiving MTX and remained on a stable dose of MTX. Patients received weekly open-label ORENCIA subcutaneously by a weight-tiered dosing regimen. The primary <a href="/objective/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">objective</a> of the study was evaluation of PK in order to support the extrapolation of efficacy based on exposure to ORENCIA supported by descriptive efficacy [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p>JIA ACR 30/50/70 responses assessed at 4 months in the 2-to 17-year-old patients treated with subcutaneous ORENCIA were consistent with the results from intravenous ORENCIA in Study JIA-1.</p> <h4>Adult Psoriatic Arthritis</h4> <p>The efficacy of ORENCIA was assessed in 594 adult patients (18 years and older) with psoriatic arthritis (PsA), in two randomized, double-blind, placebo-controlled studies (Studies PsA-I and PsA-II). Patients had active PsA (≥3 swollen joints and ≥3 tender joints) despite prior treatment with DMARD therapy and had one qualifying psoriatic skin <a href="/lesion/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lesion</a> of at least 2 cm in diameter. In PsA-I and PsA-II, 37% and 61% of patients, respectively, were treated with TNF antagonists previously.</p> <p>During the initial 24-week, double-blind period of Study PsA-I, 170 patients were randomized to receive one of four intravenous treatments on Days 1, 15, 29, and then every 28 days (there was no escape during the 24-week period):</p> <ul> <li>Placebo</li> <li>ORENCIA 3 mg/kg</li> <li>ORENCIA 500 mg for patients weighing less than 60 kg, ORENCIA 750 mg for patients weighing 60 to 100 kg, and ORENCIA 1,000 mg for patients weighing greater than 100 kg (weight-range-based dosing), or</li> <li>ORENCIA 30 mg/kg on Days 1 and 15 followed by weight range-based ORENCIA dosing (i.e., 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg).</li> </ul> <p>After the 24-week double blind period in Study PsA-I, patients received open-label intravenous ORENCIA every 28 days.</p> <p>Patients were allowed to receive stable doses of concomitant MTX, low dose corticosteroids (equivalent to ≤10 mg of prednisone) and/or NSAIDs during the trial. At enrollment, approximately 60% of patients were receiving MTX. At baseline, the mean (SD) CRP for ORENCIA IV was 17 mg/L (33.0) and mean number (SD) of tender joints and swollen joints was 22.2 (14.3) and 10.9 (7.6), respectively.</p> <p>In PsA-II, 424 patients were randomized 1:1 to receive weekly doses of subcutaneous placebo or ORENCIA 125 mg without a loading dose for 24 weeks-in a double-blind manner, followed by open-label subcutaneous ORENCIA 125 mg weekly. Patients were allowed to receive stable doses of concomitant MTX, sulfasalazine, leflunomide, hydroxychloroquine, low dose corticosteroids (equivalent to ≤10 mg of prednisone) and/or NSAIDs during the trial. At <a href="/randomization/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">randomization</a>, 60% of patients were receiving MTX. The baseline disease characteristics included presence of joint erosion on <a href="/x-rays/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">X-rays</a> in 84% (341/407) with a mean (SD) PsA-modified Sharp van der Heijde erosion score (SHS) of 10.8 (24.2), elevated serum C reactive protein (CRP) in 66% [277/421]) with a mean (SD) of 14.1 mg/L (25.9), and polyarticular disease in 98% (416/424) of patients with a mean number (SD) of tender joints and swollen joints of 20.2 (13.3) and 11.6 (7.5), respectively. Patients who had not achieved at least a 20% improvement from baseline in their swollen and tender joint counts by Week 16 escaped to open-label subcutaneous ORENCIA 125 mg weekly.</p> <p>The primary endpoint for both PsA-I and PsA-II was the proportion of patients achieving ACR 20 response at Week 24 (Day 169).</p> <h5>Clinical Response In Adults With PsA</h5> <p>A greater proportion of adult patients with PsA achieved an ACR 20 response after treatment with intravenous ORENCIA (weight-range-based dosing as described above) compared to placebo in Study PsA-I and a greater proportion of adult patients with PsA achieved an ACR 20 response after treatment with subcutaneous 125 mg compared to placebo in Study PsA-II at Week 24. Responses were seen regardless of prior TNF antagonist treatment and regardless of concomitant non-biologic DMARD treatment. The percent of patients achieving ACR 20, 50, or 70 responses in Studies PsA-I and PsA-II are presented in Table 12 below.</p> <p align="center"><b>Table 12: Proportion of Patients With ACR Responses at Week 24 in Studies PsA-I and PsA-II<sup>a</sup></b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="20%"></td> <td class="EmphTd">PsA-I</td> <td class="EmphTd"></td> <td class="EmphTd">PsA-II</td> <td class="EmphTd"></td> </tr> <tr> <td class="EmphTd" width="20%">ORENCIA Weight-Range-Based Intravenous Dosing<sup>b</sup><br /> N=40</td> <td class="EmphTd" width="20%">Placebo<br /> N=42</td> <td class="EmphTd" width="20%">ORENCIA 125 mg Subcutaneous<br /> N=213</td> <td class="EmphTd" width="20%">Placebo<br /> N=211</td> </tr> <tr> <td>ACR 20</td> <td align="center">47.5%*</td> <td align="center">19.0%</td> <td align="center">39.4%*</td> <td align="center">22.3%</td> </tr> <tr> <td>ACR 50</td> <td align="center">25.0%</td> <td align="center">2.4%</td> <td align="center">19.2%</td> <td align="center">12.3%</td> </tr> <tr> <td>ACR 70</td> <td align="center">12.5%</td> <td align="center">0%</td> <td align="center">10.3%</td> <td align="center">6.6%</td> </tr> <tr> <td class="credit" colspan="5">* p<0.05 versus placebo.<br /> <sup>a</sup> Patients who had less than 20% improvement in tender or swollen joint counts at Week 16 met escape criteria and were considered non-responders.<br /> <sup>b</sup> Weight range-based intravenous dosing: ORENCIA 500 mg for patients weighing less than 60 kg, ORENCIA 750 mg for patients weighing 60 to 100 kg, and ORENCIA 1,000 mg for patients weighing greater than 100 kg.</td> </tr> </tbody> </table> </center> <p></p> <p>The percentage of patients in PsA-II achieving ACR 20 response through Week 24 is shown below in Figure 2.</p> <p align="center"><b>Figure 2: Percent of Patients Achieving ACR 20 Response<sup>a</sup> in PsA-II Study Through Week 24 (Day 169)</b></p> <center> <table cellspacing="0" class="blackpic" width="643"> <tbody> <tr> <td><img alt="Percent of Patients Achieving ACR 20 Response<sup>a</sup> in PsA-II Study Through Week 24 (Day 169) - Illustration" height="310" src="https://images.rxlist.com/images/rxlist/orencia2.gif" width="643" /></td> </tr> </tbody> </table> </center> <p></p> <p>Results were generally consistent across the ACR components in Study PsA-I and PsA-II.</p> <p>Improvements in enthesitis and <a href="/dactylitis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">dactylitis</a> were seen with ORENCIA treatment at Week 24 in both PsA-I and PsA-II.</p> <h5>Physical Function Response In Adults With PsA</h5> <p>In study PsA-I, there was a higher proportion of patients with at least a 0.30 decrease from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 24, with an estimated difference for ORENCIA weight range-based dosing as described above (45%) vs. placebo (19%) of 26.1 (95% confidence interval: 6.8, 45.5). In study PsA-II, the proportion of patients with at least a 0.35 decrease from baseline in HAQ-DI on ORENCIA was 31%, as compared to 24% on placebo (estimated difference: 7%; 95% confidence interval: -1%, 16%). There was a higher adjusted mean change from baseline in HAQ-DI on ORENCIA (-0.33) vs. placebo (-0.20) at Week 24, with an estimated difference of -0.13 (95% confidence interval: -0.25, -0.01).</p> <h4>Prophylaxis Of Acute Graft Versus Host Disease</h4> <h5>Study GVHD-1</h5> <p>The efficacy of ORENCIA, in combination with a calcineurin inhibitor (CNI) and methotrexate (MTX), for the prophylaxis of acute graft versus host disease (aGVHD), was evaluated in a multicenter, two cohort clinical study (GVHD-1, NCT01743131) in patients age 6 years and older who underwent hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated donor (URD). The two cohorts in GVHD-1 included:</p> <ol> <li>an open-label, single-arm study of 43 patients who underwent a 7 of 8 Human Leukocyte Antigen (HLA)-matched HSCT (7 of 8 cohort); and</li> <li>a randomized (1:1), double-blind, placebo-controlled study of patients who underwent an 8 of 8 HLA-matched HSCT who received ORENCIA or placebo in combination with a CNI and MTX (8 of 8 cohort).</li> </ol> <p>In both the 7/8 and 8/8 cohorts, ORENCIA was administered at a dose of 10 mg/kg (1,000 mg maximum dose) as an intravenous infusion over 60 minutes, beginning on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation. Baseline demographic and clinical characteristics of both the 7 of 8 and 8 of 8 cohorts are outlined below in Table 13.</p> <p align="center"><b>Table 13: Baseline Demographic and Clinical Characteristics: 7 of 8 and 8 of 8 Cohort Treated Analysis Population in Study GVHD-1</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="40%"></td> <td class="EmphTd">7 of 8 Cohort</td> <td class="EmphTd" colspan="2">8 of 8 Cohort</td> </tr> <tr> <td class="EmphTd" width="20%">ORENCIA (+ CNI and MTX)<br /> N=43</td> <td class="EmphTd" width="20%">ORENCIA (+ CNI and MTX)<br /> N=73</td> <td class="EmphTd" width="20%">Placebo (+CNI and MTX)<br /> N=69</td> </tr> <tr> <td>Age - Median</td> <td align="center">38</td> <td align="center">44</td> <td align="center">40</td> </tr> <tr> <td>Age - Range</td> <td align="center">6-76</td> <td align="center">6-71</td> <td align="center">7-74</td> </tr> <tr> <td>Gender - Male</td> <td align="center">27 (63)</td> <td align="center">41 (56)</td> <td align="center">37 (54)</td> </tr> <tr> <td>White</td> <td align="center">31 (72)</td> <td align="center">63 (86)</td> <td align="center">61 (88)</td> </tr> <tr> <td>Black or African American</td> <td align="center">7 (16)</td> <td align="center">3 (4.1)</td> <td align="center">2 (2.9)</td> </tr> <tr> <td>Asian</td> <td align="center">2 (4.7)</td> <td align="center">4 (6)</td> <td align="center">2 (2.9)</td> </tr> <tr> <td>Hispanic</td> <td align="center">7 (16)</td> <td align="center">4 (6)</td> <td align="center">2 (2.9)</td> </tr> <tr> <td colspan="4"><b>Malignancy type</b></td> </tr> <tr> <td>Acute Myeloid Leukemia (AML)</td> <td align="center">15 (35)</td> <td align="center">30 (41)</td> <td align="center">22 (32)</td> </tr> <tr> <td>Myelodysplastic Syndrome (MDS)</td> <td align="center">11 (26)</td> <td align="center">15 (21)</td> <td align="center">12 (17)</td> </tr> <tr> <td>Acute Lymphoblastic Leukemia (ALL)</td> <td align="center">8 (19)</td> <td align="center">20 (27)</td> <td align="center">22 (32)</td> </tr> <tr> <td>Acute leukemia or ambiguous lineage</td> <td align="center">1 (2.3)</td> <td align="center">0</td> <td align="center">1 (1.4)</td> </tr> <tr> <td>Hodgkin and Non-Hodgkin lymphoma</td> <td align="center">1 (2.3)</td> <td align="center">1 (1.4)</td> <td align="center">1 (1.4)</td> </tr> <tr> <td>Acute Lymphoblastic Lymphoma in 2nd or Greater Complete Remission</td> <td align="center">1 (2.3)</td> <td align="center">4 (6)</td> <td align="center">1 (1.4)</td> </tr> <tr> <td>Chronic Myelomonocytic leukemia</td> <td align="center">1 (2.3)</td> <td align="center">1 (1.4)</td> <td align="center">4 (6)</td> </tr> <tr> <td>Chronic Myelogenous leukemia</td> <td align="center">4 (9)</td> <td align="center">1 (1.4)</td> <td align="center">5 (7)</td> </tr> <tr> <td>Not reported</td> <td align="center">1 (2.3)</td> <td align="center">1 (1.4)</td> <td align="center">1 (1.4)</td> </tr> <tr> <td colspan="4"><b>GVHD Prophylaxis</b></td> </tr> <tr> <td>Cyclosporine</td> <td align="center">16 (37)</td> <td align="center">11 (15)</td> <td align="center">11 (16)</td> </tr> <tr> <td>Tacrolimus</td> <td align="center">27 (63)</td> <td align="center">62 (85)</td> <td align="center">58 (84)</td> </tr> <tr> <td colspan="4"><b>Type of Graft</b></td> </tr> <tr> <td>Bone Marrow</td> <td align="center">21 (49)</td> <td align="center">33 (45)</td> <td align="center">26 (38)</td> </tr> <tr> <td>Cytokine Mobilized Peripheral Blood (PBSC)</td> <td align="center">22 (51)</td> <td align="center">40 (55)</td> <td align="center">43 (62)</td> </tr> <tr> <td colspan="4"><b>Conditioning Regimen</b></td> </tr> <tr> <td>TBI and Chemotherapy</td> <td align="center">11 (26)</td> <td align="center">20 (27)</td> <td align="center">26 (38)</td> </tr> <tr> <td>Busulfan and Cyclophosphamide</td> <td align="center">13 (30)</td> <td align="center">28 (38)</td> <td align="center">21 (30)</td> </tr> <tr> <td>Busulfan and Fludarabine</td> <td align="center">8 (19)</td> <td align="center">7 (10)</td> <td align="center">2 (2.9)</td> </tr> <tr> <td>Melphalan and Fludarabine</td> <td align="center">11 (26)</td> <td align="center">18 (25)</td> <td align="center">20 (29)</td> </tr> </tbody> </table> </center> <p></p> <p>Efficacy was established based on overall survival (<a href="/os/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">OS</a>) and grade II-IV aGVHD free survival (GFS) results assessed at Day 180 post-transplantation. ORENCIA + CNI and MTX did not significantly improve grade III-IV GFS versus placebo + CNI and MTX at Day 180 post-transplantation. The efficacy results of the GVHD-1 8 of 8 cohort are shown in Table 14.</p> <p align="center"><b>Table 14: Efficacy Results in 8 of 8 Cohort in Study GVHD-1 at Day 180 Post-Transplantation</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Endpoint</td> <td class="EmphTd" width="25%">ORENCIA (+CNI and MTX)<br /> n =73</td> <td class="EmphTd" width="25%">Placebo (+CNI and MTX)<br /> n=69</td> </tr> <tr> <td>Gr III-IV aGVHD Free Survival<sup>a</sup> Rate (95% CI)</td> <td align="center">87% (77%, 93%)</td> <td align="center">75% (63%, 84%)</td> </tr> <tr> <td>Hazard Ratio (95% CI)</td> <td align="center" colspan="2">0.55 (0.26, 1.18)</td> </tr> <tr> <td>Gr II-IV aGVHD Free Survival<sup>b</sup> Rate (95% CI)</td> <td align="center">50% (38%, 61%)</td> <td align="center">32% (21%, 43%)</td> </tr> <tr> <td>Hazard Ratio (95% CI)</td> <td align="center" colspan="2">0.54 (0.35, 0.83)</td> </tr> <tr> <td>Overall Survival Rate (95% CI)</td> <td align="center">97% (89%, 99%)</td> <td align="center">84% (73%, 91%)</td> </tr> <tr> <td>Hazard Ratio (95% CI)</td> <td align="center" colspan="2">0.33 (0.12, 0.93)</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Gr III-IV aGVHD Free Survival was measured from the date of transplantation until the onset of documented Grade III-IV aGVHD, or death by any cause up to Day 180 post-transplantation.<br /> <sup>b</sup> Gr II-IV aGVHD Free Survival was measured from the date of transplantation until the onset of documented Grade II-IV aGVHD, or death by any cause up to Day 180 post-transplantation.</td> </tr> </tbody> </table> </center> <p></p> <p>In an exploratory analysis of the 7 of 8 cohort of ORENCIA-treated patients (n=43), the rates of Grade III-IV GVHD-free survival, Grade II-IV GVHD-free survival, and overall survival at day 180 post-transplantation were 95% (95% CI 83%, 99%), 53% (95% CI 38%, 67%), and 98% (95% CI 85%, 100%), respectively.</p> <h5>Study GVHD-2</h5> <p>GVHD-2 was a clinical study that used data from the Center for International Blood and Marrow Transplant Research (CIBMTR). The study analyzed outcomes of ORENCIA in combination with a CNI and MTX, versus a CNI and MTX alone, for the prophylaxis of aGVHD, in patients 6 years of age or older who underwent HSCT from a 1 allele-mismatched URD between 2011 and 2018. The ORENCIA + CNI and MTX-treated group (n=54) included 42 patients from GVHD-1, in addition to 12 patients treated with ORENCIA outside of GVHD-1. The comparator group (n=162) was randomly selected in a 3:1 ratio to the ORENCIA-treated group from the CIBMTR registry from patients who had not received ORENCIA during the study period. Analyses used propensity score matching and inverse probability of treatment weighting to help address the impact of selection bias.</p> <p>Efficacy was based on Overall Survival (OS) at Day 180 post-HSCT. The OS rate at Day 180 in the ORENCIA in combination with CNI and MTX group was 98% (95% CI: 78, 100) and the OS rate at Day 180 in the CNI and MTX group was 75% (95% CI: 67, 82).</p> </div> </div> </div> | <a name="CP"></a> <h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism Of Action</h4> <p>Abatacept, a selective costimulation modulator, inhibits T cell (T <a href="/lymphocyte/definition.htm" ">lymphocyte</a>) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. Activated T lymphocytes are implicated in the <a href="/pathogenesis/definition.htm" ">pathogenesis</a> of RA, pJIA and PsA and are found in the synovium of patients with RA, pJIA and PsA.</p> <p>In vitro, abatacept decreases T cell proliferation and inhibits the production of the cytokines TNF alpha (TNFα), interferon-γ, and <a href="/interleukin-2/definition.htm" ">interleukin-2</a>. In a rat <a href="/collagen/definition.htm" ">collagen</a>-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production, and reduces antigen specific production of interferon-γ. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its clinical effects is unknown.</p> <h4>Pharmacodynamics</h4> <p>In clinical trials with ORENCIA at doses approximating 10 mg/kg, decreases were observed in serum levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), <a href="/rheumatoid_factor/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">rheumatoid factor</a> (<a href="/rf/definition.htm" ">RF</a>), <a href="/c-reactive_protein_test_crp/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">C-reactive protein</a> (<a href="/crp/definition.htm" ">CRP</a>), matrix metalloproteinase-3 (MMP3), and TNFα. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its clinical effects is unknown.</p> <p>No formal pharmacodynamic analyses of biologic response markers have been performed in patients exposed to ORENCIA as prophylaxis for aGVHD.</p> <h4>Pharmacokinetics</h4> <h5>Healthy Adults And Adult RA -Intravenous Administration</h5> <p>The pharmacokinetics of abatacept were studied in healthy adult subjects after a single 10 mg/kg intravenous infusion and in RA patients after multiple 10 mg/kg intravenous infusions of ORENCIA (see Table 6).</p> <p align="center"><b>Table 6: Pharmacokinetic Parameters (Mean, Range) in Healthy Subjects and RA Patients After 10 mg/kg ORENCIA Intravenous Infusion(s)</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">PK Parameter</td> <td class="EmphTd" width="25%">Healthy Subjects (After 10 mg/kg Single Dose)<br /> n=13</td> <td class="EmphTd" width="25%">RA Patients (After 10 mg/kg Multiple Doses<sup>a</sup>)<br /> n=14</td> </tr> <tr> <td>Peak Concentration (Cmax) [mcg/mL]</td> <td align="center">292 (175-427)</td> <td align="center">295 (171-398)</td> </tr> <tr> <td>Terminal half-life (t½) [days]</td> <td align="center">16.7 (12-23)</td> <td align="center">13.1 (8-25)</td> </tr> <tr> <td>Systemic clearance (CL) [mL/h/kg]</td> <td align="center">0.23 (0.16-0.30)</td> <td align="center">0.22 (0.13-0.47)</td> </tr> <tr> <td>Volume of distribution (Vss) [L/kg]</td> <td align="center">0.09 (0.06-0.13)</td> <td align="center">0.07 (0.02-0.13)</td> </tr> <tr> <td class="credit" colspan="3"><sup>a </sup>Multiple intravenous infusions of ORENCIA were administered at days 1, 15, 30, and monthly thereafter.</td> </tr> </tbody> </table> </center> <p></p> <p>The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be comparable. In RA patients, after multiple intravenous infusions, the pharmacokinetics of abatacept showed proportional increases of Cmax and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady state by day 60 with a mean (range) trough concentration of 24 mcg/mL (1 to 66 mcg/mL). No systemic accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at monthly intervals in RA patients.</p> <p>Population pharmacokinetic analyses in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect clearance. Concomitant methotrexate, NSAIDs, corticosteroids, and TNF antagonists did not influence abatacept clearance.</p> <p>No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of abatacept.</p> <h5>Adult RA -Subcutaneous Administration</h5> <p>Abatacept exhibited linear pharmacokinetics following subcutaneous administration. The mean (range) for Cmin and Cmax at steady state observed after 85 days of treatment was 32.5 mcg/mL (6.6 to 113.8 mcg/mL) and 48.1 mcg/mL (9.8 to 132.4 mcg/mL), respectively. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration was 79%. Mean estimates for systemic clearance (0.28 mL/h/kg), volume of distribution (0.11 L/kg), and terminal half-life (14.3 days) were comparable between subcutaneous and intravenous administration.</p> <p>Study SC-2 was conducted to determine the effect of subcutaneous monotherapy use of ORENCIA on immunogenicity (without an intravenous loading dose) in 100 RA patients [see <b>ADVERSE REACTIONS</b>]. In this study, a mean trough concentration of 12.6 mcg/mL was achieved after 2 weeks of dosing.</p> <p>Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous ORENCIA in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight [see<b> DOSAGE AND ADMINISTRATION</b>]. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent clearance.</p> <h5>Polyarticular Juvenile Idiopathic Arthritis -Intravenous Administration</h5> <p>In Study JIA-1 among patients 6 to 17 years of age, the mean (range) steady state serum peak and trough concentrations of abatacept were 217 mcg/mL (57 to 700 mcg/mL) and 11.9 mcg/mL (0.15 to 44.6 mcg/mL) [see <b>Clinical Studies</b>]. Population pharmacokinetic analyses of the serum concentration data showed that clearance of abatacept increased with baseline body weight [see<b> DOSAGE AND ADMINISTRATION</b>]. The estimated mean (range) clearance of abatacept in the juvenile idiopathic arthritis patients was 0.4 mL/h/kg (0.20 to 1.12 mL/h/kg). After accounting for the effect of body weight, the clearance of abatacept was not related to age and gender. Concomitant methotrexate, corticosteroids, and NSAIDs were also shown not to influence abatacept clearance.</p> <h5>Polyarticular Juvenile Idiopathic Arthritis -Subcutaneous Administration</h5> <p>In Study JIA-2 among patients 2 to 17 years of age, steady state of abatacept was achieved by Day 85 following the weekly body-weight–tiered subcutaneous ORENCIA dosing [see <b>Clinical Studies</b>]. Comparable trough concentrations across weight tiers and age groups were achieved by the body-weight–tiered subcutaneous dosing regimen. The mean (range) trough concentration of abatacept at Day 113 was 44.4 mcg/mL (13.4 to 88.1 mcg/mL), 46.6 mcg/mL (22.4 to 97.0 mcg/mL), and 38.5 mcg/mL (9.3 to 73.2 mcg/mL) in pediatric JIA patients weighing 10 to <25 kg, 25 to <50 kg, and ≥50 kg, respectively.</p> <p>Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous ORENCIA in JIA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight [see <b>DOSAGE AND ADMINISTRATION</b>]. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent clearance.</p> <h5>Adult Psoriatic Arthritis -Intravenous And Subcutaneous Administration</h5> <p>In Study PsA-I, a dose ranging study, intravenous ORENCIA was administered at 3 mg/kg, weight range-based dosing: 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg, or doses of 30 mg/kg on Days 1 and 15 followed by weight-range-based dosing [see <b>Clinical Studies</b>]. Following monthly intravenous ORENCIA administration, abatacept showed linear PK over the dose range in this study. At the weight-range-based dosing (see above), the steady state of abatacept was reached by Day 57 and the geometric mean (CV%) trough concentration (Cmin) was 24.3 mcg/mL (40.8%) at Day 169. In Study PsA-II following weekly subcutaneous administration of ORENCIA at 125 mg, the steady state of abatacept was reached at Day 57 and the geometric mean (CV%) Cmin was 25.6 mcg/mL (47.7%) at Day 169.</p> <p>Consistent with the RA results, population pharmacokinetic analyses for abatacept in PsA patients revealed that there was a trend toward higher clearance (L/h) of abatacept with increasing body weight [see <b>DOSAGE AND ADMINISTRATION</b>]. In addition, relative to the RA patients with the same body weight, abatacept clearance in PsA patients was approximately 8% lower, resulting in higher abatacept exposures in patients with PsA. This slight difference in exposures, however, is not considered to be clinically meaningful.</p> <h5>Prophylaxis Of Acute Graft versus Host Disease – Intravenous Administration</h5> <p align="center"><b>Table 7: Pharmacokinetic Parameters (Mean, Range) in Subjects Undergoing HSCT from a Matched or 1 Allele-Mismatched Unrelated Donor in Study GVHD-1</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">PK Parameter</td> <td class="EmphTd" width="25%">7 of 8 Cohort<br /> n=42</td> <td class="EmphTd" width="25%">8 of 8 Cohort<br /> n=73</td> </tr> <tr> <td>Minimum Concentration (Cmin) <sup>a</sup> [mcg/mL]</td> <td align="center">59 (26-112)</td> <td align="center">43 (25-73)</td> </tr> <tr> <td>Peak Concentration (Cmax) [mcg/mL]</td> <td align="center">221 (163-292)</td> <td align="center">172 (107-254)</td> </tr> <tr> <td>Terminal half-life (t½) [days]</td> <td align="center">20.6 (6-43)</td> <td align="center">20.8 (12-38)</td> </tr> <tr> <td>Systemic clearance (CL) [mL/h/kg]</td> <td align="center">0.26 (0.15-0.65)</td> <td align="center">0.32 (0.18-0.56)</td> </tr> <tr> <td>Volume of distribution (Vss) [L/kg]</td> <td align="center">0.13 (0.08-0.27)</td> <td align="center">0.17 (0.11-0.26)</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Cmin observed on Day 5 of the treatment period; n = 18 for the 7/8 Cohort; n = 32 for the 8/8 Cohort. Cmax, t½, CL, and Vss are model predicted after first 10 mg/kg ORENCIA intravenous infusion.</td> </tr> </tbody> </table> </center> <p></p> <p>In a study of patients who received ORENCIA for prophylaxis of acute Graft Versus Host Disease (aGVHD) aged 6 years and older, the geometric mean (%CV) trough concentrations (Cmin) of abatacept on Day 63 after transplant after 4 doses utilizing weight-based dosing of 10 mg/kg (maximum dose of 1,000 mg) administered on the day before transplantation (Day -1), followed by a dose on Day 5, 14, and 28 after transplant, were 22.5 mcg/mL (243.9 %CV) for recipients of 8 of 8 Human leukocyte antigen (HLA)-matched HSCTs from unrelated donors (URD), and 31.1 mcg/mL (114.4 %CV) for recipients of 7 of 8 HLA-matched HSCTs from unrelated donors (URD), respectively.</p> <p>Population pharmacokinetic analyses in patients with aGVHD demonstrated that 7 of 8 HLA-matched HSCT recipients had 29% lower clearance compared to 8 of 8 HLA-matched HSCT recipients. Consistent with previous data, increasing body weight was associated with higher clearance of abatacept, while age (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate and calcineurin inhibitors (e.g., cyclosporine and tacrolimus), did not influence abatacept clearance.</p> <p>Based on population PK modeling and simulation with data from patients aged 6 and older, simulated exposures of abatacept following the first and last dose in pediatric subjects 2 to less than 6 years of age who received 15 mg/kg of ORENCIA via 60-minute intravenous infusion on Day -1, followed by 12 mg/kg via 60-minute intravenous infusion on Day 5, 14, and 28 are comparable to those in pediatric patients 6 to less than 17 years of age and adults patients who received 10 mg/kg via 60-minute intravenous infusion on Day -1, 5, 14, and 28.</p> <a name="AP"></a> <h4>Animal Toxicology And/Or Pharmacology</h4> <p>In studies of adult mice and monkeys, inhibition of TDAR was apparent. However, infection and mortality, altered T-helper cells, and inflammation of thyroid and pancreas were not observed.</p> <a name="CS"></a> <h4>Clinical Studies</h4> <h4>Adult Rheumatoid Arthritis</h4> <h5>Description Of Clinical Studies Of Intravenous ORENCIA For The Treatment Of Patients With RA</h5> <p>The efficacy and safety of ORENCIA for intravenous administration were assessed in six randomized, double-blind, controlled studies (five placebo-controlled and one active-controlled) in patients ≥18 years of age with active RA diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, IV, and VI required patients to have at least 12 tender and 10 swollen joints at randomization, and Study V did not require any specific number of tender or swollen joints. ORENCIA or placebo treatment was given intravenously at weeks 0, 2, and 4 and then every 4 weeks thereafter in Studies I, II, III, IV, and VI.</p> <ul> <li>Study I evaluated ORENCIA as monotherapy in 122 patients with active RA who had failed at least one non-biologic DMARD or etanercept.</li> <li>In Study II and Study III, the efficacy of ORENCIA were assessed in patients with an inadequate response to MTX and who were continued on their stable dose of MTX.</li> <li>In Study IV, the efficacy of ORENCIA was assessed in patients with an inadequate response to a TNF antagonist, with the TNF antagonist discontinued prior to randomization; other DMARDs were permitted.</li> <li>Study V primarily assessed safety in patients with active RA requiring additional intervention in spite of current therapy with DMARDs; all DMARDs used at enrollment were continued. Patients in Study V were not excluded for comorbid medical conditions.</li> <li>In Study VI, the efficacy and safety of ORENCIA were assessed in methotrexate-naive patients with RA of less than 2 years disease duration. In Study VI, patients previously naive to methotrexate were randomized to receive ORENCIA plus methotrexate or methotrexate plus placebo.</li> </ul> <p>Study I patients were randomized to receive one of three doses of ORENCIA (0.5, 2, or 10 mg/kg) or placebo ending at week 8. Study II patients were randomized to receive ORENCIA 2 or 10 mg/kg or placebo for 12 months. Study III, IV, V, and VI patients were randomized to receive a dose of ORENCIA based on weight range or placebo for 12 months (Studies III, V, and VI) or 6 months (Study IV). The dose of ORENCIA was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg.</p> <p><i>Description Of Clinical Studies Of Subcutaneous Or Intravenous ORENCIA For The Treatment Of Patients With Adult RA</i></p> <p>The efficacy of ORENCIA for subcutaneous administration were assessed in Study SC-1, which was a randomized, double-blind, double-dummy, non-inferiority study that compared ORENCIA administered subcutaneously to ORENCIA administered intravenously in 1457 patients with moderate to severely active RA, receiving background methotrexate (MTX), and experiencing an inadequate response to methotrexate (MTX-IR). In Study SC-1, patients were randomized with stratification by body weight (<60 kg, 60 to 100 kg, >100 kg) to receive (1) ORENCIA 125 mg subcutaneous injections weekly, after a single intravenous loading dose of ORENCIA based on body weight or (2) ORENCIA intravenously on Days 1, 15, 29, and every four weeks thereafter. Subjects continued taking their current dose of MTX from the day of randomization.</p> <h5>Clinical Response In Adult RA Patients</h5> <p>The percent of ORENCIA-treated patients achieving ACR 20, 50, and 70 responses and major clinical response in Studies I, III, IV, and VI are shown in Table 8. ORENCIA-treated patients had higher ACR 20, 50, and 70 response rates at 6 months compared to placebo-treated patients. Month 6 ACR response rates in Study II for the 10 mg/kg group were similar to the ORENCIA group in Study III.</p> <p>In Studies III and IV, improvement in the ACR 20 response rate versus placebo was observed within 15 days in some patients and within 29 days versus MTX in Study VI. In Studies II, III, and VI, ACR response rates were maintained to 12 months in ORENCIA-treated patients. ACR responses were maintained up to three years in the open-label extension of Study II. In Study III, ORENCIA-treated patients experienced greater improvement than placebo-treated patients in morning stiffness.</p> <p>In Study VI, a greater proportion of patients treated with ORENCIA plus MTX achieved a low level of disease activity as measured by a DAS28-CRP less than 2.6 at 12 months compared to those treated with MTX plus placebo (Table 8). Of patients treated with ORENCIA plus MTX who achieved DAS28-CRP less than 2.6, 54% had no active joints, 17% had one active joint, 7% had two active joints, and 22% had three or more active joints, where an active joint was a joint that was rated as tender or swollen or both.</p> <p>In Study SC-1, the main outcome measure was ACR 20 at 6 months. The pre-specified non-inferiority margin was a treatment difference of -7.5%. As shown in Table 9, the study demonstrated non-inferiority of ORENCIA administered subcutaneously to intravenous infusions of ORENCIA with respect to ACR 20 responses up to 6 months of treatment. ACR 50 and 70 responses are also shown in Table 8. No major differences in ACR responses were observed between intravenous and subcutaneous treatment groups in subgroups based on weight categories (less than 60 kg, 60 to 100 kg, and more than 100 kg; data not shown).</p> <p align="center"><b>Table 8: Clinical Responses in Controlled Trials in Patients with RA</b></p> <center> <table cellspacing="0" class="blacktbl" width="750"> <tbody> <tr> <td class="EmphTd" rowspan="5" width="20%">Response Rate</td> <td class="EmphTd" colspan="8">Percent of Patients</td> <td class="EmphTd" colspan="2" rowspan="2">Subcutaneous or Intravenous Administration</td> </tr> <tr> <td class="EmphTd" colspan="8">Intravenous Administration</td> </tr> <tr> <td class="EmphTd" colspan="2">Inadequate Response to DMARDs</td> <td class="EmphTd" colspan="2">Inadequate Response to Methotrexate (MTX)</td> <td class="EmphTd" colspan="2">Inadequate Response to TNF Antagonists</td> <td class="EmphTd" colspan="2">MTX-Naive</td> <td class="EmphTd" colspan="2">Inadequate Response to MTX</td> </tr> <tr> <td class="EmphTd" colspan="2">Study 1</td> <td class="EmphTd" colspan="2">Study III</td> <td class="EmphTd" colspan="2">Study IV</td> <td class="EmphTd" colspan="2">Study VI</td> <td class="EmphTd" colspan="2">Study SC-1</td> </tr> <tr> <td class="EmphTd" width="8%">ORN<sup>a</sup><br /> n=32</td> <td class="EmphTd" width="8%">PBO<br /> n=32</td> <td class="EmphTd" width="8%">ORN<sup>b</sup> +MTX<br /> n=424</td> <td class="EmphTd" width="8%">PBO +MTX<br /> n=214</td> <td class="EmphTd" width="8%">ORN<sup>b</sup> + DMARDs<br /> n=256</td> <td class="EmphTd" width="8%">PBO + DMARDs<br /> n=133</td> <td class="EmphTd" width="8%">ORN<sup>b</sup> +MTX<br /> n=256</td> <td class="EmphTd" width="8%">PBO +MTX<br /> n=253</td> <td class="EmphTd" width="8%">ORN<sup>e</sup> SC +MTX<br /> n=693</td> <td class="EmphTd" width="8%">ORN<sup>e</sup> IV +MTX<br /> n=678</td> </tr> <tr> <td colspan="11"><b>ACR 20</b></td> </tr> <tr> <td>Month 3</td> <td align="center">53%</td> <td align="center">31%</td> <td align="center">62%‡</td> <td align="center">37%</td> <td align="center">46%‡</td> <td align="center">18%</td> <td align="center">64%*</td> <td align="center">53%</td> <td align="center">68%</td> <td align="center">69%</td> </tr> <tr> <td>Month 6</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">68%‡</td> <td align="center">40%</td> <td align="center">50%‡</td> <td align="center">20%</td> <td align="center">75%†</td> <td align="center">62%</td> <td align="center">76%§</td> <td align="center">76%</td> </tr> <tr> <td>Month 12</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">73%‡</td> <td align="center">40%</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">76%‡</td> <td align="center">62%</td> <td align="center">NA</td> <td align="center">NA</td> </tr> <tr> <td colspan="11"><b>ACR 50</b></td> </tr> <tr> <td>Month 3</td> <td align="center">16%</td> <td align="center">6%</td> <td align="center">32%‡</td> <td align="center">8%</td> <td align="center">18%†</td> <td align="center">6%</td> <td align="center">40%‡</td> <td align="center">23%</td> <td align="center">33%</td> <td align="center">39%</td> </tr> <tr> <td>Month 6</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">40%‡</td> <td align="center">17%</td> <td align="center">20%‡</td> <td align="center">4%</td> <td align="center">53%‡</td> <td align="center">38%</td> <td align="center">52%</td> <td align="center">50%</td> </tr> <tr> <td>Month 12</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">48%‡</td> <td align="center">18%</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">57%‡</td> <td align="center">42%</td> <td align="center">NA</td> <td align="center">NA</td> </tr> <tr> <td colspan="11"><b>ACR 70</b></td> </tr> <tr> <td>Month 3</td> <td align="center">6%</td> <td align="center">0</td> <td align="center">13%‡</td> <td align="center">3%</td> <td align="center">6%*</td> <td align="center">1%</td> <td align="center">19%†</td> <td align="center">10%</td> <td align="center">13%</td> <td align="center">16%</td> </tr> <tr> <td>Month 6</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">20%‡</td> <td align="center">7%</td> <td align="center">10%†</td> <td align="center">2%</td> <td align="center">32%†</td> <td align="center">20%</td> <td align="center">26%</td> <td align="center">25%</td> </tr> <tr> <td>Month 12</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">29%‡</td> <td align="center">6%</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">43%‡</td> <td align="center">27%</td> <td align="center">NA</td> <td align="center">NA</td> </tr> <tr> <td><b>Major Clinical Response <sup>c</sup></b></td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">14%‡</td> <td align="center">2%</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">27%‡</td> <td align="center">12%</td> <td align="center">NA</td> <td align="center">NA</td> </tr> <tr> <td colspan="11"><b>DAS28- CRP <2.6<sup>d</sup></b></td> </tr> <tr> <td>Month 12</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">NA</td> <td align="center">41%‡</td> <td align="center">23%</td> <td align="center">NA</td> <td align="center">NA</td> </tr> <tr> <td class="credit" colspan="11">* p<0.05, ORENCIA (ORN) vs placebo (PBO) or MTX.<br /> † p<0.01, ORENCIA vs placebo or MTX.<br /> ‡ p<0.001, ORENCIA vs placebo or MTX. § 95% CI: -4.2, 4.8 (based on prespecified margin for non-inferiority of -7.5%).<br /> <sup>a</sup> 10 mg/kg.<br /> <sup>b</sup> Dosing based on weight range [see <b>DOSAGE AND ADMINISTRATION</b>].<br /> <sup>c</sup> Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period.<br /> <sup>d</sup> Refer to text for additional description of remaining joint activity.<br /> <sup>e</sup> Per protocol data is presented in table. For ITT; n=736, 721 for SC and IV ORENCIA, respectively.</td> </tr> </tbody> </table> </center> <p></p> <p>The results of the components of the ACR response criteria for Studies III, IV, and SC-1 are shown in Table 9 (results at Baseline [BL] and 6 months [6 M]). In ORENCIA-treated patients, greater improvement was seen in all ACR response criteria components through 6 and 12 months than in placebo-treated patients.</p> <p align="center"><b>Table 9: Components of ACR Responses at 6 Months in Adult Patients with RA</b></p> <center> <table cellspacing="0" class="blacktbl" width="750"> <tbody> <tr> <td class="EmphTd" rowspan="5" width="16%">Component (median)</td> <td class="EmphTd" colspan="8">Intravenous Administration</td> <td class="EmphTd" colspan="4">Subcutaneous or Intravenous Administration</td> </tr> <tr> <td class="EmphTd" colspan="4">Inadequate Response to MTX</td> <td class="EmphTd" colspan="4">Inadequate Response to TNF Antagonists</td> <td class="EmphTd" colspan="4">Inadequate Response to MTX</td> </tr> <tr> <td class="EmphTd" colspan="4">Study III</td> <td class="EmphTd" colspan="4">Study IV</td> <td class="EmphTd" colspan="4">Study SC-1<sup>c</sup></td> </tr> <tr> <td class="EmphTd" colspan="2">ORN +MTX<br /> n=424</td> <td class="EmphTd" colspan="2">PBO +MTX<br /> n=214</td> <td class="EmphTd" colspan="2">ORN +DMARDs<br /> n=256</td> <td class="EmphTd" colspan="2">PBO +DMARDs<br /> n=133</td> <td class="EmphTd" colspan="2">ORN SC +MTX<br /> n=693</td> <td class="EmphTd" colspan="2">ORN IV +MTX<br /> n=678</td> </tr> <tr> <td class="EmphTd" width="7%">BL</td> <td class="EmphTd" width="7%">6 M</td> <td class="EmphTd" width="7%">BL</td> <td class="EmphTd" width="7%">6 M</td> <td class="EmphTd" width="7%">BL</td> <td class="EmphTd" width="7%">6 M</td> <td class="EmphTd" width="7%">BL</td> <td class="EmphTd" width="7%">6 M</td> <td class="EmphTd" width="7%">BL</td> <td class="EmphTd" width="7%">6 M</td> <td class="EmphTd" width="7%">BL</td> <td class="EmphTd" width="7%">6 M</td> </tr> <tr> <td>Number of tender joints (0-68)</td> <td align="center">28</td> <td align="center">7‡</td> <td align="center">31</td> <td align="center">14</td> <td align="center">30</td> <td align="center">13‡</td> <td align="center">31</td> <td align="center">24</td> <td align="center">27</td> <td align="center">5</td> <td align="center">27</td> <td align="center">6</td> </tr> <tr> <td>Number of swollen joints (0-66)</td> <td align="center">19</td> <td align="center">5‡</td> <td align="center">20</td> <td align="center">11</td> <td align="center">21</td> <td align="center">10‡</td> <td align="center">20</td> <td align="center">14</td> <td align="center">18</td> <td align="center">4</td> <td align="center">18</td> <td align="center">3</td> </tr> <tr> <td>Pain<sup>a</sup></td> <td align="center">67</td> <td align="center">27‡</td> <td align="center">70</td> <td align="center">50</td> <td align="center">73</td> <td align="center">43†</td> <td align="center">74</td> <td align="center">64</td> <td align="center">71</td> <td align="center">25</td> <td align="center">70</td> <td align="center">28</td> </tr> <tr> <td>Patient global assessment<sup>a</sup></td> <td align="center">66</td> <td align="center">29‡</td> <td align="center">64</td> <td align="center">48</td> <td align="center">71</td> <td align="center">44‡</td> <td align="center">73</td> <td align="center">63</td> <td align="center">70</td> <td align="center">26</td> <td align="center">68</td> <td align="center">27</td> </tr> <tr> <td>Disability index<sup>b</sup></td> <td align="center">1.75</td> <td align="center">1.13‡</td> <td align="center">1.75</td> <td align="center">1.38</td> <td align="center">1.88</td> <td align="center">1.38‡</td> <td align="center">2.00</td> <td align="center">1.75</td> <td align="center">1.88</td> <td align="center">1.00</td> <td align="center">1.75</td> <td align="center">1.00</td> </tr> <tr> <td>Physician global assessment<sup>a</sup></td> <td align="center">69</td> <td align="center">21‡</td> <td align="center">68</td> <td align="center">40</td> <td align="center">71</td> <td align="center">32‡</td> <td align="center">69</td> <td align="center">54</td> <td align="center">65</td> <td align="center">16</td> <td align="center">65</td> <td align="center">15</td> </tr> <tr> <td>CRP (mg/dL)</td> <td align="center">2.2</td> <td align="center">0.9‡</td> <td align="center">2.1</td> <td align="center">1.8</td> <td align="center">3.4</td> <td align="center">1.3‡</td> <td align="center">2.8</td> <td align="center">2.3</td> <td align="center">1.6</td> <td align="center">0.7</td> <td align="center">1.8</td> <td align="center">0.7</td> </tr> <tr> <td class="credit" colspan="13">† p<0.01, ORENCIA (ORN) vs placebo (PBO), based on mean percent change from baseline.<br /> ‡ p<0.001, ORENCIA vs placebo, based on mean percent change from baseline.<br /> <sup>a</sup> Visual analog scale: 0 = best, 100 = worst.<br /> <sup>b</sup> Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, alking, hygiene, reach, grip, and activities.<br /> <sup>c</sup> SC-1 is a non-inferiority study. Per protocol data is presented in table.</td> </tr> </tbody> </table> </center> <p></p> <p>The percent of patients achieving the ACR 50 response for Study III by visit is shown in Figure 1. The time course for the ORENCIA group in Study VI was similar to that in Study III.</p> <p align="center"><b>Figure 1: Percent of Patients Achieving ACR 50 Response by Visit* (Study III)</b></p> <center> <table cellspacing="0" class="blackpic" width="432"> <tbody> <tr> <td><img alt="Percent of Patients Achieving ACR 50 Response by Visit* - Illustration" height="393" src="https://images.rxlist.com/images/rxlist/orencia1.gif" width="432" /></td> </tr> </tbody> </table> </center> <p></p> <p>The percent of patients achieving the ACR 50 response for Study SC-1 in the ORENCIA subcutaneous (SC) and intravenous (IV) treatment arms at each treatment visit was as follows: Day 15—SC 3%, IV 5%; Day 29—SC 11%, IV 14%; Day 57—SC 24%, IV 30%; Day 85— SC 33%, IV 38%; Day 113—SC 39%, IV 41%; Day 141—SC 46%, IV 47%; Day 169—SC 51%, IV 50%.</p> <h5>Radiographic Response In Adult RA Patients</h5> <p>In Study III and Study VI, structural joint damage was assessed radiographically and expressed as change from baseline in the Genant-modified Total Sharp Score (TSS) and its components, the <a href="/erosion/definition.htm" ">Erosion</a> Score (ES) and Joint Space Narrowing (JSN) score. ORENCIA/MTX slowed the progression of structural damage compared to placebo/MTX after 12 months of treatment as shown in Table 10.</p> <p align="center"><b>Table 10: Mean Radiographic Changes in Study III<sup>a</sup> and Study VI<sup>b</sup></b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="20%">Parameter</td> <td class="EmphTd" width="20%">ORENCIA/ MTX</td> <td class="EmphTd" width="20%">Placebo/ MTX</td> <td class="EmphTd" width="20%">Differences</td> <td class="EmphTd" width="20%">P-value<sup>d</sup></td> </tr> <tr> <td colspan="5"><b>Study III</b></td> </tr> <tr> <td colspan="5"><b>First Year</b></td> </tr> <tr> <td>TSS</td> <td align="center">1.07</td> <td align="center">2.43</td> <td align="center">1.36</td> <td align="center"><0.01</td> </tr> <tr> <td>ES</td> <td align="center">0.61</td> <td align="center">1.47</td> <td align="center">0.86</td> <td align="center"><0.01</td> </tr> <tr> <td>JSN score</td> <td align="center">0.46</td> <td align="center">0.97</td> <td align="center">0.51</td> <td align="center"><0.01</td> </tr> <tr> <td colspan="5"><b>Second Year</b></td> </tr> <tr> <td>TSS</td> <td align="center">0.48</td> <td align="center">0.74<sup>c</sup></td> <td align="center">-</td> <td align="center">-</td> </tr> <tr> <td>ES</td> <td align="center">0.23</td> <td align="center">0.22<sup>c</sup></td> <td align="center">-</td> <td align="center">-</td> </tr> <tr> <td>JSN score</td> <td align="center">0.25</td> <td align="center">0.51<sup>c</sup></td> <td align="center">-</td> <td align="center">-</td> </tr> <tr> <td colspan="5"><b>Study VI</b></td> </tr> <tr> <td colspan="5"><b>First Year</b></td> </tr> <tr> <td>TSS</td> <td align="center">0.6</td> <td align="center">1.1</td> <td align="center">0.5</td> <td align="center">0.04</td> </tr> <tr> <td class="credit" colspan="5"><sup>a </sup>Patients with an inadequate response to MTX.<br /> <sup>b</sup> MTX-naive patients.<br /> <sup>c</sup> Patients received 1 year of placebo/MTX followed by 1 year of ORENCIA/MTX.<br /> <sup>d</sup> Based on a nonparametric ANCOVA model.</td> </tr> </tbody> </table> </center> <p></p> <p>In the open-label extension of Study III, 75% of patients initially randomized to ORENCIA/MTX and 65% of patients initially randomized to placebo/MTX were evaluated radiographically at Year 2. As shown in Table 10, progression of structural damage in ORENCIA/MTX-treated patients was further reduced in the second year of treatment.</p> <p>Following 2 years of treatment with ORENCIA/MTX, 51% of patients had no progression of structural damage as defined by a change in the TSS of zero or less compared with baseline. Fifty-six percent (56%) of ORENCIA/MTX-treated patients had no progression during the first year compared to 45% of placebo/MTX-treated patients. In their second year of treatment with ORENCIA/MTX, more patients had no progression than in the first year (65% vs 56%).</p> <h5>Physical Function Response And Health-Related Outcomes In Adult RA Patients</h5> <p>Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). In the HAQ-DI, ORENCIA demonstrated greater improvement from baseline versus placebo in Studies II-V and versus MTX in Study VI. In Study SC-1, improvement from baseline as measured by HAQ-DI at 6 months and over time was similar between subcutaneous and intravenous ORENCIA administration. The results from Studies II and III are shown in Table 11. Similar results were observed in Study V compared to placebo and in Study VI compared to MTX. During the open-label period of Study II, the improvement in physical function has been maintained for up to 3 years.</p> <p align="center"><b>Table 11: Mean Improvement from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) in Adult Patients with RA</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="3" width="40%">HAQ Disability Index</td> <td class="EmphTd" colspan="4">Inadequate Response to Methotrexate</td> </tr> <tr> <td class="EmphTd" colspan="2">Study II</td> <td class="EmphTd" colspan="2">Study III</td> </tr> <tr> <td class="EmphTd" width="15%">ORENCIA<sup>a</sup>+MTX<br /> (n=115)</td> <td class="EmphTd" width="15%">Placebo+ MTX<br /> (n=119)</td> <td class="EmphTd" width="15%">ORENCIA<sup>b</sup>+ MTX<br /> (n=422)</td> <td class="EmphTd" width="15%">Placebo+ MTX<br /> (n=212)</td> </tr> <tr> <td>Baseline (Mean)</td> <td align="center">0.98<sup>c</sup></td> <td align="center">0.97<sup>c</sup></td> <td align="center">1.69<sup>d</sup></td> <td align="center">1.69<sup>d</sup></td> </tr> <tr> <td colspan="5">Mean Improvement</td> </tr> <tr> <td>Year 1</td> <td align="center">0 40<sup>c</sup>,***</td> <td align="center">0.15<sup>c</sup></td> <td align="center">0.66<sup>d</sup>,***</td> <td align="center">0.37<sup>d</sup></td> </tr> <tr> <td class="credit" colspan="5">*** p<0.001, ORENCIA vs placebo.<br /> <sup>a</sup> 10 mg/kg.<br /> <sup>b</sup> Dosing based on weight range [see <b>DOSAGE AND ADMINISTRATION</b>].<br /> <sup>c</sup> Modified Health Assessment Questionnaire: 0 = best, 3 = worst; 8 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.<br /> <sup>d</sup> Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.</td> </tr> </tbody> </table> </center> <p></p> <p>Health-related <a href="/quality_of_life/definition.htm" ">quality of life</a> was assessed by the SF-36 questionnaire at 6 months in Studies II, III, and IV and at 12 months in Studies II and III. In these studies, improvement was observed in the ORENCIA group as compared with the placebo group in all 8 domains of the SF-36 as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS).</p> <h4>Polyarticular Juvenile Idiopathic Arthritis</h4> <h5>Polyarticular Juvenile Idiopathic Arthritis -Intravenous Administration</h5> <p>The safety and efficacy of ORENCIA with intravenous administration were assessed in Study JIA-1, a three-part study including an open-label extension in pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA). Patients 6 to 17 years of age (n=190) with moderately to severely active pJIA who had an inadequate response to one or more DMARDs, such as MTX or TNF antagonists, were treated. Patients had a disease duration of approximately 4 years with moderately to severely active disease at study entry, as determined by baseline counts of active joints (mean, 16) and joints with loss of motion (mean, 16); patients had elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dL) and <a href="/esr/definition.htm" ">ESR</a> (mean, 32 mm/h). The patients enrolled had JIA subtypes that at disease onset included oligoarticular (16%), polyarticular (64%; 20% were rheumatoid factor positive), and systemic JIA without systemic manifestations (20%). At study entry, 74% of patients were receiving MTX (mean dose, 13.2 mg/m² per week) and remained on a stable dose of MTX (those not receiving MTX did not initiate MTX treatment during the study).</p> <p>In Period A (open-label, lead-in), patients received 10 mg/kg (maximum 1,000 mg per dose) intravenously on days 1, 15, 29, and monthly thereafter. Response was assessed utilizing the ACR Pediatric 30 definition of improvement, defined as ≥30% improvement in at least 3 of the 6 JIA core set variables and ≥30% worsening in not more than 1 of the 6 JIA core set variables. Patients demonstrating an ACR Pedi 30 response at the end of Period A were randomized into the double-blind phase (Period B) and received either ORENCIA or placebo for 6 months or until disease flare. Disease flare was defined as a ≥30% worsening in at least 3 of the 6 JIA core set variables with ≥30% improvement in not more than 1 of the 6 JIA core set variables; ≥2 cm of worsening of the Physician or Parent Global Assessment was necessary if used as 1 of the 3 JIA core set variables used to define flare, and worsening in ≥2 joints was necessary if the number of active joints or joints with limitation of motion was used as 1 of the 3 JIA core set variables used to define flare.</p> <p>At the conclusion of Period A, pediatric ACR 30/50/70 responses were 65%, 50%, and 28%, respectively. Pediatric ACR 30 responses were similar in all subtypes of JIA studied.</p> <p>During the double-blind randomized withdrawal phase (Period B), ORENCIA-treated patients (intravenous) experienced significantly fewer disease flares compared to placebo-treated patients (20% vs 53%); 95% CI of the difference (15%, 52%). The risk of disease flare among patients continuing on intravenous ORENCIA was less than one-third than that for patients withdrawn from intravenous ORENCIA treatment (hazard ratio=0.31, 95% CI [0.16, 0.59]). Among patients who received intravenous ORENCIA throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR 30/50/70 responders has remained consistent for 1 year.</p> <h5>Polyarticular Juvenile Idiopathic Arthritis -Subcutaneous Administration</h5> <p>ORENCIA for subcutaneous administration without an intravenous loading dose was assessed in Study JIA-2, a 2-period, open-label study that included pediatric patients 2 to 17 years of age (n=205). Patients had active polyarticular disease at the time of the study and had inadequate response to at least one nonbiologic or biologic DMARD. The JIA patient subtypes at study entry included polyarticular (79%; 22% were rheumatoid factor positive), extended and persistent oligoarticular (14%), enthesitis-related arthritis (1%), and systemic JIA without systemic manifestations (2%). Patients had a mean disease duration of 2.5 years with active joints (mean, 11.9), joints with loss of motion (mean, 10.4), and elevated C-reactive protein (CRP) levels (mean, 1.2 mg/dL). At study entry, 80% of patients were receiving MTX and remained on a stable dose of MTX. Patients received weekly open-label ORENCIA subcutaneously by a weight-tiered dosing regimen. The primary <a href="/objective/definition.htm" ">objective</a> of the study was evaluation of PK in order to support the extrapolation of efficacy based on exposure to ORENCIA supported by descriptive efficacy [see <b>CLINICAL PHARMACOLOGY</b>].</p> <p>JIA ACR 30/50/70 responses assessed at 4 months in the 2-to 17-year-old patients treated with subcutaneous ORENCIA were consistent with the results from intravenous ORENCIA in Study JIA-1.</p> <h4>Adult Psoriatic Arthritis</h4> <p>The efficacy of ORENCIA was assessed in 594 adult patients (18 years and older) with psoriatic arthritis (PsA), in two randomized, double-blind, placebo-controlled studies (Studies PsA-I and PsA-II). Patients had active PsA (≥3 swollen joints and ≥3 tender joints) despite prior treatment with DMARD therapy and had one qualifying psoriatic skin <a href="/lesion/definition.htm" ">lesion</a> of at least 2 cm in diameter. In PsA-I and PsA-II, 37% and 61% of patients, respectively, were treated with TNF antagonists previously.</p> <p>During the initial 24-week, double-blind period of Study PsA-I, 170 patients were randomized to receive one of four intravenous treatments on Days 1, 15, 29, and then every 28 days (there was no escape during the 24-week period):</p> <ul> <li>Placebo</li> <li>ORENCIA 3 mg/kg</li> <li>ORENCIA 500 mg for patients weighing less than 60 kg, ORENCIA 750 mg for patients weighing 60 to 100 kg, and ORENCIA 1,000 mg for patients weighing greater than 100 kg (weight-range-based dosing), or</li> <li>ORENCIA 30 mg/kg on Days 1 and 15 followed by weight range-based ORENCIA dosing (i.e., 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg).</li> </ul> <p>After the 24-week double blind period in Study PsA-I, patients received open-label intravenous ORENCIA every 28 days.</p> <p>Patients were allowed to receive stable doses of concomitant MTX, low dose corticosteroids (equivalent to ≤10 mg of prednisone) and/or NSAIDs during the trial. At enrollment, approximately 60% of patients were receiving MTX. At baseline, the mean (SD) CRP for ORENCIA IV was 17 mg/L (33.0) and mean number (SD) of tender joints and swollen joints was 22.2 (14.3) and 10.9 (7.6), respectively.</p> <p>In PsA-II, 424 patients were randomized 1:1 to receive weekly doses of subcutaneous placebo or ORENCIA 125 mg without a loading dose for 24 weeks-in a double-blind manner, followed by open-label subcutaneous ORENCIA 125 mg weekly. Patients were allowed to receive stable doses of concomitant MTX, sulfasalazine, leflunomide, hydroxychloroquine, low dose corticosteroids (equivalent to ≤10 mg of prednisone) and/or NSAIDs during the trial. At <a href="/randomization/definition.htm" ">randomization</a>, 60% of patients were receiving MTX. The baseline disease characteristics included presence of joint erosion on <a href="/x-rays/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">X-rays</a> in 84% (341/407) with a mean (SD) PsA-modified Sharp van der Heijde erosion score (SHS) of 10.8 (24.2), elevated serum C reactive protein (CRP) in 66% [277/421]) with a mean (SD) of 14.1 mg/L (25.9), and polyarticular disease in 98% (416/424) of patients with a mean number (SD) of tender joints and swollen joints of 20.2 (13.3) and 11.6 (7.5), respectively. Patients who had not achieved at least a 20% improvement from baseline in their swollen and tender joint counts by Week 16 escaped to open-label subcutaneous ORENCIA 125 mg weekly.</p> <p>The primary endpoint for both PsA-I and PsA-II was the proportion of patients achieving ACR 20 response at Week 24 (Day 169).</p> <h5>Clinical Response In Adults With PsA</h5> <p>A greater proportion of adult patients with PsA achieved an ACR 20 response after treatment with intravenous ORENCIA (weight-range-based dosing as described above) compared to placebo in Study PsA-I and a greater proportion of adult patients with PsA achieved an ACR 20 response after treatment with subcutaneous 125 mg compared to placebo in Study PsA-II at Week 24. Responses were seen regardless of prior TNF antagonist treatment and regardless of concomitant non-biologic DMARD treatment. The percent of patients achieving ACR 20, 50, or 70 responses in Studies PsA-I and PsA-II are presented in Table 12 below.</p> <p align="center"><b>Table 12: Proportion of Patients With ACR Responses at Week 24 in Studies PsA-I and PsA-II<sup>a</sup></b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="20%"></td> <td class="EmphTd">PsA-I</td> <td class="EmphTd"></td> <td class="EmphTd">PsA-II</td> <td class="EmphTd"></td> </tr> <tr> <td class="EmphTd" width="20%">ORENCIA Weight-Range-Based Intravenous Dosing<sup>b</sup><br /> N=40</td> <td class="EmphTd" width="20%">Placebo<br /> N=42</td> <td class="EmphTd" width="20%">ORENCIA 125 mg Subcutaneous<br /> N=213</td> <td class="EmphTd" width="20%">Placebo<br /> N=211</td> </tr> <tr> <td>ACR 20</td> <td align="center">47.5%*</td> <td align="center">19.0%</td> <td align="center">39.4%*</td> <td align="center">22.3%</td> </tr> <tr> <td>ACR 50</td> <td align="center">25.0%</td> <td align="center">2.4%</td> <td align="center">19.2%</td> <td align="center">12.3%</td> </tr> <tr> <td>ACR 70</td> <td align="center">12.5%</td> <td align="center">0%</td> <td align="center">10.3%</td> <td align="center">6.6%</td> </tr> <tr> <td class="credit" colspan="5">* p<0.05 versus placebo.<br /> <sup>a</sup> Patients who had less than 20% improvement in tender or swollen joint counts at Week 16 met escape criteria and were considered non-responders.<br /> <sup>b</sup> Weight range-based intravenous dosing: ORENCIA 500 mg for patients weighing less than 60 kg, ORENCIA 750 mg for patients weighing 60 to 100 kg, and ORENCIA 1,000 mg for patients weighing greater than 100 kg.</td> </tr> </tbody> </table> </center> <p></p> <p>The percentage of patients in PsA-II achieving ACR 20 response through Week 24 is shown below in Figure 2.</p> <p align="center"><b>Figure 2: Percent of Patients Achieving ACR 20 Response<sup>a</sup> in PsA-II Study Through Week 24 (Day 169)</b></p> <center> <table cellspacing="0" class="blackpic" width="643"> <tbody> <tr> <td><img alt="Percent of Patients Achieving ACR 20 Response<sup>a</sup> in PsA-II Study Through Week 24 (Day 169) - Illustration" height="310" src="https://images.rxlist.com/images/rxlist/orencia2.gif" width="643" /></td> </tr> </tbody> </table> </center> <p></p> <p>Results were generally consistent across the ACR components in Study PsA-I and PsA-II.</p> <p>Improvements in enthesitis and <a href="/dactylitis/definition.htm" ">dactylitis</a> were seen with ORENCIA treatment at Week 24 in both PsA-I and PsA-II.</p> <h5>Physical Function Response In Adults With PsA</h5> <p>In study PsA-I, there was a higher proportion of patients with at least a 0.30 decrease from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 24, with an estimated difference for ORENCIA weight range-based dosing as described above (45%) vs. placebo (19%) of 26.1 (95% confidence interval: 6.8, 45.5). In study PsA-II, the proportion of patients with at least a 0.35 decrease from baseline in HAQ-DI on ORENCIA was 31%, as compared to 24% on placebo (estimated difference: 7%; 95% confidence interval: -1%, 16%). There was a higher adjusted mean change from baseline in HAQ-DI on ORENCIA (-0.33) vs. placebo (-0.20) at Week 24, with an estimated difference of -0.13 (95% confidence interval: -0.25, -0.01).</p> <h4>Prophylaxis Of Acute Graft Versus Host Disease</h4> <h5>Study GVHD-1</h5> <p>The efficacy of ORENCIA, in combination with a calcineurin inhibitor (CNI) and methotrexate (MTX), for the prophylaxis of acute graft versus host disease (aGVHD), was evaluated in a multicenter, two cohort clinical study (GVHD-1, NCT01743131) in patients age 6 years and older who underwent hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated donor (URD). The two cohorts in GVHD-1 included:</p> <ol> <li>an open-label, single-arm study of 43 patients who underwent a 7 of 8 Human Leukocyte Antigen (HLA)-matched HSCT (7 of 8 cohort); and</li> <li>a randomized (1:1), double-blind, placebo-controlled study of patients who underwent an 8 of 8 HLA-matched HSCT who received ORENCIA or placebo in combination with a CNI and MTX (8 of 8 cohort).</li> </ol> <p>In both the 7/8 and 8/8 cohorts, ORENCIA was administered at a dose of 10 mg/kg (1,000 mg maximum dose) as an intravenous infusion over 60 minutes, beginning on the day before transplantation (Day -1), followed by administration on Days 5, 14, and 28 after transplantation. Baseline demographic and clinical characteristics of both the 7 of 8 and 8 of 8 cohorts are outlined below in Table 13.</p> <p align="center"><b>Table 13: Baseline Demographic and Clinical Characteristics: 7 of 8 and 8 of 8 Cohort Treated Analysis Population in Study GVHD-1</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="40%"></td> <td class="EmphTd">7 of 8 Cohort</td> <td class="EmphTd" colspan="2">8 of 8 Cohort</td> </tr> <tr> <td class="EmphTd" width="20%">ORENCIA (+ CNI and MTX)<br /> N=43</td> <td class="EmphTd" width="20%">ORENCIA (+ CNI and MTX)<br /> N=73</td> <td class="EmphTd" width="20%">Placebo (+CNI and MTX)<br /> N=69</td> </tr> <tr> <td>Age - Median</td> <td align="center">38</td> <td align="center">44</td> <td align="center">40</td> </tr> <tr> <td>Age - Range</td> <td align="center">6-76</td> <td align="center">6-71</td> <td align="center">7-74</td> </tr> <tr> <td>Gender - Male</td> <td align="center">27 (63)</td> <td align="center">41 (56)</td> <td align="center">37 (54)</td> </tr> <tr> <td>White</td> <td align="center">31 (72)</td> <td align="center">63 (86)</td> <td align="center">61 (88)</td> </tr> <tr> <td>Black or African American</td> <td align="center">7 (16)</td> <td align="center">3 (4.1)</td> <td align="center">2 (2.9)</td> </tr> <tr> <td>Asian</td> <td align="center">2 (4.7)</td> <td align="center">4 (6)</td> <td align="center">2 (2.9)</td> </tr> <tr> <td>Hispanic</td> <td align="center">7 (16)</td> <td align="center">4 (6)</td> <td align="center">2 (2.9)</td> </tr> <tr> <td colspan="4"><b>Malignancy type</b></td> </tr> <tr> <td>Acute Myeloid Leukemia (AML)</td> <td align="center">15 (35)</td> <td align="center">30 (41)</td> <td align="center">22 (32)</td> </tr> <tr> <td>Myelodysplastic Syndrome (MDS)</td> <td align="center">11 (26)</td> <td align="center">15 (21)</td> <td align="center">12 (17)</td> </tr> <tr> <td>Acute Lymphoblastic Leukemia (ALL)</td> <td align="center">8 (19)</td> <td align="center">20 (27)</td> <td align="center">22 (32)</td> </tr> <tr> <td>Acute leukemia or ambiguous lineage</td> <td align="center">1 (2.3)</td> <td align="center">0</td> <td align="center">1 (1.4)</td> </tr> <tr> <td>Hodgkin and Non-Hodgkin lymphoma</td> <td align="center">1 (2.3)</td> <td align="center">1 (1.4)</td> <td align="center">1 (1.4)</td> </tr> <tr> <td>Acute Lymphoblastic Lymphoma in 2nd or Greater Complete Remission</td> <td align="center">1 (2.3)</td> <td align="center">4 (6)</td> <td align="center">1 (1.4)</td> </tr> <tr> <td>Chronic Myelomonocytic leukemia</td> <td align="center">1 (2.3)</td> <td align="center">1 (1.4)</td> <td align="center">4 (6)</td> </tr> <tr> <td>Chronic Myelogenous leukemia</td> <td align="center">4 (9)</td> <td align="center">1 (1.4)</td> <td align="center">5 (7)</td> </tr> <tr> <td>Not reported</td> <td align="center">1 (2.3)</td> <td align="center">1 (1.4)</td> <td align="center">1 (1.4)</td> </tr> <tr> <td colspan="4"><b>GVHD Prophylaxis</b></td> </tr> <tr> <td>Cyclosporine</td> <td align="center">16 (37)</td> <td align="center">11 (15)</td> <td align="center">11 (16)</td> </tr> <tr> <td>Tacrolimus</td> <td align="center">27 (63)</td> <td align="center">62 (85)</td> <td align="center">58 (84)</td> </tr> <tr> <td colspan="4"><b>Type of Graft</b></td> </tr> <tr> <td>Bone Marrow</td> <td align="center">21 (49)</td> <td align="center">33 (45)</td> <td align="center">26 (38)</td> </tr> <tr> <td>Cytokine Mobilized Peripheral Blood (PBSC)</td> <td align="center">22 (51)</td> <td align="center">40 (55)</td> <td align="center">43 (62)</td> </tr> <tr> <td colspan="4"><b>Conditioning Regimen</b></td> </tr> <tr> <td>TBI and Chemotherapy</td> <td align="center">11 (26)</td> <td align="center">20 (27)</td> <td align="center">26 (38)</td> </tr> <tr> <td>Busulfan and Cyclophosphamide</td> <td align="center">13 (30)</td> <td align="center">28 (38)</td> <td align="center">21 (30)</td> </tr> <tr> <td>Busulfan and Fludarabine</td> <td align="center">8 (19)</td> <td align="center">7 (10)</td> <td align="center">2 (2.9)</td> </tr> <tr> <td>Melphalan and Fludarabine</td> <td align="center">11 (26)</td> <td align="center">18 (25)</td> <td align="center">20 (29)</td> </tr> </tbody> </table> </center> <p></p> <p>Efficacy was established based on overall survival (<a href="/os/definition.htm" ">OS</a>) and grade II-IV aGVHD free survival (GFS) results assessed at Day 180 post-transplantation. ORENCIA + CNI and MTX did not significantly improve grade III-IV GFS versus placebo + CNI and MTX at Day 180 post-transplantation. The efficacy results of the GVHD-1 8 of 8 cohort are shown in Table 14.</p> <p align="center"><b>Table 14: Efficacy Results in 8 of 8 Cohort in Study GVHD-1 at Day 180 Post-Transplantation</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="50%">Endpoint</td> <td class="EmphTd" width="25%">ORENCIA (+CNI and MTX)<br /> n =73</td> <td class="EmphTd" width="25%">Placebo (+CNI and MTX)<br /> n=69</td> </tr> <tr> <td>Gr III-IV aGVHD Free Survival<sup>a</sup> Rate (95% CI)</td> <td align="center">87% (77%, 93%)</td> <td align="center">75% (63%, 84%)</td> </tr> <tr> <td>Hazard Ratio (95% CI)</td> <td align="center" colspan="2">0.55 (0.26, 1.18)</td> </tr> <tr> <td>Gr II-IV aGVHD Free Survival<sup>b</sup> Rate (95% CI)</td> <td align="center">50% (38%, 61%)</td> <td align="center">32% (21%, 43%)</td> </tr> <tr> <td>Hazard Ratio (95% CI)</td> <td align="center" colspan="2">0.54 (0.35, 0.83)</td> </tr> <tr> <td>Overall Survival Rate (95% CI)</td> <td align="center">97% (89%, 99%)</td> <td align="center">84% (73%, 91%)</td> </tr> <tr> <td>Hazard Ratio (95% CI)</td> <td align="center" colspan="2">0.33 (0.12, 0.93)</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Gr III-IV aGVHD Free Survival was measured from the date of transplantation until the onset of documented Grade III-IV aGVHD, or death by any cause up to Day 180 post-transplantation.<br /> <sup>b</sup> Gr II-IV aGVHD Free Survival was measured from the date of transplantation until the onset of documented Grade II-IV aGVHD, or death by any cause up to Day 180 post-transplantation.</td> </tr> </tbody> </table> </center> <p></p> <p>In an exploratory analysis of the 7 of 8 cohort of ORENCIA-treated patients (n=43), the rates of Grade III-IV GVHD-free survival, Grade II-IV GVHD-free survival, and overall survival at day 180 post-transplantation were 95% (95% CI 83%, 99%), 53% (95% CI 38%, 67%), and 98% (95% CI 85%, 100%), respectively.</p> <h5>Study GVHD-2</h5> <p>GVHD-2 was a clinical study that used data from the Center for International Blood and Marrow Transplant Research (CIBMTR). The study analyzed outcomes of ORENCIA in combination with a CNI and MTX, versus a CNI and MTX alone, for the prophylaxis of aGVHD, in patients 6 years of age or older who underwent HSCT from a 1 allele-mismatched URD between 2011 and 2018. The ORENCIA + CNI and MTX-treated group (n=54) included 42 patients from GVHD-1, in addition to 12 patients treated with ORENCIA outside of GVHD-1. The comparator group (n=162) was randomly selected in a 3:1 ratio to the ORENCIA-treated group from the CIBMTR registry from patients who had not received ORENCIA during the study period. Analyses used propensity score matching and inverse probability of treatment weighting to help address the impact of selection bias.</p> <p>Efficacy was based on Overall Survival (OS) at Day 180 post-HSCT. The OS rate at Day 180 in the ORENCIA in combination with CNI and MTX group was 98% (95% CI: 78, 100) and the OS rate at Day 180 in the CNI and MTX group was 75% (95% CI: 67, 82).</p> </div> </div> </div> | 10 | 2023-02-01 17:39:31 | Abatacept (Orencia) | A | DMARDs, Immunomodulators | Orencia | abatacept | Orencia | |
