Database
4.15K Medications & Drugs Data for Consumers & Medical Health Professionals
drug description, dosage, warnings, side effects, interactions, use, precautions, illustration images
Samples
Online API (JSON, Excel, CSV)
http://n3.datasn.io/data/api/v1/n3_chennan/medical_condition/main/list/
CSV
Listed below are the first 10 - 100 (or more) records of each of the 11 tables.
- letter
- medication
- detail
- related_drug
- medication_x_related_drug
- drug_comparison
- comparison_detail
- medication_x_drug_comparison
- supplement
- supplement_detail
- medication_x_supplement
letter top
| letter.id | letter.ts | letter.letter |
|---|---|---|
| 1 | 2023-02-01 15:01:37 | A |
| 2 | 2023-02-01 15:01:37 | B |
| 3 | 2023-02-01 15:01:37 | C |
| 4 | 2023-02-01 15:01:37 | D |
| 5 | 2023-02-01 15:01:37 | E |
| 6 | 2023-02-01 15:01:37 | F |
| 7 | 2023-02-01 15:01:37 | G |
| 8 | 2023-02-01 15:01:37 | H |
| 9 | 2023-02-01 15:01:37 | I |
| 10 | 2023-02-01 15:01:37 | J |
| 11 | 2023-02-01 15:01:37 | K |
| 12 | 2023-02-01 15:01:37 | L |
| 13 | 2023-02-01 15:01:37 | M |
| 14 | 2023-02-01 15:01:37 | N |
| 15 | 2023-02-01 15:01:37 | O |
| 16 | 2023-02-01 15:01:37 | P |
| 17 | 2023-02-01 15:01:37 | Q |
| 18 | 2023-02-01 15:01:37 | R |
| 19 | 2023-02-01 15:01:37 | S |
| 20 | 2023-02-01 15:01:37 | T |
| 21 | 2023-02-01 15:01:37 | U |
| 22 | 2023-02-01 15:01:37 | V |
| 23 | 2023-02-01 15:01:37 | W |
| 24 | 2023-02-01 15:01:37 | X |
| 25 | 2023-02-01 15:01:37 | Y |
| 26 | 2023-02-01 15:01:37 | Z |
- letter
- medication
- detail
- related_drug
- medication_x_related_drug
- drug_comparison
- comparison_detail
- medication_x_drug_comparison
- supplement
- supplement_detail
- medication_x_supplement
medication top
| medication.id | medication.ts | medication.medication | medication.letter | medication.class | medication.title | medication.generic_name | medication.brand_name | medication.editor |
|---|---|---|---|---|---|---|---|---|
| 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 | 2023-02-01 17:38:10 | Abacavir and Lamivudine Film-coated Tablets (Kivexa) | A | Kivexa | abacavir and lamivudine film-coated tablets | Kivexa | John P. Cunha, DO, FACOEP | |
| 3 | 2023-02-01 17:38:21 | Abacavir Sulfate (Ziagen) | A | HIV, NNRTIs, Antiretroviral Agents | Ziagen | abacavir sulfate | Ziagen | John P. Cunha, DO, FACOEP |
| 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 |
| 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 |
| 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 |
| 7 | 2023-02-01 17:38:38 | Abaloparatide Injection (Tymlos) | A | Parathyroid Hormone Analogs | Tymlos | abaloparatide injection | Tymlos | John P. Cunha, DO, FACOEP |
| 8 | 2023-02-01 17:39:00 | Abametapir Lotion (Xeglyze) | A | Topical Pediculicide | Xeglyze | abametapir lotion | Xeglyze | John P. Cunha, DO, FACOEP |
| 9 | 2023-02-01 17:39:09 | Abarelix (Plenaxis) | A | Gonadotropin Releasing Hormone Antagonists | Plenaxis | abarelix | Plenaxis | John P. Cunha, DO, FACOEP |
| 10 | 2023-02-01 17:39:31 | Abatacept (Orencia) | A | DMARDs, Immunomodulators | Orencia | abatacept | Orencia | |
| 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 |
