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10,312 Drugs Database: Alias, Description, Authentication, Warning, Pharmacology

10,312 drugs & 56,662 Properties by Alphabet: alias, description, authentication, warning, pharmacology

Samples

Online API (JSON, Excel, CSV)

http://n3.datasn.io/data/api/v1/n3a2/drug_2/main/list/

CSV

Listed below are the first 10 - 100 (or more) records of each of the 4 tables.

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alphabet top

alphabet.id alphabet.ts alphabet.title
12017-09-01 10:18:43A
22017-09-01 10:18:43B
32017-09-01 10:18:43C
42017-09-01 10:18:43D
52017-09-01 10:18:43E
62017-09-01 10:18:43F
72017-09-01 10:18:43G
82017-09-01 10:18:43H
92017-09-01 10:18:43I
102017-09-01 10:18:43J
112017-09-01 10:18:43K
122017-09-01 10:18:43L
132017-09-01 10:18:43M
142017-09-01 10:18:43N
152017-09-01 10:18:43O
162017-09-01 10:18:43P
172017-09-01 10:18:43Q
182017-09-01 10:18:43R
192017-09-01 10:18:43S
202017-09-01 10:18:43T
212017-09-01 10:18:43U
222017-09-01 10:18:43V
232017-09-01 10:18:43W
242017-09-01 10:18:43X
252017-09-01 10:18:43Y
262017-09-01 10:18:43Z
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drug top

drug.id drug.ts drug.title drug.alias drug.az_source
12017-12-04 17:37:08A-MethapredMethylprednisolone Sodium SuccinateFDA
22017-12-04 17:37:19Abacavir SulfateZiagenFDA
32017-09-01 11:12:57Abacavir SulfateZiagenMultum
42017-12-04 17:37:28Abacavir Sulfate and Lamivudine TabletsEpzicomFDA
52017-09-01 11:12:57Abacavir Sulfate and Lamivudine TabletsEpzicomMultum
62017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirFDA
72017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirMultum
82017-09-01 11:12:57Abacavir, Dolutegravir, and Lamivudine Film-coated TabletsTriumeqFDA
92017-09-01 11:12:57Abaloparatide InjectionTymlosFDA
102017-09-01 11:12:57AbarelixPlenaxisFDA
112017-09-01 11:12:57AbataceptOrenciaFDA
122017-09-01 11:12:57AbataceptOrenciaMultum
132017-09-01 11:12:57AbciximabReoProFDA
142017-09-01 11:12:57AbelcetAmphotericin B InjectionFDA
152017-09-01 11:12:57AbilifyAripiprazoleFDA
162017-09-01 11:12:57AbilifyAripiprazoleMultum
172017-09-01 11:12:57Abilify MaintenaAripiprazole Extended-Release Injectable SuspensionFDA
182017-09-01 11:12:57Abiraterone Acetate TabletsZytigaFDA
192017-09-01 11:12:57Abiraterone Acetate TabletsZytigaMultum
202017-09-01 11:12:57AblavarGadofosveset Trisodium InjectionFDA
212017-09-01 11:12:57AblavarGadofosveset Trisodium InjectionMultum
222017-09-01 11:12:57Abobotulinumtoxin A InjectionDysportFDA
232017-09-01 11:12:57Abobotulinumtoxin A InjectionDysportMultum
242017-09-01 11:12:57AbraxaneAlbumin-bound Paclitaxel for Injectable SuspensionFDA
252017-09-01 11:12:57AbraxaneAlbumin-bound Paclitaxel for Injectable SuspensionMultum
262017-09-01 11:12:57Absorbable Gelatin Compressed Sponge, USPGelfoam Compressed SpongeFDA
272017-09-01 11:12:57Absorbable Gelatin Dental SpongeGelfoam Dental SpongeFDA
282017-09-01 11:12:57Absorbable Gelatin PowderGelfoamFDA
292017-09-01 11:12:57Absorbable Gelatin Sponge, USPGelfoam SpongeFDA
302017-09-01 11:12:57Absorbable Gelatin Sterile Ophthalmic FilmGelfilmFDA
312017-09-01 11:12:57AbsoricaIsotretinoinFDA
322017-09-01 11:12:57AbstralFentanyl Sublingual TabletsFDA
332017-09-01 11:12:57AbstralFentanyl Sublingual TabletsMultum
342017-09-01 11:12:57ACAM2000Smallpox (Vaccinia) Vaccine, LiveFDA
352017-09-01 11:12:57Acamprosate CalciumCampralFDA
362017-09-01 11:12:57Acamprosate CalciumCampralMultum
372017-09-01 11:12:57Acanya GelClindamycin Phosphate 1.2% and Benzoyl Peroxide 2.5%FDA
382017-09-01 11:12:57Acanya GelClindamycin Phosphate 1.2% and Benzoyl Peroxide 2.5%Multum
392017-09-01 11:12:57AcarbosePrecoseFDA
402017-09-01 11:12:57AcarbosePrecoseMultum
412017-09-01 11:12:57AccolateZafirlukastFDA
422017-09-01 11:12:57AccolateZafirlukastMultum
432017-09-01 11:12:57AccretropinSomatropin InjectionFDA
442017-09-01 11:12:57AccuNebAlbuterol Sulfate Inhalation SolutionFDA
452017-09-01 11:12:57AccuNebAlbuterol Sulfate Inhalation SolutionMultum
462017-09-01 11:12:57AccuprilQuinapril HydrochlorideFDA
472017-09-01 11:12:57AccuprilQuinapril HydrochlorideMultum
482017-09-01 11:12:57AccureticQuinapril HCl/HydrochlorothiazideFDA
492017-09-01 11:12:57AccureticQuinapril HCl/HydrochlorothiazideMultum
502017-09-01 11:12:57AccutaneIsotretinoinFDA
512017-09-01 11:12:57AccutaneIsotretinoinMultum
522017-09-01 11:12:57AccuzymePapain and UreaFDA
532017-09-01 11:12:57AcebutololSectralFDA
542017-09-01 11:12:57AcebutololSectralMultum
552017-09-01 11:12:57AceonPerindopril ErbumineFDA
562017-09-01 11:12:57AceonPerindopril ErbumineMultum
572017-09-01 11:12:57AcetadoteAcetylcysteine InjectionFDA
582017-09-01 11:12:57AcetaminophenTylenolFDA
592017-09-01 11:12:57AcetaminophenTylenolMultum
602017-09-01 11:12:57Acetaminophen and CodeineTylenol-CodeineFDA
612017-09-01 11:12:57Acetaminophen and CodeineTylenol-CodeineMultum
622017-09-01 11:12:57Acetaminophen, Caffeine and Dihydrocodeine BitartrateTrezix CapsulesFDA
632017-09-01 11:12:57Acetaminophen, Isometheptene and DichloralphenazoneMidrinFDA
642017-09-01 11:12:57Acetaminophen, Isometheptene and DichloralphenazoneMidrinMultum
652017-09-01 11:12:57Acetaminphen for InjectionOfirmevFDA
662017-09-01 11:12:57Acetaminphen for InjectionOfirmevMultum
672017-09-01 11:12:57Acetazolamide InjectionAcetazolamide InjectionFDA
682017-09-01 11:12:57Acetazolamide TabletsAcetazolamide TabletsFDA
692017-09-01 11:12:57Acetazolamide XRDiamox SequelsFDA
702017-09-01 11:12:57Acetazolamide XRDiamox SequelsMultum
712017-09-01 11:12:57Acetic AcidAcetic AcidFDA
722017-09-01 11:12:57Acetic AcidAcetic AcidMultum
732017-09-01 11:12:57Acetohydroxamic Acid TabletsLithostatFDA
742017-09-01 11:12:57Acetyl Sulfisoxazole Pediatric SuspensionGantrisinFDA
752017-09-01 11:12:57Acetyl Sulfisoxazole Pediatric SuspensionGantrisinMultum
762017-09-01 11:12:57Acetylcholine Chloride Intraocular SolutionMiochol-EFDA
772017-09-01 11:12:57Acetylcysteine Effervescent Tablets for Oral SolutionCetylevFDA
782017-09-01 11:12:57Acetylcysteine InjectionAcetadoteFDA
792017-09-01 11:12:57Acetylcysteine SolutionN-acetyl-L-cysteineFDA
802017-09-01 11:12:57Achromycin VtetracyclineFDA
812017-09-01 11:12:57Aci-JelVaginal JellyFDA
822017-09-01 11:12:57AcidulFluorideFDA
832017-09-01 11:12:57AciphexRabeprazole SodiumFDA
842017-09-01 11:12:57AciphexRabeprazole SodiumMultum
852017-09-01 11:12:57Aciphex Sprinklerabeprazole sodiumFDA
862017-09-01 11:12:57AcitretinSoriataneFDA
872017-09-01 11:12:57AcitretinSoriataneMultum
882017-09-01 11:12:57Aclidinium BromideTudorza PressairFDA
892017-09-01 11:12:57AclovateAlclometasone Dipropionate Cream, OintmentFDA
902017-09-01 11:12:57AclovateAlclometasone Dipropionate Cream, OintmentMultum
912017-09-01 11:12:57Acrivastine and PseudoephedrineSemprex DFDA
922017-09-01 11:12:57Acrivastine and PseudoephedrineSemprex DMultum
932017-09-01 11:12:57ActemraTocilizumab InjectionFDA
942017-09-01 11:12:57ActemraTocilizumab InjectionMultum
952017-09-01 11:12:57ActHIBHaemophilus b Conjugate VaccineFDA
962017-09-01 11:12:57ActHIBHaemophilus b Conjugate VaccineMultum
972017-09-01 11:12:57ActhrelCorticorelin Ovine Triflutate for InjectionFDA
982017-09-01 11:12:57ActhrelCorticorelin Ovine Triflutate for InjectionMultum
992017-09-01 11:12:57ActicinPermethrinFDA
1002017-09-01 11:12:57ActiclateDoxycycline Hyclate Tablets, USPFDA
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alphabet_x_drug top

alphabet_x_drug.id alphabet_x_drug.ts alphabet.id alphabet.ts alphabet.title drug.id drug.ts drug.title drug.alias drug.az_source
12017-09-01 11:12:5712017-09-01 10:18:43A12017-12-04 17:37:08A-MethapredMethylprednisolone Sodium SuccinateFDA
22017-09-01 11:12:5712017-09-01 10:18:43A22017-12-04 17:37:19Abacavir SulfateZiagenFDA
32017-09-01 11:12:5712017-09-01 10:18:43A32017-09-01 11:12:57Abacavir SulfateZiagenMultum
42017-09-01 11:12:5712017-09-01 10:18:43A42017-12-04 17:37:28Abacavir Sulfate and Lamivudine TabletsEpzicomFDA
52017-09-01 11:12:5712017-09-01 10:18:43A52017-09-01 11:12:57Abacavir Sulfate and Lamivudine TabletsEpzicomMultum
62017-09-01 11:12:5712017-09-01 10:18:43A62017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirFDA
72017-09-01 11:12:5712017-09-01 10:18:43A72017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirMultum
82017-09-01 11:12:5712017-09-01 10:18:43A82017-09-01 11:12:57Abacavir, Dolutegravir, and Lamivudine Film-coated TabletsTriumeqFDA
92017-09-01 11:12:5712017-09-01 10:18:43A92017-09-01 11:12:57Abaloparatide InjectionTymlosFDA
102017-09-01 11:12:5712017-09-01 10:18:43A102017-09-01 11:12:57AbarelixPlenaxisFDA
112017-09-01 11:12:5712017-09-01 10:18:43A112017-09-01 11:12:57AbataceptOrenciaFDA
122017-09-01 11:12:5712017-09-01 10:18:43A122017-09-01 11:12:57AbataceptOrenciaMultum
132017-09-01 11:12:5712017-09-01 10:18:43A132017-09-01 11:12:57AbciximabReoProFDA
142017-09-01 11:12:5712017-09-01 10:18:43A142017-09-01 11:12:57AbelcetAmphotericin B InjectionFDA
152017-09-01 11:12:5712017-09-01 10:18:43A152017-09-01 11:12:57AbilifyAripiprazoleFDA
162017-09-01 11:12:5712017-09-01 10:18:43A162017-09-01 11:12:57AbilifyAripiprazoleMultum
172017-09-01 11:12:5712017-09-01 10:18:43A172017-09-01 11:12:57Abilify MaintenaAripiprazole Extended-Release Injectable SuspensionFDA
182017-09-01 11:12:5712017-09-01 10:18:43A182017-09-01 11:12:57Abiraterone Acetate TabletsZytigaFDA
192017-09-01 11:12:5712017-09-01 10:18:43A192017-09-01 11:12:57Abiraterone Acetate TabletsZytigaMultum
202017-09-01 11:12:5712017-09-01 10:18:43A202017-09-01 11:12:57AblavarGadofosveset Trisodium InjectionFDA
212017-09-01 11:12:5712017-09-01 10:18:43A212017-09-01 11:12:57AblavarGadofosveset Trisodium InjectionMultum
222017-09-01 11:12:5712017-09-01 10:18:43A222017-09-01 11:12:57Abobotulinumtoxin A InjectionDysportFDA
232017-09-01 11:12:5712017-09-01 10:18:43A232017-09-01 11:12:57Abobotulinumtoxin A InjectionDysportMultum
242017-09-01 11:12:5712017-09-01 10:18:43A242017-09-01 11:12:57AbraxaneAlbumin-bound Paclitaxel for Injectable SuspensionFDA
252017-09-01 11:12:5712017-09-01 10:18:43A252017-09-01 11:12:57AbraxaneAlbumin-bound Paclitaxel for Injectable SuspensionMultum
262017-09-01 11:12:5712017-09-01 10:18:43A262017-09-01 11:12:57Absorbable Gelatin Compressed Sponge, USPGelfoam Compressed SpongeFDA
272017-09-01 11:12:5712017-09-01 10:18:43A272017-09-01 11:12:57Absorbable Gelatin Dental SpongeGelfoam Dental SpongeFDA
282017-09-01 11:12:5712017-09-01 10:18:43A282017-09-01 11:12:57Absorbable Gelatin PowderGelfoamFDA
292017-09-01 11:12:5712017-09-01 10:18:43A292017-09-01 11:12:57Absorbable Gelatin Sponge, USPGelfoam SpongeFDA
302017-09-01 11:12:5712017-09-01 10:18:43A302017-09-01 11:12:57Absorbable Gelatin Sterile Ophthalmic FilmGelfilmFDA
312017-09-01 11:12:5712017-09-01 10:18:43A312017-09-01 11:12:57AbsoricaIsotretinoinFDA
322017-09-01 11:12:5712017-09-01 10:18:43A322017-09-01 11:12:57AbstralFentanyl Sublingual TabletsFDA
332017-09-01 11:12:5712017-09-01 10:18:43A332017-09-01 11:12:57AbstralFentanyl Sublingual TabletsMultum
342017-09-01 11:12:5712017-09-01 10:18:43A342017-09-01 11:12:57ACAM2000Smallpox (Vaccinia) Vaccine, LiveFDA
352017-09-01 11:12:5712017-09-01 10:18:43A352017-09-01 11:12:57Acamprosate CalciumCampralFDA
362017-09-01 11:12:5712017-09-01 10:18:43A362017-09-01 11:12:57Acamprosate CalciumCampralMultum
372017-09-01 11:12:5712017-09-01 10:18:43A372017-09-01 11:12:57Acanya GelClindamycin Phosphate 1.2% and Benzoyl Peroxide 2.5%FDA
382017-09-01 11:12:5712017-09-01 10:18:43A382017-09-01 11:12:57Acanya GelClindamycin Phosphate 1.2% and Benzoyl Peroxide 2.5%Multum
392017-09-01 11:12:5712017-09-01 10:18:43A392017-09-01 11:12:57AcarbosePrecoseFDA
402017-09-01 11:12:5712017-09-01 10:18:43A402017-09-01 11:12:57AcarbosePrecoseMultum
412017-09-01 11:12:5712017-09-01 10:18:43A412017-09-01 11:12:57AccolateZafirlukastFDA
422017-09-01 11:12:5712017-09-01 10:18:43A422017-09-01 11:12:57AccolateZafirlukastMultum
432017-09-01 11:12:5712017-09-01 10:18:43A432017-09-01 11:12:57AccretropinSomatropin InjectionFDA
442017-09-01 11:12:5712017-09-01 10:18:43A442017-09-01 11:12:57AccuNebAlbuterol Sulfate Inhalation SolutionFDA
452017-09-01 11:12:5712017-09-01 10:18:43A452017-09-01 11:12:57AccuNebAlbuterol Sulfate Inhalation SolutionMultum
462017-09-01 11:12:5712017-09-01 10:18:43A462017-09-01 11:12:57AccuprilQuinapril HydrochlorideFDA
472017-09-01 11:12:5712017-09-01 10:18:43A472017-09-01 11:12:57AccuprilQuinapril HydrochlorideMultum
482017-09-01 11:12:5712017-09-01 10:18:43A482017-09-01 11:12:57AccureticQuinapril HCl/HydrochlorothiazideFDA
492017-09-01 11:12:5712017-09-01 10:18:43A492017-09-01 11:12:57AccureticQuinapril HCl/HydrochlorothiazideMultum
502017-09-01 11:12:5712017-09-01 10:18:43A502017-09-01 11:12:57AccutaneIsotretinoinFDA
512017-09-01 11:12:5712017-09-01 10:18:43A512017-09-01 11:12:57AccutaneIsotretinoinMultum
522017-09-01 11:12:5712017-09-01 10:18:43A522017-09-01 11:12:57AccuzymePapain and UreaFDA
532017-09-01 11:12:5712017-09-01 10:18:43A532017-09-01 11:12:57AcebutololSectralFDA
542017-09-01 11:12:5712017-09-01 10:18:43A542017-09-01 11:12:57AcebutololSectralMultum
552017-09-01 11:12:5712017-09-01 10:18:43A552017-09-01 11:12:57AceonPerindopril ErbumineFDA
562017-09-01 11:12:5712017-09-01 10:18:43A562017-09-01 11:12:57AceonPerindopril ErbumineMultum
572017-09-01 11:12:5712017-09-01 10:18:43A572017-09-01 11:12:57AcetadoteAcetylcysteine InjectionFDA
582017-09-01 11:12:5712017-09-01 10:18:43A582017-09-01 11:12:57AcetaminophenTylenolFDA
592017-09-01 11:12:5712017-09-01 10:18:43A592017-09-01 11:12:57AcetaminophenTylenolMultum
602017-09-01 11:12:5712017-09-01 10:18:43A602017-09-01 11:12:57Acetaminophen and CodeineTylenol-CodeineFDA
612017-09-01 11:12:5712017-09-01 10:18:43A612017-09-01 11:12:57Acetaminophen and CodeineTylenol-CodeineMultum
622017-09-01 11:12:5712017-09-01 10:18:43A622017-09-01 11:12:57Acetaminophen, Caffeine and Dihydrocodeine BitartrateTrezix CapsulesFDA
632017-09-01 11:12:5712017-09-01 10:18:43A632017-09-01 11:12:57Acetaminophen, Isometheptene and DichloralphenazoneMidrinFDA
642017-09-01 11:12:5712017-09-01 10:18:43A642017-09-01 11:12:57Acetaminophen, Isometheptene and DichloralphenazoneMidrinMultum
652017-09-01 11:12:5712017-09-01 10:18:43A652017-09-01 11:12:57Acetaminphen for InjectionOfirmevFDA
662017-09-01 11:12:5712017-09-01 10:18:43A662017-09-01 11:12:57Acetaminphen for InjectionOfirmevMultum
672017-09-01 11:12:5712017-09-01 10:18:43A672017-09-01 11:12:57Acetazolamide InjectionAcetazolamide InjectionFDA
682017-09-01 11:12:5712017-09-01 10:18:43A682017-09-01 11:12:57Acetazolamide TabletsAcetazolamide TabletsFDA
692017-09-01 11:12:5712017-09-01 10:18:43A692017-09-01 11:12:57Acetazolamide XRDiamox SequelsFDA
702017-09-01 11:12:5712017-09-01 10:18:43A702017-09-01 11:12:57Acetazolamide XRDiamox SequelsMultum
712017-09-01 11:12:5712017-09-01 10:18:43A712017-09-01 11:12:57Acetic AcidAcetic AcidFDA
722017-09-01 11:12:5712017-09-01 10:18:43A722017-09-01 11:12:57Acetic AcidAcetic AcidMultum
732017-09-01 11:12:5712017-09-01 10:18:43A732017-09-01 11:12:57Acetohydroxamic Acid TabletsLithostatFDA
742017-09-01 11:12:5712017-09-01 10:18:43A742017-09-01 11:12:57Acetyl Sulfisoxazole Pediatric SuspensionGantrisinFDA
752017-09-01 11:12:5712017-09-01 10:18:43A752017-09-01 11:12:57Acetyl Sulfisoxazole Pediatric SuspensionGantrisinMultum
762017-09-01 11:12:5712017-09-01 10:18:43A762017-09-01 11:12:57Acetylcholine Chloride Intraocular SolutionMiochol-EFDA
772017-09-01 11:12:5712017-09-01 10:18:43A772017-09-01 11:12:57Acetylcysteine Effervescent Tablets for Oral SolutionCetylevFDA
782017-09-01 11:12:5712017-09-01 10:18:43A782017-09-01 11:12:57Acetylcysteine InjectionAcetadoteFDA
792017-09-01 11:12:5712017-09-01 10:18:43A792017-09-01 11:12:57Acetylcysteine SolutionN-acetyl-L-cysteineFDA
802017-09-01 11:12:5712017-09-01 10:18:43A802017-09-01 11:12:57Achromycin VtetracyclineFDA
812017-09-01 11:12:5712017-09-01 10:18:43A812017-09-01 11:12:57Aci-JelVaginal JellyFDA
822017-09-01 11:12:5712017-09-01 10:18:43A822017-09-01 11:12:57AcidulFluorideFDA
832017-09-01 11:12:5712017-09-01 10:18:43A832017-09-01 11:12:57AciphexRabeprazole SodiumFDA
842017-09-01 11:12:5712017-09-01 10:18:43A842017-09-01 11:12:57AciphexRabeprazole SodiumMultum
852017-09-01 11:12:5712017-09-01 10:18:43A852017-09-01 11:12:57Aciphex Sprinklerabeprazole sodiumFDA
862017-09-01 11:12:5712017-09-01 10:18:43A862017-09-01 11:12:57AcitretinSoriataneFDA
872017-09-01 11:12:5712017-09-01 10:18:43A872017-09-01 11:12:57AcitretinSoriataneMultum
882017-09-01 11:12:5712017-09-01 10:18:43A882017-09-01 11:12:57Aclidinium BromideTudorza PressairFDA
892017-09-01 11:12:5712017-09-01 10:18:43A892017-09-01 11:12:57AclovateAlclometasone Dipropionate Cream, OintmentFDA
902017-09-01 11:12:5712017-09-01 10:18:43A902017-09-01 11:12:57AclovateAlclometasone Dipropionate Cream, OintmentMultum
912017-09-01 11:12:5712017-09-01 10:18:43A912017-09-01 11:12:57Acrivastine and PseudoephedrineSemprex DFDA
922017-09-01 11:12:5712017-09-01 10:18:43A922017-09-01 11:12:57Acrivastine and PseudoephedrineSemprex DMultum
932017-09-01 11:12:5712017-09-01 10:18:43A932017-09-01 11:12:57ActemraTocilizumab InjectionFDA
942017-09-01 11:12:5712017-09-01 10:18:43A942017-09-01 11:12:57ActemraTocilizumab InjectionMultum
952017-09-01 11:12:5712017-09-01 10:18:43A952017-09-01 11:12:57ActHIBHaemophilus b Conjugate VaccineFDA
962017-09-01 11:12:5712017-09-01 10:18:43A962017-09-01 11:12:57ActHIBHaemophilus b Conjugate VaccineMultum
972017-09-01 11:12:5712017-09-01 10:18:43A972017-09-01 11:12:57ActhrelCorticorelin Ovine Triflutate for InjectionFDA
982017-09-01 11:12:5712017-09-01 10:18:43A982017-09-01 11:12:57ActhrelCorticorelin Ovine Triflutate for InjectionMultum
992017-09-01 11:12:5712017-09-01 10:18:43A992017-09-01 11:12:57ActicinPermethrinFDA
1002017-09-01 11:12:5712017-09-01 10:18:43A1002017-09-01 11:12:57ActiclateDoxycycline Hyclate Tablets, USPFDA
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12017-09-01 17:33:41Drug DescriptionA-METHAPRED (methylprednisolone sodium succinate) Injection, Powder, Lyophilized, for Solution For Intravenous or Intramuscular Administration DESCRIPTION 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 chloroform and is very slightly soluble in acetone. 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. The structural formula is represented below: 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. A-Methapred (methylprednisolone sodium succinate) is available in several strengths and packages for intravenous or intramuscular administration. 40 mg Single-Dose Vial- Each mL (when mixed) contains methylprednisolone sodium succinate equivalent to 40 mg methylprednisolone; also 1.6 mg monobasic sodium phosphate anhydrous; 17.46 mg dibasic sodium phosphate anhydrous; 25 mg lactose anhydrous; 8.8 mg benzyl alcohol added as preservative. 125 mg Single-Dose Vial- 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. 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 osmolar; for the 125 mg per 2 mL, 0.40 osmolar; (Isotonic saline = 0.28 osmolar). IMPORTANT- Use only Bacteriostatic Water For Injection with Benzyl Alcohol when reconstituting A-Methapred (methylprednisolone sodium succinate) . Use within 48 hours after mixing.12017-12-04 17:37:08A-MethapredMethylprednisolone Sodium SuccinateFDA
22017-09-01 17:33:41Indications & DosageINDICATIONS 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: Endocrine Disorders Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance) Acute adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; mineralocorticoid supplementation may be necessary, particularly when synthetic analogs are used) Preoperatively and in the event of serious trauma or illness, in patients with known adrenal insufficiency or when adrenocortical reserve is doubtful Shock unresponsive to conventional therapy if adrenocortical insufficiency exists or is suspected Congenital adrenal hyperplasia Hypercalcemia associated with cancer Nonsuppurative thyroiditis Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Post-traumatic osteoarthritis Synovitis of osteoarthritis Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy) Acute and subacute bursitis Epicondylitis Acute nonspecific tenosynovitis Acute gouty arthritis Psoriatic arthritis Ankylosing spondylitis Collagen Diseases During an exacerbation or as maintenance therapy in selected cases of: Systemic lupus erythematosus Systemic dermatomyositis (polymyositis) Acute rheumatic carditis Dermatologic Diseases Pemphigus Severe erythema multi-forme (Stevens-Johnson syndrome) Exfoliative dermatitis Bullous dermatitis herpetiformis Severe seborrheic dermatitis Severe psoriasis Mycosis fungoides Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in: Bronchial asthma Contact dermatitis Atopic dermatitis Serum sickness Seasonal or perennial allergic rhinitis Drug hypersensitivity reactions Urticarial transfusion reactions Acute noninfectious laryngeal edema (epinephrine is the drug of first choice) Ophthalmic Diseases Severe acute and chronic allergic and inflammatory processes involving the eye, such as: Herpes zoster ophthalmicus Iritis, iridocyclitis Chorioretinitis Diffuse posterior uveitis and choroiditis Optic neuritis Sympathetic ophthalmia Anterior segment inflammation Allergic conjunctivitis Allergic corneal marginal ulcers Keratitis Gastrointestinal Diseases To tide the patient over a critical period of the disease in: Ulcerative colitis (systemic therapy) Regional enteritis (systemic therapy) Respiratory Diseases Symptomatic sarcoidosis Berylliosis Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy Loeffler's syndrome not manageable by other means Aspiration pneumonitis Hematologic Disorders Acquired (autoimmune) hemolytic anemia Idiopathic thrombocytopenic purpura in adults (IV only; IM administration is contraindicated) Secondary thrombocytopenia in adults Erythroblastopenia (RBC anemia) Congenital (erythroid) hypoplastic anemia Neoplastic Diseases For palliative management of: Leukemias and lymphomas in adults Acute leukemia of childhood Edematous States To induce diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus Nervous System Acute exacerbations of multiple sclerosis Miscellaneous Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy Trichinosis with neurologic or myocardial involvement DOSAGE AND ADMINISTRATION 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. In general, high dose corticosteroid therapy should be continued only until the patient's condition has stabilized; usually not beyond 48 to 72 hours. Although adverse effects associated with high dose short-term corticoid therapy are uncommon, peptic ulceration may occur. Prophylactic antacid therapy may be indicated. 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. 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. 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 laboratory studies, such as urinalysis, two-hour postprandial blood sugar, determination of blood pressure and body weight, and a chest X-ray should be made at regular intervals during prolonged therapy. Upper GI X-rays are desirable in patients with an ulcer history or significant dyspepsia. 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. 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% dextrose in water, isotonic saline solution or 5% dextrose in isotonic saline solution. Multiple Sclerosis 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). Directions for Reconstitution Remove protective cap. Cleanse stopper with suitable germicide. Aseptically add 1 mL Bacteriostatic 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. Agitate to effect solution. Invert vial. Insert needle through target area of stopper until tip is just visible. Withdraw dose. Storage Conditions Protect from light. Store unreconstituted product at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Store solution at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Use solution within 48 hours after mixing. HOW SUPPLIED A-Methapred (methylprednisolone sodium succinate) sterile powder is available in the following packages: List Container Concentration 3217 Single-Dose Vial 40 mg/vial 3218 Single-Dose Vial 125 mg/vial Rev: October, 2005. Hospira Inc., Lake Forest, IL 60045, USA. FDA rev date: 11/25/200812017-12-04 17:37:08A-MethapredMethylprednisolone Sodium SuccinateFDA
32017-09-01 17:33:41Side Effects & Drug InteractionsSIDE EFFECTS Fluid and Electrolyte Disturbances Sodium retention, Fluid retention, Congestive heart failure in susceptible patients, Potassium loss, Hypokalemic alkalosis, Hypertension Musculoskeletal Muscle weakness, Steroid myopathy, Loss of muscle mass, Severe arthralgia, Vertebral compression fractures, Aseptic necrosis of femoral and humeral heads, Pathologic fracture of long bones, Osteoporosis Gastrointestinal Peptic ulcer with possible perforation and hemorrhage, Pancreatitis, Abdominal distention, and Ulcerative esophagitis Dermatologic Impaired wound healing, Thin fragile skin, Petechiae and ecchymoses, Facial erythema, Increased sweating, May suppress reactions to skin tests Neurological Increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after treatment, Convulsions, Vertigo, Headache Endocrine Development of Cushingoid state, Suppression of growth in children, Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness, Menstrual irregularities, Decreased carbohydrate tolerance, Manifestations of latent diabetes mellitus, Increased requirements for insulin or oral hypoglycemic agents in diabetics Ophthalmic Posterior subcapsular cataracts, Increased intraocular pressure, Glaucoma, Exophthalmos Metabolic Negative nitrogen balance due to protein catabolism The following additional adverse reactions are related to parenteral corticosteroid therapy: Hyperpigmentation or hypopigmentation, Subcutaneous and cutaneous atrophy, Sterile abscess, Anaphylactic reaction with or without circulatory collapse, cardiac arrest, bronchospasm, Urticaria, Nausea and vomiting, Cardiac arrhythmias; hypotension or hypertension DRUG INTERACTIONS The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism 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.12017-12-04 17:37:08A-MethapredMethylprednisolone Sodium SuccinateFDA
42017-09-01 17:33:41Warnings & PrecautionsWARNINGS 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. 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. 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. A study has failed to establish the efficacy of Methylprednisolone Sodium Succinate for Injection, USP in the treatment of sepsis syndrome and septic 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. Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses. Usage in pregnancy 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 embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Average and large doses of cortisone or hydrocortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. 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. 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. The use of Methylprednisolone Sodium Succinate for Injection, USP sterile powder in active tuberculosis should be restricted to those cases of fulminatingor disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. 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 allergy to any drug. 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 gram administered over a period of less than 10 minutes). Bradycardia has been reported during or after the administration of large doses of Methylprednisolone sodium succinate, and may be unrelated to the speed or duration of infusion. Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles, 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, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered. PRECAUTIONS General Precautions 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, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. There is an enhanced effect of corticosteroids on patients with hypothyroidism and in those with cirrhosis. Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation. 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. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. Steroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection; diverticulitis; fresh intestinal anastomoses; active or latent peptic ulcer; renal insufficiency; hypertension; osteoporosis; and myasthenia gravis. Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, 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 DOSAGE AND ADMINISTRATION.) 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.12017-12-04 17:37:08A-MethapredMethylprednisolone Sodium SuccinateFDA
52017-09-01 17:33:41Overdosage & ContraindicationsOVERDOSE No information provided. CONTRAINDICATIONS 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 Syndrome" in premature infants. A-Methapred (methylprednisolone sodium succinate) sterile powder is also contraindicated in systemic fungal infections and patients with known hypersensitivity to the product and its constituents.12017-12-04 17:37:08A-MethapredMethylprednisolone Sodium SuccinateFDA
62017-09-01 17:33:41Clinical PharmacologyCLINICAL PHARMACOLOGY Methylprednisolone is a potent anti-inflammatory steroid with greater anti-inflammatory potency than prednisolone and even less tendency than prednisolone to induce sodium and water retention. Methylprednisolone sodium succinate has the same metabolic 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 depression of eosinophil count, following intravenous administration, is at least four to one. This is in good agreement with the relative oral potency of methylprednisolone and hydrocortisone.12017-12-04 17:37:08A-MethapredMethylprednisolone Sodium SuccinateFDA
72017-09-01 17:33:41Medication GuidePATIENT INFORMATION Persons who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.12017-12-04 17:37:08A-MethapredMethylprednisolone Sodium SuccinateFDA
82017-09-01 17:33:52Drug DescriptionFind Lowest Prices on ZIAGEN® (abacavir) Tablets, Oral Solution WARNING HYPERSENSITIVITY REACTIONS, and LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with ZIAGEN (abacavir). 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 PRECAUTIONS]. ZIAGEN is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. 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 CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. 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 PRECAUTIONS]. Lactic Acidosis and Severe Hepatomegaly with Steatosis 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 PRECAUTIONS]. DESCRIPTION ZIAGEN is the brand name for abacavir sulfate, a synthetic carbocyclic nucleoside analogue with inhibitory activity against HIV-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 (C14H18N6O)2•H2SO4 and a molecular weight of 670.76 g per mol. It has the following structural formula: Abacavir sulfate is a white to off-white solid and is soluble in water. 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. 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, saccharin sodium, sodium citrate (dihydrate), sorbitol solution, and water. In vivo, abacavir sulfate dissociates to its free base, abacavir. Dosages are expressed in terms of abacavir.22017-12-04 17:37:19Abacavir SulfateZiagenFDA
92017-09-01 17:33:52Indications & DosageINDICATIONS ZIAGEN tablets and oral solution, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV-1) infection. DOSAGE AND ADMINISTRATION Screening For HLA-B*5701 Allele Prior To Starting ZIAGEN Screen for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Recommended Dosage For Adult Patients 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. Recommended Dosage For Pediatric Patients 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. 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. Table 1: Dosing Recommendations for ZIAGEN Scored Tablets in Pediatric Patients Weight (ks) Once-Daily Dosing Regimena Twice-Daily Dosing Regimen AM Dose PM Dose Total Daily Dose 14 to < 20 1 tablet (300 mg) ½tablet (150 mg) ½tablet (150 mg) 300 mg ≥ 20 to < 25 1½tablets (450 mg) ½tablet (150 mg) 1 tablet (300 mg) 450 mg ≥ 25 2 tablets (600 mg) 1 tablet (300 mg) 1 tablet (300 mg) 600 mg a 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 Clinical Studies]. Recommended Dosage For Patients With Hepatic Impairment 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. HOW SUPPLIED Dosage Forms And Strengths 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. 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. Storage And Handling ZIAGEN tablets, 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: Bottles of 60 tablets (NDC 49702-221-18). Unit dose blister packs of 60 tablets (NDC 49702-221-44). Each pack contains 6 blister cards of 10 tablets each. Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see USP). ZIAGEN oral solution is a clear to opalescent, yellowish, strawberry-banana-flavored liquid. Each mL of the solution contains abacavir sulfate equivalent to 20 mg of abacavir. It is packaged in plastic bottles as follows: Bottles of 240 mL (NDC 49702-222-48) with child-resistant closure. This product does not require reconstitution. Store at controlled room temperature of 20° to 25°C (68° to 77°F) (see USP). DO NOT FREEZE. May be refrigerated. Manufactured For:ViiV Healthecare, Research Triangle Park, NC 27709. by: Research Triangle Park, NC 27709. Revised: Mar 201722017-12-04 17:37:19Abacavir SulfateZiagenFDA