| 79 | 2023-02-23 12:07:03 | Medication Guide | <a name="PI"></a> <h3>PATIENT INFORMATION</h3> <p><b>ORENCIA®</b><br /> (oh-REN-see-ah)<br /> (abatacept) for injection, for intravenous use</p> <p><b>ORENCIA®</b><br /> (oh-REN-see-ah)<br /> (abatacept) injection, for subcutaneous use</p> <p><b>What is ORENCIA?</b></p> <p>ORENCIA is a prescription medicine that reduces signs and symptoms in:</p> <ul> <li>adults with moderate to severe rheumatoid arthritis (RA), including those who have not been helped enough by other medicines for RA. ORENCIA may prevent further damage to your bones and joints and may help your ability to perform daily activities. In adults, ORENCIA may be used alone or with other RA treatments other than tumor necrosis factor (TNF) antagonists.</li> <li>people 2 years of age and older with moderate to severe polyarticular juvenile idiopathic arthritis (pJIA). ORENCIA may be used alone or with methotrexate.</li> <li>adults with active psoriatic arthritis (PsA). In adults, ORENCIA can be used alone or with other PsA treatments.</li> </ul> <p>ORENCIA is also used for the preventative treatment of acute graft versus host disease (aGVHD), in combination with a calcineurin inhibitor and methotrexate, in:</p> <ul> <li>people 2 years of age and older undergoing hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated-donor.</li> </ul> <p>It is not known if ORENCIA is safe and effective in children less than two years of age for the treatment of pJIA.</p> <p>It is not known if ORENCIA is safe and effective in children less than two years of age for the preventative treatment of aGVHD.</p> <p><b>Before you receive or use ORENCIA, tell your healthcare provider about all of your medicalconditions, including if you:</b></p> <ul> <li>have any kind of infection even if it is small (such as an open cut or sore), or an infection that is in your whole body (such as the flu). If you have an infection during treatment with ORENCIA, you may have a higher chance for getting serious side effects.</li> <li>have an infection that will not go away or an infection that keeps coming back.</li> <li>are allergic to abatacept or any of the ingredients in ORENCIA. See the end of this Patient Information leaflet for a complete list of ingredients in ORENCIA.</li> <li>have or have had inflammation of your liver due to an infection (viral hepatitis). Your healthcare provider may examine you for hepatitis before treatment with ORENCIA.</li> <li>have had a lung infection called tuberculosis (TB), a positive skin test for TB, or you recently have been in close contact with someone who has had TB. Your healthcare provider may examine you for TB or perform a skin test before treatment with ORENCIA. Symptoms of TB may include: <ul> <li>a cough that does not go away</li> <li>weight loss</li> <li>fever</li> <li>night sweats</li> </ul> </li> <li>have a history of Epstein-Barr Virus (EBV) or Cytomegalovirus (CMV) in people receiving ORENCIA for preventative treatment of aGVHD during HSCT from an unrelated donor.</li> <li>are scheduled to have surgery.</li> <li>recently received a vaccination or are scheduled for a vaccination.</li> <li>have a history of a breathing problem called chronic obstructive pulmonary disease (COPD).</li> <li>have diabetes and use a blood glucose monitor to check your blood sugar (blood glucose) levels. ORENCIA for intravenous infusion (given through a needle placed in a vein) contains maltose, a type of sugar, that can give false high blood sugar readings with certain types of blood glucose monitors on the day of ORENCIA infusion. Your healthcare provider may tell you to use a different way to monitor your blood sugar levels.</li> <li>ORENCIA for subcutaneous injection (injected under the skin) does not contain maltose. You do not need to change your blood sugar monitoring if you are using ORENCIA subcutaneously.</li> <li>are pregnant or plan to become pregnant. It is not known if ORENCIA can harm your unborn baby. If you took ORENCIA during pregnancy, talk to your healthcare provider before your baby receives any vaccines.</li> <li>There is a registry for pregnant women exposed to ORENCIA. The purpose of this registry is to check the health of the pregnant mother and her child. Women are encouraged to call the registry themselves or ask their healthcare provider to contact the registry for them by calling 1-877-3118972.</li> <li>are breastfeeding or plan to breastfeed. It is not known if ORENCIA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use ORENCIA.</li> <li>Some people treated with ORENCIA have developed skin cancer. Tell your healthcare provider if you have a family or personal history of skin cancer, and if you see any growths or changes in the appearance of your skin during or after your treatment with ORENCIA.</li> </ul> <p><b>Tell your healthcare provider about all the medicines you take,</b> including prescription and over-thecounter medicines, vitamins, and herbal supplements.</p> <p>ORENCIA may affect the way other medicines work, and other medicines may affect the way ORENCIA works causing serious side effects.</p> <p>Especially tell your healthcare provider if you take other biologic medicines that may affect your immune system, such as:</p> <ul> <li>Enbrel® (etanercept)</li> <li>Kineret® (anakinra)</li> <li>Cimzia® (certolizumab pegol)</li> <li>Humira® (adalimumab)</li> <li>Rituxan® (rituximab)</li> <li>Actemra® (tocilizumab)</li> <li>Remicade® (infliximab)</li> <li>Simponi® (golimumab)</li> </ul> <p>You may have a higher chance of getting a serious infection if you take ORENCIA with other biologic medicines that may affect your immune system.</p> <p>Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new prescription.</p> <p><b>How will I receive or use ORENCIA?</b></p> <p><b>For treatment of RA, pJIA or PsA:</b></p> <ul> <li>You may receive ORENCIA given by a healthcare provider through a vein in your arm (intravenous infusion). It takes about 30 minutes to give you the full dose of medicine. You will then receive ORENCIA 2 weeks and 4 weeks after the first dose and then every 4 weeks.</li> <li>You may also receive ORENCIA as an injection under your skin (subcutaneous). For home use, ORENCIA comes in a prefilled syringe or prefilled ClickJect autoinjector. Your healthcare provider will prescribe the type that is best for you. If your healthcare provider decides that you or a caregiver can give your injections of ORENCIA prefilled syringes or ORENCIA ClickJect autoinjectors at home, you or your caregiver should receive training on the right way to prepare and inject ORENCIA. Do not try to inject ORENCIA until you have been shown the right way to give the injections by your healthcare provider.</li> <li>Your healthcare provider will tell you how much ORENCIA to use and when to use it.</li> </ul> <p><b>See the Instructions for Use at the end of this Patient Information leaflet for instructions about the right way to prepare and give your ORENCIA injections at home.</b></p> <p><b>For preventative treatment of aGVHD:</b></p> <ul> <li>You will receive ORENCIA by a healthcare provider through a vein in your arm (intravenous infusion) over 60 minutes on the day before transplantation (Day -1). You will then receive ORENCIA on Days 5, 14, and 28 after transplantation.</li> <li>Your healthcare provider may give you antiviral medicines before, during, and after your transplantation to help prevent Epstein-Barr Virus (EBV) and Cytomegalovirus (CMV) infections.</li> </ul> <p><b>What are the possible side effects of ORENCIA?</b></p> <p><b>ORENCIA can cause serious side effects including:</b></p> <ul> <li>infections. ORENCIA can make you more likely to get infections or make the infection that you have get worse. Some people have died from these infections. Call your healthcare provider right away if you have any symptoms of an infection. Symptoms of an infection may include: <ul> <li>fever</li> <li>feel very tired</li> <li>have a cough</li> <li>have flu-like symptoms</li> <li>warm, red, or painful skin</li> </ul> </li> <li>allergic reactions. Allergic reactions can happen to people who are treated with ORENCIA. Call your healthcare provider or go to the emergency room right away if you have any symptoms of an allergic reaction. Symptoms of an allergic reaction may include: <ul> <li>hives</li> <li>swollen face, eyelids, lips, or tongue</li> <li>trouble breathing</li> </ul> </li> <li><b>hepatitis B infection in people who carry the virus in their blood.</b> If you are a carrier of the hepatitis B virus (a virus that affects the liver), the virus can become active during treatment with ORENCIA. Your healthcare provider may do a blood test before you start treatment with ORENCIA.</li> <li><b>vaccinations.</b> You should not receive ORENCIA with certain types of vaccines (live vaccines). You can receive non-live vaccines, such as pneumococcal and inactivated influenza (flu) vaccines. ORENCIA may also cause some vaccinations to be less effective. Talk with your healthcare provider about your vaccination plans.</li> <li><b>breathing problems in people with Chronic Obstructive Pulmonary Disease (COPD).</b> You may get certain respiratory problems more often if you receive ORENCIA and have COPD. Symptoms of respiratory problems include: <ul> <li>COPD that becomes worse</li> <li>cough</li> <li>trouble breathing</li> </ul> </li> <li><b>cancer (malignancies).</b> Certain kinds of cancer have been reported in people using ORENCIA. It is not known if ORENCIA increases your chance of getting certain kinds of cancer.</li> <li><b>Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) infections.</b> CMV and EBV infections and return of CMV and EBV (reactivation) have happened in people receiving ORENCIA for preventative treatment of aGVHD during unrelated HSCT. Your healthcare provider will monitor you for 6 months after transplantation and may treat you with medicines to help prevent CMV and EBV infection if needed.</li> </ul> <p><b>The most common side effects of ORENCIA in people with RA include:</b></p> <ul> <li>headache</li> <li>upper respiratory tract infection</li> <li>sore throat</li> <li>nausea</li> </ul> <p><b>In children and adolescents, other side effects may include:</b></p> <ul> <li>diarrhea</li> <li>cough</li> <li>fever</li> <li>abdominal pain</li> </ul> <p><b>The most common side effects of ORENCIA in prevention of aGVHD include:</b></p> <ul> <li>low red blood cell count</li> <li>high blood pressure</li> <li>CMV infection</li> <li>fever</li> <li>pneumonia</li> <li>nosebleed</li> <li>decreased CD4 lymphocytes</li> <li>increased levels of magnesium in the blood</li> <li>kidney problems</li> </ul> <p>These are not all of the possible side effects of ORENCIA.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088.</p> <p><b>How should I store ORENCIA?</b></p> <ul> <li>Store ORENCIA in the refrigerator at 36°F to 46°F (2°C to 8°C).</li> <li>Keep ORENCIA in the original package and out of the light.</li> <li>Do not freeze ORENCIA.</li> <li>Safely throw away medicine that is out of date or no longer needed.</li> </ul> <p><b>Keep ORENCIA and all medicines out of the reach of children.</b></p> <p><b>General information about the safe and effective use of ORENCIA.</b></p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ORENCIA for a condition for which it was not prescribed. Do not give ORENCIA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ORENCIA that is written for health professionals.</p> <p><b>What are the ingredients in ORENCIA?</b></p> <p><b>Active ingredient:</b> abatacept</p> <p><b>Intravenous inactive ingredients:</b> maltose, monobasic sodium phosphate, sodium chloride for administration</p> <p><b>Subcutaneous inactive ingredients:</b> sucrose, poloxamer 188, monobasic sodium phosphate monohydrate, dibasic sodium phosphate anhydrous, water for injection.</p> <p><b>INSTRUCTIONS FOR USE</b></p> <p><b>ORENCIA®</b><br /> (oh-REN-see-ah) (abatacept)</p> <p><b>Prefilled Syringe with BD UltraSafe Passive™ Needle Guard</b></p> <p><b>ORENCIA® Prefilled Syringe with BD UltraSafe Passive™ Needle Guard (abatacept) Injection</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="350"> <tbody> <tr> <td><img alt="ORENCIA® Prefilled Syringe - Illustration" height="117" src="https://images.rxlist.com/images/rxlist/orencia3.gif" width="350" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Read these instructions before you start using your ORENCIA Prefilled Syringe </b>and each time you get a refill. There may be new information. Before you use the prefilled syringe for the first time, make sure your healthcare provider shows you the right way to use it and decides that you or a caregiver may be able to give your injections of ORENCIA at home.</p> <p><b>Important:</b></p> <ul> <li><b>Keep the Prefilled Syringe in the refrigerator until ready to use.</b></li> <li><b>Do not freeze.</b></li> </ul> <p><b>Before You Begin: Get to Know Your Prefilled Syringe</b></p> <p>There are 3 types of prefilled syringes:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="729"> <tbody> <tr> <td><img alt="The 3 types of prefilled syringes - Illustration" height="115" src="https://images.rxlist.com/images/rxlist/orencia4.gif" width="729" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>The type of prefilled syringe you receive depends on the dose prescribed by your healthcare provider. The 125 mg/mL prefilled syringe is shown below.</b></p> <p><b>Before Use</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="504"> <tbody> <tr> <td><img alt="Before Use - Illustration" height="193" src="https://images.rxlist.com/images/rxlist/orencia5.gif" width="504" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>After Use</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="487"> <tbody> <tr> <td><img alt="After Use - Illustration" height="189" src="https://images.rxlist.com/images/rxlist/orencia6.gif" width="487" /></td> </tr> </tbody> </table> </center> <p></p> <p>The prefilled syringe has a flange extender that makes it easier to hold and inject, and a needle guard that automatically covers the needle after a complete injection.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="91"> <tbody> <tr> <td><img alt="Caution - Illustration" height="106" src="https://images.rxlist.com/images/rxlist/orencia7.gif" width="91" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>DO NOT</b> remove the needle cover until you are ready to inject.</p> <p><b>DO NOT PULL</b> back on the plunger at any time.</p> <p><b>DO NOT RECAP</b> the prefilled syringe at any time, as this may damage, bend, or break the needle.</p> <p><b>Go to Step 1</b></p> <p><b>Step 1: Preparing for an ORENCIA Injection</b></p> <p><b>Gather and place supplies for your injection on a clean, flat surface.</b></p> <p>Only the prefilled syringe is included in the package:</p> <ul> <li>Alcohol swab</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="123"> <tbody> <tr> <td><img alt="Alcohol swab - Illustration" height="92" src="https://images.rxlist.com/images/rxlist/orencia8.gif" width="123" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Prefilled Syringe withUltraSafe Passive Needle Guard</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="128"> <tbody> <tr> <td><img alt="Prefilled Syringe withUltraSafe Passive Needle Guard - Illustration" height="130" src="https://images.rxlist.com/images/rxlist/orencia9.gif" width="128" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Adhesive bandage</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="153"> <tbody> <tr> <td><img alt="Adhesive bandage - Illustration" height="120" src="https://images.rxlist.com/images/rxlist/orencia10.gif" width="153" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Sharps disposal container</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="95"> <tbody> <tr> <td><img alt="Sharps disposal container - Illustration" height="141" src="https://images.rxlist.com/images/rxlist/orencia11.gif" width="95" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li><a href="/cotton/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">Cotton</a> ball or gauze</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="116"> <tbody> <tr> <td><img alt="Cotton ball or gauze - Illustration" height="111" src="https://images.rxlist.com/images/rxlist/orencia12.gif" width="116" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Let your Prefilled Syringe warm up.</b></p> <p>Remove one prefilled syringe from the refrigerator and wait 30 minutes to allow it to reach room temperature.</p> <ul> <li><b>Do not</b> <a href="/speed/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">speed</a> up the warming process in any way, such as using the microwave or placing the syringe in warm water.</li> <li><b>Do not</b> remove the needle cover while allowing the prefilled syringe to reach room temperature.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="162"> <tbody> <tr> <td><img alt="Let your Prefilled Syringe warm up - Illustration" height="201" src="https://images.rxlist.com/images/rxlist/orencia13.gif" width="162" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Wash your hands well with soap and water.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="211"> <tbody> <tr> <td><img alt="Wash your hands well with soap and water - Illustration" height="165" src="https://images.rxlist.com/images/rxlist/orencia14.gif" width="211" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Go to Step 2</b></p> <p><b>Step 2: Examine the Prefilled Syringe</b></p> <p>Hold the prefilled syringe by the body with the needle cover pointing down as shown.</p> <ul> <li><b>Check the expiration date</b> printed on the label. Do not use if the expiration date has passed.</li> <li><b>Check the prefilled syringe for damage.</b> Do not use if it is cracked or broken.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="261"> <tbody> <tr> <td><img alt="Examine the Prefilled Syringe - Illustration" height="335" src="https://images.rxlist.com/images/rxlist/orencia15.gif" width="261" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Check the Liquid.</b></p> <ul> <li><b>Check the liquid</b> in the prefilled syringe through the viewing window. It should be clear and colorless to pale yellow<</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="226"> <tbody> <tr> <td><img alt="heck the Liquid - Illustration" height="313" src="https://images.rxlist.com/images/rxlist/orencia16.gif" width="226" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Do not inject if the liquid is cloudy, discolored, or has particles in it.</b></p> <p>*Note: the 50 mg prefilled syringe is shown.</p> <p><b>Note:</b> It is normal to see an air bubble. Do not attempt to remove it. Go to Step 3</p> <p><b>Step 3: Check the Dose on the Prefilled Syringe</b></p> <p>Hold the syringe at eye level. Look closely to make sure that the amount of liquid in the prefilled syringe is at or just above the fill line for your prescribed dose:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="510"> <tbody> <tr> <td><img alt=" Check the Dose on the Prefilled Syringe - Illustration" height="468" src="https://images.rxlist.com/images/rxlist/orencia17.gif" width="510" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Do not</b> use if your prefilled syringe does not have the correct amount of liquid. Call your pharmacist immediately.</p> <p><b>Go to Step 4</b></p> <p><b>Step 4: Choose and Prepare an Injection Site</b></p> <p><b>Choose your injection site.</b></p> <p>Choose your injection site in either the stomach (abdomen), front of the thighs, or outer area of upper arm (only if caregiver administered).</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="376"> <tbody> <tr> <td><img alt="Choose and Prepare an Injection Site - Illustration" height="213" src="https://images.rxlist.com/images/rxlist/orencia18.gif" width="376" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Rotate injection site.</b></p> <ul> <li>Each week you can use the same area of your body, but use a different injection site in that area.</li> <li><b>Do not</b> inject into an area where the skin is tender, bruised, red, scaly, or hard. <b>Do not</b> give the injection in any areas with <a href="/scars/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">scars</a> or stretch marks.</li> <li>Record the date, time, and site where you inject.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="358"> <tbody> <tr> <td><img alt="Rotate injection site - Illustration" height="224" src="https://images.rxlist.com/images/rxlist/orencia19.gif" width="358" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Gently clean injection site.</b></p> <ul> <li>Wipe the injection site with an alcohol swab and let it air dry.</li> <li><b>Do not</b> touch the injection site again before giving the injection.</li> <li><b>Do not</b> fan or blow on the clean area.</li> </ul> <p><b>Remove the needle cover</b> by holding the body of the prefilled syringe with one hand and pulling the cover straight off with your other hand.</p> <p><b>Do not put the needle cover back on the needle after you remove it.</b> Throw away the needle cover in your household trash.</p> <ul> <li><b>Do not</b> use the prefilled syringe if it is dropped after the needle cover is removed.</li> <li><b>Do not</b> use the prefilled syringe if the needle is damaged or bent.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="262"> <tbody> <tr> <td><img alt="Wipe the injection site with an alcohol swab and let it air dry - Illustration" height="234" src="https://images.rxlist.com/images/rxlist/orencia20.gif" width="262" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Note:</b> It is normal to see a drop of fluid leaving the needle.</p> <p><b>DO NOT RECAP</b> the Prefilled Syringe, as this may damage the needle.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="69"> <tbody> <tr> <td><img alt="Caution - Illustration" height="74" src="https://images.rxlist.com/images/rxlist/orencia21.gif" width="69" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Go to Step 5</b></p> <p><b>Step 5: Inject Your Dose of ORENCIA</b></p> <p><b>Hold the body</b> of the prefilled syringe in your hand using your thumb and index finger. With your other hand, <b>pinch the area of skin you cleaned.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="197"> <tbody> <tr> <td><img alt="Inject Your Dose of ORENCIA - Illustration" height="190" src="https://images.rxlist.com/images/rxlist/orencia22.gif" width="197" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Insert the needle.</b></p> <p><b>Gently insert</b> the needle into the pinched skin at a 45° angle.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="194"> <tbody> <tr> <td><img alt="Gently insert the needle into the pinched skin at a 45° angle - Illustration" height="195" src="https://images.rxlist.com/images/rxlist/orencia23.gif" width="194" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Complete all steps to deliver your full dose of the medicine.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="640"> <tbody> <tr> <td><img alt="Complete all steps to deliver your full dose of the medicine - Illustration" height="193" src="https://images.rxlist.com/images/rxlist/orencia24.gif" width="640" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Inject: push the plunger with your thumb as far as it will go.</b></p> <p><b>Release Needle Guard: slowly lift your thumb from the plunger</b> to activate the needle guard.</p> <p><b>Confirm: after a complete injection, the needle </b>guard will cover the needle and you may hear a click.</p> <p><b>Remove the prefilled syringe and let go of the pinched skin.</b></p> <p><b>Go to Step 6</b></p> <p><b>Step 6: After the Injection</b></p> <p><b>Care of injection site:</b></p> <ul> <li>There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="278"> <tbody> <tr> <td><img alt="After the Injection - Illustration" height="73" src="https://images.rxlist.com/images/rxlist/orencia25.gif" width="278" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li><b>Do not</b> rub the injection site.</li> <li>If needed, you may cover the injection site with an adhesive bandage.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="277"> <tbody> <tr> <td><img alt="If needed, you may cover the injection site with an adhesive bandage - Illustration" height="89" src="https://images.rxlist.com/images/rxlist/orencia26.gif" width="277" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Disposing of used Prefilled Syringes:</b></p> <ul> <li>Put your used ORENCIA prefilled syringes in a FDA-cleared sharps disposal container right away after use. <b>Do not throw away (dispose of) loose needles and prefilled syringes in your household trash.</b></li> <li>If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: <ul> <li>made of a heavy-duty <a href="/plastic/article.htm" rel="sub" onclick="wmdTrack('embd-lnk');">plastic</a>,</li> <li>can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,</li> <li>upright and stable during use,</li> <li>leak resistant, and</li> <li>properly labeled to warn of hazardous waste inside the container.</li> </ul> </li> <li>When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.</li> <li><b>Do not</b> throw away (dispose of) your used sharps disposal container in your household trash unless your community guidelines permit this. <b>Do not</b> recycle your used sharps disposal container.</li> </ul> <p>See <b>Frequently Asked Questions</b> for additional disposal information.</p> <p>If your injection is administered by a caregiver, this person must also be careful handling the syringe to prevent accidental <a href="/needle_stick/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">needle stick</a> injury and possibly spreading infection.</p> <p><b>Keep ORENCIA prefilled syringes and the disposal container out of the reach of children.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="263"> <tbody> <tr> <td><img alt="Keep ORENCIA prefilled syringes and the disposal container out of the reach of children - Illustration" height="301" src="https://images.rxlist.com/images/rxlist/orencia27.gif" width="263" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>How to store ORENCIA Prefilled Syringe</b></p> <ul> <li>Store ORENCIA in the refrigerator at 36°F to 46°F (2°C to 8°C).</li> <li>Keep ORENCIA in the original package and out of the light.</li> <li>Do not freeze ORENCIA.</li> <li>Safely throw away medicine that is out of date or no longer needed.</li> </ul> <p><b>Go to Next Page</b></p> <p><b>Frequently Asked Questions</b></p> <p><b>Q. Why do I need to allow the prefilled syringe to warm up at room temperature for 30 minutesprior to injecting?</b></p> <p>A. This step is primarily for your comfort. Never try to speed up the warming process in any way, like using the microwave or placing the syringe in warm water.</p> <p><b>Q. Is it necessary to hold the skin pinch during the entire time I inject the dose?</b></p> <p>A. You must pinch the skin during needle insertion however, for your comfort you may release the skin pinch as you deliver the injection.</p> <p><b>Q. What if my prefilled syringe appears to be broken or damaged?</b></p> <p>A. Do not use the prefilled syringe. Contact your healthcare provider or pharmacist for further instructions.</p> <p><b>Q. What if I cannot clearly see the liquid inside the syringe?</b></p> <p>A. Look at the syringe closely by holding at eye level and up to the light. You may tilt the syringe slowly to get a better view of the drug fluid. If you still have trouble, contact your healthcare provider or pharmacist for further instructions.</p> <p><b>Q. Is it normal to feel a little bit of burning or pain during injection?</b></p> <p>A. You may feel a prick from the needle. Sometimes, the medicine can cause slight irritation near the injection site. Discomfort should be mild to moderate. If you have any side effects, including pain, swelling, or discoloration near the injection site, contact your healthcare provider.</p> <p><b>Go to next page</b></p> <p><b>Frequently Asked Questions</b></p> <p><b>Q. How should I dispose of a used prefilled syringe?</b></p> <p>A. Place the used prefilled syringe into an FDA-cleared sharps disposal container. If you do not have one you may use a household container that is:</p> <ul> <li>made of a heavy-duty plastic,</li> <li>can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,</li> <li>upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container.</li> </ul> <p>When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and injector pens. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.</p> <p><b>Q. How should I keep my prefilled syringes cool while traveling?</b></p> <p>A. Store them in a cool carrier between 36°F to 46°F (2°C to 8°C). Do not freeze them. Keep them in the original carton and protected from light. Your healthcare provider may know about special carrying cases.</p> <p><b>Q. Can I take my prefilled syringes on an airplane?</b></p> <p>A. Generally you are allowed to carry your prefilled syringes with you on an airplane. Do not put them in your checked luggage. You should carry your prefilled syringes with you in your travel cooler at a temperature of 36°F to 46°F (2°C to 8°C). Keep your prefilled syringes in the original carton, and with its original preprinted labels and protected from light.</p> <p><b>Q. What if my prefilled syringe does not stay cool for an extended period of time? Is itdangerous to use?</b></p> <p>A. Contact 1-800-673-6242 for more information.</p> <p><b>Go to Back Cover</b></p> <p><b>If you have questions or concerns about your prefilled syringe, please contact your healthcare provider or call our toll-free help line at 1-800-673-6242.</b></p> <p><b>INSTRUCTIONS FOR USE</b></p> <p><b>ORENCIA® ClickJect™</b><br /> (oh-REN-see-ah)(abatacept)Prefilled Autoinjector</p> <p><b>ORENCIA®ClickJect™</b><br /> (abatacept) Injection Prefilled Autoinjector</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="362"> <tbody> <tr> <td><img alt="Prefilled Autoinjector - Illustration" height="94" src="https://images.rxlist.com/images/rxlist/orencia28.gif" width="362" /></td> </tr> </tbody> </table> </center> <p></p> <p>125 mg/mL, Single-Dose Autoinjector, For Subcutaneous Use Only</p> <p><b>Read these instructions before you use the ClickJect Autoinjector</b> and each time you get a refill. There may be new information. Before you use the Autoinjector for the first time, make sure your healthcare provider shows you the right way to use it.</p> <p><b>Important:</b></p> <ul> <li><b>Keep the ClickJect Autoinjector in the refrigerator until ready to use.</b></li> <li><b>Do not freeze.</b></li> </ul> <p><b>Before You Begin</b></p> <p><b>Get to know the ClickJect Autoinjector</b></p> <ul> <li>The Autoinjector automatically delivers the medicine. The transparent tip locks over the needle once the injection is complete and the Autoinjector is removed from the skin.</li> <li><b>Do not remove the orange needle cover until you are ready to inject.</b></li> </ul> <p><b>Before Use</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="447"> <tbody> <tr> <td><img alt="Before Use - Illustration" height="141" src="https://images.rxlist.com/images/rxlist/orencia29.gif" width="447" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>After Use</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="367"> <tbody> <tr> <td><img alt="After Use - Illustration" height="150" src="https://images.rxlist.com/images/rxlist/orencia30.gif" width="367" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Gather supplies for your injection on a clean, flat surface</b></p> <p>(only the ClickJect Autoinjector is included in the package):</p> <ul> <li>Alcohol swab</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="132"> <tbody> <tr> <td><img alt="Alcohol swab - Illustration" height="106" src="https://images.rxlist.com/images/rxlist/orencia31.gif" width="132" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>ClickJect Autoinjector</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="119"> <tbody> <tr> <td><img alt="ClickJect Autoinjector - Illustration" height="112" src="https://images.rxlist.com/images/rxlist/orencia32.gif" width="119" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Adhesive bandage</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="155"> <tbody> <tr> <td><img alt="Adhesive bandage - Illustration" height="149" src="https://images.rxlist.com/images/rxlist/orencia33.gif" width="155" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Sharps disposal container</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="120"> <tbody> <tr> <td><img alt="Sharps disposal container - Illustration" height="133" src="https://images.rxlist.com/images/rxlist/orencia34.gif" width="120" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Cotton ball or gauze</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="112"> <tbody> <tr> <td><img alt="Cotton ball or gauze - Illustration" height="116" src="https://images.rxlist.com/images/rxlist/orencia35.gif" width="112" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 1: Prepare Your Autoinjector</b></p> <p><b>Go to Step 1</b></p> <p><b>Let your ClickJect Autoinjector warm up.</b></p> <p>Remove one Autoinjector from the refrigerator and let it rest at room temperature for 30 minutes.</p> <p><b>Do not</b> remove the Autoinjector needle cover while allowing it to reach room temperature.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="178"> <tbody> <tr> <td><img alt="Remove one Autoinjector from the refrigerator and let it rest at room temperature for 30 minutes - Illustration" height="227" src="https://images.rxlist.com/images/rxlist/orencia36.gif" width="178" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Wash your hands well with soap and water.</b></p> <p><b>Examine the ClickJect Autoinjector:</b></p> <ul> <li><b>Check expiration date</b> printed on the label. Do not use if past the expiration date.</li> <li><b>Check the Autoinjector for damage.</b> Do not use if it is cracked or broken.</li> <li><b>Check the liquid </b>through the viewing window. It should be clear and colorless to pale yellow. You may see a small air bubble. You do not need to remove it. <b>Do not inject</b> if the liquid is cloudy, discolored, or has particles in it.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="240"> <tbody> <tr> <td><img alt="Examine the ClickJect Autoinjector - Illustration" height="229" src="https://images.rxlist.com/images/rxlist/orencia37.gif" width="240" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Go to Step 2</b></p> <p><b>Step 2: Prepare for Injection</b></p> <p><b>Choose your injection site </b>in either the stomach (abdomen), front of the thighs, or outer area of upper arm (only if caregiver administered).</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="354"> <tbody> <tr> <td><img alt="Prepare for Injection - Illustration" height="202" src="https://images.rxlist.com/images/rxlist/orencia38.gif" width="354" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Rotate injection site.</b></p> <ul> <li>Each week you can use the same area of your body, but use a different injection site in that area.</li> <li><b>Do not</b> inject into an area where the skin is tender, bruised, red, scaly, or hard. Do not give the injection in any areas with scars or stretch marks.</li> <li>Record the date, time, and site where you inject.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="347"> <tbody> <tr> <td><img alt="Rotate injection site - Illustration" height="197" src="https://images.rxlist.com/images/rxlist/orencia39.gif" width="347" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Gently clean injection site:</b></p> <ul> <li>Wipe the injection site with an alcohol swab and let it air dry.</li> <li><b>Do not</b> touch the injection site again before giving the injection.</li> <li><b>Do not</b> fan or blow on the clean area.</li> </ul> <p><b>Pull orange needle cover STRAIGHT off.</b></p> <ul> <li><b>DO NOT RECAP</b> the Autoinjector.</li> <li>Throw away (discard) the needle cover in your household trash.</li> <li><b>Do not</b> use the Autoinjector if it is dropped after the needle cover is removed.</li> </ul> <p>Note: It is normal to see a drop of fluid leaving the needle.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="254"> <tbody> <tr> <td><img alt="Pull orange needle cover STRAIGHT off - Illustration" height="282" src="https://images.rxlist.com/images/rxlist/orencia40.gif" width="254" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Go to Step 3</b></p> <p><b>Step 3: Inject Your Dose</b></p> <p><b>Position the Auto injector</b> so you can see the viewing window and it is at a 90° angle to the injection site. With your other hand, gently pinch the cleaned skin.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="199"> <tbody> <tr> <td><img alt="Inject Your Dose - Illustration" height="200" src="https://images.rxlist.com/images/rxlist/orencia41.gif" width="199" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Complete all steps to deliver your full dose of medicine:</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="737"> <tbody> <tr> <td><img alt="Complete all steps to deliver your full dose of medicine - Illustration" height="217" src="https://images.rxlist.com/images/rxlist/orencia42.gif" width="737" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Push DOWN </b>on the skin to unlock the Autoinjector.</p> <p><b>Press button, HOLD for 15 seconds AND watch window.</b></p> <ul> <li>You will hear a click as the injection begins.</li> <li>To deliver the full dose of medicine, hold the Autoinjector in place for 15 seconds AND wait until the blue indicator stops moving in window.</li> </ul> <p><b>Remove the ClickJect Autoinjector</b> from the injection site by lifting it straight up. After you remove it from your skin, the transparent tip will lock over the needle. Release skin pinch.</p> <p><b>Go to Step 4</b></p> <p><b>Step 4: After the Injection</b></p> <p><b>Care of injection site:</b></p> <ul> <li>There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="300"> <tbody> <tr> <td><img alt="There may be a little bleeding at the injection site - Illustration" height="114" src="https://images.rxlist.com/images/rxlist/orencia43.gif" width="300" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li><b>Do not</b> rub the injection site.</li> <li>If needed, you may cover the injection site with an adhesive bandage.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="317"> <tbody> <tr> <td><img alt="If needed, you may cover the injection site with an adhesive bandage - Illustration" height="122" src="https://images.rxlist.com/images/rxlist/orencia44.gif" width="317" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Disposing of used ClickJect Autoinjectors:</li> <li>Put your used ClickJect Autoinjector in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and prefilled syringes in your household trash.</li> <li>If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:</li> <li>made of a heavy-duty plastic,</li> <li>can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,</li> <li>upright and stable during use,</li> <li>leak resistant, and</li> <li>properly labeled to warn of hazardous waste inside the container.</li> <li>When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.</li> <li>Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.</li> </ul> <p>See <b>Frequently Asked Questions</b> for additional disposal information.</p> <p>If your injection is administered by a caregiver, this person must also handle the Autoinjector carefully to prevent accidental needle stick injury and possibly spreading infection.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="232"> <tbody> <tr> <td><img alt="Keep Autoinjector and the disposal container out of the reach of children - Illustration" height="236" src="https://images.rxlist.com/images/rxlist/orencia45.gif" width="232" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Keep Autoinjector and the disposal container out of the reach of children.</b></p> <p><b>How to store ORENCIA ClickJect Autoinjector</b></p> <ul> <li>Store ORENCIA in the refrigerator at 36°F to 46°F (2°C to 8°C).</li> <li>Keep ORENCIA in the original package and out of the light.</li> <li>Do not freeze ORENCIA.</li> <li>Safely throw away medicine that is out of date or no longer needed.</li> </ul> <p><b>Continued on next page</b></p> <p><b>Frequently Asked Questions</b></p> <p><b>Q. Why do I need to allow the Autoinjector to warm up at room temperature for 30 minutes prior to injecting?</b></p> <p>A. This step is primarily for your comfort. If the medicine is cold, the injection may take longer than 15 seconds. Never try to speed the warming process in any way, like using the microwave or placing the Autoinjector in warm water.</p> <p><b>Q. What if I accidentally remove the needle cover (orange cap) before I’m ready to use the Autoinjector?</b></p> <p>A. If you remove the cover before you are ready to use the Autoinjector, be careful. Do not try to replace it. Use the Autoinjector as soon as possible. While you prepare for the injection, carefully place the Autoinjector on its side on a clean, flat surface. Be sure to keep the Autoinjector away from children.</p> <p><b>Q. What if the Autoinjector appears to be broken or damaged?</b></p> <p>A. Do not use the Autoinjector. Contact your healthcare provider or pharmacist for further instructions.</p> <p><b>Q. What if the injection was not triggered?</b></p> <p>A. Before the injection can be triggered, the device must be unlocked. To unlock, firmly push the Autoinjector down on the skin without touching the button. Once the stop-point is felt, the device is unlocked and can be triggered by pushing the button.</p> <p><b>Q. I feel a little bit of burning or pain during injection. Is this normal?</b></p> <p>A. When giving an injection, you may feel a prick from the needle. Sometimes, the medicine can cause slight irritation near the injection site. If this occurs, the discomfort should be mild to moderate. If you experience any side effects, including pain, swelling, or discoloration near the injection site, contact your healthcare provider or pharmacist immediately. You are encouraged to report side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.</p> <p><b>Q. How do I know I received my full dose?</b></p> <p>A. Before lifting the Autoinjector from the injection site, check to ensure that the blue indicator has stopped moving. Then, before disposing of the Autoinjector, check the bottom of the transparent viewing window to make sure there is no liquid left inside. If the medicine has not been completely injected, consult your healthcare provider or pharmacist.</p> <p><b>Continued on next page</b></p> <p><b>Frequently Asked Questions</b></p> <p><b>Q. How should I dispose of a used Autoinjector?</b></p> <p>A. Place used Autoinjector into an FDA-cleared sharps disposal container right away after use.</p> <ul> <li>If you do not have one, you may use a household container that is:</li> <li>made of a heavy-duty plastic,</li> <li>can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,</li> <li>upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container.</li> <li>When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and Autoinjectors. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.</li> </ul> <p><b>Do not</b> recycle your used sharps disposal container.</p> <p><b>Q. How should I keep my Autoinjector cool while traveling?</b></p> <p>A. Your healthcare provider or pharmacist may be familiar with special carrying cases for injectable medicines. Store at 36°F to 46°F (2°C to 8°C). Do not freeze. Protect from light.</p> <p><b>Q. Can I take my Autoinjector on board an aircraft?</b></p> <p>A. Generally, this is allowed. Be sure to pack your Autoinjector in your carry-on, and do not put it in your checked luggage. You should carry it with you in your travel cooler at a temperature of 36°F to 46°F (2°C to 8°C) until you are ready to use it. Airport security procedures and airline policies change from time to time, so it’s best to check with airport authorities and the airline for any special rules. Prior to flying, get a letter from your healthcare provider to explain that you are traveling with prescription medicine that uses a device with a needle; if you are carrying a sharps container in your carry-on baggage, notify the screener at the airport.</p> <p><b>Q. What if my Autoinjector does not stay cool for an extended period of time? Is it dangerous to use?</b></p> <p>A. Contact 1-800-673-6242 for details.</p> <p><b>If you have questions or concerns about your Autoinjector, please contact a healthcare provider or call our toll-free help line at 1-800-673-6242.</b></p> <p class="credit">This Instructions for Use has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | <a name="PI"></a> <h3>PATIENT INFORMATION</h3> <p><b>ORENCIA®</b><br /> (oh-REN-see-ah)<br /> (abatacept) for injection, for intravenous use</p> <p><b>ORENCIA®</b><br /> (oh-REN-see-ah)<br /> (abatacept) injection, for subcutaneous use</p> <p><b>What is ORENCIA?</b></p> <p>ORENCIA is a prescription medicine that reduces signs and symptoms in:</p> <ul> <li>adults with moderate to severe rheumatoid arthritis (RA), including those who have not been helped enough by other medicines for RA. ORENCIA may prevent further damage to your bones and joints and may help your ability to perform daily activities. In adults, ORENCIA may be used alone or with other RA treatments other than tumor necrosis factor (TNF) antagonists.</li> <li>people 2 years of age and older with moderate to severe polyarticular juvenile idiopathic arthritis (pJIA). ORENCIA may be used alone or with methotrexate.</li> <li>adults with active psoriatic arthritis (PsA). In adults, ORENCIA can be used alone or with other PsA treatments.</li> </ul> <p>ORENCIA is also used for the preventative treatment of acute graft versus host disease (aGVHD), in combination with a calcineurin inhibitor and methotrexate, in:</p> <ul> <li>people 2 years of age and older undergoing hematopoietic stem cell transplantation (HSCT) from a matched or 1 allele-mismatched unrelated-donor.</li> </ul> <p>It is not known if ORENCIA is safe and effective in children less than two years of age for the treatment of pJIA.</p> <p>It is not known if ORENCIA is safe and effective in children less than two years of age for the preventative treatment of aGVHD.</p> <p><b>Before you receive or use ORENCIA, tell your healthcare provider about all of your medicalconditions, including if you:</b></p> <ul> <li>have any kind of infection even if it is small (such as an open cut or sore), or an infection that is in your whole body (such as the flu). If you have an infection during treatment with ORENCIA, you may have a higher chance for getting serious side effects.</li> <li>have an infection that will not go away or an infection that keeps coming back.</li> <li>are allergic to abatacept or any of the ingredients in ORENCIA. See the end of this Patient Information leaflet for a complete list of ingredients in ORENCIA.</li> <li>have or have had inflammation of your liver due to an infection (viral hepatitis). Your healthcare provider may examine you for hepatitis before treatment with ORENCIA.</li> <li>have had a lung infection called tuberculosis (TB), a positive skin test for TB, or you recently have been in close contact with someone who has had TB. Your healthcare provider may examine you for TB or perform a skin test before treatment with ORENCIA. Symptoms of TB may include: <ul> <li>a cough that does not go away</li> <li>weight loss</li> <li>fever</li> <li>night sweats</li> </ul> </li> <li>have a history of Epstein-Barr Virus (EBV) or Cytomegalovirus (CMV) in people receiving ORENCIA for preventative treatment of aGVHD during HSCT from an unrelated donor.</li> <li>are scheduled to have surgery.</li> <li>recently received a vaccination or are scheduled for a vaccination.</li> <li>have a history of a breathing problem called chronic obstructive pulmonary disease (COPD).</li> <li>have diabetes and use a blood glucose monitor to check your blood sugar (blood glucose) levels. ORENCIA for intravenous infusion (given through a needle placed in a vein) contains maltose, a type of sugar, that can give false high blood sugar readings with certain types of blood glucose monitors on the day of ORENCIA infusion. Your healthcare provider may tell you to use a different way to monitor your blood sugar levels.</li> <li>ORENCIA for subcutaneous injection (injected under the skin) does not contain maltose. You do not need to change your blood sugar monitoring if you are using ORENCIA subcutaneously.</li> <li>are pregnant or plan to become pregnant. It is not known if ORENCIA can harm your unborn baby. If you took ORENCIA during pregnancy, talk to your healthcare provider before your baby receives any vaccines.</li> <li>There is a registry for pregnant women exposed to ORENCIA. The purpose of this registry is to check the health of the pregnant mother and her child. Women are encouraged to call the registry themselves or ask their healthcare provider to contact the registry for them by calling 1-877-3118972.</li> <li>are breastfeeding or plan to breastfeed. It is not known if ORENCIA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use ORENCIA.</li> <li>Some people treated with ORENCIA have developed skin cancer. Tell your healthcare provider if you have a family or personal history of skin cancer, and if you see any growths or changes in the appearance of your skin during or after your treatment with ORENCIA.</li> </ul> <p><b>Tell your healthcare provider about all the medicines you take,</b> including prescription and over-thecounter medicines, vitamins, and herbal supplements.</p> <p>ORENCIA may affect the way other medicines work, and other medicines may affect the way ORENCIA works causing serious side effects.</p> <p>Especially tell your healthcare provider if you take other biologic medicines that may affect your immune system, such as:</p> <ul> <li>Enbrel® (etanercept)</li> <li>Kineret® (anakinra)</li> <li>Cimzia® (certolizumab pegol)</li> <li>Humira® (adalimumab)</li> <li>Rituxan® (rituximab)</li> <li>Actemra® (tocilizumab)</li> <li>Remicade® (infliximab)</li> <li>Simponi® (golimumab)</li> </ul> <p>You may have a higher chance of getting a serious infection if you take ORENCIA with other biologic medicines that may affect your immune system.</p> <p>Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new prescription.</p> <p><b>How will I receive or use ORENCIA?</b></p> <p><b>For treatment of RA, pJIA or PsA:</b></p> <ul> <li>You may receive ORENCIA given by a healthcare provider through a vein in your arm (intravenous infusion). It takes about 30 minutes to give you the full dose of medicine. You will then receive ORENCIA 2 weeks and 4 weeks after the first dose and then every 4 weeks.</li> <li>You may also receive ORENCIA as an injection under your skin (subcutaneous). For home use, ORENCIA comes in a prefilled syringe or prefilled ClickJect autoinjector. Your healthcare provider will prescribe the type that is best for you. If your healthcare provider decides that you or a caregiver can give your injections of ORENCIA prefilled syringes or ORENCIA ClickJect autoinjectors at home, you or your caregiver should receive training on the right way to prepare and inject ORENCIA. Do not try to inject ORENCIA until you have been shown the right way to give the injections by your healthcare provider.</li> <li>Your healthcare provider will tell you how much ORENCIA to use and when to use it.</li> </ul> <p><b>See the Instructions for Use at the end of this Patient Information leaflet for instructions about the right way to prepare and give your ORENCIA injections at home.</b></p> <p><b>For preventative treatment of aGVHD:</b></p> <ul> <li>You will receive ORENCIA by a healthcare provider through a vein in your arm (intravenous infusion) over 60 minutes on the day before transplantation (Day -1). You will then receive ORENCIA on Days 5, 14, and 28 after transplantation.</li> <li>Your healthcare provider may give you antiviral medicines before, during, and after your transplantation to help prevent Epstein-Barr Virus (EBV) and Cytomegalovirus (CMV) infections.</li> </ul> <p><b>What are the possible side effects of ORENCIA?</b></p> <p><b>ORENCIA can cause serious side effects including:</b></p> <ul> <li>infections. ORENCIA can make you more likely to get infections or make the infection that you have get worse. Some people have died from these infections. Call your healthcare provider right away if you have any symptoms of an infection. Symptoms of an infection may include: <ul> <li>fever</li> <li>feel very tired</li> <li>have a cough</li> <li>have flu-like symptoms</li> <li>warm, red, or painful skin</li> </ul> </li> <li>allergic reactions. Allergic reactions can happen to people who are treated with ORENCIA. Call your healthcare provider or go to the emergency room right away if you have any symptoms of an allergic reaction. Symptoms of an allergic reaction may include: <ul> <li>hives</li> <li>swollen face, eyelids, lips, or tongue</li> <li>trouble breathing</li> </ul> </li> <li><b>hepatitis B infection in people who carry the virus in their blood.</b> If you are a carrier of the hepatitis B virus (a virus that affects the liver), the virus can become active during treatment with ORENCIA. Your healthcare provider may do a blood test before you start treatment with ORENCIA.</li> <li><b>vaccinations.</b> You should not receive ORENCIA with certain types of vaccines (live vaccines). You can receive non-live vaccines, such as pneumococcal and inactivated influenza (flu) vaccines. ORENCIA may also cause some vaccinations to be less effective. Talk with your healthcare provider about your vaccination plans.</li> <li><b>breathing problems in people with Chronic Obstructive Pulmonary Disease (COPD).</b> You may get certain respiratory problems more often if you receive ORENCIA and have COPD. Symptoms of respiratory problems include: <ul> <li>COPD that becomes worse</li> <li>cough</li> <li>trouble breathing</li> </ul> </li> <li><b>cancer (malignancies).</b> Certain kinds of cancer have been reported in people using ORENCIA. It is not known if ORENCIA increases your chance of getting certain kinds of cancer.</li> <li><b>Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) infections.</b> CMV and EBV infections and return of CMV and EBV (reactivation) have happened in people receiving ORENCIA for preventative treatment of aGVHD during unrelated HSCT. Your healthcare provider will monitor you for 6 months after transplantation and may treat you with medicines to help prevent CMV and EBV infection if needed.</li> </ul> <p><b>The most common side effects of ORENCIA in people with RA include:</b></p> <ul> <li>headache</li> <li>upper respiratory tract infection</li> <li>sore throat</li> <li>nausea</li> </ul> <p><b>In children and adolescents, other side effects may include:</b></p> <ul> <li>diarrhea</li> <li>cough</li> <li>fever</li> <li>abdominal pain</li> </ul> <p><b>The most common side effects of ORENCIA in prevention of aGVHD include:</b></p> <ul> <li>low red blood cell count</li> <li>high blood pressure</li> <li>CMV infection</li> <li>fever</li> <li>pneumonia</li> <li>nosebleed</li> <li>decreased CD4 lymphocytes</li> <li>increased levels of magnesium in the blood</li> <li>kidney problems</li> </ul> <p>These are not all of the possible side effects of ORENCIA.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088.</p> <p><b>How should I store ORENCIA?</b></p> <ul> <li>Store ORENCIA in the refrigerator at 36°F to 46°F (2°C to 8°C).</li> <li>Keep ORENCIA in the original package and out of the light.</li> <li>Do not freeze ORENCIA.</li> <li>Safely throw away medicine that is out of date or no longer needed.</li> </ul> <p><b>Keep ORENCIA and all medicines out of the reach of children.</b></p> <p><b>General information about the safe and effective use of ORENCIA.</b></p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ORENCIA for a condition for which it was not prescribed. Do not give ORENCIA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ORENCIA that is written for health professionals.</p> <p><b>What are the ingredients in ORENCIA?</b></p> <p><b>Active ingredient:</b> abatacept</p> <p><b>Intravenous inactive ingredients:</b> maltose, monobasic sodium phosphate, sodium chloride for administration</p> <p><b>Subcutaneous inactive ingredients:</b> sucrose, poloxamer 188, monobasic sodium phosphate monohydrate, dibasic sodium phosphate anhydrous, water for injection.</p> <p><b>INSTRUCTIONS FOR USE</b></p> <p><b>ORENCIA®</b><br /> (oh-REN-see-ah) (abatacept)</p> <p><b>Prefilled Syringe with BD UltraSafe Passive™ Needle Guard</b></p> <p><b>ORENCIA® Prefilled Syringe with BD UltraSafe Passive™ Needle Guard (abatacept) Injection</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="350"> <tbody> <tr> <td><img alt="ORENCIA® Prefilled Syringe - Illustration" height="117" src="https://images.rxlist.com/images/rxlist/orencia3.gif" width="350" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Read these instructions before you start using your ORENCIA Prefilled Syringe </b>and each time you get a refill. There may be new information. Before you use the prefilled syringe for the first time, make sure your healthcare provider shows you the right way to use it and decides that you or a caregiver may be able to give your injections of ORENCIA at home.</p> <p><b>Important:</b></p> <ul> <li><b>Keep the Prefilled Syringe in the refrigerator until ready to use.</b></li> <li><b>Do not freeze.</b></li> </ul> <p><b>Before You Begin: Get to Know Your Prefilled Syringe</b></p> <p>There are 3 types of prefilled syringes:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="729"> <tbody> <tr> <td><img alt="The 3 types of prefilled syringes - Illustration" height="115" src="https://images.rxlist.com/images/rxlist/orencia4.gif" width="729" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>The type of prefilled syringe you receive depends on the dose prescribed by your healthcare provider. The 125 mg/mL prefilled syringe is shown below.</b></p> <p><b>Before Use</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="504"> <tbody> <tr> <td><img alt="Before Use - Illustration" height="193" src="https://images.rxlist.com/images/rxlist/orencia5.gif" width="504" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>After Use</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="487"> <tbody> <tr> <td><img alt="After Use - Illustration" height="189" src="https://images.rxlist.com/images/rxlist/orencia6.gif" width="487" /></td> </tr> </tbody> </table> </center> <p></p> <p>The prefilled syringe has a flange extender that makes it easier to hold and inject, and a needle guard that automatically covers the needle after a complete injection.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="91"> <tbody> <tr> <td><img alt="Caution - Illustration" height="106" src="https://images.rxlist.com/images/rxlist/orencia7.gif" width="91" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>DO NOT</b> remove the needle cover until you are ready to inject.</p> <p><b>DO NOT PULL</b> back on the plunger at any time.</p> <p><b>DO NOT RECAP</b> the prefilled syringe at any time, as this may damage, bend, or break the needle.</p> <p><b>Go to Step 1</b></p> <p><b>Step 1: Preparing for an ORENCIA Injection</b></p> <p><b>Gather and place supplies for your injection on a clean, flat surface.</b></p> <p>Only the prefilled syringe is included in the package:</p> <ul> <li>Alcohol swab</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="123"> <tbody> <tr> <td><img alt="Alcohol swab - Illustration" height="92" src="https://images.rxlist.com/images/rxlist/orencia8.gif" width="123" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Prefilled Syringe withUltraSafe Passive Needle Guard</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="128"> <tbody> <tr> <td><img alt="Prefilled Syringe withUltraSafe Passive Needle Guard - Illustration" height="130" src="https://images.rxlist.com/images/rxlist/orencia9.gif" width="128" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Adhesive bandage</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="153"> <tbody> <tr> <td><img alt="Adhesive bandage - Illustration" height="120" src="https://images.rxlist.com/images/rxlist/orencia10.gif" width="153" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Sharps disposal container</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="95"> <tbody> <tr> <td><img alt="Sharps disposal container - Illustration" height="141" src="https://images.rxlist.com/images/rxlist/orencia11.gif" width="95" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li><a href="/cotton/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">Cotton</a> ball or gauze</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="116"> <tbody> <tr> <td><img alt="Cotton ball or gauze - Illustration" height="111" src="https://images.rxlist.com/images/rxlist/orencia12.gif" width="116" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Let your Prefilled Syringe warm up.</b></p> <p>Remove one prefilled syringe from the refrigerator and wait 30 minutes to allow it to reach room temperature.</p> <ul> <li><b>Do not</b> <a href="/speed/definition.htm" ">speed</a> up the warming process in any way, such as using the microwave or placing the syringe in warm water.</li> <li><b>Do not</b> remove the needle cover while allowing the prefilled syringe to reach room temperature.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="162"> <tbody> <tr> <td><img alt="Let your Prefilled Syringe warm up - Illustration" height="201" src="https://images.rxlist.com/images/rxlist/orencia13.gif" width="162" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Wash your hands well with soap and water.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="211"> <tbody> <tr> <td><img alt="Wash your hands well with soap and water - Illustration" height="165" src="https://images.rxlist.com/images/rxlist/orencia14.gif" width="211" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Go to Step 2</b></p> <p><b>Step 2: Examine the Prefilled Syringe</b></p> <p>Hold the prefilled syringe by the body with the needle cover pointing down as shown.</p> <ul> <li><b>Check the expiration date</b> printed on the label. Do not use if the expiration date has passed.</li> <li><b>Check the prefilled syringe for damage.</b> Do not use if it is cracked or broken.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="261"> <tbody> <tr> <td><img alt="Examine the Prefilled Syringe - Illustration" height="335" src="https://images.rxlist.com/images/rxlist/orencia15.gif" width="261" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Check the Liquid.</b></p> <ul> <li><b>Check the liquid</b> in the prefilled syringe through the viewing window. It should be clear and colorless to pale yellow<</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="226"> <tbody> <tr> <td><img alt="heck the Liquid - Illustration" height="313" src="https://images.rxlist.com/images/rxlist/orencia16.gif" width="226" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Do not inject if the liquid is cloudy, discolored, or has particles in it.</b></p> <p>*Note: the 50 mg prefilled syringe is shown.</p> <p><b>Note:</b> It is normal to see an air bubble. Do not attempt to remove it. Go to Step 3</p> <p><b>Step 3: Check the Dose on the Prefilled Syringe</b></p> <p>Hold the syringe at eye level. Look closely to make sure that the amount of liquid in the prefilled syringe is at or just above the fill line for your prescribed dose:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="510"> <tbody> <tr> <td><img alt=" Check the Dose on the Prefilled Syringe - Illustration" height="468" src="https://images.rxlist.com/images/rxlist/orencia17.gif" width="510" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Do not</b> use if your prefilled syringe does not have the correct amount of liquid. Call your pharmacist immediately.</p> <p><b>Go to Step 4</b></p> <p><b>Step 4: Choose and Prepare an Injection Site</b></p> <p><b>Choose your injection site.</b></p> <p>Choose your injection site in either the stomach (abdomen), front of the thighs, or outer area of upper arm (only if caregiver administered).</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="376"> <tbody> <tr> <td><img alt="Choose and Prepare an Injection Site - Illustration" height="213" src="https://images.rxlist.com/images/rxlist/orencia18.gif" width="376" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Rotate injection site.</b></p> <ul> <li>Each week you can use the same area of your body, but use a different injection site in that area.</li> <li><b>Do not</b> inject into an area where the skin is tender, bruised, red, scaly, or hard. <b>Do not</b> give the injection in any areas with <a href="/scars/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">scars</a> or stretch marks.</li> <li>Record the date, time, and site where you inject.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="358"> <tbody> <tr> <td><img alt="Rotate injection site - Illustration" height="224" src="https://images.rxlist.com/images/rxlist/orencia19.gif" width="358" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Gently clean injection site.</b></p> <ul> <li>Wipe the injection site with an alcohol swab and let it air dry.</li> <li><b>Do not</b> touch the injection site again before giving the injection.</li> <li><b>Do not</b> fan or blow on the clean area.</li> </ul> <p><b>Remove the needle cover</b> by holding the body of the prefilled syringe with one hand and pulling the cover straight off with your other hand.</p> <p><b>Do not put the needle cover back on the needle after you remove it.</b> Throw away the needle cover in your household trash.</p> <ul> <li><b>Do not</b> use the prefilled syringe if it is dropped after the needle cover is removed.</li> <li><b>Do not</b> use the prefilled syringe if the needle is damaged or bent.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="262"> <tbody> <tr> <td><img alt="Wipe the injection site with an alcohol swab and let it air dry - Illustration" height="234" src="https://images.rxlist.com/images/rxlist/orencia20.gif" width="262" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Note:</b> It is normal to see a drop of fluid leaving the needle.</p> <p><b>DO NOT RECAP</b> the Prefilled Syringe, as this may damage the needle.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="69"> <tbody> <tr> <td><img alt="Caution - Illustration" height="74" src="https://images.rxlist.com/images/rxlist/orencia21.gif" width="69" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Go to Step 5</b></p> <p><b>Step 5: Inject Your Dose of ORENCIA</b></p> <p><b>Hold the body</b> of the prefilled syringe in your hand using your thumb and index finger. With your other hand, <b>pinch the area of skin you cleaned.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="197"> <tbody> <tr> <td><img alt="Inject Your Dose of ORENCIA - Illustration" height="190" src="https://images.rxlist.com/images/rxlist/orencia22.gif" width="197" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Insert the needle.</b></p> <p><b>Gently insert</b> the needle into the pinched skin at a 45° angle.