| 12 | 2023-02-01 17:39:58 | Abecma (Idecabtagene Vicleucel Suspension) | A | CAR-T Cell Therapies | Abecma | idecabtagene vicleucel suspension | Abecma | |
| 13 | 2023-02-01 17:40:18 | Abelcet (Amphotericin B Injection) | A | Antifungals, Systemic | Abelcet | amphotericin b injection | Abelcet | |
| 14 | 2023-02-01 17:40:26 | Abemaciclib Tablets (Verzenio) | A | Antineoplastics CDK Inhibitors | Verzenio | abemaciclib tablets | Verzenio | John P. Cunha, DO, FACOEP |
| 15 | 2023-02-01 17:40:33 | Abilify (Aripiprazole) | A | Antipsychotics, Second Generation, Antimanic Agents | Abilify | aripiprazole | Abilify | |
| 16 | 2023-02-01 17:40:37 | Abilify Maintena (Aripiprazole Extended-Release Injectable Suspension) | A | How Do Second Generation Antipsychotics Work?, Antimanic Agents | Abilify Maintena | aripiprazole extended-release injectable suspension | Abilify Maintena | |
| 17 | 2023-02-01 17:40:54 | Abilify MyCite (Aripiprazole Tablets with Sensor) | A | Antipsychotics, Second Generation, Antimanic Agents | Abilify MyCite | aripiprazole tablets with sensor | Abilify MyCite | John P. Cunha, DO, FACOEP |
| 18 | 2023-02-01 17:40:59 | Abiraterone Acetate Tablets (Zytiga) | A | Antineoplastics, Antiandrogen, Antiandrogens | Zytiga | abiraterone acetate tablets | Zytiga | John P. Cunha, DO, FACOEP |
| 19 | 2023-02-01 17:41:06 | Abiraterone Acetate Tablets (Yonsa) | A | Antineoplastics, Antiandrogen, Antiandrogens | Yonsa | abiraterone acetate tablets | Yonsa | John P. Cunha, DO, FACOEP |
| 20 | 2023-02-01 17:41:11 | Ablavar (Gadofosveset Trisodium Injection) | A | Ablavar | gadofosveset trisodium injection | Ablavar | ||
| 21 | 2023-02-01 17:41:30 | Ablysinol (Dehydrated Alcohol) | A | Ablysinol | dehydrated alcohol | Ablysinol | John P. Cunha, DO, FACOEP | |
| 22 | 2023-02-01 17:41:51 | Abobotulinumtoxin A Injection (Dysport) | A | Neuromuscular Blockers, Depolarizing, Botulinum Toxins | Dysport | abobotulinumtoxin a injection | Dysport | John P. Cunha, DO, FACOEP |
| 23 | 2023-02-01 17:41:56 | Abraxane (Albumin-bound Paclitaxel for Injectable Suspension) | A | Antineoplastics, Antimicrotubular | Abraxane | albumin-bound paclitaxel for injectable suspension | Abraxane | |
| 24 | 2023-02-01 17:42:13 | Abreva (Docosanol Cream) | A | Antivirals, Topical | Abreva | docosanol cream | Abreva | |
| 25 | 2023-02-01 17:42:32 | Abrilada (Adalimumab-afzb Injection, for Subcutaneous Use) | A | DMARDs, TNF Inhibitors, Monoclonal Antibodies | Abrilada | adalimumab-afzb injection, for subcutaneous use | Abrilada | John P. Cunha, DO, FACOEP |
| 26 | 2023-02-01 17:42:42 | Abrocitinib Tablets (Cibinqo) | A | Cibinqo | abrocitinib tablets | Cibinqo | John P. Cunha, DO, FACOEP | |
| 27 | 2023-02-01 17:42:49 | Absorbable Gelatin Compressed Sponge, USP (Gelfoam Compressed Sponge) | A | Hemostatics | Gelfoam Compressed Sponge | absorbable gelatin compressed sponge, usp | Gelfoam Compressed Sponge | John P. Cunha, DO, FACOEP |
| 28 | 2023-02-01 17:43:08 | Absorbable Gelatin Dental Sponge (Gelfoam Dental Sponge) | A | Gelfoam Dental Sponge | absorbable gelatin dental sponge | Gelfoam Dental Sponge | ||
| 29 | 2023-02-01 17:43:19 | Absorbable Gelatin Powder (Gelfoam) | A | Gelfoam | absorbable gelatin powder | Gelfoam | John P. Cunha, DO, FACOEP | |