102017-09-01 17:33:52Side Effects & Drug InteractionsSIDE EFFECTS The following adverse reactions are discussed in other sections of the labeling: Serious and sometimes fatal hypersensitivity reactions [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS]. Fat redistribution [see WARNINGS AND PRECAUTIONS]. Myocardial infarction [see WARNINGS AND PRECAUTIONS]. Clinical Trials Experience In Adult Subjects 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. Serious And Fatal Abacavir-Associated Hypersensitivity Reactions In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. 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. 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). Additional Adverse Reactions With Use Of ZIAGEN Therapy-Naive Adults: 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. 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 (CNA30024a) through 48 Weeks of Treatment Adverse Reaction ZIAGEN plus Lamivudine plus Efavirenz (n = 324) Zidovudine plusLamivudine plus Efavirenz (n = 325) Dreams/sleep disorders 10% 10% Drug hypersensitivity 9% < 1%b Headaches/migraine 7% 11% Nausea 7% 11% Fatigue/malaise 7% 10% Diarrhea 7% 6% Rashes 6% 12% Abdominal pain/gastritis/gastrointestinal signs and symptoms 6% 8% Depressive disorders 6% 6% Dizziness 6% 6% Musculoskeletal pain 6% 5% Bronchitis 4% 5% Vomiting 2% 9% a 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. b Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding. 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. 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 Adverse Reaction ZIAGEN plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264) Nausea 19% 17% Headache 13% 9% Malaise and fatigue 12% 12% Nausea and vomiting 10% 10% Hypersensitivity reaction 8% 2% Diarrhea 7% 5% Fever and/or chills 6% 3% Depressive disorders 6% 4% Musculoskeletal pain 5% 7% Skin rashes 5% 4% Ear/nose/throat infections 5% 4% Viral respiratory infections 5% 5% Anxiety 5% 3% Renal signs/symptoms < 1% 5% Pain (non-site-specific) < 1% 5% 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. ZIAGEN Once Daily versus ZIAGEN Twice Daily (CNA30021): 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. Laboratory Abnormalities: 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. Table 4: Laboratory Abnormalities (Grades 3-4) in Therapy-Naive Adults (CNA30024) through 48 Weeks of Treatment Grade 3/4 Laboratory Abnormalities ZIAGEN plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325) Elevated CPK ( > 4 X ULN) 8% 8% Elevated ALT ( > 5 X ULN) 6% 6% Elevated AST ( > 5 X ULN) 6% 5% Hypertriglyceridemia ( > 750 mg/dL) 6% 5% Hyperamylasemia ( > 2 X ULN) 4% 5% Neutropenia (ANC < 750/mm³) 2% 4% Anemia (Hgb ≤ 6.9 gm/dL) < 1% 2% Thrombocytopenia (Platelets < 50,000/mm³) 1% < 1% Leukopenia (WBC ≤ 1,500/mm³) < 1% 2% ULN = Upper limit of normal. n = Number of subjects assessed. Laboratory abnormalities in CNA3005 are listed in Table 5. Table 5: Treatment-Emergent Laboratory Abnormalities (Grades 3-4) in CNA3005 Grade 3/4 Laboratory Abnormalities ZIAGEN plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264) Elevated CPK ( > 4 x ULN) 18 (7%) 18 (7%) ALT ( > 5.0 x ULN) 16 (6%) 16 (6%) Neutropenia ( < 750/mm ) 13 (5%) 13 (5%) Hypertriglyceridemia ( > 750 mg/dL) 5 (2%) 3 (1%) Hyperamylasemia ( > 2.0 x ULN) 5 (2%) 1 ( < 1%) Hyperglycemia ( > 13.9 mmol/L) 2 ( < 1%) 2 ( < 1%) Anemia (Hgb ≤ 6.9 g/dL) 0 (0%) 3 (1%) ULN = Upper limit of normal. n = Number of subjects assessed. The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021. Clinical Trials Experience In Pediatric Subjects Therapy-Experienced Pediatric Subjects (Twice-Daily Dosing) 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 m² twice daily compared with lamivudine 4 mg per kg twice daily and zidovudine 180 mg per m² twice daily from CNA3006 are listed in Table 6. 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 Adverse Reaction ZIAGEN plus Lamivudine plus Zidovudine (n = 102) Lamivudine plus Zidovudine (n = 103) Fever and/or chills 9% 7% Nausea and vomiting 9% 2% Skin rashes 7% 1% Ear/nose/throat infections 5% 1% Pneumonia 4% 5% Headache 1% 5% Laboratory Abnormalities: 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). Other Adverse Events 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. Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677): 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. Postmarketing Experience 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. Body as a Whole Redistribution/accumulation of body fat. Cardiovascular Myocardial infarction. Hepatic Lactic acidosis and hepatic steatosis [see WARNINGS AND PRECAUTIONS]. Skin 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 ADVERSE REACTIONS]. DRUG INTERACTIONS Methadone 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 CLINICAL PHARMACOLOGY]. 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.22017-12-04 17:37:19Abacavir SulfateZiagenFDA
112017-09-01 17:33:52Warnings & PrecautionsWARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions 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 ADVERSE REACTIONS]. 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. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with ZIAGEN: 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. ZIAGEN is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. Before starting ZIAGEN, review medical history for prior exposure to any abacavir-containing product. NEVER restart ZIAGEN or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status. 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). 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. 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. A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill. Lactic Acidosis And Severe Hepatomegaly With Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering ZIAGEN to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. 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). Immune Reconstitution Syndrome 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 Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barr 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. Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Myocardial Infarction In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive. 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). Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). Hypersensitivity Reactions Inform patients: 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. to carry the Warning Card with them. how to identify a hypersensitivity reaction [see WARNINGS AND PRECAUTIONS, Medication Guide]. 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. that a hypersensitivity reaction can worsen and lead to hospitalization or death if ZIAGEN is not immediately discontinued. 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. that if they have a hypersensitivity reaction, they should dispose of any unused ZIAGEN to avoid restarting abacavir. that a hypersensitivity reaction is usually reversible if it is detected promptly and ZIAGEN is stopped right away. 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. 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. Lactic Acidosis/Hepatomegaly With Steatosis 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 ZIAGEN if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Immune Reconstitution Syndrome 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 WARNINGS AND PRECAUTIONS]. Redistribution/Accumulation Of Body Fat Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see WARNINGS AND PRECAUTIONS]. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZIAGEN during pregnancy [see Use in Specific Populations]. Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations]. Missed Dose 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 DOSAGE AND ADMINISTRATION]. Availability of Medication Guide 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. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity 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. Mutagenicity 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. Impairment Of Fertility 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. Use In Specific Populations Pregnancy Pregnancy Exposure Registry 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. Risk Summary 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 Data]. 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. 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 Data]. Data Human Data: Based on prospective reports to the APR of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 1,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 2.9% (95% CI: 2.0% to 4.1%) following first trimester exposure to abacavir-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) following second/third trimester exposure to abacavir-containing regimens. 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 CLINICAL PHARMACOLOGY]. Animal Data: 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. Lactation Risk Summary The Centers for Disease Control and Prevention recommend 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) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving ZIAGEN. Pediatric Use 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 DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Clinical Studies]. Geriatric Use 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. Patients With Impaired Hepatic Function A dose reduction is required for patients with mild hepatic impairment (Child-Pugh Class A) [see DOSAGE AND ADMINISTRATION]. 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 CONTRAINDICATIONS, CLINICAL PHARMACOLOGY].22017-12-04 17:37:19Abacavir SulfateZiagenFDA
122017-09-01 17:33:52Overdosage & Contraindications22017-12-04 17:37:19Abacavir SulfateZiagenFDA
132017-12-04 17:37:19Clinical PharmacologyCLINICAL PHARMACOLOGY Mechanism Of Action Abacavir is an antiretroviral agent [see Microbiology]. Pharmacokinetics Pharmacokinetics In Adults The pharmacokinetic properties of abacavir were independent of dose over the range of 300 to 1,200 mg per day. Absorption and Bioavailability: 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 &plusmn; 0.89 mcg per mL (mean &plusmn; SD) and AUC(0-12 h) was 6.02 &plusmn; 1.73 mcg&bull;hour per mL. After oral administration of a single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 &plusmn; 1.19 mcg per mL (mean &plusmn; SD) and AUC&infin; was 11.95 &plusmn; 2.51 mcg&bull;hour per mL. Distribution: The apparent volume of distribution after IV administration of abacavir was 0.86 &plusmn; 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%. 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. Metabolism and Elimination: 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. In vitro experiments reveal that abacavir does not inhibit human CYP3A4, CYP2D6, or CYP2C9 activity at clinically relevant concentrations. Elimination of abacavir was quantified in a mass balance trial following administration of a 600-mg dose of 14C-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. In single-dose trials, the observed elimination half-life (t&frac12;) was 1.54 &plusmn; 0.63 hours. After intravenous administration, total clearance was 0.80 &plusmn; 0.24 L per hour per kg (mean &plusmn; SD). Effects Of Food On Oral Absorption Bioavailability of abacavir tablets was assessed in the fasting and fed states with no significant difference in systemic exposure (AUC&infin;); 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. Specific Populations Renal Impairment: 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. Hepatic Impairment: 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 CONTRAINDICATIONS, Use in Specific Populations]. Pregnancy: Abacavir: 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. Pediatric Patients: 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. 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. Geriatric Patients: The pharmacokinetics of ZIAGEN have not been studied in subjects older than 65 years. Gender: 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. Race: There are no significant or clinically relevant racial differences between blacks and whites in abacavir pharmacokinetics. Drug Interactions In human liver microsomes, abacavir did not inhibit cytochrome P450 isoforms (2C9, 2D6, 3A4). Based on these data, it is unlikely that clinically significant drug interactions will occur between abacavir and drugs metabolized through these pathways. Lamivudine and/or Zidovudine: 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. Ethanol: 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&infin; and a 26% increase in abacavir t&frac12;. 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. Methadone: 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 DRUG INTERACTIONS]. The addition of methadone had no clinically significant effect on the pharmacokinetic properties of abacavir. Microbiology 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. Antiviral Activity 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). 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 &plusmn; 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 viruses (n = 3 except n = 2 for clade B), respectively. The EC50 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. Resistance 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 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. 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). Cross-Resistance 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. Animal Toxicology And/Or Pharmacology 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. Clinical Studies Adult Trials Therapy-Naive Adults 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&sup3;, and median plasma HIV-1 RNA was 4.79 log10 copies per mL. The outcomes of randomized treatment are provided in Table 7. Table 7: Outcomes of Randomized Treatment through Week 48 (CNA30024) Outcome ZIAGEN plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325) Respondera 69% (73%) 69% (71%) Virologic failuresb 6% 4% Discontinued due to adverse reactions 14% 16% Discontinued due to other reasonsc 10% 11% a 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&reg; standard test 1.0 PCR). b 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. c Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, clinical progression, and other. After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 209 cells per mm&sup3; in the group receiving ZIAGEN and 155 cells per mm&sup3; 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. 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&reg; (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&sup3;, and median baseline plasma HIV-1 RNA was 4.8 log10 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. Table 8. Outcomes of Randomized Treatment through Week 48 (CNA3005) Outcome ZIAGEN plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 265) Respondera 49% 50% Virologic failureb 31% 28% Discontinued due to adverse reactions 10% 12% Discontinued due to other reasonsc 11% 10% a Subjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL. b Includes viral rebound and failure to achieve confirmed less than 400 copies per mL by Week 48. c Includes consent withdrawn, lost to follow up, protocol violations, those with missing data, clinical progression, and other. Treatment response by plasma HIV-1 RNA strata is shown in Table 9. Table 9: Proportions of Responders through Week 48 by Screening Plasma HIV-1 RNA Levels (CNA3005) Screening HIV-1 RNA (copies/mL) ZIAGEN plus Lamivudine/ Zidovudine (n = 262) Indinavir plus Lamivudine/ Zidovudine (n = 265) < 400 copies/mL n < 400 copies/mL n &ge; 10,000 - &le; 100,000 50% 166 48% 165 > 100,000 48% 96 52% 100 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. Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells per mm&sup3; 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. 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&sup3; (range: 21 to 918 cells per mm&sup3;) 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). The outcomes of randomized treatment are provided in Table 10. Table 10: Outcomes of Randomized Treatment through Week 48 (CNA30021) Outcome ZIAGEN 600 mg q.d. plus EPIVIR&reg; plus Efavirenz (n = 384) ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz (n = 386) Respondera 64% (71%) 65% (72%) Virologic failureb 11% (5%) 11% (5%) Discontinued due to adverse reactions 13% 11% Discontinued due to other reasonsc 11% 13% a 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). b 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. c Includes consent withdrawn, lost to follow up, protocol violations, clinical progression, and other. After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells per mm&sup3; in the group receiving abacavir 600 mg once daily and 200 cells per mm&sup3; 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. Pediatric Trials Therapy-Experienced Pediatric Subjects 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&sup2; twice daily versus lamivudine 4 mg per kg twice daily plus zidovudine 180 mg per m&sup2; 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 log10 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 log10 copies per mL in the group receiving ZIAGEN plus lamivudine plus zidovudine compared with -0.21 log10 copies per mL in the group receiving lamivudine plus zidovudine. Median CD4+ cell count increases from baseline were 69 cells per mm&sup3; in the group receiving ZIAGEN plus lamivudine plus zidovudine and 9 cells per mm&sup3; in the group receiving lamivudine plus zidovudine. Once-Daily Dosing 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. 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. Table 11: Virologic Outcome of Randomized Treatment at Week 96a (ARROW Randomization 3) Outcome ZIAGEN plus Lamivudine Twice-Daily Dosing (n = 333) ZIAGEN plus Lamivudine Once-Daily Dosing (n = 336) HIV-1 RNA < 80 copies/mLb 70% 67% HIV-1 RNA &ge; 80 copies/mLc 28% 31% No virologic data Discontinued due to adverse event or death 1% < 1% Discontinued study for other reasonsd 0% < 1% Missing data during window but on study 1% 1% a Analyses were based on the last observed viral load data within the Week 96 window. b Predicted difference (95% CI) of response rate is -4.5% (-11% to 2%) at Week 96. c 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. d 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).22017-12-04 17:37:19Abacavir SulfateZiagenFDA
142017-09-01 17:33:52Medication GuidePATIENT INFORMATION ZIAGEN&reg; (ZY-uh-jen) (abacavir) Tablets ZIAGEN&reg; (abacavir) Oral Solution What is the most important information I should know about ZIAGEN? ZIAGEN can cause serious side effects, including: Serious allergic reactions (hypersensitivity reaction) 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 HLA-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation. 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. Symptom(s) Group 1 Fever Group 2 Rash Group 3 Nausea, vomiting, diarrhea, abdominal (stomach area) pain Group 4 Generally ill feeling, extreme tiredness, or achiness Group 5 Shortness of breath, cough, sore throat A list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card with you at all times. If you stop ZIAGEN because of an allergic reaction, never take ZIAGEN (abacavir) or any other abacavir-containing medicine (EPZICOM&reg;, TRIUMEQ&reg;, or TRIZIVIR&reg;) again. If you have an allergic reaction, dispose of any unused ZIAGEN. Ask your pharmacist how to properly dispose of medicines. If you take ZIAGEN 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 low blood pressure or death. 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. 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. Build-up of acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take ZIAGEN. 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: feel very weak or tired unusual (not normal) muscle pain trouble breathing stomach pain with nausea and vomiting feel cold, especially in your arms and legs feel dizzy or light-headed have a fast or irregular heartbeat Serious liver problems can happen in people who take ZIAGEN. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis) when you take ZIAGEN. Call your healthcare provider right away if you have any of the following signs of liver problems: your skin or the white part of your eyes turns yellow (jaundice) dark or &ldquo;tea-colored&rdquo; urine light-colored stools (bowel movements) loss of appetite for several days or longer nausea pain, aching, or tenderness on the right side of your stomach area You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight (obese), or have been taking nucleoside analogue medicines for a long time. What is ZIAGEN? ZIAGEN is a prescription HIV-1 (Human Immunodeficiency Virus type 1) medicine used with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). The safety and effectiveness of ZIAGEN has not been established in children under 3 months of age. When used with other antiretroviral medicines to treat HIV-1 infection, ZIAGEN may help: reduce the amount of HIV-1 in your blood. This is called &ldquo;viral load&rdquo;. increase the number of CD4+ (T) cells in your blood, that help fight off other infections. Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections). ZIAGEN does not cure HIV-1 infection or AIDS. You must keep taking HIV-1 medicines to control HIV1 infection and decrease HIV-related illnesses. Who should not take ZIAGEN? Do not take ZIAGEN if you: 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 ZIAGEN. 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. have liver problems. What should I tell my healthcare provider before taking ZIAGEN? Before you take ZIAGEN, tell your healthcare provider if you: have been tested and know whether or not you have a particular gene variation called HLA-B*5701. have or have had liver problems, including hepatitis B or C virus infection. have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes. drink alcohol or take medicines that contain alcohol. are pregnant or plan to become pregnant. Talk to your healthcare provider if you are pregnant or plan to become pregnant. Pregnancy Registry. 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. are breastfeeding or plan to breastfeed. Do not breastfeed if you take ZIAGEN. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. Some medicines interact with ZIAGEN. Keep a list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for a list of medicines that interact with ZIAGEN. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take ZIAGEN with other medicines. Tell your healthcare provider if you take: any other medicine to treat HIV-1 methadone How should I take ZIAGEN? Take ZIAGEN exactly as your healthcare provider tells you. 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. Stay under the care of a healthcare provider while taking ZIAGEN. ZIAGEN may be taken with or without food. For children aged 3 months and older, your healthcare provider will prescribe a dose of ZIAGEN based on your child's body weight. Tell your healthcare provider if you or your child has trouble swallowing tablets. ZIAGEN comes as a tablet or as a liquid (oral solution). 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. If you take too much ZIAGEN, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of ZIAGEN? ZIAGEN can cause serious side effects including: See &ldquo;What is the most important information I should know about ZIAGEN?&rdquo; Changes in your immune system (Immune Reconstitution Syndrome) can happen when your 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. Changes in body fat can happen in people who take HIV-1 medicines. These changes may include an increased amount of fat in the upper back and neck (&ldquo;buffalo hump&rdquo;), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known. Heart attack (myocardial infarction). Some HIV-1 medicines including ZIAGEN may increase your risk of heart attack. The most common side effects of ZIAGEN in adults include: nausea headache generally not feeling well tiredness vomiting bad dreams or sleep problems The most common side effects of ZIAGEN in children include: fever and chills nausea vomiting rash ear, nose, or throat infections Tell your healthcare provider if you have any side effect that bothers you or that does not go away. 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. How should I store ZIAGEN? Store ZIAGEN at room temperature, between 68&deg;F to 77&deg;F (20&deg;C to 25&deg;C). Do not freeze ZIAGEN oral solution. You may store ZIAGEN oral solution in a refrigerator. Keep ZIAGEN and all medicines out of the reach of children. General information for safe and effective use of ZIAGEN 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. 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. For more information go to www.ZIAGEN.com or call 1-877-844-8872. What are the ingredients in ZIAGEN? Active ingredient: abacavir Inactive ingredients: Tablets: Colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate Tablet film-coating contains: hypromellose, polysorbate 80, synthetic yellow iron oxide, titanium dioxide, and triacetin. Oral Solution: Artificial strawberry and banana flavors, citric acid (anhydrous), methylparaben and propylparaben (added as preservatives), propylene glycol, saccharin sodium, sodium citrate (dihydrate), sorbitol solution, and water. WARNING CARD ZIAGEN&reg; (abacavir) Tablets and Oral Solution Patients taking ZIAGEN may have a serious allergic reaction (hypersensitivity reaction) that can cause death. 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 this medicine. Symptom(s) Group 1 Fever Group 2 Rash Group 3 Nausea, vomiting, diarrhea, or abdominal (stomach area) pain Group 4 Generally ill feeling, extreme tiredness, or achiness Group 5 Shortness of breath, cough, or sore throat Always carry this Warning Card with you to help recognize symptoms of this allergic reaction. (Back of Card) WARNING CARD ZIAGEN&reg; (abacavir) tablets and oral solution If you must stop treatment with ZIAGEN because you have had an allergic reaction to abacavir, NEVER take ZIAGEN or another abacavir-containing medicine (EPZICOM&reg;, TRIUMEQ&reg;, or TRIZIVIR&reg;) again. If you have an allergic reaction, dispose of any unused ZIAGEN. Ask your pharmacist how to properly dispose of medicines. If you take ZIAGEN 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 low blood pressure or death. Please read the Medication Guide for additional information on ZIAGEN.22017-12-04 17:37:19Abacavir SulfateZiagenFDA
152017-12-04 17:37:23Ziagen Patient Information Including Side EffectsFind Lowest Prices on Brand Names: Ziagen Generic Name: abacavir (Pronunciation: a BAK a veer) What is abacavir (Ziagen)? What are the possible side effects of abacavir (Ziagen)? What is the most important information I should know about abacavir (Ziagen)? What should I discuss with my healthcare provider before taking abacavir (Ziagen)? How should I take abacavir (Ziagen)? What happens if I miss a dose (Ziagen)? What happens if I overdose (Ziagen)? What should I avoid while taking abacavir (Ziagen)? What other drugs will affect abacavir (Ziagen)? Where can I get more information? What is abacavir (Ziagen)? Abacavir is an antiviral medication that prevents human immunodeficiency virus (HIV) cells from multiplying in your body.Abacavir is used to treat HIV, which causes the acquired immunodeficiency syndrome (AIDS). Abacavir is not a cure for HIV or AIDS.Abacavir may also be used for purposes not listed in this medication guide. What are the possible side effects of abacavir (Ziagen)? Stop using abacavir and call your doctor at once if you have symptoms of an allergic reaction from two or more of these specific side effect groups:Group 1 - fever;Group 2 - rash;Group 3 - nausea, vomiting, diarrhea, stomach pain;Group 4 - general ill feeling, extreme tiredness, body aches;Group 5 - shortness of breath, cough, sore throat.Once you have had an allergic reaction to abacavir, you must never use it again. If you stop taking abacavir for any reason, talk to your doctor before you start taking the medication again.Abacavir may cause lactic acidosis (a build-up of lactic acid in the body, which can be fatal). Lactic acidosis can start slowly and get worse over time. Get emergency medical help if you have even mild symptoms of lactic acidosis, such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.Abacavir can cause other serious side effects that may not be signs of an allergic reaction. Call your doctor at once if you have:the first sign of any skin rash, no matter how mild;signs of a new infection such as flu symptoms, chills, easy bruising or unusual bleeding, loss of appetite, mouth sores;severe pain in your upper stomach spreading to your back;itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);increased sweating, tremors in your hands, anxiety, feeling irritable, sleep problems (insomnia);diarrhea, unexplained weight loss, menstrual changes, impotence, loss of interest in sex;swelling in your neck or throat (enlarged thyroid);weakness or prickly feeling in your fingers or toes;problems with walking, breathing, speech, swallowing, or eye movement; orsevere lower back pain, loss of bladder or bowel control.Less serious side effects may include:strange dreams;headache, ear pain;cold symptoms such as stuffy nose, sneezing, sinus pain; orchanges in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and trunk).This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What is the most important information I should know about abacavir (Ziagen)? Stop using abacavir and call your doctor at once if you have any of these signs of an allergic reaction: fever; rash; nausea, vomiting, diarrhea, stomach pain; general ill feeling, extreme tiredness, body aches; shortness of breath, cough, sore throat.Once you have had an allergic reaction to abacavir, you must never use it again.Read the Warning Card that comes with this medication, and carry it with you at all times so you will know the symptoms of allergic reaction to watch for.Some people develop lactic acidosis while taking abacavir. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired. Abacavir can also cause severe or life-threatening effects on your liver. Call your doctor at once if you have any of these symptoms while taking abacavir: pain in your upper stomach, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).Do not allow this medicine to run out completely before you get your prescription refilled. It is important that you not stop taking abacavir once you have started. If you miss several doses in a row, you may have a dangerous or even fatal allergic reaction once you start taking abacavir again. If you stop taking abacavir for any reason, talk to your doctor before you start taking the medication again.32017-09-01 11:12:57Abacavir SulfateZiagenMultum
162017-09-01 17:33:56Ziagen Patient Information including How Should I TakeWhat should I discuss with my healthcare provider before taking abacavir (Ziagen)? Do not take this medication if you have ever had an allergic reaction to any medicine that contains abacavir, including Ziagen, Epzicom, or Trizivir. Once you have had an allergic reaction to abacavir, you must never use it again.Some people develop a life-threatening condition called lactic acidosis while taking abacavir. You may be more likely to develop lactic acidosis if you are overweight or have liver disease, if you are a woman, or if you have taken HIV or AIDS medications for a long time. Talk with your doctor about your individual risk.Abacavir can also cause severe or life-threatening effects on your liver. You should not take abacavir if you have moderate or severe liver disease.Do not take abacavir with any other medication that contains abacavir, such as Epzicom or Trizivir.To make sure you can safely take abacavir, tell your doctor if you have any of these other conditions:heart disease, high blood pressure;liver disease;a risk factor for heart disease such as smoking, diabetes, or high cholesterol; orif you have used an HIV medication in the past, such as didanosine (Videx), emtricitabine (Atripla, Complera, Emtriva, Truvada), lamivudine (Combivir, Epivir, Epzicom, Trizivir), stavudine (Zerit), tenofovir (Viread), zalcitabine (Hivid), or zidovudine (Retrovir).You may need a blood test before you start taking abacavir for the first time, or if you are restarting the medication after stopping for reasons not related to an allergic reaction.FDA pregnancy category C. It is not known whether abacavir will harm an unborn baby. HIV can be passed to your baby if you are not properly treated during pregnancy. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Take all of your HIV medicines as directed to control your infection.If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of abacavir on the baby.Women with HIV or AIDS should not breast feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk. How should I take abacavir (Ziagen)? Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.This medication comes with patient instructions for safe and effective use. Follow these directions carefully. Ask your doctor or pharmacist if you have any questions.Abacavir can be taken with or without food.Measure liquid medicine with a special dose-measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.Abacavir comes with a Medication Guide and a Warning Card that lists the symptoms of an allergic reaction. Read this information carefully and carry the Warning Card with you at all times so you will know what symptoms to watch for.Use abacavir regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.HIV/AIDS is usually treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice. Every person with HIV or AIDS should remain under the care of a doctor.To be sure this medicine is helping your condition and is not causing harmful effects, your blood will need to be tested often. Your liver function may also need to be tested. Visit your doctor regularly.Store at room temperature away from moisture and heat. You may store the oral solution (liquid) in the refrigerator but do not let it freeze.32017-09-01 11:12:57Abacavir SulfateZiagenMultum
172017-09-01 17:33:56Ziagen Patient Information including If I Miss a Dose32017-09-01 11:12:57Abacavir SulfateZiagenMultum
182017-12-04 17:37:28Drug DescriptionFind Lowest Prices on EPZICOM&reg; (abacavir and lamivudine) Tablets WARNING HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B Hypersensitivity Reactions 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 WARNINGS AND PRECAUTIONS]. EPZICOM is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. 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. Discontinue EPZICOM immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. 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 PRECAUTIONS]. Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue EPZICOM if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see WARNINGS AND PRECAUTIONS]. Exacerbations of Hepatitis 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, 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 WARNINGS AND PRECAUTIONS]. DESCRIPTION EPZICOM EPZICOM tablets contain the following 2 synthetic nucleoside analogues: abacavir (ZIAGEN, also a component of TRIZIVIR&reg;) and lamivudine (also known as EPIVIR or 3TC) with inhibitory activity against HIV-1. 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&reg; orange YS-1-13065-A) that is made of FD&C Yellow No. 6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide. Abacavir Sulfate 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). Abacavir sulfate is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C14H18N6O)2&bull;H2SO4 and a molecular weight of 670.76 g per mol. It has the following structural formula: Abacavir sulfate is a white to off-white solid and is soluble in water. In vivo, abacavir sulfate dissociates to its free base, abacavir. Dosages are expressed in terms of abacavir. Lamivudine 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 C8H11N3O3S and a molecular weight of 229.3 g per mol. It has the following structural formula: Lamivudine is a white to off-white crystalline solid and is soluble in water.42017-12-04 17:37:28Abacavir Sulfate and Lamivudine TabletsEpzicomFDA