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="194"> <tbody> <tr> <td><img alt="Gently insert the needle into the pinched skin at a 45° angle - Illustration" height="195" src="https://images.rxlist.com/images/rxlist/orencia23.gif" width="194" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Complete all steps to deliver your full dose of the medicine.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="640"> <tbody> <tr> <td><img alt="Complete all steps to deliver your full dose of the medicine - Illustration" height="193" src="https://images.rxlist.com/images/rxlist/orencia24.gif" width="640" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Inject: push the plunger with your thumb as far as it will go.</b></p> <p><b>Release Needle Guard: slowly lift your thumb from the plunger</b> to activate the needle guard.</p> <p><b>Confirm: after a complete injection, the needle </b>guard will cover the needle and you may hear a click.</p> <p><b>Remove the prefilled syringe and let go of the pinched skin.</b></p> <p><b>Go to Step 6</b></p> <p><b>Step 6: After the Injection</b></p> <p><b>Care of injection site:</b></p> <ul> <li>There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="278"> <tbody> <tr> <td><img alt="After the Injection - Illustration" height="73" src="https://images.rxlist.com/images/rxlist/orencia25.gif" width="278" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li><b>Do not</b> rub the injection site.</li> <li>If needed, you may cover the injection site with an adhesive bandage.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="277"> <tbody> <tr> <td><img alt="If needed, you may cover the injection site with an adhesive bandage - Illustration" height="89" src="https://images.rxlist.com/images/rxlist/orencia26.gif" width="277" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Disposing of used Prefilled Syringes:</b></p> <ul> <li>Put your used ORENCIA prefilled syringes in a FDA-cleared sharps disposal container right away after use. <b>Do not throw away (dispose of) loose needles and prefilled syringes in your household trash.</b></li> <li>If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: <ul> <li>made of a heavy-duty <a href="/plastic/article.htm" rel="sub" onclick="wmdTrack('embd-lnk');">plastic</a>,</li> <li>can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,</li> <li>upright and stable during use,</li> <li>leak resistant, and</li> <li>properly labeled to warn of hazardous waste inside the container.</li> </ul> </li> <li>When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.</li> <li><b>Do not</b> throw away (dispose of) your used sharps disposal container in your household trash unless your community guidelines permit this. <b>Do not</b> recycle your used sharps disposal container.</li> </ul> <p>See <b>Frequently Asked Questions</b> for additional disposal information.</p> <p>If your injection is administered by a caregiver, this person must also be careful handling the syringe to prevent accidental <a href="/needle_stick/definition.htm" ">needle stick</a> injury and possibly spreading infection.</p> <p><b>Keep ORENCIA prefilled syringes and the disposal container out of the reach of children.</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="263"> <tbody> <tr> <td><img alt="Keep ORENCIA prefilled syringes and the disposal container out of the reach of children - Illustration" height="301" src="https://images.rxlist.com/images/rxlist/orencia27.gif" width="263" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>How to store ORENCIA Prefilled Syringe</b></p> <ul> <li>Store ORENCIA in the refrigerator at 36°F to 46°F (2°C to 8°C).</li> <li>Keep ORENCIA in the original package and out of the light.</li> <li>Do not freeze ORENCIA.</li> <li>Safely throw away medicine that is out of date or no longer needed.</li> </ul> <p><b>Go to Next Page</b></p> <p><b>Frequently Asked Questions</b></p> <p><b>Q. Why do I need to allow the prefilled syringe to warm up at room temperature for 30 minutesprior to injecting?</b></p> <p>A. This step is primarily for your comfort. Never try to speed up the warming process in any way, like using the microwave or placing the syringe in warm water.</p> <p><b>Q. Is it necessary to hold the skin pinch during the entire time I inject the dose?</b></p> <p>A. You must pinch the skin during needle insertion however, for your comfort you may release the skin pinch as you deliver the injection.</p> <p><b>Q. What if my prefilled syringe appears to be broken or damaged?</b></p> <p>A. Do not use the prefilled syringe. Contact your healthcare provider or pharmacist for further instructions.</p> <p><b>Q. What if I cannot clearly see the liquid inside the syringe?</b></p> <p>A. Look at the syringe closely by holding at eye level and up to the light. You may tilt the syringe slowly to get a better view of the drug fluid. If you still have trouble, contact your healthcare provider or pharmacist for further instructions.</p> <p><b>Q. Is it normal to feel a little bit of burning or pain during injection?</b></p> <p>A. You may feel a prick from the needle. Sometimes, the medicine can cause slight irritation near the injection site. Discomfort should be mild to moderate. If you have any side effects, including pain, swelling, or discoloration near the injection site, contact your healthcare provider.</p> <p><b>Go to next page</b></p> <p><b>Frequently Asked Questions</b></p> <p><b>Q. How should I dispose of a used prefilled syringe?</b></p> <p>A. Place the used prefilled syringe into an FDA-cleared sharps disposal container. If you do not have one you may use a household container that is:</p> <ul> <li>made of a heavy-duty plastic,</li> <li>can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,</li> <li>upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container.</li> </ul> <p>When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and injector pens. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.</p> <p><b>Q. How should I keep my prefilled syringes cool while traveling?</b></p> <p>A. Store them in a cool carrier between 36°F to 46°F (2°C to 8°C). Do not freeze them. Keep them in the original carton and protected from light. Your healthcare provider may know about special carrying cases.</p> <p><b>Q. Can I take my prefilled syringes on an airplane?</b></p> <p>A. Generally you are allowed to carry your prefilled syringes with you on an airplane. Do not put them in your checked luggage. You should carry your prefilled syringes with you in your travel cooler at a temperature of 36°F to 46°F (2°C to 8°C). Keep your prefilled syringes in the original carton, and with its original preprinted labels and protected from light.</p> <p><b>Q. What if my prefilled syringe does not stay cool for an extended period of time? Is itdangerous to use?</b></p> <p>A. Contact 1-800-673-6242 for more information.</p> <p><b>Go to Back Cover</b></p> <p><b>If you have questions or concerns about your prefilled syringe, please contact your healthcare provider or call our toll-free help line at 1-800-673-6242.</b></p> <p><b>INSTRUCTIONS FOR USE</b></p> <p><b>ORENCIA® ClickJect™</b><br /> (oh-REN-see-ah)(abatacept)Prefilled Autoinjector</p> <p><b>ORENCIA®ClickJect™</b><br /> (abatacept) Injection Prefilled Autoinjector</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="362"> <tbody> <tr> <td><img alt="Prefilled Autoinjector - Illustration" height="94" src="https://images.rxlist.com/images/rxlist/orencia28.gif" width="362" /></td> </tr> </tbody> </table> </center> <p></p> <p>125 mg/mL, Single-Dose Autoinjector, For Subcutaneous Use Only</p> <p><b>Read these instructions before you use the ClickJect Autoinjector</b> and each time you get a refill. There may be new information. Before you use the Autoinjector for the first time, make sure your healthcare provider shows you the right way to use it.</p> <p><b>Important:</b></p> <ul> <li><b>Keep the ClickJect Autoinjector in the refrigerator until ready to use.</b></li> <li><b>Do not freeze.</b></li> </ul> <p><b>Before You Begin</b></p> <p><b>Get to know the ClickJect Autoinjector</b></p> <ul> <li>The Autoinjector automatically delivers the medicine. The transparent tip locks over the needle once the injection is complete and the Autoinjector is removed from the skin.</li> <li><b>Do not remove the orange needle cover until you are ready to inject.</b></li> </ul> <p><b>Before Use</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="447"> <tbody> <tr> <td><img alt="Before Use - Illustration" height="141" src="https://images.rxlist.com/images/rxlist/orencia29.gif" width="447" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>After Use</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="367"> <tbody> <tr> <td><img alt="After Use - Illustration" height="150" src="https://images.rxlist.com/images/rxlist/orencia30.gif" width="367" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Gather supplies for your injection on a clean, flat surface</b></p> <p>(only the ClickJect Autoinjector is included in the package):</p> <ul> <li>Alcohol swab</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="132"> <tbody> <tr> <td><img alt="Alcohol swab - Illustration" height="106" src="https://images.rxlist.com/images/rxlist/orencia31.gif" width="132" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>ClickJect Autoinjector</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="119"> <tbody> <tr> <td><img alt="ClickJect Autoinjector - Illustration" height="112" src="https://images.rxlist.com/images/rxlist/orencia32.gif" width="119" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Adhesive bandage</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="155"> <tbody> <tr> <td><img alt="Adhesive bandage - Illustration" height="149" src="https://images.rxlist.com/images/rxlist/orencia33.gif" width="155" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Sharps disposal container</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="120"> <tbody> <tr> <td><img alt="Sharps disposal container - Illustration" height="133" src="https://images.rxlist.com/images/rxlist/orencia34.gif" width="120" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Cotton ball or gauze</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="112"> <tbody> <tr> <td><img alt="Cotton ball or gauze - Illustration" height="116" src="https://images.rxlist.com/images/rxlist/orencia35.gif" width="112" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Step 1: Prepare Your Autoinjector</b></p> <p><b>Go to Step 1</b></p> <p><b>Let your ClickJect Autoinjector warm up.</b></p> <p>Remove one Autoinjector from the refrigerator and let it rest at room temperature for 30 minutes.</p> <p><b>Do not</b> remove the Autoinjector needle cover while allowing it to reach room temperature.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="178"> <tbody> <tr> <td><img alt="Remove one Autoinjector from the refrigerator and let it rest at room temperature for 30 minutes - Illustration" height="227" src="https://images.rxlist.com/images/rxlist/orencia36.gif" width="178" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Wash your hands well with soap and water.</b></p> <p><b>Examine the ClickJect Autoinjector:</b></p> <ul> <li><b>Check expiration date</b> printed on the label. Do not use if past the expiration date.</li> <li><b>Check the Autoinjector for damage.</b> Do not use if it is cracked or broken.</li> <li><b>Check the liquid </b>through the viewing window. It should be clear and colorless to pale yellow. You may see a small air bubble. You do not need to remove it. <b>Do not inject</b> if the liquid is cloudy, discolored, or has particles in it.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="240"> <tbody> <tr> <td><img alt="Examine the ClickJect Autoinjector - Illustration" height="229" src="https://images.rxlist.com/images/rxlist/orencia37.gif" width="240" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Go to Step 2</b></p> <p><b>Step 2: Prepare for Injection</b></p> <p><b>Choose your injection site </b>in either the stomach (abdomen), front of the thighs, or outer area of upper arm (only if caregiver administered).</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="354"> <tbody> <tr> <td><img alt="Prepare for Injection - Illustration" height="202" src="https://images.rxlist.com/images/rxlist/orencia38.gif" width="354" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Rotate injection site.</b></p> <ul> <li>Each week you can use the same area of your body, but use a different injection site in that area.</li> <li><b>Do not</b> inject into an area where the skin is tender, bruised, red, scaly, or hard. Do not give the injection in any areas with scars or stretch marks.</li> <li>Record the date, time, and site where you inject.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="347"> <tbody> <tr> <td><img alt="Rotate injection site - Illustration" height="197" src="https://images.rxlist.com/images/rxlist/orencia39.gif" width="347" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Gently clean injection site:</b></p> <ul> <li>Wipe the injection site with an alcohol swab and let it air dry.</li> <li><b>Do not</b> touch the injection site again before giving the injection.</li> <li><b>Do not</b> fan or blow on the clean area.</li> </ul> <p><b>Pull orange needle cover STRAIGHT off.</b></p> <ul> <li><b>DO NOT RECAP</b> the Autoinjector.</li> <li>Throw away (discard) the needle cover in your household trash.</li> <li><b>Do not</b> use the Autoinjector if it is dropped after the needle cover is removed.</li> </ul> <p>Note: It is normal to see a drop of fluid leaving the needle.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="254"> <tbody> <tr> <td><img alt="Pull orange needle cover STRAIGHT off - Illustration" height="282" src="https://images.rxlist.com/images/rxlist/orencia40.gif" width="254" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Go to Step 3</b></p> <p><b>Step 3: Inject Your Dose</b></p> <p><b>Position the Auto injector</b> so you can see the viewing window and it is at a 90° angle to the injection site. With your other hand, gently pinch the cleaned skin.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="199"> <tbody> <tr> <td><img alt="Inject Your Dose - Illustration" height="200" src="https://images.rxlist.com/images/rxlist/orencia41.gif" width="199" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Complete all steps to deliver your full dose of medicine:</b></p> <p></p> <center> <table cellspacing="0" class="blackpic" width="737"> <tbody> <tr> <td><img alt="Complete all steps to deliver your full dose of medicine - Illustration" height="217" src="https://images.rxlist.com/images/rxlist/orencia42.gif" width="737" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Push DOWN </b>on the skin to unlock the Autoinjector.</p> <p><b>Press button, HOLD for 15 seconds AND watch window.</b></p> <ul> <li>You will hear a click as the injection begins.</li> <li>To deliver the full dose of medicine, hold the Autoinjector in place for 15 seconds AND wait until the blue indicator stops moving in window.</li> </ul> <p><b>Remove the ClickJect Autoinjector</b> from the injection site by lifting it straight up. After you remove it from your skin, the transparent tip will lock over the needle. Release skin pinch.</p> <p><b>Go to Step 4</b></p> <p><b>Step 4: After the Injection</b></p> <p><b>Care of injection site:</b></p> <ul> <li>There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="300"> <tbody> <tr> <td><img alt="There may be a little bleeding at the injection site - Illustration" height="114" src="https://images.rxlist.com/images/rxlist/orencia43.gif" width="300" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li><b>Do not</b> rub the injection site.</li> <li>If needed, you may cover the injection site with an adhesive bandage.</li> </ul> <p></p> <center> <table cellspacing="0" class="blackpic" width="317"> <tbody> <tr> <td><img alt="If needed, you may cover the injection site with an adhesive bandage - Illustration" height="122" src="https://images.rxlist.com/images/rxlist/orencia44.gif" width="317" /></td> </tr> </tbody> </table> </center> <p></p> <ul> <li>Disposing of used ClickJect Autoinjectors:</li> <li>Put your used ClickJect Autoinjector in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and prefilled syringes in your household trash.</li> <li>If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:</li> <li>made of a heavy-duty plastic,</li> <li>can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,</li> <li>upright and stable during use,</li> <li>leak resistant, and</li> <li>properly labeled to warn of hazardous waste inside the container.</li> <li>When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.</li> <li>Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.</li> </ul> <p>See <b>Frequently Asked Questions</b> for additional disposal information.</p> <p>If your injection is administered by a caregiver, this person must also handle the Autoinjector carefully to prevent accidental needle stick injury and possibly spreading infection.</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="232"> <tbody> <tr> <td><img alt="Keep Autoinjector and the disposal container out of the reach of children - Illustration" height="236" src="https://images.rxlist.com/images/rxlist/orencia45.gif" width="232" /></td> </tr> </tbody> </table> </center> <p></p> <p><b>Keep Autoinjector and the disposal container out of the reach of children.</b></p> <p><b>How to store ORENCIA ClickJect Autoinjector</b></p> <ul> <li>Store ORENCIA in the refrigerator at 36°F to 46°F (2°C to 8°C).</li> <li>Keep ORENCIA in the original package and out of the light.</li> <li>Do not freeze ORENCIA.</li> <li>Safely throw away medicine that is out of date or no longer needed.</li> </ul> <p><b>Continued on next page</b></p> <p><b>Frequently Asked Questions</b></p> <p><b>Q. Why do I need to allow the Autoinjector to warm up at room temperature for 30 minutes prior to injecting?</b></p> <p>A. This step is primarily for your comfort. If the medicine is cold, the injection may take longer than 15 seconds. Never try to speed the warming process in any way, like using the microwave or placing the Autoinjector in warm water.</p> <p><b>Q. What if I accidentally remove the needle cover (orange cap) before I’m ready to use the Autoinjector?</b></p> <p>A. If you remove the cover before you are ready to use the Autoinjector, be careful. Do not try to replace it. Use the Autoinjector as soon as possible. While you prepare for the injection, carefully place the Autoinjector on its side on a clean, flat surface. Be sure to keep the Autoinjector away from children.</p> <p><b>Q. What if the Autoinjector appears to be broken or damaged?</b></p> <p>A. Do not use the Autoinjector. Contact your healthcare provider or pharmacist for further instructions.</p> <p><b>Q. What if the injection was not triggered?</b></p> <p>A. Before the injection can be triggered, the device must be unlocked. To unlock, firmly push the Autoinjector down on the skin without touching the button. Once the stop-point is felt, the device is unlocked and can be triggered by pushing the button.</p> <p><b>Q. I feel a little bit of burning or pain during injection. Is this normal?</b></p> <p>A. When giving an injection, you may feel a prick from the needle. Sometimes, the medicine can cause slight irritation near the injection site. If this occurs, the discomfort should be mild to moderate. If you experience any side effects, including pain, swelling, or discoloration near the injection site, contact your healthcare provider or pharmacist immediately. You are encouraged to report side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.</p> <p><b>Q. How do I know I received my full dose?</b></p> <p>A. Before lifting the Autoinjector from the injection site, check to ensure that the blue indicator has stopped moving. Then, before disposing of the Autoinjector, check the bottom of the transparent viewing window to make sure there is no liquid left inside. If the medicine has not been completely injected, consult your healthcare provider or pharmacist.</p> <p><b>Continued on next page</b></p> <p><b>Frequently Asked Questions</b></p> <p><b>Q. How should I dispose of a used Autoinjector?</b></p> <p>A. Place used Autoinjector into an FDA-cleared sharps disposal container right away after use.</p> <ul> <li>If you do not have one, you may use a household container that is:</li> <li>made of a heavy-duty plastic,</li> <li>can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,</li> <li>upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container.</li> <li>When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and Autoinjectors. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.</li> </ul> <p><b>Do not</b> recycle your used sharps disposal container.</p> <p><b>Q. How should I keep my Autoinjector cool while traveling?</b></p> <p>A. Your healthcare provider or pharmacist may be familiar with special carrying cases for injectable medicines. Store at 36°F to 46°F (2°C to 8°C). Do not freeze. Protect from light.</p> <p><b>Q. Can I take my Autoinjector on board an aircraft?</b></p> <p>A. Generally, this is allowed. Be sure to pack your Autoinjector in your carry-on, and do not put it in your checked luggage. You should carry it with you in your travel cooler at a temperature of 36°F to 46°F (2°C to 8°C) until you are ready to use it. Airport security procedures and airline policies change from time to time, so it’s best to check with airport authorities and the airline for any special rules. Prior to flying, get a letter from your healthcare provider to explain that you are traveling with prescription medicine that uses a device with a needle; if you are carrying a sharps container in your carry-on baggage, notify the screener at the airport.</p> <p><b>Q. What if my Autoinjector does not stay cool for an extended period of time? Is it dangerous to use?</b></p> <p>A. Contact 1-800-673-6242 for details.</p> <p><b>If you have questions or concerns about your Autoinjector, please contact a healthcare provider or call our toll-free help line at 1-800-673-6242.</b></p> <p class="credit">This Instructions for Use has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | 10 | 2023-02-01 17:39:31 | Abatacept (Orencia) | A | DMARDs, Immunomodulators | Orencia | abatacept | Orencia | |
| 80 | 2023-02-23 12:07:03 | Drug Description | <h4>What is ReoPro and how is it used?</h4> <p>ReoPro (abciximab) is a prescription medicine used to treat the symptoms of Unstable <a href="/angina/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Angina</a> (Chest Pain) and Adjunct to PCI. ReoPro may be used alone or with other medications.</p> <p>ReoPro belongs to a class of drugs called Antiplatelet Agents, <a href="/cardiovascular/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Cardiovascular</a>; Glycoprotein IIB/IIIa Inhibitors.</p> <p>It is not known if ReoPro is safe and effective in children.</p> <h4>What are the possible side effects of ReoPro?</h4> <p>ReoPro may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>severe dizziness,</li> <li>bleeding,</li> <li>blurred vision,</li> <li>confusion,</li> <li>faintness,</li> <li><a href="/lightheadedness/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lightheadedness</a>,</li> <li>sweating,</li> <li>unusual tiredness,</li> <li>weakness,</li> <li>black or tarry stools,</li> <li>bleeding gums,</li> <li><a href="/blood_in_urine/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">blood in urine</a> or stools,</li> <li>pinpoint red spots on skin,</li> <li>unusual bleeding or bruising,</li> <li>chest pain or pressure,</li> <li>chills,</li> <li>cough,</li> <li>eye pain,</li> <li>fever,</li> <li>general feeling of illness,</li> <li>headache,</li> <li>pale skin,</li> <li>rapid weight gain,</li> <li>shortness of breath,</li> <li>slow or irregular heartbeat,</li> <li>sneezing,</li> <li><a href="/sore_throat_pharyngitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">sore throat</a>,</li> <li>swelling of hands, ankles, feet, or lower legs,</li> <li>tightness in the chest,</li> <li>tingling of hands or feet,</li> <li>unusual tiredness, and</li> <li><a href="/wheezing/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">wheezing</a></li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of ReoPro include:</p> <ul> <li><a href="/back_pain/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">back pain</a>,</li> <li><a href="/dyspepsia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">indigestion</a>,</li> <li>burping,</li> <li>burning or crawling in <a href="/skin_anatomy_picture_definition_function/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">the skin</a>,</li> <li>itching,</li> <li>numbness or tingling,</li> <li>vision changes,</li> <li>delusions,</li> <li><a href="/dementia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">dementia</a>,</li> <li>fear,</li> <li><a href="/heartburn/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">heartburn</a>,</li> <li>mood changes,</li> <li>nausea,</li> <li>vomiting,</li> <li>nervousness, and</li> <li>agitation</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of ReoPro. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <a name="D"></a> <h3>DESCRIPTION</h3> <p>Abciximab, ReoPro®, is the Fab fragment of the chimeric human-murine <a href="/script/main/art.asp?articlekey=4425" onclick="wmdTrack('embd-lnk');" rel="dict">monoclonal antibody</a> 7E3. Abciximab binds to the <a href="/script/main/art.asp?articlekey=16842" onclick="wmdTrack('embd-lnk');" rel="dict">glycoprotein</a> (GP) IIb/IIIa receptor of human platelets and inhibits <a href="/script/main/art.asp?articlekey=33673" onclick="wmdTrack('embd-lnk');" rel="dict">platelet aggregation</a>. Abciximab also binds to the vitronectin (α<sub>v</sub>β<sub>3</sub>) receptor found on platelets and vessel wall <a href="/script/main/art.asp?articlekey=20648" onclick="wmdTrack('embd-lnk');" rel="dict">endothelial</a> and <a href="/script/main/art.asp?articlekey=5514" onclick="wmdTrack('embd-lnk');" rel="dict">smooth muscle</a> cells.</p> <p>The chimeric 7E3 antibody is produced by continuous <a href="/script/main/art.asp?articlekey=4844" onclick="wmdTrack('embd-lnk');" rel="dict"> perfusion</a> in mammalian cell culture. The 47,615 dalton Fab fragment is purified from cell culture supernatant by a series of steps involving specific viral inactivation and removal procedures, digestion with <a href="/papain/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">papain</a> and column chromatography.</p> <p>ReoPro® is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use. Each single use vial contains 2 mg/mL of Abciximab in a buffered solution (pH 7.2) of 0.01 M sodium phosphate, 0.15 M sodium chloride and 0.001% polysorbate 80 in Water for Injection. No preservatives are added.</p> </div> <div id="667441035-1" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-1", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <h4>What is ReoPro and how is it used?</h4> <p>ReoPro (abciximab) is a prescription medicine used to treat the symptoms of Unstable <a href="/angina/definition.htm" ">Angina</a> (Chest Pain) and Adjunct to PCI. ReoPro may be used alone or with other medications.</p> <p>ReoPro belongs to a class of drugs called Antiplatelet Agents, <a href="/cardiovascular/definition.htm" ">Cardiovascular</a>; Glycoprotein IIB/IIIa Inhibitors.</p> <p>It is not known if ReoPro is safe and effective in children.</p> <h4>What are the possible side effects of ReoPro?</h4> <p>ReoPro may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>severe dizziness,</li> <li>bleeding,</li> <li>blurred vision,</li> <li>confusion,</li> <li>faintness,</li> <li><a href="/lightheadedness/definition.htm" ">lightheadedness</a>,</li> <li>sweating,</li> <li>unusual tiredness,</li> <li>weakness,</li> <li>black or tarry stools,</li> <li>bleeding gums,</li> <li><a href="/blood_in_urine/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">blood in urine</a> or stools,</li> <li>pinpoint red spots on skin,</li> <li>unusual bleeding or bruising,</li> <li>chest pain or pressure,</li> <li>chills,</li> <li>cough,</li> <li>eye pain,</li> <li>fever,</li> <li>general feeling of illness,</li> <li>headache,</li> <li>pale skin,</li> <li>rapid weight gain,</li> <li>shortness of breath,</li> <li>slow or irregular heartbeat,</li> <li>sneezing,</li> <li><a href="/sore_throat_pharyngitis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">sore throat</a>,</li> <li>swelling of hands, ankles, feet, or lower legs,</li> <li>tightness in the chest,</li> <li>tingling of hands or feet,</li> <li>unusual tiredness, and</li> <li><a href="/wheezing/definition.htm" ">wheezing</a></li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of ReoPro include:</p> <ul> <li><a href="/back_pain/definition.htm" ">back pain</a>,</li> <li><a href="/dyspepsia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">indigestion</a>,</li> <li>burping,</li> <li>burning or crawling in <a href="/skin_anatomy_picture_definition_function/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">the skin</a>,</li> <li>itching,</li> <li>numbness or tingling,</li> <li>vision changes,</li> <li>delusions,</li> <li><a href="/dementia/definition.htm" ">dementia</a>,</li> <li>fear,</li> <li><a href="/heartburn/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">heartburn</a>,</li> <li>mood changes,</li> <li>nausea,</li> <li>vomiting,</li> <li>nervousness, and</li> <li>agitation</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of ReoPro. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <a name="D"></a> <h3>DESCRIPTION</h3> <p>Abciximab, ReoPro®, is the Fab fragment of the chimeric human-murine <a href="/script/main/art.asp?articlekey=4425" onclick="wmdTrack('embd-lnk');" rel="dict">monoclonal antibody</a> 7E3. Abciximab binds to the <a href="/script/main/art.asp?articlekey=16842" onclick="wmdTrack('embd-lnk');" rel="dict">glycoprotein</a> (GP) IIb/IIIa receptor of human platelets and inhibits <a href="/script/main/art.asp?articlekey=33673" onclick="wmdTrack('embd-lnk');" rel="dict">platelet aggregation</a>. Abciximab also binds to the vitronectin (α<sub>v</sub>β<sub>3</sub>) receptor found on platelets and vessel wall <a href="/script/main/art.asp?articlekey=20648" onclick="wmdTrack('embd-lnk');" rel="dict">endothelial</a> and <a href="/script/main/art.asp?articlekey=5514" onclick="wmdTrack('embd-lnk');" rel="dict">smooth muscle</a> cells.</p> <p>The chimeric 7E3 antibody is produced by continuous <a href="/script/main/art.asp?articlekey=4844" onclick="wmdTrack('embd-lnk');" rel="dict"> perfusion</a> in mammalian cell culture. The 47,615 dalton Fab fragment is purified from cell culture supernatant by a series of steps involving specific viral inactivation and removal procedures, digestion with <a href="/papain/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">papain</a> and column chromatography.</p> <p>ReoPro® is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use. Each single use vial contains 2 mg/mL of Abciximab in a buffered solution (pH 7.2) of 0.01 M sodium phosphate, 0.15 M sodium chloride and 0.001% polysorbate 80 in Water for Injection. No preservatives are added.</p> </div> <div id="667441035-1" class="medianet"><</div> </div> </div> | 11 | 2023-02-01 17:39:50 | Abciximab (ReoPro) | A | Antineoplastics CDK Inhibitors, Glycoprotein IIb/IIIa Inhibitors | ReoPro | abciximab | ReoPro | John P. Cunha, DO, FACOEP |
| 81 | 2023-02-23 12:07:03 | Indications | <a name="I"></a><h3>INDICATIONS</h3> <p>ReoPro<sup>®</sup> (abciximab) is indicated as an adjunct to <a href="/coronary_angioplasty/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">percutaneous coronary intervention</a> for the prevention of cardiac ischemic complications:</p> <ul> <li>in patients undergoing <a href="/percutaneous/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">percutaneous</a> coronary intervention.</li> <li>in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours.</li> </ul> <p>ReoPro<sup>®</sup> use in patients not undergoing percutaneous coronary intervention has not been studied.</p> <p>ReoPro<sup>®</sup> is intended for use with acetylsalicylic acid and <a href="/heparin/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">heparin</a> and has been studied only in that setting.</p> <h4>Geriatrics (> 65 Years Of Age)</h4> <p>See <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Special Populations, Geriatrics</b></p> <h4>Pediatrics (< 18 Years Of Age)</h4> <p>See <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Special Populations, Pediatrics</b></p> </div> <a class="mediaPrmo ss" href="/heart_disease_slideshow/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/heart_disease_s1_heart.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">Heart Disease: Symptoms, Signs, and Causes</span> <span class="btn">See Slideshow</span> </a> </div> </div> | <a name="I"></a><h3>INDICATIONS</h3> <p>ReoPro<sup>®</sup> (abciximab) is indicated as an adjunct to <a href="/coronary_angioplasty/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">percutaneous coronary intervention</a> for the prevention of cardiac ischemic complications:</p> <ul> <li>in patients undergoing <a href="/percutaneous/definition.htm" ">percutaneous</a> coronary intervention.</li> <li>in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours.</li> </ul> <p>ReoPro<sup>®</sup> use in patients not undergoing percutaneous coronary intervention has not been studied.</p> <p>ReoPro<sup>®</sup> is intended for use with acetylsalicylic acid and <a href="/heparin/definition.htm" ">heparin</a> and has been studied only in that setting.</p> <h4>Geriatrics (> 65 Years Of Age)</h4> <p>See <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Special Populations, Geriatrics</b></p> <h4>Pediatrics (< 18 Years Of Age)</h4> <p>See <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Special Populations, Pediatrics</b></p> </div> <a class="mediaPrmo ss" href="/heart_disease_slideshow/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/heart_disease_s1_heart.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">Heart Disease: Symptoms, Signs, and Causes</span> <span class="btn">See Slideshow</span> </a> </div> </div> | 11 | 2023-02-01 17:39:50 | Abciximab (ReoPro) | A | Antineoplastics CDK Inhibitors, Glycoprotein IIb/IIIa Inhibitors | ReoPro | abciximab | ReoPro | John P. Cunha, DO, FACOEP |
| 82 | 2023-02-23 12:07:03 | Dosage | <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3> <h4>Dosing Considerations</h4> <ul> <li>The safety and efficacy of ReoPro<sup>®</sup> (abciximab) have only been investigated with concomitant administration of heparin and acetylsalicylic acid.</li> <li>Acetylsalicylic acid should be administered orally at a daily dose of 300 to 325 mg.</li> <li>For heparin anticoagulation guidelines see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Bleeding Precautions,</b> Heparin.</li> <li>In patients with failed PTCAs, the continuous infusion of ReoPro<sup>®</sup> should be stopped because there is no evidence for ReoPro<sup>®</sup> efficacy in that setting.</li> <li>In the event of serious bleeding that cannot be controlled by <a href="/compression/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">compression</a>, ReoPro<sup>®</sup> and heparin should be discontinued immediately (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Restoration of Platelet Function</b>).</li> </ul> <h4>Recommended Dose And Dosage Adjustment</h4> <h5>Adults</h5> <p>The recommended dose of ReoPro<sup>®</sup> is a 0.25 mg/kg intravenous bolus followed by a 0.125 μg/kg/min (to a maximum of 10 μg/min) continuous intravenous infusion.</p> <p>For the stabilization of unstable angina patients, the bolus dose followed by the infusion should be started up to 24 hours prior to the possible intervention.</p> <p>For the prevention of ischemic cardiac complications in patients undergoing PCI, and who are not currently receiving a ReoPro<sup>®</sup> infusion, the bolus should be administered 10-60 minutes prior to the intervention, followed by the infusion for twelve (12) hours.</p> <h4>Administration</h4> <ol> <li><a href="/parenteral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Parenteral</a> drug products should be inspected visually for particulate matter prior to administration. Preparations of ReoPro<sup>®</sup> containing visibly opaque particles should NOT be used.</li> <li>Hypersensitivity reactions should be anticipated whenever protein solutions such as ReoPro<sup>®</sup> are administered. <a href="/epinephrine/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Epinephrine</a>, <a href="/dopamine/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">dopamine</a>, theophylline, <a href="/antihistamines/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antihistamines</a> and corticosteroids should be available for immediate use. If symptoms of an allergic reaction or <a href="/anaphylaxis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anaphylaxis</a> appear, the infusion should be stopped and appropriate treatment given.</li> <li>As with all parenteral drug products, <a href="/aseptic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">aseptic</a> procedures should be used during the administration of ReoPro<sup>®</sup>.</li> <li>Withdraw the necessary amount of ReoPro<sup>®</sup> for bolus injection into a syringe. Filter the bolus injection using a sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 μm filter.</li> <li>Withdraw the necessary amount of ReoPro<sup>®</sup> for the continuous infusion into a syringe. Inject into an appropriate container of sterile 0.9% <a href="/saline/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">saline</a> or 5% dextrose and <a href="/infuse/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">infuse</a> at the calculated rate via a continuous infusion pump. The continuous infusion should be filtered either upon admixture using a sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 μm syringe filter or upon administration using an in-line, sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 μm filter.</li> <li>Discard the unused portion at the end of the infusion.</li> <li>Although incompatibilities have not been observed with intravenous infusion fluids or commonly used cardiovascular drugs, it is recommended that ReoPro<sup>®</sup> be administered in a separate intravenous line whenever possible and not mixed with other medications.</li> <li>No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets.</li> </ol> <a name="HS"></a><h3>HOW SUPPLIED</h3> <h4>Dosage Forms, Composition And Packaging</h4> <p>ReoPro<sup>®</sup> (abciximab) is available in solution for intravenous injection and supplied in a 5 mL (10 mg) vial in packages of single vials. The vial stopper is free of natural rubber latex.</p> <p>Each mL contains 2 mg of abciximab in a buffered solution (pH 7.2) of 0.01 M sodium phosphate, 0.15 M sodium chloride and 0.001% polysorbate 80. No preservatives are added.</p> <h5>Storage And Stability</h5> <p>Vials should be stored at 2 to 8°C (36 to 46°F). Do not freeze. Do not shake. Do not use beyond the expiration date. Discard any unused portion left in the vial.</p> <h4>Drug Substance</h4> <p>Proper name: abciximab (ReoPro<sup>®</sup>)</p> <p>Chemical name: abciximab</p> <p>Molecular mass: 47,615 daltons</p> <p>Physicochemical properties: ReoPro<sup>®</sup> is a clear, colourless, sterile, non-pyrogenic solution for intravenous (IV) use.</p> <h4>Product Characteristics</h4> <p>ReoPro<sup>®</sup> (abciximab) is a chimeric Fab fragment that binds to platelet glycoprotein IIb/IIIa. Abciximab is generated by papain cleavage of the intact chimeric <a href="/monoclonal/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">monoclonal</a> antibody 7E3 comprising <a href="/antigen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antigen</a>-binding variable regions of murine monoclonal antibody 7E3 and constant regions of human <a href="/igg/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">IgG</a><sub>1κ</sub>.</p> <p class="credit"><b>REFERENCES</b></p> <p class="credit">10. Coller BS, Folts JD, Scudder LE, Smith SR. Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model. <i>Blood</i> 1986;68:783-786.</p> <p class="credit">11. Coller BS, Folts JD, Smith SR, Scudder LE, Jordan R. Abolition of<i> in vivo</i> platelet <a href="/thrombus/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">thrombus</a> formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. <i>Circ</i> 1989;80:1766-1773.</p> <p class="credit">12. Sherman <a href="/ct/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">CT</a>, Litvock F, Grundfest W, Lee M, Hickey A, Chaux A, Kass R, Blanche C, Matloff J, Morgenstern L, Ganz W, Swan HJC, Forrester J. Coronary angioscopy in patients with unstable <a href="/angina_pectoris/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">angina pectoris</a>. <i>N Eng J Med</i> 1986;315:913-919.</p> <p class="credit">Prepared by Janssen Inc. Toronto, Ontario M3C 1L9. Revised: June 2019</p> </div> <div id="667441035-3" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-3", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3> <h4>Dosing Considerations</h4> <ul> <li>The safety and efficacy of ReoPro<sup>®</sup> (abciximab) have only been investigated with concomitant administration of heparin and acetylsalicylic acid.</li> <li>Acetylsalicylic acid should be administered orally at a daily dose of 300 to 325 mg.</li> <li>For heparin anticoagulation guidelines see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Bleeding Precautions,</b> Heparin.</li> <li>In patients with failed PTCAs, the continuous infusion of ReoPro<sup>®</sup> should be stopped because there is no evidence for ReoPro<sup>®</sup> efficacy in that setting.</li> <li>In the event of serious bleeding that cannot be controlled by <a href="/compression/definition.htm" ">compression</a>, ReoPro<sup>®</sup> and heparin should be discontinued immediately (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Restoration of Platelet Function</b>).</li> </ul> <h4>Recommended Dose And Dosage Adjustment</h4> <h5>Adults</h5> <p>The recommended dose of ReoPro<sup>®</sup> is a 0.25 mg/kg intravenous bolus followed by a 0.125 μg/kg/min (to a maximum of 10 μg/min) continuous intravenous infusion.</p> <p>For the stabilization of unstable angina patients, the bolus dose followed by the infusion should be started up to 24 hours prior to the possible intervention.</p> <p>For the prevention of ischemic cardiac complications in patients undergoing PCI, and who are not currently receiving a ReoPro<sup>®</sup> infusion, the bolus should be administered 10-60 minutes prior to the intervention, followed by the infusion for twelve (12) hours.</p> <h4>Administration</h4> <ol> <li><a href="/parenteral/definition.htm" ">Parenteral</a> drug products should be inspected visually for particulate matter prior to administration. Preparations of ReoPro<sup>®</sup> containing visibly opaque particles should NOT be used.</li> <li>Hypersensitivity reactions should be anticipated whenever protein solutions such as ReoPro<sup>®</sup> are administered. <a href="/epinephrine/definition.htm" ">Epinephrine</a>, <a href="/dopamine/definition.htm" ">dopamine</a>, theophylline, <a href="/antihistamines/definition.htm" ">antihistamines</a> and corticosteroids should be available for immediate use. If symptoms of an allergic reaction or <a href="/anaphylaxis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anaphylaxis</a> appear, the infusion should be stopped and appropriate treatment given.</li> <li>As with all parenteral drug products, <a href="/aseptic/definition.htm" ">aseptic</a> procedures should be used during the administration of ReoPro<sup>®</sup>.</li> <li>Withdraw the necessary amount of ReoPro<sup>®</sup> for bolus injection into a syringe. Filter the bolus injection using a sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 μm filter.</li> <li>Withdraw the necessary amount of ReoPro<sup>®</sup> for the continuous infusion into a syringe. Inject into an appropriate container of sterile 0.9% <a href="/saline/definition.htm" ">saline</a> or 5% dextrose and <a href="/infuse/definition.htm" ">infuse</a> at the calculated rate via a continuous infusion pump. The continuous infusion should be filtered either upon admixture using a sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 μm syringe filter or upon administration using an in-line, sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 μm filter.</li> <li>Discard the unused portion at the end of the infusion.</li> <li>Although incompatibilities have not been observed with intravenous infusion fluids or commonly used cardiovascular drugs, it is recommended that ReoPro<sup>®</sup> be administered in a separate intravenous line whenever possible and not mixed with other medications.</li> <li>No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets.</li> </ol> <a name="HS"></a><h3>HOW SUPPLIED</h3> <h4>Dosage Forms, Composition And Packaging</h4> <p>ReoPro<sup>®</sup> (abciximab) is available in solution for intravenous injection and supplied in a 5 mL (10 mg) vial in packages of single vials. The vial stopper is free of natural rubber latex.</p> <p>Each mL contains 2 mg of abciximab in a buffered solution (pH 7.2) of 0.01 M sodium phosphate, 0.15 M sodium chloride and 0.001% polysorbate 80. No preservatives are added.</p> <h5>Storage And Stability</h5> <p>Vials should be stored at 2 to 8°C (36 to 46°F). Do not freeze. Do not shake. Do not use beyond the expiration date. Discard any unused portion left in the vial.</p> <h4>Drug Substance</h4> <p>Proper name: abciximab (ReoPro<sup>®</sup>)</p> <p>Chemical name: abciximab</p> <p>Molecular mass: 47,615 daltons</p> <p>Physicochemical properties: ReoPro<sup>®</sup> is a clear, colourless, sterile, non-pyrogenic solution for intravenous (IV) use.</p> <h4>Product Characteristics</h4> <p>ReoPro<sup>®</sup> (abciximab) is a chimeric Fab fragment that binds to platelet glycoprotein IIb/IIIa. Abciximab is generated by papain cleavage of the intact chimeric <a href="/monoclonal/definition.htm" ">monoclonal</a> antibody 7E3 comprising <a href="/antigen/definition.htm" ">antigen</a>-binding variable regions of murine monoclonal antibody 7E3 and constant regions of human <a href="/igg/definition.htm" ">IgG</a><sub>1κ</sub>.</p> <p class="credit"><b>REFERENCES</b></p> <p class="credit">10. Coller BS, Folts JD, Scudder LE, Smith SR. Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model. <i>Blood</i> 1986;68:783-786.</p> <p class="credit">11. Coller BS, Folts JD, Smith SR, Scudder LE, Jordan R. Abolition of<i> in vivo</i> platelet <a href="/thrombus/definition.htm" ">thrombus</a> formation in primates with monoclonal antibodies to the platelet GPIIb/IIIa receptor. <i>Circ</i> 1989;80:1766-1773.</p> <p class="credit">12. Sherman <a href="/ct/definition.htm" ">CT</a>, Litvock F, Grundfest W, Lee M, Hickey A, Chaux A, Kass R, Blanche C, Matloff J, Morgenstern L, Ganz W, Swan HJC, Forrester J. Coronary angioscopy in patients with unstable <a href="/angina_pectoris/definition.htm" ">angina pectoris</a>. <i>N Eng J Med</i> 1986;315:913-919.</p> <p class="credit">Prepared by Janssen Inc. Toronto, Ontario M3C 1L9. Revised: June 2019</p> </div> <div id="667441035-3" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-3", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | 11 | 2023-02-01 17:39:50 | Abciximab (ReoPro) | A | Antineoplastics CDK Inhibitors, Glycoprotein IIb/IIIa Inhibitors | ReoPro | abciximab | ReoPro | John P. Cunha, DO, FACOEP |
| 83 | 2023-02-23 12:07:03 | Side Effects | <a name="AR"></a><h3>SIDE EFFECTS</h3> <h4>Adverse Drug Reaction Overview</h4> <h5>Bleeding</h5> <p>Bleeding was classified as major or minor by the criteria of the Thrombolysis in Myocardial <a href="/infarction/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Infarction</a> (TIMI) study group. Major bleeding events were defined as either an intracranial <a href="/hemorrhage/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hemorrhage</a> or decrease in <a href="/hemoglobin/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hemoglobin</a> greater than 5 g/dL. Minor bleeding events included spontaneous <a href="/gross_hematuria/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">gross hematuria</a> or <a href="/hematemesis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hematemesis</a> or observed blood loss with a hemoglobin decreasing more than 3 g/dL or with a decrease in hemoglobin of at least 4 g/dL with no observed blood loss.</p> <p>In the EPIC trial, in which a non-weight-adjusted, standard heparin dose regimen was used, the most common <a href="/complication/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">complication</a> during ReoPro<sup>®</sup> (abciximab) therapy was bleeding during the first 36 hours. The incidences of major bleeding, minor bleeding and <a href="/transfusion/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">transfusion</a> of blood products were approximately doubled. Approximately 70% of ReoPro<sup>®</sup>-treated patients with major bleeding had bleeding at the arterial <a href="/access/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">access</a> site in the <a href="/groin/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">groin</a>. ReoPro<sup>®</sup>-treated patients also had a higher incidence of major bleeding events from gastrointestinal, genitourinary, retroperitoneal, and other sites.</p> <p>In a subsequent clinical trial, EPILOG, using the heparin and ReoPro<sup>®</sup> dosing, sheath removal and arterial access site guidelines described under <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b>, the incidence of major bleeding in patients treated with ReoPro<sup>®</sup> and low-dose, weight-adjusted heparin (1.8%) was not significantly different from patients receiving placebo (3.1%) and there was no significant increase in the incidence of intracranial hemorrhage. The reduction in bleeding observed in the EPILOG trial was achieved without loss of efficacy.</p> <p>The rates of major bleeding, minor bleeding and bleeding events requiring transfusions in the EPIC, CAPTURE and EPILOG trials are shown in Table 1.</p> <p align="center"><b>Table 1: Non-CABG Bleeding in the EPIC, EPILOG and CAPTURE Trials Number of Patients with Bleeds (%)</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="40%" rowspan="2"> </td> <td colspan="3" class="EmphTd">EPIC:</td> </tr> <tr> <td class="EmphTd" width="20%">Placebo<br /> (n=696)</td> <td class="EmphTd" colspan="2">ReoPro<sup>®</sup><br /> (Bolus+Infusion)<br /> (n=708)</td> </tr> <tr> <td>Major<sup>a</sup></td> <td align="center">23 (3.3)</td> <td colspan="2" align="center">75 (10.6)</td> </tr> <tr> <td>Minor</td> <td align="center">64 (9.2)</td> <td colspan="2" align="center">119 (16.8)</td> </tr> <tr> <td>Requiring Transfusion<sup>b</sup></td> <td align="center">14 (2.0)</td> <td colspan="2" align="center">55 (7.8)</td> </tr> <tr> <td class="EmphTd" align="center"> </td> <td class="EmphTd" colspan="3">CAPTURE<b>:</b></td> </tr> <tr> <td class="EmphTd"> </td> <td class="EmphTd">Placebo<br /> (n=635)</td> <td class="EmphTd" colspan="2">ReoPro<sup>®</sup><br /> (n=630)</td> </tr> <tr> <td>Major<sup>a</sup></td> <td align="center">12 (1.9)</td> <td colspan="2" align="center">24 (3.8)</td> </tr> <tr> <td>Minor</td> <td align="center">13 (2.0)</td> <td colspan="2" align="center">30 (4.8)</td> </tr> <tr> <td>Requiring Transfusion<sup>b</sup></td> <td align="center">9 (1.4)</td> <td colspan="2" align="center">15 (2.4)</td> </tr> <tr> <td class="EmphTd"> </td> <td class="EmphTd" colspan="3">EPILOG:</td> </tr> <tr> <td class="EmphTd"> </td> <td class="EmphTd">Placebo + Std-dose<br /> Heparin<br /> (n=939)</td> <td class="EmphTd" width="20%">ReoPro<sup>®</sup> + Std-dose<br /> Heparin<br /> (n=918)</td> <td class="EmphTd" width="20%">ReoPro<sup>®</sup> + Lowdose<br /> Heparin<br /> (n=935)</td> </tr> <tr> <td>Major<sup>a</sup></td> <td align="center">10 (1.1)</td> <td align="center">17 (1.9)</td> <td align="center">10 (1.1)</td> </tr> <tr> <td>Minor</td> <td align="center">32 (3.4)</td> <td align="center">70 (7.6)</td> <td align="center">37 (4.0)</td> </tr> <tr> <td>Requiring Transfusion<sup>b</sup></td> <td align="center">10 (1.1)</td> <td align="center">7 (0.8)</td> <td align="center">6 (0.6)</td> </tr> <tr> <td class="credit" colspan="4"> <sup>a</sup>Patients who had bleeding in more than one classification are counted only once according to the most severe classification. Patients with multiple bleeding events of the same classification are also counted once within that classification.<br /> <sup>b</sup>Packed red blood cells or whole blood</td> </tr> </table> </center></p> <p>Although data are limited, ReoPro<sup>®</sup> treatment was not associated with excess major bleeding in patients who underwent <a href="/cabg/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">CABG</a> surgery. Some patients with prolonged bleeding times received platelet transfusions to correct the bleeding time prior to surgery. (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Restoration of Platelet Function</b>).</p> <p>The total incidence of intracranial hemorrhage and non-<a href="/hemorrhagic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hemorrhagic</a> <a href="/stroke/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">stroke</a> across all three trials was similar, 7/2225 (0.31%) for placebo patients and 10/3112 (0.32%) for ReoPro<sup>®</sup>-treated patients. The incidence of intracranial hemorrhage was 0.13% in placebo patients and 0.19% in ReoPro<sup>®</sup> patients.</p> <p>Pulmonary hemorrhage with fatal outcome following administration of ReoPro<sup>®</sup> has been reported. In many cases, patients received at least two co-suspect or concomitant medications such as heparin or aspirin. Although the outcomes of most cases were not provided, approximately 2/3 had fatal outcomes. Based on exposure data, the reporting rate for pulmonary hemorrhage is less than 1 case report per 10,000 patients (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b>, <b>Pulmonary Hemorrhage</b>).</p> <h5>Thrombocytopenia</h5> <p>In the clinical trials, patients treated with ReoPro<sup>®</sup> were more likely than patients treated with placebo to experience decreases in platelet counts. The overall rates of thrombocytopenia (platelet counts < 100,000 cells/μL) in the EPIC, EPILOG and CAPTURE trials were 0.5% for placebo-treated patients and 2.9% for patients receiving ReoPro<sup>®</sup> bolus plus infusion. The incidence of thrombocytopenia was lowest in the EPILOG trial (placebo: 1.5%; ReoPro<sup>®</sup> and standard-dose, weight-adjusted heparin: 2.6%; ReoPro<sup>®</sup> and low-dose, weight-adjusted heparin: 2.5%). The lowest rates of platelet transfusions in ReoPro<sup>®</sup>-treated patients were also observed in the EPILOG trial, (placebo: 1.1%; ReoPro<sup>®</sup> and standard-dose, weight-adjusted heparin: 1.6%; ReoPro<sup>®</sup> and low-dose, weight-adjusted heparin: 0.9%).</p> <p>In a readministration registry study of patients receiving a second or subsequent exposure to ReoPro<sup>®</sup> (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Re-administration</b>) the incidence of any degree of thrombocytopenia was 5%, with an incidence of profound thrombocytopenia of 2% (<20,000 cell/μL). Factors associated with an increased risk of thrombocytopenia were a history of thrombocytopenia on previous ReoPro<sup>®</sup> exposure, readministration within 30 days, and a positive HACA assay prior to the readministration.</p> <p>Among 14 patients who had thrombocytopenia associated with a prior exposure to ReoPro<sup>®</sup>, 7 (50%) had <a href="/recurrent/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">recurrent</a> thrombocytopenia. In 130 patients with a readministration interval of 30 days or less, 25 (19%) developed thrombocytopenia. Severe thrombocytopenia occurred in 19 of these patients. Among the 71 patients who had a positive HACA assay at baseline, 11 (15%) developed thrombocytopenia, 7 of which were severe.</p> <h5>Human Antichimeric Antibody (HACA)</h5> <p>Human antichimeric antibody (HACA) may appear in response to the administration of ReoPro<sup>®</sup>. In the EPIC, EPILOG, and CAPTURE trials, positive responses occurred in approximately 5.8% of the ReoPro<sup>®</sup>-treated patients. There was no excess of hypersensitivity or allergic reactions related to ReoPro<sup>®</sup> treatment compared with placebo treatment. See also <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Hypersensitivity Reactions.</b></p> <p>In a study of readministration of ReoPro<sup>®</sup> to patients (See <a href="/reopro-drug.htm#P"><b>PRECAUTIONS</b></a>: <b>Readministration</b>) the overall rate of HACA positivity prior to the readministration was 6% and increased postreadministration to 27%. Among the 36 subjects receiving a fourth or greater ReoPro<sup>®</sup> exposure, HACA positive assays were observed post-readministration in 16 subjects (44%). There were no reports of serious allergic reactions or anaphylaxis. HACA positive status was associated with an increased risk of thrombocytopenia (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Thrombocytopenia</b>).</p> <p>The data reflect the percentage of patients whose test results were considered positive for antibodies to ReoPro<sup>®</sup> using an <a href="/elisa/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ELISA</a> assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ReoPro<sup>®</sup> with the incidence of antibodies to other products may be misleading.</p> <h4>Clinical Trial Adverse Drug Reactions</h4> <p><i>Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.</i></p> <p>Table 2 below shows adverse drug reactions other than bleeding, intracranial hemorrhage and thrombocytopenia from the combined EPIC, EPILOG and CAPTURE trials which occurred in ≥1% of patients in either the ReoPro<sup>®</sup> or placebo treatment arms.</p> <p align="center"><b>Table 2: Adverse Drug Reactions Among Treated Patients in the EPIC, EPILOG and CAPTURE Trials</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="50%"> </td> <td class="EmphTd" width="25%">ReoPro<sup>®</sup> Bolus + Infusion<br /> n= 3111<br /> (%)</td> <td class="EmphTd" width="25%">Placebo<br /> n= 2226<br /> (%)</td> </tr> <tr> <td><b>Cardiac disorders</b></td> <td> </td> <td> </td> </tr> <tr> <td> Bradycardia</td> <td align="center">4.5%</td> <td align="center">3.5%</td> </tr> <tr> <td><b>Gastrointestinal disorders</b></td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Nausea</td> <td align="center">13.6%</td> <td align="center">11.5%</td> </tr> <tr> <td> Vomiting</td> <td align="center">7.3%</td> <td align="center">6.8%</td> </tr> <tr> <td><b>General disorders and administration site conditions</b></td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Chest pain</td> <td align="center">11.4%</td> <td align="center">9.3%</td> </tr> <tr> <td> Puncture site pain</td> <td align="center">3.6%</td> <td align="center">2.6%</td> </tr> <tr> <td> Abdominal pain</td> <td align="center">3.1%</td> <td align="center">2.2%</td> </tr> <tr> <td><b>Musculoskeletal and connective tissue disorders</b></td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Back pain</td> <td align="center">17.6%</td> <td align="center">13.7%</td> </tr> <tr> <td><b>Nervous system disorders</b></td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Headache</td> <td align="center">6.4%</td> <td align="center">5.5%</td> </tr> <tr> <td><b>Vascular disorders</b></td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Hypotension</td> <td align="center">14.4%</td> <td align="center">10.3%</td> </tr> <tr> <td> Peripheral edema</td> <td align="center">1.6%</td> <td align="center">1.1%</td> </tr> </table> </center></p> <h4>Less Common Clinical Trial Adverse Drug Reactions (<1%)</h4> <p><i><b>General disorders and administration site conditions:</b></i> Injection site reaction</p> <p><i><b>Immune system disorders:</b></i> Allergic reactions</p> <h4>Post-Market Adverse Drug Reactions</h4> <p>Cases of anaphylaxis, sometimes fatal, have been very rarely observed and reported following marketing of ReoPro<sup>®</sup>. Gastrointestinal hemorrhage has also been very rarely reported following marketing of ReoPro<sup>®</sup>. Cases of fatal bleeding have been rarely reported following marketing of ReoPro<sup>®</sup> (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Bleeding Events</b>).</p> </div> <a class="mediaPrmo img" href="/collection-of-images/heart_picture/pictures.htm" onclick="wmdTrack('imgprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/featured/detail_heart3.jpg"> <span class="skew"></span> <span class="icon-image"></span> <h4 class="label">IMAGES</h4> <span class="caption"></span> <span class="desc"></span> <span class="btn">See Images</span> </a> </div> </div> | <a name="AR"></a><h3>SIDE EFFECTS</h3> <h4>Adverse Drug Reaction Overview</h4> <h5>Bleeding</h5> <p>Bleeding was classified as major or minor by the criteria of the Thrombolysis in Myocardial <a href="/infarction/definition.htm" ">Infarction</a> (TIMI) study group. Major bleeding events were defined as either an intracranial <a href="/hemorrhage/definition.htm" ">hemorrhage</a> or decrease in <a href="/hemoglobin/definition.htm" ">hemoglobin</a> greater than 5 g/dL. Minor bleeding events included spontaneous <a href="/gross_hematuria/definition.htm" ">gross hematuria</a> or <a href="/hematemesis/definition.htm" ">hematemesis</a> or observed blood loss with a hemoglobin decreasing more than 3 g/dL or with a decrease in hemoglobin of at least 4 g/dL with no observed blood loss.</p> <p>In the EPIC trial, in which a non-weight-adjusted, standard heparin dose regimen was used, the most common <a href="/complication/definition.htm" ">complication</a> during ReoPro<sup>®</sup> (abciximab) therapy was bleeding during the first 36 hours. The incidences of major bleeding, minor bleeding and <a href="/transfusion/definition.htm" ">transfusion</a> of blood products were approximately doubled. Approximately 70% of ReoPro<sup>®</sup>-treated patients with major bleeding had bleeding at the arterial <a href="/access/definition.htm" ">access</a> site in the <a href="/groin/definition.htm" ">groin</a>. ReoPro<sup>®</sup>-treated patients also had a higher incidence of major bleeding events from gastrointestinal, genitourinary, retroperitoneal, and other sites.</p> <p>In a subsequent clinical trial, EPILOG, using the heparin and ReoPro<sup>®</sup> dosing, sheath removal and arterial access site guidelines described under <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b>, the incidence of major bleeding in patients treated with ReoPro<sup>®</sup> and low-dose, weight-adjusted heparin (1.8%) was not significantly different from patients receiving placebo (3.1%) and there was no significant increase in the incidence of intracranial hemorrhage. The reduction in bleeding observed in the EPILOG trial was achieved without loss of efficacy.</p> <p>The rates of major bleeding, minor bleeding and bleeding events requiring transfusions in the EPIC, CAPTURE and EPILOG trials are shown in Table 1.</p> <p align="center"><b>Table 1: Non-CABG Bleeding in the EPIC, EPILOG and CAPTURE Trials Number of Patients with Bleeds (%)</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="40%" rowspan="2"> </td> <td colspan="3" class="EmphTd">EPIC:</td> </tr> <tr> <td class="EmphTd" width="20%">Placebo<br /> (n=696)</td> <td class="EmphTd" colspan="2">ReoPro<sup>®</sup><br /> (Bolus+Infusion)<br /> (n=708)</td> </tr> <tr> <td>Major<sup>a</sup></td> <td align="center">23 (3.3)</td> <td colspan="2" align="center">75 (10.6)</td> </tr> <tr> <td>Minor</td> <td align="center">64 (9.2)</td> <td colspan="2" align="center">119 (16.8)</td> </tr> <tr> <td>Requiring Transfusion<sup>b</sup></td> <td align="center">14 (2.0)</td> <td colspan="2" align="center">55 (7.8)</td> </tr> <tr> <td class="EmphTd" align="center"> </td> <td class="EmphTd" colspan="3">CAPTURE<b>:</b></td> </tr> <tr> <td class="EmphTd"> </td> <td class="EmphTd">Placebo<br /> (n=635)</td> <td class="EmphTd" colspan="2">ReoPro<sup>®</sup><br /> (n=630)</td> </tr> <tr> <td>Major<sup>a</sup></td> <td align="center">12 (1.9)</td> <td colspan="2" align="center">24 (3.8)</td> </tr> <tr> <td>Minor</td> <td align="center">13 (2.0)</td> <td colspan="2" align="center">30 (4.8)</td> </tr> <tr> <td>Requiring Transfusion<sup>b</sup></td> <td align="center">9 (1.4)</td> <td colspan="2" align="center">15 (2.4)</td> </tr> <tr> <td class="EmphTd"> </td> <td class="EmphTd" colspan="3">EPILOG:</td> </tr> <tr> <td class="EmphTd"> </td> <td class="EmphTd">Placebo + Std-dose<br /> Heparin<br /> (n=939)</td> <td class="EmphTd" width="20%">ReoPro<sup>®</sup> + Std-dose<br /> Heparin<br /> (n=918)</td> <td class="EmphTd" width="20%">ReoPro<sup>®</sup> + Lowdose<br /> Heparin<br /> (n=935)</td> </tr> <tr> <td>Major<sup>a</sup></td> <td align="center">10 (1.1)</td> <td align="center">17 (1.9)</td> <td align="center">10 (1.1)</td> </tr> <tr> <td>Minor</td> <td align="center">32 (3.4)</td> <td align="center">70 (7.6)</td> <td align="center">37 (4.0)</td> </tr> <tr> <td>Requiring Transfusion<sup>b</sup></td> <td align="center">10 (1.1)</td> <td align="center">7 (0.8)</td> <td align="center">6 (0.6)</td> </tr> <tr> <td class="credit" colspan="4"> <sup>a</sup>Patients who had bleeding in more than one classification are counted only once according to the most severe classification. Patients with multiple bleeding events of the same classification are also counted once within that classification.<br /> <sup>b</sup>Packed red blood cells or whole blood</td> </tr> </table> </center></p> <p>Although data are limited, ReoPro<sup>®</sup> treatment was not associated with excess major bleeding in patients who underwent <a href="/cabg/definition.htm" ">CABG</a> surgery. Some patients with prolonged bleeding times received platelet transfusions to correct the bleeding time prior to surgery. (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Restoration of Platelet Function</b>).</p> <p>The total incidence of intracranial hemorrhage and non-<a href="/hemorrhagic/definition.htm" ">hemorrhagic</a> <a href="/stroke/definition.htm" ">stroke</a> across all three trials was similar, 7/2225 (0.31%) for placebo patients and 10/3112 (0.32%) for ReoPro<sup>®</sup>-treated patients. The incidence of intracranial hemorrhage was 0.13% in placebo patients and 0.19% in ReoPro<sup>®</sup> patients.</p> <p>Pulmonary hemorrhage with fatal outcome following administration of ReoPro<sup>®</sup> has been reported. In many cases, patients received at least two co-suspect or concomitant medications such as heparin or aspirin. Although the outcomes of most cases were not provided, approximately 2/3 had fatal outcomes. Based on exposure data, the reporting rate for pulmonary hemorrhage is less than 1 case report per 10,000 patients (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b>, <b>Pulmonary Hemorrhage</b>).</p> <h5>Thrombocytopenia</h5> <p>In the clinical trials, patients treated with ReoPro<sup>®</sup> were more likely than patients treated with placebo to experience decreases in platelet counts. The overall rates of thrombocytopenia (platelet counts < 100,000 cells/μL) in the EPIC, EPILOG and CAPTURE trials were 0.5% for placebo-treated patients and 2.9% for patients receiving ReoPro<sup>®</sup> bolus plus infusion. The incidence of thrombocytopenia was lowest in the EPILOG trial (placebo: 1.5%; ReoPro<sup>®</sup> and standard-dose, weight-adjusted heparin: 2.6%; ReoPro<sup>®</sup> and low-dose, weight-adjusted heparin: 2.5%). The lowest rates of platelet transfusions in ReoPro<sup>®</sup>-treated patients were also observed in the EPILOG trial, (placebo: 1.1%; ReoPro<sup>®</sup> and standard-dose, weight-adjusted heparin: 1.6%; ReoPro<sup>®</sup> and low-dose, weight-adjusted heparin: 0.9%).</p> <p>In a readministration registry study of patients receiving a second or subsequent exposure to ReoPro<sup>®</sup> (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Re-administration</b>) the incidence of any degree of thrombocytopenia was 5%, with an incidence of profound thrombocytopenia of 2% (<20,000 cell/μL). Factors associated with an increased risk of thrombocytopenia were a history of thrombocytopenia on previous ReoPro<sup>®</sup> exposure, readministration within 30 days, and a positive HACA assay prior to the readministration.</p> <p>Among 14 patients who had thrombocytopenia associated with a prior exposure to ReoPro<sup>®</sup>, 7 (50%) had <a href="/recurrent/definition.htm" ">recurrent</a> thrombocytopenia. In 130 patients with a readministration interval of 30 days or less, 25 (19%) developed thrombocytopenia. Severe thrombocytopenia occurred in 19 of these patients. Among the 71 patients who had a positive HACA assay at baseline, 11 (15%) developed thrombocytopenia, 7 of which were severe.</p> <h5>Human Antichimeric Antibody (HACA)</h5> <p>Human antichimeric antibody (HACA) may appear in response to the administration of ReoPro<sup>®</sup>. In the EPIC, EPILOG, and CAPTURE trials, positive responses occurred in approximately 5.8% of the ReoPro<sup>®</sup>-treated patients. There was no excess of hypersensitivity or allergic reactions related to ReoPro<sup>®</sup> treatment compared with placebo treatment. See also <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Hypersensitivity Reactions.</b></p> <p>In a study of readministration of ReoPro<sup>®</sup> to patients (See <a href="/reopro-drug.htm#P"><b>PRECAUTIONS</b></a>: <b>Readministration</b>) the overall rate of HACA positivity prior to the readministration was 6% and increased postreadministration to 27%. Among the 36 subjects receiving a fourth or greater ReoPro<sup>®</sup> exposure, HACA positive assays were observed post-readministration in 16 subjects (44%). There were no reports of serious allergic reactions or anaphylaxis. HACA positive status was associated with an increased risk of thrombocytopenia (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Thrombocytopenia</b>).</p> <p>The data reflect the percentage of patients whose test results were considered positive for antibodies to ReoPro<sup>®</sup> using an <a href="/elisa/definition.htm" ">ELISA</a> assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ReoPro<sup>®</sup> with the incidence of antibodies to other products may be misleading.</p> <h4>Clinical Trial Adverse Drug Reactions</h4> <p><i>Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.</i></p> <p>Table 2 below shows adverse drug reactions other than bleeding, intracranial hemorrhage and thrombocytopenia from the combined EPIC, EPILOG and CAPTURE trials which occurred in ≥1% of patients in either the ReoPro<sup>®</sup> or placebo treatment arms.</p> <p align="center"><b>Table 2: Adverse Drug Reactions Among Treated Patients in the EPIC, EPILOG and CAPTURE Trials</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="50%"> </td> <td class="EmphTd" width="25%">ReoPro<sup>®</sup> Bolus + Infusion<br /> n= 3111<br /> (%)</td> <td class="EmphTd" width="25%">Placebo<br /> n= 2226<br /> (%)</td> </tr> <tr> <td><b>Cardiac disorders</b></td> <td> </td> <td> </td> </tr> <tr> <td> Bradycardia</td> <td align="center">4.5%</td> <td align="center">3.5%</td> </tr> <tr> <td><b>Gastrointestinal disorders</b></td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Nausea</td> <td align="center">13.6%</td> <td align="center">11.5%</td> </tr> <tr> <td> Vomiting</td> <td align="center">7.3%</td> <td align="center">6.8%</td> </tr> <tr> <td><b>General disorders and administration site conditions</b></td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Chest pain</td> <td align="center">11.4%</td> <td align="center">9.3%</td> </tr> <tr> <td> Puncture site pain</td> <td align="center">3.6%</td> <td align="center">2.6%</td> </tr> <tr> <td> Abdominal pain</td> <td align="center">3.1%</td> <td align="center">2.2%</td> </tr> <tr> <td><b>Musculoskeletal and connective tissue disorders</b></td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Back pain</td> <td align="center">17.6%</td> <td align="center">13.7%</td> </tr> <tr> <td><b>Nervous system disorders</b></td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Headache</td> <td align="center">6.4%</td> <td align="center">5.5%</td> </tr> <tr> <td><b>Vascular disorders</b></td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Hypotension</td> <td align="center">14.4%</td> <td align="center">10.3%</td> </tr> <tr> <td> Peripheral edema</td> <td align="center">1.6%</td> <td align="center">1.1%</td> </tr> </table> </center></p> <h4>Less Common Clinical Trial Adverse Drug Reactions (<1%)</h4> <p><i><b>General disorders and administration site conditions:</b></i> Injection site reaction</p> <p><i><b>Immune system disorders:</b></i> Allergic reactions</p> <h4>Post-Market Adverse Drug Reactions</h4> <p>Cases of anaphylaxis, sometimes fatal, have been very rarely observed and reported following marketing of ReoPro<sup>®</sup>. Gastrointestinal hemorrhage has also been very rarely reported following marketing of ReoPro<sup>®</sup>. Cases of fatal bleeding have been rarely reported following marketing of ReoPro<sup>®</sup> (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Bleeding Events</b>).</p> </div> <a class="mediaPrmo img" href="/collection-of-images/heart_picture/pictures.htm" onclick="wmdTrack('imgprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/featured/detail_heart3.jpg"> <span class="skew"></span> <span class="icon-image"></span> <h4 class="label">IMAGES</h4> <span class="caption"></span> <span class="desc"></span> <span class="btn">See Images</span> </a> </div> </div> | 11 | 2023-02-01 17:39:50 | Abciximab (ReoPro) | A | Antineoplastics CDK Inhibitors, Glycoprotein IIb/IIIa Inhibitors | ReoPro | abciximab | ReoPro | John P. Cunha, DO, FACOEP |