| 30 | 2023-02-01 17:43:30 | Absorbable Gelatin Sponge, USP (Gelfoam Sponge) | A | Gelfoam Sponge | absorbable gelatin sponge, usp | Gelfoam Sponge | ||
| 31 | 2023-02-01 17:43:33 | Absorbable Gelatin Sterile Ophthalmic Film (Gelfilm ) | A | Gelfilm | absorbable gelatin sterile ophthalmic film | Gelfilm | John P. Cunha, DO, FACOEP | |
| 32 | 2023-02-01 17:43:39 | Absorica (Isotretinoin) | A | Acne Agents, Systemic | Absorica | isotretinoin | Absorica | John P. Cunha, DO, FACOEP |
| 33 | 2023-02-01 17:43:41 | Absorica LD (Isotretinoin Capsules) | A | Retinoid-like Agents, Topical, Acne Agents, Topical | Absorica LD | isotretinoin capsules | Absorica LD | John P. Cunha, DO, FACOEP |
| 34 | 2023-02-01 17:43:56 | Abstral (Fentanyl Sublingual Tablets) | A | Abstral | fentanyl sublingual tablets | Abstral | ||
| 35 | 2023-02-01 17:44:04 | Acalabrutinib Capsules (Calquence) | A | Antineoplastic Tyrosine Kinase Inhibitors | Calquence | acalabrutinib capsules | Calquence | John P. Cunha, DO, FACOEP |
| 36 | 2023-02-01 17:44:17 | ACAM2000 (Smallpox (Vaccinia) Vaccine, Live) | A | Vaccines, Live, Viral | ACAM2000 | smallpox (vaccinia) vaccine, live | ACAM2000 | John P. Cunha, DO, FACOEP |
| 37 | 2023-02-01 17:44:29 | Acamprosate Calcium (Campral) | A | Psychiatry Agents Other, GABA Analogs | Campral | acamprosate calcium | Campral | John P. Cunha, DO, FACOEP |
| 38 | 2023-02-01 17:44:36 | Acanya Gel (Clindamycin Phosphate 1.2% and Benzoyl Peroxide 2.5%) | A | Acne Agents, Topical Combos | Acanya | clindamycin phosphate 1.2% and benzoyl peroxide 2.5% | Acanya Gel | |
| 39 | 2023-02-01 17:44:46 | Acarbose (Precose) | A | Antidiabetics, Alpha-Glucosidase Inhibitors | Precose | acarbose | Precose | John P. Cunha, DO, FACOEP |
| 40 | 2023-02-01 17:45:08 | Accolate (Zafirlukast) | A | Leukotriene Receptor Antagonists | Accolate | zafirlukast | Accolate | John P. Cunha, DO, FACOEP |
| 41 | 2023-02-01 17:45:25 | Accretropin (Somatropin Injection) | A | Accretropin | somatropin injection | Accretropin | ||
| 42 | 2023-02-01 17:45:43 | Accrufer (Ferric Maltol Capsules) | A | Iron Products | Accrufer | ferric maltol capsules | Accrufer | John P. Cunha, DO, FACOEP |
| 43 | 2023-02-01 17:45:46 | AccuNeb (Albuterol Sulfate Inhalation Solution) | A | Beta2 Agonists | AccuNeb | albuterol sulfate inhalation solution | AccuNeb | |
| 44 | 2023-02-01 17:46:05 | Accupril (Quinapril Hydrochloride) | A | ACE Inhibitors | Accupril | quinapril hydrochloride | Accupril | |
| 45 | 2023-02-01 17:46:18 | Accuretic (Quinapril HCl/Hydrochlorothiazide) | A | ACEIHCTZ Combos | Accuretic | quinapril hcl/hydrochlorothiazide | Accuretic | John P. Cunha, DO, FACOEP |
| 46 | 2023-02-01 17:46:33 | Accutane (Isotretinoin) | A | Acne Agents, Topical | Accutane | isotretinoin | Accutane | John P. Cunha, DO, FACOEP |
| 47 | 2023-02-01 17:46:35 | Accuzyme (Papain and Urea) | A | Wound Care | Accuzyme | papain and urea | Accuzyme | John P. Cunha, DO, FACOEP |
| 48 | 2023-02-01 17:46:45 | Acebutolol (Sectral) | A | Antidysrhythmics, II, Beta-Blockers, Intrinsic Sympathomimetic | Sectral | acebutolol | Sectral | John P. Cunha, DO, FACOEP |
| 49 | 2023-02-01 17:46:48 | Aceclofenac Tablet, Film Coated (Clanza CR) | A | Clanza CR | aceclofenac tablet, film coated | Clanza CR | ||