192017-09-01 17:34:03Indications &amp; DosageINDICATIONS EPZICOM, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. DOSAGE AND ADMINISTRATION Screening For HLA-B*5701 Allele Prior To Starting EPZICOM Screen for the HLA-B*5701 allele prior to initiating therapy with EPZICOM [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Recommended Dosage For Adult Patients The recommended dosage of EPZICOM for adults is one tablet taken orally once daily, in combination with other antiretroviral agents, with or without food. Recommended Dosage For Pediatric Patients 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 Clinical Studies]. Before prescribing EPZICOM tablets, pediatric patients should be assessed for the ability to swallow tablets. Not Recommended Due To Lack of Dosage Adjustment Because EPZICOM is a fixed-dose tablet and cannot be dose adjusted, EPZICOM is not recommended for: patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations]. patients with mild hepatic impairment. EPZICOM is contraindicated in patients with moderate or severe hepatic impairment [see CONTRAINDICATIONS, Use in Specific Populations]. Use of EPIVIR&reg; (lamivudine) oral solution or tablets and ZIAGEN&reg; (abacavir) oral solution may be considered. HOW SUPPLIED Dosage Forms And Strengths 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 &ldquo;GS FC2&rdquo; on one side with no markings on the reverse side. Storage And Handling EPZICOM 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: Bottles of 30 tablets (NDC 49702-206-13). Store at 25&deg;C (77&deg;F); excursions permitted to 15&deg; to 30&deg;C (59&deg; to 86&deg;F) (see USP Controlled Room Temperature). Manufactured for : ViiV Healthcare, Research Triangle Park, NC 27709. by: GlaxoSmithKline Research Triangle Park, NC 27709. Revised: September 201542017-12-04 17:37:28Abacavir Sulfate and Lamivudine TabletsEpzicomFDA
202017-09-01 17:34:03Side Effects &amp; Drug InteractionsSIDE EFFECTS The following adverse reactions are discussed in other sections of the labeling: Serious and sometimes fatal hypersensitivity reactions [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Exacerbations of hepatitis B [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see WARNINGS AND PRECAUTIONS]. Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS]. Fat redistribution [see WARNINGS AND PRECAUTIONS]. Myocardial infarction [see WARNINGS AND PRECAUTIONS]. Clinical Trials Experience In Adult Subjects 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. Serious And Fatal Abacavir-Associated Hypersensitivity Reactions In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of EPZICOM [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. 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. 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). Additional Adverse Reactions With Use Of EPZICOM Therapy-Naive Adults: 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. 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 Adverse Event ZIAGEN 600 mg q.d. plus EPIVIR plus Efavirenz (n = 384) ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz (n = 386) Drug hypersensitivitya, b 9% 7% Insomnia 7% 9% Depression/Depressed mood 7% 7% Headache/Migraine 7% 6% Fatigue/Malaise 6% 8% Dizziness/Vertigo 6% 6% Nausea 5% 6% Diarrheaa 5% 6% Rash 5% 5% Pyrexia 5% 3% Abdominal pain/gastritis 4% 5% Abnormal dreams 4% 5% Anxiety 3% 5% a 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. b 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. Laboratory Abnormalities: 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. The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021. Other Adverse Events: In addition to adverse reactions listed above, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT. Clinical Trials Experience In Pediatric Subjects 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 ADVERSE REACTIONS]. Postmarketing Experience 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. Abacavir Cardiovascular: Myocardial infarction. Skin: 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 ADVERSE REACTIONS]. Abacavir And Lamivudine Body as a Whole: Redistribution/accumulation of body fat [see WARNINGS AND PRECAUTIONS]. Digestive: Stomatitis. Endocrine and Metabolic: Hyperglycemia. General: Weakness. Hemic and Lymphatic: Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly. Hepatic: Lactic acidosis and hepatic steatosis [see WARNINGS AND PRECAUTIONS], posttreatment exacerbations of hepatitis B [see WARNINGS AND PRECAUTIONS]. Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria. Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis. Nervous: Paresthesia, peripheral neuropathy, seizures. Respiratory: Abnormal breath sounds/wheezing. Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome. DRUG INTERACTIONS Methadone 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 CLINICAL PHARMACOLOGY]. 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.42017-12-04 17:37:28Abacavir Sulfate and Lamivudine TabletsEpzicomFDA
212017-09-01 17:34:03Warnings &amp; PrecautionsWARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions 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 ADVERSE REACTIONS]. 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. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir: 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. EPZICOM is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. 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. 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). 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. 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. A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill. Lactic Acidosis And Severe Hepatomegaly With Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. 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). Patients With Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis 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. Emergence of Lamivudine-resistant HBV 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). Use With Interferon-And Ribavirin-Based Regimens Patients receiving interferon alfa with or without ribavirin and EPZICOM should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. See full prescribing information for EPIVIR (lamivudine). Discontinuation of EPZICOM 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). Immune Reconstitution Syndrome 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 Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barr&eacute; 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. Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and &ldquo;cushingoid appearance&rdquo; have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Myocardial Infarction In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive. 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). Related Products That Are Not Recommended EPZICOM contains fixed doses of 2 nucleoside analogue reverse transcriptase inhibitors (abacavir and lamivudine); concomitant administration of EPZICOM with other products containing abacavir or lamivudine is not recommended. In addition, do not administer EPZICOM in combination with products containing emtricitabine. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). Hypersensitivity Reactions Inform patients: 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. to carry the Warning Card with them. how to identify a hypersensitivity reaction [see WARNINGS AND PRECAUTIONS, Medication Guide]. 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. that a hypersensitivity reaction can worsen and lead to hospitalization or death if EPZICOM is not immediately discontinued. 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. that a hypersensitivity reaction is usually reversible if it is detected promptly and EPZICOM is stopped right away. 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. 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. Related Products that are Not Recommended Inform patients that they should not take EPZICOM with ATRIPLA&reg;, COMBIVIR&reg;, COMPLERA&reg;, DUTREBIS&trade;, EMTRIVA&reg;, EPIVIR, EPIVIR-HBV&reg;, STRIBILD&reg;, TRIUMEQ&reg;, TRIZIVIR, TRUVADA&reg;, or ZIAGEN. Lactic Acidosis/Hepatomegaly Inform patients that some HIV medicines, including EPZICOM, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see WARNINGS AND PRECAUTIONS]. Patients with Hepatitis B or C Co-infection 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 WARNINGS AND PRECAUTIONS]. 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 WARNINGS AND PRECAUTIONS]. Immune Reconstitution Syndrome In some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see WARNINGS AND PRECAUTIONS]. Redistribution/Accumulation of Body Fat Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see WARNINGS AND PRECAUTIONS]. Information about HIV-1 Infection EPZICOM is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illness. Inform patients that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Advise patients to remain under the care of a physician when using EPZICOM. Advise patients to take all HIV medications exactly as prescribed. Advise patients to avoid doing things that can spread HIV-1 infection to others. Advise patients not to re-use or share needles or other injection equipment. Advise patients not to share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. Advise patients to always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. Female patients should be advised not to breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Instruct patients to read the Medication Guide before starting EPZICOM and to reread 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. Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity Abacavir: Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of 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. Lamivudine: 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. Mutagenicity Abacavir: 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. Lamivudine: 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. Impairment of Fertility Abacavir or lamivudine did not affect male or female fertility in rats at a dose associated with exposures approximately 8 or 130 times, respectively, higher than the exposures in humans at the doses of 600 mg and 300 mg (respectively). Use In Specific Populations Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EPZICOM during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Risk Summary Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for abacavir or lamivudine compared with the background rate for major birth defects of 2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Abacavir produced fetal malformations and other embryonic and fetal toxicities in rats at 35 times the human exposure at the recommended clinical dose. Lamivudine produced embryonic toxicity in rabbits at a dose that produced similar human exposures to the recommended clinical dose. The relevance of animal findings to human pregnancy registry data is not known. Data Human Data: Abacavir: Based on prospective reports from the Antiretroviral Pregnancy Registry of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 900 exposed in the first trimester), there was no difference between abacavir and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population of the MACDP. The prevalence of defects in the first trimester was 3.0% (95% CI: 2.0% to 4.4%). Lamivudine: Based on prospective reports from the Antiretroviral Pregnancy Registry of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,300 exposed in the first trimester), there was no difference between lamivudine and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in the first trimester was 3.1% (95% CI: 2.6% to 3.7%). 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 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 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. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg per mL (150 mg twice daily) and 2.1 to 5.2 mcg per mL (300 mg twice daily). Animal Data: Abacavir: Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35 times the human exposure, based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5 times the human exposure at the recommended dose based on AUC. Lamivudine: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Lactation The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for HIV-1 transmission mothers should be instructed not to breastfeed. Pediatric Use 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 DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, Clinical Studies]. In pediatric patients weighing less than 25 kg, use of abacavir and lamivudine as single products is recommended to achieve appropriate dosing. Geriatric Use 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 DOSAGE AND ADMINISTRATION, Use In Specific Populations]. Patients With Impaired Renal Function EPZICOM is not recommended for patients with creatinine clearance less than 50 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 50 mL per min, then the individual components should be used [see CLINICAL PHARMACOLOGY]. Patients With Impaired Hepatic Function 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 CLINICAL PHARMACOLOGY]. 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 CONTRAINDICATIONS].42017-12-04 17:37:28Abacavir Sulfate and Lamivudine TabletsEpzicomFDA
222017-09-01 17:34:03Overdosage &amp; Contraindications42017-12-04 17:37:28Abacavir Sulfate and Lamivudine TabletsEpzicomFDA
232017-12-04 17:37:28Clinical PharmacologyCLINICAL PHARMACOLOGY Mechanism Of Action EPZICOM is an antiretroviral agent [see Microbiology]. Pharmacokinetics Pharmacokinetics in Adults 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. Abacavir: 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 &plusmn; 1.19 mcg per mL (mean &plusmn; SD) and AUC&infin;was 11.95 &plusmn; 2.51 mcg&bull;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. Lamivudine: 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 &plusmn; 0.54 mcg per mL (mean &plusmn; SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 &plusmn; 1.83 mcg&bull;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). In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes. The pharmacokinetic properties of abacavir and lamivudine in fasting subjects are summarized in Table 2. Table 2: Pharmacokinetic Parametersa for Abacavir and Lamivudine in Adults Parameter Abacavir Lamivudine Oral bioavailability (%) 86 &plusmn; 25 n = 6 86 &plusmn; 16 n = 12 Apparent volume of distribution (L/kg) 0.86 &plusmn; 0.15 n = 6 1.3 &plusmn; 0.4 n = 20 Systemic clearance (L/h/kg) 0.80 &plusmn; 0.24 n = 6 0.33 &plusmn; 0.06 n = 20 Renal clearance (L/h/kg) 0.007 &plusmn; 0.008 n = 6 0.22 &plusmn; 0.06 n = 20 Elimination half-life (h) 1.45 &plusmn; 0.32 n = 20 5 to 7b aData presented as mean &plusmn;standard deviation except where noted. bApproximate range. Effect of Food on Absorption of EPZICOM 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&infin;, and Cmax for lamivudine. Food did not alter the extent of systemic exposure to abacavir (AUC&infin;), 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. Special Populations Renal Impairment: EPZICOM: The effect of renal impairment on the combination of abacavir and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir and lamivudine components). Hepatic Impairment: EPZICOM: The effect of hepatic impairment on the combination of abacavir and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir and lamivudine components). Pregnancy: Abacavir: No data are available on the pharmacokinetics of abacavir during pregnancy. Lamivudine: 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 umbilical cord serum samples. Pediatric Patients: Abacavir and Lamivudine: 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 DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, Clinical Studies]. Geriatric Patients: The pharmacokinetics of abacavir and lamivudine have not been studied in subjects over 65 years of age. Gender: 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. Race: 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. Drug Interactions 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. Cytochrome P450 Enzymes: In humans, abacavir and lamivudine are not significantly metabolized by cytochrome P450 enzymes nor do they inhibit or induce this enzyme system; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. Abacavir: Lamivudine and/or Zidovudine: 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. Lamivudine: Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic 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). Other Interactions Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure. Methadone: 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%) [see DRUG INTERACTIONS]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. Ribavirin: In vitro data indicate ribavirin reduces phosphorylation 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 WARNINGS AND PRECAUTIONS]. Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects. The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 3. Table 3: Effect of Coadministered Drugs on Abacavir or Lamivudine Coadministered Drug and Dose Drug and Dose n Concentrations of Abacavir or Lamivudine Concentration of Coadministered Drug AUC Variability Ethanol 0.7 g/kg Abacavir Single 600 mg 24 &uarr;41% 90% CI: 35% to 48% &harr;a Nelfinavir 750 mg every 8 h x 7 to 10 days Lamivudine Single 150 mg 11 &uarr;10% 95% CI: 1% to 20% &harr; Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days Lamivudine Single 300 mg 14 &uarr;43% 90% CI: 32% to 55% &harr; &uarr; = Increase; &harr; = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval. aThe drug-drug interaction was only evaluated in males. Microbiology Mechanism of Action Abacavir: 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. Lamivudine: 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. Antiviral Activity Abacavir: 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). 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 &plusmn; 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 viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM. Lamivudine: 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 AG 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. 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. Resistance 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. Cross-resistance 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. Animal Toxicology And/Or Pharmacology 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. Clinical Studies Adults 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. The following trial was conducted with the individual components of EPZICOM. Therapy-naive Adults CNA30021 was an international, multi-center, 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&sup3; (range: 21 to 918 cells per mm3) 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). The outcomes of randomized treatment are provided in Table 4. Table 4: Outcomes of Randomized Treatment through Week 48 (CNA30021) Outcome ZIAGEN 600 mg q.d. plus EPIVIR plus Efavirenz (n = 384) ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz (n = 386) Respondera 64% (71%) 65% (72%) Virologic failure b 11% (5%) 11% (5%) Discontinued due to adverse reactions 13% 11% Discontinued due to other reasonsc 11% 13% aSubjects 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&reg; standard test version 1.0). bIncludes 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. cIncludes consent withdrawn, lost to follow-up, protocol violations, clinical progression, and other. After 48 weeks of therapy, the median CD4+ cell count increases from baseline were 188 cells per mm&sup3; in the group receiving ZIAGEN 600 mg once daily and 200 cells per mm&sup3; 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. Pediatric Subjects 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&ndash;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 to 71% of subjects in the once-daily cohort. 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. 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. Table 5: Virologic Outcome of Randomized Treatment at Week 96a (ARROW Randomization 3) Outcome Abacavir plus LamivudineTwice-daily Dosing (n = 333) Abacavir plus LamivudineOnce-daily Dosing (n = 336) HIV-1 RNA < 80 copies/mLb 70% 67% HIV-1 RNA &ge; 80 copies/mLc 28% 31% No virologic data Discontinued due to adverse event or death 1% < 1% Discontinued study for other reasonsd 0% < 1% Missing data during window but on study 1% 1% aAnalyses were based on the last observed viral load data within the Week 96 window. bRisk difference (95% CI) of response rate is -2.4% (-9% to 5%) at Week 96. cIncludes 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. dOther 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).42017-12-04 17:37:28Abacavir Sulfate and Lamivudine TabletsEpzicomFDA
242017-12-04 17:37:28Medication GuidePATIENT INFORMATION EPZICOM&reg; (ep' zih com) (abacavir and lamivudine) Tablets What is the most important information I should know about EPZICOM? EPZICOM can cause serious side effects, including: Serious allergic reactions (hypersensitivity reaction) 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. 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. Symptom(s) Group 1 Fever Group 2 Rash Group 3 Nausea, vomiting, diarrhea, abdominal (stomach area) pain Group 4 Generally ill feeling, extreme tiredness, or achiness Group 5 Shortness of breath, cough, sore throat A list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card with you at all times. If you stop EPZICOM because of an allergic reaction, never take EPZICOM (abacavir and lamivudine) or any other abacavir-containing medicine (TRIUMEQ&reg;, TRIZIVIR&reg; or ZIAGEN&reg;) again. 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 low blood pressure or death. 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. 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. Build-up of acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take EPZICOM. 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: feel very weak or tired feel cold, especially in your arms and legs unusual (not normal) muscle pain feel dizzy or light-headed trouble breathing have a fast or irregular heartbeat stomach pain with nausea and vomiting Serious liver problems can happen in people who take EPZICOM. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems: your skin or the white part of your eyes turns yellow (jaundice) loss of appetite for several days or longer nausea dark or &ldquo;tea-colored&rdquo; urine pain, aching, or tenderness on the right side of your stomach area light-colored stools (bowel movements) You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight (obese), or have been taking nucleoside analogue medicines for a long time. Worsening of hepatitis B virus in people who have HIV-1 infection. If you have HIV-1 and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking EPZICOM. A &ldquo;flare-up&rdquo; is when your HBV infection suddenly returns in a worse way than before. W orsening liver disease can be serious and may lead to death Do not run out of EPZICOM. Refill your prescription or talk to your healthcare provider before your EPZICOM is all gone. Do not stop EPZICOM without first talking to your healthcare provider. 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. Resistant Hepatitis B Virus (HBV). If you have HIV-1 and hepatitis B, the hepatitis B virus can change (mutate) during your treatment with EPZICOM and become harder to treat (resistant). Use with interferon and ribavirin-based regimens. Worsening of liver disease that has caused death has happened in people infected with both HIV-1 and hepatitis C virus who are taking antiretroviral medicines and are also being treated for hepatitis C with interferon with or without ribavirin. If you are taking EPZICOM and interferon with or without ribavirin tell your healthcare provider if you have any new symptoms. What is EPZICOM? EPZICOM is a prescription HIV-1 (Human Immunodeficiency Virus-type 1) medicine used with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). EPZICOM contains 2 prescription medicines, abacavir (ZIAGEN) and lamivudine (EPIVIR&reg;). EPZICOM should not be used in children weighing less than 55 pounds (25 kg). When used with other antiretroviral medicines to treat HIV-1 infection, EPZICOM may help: reduce the amount of HIV-1 in your blood. This is called &ldquo;viral load&rdquo;. increase the number of CD4+ (T) cells in your blood, that help fight off other infections. Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections). EPZICOM does not cure HIV-1 infection or AIDS. You must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses. Avoid doing things that can spread HIV-1 infection to others. Do not share or re-use needles or other injection equipment. Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood. Ask your healthcare provider if you have any questions about how to prevent passing HIV to other people. Who should not take EPZICOM? Do not take EPZICOM if you: 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. are allergic to abacavir or any of the ingredients in EPZICOM. See the end of this Medication Guide for a complete list of ingredients in EPZICOM. have liver problems. What should I tell my healthcare provider before taking EPZICOM? Before you take EPZICOM tell your healthcare provider if you: have been tested and know whether or not you have a particular gene variation called HLA-B*5701. have or have had liver problems, including hepatitis B or C virus infection. have kidney problems. have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes. drink alcohol or take medicines that contain alcohol. are pregnant or plan to become pregnant. Taking EPZICOM during pregnancy has not been associated with an increased risk of birth defects. Talk to your healthcare provider if you are pregnant or plan to become pregnant. Pregnancy Registry. 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. are breastfeeding or plan to breastfeed. Do not breastfeed if you take EPZICOM. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. Some medicines interact with EPZICOM. Keep a list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for a list of medicines that interact with EPZICOM. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take EPZICOM with other medicines. You should not take EPZICOM if you also take: abacavir (TRIUMEQ, TRIZIVIR or ZIAGEN) lamivudine (COMBIVIR&reg;, DUTREBIS&trade;, EPIVIR, EPIVIR-HBV&reg;, TRIUMEQ, or TRIZIVIR) emtricitabine (EMTRIVA&reg;, ATRIPLA&reg;, COMPLERA&reg;, STRIBILD&reg;, or TRUVADA&reg;) Tell your healthcare provider if you take: any other medicine to treat HIV-1 medicines to treat hepatitis viruses such as interferon or ribavirin methadone How should I take EPZICOM? Take EPZICOM exactly as your healthcare provider tells you. Do not change your dose or stop taking EPZICOM without talking with your healthcare provider. If you miss a dose of EPZICOM, 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. Stay under the care of a healthcare provider while taking EPZICOM. EPZICOM may be taken with or without food. Tell your healthcare provider if your child has trouble swallowing EPZICOM tablets. Do not run out of EPZICOM. The virus in your blood may increase and the virus may become harder to treat. W hen your supply starts to run low, get more from your healthcare provider or pharmacy If you take too much EPZICOM, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of EPZICOM? EPZICOM can cause serious side effects including: See &ldquo;What is the most important information I should know about EPZICOM?&rdquo; Changes in your immune system (Immune Reconstitution Syndrome) 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 EPZICOM. Changes in body fat can happen in people who take HIV-1 medicines. These changes may include an increased amount of fat in the upper back and neck (&ldquo;buffalo hump&rdquo;), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known. Heart attack (myocardial infarction). Some HIV-1 medicines including EPZICOM may increase your risk of heart attack. The most common side effects of EPZICOM include: trouble sleeping depression headache tiredness dizziness nausea diarrhea rash fever Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of EPZICOM. 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. How should I store EPZICOM? Store EPZICOM at 59&deg;F to 86&deg;F (15&deg;C to 30&deg;C). Keep EPZICOM and all medicines out of the reach of children. General information for safe and effective use of EPZICOM. 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. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for the information about EPZICOM that is written for health professionals. For more information go to www.EPZICOM.com or call 1-877-844-8872. What are the ingredients in EPZICOM? Active ingredients: abacavir sulfate and lamivudine Inactive ingredients: magnesium stearate, microcrystalline cellulose, sodium starch glycolate. Tablet film coating contains: OPADRY&reg; orange YS-1-13065-A made of FD&C Yellow No. 6, hypromellose, polyethylene glycol 400, polysorbate 80, and titanium dioxide. (Front of card) WARNING CARD EPZICOM&reg; (abacavir and lamivudine) tablets Patients taking EPZICOM may have a serious allergic reaction (hypersensitivity reaction) that can cause death. If you get a symptom from 2 or more of the following groups whiletaking EPZICOM, call your healthcare provider right away to find out if you should stop taking this medicine. Symptom(s) Group 1 Fever Group 2 Rash Group 3 Nausea, vomiting, diarrhea, or abdominal (stomach area) pain Group 4 Generally ill feeling, extreme tiredness, or achiness Group 5 Shortness of breath, cough, or sore throat Always carry this Warning Card with you to help recognize symptoms of this allergic reaction. (Back of Card) WARNING CARD EPZICOM&reg; (abacavir and lamivudine) tablets If you must stop treatment with EPZICOM because you have had an allergic reaction to abacavir, NEVER take EPZICOM or another abacavir-containing medicine (ZIAGEN&reg;, TRIUMEQ&reg;, or TRIZIVIR&reg;) again. If you take EPZICOM 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 low blood pressure or death.42017-12-04 17:37:28Abacavir Sulfate and Lamivudine TabletsEpzicomFDA
252017-12-04 17:37:31Epzicom Patient Information Including Side EffectsFind Lowest Prices on Brand Names: Epzicom Generic Name: abacavir and lamivudine (Pronunciation: a BAK a veer and la MIV yoo deen) What is abacavir and lamivudine (Epzicom)? What are the possible side effects of abacavir and lamivudine (Epzicom)? What is the most important information I should know about abacavir and lamivudine (Epzicom)? What should I discuss with my healthcare provider before taking abacavir and lamivudine (Epzicom)? How should I take abacavir and lamivudine (Epzicom)? What happens if I miss a dose (Epzicom)? What happens if I overdose (Epzicom)? What should I avoid while taking abacavir and lamivudine (Epzicom)? What other drugs will affect abacavir and lamivudine (Epzicom)? Where can I get more information? What is abacavir and lamivudine (Epzicom)? Abacavir and lamivudine are antiviral medications that prevent human immunodeficiency virus (HIV) cells from multiplying in your body.The combination of abacavir and lamivudine is used to treat HIV, which causes the acquired immunodeficiency syndrome (AIDS). This medication is not a cure for HIV or AIDS.Abacavir and lamivudine may also be used for purposes not listed in this medication guide. What are the possible side effects of abacavir and lamivudine (Epzicom)? Stop using this medication and call your doctor at once if you have symptoms of an allergic reaction from two or more of these specific side effect groups:Group 1 - fever;Group 2 - rash;Group 3 - nausea, vomiting, diarrhea, stomach pain;Group 4 - general ill feeling, extreme tiredness, body aches;Group 5 - shortness of breath, cough, sore throat.Once you have had an allergic reaction to this medication, you must never use it again. If you stop taking abacavir and lamivudine for any reason, talk to your doctor before you start taking it again.This medication may cause lactic acidosis (a build-up of lactic acid in the body, which can be fatal). Lactic acidosis can start slowly and get worse over time. Get emergency medical help if you have even mild symptoms of lactic acidosis, such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.Abacavir and lamivudine can cause serious side effects that may not be signs of an allergic reaction. Call your doctor at once if you have:the first sign of any skin rash, no matter how mild;signs of a new infection such as flu symptoms, easy bruising or unusual bleeding, loss of appetite, mouth sores;severe pain in your upper stomach spreading to your back;itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);increased sweating, tremors in your hands, anxiety, feeling irritable, sleep problems (insomnia);diarrhea, unexplained weight loss, menstrual changes, impotence, loss of interest in sex;swelling in your neck or throat (enlarged thyroid);weakness or prickly feeling in your fingers or toes;problems with walking, breathing, speech, swallowing, or eye movement; orsevere lower back pain, loss of bladder or bowel control.Less serious side effects include:strange dreams;headache, dizziness, depression, anxiety;mild nausea or diarrhea; orchanges in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and trunk).This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What is the most important information I should know about abacavir and lamivudine (Epzicom)? Stop using this medication and call your doctor at once if you have any of these signs of an allergic reaction: fever; rash; nausea, vomiting, diarrhea, stomach pain; general ill feeling, extreme tiredness, body aches; shortness of breath, cough, sore throat.Once you have had an allergic reaction to abacavir, you must never use it again.Read the Warning Card that comes with this medication, and carry it with you at all times so you will know the symptoms of allergic reaction to watch for.Some people develop lactic acidosis while taking abacavir and lamivudine. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.Abacavir and lamivudine can also cause severe or life-threatening effects on your liver. Call your doctor at once if you have any of these symptoms while taking this medication: pain in your upper stomach, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).If you have hepatitis B you may develop liver symptoms after you stop taking this medication, even months after stopping. Your doctor may want to check your liver function for several months after you stop using abacavir and lamivudine. Visit your doctor regularly.Do not allow your medicine to run out completely before you get your prescription refilled. It is important that you not stop taking abacavir and lamivudine once you have started. If you miss several doses, you may have a dangerous or even fatal allergic reaction once you start taking the medicine again. If you stop taking abacavir and lamivudine for any reason, talk to your doctor before you start taking the medication again.52017-09-01 11:12:57Abacavir Sulfate and Lamivudine TabletsEpzicomMultum