| 84 | 2023-02-23 12:07:03 | Drug Interactions | <a name="DI"></a><h3>DRUG INTERACTIONS</h3> <p>Formal drug interaction studies with ReoPro<sup>®</sup> have not been conducted. ReoPro<sup>®</sup> has been administered to patients with ischemic <a href="/heart_disease/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">heart disease</a> treated concomitantly with a broad range of medications used in the treatment of angina, <a href="/myocardial_infarction/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">myocardial infarction</a> and hypertension. These medications have included heparin, warfarin, beta-adrenergic receptor blockers, calcium channel antagonists, <a href="/angiotensin_converting_enzyme/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">angiotensin converting enzyme</a> inhibitors, intravenous and oral nitrates, and acetylsalicylic acid. Heparin, other anticoagulants, thrombolytics, and antiplatelet agents are associated with an increase in bleeding. Because ReoPro<sup>®</sup> inhibits platelet aggregation, caution should be employed when used with other drugs affecting <a href="/hemostasis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hemostasis</a>.</p> <p>Patients with HACA titers may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.</p> <p>Because of concern about observed synergistic effects on bleeding, ReoPro<sup>®</sup> therapy should be used judiciously in patients who have received systemic thrombolytic therapy. The GUSTO V trial randomized patients with <a href="/acute_myocardial_infarction/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">acute myocardial infarction</a> to treatment with combined ReoPro<sup>®</sup> and half-dose Reteplase, or full-dose Reteplase alone (7). In this trial, the incidence of moderate or severe nonintracranial bleeding was increased in those patients receiving ReoPro<sup>®</sup> and halfdose Reteplase versus those receiving Reteplase alone (4.6% versus 2.3%, respectively). This increase was more pronounced in patients above age 75. Also noted in this age group, but not in other age groups, was a trend towards increased incidence of intracranial hemorrhage in those patients receiving ReoPro<sup>®</sup> and half-dose Reteplase versus those receiving Reteplase alone.</p> <p>If urgent intervention is required for <a href="/refractory/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">refractory</a> symptoms, it is recommended that <a href="/ptca/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">PTCA</a> using ReoPro<sup>®</sup> be attempted first to salvage the situation. Should PTCA and any other appropriate procedures fail, and should the angiographic appearance suggest that the <a href="/etiology/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">etiology</a> is due to <a href="/thrombosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">thrombosis</a>, consideration may be given to the administration of adjunctive thrombolytic therapy via the intracoronary route. Prior to surgical interventions, the bleeding time should be determined by the Ivy method and should be 12 minutes or less (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Restoration of Platelet Function</b>).</p> <p class="credit"><b>REFERENCES</b></p> <p class="credit">7. Data on file.</p> </div> <div id="667441035-5" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-5", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <a name="DI"></a><h3>DRUG INTERACTIONS</h3> <p>Formal drug interaction studies with ReoPro<sup>®</sup> have not been conducted. ReoPro<sup>®</sup> has been administered to patients with ischemic <a href="/heart_disease/definition.htm" ">heart disease</a> treated concomitantly with a broad range of medications used in the treatment of angina, <a href="/myocardial_infarction/definition.htm" ">myocardial infarction</a> and hypertension. These medications have included heparin, warfarin, beta-adrenergic receptor blockers, calcium channel antagonists, <a href="/angiotensin_converting_enzyme/definition.htm" ">angiotensin converting enzyme</a> inhibitors, intravenous and oral nitrates, and acetylsalicylic acid. Heparin, other anticoagulants, thrombolytics, and antiplatelet agents are associated with an increase in bleeding. Because ReoPro<sup>®</sup> inhibits platelet aggregation, caution should be employed when used with other drugs affecting <a href="/hemostasis/definition.htm" ">hemostasis</a>.</p> <p>Patients with HACA titers may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.</p> <p>Because of concern about observed synergistic effects on bleeding, ReoPro<sup>®</sup> therapy should be used judiciously in patients who have received systemic thrombolytic therapy. The GUSTO V trial randomized patients with <a href="/acute_myocardial_infarction/definition.htm" ">acute myocardial infarction</a> to treatment with combined ReoPro<sup>®</sup> and half-dose Reteplase, or full-dose Reteplase alone (7). In this trial, the incidence of moderate or severe nonintracranial bleeding was increased in those patients receiving ReoPro<sup>®</sup> and halfdose Reteplase versus those receiving Reteplase alone (4.6% versus 2.3%, respectively). This increase was more pronounced in patients above age 75. Also noted in this age group, but not in other age groups, was a trend towards increased incidence of intracranial hemorrhage in those patients receiving ReoPro<sup>®</sup> and half-dose Reteplase versus those receiving Reteplase alone.</p> <p>If urgent intervention is required for <a href="/refractory/definition.htm" ">refractory</a> symptoms, it is recommended that <a href="/ptca/definition.htm" ">PTCA</a> using ReoPro<sup>®</sup> be attempted first to salvage the situation. Should PTCA and any other appropriate procedures fail, and should the angiographic appearance suggest that the <a href="/etiology/definition.htm" ">etiology</a> is due to <a href="/thrombosis/definition.htm" ">thrombosis</a>, consideration may be given to the administration of adjunctive thrombolytic therapy via the intracoronary route. Prior to surgical interventions, the bleeding time should be determined by the Ivy method and should be 12 minutes or less (see <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b><b>, Restoration of Platelet Function</b>).</p> <p class="credit"><b>REFERENCES</b></p> <p class="credit">7. Data on file.</p> </div> <div id="667441035-5" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-5", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | 11 | 2023-02-01 17:39:50 | Abciximab (ReoPro) | A | Antineoplastics CDK Inhibitors, Glycoprotein IIb/IIIa Inhibitors | ReoPro | abciximab | ReoPro | John P. Cunha, DO, FACOEP |
| 85 | 2023-02-23 12:07:03 | Warnings & Precautions | <a name="W"></a><h3>WARNINGS</h3> <p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a><h3>PRECAUTIONS</h3> <h4>General</h4> <h5>Requirement For Specialist Facilities</h5> <p><b>ReoPro<sup>®</sup> (abciximab) should only be administered in conjunction with extensive specialist medical and nursing care. In addition, there must be availability of laboratory tests of hematology function and facilities for administration of blood products.</b></p> <h4>Carcinogenesis And Mutagenesis</h4> <p><i>In vitro</i> and <i>in vivo</i> mutagenicity studies have not demonstrated any mutagenic effect. Long-term studies in animals have not been performed to evaluate <a href="/carcinogenic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">carcinogenic</a> potential. See <a href="/reopro-drug.htm#CP"><b>Toxicology</b></a> section.</p> <h4>Hematologic</h4> <p><b>Use of Thrombolytics, Anticoagulants and Other Antiplatelet Agents</b></p> <p>Because ReoPro<sup>®</sup> inhibits platelet aggregation, caution should be employed when used with other drugs affecting hemostasis such as heparin, oral anticoagulants such as warfarin, nonsteroidal anti-inflammatory drugs, thrombolytics, and antiplatelet agents other than acetylsalicylic acid, such as dipyridamole, ticlopidine or low molecular weight dextrans.</p> <p>ReoPro<sup>®</sup> has the potential to increase the risk of bleeding, particularly in the presence of excessive anticoagulation, e.g., from heparin or thrombolytics. Cases of fatal bleeding have been reported (See <a href="/reopro-drug.htm#AR"><b>ADVERSE REACTIONS</b></a><b>, Bleeding</b>).</p> <p>The risks of major bleeds due to ReoPro<sup>®</sup> therapy is increased in patients receiving thrombolytics and should be weighed against the anticipated benefits .</p> <p>Should serious bleeding occur that is not controllable with pressure, the infusion of ReoPro<sup>®</sup> and any concomitant heparin should be stopped.</p> <h5>Bleeding Precautions</h5> <p>Results of the EPILOG clinical trial show that bleeding can be reduced to the level of placebo by the use of low-dose, weight-adjusted heparin regimens, early sheath removal, careful patient and access site management and weight-adjustment of the ReoPro<sup>®</sup> infusion dose.</p> <p>Before infusion of ReoPro<sup>®</sup>, <a href="/platelet_count/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">platelet count</a>, <a href="/prothrombin/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">prothrombin</a> time, activated clotting time (ACT) and activated partial thromboplastin time (APTT) should be measured to identify pre-existing hemostatic abnormalities.</p> <h5>Low-Dose, Weight-Adjusted Heparin</h5> <ol> <li>Percutaneous Coronary Intervention (PCI)</li> <p><i>Heparin Bolus Pre-PTCA</i></p> <p>If a patient's ACT is less than 200 seconds prior to the start of the PTCA procedure, an initial bolus of heparin should be given upon gaining arterial access according to the following algorithm:</p> <p> ACT <150 seconds: administer 70 U/kg<br /> ACT 150-199 seconds: administer 50 U/kg</p> <p>The initial heparin bolus dose should not exceed 7,000 U.</p> <p>ACT should be checked a minimum of 2 minutes after the heparin bolus. If the ACT is < 200 seconds, additional heparin boluses of 20 U/kg may be administered. Should the ACT remain < 200 seconds, additional 20 U/kg boluses are to be given until an ACT ≥ 200 seconds is achieved.</p> <p>Should a situation arise where higher doses of heparin are considered clinically necessary in spite of the possibility of a greater bleeding risk, it is recommended that heparin be carefully titrated using weight-adjusted boluses and that the target ACT not exceed 300 seconds.</p> <p><i>Heparin Bolus during PTCA</i></p> <p>During the PTCA procedure, ACT should be checked every 30 minutes. If ACT is < 200 seconds, additional heparin boluses of 20 U/kg may be administered. Should the ACT remain < 200 seconds, additional 20 U/kg boluses may be given until an ACT ≥ 200 seconds is achieved.</p> <p>ACT should be checked prior to and a minimum of 2 minutes after each heparin bolus.</p> <p><i>Heparin Infusion after PTCA</i></p> <p>Discontinuation of heparin immediately following completion of the procedure, with removal of the arterial sheath within 6 hours, is <i>strongly recommended</i>. In individual patients, if prolonged heparin therapy after PTCA or later sheath removal is used, then an initial infusion rate of 7 U/kg/hr is recommended (see Bleeding Precautions: <a href="/femoral_artery/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Femoral Artery</a> Sheath Removal). In all circumstances, heparin should be discontinued at least 2 hours prior to arterial sheath removal.</p> <li>Stabilization of unstable Angina</li> </ol> <p>Anticoagulation should be initiated with heparin to a target APTT of 60-85 seconds. The heparin infusion should be maintained during the ReoPro<sup>®</sup> infusion. Following <a href="/angioplasty/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">angioplasty</a>, heparin management is outlined above under 1. Percutaneous Coronary Intervention.</p> <h5>Femoral Artery Access Site</h5> <p>ReoPro<sup>®</sup> is associated with an increase in bleeding rate particularly at the site of arterial access for <a href="/femoral/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">femoral</a> artery sheath placement. The following are specific recommendations for access site care:</p> <p><i>Femoral artery Sheath Insertion</i></p> <ul> <li>When appropriate, place only an arterial sheath for <a href="/vascular/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">vascular</a> access (avoid venous sheath placement)</li> <li>Puncture only the <a href="/anterior/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">anterior</a> wall of the artery or vein when establishing vascular access</li> <li>The use of a through and through technique to identify the vascular structure is <i>strongly discouraged</i></li> </ul> <p><i>While Femoral Artery Sheath Is In Place</i></p> <ul> <li>Check sheath insertion site and <a href="/distal/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">distal</a> pulses of affected leg(s) every 15 minutes for 1 hour, then hourly for 6 hours</li> <li>Maintain complete bed rest with head of bed ≤ 30°</li> <li>Maintain affected leg(s) straight via sheet tuck method or soft restraint</li> <li>Medicate for back/groin pain as necessary</li> <li>Educate patient on post-PTCA care via verbal instructions</li> </ul> <p><i>Femoral Artery Sheath Removal</i></p> <ul> <li>Heparin should be discontinued at least 2 hours prior to arterial sheath removal</li> <li>Check APTT or ACT prior to arterial sheath removal: do not remove sheath unless APTT ≤ 50 seconds or ACT ≤ 175 seconds</li> <li>Apply pressure to access site for at least 30 min following sheath removal, using either manual compression or a mechanical device</li> <li>Apply pressure dressing after hemostasis has been achieved</li> </ul> <p><i>After Femoral Artery Sheath Removal</i></p> <ul> <li>Check groin for bleeding/<a href="/hematoma/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hematoma</a> and distal pulses every 15 minutes for the first hour or until stable, then hourly</li> <li>Continue complete bed rest with head of bed ≤ 30° and affected leg(s) straight for 6-8 hours following femoral artery sheath removal, 6-8 hours following discontinuation of ReoPro<sup>®</sup> or 4 hours following discontinuation of heparin, whichever is later</li> <li>Remove pressure dressing prior to ambulation</li> <li>Continue to medicate for discomfort</li> </ul> <p><i>Management of Femoral Access Site Bleeding/Hematoma Formation</i></p> <p>In the event of groin bleeding with or without hematoma formation, the following procedures are recommended:</p> <ul> <li>Lower head of bed to 0°</li> <li>Apply manual pressure/compression device until hemostasis has been achieved</li> <li>Any hematoma should be measured and monitored for enlargement</li> <li>Change pressure dressing as needed</li> <li>If heparin is being given, obtain APTT and adjust heparin as needed</li> <li>Maintain intravenous access if sheath has been removed</li> </ul> <p>If groin bleed continues or the hematoma expands during ReoPro<sup>®</sup> infusion despite the above measures, the ReoPro<sup>®</sup> infusion should be immediately discontinued and the arterial sheath removed according to the guidelines listed above. After sheath removal intravenous access should be maintained until bleeding is controlled.</p> <h5>Potential Bleeding Sites</h5> <p>Careful attention should be paid to all potential bleeding sites, including arterial and venous puncture sites, <a href="/catheter/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">catheter</a> insertion sites, cutdown sites, and needle puncture sites.</p> <h5>Retroperitoneal Bleeding</h5> <p>ReoPro<sup>®</sup> is associated with an increased risk of retroperitoneal bleeding in association with femoral vascular puncture. The use of venous sheaths should be minimized and only the anterior wall of the artery or vein should be punctured when establishing vascular access.</p> <h5>Pulmonary (Mostly Alveolar) Hemorrhage</h5> <p>ReoPro<sup>®</sup> has rarely been associated with pulmonary (mostly <a href="/alveolar/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">alveolar</a>) hemorrhage (6). This can present with any or all of the following in close association with ReoPro<sup>®</sup> administration: <a href="/hypoxemia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypoxemia</a>, alveolar infiltrates on chest <a href="/x-ray/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">x-ray</a>, <a href="/hemoptysis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hemoptysis</a>, or an unexplained drop in hemoglobin. If confirmed, ReoPro<sup>®</sup> and all <a href="/anticoagulant/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">anticoagulant</a> and other antiplatelet drugs should immediately be discontinued.</p> <h5>GI Bleeding Prophylaxis</h5> <p>In order to prevent spontaneous <a href="/gi/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">GI</a> bleeding it is recommended that patients are pretreated with H<sub>2</sub>-<a href="/histamine/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">histamine</a> receptor antagonists or liquid antacids. <a href="/antiemetics/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Antiemetics</a> should be given as needed to prevent vomiting.</p> <h5>General Nursing Care</h5> <p>Unnecessary arterial and venous punctures, <a href="/intramuscular_im/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">intramuscular</a> injections, routine use of urinary catheters, nasotracheal <a href="/intubation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">intubation</a>, <a href="/nasogastric/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">nasogastric</a> <a href="/tubes/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">tubes</a> and automatic blood pressure cuffs should be avoided. When obtaining intravenous access, non-compressible sites (e.g., <a href="/subclavian/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">subclavian</a> or <a href="/jugular/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">jugular</a> veins) should be avoided. Saline or heparin locks should be considered for blood drawing. Vascular puncture sites should be documented and monitored. Gentle care should be provided when removing dressings.</p> <h5>Patient Monitoring</h5> <p>Before administration of ReoPro<sup>®</sup>, platelet count, ACT, prothrombin time (PT) and APTT should be measured to identify pre-existing <a href="/coagulation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">coagulation</a> abnormalities. Hemoglobin and <a href="/hematocrit/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hematocrit</a> measurements should be obtained prior to the ReoPro<sup>®</sup> administration, at 12 hours following the ReoPro<sup>®</sup> bolus injection, and again at 24 hours following the bolus injection. Twelve lead electrocardiograms (<a href="/ecg/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ECG</a>) should be obtained prior to the bolus injection of ReoPro<sup>®</sup>, and repeated once the patient has returned to the hospital ward from the catheterization laboratory, and at 24 hours after the bolus injection of ReoPro<sup>®</sup>. Vital signs (including blood pressure and <a href="/pulse/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pulse</a>) should be obtained hourly for the first 4 hours following the ReoPro<sup>®</sup> bolus injection, and then at 6, 12, 18 and 24 hours following the ReoPro<sup>®</sup> bolus injection.</p> <p><i>Thrombocytopenia</i></p> <p>To reduce the possibility of thrombocytopenia, platelet counts should be monitored prior to treatment, 2 to 4 hours following the bolus dose of ReoPro<sup>®</sup>, at 24 hours, and periodically for 2 weeks. If a patient experiences an acute platelet decrease, (e.g., a platelet decrease to less than 100,000 cells/μL and a decrease of at least 25% from pretreatment value), additional platelet counts should be determined. These platelet counts should be drawn in three separate tubes containing ethylenediaminetetraacetic acid (<a href="/edta/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">EDTA</a>), citrate and heparin, respectively, to exclude pseudothrombocytopenia due to <i>in vitro</i> anticoagulant interaction. If true thrombocytopenia is verified, ReoPro<sup>®</sup> should be immediately discontinued and the condition appropriately monitored and treated. A daily platelet count should be obtained until it returns to normal. If a patient's platelet count drops to 60,000 cells/μL, heparin and acetylsalicylic acid should be discontinued. If a patient's platelet count drops below 50,000 cells/μL, platelets should be transfused.</p> <p>In a registry study of ReoPro<sup>®</sup> re-administration, a history of thrombocytopenia associated with prior use of ReoPro<sup>®</sup> was predictive of an increased risk of recurrent thrombocytopenia. Readministration within 30 days was associated with an increased incidence and severity of thrombocytopenia, as was a positive human anti-chimeric antibody (HACA) test at baseline, compared to the rates seen in studies with first administration.</p> <p><i>Restoration of Platelet Function</i></p> <p>Transfusion of <a href="/donor/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">donor</a> platelets has been shown to restore platelet function following ReoPro<sup>®</sup> administration in animal studies and transfusions of fresh random donor platelets have been given empirically to restore platelet function in humans. In the event of serious uncontrolled bleeding or the need for surgery, a bleeding time should be determined. If the bleeding time is greater than 12 minutes, 10 units of platelets may be given. ReoPro<sup>®</sup> may be displaced from <a href="/endogenous/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">endogenous</a> platelet receptors and subsequently bind to platelets which have been transfused. Nevertheless, a single transfusion may be sufficient to reduce receptor blockade to 60% to 70% at which level platelet function is restored. Repeat platelet transfusions may be required to maintain the bleeding time at or below 12 minutes.</p> <h5>Immune</h5> <p><i>Re-administration</i></p> <p>Administration of ReoPro<sup>®</sup> may result in human anti-chimeric antibody (HACA) formation (see <a href="/reopro-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>) that could potentially cause allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia or diminished benefit upon re-administration of ReoPro<sup>®</sup>. Re-administration of ReoPro<sup>®</sup> to 29 patients known to be HACA-negative has not led to any change in ReoPro<sup>®</sup> pharmacokinetics or to any reduction in antiplatelet potency.</p> <p>Re-administration of ReoPro<sup>®</sup> to patients undergoing PCI was assessed in a registry that included 1342 treatments in 1286 patients. Most patients were receiving their second ReoPro<sup>®</sup> exposure; 15% were receiving the third or subsequent exposure. The overall rate of HACA positivity prior to the re-administration was 6% and increased to 27% post-re-administration. There were no reports of serious allergic reactions or anaphylaxis. Thrombocytopenia was observed at higher rates in the re-administration study than in the phase 3 studies of first-time administration (see <b>WARNINGS AND PRECAUTIONS</b>, <b>Thrombocytopenia</b> and <a href="/reopro-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>: <b>Thrombocytopenia</b>), suggesting that re-administration may be associated with an increased incidence and severity of thrombocytopenia.</p> <p><i>Hypersensitivity Reactions</i></p> <p>Anaphylactic reactions have occurred very rarely in patients treated with ReoPro<sup>®</sup>. Epinephrine, antihistamines and corticosteroids should be available for immediate use, in addition to equipment for <a href="/resuscitation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">resuscitation</a>, in the event of a hypersensitivity reaction. Immediately, upon occurrence of anaphylaxis, administration of ReoPro<sup>®</sup> should be stopped and appropriate resuscitative measures should be initiated.</p> <h5>Respiratory</h5> <p>Pulmonary hemorrhage associated with ReoPro<sup>®</sup> use, although a very rare occurrence, can be a serious life-threatening complication that can be misdiagnosed and result in the patient not receiving timely treatment. Respiratory symptoms should be monitored closely for early detection of serious pulmonary hemorrhage in patients receiving ReoPro<sup>®</sup>.</p> <h4>Special Populations</h4> <h5>Pregnant Women</h5> <p>Animal reproduction studies have not been conducted with ReoPro<sup>®</sup> and the effects on fertility in male or female animals are unknown. It is also not known whether ReoPro<sup>®</sup> can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ReoPro<sup>®</sup> should be given to a pregnant woman only if clearly needed.</p> <h5>Nursing Women</h5> <p>It is not known if this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ReoPro<sup>®</sup> is administered to a nursing woman.</p> <h5>Pediatrics (< 18 Years Of Age)</h5> <p>Safety and effectiveness of ReoPro<sup>®</sup> in children below the age of 18 have not been established.</p> <h5>Geriatrics (> 65 Years Of Age)</h5> <p>There is insufficient clinical experience to determine whether patients aged 75 years old or greater respond differently to ReoPro<sup>®</sup> than younger patients.</p> <p class="credit"><b>REFERENCES</b></p> <p class="credit">6. Kalra S, <a href="/bell/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Bell</a> MR, Rihal CS. Alveolar Hemorrhage as a Complication of Treatment with Abciximab. <i>Chest</i> 2001;120:126-131.</p> </div> <a class="mediaPrmo quiz" href="/quiz_heart_disease/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/heart-disease/s7.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">In the U.S., 1 in every 4 deaths is caused by heart disease.</span> <span class="btn">See Answer</span> </a> </div> </div> | <a name="W"></a><h3>WARNINGS</h3> <p>Included as part of the <b>"PRECAUTIONS"</b> Section</p> <a name="P"></a><h3>PRECAUTIONS</h3> <h4>General</h4> <h5>Requirement For Specialist Facilities</h5> <p><b>ReoPro<sup>®</sup> (abciximab) should only be administered in conjunction with extensive specialist medical and nursing care. In addition, there must be availability of laboratory tests of hematology function and facilities for administration of blood products.</b></p> <h4>Carcinogenesis And Mutagenesis</h4> <p><i>In vitro</i> and <i>in vivo</i> mutagenicity studies have not demonstrated any mutagenic effect. Long-term studies in animals have not been performed to evaluate <a href="/carcinogenic/definition.htm" ">carcinogenic</a> potential. See <a href="/reopro-drug.htm#CP"><b>Toxicology</b></a> section.</p> <h4>Hematologic</h4> <p><b>Use of Thrombolytics, Anticoagulants and Other Antiplatelet Agents</b></p> <p>Because ReoPro<sup>®</sup> inhibits platelet aggregation, caution should be employed when used with other drugs affecting hemostasis such as heparin, oral anticoagulants such as warfarin, nonsteroidal anti-inflammatory drugs, thrombolytics, and antiplatelet agents other than acetylsalicylic acid, such as dipyridamole, ticlopidine or low molecular weight dextrans.</p> <p>ReoPro<sup>®</sup> has the potential to increase the risk of bleeding, particularly in the presence of excessive anticoagulation, e.g., from heparin or thrombolytics. Cases of fatal bleeding have been reported (See <a href="/reopro-drug.htm#AR"><b>ADVERSE REACTIONS</b></a><b>, Bleeding</b>).</p> <p>The risks of major bleeds due to ReoPro<sup>®</sup> therapy is increased in patients receiving thrombolytics and should be weighed against the anticipated benefits .</p> <p>Should serious bleeding occur that is not controllable with pressure, the infusion of ReoPro<sup>®</sup> and any concomitant heparin should be stopped.</p> <h5>Bleeding Precautions</h5> <p>Results of the EPILOG clinical trial show that bleeding can be reduced to the level of placebo by the use of low-dose, weight-adjusted heparin regimens, early sheath removal, careful patient and access site management and weight-adjustment of the ReoPro<sup>®</sup> infusion dose.</p> <p>Before infusion of ReoPro<sup>®</sup>, <a href="/platelet_count/definition.htm" ">platelet count</a>, <a href="/prothrombin/definition.htm" ">prothrombin</a> time, activated clotting time (ACT) and activated partial thromboplastin time (APTT) should be measured to identify pre-existing hemostatic abnormalities.</p> <h5>Low-Dose, Weight-Adjusted Heparin</h5> <ol> <li>Percutaneous Coronary Intervention (PCI)</li> <p><i>Heparin Bolus Pre-PTCA</i></p> <p>If a patient's ACT is less than 200 seconds prior to the start of the PTCA procedure, an initial bolus of heparin should be given upon gaining arterial access according to the following algorithm:</p> <p> ACT <150 seconds: administer 70 U/kg<br /> ACT 150-199 seconds: administer 50 U/kg</p> <p>The initial heparin bolus dose should not exceed 7,000 U.</p> <p>ACT should be checked a minimum of 2 minutes after the heparin bolus. If the ACT is < 200 seconds, additional heparin boluses of 20 U/kg may be administered. Should the ACT remain < 200 seconds, additional 20 U/kg boluses are to be given until an ACT ≥ 200 seconds is achieved.</p> <p>Should a situation arise where higher doses of heparin are considered clinically necessary in spite of the possibility of a greater bleeding risk, it is recommended that heparin be carefully titrated using weight-adjusted boluses and that the target ACT not exceed 300 seconds.</p> <p><i>Heparin Bolus during PTCA</i></p> <p>During the PTCA procedure, ACT should be checked every 30 minutes. If ACT is < 200 seconds, additional heparin boluses of 20 U/kg may be administered. Should the ACT remain < 200 seconds, additional 20 U/kg boluses may be given until an ACT ≥ 200 seconds is achieved.</p> <p>ACT should be checked prior to and a minimum of 2 minutes after each heparin bolus.</p> <p><i>Heparin Infusion after PTCA</i></p> <p>Discontinuation of heparin immediately following completion of the procedure, with removal of the arterial sheath within 6 hours, is <i>strongly recommended</i>. In individual patients, if prolonged heparin therapy after PTCA or later sheath removal is used, then an initial infusion rate of 7 U/kg/hr is recommended (see Bleeding Precautions: <a href="/femoral_artery/definition.htm" ">Femoral Artery</a> Sheath Removal). In all circumstances, heparin should be discontinued at least 2 hours prior to arterial sheath removal.</p> <li>Stabilization of unstable Angina</li> </ol> <p>Anticoagulation should be initiated with heparin to a target APTT of 60-85 seconds. The heparin infusion should be maintained during the ReoPro<sup>®</sup> infusion. Following <a href="/angioplasty/definition.htm" ">angioplasty</a>, heparin management is outlined above under 1. Percutaneous Coronary Intervention.</p> <h5>Femoral Artery Access Site</h5> <p>ReoPro<sup>®</sup> is associated with an increase in bleeding rate particularly at the site of arterial access for <a href="/femoral/definition.htm" ">femoral</a> artery sheath placement. The following are specific recommendations for access site care:</p> <p><i>Femoral artery Sheath Insertion</i></p> <ul> <li>When appropriate, place only an arterial sheath for <a href="/vascular/definition.htm" ">vascular</a> access (avoid venous sheath placement)</li> <li>Puncture only the <a href="/anterior/definition.htm" ">anterior</a> wall of the artery or vein when establishing vascular access</li> <li>The use of a through and through technique to identify the vascular structure is <i>strongly discouraged</i></li> </ul> <p><i>While Femoral Artery Sheath Is In Place</i></p> <ul> <li>Check sheath insertion site and <a href="/distal/definition.htm" ">distal</a> pulses of affected leg(s) every 15 minutes for 1 hour, then hourly for 6 hours</li> <li>Maintain complete bed rest with head of bed ≤ 30°</li> <li>Maintain affected leg(s) straight via sheet tuck method or soft restraint</li> <li>Medicate for back/groin pain as necessary</li> <li>Educate patient on post-PTCA care via verbal instructions</li> </ul> <p><i>Femoral Artery Sheath Removal</i></p> <ul> <li>Heparin should be discontinued at least 2 hours prior to arterial sheath removal</li> <li>Check APTT or ACT prior to arterial sheath removal: do not remove sheath unless APTT ≤ 50 seconds or ACT ≤ 175 seconds</li> <li>Apply pressure to access site for at least 30 min following sheath removal, using either manual compression or a mechanical device</li> <li>Apply pressure dressing after hemostasis has been achieved</li> </ul> <p><i>After Femoral Artery Sheath Removal</i></p> <ul> <li>Check groin for bleeding/<a href="/hematoma/definition.htm" ">hematoma</a> and distal pulses every 15 minutes for the first hour or until stable, then hourly</li> <li>Continue complete bed rest with head of bed ≤ 30° and affected leg(s) straight for 6-8 hours following femoral artery sheath removal, 6-8 hours following discontinuation of ReoPro<sup>®</sup> or 4 hours following discontinuation of heparin, whichever is later</li> <li>Remove pressure dressing prior to ambulation</li> <li>Continue to medicate for discomfort</li> </ul> <p><i>Management of Femoral Access Site Bleeding/Hematoma Formation</i></p> <p>In the event of groin bleeding with or without hematoma formation, the following procedures are recommended:</p> <ul> <li>Lower head of bed to 0°</li> <li>Apply manual pressure/compression device until hemostasis has been achieved</li> <li>Any hematoma should be measured and monitored for enlargement</li> <li>Change pressure dressing as needed</li> <li>If heparin is being given, obtain APTT and adjust heparin as needed</li> <li>Maintain intravenous access if sheath has been removed</li> </ul> <p>If groin bleed continues or the hematoma expands during ReoPro<sup>®</sup> infusion despite the above measures, the ReoPro<sup>®</sup> infusion should be immediately discontinued and the arterial sheath removed according to the guidelines listed above. After sheath removal intravenous access should be maintained until bleeding is controlled.</p> <h5>Potential Bleeding Sites</h5> <p>Careful attention should be paid to all potential bleeding sites, including arterial and venous puncture sites, <a href="/catheter/definition.htm" ">catheter</a> insertion sites, cutdown sites, and needle puncture sites.</p> <h5>Retroperitoneal Bleeding</h5> <p>ReoPro<sup>®</sup> is associated with an increased risk of retroperitoneal bleeding in association with femoral vascular puncture. The use of venous sheaths should be minimized and only the anterior wall of the artery or vein should be punctured when establishing vascular access.</p> <h5>Pulmonary (Mostly Alveolar) Hemorrhage</h5> <p>ReoPro<sup>®</sup> has rarely been associated with pulmonary (mostly <a href="/alveolar/definition.htm" ">alveolar</a>) hemorrhage (6). This can present with any or all of the following in close association with ReoPro<sup>®</sup> administration: <a href="/hypoxemia/definition.htm" ">hypoxemia</a>, alveolar infiltrates on chest <a href="/x-ray/definition.htm" ">x-ray</a>, <a href="/hemoptysis/definition.htm" ">hemoptysis</a>, or an unexplained drop in hemoglobin. If confirmed, ReoPro<sup>®</sup> and all <a href="/anticoagulant/definition.htm" ">anticoagulant</a> and other antiplatelet drugs should immediately be discontinued.</p> <h5>GI Bleeding Prophylaxis</h5> <p>In order to prevent spontaneous <a href="/gi/definition.htm" ">GI</a> bleeding it is recommended that patients are pretreated with H<sub>2</sub>-<a href="/histamine/definition.htm" ">histamine</a> receptor antagonists or liquid antacids. <a href="/antiemetics/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Antiemetics</a> should be given as needed to prevent vomiting.</p> <h5>General Nursing Care</h5> <p>Unnecessary arterial and venous punctures, <a href="/intramuscular_im/definition.htm" ">intramuscular</a> injections, routine use of urinary catheters, nasotracheal <a href="/intubation/definition.htm" ">intubation</a>, <a href="/nasogastric/definition.htm" ">nasogastric</a> <a href="/tubes/definition.htm" ">tubes</a> and automatic blood pressure cuffs should be avoided. When obtaining intravenous access, non-compressible sites (e.g., <a href="/subclavian/definition.htm" ">subclavian</a> or <a href="/jugular/definition.htm" ">jugular</a> veins) should be avoided. Saline or heparin locks should be considered for blood drawing. Vascular puncture sites should be documented and monitored. Gentle care should be provided when removing dressings.</p> <h5>Patient Monitoring</h5> <p>Before administration of ReoPro<sup>®</sup>, platelet count, ACT, prothrombin time (PT) and APTT should be measured to identify pre-existing <a href="/coagulation/definition.htm" ">coagulation</a> abnormalities. Hemoglobin and <a href="/hematocrit/definition.htm" ">hematocrit</a> measurements should be obtained prior to the ReoPro<sup>®</sup> administration, at 12 hours following the ReoPro<sup>®</sup> bolus injection, and again at 24 hours following the bolus injection. Twelve lead electrocardiograms (<a href="/ecg/definition.htm" ">ECG</a>) should be obtained prior to the bolus injection of ReoPro<sup>®</sup>, and repeated once the patient has returned to the hospital ward from the catheterization laboratory, and at 24 hours after the bolus injection of ReoPro<sup>®</sup>. Vital signs (including blood pressure and <a href="/pulse/definition.htm" ">pulse</a>) should be obtained hourly for the first 4 hours following the ReoPro<sup>®</sup> bolus injection, and then at 6, 12, 18 and 24 hours following the ReoPro<sup>®</sup> bolus injection.</p> <p><i>Thrombocytopenia</i></p> <p>To reduce the possibility of thrombocytopenia, platelet counts should be monitored prior to treatment, 2 to 4 hours following the bolus dose of ReoPro<sup>®</sup>, at 24 hours, and periodically for 2 weeks. If a patient experiences an acute platelet decrease, (e.g., a platelet decrease to less than 100,000 cells/μL and a decrease of at least 25% from pretreatment value), additional platelet counts should be determined. These platelet counts should be drawn in three separate tubes containing ethylenediaminetetraacetic acid (<a href="/edta/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">EDTA</a>), citrate and heparin, respectively, to exclude pseudothrombocytopenia due to <i>in vitro</i> anticoagulant interaction. If true thrombocytopenia is verified, ReoPro<sup>®</sup> should be immediately discontinued and the condition appropriately monitored and treated. A daily platelet count should be obtained until it returns to normal. If a patient's platelet count drops to 60,000 cells/μL, heparin and acetylsalicylic acid should be discontinued. If a patient's platelet count drops below 50,000 cells/μL, platelets should be transfused.</p> <p>In a registry study of ReoPro<sup>®</sup> re-administration, a history of thrombocytopenia associated with prior use of ReoPro<sup>®</sup> was predictive of an increased risk of recurrent thrombocytopenia. Readministration within 30 days was associated with an increased incidence and severity of thrombocytopenia, as was a positive human anti-chimeric antibody (HACA) test at baseline, compared to the rates seen in studies with first administration.</p> <p><i>Restoration of Platelet Function</i></p> <p>Transfusion of <a href="/donor/definition.htm" ">donor</a> platelets has been shown to restore platelet function following ReoPro<sup>®</sup> administration in animal studies and transfusions of fresh random donor platelets have been given empirically to restore platelet function in humans. In the event of serious uncontrolled bleeding or the need for surgery, a bleeding time should be determined. If the bleeding time is greater than 12 minutes, 10 units of platelets may be given. ReoPro<sup>®</sup> may be displaced from <a href="/endogenous/definition.htm" ">endogenous</a> platelet receptors and subsequently bind to platelets which have been transfused. Nevertheless, a single transfusion may be sufficient to reduce receptor blockade to 60% to 70% at which level platelet function is restored. Repeat platelet transfusions may be required to maintain the bleeding time at or below 12 minutes.</p> <h5>Immune</h5> <p><i>Re-administration</i></p> <p>Administration of ReoPro<sup>®</sup> may result in human anti-chimeric antibody (HACA) formation (see <a href="/reopro-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>) that could potentially cause allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia or diminished benefit upon re-administration of ReoPro<sup>®</sup>. Re-administration of ReoPro<sup>®</sup> to 29 patients known to be HACA-negative has not led to any change in ReoPro<sup>®</sup> pharmacokinetics or to any reduction in antiplatelet potency.</p> <p>Re-administration of ReoPro<sup>®</sup> to patients undergoing PCI was assessed in a registry that included 1342 treatments in 1286 patients. Most patients were receiving their second ReoPro<sup>®</sup> exposure; 15% were receiving the third or subsequent exposure. The overall rate of HACA positivity prior to the re-administration was 6% and increased to 27% post-re-administration. There were no reports of serious allergic reactions or anaphylaxis. Thrombocytopenia was observed at higher rates in the re-administration study than in the phase 3 studies of first-time administration (see <b>WARNINGS AND PRECAUTIONS</b>, <b>Thrombocytopenia</b> and <a href="/reopro-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>: <b>Thrombocytopenia</b>), suggesting that re-administration may be associated with an increased incidence and severity of thrombocytopenia.</p> <p><i>Hypersensitivity Reactions</i></p> <p>Anaphylactic reactions have occurred very rarely in patients treated with ReoPro<sup>®</sup>. Epinephrine, antihistamines and corticosteroids should be available for immediate use, in addition to equipment for <a href="/resuscitation/definition.htm" ">resuscitation</a>, in the event of a hypersensitivity reaction. Immediately, upon occurrence of anaphylaxis, administration of ReoPro<sup>®</sup> should be stopped and appropriate resuscitative measures should be initiated.</p> <h5>Respiratory</h5> <p>Pulmonary hemorrhage associated with ReoPro<sup>®</sup> use, although a very rare occurrence, can be a serious life-threatening complication that can be misdiagnosed and result in the patient not receiving timely treatment. Respiratory symptoms should be monitored closely for early detection of serious pulmonary hemorrhage in patients receiving ReoPro<sup>®</sup>.</p> <h4>Special Populations</h4> <h5>Pregnant Women</h5> <p>Animal reproduction studies have not been conducted with ReoPro<sup>®</sup> and the effects on fertility in male or female animals are unknown. It is also not known whether ReoPro<sup>®</sup> can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ReoPro<sup>®</sup> should be given to a pregnant woman only if clearly needed.</p> <h5>Nursing Women</h5> <p>It is not known if this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ReoPro<sup>®</sup> is administered to a nursing woman.</p> <h5>Pediatrics (< 18 Years Of Age)</h5> <p>Safety and effectiveness of ReoPro<sup>®</sup> in children below the age of 18 have not been established.</p> <h5>Geriatrics (> 65 Years Of Age)</h5> <p>There is insufficient clinical experience to determine whether patients aged 75 years old or greater respond differently to ReoPro<sup>®</sup> than younger patients.</p> <p class="credit"><b>REFERENCES</b></p> <p class="credit">6. Kalra S, <a href="/bell/definition.htm" ">Bell</a> MR, Rihal CS. Alveolar Hemorrhage as a Complication of Treatment with Abciximab. <i>Chest</i> 2001;120:126-131.</p> </div> <a class="mediaPrmo quiz" href="/quiz_heart_disease/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/heart-disease/s7.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">In the U.S., 1 in every 4 deaths is caused by heart disease.</span> <span class="btn">See Answer</span> </a> </div> </div> | 11 | 2023-02-01 17:39:50 | Abciximab (ReoPro) | A | Antineoplastics CDK Inhibitors, Glycoprotein IIb/IIIa Inhibitors | ReoPro | abciximab | ReoPro | John P. Cunha, DO, FACOEP |
| 86 | 2023-02-23 12:07:03 | Overdose & Contraindications | <a name="OD"></a><h3>OVERDOSE</h3> <p>There has been no experience of overdosage in human clinical trials.</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3> <p>Because Abciximab may increase the risk of bleeding, Abciximab is contraindicated in the following clinical situations:</p> <ul> <li>Active <a href="/script/main/art.asp?articlekey=101070" rel="dict" onclick="wmdTrack('embd-lnk');">internal bleeding</a></li> <li>Recent (within six weeks) <a href="/script/main/art.asp?articlekey=3555" rel="dict" onclick="wmdTrack('embd-lnk');">gastrointestinal</a> (GI) or <a href="/script/main/art.asp?articlekey=3579" rel="dict" onclick="wmdTrack('embd-lnk');">genitourinary</a> (GU) bleeding of clinical significance.</li> <li>History of <a href="/script/main/art.asp?articlekey=2677" rel="dict" onclick="wmdTrack('embd-lnk');">cerebrovascular accident</a> (<a href="/cva/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">CVA</a>) within two years, or CVA with a significant <a href="/script/main/art.asp?articlekey=5321" rel="dict" onclick="wmdTrack('embd-lnk');">residual</a> <a href="/script/main/art.asp?articlekey=11748" rel="dict" onclick="wmdTrack('embd-lnk');">neurological</a> deficit</li> <li>Bleeding <a href="/script/main/art.asp?articlekey=2988" rel="dict" onclick="wmdTrack('embd-lnk');">diathesis</a></li> <li>Administration of oral anticoagulants within seven days unless <a href="/script/main/art.asp?articlekey=8386" rel="dict" onclick="wmdTrack('embd-lnk');">prothrombin time</a> is ≤ 1.2 times control</li> <li><a href="/script/main/art.asp?articlekey=97574" rel="dict" onclick="wmdTrack('embd-lnk');">Thrombocytopenia</a> ( < 100,000 cells/μL)</li> <li>Recent (within six weeks) major surgery or <a href="/script/main/art.asp?articlekey=8171" rel="dict" onclick="wmdTrack('embd-lnk');">trauma</a></li> <li><a href="/script/main/art.asp?articlekey=13759" rel="dict" onclick="wmdTrack('embd-lnk');">Intracranial</a> <a href="/script/main/art.asp?articlekey=4526" rel="dict" onclick="wmdTrack('embd-lnk');">neoplasm</a>, <a href="/script/main/art.asp?articlekey=9686" rel="dict" onclick="wmdTrack('embd-lnk');">arteriovenous malformation</a>, or <a href="/script/main/art.asp?articlekey=6141" rel="dict" onclick="wmdTrack('embd-lnk');">aneurysm</a></li> <li>Severe uncontrolled <a href="/script/main/art.asp?articlekey=3846" rel="dict" onclick="wmdTrack('embd-lnk');">hypertension</a></li> <li>Presumed or documented history of <a href="/script/main/art.asp?articlekey=7075" rel="dict" onclick="wmdTrack('embd-lnk');">vasculitis</a></li> <li>Use of intravenous dextran before PCI, or intent to use it during an intervention</li> </ul> <p>Abciximab is also contraindicated in patients with known hypersensitivity to any component of this product or to murine proteins.</p> </div> </div> </div> | <a name="OD"></a><h3>OVERDOSE</h3> <p>There has been no experience of overdosage in human clinical trials.</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3> <p>Because Abciximab may increase the risk of bleeding, Abciximab is contraindicated in the following clinical situations:</p> <ul> <li>Active <a href="/script/main/art.asp?articlekey=101070" ">internal bleeding</a></li> <li>Recent (within six weeks) <a href="/script/main/art.asp?articlekey=3555" ">gastrointestinal</a> (GI) or <a href="/script/main/art.asp?articlekey=3579" ">genitourinary</a> (GU) bleeding of clinical significance.</li> <li>History of <a href="/script/main/art.asp?articlekey=2677" ">cerebrovascular accident</a> (<a href="/cva/definition.htm" ">CVA</a>) within two years, or CVA with a significant <a href="/script/main/art.asp?articlekey=5321" ">residual</a> <a href="/script/main/art.asp?articlekey=11748" ">neurological</a> deficit</li> <li>Bleeding <a href="/script/main/art.asp?articlekey=2988" ">diathesis</a></li> <li>Administration of oral anticoagulants within seven days unless <a href="/script/main/art.asp?articlekey=8386" ">prothrombin time</a> is ≤ 1.2 times control</li> <li><a href="/script/main/art.asp?articlekey=97574" ">Thrombocytopenia</a> ( < 100,000 cells/μL)</li> <li>Recent (within six weeks) major surgery or <a href="/script/main/art.asp?articlekey=8171" ">trauma</a></li> <li><a href="/script/main/art.asp?articlekey=13759" ">Intracranial</a> <a href="/script/main/art.asp?articlekey=4526" ">neoplasm</a>, <a href="/script/main/art.asp?articlekey=9686" ">arteriovenous malformation</a>, or <a href="/script/main/art.asp?articlekey=6141" ">aneurysm</a></li> <li>Severe uncontrolled <a href="/script/main/art.asp?articlekey=3846" ">hypertension</a></li> <li>Presumed or documented history of <a href="/script/main/art.asp?articlekey=7075" ">vasculitis</a></li> <li>Use of intravenous dextran before PCI, or intent to use it during an intervention</li> </ul> <p>Abciximab is also contraindicated in patients with known hypersensitivity to any component of this product or to murine proteins.</p> </div> </div> </div> | 11 | 2023-02-01 17:39:50 | Abciximab (ReoPro) | A | Antineoplastics CDK Inhibitors, Glycoprotein IIb/IIIa Inhibitors | ReoPro | abciximab | ReoPro | John P. Cunha, DO, FACOEP |
| 87 | 2023-02-23 12:07:03 | Clinical Pharmacology | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism Of Action</h4> <p>ReoPro<sup>®</sup> (abciximab) is the Fab fragment of the chimeric monoclonal antibody 7E3. It selectively binds to the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor located on the surface of human platelets. ReoPro<sup>®</sup> inhibits platelet aggregation by preventing the binding of <a href="/fibrinogen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">fibrinogen</a>, von Willebrand factor and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. ReoPro<sup>®</sup> also binds with similar <a href="/affinity/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">affinity</a> to the vitronectin (α<sub>ν</sub>β<sub>3</sub>) receptor found on platelets and vessel wall endothelial and smooth muscle cells. The vitronectin receptor mediates pro-coagulant properties of platelets and <a href="/proliferative/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">proliferative</a> properties of vascular endothelial cells and smooth muscle cells.</p> <h4>Pharmacodynamics</h4> <p>Intravenous administration in humans of single bolus doses of ReoPro<sup>®</sup> from 0.15 mg/kg to 0.30 mg/kg resulted in a dose-dependent blockade of platelet GPIIb/IIIa receptors and produced dosedependent inhibition of platelet function as measured by <i>ex vivo</i> platelet aggregation in response to ADP or by prolongation of bleeding time. At the two highest doses (0.25 and 0.30 mg/kg) at 2 hours post injection, over 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20 μM ADP was almost abolished. The median bleeding time increased to over 30 minutes at both doses compared with a baseline value of approximately 5 minutes.</p> <p>Intravenous administration in humans of a single bolus dose of 0.25 mg/kg followed by a continuous infusion of 10 μg/min for periods of 12 to 96 hours produced sustained high-grade platelet inhibition (<i>ex vivo</i> platelet aggregation in response to 5 or 20 μM ADP less than 20% of baseline and bleeding time greater than 30 minutes) for the duration of the infusion in most patients. Equivalent results were obtained when a weight adjusted infusion dose (0.125 μg/kg/min to a maximum of 10 μg/min) was used in patients up to 80 kg. Results in patients who received the 0.25 mg/kg bolus followed by a 5 μg/min infusion for 24 hours showed a similar initial inhibition of platelet aggregation, but the response was not maintained throughout the infusion period. Following cessation of the infusion, platelet function typically returned to baseline values over a period of 24 to 48 hours.</p> <h4>Pharmacokinetics</h4> <p>Following intravenous administration of ReoPro<sup>®</sup>, free plasma concentrations decreased very rapidly with an initial half-life of several minutes and a second phase half-life of about 30 minutes. This disappearance from the plasma is probably related to rapid binding to the platelet GPIIb/IIIa receptors (approximately 80,000 to 100,000 GPIIb/IIIa receptors on the surface of each platelet).</p> <p>After a single bolus injection of ReoPro<sup>®</sup>, the inhibitory effects on platelet function, as measured by inhibition of platelet aggregation, were evident within 10 minutes. The antibody remains in the <a href="/circulation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">circulation</a> for 15 days or more in a platelet-bound state. Its disappearance follows a monoexponential time course.</p> <p>Intravenous administration of a 0.25 mg/kg bolus dose of ReoPro<sup>®</sup> followed by continuous infusion of 5 or 10 μg/min for periods of 12 to 96 hours produced relatively constant total plasma concentrations from the first time point measured (usually 2 hours) for all infusion rates and durations. However, although the total plasma concentrations resulting from the 5 μg/min infusion were only slightly lower than those from the 10 μg/min infusion, the 5 μg/min infusion was ineffective in inhibiting platelet function over the whole infusion period. At the termination of the infusion period, plasma concentrations fell rapidly for approximately 6 hours, then declined at a much slower rate.</p> <a name="CS"></a><h4>Clinical Studies</h4> <h5>Study Demographics And Trial Design</h5> <p align="center"><b>Table 3: Summary of patient demographics for clinical trials in specific indication</b><br /> <center> <table class="blacktbl" width="650" cellspacing="0"> <tr> <td class="EmphTd" width="12%">Study #</td> <td class="EmphTd" width="24%">Trial design</td> <td class="EmphTd" width="25%">Dosage, route of administration and duration</td> <td class="EmphTd" width="12%">Study subjects<br /> (n=number)</td> <td class="EmphTd" width="15%">Mean age<br /> (Range)</td> <td class="EmphTd" width="12%">Gender<br /> (% Female)</td> </tr> <tr> <td rowspan="4">EPIC<br /> Trial</td> <td rowspan="4">Multicenter, doubleblind, placebocontrolled</td> <td>ReoPro<sup>®</sup> bolus (0.25 mg/kg)/ ReoPro<sup>®</sup> infusion (10 μg/min) for 12 hours</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>Bolus + Infusion</td> <td align="center">708</td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td>Bolus</td> <td align="center">695</td> <td align="center">60.0±10.6 <br /> (26, 83)</td> <td align="center">27.9%</td> </tr> <tr> <td>Placebo</td> <td align="center">696</td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td rowspan="5">EPILOG<br /> Trial</td> <td rowspan="5">Randomized, doubleblind, multicenter, placebo-controlled</td> <td>ReoPro<sup>®</sup> bolus (0.25 mg/kg)/ ReoPro<sup>®</sup> infusion (0.125 μg/kg/min – maximum 10 μg/min) for 12 hours + heparin</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>ReoPro<sup>®</sup> + Low-Dose Heparin</td> <td align="center">935</td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td>ReoPro<sup>®</sup> + Standard<br /> Dose Heparin</td> <td align="center">918</td> <td align="center">59.7±11.0<br /> (29, 89)</td> <td align="center">27.9%</td> </tr> <tr> <td>Placebo + Standard<br /> Dose Heparin</td> <td align="center">939</td> <td align="center"> </td> <td align="center"> </td> </tr> </table> </center></p> <p><i>The EPIC Trial</i></p> <p>The Evaluation of c7E3 to Prevent Ischemic Complications (EPIC) trial was a multicenter, double-blind, placebo-controlled trial of ReoPro<sup>®</sup> (abciximab) in patients undergoing <a href="/percutaneous_transluminal_coronary_angioplasty/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">percutaneous transluminal coronary angioplasty</a> or <a href="/atherectomy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">atherectomy</a> (PTCA) (1-3). In the EPIC trial, 2099 patients between 26 and 83 years of age who were at high risk for abrupt closure of the treated coronary vessel were <a href="/randomly/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">randomly</a> allocated to one of three treatments: 1) a ReoPro<sup>®</sup> bolus (0.25 mg/kg) followed by a ReoPro<sup>®</sup> infusion (10 μg/min) for twelve hours (bolus plus infusion group); 2) a ReoPro<sup>®</sup> bolus (0.25 mg/kg) followed by a placebo infusion (bolus group), or; 3) a placebo bolus followed by a placebo infusion (placebo group). Patients at high risk during or following PTCA were defined as those with unstable angina or a non-Q-wave myocardial infarction (n=489), those with an acute Q-wave myocardial infarction within twelve hours of symptom onset (n=66), and those who were at high risk because of coronary <a href="/morphology/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">morphology</a> and/or clinical characteristics (n=1544). Treatment with study agent in each of the three arms was initiated 10-60 minutes before the onset of PTCA. All patients initially received an intravenous heparin bolus (10,000 to 12,000 units) and boluses of up to 3,000 units thereafter to a maximum of 20,000 units during PTCA. Heparin infusion was continued for twelve hours to maintain a therapeutic elevation of activated partial thromboplastin time (APTT, 1.5-2.5 times normal). Unless contraindicated, acetylsalicylic acid (325 mg) was administered orally two hours prior to the planned procedure and then once daily.</p> <p><i>The EPILOG Trial</i></p> <p>A second trial (Evaluation of PTCA to Improve Long-term Outcome by c7E3 GPIIb/IIIa Receptor Blockade or EPILOG), also a randomized, double-blind, multicenter, placebocontrolled trial, evaluated ReoPro<sup>®</sup> in a broad population of PTCA patients (but excluding patients myocardial infarction and unstable angina meeting the EPIC high risk criteria) (4). EPILOG tested the hypothesis that use of a low-dose, weight-adjusted heparin regimen, early sheath removal, better access site management and weight-adjustment of the ReoPro<sup>®</sup> infusion dose could significantly lower the bleeding rate yet maintain the efficacy seen in the EPIC trial. EPILOG was a three treatment-arm trial of ReoPro<sup>®</sup> plus standard dose, weight-adjusted heparin<sup>1</sup>, ReoPro<sup>®</sup> plus low dose, weight-adjusted heparin<sup>2</sup> and placebo plus standard dose, weight-adjusted heparin. The ReoPro<sup>®</sup> dose regimen was the same as that used in the EPIC trial, except that the continuous infusion dose was weight adjusted in patients up to 80 kg<sup>3</sup>. Improved patient and access site management as well as a strong recommendation for early sheath removal were also incorporated into the trial. The 30-day Kaplan-Meier primary endpoint events for each treatment group by intention-to-treat analysis of all 2792 randomized patients are shown in Table 5. The EPILOG trial also achieved the <a href="/objective/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">objective</a> of lowering the bleeding rate: in the ReoPro<sup>®</sup> treatment arms major bleeding was reduced to the level of placebo (see <a href="/reopro-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>: <b>Bleeding</b>).</p> <p><sup>1</sup> Bolus administration of 100 U/kg weight-adjusted heparin to achieve an activated clotting time (ACT) of ≥ 300 seconds (maximum initial bolus 10,000 units).</p> <p><sup>2</sup> Bolus administration of 70 U/kg weight-adjusted heparin to achieve an activated clotting time (ACT) of 200 seconds (maximum initial bolus 7,000 units).</p> <p><sup>3</sup> Bolus administration of 0.25 mg/kg ReoPro<sup>®</sup> 10 to 60 minutes before PTCA immediately followed by a 0.125 μg/kg/min infusion (maximum 10 μg/min) for 12 hours.</p> <h5>Study Results</h5> <p><i>The EPIC Trial</i></p> <p>The primary endpoint was the occurrence of any of the following events within 30 days of PTCA: death, myocardial infarction (MI), or the need for urgent intervention for recurrent <a href="/ischemia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ischemia</a> (i.e. urgent PTCA, urgent <a href="/coronary_artery_bypass_graft/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">coronary artery bypass graft</a> (CABG) surgery, a coronary <a href="/stent/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">stent</a>, or an intra-<a href="/aortic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">aortic</a> balloon pump). The 30-day (Kaplan-Meier) primary endpoint events for each treatment group by intention-to-treat analysis of all randomized patients are shown in Table 4. The 4.5% lower incidence of the primary endpoint in the bolus plus infusion treatment group, compared with the placebo group, was statistically significant, whereas the 1.3% lower incidence in the bolus treatment group was not. A lower incidence of the primary endpoint was observed in the bolus plus infusion treatment arm for all three high-risk subgroups: patients with unstable angina, patients presenting within twelve hours of the onset of symptoms of an acute myocardial infarction, and patients with other high-risk clinical and/or morphologic characteristics. The treatment effect was largest in the first two subgroups and smallest in the third subgroup.</p> <p align="center"><b>Table 4: Primary Endpoint Events at 30-Days -EPIC Trial</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="40%"> </td> <td class="EmphTd" width="20%">Placebo<br /> (n=696)</td> <td class="EmphTd" width="20%">Bolus<br /> (n=695)</td> <td class="EmphTd" width="20%">Infusion<br /> (n=708)</td> </tr> <tr> <td class="EmphTd">Event</td> <td colspan="3" class="EmphTd">Number of Patients (%)</td> </tr> <tr> <td>Primary Endpoint<sup>a</sup></td> <td align="center">89 (12.8)</td> <td align="center">79 (11.5)</td> <td align="center">59 (8.3)</td> </tr> <tr> <td> p-value vs. placebo</td> <td align="center"> </td> <td align="center">0.428</td> <td align="center"> </td> </tr> <tr> <td colspan="4">Components of Primary Endpoint<sup>b</sup></td> </tr> <tr> <td> Death</td> <td align="center">12 (1.7)</td> <td align="center">9 (1.3)</td> <td align="center">12 (1.7)</td> </tr> <tr> <td> Acute myocardial infarctions in surviving patients</td> <td align="center">55 (7.9)</td> <td align="center">40 (5.8)</td> <td align="center">31 (4.4)</td> </tr> <tr> <td> Urgent interventions in surviving patients without an acute myocardial infarction</td> <td align="center">22 (3.2)</td> <td align="center">30 (4.4)</td> <td align="center">16 (2.2)</td> </tr> <tr> <td class="credit" colspan="4"> <sup>a</sup> Patients who experienced more than one event in the first 30 days are counted only once.<br /> <sup>b</sup> Patients are counted only once under the most serious component (death > acute MI > urgent intervention).</td> </tr> </table> </center></p> <p>The primary endpoint events in the bolus plus infusion treatment group were reduced mostly in the first 48 hours and this benefit was sustained through blinded evaluations at 30 days (1), 6 months (2) and 3 years (3). At the 6 months follow-up visit this event rate remained lower in the bolus plus infusion arm (12.3%) than in the placebo arm (17.6%) (p=0.006 vs. placebo). At 3 years the absolute reduction in events was maintained with an event rate of 19.6% in the bolus plus infusion arm and 24.4% in the placebo arm (p=0.027).</p> <p><i>The EPILOG Trial</i></p> <p>The 30-day Kaplan-Meier primary endpoint events for each treatment group by intention-to-treat analysis of all 2792 randomized patients are shown in Table 5. The EPILOG trial also achieved the objective of lowering the bleeding rate: in the ReoPro<sup>®</sup> treatment arms major bleeding was reduced to the level of placebo (see <a href="/reopro-drug.htm#AR"><b>ADVERSE REACTIONS</b></a><b>, Bleeding</b>).