| 50 | 2023-02-01 17:47:05 | Aceon (Perindopril Erbumine) | A | Aceon | perindopril erbumine | Aceon | ||
| 51 | 2023-02-01 17:47:12 | Acephen (Acetaminophen Suppositories) | A | Acephen | acephen | Acetaminophen Suppositories | ||
| 52 | 2023-02-01 17:47:17 | Acetadote (Acetylcysteine Injection) | A | Antidotes, Other | Acetadote | acetylcysteine injection | Acetadote | John P. Cunha, DO, FACOEP |
| 53 | 2023-02-01 17:47:25 | Acetaminophen (Tylenol) | A | Other analgesics, acetaminophen | Tylenol | acetaminophen | Tylenol | John P. Cunha, DO, FACOEP |
| 54 | 2023-02-01 17:47:45 | Acetaminophen and Codeine (Tylenol-Codeine) | A | Tylenol-Codeine | acetaminophen and codeine | Tylenol-Codeine | John P. Cunha, DO, FACOEP | |
| 56 | 2023-02-01 17:47:51 | Acetaminophen, Caffeine and Dihydrocodeine Bitartrate (Trezix Capsules) | A | Trezix | acetaminophen, caffeine and dihydrocodeine bitartrate | Trezix Capsules | ||
| 57 | 2023-02-01 17:48:06 | Acetaminophen, Isometheptene and Dichloralphenazone (Midrin) | A | Midrin | acetaminophen, isometheptene and dichloralphenazone | Midrin | ||
| 58 | 2023-02-01 17:48:26 | Acetaminphen for Injection (Ofirmev) | A | Ofirmev | acetaminphen for injection | Ofirmev | ||
| 59 | 2023-02-01 17:48:36 | Acetazolamide Injection (Acetazolamide Injection) | A | Acetazolamide Injection | acetazolamide injection | Acetazolamide Injection | ||
| 60 | 2023-02-01 17:48:38 | Acetazolamide Tablets (Acetazolamide Tablets) | A | Anticonvulsants, Other | Acetazolamide | acetazolamide tablets | Acetazolamide Tablets | |
| 61 | 2023-02-01 17:48:52 | Acetazolamide Tablets and Injection (Diamox Tablets and Injection) | A | Anticonvulsants, Other, Antiglaucoma, Carbonic Anhydrase Inhibitors | Diamox Tablets and Injection | acetazolamide tablets and injection | Diamox Tablets and Injection | John P. Cunha, DO, FACOEP |
| 62 | 2023-02-01 17:49:13 | Acetazolamide XR (Diamox Sequels) | A | Anticonvulsants, Other | Diamox Sequels | acetazolamide xr | Diamox Sequels | John P. Cunha, DO, FACOEP |
| 63 | 2023-02-01 17:49:16 | Acetic Acid (Acetic Acid) | A | Acetic Acid | acetic acid | Acetic Acid | ||
| 64 | 2023-02-01 17:49:27 | Acetohydroxamic Acid Tablets (Lithostat) | A | Antimicrobials, Adjunct | Lithostat | acetohydroxamic acid tablets | Lithostat | John P. Cunha, DO, FACOEP |
| 65 | 2023-02-01 17:49:38 | Acetyl Sulfisoxazole Pediatric Suspension (Gantrisin) | A | Sulfonamides | Gantrisin | acetyl sulfisoxazole pediatric suspension | Gantrisin | John P. Cunha, DO, FACOEP |
| 66 | 2023-02-01 17:49:42 | Acetylcholine Chloride Intraocular Solution (Miochol-E) | A | Miotics, Direct-Acting | Miochol-E | acetylcholine chloride intraocular solution | Miochol-E | John P. Cunha, DO, FACOEP |
| 67 | 2023-02-01 17:50:01 | Acetylcysteine Effervescent Tablets for Oral Solution (Cetylev) | A | Antidotes, Other | Cetylev | acetylcysteine effervescent tablets for oral solution | Cetylev | John P. Cunha, DO, FACOEP |
| 69 | 2023-02-01 17:50:05 | Acetylcysteine Solution (Mucomyst) (N-acetyl-L-cysteine) | A | Pulmonary, Other | Acetylcysteine Solution | n-acetyl-l-cysteine | Acetylcysteine Solution (Mucomyst) | |