262017-09-01 17:34:07Epzicom Patient Information including How Should I TakeWhat should I discuss with my healthcare provider before taking abacavir and lamivudine (Epzicom)? Do not take this medication if you have ever had an allergic reaction to Epzicom or any medicine that contains abacavir or lamivudine, including: Combivir, Epivir, Trizivir, or Ziagen. Once you have had an allergic reaction to abacavir, you must never use it again.Some people develop a life-threatening condition called lactic acidosis while taking abacavir and lamivudine. You may be more likely to develop lactic acidosis if you are overweight or have liver disease, if you are a woman, or if you have taken HIV or AIDS medications for a long time. Talk with your doctor about your individual risk.Abacavir and lamivudine can also cause severe or life-threatening effects on your liver. You should not take abacavir and lamivudine if you have liver disease.Do not take abacavir and lamivudine with any of the following HIV medications: Atripla, Combivir, Complera, Emtriva, Epivir, Trizivir, Truvada, Zerit, or Ziagen.To make sure you can safely take abacavir and lamivudine, tell your doctor if you have any of these other conditions:kidney disease;heart disease or high blood pressure;a risk factor for heart disease such as smoking, diabetes, or high cholesterol; orif you have used an HIV medication in the past, such as abacavir (Ziagen), didanosine (Videx), emtricitabine (Atripla, Complera, Emtriva, Truvada), lamivudine (Combivir, Epivir, Trizivir), stavudine (Zerit), tenofovir (Viread), zalcitabine (Hivid), or zidovudine (Retrovir).You may need a blood test before you start taking abacavir and lamivudine for the first time, or if you are restarting the medication after stopping for reasons not related to an allergic reaction.FDA pregnancy category C. It is not known whether abacavir and lamivudine will harm an unborn baby. HIV can be passed to your baby if you are not properly treated during pregnancy. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Take all of your HIV medicines as directed to control your infection.If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of this medication on the baby.Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk. How should I take abacavir and lamivudine (Epzicom)? Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.Abacavir and lamivudine may be taken with or without food.This medicine comes with a Medication Guide and a Warning Card that lists the symptoms of an allergic reaction. Read this information carefully and carry the Warning Card with you at all times so you will know what symptoms to watch for.Use this medication regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.HIV/AIDS is usually treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice. Every person with HIV or AIDS should remain under the care of a doctor.If you have hepatitis B you may develop liver symptoms after you stop taking this medication, even months after stopping. Your doctor may want to check your liver function for several months after you stop using abacavir and lamivudine. Visit your doctor regularly.Store at room temperature away from moisture and heat.52017-09-01 11:12:57Abacavir Sulfate and Lamivudine TabletsEpzicomMultum
272017-09-01 17:34:07Epzicom Patient Information including If I Miss a Dose52017-09-01 11:12:57Abacavir Sulfate and Lamivudine TabletsEpzicomMultum
292017-12-04 17:37:08Indications & DosageINDICATIONS 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: Endocrine Disorders Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance) Acute adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; mineralocorticoid supplementation may be necessary, particularly when synthetic analogs are used) Preoperatively and in the event of serious trauma or illness, in patients with known adrenal insufficiency or when adrenocortical reserve is doubtful Shock unresponsive to conventional therapy if adrenocortical insufficiency exists or is suspected Congenital adrenal hyperplasia Hypercalcemia associated with cancer Nonsuppurative thyroiditis Rheumatic Disorders As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in: Post-traumatic osteoarthritis Synovitis of osteoarthritis Rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy) Acute and subacute bursitis Epicondylitis Acute nonspecific tenosynovitis Acute gouty arthritis Psoriatic arthritis Ankylosing spondylitis Collagen Diseases During an exacerbation or as maintenance therapy in selected cases of: Systemic lupus erythematosus Systemic dermatomyositis (polymyositis) Acute rheumatic carditis Dermatologic Diseases Pemphigus Severe erythema multi-forme (Stevens-Johnson syndrome) Exfoliative dermatitis Bullous dermatitis herpetiformis Severe seborrheic dermatitis Severe psoriasis Mycosis fungoides Allergic States Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in: Bronchial asthma Contact dermatitis Atopic dermatitis Serum sickness Seasonal or perennial allergic rhinitis Drug hypersensitivity reactions Urticarial transfusion reactions Acute noninfectious laryngeal edema (epinephrine is the drug of first choice) Ophthalmic Diseases Severe acute and chronic allergic and inflammatory processes involving the eye, such as: Herpes zoster ophthalmicus Iritis, iridocyclitis Chorioretinitis Diffuse posterior uveitis and choroiditis Optic neuritis Sympathetic ophthalmia Anterior segment inflammation Allergic conjunctivitis Allergic corneal marginal ulcers Keratitis Gastrointestinal Diseases To tide the patient over a critical period of the disease in: Ulcerative colitis (systemic therapy) Regional enteritis (systemic therapy) Respiratory Diseases Symptomatic sarcoidosis Berylliosis Fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy Loeffler's syndrome not manageable by other means Aspiration pneumonitis Hematologic Disorders Acquired (autoimmune) hemolytic anemia Idiopathic thrombocytopenic purpura in adults (IV only; IM administration is contraindicated) Secondary thrombocytopenia in adults Erythroblastopenia (RBC anemia) Congenital (erythroid) hypoplastic anemia Neoplastic Diseases For palliative management of: Leukemias and lymphomas in adults Acute leukemia of childhood Edematous States To induce diuresis or remission of proteinuria in the nephrotic syndrome, without uremia, of the idiopathic type or that due to lupus erythematosus Nervous System Acute exacerbations of multiple sclerosis Miscellaneous Tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy Trichinosis with neurologic or myocardial involvement DOSAGE AND ADMINISTRATION 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. In general, high dose corticosteroid therapy should be continued only until the patient's condition has stabilized; usually not beyond 48 to 72 hours. Although adverse effects associated with high dose short-term corticoid therapy are uncommon, peptic ulceration may occur. Prophylactic antacid therapy may be indicated. 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. 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. 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 laboratory studies, such as urinalysis, two-hour postprandial blood sugar, determination of blood pressure and body weight, and a chest X-ray should be made at regular intervals during prolonged therapy. Upper GI X-rays are desirable in patients with an ulcer history or significant dyspepsia. 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. 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% dextrose in water, isotonic saline solution or 5% dextrose in isotonic saline solution. Multiple Sclerosis 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). Directions for Reconstitution Remove protective cap. Cleanse stopper with suitable germicide. Aseptically add 1 mL Bacteriostatic 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. Agitate to effect solution. Invert vial. Insert needle through target area of stopper until tip is just visible. Withdraw dose. Storage Conditions Protect from light. Store unreconstituted product at 20 to 25&deg;C (68 to 77&deg;F). [See USP Controlled Room Temperature.] Store solution at 20 to 25&deg;C (68 to 77&deg;F). [See USP Controlled Room Temperature.] Use solution within 48 hours after mixing. HOW SUPPLIED A-Methapred (methylprednisolone sodium succinate) sterile powder is available in the following packages: List Container Concentration 3217 Single-Dose Vial 40 mg/vial 3218 Single-Dose Vial 125 mg/vial Rev: October, 2005. Hospira Inc., Lake Forest, IL 60045, USA. FDA rev date: 11/25/200812017-12-04 17:37:08A-MethapredMethylprednisolone Sodium SuccinateFDA
302017-12-04 17:37:08Side Effects & Drug InteractionsSIDE EFFECTS Fluid and Electrolyte Disturbances Sodium retention, Fluid retention, Congestive heart failure in susceptible patients, Potassium loss, Hypokalemic alkalosis, Hypertension Musculoskeletal Muscle weakness, Steroid myopathy, Loss of muscle mass, Severe arthralgia, Vertebral compression fractures, Aseptic necrosis of femoral and humeral heads, Pathologic fracture of long bones, Osteoporosis Gastrointestinal Peptic ulcer with possible perforation and hemorrhage, Pancreatitis, Abdominal distention, and Ulcerative esophagitis Dermatologic Impaired wound healing, Thin fragile skin, Petechiae and ecchymoses, Facial erythema, Increased sweating, May suppress reactions to skin tests Neurological Increased intracranial pressure with papilledema (pseudo-tumor cerebri) usually after treatment, Convulsions, Vertigo, Headache Endocrine Development of Cushingoid state, Suppression of growth in children, Secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress, as in trauma, surgery or illness, Menstrual irregularities, Decreased carbohydrate tolerance, Manifestations of latent diabetes mellitus, Increased requirements for insulin or oral hypoglycemic agents in diabetics Ophthalmic Posterior subcapsular cataracts, Increased intraocular pressure, Glaucoma, Exophthalmos Metabolic Negative nitrogen balance due to protein catabolism The following additional adverse reactions are related to parenteral corticosteroid therapy: Hyperpigmentation or hypopigmentation, Subcutaneous and cutaneous atrophy, Sterile abscess, Anaphylactic reaction with or without circulatory collapse, cardiac arrest, bronchospasm, Urticaria, Nausea and vomiting, Cardiac arrhythmias; hypotension or hypertension DRUG INTERACTIONS The pharmacokinetic interactions listed below are potentially clinically important. Mutual inhibition of metabolism 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.12017-12-04 17:37:08A-MethapredMethylprednisolone Sodium SuccinateFDA
312017-12-04 17:37:08Warnings & PrecautionsWARNINGS 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. 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. 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. A study has failed to establish the efficacy of Methylprednisolone Sodium Succinate for Injection, USP in the treatment of sepsis syndrome and septic 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. Prolonged use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to fungi or viruses. Usage in pregnancy 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 embryo or fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism. Average and large doses of cortisone or hydrocortisone can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. 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. 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. The use of Methylprednisolone Sodium Succinate for Injection, USP sterile powder in active tuberculosis should be restricted to those cases of fulminatingor disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with appropriate antituberculous regimen. If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis. 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 allergy to any drug. 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 gram administered over a period of less than 10 minutes). Bradycardia has been reported during or after the administration of large doses of Methylprednisolone sodium succinate, and may be unrelated to the speed or duration of infusion. Persons who are on drugs which suppress the immune system are more susceptible to infections than healthy individuals. Chicken pox and measles, 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, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents may be considered. PRECAUTIONS General Precautions 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, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. There is an enhanced effect of corticosteroids on patients with hypothyroidism and in those with cirrhosis. Corticosteroids should be used cautiously in patients with ocular herpes simplex because of possible corneal perforation. 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. Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression, to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. Steroids should be used with caution in nonspecific ulcerative colitis, if there is a probability of impending perforation, abscess or other pyogenic infection; diverticulitis; fresh intestinal anastomoses; active or latent peptic ulcer; renal insufficiency; hypertension; osteoporosis; and myasthenia gravis. Growth and development of infants and children on prolonged corticosteroid therapy should be carefully observed. Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, 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 DOSAGE AND ADMINISTRATION.) 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.12017-12-04 17:37:08A-MethapredMethylprednisolone Sodium SuccinateFDA
322017-12-04 17:37:08Overdosage & ContraindicationsOVERDOSE No information provided. CONTRAINDICATIONS 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 Syndrome" in premature infants. A-Methapred (methylprednisolone sodium succinate) sterile powder is also contraindicated in systemic fungal infections and patients with known hypersensitivity to the product and its constituents.12017-12-04 17:37:08A-MethapredMethylprednisolone Sodium SuccinateFDA
362017-12-04 17:37:19Indications & DosageINDICATIONS ZIAGEN tablets and oral solution, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV-1) infection. DOSAGE AND ADMINISTRATION Screening For HLA-B*5701 Allele Prior To Starting ZIAGEN Screen for the HLA-B*5701 allele prior to initiating therapy with ZIAGEN [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Recommended Dosage For Adult Patients 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. Recommended Dosage For Pediatric Patients 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. 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. Table 1: Dosing Recommendations for ZIAGEN Scored Tablets in Pediatric Patients Weight (ks) Once-Daily Dosing Regimena Twice-Daily Dosing Regimen AM Dose PM Dose Total Daily Dose 14 to < 20 1 tablet (300 mg) &frac12;tablet (150 mg) &frac12;tablet (150 mg) 300 mg &ge; 20 to < 25 1&frac12;tablets (450 mg) &frac12;tablet (150 mg) 1 tablet (300 mg) 450 mg &ge; 25 2 tablets (600 mg) 1 tablet (300 mg) 1 tablet (300 mg) 600 mg a 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 Clinical Studies]. Recommended Dosage For Patients With Hepatic Impairment 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. HOW SUPPLIED Dosage Forms And Strengths ZIAGEN tablets contain 300 mg of abacavir as abacavir sulfate. The tablets are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with &ldquo;GX 623&rdquo; on both sides. 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. Storage And Handling ZIAGEN tablets, containing abacavir sulfate equivalent to 300 mg abacavir are yellow, biconvex, scored, capsule-shaped, film-coated, and imprinted with &ldquo;GX 623&rdquo; on both sides. They are packaged as follows: Bottles of 60 tablets (NDC 49702-221-18). Unit dose blister packs of 60 tablets (NDC 49702-221-44). Each pack contains 6 blister cards of 10 tablets each. Store at controlled room temperature of 20&deg; to 25&deg;C (68&deg; to 77&deg;F) (see USP). ZIAGEN oral solution is a clear to opalescent, yellowish, strawberry-banana-flavored liquid. Each mL of the solution contains abacavir sulfate equivalent to 20 mg of abacavir. It is packaged in plastic bottles as follows: Bottles of 240 mL (NDC 49702-222-48) with child-resistant closure. This product does not require reconstitution. Store at controlled room temperature of 20&deg; to 25&deg;C (68&deg; to 77&deg;F) (see USP). DO NOT FREEZE. May be refrigerated. Manufactured For:ViiV Healthecare, Research Triangle Park, NC 27709. by: Research Triangle Park, NC 27709. Revised: Mar 201722017-12-04 17:37:19Abacavir SulfateZiagenFDA
372017-12-04 17:37:19Side Effects & Drug InteractionsSIDE EFFECTS The following adverse reactions are discussed in other sections of the labeling: Serious and sometimes fatal hypersensitivity reactions [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS]. Fat redistribution [see WARNINGS AND PRECAUTIONS]. Myocardial infarction [see WARNINGS AND PRECAUTIONS]. Clinical Trials Experience In Adult Subjects 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. Serious And Fatal Abacavir-Associated Hypersensitivity Reactions In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. 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. 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). Additional Adverse Reactions With Use Of ZIAGEN Therapy-Naive Adults: 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. 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 (CNA30024a) through 48 Weeks of Treatment Adverse Reaction ZIAGEN plus Lamivudine plus Efavirenz (n = 324) Zidovudine plusLamivudine plus Efavirenz (n = 325) Dreams/sleep disorders 10% 10% Drug hypersensitivity 9% < 1%b Headaches/migraine 7% 11% Nausea 7% 11% Fatigue/malaise 7% 10% Diarrhea 7% 6% Rashes 6% 12% Abdominal pain/gastritis/gastrointestinal signs and symptoms 6% 8% Depressive disorders 6% 6% Dizziness 6% 6% Musculoskeletal pain 6% 5% Bronchitis 4% 5% Vomiting 2% 9% a 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. b Ten (3%) cases of suspected drug hypersensitivity were reclassified as not being due to abacavir following unblinding. 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. 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 Adverse Reaction ZIAGEN plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264) Nausea 19% 17% Headache 13% 9% Malaise and fatigue 12% 12% Nausea and vomiting 10% 10% Hypersensitivity reaction 8% 2% Diarrhea 7% 5% Fever and/or chills 6% 3% Depressive disorders 6% 4% Musculoskeletal pain 5% 7% Skin rashes 5% 4% Ear/nose/throat infections 5% 4% Viral respiratory infections 5% 5% Anxiety 5% 3% Renal signs/symptoms < 1% 5% Pain (non-site-specific) < 1% 5% 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. ZIAGEN Once Daily versus ZIAGEN Twice Daily (CNA30021): 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. Laboratory Abnormalities: 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. Table 4: Laboratory Abnormalities (Grades 3-4) in Therapy-Naive Adults (CNA30024) through 48 Weeks of Treatment Grade 3/4 Laboratory Abnormalities ZIAGEN plus Lamivudine plus Efavirenz (n = 324) Zidovudine plus Lamivudine plus Efavirenz (n = 325) Elevated CPK ( > 4 X ULN) 8% 8% Elevated ALT ( > 5 X ULN) 6% 6% Elevated AST ( > 5 X ULN) 6% 5% Hypertriglyceridemia ( > 750 mg/dL) 6% 5% Hyperamylasemia ( > 2 X ULN) 4% 5% Neutropenia (ANC < 750/mm&sup3;) 2% 4% Anemia (Hgb &le; 6.9 gm/dL) < 1% 2% Thrombocytopenia (Platelets < 50,000/mm&sup3;) 1% < 1% Leukopenia (WBC &le; 1,500/mm&sup3;) < 1% 2% ULN = Upper limit of normal. n = Number of subjects assessed. Laboratory abnormalities in CNA3005 are listed in Table 5. Table 5: Treatment-Emergent Laboratory Abnormalities (Grades 3-4) in CNA3005 Grade 3/4 Laboratory Abnormalities ZIAGEN plus Lamivudine/Zidovudine (n = 262) Indinavir plus Lamivudine/Zidovudine (n = 264) Elevated CPK ( > 4 x ULN) 18 (7%) 18 (7%) ALT ( > 5.0 x ULN) 16 (6%) 16 (6%) Neutropenia ( < 750/mm ) 13 (5%) 13 (5%) Hypertriglyceridemia ( > 750 mg/dL) 5 (2%) 3 (1%) Hyperamylasemia ( > 2.0 x ULN) 5 (2%) 1 ( < 1%) Hyperglycemia ( > 13.9 mmol/L) 2 ( < 1%) 2 ( < 1%) Anemia (Hgb &le; 6.9 g/dL) 0 (0%) 3 (1%) ULN = Upper limit of normal. n = Number of subjects assessed. The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021. Clinical Trials Experience In Pediatric Subjects Therapy-Experienced Pediatric Subjects (Twice-Daily Dosing) 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&sup2; twice daily compared with lamivudine 4 mg per kg twice daily and zidovudine 180 mg per m&sup2; twice daily from CNA3006 are listed in Table 6. 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 Adverse Reaction ZIAGEN plus Lamivudine plus Zidovudine (n = 102) Lamivudine plus Zidovudine (n = 103) Fever and/or chills 9% 7% Nausea and vomiting 9% 2% Skin rashes 7% 1% Ear/nose/throat infections 5% 1% Pneumonia 4% 5% Headache 1% 5% Laboratory Abnormalities: 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). Other Adverse Events 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. Pediatric Subjects Once-Daily versus Twice-Daily Dosing (COL105677): 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. Postmarketing Experience 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. Body as a Whole Redistribution/accumulation of body fat. Cardiovascular Myocardial infarction. Hepatic Lactic acidosis and hepatic steatosis [see WARNINGS AND PRECAUTIONS]. Skin 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 ADVERSE REACTIONS]. DRUG INTERACTIONS Methadone 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 CLINICAL PHARMACOLOGY]. 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.22017-12-04 17:37:19Abacavir SulfateZiagenFDA
382017-12-04 17:37:19Warnings & PrecautionsWARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions 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 ADVERSE REACTIONS]. 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. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with ZIAGEN: 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. ZIAGEN is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. Before starting ZIAGEN, review medical history for prior exposure to any abacavir-containing product. NEVER restart ZIAGEN or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status. 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). 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. 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. A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill. Lactic Acidosis And Severe Hepatomegaly With Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Caution should be exercised when administering ZIAGEN to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. 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). Immune Reconstitution Syndrome 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 Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barr 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. Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and &ldquo;cushingoid appearance&rdquo; have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Myocardial Infarction In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive. 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). Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). Hypersensitivity Reactions Inform patients: 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. to carry the Warning Card with them. how to identify a hypersensitivity reaction [see WARNINGS AND PRECAUTIONS, Medication Guide]. 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. that a hypersensitivity reaction can worsen and lead to hospitalization or death if ZIAGEN is not immediately discontinued. 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. that if they have a hypersensitivity reaction, they should dispose of any unused ZIAGEN to avoid restarting abacavir. that a hypersensitivity reaction is usually reversible if it is detected promptly and ZIAGEN is stopped right away. 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. 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. Lactic Acidosis/Hepatomegaly With Steatosis 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 ZIAGEN if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Immune Reconstitution Syndrome 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 WARNINGS AND PRECAUTIONS]. Redistribution/Accumulation Of Body Fat Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see WARNINGS AND PRECAUTIONS]. Pregnancy Registry Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ZIAGEN during pregnancy [see Use in Specific Populations]. Lactation Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations]. Missed Dose 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 DOSAGE AND ADMINISTRATION]. Availability of Medication Guide 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. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity 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. Mutagenicity 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. Impairment Of Fertility 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. Use In Specific Populations Pregnancy Pregnancy Exposure Registry 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. Risk Summary 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 Data]. 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. 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 Data]. Data Human Data: Based on prospective reports to the APR of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 1,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 2.9% (95% CI: 2.0% to 4.1%) following first trimester exposure to abacavir-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) following second/third trimester exposure to abacavir-containing regimens. 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 CLINICAL PHARMACOLOGY]. Animal Data: 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. Lactation Risk Summary The Centers for Disease Control and Prevention recommend 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) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving ZIAGEN. Pediatric Use 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 DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Clinical Studies]. Geriatric Use 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. Patients With Impaired Hepatic Function A dose reduction is required for patients with mild hepatic impairment (Child-Pugh Class A) [see DOSAGE AND ADMINISTRATION]. 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 CONTRAINDICATIONS, CLINICAL PHARMACOLOGY].22017-12-04 17:37:19Abacavir SulfateZiagenFDA
392017-12-04 17:37:19Overdosage & Contraindications22017-12-04 17:37:19Abacavir SulfateZiagenFDA
462017-12-04 17:37:28Indications & DosageINDICATIONS EPZICOM, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. DOSAGE AND ADMINISTRATION Screening For HLA-B*5701 Allele Prior To Starting EPZICOM Screen for the HLA-B*5701 allele prior to initiating therapy with EPZICOM [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Recommended Dosage For Adult Patients The recommended dosage of EPZICOM for adults is one tablet taken orally once daily, in combination with other antiretroviral agents, with or without food. Recommended Dosage For Pediatric Patients 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 Clinical Studies]. Before prescribing EPZICOM tablets, pediatric patients should be assessed for the ability to swallow tablets. Not Recommended Due To Lack of Dosage Adjustment Because EPZICOM is a fixed-dose tablet and cannot be dose adjusted, EPZICOM is not recommended for: patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations]. patients with mild hepatic impairment. EPZICOM is contraindicated in patients with moderate or severe hepatic impairment [see CONTRAINDICATIONS, Use in Specific Populations]. Use of EPIVIR&reg; (lamivudine) oral solution or tablets and ZIAGEN&reg; (abacavir) oral solution may be considered. HOW SUPPLIED Dosage Forms And Strengths 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 &ldquo;GS FC2&rdquo; on one side with no markings on the reverse side. Storage And Handling EPZICOM 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: Bottles of 30 tablets (NDC 49702-206-13). Store at 25&deg;C (77&deg;F); excursions permitted to 15&deg; to 30&deg;C (59&deg; to 86&deg;F) (see USP Controlled Room Temperature). Manufactured for : ViiV Healthcare, Research Triangle Park, NC 27709. by: GlaxoSmithKline Research Triangle Park, NC 27709. Revised: September 201542017-12-04 17:37:28Abacavir Sulfate and Lamivudine TabletsEpzicomFDA
472017-12-04 17:37:28Side Effects & Drug InteractionsSIDE EFFECTS The following adverse reactions are discussed in other sections of the labeling: Serious and sometimes fatal hypersensitivity reactions [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Exacerbations of hepatitis B [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see WARNINGS AND PRECAUTIONS]. Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS]. Fat redistribution [see WARNINGS AND PRECAUTIONS]. Myocardial infarction [see WARNINGS AND PRECAUTIONS]. Clinical Trials Experience In Adult Subjects 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. Serious And Fatal Abacavir-Associated Hypersensitivity Reactions In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of EPZICOM [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. 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. 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). Additional Adverse Reactions With Use Of EPZICOM Therapy-Naive Adults: 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. 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 Adverse Event ZIAGEN 600 mg q.d. plus EPIVIR plus Efavirenz (n = 384) ZIAGEN 300 mg b.i.d. plus EPIVIR plus Efavirenz (n = 386) Drug hypersensitivitya, b 9% 7% Insomnia 7% 9% Depression/Depressed mood 7% 7% Headache/Migraine 7% 6% Fatigue/Malaise 6% 8% Dizziness/Vertigo 6% 6% Nausea 5% 6% Diarrheaa 5% 6% Rash 5% 5% Pyrexia 5% 3% Abdominal pain/gastritis 4% 5% Abnormal dreams 4% 5% Anxiety 3% 5% a 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. b 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. Laboratory Abnormalities: 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. The frequencies of treatment-emergent laboratory abnormalities were comparable between treatment groups in CNA30021. Other Adverse Events: In addition to adverse reactions listed above, other adverse events observed in the expanded access program for abacavir were pancreatitis and increased GGT. Clinical Trials Experience In Pediatric Subjects 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 ADVERSE REACTIONS]. Postmarketing Experience 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. Abacavir Cardiovascular: Myocardial infarction. Skin: 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 ADVERSE REACTIONS]. Abacavir And Lamivudine Body as a Whole: Redistribution/accumulation of body fat [see WARNINGS AND PRECAUTIONS]. Digestive: Stomatitis. Endocrine and Metabolic: Hyperglycemia. General: Weakness. Hemic and Lymphatic: Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly. Hepatic: Lactic acidosis and hepatic steatosis [see WARNINGS AND PRECAUTIONS], posttreatment exacerbations of hepatitis B [see WARNINGS AND PRECAUTIONS]. Hypersensitivity: Sensitization reactions (including anaphylaxis), urticaria. Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis. Nervous: Paresthesia, peripheral neuropathy, seizures. Respiratory: Abnormal breath sounds/wheezing. Skin: Alopecia, erythema multiforme, Stevens-Johnson syndrome. DRUG INTERACTIONS Methadone 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 CLINICAL PHARMACOLOGY]. 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.42017-12-04 17:37:28Abacavir Sulfate and Lamivudine TabletsEpzicomFDA