</p> <p align="center"><b>Table 5: Primary Endpoint Events at 30 Days -EPILOG Trial</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="40%" rowspan="2"> </td> <td class="EmphTd" width="20%">Placebo + Standard Dose</td> <td class="EmphTd" width="20%">ReoPro<sup>®</sup> + Standard Dose</td> <td class="EmphTd" width="20%">ReoPro<sup>®</sup> + Low Dose</td> </tr> <tr> <td class="EmphTd">Heparin<br /> (n=939)</td> <td class="EmphTd">Heparin<br /> (n=918)</td> <td class="EmphTd">Heparin<br /> (n=935)</td> </tr> <tr> <td class="EmphTd">Event</td> <td colspan="3" class="EmphTd">Number of Patients (%)</td> </tr> <tr> <td>Death or MI<sup>a</sup></td> <td align="center">85 (9.1)</td> <td align="center">38 (4.2)</td> <td align="center">35 (3.8)</td> </tr> <tr> <td> p-value vs. Placebo</td> <td align="center"> </td> <td align="center"><0.0001</td> <td align="center"><0.0001</td> </tr> <tr> <td>Death, MI or urgent intervention<sup>a</sup></td> <td align="center">109 (11.7)</td> <td align="center">49 (5.4)</td> <td align="center">48 (5.2)</td> </tr> <tr> <td> p-value vs. Placebo</td> <td align="center"> </td> <td align="center"><0.0001</td> <td align="center"><0.0001</td> </tr> <tr> <td>Endpoint components<sup>b</sup></td> <td align="center"> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Death</td> <td align="center">7 (0.8)</td> <td align="center">4 (0.4)</td> <td align="center">3 (0.3)</td> </tr> <tr> <td> MI in surviving patients</td> <td align="center">78 (8.4)</td> <td align="center">34 (3.7)</td> <td align="center">32 (3.4)</td> </tr> <tr> <td> Urgent intervention in surviving patients without acute MI</td> <td align="center">24 (2.6)</td> <td align="center">11 (1.2)</td> <td align="center">13 (1.4)</td> </tr> <tr> <td class="credit" colspan="4"><sup>a</sup> Patients who experienced more than 1 event in the first 30 days are counted only once.<br /> <sup>b</sup> Patients are counted only once under the most serious component (death > acute MI > urgent intervention)</td> </tr> </table> </center></p> <p>As seen in the EPIC trial, the endpoint events in the ReoPro<sup>®</sup> treatment groups were reduced mostly in the first 48 hours and this benefit was sustained through blinded evaluations at 30 days and 6 months. At the 6 month follow-up visit the event rate for death, MI or urgent intervention remained lower in the combined ReoPro<sup>®</sup> treatment arms (8.3% and 8.4%, respectively, for the standard- and low-dose heparin arms) than in the placebo arm (14.7%) (p<0.001 for both treatment arms vs. placebo).</p> <p>The proportionate reductions in the composite endpoints death and MI, and death, MI and urgent intervention, were similar in high and low risk patients, although overall event rates were higher in high risk patients. The proportionate reductions in endpoints were also similar irrespective of the type of coronary intervention used (balloon angioplasty, atherectomy or stent placement).</p> <p>Mortality was uncommon in both the EPIC and EPILOG trials. Similar mortality rates were observed in all arms in the EPIC trial; mortality rates were lower in the ReoPro<sup>®</sup> treatment arms than the placebo treatment arm in the EPILOG trial. In both trials the rate of acute myocardial infarctions was significantly lower in the groups treated with ReoPro<sup>®</sup>. While most myocardial infarctions in both studies were non-Q-wave infarctions, patients in the ReoPro<sup>®</sup> treated groups experienced a lower incidence of both Q-wave and non-Q-wave infarctions. Urgent intervention rates were also lower in the groups treated with ReoPro<sup>®</sup>, mostly because of lower rates of emergency PTCA and, to a lesser extent, emergency CABG surgery.</p> <h5>Unstable Angina</h5> <p><i>Study demographics and trial design</i></p> <p align="center"><b>Table 6: Summary of patient demographics for clinical trials in specific indication</b><br /> <center><table class="blacktbl" width="650" cellspacing="0"> <tr> <td class="EmphTd" width="15%">Study #</td> <td class="EmphTd" width="20%">Trial design</td> <td class="EmphTd" width="20%">Dosage, route of administration and duration</td> <td class="EmphTd" width="15%">Study subjects<br /> (n=number)</td> <td class="EmphTd" width="15%">Mean age<br /> (Range)</td> <td class="EmphTd" width="15%">Gender<br /> (% Female)</td> </tr> <tr> <td rowspan="3">CAPTURE Trial</td> <td rowspan="3">Randomized, doubleblind, multicenter, placebo-controlled</td> <td>ReoPro<sup>®</sup> bolus (0.25 mg/kg)/ ReoPro<sup>®</sup> infusion (10 μg/min)</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>ReoPro<sup>®</sup></td> <td align="center">630</td> <td align="center">60.8 ± 10.0</td> <td align="center">27.3%</td> </tr> <tr> <td>Placebo</td> <td align="center">635</td> <td align="center">(32, 80)</td> <td align="center"> </td> </tr> </table> </center></p> <p><i>The CAPTURE Trial</i></p> <p>The CAPTURE (Chimeric Anti-Platelet Therapy in Unstable angina Refractory to standard medical therapy) trial was a randomized, double-blind, multicenter, placebo-controlled trial designed to determine if potent antiplatelet therapy would reduce ischemic complications and stabilize unstable angina patients not responding to conventional therapy who were candidates for percutaneous coronary intervention (5). In contrast to the EPIC and EPILOG trials, the CAPTURE trial involved the administration, in addition to conventional therapy, of placebo or ReoPro<sup>®</sup> starting up to 24 hours prior to PTCA and continuing until 1 hour after completion of PTCA. The ReoPro<sup>®</sup> dose was a 0.25 mg/kg bolus followed by a continuous infusion at a rate of 10 μg/min. The CAPTURE trial did incorporate weight adjustment of the standard heparin dose, but did not investigate the effect of a lower heparin dose, and arterial sheaths were left in place for approximately 40 hours.</p> <h5>Study Results</h5> <p><i>The CAPTURE Trial</i></p> <p>The 30-day Kaplan-Meier primary endpoint events for each treatment group by intention-to-treat analysis of all 1265 randomized patients are shown in Table 7.</p> <p align="center"><b>Table 7: Primary Outcome Events at 30 Days -CAPTURE Trial</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="50%"> </td> <td class="EmphTd" width="25%">Placebo<br /> (n=635)</td> <td class="EmphTd" width="25%">ReoPro<sup>®</sup><br /> (n=630)</td> </tr> <tr> <td class="EmphTd">Event</td> <td class="EmphTd" colspan="2">Number of Patients (%)</td> </tr> <tr> <td>Death, MI or urgent intervention<sup>a</sup></td> <td align="center">101 (15.9%)</td> <td align="center">71 (11.3%)</td> </tr> <tr> <td> p-value vs. placebo</td> <td align="center"> </td> <td align="center">(p=0.012)</td> </tr> <tr> <td>Endpoint components<sup>b</sup></td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Death</td> <td align="center">8 (1.3%)</td> <td align="center">6 (1.0%)</td> </tr> <tr> <td> MI in surviving patients</td> <td align="center">49 (7.7%)</td> <td align="center">24 (3.8%)</td> </tr> <tr> <td> Urgent intervention in surviving patients without acute MI</td> <td align="center">44 (6.9%)</td> <td align="center">41 (6.6%)</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Patients who experienced more than one event in the first 30 days are counted only once.<br /> <sup>b</sup> Patients are counted only once under the most serious component (death>acute MI>urgent intervention).</td> </tr> </table> </center></p> <p>Figure 1 shows the Kaplan-Meier event rate curves for myocardial infarction for the periods from randomization to angioplasty and from angioplasty through 24 hours post angioplasty. A reduction in myocardial infarction is apparent both pre-and post-angioplasty. The 30-day results are consistent with the EPIC and EPILOG trials, with the greatest effects on the myocardial infarction and urgent revascularization components of the composite endpoint.</p> <p align="center"><b>Figure 1. Kaplan-Meier event rates for myocardial infarction before and after PTCA.</b><br /> <center><table class="blackpic" width="557" cellspacing="0"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/abcixim1.gif" alt="Kaplan-Meier event rates for myocardial infarction before and after PTCA. - Illustration" width="557" height="328"/></td> </tr> </table> </center></p> <h4>Detailed Pharmacology</h4> <h5>In Vitro Studies</h5> <p>c7E3 Fab has been studied extensively with regard to both antigen binding and functional ability to inhibit platelet aggregation. Using platelets from humans, cynomolgus monkey, and baboons, the chimeric 7E3 Fab fragment displayed a dose-dependent inhibition of platelet aggregation. Similar binding characteristics were observed to affinity-isolated human GPIIb/IIIa receptors.</p> <h5>Animal Studies</h5> <p>To determine whether the ability of 7E3 to inhibit platelet aggregation correlates with therapeutic potential in the treatment of vascular disease, 7E3 has been investigated in several animal models of vaso-occlusive disease. Dogs, monkeys, and baboons were employed in these studies because 7E3 cross-reacts with the GPIIb/IIIa receptor on canine and nonhuman primate platelets. Because the m7E3 F(ab')<sub>2</sub> and Fab fragments and the c7E3 Fab fragment are functionally equivalent with respect to platelet GPIIb/IIIa binding and inhibition of platelet aggregation, preclinical efficacy studies with any of these test materials provide valid data for determining potential clinical utility associated with 7E3 inhibition of platelet aggregation.</p> <p><i>Establishment of In Vivo Dose-Response</i></p> <p>A dose-response study in dogs established that doses of 0.81 mg/kg of m7E3 F(ab')<sub>2</sub> blocked 85% of GPIIb/IIIa receptors and almost completely abolished platelet aggregation in response to ADP 30 minutes after infusion (8). Both the inhibition of platelet aggregation and the number of blocked GPIIb/IIIa sites progressively decreased over the next days. No obvious ill effects were detected; there was no spontaneous bleeding and no evidence of coagulopathy.</p> <p><i>In Vivo Equivalence of 7E3 Fab and F(ab')<sub>2</sub> </i></p> <p>A direct comparison of the <i>in vivo</i> activity of 7E3 Fab and m7E3 F(ab')<sub>2</sub> was performed in cynomolgus monkeys (9). Both fragments of m7E3 were found to inhibit ADP-induced platelet aggregation to a similar degree. Blockade of platelet GPIIb/IIIa receptors was also comparable in the two groups. To explore the comparative immunogenicity of the Fab and the F(ab')<sub>2</sub> fragments of m7E3, animals were administered several follow-up injections of antibody. The results of this comparative study established that while the <i>in vivo</i> antiplatelet activities of m7E3 Fab and m7E3 F(ab')<sub>2</sub> were comparable, Fab fragment exhibited decreased immunogenicity (9).</p> <p><i>Prevention of Thrombosis at Sites of Vessel Wall Injury</i></p> <p>The m7E3 F(ab')<sub>2</sub> fragment was tested <i>in vivo</i> models of platelet thrombus formation in stenosed <a href="/coronary_arteries/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">coronary arteries</a> in dogs and <a href="/carotid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">carotid</a> arteries of monkeys developed by Folts (10, 11). This model was specifically designed to simulate the situation in partially stenosed vessels with underlying <a href="/atherosclerotic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">atherosclerotic</a> lesions when patients suffer acute intermittent ischemia from injured (ruptured or fissured) atherosclerotic plaques, as in unstable angina and post-PTCA abrupt closure (cardiac circulation) or transient ischemic attacks (cerebral circulation) (12). An intravenous dose (0.8 mg/kg) of m7E3 F(ab')<sub>2</sub> , which completely inhibits <i>ex vivo</i> platelet aggregation, not only abolished thrombotic cycles, but also protected against their return by a variety of provocations. On occasion, a dose as low as 0.1 mg/kg, which produced only 41% platelet inhibition, could also abolish thrombus formation. More recent work in monkeys has demonstrated that both m7E3 Fab and c7E3 Fab are as effective as the m7E3 F(ab')<sub>2</sub> fragment in abolishing<i> in vivo</i> thrombus formation in the Folts mode (13).</p> <p><i>Direct Current Internal Injury Model of Thrombosis</i></p> <p>Mickelson et al. (14) confirmed that 7E3 F(ab')<sub>2</sub> prevents coronary artery thrombosis in an experimental dog model of vascular wall injury. In this model dose intimal injury is induced at the site of <a href="/stenosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">stenosis</a> by delivery of anodal direct current which results in spontaneous oscillations in coronary blood flow preceding a final complete thrombotic <a href="/occlusion/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">occlusion</a>. Compared to controls, a dose of 0.8 mg/kg F(ab')<sub>2</sub> : 1) prevented thrombotic left <a href="/circumflex/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">circumflex</a> coronary artery occlusion, 2) inhibited platelet aggregation, 3) minimized platelet deposition on injured vascular <a href="/endothelium/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">endothelium</a> and in established <a href="/thrombi/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">thrombi</a>, and 4) stabilized left circumflex coronary artery blood flow for 5 hours after injury.</p> <p>The 7E3 antibody has also been investigated in a model of acute thrombosis following injury induced by coronary angioplasty in dogs (15). This investigation established an effective model of acute occlusion that was dependent on platelet deposition following balloon-induced deep arterial injury. Treatment with m7E3F(ab')<sub>2</sub> prior to angioplasty prevented the formation of either occlusive or non-occlusive thrombi in 8 dogs. Acetylsalicylic acid, in contrast, was only partially effective.</p> <p><i>Coronary Angioplasty Model</i></p> <p>Studies by Bates et al. (15) examined whether m7E3 F(ab')<sub>2</sub> could prevent acute thrombosis following coronary angioplasty in a canine model. Coronary angioplasty was performed in the left anterior descending coronary artery of dogs pretreated with a bolus injection of either 0.8 mg/kg of 7E3 F(ab')<sub>2</sub> , 325 mg acetylsalicylic acid or saline control. This study demonstrated that m7E3 F(ab')<sub>2</sub> was superior to acetylsalicylic acid in inhibiting platelet aggregation, thrombosis and acute closure.</p> <p><i>Enhancement of Thrombolytic Efficacy</i></p> <p>Several studies have examined the combination of 7E3 with thrombolytic agents in promoting thrombolysis using different models of arterial thrombosis in dogs and primates. All have reported that the addition of 7E3 to a standard thrombolytic regiment enhances thrombolysis and prevents reocclusion.</p> <p><i>Instilled Coronary Model</i></p> <p>To test the role of 7E3 in enhancing the action of <a href="/recombinant/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">recombinant</a> tissuetype plasminogen activator (rt-PA), Yasuda <i>et al.</i> (16) used a localized coronary thrombosis model in open chest dogs. A performed thrombus was placed at a site of intimal damage, immediately <a href="/proximal/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">proximal</a> to a constricted segment of the left anterior descending coronary artery in heparinized animals. Intravenous infusion of rt-PA at a rate of 15 μg/kg/minute (two-chain rt- PA) or 30 μg/kg/minute (single chain rt-PA) alone for 30-60 minutes failed to prevent reocclusion despite heparin anticoagulation. Intravenous injection of 0.8 mg/kg of m7E3 F(ab')<sub>2</sub> in addition to rt-PA prevented reocclusion during a 2-hour observation period. The antibody abolished ADP-induced platelet aggregation and prolonged bleeding time.</p> <p>In another study, Gold <i>et al.</i> (17), using the canine model described above, administered intravenous bolus doses of rt-PA alone and in combination with m7E3 F(ab')<sub>2</sub> to determine whether thrombolysis could be accelerated in addition to preventing reocclusion. In this model, reocclusion occurred in animals treated with 450 μg/kg rt-PA alone. In contrast, accelerated thrombolysis without reocclusion was observed when bolus injections of 0.8 mg/kg m7E3 F(ab')<sub>2</sub> alone, without rt-PA.</p> <p>Ziskind <i>et al.</i> demonstrated similar benefit of adding m7E3 F(ab')<sub>2</sub> to the combined thrombolytic regimen of rt-PA and single-chain urokinase-type plasminogen activator (scu-PA) in the same dog coronary thrombosis model (18). Although various dosage combinations of rt-PA and scu- PA produced synergistic effects in achieving thrombolysis, all animals experienced reocclusion. Reocclusion was abolished by combining a single pretreatment dose of 0.6 mg/kg m7E3 F(ab')<sub>2</sub>.</p> <p><i>Everted Coronary Artery Model</i></p> <p>The ability of m7E3 F(ab')<sub>2</sub> to enhance rt-PA thrombolysis was also examined in a dog model of platelet-rich coronary artery thrombus using eversion of a circumflex coronary artery segment (19). In this model of highly resistant coronary thrombolysis, in which no animals treated with rt-PA alone had enduring successful thrombolysis, m7E3 F(ab')<sub>2</sub> was able to facilitate and maintain <a href="/reperfusion/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">reperfusion</a> with reduced doses of rt-PA. Again, occasional animals achieved sustained reperfusion with infusion of m7E3 F(ab')<sub>2</sub> alone, without rt-PA.</p> <p><i>Direct Current Intimal Injury Model</i></p> <p>The efficacy of m7E3 F(ab')<sub>2</sub> as an adjunct to thrombolytic therapy was demonstrated by Fitzgerald <i>et al.</i> (20) using an electrical current intimal injury model of coronary thrombosis in dogs. Coadministrations of several adjunctive antiplatelet regimens with 10 μg/kg/minute rt-PA were compared. Compared to prostacyclin (PGl2), acetylsalicylic acid, or <a href="/thromboxane/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">thromboxane</a>, At (<a href="/txa2/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">TXA2</a>) at doses sufficient to inhibit platelet aggregation, only m7E3 F(ab')<sub>2</sub> achieved accelerated thrombolysis without reocclusion, using reduced thrombolytic doses.</p> <p><i>Instilled Femoral Artery Thrombus Model in Baboons</i></p> <p>Chimeric 7E3 Fab was investigated in a baboon model of <a href="/thrombin/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">thrombin</a>-induced thrombus formation (21) similar to the dog model developed by Gold <i>et al.</i> (22). An occlusive thrombus was instilled in the femoral artery after which intravenous bolus doses of rt-PA were administered to heparinized animals in combination with either c7E3 Fab or acetylsalicylic acid. Administration of c7E3 Fab in combination with rt-PA produced a more rapid and more stable reperfusion of the baboon femoral artery with a lower total dose of rt-PA in comparison to acetylsalicylic acid administered in combination with rt-PA.</p> <a name="AP"></a><h4>Animal Toxicology</h4> <h5>Acute Intravenous Studies</h5> <p><i>Single Dose Studies</i></p> <p>Sprague-Dawley rats were injected with saline or 26.4 mg/kg c7E3 Fab. No mortality or drug related signs of toxicity were observed. <a href="/necropsy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Necropsy</a> revealed no gross pathological changes.</p> <p>Single intravenous dose studies in cynomolgus monkeys revealed that c7E3 Fab was well tolerated at doses up to 8 μg/kg. Transient gingival bleeding, <a href="/epistaxis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">epistaxis</a> and bruising were observed post-dosing.</p> <h5>Multiple-Day Intravenous Studies</h5> <p><i>One-month Rat:</i> rats were given c7E3 Fab once daily at 0, 0.5, 5.0, or 10.0 mg/kg/day for 30 days. No deaths or signs of toxicity considered to be c7E3 Fab-related were observed during the study.</p> <p><i>Two-day Monkey:</i> c7E3 Fab was given to cynomolgus monkeys as a 0.3 mg/kg bolus followed immediately by a 0.45 μg/kg/minute infusion. No signs of toxicity considered to be c7E3 Fabrelated were observed.</p> <p><i>Four-day Monkey:</i> c7E3 Fab as a 0.6 μg/kg bolus injection immediately followed by a 0.8 μg/kg/minute I.V. infusion over 96 hours was well tolerated in rhesus monkeys.</p> <p><i>Two-week Monkey:</i> Cynomolgus monkeys given c7E3 Fab once daily intravenously for fourteen days at doses up to 1 μg/kg/day tolerated the drug well for the first week of treatment. On days 11 through 13, significant signs of toxicity in all treatment groups became severe and frequent, especially in the high-dose animals. Due to the deteriorating condition and adverse hematological findings for some of the monkeys, treatment was discontinued. As expected following repeat bolus intravenous doses of a foreign protein, a monkey anti-chimeric antibody response was detected in the serum of animals in all c7E3 Fab treatment groups, which induced thrombocytopenia and consequent hemorrhaging and <a href="/anemia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anemia</a> during the second week of treatment. Following a 2-week recovery period, evidence of reversibility of effects was observed.</p> <h5>Interaction With Other Drugs</h5> <p>Concomitant administration of c7E3 Fab (0.3 μg/kg bolus dose followed by 0.45 or 0.5 μg/kg/min infusion for 48 hours) with heparin (100 U/kg bolus doses followed by 50 U/kg/hr infusion for 48 hours), rt-PA (1.25 mg/kg dose of Activase<sup>®</sup> over 3 hours or Streptokinase at 30,000 U/kg over 1 hour) and acetylsalicylic acid (25 mg/day oral dose) was well tolerated in rhesus monkeys.</p> <h5>In Vitro Human Tissue Cross-Reactivity Studies</h5> <p>Immunohistochemical studies demonstrated that Murine 7E3 Fab and c7E3 Fab reacted with platelets from blood smears and <a href="/megakaryocyte/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">megakaryocyte</a> in the <a href="/bone_marrow/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">bone marrow</a> at 3 different antibody dilutions. No cross-reactivity was observed with any other tissues or organs.<br /> <i>In Vitro</i> and<i> In Vivo</i> Mutagenicity Studies</p> <p>The mutagenic potential of c7E3 Fab was evaluated in three separate assays. c7E3 Fab did not exhibit mutagenic activity in the <i>in vitro</i> mammalian forward gene mutation assay (Chinese hamster ovary cells/hypoxanthine-<a href="/guanine/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">guanine</a> phosphoribosyl transferase; CHO/HPRT), <i>in vitro</i> chromosomal aberration analysis (CHO cells), or<i> in vivo</i> mouse micronucleus test.</p> <p class="credit"><b>REFERENCES</b></p> <p class="credit">1. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. <i>N Eng J Med</i> 1994; 300:956-961.</p> <p class="credit">2. Topol EJ, Califf RM, Weisman HF, et al: Randomised trial of coronary intervention with antibody against platelet IIb/IIIa <a href="/integrin/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">integrin</a> for reduction of clinical <a href="/restenosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">restenosis</a>: results at six months. <i>Lancet</i> 1994:343:881-886.</p> <p class="credit">3. Topol EJ, Ferguson JJ, Weisman HF, et al. for the EPIC Investigators. Long term protection from myocardial ischemic events in a randomized trial of brief integrin blockade with percutaneous coronary intervention. <i>JAMA</i> 1997;278:479-484.</p> <p class="credit">4. EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low dose heparin during percutaneous coronary revascularization. <i>N Eng J Med.</i> 1997;336:1689- 1696.</p> <p class="credit">5. CAPTURE Investigators. Randomized placebo-controlled trial of abciximab before, during and after coronary intervention in refractory unstable angina: the CAPTURE study. <i>Lancet</i> 1997;349:1429-1435.</p> <p class="credit">8. Coller BS, Scudder LE. Inhibition of dog platelet function by<i> in vivo</i> infusion of F(ab’)<sub>2</sub> fragments of a monoclonal antibody. <i>Blood</i> 1985;66:1456-1459.</p> <p class="credit">9. Jordan RE, Wagner CL, McAleer MF, Spitz MS, Mattis JA. Evaluation of the potency and immunogenicity of 7E3 F(ab’)<sub>2</sub> and Fab fragments in monkeys. <i>Circ</i> (Suppl III) 1990;82:661.</p> <p class="credit">12. Sherman CT, Litvock F, Grundfest W, Lee M, Hickey A, Chaux A, Kass R, Blanche C, Matloff J, Morgenstern L, Ganz W, Swan HJC, Forrester J. Coronary angioscopy in patients with unstable angina pectoris. <i>N Eng J Med</i> 1986;315:913-919.</p> <p class="credit">13. Folts Jd, University of Wisconsin, Madison, WI. Personal Communication.</p> <p class="credit">14. Mickelson JK, Simpson PJ, Lucchesi BR. Antiplatelet monoclonal F(ab’)<sub>2</sub> antibody directed against the platelet GPIIb/IIIa receptor complex prevents coronary artery thrombosis in the canine heart. <i>J Mol Cell Cardiol</i> 1989;21:393-405.</p> <p class="credit">15. Bates <a href="/er/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ER</a>, McGillem MJ, Mickelson JK, Pitt B, Mancini GBJ. A monoclonal antibody against the platelet glycoprotein IIb/IIIa receptor complex prevents platelet aggregation and thrombosis in a canine model of coronary angioplasty. <i>Circ</i> 1991;84:2463-2469.</p> <p class="credit">16. Yasuda T, Gold HK, Fallon JT, Leinbach RC, Guerrero JL, Scudder LE, Kanke M, Shealy D, Ross MJ, Collen D, Coller BS. Monoclonal antibody against the platelet glycoprotein (GP) IIb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue-type plasminogen activator in dogs. <i>J Clin Invest</i> 1988;81:1284- 1291.</p> <p class="credit">17. Gold HK, Coller BS, Yasuda T, Saito T, Fallon JT, Guerrero JL, Leinbach RC, Ziskind AA, Collen D. Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation. <i>Circ</i> 1988;77:670-677.</p> <p class="credit">18. Ziskind AA, Gold HK, Yasuda T, Kanke M, Guerrero JL, Fallon JT, Saito T, Collen D. Synergistic combinations of recombinant human tissue-type plasminogen activator and human single-chain urokinase-type plasminogen activator. <i>Circ</i> 1989;79:393-399.</p> <p class="credit">19. Yasuda T, Gold HK, Leinbach RC, Saito T, Guerrero JL, Jang I-K, Holt R, Fallong JT, Collen D. <a href="/lysis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Lysis</a> of plasminogen activator-resistant platelet-rich coronary artery thrombus with combined bolus injection of recombinant tissue-type plasminogen activator and antiplatelet GPIIb/IIIa antibody. <i>J Am Coll Card</i> 1990;16:1728-1735.</p> <p class="credit">20. Fitzgerald DJ, Wright F, Fitzgerald GA. Increased thromboxane biosynthesis during coronary thrombolysis. <i>Circ Res</i> 1989;65:83-94.</p> <p class="credit">21. Kohmura C, Gold HK, Yasuda T, Holt R, Nedelman MA, Guerrero JL, Weisman HF, Collen D. A chimeric murine/human antibody Fab fragment directed against the platelet GPIIb/IIIa receptor enhances and sustains arterial thrombolysis with recombinant tissuetype plasminogen activator in baboons. <i>Artherio Thromb</i> 1993;13:1837-1842.</p> <p class="credit">22. Gold HK, Gimple LW, Yasuda T, Leinbach RC, Werner W, Jordan R, Berger H, Collen D, Coller B. Pharmacodynamic study of F(ab’)<sub>2</sub> fragments of murine monoclonal antibody 7E3 directed against human platelet glycoprotein IIb/IIIa in patients with unstable angina pectoris. <i>J Clin Invest</i> 1990;86:651-659.</p> </div> </div> </div> | <a name="CP"></a><h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism Of Action</h4> <p>ReoPro<sup>®</sup> (abciximab) is the Fab fragment of the chimeric monoclonal antibody 7E3. It selectively binds to the glycoprotein IIb/IIIa (GPIIb/IIIa) receptor located on the surface of human platelets. ReoPro<sup>®</sup> inhibits platelet aggregation by preventing the binding of <a href="/fibrinogen/definition.htm" ">fibrinogen</a>, von Willebrand factor and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. ReoPro<sup>®</sup> also binds with similar <a href="/affinity/definition.htm" ">affinity</a> to the vitronectin (α<sub>ν</sub>β<sub>3</sub>) receptor found on platelets and vessel wall endothelial and smooth muscle cells. The vitronectin receptor mediates pro-coagulant properties of platelets and <a href="/proliferative/definition.htm" ">proliferative</a> properties of vascular endothelial cells and smooth muscle cells.</p> <h4>Pharmacodynamics</h4> <p>Intravenous administration in humans of single bolus doses of ReoPro<sup>®</sup> from 0.15 mg/kg to 0.30 mg/kg resulted in a dose-dependent blockade of platelet GPIIb/IIIa receptors and produced dosedependent inhibition of platelet function as measured by <i>ex vivo</i> platelet aggregation in response to ADP or by prolongation of bleeding time. At the two highest doses (0.25 and 0.30 mg/kg) at 2 hours post injection, over 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20 μM ADP was almost abolished. The median bleeding time increased to over 30 minutes at both doses compared with a baseline value of approximately 5 minutes.</p> <p>Intravenous administration in humans of a single bolus dose of 0.25 mg/kg followed by a continuous infusion of 10 μg/min for periods of 12 to 96 hours produced sustained high-grade platelet inhibition (<i>ex vivo</i> platelet aggregation in response to 5 or 20 μM ADP less than 20% of baseline and bleeding time greater than 30 minutes) for the duration of the infusion in most patients. Equivalent results were obtained when a weight adjusted infusion dose (0.125 μg/kg/min to a maximum of 10 μg/min) was used in patients up to 80 kg. Results in patients who received the 0.25 mg/kg bolus followed by a 5 μg/min infusion for 24 hours showed a similar initial inhibition of platelet aggregation, but the response was not maintained throughout the infusion period. Following cessation of the infusion, platelet function typically returned to baseline values over a period of 24 to 48 hours.</p> <h4>Pharmacokinetics</h4> <p>Following intravenous administration of ReoPro<sup>®</sup>, free plasma concentrations decreased very rapidly with an initial half-life of several minutes and a second phase half-life of about 30 minutes. This disappearance from the plasma is probably related to rapid binding to the platelet GPIIb/IIIa receptors (approximately 80,000 to 100,000 GPIIb/IIIa receptors on the surface of each platelet).</p> <p>After a single bolus injection of ReoPro<sup>®</sup>, the inhibitory effects on platelet function, as measured by inhibition of platelet aggregation, were evident within 10 minutes. The antibody remains in the <a href="/circulation/definition.htm" ">circulation</a> for 15 days or more in a platelet-bound state. Its disappearance follows a monoexponential time course.</p> <p>Intravenous administration of a 0.25 mg/kg bolus dose of ReoPro<sup>®</sup> followed by continuous infusion of 5 or 10 μg/min for periods of 12 to 96 hours produced relatively constant total plasma concentrations from the first time point measured (usually 2 hours) for all infusion rates and durations. However, although the total plasma concentrations resulting from the 5 μg/min infusion were only slightly lower than those from the 10 μg/min infusion, the 5 μg/min infusion was ineffective in inhibiting platelet function over the whole infusion period. At the termination of the infusion period, plasma concentrations fell rapidly for approximately 6 hours, then declined at a much slower rate.</p> <a name="CS"></a><h4>Clinical Studies</h4> <h5>Study Demographics And Trial Design</h5> <p align="center"><b>Table 3: Summary of patient demographics for clinical trials in specific indication</b><br /> <center> <table class="blacktbl" width="650" cellspacing="0"> <tr> <td class="EmphTd" width="12%">Study #</td> <td class="EmphTd" width="24%">Trial design</td> <td class="EmphTd" width="25%">Dosage, route of administration and duration</td> <td class="EmphTd" width="12%">Study subjects<br /> (n=number)</td> <td class="EmphTd" width="15%">Mean age<br /> (Range)</td> <td class="EmphTd" width="12%">Gender<br /> (% Female)</td> </tr> <tr> <td rowspan="4">EPIC<br /> Trial</td> <td rowspan="4">Multicenter, doubleblind, placebocontrolled</td> <td>ReoPro<sup>®</sup> bolus (0.25 mg/kg)/ ReoPro<sup>®</sup> infusion (10 μg/min) for 12 hours</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>Bolus + Infusion</td> <td align="center">708</td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td>Bolus</td> <td align="center">695</td> <td align="center">60.0±10.6 <br /> (26, 83)</td> <td align="center">27.9%</td> </tr> <tr> <td>Placebo</td> <td align="center">696</td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td rowspan="5">EPILOG<br /> Trial</td> <td rowspan="5">Randomized, doubleblind, multicenter, placebo-controlled</td> <td>ReoPro<sup>®</sup> bolus (0.25 mg/kg)/ ReoPro<sup>®</sup> infusion (0.125 μg/kg/min – maximum 10 μg/min) for 12 hours + heparin</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>ReoPro<sup>®</sup> + Low-Dose Heparin</td> <td align="center">935</td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td>ReoPro<sup>®</sup> + Standard<br /> Dose Heparin</td> <td align="center">918</td> <td align="center">59.7±11.0<br /> (29, 89)</td> <td align="center">27.9%</td> </tr> <tr> <td>Placebo + Standard<br /> Dose Heparin</td> <td align="center">939</td> <td align="center"> </td> <td align="center"> </td> </tr> </table> </center></p> <p><i>The EPIC Trial</i></p> <p>The Evaluation of c7E3 to Prevent Ischemic Complications (EPIC) trial was a multicenter, double-blind, placebo-controlled trial of ReoPro<sup>®</sup> (abciximab) in patients undergoing <a href="/percutaneous_transluminal_coronary_angioplasty/definition.htm" ">percutaneous transluminal coronary angioplasty</a> or <a href="/atherectomy/definition.htm" ">atherectomy</a> (PTCA) (1-3). In the EPIC trial, 2099 patients between 26 and 83 years of age who were at high risk for abrupt closure of the treated coronary vessel were <a href="/randomly/definition.htm" ">randomly</a> allocated to one of three treatments: 1) a ReoPro<sup>®</sup> bolus (0.25 mg/kg) followed by a ReoPro<sup>®</sup> infusion (10 μg/min) for twelve hours (bolus plus infusion group); 2) a ReoPro<sup>®</sup> bolus (0.25 mg/kg) followed by a placebo infusion (bolus group), or; 3) a placebo bolus followed by a placebo infusion (placebo group). Patients at high risk during or following PTCA were defined as those with unstable angina or a non-Q-wave myocardial infarction (n=489), those with an acute Q-wave myocardial infarction within twelve hours of symptom onset (n=66), and those who were at high risk because of coronary <a href="/morphology/definition.htm" ">morphology</a> and/or clinical characteristics (n=1544). Treatment with study agent in each of the three arms was initiated 10-60 minutes before the onset of PTCA. All patients initially received an intravenous heparin bolus (10,000 to 12,000 units) and boluses of up to 3,000 units thereafter to a maximum of 20,000 units during PTCA. Heparin infusion was continued for twelve hours to maintain a therapeutic elevation of activated partial thromboplastin time (APTT, 1.5-2.5 times normal). Unless contraindicated, acetylsalicylic acid (325 mg) was administered orally two hours prior to the planned procedure and then once daily.</p> <p><i>The EPILOG Trial</i></p> <p>A second trial (Evaluation of PTCA to Improve Long-term Outcome by c7E3 GPIIb/IIIa Receptor Blockade or EPILOG), also a randomized, double-blind, multicenter, placebocontrolled trial, evaluated ReoPro<sup>®</sup> in a broad population of PTCA patients (but excluding patients myocardial infarction and unstable angina meeting the EPIC high risk criteria) (4). EPILOG tested the hypothesis that use of a low-dose, weight-adjusted heparin regimen, early sheath removal, better access site management and weight-adjustment of the ReoPro<sup>®</sup> infusion dose could significantly lower the bleeding rate yet maintain the efficacy seen in the EPIC trial. EPILOG was a three treatment-arm trial of ReoPro<sup>®</sup> plus standard dose, weight-adjusted heparin<sup>1</sup>, ReoPro<sup>®</sup> plus low dose, weight-adjusted heparin<sup>2</sup> and placebo plus standard dose, weight-adjusted heparin. The ReoPro<sup>®</sup> dose regimen was the same as that used in the EPIC trial, except that the continuous infusion dose was weight adjusted in patients up to 80 kg<sup>3</sup>. Improved patient and access site management as well as a strong recommendation for early sheath removal were also incorporated into the trial. The 30-day Kaplan-Meier primary endpoint events for each treatment group by intention-to-treat analysis of all 2792 randomized patients are shown in Table 5. The EPILOG trial also achieved the <a href="/objective/definition.htm" ">objective</a> of lowering the bleeding rate: in the ReoPro<sup>®</sup> treatment arms major bleeding was reduced to the level of placebo (see <a href="/reopro-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>: <b>Bleeding</b>).</p> <p><sup>1</sup> Bolus administration of 100 U/kg weight-adjusted heparin to achieve an activated clotting time (ACT) of ≥ 300 seconds (maximum initial bolus 10,000 units).</p> <p><sup>2</sup> Bolus administration of 70 U/kg weight-adjusted heparin to achieve an activated clotting time (ACT) of 200 seconds (maximum initial bolus 7,000 units).</p> <p><sup>3</sup> Bolus administration of 0.25 mg/kg ReoPro<sup>®</sup> 10 to 60 minutes before PTCA immediately followed by a 0.125 μg/kg/min infusion (maximum 10 μg/min) for 12 hours.</p> <h5>Study Results</h5> <p><i>The EPIC Trial</i></p> <p>The primary endpoint was the occurrence of any of the following events within 30 days of PTCA: death, myocardial infarction (MI), or the need for urgent intervention for recurrent <a href="/ischemia/definition.htm" ">ischemia</a> (i.e. urgent PTCA, urgent <a href="/coronary_artery_bypass_graft/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">coronary artery bypass graft</a> (CABG) surgery, a coronary <a href="/stent/definition.htm" ">stent</a>, or an intra-<a href="/aortic/definition.htm" ">aortic</a> balloon pump). The 30-day (Kaplan-Meier) primary endpoint events for each treatment group by intention-to-treat analysis of all randomized patients are shown in Table 4. The 4.5% lower incidence of the primary endpoint in the bolus plus infusion treatment group, compared with the placebo group, was statistically significant, whereas the 1.3% lower incidence in the bolus treatment group was not. A lower incidence of the primary endpoint was observed in the bolus plus infusion treatment arm for all three high-risk subgroups: patients with unstable angina, patients presenting within twelve hours of the onset of symptoms of an acute myocardial infarction, and patients with other high-risk clinical and/or morphologic characteristics. The treatment effect was largest in the first two subgroups and smallest in the third subgroup.</p> <p align="center"><b>Table 4: Primary Endpoint Events at 30-Days -EPIC Trial</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="40%"> </td> <td class="EmphTd" width="20%">Placebo<br /> (n=696)</td> <td class="EmphTd" width="20%">Bolus<br /> (n=695)</td> <td class="EmphTd" width="20%">Infusion<br /> (n=708)</td> </tr> <tr> <td class="EmphTd">Event</td> <td colspan="3" class="EmphTd">Number of Patients (%)</td> </tr> <tr> <td>Primary Endpoint<sup>a</sup></td> <td align="center">89 (12.8)</td> <td align="center">79 (11.5)</td> <td align="center">59 (8.3)</td> </tr> <tr> <td> p-value vs. placebo</td> <td align="center"> </td> <td align="center">0.428</td> <td align="center"> </td> </tr> <tr> <td colspan="4">Components of Primary Endpoint<sup>b</sup></td> </tr> <tr> <td> Death</td> <td align="center">12 (1.7)</td> <td align="center">9 (1.3)</td> <td align="center">12 (1.7)</td> </tr> <tr> <td> Acute myocardial infarctions in surviving patients</td> <td align="center">55 (7.9)</td> <td align="center">40 (5.8)</td> <td align="center">31 (4.4)</td> </tr> <tr> <td> Urgent interventions in surviving patients without an acute myocardial infarction</td> <td align="center">22 (3.2)</td> <td align="center">30 (4.4)</td> <td align="center">16 (2.2)</td> </tr> <tr> <td class="credit" colspan="4"> <sup>a</sup> Patients who experienced more than one event in the first 30 days are counted only once.<br /> <sup>b</sup> Patients are counted only once under the most serious component (death > acute MI > urgent intervention).</td> </tr> </table> </center></p> <p>The primary endpoint events in the bolus plus infusion treatment group were reduced mostly in the first 48 hours and this benefit was sustained through blinded evaluations at 30 days (1), 6 months (2) and 3 years (3). At the 6 months follow-up visit this event rate remained lower in the bolus plus infusion arm (12.3%) than in the placebo arm (17.6%) (p=0.006 vs. placebo). At 3 years the absolute reduction in events was maintained with an event rate of 19.6% in the bolus plus infusion arm and 24.4% in the placebo arm (p=0.027).</p> <p><i>The EPILOG Trial</i></p> <p>The 30-day Kaplan-Meier primary endpoint events for each treatment group by intention-to-treat analysis of all 2792 randomized patients are shown in Table 5. The EPILOG trial also achieved the objective of lowering the bleeding rate: in the ReoPro<sup>®</sup> treatment arms major bleeding was reduced to the level of placebo (see <a href="/reopro-drug.htm#AR"><b>ADVERSE REACTIONS</b></a><b>, Bleeding</b>).</p> <p align="center"><b>Table 5: Primary Endpoint Events at 30 Days -EPILOG Trial</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="40%" rowspan="2"> </td> <td class="EmphTd" width="20%">Placebo + Standard Dose</td> <td class="EmphTd" width="20%">ReoPro<sup>®</sup> + Standard Dose</td> <td class="EmphTd" width="20%">ReoPro<sup>®</sup> + Low Dose</td> </tr> <tr> <td class="EmphTd">Heparin<br /> (n=939)</td> <td class="EmphTd">Heparin<br /> (n=918)</td> <td class="EmphTd">Heparin<br /> (n=935)</td> </tr> <tr> <td class="EmphTd">Event</td> <td colspan="3" class="EmphTd">Number of Patients (%)</td> </tr> <tr> <td>Death or MI<sup>a</sup></td> <td align="center">85 (9.1)</td> <td align="center">38 (4.2)</td> <td align="center">35 (3.8)</td> </tr> <tr> <td> p-value vs. Placebo</td> <td align="center"> </td> <td align="center"><0.0001</td> <td align="center"><0.0001</td> </tr> <tr> <td>Death, MI or urgent intervention<sup>a</sup></td> <td align="center">109 (11.7)</td> <td align="center">49 (5.4)</td> <td align="center">48 (5.2)</td> </tr> <tr> <td> p-value vs. Placebo</td> <td align="center"> </td> <td align="center"><0.0001</td> <td align="center"><0.0001</td> </tr> <tr> <td>Endpoint components<sup>b</sup></td> <td align="center"> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Death</td> <td align="center">7 (0.8)</td> <td align="center">4 (0.4)</td> <td align="center">3 (0.3)</td> </tr> <tr> <td> MI in surviving patients</td> <td align="center">78 (8.4)</td> <td align="center">34 (3.7)</td> <td align="center">32 (3.4)</td> </tr> <tr> <td> Urgent intervention in surviving patients without acute MI</td> <td align="center">24 (2.6)</td> <td align="center">11 (1.2)</td> <td align="center">13 (1.4)</td> </tr> <tr> <td class="credit" colspan="4"><sup>a</sup> Patients who experienced more than 1 event in the first 30 days are counted only once.<br /> <sup>b</sup> Patients are counted only once under the most serious component (death > acute MI > urgent intervention)</td> </tr> </table> </center></p> <p>As seen in the EPIC trial, the endpoint events in the ReoPro<sup>®</sup> treatment groups were reduced mostly in the first 48 hours and this benefit was sustained through blinded evaluations at 30 days and 6 months. At the 6 month follow-up visit the event rate for death, MI or urgent intervention remained lower in the combined ReoPro<sup>®</sup> treatment arms (8.3% and 8.4%, respectively, for the standard- and low-dose heparin arms) than in the placebo arm (14.7%) (p<0.001 for both treatment arms vs. placebo).</p> <p>The proportionate reductions in the composite endpoints death and MI, and death, MI and urgent intervention, were similar in high and low risk patients, although overall event rates were higher in high risk patients. The proportionate reductions in endpoints were also similar irrespective of the type of coronary intervention used (balloon angioplasty, atherectomy or stent placement).</p> <p>Mortality was uncommon in both the EPIC and EPILOG trials. Similar mortality rates were observed in all arms in the EPIC trial; mortality rates were lower in the ReoPro<sup>®</sup> treatment arms than the placebo treatment arm in the EPILOG trial. In both trials the rate of acute myocardial infarctions was significantly lower in the groups treated with ReoPro<sup>®</sup>. While most myocardial infarctions in both studies were non-Q-wave infarctions, patients in the ReoPro<sup>®</sup> treated groups experienced a lower incidence of both Q-wave and non-Q-wave infarctions. Urgent intervention rates were also lower in the groups treated with ReoPro<sup>®</sup>, mostly because of lower rates of emergency PTCA and, to a lesser extent, emergency CABG surgery.</p> <h5>Unstable Angina</h5> <p><i>Study demographics and trial design</i></p> <p align="center"><b>Table 6: Summary of patient demographics for clinical trials in specific indication</b><br /> <center><table class="blacktbl" width="650" cellspacing="0"> <tr> <td class="EmphTd" width="15%">Study #</td> <td class="EmphTd" width="20%">Trial design</td> <td class="EmphTd" width="20%">Dosage, route of administration and duration</td> <td class="EmphTd" width="15%">Study subjects<br /> (n=number)</td> <td class="EmphTd" width="15%">Mean age<br /> (Range)</td> <td class="EmphTd" width="15%">Gender<br /> (% Female)</td> </tr> <tr> <td rowspan="3">CAPTURE Trial</td> <td rowspan="3">Randomized, doubleblind, multicenter, placebo-controlled</td> <td>ReoPro<sup>®</sup> bolus (0.25 mg/kg)/ ReoPro<sup>®</sup> infusion (10 μg/min)</td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td>ReoPro<sup>®</sup></td> <td align="center">630</td> <td align="center">60.8 ± 10.0</td> <td align="center">27.3%</td> </tr> <tr> <td>Placebo</td> <td align="center">635</td> <td align="center">(32, 80)</td> <td align="center"> </td> </tr> </table> </center></p> <p><i>The CAPTURE Trial</i></p> <p>The CAPTURE (Chimeric Anti-Platelet Therapy in Unstable angina Refractory to standard medical therapy) trial was a randomized, double-blind, multicenter, placebo-controlled trial designed to determine if potent antiplatelet therapy would reduce ischemic complications and stabilize unstable angina patients not responding to conventional therapy who were candidates for percutaneous coronary intervention (5). In contrast to the EPIC and EPILOG trials, the CAPTURE trial involved the administration, in addition to conventional therapy, of placebo or ReoPro<sup>®</sup> starting up to 24 hours prior to PTCA and continuing until 1 hour after completion of PTCA. The ReoPro<sup>®</sup> dose was a 0.25 mg/kg bolus followed by a continuous infusion at a rate of 10 μg/min. The CAPTURE trial did incorporate weight adjustment of the standard heparin dose, but did not investigate the effect of a lower heparin dose, and arterial sheaths were left in place for approximately 40 hours.</p> <h5>Study Results</h5> <p><i>The CAPTURE Trial</i></p> <p>The 30-day Kaplan-Meier primary endpoint events for each treatment group by intention-to-treat analysis of all 1265 randomized patients are shown in Table 7.</p> <p align="center"><b>Table 7: Primary Outcome Events at 30 Days -CAPTURE Trial</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td class="EmphTd" width="50%"> </td> <td class="EmphTd" width="25%">Placebo<br /> (n=635)</td> <td class="EmphTd" width="25%">ReoPro<sup>®</sup><br /> (n=630)</td> </tr> <tr> <td class="EmphTd">Event</td> <td class="EmphTd" colspan="2">Number of Patients (%)</td> </tr> <tr> <td>Death, MI or urgent intervention<sup>a</sup></td> <td align="center">101 (15.9%)</td> <td align="center">71 (11.3%)</td> </tr> <tr> <td> p-value vs. placebo</td> <td align="center"> </td> <td align="center">(p=0.012)</td> </tr> <tr> <td>Endpoint components<sup>b</sup></td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Death</td> <td align="center">8 (1.3%)</td> <td align="center">6 (1.0%)</td> </tr> <tr> <td> MI in surviving patients</td> <td align="center">49 (7.7%)</td> <td align="center">24 (3.8%)</td> </tr> <tr> <td> Urgent intervention in surviving patients without acute MI</td> <td align="center">44 (6.9%)</td> <td align="center">41 (6.6%)</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Patients who experienced more than one event in the first 30 days are counted only once.<br /> <sup>b</sup> Patients are counted only once under the most serious component (death>acute MI>urgent intervention).</td> </tr> </table> </center></p> <p>Figure 1 shows the Kaplan-Meier event rate curves for myocardial infarction for the periods from randomization to angioplasty and from angioplasty through 24 hours post angioplasty. A reduction in myocardial infarction is apparent both pre-and post-angioplasty. The 30-day results are consistent with the EPIC and EPILOG trials, with the greatest effects on the myocardial infarction and urgent revascularization components of the composite endpoint.</p> <p align="center"><b>Figure 1. Kaplan-Meier event rates for myocardial infarction before and after PTCA.</b><br /> <center><table class="blackpic" width="557" cellspacing="0"> <tr> <td><img src="https://images.rxlist.com/images/rxlist/abcixim1.gif" alt="Kaplan-Meier event rates for myocardial infarction before and after PTCA. - Illustration" width="557" height="328"/></td> </tr> </table> </center></p> <h4>Detailed Pharmacology</h4> <h5>In Vitro Studies</h5> <p>c7E3 Fab has been studied extensively with regard to both antigen binding and functional ability to inhibit platelet aggregation. Using platelets from humans, cynomolgus monkey, and baboons, the chimeric 7E3 Fab fragment displayed a dose-dependent inhibition of platelet aggregation. Similar binding characteristics were observed to affinity-isolated human GPIIb/IIIa receptors.</p> <h5>Animal Studies</h5> <p>To determine whether the ability of 7E3 to inhibit platelet aggregation correlates with therapeutic potential in the treatment of vascular disease, 7E3 has been investigated in several animal models of vaso-occlusive disease. Dogs, monkeys, and baboons were employed in these studies because 7E3 cross-reacts with the GPIIb/IIIa receptor on canine and nonhuman primate platelets. Because the m7E3 F(ab')<sub>2</sub> and Fab fragments and the c7E3 Fab fragment are functionally equivalent with respect to platelet GPIIb/IIIa binding and inhibition of platelet aggregation, preclinical efficacy studies with any of these test materials provide valid data for determining potential clinical utility associated with 7E3 inhibition of platelet aggregation.</p> <p><i>Establishment of In Vivo Dose-Response</i></p> <p>A dose-response study in dogs established that doses of 0.81 mg/kg of m7E3 F(ab')<sub>2</sub> blocked 85% of GPIIb/IIIa receptors and almost completely abolished platelet aggregation in response to ADP 30 minutes after infusion (8). Both the inhibition of platelet aggregation and the number of blocked GPIIb/IIIa sites progressively decreased over the next days. No obvious ill effects were detected; there was no spontaneous bleeding and no evidence of coagulopathy.</p> <p><i>In Vivo Equivalence of 7E3 Fab and F(ab')<sub>2</sub> </i></p> <p>A direct comparison of the <i>in vivo</i> activity of 7E3 Fab and m7E3 F(ab')<sub>2</sub> was performed in cynomolgus monkeys (9). Both fragments of m7E3 were found to inhibit ADP-induced platelet aggregation to a similar degree. Blockade of platelet GPIIb/IIIa receptors was also comparable in the two groups. To explore the comparative immunogenicity of the Fab and the F(ab')<sub>2</sub> fragments of m7E3, animals were administered several follow-up injections of antibody. The results of this comparative study established that while the <i>in vivo</i> antiplatelet activities of m7E3 Fab and m7E3 F(ab')<sub>2</sub> were comparable, Fab fragment exhibited decreased immunogenicity (9).</p> <p><i>Prevention of Thrombosis at Sites of Vessel Wall Injury</i></p> <p>The m7E3 F(ab')<sub>2</sub> fragment was tested <i>in vivo</i> models of platelet thrombus formation in stenosed <a href="/coronary_arteries/definition.htm" ">coronary arteries</a> in dogs and <a href="/carotid/definition.htm" ">carotid</a> arteries of monkeys developed by Folts (10, 11). This model was specifically designed to simulate the situation in partially stenosed vessels with underlying <a href="/atherosclerotic/definition.htm" ">atherosclerotic</a> lesions when patients suffer acute intermittent ischemia from injured (ruptured or fissured) atherosclerotic plaques, as in unstable angina and post-PTCA abrupt closure (cardiac circulation) or transient ischemic attacks (cerebral circulation) (12). An intravenous dose (0.8 mg/kg) of m7E3 F(ab')<sub>2</sub> , which completely inhibits <i>ex vivo</i> platelet aggregation, not only abolished thrombotic cycles, but also protected against their return by a variety of provocations. On occasion, a dose as low as 0.1 mg/kg, which produced only 41% platelet inhibition, could also abolish thrombus formation. More recent work in monkeys has demonstrated that both m7E3 Fab and c7E3 Fab are as effective as the m7E3 F(ab')<sub>2</sub> fragment in abolishing<i> in vivo</i> thrombus formation in the Folts mode (13).</p> <p><i>Direct Current Internal Injury Model of Thrombosis</i></p> <p>Mickelson et al. (14) confirmed that 7E3 F(ab')<sub>2</sub> prevents coronary artery thrombosis in an experimental dog model of vascular wall injury. In this model dose intimal injury is induced at the site of <a href="/stenosis/definition.htm" ">stenosis</a> by delivery of anodal direct current which results in spontaneous oscillations in coronary blood flow preceding a final complete thrombotic <a href="/occlusion/definition.htm" ">occlusion</a>. Compared to controls, a dose of 0.8 mg/kg F(ab')<sub>2</sub> : 1) prevented thrombotic left <a href="/circumflex/definition.htm" ">circumflex</a> coronary artery occlusion, 2) inhibited platelet aggregation, 3) minimized platelet deposition on injured vascular <a href="/endothelium/definition.htm" ">endothelium</a> and in established <a href="/thrombi/definition.htm" ">thrombi</a>, and 4) stabilized left circumflex coronary artery blood flow for 5 hours after injury.</p> <p>The 7E3 antibody has also been investigated in a model of acute thrombosis following injury induced by coronary angioplasty in dogs (15). This investigation established an effective model of acute occlusion that was dependent on platelet deposition following balloon-induced deep arterial injury. Treatment with m7E3F(ab')<sub>2</sub> prior to angioplasty prevented the formation of either occlusive or non-occlusive thrombi in 8 dogs. Acetylsalicylic acid, in contrast, was only partially effective.</p> <p><i>Coronary Angioplasty Model</i></p> <p>Studies by Bates et al. (15) examined whether m7E3 F(ab')<sub>2</sub> could prevent acute thrombosis following coronary angioplasty in a canine model. Coronary angioplasty was performed in the left anterior descending coronary artery of dogs pretreated with a bolus injection of either 0.8 mg/kg of 7E3 F(ab')<sub>2</sub> , 325 mg acetylsalicylic acid or saline control. This study demonstrated that m7E3 F(ab')<sub>2</sub> was superior to acetylsalicylic acid in inhibiting platelet aggregation, thrombosis and acute closure.</p> <p><i>Enhancement of Thrombolytic Efficacy</i></p> <p>Several studies have examined the combination of 7E3 with thrombolytic agents in promoting thrombolysis using different models of arterial thrombosis in dogs and primates. All have reported that the addition of 7E3 to a standard thrombolytic regiment enhances thrombolysis and prevents reocclusion.</p> <p><i>Instilled Coronary Model</i></p> <p>To test the role of 7E3 in enhancing the action of <a href="/recombinant/definition.htm" ">recombinant</a> tissuetype plasminogen activator (rt-PA), Yasuda <i>et al.</i> (16) used a localized coronary thrombosis model in open chest dogs. A performed thrombus was placed at a site of intimal damage, immediately <a href="/proximal/definition.htm" ">proximal</a> to a constricted segment of the left anterior descending coronary artery in heparinized animals. Intravenous infusion of rt-PA at a rate of 15 μg/kg/minute (two-chain rt- PA) or 30 μg/kg/minute (single chain rt-PA) alone for 30-60 minutes failed to prevent reocclusion despite heparin anticoagulation. Intravenous injection of 0.8 mg/kg of m7E3 F(ab')<sub>2</sub> in addition to rt-PA prevented reocclusion during a 2-hour observation period. The antibody abolished ADP-induced platelet aggregation and prolonged bleeding time.</p> <p>In another study, Gold <i>et al.</i> (17), using the canine model described above, administered intravenous bolus doses of rt-PA alone and in combination with m7E3 F(ab')<sub>2</sub> to determine whether thrombolysis could be accelerated in addition to preventing reocclusion. In this model, reocclusion occurred in animals treated with 450 μg/kg rt-PA alone. In contrast, accelerated thrombolysis without reocclusion was observed when bolus injections of 0.8 mg/kg m7E3 F(ab')<sub>2</sub> alone, without rt-PA.</p> <p>Ziskind <i>et al.</i> demonstrated similar benefit of adding m7E3 F(ab')<sub>2</sub> to the combined thrombolytic regimen of rt-PA and single-chain urokinase-type plasminogen activator (scu-PA) in the same dog coronary thrombosis model (18). Although various dosage combinations of rt-PA and scu- PA produced synergistic effects in achieving thrombolysis, all animals experienced reocclusion. Reocclusion was abolished by combining a single pretreatment dose of 0.6 mg/kg m7E3 F(ab')<sub>2</sub>.</p> <p><i>Everted Coronary Artery Model</i></p> <p>The ability of m7E3 F(ab')<sub>2</sub> to enhance rt-PA thrombolysis was also examined in a dog model of platelet-rich coronary artery thrombus using eversion of a circumflex coronary artery segment (19). In this model of highly resistant coronary thrombolysis, in which no animals treated with rt-PA alone had enduring successful thrombolysis, m7E3 F(ab')<sub>2</sub> was able to facilitate and maintain <a href="/reperfusion/definition.htm" ">reperfusion</a> with reduced doses of rt-PA. Again, occasional animals achieved sustained reperfusion with infusion of m7E3 F(ab')<sub>2</sub> alone, without rt-PA.</p> <p><i>Direct Current Intimal Injury Model</i></p> <p>The efficacy of m7E3 F(ab')<sub>2</sub> as an adjunct to thrombolytic therapy was demonstrated by Fitzgerald <i>et al.</i> (20) using an electrical current intimal injury model of coronary thrombosis in dogs. Coadministrations of several adjunctive antiplatelet regimens with 10 μg/kg/minute rt-PA were compared. Compared to prostacyclin (PGl2), acetylsalicylic acid, or <a href="/thromboxane/definition.htm" ">thromboxane</a>, At (<a href="/txa2/definition.htm" ">TXA2</a>) at doses sufficient to inhibit platelet aggregation, only m7E3 F(ab')<sub>2</sub> achieved accelerated thrombolysis without reocclusion, using reduced thrombolytic doses.</p> <p><i>Instilled Femoral Artery Thrombus Model in Baboons</i></p> <p>Chimeric 7E3 Fab was investigated in a baboon model of <a href="/thrombin/definition.htm" ">thrombin</a>-induced thrombus formation (21) similar to the dog model developed by Gold <i>et al.</i> (22). An occlusive thrombus was instilled in the femoral artery after which intravenous bolus doses of rt-PA were administered to heparinized animals in combination with either c7E3 Fab or acetylsalicylic acid. Administration of c7E3 Fab in combination with rt-PA produced a more rapid and more stable reperfusion of the baboon femoral artery with a lower total dose of rt-PA in comparison to acetylsalicylic acid administered in combination with rt-PA.</p> <a name="AP"></a><h4>Animal Toxicology</h4> <h5>Acute Intravenous Studies</h5> <p><i>Single Dose Studies</i></p> <p>Sprague-Dawley rats were injected with saline or 26.4 mg/kg c7E3 Fab. No mortality or drug related signs of toxicity were observed. <a href="/necropsy/definition.htm" ">Necropsy</a> revealed no gross pathological changes.</p> <p>Single intravenous dose studies in cynomolgus monkeys revealed that c7E3 Fab was well tolerated at doses up to 8 μg/kg. Transient gingival bleeding, <a href="/epistaxis/definition.htm" ">epistaxis</a> and bruising were observed post-dosing.</p> <h5>Multiple-Day Intravenous Studies</h5> <p><i>One-month Rat:</i> rats were given c7E3 Fab once daily at 0, 0.5, 5.0, or 10.0 mg/kg/day for 30 days. No deaths or signs of toxicity considered to be c7E3 Fab-related were observed during the study.</p> <p><i>Two-day Monkey:</i> c7E3 Fab was given to cynomolgus monkeys as a 0.3 mg/kg bolus followed immediately by a 0.45 μg/kg/minute infusion. No signs of toxicity considered to be c7E3 Fabrelated were observed.</p> <p><i>Four-day Monkey:</i> c7E3 Fab as a 0.6 μg/kg bolus injection immediately followed by a 0.8 μg/kg/minute I.V. infusion over 96 hours was well tolerated in rhesus monkeys.</p> <p><i>Two-week Monkey:</i> Cynomolgus monkeys given c7E3 Fab once daily intravenously for fourteen days at doses up to 1 μg/kg/day tolerated the drug well for the first week of treatment. On days 11 through 13, significant signs of toxicity in all treatment groups became severe and frequent, especially in the high-dose animals. Due to the deteriorating condition and adverse hematological findings for some of the monkeys, treatment was discontinued. As expected following repeat bolus intravenous doses of a foreign protein, a monkey anti-chimeric antibody response was detected in the serum of animals in all c7E3 Fab treatment groups, which induced thrombocytopenia and consequent hemorrhaging and <a href="/anemia/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">anemia</a> during the second week of treatment. Following a 2-week recovery period, evidence of reversibility of effects was observed.</p> <h5>Interaction With Other Drugs</h5> <p>Concomitant administration of c7E3 Fab (0.3 μg/kg bolus dose followed by 0.45 or 0.5 μg/kg/min infusion for 48 hours) with heparin (100 U/kg bolus doses followed by 50 U/kg/hr infusion for 48 hours), rt-PA (1.25 mg/kg dose of Activase<sup>®</sup> over 3 hours or Streptokinase at 30,000 U/kg over 1 hour) and acetylsalicylic acid (25 mg/day oral dose) was well tolerated in rhesus monkeys.</p> <h5>In Vitro Human Tissue Cross-Reactivity Studies</h5> <p>Immunohistochemical studies demonstrated that Murine 7E3 Fab and c7E3 Fab reacted with platelets from blood smears and <a href="/megakaryocyte/definition.htm" ">megakaryocyte</a> in the <a href="/bone_marrow/definition.htm" ">bone marrow</a> at 3 different antibody dilutions. No cross-reactivity was observed with any other tissues or organs.<br /> <i>In Vitro</i> and<i> In Vivo</i> Mutagenicity Studies</p> <p>The mutagenic potential of c7E3 Fab was evaluated in three separate assays. c7E3 Fab did not exhibit mutagenic activity in the <i>in vitro</i> mammalian forward gene mutation assay (Chinese hamster ovary cells/hypoxanthine-<a href="/guanine/definition.htm" ">guanine</a> phosphoribosyl transferase; CHO/HPRT), <i>in vitro</i> chromosomal aberration analysis (CHO cells), or<i> in vivo</i> mouse micronucleus test.</p> <p class="credit"><b>REFERENCES</b></p> <p class="credit">1. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. <i>N Eng J Med</i> 1994; 300:956-961.</p> <p class="credit">2. Topol EJ, Califf RM, Weisman HF, et al: Randomised trial of coronary intervention with antibody against platelet IIb/IIIa <a href="/integrin/definition.htm" ">integrin</a> for reduction of clinical <a href="/restenosis/definition.htm" ">restenosis</a>: results at six months. <i>Lancet</i> 1994:343:881-886.</p> <p class="credit">3. Topol EJ, Ferguson JJ, Weisman HF, et al. for the EPIC Investigators. Long term protection from myocardial ischemic events in a randomized trial of brief integrin blockade with percutaneous coronary intervention. <i>JAMA</i> 1997;278:479-484.</p> <p class="credit">4. EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low dose heparin during percutaneous coronary revascularization. <i>N Eng J Med.</i> 1997;336:1689- 1696.</p> <p class="credit">5. CAPTURE Investigators. Randomized placebo-controlled trial of abciximab before, during and after coronary intervention in refractory unstable angina: the CAPTURE study. <i>Lancet</i> 1997;349:1429-1435.</p> <p class="credit">8. Coller BS, Scudder LE. Inhibition of dog platelet function by<i> in vivo</i> infusion of F(ab’)<sub>2</sub> fragments of a monoclonal antibody. <i>Blood</i> 1985;66:1456-1459.</p> <p class="credit">9. Jordan RE, Wagner CL, McAleer MF, Spitz MS, Mattis JA. Evaluation of the potency and immunogenicity of 7E3 F(ab’)<sub>2</sub> and Fab fragments in monkeys. <i>Circ</i> (Suppl III) 1990;82:661.</p> <p class="credit">12. Sherman CT, Litvock F, Grundfest W, Lee M, Hickey A, Chaux A, Kass R, Blanche C, Matloff J, Morgenstern L, Ganz W, Swan HJC, Forrester J. Coronary angioscopy in patients with unstable angina pectoris. <i>N Eng J Med</i> 1986;315:913-919.</p> <p class="credit">13. Folts Jd, University of Wisconsin, Madison, WI. Personal Communication.</p> <p class="credit">14. Mickelson JK, Simpson PJ, Lucchesi BR. Antiplatelet monoclonal F(ab’)<sub>2</sub> antibody directed against the platelet GPIIb/IIIa receptor complex prevents coronary artery thrombosis in the canine heart. <i>J Mol Cell Cardiol</i> 1989;21:393-405.</p> <p class="credit">15. Bates <a href="/er/definition.htm" ">ER</a>, McGillem MJ, Mickelson JK, Pitt B, Mancini GBJ. A monoclonal antibody against the platelet glycoprotein IIb/IIIa receptor complex prevents platelet aggregation and thrombosis in a canine model of coronary angioplasty. <i>Circ</i> 1991;84:2463-2469.</p> <p class="credit">16. Yasuda T, Gold HK, Fallon JT, Leinbach RC, Guerrero JL, Scudder LE, Kanke M, Shealy D, Ross MJ, Collen D, Coller BS. Monoclonal antibody against the platelet glycoprotein (GP) IIb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue-type plasminogen activator in dogs. <i>J Clin Invest</i> 1988;81:1284- 1291.</p> <p class="credit">17. Gold HK, Coller BS, Yasuda T, Saito T, Fallon JT, Guerrero JL, Leinbach RC, Ziskind AA, Collen D. Rapid and sustained coronary artery recanalization with combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GPIIb/IIIa antibody in a canine preparation. <i>Circ</i> 1988;77:670-677.</p> <p class="credit">18. Ziskind AA, Gold HK, Yasuda T, Kanke M, Guerrero JL, Fallon JT, Saito T, Collen D. Synergistic combinations of recombinant human tissue-type plasminogen activator and human single-chain urokinase-type plasminogen activator. <i>Circ</i> 1989;79:393-399.</p> <p class="credit">19. Yasuda T, Gold HK, Leinbach RC, Saito T, Guerrero JL, Jang I-K, Holt R, Fallong JT, Collen D. <a href="/lysis/definition.htm" ">Lysis</a> of plasminogen activator-resistant platelet-rich coronary artery thrombus with combined bolus injection of recombinant tissue-type plasminogen activator and antiplatelet GPIIb/IIIa antibody. <i>J Am Coll Card</i> 1990;16:1728-1735.</p> <p class="credit">20. Fitzgerald DJ, Wright F, Fitzgerald GA. Increased thromboxane biosynthesis during coronary thrombolysis. <i>Circ Res</i> 1989;65:83-94.</p> <p class="credit">21. Kohmura C, Gold HK, Yasuda T, Holt R, Nedelman MA, Guerrero JL, Weisman HF, Collen D. A chimeric murine/human antibody Fab fragment directed against the platelet GPIIb/IIIa receptor enhances and sustains arterial thrombolysis with recombinant tissuetype plasminogen activator in baboons. <i>Artherio Thromb</i> 1993;13:1837-1842.</p> <p class="credit">22. Gold HK, Gimple LW, Yasuda T, Leinbach RC, Werner W, Jordan R, Berger H, Collen D, Coller B. Pharmacodynamic study of F(ab’)<sub>2</sub> fragments of murine monoclonal antibody 7E3 directed against human platelet glycoprotein IIb/IIIa in patients with unstable angina pectoris. <i>J Clin Invest</i> 1990;86:651-659.</p> </div> </div> </div> | 11 | 2023-02-01 17:39:50 | Abciximab (ReoPro) | A | Antineoplastics CDK Inhibitors, Glycoprotein IIb/IIIa Inhibitors | ReoPro | abciximab | ReoPro | John P. Cunha, DO, FACOEP |