| 70 | 2023-02-01 17:50:27 | Achromycin V (tetracycline) | A | Tetracyclines | Achromycin V | tetracycline | Achromycin V | John P. Cunha, DO, FACOEP |
| 71 | 2023-02-01 17:50:44 | Aci-Jel (Vaginal Jelly) | A | Aci-Jel | vaginal jelly | Aci-Jel | ||
| 72 | 2023-02-01 17:50:59 | Acidul (Fluoride) | A | Minerals, Other | Acidul | fluoride | Acidul | John P. Cunha, DO, FACOEP |
| 73 | 2023-02-01 17:51:20 | Aciphex (Rabeprazole Sodium) | A | Proton Pump Inhibitors | Aciphex | rabeprazole sodium | Aciphex | John P. Cunha, DO, FACOEP |
| 74 | 2023-02-01 17:51:32 | Aciphex Sprinkle (rabeprazole sodium) | A | Aciphex Sprinkle | rabeprazole sodium | Aciphex Sprinkle | John P. Cunha, DO, FACOEP | |
| 75 | 2023-02-01 17:51:34 | Acitretin (Soriatane) | A | Retinoid-like Agents, Topical, Antipsoriatics, Systemic | Soriatane | acitretin | Soriatane | John P. Cunha, DO, FACOEP |
| 76 | 2023-02-01 17:51:44 | Aclidinium Bromide (Tudorza Pressair) | A | Anticholinergics, Respiratory | Tudorza Pressair | aclidinium bromide | Tudorza Pressair | John P. Cunha, DO, FACOEP |
| 77 | 2023-02-01 17:52:00 | Aclidinium Bromide and Formoterol Fumarate Inhalation Powder (Duaklir Pressair) | A | Respiratory Inhalant Combos, Respiratory Inhalant Combos | Duaklir Pressair | aclidinium bromide and formoterol fumarate inhalation powder | Duaklir Pressair | |
| 78 | 2023-02-01 17:52:14 | Aclovate (Alclometasone Dipropionate Cream, Ointment) | A | Corticosteroids, Topical | Aclovate | alclometasone dipropionate cream, ointment | Aclovate | John P. Cunha, DO, FACOEP |
| 79 | 2023-02-01 17:52:15 | Acova (Argatroban) | A | Anticoagulants, Cardiovascular, Thrombin Inhibitors | Acova | argatroban | Acova | John P. Cunha, DO, FACOEP |
| 80 | 2023-02-01 17:52:22 | Acrivastine and Pseudoephedrine (Semprex D) | A | Antihistamine/Decongestant Combos | Semprex D | acrivastine and pseudoephedrine | Semprex D | John P. Cunha, DO, FACOEP |
| 81 | 2023-02-01 17:52:44 | Actemra (Tocilizumab Injection) | A | DMARDs, Immunomodulators, Monoclonal Antibodies | Actemra | tocilizumab injection | Actemra | John P. Cunha, DO, FACOEP |
| 82 | 2023-02-01 17:52:51 | ActHIB (Haemophilus b Conjugate Vaccine) | A | Vaccines, Inactivated, Bacterial | Acthib | haemophilus b conjugate vaccine | ActHIB | |
| 83 | 2023-02-01 17:53:04 | Acthrel (Corticorelin Ovine Triflutate for Injection) | A | Enzyme Cofactors, Diagnostics, Endocrine | Acthrel | corticorelin ovine triflutate for injection | Acthrel | John P. Cunha, DO, FACOEP |
| 84 | 2023-02-01 17:53:08 | Acticin (Permethrin) | A | Acticin | permethrin | Acticin | ||
| 85 | 2023-02-01 17:53:18 | Acticlate (Doxycycline Hyclate Tablets, USP) | A | Tetracyclines | Acticlate | doxycycline hyclate tablets, usp | Acticlate | |
| 86 | 2023-02-01 17:53:27 | Actidose with Sorbitol and Actidose-Aqua (Activated Charcoal Suspension) | A | Actidose with Sorbitol and Actidose-Aqua | activated charcoal suspension | Actidose with Sorbitol and Actidose-Aqua | John P. Cunha, DO, FACOEP | |
| 87 | 2023-02-01 17:53:46 | Actigall (Ursodiol, USP Capsules) | A | Gallstone Solubilizing Agents | Actigall | ursodiol, usp capsules | Actigall | John P. Cunha, DO, FACOEP |