482017-12-04 17:37:28Warnings & PrecautionsWARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions 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 ADVERSE REACTIONS]. 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. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir: 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. EPZICOM is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. 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. 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). 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. 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. A Medication Guide and Warning Card that provide information about recognition of hypersensitivity reactions should be dispensed with each new prescription and refill. Lactic Acidosis And Severe Hepatomegaly With Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. 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). Patients With Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis 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. Emergence of Lamivudine-resistant HBV 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). Use With Interferon-And Ribavirin-Based Regimens Patients receiving interferon alfa with or without ribavirin and EPZICOM should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. See full prescribing information for EPIVIR (lamivudine). Discontinuation of EPZICOM 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). Immune Reconstitution Syndrome 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 Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barr&eacute; 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. Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and &ldquo;cushingoid appearance&rdquo; have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Myocardial Infarction In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive. 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). Related Products That Are Not Recommended EPZICOM contains fixed doses of 2 nucleoside analogue reverse transcriptase inhibitors (abacavir and lamivudine); concomitant administration of EPZICOM with other products containing abacavir or lamivudine is not recommended. In addition, do not administer EPZICOM in combination with products containing emtricitabine. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). Hypersensitivity Reactions Inform patients: 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. to carry the Warning Card with them. how to identify a hypersensitivity reaction [see WARNINGS AND PRECAUTIONS, Medication Guide]. 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. that a hypersensitivity reaction can worsen and lead to hospitalization or death if EPZICOM is not immediately discontinued. 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. that a hypersensitivity reaction is usually reversible if it is detected promptly and EPZICOM is stopped right away. 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. 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. Related Products that are Not Recommended Inform patients that they should not take EPZICOM with ATRIPLA&reg;, COMBIVIR&reg;, COMPLERA&reg;, DUTREBIS&trade;, EMTRIVA&reg;, EPIVIR, EPIVIR-HBV&reg;, STRIBILD&reg;, TRIUMEQ&reg;, TRIZIVIR, TRUVADA&reg;, or ZIAGEN. Lactic Acidosis/Hepatomegaly Inform patients that some HIV medicines, including EPZICOM, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see WARNINGS AND PRECAUTIONS]. Patients with Hepatitis B or C Co-infection 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 WARNINGS AND PRECAUTIONS]. 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 WARNINGS AND PRECAUTIONS]. Immune Reconstitution Syndrome In some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see WARNINGS AND PRECAUTIONS]. Redistribution/Accumulation of Body Fat Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see WARNINGS AND PRECAUTIONS]. Information about HIV-1 Infection EPZICOM is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illness. Inform patients that sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Advise patients to remain under the care of a physician when using EPZICOM. Advise patients to take all HIV medications exactly as prescribed. Advise patients to avoid doing things that can spread HIV-1 infection to others. Advise patients not to re-use or share needles or other injection equipment. Advise patients not to share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. Advise patients to always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. Female patients should be advised not to breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Instruct patients to read the Medication Guide before starting EPZICOM and to reread 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. Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity Abacavir: Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of 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. Lamivudine: 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. Mutagenicity Abacavir: 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. Lamivudine: 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. Impairment of Fertility Abacavir or lamivudine did not affect male or female fertility in rats at a dose associated with exposures approximately 8 or 130 times, respectively, higher than the exposures in humans at the doses of 600 mg and 300 mg (respectively). Use In Specific Populations Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EPZICOM during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Risk Summary Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for abacavir or lamivudine compared with the background rate for major birth defects of 2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Abacavir produced fetal malformations and other embryonic and fetal toxicities in rats at 35 times the human exposure at the recommended clinical dose. Lamivudine produced embryonic toxicity in rabbits at a dose that produced similar human exposures to the recommended clinical dose. The relevance of animal findings to human pregnancy registry data is not known. Data Human Data: Abacavir: Based on prospective reports from the Antiretroviral Pregnancy Registry of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 900 exposed in the first trimester), there was no difference between abacavir and overall birth defects compared with the background birth defect rate of 2.7% in the US reference population of the MACDP. The prevalence of defects in the first trimester was 3.0% (95% CI: 2.0% to 4.4%). Lamivudine: Based on prospective reports from the Antiretroviral Pregnancy Registry of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,300 exposed in the first trimester), there was no difference between lamivudine and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in the first trimester was 3.1% (95% CI: 2.6% to 3.7%). 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 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 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. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg per mL (150 mg twice daily) and 2.1 to 5.2 mcg per mL (300 mg twice daily). Animal Data: Abacavir: Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35 times the human exposure, based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5 times the human exposure at the recommended dose based on AUC. Lamivudine: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Lactation The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for HIV-1 transmission mothers should be instructed not to breastfeed. Pediatric Use 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 DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, Clinical Studies]. In pediatric patients weighing less than 25 kg, use of abacavir and lamivudine as single products is recommended to achieve appropriate dosing. Geriatric Use 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 DOSAGE AND ADMINISTRATION, Use In Specific Populations]. Patients With Impaired Renal Function EPZICOM is not recommended for patients with creatinine clearance less than 50 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 50 mL per min, then the individual components should be used [see CLINICAL PHARMACOLOGY]. Patients With Impaired Hepatic Function 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 CLINICAL PHARMACOLOGY]. 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 CONTRAINDICATIONS].42017-12-04 17:37:28Abacavir Sulfate and Lamivudine TabletsEpzicomFDA
492017-12-04 17:37:28Overdosage & Contraindications42017-12-04 17:37:28Abacavir Sulfate and Lamivudine TabletsEpzicomFDA
552017-12-04 17:37:41Drug DescriptionFind Lowest Prices on TRIZIVIR&reg; (abacavir, lamivudine, and zidovudine)Tablets WARNING HYPERSENSITIVITY REACTIONS, HEMATOLOGIC TOXICITY, MYOPATHY, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, and EXACERBATIONS OF HEPATITIS B Hypersensitivity Reactions 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 WARNINGS AND PRECAUTIONS]. TRIZIVIR is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. 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. Discontinue TRIZIVIR immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. Following a hypersensitivity reaction to TRIZIVIR, NEVER restart TRIZIVIR 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 PRECAUTIONS]. Hematologic Toxicity Zidovudine, a component of TRIZIVIR, has been associated with hematologic toxicity, including neutropenia and severe anemia, particularly in patients with advanced Human Immunodeficiency Virus (HIV-1) disease [see WARNINGS AND PRECAUTIONS]. Myopathy Prolonged use of zidovudine has been associated with symptomatic myopathy [see WARNINGS AND PRECAUTIONS]. Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue TRIZIVIR if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see WARNINGS AND PRECAUTIONS]. Exacerbations of Hepatitis B Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine, a component of TRIZIVIR. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue TRIZIVIR and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see WARNINGS AND PRECAUTIONS]. DESCRIPTION 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. 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&reg; green 03B11434) that is made of FD&C Blue No. 2, hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide. Abacavir Sulfate 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 (C14H18N6O)2&bull;H2SO4 and a molecular weight of 670.76 g per mol. It has the following structural formula: Abacavir sulfate is a white to off-white solid and soluble in water. Dosages are expressed in terms of abacavir. Lamivudine The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3oxathiolan-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 C8H11N3O3S and a molecular weight of 229.3 g per mol. It has the following structural formula: Lamivudine is a white to off-white crystalline solid and is soluble in water. Zidovudine The chemical name of zidovudine is 3'-azido-3'-deoxythymidine. It has a molecular formula of C10H13N5O4 and a molecular weight of 267.24 g per mol. It has the following structural formula: Zidovudine is a white to beige, odorless, crystalline solid with a solubility of 20.1 mg per mL in water at 25&deg;C.62017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirFDA
562017-12-04 17:37:41Indications & DosageINDICATIONS TRIZIVIR is indicated in combination with other antiretrovirals or alone for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Limitations of Use 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 Clinical Studies]. DOSAGE AND ADMINISTRATION Screening For HLA-B*5701 Allele Prior To Starting TRIZIVIR Screen for the HLA-B*5701 allele prior to initiating therapy with TRIZIVIR [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Recommended Dosage For Adults And Pediatric Patients Weighing At Least 40 kg The recommended dosage of TRIZIVIR is one tablet taken orally twice daily with or without food. Not Recommended Due To Lack Of Dosage Adjustment Because TRIZIVIR is a fixed-dose tablet and cannot be dose adjusted, TRIZIVIR is not recommended in: pediatric patients who weigh less than 40 kg [see Use in Specific Populations] patients with creatinine clearance less than 50 mL per minute [see Use In Specific Populations] patients with mild hepatic impairment. TRIZIVIR is contraindicated in patients with moderate or severe hepatic impairment [see CONTRAINDICATIONS, Use In Specific Populations]. HOW SUPPLIED Dosage Forms And Strengths 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 &ldquo;GX LL1&rdquo; on one side with no markings on the reverse side. Storage And Handling TRIZIVIR 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: Bottles of 60 tablets (NDC 49702-217-18). Store at 25&deg;C (77&deg;F); excursions permitted to 15&deg; to 30&deg;C (59&deg; to 86&deg;F) (see USP Controlled Room Temperature). Manufactured for: ViiV Healthcare, Research Triangle Park, NC 27709 by: GlaxoSmithKline Research Triangle Park, NC 27709. Revised: September 201562017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirFDA
572017-12-04 17:37:41Side Effects & Drug Interactions62017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirFDA
582017-12-04 17:37:41Warnings & PrecautionsWARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions 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 ADVERSE REACTIONS]. 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. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir: 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. TRIZIVIR is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. 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. 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). 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. 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. A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill. Hematologic Toxicity/Bone Marrow Suppression 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 mm&sup3; or hemoglobin less than 9.5 grams per dL [see ADVERSE REACTIONS]. 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. Myopathy 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. Lactic Acidosis And Severe Hepatomegaly With Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. See full prescribing information for ZIAGEN&reg; (abacavir), EPIVIR&reg; (lamivudine), and RETROVIR&reg; (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). Patients With Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis 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. Emergence of Lamivudine-resistant HBV 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&ndash;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). Use With Interferon-And Ribavirin-Based Regimens 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 EPIVIR (lamivudine) and 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). 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. Immune Reconstitution Syndrome 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, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barr&eacute; 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. Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and &ldquo;cushingoid appearance&rdquo; have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Myocardial Infarction In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive. 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). Therapy-Experienced Patients 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 Microbiology]. Related Products That Are Not Recommended TRIZIVIR is a fixed-dose combination of 3 nucleoside analogue reverse transcriptase inhibitors (abacavir, lamivudine, and zidovudine). Concomitant administration of TRIZIVIR with other products containing abacavir, lamivudine, or zidovudine is not recommended. In addition, do not administer TRIZIVIR in combination with products containing emtricitabine. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). Hypersensitivity Reaction Inform patients 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. to carry the Warning Card with them. how to identify a hypersensitivity reaction [see WARNINGS AND PRECAUTIONS, Medication Guide]. 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. that a hypersensitivity reaction can worsen and lead to hospitalization or death if TRIZIVIR is not immediately discontinued. 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. that a hypersensitivity reaction is usually reversible if it is detected promptly and TRIZIVIR is stopped right away. 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. 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. Related Products that are Not Recommended Inform patients that they should not take TRIZIVIR with ATRIPLA&reg;, COMBIVIR, COMPLERA&reg;, DUTREBIS&trade;, EMTRIVA&reg;, EPIVIR, EPIVIR-HBV&reg;, EPZICOM&reg; , RETROVIR, STRIBILD&reg;, TRIUMEQ&reg;, TRUVADA&reg;, or ZIAGEN. Neutropenia and Anemia 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 BOXED WARNING, WARNINGS AND PRECAUTIONS]. Myopathy 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 WARNINGS AND PRECAUTIONS]. Lactic Acidosis/Hepatomegaly Inform patients that some HIV medicines, including TRIZIVIR, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see WARNINGS AND PRECAUTIONS]. Patients with Hepatitis B or C Co-infection 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 WARNINGS AND PRECAUTIONS]. 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 WARNINGS AND PRECAUTIONS]. Immune Reconstitution Syndrome In some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see WARNINGS AND PRECAUTIONS]. Redistribution/Accumulation of Body Fat Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see WARNINGS AND PRECAUTIONS]. Information about HIV-1 Infection TRIZIVIR is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illness. Inform patients that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Advise patients to remain under the care of a physician when using TRIZIVIR. Advise patients to take all HIV medications exactly as prescribed. Advise patients to avoid doing things that can spread HIV-1 infection to others. Advise patients not to re-use or share needles or other injection equipment. Advise patients not to share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. Advise patients to always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. Female patients should be advised not to breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose. Instruct patients to read the Medication Guide before starting TRIZIVIR and to reread 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. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity Abacavir: Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of 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. Lamivudine: 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. Zidovudine: 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. In mice, 7 late-appearing (after 19 months) vaginal neoplasms (5 nonmetastasizing 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. In rats, 2 late-appearing (after 20 months), nonmetastasizing 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. 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. It is not known how predictive the results of rodent carcinogenicity studies may be for humans. 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. Mutagenicity Abacavir: 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. Lamivudine: 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. Zidovudine: 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. Impairment of Fertility Abacavir or Lamivudine: Abacavir or lamivudine did not affect male or female fertility in rats at a dose associated with exposures approximately 8 or 130 times, respectively, higher than the exposures in humans at the doses of 600 mg and 300 mg (respectively). Zidovudine: Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area considerations, had no effect on fertility judged by conception rates. Use In Specific Populations Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of TRIZIVIR in pregnant women. Reproduction studies with abacavir, lamivudine, and zidovudine have been performed in animals (see Abacavir, Lamivudine, and Zidovudine sections below). TRIZIVIR should be used during pregnancy only if the potential benefits outweigh the risks. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRIZIVIR during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263. Abacavir Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 35 times the human exposure, based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 8.5 times the human exposure at the recommended dose based on AUC. Lamivudine Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Zidovudine Reproduction studies with orally administered zidovudine in the rat and in the rabbit at doses up to 500 mg per kg per day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg per kg per day and rabbits given 500 mg per kg per day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an additional teratology study in rats, a dose of 3,000 mg per kg per day (very near the oral median lethal dose in rats of approximately 3,700 mg per kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. No evidence of teratogenicity was seen in this experiment at doses of 600 mg per kg per day or less. Two rodent carcinogenicity studies were conducted [see Nonclinical Toxicology]. Lactation The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for HIV-1 transmission mothers should be instructed not to breastfeed. Pediatric Use 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 DOSAGE AND ADMINISTRATION]. Therapy-Experienced Pediatric Trial 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. Geriatric Use 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 CLINICAL PHARMACOLOGY]. Patients With Impaired Renal Function 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 DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY]. Patients With Impaired Hepatic Function 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 CLINICAL PHARMACOLOGY]. 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 CONTRAINDICATIONS]. 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.62017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirFDA
592017-12-04 17:37:41Overdosage & Contraindications62017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirFDA
602017-12-04 17:37:41Clinical PharmacologyCLINICAL PHARMACOLOGY Mechanism Of Action TRIZIVIR is an antiretroviral agent [see Microbiology]. Pharmacokinetics Pharmacokinetics in Adults 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). Abacavir: 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 &plusmn; 0.89 mcg per mL (mean &plusmn; SD) and AUC(0-12 h) was 6.02 &plusmn; 1.73 mcg&bull;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. Lamivudine: 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). Zidovudine: 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. In humans, abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 enzymes. The pharmacokinetic properties of abacavir, lamivudine, and zidovudine in fasting subjects are summarized in Table 3. Table 3: Pharmacokinetic Parametersa for Abacavir, Lamivudine, and Zidovudine in Adults Parameter Abacavir Lamivudine Zidovudine Oral bioavailability (%) 86 &plusmn; 25 n = 6 86 &plusmn; 16 n = 12 64 &plusmn; 10 n = 5 Apparent volume of distribution (L/kg) 0.86 &plusmn; 0.15 n = 6 1.3 &plusmn; 0.4 n = 20 1.6 &plusmn; 0.6 n = 8 Systemic clearance (L/h/kg) 0.80 &plusmn; 0.24 n = 6 0.33 &plusmn; 0.06 n = 20 1.6 &plusmn; 0.6 n = 6 Renal clearance (L/h/kg) 0.007 &plusmn; 0.008 n = 6 0.22 &plusmn; 0.06 n = 20 0.34 &plusmn; 0.05 n = 9 Elimination half-life (h) 1.45 &plusmn; 0.32 n = 20 5 to 7b 0.5 to 3b aData presented as mean &plusmn; standard deviation except where noted. bApproximate range. Effect of Food on Absorption of TRIZIVIR 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 DOSAGE AND ADMINISTRATION]. Special Populations Renal Impairment: TRIZIVIR: 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). Hepatic Impairment: TRIZIVIR: 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). Pregnancy: Abacavir: No data are available on the pharmacokinetics of abacavir during pregnancy. Lamivudine: 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 umbilical cord serum samples. Zidovudine: 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. Although data are limited, methadone maintenance therapy in 5 pregnant women did not appear to alter zidovudine pharmacokinetics. Geriatric Patients: The pharmacokinetics of abacavir, lamivudine, and zidovudine have not been studied in subjects over 65 years of age. Gender: 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. Race: 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. Zidovudine: The pharmacokinetics of zidovudine with respect to race have not been determined. Drug Interactions 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. Cytochrome P450 Enzymes: Abacavir, lamivudine, and zidovudine are not significantly metabolized by cytochrome P450 enzymes; therefore, it is unlikely that clinically significant drug interactions will occur with drugs metabolized through these pathways. Glucuronyl Transferase: 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. Other Interactions Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure. Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects. Methadone: 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 DRUG INTERACTIONS]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. Ribavirin: In vitro data indicate ribavirin reduces phosphorylation 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 WARNINGS AND PRECAUTIONS]. The effects of other coadministered drugs on abacavir, lamivudine, or zidovudine are provided in Table 4. Table 4: Effect of Coadministered Drugs on Abacavir, Lamivudine, and Zidovudine AUCa Coadministered Drug and Dose Drug and Dose n Concentrations of Abacavir, Lamivudine, or Zidovudine Concentration of Coadministered Drug AUC Variability Ethanol 0.7 g/kg Abacavir single 600 mg 24 &uarr;41% 90% CI: 35% to 48% &harr;b Nelfinavir 750 mg every 8 h x 7 to 10 days Lamivudine Single 150 mg 11 &uarr;10% 95% CI: 1% to 20% &harr; Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days Lamivudine Single 300 mg 14 &uarr;43% 90% CI: 32% to 55% &harr; Atovaquone 750 mg every 12 h with food Zidovudine 200 mg every 8 h 14 &uarr;31% Range: 23% to 78%c &harr; Clarithromycin 500 mg twice daily Zidovudine 100 mg every 4 h x 7 days 4 &darr;12% Range: &darr;34% to &uarr;14% Not Reported Fluconazole 400 mg daily Zidovudine 200 mg every 8 h 12 &uarr;74% 95% CI: 54% to 98% Not Reported Methadone 30 to 90 mg daily Zidovudine 200 mg every 4 h 9 &uarr;43% Range: 16% to 64%c &harr; Nelfinavir 750 mg every 8 h x 7 to 10 days Zidovudine single 200 mg 11 &darr;35% Range: 28% to 41% &harr; Probenecid 500 mg every 6 h x 2 days Zidovudine 2 mg/kg every 8 h x 3 days 3 &uarr;106% Range: 100% to 170%c Not Assessed Rifampin 600 mg daily x 14 days Zidovudine 200 mg every 8 h x 14 days 8 &darr;47% 90% CI: 41% to 53% Not Assessed Ritonavir 300 mg every 6 h x 4 days Zidovudine 200 mg every 8 h x 4 days 9 &darr;25% 95% CI: 15% to 34% &harr; Valproic acid 250 mg or 500 mg every 8 h x 4 days Zidovudine 100 mg every 8 h x 4 days 6 &uarr;80% Range: 64% to 130%c Not Assessed &uarr; = Increase; &darr; = Decrease; &harr; = no significant change; AUC = area under the concentration versus time curve; CI = confidence interval. aSee DRUG INTERACTIONS for additional information on drug interactions. bThe drug-drug interaction was only evaluated in males. cEstimated range of percent difference. Microbiology Mechanism of Action Abacavir: 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. Lamivudine: 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. Zidovudine: 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. Antiviral Activity Abacavir: 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). 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 &plusmn; 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 viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM. Lamivudine: 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 AG 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. Zidovudine: 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 amino acid 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. Neither abacavir, lamivudine, nor zidovudine were 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). Resistance 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. Abacavir and Lamivudine: 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. Zidovudine: Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated subjects showed thymidine analog 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. Cross-resistance 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. 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. Animal Toxicology And/Or Pharmacology 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. Clinical Studies The following trial was conducted with the individual components of TRIZIVIR [see CLINICAL PHARMACOLOGY]. 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&reg; (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%), 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 mm&sup3;, and median plasma HIV-1 RNA was 4.8 log10 copies per mL. Proportions of subjects with plasma HIV-1 RNA less than 400 copies per mL (using Roche AMPLICOR HIV-1 MONITOR&reg; Test) through 48 weeks of treatment are summarized in Table 5. Table 5: Outcomes of Randomized Treatment through Week 48 (CNA3005) Outcome ZIAGEN plus Lamivudine/ Zidovudine (n = 262) Indinavir plus Lamivudine/ Zidovudine (n = 265) Respondera 49% 50% Virologic failureb 31% 28% Discontinued due to adverse reactions 10% 12% Discontinued due to other reasonsc 11% 10% aSubjects achieved and maintained confirmed HIV-1 RNA less than 400 copies per mL. bIncludes viral rebound and failure to achieve confirmed less than 400 copies per mL by Week 48. cIncludes consent withdrawn, lost to follow-up, protocol violations, those with missing data, clinical progression, and other. Treatment response by plasma HIV-1 RNA strata is shown in Table 6. Table 6: Proportions of Responders through Week 48 by Screening Plasma HIV-1 RNA Levels (CNA3005) Screening HIV-1 RNA (copies/mL) ZIAGEN plus Lamivudine/ Zidovudine (n = 262) Indinavir plus Lamivudine/ Zidovudine (n = 265) < 400 copies/mL n < 400 copies/mL n &ge; 10,000 - &le; 100,000 50% 166 48% 165 > 100,000 48% 96 52% 100 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. Through Week 48, an overall mean increase in CD4+ cell count of about 150 cells per mm&sup3; 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.62017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirFDA
612017-12-04 17:37:41Medication GuidePATIENT INFORMATION TRIZIVIR&reg; (TRY-zih-veer) (abacavir, lamivudine, and zidovudine) tablets What is the most important information I should know about TRIZIVIR? TRIZIVIR can cause serious side effects, including: Serious allergic reactions (hypersensitivity reaction) 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. 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. Symptom(s) Group 1 Fever Group 2 Rash Group 3 Nausea, vomiting, diarrhea, abdominal (stomach area) pain Group 4 Generally ill feeling, extreme tiredness, or achiness Group 5 Shortness of breath, cough, sore throat A list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card with you at all times. If you stop TRIZIVIR because of an allergic reaction, never take TRIZIVIR (abacavir, lamivudine and zidovudine) or any other abacavir-containing medicine (EPZICOM&reg; , TRIUMEQ&reg;, or ZIAGEN&reg;) again. If you take TRIZIVIR 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 low blood pressure or death. 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. 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. Blood problems. Zidovudine (RETROVIR&reg;), one of the medicines in TRIZIVIR, can cause serious blood cell problems. These include reduced numbers of white blood cells (neutropenia) and extremely reduced numbers of red blood cells (anemia). These blood cell problems are especially likely to happen in people with advanced human immunodeficiency virus type 1 (HIV-1) disease or AIDS. Your healthcare provider should check your blood cell counts regularly during treatment with TRIZIVIR. Muscle pain or weakness (myopathy) can happen during treatment with TRIZIVIR. Zidovudine (RETROVIR&reg;), one of the medicines in TRIZIVIR, can cause muscle pain or weakness when used for a long time. Build-up of acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take TRIZIVIR. 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: feel very weak or tired feel cold, especially in your arms and legs unusual (not normal) muscle pain feel dizzy or light-headed trouble breathing have a fast or irregular heartbeat stomach pain with nausea and vomiting Serious liver problems can happen in people who take TRIZIVIR. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems: your skin or the white part of your eyes turns yellow (jaundice) loss of appetite for several days or longer nausea dark or &ldquo;tea-colored&rdquo; urine pain, aching, or tenderness on the right side of your stomach area light colored stools (bowel movements) You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight (obese), or have been taking nucleoside analogue medicines for a long time. Worsening of hepatitis B virus in people who have HIV-1 infection. If you have HIV-1 and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking TRIZIVIR. A &ldquo;flare-up&rdquo; is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease is serious and may lead to death. Do not run out of TRIZIVIR. Refill your prescription or talk to your healthcare provider before your TRIZIVIR is all gone. &bull; Do not stop TRIZIVIR without first talking to your healthcare provider. 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. Resistant Hepatitis B Virus (HBV). If you have HIV-1 and hepatitis B, the hepatitis B virus can change (mutate) during your treatment with TRIZIVIR and become harder to treat (resistant). Use with interferon and ribavirin-based regimens. Worsening of liver disease that has caused death has happened in people infected with both HIV-1 and hepatitis C virus who are taking antiretroviral medicines, and are also being treated for hepatitis C with interferon with or without ribavirin. If you are taking TRIZIVIR and interferon with or without ribavirin, tell your healthcare provider if you have any new symptoms. What is TRIZIVIR? TRIZIVIR is a prescription HIV-1 (Human Immunodeficiency Virus type 1) medicine used alone or with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). TRIZIVIR contains 3 prescription medicines, abacavir (ZIAGEN&reg;), lamivudine (EPIVIR&reg;) and zidovudine (RETROVIR&reg;). TRIZIVIR should not be used in children weighing less than 88 pounds (40 kg). When used alone or with other antiretroviral medicines to treat HIV-1 infection, TRIZIVIR may help: reduce the amount of HIV-1 in your blood. This is called &ldquo;viral load&rdquo;. increase the number of CD4+ (T) cells in your blood, that help fight off other infections. Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections). TRIZIVIR does not cure HIV-1 infection or AIDS. You must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses. Avoid doing things that can spread HIV-1 infection to others. Do not share or re-use needles or other injection equipment. Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood. Ask your healthcare provider if you have any questions about how to prevent passing HIV to other people. Who should not take TRIZIVIR? Do not take TRIZIVIR if you: 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. are allergic to abacavir or any of the ingredients in TRIZIVIR. See the end of this Medication Guide for a complete list of ingredients in TRIZIVIR. have liver problems. What should I tell my healthcare provider before taking TRIZIVIR? Before you take TRIZIVIR, tell your healthcare provider if you: have been tested and know whether or not you have a particular gene variation called HLA-B*5701. have or have had liver problems, including hepatitis B or C virus infection. have kidney problems. have low blood cell counts (bone marrow problem). Ask your healthcare provider if you are not sure. have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes. drink alcohol or take medicines that contain alcohol. are pregnant or plan to become pregnant. It is not known if TRIZIVIR will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. Pregnancy Registry. 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. are breastfeeding or plan to breastfeed. Do not breastfeed if you take TRIZIVIR. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. Some medicines interact with TRIZIVIR. Keep a list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for a list of medicines that interact with TRIZIVIR. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TRIZIVIR with other medicines. You should not take TRIZIVIR if you also take: abacavir (EPZICOM, TRIUMEQ, or ZIAGEN) lamivudine (COMBIVIR&reg;, DUTREBIS&trade;, EPIVIR&reg;, EPIVIR-HBV&reg;, EPZICOM, or TRIUMEQ) zidovudine (COMBIVIR or RETROVIR) emtricitabine (EMTRIVA&reg;, ATRIPLA&reg;, COMPLERA&reg;, STRIBILD&reg;, or TRUVADA&reg;) Tell your healthcare provider if you take: any other medicine to treat HIV-1 ADRIAMYCIN&reg; (doxorubicin) CYTOVENE&reg; (ganciclovir), interferon alfa, ribavirin, or other bone marrow suppressive medicines or cytotoxic medicines methadone How should I take TRIZIVIR? Take TRIZIVIR exactly as your healthcare provider tells you. Do not change your dose or stop taking TRIZIVIR without talking with your healthcare provider. If you miss a dose of TRIZIVIR, 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. Stay under the care of a healthcare provider while taking TRIZIVIR. TRIZIVIR may be taken with or without food. Tell your healthcare provider if you or your child has trouble swallowing TRIZIVIR tablets. Do not run out of TRZIVIR. 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. If you take too much TRIZIVIR, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of TRIZIVIR? TRIZIVIR can cause serious side effects including: See &ldquo;What is the most important information I should know about TRIZIVIR?&rdquo; Changes in your immune system (Immune Reconstitution Syndrome) 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 TRIZIVIR. Changes in body fat can happen in people who take HIV-1 medicines. These changes may include an increased amount of fat in the upper back and neck (&ldquo;buffalo hump&rdquo;), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known. Heart attack (myocardial infarction). Some HIV-1 medicines including TRIZIVIR may increase your risk of heart attack. The most common side effects of TRIZIVIR include: nausea headache weakness or tiredness vomiting Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of TRIZIVIR. 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. How should I store TRIZIVIR? Store TRIZIVIR at 59&deg;F to 86&deg;F (15&deg;C to 30&deg;C). Keep TRIZIVIR and all medicines out of the reach of children. General information for safe and effective use of TRIZIVIR. 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. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for the information about TRIZIVIR that is written for health professionals. For more information go to www.TRIZIVIR.com or call 1-877-844-8872. What are the ingredients in TRIZIVIR? Active ingredients: abacavir, lamivudine, and zidovudine Inactive ingredients: magnesium stearate, microcrystalline cellulose, sodium starch glycolate Tablet film coating contains: OPADRY&reg; green 03B11434 made of FD&C Blue No. 2, hypromellose, polyethylene glycol, titanium dioxide, and yellow iron oxide.62017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirFDA
622017-12-04 17:37:48Trizivir Patient Information Including Side EffectsFind Lowest Prices on Brand Names: Trizivir Generic Name: abacavir, lamivudine, and zidovudine (Pronunciation: a BACK a veer, la MIV yoo deen, zye DOE vyoo deen) What is abacavir, lamivudine, and zidovudine (Trizivir) (Trizivir)? What are the possible side effects of this medication (Trizivir)? What is the most important information I should know about abacavir, lamivudine, and zidovudine (Trizivir) (Trizivir)? What should I discuss with my healthcare provider before taking this medication (Trizivir)? How should I take this medication (Trizivir)? What happens if I miss a dose (Trizivir)? What happens if I overdose (Trizivir)? What should I avoid while taking this medication (Trizivir)? What other drugs will affect this medication (Trizivir)? Where can I get more information? What is abacavir, lamivudine, and zidovudine (Trizivir) (Trizivir)? Abacavir, lamivudine, and zidovudine are antiviral medications that prevent human immunodeficiency virus (HIV) cells from multiplying in your body.The combination of abacavir, lamivudine, and zidovudine is used to treat HIV, which causes the acquired immunodeficiency syndrome (AIDS). This medication is not a cure for HIV or AIDS.Abacavir, lamivudine, and zidovudine may also be used for purposes not listed in this medication guide. What are the possible side effects of this medication (Trizivir)? Stop using Trizivir and call your doctor at once if you have symptoms of an allergic reaction from two or more of these specific side effect groups:Group 1 - fever;Group 2 - rash;Group 3 - nausea, vomiting, diarrhea, stomach pain;Group 4 - general ill feeling, extreme tiredness, body aches;Group 5 - shortness of breath, cough, sore throat.Once you have had an allergic reaction to this medication, you must never use it again. If you stop taking Trizivir for any reason, talk to your doctor before you start taking it again.Trizivir may cause lactic acidosis (a build-up of lactic acid in the body, which can be fatal). Lactic acidosis can start slowly and get worse over time. Get emergency medical help if you have even mild symptoms of lactic acidosis, such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.Trizivir can cause other serious side effects that may not be signs of an allergic reaction. Call your doctor at once if you have:the first sign of any skin rash, no matter how mild;signs of a new infection such as flu symptoms, easy bruising or unusual bleeding, loss of appetite, mouth sores;severe pain in your upper stomach spreading to your back;pale skin, feeling light-headed, rapid heart rate, trouble concentrating;itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);increased sweating, tremors in your hands, anxiety, feeling irritable, sleep problems (insomnia);diarrhea, unexplained weight loss, menstrual changes, impotence, loss of interest in sex;swelling in your neck or throat (goiter);problems with walking, breathing, speech, swallowing, or eye movement;severe lower back pain, loss of bladder or bowel control; orchest pain or heavy feeling, pain spreading to the arm or shoulder.Less serious side effects may include:headache, joint pain, depression, nervousness;cold symptoms such as stuffy nose, sneezing, sinus pain;mild nausea or diarrhea; orchanges in the shape or location of body fat (especially in your arms, legs, face, neck, breasts, and trunk);This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What is the most important information I should know about abacavir, lamivudine, and zidovudine (Trizivir) (Trizivir)? Stop using this medication and call your doctor at once if you have any of these signs of an allergic reaction: fever; rash; nausea, vomiting, diarrhea, stomach pain; general ill feeling, extreme tiredness, body aches; shortness of breath, cough, sore throat.Once you have had an allergic reaction to this medication, you must never use it again.Some people develop lactic acidosis while taking Trizivir. Early symptoms may get worse over time and this condition can be fatal. Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired.This medication can also cause severe or life-threatening effects on your liver. Call your doctor at once if you have any of these symptoms while taking Trizivir: pain in your upper stomach, itching, loss of appetite, dark urine, clay-colored stools, or jaundice (yellowing of the skin or eyes).If you have hepatitis B you may develop liver symptoms after you stop taking Trizivir, even months after stopping. Your doctor may want to check your liver function for several months after you stop using the medication. Visit your doctor regularly.Do not allow your medicine to run out completely before you get your prescription refilled. It is important that you not stop taking Trizivir once you have started. If you miss several doses, you may have a dangerous or even fatal allergic reaction once you start taking the medication again. If you stop taking Trizivir for any reason, talk to your doctor before you start taking it again.72017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirMultum
632017-12-04 17:37:48Trizivir Patient Information including How Should I TakeWhat should I discuss with my healthcare provider before taking this medication (Trizivir)? Do not take this medication if you have ever had an allergic reaction to Trizivir or any medicine that contains abacavir, lamivudine, or zidovudine, including: Combivir, Epivir, Epzicom, Retrovir, or Ziagen. Once you have had an allergic reaction to abacavir, you must never use it again.Some people develop a life-threatening condition called lactic acidosis while taking Trizivir. You may be more likely to develop lactic acidosis if you are overweight or have liver disease, if you are a woman, or if you have taken HIV or AIDS medications for a long time. Talk with your doctor about your individual risk.This medication can also cause severe or life-threatening effects on your liver. You should not take this medication if you have liver disease, especially hepatitis B or C.Do not take Trizivir with any of the following HIV medications: Atripla, Combivir, Complera, Emtriva, Epivir, Epzicom, Retrovir, Truvada, Zerit, or Ziagen.To make sure you can safely take Trizivir, tell your doctor if you have any of these other conditions:bone marrow suppression;kidney disease;heart disease or high blood pressure;a risk factor for heart disease such as smoking, diabetes, or high cholesterol; orif you have used an HIV medication in the past, such as abacavir (Ziagen), didanosine (Videx), emtricitabine (Atripla, Complera, Emtriva, Truvada), lamivudine (Combivir, Epivir, Epzicom), stavudine (Zerit), tenofovir (Viread), zalcitabine (Hivid), or zidovudine (Retrovir).You may need a blood test before you start taking Trizivir for the first time, or if you are restarting the medication after stopping for reasons not related to an allergic reaction.FDA pregnancy category C. It is not known whether this medication will harm an unborn baby. HIV can be passed to your baby if you are not properly treated during pregnancy. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Take all of your HIV medicines as directed to control your infection.Women with HIV or AIDS should not breast-feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.Trizivir should not be used to treat HIV in adolescents weighing less than 90 pounds. How should I take this medication (Trizivir)? Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.You may take Trizivir with or without food.Trizivir comes with a Medication Guide and a Warning Card that lists the symptoms of an allergic reaction. Read this information carefully and carry the Warning Card with you at all times so you will know what symptoms to watch for.Use this medication regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.HIV/AIDS is usually treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice. Every person with HIV or AIDS should remain under the care of a doctor.While using Trizivir, you may need blood tests at your doctor's office. If you have hepatitis B you may develop liver symptoms after you stop taking this medication, even months after stopping. Your doctor may want to check your liver function for several months after you stop using the medication. Visit your doctor regularly.Store at room temperature away from moisture and heat.72017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirMultum
642017-12-04 17:37:48Trizivir Patient Information including If I Miss a Dose72017-09-01 11:12:57Abacavir Sulfate, Lamivudine, and ZidovudineTrizivirMultum
652017-12-04 17:37:54Drug DescriptionFind Lowest Prices on TRIUMEQ&reg; (abacavir, dolutegravir, and lamivudine) Tablet WARNING HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS B Hypersensitivity Reactions 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 PRECAUTIONS]. TRIUMEQ is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. 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 CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS]. 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 PRECAUTIONS]. Lactic Acidosis and Severe Hepatomegaly with Steatosis 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 PRECAUTIONS]. Exacerbations of Hepatitis 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 PRECAUTIONS]. DESCRIPTION TRIUMEQ TRIUMEQ contains an INSTI (dolutegravir) and 2 nucleoside analogues (abacavir and lamivudine) with inhibitory activity against HIV. 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 &ldquo;572 Tr1&rdquo; on one side and contain the inactive ingredients D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. The tablet film-coating (OPADRY&reg; II Purple 85F90057) contains the inactive ingredients iron oxide black, iron oxide red, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium oxide. Abacavir Sulfate 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 (C14H18N6O)2&bull;H2SO4 and a molecular weight of 670.76 g per mol. It has the following structural formula: Abacavir sulfate is a white to off-white solid and is soluble in water. Dolutegravir 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 C20H18F2N3NaO5 and the molecular weight is 441.36 g per mol. It has the following structural formula: Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water. Lamivudine 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 C8H11N3O3S and a molecular weight of 229.3 g per mol. It has the following structural formula: Lamivudine is a white to off-white crystalline solid and is soluble in water.82017-09-01 11:12:57Abacavir, Dolutegravir, and Lamivudine Film-coated TabletsTriumeqFDA
662017-12-04 17:37:54Indications & DosageINDICATIONS TRIUMEQ is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Limitations Of Use TRIUMEQ alone is not recommended for use in patients with current or past history of resistance to any components of TRIUMEQ [see Microbiology]. TRIUMEQ alone is not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of dolutegravir in TRIUMEQ is insufficient in these subpopulations. See full prescribing information for dolutegravir. DOSAGE AND ADMINISTRATION Screening For HLA-B*5701 Allele Prior To Starting TRIUMEQ Screen for the HLA-B*5701 allele prior to initiating therapy with TRIUMEQ [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Recommended Dosage 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. Dosage Recommendation With Certain Concomitant Medications The dolutegravir dose (50 mg) in TRIUMEQ is insufficient when coadministered with medications listed in Table 1 that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended. Table 1: Dosing Recommendations for TRIUMEQ with Coadministered Medications Coadministered Drug Dosing Recommendation Efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin The recommended dolutegravir dosage regimen is 50 mg twice daily. An additional dolutegravir 50-mg tablet, separated by 12 hours from TRIUMEQ, should be taken. Not Recommended Due To Lack Of Dosage Adjustment Because TRIUMEQ is a fixed-dose tablet and cannot be dose adjusted, TRIUMEQ is not recommended in: patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations]. patients with mild hepatic impairment. TRIUMEQ is contraindicated in patients with moderate or severe hepatic impairment [see CONTRAINDICATIONS, Use in Specific Populations]. HOW SUPPLIED Dosage Forms And Strengths TRIUMEQ tablets are purple, biconvex, oval, and debossed with &ldquo;572 Tr1&rdquo; on one side. 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 [see DESCRIPTION]. Storage And Handling TRIUMEQ tablets, 600 mg of abacavir as abacavir sulfate, 50 mg of dolutegravir as dolutegravir sodium, and 300 mg lamivudine, are purple, oval, film-coated, biconvex tablets debossed with &ldquo;572 Tr1&rdquo; on one side. Bottle of 30 with child-resistant closure NDC 49702-231-13. Store and dispense in the original package, protect from moisture, and keep the bottle tightly closed. Do not remove desiccant. Store at 25&deg;C (77&deg;F); excursions permitted 15&deg; to 30&deg;C (59&deg; to 86&deg;F). [See USP Controlled Room Temperature]. Manufactured for: ViiV Healthcare Research Triangle Park, NC 27709. by: GlaxoSmithKline Research Triangle Park, NC 27709 Lamivudine is manufactured under agreement from Shire Pharmaceuticals Group plc, Basingstoke, UK Revised: Mar 201782017-09-01 11:12:57Abacavir, Dolutegravir, and Lamivudine Film-coated TabletsTriumeqFDA
672017-12-04 17:37:54Side Effects & Drug InteractionsSIDE EFFECTS The following adverse reactions are discussed in other sections of the labeling: Serious and sometimes fatal hypersensitivity reaction [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Effects on serum liver biochemistries in patients with hepatitis B or C co-infection [see WARNINGS AND PRECAUTIONS]. Exacerbations of hepatitis B [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see WARNINGS AND PRECAUTIONS]. Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS]. Fat redistribution [see WARNINGS AND PRECAUTIONS]. Myocardial infarction [see WARNINGS AND PRECAUTIONS]. Clinical Trials Experience 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. Serious And Fatal Abacavir-Associated Hypersensitivity Reactions In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIUMEQ [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. 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. 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). Serious Dolutegravir Hypersensitivity Reactions In clinical trials, hypersensitivity reactions have occurred with dolutegravir, a component of TRIUMEQ [see WARNINGS AND PRECAUTIONS]. These hypersensitivity reactions have been characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. Additional Treatment-Emergent Adverse Drug Reactions (ADRs) With Use Of TRIUMEQ The safety assessment of TRIUMEQ is primarily based on the analyses of data from a randomized, international, multicenter, double-blind, active-controlled trial, SINGLE (ING114467) and supported by data in treatment-experienced, INSTI-naïve subjects from SAILING (ING111762) and by data from other treatment-naïve trials. See full prescribing information for TIVICAY. Treatment-Naïve Subjects: In SINGLE, 833 adult subjects were randomized and received at least one dose of either dolutegravir (TIVICAY) 50 mg with fixed-dose abacavir and lamivudine (EPZICOM&reg;) once daily (n = 414) or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA&reg;) once daily (n = 419) (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, the rate of adverse events leading to discontinuation was 4% in subjects receiving TIVICAY + EPZICOM and 14% in subjects receiving ATRIPLA once daily. Treatment-emergent ADRs of moderate to severe intensity observed in at least 2% of subjects in either treatment arm of SINGLE are provided in Table 2. Table 2: Treatment-Emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in Treatment-Naïve Subjects in SINGLE (Week 144 Analysis) Adverse Reaction TIVICAY + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) Psychiatric Insomnia 3% 3% Depression 1% 2% Abnormal dreams < 1% 2% Nervous System Dizziness < 1% 5% Headache 2% 2% Gastrointestinal Nausea < 1% 3% Diarrhea < 1% 2% General Disorders Fatigue 2% 2% Skin and Subcutaneous Tissue Rasha < 1% 6% Ear and Labyrinth Vertigo 0 2% a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption. Treatment-Experienced Subjects: SAILING is an international, double-blind trial in INSTI-naïve, antiretroviral treatment-experienced adult subjects. Subjects were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rate of adverse events leading to discontinuation was consistent with that seen in the overall treatment-naïve patient population. See full prescribing information for TIVICAY. The ADRs observed in the subset of subjects who received TIVICAY + EPZICOM were generally consistent with those seen in the overall treatment-naïve patient population. Less Common Adverse Reactions Observed In Clinical Trials The following adverse reactions occurred in less than 2% of treatment-naïve or treatment-experienced subjects in any one trial. These events have been included because of their seriousness and/or assessment of potential causal relationship. Gastrointestinal Disorders: Abdominal pain, abdominal distention, abdominal discomfort, dyspepsia, flatulence, gastroesophageal reflux disease, upper abdominal pain, vomiting. General Disorders: Fever, lethargy. Hepatobiliary Disorders: Hepatitis. Metabolism and Nutrition Disorders: Anorexia, hypertriglyceridemia. Musculoskeletal Disorders: Arthralgia, myositis. Nervous: Somnolence. Psychiatric: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Nightmare and sleep disorder. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities Treatment-Naïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects in SINGLE are presented in Table 3. The mean change from baseline observed for selected lipid values is presented in Table 4. Table 3: Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Naïve Subjects in SINGLE (Week 144 Analysis) Laboratory Abnormality TIVICAY + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) ALT Grade 2 ( > 2.5-5.0 x ULN) 3% 5% Grade 3 to 4 ( > 5.0 x ULN) 1% < 1% AST Grade 2 ( > 2.5-5.0 x ULN) 3% 4% Grade 3 to 4 ( > 5.0 x ULN) 1% 3% Creatine kinase Grade 2 (6.0-9.9 x ULN) 5% 3% Grade 3 to 4 ( &ge; 10.0 x ULN) 7% 8% Hyperglycemia Grade 2 (126-250 mg/dL) 9% 6% Grade 3 ( > 250 mg/dL) 2% < 1% Lipase Grade 2 ( > 15-3.0 x ULN) 11% 11% Grade 3 to 4 ( > 3.0 ULN) 5% 4% Total neutrophils Grade 2 (0.75-0.99 x 109) 4% 5% Grade 3 to 4 ( < 0.75 x 109) 3% 3% ULN = Upper limit of normal. Table 4: Mean Change from Baseline in Fasted Lipid Values in Treatment-Naïve Subjects in SINGLE (Week 144 Analysisa) Lipid TIVICAY + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) Cholesterol (mg/dL) 24.0 26.7 HDL cholesterol (mg/dL) 5.4 7.2 LDL cholesterol (mg/dL) 16.0 14.6 Triglycerides (mg/dL) 13.6 31.9 a Subjects on lipid-lowering agents at baseline were excluded from these analyses (TIVICAY + EPZICOM n = 30 and ATRIPLA n = 27). Seventy-two subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless if they discontinued the agent (TIVICAY + EPZICOM n = 36 and ATRIPLA: n = 36). Treatment-Experienced Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naïve trials. Hepatitis C Virus Co-infection In SINGLE, the pivotal Phase 3 trial, subjects with hepatitis C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal; subjects with hepatitis B co-infection were excluded. Overall, the safety profile in subjects with hepatitis C virus co-infection was similar to that observed in subjects without hepatitis C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis C virus co-infection for both treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis C co-infected compared with HIV mono-infected subjects receiving TRIUMEQ were observed in 15% and 2% (vs. 24% and 4% of subjects treated with ATRIPLA) (Week 96 analysis), respectively [see WARNINGS AND PRECAUTIONS]. See also full prescribing information for TIVICAY. Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see CLINICAL PHARMACOLOGY]. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 144 weeks. In SINGLE, a mean change from baseline of 0.14 mg per dL (range: -0.25 mg per dL to 0.81 mg per dL) was observed after 144 weeks of treatment. Creatinine increases were similar in treatment-experienced subjects. Abacavir And Lamivudine Laboratory abnormalities observed in clinical trials of ZIAGEN (in combination with other antiretroviral treatment) were anemia, neutropenia, liver function test abnormalities, and elevations of CPK, blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR (in combination with other antiretroviral treatment) were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase. Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use with one or more of the components of TRIUMEQ. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Digestive Stomatitis. Gastrointestinal Pancreatitis. General Weakness. Blood and Lymphatic Systems Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly. Hypersensitivity Sensitization reactions (including anaphylaxis), urticaria [see WARNINGS AND PRECAUTIONS, Clinical Trials Experience]. Metabolism and Nutrition Disorders Hyperlactemia. Musculoskeletal CPK elevation, muscle weakness, myalgia, rhabdomyolysis. Nervous Paresthesia, peripheral neuropathy, seizures. Respiratory Abnormal breath sounds/wheezing. Skin Alopecia, erythema multiforme. 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 [see Clinical Trials Experience]. DRUG INTERACTIONS Effect Of Dolutegravir On The Pharmacokinetics Of Other Agents In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC50 = 1.93 microM) and multidrug and toxin extrusion transporter (MATE) 1 (IC50 = 6.34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin) [see CONTRAINDICATIONS, Established and Other Potentially Significant Drug Interactions]. In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 microM) and OAT3 (IC50 = 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3. In vitro, dolutegravir did not inhibit (IC50 greater than 50 microM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, or multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters. In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs: daclatasvir, tenofovir, methadone, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol. Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, and boceprevir. Effect Of Other Agents On The Pharmacokinetics Of Dolutegravir Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations. Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir (Table 5) [see Established and Other Potentially Significant Drug Interactions, CLINICAL PHARMACOLOGY]. In vitro, dolutegravir was not a substrate of OATP1B1, or OATP1B3. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, daclatasvir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir. Established And Other Potentially Significant Drug Interactions There were no drug-drug interaction trials conducted with the abacavir, dolutegravir, and lamivudine fixed-dose combination tablets. Information regarding potential drug interactions with dolutegravir (Table 5) and abacavir are provided below. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. [See CLINICAL PHARMACOLOGY] Table 5: Established and Other Potentially Significant Drug Interactions for Dolutegravir: Alterations in Dose May Be Recommended Based on Drug Interaction Trials or Predicted Interactions Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment HIV-1 Antiviral Agents Non-nucleoside reverse transcriptase inhibitor: Etravirinea &darr;Dolutegravir Use of TRIUMEQ with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended. Non-nucleoside reverse transcriptase inhibitor: Efavirenza &darr;Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from TRIUMEQ. Non-nucleoside reverse transcriptase inhibitor: Nevirapine &darr;Dolutegravir Avoid coadministration with TRIUMEQ because there are insufficient data to make dosing recommendations. Protease inhibitor: Fosamprenavir/ritonavira Tipranavir/ritonavira &darr;Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from TRIUMEQ. Other Agents Carbamazepinea ^Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from TRIUMEQ. Oxcarbazepine Phenytoin Phenobarbital St. John&rsquo;s wort (Hypericum perforatum) &darr;Dolutegravir Avoid coadministration with TRIUMEQ because there are insufficient data to make dosing recommendations. Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacidsa or laxatives Sucralfate Buffered medications &darr;Dolutegravir Administer TRIUMEQ 2 hours before or 6 hours after taking medications containing polyvalent cations. Oral calcium and iron supplements, including multivitamins containing calcium or irona &darr;Dolutegravir Administer TRIUMEQ 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, TRIUMEQ and supplements containing calcium or iron can be taken together with food. Metformina &uarr;Metformin With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TRIUMEQ. When stopping TRIUMEQ, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of TRIUMEQ is recommended. Rifampina &darr;Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from TRIUMEQ. a See CLINICAL PHARMACOLOGY  Table 8 or Table 9 for magnitude of interaction. Methadone Abacavir: In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased [see CLINICAL PHARMACOLOGY]. 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.82017-09-01 11:12:57Abacavir, Dolutegravir, and Lamivudine Film-coated TabletsTriumeqFDA
682017-12-04 17:37:54Warnings & PrecautionsWARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions have been reported with the use of abacavir or dolutegravir, components of TRIUMEQ. Abacavir Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir containing regimens. See full prescribing information for ZIAGEN&reg; (abacavir). Abacavir 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 ADVERSE REACTIONS]. 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. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir: 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. TRIUMEQ is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. Before starting TRIUMEQ, review medical history for prior exposure to any abacavircontaining product. NEVER restart TRIUMEQ or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA-B*5701 status. To reduce the risk of a life-threatening hypersensitivity reaction, regardless of HLA-B*5701 status, discontinue TRIUMEQ 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). Clinical status, including liver chemistries, should be monitored and appropriate therapy initiated. If a hypersensitivity reaction cannot be ruled out, do not restart TRIUMEQ or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours. Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or any other abacavir-or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ due to a hypersensitivity reaction. If a hypersensitivity reaction is ruled out, patients may restart TRIUMEQ. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of TRIUMEQ, or any other abacavir-containing product, is recommended only if medical care can be readily accessed. A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill. Dolutegravir Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving TIVICAY&reg; in Phase 3 clinical trials. Discontinue TRIUMEQ and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with TRIUMEQ or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or any other abacavir-or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ due to a hypersensitivity reaction. Lactic Acidosis And Severe Hepatomegaly With Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues and other antiretrovirals. See full prescribing information for ZIAGEN (abacavir) and EPIVIR&reg; (lamivudine). Treatment with TRIUMEQ 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). Patients With Hepatitis B Or C Virus Co-infection Effects On Serum Liver Biochemistries Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TRIUMEQ [see ADVERSE REACTIONS]. See full prescribing information for TIVICAY&reg; (dolutegravir). In some cases the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with TRIUMEQ are recommended in patients with underlying hepatic disease such as hepatitis B or C. Posttreatment Exacerbations Of Hepatitis 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. Emergence Of Lamivudine-Resistant HBV 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-HBV&reg; (lamivudine). Use With Interferon-And Ribavirin-Based Regimens Patients receiving interferon alfa with or without ribavirin and TRIUMEQ should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. See full prescribing information for EPIVIR (lamivudine). Discontinuation of TRIUMEQ 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). Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRIUMEQ. 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, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-BarrÃ&copy; 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. Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and &ldquo;cushingoid appearance&rdquo; have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Myocardial Infarction In a published prospective, observational, epidemiological trial designed to investigate the rate of myocardial infarction (MI) in patients on combination antiretroviral therapy, the use of abacavir within the previous 6 months was correlated with an increased risk of MI. In a sponsor-conducted pooled analysis of clinical trials, no excess risk of MI was observed in abacavir-treated subjects as compared with control subjects. In totality, the available data from the observational cohort and from clinical trials are inconclusive. 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). Related Products That Are Not Recommended TRIUMEQ contains fixed doses of an INSTI (dolutegravir) and 2 nucleoside analogue reverse transcriptase inhibitors (abacavir and lamivudine); concomitant administration of TRIUMEQ with other products containing abacavir or lamivudine is not recommended. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide). Drug Interactions Do not coadminister TRIUMEQ with dofetilide (TIKOSYN&reg;) because the interaction between dofetilide and dolutegravir can result in potentially life-threatening adverse events [see CONTRAINDICATIONS]. Patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products. Hypersensitivity Reaction Inform patients: that a Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of TRIUMEQ, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about TRIUMEQ. The complete text of the Medication Guide is reprinted at the end of this document. to carry the Warning Card with them. how to identify a hypersensitivity reaction [see WARNINGS AND PRECAUTIONS, Medication Guide]. that if they develop symptoms consistent with a hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking TRIUMEQ. that a hypersensitivity reaction can worsen and lead to hospitalization or death if TRIUMEQ is not immediately discontinued. to not restart TRIUMEQ 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. that if they have a hypersensitivity reaction, they should dispose of any unused TRIUMEQ to avoid restarting abacavir. that a hypersensitivity reaction is usually reversible if it is detected promptly and TRIUMEQ is stopped right away. that if they have interrupted TRIUMEQ 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. to not restart TRIUMEQ or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others. to not restart TRIUMEQ or any other dolutegravir-containing product following a hypersensitivity reaction to TRIUMEQ. Related Products That Are Not Recommended Inform patients that they should not take TRIUMEQ with ATRIPLA, COMBIVIR&reg; , COMPLERA&reg;, DUTREBIS&trade;, EMTRIVA&reg;, EPIVIR, EPIVIR-HBV, EPZICOM, STRIBILD&reg; , TRIZIVIR, TRUVADA&reg;, or ZIAGEN. Lactic Acidosis/Hepatomegaly Inform patients that some HIV medicines, including TRIUMEQ, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Patients With Hepatitis B Or C Co-infection Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TRIUMEQ and advise patients to have laboratory testing before and during therapy [see WARNINGS AND PRECAUTIONS]. 