| 88 | 2023-02-23 12:07:03 | Medication Guide | <a name="OD"></a><h3>OVERDOSE</h3> <p>There has been no experience of overdosage with ReoPro<sup>®</sup> (abciximab) in human clinical trials. However, refer to Reversal of Antiplatelet Effects in the <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b> section.</p> <p>For management of a suspected drug overdose, contact your regional Poison Control Centre.</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3> <ul> <li>ReoPro<sup>®</sup> (abciximab) should not be administered to patients with known sensitivity to ReoPro<sup>®</sup>, to murine monoclonal antibodies, or to any component of the product. For a complete listing, see the <b><a href="/reopro-drug.htm#HS">Dosage Forms, Composition And Packaging</a></b> section of the product monograph.</li> <li>ReoPro<sup>®</sup> is contraindicated in the following clinical situations: active internal bleeding; recent (within six weeks) gastrointestinal or genitourinary bleeding of clinical significance; history of <a href="/cerebrovascular/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cerebrovascular</a> accident (CVA) within two years or a CVA with a significant residual neurological deficit; recent (within six weeks) major surgery or trauma; intracranial neoplasm, arteriovenous <a href="/malformation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">malformation</a> or aneurysm; known bleeding diathesis or severe uncontrolled hypertension; pre-existing thrombocytopenia; vasculitis; use of intravenous dextran before percutaneous transluminal coronary angioplasty or atherectomy (PTCA), or intent to use it during PTCA; administration of oral anticoagulants within seven days unless prothrombin time is ≤ 1.2 times control.</li> </ul> </div> </div> </div> | <a name="OD"></a><h3>OVERDOSE</h3> <p>There has been no experience of overdosage with ReoPro<sup>®</sup> (abciximab) in human clinical trials. However, refer to Reversal of Antiplatelet Effects in the <b>WARNINGS AND <a href="/reopro-drug.htm#P">PRECAUTIONS</a></b> section.</p> <p>For management of a suspected drug overdose, contact your regional Poison Control Centre.</p> <a name="CI"></a><h3>CONTRAINDICATIONS</h3> <ul> <li>ReoPro<sup>®</sup> (abciximab) should not be administered to patients with known sensitivity to ReoPro<sup>®</sup>, to murine monoclonal antibodies, or to any component of the product. For a complete listing, see the <b><a href="/reopro-drug.htm#HS">Dosage Forms, Composition And Packaging</a></b> section of the product monograph.</li> <li>ReoPro<sup>®</sup> is contraindicated in the following clinical situations: active internal bleeding; recent (within six weeks) gastrointestinal or genitourinary bleeding of clinical significance; history of <a href="/cerebrovascular/definition.htm" ">cerebrovascular</a> accident (CVA) within two years or a CVA with a significant residual neurological deficit; recent (within six weeks) major surgery or trauma; intracranial neoplasm, arteriovenous <a href="/malformation/definition.htm" ">malformation</a> or aneurysm; known bleeding diathesis or severe uncontrolled hypertension; pre-existing thrombocytopenia; vasculitis; use of intravenous dextran before percutaneous transluminal coronary angioplasty or atherectomy (PTCA), or intent to use it during PTCA; administration of oral anticoagulants within seven days unless prothrombin time is ≤ 1.2 times control.</li> </ul> </div> </div> </div> | 11 | 2023-02-01 17:39:50 | Abciximab (ReoPro) | A | Antineoplastics CDK Inhibitors, Glycoprotein IIb/IIIa Inhibitors | ReoPro | abciximab | ReoPro | John P. Cunha, DO, FACOEP |
| 89 | 2023-02-23 12:07:03 | Drug Description | <p><b>What is ABECMA and how is it used?</b></p> <p>ABECMA is for the treatment of <a href="/multiple_myeloma/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">multiple myeloma</a> in patients who have received at least four kinds of treatment regimens that have not worked or have stopped working. ABECMA is a medicine made from your own white blood cells; the cells are genetically modified to recognize and attack your multiple <a href="/myeloma/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">myeloma</a> cells.</p> <p><b>What are the possible or reasonably likely side effects of ABECMA?</b></p> <p>The most common side effects of ABECMA are:</p> <ul> <li>fatigue</li> <li>fever (100.4°F/38°C or higher)</li> <li>chills/shivering</li> <li>severe nausea or diarrhea</li> <li>decreased appetite</li> <li>headache</li> <li>dizziness/<a href="/lightheadedness/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lightheadedness</a></li> <li>confusion</li> <li>difficulty speaking or slurred speech</li> <li>cough</li> <li>difficulty breathing</li> <li>fast or irregular heartbeat</li> </ul> <p>ABECMA can cause a very common side effect called <a href="/cytokine/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cytokine</a> release syndrome or CRS, which can be severe or fatal. Symptoms of CRS include fever, difficulty breathing, dizziness or light-headedness, nausea, headache, fast heartbeat, <a href="/low_blood_pressure/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">low blood pressure</a>, or fatigue. Tell your healthcare provider right away if you develop fever or any of these other symptoms after receiving ABECMA.</p> <p>ABECMA can increase the risk of life-threatening infections that may lead to death. Tell your healthcare provider right away if you develop fever, chills, or any signs or symptoms of an infection.</p> <p>ABECMA can lower one or more types of your blood cells (<a href="/red_blood_cells/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">red blood cells</a>, white blood cells, or platelets), which may make you feel weak or tired or increase your risk of severe infection or bleeding. After treatment, your healthcare provider will test your blood to check for this. Tell your healthcare provider right away if you get a fever, are feeling tired, or have bruising or bleeding.</p> <p>Having ABECMA in your blood may cause a false-positive <a href="/human_immunodeficiency_virus/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">human immunodeficiency virus</a> (<a href="/hiv/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">HIV</a>) test result by some commercial tests.</p> <p>These are not all the possible side effects of ABECMA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p align="center"><b>CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA</b></p> <ul> <li><b>Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred inpatients following treatment with ABECMA. Do not administer ABECMA to patients with activeinfection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab ortocilizumab and corticosteroids [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS].</b></li> <li><b>Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA. Provide supportive care and/orcorticosteroids as needed [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].</b></li> <li><b>Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) includingfatal and life-threatening reactions, occurred in patients following treatment with ABECMA.HLH/MAS can occur with CRS or neurologic toxicities [see WARNINGS AND PRECAUTIONS].</b></li> <li><b>Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem celltransplantation for hematopoietic recovery, occurred following treatment with ABECMA [see WARNINGS AND PRECAUTIONS].</b></li> <li><b>ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS [see WARNINGS AND PRECAUTIONS].</b></li> </ul> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <p>ABECMA is a BCMA-directed genetically modified <a href="/autologous/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">autologous</a> <a href="/t_cell/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">T cell</a> <a href="/immunotherapy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">immunotherapy</a> product consisting of a patient’s own T cells that are harvested and genetically modified ex vivo through transduction with an anti-BCMA02 <a href="/chimeric_antigen_receptor_car_t_cell_treatment/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">chimeric antigen receptor</a> (CAR) lentiviral <a href="/vector/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">vector</a> (LVV). Autologous T cells transduced with the anti-BCMA02 CAR LVV express the anti-BCMA CAR on the T cell surface. The CAR is comprised of a murine <a href="/extracellular/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">extracellular</a> single-chain variable fragment (scFv) specific for recognizing <a href="/b_cell/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">B cell</a> maturation <a href="/antigen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antigen</a> (BCMA) followed by a human CD8α hinge and transmembrane <a href="/domain/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">domain</a> fused to the T cell cytoplasmic signaling domains of CD137 (4-1BB) and CD3ζ chain, in tandem. Binding of ABECMA to BCMA-expressing target cells leads to signaling initiated by CD3ζ and 4-1BB domains, and subsequent CAR-positive T cell activation. Antigen-specific activation of ABECMA results in CAR-positive T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.</p> <p>ABECMA is prepared from the patient’s peripheral blood mononuclear cells (PBMCs), which are obtained via a standard leukapheresis procedure. The mononuclear cells are enriched for T cells, through activation with anti-CD3 and anti-CD28 antibodies in the presence of <a href="/il-2/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">IL-2</a>, which are then transduced with the replication-incompetent lentiviral vector containing the anti-BCMA CAR transgene. The transduced T cells are expanded in cell culture, washed, formulated into a suspension, and cryopreserved. The product must pass a sterility test before release for shipping as a frozen suspension in one or more patient-specific infusion bag(s). The product is thawed prior to infusion back into the patient [see <b>DOSAGE AND ADMINISTRATION</b> and <b>HOW SUPPLIED</b>/<b>Storage And Handling</b>].</p> <p>The ABECMA formulation contains 50% Plasma-Lyte A and 50% CryoStor® CS10, resulting in a final DMSO concentration of 5%.</p> </div> <div id="667441035-1" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-1", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <p><b>What is ABECMA and how is it used?</b></p> <p>ABECMA is for the treatment of <a href="/multiple_myeloma/definition.htm" ">multiple myeloma</a> in patients who have received at least four kinds of treatment regimens that have not worked or have stopped working. ABECMA is a medicine made from your own white blood cells; the cells are genetically modified to recognize and attack your multiple <a href="/myeloma/definition.htm" ">myeloma</a> cells.</p> <p><b>What are the possible or reasonably likely side effects of ABECMA?</b></p> <p>The most common side effects of ABECMA are:</p> <ul> <li>fatigue</li> <li>fever (100.4°F/38°C or higher)</li> <li>chills/shivering</li> <li>severe nausea or diarrhea</li> <li>decreased appetite</li> <li>headache</li> <li>dizziness/<a href="/lightheadedness/definition.htm" ">lightheadedness</a></li> <li>confusion</li> <li>difficulty speaking or slurred speech</li> <li>cough</li> <li>difficulty breathing</li> <li>fast or irregular heartbeat</li> </ul> <p>ABECMA can cause a very common side effect called <a href="/cytokine/definition.htm" ">cytokine</a> release syndrome or CRS, which can be severe or fatal. Symptoms of CRS include fever, difficulty breathing, dizziness or light-headedness, nausea, headache, fast heartbeat, <a href="/low_blood_pressure/definition.htm" ">low blood pressure</a>, or fatigue. Tell your healthcare provider right away if you develop fever or any of these other symptoms after receiving ABECMA.</p> <p>ABECMA can increase the risk of life-threatening infections that may lead to death. Tell your healthcare provider right away if you develop fever, chills, or any signs or symptoms of an infection.</p> <p>ABECMA can lower one or more types of your blood cells (<a href="/red_blood_cells/definition.htm" ">red blood cells</a>, white blood cells, or platelets), which may make you feel weak or tired or increase your risk of severe infection or bleeding. After treatment, your healthcare provider will test your blood to check for this. Tell your healthcare provider right away if you get a fever, are feeling tired, or have bruising or bleeding.</p> <p>Having ABECMA in your blood may cause a false-positive <a href="/human_immunodeficiency_virus/definition.htm" ">human immunodeficiency virus</a> (<a href="/hiv/definition.htm" ">HIV</a>) test result by some commercial tests.</p> <p>These are not all the possible side effects of ABECMA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <div class="blackBorderBox_fmt"><a name="BW"></a> <p align="center"><b>WARNING</b></p> <p align="center"><b>CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA</b></p> <ul> <li><b>Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred inpatients following treatment with ABECMA. Do not administer ABECMA to patients with activeinfection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab ortocilizumab and corticosteroids [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS].</b></li> <li><b>Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA. Provide supportive care and/orcorticosteroids as needed [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].</b></li> <li><b>Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) includingfatal and life-threatening reactions, occurred in patients following treatment with ABECMA.HLH/MAS can occur with CRS or neurologic toxicities [see WARNINGS AND PRECAUTIONS].</b></li> <li><b>Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem celltransplantation for hematopoietic recovery, occurred following treatment with ABECMA [see WARNINGS AND PRECAUTIONS].</b></li> <li><b>ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS [see WARNINGS AND PRECAUTIONS].</b></li> </ul> </div> <a name="D"></a> <h3>DESCRIPTION</h3> <p>ABECMA is a BCMA-directed genetically modified <a href="/autologous/definition.htm" ">autologous</a> <a href="/t_cell/definition.htm" ">T cell</a> <a href="/immunotherapy/definition.htm" ">immunotherapy</a> product consisting of a patient’s own T cells that are harvested and genetically modified ex vivo through transduction with an anti-BCMA02 <a href="/chimeric_antigen_receptor_car_t_cell_treatment/definition.htm" ">chimeric antigen receptor</a> (CAR) lentiviral <a href="/vector/definition.htm" ">vector</a> (LVV). Autologous T cells transduced with the anti-BCMA02 CAR LVV express the anti-BCMA CAR on the T cell surface. The CAR is comprised of a murine <a href="/extracellular/definition.htm" ">extracellular</a> single-chain variable fragment (scFv) specific for recognizing <a href="/b_cell/definition.htm" ">B cell</a> maturation <a href="/antigen/definition.htm" ">antigen</a> (BCMA) followed by a human CD8α hinge and transmembrane <a href="/domain/definition.htm" ">domain</a> fused to the T cell cytoplasmic signaling domains of CD137 (4-1BB) and CD3ζ chain, in tandem. Binding of ABECMA to BCMA-expressing target cells leads to signaling initiated by CD3ζ and 4-1BB domains, and subsequent CAR-positive T cell activation. Antigen-specific activation of ABECMA results in CAR-positive T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.</p> <p>ABECMA is prepared from the patient’s peripheral blood mononuclear cells (PBMCs), which are obtained via a standard leukapheresis procedure. The mononuclear cells are enriched for T cells, through activation with anti-CD3 and anti-CD28 antibodies in the presence of <a href="/il-2/definition.htm" ">IL-2</a>, which are then transduced with the replication-incompetent lentiviral vector containing the anti-BCMA CAR transgene. The transduced T cells are expanded in cell culture, washed, formulated into a suspension, and cryopreserved. The product must pass a sterility test before release for shipping as a frozen suspension in one or more patient-specific infusion bag(s). The product is thawed prior to infusion back into the patient [see <b>DOSAGE AND ADMINISTRATION</b> and <b>HOW SUPPLIED</b>/<b>Storage And Handling</b>].</p> <p>The ABECMA formulation contains 50% Plasma-Lyte A and 50% CryoStor® CS10, resulting in a final DMSO concentration of 5%.</p> </div> <div id="667441035-1" class="medianet"><</div> </div> </div> | 12 | 2023-02-01 17:39:58 | Abecma (Idecabtagene Vicleucel Suspension) | A | CAR-T Cell Therapies | Abecma | idecabtagene vicleucel suspension | Abecma | |
| 90 | 2023-02-23 12:07:03 | Indications & Dosage | <a name="I"></a> <h3>INDICATIONS</h3> <p>ABECMA is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or <a href="/refractory/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">refractory</a> multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a <a href="/proteasome/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">proteasome</a> inhibitor, and an anti-CD38 <a href="/monoclonal_antibody/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">monoclonal antibody</a>.</p> <a name="D"></a> <h3>DOSAGE AND ADMINISTRATION</h3> <p>For autologous use only. For intravenous use only.</p> <h4>Dose</h4> <p>ABECMA is provided as a single dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive T cells in one or more infusion bags. The recommended dose range is 300 to 460 x 10<sup>6</sup> CAR-positive T cells.</p> <p>See the accompanying Release for Infusion Certificate (RFI Certificate) for additional information pertaining to dose [see <b>HOW SUPPLIED</b>/<b>Storage And Handling</b>].</p> <h4>Administration</h4> <p>ABECMA is for autologous use only. The patient’s identity must match the patient identifiers on the ABECMA <a href="/cassette/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cassette</a>(s) and infusion bag(s). Do not <a href="/infuse/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">infuse</a> ABECMA if the information on the patient-specific label(s) does not match the intended patient.</p> <h5>Preparing Patient For ABECMA Infusion</h5> <p>Confirm the availability of ABECMA prior to starting the lymphodepleting <a href="/chemotherapy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">chemotherapy</a> regimen.</p> <p><i>Pretreatment</i></p> <p>Administer the lymphodepleting chemotherapy regimen: cyclophosphamide 300 mg/m² intravenously (IV) and fludarabine 30 mg/m² IV for 3 days.</p> <p>See the prescribing information of cyclophosphamide and fludarabine for information on dose adjustment in renal impairment.</p> <p>Administer ABECMA 2 days after completion of lymphodepleting chemotherapy.</p> <p>Delay the infusion of ABECMA up to 7 days if a patient has any of the following conditions:</p> <ul> <li>unresolved serious adverse events (especially pulmonary events, cardiac events, or <a href="/hypotension/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypotension</a>),including those after preceding chemotherapies</li> <li>active infections or inflammatory disorders [see <b>WARNINGS AND PRECAUTIONS</b>].</li> </ul> <p><i>Premedication</i></p> <p>Administer <a href="/acetaminophen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">acetaminophen</a> (650 mg orally) and <a href="/diphenhydramine/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">diphenhydramine</a> (12.5 mg IV or 25 to 50 mg orally, or another H1-antihistamine) approximately 30 to 60 minutes before infusion of ABECMA.</p> <p>Avoid <a href="/prophylactic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">prophylactic</a> use of <a href="/dexamethasone_decadron/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">dexamethasone</a> or other systemic corticosteroids, as the use may interfere with the activity of ABECMA.</p> <h5>Receipt Of ABECMA</h5> <ul> <li>ABECMA is shipped directly to the cell laboratory or clinical pharmacy associated with the infusioncenter in the vapor phase of a <a href="/liquid_nitrogen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">liquid nitrogen</a> shipper.</li> <li>Confirm the patient’s identity with the patient identifiers on the shipper.</li> <li>If the patient is not expected to be ready for same-day administration before the shipper expires and theinfusion site is qualified for onsite storage, transfer ABECMA to onsite vapor phase of liquid nitrogenstorage.</li> <li>If the patient is not expected to be ready for same day administration before the shipper expires and theinfusion site is not qualified for onsite storage, contact Bristol-Myers Squibb at 1-888-805-4555 toarrange for return shipment.</li> </ul> <h5>Preparation Of ABECMA for Infusion</h5> <p align="center"><b>Figure 1: ABECMA Bag Label(s)</b></p> <center> <table cellspacing="0" class="blackpic" width="380"> <tbody> <tr> <td><img alt="ABECMA Bag Label(s) - Illustration" height="173" src="https://images.rxlist.com/images/rxlist/abecma1.gif" width="380" /></td> </tr> </tbody> </table> </center> <p></p> <ol> <li>Coordinate the timing of ABECMA thaw and infusion. Confirm the infusion time in advance and adjustthe start time of the thaw of ABECMA so that it will be available for infusion when the patient is ready.</li> <li>Prior to thawing the product, confirm that tocilizumab and emergency equipment are available prior tothe infusion and during the recovery period.</li> <li>An ABECMA dose may be contained in one or more patient-specific infusion bag(s). Verify the numberof bags received for the indicated dose of ABECMA prior to preparation of ABECMA for infusion.</li> <li>Confirm patient identity: Prior to preparation of ABECMA, match the patient’s identity with the patientidentifiers on the ABECMA cassette(s), infusion bag(s), and the RFI Certificate.<br /> <b>Note:</b> The patient identifier number may be preceded by the letters DIN or Aph <a href="/id/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ID</a>.</li> <li>Do not remove the ABECMA infusion bag(s) from the cassette(s) if the information on the patient-specific cassette label(s) does not match the intended patient. Contact Bristol-Myers Squibb at 1-888-805-4555 if there are any discrepancies between the labels and the patient identifiers.</li> <li>Once patient identity is confirmed, remove the ABECMA infusion bag(s) from the cassette(s) and checkthat the patient information on the cassette label(s) matches the patient information on the bag label(s).</li> <li>Inspect the infusion bag(s) for any breaches of container integrity such as breaks or cracks beforethawing. If the bag(s) is compromised, contact Bristol-Myers Squibb at 1-888-805-4555.</li> <li>If more than one infusion bag has been received to achieve the treatment dose, thaw each infusion bagone at a time. Do not initiate thaw of the next bag until infusion of the previous bag is complete.</li> <li>Place the infusion bag(s) inside a second sterile bag per local guidelines.5</li> <li>Thaw ABECMA infusion bag(s) at approximately 37°C using an approved thaw device or water bath until there is no visible ice in the infusion bag. Gently mix the contents of the bag to disperse clumps of cellular material. If visible cell clumps remain, continue to gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not wash, spin down, and/or resuspend ABECMA in new media prior to infusion.</li> <li>ABECMA should be administered within 1 hour of the start of thaw. ABECMA is stable for 2 hours at room temperature once thawed.</li> </ol> <h5>ABECMA Administration</h5> <ul> <li>For autologous use only.</li> <li>Do NOT use a leukodepleting filter.</li> <li>Ensure that a minimum of 2 doses of tocilizumab and emergency equipment are available prior to infusion and during the recovery period.</li> <li>Central venous <a href="/access/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">access</a> may be utilized for the infusion of ABECMA and is encouraged in patients with poor peripheral access.</li> </ul> <ol> <li>Confirm that the patient’s identity matches the patient identifiers on the ABECMA infusion bag(s).</li> <li>Prime the tubing of the infusion set with normal <a href="/saline/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">saline</a> prior to infusion.</li> <li>Infuse the entire contents of the ABECMA infusion bag within 1 hour after start of thaw by gravity flow.</li> <li>After the entire content of the infusion bag is infused, rinse the tubing with 30 to 60 mL of normal saline at the same infusion rate to ensure all product is delivered.</li> <li>If more than one infusion bag has been received, administer all bags as directed, following steps 1-4 for all subsequent infusion bags. Do not initiate thaw of the next bag until infusion of the previous bag is complete.</li> </ol> <p>ABECMA contains human blood cells that are genetically modified with replication-incompetent, self-inactivating lentiviral vector. Follow universal precautions and local <a href="/biosafety/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">biosafety</a> guidelines for handling and disposal of ABECMA to avoid potential transmission of infectious diseases.</p> <h5>Monitoring</h5> <ul> <li>Administer ABECMA at a REMS-certified healthcare facility.</li> <li>Monitor patients at least daily for 7 days following ABECMA infusion at the certified healthcare facility for signs and symptoms of CRS and neurologic toxicities [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Instruct patients to remain within proximity of the certified healthcare facility for at least 4 weeks following infusion.</li> <li>Instruct patients to refrain from driving or hazardous activities for at least 8 weeks following infusion.</li> </ul> <h4>Management Of Severe Adverse Reactions</h4> <h5>Cytokine Release Syndrome (CRS)</h5> <p>Identify CRS based on clinical presentation [see <b>WARNINGS AND PRECAUTIONS</b>]. Evaluate for and treat other causes of fever, <a href="/hypoxia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypoxia</a>, and hypotension.</p> <p>If CRS is suspected, manage according to the recommendations in Table 1.</p> <p>Patients who experience CRS should be closely monitored for cardiac and organ function until <a href="/resolution/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">resolution</a> of symptoms. Consider antiseizure <a href="/prophylaxis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">prophylaxis</a> with levetiracetam in patients who experience CRS.</p> <p>Patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental <a href="/oxygenation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">oxygenation</a>) should be monitored with continuous cardiac telemetry and <a href="/pulse/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pulse</a> oximetry.</p> <p>For severe or life-threatening CRS, consider <a href="/intensive_care/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">intensive care</a> unit level monitoring and supportive therapy.</p> <p>For CRS refractory to first line interventions such as tocilizumab or tocilizumab and corticosteroids, consider alternate treatment options (i.e., higher <a href="/corticosteroid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">corticosteroid</a> dose, alternative anti-cytokine agents, anti-T cell therapies). Refractory CRS is characterized by fevers, end-organ toxicity (e.g., hypoxia, hypotension) not improving within 12 hours of first line interventions or development of <a href="/hemophagocytic_lymphohistiocytosis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hemophagocytic lymphohistiocytosis</a>/<a href="/macrophage/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">macrophage</a> activation syndrome (HLH/MAS).</p> <p>If concurrent neurologic toxicity is suspected during CRS, administer:</p> <ul> <li>Corticosteroids according to the more aggressive intervention based on the CRS and neurologictoxicity grades in Tables 1 and 2</li> <li>Tocilizumab according to the CRS grade in Table 1</li> <li>Antiseizure medication according to the neurologic toxicity in Table 2</li> </ul> <p align="center"><b>Table 1: CRS Grading and Management Guidance</b></p> <center> <table cellspacing="0" class="blacktbl" width="650"> <tbody> <tr> <td class="EmphTd" width="30%">CRS Grade<sup>a</sup></td> <td class="EmphTd" width="35%">Tocilizumab<sup>c</sup></td> <td class="EmphTd" width="35%">Corticosteroids<sup>b</sup></td> </tr> <tr> <td>Grade 1 Symptoms require symptomatic treatment only (e.g., fever, nausea, fatigue, headache, myalgia, malaise).</td> <td>If onset 72 hours or more after infusion, treat symptomatically.<br /> If onset less than 72 hours after infusion, consider tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg).</td> <td>Consider dexamethasone 10 mg IV every 24 hours.</td> </tr> <tr> <td>Grade 2 Symptoms require and respond to moderate intervention.</td> <td>Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen.<br /> Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses.</td> <td>Consider dexamethasone 10 mg IV every 12-24 hours.</td> </tr> <tr> <td>Oxygen requirement less than 40% FiO<sub>2</sub> or hypotension responsive to fluids, or low dose of one vasopressor, or Grade 2 organ toxicity.</td> <td colspan="2">If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours).<br /> If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg followed by 2 mg/kg divided 4 times per day.<br /> After 2 doses of tocilizumab, consider alternative anti-cytokine agents. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total.</td> </tr> <tr> <td rowspan="2">Grade 3 Symptoms require and respond to aggressive intervention.<br /> Fever, oxygen requirement greater than or equal to 40% FiO<sub>2</sub>, or hypotension requiring high-dose or multiple vasopressors, or Grade 3 organ toxicity or Grade 4 transaminitis.</td> <td>Per Grade 2</td> <td>Administer dexamethasone 10 mg IV every 12 hours).</td> </tr> <tr> <td colspan="2">If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg followed by 2 mg/kg divided 4 times per day.<br /> After 2 doses of tocilizumab, consider alternative anti-cytokine agents.<br /> Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total.</td> </tr> <tr> <td rowspan="2">Grade 4 Life-threatening symptoms. Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD), or Grade 4 organ toxicity (excluding transaminitis).</td> <td>Per Grade 2</td> <td>Administer dexamethasone 20 mg IV every 6 hours.</td> </tr> <tr> <td colspan="2">After 2 doses of tocilizumab, consider alternative anti-cytokine agents. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total.<br /> If no improvement within 24 hours, consider methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated) or other anti-T cell therapies.</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Lee criteria for grading CRS (Lee et al., 2014).<br /> <sup>b</sup> If corticosteroids are initiated, continue corticosteroids for at least 3 doses, and taper over a maximum of 7 days.<br /> c Refer to tocilizumab Prescribing Information for details.</td> </tr> </tbody> </table> </center> <p></p> <h5>Neurologic Toxicity</h5> <p>Monitor patients for signs and symptoms of neurologic toxicities (Table 2). Rule out other causes of neurologic signs or symptoms. Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities. If neurologic toxicity is suspected, manage according to the recommendations in Table 2.</p> <p>If concurrent CRS is suspected during the neurologic toxicity event, administer:</p> <ul> <li>Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2</li> <li>Tocilizumab according to CRS grade in Table 1</li> <li>Antiseizure medication according to neurologic toxicity in Table 2</li> </ul> <p align="center"><b>Table 2: Neurologic Toxicity Grading and Management Guidance</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="30%">Neurologic Toxicity Grade<sup>a</sup></td> <td class="EmphTd" width="70%">Corticosteroids and Antiseizure Medications</td> </tr> <tr> <td>Grade 1</td> <td>Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis.<br /> If 72 hours or more after infusion, observe patient.<br /> If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 12 to 24 hours for 2 to 3 days.</td> </tr> <tr> <td>Grade 2</td> <td>Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Start dexamethasone 10 mg IV every 12 hours for 2-3 days, or longer for persistent symptoms. Consider taper for a total corticosteroid exposure of greater than 3 days. Corticosteroids are not recommended for isolated Grade 2 headaches.<br /> If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours.</td> </tr> <tr> <td>Grade 3</td> <td>Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Start dexamethasone 10 to 20 mg IV every 6 to 12 hours. Corticosteroids are not recommended for isolated Grade 3 headaches.<br /> If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (2 mg/kg loading dose, followed by 2 mg/kg divided into 4 times a day; taper within 7 days).<br /> If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5 g/m².</td> </tr> <tr> <td>Grade 4</td> <td>Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis.<br /> Start dexamethasone 20 mg IV every 6 hours.<br /> If no improvement after 24 hours or worsening of neurologic toxicity, escalate to high-dose methylprednisolone (1-2 g, repeated every 24 hours if needed; taper as clinically indicated).<br /> If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated), and cyclophosphamide 1.5 g/m².</td> </tr> <tr> <td class="credit" colspan="2"><sup>a</sup> NCI CTCAE criteria for grading neurologic toxicities version 4.03.</td> </tr> </tbody> </table> </center> <p></p> <a name="HS"></a> <h3>HOW SUPPLIED</h3> <h4>Dosage Forms And Strengths</h4> <p>ABECMA is a cell suspension for intravenous infusion.</p> <p>A single dose of ABECMA contains a cell suspension of 300 to 460 x 10<sup>6</sup> chimeric antigen receptor (CAR)-positive T cells in one or more infusion bags [see <b>HOW SUPPLIED</b>/<b>Storage And Handling</b>].</p> <h4>Storage And Handling</h4> <p><b>ABECMA</b> is supplied in one or more infusion bag(s) (see below) containing a frozen suspension of genetically modified autologous T cells in 5% DMSO.</p> <p>Each infusion bag of ABECMA is individually packed in a metal cassette. ABECMA is stored in the vapor phase of liquid <a href="/nitrogen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">nitrogen</a> and supplied in a liquid nitrogen dry vapor shipper. An RFI Certificate is affixed inside the shipper.</p> <ul> <li>50 mL infusion bag and metal cassette (<b>NDC</b> 59572-515-01)</li> <li>250 mL infusion bag and metal cassette (<b>NDC</b> 59572-515-02)</li> <li>500 mL infusion bag and metal cassette (<b>NDC</b> 59572-515-03)</li> </ul> <p>Match the identity of the patient with the patient identifiers on the cassette(s) and infusion bag(s) upon receipt.</p> <p>Store ABECMA frozen in the vapor phase of liquid nitrogen (less than or equal to minus 130°C).</p> <p>Thaw ABECMA prior to infusion [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p class="credit">Manufactured by: Celgene Corporation, a Bristol-Myers Squibb Company, 556 Morris Avenue, Summit, NJ 07901. Marketed by: Celgene Corporation, a Bristol-Myers Squibb Company (Summit, NJ 07901), and bluebird bio, Inc. (Cambridge, MA 02142). Revised: Mar /2021</p> </div> <a class="mediaPrmo ss" href="/cancer_101_slideshow_pictures/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/cancer-101-s1-what-is-cancer-cell.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">Understanding Cancer: Metastasis, Stages of Cancer, and More</span> <span class="btn">See Slideshow</span> </a> </div> </div> | <a name="I"></a> <h3>INDICATIONS</h3> <p>ABECMA is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or <a href="/refractory/definition.htm" ">refractory</a> multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a <a href="/proteasome/definition.htm" ">proteasome</a> inhibitor, and an anti-CD38 <a href="/monoclonal_antibody/definition.htm" ">monoclonal antibody</a>.</p> <a name="D"></a> <h3>DOSAGE AND ADMINISTRATION</h3> <p>For autologous use only. For intravenous use only.</p> <h4>Dose</h4> <p>ABECMA is provided as a single dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive T cells in one or more infusion bags. The recommended dose range is 300 to 460 x 10<sup>6</sup> CAR-positive T cells.</p> <p>See the accompanying Release for Infusion Certificate (RFI Certificate) for additional information pertaining to dose [see <b>HOW SUPPLIED</b>/<b>Storage And Handling</b>].</p> <h4>Administration</h4> <p>ABECMA is for autologous use only. The patient’s identity must match the patient identifiers on the ABECMA <a href="/cassette/definition.htm" ">cassette</a>(s) and infusion bag(s). Do not <a href="/infuse/definition.htm" ">infuse</a> ABECMA if the information on the patient-specific label(s) does not match the intended patient.</p> <h5>Preparing Patient For ABECMA Infusion</h5> <p>Confirm the availability of ABECMA prior to starting the lymphodepleting <a href="/chemotherapy/definition.htm" ">chemotherapy</a> regimen.</p> <p><i>Pretreatment</i></p> <p>Administer the lymphodepleting chemotherapy regimen: cyclophosphamide 300 mg/m² intravenously (IV) and fludarabine 30 mg/m² IV for 3 days.</p> <p>See the prescribing information of cyclophosphamide and fludarabine for information on dose adjustment in renal impairment.</p> <p>Administer ABECMA 2 days after completion of lymphodepleting chemotherapy.</p> <p>Delay the infusion of ABECMA up to 7 days if a patient has any of the following conditions:</p> <ul> <li>unresolved serious adverse events (especially pulmonary events, cardiac events, or <a href="/hypotension/definition.htm" ">hypotension</a>),including those after preceding chemotherapies</li> <li>active infections or inflammatory disorders [see <b>WARNINGS AND PRECAUTIONS</b>].</li> </ul> <p><i>Premedication</i></p> <p>Administer <a href="/acetaminophen/definition.htm" ">acetaminophen</a> (650 mg orally) and <a href="/diphenhydramine/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">diphenhydramine</a> (12.5 mg IV or 25 to 50 mg orally, or another H1-antihistamine) approximately 30 to 60 minutes before infusion of ABECMA.</p> <p>Avoid <a href="/prophylactic/definition.htm" ">prophylactic</a> use of <a href="/dexamethasone_decadron/drugs-condition.htm" rel="rx-art" onclick="wmdTrack('embd-lnk');">dexamethasone</a> or other systemic corticosteroids, as the use may interfere with the activity of ABECMA.</p> <h5>Receipt Of ABECMA</h5> <ul> <li>ABECMA is shipped directly to the cell laboratory or clinical pharmacy associated with the infusioncenter in the vapor phase of a <a href="/liquid_nitrogen/definition.htm" ">liquid nitrogen</a> shipper.</li> <li>Confirm the patient’s identity with the patient identifiers on the shipper.</li> <li>If the patient is not expected to be ready for same-day administration before the shipper expires and theinfusion site is qualified for onsite storage, transfer ABECMA to onsite vapor phase of liquid nitrogenstorage.</li> <li>If the patient is not expected to be ready for same day administration before the shipper expires and theinfusion site is not qualified for onsite storage, contact Bristol-Myers Squibb at 1-888-805-4555 toarrange for return shipment.</li> </ul> <h5>Preparation Of ABECMA for Infusion</h5> <p align="center"><b>Figure 1: ABECMA Bag Label(s)</b></p> <center> <table cellspacing="0" class="blackpic" width="380"> <tbody> <tr> <td><img alt="ABECMA Bag Label(s) - Illustration" height="173" src="https://images.rxlist.com/images/rxlist/abecma1.gif" width="380" /></td> </tr> </tbody> </table> </center> <p></p> <ol> <li>Coordinate the timing of ABECMA thaw and infusion. Confirm the infusion time in advance and adjustthe start time of the thaw of ABECMA so that it will be available for infusion when the patient is ready.</li> <li>Prior to thawing the product, confirm that tocilizumab and emergency equipment are available prior tothe infusion and during the recovery period.</li> <li>An ABECMA dose may be contained in one or more patient-specific infusion bag(s). Verify the numberof bags received for the indicated dose of ABECMA prior to preparation of ABECMA for infusion.</li> <li>Confirm patient identity: Prior to preparation of ABECMA, match the patient’s identity with the patientidentifiers on the ABECMA cassette(s), infusion bag(s), and the RFI Certificate.<br /> <b>Note:</b> The patient identifier number may be preceded by the letters DIN or Aph <a href="/id/definition.htm" ">ID</a>.</li> <li>Do not remove the ABECMA infusion bag(s) from the cassette(s) if the information on the patient-specific cassette label(s) does not match the intended patient. Contact Bristol-Myers Squibb at 1-888-805-4555 if there are any discrepancies between the labels and the patient identifiers.</li> <li>Once patient identity is confirmed, remove the ABECMA infusion bag(s) from the cassette(s) and checkthat the patient information on the cassette label(s) matches the patient information on the bag label(s).</li> <li>Inspect the infusion bag(s) for any breaches of container integrity such as breaks or cracks beforethawing. If the bag(s) is compromised, contact Bristol-Myers Squibb at 1-888-805-4555.</li> <li>If more than one infusion bag has been received to achieve the treatment dose, thaw each infusion bagone at a time. Do not initiate thaw of the next bag until infusion of the previous bag is complete.</li> <li>Place the infusion bag(s) inside a second sterile bag per local guidelines.5</li> <li>Thaw ABECMA infusion bag(s) at approximately 37°C using an approved thaw device or water bath until there is no visible ice in the infusion bag. Gently mix the contents of the bag to disperse clumps of cellular material. If visible cell clumps remain, continue to gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not wash, spin down, and/or resuspend ABECMA in new media prior to infusion.</li> <li>ABECMA should be administered within 1 hour of the start of thaw. ABECMA is stable for 2 hours at room temperature once thawed.</li> </ol> <h5>ABECMA Administration</h5> <ul> <li>For autologous use only.</li> <li>Do NOT use a leukodepleting filter.</li> <li>Ensure that a minimum of 2 doses of tocilizumab and emergency equipment are available prior to infusion and during the recovery period.</li> <li>Central venous <a href="/access/definition.htm" ">access</a> may be utilized for the infusion of ABECMA and is encouraged in patients with poor peripheral access.</li> </ul> <ol> <li>Confirm that the patient’s identity matches the patient identifiers on the ABECMA infusion bag(s).</li> <li>Prime the tubing of the infusion set with normal <a href="/saline/definition.htm" ">saline</a> prior to infusion.</li> <li>Infuse the entire contents of the ABECMA infusion bag within 1 hour after start of thaw by gravity flow.</li> <li>After the entire content of the infusion bag is infused, rinse the tubing with 30 to 60 mL of normal saline at the same infusion rate to ensure all product is delivered.</li> <li>If more than one infusion bag has been received, administer all bags as directed, following steps 1-4 for all subsequent infusion bags. Do not initiate thaw of the next bag until infusion of the previous bag is complete.</li> </ol> <p>ABECMA contains human blood cells that are genetically modified with replication-incompetent, self-inactivating lentiviral vector. Follow universal precautions and local <a href="/biosafety/definition.htm" ">biosafety</a> guidelines for handling and disposal of ABECMA to avoid potential transmission of infectious diseases.</p> <h5>Monitoring</h5> <ul> <li>Administer ABECMA at a REMS-certified healthcare facility.</li> <li>Monitor patients at least daily for 7 days following ABECMA infusion at the certified healthcare facility for signs and symptoms of CRS and neurologic toxicities [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Instruct patients to remain within proximity of the certified healthcare facility for at least 4 weeks following infusion.</li> <li>Instruct patients to refrain from driving or hazardous activities for at least 8 weeks following infusion.</li> </ul> <h4>Management Of Severe Adverse Reactions</h4> <h5>Cytokine Release Syndrome (CRS)</h5> <p>Identify CRS based on clinical presentation [see <b>WARNINGS AND PRECAUTIONS</b>]. Evaluate for and treat other causes of fever, <a href="/hypoxia/definition.htm" ">hypoxia</a>, and hypotension.</p> <p>If CRS is suspected, manage according to the recommendations in Table 1.</p> <p>Patients who experience CRS should be closely monitored for cardiac and organ function until <a href="/resolution/definition.htm" ">resolution</a> of symptoms. Consider antiseizure <a href="/prophylaxis/definition.htm" ">prophylaxis</a> with levetiracetam in patients who experience CRS.</p> <p>Patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental <a href="/oxygenation/definition.htm" ">oxygenation</a>) should be monitored with continuous cardiac telemetry and <a href="/pulse/definition.htm" ">pulse</a> oximetry.</p> <p>For severe or life-threatening CRS, consider <a href="/intensive_care/definition.htm" ">intensive care</a> unit level monitoring and supportive therapy.</p> <p>For CRS refractory to first line interventions such as tocilizumab or tocilizumab and corticosteroids, consider alternate treatment options (i.e., higher <a href="/corticosteroid/definition.htm" ">corticosteroid</a> dose, alternative anti-cytokine agents, anti-T cell therapies). Refractory CRS is characterized by fevers, end-organ toxicity (e.g., hypoxia, hypotension) not improving within 12 hours of first line interventions or development of <a href="/hemophagocytic_lymphohistiocytosis/definition.htm" ">hemophagocytic lymphohistiocytosis</a>/<a href="/macrophage/definition.htm" ">macrophage</a> activation syndrome (HLH/MAS).</p> <p>If concurrent neurologic toxicity is suspected during CRS, administer:</p> <ul> <li>Corticosteroids according to the more aggressive intervention based on the CRS and neurologictoxicity grades in Tables 1 and 2</li> <li>Tocilizumab according to the CRS grade in Table 1</li> <li>Antiseizure medication according to the neurologic toxicity in Table 2</li> </ul> <p align="center"><b>Table 1: CRS Grading and Management Guidance</b></p> <center> <table cellspacing="0" class="blacktbl" width="650"> <tbody> <tr> <td class="EmphTd" width="30%">CRS Grade<sup>a</sup></td> <td class="EmphTd" width="35%">Tocilizumab<sup>c</sup></td> <td class="EmphTd" width="35%">Corticosteroids<sup>b</sup></td> </tr> <tr> <td>Grade 1 Symptoms require symptomatic treatment only (e.g., fever, nausea, fatigue, headache, myalgia, malaise).</td> <td>If onset 72 hours or more after infusion, treat symptomatically.<br /> If onset less than 72 hours after infusion, consider tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg).</td> <td>Consider dexamethasone 10 mg IV every 24 hours.</td> </tr> <tr> <td>Grade 2 Symptoms require and respond to moderate intervention.</td> <td>Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen.<br /> Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses.</td> <td>Consider dexamethasone 10 mg IV every 12-24 hours.</td> </tr> <tr> <td>Oxygen requirement less than 40% FiO<sub>2</sub> or hypotension responsive to fluids, or low dose of one vasopressor, or Grade 2 organ toxicity.</td> <td colspan="2">If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours).<br /> If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg followed by 2 mg/kg divided 4 times per day.<br /> After 2 doses of tocilizumab, consider alternative anti-cytokine agents. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total.</td> </tr> <tr> <td rowspan="2">Grade 3 Symptoms require and respond to aggressive intervention.<br /> Fever, oxygen requirement greater than or equal to 40% FiO<sub>2</sub>, or hypotension requiring high-dose or multiple vasopressors, or Grade 3 organ toxicity or Grade 4 transaminitis.</td> <td>Per Grade 2</td> <td>Administer dexamethasone 10 mg IV every 12 hours).</td> </tr> <tr> <td colspan="2">If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg followed by 2 mg/kg divided 4 times per day.<br /> After 2 doses of tocilizumab, consider alternative anti-cytokine agents.<br /> Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total.</td> </tr> <tr> <td rowspan="2">Grade 4 Life-threatening symptoms. Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD), or Grade 4 organ toxicity (excluding transaminitis).</td> <td>Per Grade 2</td> <td>Administer dexamethasone 20 mg IV every 6 hours.</td> </tr> <tr> <td colspan="2">After 2 doses of tocilizumab, consider alternative anti-cytokine agents. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total.<br /> If no improvement within 24 hours, consider methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated) or other anti-T cell therapies.</td> </tr> <tr> <td class="credit" colspan="3"><sup>a</sup> Lee criteria for grading CRS (Lee et al., 2014).<br /> <sup>b</sup> If corticosteroids are initiated, continue corticosteroids for at least 3 doses, and taper over a maximum of 7 days.<br /> c Refer to tocilizumab Prescribing Information for details.</td> </tr> </tbody> </table> </center> <p></p> <h5>Neurologic Toxicity</h5> <p>Monitor patients for signs and symptoms of neurologic toxicities (Table 2). Rule out other causes of neurologic signs or symptoms. Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities. If neurologic toxicity is suspected, manage according to the recommendations in Table 2.</p> <p>If concurrent CRS is suspected during the neurologic toxicity event, administer:</p> <ul> <li>Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2</li> <li>Tocilizumab according to CRS grade in Table 1</li> <li>Antiseizure medication according to neurologic toxicity in Table 2</li> </ul> <p align="center"><b>Table 2: Neurologic Toxicity Grading and Management Guidance</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="30%">Neurologic Toxicity Grade<sup>a</sup></td> <td class="EmphTd" width="70%">Corticosteroids and Antiseizure Medications</td> </tr> <tr> <td>Grade 1</td> <td>Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis.<br /> If 72 hours or more after infusion, observe patient.<br /> If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 12 to 24 hours for 2 to 3 days.</td> </tr> <tr> <td>Grade 2</td> <td>Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Start dexamethasone 10 mg IV every 12 hours for 2-3 days, or longer for persistent symptoms. Consider taper for a total corticosteroid exposure of greater than 3 days. Corticosteroids are not recommended for isolated Grade 2 headaches.<br /> If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours.</td> </tr> <tr> <td>Grade 3</td> <td>Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis. Start dexamethasone 10 to 20 mg IV every 6 to 12 hours. Corticosteroids are not recommended for isolated Grade 3 headaches.<br /> If no improvement after 24 hours or worsening of neurologic toxicity, escalate to methylprednisolone (2 mg/kg loading dose, followed by 2 mg/kg divided into 4 times a day; taper within 7 days).<br /> If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated) and cyclophosphamide 1.5 g/m².</td> </tr> <tr> <td>Grade 4</td> <td>Start non-sedating, antiseizure medicines (e.g., levetiracetam) for seizure prophylaxis.<br /> Start dexamethasone 20 mg IV every 6 hours.<br /> If no improvement after 24 hours or worsening of neurologic toxicity, escalate to high-dose methylprednisolone (1-2 g, repeated every 24 hours if needed; taper as clinically indicated).<br /> If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated), and cyclophosphamide 1.5 g/m².</td> </tr> <tr> <td class="credit" colspan="2"><sup>a</sup> NCI CTCAE criteria for grading neurologic toxicities version 4.03.</td> </tr> </tbody> </table> </center> <p></p> <a name="HS"></a> <h3>HOW SUPPLIED</h3> <h4>Dosage Forms And Strengths</h4> <p>ABECMA is a cell suspension for intravenous infusion.</p> <p>A single dose of ABECMA contains a cell suspension of 300 to 460 x 10<sup>6</sup> chimeric antigen receptor (CAR)-positive T cells in one or more infusion bags [see <b>HOW SUPPLIED</b>/<b>Storage And Handling</b>].</p> <h4>Storage And Handling</h4> <p><b>ABECMA</b> is supplied in one or more infusion bag(s) (see below) containing a frozen suspension of genetically modified autologous T cells in 5% DMSO.</p> <p>Each infusion bag of ABECMA is individually packed in a metal cassette. ABECMA is stored in the vapor phase of liquid <a href="/nitrogen/definition.htm" ">nitrogen</a> and supplied in a liquid nitrogen dry vapor shipper. An RFI Certificate is affixed inside the shipper.</p> <ul> <li>50 mL infusion bag and metal cassette (<b>NDC</b> 59572-515-01)</li> <li>250 mL infusion bag and metal cassette (<b>NDC</b> 59572-515-02)</li> <li>500 mL infusion bag and metal cassette (<b>NDC</b> 59572-515-03)</li> </ul> <p>Match the identity of the patient with the patient identifiers on the cassette(s) and infusion bag(s) upon receipt.</p> <p>Store ABECMA frozen in the vapor phase of liquid nitrogen (less than or equal to minus 130°C).</p> <p>Thaw ABECMA prior to infusion [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p class="credit">Manufactured by: Celgene Corporation, a Bristol-Myers Squibb Company, 556 Morris Avenue, Summit, NJ 07901. Marketed by: Celgene Corporation, a Bristol-Myers Squibb Company (Summit, NJ 07901), and bluebird bio, Inc. (Cambridge, MA 02142). Revised: Mar /2021</p> </div> <a class="mediaPrmo ss" href="/cancer_101_slideshow_pictures/article.htm" onclick="wmdTrack('ssprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com//images/slideshow/cancer-101-s1-what-is-cancer-cell.jpg"> <span class="skew"></span> <span class="icon-slideshow"></span> <h4 class="label">SLIDESHOW</h4> <span class="caption">Understanding Cancer: Metastasis, Stages of Cancer, and More</span> <span class="btn">See Slideshow</span> </a> </div> </div> | 12 | 2023-02-01 17:39:58 | Abecma (Idecabtagene Vicleucel Suspension) | A | CAR-T Cell Therapies | Abecma | idecabtagene vicleucel suspension | Abecma | |
| 91 | 2023-02-23 12:07:03 | Side Effects & Drug Interactions | <a name="AR"></a> <h3>SIDE EFFECTS</h3> <p>The following adverse reactions are described elsewhere in the labeling:</p> <ul> <li>Cytokine Release Syndrome [see <b>WARNINGS AND PRECAUTIONS</b>]</li> <li>Neurologic Toxicities [see <b>WARNINGS AND PRECAUTIONS</b>]</li> <li>Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Hypersensitivity Reactions [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Infections [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Prolonged Cytopenias [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Hypogammaglobulinemia [see<b> WARNINGS AND PRECAUTIONS</b>]</li> </ul> <h4>Clinical Trials Experience</h4> <p>Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.</p> <p>The safety data described in this section reflect the exposure to ABECMA in the KarMMa study, in which 127 patients with relapsed/refractory multiple myeloma received ABECMA across a dose range of 150 to 518 x 10<sup>6</sup> CAR-positive T cells [see <b>Clinical Studies</b>]. Patients with a history of CNS disease (such as <a href="/seizure/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">seizure</a> or <a href="/cerebrovascular/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cerebrovascular</a> <a href="/ischemia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ischemia</a>) or requiring ongoing treatment with chronic <a href="/immunosuppression/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">immunosuppression</a> were excluded. The median duration of follow-up was 11.4 months. The median age of the <a href="/study_population/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">study population</a> was 61 years (range: 33 to 78 years); 35% were 65 years or older, and 60% were men. The Eastern Cooperative <a href="/oncology/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Oncology</a> Group (<a href="/ecog/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ECOG</a>) performance status at baseline was 0 in 45%, 1 in 53%, and 2 in 2% of patients. Seven percent of the patients treated with ABECMA had creatinine clearance <45 ml/min. For details about the study population, see <b>Clinical Studies</b>.</p> <p>The most common (greater than or equal to 10%) Grade 3 or 4 nonlaboratory adverse reactions were <a href="/febrile/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">febrile</a> <a href="/neutropenia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">neutropenia</a> (16%) and infections - <a href="/pathogen/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pathogen</a> unspecified (15%).</p> <p>The most common nonlaboratory adverse reactions (incidence greater than or equal to 20%) included CRS, infections - pathogen unspecified, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, <a href="/encephalopathy/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">encephalopathy</a>, edema, pyrexia, cough, headache, and decreased appetite.</p> <p>Serious adverse reactions occurred in 67% of patients. The most common nonlaboratory (greater than or equal to 5%) serious adverse reactions included CRS (18%), general physical health deterioration (10%), <a href="/pneumonia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pneumonia</a> (12%), infections-pathogen unspecified (19%), viral infections (9%), <a href="/sepsis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">sepsis</a> (7%), and febrile neutropenia (6%). Fatal adverse reactions occurred in 6%.</p> <p>Table 3 summarizes the adverse reactions that occurred in at least 10% of patients treated with ABECMA. Table 4 describes the most common Grade 3 or 4 laboratory abnormalities.</p> <p align="center"><b>Table 3: Adverse Reactions Observed in at Least 10% of Patients Treated with ABECMA in the KarMMa Study</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="3" width="40%">System Organ Class<br /> Preferred Term</td> <td class="EmphTd" colspan="2">Target Dose of ABECMA (CAR-Positive T Cells)</td> </tr> <tr> <td class="EmphTd">Any Grade</td> <td class="EmphTd">Grade 3 or Higher</td> </tr> <tr> <td class="EmphTd" width="30%">[150 to 450 x 10<sup>6</sup>]<br /> (N=127) %</td> <td class="EmphTd" width="30%">[150 to 450 x 10<sup>6</sup>]<br /> (N=127) %</td> </tr> <tr> <td colspan="3"><b>Blood and lymphatic system disorders</b></td> </tr> <tr> <td>Febrile neutropenia</td> <td align="center">16</td> <td align="center">16</td> </tr> <tr> <td colspan="3"><b>Cardiac disorders</b></td> </tr> <tr> <td>Tachycardia<sup>a</sup></td> <td align="center">19</td> <td align="center">0</td> </tr> <tr> <td colspan="3"><b>Gastrointestinal disorders</b></td> </tr> <tr> <td>Diarrhea</td> <td align="center">35</td> <td align="center">1.6</td> </tr> <tr> <td>Nausea</td> <td align="center">29</td> <td align="center">0</td> </tr> <tr> <td>Constipation</td> <td align="center">16</td> <td align="center">0</td> </tr> <tr> <td>Vomiting</td> <td align="center">15</td> <td align="center">0</td> </tr> <tr> <td>Oral pain<sup>b</sup></td> <td align="center">12</td> <td align="center">0</td> </tr> <tr> <td colspan="3"><b>General disorders and administration site conditions</b></td> </tr> <tr> <td>Fatigue<sup>c</sup></td> <td align="center">45</td> <td align="center">3.1</td> </tr> <tr> <td>Pyrexia</td> <td align="center">25</td> <td align="center">1.6</td> </tr> <tr> <td>General physical health deterioration</td> <td align="center">11</td> <td align="center">10</td> </tr> <tr> <td>Edema<sup>d</sup></td> <td align="center">25</td> <td align="center">0</td> </tr> <tr> <td>Chills</td> <td align="center">11</td> <td align="center">0</td> </tr> <tr> <td colspan="3"><b>Immune system disorders</b></td> </tr> <tr> <td>Cytokine release syndrome</td> <td align="center">85</td> <td align="center">9</td> </tr> <tr> <td>Hypogammaglobulinemia<sup>e</sup></td> <td align="center">41</td> <td align="center">0.8</td> </tr> <tr> <td colspan="3"><b>Infections and infestations<sup>f</sup></b></td> </tr> <tr> <td>Infections - Pathogen unspecified</td> <td align="center">51</td> <td align="center">15</td> </tr> <tr> <td>Viral infections</td> <td align="center">27</td> <td align="center">9</td> </tr> <tr> <td>Bacterial infections</td> <td align="center">15</td> <td align="center">3.9</td> </tr> <tr> <td>Pneumonia<sup>g</sup></td> <td align="center">17</td> <td align="center">9</td> </tr> <tr> <td>Upper respiratory tract infection<sup>h</sup></td> <td align="center">34</td> <td align="center">1.6</td> </tr> <tr> <td colspan="3"><b>Investigations</b></td> </tr> <tr> <td>Weight decreased</td> <td align="center">13</td> <td align="center">1.6</td> </tr> <tr> <td colspan="3"><b>Metabolism and nutrition disorders</b></td> </tr> <tr> <td>Decreased appetite<sup>i</sup></td> <td align="center">22</td> <td align="center">0.8</td> </tr> <tr> <td colspan="3"><b>Musculoskeletal and connective tissue disorders</b></td> </tr> <tr> <td>Musculoskeletal pain<sup>j</sup></td> <td align="center">45</td> <td align="center">3.1</td> </tr> <tr> <td>Motor dysfunction<sup>k</sup></td> <td align="center">11</td> <td align="center">0</td> </tr> <tr> <td colspan="3"><b>Nervous system disorders</b></td> </tr> <tr> <td>Encephalopathy<sup>l</sup></td> <td align="center">26</td> <td align="center">6</td> </tr> <tr> <td>Headache<sup>m</sup></td> <td align="center">23</td> <td align="center">0</td> </tr> <tr> <td>Dizziness<sup>n</sup></td> <td align="center">17</td> <td align="center">0.8</td> </tr> <tr> <td>Neuropathy peripheral<sup>o</sup></td> <td align="center">17</td> <td align="center">0.8</td> </tr> <tr> <td>Tremor<sup>p</sup></td> <td align="center">10</td> <td align="center">0</td> </tr> <tr> <td colspan="3"><b>Psychiatric disorders</b></td> </tr> <tr> <td>Insomnia<sup>q</sup></td> <td align="center">13</td> <td align="center">0</td> </tr> <tr> <td>Anxiety<sup>r</sup></td> <td align="center">12</td> <td align="center">0.8</td> </tr> <tr> <td colspan="3"><b>Renal and urinary disorders</b></td> </tr> <tr> <td>Renal failure<sup>s</sup></td> <td align="center">10</td> <td align="center">2.4</td> </tr> <tr> <td colspan="3"><b>Respiratory, thoracic, and mediastinal disorders</b></td> </tr> <tr> <td>Cough<sup>t</sup></td> <td align="center">23</td> <td align="center">0</td> </tr> <tr> <td>Dyspnea<sup>u</sup></td> <td align="center">13</td> <td align="center">2.4</td> </tr> <tr> <td colspan="3"><b>Skin and subcutaneous tissue disorder</b></td> </tr> <tr> <td>Rash<sup>v</sup></td> <td align="center">14</td> <td align="center">0.8</td> </tr> <tr> <td>Xerosis<sup>w</sup></td> <td align="center">11</td> <td align="center">0</td> </tr> <tr> <td colspan="3"><b>Vascular disorders</b></td> </tr> <tr> <td>Hypotension<sup>x</sup></td> <td align="center">17</td> <td align="center">0</td> </tr> <tr> <td>Hypertension</td> <td align="center">11</td> <td align="center">3.1</td> </tr> <tr> <td class="credit" colspan="3">CAR=chimeric antigen receptor.<br /> <sup>a</sup> Tachycardia includes sinus tachycardia, tachycardia.<br /> <sup>b</sup> Oral pain includes oral pain, oropharyngeal pain, toothache.<br /> <sup>c</sup> Fatigue includes asthenia, fatigue, malaise.<br /> <sup>d</sup> Edema includes edema, face edema, fluid overload, fluid retention, generalized edema, peripheral edema, peripheral swelling, scrotal swelling, swelling.<br /> <sup>e</sup> Hypogammaglobulinemia includes patients with adverse events (21%) of blood immunoglobulin G decreased, hypogammaglobulinemia, hypoglobulinemia; and/or patients with laboratory IgG levels below 500 mg/dL following ABECMA infusion (25%).<br /> <sup>f</sup> Infections and infestations System Organ Class Adverse Events are grouped by pathogen type and selected clinical syndromes.<br /> <sup>g</sup> Pneumonia includes bronchopulmonary aspergillosis, lung infection, pneumonia, pneumonia aspiration, pneumonia cytomegaloviral, pneumonia pneumococcal, pneumonia pseudomonal. Pneumonias may also be included under pathogen categories.<br /> <sup>h</sup> Upper respiratory tract infection includes laryngitis, nasopharyngitis, pharyngeal erythema, pharyngitis, respiratory tract congestion, respiratory tract infection, rhinitis, rhinovirus infection, sinusitis, upper respiratory tract infection, upper respiratory tract infection bacterial. Upper respiratory tract infections may also be included under pathogen categories.<br /> <sup>i</sup> Decreased appetite includes decreased appetite, hypophagia.<br /> <sup>j</sup> Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, spinal pain.<br /> <sup>k</sup> Motor dysfunction includes dysphonia, eyelid ptosis, hypotonia, motor dysfunction, muscle spasms, muscular weakness, restless legs syndrome.<br /> <sup>l</sup>Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, depressed level of consciousness,disturbance in attention, dyscalculia, dysgraphia, encephalopathy, lethargy, memory impairment, mental status changes,metabolic encephalopathy, somnolence, toxic encephalopathy.<br /> <sup>m</sup> Headache includes headache, head discomfort, sinus headache.<br /> <sup>n</sup> Dizziness includes dizziness, presyncope, syncope, vertigo.<br /> <sup>o</sup>Neuropathy peripheral includes carpal tunnel syndrome, hypoesthesia, hypoesthesia oral, neuralgia, neuropathyperipheral, paresthesia, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, sciatica.<br /> <sup>p</sup> Tremor includes asterixis, tremor.<br /> q Insomnia includes insomnia, sleep deficit, sleep disorder.<br /> <sup>r</sup> Anxiety includes anxiety, feeling jittery, nervousness.<br /> <sup>s</sup> Renal failure includes acute kidney injury, blood creatinine increased, chronic kidney disease, renal failure, renal impairment.<br /> <sup>t </sup>Cough includes cough, productive cough, upper-airway cough syndrome.<br /> <sup>u</sup>Dyspnea includes acute respiratory failure, dyspnea, dyspnea exertional, respiratory failure.<br /> <sup>v</sup> Rash includes acne, dermatitis, dermatitis bullous, erythema, rash, rash macular, rash papular, urticaria.<br /> <sup>w</sup> Xerosis includes dry eye, dry mouth, dry skin, lip dry, xerosis.<br /> <sup>x</sup> Hypotension includes hypotension, orthostatic hypotension.</td> </tr> </tbody> </table> </center> <p></p> <p>Other clinically important adverse reactions that occurred in less than 10% of patients treated with ABECMA include the following:</p> <ul> <li><b>Blood and lymphatic system disorders:</b> coagulopathy<sup>a</sup> (9%)</li> <li><b>Cardiac disorders:</b> atrial fibrillation (4.7%), cardiomyopathy<sup>b</sup> (1.6%)</li> <li><b>Gastrointestinal disorders:</b> gastrointestinal hemorrhage<sup>c</sup> (3.1%)</li> <li><b>Immune system disorders:</b> hemophagocytic lymphohistiocytosis (3.1%)</li> <li><b>Infections and infestations:</b> fungal infections (8%), sepsis<sup>d</sup> (9%)</li> <li><b>Nervous system disorders:</b> aphasia<sup>e</sup> (7%), ataxia<sup>f</sup> (3.1%), paresis<sup>g</sup> (2.4%), seizure (1.6%)</li> <li><b>Psychiatric disorders:</b> delirium<sup>h</sup> (6%)</li> <li><b>Respiratory, thoracic, and mediastinal disorders:</b> hypoxia (2.4%), pulmonary edema (2.4%)</li> <li><b>Vascular disorders:</b> thrombosis<sup>i</sup> (3.1%)</li> </ul> <p class="credit"><sup>a </sup>Coagulopathy includes activated partial thromboplastin time prolonged, anticoagulation drug level above therapeutic, disseminated intravascular coagulation, international normalized ratio increased.<br /> <sup>b </sup>Cardiomyopathy includes stress cardiomyopathy, ventricular hypertrophy.<br /> <sup>c</sup> Gastrointestinal hemorrhage includes gastrointestinal hemorrhage, hemorrhoidal hemorrhage, melena.<br /> <sup>d</sup> Sepsis includes bacteremia, enterococcal bacteremia, Escherichia bacteremia, sepsis, septic shock, Serratia bacteremia, streptococcal bacteremia.<br /> <sup>e</sup> Aphasia includes aphasia, dysarthria.<br /> <sup>f</sup> Ataxia includes ataxia, gait disturbance, Romberg test positive.<br /> <sup>g</sup> Paresis includes cranial nerve disorder, hemiparesis.<br /> <sup>h</sup> Delirium includes delirium, disorientation, hallucination.<br /> <sup>i</sup> Thrombosis includes deep vein thrombosis, jugular vein thrombosis, portal vein thrombosis, pulmonary embolism.</p> <h5>Laboratory Abnormalities</h5> <p>Table 4 presents the most common Grade 3 or 4 laboratory abnormalities, based on laboratory data, occurring in at least 10% of patients.</p> <p align="center"><b>Table 4: Grade 3 or 4<sup>a</sup> Laboratory Abnormalities Worsening from Baseline in at Least 10% of Patients Treated with ABECMA in the KarMMa Study</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="50%">Laboratory Abnormality</td> <td class="EmphTd">Dose=[150 to 450 x 10<sup>6</sup> CAR-Positive T cells]<br /> (N=127) %</td> </tr> <tr> <td width="50%">Grade 3 or 4 (%)</td> </tr> <tr> <td>Neutropenia</td> <td align="center">96</td> </tr> <tr> <td>Leukopenia</td> <td align="center">96</td> </tr> <tr> <td>Lymphopenia</td> <td align="center">92</td> </tr> <tr> <td>Thrombocytopenia</td> <td align="center">63</td> </tr> <tr> <td>Anemia</td> <td align="center">63</td> </tr> <tr> <td>Hypophosphatemia</td> <td align="center">45</td> </tr> <tr> <td>Hyponatremia</td> <td align="center">10</td> </tr> <tr> <td>aPTT Increased (seconds)</td> <td align="center">10</td> </tr> <tr> <td class="credit" colspan="2"><sup>a</sup>NCI CTCAE=Common Terminology Criteria for Adverse Events version 4.03.<br /> aPTT=activated partial thromboplastin time; CAR=chimeric antigen receptor; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute.<br /> Laboratory tests were graded according to NCI CTCAE Version 4.03. Laboratory abnormalities are sorted by decreasing frequency in the 150 to 450 x 10<sup>6</sup> column.</td> </tr> </tbody> </table> </center> <p></p> <p>Other clinically important Grade 3 or 4 laboratory abnormalities (based on laboratory data) that occurred in less than 10% of patients treated with ABECMA include the following: alanine aminotransferase increased, aspartate aminotransferase increased, hypoalbuminemia, alkaline phosphatase increased, hyperglycemia, hypokalemia, bilirubin increased, hypofibrinogenemia, and hypocalcemia.</p> <h4>Immunogenicity</h4> <p>ABECMA has the potential to induce anti-product antibodies. In clinical studies, humoral immunogenicity of ABECMA was measured by determination of anti-CAR antibody in serum pre- and post-administration. In the KarMMa study, 3% of patients (4/127) tested positive for pre-infusion anti-CAR antibodies and treatment-induced anti-CAR antibodies were detected in 47% (60/127) of the patients. There is no evidence that the presence of pre-existing or post-infusion anti-CAR antibodies impact the cellular expansion, safety, or effectiveness of ABECMA. 