| 88 | 2023-02-01 17:54:07 | Actimmune (Interferon Gamma 1 b) | A | Biological Response Modifiers | Actimmune | interferon gamma 1 b | Actimmune | John P. Cunha, DO, FACOEP |
| 89 | 2023-02-01 17:54:27 | Actiq (Fentanyl Citrate) | A | Opioid Analgesics, Opioids, Anilidopiperidine | Actiq | fentanyl citrate | Actiq | John P. Cunha, DO, FACOEP |
| 90 | 2023-02-01 17:54:33 | Actisite (Tetracycline Periodontal) | A | Tetracyclines | Actisite | tetracycline periodontal | Actisite | John P. Cunha, DO, FACOEP |
| 91 | 2023-02-01 17:54:47 | Activase (Alteplase) | A | Thrombolytics | Activase | alteplase | Activase | John P. Cunha, DO, FACOEP |
| 93 | 2023-02-01 17:55:03 | Activella (Estradiol, Norethindrone Acetate) | A | Estrogens/Progestins-HRT | Activella | estradiol, norethindrone acetate | Activella | John P. Cunha, DO, FACOEP |
| 94 | 2023-02-01 17:55:20 | Actonel (Risedronate Sodium) | A | Bisphosphonate Derivatives, Calcium Metabolism Modifiers | Actonel | risedronate sodium | Actonel | |
| 95 | 2023-02-01 17:55:28 | Actonel with Calcium (Risedronate Sodium with Calcium Carbonate) | A | Bisphosphonate Derivatives, Calcium Metabolism Modifiers | Actonel with Calcium | risedronate sodium with calcium carbonate | Actonel with Calcium | John P. Cunha, DO, FACOEP |
| 96 | 2023-02-01 17:55:34 | Actoplus MET, Actoplus MET XR (Pioglitazone Hcl and Metformin Hcl) | A | Actoplus MET | pioglitazone hcl and metformin hcl | Actoplus MET, Actoplus MET XR | ||
| 97 | 2023-02-01 17:55:55 | Actos (Pioglitazone Hydrochloride) | A | Antidiabetics, Thiazolidinediones | Actos | pioglitazone hydrochloride | Actos | |
| 98 | 2023-02-01 17:55:59 | Acular (Ketorolac Tromethamine) | A | Ophthalmic NSAIDs | Acular | ketorolac tromethamine | Acular | |
| 99 | 2023-02-01 17:56:08 | Acular LS (Ketorolac Tromethamine Ophthalmic Solution) | A | Ophthalmic NSAIDs | Acular LS | ketorolac tromethamine ophthalmic solution | Acular LS | |
| 100 | 2023-02-01 17:56:14 | Acuvail (Ketorolac Tromethamine Ophthalmic Solution) | A | Acuvail | ketorolac tromethamine ophthalmic solution | Acuvail | ||
| 101 | 2023-02-01 17:56:20 | ACUVUE Theravision with Ketotifen (Etafilcon A with Ketotifen Daily Disposable Contact Lenses) | A | ACUVUE Theravision with Ketotifen | etafilcon a with ketotifen daily disposable contact lenses | ACUVUE Theravision with Ketotifen | John P. Cunha, DO, FACOEP | |
| 102 | 2023-02-01 17:56:26 | Acyclovir (Zovirax) | A | Antivirals, VZV, Antivirals, HSV, Antivirals, Other | Zovirax | acyclovir | Zovirax | John P. Cunha, DO, FACOEP |
| 103 | 2023-02-01 17:56:42 | Acyclovir (Zovirax Suspension) | A | Antivirals, Other | Zovirax Suspension | acyclovir | Zovirax Suspension | John P. Cunha, DO, FACOEP |
- letter
- medication
- detail
- related_drug
- medication_x_related_drug
- drug_comparison
- comparison_detail
- medication_x_drug_comparison
- supplement
- supplement_detail
- medication_x_supplement
detail top
| detail.id | detail.ts | detail.name | detail.content | detail.content_filter | medication.id | medication.ts | medication.medication | medication.letter | medication.class | medication.title | medication.generic_name | medication.brand_name | medication.editor |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 |