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 WARNINGS AND PRECAUTIONS]. 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 WARNINGS AND PRECAUTIONS]. Immune Reconstitution Syndrome In some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see WARNINGS AND PRECAUTIONS]. Redistribution/Accumulation Of Body Fat Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see WARNINGS AND PRECAUTIONS]. Information About HIV-1 Infection TRIUMEQ is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients must remain on continuous HIV therapy to control HIV-1infection and decrease HIV-related illness. Inform patients that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Advise patients to remain under the care of a physician when using TRIUMEQ. Advise patients to take all HIV medications exactly as prescribed. Advise patients to avoid doing things that can spread HIV-1 infection to others. Advise patients not to re-use or share needles or other injection equipment. Advise patients not to share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. Advise patients to always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. Female patients should be advised not to breastfeed because it is not known if TRIUMEQ can be passed to your baby in your breast milk and whether it could harm your baby. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. Instruct patients to read the Medication Guide before starting TRIUMEQ and to reread 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. Instruct patients that if they miss a dose, they should take it as soon as they remember. If they do not remember until it is within 4 hours of the time for the next dose, they should be instructed to skip the missed dose and go back to the regular schedule. Patients should not double their next dose or take more than the prescribed dose. Instruct patients to store TRIUMEQ in the original package, protect from moisture, and keep the bottle tightly closed. Do not remove desiccant. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenicity Dolutegravir: Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg, and rats were administered doses of up to 50 mg per kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 26-fold higher than those in humans at the recommended dose of 50 mg once daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 17-fold and 30-fold higher in males and females, respectively, than those in humans at the recommended dose of 50 mg once daily. Abacavir: Abacavir was administered orally at 3 dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of 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 7 to 28 times the human exposure at the recommended dose of 600 mg. Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 12 times (mice) and 57 times (rats) the human exposures at the recommended dose of 300 mg. Mutagenicity Dolutegravir: Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay. Abacavir: 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. Lamivudine: 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. Impairment Of Fertility Dolutegravir, abacavir, or lamivudine did not affect male or female fertility in rats at doses associated with exposures approximately 44, 9, or 112 times (respectively) higher than the exposures in humans at the doses of 50 mg, 600 mg, and 300 mg (respectively). Use In Specific Populations Pregnancy Pregnancy Category C. There are no adequate and well-controlled trials in pregnant women. Reproduction studies with the components of TRIUMEQ have been performed in animals (see Dolutegravir, Abacavir, and Lamivudine sections below). Animal reproduction studies are not always predictive of human response. TRIUMEQ should be used during pregnancy only if the potential benefit outweigh the risks. Antiretroviral Pregnancy Registry To monitor maternal-fetal outcomes of pregnant women exposed to TRIUMEQ or other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Animal Data Dolutegravir: Reproduction studies performed in rats and rabbits at doses up to 50 times the human dose of 50 mg once daily have revealed no evidence of impaired fertility or harm to the fetus due to dolutegravir. Oral administration of dolutegravir to pregnant rats at doses up to 1,000 mg per kg daily, approximately 50 times the 50-mg once-daily human clinical exposure based on AUC, from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity, or teratogenicity. Oral administration of dolutegravir to pregnant rabbits at doses up to 1,000 mg per kg daily, approximately 0.74 times the 50-mg once-daily human clinical exposure based on AUC, from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity. In rabbits, maternal toxicity (decreased food consumption, scant/no feces/urine, suppressed body weight gain) was observed at 1,000 mg per kg. Abacavir: Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) and developmental toxicity (depressed fetal body weight and reduced crown-rump length) were observed in rats at a dose which produced 28 times the human exposure for a dose of 600 mg based on AUC. Embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) and toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at half of the above-mentioned dose in separate fertility studies conducted in rats. In the rabbit, no developmental toxicity and no increases in fetal malformations occurred at doses that produced 7 times the human exposure at the recommended dose based on AUC. Lamivudine: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 32 times the human exposure for a dose of 300 mg. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at plasma levels up to 32 times those in humans. Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, instruct mothers not to breastfeed. Dolutegravir Studies in lactating rats and their offspring indicate that dolutegravir was present in rat milk. It is not known whether dolutegravir is excreted in human breast milk. Abacavir Abacavir is excreted in the milk of lactating rats. Lamivudine Lamivudine is excreted in human breast milk. Pediatric Use Safety and effectiveness of TRIUMEQ in pediatric patients have not been established [see CLINICAL PHARMACOLOGY]. Geriatric Use Clinical trials of abacavir, dolutegravir, or lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TRIUMEQ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see CLINICAL PHARMACOLOGY]. Patients With Impaired Renal Function TRIUMEQ is not recommended for patients with creatinine clearance less than 50 mL per min because TRIUMEQ is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of TRIUMEQ, is required for patients with creatinine clearance less than 50 mL per min, then the individual components should be used [see CLINICAL PHARMACOLOGY]. Patients With Impaired Hepatic Function TRIUMEQ is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of TRIUMEQ, is required for patients with mild hepatic impairment (Child-Pugh Score A), then the individual components should be used [see CLINICAL PHARMACOLOGY]. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Score B) or severe (Child-Pugh Score C) hepatic impairment; therefore, TRIUMEQ is contraindicated in these patients [see CONTRAINDICATIONS].82017-09-01 11:12:57Abacavir, Dolutegravir, and Lamivudine Film-coated TabletsTriumeqFDA
692017-12-04 17:37:54Overdosage & Contraindications82017-09-01 11:12:57Abacavir, Dolutegravir, and Lamivudine Film-coated TabletsTriumeqFDA
702017-12-04 17:37:54Clinical PharmacologyCLINICAL PHARMACOLOGY Mechanism Of Action TRIUMEQ is an HIV-1 antiviral agent [see Microbiology]. Pharmacodynamics Effects On Electrocardiogram A thorough QT trial has been conducted for dolutegravir. Neither the effects of abacavir nor lamivudine as single entities or the combination of abacavir, dolutegravir, and lamivudine on the QT interval have been evaluated. In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3- fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours postdose. Effects On Renal Function The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo. Pharmacokinetics Pharmacokinetics In Adults One TRIUMEQ tablet was bioequivalent to one dolutegravir (TIVICAY) tablet (50 mg) plus one abacavir and lamivudine fixed-dose combination tablet (EPZICOM) under fasted conditions in healthy subjects (n = 62). Abacavir: 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 &plusmn; 1.19 mcg per mL (mean &plusmn; SD) and AUC&infin; was 11.95 &plusmn; 2.51 mcg&bull;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. In single-dose trials, the observed elimination half-life (t&frac12;) was 1.54 &plusmn; 0.63 hours. After intravenous administration, total clearance was 0.80 &plusmn; 0.24 L per hour per kg (mean &plusmn; SD). Dolutegravir: Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, Cmax, and C24 h ranging from 1.2 to 1.5. Dolutegravir is a P-glycoprotein substrate in vitro. The absolute bioavailability of dolutegravir has not been established. Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis. Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After a single oral dose of [14C] dolutegravir, 53% of the total oral dose is excreted unchanged in the feces. Thirty-one percent of the total oral dose is excreted in the urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was less than 1% of the dose. Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L per hour based on population pharmacokinetic analyses. The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV-1-infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV-1-infected subjects. Table 6: Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1- Infected Adults Parameter 50 mg Once Daily Geometric Mean (%CV) AUC(0-24) (mcg&bull;h/mL) 53.6 (27) Cmax (mcg/mL) 3.67 (20) Cmin (mcg/mL) 1.11 (46) Cerebrospinal Fluid (CSF): In 11 treatment-naïve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 18 ng per mL (range: 4 ng per mL to 23.2 ng per mL) 2 to 6 hours postdose after 2 weeks of treatment. The clinical relevance of this finding has not been established. Lamivudine: 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 &plusmn; 0.54 mcg per mL (mean &plusmn; SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 &plusmn; 1.83 mcg&bull;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). In most single-dose trials in HIV-1-infected subjects, HBV-infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t&frac12;) ranged from 5 to 7 hours. In HIV-1-infected subjects, total clearance was 398.5 &plusmn; 69.1 mL per min (mean &plusmn; SD). Effect Of Food On Oral Absorption TRIUMEQ may be taken with or without food. Overall, when compared with fasted conditions, administration of TRIUMEQ to healthy adult subjects with a high-fat meal (53% fat, 869 calories) resulted in decreased Cmax for abacavir and increased Cmax and AUC for dolutegravir. Lamivudine exposures were not affected by food. With a high-fat meal, the Cmax of abacavir decreased 23% and the Cmax and AUC of dolutegravir increased 37% and 48%, respectively. Special Populations Renal Impairment: The effect of renal impairment on the combination of abacavir, dolutegravir, and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, dolutegravir and lamivudine components). Hepatic Impairment: The effect of hepatic impairment on the combination of abacavir, dolutegravir, and lamivudine has not been evaluated (see the U.S. prescribing information for the individual abacavir, dolutegravir and lamivudine components). Pediatric Patients: The pharmacokinetics of the combination of abacavir, dolutegravir, and lamivudine in pediatric subjects have not been established. Geriatric Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir. The pharmacokinetics of abacavir or lamivudine have not been studied in subjects older than 65 years. Gender: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components. Race: There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components. Drug Interactions The drug interaction trials described were conducted with dolutegravir, abacavir, and/or lamivudine as single entities; no drug interaction trials have been conducted using the combination of abacavir, dolutegravir, and lamivudine. No clinically significant drug interactions are expected between dolutegravir, abacavir, and lamivudine. Dosing recommendations as a result of established and other potentially significant drug-drug interactions with dolutegravir or abacavir are provided in Section 7.3 [see DRUG INTERACTIONS]. Table 7: Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs Coadministered Drug(s) and Dose(s) Dose of Dolutegravir n Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect = 1.00 Cmax AUC C&tau; or C24 Daclatasvir 60 mg once daily 50 mg once daily 12 1.03 (0.84 to 1.25) 0.98 (0.83 to 1.15) 1.06 (0.88 to 1.29) Ethinyl estradiol 0.035 mg 50 mg twice daily 15 0.99 (0.91 to 1.08) 1.03 (0.96 to 1.11) 1.02 (0.93 to 1.11) Metformin 500 mg twice daily 50 mg once daily 15a 1.66 (1.53 to 1.81) 1.79 (1.65 to 1.93) _ Metformin 500 mg twice daily 50 mg twice daily 15a 2.11 (1.91 to 2.33) 2.45 (2.25 to 2.66) _ Methadone 16 to 150 mg 50 mg twice daily 11 1.00 (0. 94 to 1.06) 0.98 (0.91 to 1.06) 0.99 (0.91 to 1.07) Midazolam 3 mg 25 mg once daily 10 _ 0.95 (0.79 to 1.15) _ Norelgestromin 0.25 mg 50 mg twice daily 15 0.89 (0.82 to 0.97) 0.98 (0.91 to 1.04) 0.93 (0.85 to 1.03) Rilpivirine 25 mg once daily 50 mg once daily 16 1.10 (0.99 to 1.22) 1.06 (0.98 to 1.16) 1.21 (1.07 to 1.38) Tenofovir disoproxil fumarate 300 mg once daily 50 mg once daily 15 1.09 (0.97 to 1.23) 1.12 (1.01 to 1.24) 1.19 (1.04 to 1.35) a The number of subjects represents the maximum number of subjects that were evaluated. Table 8: Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir Coadministered Drug(s) and Dose(s) Dose of Dolutegravir n Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00 Cmax AUC C&tau; or C24 Atazanavir 400 mg once daily 30 mg once daily 12 1.50 (1.40 to 1.59) 1.91 (1.80 to 2.03) 2.80 (2.52 to 3.11) Atazanavir/ritonavir 300/100 mg once daily 30 mg once daily 12 1.34 (1.25 to 1.42) 1.62 (1.50 to 1.74) 2.21 (1.97 to 2.47) Darunavir/ritonavir 600/100 mg twice daily 30 mg once daily 15 0.89 (0.83 to 0.97) 0.78 (0.72 to 0.85) 0.62 (0.56 to 0.69) Efavirenz 600 mg once daily 50 mg once daily 12 0.61 (0.51 to 0.73) 0.43 (0.35 to 0.54) 0.25 (0.18 to 0.34) Etravirine 200 mg twice daily 50 mg once daily 16 0.48 (0.43 to 0.54) 0.29 (0.26 to 0.34) 0.12 (0.09 to 0.16) Etravirine + darunavir/ritonavir 200 mg + 600/100 mg twice daily 50 mg once daily 9 0.88 (0.78 to 1.00) 0.75 (0.69 to 0.81) 0.63 (0.52 to 0.76) Etravirine + lopinavir/ritonavir 200 mg + 400/100 mg twice daily 50 mg once daily 8 1.07 (1.02 to 1.13) 1.11 (1.02 to 1.20) 1.28 (1.13 to 1.45) Fosamprenavir/ritonavir 700 mg /100 mg twice daily 50 mg once daily 12 0.76 (0.63 to 0.92) 0.65 (0.54 to 0.78) 0.51 (0.41 to 0.63) Lopinavir/ritonavir 400/100 mg twice daily 30 mg once daily 15 1.00 (0.94 to 1.07) 0.97 (0.91 to 1.04) 0.94 (0.85 to 1.05) Rilpivirine 25 mg once daily 50 mg once daily 16 1.13 (1.06 to 1.21) 1.12 (1.05 to 1.19) 1.22 (1.15 to 1.30) Tenofovir 300 mg once daily 50 mg once daily 15 0.97 (0.87 to 1.08) 1.01 (0.91 to 1.11) 0.92 (0.82 to 1.04) Tipranavir/ritonavir 500/200 mg twice daily 50 mg once daily 14 0.54 (0.50 to 0.57) 0.41 (0.38 to 0.44) 0.24 (0.21 to 0.27) Antacid (Maalox&reg;) simultaneous administration 50 mg single dose 16 0.28 (0.23 to 0.33) 0.26 (0.22 to 0.32) 0.26 (0.21 to 0.31) Antacid (Maalox&reg;) 2 h after dolutegravir 50 mg single dose 16 0.82 (0.69 to 0.98) 0.74 (0.62 to 0.90) 0.70 (0.58 to 0.85) Boceprevir 800 mg every 8 h 50 mg once daily 13 1.05 (0.96 to 1.15) 1.07 (0.95 to 1.20) 1.08 (0.91 to 1.28) Calcium carbonate 1,200 mg simultaneous administration (fasted) 50 mg single dose 12 0.63 (0.50 to 0.81) 0.61 (0.47 to 0.80) 0.61 (0.47 to 0.80) Calcium carbonate 1,200 mg simultaneous administration (fed) 50 mg single dose 11 1.07 (0.83 to 1.38) 1.09 (0.84 to 1.43) 1.08 (0.81 to 1.42) Calcium carbonate 1,200 mg 2 h after dolutegravir 50 mg single dose 11 1.00 (0.78 to 1.29) 0.94 (0.72 to 1.23) 0.90 (0.68 to 1.19) Carbamazepine 300 mg twice daily 50 mg once daily 16c 0.67 (0.61 to 0.73) 0.51 (0.48 to 0.55) 0.27 (0.24 to 0.31) Daclatasvir 60 mg once daily 50 mg once daily 12 1.29 (1.07 to 1.57) 1.33 (1.11 to 1.59) 1.45 (1.25 to 1.68) Ferrous fumarate 324 mg simultaneous administration (fasted) 50 mg single dose 11 0.43 (0.35 to 0.52) 0.46 (0.38 to 0.56) 0.44 (0.36 to 0.54) Ferrous fumarate 324 mg simultaneous administration (fed) 50 mg single dose 11 1.03 (0.84 to 1.26) 0.98 (0.81 to 1.20) 1.00 (0.81 to 1.23) Ferrous fumarate 324 mg 2 h after dolutegravir 50 mg single dose 10 0.99 (0.81 to 1.21) 0.95 (0.77 to 1.15) 0.92 (0.74 to 1.13) Multivitamin (One-A-Day&reg;) simultaneous administration 50 mg single dose 16 0.65 (0.54 to 0.77) 0.67 (0.55 to 0.81) 0.68 (0.56 to 0.82) Omeprazole 40 mg once daily 50 mg single dose 12 0.92 (0.75 to 1.11) 0.97 (0.78 to 1.20) 0.95 (0.75 to 1.21) Prednisone 60 mg once daily with taper 50 mg once daily 12 1.06 (0.99 to 1.14) 1.11 (1.03 to 1.20) 1.17 (1.06 to 1.28) Rifampina 600 mg once daily 50 mg twice daily 11 0.57 (0.49 to 0.65) 0.46 (0.38 to 0.55) 0.28 (0.23 to 0.34) Rifampinb 600 mg once daily 50 mg twice daily 11 1.18 (1.03 to 1.37) 1.33 (1.15 to 1.53) 1.22 (1.01 to 1.48) Rifabutin 300 mg once daily 50 mg once daily 9 1.16 (0.98 to 1.37) 0.95 (0.82 to 1.10) 0.70 (0.57 to 0.87) a Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. b Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily. c The number of subjects represents the maximum number of subjects that were evaluated. Abacavir or Lamivudine: The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities. Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure. Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects. Methadone: 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 DRUG INTERACTIONS]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. Ribavirin: In vitro data indicate ribavirin reduces phosphorylation 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 WARNINGS AND PRECAUTIONS]. Abacavir, Lamivudine, Zidovudine: 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. Lamivudine and Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours). The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 9. Table 9: Effect of Coadministered Drugs on Abacavir or Lamivudine Coadministered Drug and Dose Drug and Dose n Concentrations of Abacavir or Lamivudine Concentration of Coadministered Drug AUC Variability Ethanol 0.7 g/kg Abacavir Single 600 mg 24 &uarr;41% 90% CI: 35% to 48% &harr;a Nelfinavir 750 mg every 8 h x 7 to 10 days Lamivudine Single 150 mg 11 &uarr;10% 95% CI: 1% to 20% &harr; Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily x 5 days Lamivudine Single 300 mg 14 &uarr;43% 90% CI: 32% to 55% &harr; &uarr; = Increase; &harr; = no significant change; AUC = area under the concentration versus time curve; CI = Confidence interval. a The drug-drug interaction was only evaluated in males. Microbiology Mechanism Of Action Dolutegravir: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified recombinant HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM. Abacavir: 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. Lamivudine: 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. Antiviral Activity In Cell Culture Dolutegravir: Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean concentration of drug necessary to effect viral replication by 50 percent (EC50) values of 0.5 nM (0.21 ng per mL) to 2.1 nM (0.85 ng per mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a median EC50 value of 0.54 nM (range: 0.41 to 0.60 nM) in a viral susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV-1 clinical isolates with median EC50 values of 0.18 nM (n = 3, range: 0.09 to 0.5 nM), 0.08 nM (n = 5, range: 0.05 to 2.14 nM) 0.12 nM (n = 4, range: 0.05 to 0.51 nM), 0.17 nM (n = 3, range: 0.16 to 0.35 nM), 0.24 nM (n = 3, range: 0.09 to 0.32 nM), 0.17 nM (range: 0.07 to 0.44 nM), 0.2 nM (n = 3, range: 0.02 to 0.87 nM), and 0.42 nM (n = 3, range: 0.41 to 1.79 nM) for clades A, B, C, D, E, F, and G, and group O viruses, respectively. Dolutegravir EC50 values against three HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM. Abacavir: The antiviral activity of abacavir against HIV-1 was assessed in a number of cell lines including in primary monocytes/macrophages and 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 &plusmn; 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 viruses (n = 3 except n = 2 for clade B), respectively. The EC50 values against HIV-2 isolates (n = 4), ranged from 0.024 to 0.49 microM. Lamivudine: 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) 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. Antiviral Activity In Combination With Other Antiviral Agents Neither dolutegravir, abacavir, nor lamivudine were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir), TIVICAY (dolutegravir), and EPIVIR (lamivudine). Resistance In Cell Culture Dolutegravir: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold. Abacavir and Lamivudine: HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions K65R, L74V, Y115F, and M184V/I in HIV-1 RT. M184V or I substitutions resulted in high-level resistance to lamivudine and approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, 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. Resistance In Clinical Subjects Dolutegravir: No subjects in the treatment arm receiving dolutegravir + EPZICOM of SINGLE (treatment-naïve trial) had a detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n = 11 with HIV-1 RNA greater than 400 copies per mL at failure or last visit and having resistance data). Two virologic failure subjects in SINGLE had treatment-emergent G/D/E193D and G193G/E integrase substitutions at Week 84 and Week 108, respectively, and 1 subject with 275 copies per mL HIV-1 RNA had a treatment-emergent Q157Q/P integrase substitution detected at Week 24. None of these subjects had a corresponding decrease in dolutegravir susceptibility. No treatment-emergent genotypic resistance to abacavir and lamivudine, components of TRIUMEQ, was observed in the arm receiving dolutegravir + EPZICOM in the SINGLE trial through Week 144. Cross-Resistance Dolutegravir: The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, R or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference). In HIV-2 mutants, combinations of substitutions A153G/N155H/S163G and E92Q/T97A/N155H/S163D conferred 4-fold decreases in dolutegravir susceptibility, and E92Q/N155H and G140S/Q148R showed 8.5-fold and 17-fold decreases in dolutegravir susceptibility, respectively. Abacavir and Lamivudine: Cross-resistance has been observed among NRTIs. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with a K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with thymidine analog mutation (TAM) substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with a progressive reduction in abacavir susceptibility. Animal Toxicology And/Or Pharmacology Myocardial degeneration was found in mice and rats following administration of abacavir for 2 years. The systemic exposures were equivalent to 7 to 21 times the expected systemic exposure in humans at a dose of 600 mg. The clinical relevance of this finding has not been determined. Clinical Studies Adult Subjects The efficacy of TRIUMEQ is supported by data from a randomized, controlled trial (doubleblind through 96 weeks and open-label phase from 96 to 144 weeks) in antiretroviral treatment-naïve subjects, SINGLE (ING114467) and other trials in treatment-naïve subjects. See full prescribing information for TIVICAY. The efficacy of dolutegravir, in combination with at least two active background regimens in treatment-experienced, INSTI-naïve subjects is supported by data from SAILING (ING111762) (refer to the prescribing information for TIVICAY). Treatment-Naïve Subjects In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily with fixed-dose abacavir and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir disoproxil fumarate (ATRIPLA). At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis C co-infection (hepatitis B virus co-infection was excluded), 4% were CDC Class C (AIDS), 32% had HIV-1 RNA greater than 100,000 copies per mL, and 53% had CD4+ cell count less than 350 cells per mm&sup3;; these characteristics were similar between treatment groups. Week 144 (open-label-phase analysis which followed the Week 96 double-blind phase) outcomes for SINGLE are provided in Table 10. Table 10: Virologic Outcomes of Randomized Treatment in SINGLE at 144 Weeks (Snapshot Algorithm) TIVICAY + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) HIV-1 RNA < 50 copies/mL 71% 63% Treatment differencea 8.3% (95% CI: 2.0%, 14.6%)d Virologic nonresponse 10% 7% Data in window not < 50 copies/mL 4% < 1% Discontinued for lack of efficacy 3% 3% Discontinued for other reasons while not suppressed 3% 4% No virologic data 18% 30% Reasons Discontinued study/study drug due to adverse event or deathb 4% 14% Discontinued study/study drug for other reasonsc 12% 13% Missing data during window but on study 2% 3% Proportion (%) of Subjects with HIV-1 RNA < 50 copies/mL by Baseline Category Plasma viral load (copies/mL) &le; 100,000 73% 64% > 100,000 69% 61% Gender Male 72% 66% Female 69% 48% Race White 72% 71% Afri can-Ameri can/ African Heritage/Other 71% 47% a Adjusted for pre-specified stratification factors. b Includes subjects who discontinued due to an adverse event or death at any time point if this resulted in no virologic data on treatment during the analysis window. c Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation. d The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 81% in the ATRIPLA group, with a treatment difference of 7.4% and 95% CI of (2.5%, 12.3%). Treatment differences were maintained across baseline characteristics including baseline viral load, CD4+ cell count, age, gender, and race. The adjusted mean changes in CD4+ cell counts from baseline were 378 cells per mm&sup3; in the group receiving TIVICAY + EPZICOM and 332 cells per mm&sup3; for the ATRIPLA group at 144 weeks. The adjusted difference between treatment arms and 95% CI was 46.9 cells per mm&sup3; (15.6 cells per mm&sup3;, 78.2 cells per mm&sup3;) (adjusted for pre-specified stratification factors: baseline HIV-1 RNA, and baseline CD4+ cell count). Treatment-Experienced In SAILING, there were 715 subjects included in the efficacy and safety analyses (see full prescribing information for TIVICAY). At Week 48, 71% of subjects randomized to TIVICAY plus background regimen versus 64% of subjects randomized to raltegravir plus background regimen had HIV-1 RNA less than 50 copies per mL (treatment difference and 95% CI: 7.4% [0.7%, 14.2%]).82017-09-01 11:12:57Abacavir, Dolutegravir, and Lamivudine Film-coated TabletsTriumeqFDA
712017-12-04 17:37:54Medication GuidePATIENT INFORMATION TRIUMEQ&reg; (TRI-u-meck) (abacavir, dolutegravir, and lamivudine) Tablets What is the most important information I should know about TRIUMEQ? TRIUMEQ can cause serious side effects, including: Serious allergic reactions (hypersensitivity reaction) that can cause death have happened with TRIUMEQ and other abacavir-containing products. Your risk of this allergic reaction to abacavir is much higher if you have a gene variation called HLA-B*5701. Your healthcare provider can determine with a blood test if you have this gene variation. If you get a symptom from 2 or more of the following groups while taking TRIUMEQ, call your healthcare provider right away to find out if you should stop taking TRIUMEQ. Symptom(s) Group 1 Fever Group 2 Rash Group 3 Nausea, vomiting, diarrhea, abdominal (stomach area) pain Group 4 Generally ill feeling, extreme tiredness, or achiness Group 5 Shortness of breath, cough, sore throat A list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card with you at all times. If you stop TRIUMEQ because of an allergic reaction, never take TRIUMEQ (abacavir, dolutegravir and lamivudine) or any other abacavir-or dolutegravir-containing medicines (EPZICOM&reg;, TIVICAY&reg;, TRIZIVIR&reg;, or ZIAGEN&reg;) again. If you have an allergic reaction, dispose of any unused TRIUMEQ. Ask your pharmacist how to properly dispose of medicines. If you take TRIUMEQ 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 low blood pressure or death. If you stop TRIUMEQ for any other reason, even for a few days, and you are not allergic to TRIUMEQ, talk with your healthcare provider before taking it again. Taking TRIUMEQ again can cause a serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before. If your healthcare provider tells you that you can take TRIUMEQ again, start taking it when you are around medical help or people who can call a healthcare provider if you need one. Build-up of acid in your blood (lactic acidosis). Lactic acidosis can happen in some people who take TRIUMEQ. 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: feel very weak or tired feel cold, especially in your arms and legs unusual (not normal) muscle pain feel dizzy or lightheaded trouble breathing have a fast or irregular heartbeat stomach pain with nausea and vomiting Serious liver problems can happen in people who take TRIUMEQ. In some cases, these serious liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems: your skin or the white part of your eyes turns loss of appetite for several days or longer yellow (jaundice) nausea dark or &ldquo;tea-colored&rdquo; urine pain, aching, or tenderness on the right side of your stomach area light colored stools (bowel movements) You may be more likely to get lactic acidosis or serious liver problems if you are female, very overweight (obese), or have been taking nucleoside analogue medicines for a long time. Worsening of hepatitis B virus in people who have HIV-1 infection. If you have Human Immunodeficiency Virus type 1 (HIV-1) and hepatitis B virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking TRIUMEQ. A &ldquo;flare-up&rdquo; is when your HBV infection suddenly returns in a worse way than before. Worsening liver disease can be serious and may lead to death. Do not run out of TRIUMEQ. Refill your prescription or talk to your healthcare provider before your TRIUMEQ is all gone. Do not stop TRIUMEQ without first talking to your healthcare provider. If you stop taking TRIUMEQ, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver. Resistant Hepatitis B Virus (HBV). If you have HIV-1 and hepatitis B, the hepatitis B virus can change (mutate) during your treatment with TRIUMEQ and become harder to treat (resistant). Use with interferon and ribavirin-based regimens. Worsening of liver disease that has caused death has happened in people infected with both HIV-1 and hepatitis C virus who were taking antiretroviral medicines and were also being treated for hepatitis C with interferon with or without ribavirin. If you are taking TRIUMEQ and interferon with or without ribavirin, tell your healthcare provider if you have any new symptoms. What is TRIUMEQ? TRIUMEQ is a prescription HIV-1 (Human Immunodeficiency Virus type 1) medicine used alone or with other antiretroviral medicines to treat HIV-1 infection. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). TRIUMEQ contains 3 prescription medicines, abacavir (ZIAGEN), dolutegravir (TIVICAY) and lamivudine (EPIVIR&reg;). TRIUMEQ is not for use by itself in people who have or have had resistance to abacavir, dolutegravir, or lamivudine TRIUMEQ should not be used in children. When used alone or with other antiretroviral medicines to treat HIV-1 infection, TRIUMEQ may help: reduce the amount of HIV-1 in your blood. This is called &ldquo;viral load&rdquo;. increase the number of CD4+ (T) cells in your blood, which help fight off other infections. Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections). TRIUMEQ does not cure HIV-1 infection or AIDS. You must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses. Avoid doing things that can spread HIV-1 infection to others. Do not share or re-use needles or other injection equipment. Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood. Ask your healthcare provider if you have any questions about how to prevent passing HIV to other people. Who should not take TRIUMEQ? Do not take TRIUMEQ if you: have a certain type of gene variation called the HLA-B*5701 allele. Your healthcare provider will test you for this before prescribing treatment with TRIUMEQ. are allergic to abacavir, dolutegravir, or any of the ingredients in TRIUMEQ. See the end of this Medication Guide for a complete list of ingredients in TRIUMEQ. take dofetilide (TIKOSYN&reg;). Taking TRIUMEQ and dofetilide (TIKOSYN) can cause side effects that may be life-threatening. have liver problems. What should I tell my healthcare provider before taking TRIUMEQ? Before you take TRIUMEQ, tell your healthcare provider if you: have been tested and know whether or not you have a particular gene variation called HLA-B*5701. have or have had liver problems, including hepatitis B or C virus infection. have kidney problems. have heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes. drink alcohol or take medicines that contain alcohol. are pregnant or plan to become pregnant. It is not known if TRIUMEQ will harm your unborn baby. Talk to your healthcare provider if you are pregnant or plan to become pregnant. Pregnancy Registry. 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. are breastfeeding or plan to breastfeed. Do not breastfeed if you take TRIUMEQ. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. Some medicines interact with TRIUMEQ. Keep a list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for a list of medicines that interact with TRIUMEQ. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TRIUMEQ with other medicines. You should not take TRIUMEQ if you also take: abacavir (EPZICOM, TRIZIVIR, or ZIAGEN) lamivudine (COMBIVIR&reg;, DUTREBIS&trade;, EPIVIR&reg;, EPIVIR-HBV&reg;, EPZICOM, or TRIZIVIR) emtricitabine (ATRIPLA&reg;, COMPLERA&reg;, EMTRIVA&reg;, STRIBILD&reg;, or TRUVADA&reg;) Tell your healthcare provider if you take: antacids, laxatives, or other medicines that contain aluminum, magnesium, sucralfate (CARAFATE&reg;), or buffered medicines. TRIUMEQ should be taken at least 2 hours before or 6 hours after you take these medicines. anti-seizure medicines: oxcarbazepine (TRILEPTAL&reg;) phenytoin (DILANTIN&reg;, DILANTIN&reg;-125, PHENYTEK&reg;) phenobarbital carbamazepine (CARBATROL&reg;, EQUETRO&reg;, TEGRETOL&reg;, TEGRETOL&reg;-XR, TERIL&reg;, EPITOL&reg;) any other medicine to treat HIV-1 iron or calcium supplements taken by mouth. Supplements containing calcium or iron may be taken at the same time with TRIUMEQ if taken with food. Otherwise, TRIUMEQ should be taken at least 2 hours before or 6 hours after you take these medicines. medicines used to treat hepatitis virus infections, such as interferon or ribavirin a medicine that contains metformin methadone rifampin (RIFATER&reg;, RIFAMATE&reg;, RIMACTANE&reg;, RIFADIN&reg;) St. John's wort (Hypericum perforatum) How should I take TRIUMEQ? Take TRIUMEQ exactly as your healthcare provider tells you. Do not change your dose or stop taking TRIUMEQ without talking with your healthcare provider. If you miss a dose of TRIUMEQ, 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. Stay under the care of a healthcare provider while taking TRIUMEQ. TRIUMEQ may be taken with or without food. Do not run out of TRIUMEQ. The virus in your blood may increase and the virus may become harder to treat. W hen your supply starts to run low, get more from your healthcare provider or pharmacy. If you take too much TRIUMEQ, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of TRIUMEQ? TRIUMEQ can cause serious side effects including: See &ldquo;What is the most important information I should know about TRIUMEQ?&rdquo; Changes in liver tests. People with a history of hepatitis B or C virus may have an increased risk of developing new or worsening changes in certain liver tests during treatment with TRIUMEQ. Your healthcare provider may do tests to check your liver function before and during treatment with TRIUMEQ. Changes in your immune system (Immune Reconstitution Syndrome) 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 TRIUMEQ. Changes in body fat can happen in people who take HIV-1 medicines. These changes may include an increased amount of fat in the upper back and neck (&ldquo;buffalo hump&rdquo;), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known. Heart attack (myocardial infarction). Some HIV-1 medicines including TRIUMEQ may increase your risk of heart attack. The most common side effects of TRIUMEQ include: trouble sleeping headache tiredness Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of TRIUMEQ. 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. How should I store TRIUMEQ? Store TRIUMEQ at room temperature between 68&deg;F to 77&deg;F (20&deg;C to 25&deg;C). Store TRIUMEQ in the original bottle. Keep the bottle of TRIUMEQ tightly closed and protected from moisture. The bottle of TRIUMEQ contains a desiccant packet to help keep your medicine dry (protect it from moisture). Keep the desiccant packet in the bottle. Do not remove the desiccant packet. Keep TRIUMEQ and all medicines out of the reach of children. General information about the safe and effective use of TRIUMEQ Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRIUMEQ for a condition for which it was not prescribed. Do not give TRIUMEQ to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about TRIUMEQ that is written for health professionals. For more information go to www.TRIUMEQ.com or call 1-877-844-8872. What are the ingredients in TRIUMEQ? Active ingredients: abacavir, dolutegravir, and lamivudine Inactive ingredients: D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. Tablet film-coating contains: iron oxide black, iron oxide red, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium oxide. Manufactured for: ViiV Healthcare Research Triangle Park, NC 27709. by: GlaxoSmithKline, Research Triangle Park, NC 27709. Revised: 03/2017 WARNING CARD TRIUMEQ&reg; (abacavir, dolutegravir, and lamivudine) tablets Patients taking TRIUMEQ 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 TRIUMEQ, call your healthcare provider right away to find out if you should stop taking this medicine. Symptom(s) Group 1 Fever Group 2 Rash Group 3 Nausea, vomiting, diarrhea, or abdominal (stomach area) pain Group 4 Generally ill feeling, extreme tiredness, or achiness Group 5 Shortness of breath, cough, or sore throat Always carry this Warning Card with you to help recognize symptoms of this allergic reaction. (Back of Card) WARNING CARD TRIUMEQ&reg; (abacavir, dolutegravir, and lamivudine) tablets If you must stop treatment with TRIUMEQ because you have had an allergic reaction to abacavir, NEVER take TRIUMEQ or any other abacavir-containing medicine (ZIAGEN&reg; , EPZICOM&reg;, or TRIZIVIR&reg;) again. If you have an allergic reaction, dispose of any unused TRIUMEQ. Ask your pharmacist how to properly dispose of medicines. If you take TRIUMEQ 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 low blood pressure or death.82017-09-01 11:12:57Abacavir, Dolutegravir, and Lamivudine Film-coated TabletsTriumeqFDA