21</p> <a name="DI"></a> <h3>DRUG INTERACTIONS</h3> <h4>Drug/Laboratory Test Interactions</h4> <p>HIV and the lentivirus used to make ABECMA have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests may yield false-positive results in patients who have received ABECMA.</p> </div> </div> </div> | <a name="AR"></a> <h3>SIDE EFFECTS</h3> <p>The following adverse reactions are described elsewhere in the labeling:</p> <ul> <li>Cytokine Release Syndrome [see <b>WARNINGS AND PRECAUTIONS</b>]</li> <li>Neurologic Toxicities [see <b>WARNINGS AND PRECAUTIONS</b>]</li> <li>Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Hypersensitivity Reactions [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Infections [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Prolonged Cytopenias [see<b> WARNINGS AND PRECAUTIONS</b>]</li> <li>Hypogammaglobulinemia [see<b> WARNINGS AND PRECAUTIONS</b>]</li> </ul> <h4>Clinical Trials Experience</h4> <p>Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.</p> <p>The safety data described in this section reflect the exposure to ABECMA in the KarMMa study, in which 127 patients with relapsed/refractory multiple myeloma received ABECMA across a dose range of 150 to 518 x 10<sup>6</sup> CAR-positive T cells [see <b>Clinical Studies</b>]. Patients with a history of CNS disease (such as <a href="/seizure/definition.htm" ">seizure</a> or <a href="/cerebrovascular/definition.htm" ">cerebrovascular</a> <a href="/ischemia/definition.htm" ">ischemia</a>) or requiring ongoing treatment with chronic <a href="/immunosuppression/definition.htm" ">immunosuppression</a> were excluded. The median duration of follow-up was 11.4 months. The median age of the <a href="/study_population/definition.htm" ">study population</a> was 61 years (range: 33 to 78 years); 35% were 65 years or older, and 60% were men. The Eastern Cooperative <a href="/oncology/definition.htm" ">Oncology</a> Group (<a href="/ecog/definition.htm" ">ECOG</a>) performance status at baseline was 0 in 45%, 1 in 53%, and 2 in 2% of patients. Seven percent of the patients treated with ABECMA had creatinine clearance <45 ml/min. For details about the study population, see <b>Clinical Studies</b>.</p> <p>The most common (greater than or equal to 10%) Grade 3 or 4 nonlaboratory adverse reactions were <a href="/febrile/definition.htm" ">febrile</a> <a href="/neutropenia/definition.htm" ">neutropenia</a> (16%) and infections - <a href="/pathogen/definition.htm" ">pathogen</a> unspecified (15%).</p> <p>The most common nonlaboratory adverse reactions (incidence greater than or equal to 20%) included CRS, infections - pathogen unspecified, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, <a href="/encephalopathy/definition.htm" ">encephalopathy</a>, edema, pyrexia, cough, headache, and decreased appetite.</p> <p>Serious adverse reactions occurred in 67% of patients. The most common nonlaboratory (greater than or equal to 5%) serious adverse reactions included CRS (18%), general physical health deterioration (10%), <a href="/pneumonia/definition.htm" ">pneumonia</a> (12%), infections-pathogen unspecified (19%), viral infections (9%), <a href="/sepsis/definition.htm" ">sepsis</a> (7%), and febrile neutropenia (6%). Fatal adverse reactions occurred in 6%.</p> <p>Table 3 summarizes the adverse reactions that occurred in at least 10% of patients treated with ABECMA. Table 4 describes the most common Grade 3 or 4 laboratory abnormalities.</p> <p align="center"><b>Table 3: Adverse Reactions Observed in at Least 10% of Patients Treated with ABECMA in the KarMMa Study</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="3" width="40%">System Organ Class<br /> Preferred Term</td> <td class="EmphTd" colspan="2">Target Dose of ABECMA (CAR-Positive T Cells)</td> </tr> <tr> <td class="EmphTd">Any Grade</td> <td class="EmphTd">Grade 3 or Higher</td> </tr> <tr> <td class="EmphTd" width="30%">[150 to 450 x 10<sup>6</sup>]<br /> (N=127) %</td> <td class="EmphTd" width="30%">[150 to 450 x 10<sup>6</sup>]<br /> (N=127) %</td> </tr> <tr> <td colspan="3"><b>Blood and lymphatic system disorders</b></td> </tr> <tr> <td>Febrile neutropenia</td> <td align="center">16</td> <td align="center">16</td> </tr> <tr> <td colspan="3"><b>Cardiac disorders</b></td> </tr> <tr> <td>Tachycardia<sup>a</sup></td> <td align="center">19</td> <td align="center">0</td> </tr> <tr> <td colspan="3"><b>Gastrointestinal disorders</b></td> </tr> <tr> <td>Diarrhea</td> <td align="center">35</td> <td align="center">1.6</td> </tr> <tr> <td>Nausea</td> <td align="center">29</td> <td align="center">0</td> </tr> <tr> <td>Constipation</td> <td align="center">16</td> <td align="center">0</td> </tr> <tr> <td>Vomiting</td> <td align="center">15</td> <td align="center">0</td> </tr> <tr> <td>Oral pain<sup>b</sup></td> <td align="center">12</td> <td align="center">0</td> </tr> <tr> <td colspan="3"><b>General disorders and administration site conditions</b></td> </tr> <tr> <td>Fatigue<sup>c</sup></td> <td align="center">45</td> <td align="center">3.1</td> </tr> <tr> <td>Pyrexia</td> <td align="center">25</td> <td align="center">1.6</td> </tr> <tr> <td>General physical health deterioration</td> <td align="center">11</td> <td align="center">10</td> </tr> <tr> <td>Edema<sup>d</sup></td> <td align="center">25</td> <td align="center">0</td> </tr> <tr> <td>Chills</td> <td align="center">11</td> <td align="center">0</td> </tr> <tr> <td colspan="3"><b>Immune system disorders</b></td> </tr> <tr> <td>Cytokine release syndrome</td> <td align="center">85</td> <td align="center">9</td> </tr> <tr> <td>Hypogammaglobulinemia<sup>e</sup></td> <td align="center">41</td> <td align="center">0.8</td> </tr> <tr> <td colspan="3"><b>Infections and infestations<sup>f</sup></b></td> </tr> <tr> <td>Infections - Pathogen unspecified</td> <td align="center">51</td> <td align="center">15</td> </tr> <tr> <td>Viral infections</td> <td align="center">27</td> <td align="center">9</td> </tr> <tr> <td>Bacterial infections</td> <td align="center">15</td> <td align="center">3.9</td> </tr> <tr> <td>Pneumonia<sup>g</sup></td> <td align="center">17</td> <td align="center">9</td> </tr> <tr> <td>Upper respiratory tract infection<sup>h</sup></td> <td align="center">34</td> <td align="center">1.6</td> </tr> <tr> <td colspan="3"><b>Investigations</b></td> </tr> <tr> <td>Weight decreased</td> <td align="center">13</td> <td align="center">1.6</td> </tr> <tr> <td colspan="3"><b>Metabolism and nutrition disorders</b></td> </tr> <tr> <td>Decreased appetite<sup>i</sup></td> <td align="center">22</td> <td align="center">0.8</td> </tr> <tr> <td colspan="3"><b>Musculoskeletal and connective tissue disorders</b></td> </tr> <tr> <td>Musculoskeletal pain<sup>j</sup></td> <td align="center">45</td> <td align="center">3.1</td> </tr> <tr> <td>Motor dysfunction<sup>k</sup></td> <td align="center">11</td> <td align="center">0</td> </tr> <tr> <td colspan="3"><b>Nervous system disorders</b></td> </tr> <tr> <td>Encephalopathy<sup>l</sup></td> <td align="center">26</td> <td align="center">6</td> </tr> <tr> <td>Headache<sup>m</sup></td> <td align="center">23</td> <td align="center">0</td> </tr> <tr> <td>Dizziness<sup>n</sup></td> <td align="center">17</td> <td align="center">0.8</td> </tr> <tr> <td>Neuropathy peripheral<sup>o</sup></td> <td align="center">17</td> <td align="center">0.8</td> </tr> <tr> <td>Tremor<sup>p</sup></td> <td align="center">10</td> <td align="center">0</td> </tr> <tr> <td colspan="3"><b>Psychiatric disorders</b></td> </tr> <tr> <td>Insomnia<sup>q</sup></td> <td align="center">13</td> <td align="center">0</td> </tr> <tr> <td>Anxiety<sup>r</sup></td> <td align="center">12</td> <td align="center">0.8</td> </tr> <tr> <td colspan="3"><b>Renal and urinary disorders</b></td> </tr> <tr> <td>Renal failure<sup>s</sup></td> <td align="center">10</td> <td align="center">2.4</td> </tr> <tr> <td colspan="3"><b>Respiratory, thoracic, and mediastinal disorders</b></td> </tr> <tr> <td>Cough<sup>t</sup></td> <td align="center">23</td> <td align="center">0</td> </tr> <tr> <td>Dyspnea<sup>u</sup></td> <td align="center">13</td> <td align="center">2.4</td> </tr> <tr> <td colspan="3"><b>Skin and subcutaneous tissue disorder</b></td> </tr> <tr> <td>Rash<sup>v</sup></td> <td align="center">14</td> <td align="center">0.8</td> </tr> <tr> <td>Xerosis<sup>w</sup></td> <td align="center">11</td> <td align="center">0</td> </tr> <tr> <td colspan="3"><b>Vascular disorders</b></td> </tr> <tr> <td>Hypotension<sup>x</sup></td> <td align="center">17</td> <td align="center">0</td> </tr> <tr> <td>Hypertension</td> <td align="center">11</td> <td align="center">3.1</td> </tr> <tr> <td class="credit" colspan="3">CAR=chimeric antigen receptor.<br /> <sup>a</sup> Tachycardia includes sinus tachycardia, tachycardia.<br /> <sup>b</sup> Oral pain includes oral pain, oropharyngeal pain, toothache.<br /> <sup>c</sup> Fatigue includes asthenia, fatigue, malaise.<br /> <sup>d</sup> Edema includes edema, face edema, fluid overload, fluid retention, generalized edema, peripheral edema, peripheral swelling, scrotal swelling, swelling.<br /> <sup>e</sup> Hypogammaglobulinemia includes patients with adverse events (21%) of blood immunoglobulin G decreased, hypogammaglobulinemia, hypoglobulinemia; and/or patients with laboratory IgG levels below 500 mg/dL following ABECMA infusion (25%).<br /> <sup>f</sup> Infections and infestations System Organ Class Adverse Events are grouped by pathogen type and selected clinical syndromes.<br /> <sup>g</sup> Pneumonia includes bronchopulmonary aspergillosis, lung infection, pneumonia, pneumonia aspiration, pneumonia cytomegaloviral, pneumonia pneumococcal, pneumonia pseudomonal. Pneumonias may also be included under pathogen categories.<br /> <sup>h</sup> Upper respiratory tract infection includes laryngitis, nasopharyngitis, pharyngeal erythema, pharyngitis, respiratory tract congestion, respiratory tract infection, rhinitis, rhinovirus infection, sinusitis, upper respiratory tract infection, upper respiratory tract infection bacterial. Upper respiratory tract infections may also be included under pathogen categories.<br /> <sup>i</sup> Decreased appetite includes decreased appetite, hypophagia.<br /> <sup>j</sup> Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, spinal pain.<br /> <sup>k</sup> Motor dysfunction includes dysphonia, eyelid ptosis, hypotonia, motor dysfunction, muscle spasms, muscular weakness, restless legs syndrome.<br /> <sup>l</sup>Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, depressed level of consciousness,disturbance in attention, dyscalculia, dysgraphia, encephalopathy, lethargy, memory impairment, mental status changes,metabolic encephalopathy, somnolence, toxic encephalopathy.<br /> <sup>m</sup> Headache includes headache, head discomfort, sinus headache.<br /> <sup>n</sup> Dizziness includes dizziness, presyncope, syncope, vertigo.<br /> <sup>o</sup>Neuropathy peripheral includes carpal tunnel syndrome, hypoesthesia, hypoesthesia oral, neuralgia, neuropathyperipheral, paresthesia, peripheral sensorimotor neuropathy, peripheral sensory neuropathy, sciatica.<br /> <sup>p</sup> Tremor includes asterixis, tremor.<br /> q Insomnia includes insomnia, sleep deficit, sleep disorder.<br /> <sup>r</sup> Anxiety includes anxiety, feeling jittery, nervousness.<br /> <sup>s</sup> Renal failure includes acute kidney injury, blood creatinine increased, chronic kidney disease, renal failure, renal impairment.<br /> <sup>t </sup>Cough includes cough, productive cough, upper-airway cough syndrome.<br /> <sup>u</sup>Dyspnea includes acute respiratory failure, dyspnea, dyspnea exertional, respiratory failure.<br /> <sup>v</sup> Rash includes acne, dermatitis, dermatitis bullous, erythema, rash, rash macular, rash papular, urticaria.<br /> <sup>w</sup> Xerosis includes dry eye, dry mouth, dry skin, lip dry, xerosis.<br /> <sup>x</sup> Hypotension includes hypotension, orthostatic hypotension.</td> </tr> </tbody> </table> </center> <p></p> <p>Other clinically important adverse reactions that occurred in less than 10% of patients treated with ABECMA include the following:</p> <ul> <li><b>Blood and lymphatic system disorders:</b> coagulopathy<sup>a</sup> (9%)</li> <li><b>Cardiac disorders:</b> atrial fibrillation (4.7%), cardiomyopathy<sup>b</sup> (1.6%)</li> <li><b>Gastrointestinal disorders:</b> gastrointestinal hemorrhage<sup>c</sup> (3.1%)</li> <li><b>Immune system disorders:</b> hemophagocytic lymphohistiocytosis (3.1%)</li> <li><b>Infections and infestations:</b> fungal infections (8%), sepsis<sup>d</sup> (9%)</li> <li><b>Nervous system disorders:</b> aphasia<sup>e</sup> (7%), ataxia<sup>f</sup> (3.1%), paresis<sup>g</sup> (2.4%), seizure (1.6%)</li> <li><b>Psychiatric disorders:</b> delirium<sup>h</sup> (6%)</li> <li><b>Respiratory, thoracic, and mediastinal disorders:</b> hypoxia (2.4%), pulmonary edema (2.4%)</li> <li><b>Vascular disorders:</b> thrombosis<sup>i</sup> (3.1%)</li> </ul> <p class="credit"><sup>a </sup>Coagulopathy includes activated partial thromboplastin time prolonged, anticoagulation drug level above therapeutic, disseminated intravascular coagulation, international normalized ratio increased.<br /> <sup>b </sup>Cardiomyopathy includes stress cardiomyopathy, ventricular hypertrophy.<br /> <sup>c</sup> Gastrointestinal hemorrhage includes gastrointestinal hemorrhage, hemorrhoidal hemorrhage, melena.<br /> <sup>d</sup> Sepsis includes bacteremia, enterococcal bacteremia, Escherichia bacteremia, sepsis, septic shock, Serratia bacteremia, streptococcal bacteremia.<br /> <sup>e</sup> Aphasia includes aphasia, dysarthria.<br /> <sup>f</sup> Ataxia includes ataxia, gait disturbance, Romberg test positive.<br /> <sup>g</sup> Paresis includes cranial nerve disorder, hemiparesis.<br /> <sup>h</sup> Delirium includes delirium, disorientation, hallucination.<br /> <sup>i</sup> Thrombosis includes deep vein thrombosis, jugular vein thrombosis, portal vein thrombosis, pulmonary embolism.</p> <h5>Laboratory Abnormalities</h5> <p>Table 4 presents the most common Grade 3 or 4 laboratory abnormalities, based on laboratory data, occurring in at least 10% of patients.</p> <p align="center"><b>Table 4: Grade 3 or 4<sup>a</sup> Laboratory Abnormalities Worsening from Baseline in at Least 10% of Patients Treated with ABECMA in the KarMMa Study</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" rowspan="2" width="50%">Laboratory Abnormality</td> <td class="EmphTd">Dose=[150 to 450 x 10<sup>6</sup> CAR-Positive T cells]<br /> (N=127) %</td> </tr> <tr> <td width="50%">Grade 3 or 4 (%)</td> </tr> <tr> <td>Neutropenia</td> <td align="center">96</td> </tr> <tr> <td>Leukopenia</td> <td align="center">96</td> </tr> <tr> <td>Lymphopenia</td> <td align="center">92</td> </tr> <tr> <td>Thrombocytopenia</td> <td align="center">63</td> </tr> <tr> <td>Anemia</td> <td align="center">63</td> </tr> <tr> <td>Hypophosphatemia</td> <td align="center">45</td> </tr> <tr> <td>Hyponatremia</td> <td align="center">10</td> </tr> <tr> <td>aPTT Increased (seconds)</td> <td align="center">10</td> </tr> <tr> <td class="credit" colspan="2"><sup>a</sup>NCI CTCAE=Common Terminology Criteria for Adverse Events version 4.03.<br /> aPTT=activated partial thromboplastin time; CAR=chimeric antigen receptor; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute.<br /> Laboratory tests were graded according to NCI CTCAE Version 4.03. Laboratory abnormalities are sorted by decreasing frequency in the 150 to 450 x 10<sup>6</sup> column.</td> </tr> </tbody> </table> </center> <p></p> <p>Other clinically important Grade 3 or 4 laboratory abnormalities (based on laboratory data) that occurred in less than 10% of patients treated with ABECMA include the following: alanine aminotransferase increased, aspartate aminotransferase increased, hypoalbuminemia, alkaline phosphatase increased, hyperglycemia, hypokalemia, bilirubin increased, hypofibrinogenemia, and hypocalcemia.</p> <h4>Immunogenicity</h4> <p>ABECMA has the potential to induce anti-product antibodies. In clinical studies, humoral immunogenicity of ABECMA was measured by determination of anti-CAR antibody in serum pre- and post-administration. In the KarMMa study, 3% of patients (4/127) tested positive for pre-infusion anti-CAR antibodies and treatment-induced anti-CAR antibodies were detected in 47% (60/127) of the patients. There is no evidence that the presence of pre-existing or post-infusion anti-CAR antibodies impact the cellular expansion, safety, or effectiveness of ABECMA. 21</p> <a name="DI"></a> <h3>DRUG INTERACTIONS</h3> <h4>Drug/Laboratory Test Interactions</h4> <p>HIV and the lentivirus used to make ABECMA have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests may yield false-positive results in patients who have received ABECMA.</p> </div> </div> </div> | 12 | 2023-02-01 17:39:58 | Abecma (Idecabtagene Vicleucel Suspension) | A | CAR-T Cell Therapies | Abecma | idecabtagene vicleucel suspension | Abecma | |
| 92 | 2023-02-23 11:36:54 | Warnings & Precautions | <a name="W"></a> <h3>WARNINGS</h3> <p>Included as part of the <b>PRECAUTIONS</b> section.</p> <a name="P"></a> <h3>PRECAUTIONS</h3> <h4>Cytokine Release Syndrome (CRS)</h4> <p>CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA. CRS occurred in 85% (108/127) of patients receiving ABECMA. Grade 3 or higher CRS (Lee grading system<sup>1</sup>) occurred in 9% (12/127) of patients, with Grade 5 CRS reported in one (0.8%) patient. The median time-to-onset of CRS, any grade, was 1 day (range: 1 to 23 days), and the median duration of CRS was 7 days (range: 1 to 63 days) in all patients, including the patient who died. The most common manifestations of CRS included pyrexia (98%), hypotension (41%), tachycardia (35%), chills (31%), hypoxia (20%), fatigue (12%), and headache (10%). Grade 3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, ARDS, atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, multiple organ dysfunction syndrome and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) [see <b>ADVERSE REACTIONS</b>].</p> <p>Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. Please see Section 5.3; Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome.</p> <p>Overall rate of CRS was 79%, and rate of Grade 2 CRS was 23% in patients treated in the 300 x 10<sup>6</sup> CAR-positive T cells dose cohort (dose ranging from 277 to 339 x 10<sup>6</sup> CAR-positive T cells). For patients treated in the 450 x 10<sup>6</sup> CAR-positive T cells dose cohort (dose range 447 to 518 x 10<sup>6</sup> CAR-positive T cells), the overall rate of CRS was 96%, and rate of Grade 2 CRS was 40%. Rate of Grade 3 or higher CRS was similar across the dose range. The median duration of CRS for the 450 x 10<sup>6</sup> CAR-positive T cells dose cohort was 7 days (range 1 to 63 days), and was 6 days (range 2 to 28 days) for the 300 x 10<sup>6</sup> CAR-positive T cells dose cohort. In the 450 x 10<sup>6</sup> CAR-positive T cells dose cohort, 68% (36/53) of patients received tocilizumab and 23% (12/53) received at least 1 dose of corticosteroids for treatment of CRS. This was higher than the tocilizumab use of 44% (31/70) and corticosteroid use of 10% (7/70) at the 300 x 10<sup>6</sup> CAR-positive T cells dose cohort.</p> <p>Sixty-eight of 127 (54%) patients received tocilizumab; 35% (45/127) received a single dose, while 18% (23/127) received more than 1 dose of tocilizumab. Overall, across the dose levels, 15% (19/127) of patients received at least 1 dose of corticosteroids for treatment of CRS. All patients that received corticosteroids for CRS also received tocilizumab.</p> <p>Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA.</p> <p>Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see <b> PATIENT INFORMATION</b>].</p> <h4>Neurologic Toxicities</h4> <p>Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS.</p> <p>CAR T cell-associated neurotoxicity, occurred in 28% (36/127) of patients receiving ABECMA, including Grade 3 in 4% (5/127) of patients. One patient had ongoing Grade 2 neurotoxicity at the time of death. Two patients had ongoing Grade 1 tremor at the time of data cutoff. The median time to onset of neurotoxicity was 2 days (range: 1 to 42 days). CAR T cell-associated neurotoxicity resolved in 33 of 36 (92%); For patients who experienced neurotoxicity including three patients with ongoing neurotoxicity, the median duration of CAR T cell-associated neurotoxicity was 6 days (range: 1 to 578 days). Neurotoxicity resolved in 33 patients and median time to resolution was 5 days (range 1 to 61 days). Thirty-four patients with neurotoxicity had CRS. The onset of neurotoxicity during CRS was observed in 29 patients, before the onset of CRS in three patients, and after the CRS event in two patients.</p> <p>The rate of Grade 3 neurotoxicity was 8% in 450 x 10<sup>6</sup>CAR-positive T cells dose cohort and 1.4% in the 300 x 10<sup>6</sup>CAR-positive T cells dose cohort. The most frequent (greater than or equal to 5%) manifestations of CAR T cell-associated neurotoxicity include encephalopathy (20%), tremor (9%), aphasia (7%), and delirium (6%).</p> <p>Grade 4 neurotoxicity and cerebral edema have been associated with ABECMA in a patient in another study in multiple myeloma. Grade 3 myelitis and Grade 3 parkinsonism have occurred after treatment with ABECMA in another study in multiple myeloma.</p> <p>Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs and symptoms of neurologic toxicities. Rule out other causes of neurologic symptoms. Monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time [see <b> PATIENT INFORMATION</b>].</p> <h4>Hemophagocytic Lymphohistiocytosis (HLH)/ Macrophage Activation Syndrome (MAS)</h4> <p>HLH/MAS occurred in 4% (5/127) of patients receiving ABECMA. One patient treated in the 300 x10<sup>6</sup>CAR-positive T cells dose cohort developed fatal multi-organ HLH/MAS with CRS. In another patient with fatal bronchopulmonary aspergillosis, HLH/MAS was contributory to the fatal outcome. Three cases of Grade 2 HLH/MAS resolved.</p> <p>The rate of HLH/MAS was 8% in the 450 x10<sup>6</sup>CAR-positive T cells dose cohort and 1% in the 300 x10<sup>6</sup>CAR-positive T cells dose cohort. All events of HLH/MAS had onset within 10 days of receiving ABECMA, with a median onset of 7 days (range: 4 to 9 days) and occurred in the setting of ongoing or worsening CRS. Two patients with HLH/MAS had overlapping neurotoxicity.</p> <p>The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction and cytopenia.</p> <p>HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional standards.</p> <h4>Abecma Rems</h4> <p>Because of the risk of CRS and neurologic toxicities, ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS [see<b> BOXED WARNING</b> and <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>The required components of the ABECMA REMS are:</p> <ul> <li>Healthcare facilities that dispense and administer ABECMA must be enrolled and comply with the REMSrequirements.</li> <li>Certified healthcare facilities must have on-site, immediate access to tocilizumab.</li> <li>Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hoursafter ABECMA infusion, if needed for treatment of CRS.</li> <li>Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administerABECMA are trained in the management of CRS and neurologic toxicities.</li> <li>Further information is available at www.AbecmaREMS.com or contact Bristol-Myers Squibb at1-888-423-5436.</li> </ul> <h4>Hypersensitivity Reactions</h4> <p>Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA.</p> <h4>Infections</h4> <p>ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after ABECMA infusion. Infections (all grades) occurred in 70% of patients. Grade 3 or 4 infections occurred in 23% of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 15%, viral infections in 9%, bacterial infections in 3.9%, and fungal infections in 0.8% of patients. Overall, four patients had Grade 5 infections (3%); two patients (1.6%) had Grade 5 events of pneumonia, 1 patient (0.8%) had Grade 5 bronchopulmonary aspergillosis, and 1 patient (0.8%) had cytomegalovirus (CMV) pneumonia associated with Pneumocystis jirovecii. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, pre-emptive, and/or therapeutic antimicrobials according to standard institutional guidelines.</p> <p>Febrile neutropenia (was observed in 16% (20/127) of patients after ABECMA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.13</p> <h5>Viral Reactivation</h5> <p>Cytomegalovirus (CMV) infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines.</p> <p>Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against plasma cells.</p> <p>Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing.</p> <p>Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.</p> <h4>Prolonged Cytopenias</h4> <p>Patients may exhibit prolonged cytopenias following lymphodepleting chemotherapy and ABECMA infusion. In the KarMMa study, 41% of patients (52/127) experienced prolonged Grade 3 or 4 neutropenia and 49% (62/127) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion. Rate of prolonged neutropenia was 49% in the 450 x 10<sup>6</sup> CAR-positive T cells dose cohort and 34% in the 300 x 10<sup>6</sup> CAR-positive T cells dose cohort. In 83% (43/52) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months. In 65% (40/62) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 2.1 months. Median time to cytopenia recovery was similar across the 300 and 450 x 10<sup>6</sup> CAR-positive T cells dose cohort.</p> <p>Three patients underwent stem cell therapy (2 patients with autologous and 1 with allogeneic cells) for hematopoietic reconstitution due to prolonged cytopenia. Two of the three patients died from complications of prolonged cytopenia, which occurred in the setting of ongoing or prior severe CRS or HLH/MAS. Cause of death included lower gastrointestinal bleeding in the setting of prolonged thrombocytopenia in one patient and bronchopulmonary aspergillosis in the setting of prolonged neutropenia in another patient. The third patient recovered from neutropenia after autologous stem cell therapy.</p> <p>Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support according to local institutional guidelines.</p> <h4>Hypogammaglobulinemia</h4> <p>Plasma cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with ABECMA. Hypogammaglobulinemia was reported as an adverse event in 21% (27/127) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 25% (32/127) of patients treated with ABECMA.</p> <p>Hypogammaglobulinemia either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion occurred in 41% (52/127) of patients treated with ABECMA. Sixty-one percent of patients received intravenous immunoglobulin (IVIG) post-ABECMA for serum IgG <400 mg/dL.</p> <p>Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.</p> <h5>Use Of Live Vaccines</h5> <p>The safety of immunization with live viral vaccines during or following ABECMA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ABECMA treatment, and until immune recovery following treatment with ABECMA.</p> <h4>Secondary Malignancies</h4> <p>Patients treated with ABECMA may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol-Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing of secondarymalignancy of T cell origin.</p> <h4>Effects On Ability To Drive And Use Machines</h4> <p>Due to the potential for neurologic events, including altered mental status or seizures, patients receiving ABECMA are at risk for altered or decreased consciousness or coordination in the 8 weeks following ABECMA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.</p> <h4>Patient Counseling Information</h4> <p>Advise the patient to read the FDA-approved patient labeling (<b>Medication Guide</b>).</p> <p>Ensure that patients understand the risk of manufacturing failure (1.5%, [2/135 in the clinical study]). In case of a manufacturing failure, a second manufacturing of ABECMA may be attempted. In addition, while the patient awaits the product, additional anticancer treatment (not the lymphodepletion) may be necessary and may increase the risk of adverse events during the pre-infusion period, which could delay or prevent the administration of ABECMA.</p> <p>Advise patients to seek immediate attention for any of the following:</p> <ul> <li><b>Cytokine Release Syndrome (CRS):</b> Signs or symptoms associated with CRS, including fever, hypotension,tachycardia, chills, hypoxia, headache, and fatigue [see <b>DOSAGE AND ADMINISTRATION</b>, <b>WARNINGS AND PRECAUTIONS</b>, and <b>ADVERSE REACTIONS</b>].</li> <li><b>Neurologic Toxicities:</b> Signs or symptoms associated with neurologic events, including encephalopathy,confusion, seizures, tremor, aphasia, delirium, and somnolence [see<b> DOSAGE AND ADMINISTRATION</b>, <b>WARNINGS AND PRECAUTIONS</b>, and <b>ADVERSE REACTIONS</b>].</li> <li><b>Infections:</b> Signs or symptoms associated with infection [see <b>WARNINGS AND PRECAUTIONS</b> and <b>ADVERSE REACTIONS</b>].</li> <li><b>Prolonged Cytopenias:</b> Signs or symptoms associated with bone marrow suppression, including neutropenia,anemia, thrombocytopenia, or febrile neutropenia [see<b> WARNINGS AND PRECAUTIONS</b> and <b>WARNINGS AND PRECAUTIONS</b>].</li> </ul> <p>Advise patients for the need to:</p> <ul> <li>Contact Bristol-Myers Squibb at 1-888-805-4555 if they are diagnosed with a secondary malignancy [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Have periodic monitoring of blood counts before and after ABECMA infusion [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Refrain from driving or operating heavy or potentially dangerous machines until at least 8 weeks after ABECMA administration [see <b>WARNINGS AND PRECAUTIONS</b>].</li> </ul> <h4>Nonclinical Toxicology</h4> <h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4> <p>Genotoxicity assays and carcinogenicity studies in rodents were not performed for ABECMA</p> <p>In vitro expansion studies with CAR-positive T cells (ABECMA) from 5 patients and 2 healthy donor drug product lots showed no evidence for transformation and/or immortalization of T cells. A genomic insertion site analysis of the lentiviral vector was performed on ABECMA samples from twenty (20) individual patient donors. There was no evidence for preferential integration near genes of concern or preferential outgrowth of cells harboring integration sites of concern.</p> <p>No studies on the effects of ABECMA on fertility have been conducted.</p> <a name="USP"></a> <h4>Use In Specific Populations</h4> <h4>Pregnancy</h4> <h5>Risk Summary</h5> <p>There are no available data with ABECMA use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with ABECMA to assess whether it can cause fetal harm when administered to a pregnant woman.</p> <p>It is not known if ABECMA has the potential to be transferred to the fetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including plasma cell aplasia or hypogammaglobulinemia. Therefore, ABECMA is not recommended for women who are pregnant, and pregnancy after ABECMA infusion should be discussed with the treating physician. Assess immunoglobulin levels in newborns of mothers treated with ABECMA.</p> <p>The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.</p> <h4>Lactation</h4> <h5>Risk Summary</h5> <p>There is no information regarding the presence of ABECMA in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ABECMA and any potential adverse effects on the breastfed infant from ABECMA or from the underlying maternal condition.</p> <h4>Females And Males Of Reproductive Potential</h4> <h5>Pregnancy Testing</h5> <p>Pregnancy status of sexually-active females with reproductive potential should be verified via pregnancy testing prior to starting treatment with ABECMA.</p> <h5>Contraception</h5> <p>See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.</p> <p>There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with ABECMA.</p> <h5>Infertility</h5> <p>There are no data on the effect of ABECMA on fertility.</p> <h4>Pediatric Use</h4> <p>The safety and efficacy of ABECMA in patients under 18 years of age have not been established.</p> <h4>Geriatric Use</h4> <p>In the clinical trial of ABECMA, 45 (35%) of the 127 patients in the KarMMa study were 65 years of age or older and 4/127 (3%) patients were 75 years of age or older. All five cases of Grade 3 neurotoxicity occurred in patients ≥65 years of age (66 to 74 years). No clinically important differences in effectiveness of ABECMA were observed between these patients and patients younger than 65 years of age.</p> <p class="credit"><b>REFERENCES</b></p> <p class="credit">1.Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine releasesyndrome. Blood 2014; 124(2): 188-95. Errata in Blood: 2015;126(8):1048. and 2016;128(11):1533.</p> </div> </div> </div> | <a name="W"></a> <h3>WARNINGS</h3> <p>Included as part of the <b>PRECAUTIONS</b> section.</p> <a name="P"></a> <h3>PRECAUTIONS</h3> <h4>Cytokine Release Syndrome (CRS)</h4> <p>CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA. CRS occurred in 85% (108/127) of patients receiving ABECMA. Grade 3 or higher CRS (Lee grading system<sup>1</sup>) occurred in 9% (12/127) of patients, with Grade 5 CRS reported in one (0.8%) patient. The median time-to-onset of CRS, any grade, was 1 day (range: 1 to 23 days), and the median duration of CRS was 7 days (range: 1 to 63 days) in all patients, including the patient who died. The most common manifestations of CRS included pyrexia (98%), hypotension (41%), tachycardia (35%), chills (31%), hypoxia (20%), fatigue (12%), and headache (10%). Grade 3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, ARDS, atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, multiple organ dysfunction syndrome and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) [see <b>ADVERSE REACTIONS</b>].</p> <p>Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. Please see Section 5.3; Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome.</p> <p>Overall rate of CRS was 79%, and rate of Grade 2 CRS was 23% in patients treated in the 300 x 10<sup>6</sup> CAR-positive T cells dose cohort (dose ranging from 277 to 339 x 10<sup>6</sup> CAR-positive T cells). For patients treated in the 450 x 10<sup>6</sup> CAR-positive T cells dose cohort (dose range 447 to 518 x 10<sup>6</sup> CAR-positive T cells), the overall rate of CRS was 96%, and rate of Grade 2 CRS was 40%. Rate of Grade 3 or higher CRS was similar across the dose range. The median duration of CRS for the 450 x 10<sup>6</sup> CAR-positive T cells dose cohort was 7 days (range 1 to 63 days), and was 6 days (range 2 to 28 days) for the 300 x 10<sup>6</sup> CAR-positive T cells dose cohort. In the 450 x 10<sup>6</sup> CAR-positive T cells dose cohort, 68% (36/53) of patients received tocilizumab and 23% (12/53) received at least 1 dose of corticosteroids for treatment of CRS. This was higher than the tocilizumab use of 44% (31/70) and corticosteroid use of 10% (7/70) at the 300 x 10<sup>6</sup> CAR-positive T cells dose cohort.</p> <p>Sixty-eight of 127 (54%) patients received tocilizumab; 35% (45/127) received a single dose, while 18% (23/127) received more than 1 dose of tocilizumab. Overall, across the dose levels, 15% (19/127) of patients received at least 1 dose of corticosteroids for treatment of CRS. All patients that received corticosteroids for CRS also received tocilizumab.</p> <p>Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA.</p> <p>Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, institute treatment with supportive care, tocilizumab and/or corticosteroids as indicated [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see <b> PATIENT INFORMATION</b>].</p> <h4>Neurologic Toxicities</h4> <p>Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS.</p> <p>CAR T cell-associated neurotoxicity, occurred in 28% (36/127) of patients receiving ABECMA, including Grade 3 in 4% (5/127) of patients. One patient had ongoing Grade 2 neurotoxicity at the time of death. Two patients had ongoing Grade 1 tremor at the time of data cutoff. The median time to onset of neurotoxicity was 2 days (range: 1 to 42 days). CAR T cell-associated neurotoxicity resolved in 33 of 36 (92%); For patients who experienced neurotoxicity including three patients with ongoing neurotoxicity, the median duration of CAR T cell-associated neurotoxicity was 6 days (range: 1 to 578 days). Neurotoxicity resolved in 33 patients and median time to resolution was 5 days (range 1 to 61 days). Thirty-four patients with neurotoxicity had CRS. The onset of neurotoxicity during CRS was observed in 29 patients, before the onset of CRS in three patients, and after the CRS event in two patients.</p> <p>The rate of Grade 3 neurotoxicity was 8% in 450 x 10<sup>6</sup>CAR-positive T cells dose cohort and 1.4% in the 300 x 10<sup>6</sup>CAR-positive T cells dose cohort. The most frequent (greater than or equal to 5%) manifestations of CAR T cell-associated neurotoxicity include encephalopathy (20%), tremor (9%), aphasia (7%), and delirium (6%).</p> <p>Grade 4 neurotoxicity and cerebral edema have been associated with ABECMA in a patient in another study in multiple myeloma. Grade 3 myelitis and Grade 3 parkinsonism have occurred after treatment with ABECMA in another study in multiple myeloma.</p> <p>Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs and symptoms of neurologic toxicities. Rule out other causes of neurologic symptoms. Monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed [see <b>DOSAGE AND ADMINISTRATION</b>].</p> <p>Counsel patients to seek immediate medical attention should signs or symptoms of neurologic toxicity occur at any time [see <b> PATIENT INFORMATION</b>].</p> <h4>Hemophagocytic Lymphohistiocytosis (HLH)/ Macrophage Activation Syndrome (MAS)</h4> <p>HLH/MAS occurred in 4% (5/127) of patients receiving ABECMA. One patient treated in the 300 x10<sup>6</sup>CAR-positive T cells dose cohort developed fatal multi-organ HLH/MAS with CRS. In another patient with fatal bronchopulmonary aspergillosis, HLH/MAS was contributory to the fatal outcome. Three cases of Grade 2 HLH/MAS resolved.</p> <p>The rate of HLH/MAS was 8% in the 450 x10<sup>6</sup>CAR-positive T cells dose cohort and 1% in the 300 x10<sup>6</sup>CAR-positive T cells dose cohort. All events of HLH/MAS had onset within 10 days of receiving ABECMA, with a median onset of 7 days (range: 4 to 9 days) and occurred in the setting of ongoing or worsening CRS. Two patients with HLH/MAS had overlapping neurotoxicity.</p> <p>The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction and cytopenia.</p> <p>HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional standards.</p> <h4>Abecma Rems</h4> <p>Because of the risk of CRS and neurologic toxicities, ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS [see<b> BOXED WARNING</b> and <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>The required components of the ABECMA REMS are:</p> <ul> <li>Healthcare facilities that dispense and administer ABECMA must be enrolled and comply with the REMSrequirements.</li> <li>Certified healthcare facilities must have on-site, immediate access to tocilizumab.</li> <li>Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hoursafter ABECMA infusion, if needed for treatment of CRS.</li> <li>Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administerABECMA are trained in the management of CRS and neurologic toxicities.</li> <li>Further information is available at www.AbecmaREMS.com or contact Bristol-Myers Squibb at1-888-423-5436.</li> </ul> <h4>Hypersensitivity Reactions</h4> <p>Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA.</p> <h4>Infections</h4> <p>ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after ABECMA infusion. Infections (all grades) occurred in 70% of patients. Grade 3 or 4 infections occurred in 23% of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 15%, viral infections in 9%, bacterial infections in 3.9%, and fungal infections in 0.8% of patients. Overall, four patients had Grade 5 infections (3%); two patients (1.6%) had Grade 5 events of pneumonia, 1 patient (0.8%) had Grade 5 bronchopulmonary aspergillosis, and 1 patient (0.8%) had cytomegalovirus (CMV) pneumonia associated with Pneumocystis jirovecii. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, pre-emptive, and/or therapeutic antimicrobials according to standard institutional guidelines.</p> <p>Febrile neutropenia (was observed in 16% (20/127) of patients after ABECMA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care as medically indicated.13</p> <h5>Viral Reactivation</h5> <p>Cytomegalovirus (CMV) infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines.</p> <p>Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against plasma cells.</p> <p>Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing.</p> <p>Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.</p> <h4>Prolonged Cytopenias</h4> <p>Patients may exhibit prolonged cytopenias following lymphodepleting chemotherapy and ABECMA infusion. In the KarMMa study, 41% of patients (52/127) experienced prolonged Grade 3 or 4 neutropenia and 49% (62/127) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion. Rate of prolonged neutropenia was 49% in the 450 x 10<sup>6</sup> CAR-positive T cells dose cohort and 34% in the 300 x 10<sup>6</sup> CAR-positive T cells dose cohort. In 83% (43/52) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months. In 65% (40/62) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 2.1 months. Median time to cytopenia recovery was similar across the 300 and 450 x 10<sup>6</sup> CAR-positive T cells dose cohort.</p> <p>Three patients underwent stem cell therapy (2 patients with autologous and 1 with allogeneic cells) for hematopoietic reconstitution due to prolonged cytopenia. Two of the three patients died from complications of prolonged cytopenia, which occurred in the setting of ongoing or prior severe CRS or HLH/MAS. Cause of death included lower gastrointestinal bleeding in the setting of prolonged thrombocytopenia in one patient and bronchopulmonary aspergillosis in the setting of prolonged neutropenia in another patient. The third patient recovered from neutropenia after autologous stem cell therapy.</p> <p>Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support according to local institutional guidelines.</p> <h4>Hypogammaglobulinemia</h4> <p>Plasma cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with ABECMA. Hypogammaglobulinemia was reported as an adverse event in 21% (27/127) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 25% (32/127) of patients treated with ABECMA.</p> <p>Hypogammaglobulinemia either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion occurred in 41% (52/127) of patients treated with ABECMA. Sixty-one percent of patients received intravenous immunoglobulin (IVIG) post-ABECMA for serum IgG <400 mg/dL.</p> <p>Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.</p> <h5>Use Of Live Vaccines</h5> <p>The safety of immunization with live viral vaccines during or following ABECMA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ABECMA treatment, and until immune recovery following treatment with ABECMA.</p> <h4>Secondary Malignancies</h4> <p>Patients treated with ABECMA may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol-Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing of secondarymalignancy of T cell origin.</p> <h4>Effects On Ability To Drive And Use Machines</h4> <p>Due to the potential for neurologic events, including altered mental status or seizures, patients receiving ABECMA are at risk for altered or decreased consciousness or coordination in the 8 weeks following ABECMA infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.</p> <h4>Patient Counseling Information</h4> <p>Advise the patient to read the FDA-approved patient labeling (<b>Medication Guide</b>).</p> <p>Ensure that patients understand the risk of manufacturing failure (1.5%, [2/135 in the clinical study]). In case of a manufacturing failure, a second manufacturing of ABECMA may be attempted. In addition, while the patient awaits the product, additional anticancer treatment (not the lymphodepletion) may be necessary and may increase the risk of adverse events during the pre-infusion period, which could delay or prevent the administration of ABECMA.</p> <p>Advise patients to seek immediate attention for any of the following:</p> <ul> <li><b>Cytokine Release Syndrome (CRS):</b> Signs or symptoms associated with CRS, including fever, hypotension,tachycardia, chills, hypoxia, headache, and fatigue [see <b>DOSAGE AND ADMINISTRATION</b>, <b>WARNINGS AND PRECAUTIONS</b>, and <b>ADVERSE REACTIONS</b>].</li> <li><b>Neurologic Toxicities:</b> Signs or symptoms associated with neurologic events, including encephalopathy,confusion, seizures, tremor, aphasia, delirium, and somnolence [see<b> DOSAGE AND ADMINISTRATION</b>, <b>WARNINGS AND PRECAUTIONS</b>, and <b>ADVERSE REACTIONS</b>].</li> <li><b>Infections:</b> Signs or symptoms associated with infection [see <b>WARNINGS AND PRECAUTIONS</b> and <b>ADVERSE REACTIONS</b>].</li> <li><b>Prolonged Cytopenias:</b> Signs or symptoms associated with bone marrow suppression, including neutropenia,anemia, thrombocytopenia, or febrile neutropenia [see<b> WARNINGS AND PRECAUTIONS</b> and <b>WARNINGS AND PRECAUTIONS</b>].</li> </ul> <p>Advise patients for the need to:</p> <ul> <li>Contact Bristol-Myers Squibb at 1-888-805-4555 if they are diagnosed with a secondary malignancy [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Have periodic monitoring of blood counts before and after ABECMA infusion [see <b>WARNINGS AND PRECAUTIONS</b>].</li> <li>Refrain from driving or operating heavy or potentially dangerous machines until at least 8 weeks after ABECMA administration [see <b>WARNINGS AND PRECAUTIONS</b>].</li> </ul> <h4>Nonclinical Toxicology</h4> <h4>Carcinogenesis, Mutagenesis, Impairment Of Fertility</h4> <p>Genotoxicity assays and carcinogenicity studies in rodents were not performed for ABECMA</p> <p>In vitro expansion studies with CAR-positive T cells (ABECMA) from 5 patients and 2 healthy donor drug product lots showed no evidence for transformation and/or immortalization of T cells. A genomic insertion site analysis of the lentiviral vector was performed on ABECMA samples from twenty (20) individual patient donors. There was no evidence for preferential integration near genes of concern or preferential outgrowth of cells harboring integration sites of concern.</p> <p>No studies on the effects of ABECMA on fertility have been conducted.</p> <a name="USP"></a> <h4>Use In Specific Populations</h4> <h4>Pregnancy</h4> <h5>Risk Summary</h5> <p>There are no available data with ABECMA use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with ABECMA to assess whether it can cause fetal harm when administered to a pregnant woman.</p> <p>It is not known if ABECMA has the potential to be transferred to the fetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including plasma cell aplasia or hypogammaglobulinemia. Therefore, ABECMA is not recommended for women who are pregnant, and pregnancy after ABECMA infusion should be discussed with the treating physician. Assess immunoglobulin levels in newborns of mothers treated with ABECMA.</p> <p>The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.</p> <h4>Lactation</h4> <h5>Risk Summary</h5> <p>There is no information regarding the presence of ABECMA in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ABECMA and any potential adverse effects on the breastfed infant from ABECMA or from the underlying maternal condition.</p> <h4>Females And Males Of Reproductive Potential</h4> <h5>Pregnancy Testing</h5> <p>Pregnancy status of sexually-active females with reproductive potential should be verified via pregnancy testing prior to starting treatment with ABECMA.</p> <h5>Contraception</h5> <p>See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.</p> <p>There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with ABECMA.</p> <h5>Infertility</h5> <p>There are no data on the effect of ABECMA on fertility.</p> <h4>Pediatric Use</h4> <p>The safety and efficacy of ABECMA in patients under 18 years of age have not been established.</p> <h4>Geriatric Use</h4> <p>In the clinical trial of ABECMA, 45 (35%) of the 127 patients in the KarMMa study were 65 years of age or older and 4/127 (3%) patients were 75 years of age or older. All five cases of Grade 3 neurotoxicity occurred in patients ≥65 years of age (66 to 74 years). No clinically important differences in effectiveness of ABECMA were observed between these patients and patients younger than 65 years of age.</p> <p class="credit"><b>REFERENCES</b></p> <p class="credit">1.Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine releasesyndrome. Blood 2014; 124(2): 188-95. Errata in Blood: 2015;126(8):1048. and 2016;128(11):1533.</p> </div> </div> </div> | 12 | 2023-02-01 17:39:58 | Abecma (Idecabtagene Vicleucel Suspension) | A | CAR-T Cell Therapies | Abecma | idecabtagene vicleucel suspension | Abecma | |
| 93 | 2023-02-23 11:36:54 | Overdosage & Contraindications | <a name="OD"></a> <h3>OVERDOSE</h3> <p>No Information provided</p> <a name="CI"></a> <h3>CONTRAINDICATIONS</h3> <p>None.</p> </div> </div> </div> | <a name="OD"></a> <h3>OVERDOSE</h3> <p>No Information provided</p> <a name="CI"></a> <h3>CONTRAINDICATIONS</h3> <p>None.</p> </div> </div> </div> | 12 | 2023-02-01 17:39:58 | Abecma (Idecabtagene Vicleucel Suspension) | A | CAR-T Cell Therapies | Abecma | idecabtagene vicleucel suspension | Abecma | |
| 94 | 2023-02-23 12:07:03 | Clinical Pharmacology | <a name="CP"></a> <h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism Of Action</h4> <p>ABECMA is a chimeric antigen receptor (CAR)-positive T cell therapy targeting B-cell maturation antigen (BCMA), which is expressed on the surface of normal and malignant plasma cells. The CAR construct includes an anti-BCMA scFv-targeting domain for antigen specificity, a transmembrane domain, a CD3-zeta T cell activation domain, and a 4-1BB costimulatory domain. Antigen-specific activation of ABECMA results in CAR-positive T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.</p> <h4>Pharmacodynamics</h4> <p>Following ABECMA infusion, pharmacodynamic responses of CAR activation and anti-tumor efficacy were evaluated. Peak elevation of plasma cytokines, chemokines, and soluble immune mediators occurred within 14 days of ABECMA infusion and returned to baseline levels within one month.</p> <p>Rapid decreases in tumor markers associated with clinical response, including serum levels of soluble BCMA, and bone marrow CD138+ cells, as well as minimal residual disease (MRD) negative responses, were observed within the first month following ABECMA infusion.</p> <h4>Pharmacokinetics</h4> <p>Following ABECMA infusion, the CAR-positive cells proliferate and undergo rapid multi-log expansion followed by a bi-exponential decline. The median time of maximal expansion in peripheral blood (Tmax) occurred 11 days after infusion.</p> <p>ABECMA can persist in peripheral blood for up to 1 year post-infusion. A summary of Tmax, AUC0-28days, and Cmax by the recommended dose range provided in Table 5.</p> <p align="center"><b>Table 5: Pharmacokinetic Parameters of ABECMA by Recommended Dose Range in Patients with Relapsed/Refractory Multiple Myeloma in the KarMMa Study</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="40%">Pharmacokinetic Parameter</td> <td class="EmphTd" width="30%">Summary Statistic</td> <td class="EmphTd" width="30%">Total [300 to 460 x 10<sup>6</sup>] CAR-Positive T Cells</td> </tr> <tr> <td>Tmax (days)</td> <td align="center">Median (Range)</td> <td align="center">11 (7-28) N = 99</td> </tr> <tr> <td>Cmax (copies/mcg)</td> <td align="center">Geometric mean (geometric CV%)</td> <td align="center">256,333 (165) N = 99</td> </tr> <tr> <td>AUC0-28days (days*copies/mcg)</td> <td align="center">Geometric mean (geometric CV%)</td> <td align="center">3,088,455 (190) N = 98</td> </tr> <tr> <td class="credit" colspan="3">AUC0-28days = area under the curve of the transgene level from time of dose to 28 days post-infusion; Cmax = the maximum transgene level; Tmax = time of maximum observed transgene level.</td> </tr> </tbody> </table> </center> <p></p> <p>ABECMA transgene levels were positively associated with <a href="/objective/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">objective</a> tumor response (partial response or better). The median Cmax levels in responders (N = 72) were approximately 4.6-fold higher than the corresponding levels in non-responders (N = 27). Median AUC0-28days in responding patients (N = 72) was approximately 5.6-fold higher than non-responders (N = 26).</p> <h5>Tocilizumab And Corticosteroid Use</h5> <p>Some patients required tocilizumab and/or corticosteroid for the management of CRS. ABECMA can continue to expand and persist following tocilizumab or corticosteroid administration [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>Patients with CRS treated with tocilizumab had higher ABECMA cellular expansion levels, as measured by 1.3-fold and 1.6-fold higher median Cmax (N = 67) and AUC0-28days (N = 66), respectively, compared to patients who did not receive tocilizumab (N = 59 for Cmax and N = 58 for AUC0-28days).</p> <p>Patients with CRS treated with corticosteroids had higher ABECMA cellular expansion levels, as measured by 1.7-fold and 2.2-fold higher median Cmax (N = 18) and AUC0-28days (N = 18), respectively, compared to patients who did not receive corticosteroids (N = 108 for Cmax and N = 10<sup>6</sup> for AUC0-28days).</p> <h4>Specific Populations</h4> <h5>Geriatric</h5> <p>Age (range: 33 to 78 years) had no significant impact on expansion parameters [see <b>Use In Special Populations</b>].</p> <h5>Pediatric</h5> <p>The pharmacokinetics of ABECMA in patients less than 18 years of age have not been evaluated.</p> <h5>Patients With Hepatic/Renal Impairment</h5> <p>Hepatic and renal impairment studies of ABECMA were not conducted.</p> <h5>Patients With Other Intrinsic Factors</h5> <p>Gender, race, and ethnicity had no significant impact on ABECMA expansion parameters. Patients with lower body weight had higher expansion. Due to high variability in pharmacokinetic cellular expansion, the overall effect of weight on the pharmacokinetics of ABECMA is considered to be not clinically relevant.</p> <a name="CS"></a> <h4>Clinical Studies</h4> <h4>Relapsed/Refractory Multiple Myeloma</h4> <p>Efficacy of ABECMA was evaluated in KarMMa (NCT03361748), an open-label, single-arm, multicenter study in adult patients with relapsed and refractory multiple myeloma who had received at least 3 prior lines of antimyeloma therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 <a href="/monoclonal/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">monoclonal</a> antibody. The study included patients with ECOG performance status of 0 or 1. The study excluded patients with a creatinine clearance of less than or equal to 45 mL/minute, <a href="/alanine_aminotransferase_alt/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">alanine aminotransferase</a> >2.5 times upper limit of normal and left <a href="/ventricular/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ventricular</a> <a href="/ejection_fraction/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">ejection fraction</a> <45%. Patients were also excluded if <a href="/absolute_neutrophil_count/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">absolute neutrophil count</a> <1000 cells/mm³ and <a href="/platelet_count/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">platelet count</a> <50,000/mm³. Patients had measurable disease by International Myeloma Working Group (IMWG) 2016 criteria at enrollment. Bridging therapy with alkylating agents, corticosteroids, immunomodulatory agents, proteasome inhibitors, and/or anti-CD38 monoclonal antibodies to which patients were previously exposed was permitted for disease control between <a href="/apheresis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">apheresis</a> and until 14 days before the start of lymphodepleting chemotherapy.</p> <p>Lymphodepleting chemotherapy consisted of cyclophosphamide (300 mg/m² IV infusion daily for 3 days) and fludarabine (30 mg/m² IV infusion daily for 3 days) starting 5 days prior to the target infusion date of ABECMA. Fludarabine was dose reduced for renal insufficiency. Patients were hospitalized for 14 days after ABECMA infusion to monitor for potential CRS, HLH/MAS, and neurotoxicity.</p> <p>Of the 135 patients who underwent leukapheresis for 300 x 10<sup>6</sup> and 450 x 10<sup>6</sup> CAR-positive T cell dose cohorts:</p> <p>11 (8%) did not receive the CAR-positive T cells either due to death (n=2), adverse event (n=1), diseaseprogression (n=1), consent withdrawal (n=3), physician decision (n=3), or inability to manufactureproduct [manufacturing failure (n=1)]. Two patients died after receiving lymphodepletion and prior toreceiving ABECMA. Deaths were from <a href="/septic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">septic</a> <a href="/shock/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">shock</a> and general physical health deterioration.</p> <p>24 (18%) either received ABECMA outside of the 300 to 460 x 10<sup>6</sup> CAR-positive T cells dose range(n=23) or received CAR-positive T cells that did not meet product release specifications for ABECMA(non-conforming product; n=1).</p> <p>The efficacy evaluable population consists of the 100 patients (74%) who received ABECMA in thedose range of 300 to 460 x 10<sup>6</sup> CAR-positive T cells.</p> <p>The overall manufacturing failure rate for patients who underwent leukapheresis for the 300 x 10<sup>6</sup> and 450 x 10<sup>6</sup>CAR-positive T cell dose cohorts was 1.5% (2 out of 135 patients). Of these 2 patients, one received CAR-positive T cells that did not meet product release specifications for ABECMA, and in one patient there was an inability to manufacture ABECMA.</p> <p>Of the 100 patients in the efficacy evaluable population, the median age was 62 years (range: 33 to 78 years), 60% were male, 78% were white, 6% were black, and 2% were Asian. Most patients (78%) were International <a href="/staging/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Staging</a> System (ISS) Stage I or II. High-risk <a href="/cytogenetics/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">cytogenetics</a> (presence of t(4:14), t(14:16), and 17p13 del) were present in 37% of patients. Thirty-six percent of the patients had presence of extramedullary disease.</p> <p>The median number of prior lines of therapy was 6 (range: 3 to 16), and 88% of the patients received 4 or more prior lines of therapy. Ninety-five percent of the patients were refractory to an anti-CD38 monoclonal antibody. Eighty-five percent were triple class refractory (refractory to a proteasome inhibitor [PI], an immunomodulatory drug [IMiD] and an anti-CD38 monoclonal antibody), and 26% were penta-refractory (refractory to 2 PIs, 2 IMiD agents, and an anti-CD38 monoclonal antibody). Ninety-two percent had received prior autologous <a href="/stem_cell_transplantation/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">stem cell transplantation</a>.</p> <p>Most patients (87%) treated with ABECMA received bridging therapy for control of their multiple myeloma during the manufacturing process. The median time from leukapheresis to product availability was 33 days (range: 26 to 49 days).</p> <p>Efficacy was established on the basis of overall response rate (ORR), complete response (CR) rate, and duration of response (DOR), as assessed by the Independent Response committee (IRC) based on the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma.</p> <p>Efficacy results for the dose range of 300 to 460 x 10<sup>6</sup> CAR-positive T cells are shown in Table 6 and Table 7, and the DOR results are shown in Table 8. The median time to first response was 30 days (range: 15 to 88 days).</p> <p align="center"><b>Table 6: Summary of Efficacy Based on Independent Response Committee Review According to IMWG Criteria</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="70%"></td> <td class="EmphTd" width="30%">ABECMA-Treated Population (300 to 460 x 10<sup>6</sup> CAR-Positive T Cells)<br /> N=100</td> </tr> <tr> <td>Overall Response Rate (sCR<sup>a</sup>+VGPR+PR), n (%)</td> <td align="center">72 (72)</td> </tr> <tr> <td>95% CI<sup>b</sup> (%)</td> <td align="center">62, 81</td> </tr> <tr> <td>sCRa, n (%)</td> <td align="center">28 (28)</td> </tr> <tr> <td>95% CI<sup>b</sup> (%)</td> <td align="center">19, 38</td> </tr> <tr> <td>VGPR, n (%)</td> <td align="center">25 (25)</td> </tr> <tr> <td>95% CI<sup>b</sup> (%)</td> <td align="center">17, 35</td> </tr> <tr> <td>PR, n (%)</td> <td align="center">19 (19)</td> </tr> <tr> <td>95% CI<sup>b</sup> (%)</td> <td align="center">12, 28</td> </tr> <tr> <td class="credit" colspan="2">CAR=chimeric antigen receptor; CI=confidence interval; CR=complete response; MRD=Minimal Residual Disease; IMWG=International Myeloma Working Group; PR=partial response; sCR=stringent complete response; VGPR=very good partial response.<br /> <sup>a</sup> All complete responses were stringent CRs.<br /> <sup>b</sup>: Clopper-Pearson exact CI.</td> </tr> </tbody> </table> </center> <p></p> <p align="center"><b>Table 7: MRD Negativity Rate</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td width="70%">MRD<sup>c</sup>-negativity rate<sup>a</sup> in all treated patients (n=100) 95% CI<sup>b</sup> (%)</td> <td align="center" width="30%">21 (21) 13, 30</td> </tr> <tr> <td>MRD<sup>c</sup>-negativity rate<sup>a</sup> in patients achieving CR or sCR status (%) (n=28) 95% CI<sup>b</sup></td> <td align="center">21 (75) 55, 89</td> </tr> <tr> <td class="credit" colspan="2"><sup>a</sup> <a href="/mrd/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">MRD</a> negativity was defined as the proportion of patients with CR or stringent CR who are MRD negative at any timepoint within 3 months prior to achieving CR or stringent CR until the time of progression or death.<br /> <sup>b</sup> Clopper-Pearson exact CI.<br /> <sup>c</sup> Based on a threshold of 10-5 using ClonoSEQ, a next-generation sequencing assay (NGS).</td> </tr> </tbody> </table> </center> <p></p> <p align="center"><b>Table 8: Duration of Response</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="70%"></td> <td class="EmphTd" width="30%">ABECMA-Treated Population (300 to 460 x 10<sup>6</sup> CAR-Positive T Cells)<br /> N=100</td> </tr> <tr> <td colspan="2"><b>Duration of Response<sup>a,b</sup> (PR or Better)</b></td> </tr> <tr> <td>n</td> <td align="center">72</td> </tr> <tr> <td>Median (months)</td> <td align="center">11.0</td> </tr> <tr> <td>95% CI</td> <td align="center">10.3, 11.4</td> </tr> <tr> <td colspan="2"><b>Duration of Response<sup>b</sup> for sCR</b></td> </tr> <tr> <td>n</td> <td align="center">28</td> </tr> <tr> <td>Median (months)</td> <td align="center">19.0</td> </tr> <tr> <td>95% CI</td> <td align="center">11.4, NE</td> </tr> <tr> <td>Median follow-up for duration of response (DOR)</td> <td align="center">10.7 months</td> </tr> <tr> <td class="credit" colspan="2">CAR=chimeric antigen receptor; CI=confidence interval; CR=complete response; PR=partial response; sCR=stringent complete response; VGPR=very good partial response; NE=not estimable.<br /> <sup>a</sup> Response is defined as achieving sCR, CR, VGPR, or PR according to IMWG criteria.<br /> <sup>b</sup> Median and 95% CI are based on Kaplan-Meier estimation.</td> </tr> </tbody> </table> </center> <p></p> <p>Response durations were longer in patients who achieved a stringent CR as compared to patients with a PR or VGPR (Table 8). Of the 28 patients who achieved a stringent CR, it is estimated that 65% (95% CI: 42%, 81%) had a <a href="/remission/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">remission</a> lasting at least 12 months.</p> <p>The median duration of response for VGPR patients (n=25) was 11.1 months (95% CI: 8.7, 11.3).</p> <p>The median duration of response for PR patients (n=19) was 4.0 months (95% CI: 2.7, 7.2).</p> <p>Within the recommended dose of 300 to 460 x 10<sup>6</sup> CAR-positive T cells, a dose-response relationship was observed with higher ORR and sCR rate in patients who received 440 to 460 x 10<sup>6</sup> compared to 300 to 340 x 10<sup>6</sup> CAR-positive T cells. Overall response rate of 79% (95% CI: 65%, 90%) and sCR rate of 31% (95% CI: 19%, 46%) was observed with 440 to 460 x 10<sup>6</sup> CAR-positive T cells. Overall response rate of 65% (95% CI: 51%, 78%) with sCR rate of 25% (95% CI: 14%, 39%) was observed in 300 to 340 x 10<sup>6</sup> CAR-positive T cells.</p> <p>One hundred and thirty-five patients underwent leukapheresis. Fifteen out of the 23 patients who received treatment outside of the recommended dose range of 300 to 460 x 10<sup>6</sup> CAR-positive T cells experienced a response in addition to the responses noted in Table 6. The IRC assessed overall response in the leukapheresis population (n=135) was 64% (95% CI: 56%, 72%) with stringent CR rate of 24% (95% CI: 17%, 32%), VGPR rate of 21% (95% CI: 14%, 29%) and PR rate of 20% (95% CI: 14%, 28%).</p> <p class="credit"><b>REFERENCES</b></p> <p class="credit">2.Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria forresponse and <a href="/minimal_residual_disease/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">minimal residual disease</a> assessment in multiple myeloma. <a href="/lancet/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Lancet</a> Oncol 2016; 17(8): e328-46.</p> </div> </div> </div> | <a name="CP"></a> <h3>CLINICAL PHARMACOLOGY</h3> <h4>Mechanism Of Action</h4> <p>ABECMA is a chimeric antigen receptor (CAR)-positive T cell therapy targeting B-cell maturation antigen (BCMA), which is expressed on the surface of normal and malignant plasma cells. The CAR construct includes an anti-BCMA scFv-targeting domain for antigen specificity, a transmembrane domain, a CD3-zeta T cell activation domain, and a 4-1BB costimulatory domain. Antigen-specific activation of ABECMA results in CAR-positive T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.</p> <h4>Pharmacodynamics</h4> <p>Following ABECMA infusion, pharmacodynamic responses of CAR activation and anti-tumor efficacy were evaluated. Peak elevation of plasma cytokines, chemokines, and soluble immune mediators occurred within 14 days of ABECMA infusion and returned to baseline levels within one month.</p> <p>Rapid decreases in tumor markers associated with clinical response, including serum levels of soluble BCMA, and bone marrow CD138+ cells, as well as minimal residual disease (MRD) negative responses, were observed within the first month following ABECMA infusion.</p> <h4>Pharmacokinetics</h4> <p>Following ABECMA infusion, the CAR-positive cells proliferate and undergo rapid multi-log expansion followed by a bi-exponential decline. The median time of maximal expansion in peripheral blood (Tmax) occurred 11 days after infusion.</p> <p>ABECMA can persist in peripheral blood for up to 1 year post-infusion. A summary of Tmax, AUC0-28days, and Cmax by the recommended dose range provided in Table 5.</p> <p align="center"><b>Table 5: Pharmacokinetic Parameters of ABECMA by Recommended Dose Range in Patients with Relapsed/Refractory Multiple Myeloma in the KarMMa Study</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="40%">Pharmacokinetic Parameter</td> <td class="EmphTd" width="30%">Summary Statistic</td> <td class="EmphTd" width="30%">Total [300 to 460 x 10<sup>6</sup>] CAR-Positive T Cells</td> </tr> <tr> <td>Tmax (days)</td> <td align="center">Median (Range)</td> <td align="center">11 (7-28) N = 99</td> </tr> <tr> <td>Cmax (copies/mcg)</td> <td align="center">Geometric mean (geometric CV%)</td> <td align="center">256,333 (165) N = 99</td> </tr> <tr> <td>AUC0-28days (days*copies/mcg)</td> <td align="center">Geometric mean (geometric CV%)</td> <td align="center">3,088,455 (190) N = 98</td> </tr> <tr> <td class="credit" colspan="3">AUC0-28days = area under the curve of the transgene level from time of dose to 28 days post-infusion; Cmax = the maximum transgene level; Tmax = time of maximum observed transgene level.</td> </tr> </tbody> </table> </center> <p></p> <p>ABECMA transgene levels were positively associated with <a href="/objective/definition.htm" ">objective</a> tumor response (partial response or better). The median Cmax levels in responders (N = 72) were approximately 4.6-fold higher than the corresponding levels in non-responders (N = 27). Median AUC0-28days in responding patients (N = 72) was approximately 5.6-fold higher than non-responders (N = 26).</p> <h5>Tocilizumab And Corticosteroid Use</h5> <p>Some patients required tocilizumab and/or corticosteroid for the management of CRS. ABECMA can continue to expand and persist following tocilizumab or corticosteroid administration [see <b>WARNINGS AND PRECAUTIONS</b>].</p> <p>Patients with CRS treated with tocilizumab had higher ABECMA cellular expansion levels, as measured by 1.3-fold and 1.6-fold higher median Cmax (N = 67) and AUC0-28days (N = 66), respectively, compared to patients who did not receive tocilizumab (N = 59 for Cmax and N = 58 for AUC0-28days).</p> <p>Patients with CRS treated with corticosteroids had higher ABECMA cellular expansion levels, as measured by 1.7-fold and 2.2-fold higher median Cmax (N = 18) and AUC0-28days (N = 18), respectively, compared to patients who did not receive corticosteroids (N = 108 for Cmax and N = 10<sup>6</sup> for AUC0-28days).</p> <h4>Specific Populations</h4> <h5>Geriatric</h5> <p>Age (range: 33 to 78 years) had no significant impact on expansion parameters [see <b>Use In Special Populations</b>].</p> <h5>Pediatric</h5> <p>The pharmacokinetics of ABECMA in patients less than 18 years of age have not been evaluated.</p> <h5>Patients With Hepatic/Renal Impairment</h5> <p>Hepatic and renal impairment studies of ABECMA were not conducted.</p> <h5>Patients With Other Intrinsic Factors</h5> <p>Gender, race, and ethnicity had no significant impact on ABECMA expansion parameters. Patients with lower body weight had higher expansion. Due to high variability in pharmacokinetic cellular expansion, the overall effect of weight on the pharmacokinetics of ABECMA is considered to be not clinically relevant.</p> <a name="CS"></a> <h4>Clinical Studies</h4> <h4>Relapsed/Refractory Multiple Myeloma</h4> <p>Efficacy of ABECMA was evaluated in KarMMa (NCT03361748), an open-label, single-arm, multicenter study in adult patients with relapsed and refractory multiple myeloma who had received at least 3 prior lines of antimyeloma therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 <a href="/monoclonal/definition.htm" ">monoclonal</a> antibody. The study included patients with ECOG performance status of 0 or 1. The study excluded patients with a creatinine clearance of less than or equal to 45 mL/minute, <a href="/alanine_aminotransferase_alt/definition.htm" ">alanine aminotransferase</a> >2.5 times upper limit of normal and left <a href="/ventricular/definition.htm" ">ventricular</a> <a href="/ejection_fraction/definition.htm" ">ejection fraction</a> <45%. Patients were also excluded if <a href="/absolute_neutrophil_count/definition.htm" ">absolute neutrophil count</a> <1000 cells/mm³ and <a href="/platelet_count/definition.htm" ">platelet count</a> <50,000/mm³. Patients had measurable disease by International Myeloma Working Group (IMWG) 2016 criteria at enrollment. Bridging therapy with alkylating agents, corticosteroids, immunomodulatory agents, proteasome inhibitors, and/or anti-CD38 monoclonal antibodies to which patients were previously exposed was permitted for disease control between <a href="/apheresis/definition.htm" ">apheresis</a> and until 14 days before the start of lymphodepleting chemotherapy.</p> <p>Lymphodepleting chemotherapy consisted of cyclophosphamide (300 mg/m² IV infusion daily for 3 days) and fludarabine (30 mg/m² IV infusion daily for 3 days) starting 5 days prior to the target infusion date of ABECMA. Fludarabine was dose reduced for renal insufficiency. Patients were hospitalized for 14 days after ABECMA infusion to monitor for potential CRS, HLH/MAS, and neurotoxicity.</p> <p>Of the 135 patients who underwent leukapheresis for 300 x 10<sup>6</sup> and 450 x 10<sup>6</sup> CAR-positive T cell dose cohorts:</p> <p>11 (8%) did not receive the CAR-positive T cells either due to death (n=2), adverse event (n=1), diseaseprogression (n=1), consent withdrawal (n=3), physician decision (n=3), or inability to manufactureproduct [manufacturing failure (n=1)]. Two patients died after receiving lymphodepletion and prior toreceiving ABECMA. Deaths were from <a href="/septic/definition.htm" ">septic</a> <a href="/shock/definition.htm" ">shock</a> and general physical health deterioration.</p> <p>24 (18%) either received ABECMA outside of the 300 to 460 x 10<sup>6</sup> CAR-positive T cells dose range(n=23) or received CAR-positive T cells that did not meet product release specifications for ABECMA(non-conforming product; n=1).</p> <p>The efficacy evaluable population consists of the 100 patients (74%) who received ABECMA in thedose range of 300 to 460 x 10<sup>6</sup> CAR-positive T cells.</p> <p>The overall manufacturing failure rate for patients who underwent leukapheresis for the 300 x 10<sup>6</sup> and 450 x 10<sup>6</sup>CAR-positive T cell dose cohorts was 1.5% (2 out of 135 patients). Of these 2 patients, one received CAR-positive T cells that did not meet product release specifications for ABECMA, and in one patient there was an inability to manufacture ABECMA.</p> <p>Of the 100 patients in the efficacy evaluable population, the median age was 62 years (range: 33 to 78 years), 60% were male, 78% were white, 6% were black, and 2% were Asian. Most patients (78%) were International <a href="/staging/definition.htm" ">Staging</a> System (ISS) Stage I or II. High-risk <a href="/cytogenetics/definition.htm" ">cytogenetics</a> (presence of t(4:14), t(14:16), and 17p13 del) were present in 37% of patients. Thirty-six percent of the patients had presence of extramedullary disease.</p> <p>The median number of prior lines of therapy was 6 (range: 3 to 16), and 88% of the patients received 4 or more prior lines of therapy. Ninety-five percent of the patients were refractory to an anti-CD38 monoclonal antibody. Eighty-five percent were triple class refractory (refractory to a proteasome inhibitor [PI], an immunomodulatory drug [IMiD] and an anti-CD38 monoclonal antibody), and 26% were penta-refractory (refractory to 2 PIs, 2 IMiD agents, and an anti-CD38 monoclonal antibody). Ninety-two percent had received prior autologous <a href="/stem_cell_transplantation/definition.htm" ">stem cell transplantation</a>.</p> <p>Most patients (87%) treated with ABECMA received bridging therapy for control of their multiple myeloma during the manufacturing process. The median time from leukapheresis to product availability was 33 days (range: 26 to 49 days).</p> <p>Efficacy was established on the basis of overall response rate (ORR), complete response (CR) rate, and duration of response (DOR), as assessed by the Independent Response committee (IRC) based on the International Myeloma Working Group (IMWG) Uniform Response Criteria for Multiple Myeloma.</p> <p>Efficacy results for the dose range of 300 to 460 x 10<sup>6</sup> CAR-positive T cells are shown in Table 6 and Table 7, and the DOR results are shown in Table 8. The median time to first response was 30 days (range: 15 to 88 days).</p> <p align="center"><b>Table 6: Summary of Efficacy Based on Independent Response Committee Review According to IMWG Criteria</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="70%"></td> <td class="EmphTd" width="30%">ABECMA-Treated Population (300 to 460 x 10<sup>6</sup> CAR-Positive T Cells)<br /> N=100</td> </tr> <tr> <td>Overall Response Rate (sCR<sup>a</sup>+VGPR+PR), n (%)</td> <td align="center">72 (72)</td> </tr> <tr> <td>95% CI<sup>b</sup> (%)</td> <td align="center">62, 81</td> </tr> <tr> <td>sCRa, n (%)</td> <td align="center">28 (28)</td> </tr> <tr> <td>95% CI<sup>b</sup> (%)</td> <td align="center">19, 38</td> </tr> <tr> <td>VGPR, n (%)</td> <td align="center">25 (25)</td> </tr> <tr> <td>95% CI<sup>b</sup> (%)</td> <td align="center">17, 35</td> </tr> <tr> <td>PR, n (%)</td> <td align="center">19 (19)</td> </tr> <tr> <td>95% CI<sup>b</sup> (%)</td> <td align="center">12, 28</td> </tr> <tr> <td class="credit" colspan="2">CAR=chimeric antigen receptor; CI=confidence interval; CR=complete response; MRD=Minimal Residual Disease; IMWG=International Myeloma Working Group; PR=partial response; sCR=stringent complete response; VGPR=very good partial response.<br /> <sup>a</sup> All complete responses were stringent CRs.<br /> <sup>b</sup>: Clopper-Pearson exact CI.</td> </tr> </tbody> </table> </center> <p></p> <p align="center"><b>Table 7: MRD Negativity Rate</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td width="70%">MRD<sup>c</sup>-negativity rate<sup>a</sup> in all treated patients (n=100) 95% CI<sup>b</sup> (%)</td> <td align="center" width="30%">21 (21) 13, 30</td> </tr> <tr> <td>MRD<sup>c</sup>-negativity rate<sup>a</sup> in patients achieving CR or sCR status (%) (n=28) 95% CI<sup>b</sup></td> <td align="center">21 (75) 55, 89</td> </tr> <tr> <td class="credit" colspan="2"><sup>a</sup> <a href="/mrd/definition.htm" ">MRD</a> negativity was defined as the proportion of patients with CR or stringent CR who are MRD negative at any timepoint within 3 months prior to achieving CR or stringent CR until the time of progression or death.<br /> <sup>b</sup> Clopper-Pearson exact CI.<br /> <sup>c</sup> Based on a threshold of 10-5 using ClonoSEQ, a next-generation sequencing assay (NGS).</td> </tr> </tbody> </table> </center> <p></p> <p align="center"><b>Table 8: Duration of Response</b></p> <center> <table cellspacing="0" class="blacktbl" width="450"> <tbody> <tr> <td class="EmphTd" width="70%"></td> <td class="EmphTd" width="30%">ABECMA-Treated Population (300 to 460 x 10<sup>6</sup> CAR-Positive T Cells)<br /> N=100</td> </tr> <tr> <td colspan="2"><b>Duration of Response<sup>a,b</sup> (PR or Better)</b></td> </tr> <tr> <td>n</td> <td align="center">72</td> </tr> <tr> <td>Median (months)</td> <td align="center">11.0</td> </tr> <tr> <td>95% CI</td> <td align="center">10.3, 11.4</td> </tr> <tr> <td colspan="2"><b>Duration of Response<sup>b</sup> for sCR</b></td> </tr> <tr> <td>n</td> <td align="center">28</td> </tr> <tr> <td>Median (months)</td> <td align="center">19.0</td> </tr> <tr> <td>95% CI</td> <td align="center">11.4, NE</td> </tr> <tr> <td>Median follow-up for duration of response (DOR)</td> <td align="center">10.7 months</td> </tr> <tr> <td class="credit" colspan="2">CAR=chimeric antigen receptor; CI=confidence interval; CR=complete response; PR=partial response; sCR=stringent complete response; VGPR=very good partial response; NE=not estimable.<br /> <sup>a</sup> Response is defined as achieving sCR, CR, VGPR, or PR according to IMWG criteria.<br /> <sup>b</sup> Median and 95% CI are based on Kaplan-Meier estimation.</td> </tr> </tbody> </table> </center> <p></p> <p>Response durations were longer in patients who achieved a stringent CR as compared to patients with a PR or VGPR (Table 8). Of the 28 patients who achieved a stringent CR, it is estimated that 65% (95% CI: 42%, 81%) had a <a href="/remission/definition.htm" ">remission</a> lasting at least 12 months.</p> <p>The median duration of response for VGPR patients (n=25) was 11.1 months (95% CI: 8.7, 11.3).</p> <p>The median duration of response for PR patients (n=19) was 4.0 months (95% CI: 2.7, 7.2).</p> <p>Within the recommended dose of 300 to 460 x 10<sup>6</sup> CAR-positive T cells, a dose-response relationship was observed with higher ORR and sCR rate in patients who received 440 to 460 x 10<sup>6</sup> compared to 300 to 340 x 10<sup>6</sup> CAR-positive T cells. Overall response rate of 79% (95% CI: 65%, 90%) and sCR rate of 31% (95% CI: 19%, 46%) was observed with 440 to 460 x 10<sup>6</sup> CAR-positive T cells. Overall response rate of 65% (95% CI: 51%, 78%) with sCR rate of 25% (95% CI: 14%, 39%) was observed in 300 to 340 x 10<sup>6</sup> CAR-positive T cells.</p> <p>One hundred and thirty-five patients underwent leukapheresis. Fifteen out of the 23 patients who received treatment outside of the recommended dose range of 300 to 460 x 10<sup>6</sup> CAR-positive T cells experienced a response in addition to the responses noted in Table 6. The IRC assessed overall response in the leukapheresis population (n=135) was 64% (95% CI: 56%, 72%) with stringent CR rate of 24% (95% CI: 17%, 32%), VGPR rate of 21% (95% CI: 14%, 29%) and PR rate of 20% (95% CI: 14%, 28%).</p> <p class="credit"><b>REFERENCES</b></p> <p class="credit">2.Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria forresponse and <a href="/minimal_residual_disease/definition.htm" ">minimal residual disease</a> assessment in multiple myeloma. <a href="/lancet/definition.htm" ">Lancet</a> Oncol 2016; 17(8): e328-46.</p> </div> </div> </div> | 12 | 2023-02-01 17:39:58 | Abecma (Idecabtagene Vicleucel Suspension) | A | CAR-T Cell Therapies | Abecma | idecabtagene vicleucel suspension | Abecma | |
| 95 | 2023-02-23 12:07:03 | Medication Guide | <a name="PI"></a> <h3>PATIENT INFORMATION</h3> <p><b>ABECMA®</b><br /> (uh-BEK-muh)<br /> (idecabtagene vicleucel)</p> <p>Read this Medication Guide before you start your ABECMA treatment. The more you know about your treatment, the more active you can be in your care. Talk with your healthcare provider if you have questions about your health condition or treatment. Reading this Medication Guide does not take the place of talking with your healthcare provider about your treatment.</p> <p><b>What is the most important information I should know about ABECMA?</b></p> <p>ABECMA may cause side effects that are life-threatening and can lead to death. Call your healthcare provider or get emergency help right away if you get any of the following:</p> <ul> <li>difficulty breathing</li> <li>fever (100.4°F/38°C or higher)</li> <li>chills/shivering</li> <li>confusion</li> <li>dizziness or lightheadedness</li> <li>shaking or <a href="/twitching/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">twitching</a> (<a href="/tremor/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">tremor</a>)</li> <li>fast or irregular heartbeat</li> <li>severe fatigue</li> <li>severe nausea, vomiting, diarrhea</li> </ul> <p>It is important that you tell your healthcare providers that you have received ABECMA and to show them your ABECMA Patient Wallet Card. Your healthcare provider may give you other medicines to treat your side effects.</p> <p><b>What is ABECMA?</b></p> <p>ABECMA is for the treatment of multiple myeloma in patients who have received at least four kinds of treatment regimens that have not worked or have stopped working. ABECMA is a medicine made from your own white blood cells; the cells are genetically modified to recognize and attack your multiple myeloma cells.</p> <p><b>How will I receive ABECMA?</b></p> <p>ABECMA is made from your own white blood cells, so your blood will be collected by a process called “leukapheresis” (LOO-kuh-feh-REE-sis).</p> <p>Your blood cells will be sent to a manufacturing center to make your ABECMA. Based on clinical trial experience, it takes about 4 weeks from the time your cells are received at the manufacturing site and are available to be shipped back to your healthcare provider, but the time may vary.</p> <p>Before you get ABECMA, your healthcare provider will give you chemotherapy for 3 days to prepare your body.</p> <p>When your ABECMA is ready, your healthcare provider will give ABECMA to you through a <a href="/catheter/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">catheter</a> (tube) placed into your vein (intravenous infusion). Your dose of ABECMA may be given in one or more infusion bags. The infusion usually takes up to 30 minutes for each infusion bag.</p> <p>You will be monitored at the certified healthcare facility where you received your treatment daily for at least 7 days after the infusion.</p> <p>You should plan to stay within 2 hours of this location for at least 4 weeks after getting ABECMA. Your healthcare provider will check to see that your treatment is working and help you with any side effects that may occur.</p> <p><b>What should I avoid after receiving ABECMA?</b></p> <ul> <li>Do not drive, operate heavy machinery, or do other activities that could be dangerous if you arenot mentally alert, for at least 8 weeks after you get ABECMA. This is because the treatmentcan cause temporary memory and coordination problems, sleepiness, confusion, dizziness, andseizures.</li> <li>Do not donate blood, organs, tissues, or cells for transplantation.</li> </ul> <p><b>What are the possible or reasonably likely side effects of ABECMA?</b></p> <p>The most common side effects of ABECMA are:</p> <ul> <li>fatigue</li> <li>fever (100.4°F/38°C or higher)</li> <li>chills/shivering</li> <li>severe nausea or diarrhea</li> <li>decreased appetite</li> <li>headache</li> <li>dizziness/lightheadedness</li> <li>confusion</li> <li>difficulty speaking or slurred speech</li> <li>cough</li> <li>difficulty breathing</li> <li>fast or irregular heartbeat</li> </ul> <p>ABECMA can cause a very common side effect called cytokine release syndrome or CRS, which can be severe or fatal. Symptoms of CRS include fever, difficulty breathing, dizziness or light-headedness, nausea, headache, fast heartbeat, low blood pressure, or fatigue. Tell your healthcare provider right away if you develop fever or any of these other symptoms after receiving ABECMA.</p> <p>ABECMA can increase the risk of life-threatening infections that may lead to death. Tell your healthcare provider right away if you develop fever, chills, or any signs or symptoms of an infection.</p> <p>ABECMA can lower one or more types of your blood cells (red blood cells, white blood cells, or platelets), which may make you feel weak or tired or increase your risk of severe infection or bleeding. After treatment, your healthcare provider will test your blood to check for this. Tell your healthcare provider right away if you get a fever, are feeling tired, or have bruising or bleeding.</p> <p>Having ABECMA in your blood may cause a false-positive human <a href="/immunodeficiency/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">immunodeficiency</a> virus (HIV) test result by some commercial tests.</p> <p>These are not all the possible side effects of ABECMA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <p><b>General information about the safe and effective use of ABECMA</b></p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about ABECMA, talk with your healthcare provider. You can ask your healthcare provider for information about ABECMA that is written for health professionals.</p> <p>For more information, go to ABECMA.com or call 1-888-805-4555.</p> <p class="credit">This Medication Guide has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | <a name="PI"></a> <h3>PATIENT INFORMATION</h3> <p><b>ABECMA®</b><br /> (uh-BEK-muh)<br /> (idecabtagene vicleucel)</p> <p>Read this Medication Guide before you start your ABECMA treatment. The more you know about your treatment, the more active you can be in your care. Talk with your healthcare provider if you have questions about your health condition or treatment. Reading this Medication Guide does not take the place of talking with your healthcare provider about your treatment.</p> <p><b>What is the most important information I should know about ABECMA?</b></p> <p>ABECMA may cause side effects that are life-threatening and can lead to death. Call your healthcare provider or get emergency help right away if you get any of the following:</p> <ul> <li>difficulty breathing</li> <li>fever (100.4°F/38°C or higher)</li> <li>chills/shivering</li> <li>confusion</li> <li>dizziness or lightheadedness</li> <li>shaking or <a href="/twitching/definition.htm" ">twitching</a> (<a href="/tremor/definition.htm" ">tremor</a>)</li> <li>fast or irregular heartbeat</li> <li>severe fatigue</li> <li>severe nausea, vomiting, diarrhea</li> </ul> <p>It is important that you tell your healthcare providers that you have received ABECMA and to show them your ABECMA Patient Wallet Card. Your healthcare provider may give you other medicines to treat your side effects.</p> <p><b>What is ABECMA?</b></p> <p>ABECMA is for the treatment of multiple myeloma in patients who have received at least four kinds of treatment regimens that have not worked or have stopped working. ABECMA is a medicine made from your own white blood cells; the cells are genetically modified to recognize and attack your multiple myeloma cells.</p> <p><b>How will I receive ABECMA?</b></p> <p>ABECMA is made from your own white blood cells, so your blood will be collected by a process called “leukapheresis” (LOO-kuh-feh-REE-sis).</p> <p>Your blood cells will be sent to a manufacturing center to make your ABECMA. Based on clinical trial experience, it takes about 4 weeks from the time your cells are received at the manufacturing site and are available to be shipped back to your healthcare provider, but the time may vary.</p> <p>Before you get ABECMA, your healthcare provider will give you chemotherapy for 3 days to prepare your body.</p> <p>When your ABECMA is ready, your healthcare provider will give ABECMA to you through a <a href="/catheter/definition.htm" ">catheter</a> (tube) placed into your vein (intravenous infusion). Your dose of ABECMA may be given in one or more infusion bags. The infusion usually takes up to 30 minutes for each infusion bag.</p> <p>You will be monitored at the certified healthcare facility where you received your treatment daily for at least 7 days after the infusion.</p> <p>You should plan to stay within 2 hours of this location for at least 4 weeks after getting ABECMA. Your healthcare provider will check to see that your treatment is working and help you with any side effects that may occur.</p> <p><b>What should I avoid after receiving ABECMA?</b></p> <ul> <li>Do not drive, operate heavy machinery, or do other activities that could be dangerous if you arenot mentally alert, for at least 8 weeks after you get ABECMA. This is because the treatmentcan cause temporary memory and coordination problems, sleepiness, confusion, dizziness, andseizures.</li> <li>Do not donate blood, organs, tissues, or cells for transplantation.</li> </ul> <p><b>What are the possible or reasonably likely side effects of ABECMA?</b></p> <p>The most common side effects of ABECMA are:</p> <ul> <li>fatigue</li> <li>fever (100.4°F/38°C or higher)</li> <li>chills/shivering</li> <li>severe nausea or diarrhea</li> <li>decreased appetite</li> <li>headache</li> <li>dizziness/lightheadedness</li> <li>confusion</li> <li>difficulty speaking or slurred speech</li> <li>cough</li> <li>difficulty breathing</li> <li>fast or irregular heartbeat</li> </ul> <p>ABECMA can cause a very common side effect called cytokine release syndrome or CRS, which can be severe or fatal. Symptoms of CRS include fever, difficulty breathing, dizziness or light-headedness, nausea, headache, fast heartbeat, low blood pressure, or fatigue. Tell your healthcare provider right away if you develop fever or any of these other symptoms after receiving ABECMA.</p> <p>ABECMA can increase the risk of life-threatening infections that may lead to death. Tell your healthcare provider right away if you develop fever, chills, or any signs or symptoms of an infection.</p> <p>ABECMA can lower one or more types of your blood cells (red blood cells, white blood cells, or platelets), which may make you feel weak or tired or increase your risk of severe infection or bleeding. After treatment, your healthcare provider will test your blood to check for this. Tell your healthcare provider right away if you get a fever, are feeling tired, or have bruising or bleeding.</p> <p>Having ABECMA in your blood may cause a false-positive human <a href="/immunodeficiency/definition.htm" ">immunodeficiency</a> virus (HIV) test result by some commercial tests.</p> <p>These are not all the possible side effects of ABECMA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <p><b>General information about the safe and effective use of ABECMA</b></p> <p>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about ABECMA, talk with your healthcare provider. You can ask your healthcare provider for information about ABECMA that is written for health professionals.</p> <p>For more information, go to ABECMA.com or call 1-888-805-4555.</p> <p class="credit">This Medication Guide has been approved by the U.S. Food and Drug Administration.</p> </div> </div> </div> | 12 | 2023-02-01 17:39:58 | Abecma (Idecabtagene Vicleucel Suspension) | A | CAR-T Cell Therapies | Abecma | idecabtagene vicleucel suspension | Abecma | |
| 96 | 2023-02-23 12:07:03 | Drug Description | <div class="webmdrx"> <a href="https://www.webmd.com/rx/drug-prices/abelcet?ecd=oo_webmdrx_rx-mono_rx/drug-prices/abelcet_dsktp_rxlist.com//rx/drug-prices/abelcet" target="_blank" onclick="wmdPageLink('webmdrx');"><p class="webmdrx_p">Find Lowest Prices on <span class="webmdrx_img"></span></p></a> </div> <h4>What is Abelcet and how is it used?</h4> <p>Abelcet is a prescription medicine used to treat the symptoms of Systemic Fungal Infection. Abelcet may be used alone or with other medications.</p> <p>Abelcet belongs to a class of drugs called Antifungals, Systemic.</p> <h4>What are the possible side effects of Abelcet?</h4> <p>Abelcet may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>fever,</li> <li><a href="/lightheadedness/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lightheadedness</a>,</li> <li>shortness of breath,</li> <li>new or worsening cough,</li> <li><a href="/wheezing/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">wheezing</a>,</li> <li>trouble breathing,</li> <li>blue lips,</li> <li>blue colored fingers or toes,</li> <li>easy bruising,</li> <li>unusual bleeding,</li> <li>purple or red spots under your skin,</li> <li>slow heart rate,</li> <li>weak <a href="/pulse/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">pulse</a>,</li> <li><a href="/fainting_syncope/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">fainting</a>,</li> <li>slow breathing (breathing may stop),</li> <li>little or no urination,</li> <li>swelling in your feet or ankles,</li> <li>tiredness,</li> <li>shortness of breath,</li> <li><a href="/muscle_spasms/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">muscle spasms</a> or contractions,</li> <li>numbness or tingling,</li> <li>dizziness,</li> <li>irregular heartbeats,</li> <li>feeling jittery,</li> <li><a href="/muscle_cramps/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">muscle cramps</a>,</li> <li>cough or <a href="/choking_object_in_airway/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">choking</a> feeling,</li> <li>leg cramps,</li> <li>constipation,</li> <li>fluttering in your chest,</li> <li>increased thirst or urination, and</li> <li>muscle weakness or limp feeling</li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Abelcet include:</p> <ul> <li>fever,</li> <li>chills,</li> <li>nausea,</li> <li>vomiting, and</li> <li>abnormal kidney function tests</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Abelcet. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <a name="D"></a> <h3>DESCRIPTION</h3> <p>ABELCET<sup>®</sup> is a sterile, pyrogen-free suspension for intravenous infusion. ABELCET<sup>®</sup> consists of amphotericin B complexed with two phospholipids in a 1:1 drug-to-<a href="/lipid/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lipid</a> <a href="/molar/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">molar</a> ratio. The two phospholipids, l-α-dimyristoylphosphatidylcholine (DMPC) and l-α-dimyristoylphosphatidylglycerol (DMPG), are present in a 7:3 molar ratio. ABELCET<sup>®</sup> is yellow and opaque in appearance, with a pH of 5 - 7.</p> <p><b>NOTE:Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug’s functional properties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipid-complexed products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect functional properties of these drug products.</b></p> <p>Amphotericin B is a polyene, <a href="/antifungal/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antifungal</a> <a href="/antibiotic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">antibiotic</a> produced from a strain of <i>Streptomyces nodosus.</i> Amphotericin B is designated chemically as [1R-(1R*, 3S*, 5R*, 6R*, 9R*, 11R*, 15S*, 16R*, 17R*, 18S*, 19E, 21E, 23E, 25E, 27E, 29E, 31E, 33R*, 35S*, 36R*, 37S*)]-33-[(3-Amino-3, 6-dideoxy- β-Dmannopyranosyl) oxy]-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39- dioxabicyclo[33.3.1] nonatriaconta-19, 21, 23, 25, 27, 29, 31-heptaene-36-carboxylic acid.</p> <p>It has a molecular weight of 924.09 and a molecular formula of C<sub>47</sub>H<sub>73</sub>NO<sub>17</sub>. The structural formula is:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="450"> <tbody> <tr> <td><img alt="ABELCET® (Amphotericin B) Structural Formula Illustration" height="218" src="https://images.rxlist.com/images/rxlist/abelcet1.gif" width="450" /></td> </tr> </tbody> </table> </center> <p></p> <p>ABELCET<sup>®</sup> is provided as a sterile, opaque suspension in 20 mL glass, single-use vials. Each 20 mL vial contains 100 mg of amphotericin B (see <a href="/abelcet-drug.htm#DAA"><b>DOSAGE AND ADMINISTRATION</b></a>), and each mL of ABELCET<sup>®</sup> contains:</p> <p class="EmphText">Amphotericin B USP 5.0 mg<br /> l-α-dimyristoylphosphatidylcholine (DMPC) 3.4 mg<br /> l-α-dimyristoylphosphatidylglycerol (DMPG) 1.5 mg<br /> Sodium Chloride USP 9.0 mg<br /> Water for Injection USP, q.s. 1 mL</p> </div> <div id="667441035-1" class="medianet"><script type="text/javascript">try { window._mNHandle.queue.push(function () { window._mNDetails.loadTag("667441035-1", "510x175", "667441035"); }); } catch (error) { }</script></div> </div> </div> | <div class="webmdrx"> <a href="https://www.webmd.com/rx/drug-prices/abelcet?ecd=oo_webmdrx_rx-mono_rx/drug-prices/abelcet_dsktp_rxlist.com//rx/drug-prices/abelcet" target="_blank" onclick="wmdPageLink('webmdrx');"><p class="webmdrx_p">Find Lowest Prices on <span class="webmdrx_img"></span></p></a> </div> <h4>What is Abelcet and how is it used?</h4> <p>Abelcet is a prescription medicine used to treat the symptoms of Systemic Fungal Infection. Abelcet may be used alone or with other medications.</p> <p>Abelcet belongs to a class of drugs called Antifungals, Systemic.</p> <h4>What are the possible side effects of Abelcet?</h4> <p>Abelcet may cause serious side effects including:</p> <ul> <li>hives,</li> <li>difficulty breathing,</li> <li>swelling of your face, lips, tongue, or throat,</li> <li>fever,</li> <li><a href="/lightheadedness/definition.htm" ">lightheadedness</a>,</li> <li>shortness of breath,</li> <li>new or worsening cough,</li> <li><a href="/wheezing/definition.htm" ">wheezing</a>,</li> <li>trouble breathing,</li> <li>blue lips,</li> <li>blue colored fingers or toes,</li> <li>easy bruising,</li> <li>unusual bleeding,</li> <li>purple or red spots under your skin,</li> <li>slow heart rate,</li> <li>weak <a href="/pulse/definition.htm" ">pulse</a>,</li> <li><a href="/fainting_syncope/definition.htm" ">fainting</a>,</li> <li>slow breathing (breathing may stop),</li> <li>little or no urination,</li> <li>swelling in your feet or ankles,</li> <li>tiredness,</li> <li>shortness of breath,</li> <li><a href="/muscle_spasms/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">muscle spasms</a> or contractions,</li> <li>numbness or tingling,</li> <li>dizziness,</li> <li>irregular heartbeats,</li> <li>feeling jittery,</li> <li><a href="/muscle_cramps/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">muscle cramps</a>,</li> <li>cough or <a href="/choking_object_in_airway/definition.htm" ">choking</a> feeling,</li> <li>leg cramps,</li> <li>constipation,</li> <li>fluttering in your chest,</li> <li>increased thirst or urination, and</li> <li>muscle weakness or limp feeling</li> </ul> <p>Get medical help right away, if you have any of the symptoms listed above.</p> <p>The most common side effects of Abelcet include:</p> <ul> <li>fever,</li> <li>chills,</li> <li>nausea,</li> <li>vomiting, and</li> <li>abnormal kidney function tests</li> </ul> <p>Tell the doctor if you have any side effect that bothers you or that does not go away.</p> <p>These are not all the possible side effects of Abelcet. For more information, ask your doctor or pharmacist.</p> <p>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</p> <a name="D"></a> <h3>DESCRIPTION</h3> <p>ABELCET<sup>®</sup> is a sterile, pyrogen-free suspension for intravenous infusion. ABELCET<sup>®</sup> consists of amphotericin B complexed with two phospholipids in a 1:1 drug-to-<a href="/lipid/definition.htm" ">lipid</a> <a href="/molar/definition.htm" ">molar</a> ratio. The two phospholipids, l-α-dimyristoylphosphatidylcholine (DMPC) and l-α-dimyristoylphosphatidylglycerol (DMPG), are present in a 7:3 molar ratio. ABELCET<sup>®</sup> is yellow and opaque in appearance, with a pH of 5 - 7.</p> <p><b>NOTE:Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug’s functional properties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipid-complexed products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect functional properties of these drug products.</b></p> <p>Amphotericin B is a polyene, <a href="/antifungal/definition.htm" ">antifungal</a> <a href="/antibiotic/definition.htm" ">antibiotic</a> produced from a strain of <i>Streptomyces nodosus.</i> Amphotericin B is designated chemically as [1R-(1R*, 3S*, 5R*, 6R*, 9R*, 11R*, 15S*, 16R*, 17R*, 18S*, 19E, 21E, 23E, 25E, 27E, 29E, 31E, 33R*, 35S*, 36R*, 37S*)]-33-[(3-Amino-3, 6-dideoxy- β-Dmannopyranosyl) oxy]-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39- dioxabicyclo[33.3.1] nonatriaconta-19, 21, 23, 25, 27, 29, 31-heptaene-36-carboxylic acid.</p> <p>It has a molecular weight of 924.09 and a molecular formula of C<sub>47</sub>H<sub>73</sub>NO<sub>17</sub>. The structural formula is:</p> <p></p> <center> <table cellspacing="0" class="blackpic" width="450"> <tbody> <tr> <td><img alt="ABELCET® (Amphotericin B) Structural Formula Illustration" height="218" src="https://images.rxlist.com/images/rxlist/abelcet1.gif" width="450" /></td> </tr> </tbody> </table> </center> <p></p> <p>ABELCET<sup>®</sup> is provided as a sterile, opaque suspension in 20 mL glass, single-use vials. Each 20 mL vial contains 100 mg of amphotericin B (see <a href="/abelcet-drug.htm#DAA"><b>DOSAGE AND ADMINISTRATION</b></a>), and each mL of ABELCET<sup>®</sup> contains:</p> <p class="EmphText">Amphotericin B USP 5.0 mg<br /> l-α-dimyristoylphosphatidylcholine (DMPC) 3.4 mg<br /> l-α-dimyristoylphosphatidylglycerol (DMPG) 1.5 mg<br /> Sodium Chloride USP 9.0 mg<br /> Water for Injection USP, q.s. 1 mL</p> </div> <div id="667441035-1" class="medianet"><</div> </div> </div> | 13 | 2023-02-01 17:40:18 | Abelcet (Amphotericin B Injection) | A | Antifungals, Systemic | Abelcet | amphotericin b injection | Abelcet | |
| 97 | 2023-02-23 11:36:54 | Indications & Dosage | <div class="webmdrx_coup"> </div> <a name="I"></a><h3>INDICATIONS</h3> <p>ABELCET<sup>®</sup> is indicated for the treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B therapy. This is based on open-label treatment of patients judged by their physicians to be intolerant to or failing conventional amphotericin B therapy (See <b>Description Of Clinical Studies</b>).</p> <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3> <p>The recommended daily dosage for adults and children is 5 mg/kg given as a single infusion. ABELCET<sup>®</sup> should be administered by intravenous infusion at a rate of 2.5 mg/kg/h. If the infusion time exceeds 2 hours, mix the contents by shaking the infusion bag every 2 hours.</p> <p>Renal toxicity of ABELCET<sup>®</sup> , as measured by serum creatinine levels, has been shown to be dose dependent. Decisions about dose adjustments should be made only after taking into account the overall clinical condition of the patient.</p> <h4>Preparation Of Admixture For Infusion</h4> <p>Shake the vial gently until there is no evidence of any yellow sediment at the bottom. Withdraw the appropriate dose of ABELCET<sup>®</sup> from the required number of vials into one or more sterile syringes using an 18-gauge needle. Remove the needle from each syringe filled with ABELCET<sup>®</sup> and replace with the 5-micron filter needle supplied with each vial. Each filter needle may be used to filter the contents of up to four 100 mg vials. Insert the filter needle of the syringe into an IV bag containing 5% Dextrose Injection USP, and empty the contents of the syringe into the bag. The final infusion concentration should be 1 mg/mL. For pediatric patients and patients with cardiovascular disease the drug may be diluted with 5% Dextrose Injection to a final infusion concentration of 2 mg/mL. Before infusion, shake the bag until the contents are thoroughly mixed. Do not use the admixture after dilution with 5% Dextrose Injection if there is any evidence of foreign matter. Vials are for single use. Unused material should be discarded. Aseptic technique must be strictly observed throughout handling of ABELCET<sup>®</sup> , since no bacteriostatic agent or preservative is present.</p> <p>DO NOT DILUTE WITH SALINE SOLUTIONS OR MIX WITH OTHER DRUGS OR ELECTROLYTES as the compatibility of ABELCET<sup>®</sup> with these materials has not been established. An existing intravenous line should be flushed with 5% Dextrose Injection before infusion of ABELCET<sup>®</sup> , or a separate infusion line should be used. DO NOT USE AN IN-LINE FILTER.</p> <p>The diluted ready-for-use admixture is stable for up to 48 hours at 2° to 8°C (36° to 46°F) and an additional 6 hours at room temperature.</p> <a name="HS"></a><h3>HOW SUPPLIED</h3> <p>Single-use vials along with 5-micron filter needles are individually packaged.</p> <p class="EmphText">100 mg of ABELCET<sup>®</sup> in 20 mL of suspension <b>NDC</b> 57665-101-41</p> <h4>Storage</h4> <p>Prior to admixture, ABELCET<sup>®</sup> should be stored at 2° to 8°C (36° to 46°F) and protected from exposure to light. Do not freeze. ABELCET<sup>®</sup> should be retained in the carton until time of use.</p> <p>The admixed ABELCET<sup>®</sup> and 5% Dextrose Injection may be stored for up to 48 hours at 2° to 8°C (36° to 46°F) and an additional 6 hours at room temperature. Do not freeze. Any unused material should be discarded.</p> <p class="credit">Manufactured by Exelead, Inc., Indianapolis, IN 46268. Revised: Dec 2017.</p> </div> <a class="mediaPrmo quiz" href="/quiz_tummy_trouble/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/tummy-trouble/s4.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">Bowel regularity means a bowel movement every day. </span> <span class="btn">See Answer</span> </a> </div> </div> | <div class="webmdrx_coup"> </div> <a name="I"></a><h3>INDICATIONS</h3> <p>ABELCET<sup>®</sup> is indicated for the treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B therapy. This is based on open-label treatment of patients judged by their physicians to be intolerant to or failing conventional amphotericin B therapy (See <b>Description Of Clinical Studies</b>).</p> <a name="DAA"></a><h3>DOSAGE AND ADMINISTRATION</h3> <p>The recommended daily dosage for adults and children is 5 mg/kg given as a single infusion. ABELCET<sup>®</sup> should be administered by intravenous infusion at a rate of 2.5 mg/kg/h. If the infusion time exceeds 2 hours, mix the contents by shaking the infusion bag every 2 hours.</p> <p>Renal toxicity of ABELCET<sup>®</sup> , as measured by serum creatinine levels, has been shown to be dose dependent. Decisions about dose adjustments should be made only after taking into account the overall clinical condition of the patient.</p> <h4>Preparation Of Admixture For Infusion</h4> <p>Shake the vial gently until there is no evidence of any yellow sediment at the bottom. Withdraw the appropriate dose of ABELCET<sup>®</sup> from the required number of vials into one or more sterile syringes using an 18-gauge needle. Remove the needle from each syringe filled with ABELCET<sup>®</sup> and replace with the 5-micron filter needle supplied with each vial. Each filter needle may be used to filter the contents of up to four 100 mg vials. Insert the filter needle of the syringe into an IV bag containing 5% Dextrose Injection USP, and empty the contents of the syringe into the bag. The final infusion concentration should be 1 mg/mL. For pediatric patients and patients with cardiovascular disease the drug may be diluted with 5% Dextrose Injection to a final infusion concentration of 2 mg/mL. Before infusion, shake the bag until the contents are thoroughly mixed. Do not use the admixture after dilution with 5% Dextrose Injection if there is any evidence of foreign matter. Vials are for single use. Unused material should be discarded. Aseptic technique must be strictly observed throughout handling of ABELCET<sup>®</sup> , since no bacteriostatic agent or preservative is present.</p> <p>DO NOT DILUTE WITH SALINE SOLUTIONS OR MIX WITH OTHER DRUGS OR ELECTROLYTES as the compatibility of ABELCET<sup>®</sup> with these materials has not been established. An existing intravenous line should be flushed with 5% Dextrose Injection before infusion of ABELCET<sup>®</sup> , or a separate infusion line should be used. DO NOT USE AN IN-LINE FILTER.</p> <p>The diluted ready-for-use admixture is stable for up to 48 hours at 2° to 8°C (36° to 46°F) and an additional 6 hours at room temperature.</p> <a name="HS"></a><h3>HOW SUPPLIED</h3> <p>Single-use vials along with 5-micron filter needles are individually packaged.</p> <p class="EmphText">100 mg of ABELCET<sup>®</sup> in 20 mL of suspension <b>NDC</b> 57665-101-41</p> <h4>Storage</h4> <p>Prior to admixture, ABELCET<sup>®</sup> should be stored at 2° to 8°C (36° to 46°F) and protected from exposure to light. Do not freeze. ABELCET<sup>®</sup> should be retained in the carton until time of use.</p> <p>The admixed ABELCET<sup>®</sup> and 5% Dextrose Injection may be stored for up to 48 hours at 2° to 8°C (36° to 46°F) and an additional 6 hours at room temperature. Do not freeze. Any unused material should be discarded.</p> <p class="credit">Manufactured by Exelead, Inc., Indianapolis, IN 46268. Revised: Dec 2017.</p> </div> <a class="mediaPrmo quiz" href="/quiz_tummy_trouble/quiz.htm" onclick="wmdTrack('quizprmo-arttop');" target="_blank"> <img src="https://images.rxlist.com/images/quiz/tummy-trouble/s4.jpg"> <span class="skew"></span> <span class="icon-quiz"></span> <h4 class="label">QUESTION</h4> <span class="caption">Bowel regularity means a bowel movement every day. </span> <span class="btn">See Answer</span> </a> </div> </div> | 13 | 2023-02-01 17:40:18 | Abelcet (Amphotericin B Injection) | A | Antifungals, Systemic | Abelcet | amphotericin b injection | Abelcet | |
| 98 | 2023-02-23 11:36:54 | Side Effects | <a name="AR"></a><h3>SIDE EFFECTS</h3> <p>The total safety data base is composed of 921 patients treated with ABELCET<sup>®</sup> (5 patients were enrolled twice and counted as separate patients), of whom 775 were treated with 5 mg/kg/day. Of these 775 patients, 194 patients were treated in four comparative studies; 25 were treated in open-label, noncomparative studies; and 556 patients were treated in an open-label, emergency-use program. Most had underlying hematologic neoplasms, and many were receiving multiple concomitant medications. Of the 556 patients treated with ABELCET<sup>®</sup> , 9% discontinued treatment due to adverse events regardless of presumed relationship to study drug.</p> <p>In general, the adverse events most commonly reported with ABELCET<sup>®</sup> were transient chills and/or fever during infusion of the drug.</p> <p align="center"><b>Adverse Events<sup>a</sup> with an Incidence of ≥3% (N=556)</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td width="50%" class="EmphTd">Adverse Event</td> <td width="50%" class="EmphTd">Percentage (%) of Patients</td> </tr> <tr> <td>Chills</td> <td align="center">18</td> </tr> <tr> <td>Fever</td> <td align="center">14</td> </tr> <tr> <td>Increased Serum Creatinine</td> <td align="center">11</td> </tr> <tr> <td>Multiple Organ Failure</td> <td align="center">11</td> </tr> <tr> <td>Nausea</td> <td align="center">9</td> </tr> <tr> <td>Hypotension</td> <td align="center">8</td> </tr> <tr> <td>Respiratory Failure</td> <td align="center">8</td> </tr> <tr> <td>Vomiting</td> <td align="center">8</td> </tr> <tr> <td>Dyspnea</td> <td align="center">7</td> </tr> <tr> <td>Sepsis</td> <td align="center">7</td> </tr> <tr> <td>Diarrhea</td> <td align="center">6</td> </tr> <tr> <td>Headache</td> <td align="center">6</td> </tr> <tr> <td>Cardiac Arrest</td> <td align="center">6</td> </tr> <tr> <td>Hypertension</td> <td align="center">5</td> </tr> <tr> <td>Hypokalemia</td> <td align="center">5</td> </tr> <tr> <td>Infection</td> <td align="center">5</td> </tr> <tr> <td>Kidney Failure</td> <td align="center">5</td> </tr> <tr> <td>Pain</td> <td align="center">5</td> </tr> <tr> <td>Thrombocytopenia</td> <td align="center">5</td> </tr> <tr> <td>Anemia</td> <td align="center">4</td> </tr> <tr> <td>Hyperbilirubinemia</td> <td align="center">4</td> </tr> <tr> <td>Gastrointestinal Hemorrhage</td> <td align="center">4</td> </tr> <tr> <td>Leukopenia</td> <td align="center">4</td> </tr> <tr> <td>Rash</td> <td align="center">4</td> </tr> <tr> <td>Respiratory Disorder</td> <td align="center">4</td> </tr> <tr> <td>Chest Pain</td> <td align="center">3</td> </tr> <tr> <td>Nausea and Vomiting</td> <td align="center">3</td> </tr> <tr> <td class="credit" colspan="2"> <sup>a</sup> The causal association between these adverse events and ABELCET<sup>®</sup> is uncertain.</td> </tr> </table> </center></p> <p>The following adverse events have also been reported in patients using ABELCET<sup>®</sup> in open-label, uncontrolled clinical studies. The causal association between these adverse events and ABELCET<sup>®</sup> is uncertain.</p> <p><b><i>Body as a whole:</i></b> malaise, weight loss, deafness, injection site reaction including inflammation</p> <p><b><i>Allergic: </i></b>bronchospasm, wheezing, asthma, anaphylactoid and other allergic reactions</p> <p><b><i>Cardiopulmonary:</i></b> cardiac failure, pulmonary edema, shock, myocardial infarction, hemoptysis, tachypnea, thrombophlebitis, pulmonary embolus, cardiomyopathy, pleural effusion, arrhythmias including ventricular fibrillation.</p> <p><b><i>Dermatological:</i></b> maculopapular rash, pruritus, exfoliative dermatitis, erythema multiforme</p> <p><b><i>Gastrointestinal:</i></b> acute liver failure, hepatitis, jaundice, melena, anorexia, dyspepsia, cramping, epigastric pain, veno-occlusive liver disease, diarrhea, hepatomegaly, cholangitis, cholecystitis</p> <p><b><i>Hematologic:</i></b> coagulation defects, leukocytosis, blood dyscrasias including eosinophilia</p> <p><b><i>Musculoskeletal:</i></b> myasthenia, including bone, muscle, and joint pains</p> <p><b><i>Neurologic:</i></b> convulsions, tinnitus, visual impairment, hearing loss, peripheral neuropathy, transient vertigo, diplopia, encephalopathy, cerebral vascular accident, extrapyramidal syndrome and other neurologic symptoms</p> <p><b><i>Urogenital: </i></b>oliguria, decreased renal function, anuria, renal tubular acidosis, impotence, dysuria</p> <p><b><i>Serum electrolyte abnormalities:</i></b> hypomagnesemia, hyperkalemia, hypocalcemia, hypercalcemia</p> <p><b><i>Liver function test abnormalities: </i></b>increased AST, ALT, alkaline phosphatase, LDH</p> <p><b><i>Renal function test abnormalities:</i></b> increased BUN</p> <p><b><i>Other test abnormalities: </i></b>acidosis, hyperamylasemia, hypoglycemia, hyperglycemia, hyperuricemia, hypophosphatemia</p> <p>To report SUSPECTED ADVERSE REACTIONS, contact Leadiant Biosciences, Inc. at 1-888-393- 4584 or by email at <a href="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="385c4a4d5f4b595e5d4c4178545d595c5159564c165b5755">[email protected]</a> or contact the FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.</p> </div> </div> </div> | <a name="AR"></a><h3>SIDE EFFECTS</h3> <p>The total safety data base is composed of 921 patients treated with ABELCET<sup>®</sup> (5 patients were enrolled twice and counted as separate patients), of whom 775 were treated with 5 mg/kg/day. Of these 775 patients, 194 patients were treated in four comparative studies; 25 were treated in open-label, noncomparative studies; and 556 patients were treated in an open-label, emergency-use program. Most had underlying hematologic neoplasms, and many were receiving multiple concomitant medications. Of the 556 patients treated with ABELCET<sup>®</sup> , 9% discontinued treatment due to adverse events regardless of presumed relationship to study drug.</p> <p>In general, the adverse events most commonly reported with ABELCET<sup>®</sup> were transient chills and/or fever during infusion of the drug.</p> <p align="center"><b>Adverse Events<sup>a</sup> with an Incidence of ≥3% (N=556)</b><br /> <center><table class="blacktbl" width="450" cellspacing="0"> <tr> <td width="50%" class="EmphTd">Adverse Event</td> <td width="50%" class="EmphTd">Percentage (%) of Patients</td> </tr> <tr> <td>Chills</td> <td align="center">18</td> </tr> <tr> <td>Fever</td> <td align="center">14</td> </tr> <tr> <td>Increased Serum Creatinine</td> <td align="center">11</td> </tr> <tr> <td>Multiple Organ Failure</td> <td align="center">11</td> </tr> <tr> <td>Nausea</td> <td align="center">9</td> </tr> <tr> <td>Hypotension</td> <td align="center">8</td> </tr> <tr> <td>Respiratory Failure</td> <td align="center">8</td> </tr> <tr> <td>Vomiting</td> <td align="center">8</td> </tr> <tr> <td>Dyspnea</td> <td align="center">7</td> </tr> <tr> <td>Sepsis</td> <td align="center">7</td> </tr> <tr> <td>Diarrhea</td> <td align="center">6</td> </tr> <tr> <td>Headache</td> <td align="center">6</td> </tr> <tr> <td>Cardiac Arrest</td> <td align="center">6</td> </tr> <tr> <td>Hypertension</td> <td align="center">5</td> </tr> <tr> <td>Hypokalemia</td> <td align="center">5</td> </tr> <tr> <td>Infection</td> <td align="center">5</td> </tr> <tr> <td>Kidney Failure</td> <td align="center">5</td> </tr> <tr> <td>Pain</td> <td align="center">5</td> </tr> <tr> <td>Thrombocytopenia</td> <td align="center">5</td> </tr> <tr> <td>Anemia</td> <td align="center">4</td> </tr> <tr> <td>Hyperbilirubinemia</td> <td align="center">4</td> </tr> <tr> <td>Gastrointestinal Hemorrhage</td> <td align="center">4</td> </tr> <tr> <td>Leukopenia</td> <td align="center">4</td> </tr> <tr> <td>Rash</td> <td align="center">4</td> </tr> <tr> <td>Respiratory Disorder</td> <td align="center">4</td> </tr> <tr> <td>Chest Pain</td> <td align="center">3</td> </tr> <tr> <td>Nausea and Vomiting</td> <td align="center">3</td> </tr> <tr> <td class="credit" colspan="2"> <sup>a</sup> The causal association between these adverse events and ABELCET<sup>®</sup> is uncertain.</td> </tr> </table> </center></p> <p>The following adverse events have also been reported in patients using ABELCET<sup>®</sup> in open-label, uncontrolled clinical studies. The causal association between these adverse events and ABELCET<sup>®</sup> is uncertain.</p> <p><b><i>Body as a whole:</i></b> malaise, weight loss, deafness, injection site reaction including inflammation</p> <p><b><i>Allergic: </i></b>bronchospasm, wheezing, asthma, anaphylactoid and other allergic reactions</p> <p><b><i>Cardiopulmonary:</i></b> cardiac failure, pulmonary edema, shock, myocardial infarction, hemoptysis, tachypnea, thrombophlebitis, pulmonary embolus, cardiomyopathy, pleural effusion, arrhythmias including ventricular fibrillation.</p> <p><b><i>Dermatological:</i></b> maculopapular rash, pruritus, exfoliative dermatitis, erythema multiforme</p> <p><b><i>Gastrointestinal:</i></b> acute liver failure, hepatitis, jaundice, melena, anorexia, dyspepsia, cramping, epigastric pain, veno-occlusive liver disease, diarrhea, hepatomegaly, cholangitis, cholecystitis</p> <p><b><i>Hematologic:</i></b> coagulation defects, leukocytosis, blood dyscrasias including eosinophilia</p> <p><b><i>Musculoskeletal:</i></b> myasthenia, including bone, muscle, and joint pains</p> <p><b><i>Neurologic:</i></b> convulsions, tinnitus, visual impairment, hearing loss, peripheral neuropathy, transient vertigo, diplopia, encephalopathy, cerebral vascular accident, extrapyramidal syndrome and other neurologic symptoms</p> <p><b><i>Urogenital: </i></b>oliguria, decreased renal function, anuria, renal tubular acidosis, impotence, dysuria</p> <p><b><i>Serum electrolyte abnormalities:</i></b> hypomagnesemia, hyperkalemia, hypocalcemia, hypercalcemia</p> <p><b><i>Liver function test abnormalities: </i></b>increased AST, ALT, alkaline phosphatase, LDH</p> <p><b><i>Renal function test abnormalities:</i></b> increased BUN</p> <p><b><i>Other test abnormalities: </i></b>acidosis, hyperamylasemia, hypoglycemia, hyperglycemia, hyperuricemia, hypophosphatemia</p> <p>To report SUSPECTED ADVERSE REACTIONS, contact Leadiant Biosciences, Inc. at 1-888-393- 4584 or by email at <a href="/cdn-cgi/l/email-protection" class="__cf_email__" data-cfemail="385c4a4d5f4b595e5d4c4178545d595c5159564c165b5755">[email protected]</a> or contact the FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.</p> </div> </div> </div> | 13 | 2023-02-01 17:40:18 | Abelcet (Amphotericin B Injection) | A | Antifungals, Systemic | Abelcet | amphotericin b injection | Abelcet | |
| 99 | 2023-02-23 12:07:03 | Drug Interactions | <a name="DI"></a><h3>DRUG INTERACTIONS</h3> <p>No formal clinical studies of drug interactions have been conducted with ABELCET<sup>®</sup> . However, when administered concomitantly, the following drugs are known to interact with amphotericin B; therefore, the following drugs may interact with ABELCET<sup>®</sup> :</p> <h4>Antineoplastic Agents</h4> <p>Concurrent use of antineoplastic agents and amphotericin B may enhance the potential for renal toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given concomitantly with ABELCET<sup>®</sup> with great caution.</p> <h4>Corticosteroids And Corticotropin (ACTH)</h4> <p>Concurrent use of corticosteroids and corticotropin (ACTH) with amphotericin B may potentiate hypokalemia which could predispose the patient to cardiac dysfunction. If used concomitantly with ABELCET<sup>®</sup> , serum electrolytes and cardiac function should be closely monitored.</p> <h4>Cyclosporin A</h4> <p>Data from a prospective study of prophylactic ABELCET<sup>®</sup> in 22 patients undergoing bone marrow transplantation suggested that concurrent initiation of cyclosporin A and ABELCET<sup>®</sup> within several days of bone marrow ablation may be associated with increased nephrotoxicity.</p> <h4>Digitalis Glycosides</h4> <p>Concurrent use of amphotericin B may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly with ABELCET<sup>®</sup> , serum potassium levels should be closely monitored.</p> <h4>Flucytosine</h4> <p>Concurrent use of flucytosine with amphotericin B-containing preparations may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Flucytosine should be given concomitantly with ABELCET<sup>®</sup> with caution.</p> <h4>Imidazoles (E.g., Ketoconazole, Miconazole, Clotrimazole, Fluconazole, Etc.)</h4> <p>Antagonism between amphotericin B and imidazole derivatives such as miconazole and ketoconazole, which inhibit ergosterol synthesis, has been reported in both <i>in vitro</i> and <i>in vivo</i> animal studies. The clinical significance of these findings has not been determined.</p> <h4>Leukocyte Transfusions</h4> <p>Acute pulmonary toxicity has been reported in patients receiving intravenous amphotericin B and leukocyte transfusions. Leukocyte transfusions and ABELCET<sup>®</sup> should not be given concurrently.</p> <h4>Other Nephrotoxic Medications</h4> <p>Concurrent use of amphotericin B and agents such as aminoglcosides and pentamidine may enhance the potential for drug-induced renal toxicity. Aminoglycosides and pentamidine should be used concomitantly with ABELCET<sup>®</sup> only with great caution. Intensive monitoring of renal function is recommended in patients requiring any combination of <a href="/nephrotoxic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">nephrotoxic</a> medications.</p> <h4>Skeletal Muscle Relaxants</h4> <p>Amphotericin B-induced <a href="/hypokalemia/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypokalemia</a> may enhance the curariform effect of <a href="/skeletal_muscle/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">skeletal muscle</a> relaxants (e.g., tubocurarine) due to hypokalemia. When administered concomitantly with ABELCET<sup>®</sup> , serum <a href="/potassium/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">potassium</a> levels should be closely monitored.</p> <h4>Zidovudine</h4> <p>Increased myelotoxicity and nephrotoxicity were observed in dogs when either ABELCET<sup>®</sup> (at doses 0.16 or 0.5 times the recommended human dose) or amphotericin B desoxycholate (at 0.5 times the recommended human dose) were administered concomitantly with zidovudine for 30 days. If zidovudine is used concomitantly with ABELCET<sup>®</sup> , renal and hematologic function should be closely monitored.</p> </div> </div> </div> | <a name="DI"></a><h3>DRUG INTERACTIONS</h3> <p>No formal clinical studies of drug interactions have been conducted with ABELCET<sup>®</sup> . However, when administered concomitantly, the following drugs are known to interact with amphotericin B; therefore, the following drugs may interact with ABELCET<sup>®</sup> :</p> <h4>Antineoplastic Agents</h4> <p>Concurrent use of antineoplastic agents and amphotericin B may enhance the potential for renal toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given concomitantly with ABELCET<sup>®</sup> with great caution.</p> <h4>Corticosteroids And Corticotropin (ACTH)</h4> <p>Concurrent use of corticosteroids and corticotropin (ACTH) with amphotericin B may potentiate hypokalemia which could predispose the patient to cardiac dysfunction. If used concomitantly with ABELCET<sup>®</sup> , serum electrolytes and cardiac function should be closely monitored.</p> <h4>Cyclosporin A</h4> <p>Data from a prospective study of prophylactic ABELCET<sup>®</sup> in 22 patients undergoing bone marrow transplantation suggested that concurrent initiation of cyclosporin A and ABELCET<sup>®</sup> within several days of bone marrow ablation may be associated with increased nephrotoxicity.</p> <h4>Digitalis Glycosides</h4> <p>Concurrent use of amphotericin B may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly with ABELCET<sup>®</sup> , serum potassium levels should be closely monitored.</p> <h4>Flucytosine</h4> <p>Concurrent use of flucytosine with amphotericin B-containing preparations may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Flucytosine should be given concomitantly with ABELCET<sup>®</sup> with caution.</p> <h4>Imidazoles (E.g., Ketoconazole, Miconazole, Clotrimazole, Fluconazole, Etc.)</h4> <p>Antagonism between amphotericin B and imidazole derivatives such as miconazole and ketoconazole, which inhibit ergosterol synthesis, has been reported in both <i>in vitro</i> and <i>in vivo</i> animal studies. The clinical significance of these findings has not been determined.</p> <h4>Leukocyte Transfusions</h4> <p>Acute pulmonary toxicity has been reported in patients receiving intravenous amphotericin B and leukocyte transfusions. Leukocyte transfusions and ABELCET<sup>®</sup> should not be given concurrently.</p> <h4>Other Nephrotoxic Medications</h4> <p>Concurrent use of amphotericin B and agents such as aminoglcosides and pentamidine may enhance the potential for drug-induced renal toxicity. Aminoglycosides and pentamidine should be used concomitantly with ABELCET<sup>®</sup> only with great caution. Intensive monitoring of renal function is recommended in patients requiring any combination of <a href="/nephrotoxic/definition.htm" ">nephrotoxic</a> medications.</p> <h4>Skeletal Muscle Relaxants</h4> <p>Amphotericin B-induced <a href="/hypokalemia/definition.htm" ">hypokalemia</a> may enhance the curariform effect of <a href="/skeletal_muscle/definition.htm" ">skeletal muscle</a> relaxants (e.g., tubocurarine) due to hypokalemia. When administered concomitantly with ABELCET<sup>®</sup> , serum <a href="/potassium/supplements.htm" rel="vit" onclick="wmdTrack('embd-lnk');">potassium</a> levels should be closely monitored.</p> <h4>Zidovudine</h4> <p>Increased myelotoxicity and nephrotoxicity were observed in dogs when either ABELCET<sup>®</sup> (at doses 0.16 or 0.5 times the recommended human dose) or amphotericin B desoxycholate (at 0.5 times the recommended human dose) were administered concomitantly with zidovudine for 30 days. If zidovudine is used concomitantly with ABELCET<sup>®</sup> , renal and hematologic function should be closely monitored.</p> </div> </div> </div> | 13 | 2023-02-01 17:40:18 | Abelcet (Amphotericin B Injection) | A | Antifungals, Systemic | Abelcet | amphotericin b injection | Abelcet | |
| 100 | 2023-02-23 12:07:03 | Warnings & Precautions | <a name="W"></a><h3>WARNINGS</h3> <p><a href="/anaphylaxis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Anaphylaxis</a> has been reported with amphotericin B desoxycholate and other amphotericin B-containing drugs. Anaphylaxis has been reported with ABELCET<sup>®</sup> with an incidence rate of <0.1%. If severe respiratory distress occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of ABELCET<sup>®</sup> .</p> <a name="P"></a><h3>PRECAUTIONS</h3> <h4>General</h4> <p>As with any amphotericin B-containing product, during the initial dosing of ABELCET<sup>®</sup> , the drug should be administered under close clinical observation by medically trained personnel.</p> <p>Acute reactions including fever and chills may occur 1 to 2 hours after starting an intravenous infusion of ABELCET<sup>®</sup> . These reactions are usually more common with the first few doses of ABELCET<sup>®</sup> and generally diminish with subsequent doses. Infusion has been rarely associated with <a href="/hypotension/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">hypotension</a>, bronchospasm, <a href="/heart_rhythm_disorders/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">arrhythmias</a>, and <a href="/shock/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">shock</a>.</p> <h4>Laboratory Tests </h4> <p>Serum creatinine should be monitored frequently during ABELCET<sup>®</sup> therapy (see <a href="/abelcet-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>). It is also advisable to regularly monitor liver function, serum <a href="/electrolytes/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">electrolytes</a> (particularly magnesium and potassium), and complete blood counts.</p> <h4>Carcinogenesis, Mutagenesis, And Impairment Of Fertility</h4> <p>No long-term studies in animals have been performed to evaluate the <a href="/carcinogenic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">carcinogenic</a> potential of ABELCET<sup>®</sup> . The following <i>in vitro</i> (with and without metabolic activation) and <i>in vivo</i> studies to assess ABELCET<sup>®</sup> for mutagenic potential were conducted: bacterial reverse mutation assay, mouse <a href="/lymphoma/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">lymphoma</a> forward mutation assay, chromosomal aberration assay in CHO cells, and <i>in vivo</i> mouse micronucleus assay. ABELCET<sup>®</sup> was found to be without mutagenic effects in all assay systems. Studies demonstrated that ABELCET<sup>®</sup> had no impact on fertility in male and female rats at doses up to 0.32 times the recommended human dose (based on body surface area considerations).</p> <h4>Pregnancy</h4> <p>There are no reports of pregnant women having been treated with ABELCET<sup>®</sup> . <a href="/teratogenic/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">Teratogenic</a> Effects. Reproductive studies in rats and rabbits at doses of ABELCET<sup>®</sup> up to 0.64 times the human dose revealed no harm to the fetus. Because animal reproductive studies are not always predictive of human response, and adequate and well-controlled studies have not been conducted in pregnant women, ABELCET<sup>®</sup> should be used during pregnancy only after taking into account the importance of the drug to the mother.</p> <h4>Nursing Mothers</h4> <p>It is not known whether ABELCET<sup>®</sup> is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in breast-fed infants from ABELCET<sup>®</sup> , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.</p> <h4>Pediatric Use</h4> <p>One hundred eleven children (2 were enrolled twice and counted as separate patients), age 16 years and under, of whom 11 were less than 1 year, have been treated with ABELCET<sup>®</sup> at 5 mg/kg/day in two open-label studies and one small, <a href="/prospective/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">prospective</a>, single-arm study. In one single-center study, 5 children with hepatosplenic <a href="/candidiasis/definition.htm" rel="dict" onclick="wmdTrack('embd-lnk');">candidiasis</a> were effectively treated with 2.5 mg/kg/day of ABELCET<sup>®</sup> . No serious unexpected adverse events have been reported.</p> <h4>Geriatric Use</h4> <p>Forty-nine elderly patients, age 65 years or over, have been treated with ABELCET<sup>®</sup> at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. No serious unexpected adverse events have been reported.</p> </div> </div> </div> | <a name="W"></a><h3>WARNINGS</h3> <p><a href="/anaphylaxis/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">Anaphylaxis</a> has been reported with amphotericin B desoxycholate and other amphotericin B-containing drugs. Anaphylaxis has been reported with ABELCET<sup>®</sup> with an incidence rate of <0.1%. If severe respiratory distress occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of ABELCET<sup>®</sup> .</p> <a name="P"></a><h3>PRECAUTIONS</h3> <h4>General</h4> <p>As with any amphotericin B-containing product, during the initial dosing of ABELCET<sup>®</sup> , the drug should be administered under close clinical observation by medically trained personnel.</p> <p>Acute reactions including fever and chills may occur 1 to 2 hours after starting an intravenous infusion of ABELCET<sup>®</sup> . These reactions are usually more common with the first few doses of ABELCET<sup>®</sup> and generally diminish with subsequent doses. Infusion has been rarely associated with <a href="/hypotension/definition.htm" ">hypotension</a>, bronchospasm, <a href="/heart_rhythm_disorders/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">arrhythmias</a>, and <a href="/shock/article.htm" rel="dt" onclick="wmdTrack('embd-lnk');">shock</a>.</p> <h4>Laboratory Tests </h4> <p>Serum creatinine should be monitored frequently during ABELCET<sup>®</sup> therapy (see <a href="/abelcet-drug.htm#AR"><b>ADVERSE REACTIONS</b></a>). It is also advisable to regularly monitor liver function, serum <a href="/electrolytes/article.htm" rel="proc" onclick="wmdTrack('embd-lnk');">electrolytes</a> (particularly magnesium and potassium), and complete blood counts.</p> <h4>Carcinogenesis, Mutagenesis, And Impairment Of Fertility</h4> <p>No long-term studies in animals have been performed to evaluate the <a href="/carcinogenic/definition.htm" ">carcinogenic</a> potential of ABELCET<sup>®</sup> . The following <i>in vitro</i> (with and without metabolic activation) and <i>in vivo</i> studies to assess ABELCET<sup>®</sup> for mutagenic potential were conducted: bacterial reverse mutation assay, mouse <a href="/lymphoma/definition.htm" ">lymphoma</a> forward mutation assay, chromosomal aberration assay in CHO cells, and <i>in vivo</i> mouse micronucleus assay. ABELCET<sup>®</sup> was found to be without mutagenic effects in all assay systems. Studies demonstrated that ABELCET<sup>®</sup> had no impact on fertility in male and female rats at doses up to 0.32 times the recommended human dose (based on body surface area considerations).</p> <h4>Pregnancy</h4> <p>There are no reports of pregnant women having been treated with ABELCET<sup>®</sup> . <a href="/teratogenic/definition.htm" ">Teratogenic</a> Effects. Reproductive studies in rats and rabbits at doses of ABELCET<sup>®</sup> up to 0.64 times the human dose revealed no harm to the fetus. Because animal reproductive studies are not always predictive of human response, and adequate and well-controlled studies have not been conducted in pregnant women, ABELCET<sup>®</sup> should be used during pregnancy only after taking into account the importance of the drug to the mother.</p> <h4>Nursing Mothers</h4> <p>It is not known whether ABELCET<sup>®</sup> is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in breast-fed infants from ABELCET<sup>®</sup> , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.</p> <h4>Pediatric Use</h4> <p>One hundred eleven children (2 were enrolled twice and counted as separate patients), age 16 years and under, of whom 11 were less than 1 year, have been treated with ABELCET<sup>®</sup> at 5 mg/kg/day in two open-label studies and one small, <a href="/prospective/definition.htm" ">prospective</a>, single-arm study. In one single-center study, 5 children with hepatosplenic <a href="/candidiasis/definition.htm" ">candidiasis</a> were effectively treated with 2.5 mg/kg/day of ABELCET<sup>®</sup> . No serious unexpected adverse events have been reported.</p> <h4>Geriatric Use</h4> <p>Forty-nine elderly patients, age 65 years or over, have been treated with ABELCET<sup>®</sup> at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. No serious unexpected adverse events have been reported.</p> </div> </div> </div> | 13 | 2023-02-01 17:40:18 | Abelcet (Amphotericin B Injection) | A | Antifungals, Systemic | Abelcet | amphotericin b injection | Abelcet | |