722017-12-04 17:37:58Drug DescriptionTYMLOS&trade; (abaloparatide) Injection, For Subcutaneous Use WARNING RISK OF OSTEOSARCOMA Abaloparatide caused a dose-dependent increase in the incidence of osteosarcoma (a malignant bone tumor) in male and female rats. The effect was observed at systemic exposures to abaloparatide ranging from 4 to 28 times the exposure in humans receiving the 80 mcg dose. It is unknown if TYMLOS will cause osteosarcoma in humans [see WARNINGS AND PRECAUTIONS  and Nonclinical Toxicology]. The use of TYMLOS is not recommended in patients at increased risk of osteosarcoma including those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, open epiphyses, bone metastases or skeletal malignancies, hereditary disorders predisposing to osteosarcoma, or prior external beam or implant radiation therapy involving the skeleton [see WARNINGS AND PRECAUTIONS]. Cumulative use of TYMLOS and parathyroid hormone analogs (e.g., teriparatide) for more than 2 years during a patient's lifetime is not recommended [see WARNINGS AND PRECAUTIONS]. DESCRIPTION TYMLOS injection for subcutaneous administration contains abaloparatide, a synthetic 34 amino acid peptide. Abaloparatide is an analog of human parathyroid hormone related peptide, PTHrP(1-34). It has 41% homology to hPTH(1-34) (human parathyroid hormone 1-34) and 76% homology to hPTHrP(1-34) (human parathyroid hormone-related peptide 1-34). Abaloparatide has a molecular formula of C174H300N56O49 and a molecular weight of 3961 daltons with the amino acid sequence shown below: Ala-Val-Ser-Glu-His-Gln-Leu-Leu-His-Asp-Lys-Gly-Lys-Ser-Ile-Gln-Asp-Leu-Arg-Arg Arg-Glu-Leu-Leu-Glu-Lys-Leu-Leu-Aib-Lys-Leu-His-Thr-Ala-NH2 TYMLOS injection is supplied as a sterile, colorless, clear solution in a glass cartridge which is pre-assembled into a disposable single-patient-use pen. The pen is intended to deliver 30 once daily abaloparatide doses of 80 mcg in 40 mcL. Each cartridge contains 1.56 mL of TYMLOS solution. Each mL contains 2000 mcg abaloparatide and the following inactive ingredients: 5 mg phenol, 5.08 mg sodium acetate trihydrate, 6.38 mg acetic acid, and water for injection.92017-09-01 11:12:57Abaloparatide InjectionTymlosFDA
732017-12-04 17:37:58Indications & DosageINDICATIONS TYMLOS is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, TYMLOS reduces the risk of vertebral fractures and nonvertebral fractures [see Clinical Studies]. Limitations Of Use Because of the unknown relevance of the rodent osteosarcoma findings to humans, cumulative use of TYMLOS and parathyroid hormone analogs (e.g., teriparatide) for more than 2 years during a patient's lifetime is not recommended [see WARNINGS AND PRECAUTIONS]. DOSAGE AND ADMINISTRATION Recommended Dosage The recommended dosage of TYMLOS is 80 mcg subcutaneously once daily. Cumulative use of TYMLOS and parathyroid hormone analogs (e.g., teriparatide) for more than 2 years during a patient's lifetime is not recommended [see WARNINGS AND PRECAUTIONS]. Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate. Administration Instructions Administer TYMLOS as a subcutaneous injection into the periumbilical region of the abdomen. Rotate the site of the injection every day and administer at approximately the same time every day. Do not administer intravenously or intramuscularly. Administer the first several doses where the patient can sit or lie down if necessary, in case symptoms of orthostatic hypotension occur [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. TYMLOS is a clear and colorless solution. Visually inspect TYMLOS for particulate matter and discoloration prior to administration. Do not use if solid particles appear or if the solution is cloudy or colored. Provide appropriate training and instruction to patients and caregivers on the proper use of the TYMLOS pen. HOW SUPPLIED Dosage Forms And Strengths Injection: 3120 mcg/1.56 mL (2000 mcg/mL) in a single-patient-use prefilled pen. The prefilled pen delivers 30 doses of TYMLOS, each containing 80 mcg of abaloparatide in 40 mcL of a sterile, clear, colorless solution. TYMLOS injection is supplied as a pre-assembled single-patient-use disposable pen (NDC 70539-001-01) packaged in a cardboard carton (NDC 70539-001-02) with the Instructions for Use and Medication Guide. Each disposable pen embodies a glass cartridge that contains 3120 mcg of abaloparatide in 1.56 mL (2000 mcg/mL) of sterilized, clear, colorless fluid. Each pen provides a 30-day supply for once daily injection of 80 mcg abaloparatide in 40 mcL. Sterile needles are not included. Storage And Handling Before first use, store TYMLOS in a refrigerator between 2&deg;C to 8&deg;C (36&deg;F to 46&deg;F). After first use, store for up to 30 days at 20&deg;C to 25&deg;C (68&deg;F to 77&deg;F). Do not freeze or subject to heat. Manufactured in Germany for: Radius Health, Inc. 950 Winter Street Waltham, MA 02451. Revised: Apr 201792017-09-01 11:12:57Abaloparatide InjectionTymlosFDA
742017-12-04 17:37:58Side Effects & Drug InteractionsSIDE EFFECTS The following adverse reactions are described in greater detail in other sections: Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS] Hypercalcemia [see WARNINGS AND PRECAUTIONS] Hypercalciuria and Urolithiasis [see WARNINGS AND PRECAUTIONS] Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Postmenopausal Women With Osteoporosis The safety of TYMLOS was evaluated in a randomized, multicenter, double-blind, placebo-controlled clinical trial in postmenopausal women with osteoporosis aged 49 to 86 years (mean age 69 years) who were randomized to receive 80 mcg of TYMLOS (N = 824) or placebo (N = 821), given subcutaneously once daily for 18 months [see Clinical Studies]. In this study, the incidence of all-cause mortality was 0.4% in the TYMLOS group and 0.6% in the placebo group. The incidence of serious adverse events was 10% in the TYMLOS group and 11% in the placebo group. The percentage of patients who discontinued study drug due to adverse events was 10% in the TYMLOS group and 6% in the placebo group. The most common adverse reactions leading to study drug discontinuation in the TYMLOS group were nausea (2%), dizziness (1%), headache (1%), and palpitations (1%). Table 1 shows the most common adverse reactions in the trial. These adverse reactions were generally not present at baseline, occurred more commonly with TYMLOS than with placebo, and occurred in at least 2% of the patients treated with TYMLOS. Table 1: Common Adverse Reactions Reported in Postmenopausal Women with Osteoporosis* Preferred term TYMLOS (N=822) (%) Placebo (N=820) (%) Hypercalciuria 11 9 Dizziness 10 6 Nausea 8 3 Headache 8 6 Palpitations 5 0.4 Fatigue 3 2 Abdominal pain upper 3 2 Vertigo 2 2 * Adverse reactions reported in &ge; 2% of TYMLOS-treated patients. Orthostatic Hypotension In the clinical trial of women with postmenopausal osteoporosis, the incidence of orthostatic blood pressure decline &ge; 20 mmHg systolic or &ge; 10 mmHg diastolic at 1 hour after the first injection was 4% in the TYMLOS group and 3% in the placebo group. At later time points the incidence was generally similar between the treatment groups. Adverse reactions of orthostatic hypotension were reported in 1% of patients receiving TYMLOS and 0.5% of patients receiving placebo. Dizziness was reported by more TYMLOS-treated patients (10%) compared to placebo (6%) [see WARNINGS AND PRECAUTIONS]. Tachycardia In women with postmenopausal osteoporosis, adverse reactions of tachycardia, including sinus tachycardia, were reported in 2% of patients receiving TYMLOS and 1% of patients in the placebo group. In 5 of the 13 patients receiving TYMLOS who experienced tachycardia, symptoms occurred within 1 hour of administration. TYMLOS has been associated with a dose-dependent increase in heart rate which developed within 15 minutes after injection and resolved in about 6 hours [see CLINICAL PHARMACOLOGY]. Injection Site Reactions During the first month of the trial, injection site reactions were assessed daily one-hour after injection. TYMLOS had a higher incidence than placebo of injection site redness (58% vs. 28%), edema (10% vs. 3%) and pain (9% vs. 7%). Severe redness, severe edema, and severe pain were reported among 2.9%, 0.4%, and 0.4% of the TYMLOS-treated patients. Laboratory Abnormalities Hypercalcemia In the clinical trial of women with postmenopausal osteoporosis, TYMLOS caused increases in serum calcium concentrations [see WARNINGS AND PRECAUTIONS]. The incidence of hypercalcemia, defined as albumin-corrected serum calcium &ge; 10.7 mg/dL at 4 hours following injection at any visit was 3% in TYMLOS-treated patients and 0.1% with placebo. Pre-dose serum calcium was similar to baseline in both groups. There were 2 (0.2%) TYMLOS-treated patients and no placebo-treated patients who discontinued from the study due to hypercalcemia. The incidence of hypercalcemia with TYMLOS was higher in patients with mild or moderate renal impairment (4%) compared to patients with normal renal function (1%). Increases In Serum Uric Acid TYMLOS increased serum uric acid concentrations. In the postmenopausal osteoporosis trial, among patients with normal baseline uric acid concentrations, 25% of patients in the TYMLOS group and 6% of patients in the placebo group had at least one post-baseline concentration above the normal range. The hyperuricemia observed in TYMLOS-treated patients was not associated with an increase in adverse reactions of gout or arthralgia over that observed with placebo. Hypercalciuria and Urolithiasis In the clinical trial of women with postmenopausal osteoporosis, the overall incidence of urine calcium:creatinine ratio > 400 mg/g was higher with TYMLOS than with placebo (20% vs 15%, respectively). Urolithiases were reported in 2.1% of TYMLOS-treated patients and 1.7% of placebo-treated patients. Adverse Reactions From The Extension Study In Postmenopausal Women With Osteoporosis Following 18 months of treatment with TYMLOS or placebo, 1139 women transitioned to treatment with alendronate 70 mg administered orally once weekly. The incidence of adverse events occurring during alendronate treatment was similar in patients with prior placebo or TYMLOS therapy [see Clinical Studies]. Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to TYMLOS in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Of the patients receiving TYMLOS for 18 months, 49% (300/610) developed anti-abaloparatide antibodies, of these, 68% (201/297) developed neutralizing antibodies to abaloparatide. Of the patients with anti-abaloparatide antibodies tested for cross-reactivity, 2.3% (7/298) developed cross-reactivity to PTHrP, 43% (3/7) developed neutralizing antibodies to PTHrP, and 0% (0/298) developed cross-reactive antibodies to PTH. Antibody formation did not appear to have any clinically significant impact on safety or efficacy endpoints, including bone mineral density (BMD) response, fracture reduction, immune-related hypersensitivity or allergic reactions, or other adverse events. Most of the patients with anti-abaloparatide antibodies during treatment with TYMLOS, 85% (256/300), had follow-up antibody measurements six months after completion of TYMLOS therapy. Among these patients, 56% (143/256) remained antibody positive. DRUG INTERACTIONS No specific drug-drug interaction studies have been performed [see CLINICAL PHARMACOLOGY].92017-09-01 11:12:57Abaloparatide InjectionTymlosFDA
752017-12-04 17:37:58Warnings & PrecautionsWARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Risk Of Osteosarcoma Abaloparatide caused a dose-dependent increase in the incidence of osteosarcoma in male and female rats after subcutaneous administration at exposures 4 to 28 times the human exposure at the clinical dose of 80 mcg [see Nonclinical Toxicology]. It is unknown whether TYMLOS will cause osteosarcoma in humans. The use of TYMLOS is not recommended in patients at increased risk of osteosarcoma including those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, open epiphyses, bone metastases or skeletal malignancies, hereditary disorders predisposing to osteosarcoma, or prior external beam or implant radiation therapy involving the skeleton. Cumulative use of TYMLOS and parathyroid hormone analogs (e.g., teriparatide) for more than 2 years during a patient's lifetime is not recommended. Orthostatic Hypotension Orthostatic hypotension may occur with TYMLOS, typically within 4 hours of injection. Associated symptoms may include dizziness, palpitations, tachycardia or nausea, and may resolve by having the patient lie down. For the first several doses, TYMLOS should be administered where the patient can sit or lie down if necessary [see ADVERSE REACTIONS]. Hypercalcemia TYMLOS may cause hypercalcemia. TYMLOS is not recommended in patients with preexisting hypercalcemia or in patients who have an underlying hypercalcemic disorder, such as primary hyperparathyroidism, because of the possibility of exacerbating hypercalcemia [see ADVERSE REACTIONS]. Hypercalciuria And Urolithiasis TYMLOS may cause hypercalciuria. It is unknown whether TYMLOS may exacerbate urolithiasis in patients with active or a history of urolithiasis. If active urolithiasis or pre-existing hypercalciuria is suspected, measurement of urinary calcium excretion should be considered [see ADVERSE REACTIONS]. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Risk Of Osteosarcoma Advise patients that the active ingredient in TYMLOS, abaloparatide, caused a dose-dependent increase in the incidence of osteosarcoma in male and female rats and that it is unknown whether TYMLOS will cause osteosarcoma in humans [see WARNINGS AND PRECAUTIONS]. Instruct patients to promptly report signs and symptoms of possible osteosarcoma such as persistent localized pain or occurrence of a new soft tissue mass that is tender to palpation. Hypercalcemia Advise patients that TYMLOS may cause hypercalcemia and discuss the symptoms of hypercalcemia (e.g., nausea, vomiting, constipation, lethargy, muscle weakness) [see WARNINGS AND PRECAUTIONS]. Instruct patients to promptly report signs and symptoms of hypercalcemia. Orthostatic Hypotension Advise patients to sit or lie down if they feel lightheaded or have palpitations after the injection until their symptoms resolve. If these symptoms persist or worsen, advise patients to consult their healthcare provider before continuing treatment [see DOSAGE AND ADMINISTRATION]. Use Of TYMLOS Pen Instruct patients and caregivers who administer TYMLOS on how to properly use the TYMLOS pen and to follow sharps disposal recommendations [see DOSAGE AND ADMINISTRATION]. Advise patients not to share their TYMLOS pen or needles with other patients and not to transfer the contents of the pen to a syringe. Advise patients that each TYMLOS pen can be used for up to 30 days, and after the 30-day use period, to discard the TYMLOS pen, even if it still contains unused solution [see HOW SUPPLIED/Storage and Handling]. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility In a 2-year carcinogenicity study, abaloparatide was administered once daily to male and female Fischer rats by subcutaneous injection at doses of 10, 25, and 50 mcg/kg. These doses resulted in systemic exposures to abaloparatide that were 4, 16, and 28 times, respectively, the systemic exposure observed in humans following the recommended subcutaneous dose of 80 mcg (based on AUC comparisons). Neoplastic changes related to treatment with abaloparatide consisted of marked dose-dependent increases in osteosarcoma and osteoblastoma incidence in all male and female dose groups. The incidence of osteosarcoma was 0-2% in untreated controls and reached 87% and 62% in male and female high-dose groups, respectively. The bone neoplasms were accompanied by marked increases in bone mass. The relevance of the rat findings to humans is uncertain. The use of TYMLOS is not recommended in patients at increased risk of osteosarcoma [see WARNINGS AND PRECAUTIONS]. Abaloparatide was not genotoxic or mutagenic in a standard battery of tests including the Ames test for bacterial mutagenesis, the chromosome aberration test using human peripheral lymphocytes, and the mouse micronucleus test. Use In Specific Populations Pregnancy Risk Summary TYMLOS is not indicated for use in females of reproductive potential. There are no human data with TYMLOS use in pregnant women to inform any drug associated risks. Animal reproduction studies with abaloparatide have not been conducted. Lactation Risk Summary TYMLOS is not indicated for use in females of reproductive potential. There is no information on the presence of abaloparatide in human milk, the effects on the breastfed infant, or the effects on milk production. Pediatric Use Safety and effectiveness of TYMLOS have not been established in pediatric patients. TYMLOS is not recommended for use in pediatric patients with open epiphyses or hereditary disorders predisposing to osteosarcoma because of an increased baseline risk of osteosarcoma [see WARNINGS AND PRECAUTIONS]. Geriatric Use Of the total number of patients in the postmenopausal osteoporosis clinical studies of TYMLOS, 82% were age 65 years and over, and 19% were age 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment No dosage adjustment is required for patients with mild, moderate, or severe renal impairment. A study of a single dose of TYMLOS 80 mcg given subcutaneously was conducted in subjects with normal renal function or mild, moderate, or severe renal impairment. The maximal concentration (Cmax ) and area under the concentration-time curve (AUC) of abaloparatide increased 1.4-and 2.1-fold, respectively, in subjects with severe renal impairment, compared to subjects with normal renal function. Patients with severe renal impairment may have increased abaloparatide exposure that may increase the risk of adverse reactions; therefore, monitor for adverse reactions [see CLINICAL PHARMACOLOGY].92017-09-01 11:12:57Abaloparatide InjectionTymlosFDA
762017-12-04 17:37:58Overdosage & ContraindicationsOVERDOSE In a clinical study, accidental overdose was reported in a patient who received 400 mcg in one day (5 times the recommended clinical dose); dosing was temporarily interrupted. The patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day the patient's serum calcium was within the normal range. The effects of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Overdosage Management There is no specific antidote for TYMLOS. Treatment of suspected overdose should include discontinuation of TYMLOS, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable. CONTRAINDICATIONS None.92017-09-01 11:12:57Abaloparatide InjectionTymlosFDA
772017-12-04 17:37:58Clinical PharmacologyCLINICAL PHARMACOLOGY Mechanism Of Action Abaloparatide is a PTHrP(1-34) analog which acts as an agonist at the PTH1 receptor (PTH1R). This results in activation of the cAMP signaling pathway in target cells. In rats and monkeys, abaloparatide had an anabolic effect on bone, demonstrated by increases in BMD and bone mineral content (BMC) that correlated with increases in bone strength at vertebral and/or nonvertebral sites [see Nonclinical Toxicology)]. Pharmacodynamics Effects On Markers Of Bone Turnover A dose-finding study of abaloparatide administered once daily for 24 weeks demonstrated a dose-response relationship for BMD and bone formation markers. Daily administration of TYMLOS to postmenopausal women with osteoporosis in clinical studies increased the bone formation marker serum procollagen type I N-propeptide (PINP). The increase in PINP levels peaked at Month 1 at 93% above baseline then decreased slowly over time. The increase in PINP was maintained above baseline throughout the treatment duration. At Month 18, PINP concentrations were approximately 45% above baseline. The increase in the bone resorption marker serum collagen type I cross-linked C-telopeptide (sCTX) peaked at Month 3 at 43% above baseline then decreased to 20% above baseline by Month 18. Cardiac Electrophysiology A 4-way cross-over thorough QT/QTc study was conducted in 55 healthy subjects who received single doses of placebo, subcutaneous doses of abaloparatide at 80 mcg and 240 mcg (three times the recommended dose), and moxifloxacin 400 mg orally. Abaloparatide increased heart rate, with a mean peak increase of 15 beats per minute (bpm) and 20 bpm at the first time point (15 minutes) after dosing with 80 mcg and 240 mcg, respectively. There were no clinically meaningful effects of abaloparatide on QTcI (individually corrected QT intervals) or cardiac electrophysiology. Pharmacokinetics Following seven days of subcutaneous administration of abaloparatide 80 mcg, the mean (SD) abaloparatide exposure was 812 (118) pg/mL for C max and 1622 (641) pg&middot;hr/mL for AUC 0-24 . Figure 1 below shows the mean (SD) abaloparatide pharmacokinetic profile in postmenopausal women (N = 8) on Day 7. Figure 1: Mean Abaloparatide Pharmacokinetic Profile in Postmenopausal Women on Day 7 Absorption The median (range) time to peak concentration of abaloparatide 80 mcg was 0.51 hr (0.25 to 0.52 hr) following subcutaneous administration. The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Distribution The in vitro plasma protein binding of abaloparatide was approximately 70%. The volume of distribution was approximately 50 L. Elimination The mean (SD) half-life of abaloparatide is 1.7 (0.7) hrs. The peptide fragments are primarily eliminated through renal excretion. Metabolism No specific metabolism or excretion studies have been performed with TYMLOS. The metabolism of abaloparatide is consistent with non-specific proteolytic degradation into smaller peptide fragments, followed by elimination by renal clearance. Specific Populations Geriatric Patients No age-related differences in abaloparatide pharmacokinetics were observed in postmenopausal women ranging from 49 to 86 years of age. Race No differences in abaloparatide pharmacokinetics based on race were observed in clinical trials. Patients with Renal Impairment A single 80 mcg subcutaneous dose of abaloparatide was administered to male and female patients with renal impairment: 8 patients with mild renal impairment (CLCr 60 to 89 mL/min), 7 patients with moderate renal impairment (CLCr 30 to 59 mL/min), 8 patients with severe renal impairment (CLCr 15 to 29 mL/min), and 8 healthy subjects with normal renal function (CLCr 90 or greater mL/min) matched by sex, age, and body mass index (BMI). Abaloparatide Cmax increased 1.0-, 1.3-, and 1.4-fold in patients with mild, moderate, and severe renal impairment, compared to the healthy subjects with normal renal function. Abaloparatide AUC increased 1.2-, 1.7-, and 2.1-fold in patients with mild, moderate, and severe renal impairment, compared to the healthy subjects with normal renal function. Patients undergoing dialysis were not included in the study. Drug Interactions In vitro studies showed that abaloparatide, at therapeutic concentrations, does not inhibit or induce Cytochrome P450 enzymes. Animal Toxicology And Pharmacology In toxicity studies in rats and monkeys of up to 26-week and 39-week duration, respectively, findings included vasodilation, increases in serum calcium, decreases in serum phosphorus, and soft tissue mineralization at doses &ge; 10 mcg/kg/day. The 10 mcg/kg/day dose resulted in systemic exposures to abaloparatide in rats and monkeys that were 2 and 3 times, respectively, the exposure in humans at daily subcutaneous doses of 80 mcg. Pharmacologic effects of abaloparatide on the skeleton were assessed in 12-and 16-month studies in ovariectomized (OVX) rats and monkeys, at doses up to 11 and 1 times human exposure at the recommended subcutaneous dose of 80 mcg, respectively (based on AUC comparisons). In these animal models of postmenopausal osteoporosis, treatment with abaloparatide resulted in dose-dependent increases in bone mass at vertebral and/or nonvertebral sites, correlating with increases in bone strength. The anabolic effect of abaloparatide was due to the predominant increase in osteoblastic bone formation and was evidenced by increases in trabecular thickness and/or cortical thickness due to endosteal bone apposition. Abaloparatide maintained or improved bone quality at all skeletal sites evaluated and did not cause any mineralization defects. Clinical Studies Efficacy Study In Women With Postmenopausal Osteoporosis The efficacy of TYMLOS for the treatment of postmenopausal osteoporosis was evaluated in Study 003 (NCT 01343004), an 18-month, randomized, multicenter, double-blind, placebo-controlled clinical trial in postmenopausal women aged 49 to 86 years (mean age of 69) who were randomized to receive TYMLOS 80 mcg (N = 824) or placebo (N = 821) given subcutaneously once daily. Approximately 80% of patients were Caucasian, 16% were Asian, and 3% were Black; 24% were Hispanic. At baseline, the mean T-scores were -2.9 at the lumbar spine, -2.1 at the femoral neck, and -1.9 at the total hip. At baseline, 24% of patients had at least one prevalent vertebral fracture and 48% had at least one prior nonvertebral fracture. Patients took daily supplemental calcium (500 to 1000 mg) and vitamin D (400 to 800 IU). The efficacy study was extended as Study 005 (NCT 01657162), an open-label study where patients were no longer receiving TYMLOS or placebo but were maintained in their original randomized treatment group and received 70 mg alendronate weekly, with calcium and vitamin D supplements for 6 months. Study 005 enrolled 1139 patients, representing 92% of patients who completed Study 003. This included 558 patients who had previously received TYMLOS and 581 patients who had previously received placebo. The cumulative 25-month efficacy dataset included 18 months of exposure to TYMLOS or placebo in Study 003, 1 month of no treatment, followed by 6 months of alendronate therapy in Study 005. Effect On New Vertebral Fractures The primary endpoint was the incidence of new vertebral fractures in patients treated with TYMLOS compared to placebo. TYMLOS resulted in a significant reduction in the incidence of new vertebral fractures compared to placebo at 18 months (0.6% TYMLOS compared to 4.2% placebo, p < 0.0001). The absolute risk reduction in new vertebral fractures was 3.6% at 18 months and the relative risk reduction was 86% for TYMLOS compared to placebo (Table 2). The incidence of new vertebral fractures at 25 months was 0.6% in patients treated with TYMLOS then alendronate, compared to 4.4% in patients treated with placebo then alendronate (p < 0.0001). The relative risk reduction in new vertebral fractures at 25 months was 87% for patients treated with TYMLOS then alendronate, compared to patients treated with placebo then alendronate, and the absolute risk reduction was 3.9% (Table 2). Table 2: Percentage of Postmenopausal Women with Osteoporosis with New Vertebral Fractures (modified Intent to Treat population)*&dagger; Percentage of Postmenopausal Women With Fractures Absolute Risk Reduction (%) (95% CI&Dagger;) Relative Risk Reduction (%) (95% CI&Dagger;) TYMLOS (N=690*) (%) Placebo (N=711*) (%) 0-18 months 0.6 4.2 3.6 (2.1, 5.4) 86 (61, 95) TYMLOS/ Alendronate (N=544&dagger;) (%) Placebo/ Alendronate (N=568&dagger;) (%) 0-25 months 0.6 4.4 3.9 (2.1, 5.9) 87 (59, 96) * Includes patients who had both pre-and post-treatment spine radiographs in Study 003 &dagger; Includes patients who had both pre-and post-treatment spine radiographs in Study 005 &Dagger; Confidence Interval Effect On Nonvertebral Fractures TYMLOS resulted in a significant reduction in the incidence of nonvertebral fractures at the end of the 18 months of treatment plus 1 month follow-up where no drug was administered (2.7% for TYMLOS-treated patients compared to 4.7% for placebo-treated patients). The relative risk reduction in nonvertebral fractures for TYMLOS compared to placebo was 43% (logrank test p = 0.049) and the absolute risk reduction was 2.0%. Following 6 months of alendronate treatment in Study 005, the cumulative incidence of nonvertebral fractures at 25 months was 2.7% for women in the prior TYMLOS group compared to 5.6% for women in the prior placebo group (Figure 2). At 25 months, the relative risk reduction in nonvertebral fractures was 52% (logrank test p = 0.017) and the absolute risk reduction was 2.9%. Figure 2: Cumulative Incidence of Nonvertebral Fractures* Over 25 Months (Intent to Treat Population)&dagger; TYMLOS demonstrated consistent reductions in the risk of vertebral and nonvertebral fractures regardless of age, years since menopause, presence or absence of prior fracture (vertebral, nonvertebral) and BMD at baseline. Effect On Bone Mineral Density (BMD) Treatment with TYMLOS for 18 months in Study 003 resulted in significant increases in BMD compared to placebo at the lumbar spine, total hip and femoral neck, each with p < 0.0001 (Table 3). Similar findings were seen following 6 months of alendronate treatment in Study 005 (Table 3). Table 3: Mean Percent Changes in Bone Mineral Density (BMD) From Baseline to Endpoint in Postmenopausal Women with Osteoporosis (Intent to Treat Population)*&dagger; &Dagger; TYMLOS (N=824 ) (%) Placebo (N=821) (%) Treatment Difference (%) (95% CI&sect;) 18 Months Lumbar Spine 9.2 0.5 8.8 (8.2, 9.3) Total Hip 3.4 -0.1 3.5 (3.3, 3.8) Femoral Neck 2.9 -0.4 3.3 (3.0, 3.7) TYMLOS/ Alendronate (N=558&dagger;) (%) Placebo/ Alendronate (N=581&dagger;) (%) 25 Months Lumbar Spine 12.8 3.5 9.3 (8.6, 10.1) Total Hip 5.5 1.4 4.1 (3.7, 4.5) Femoral Neck 4.5 0.5 4.1 (3.6, 4.6) * Includes patients randomized in Study 003 &dagger; Includes patients enrolled in Study 005 &Dagger; Last-observation-carried-forward &sect; Confidence Interval TYMLOS demonstrated consistent increases in BMD regardless of age, years since menopause, race, ethnicity, geographic region, presence or absence of prior fracture (vertebral, nonvertebral), and BMD at baseline. Effect On Bone Histology Bone biopsy specimens were obtained from 71 patients with osteoporosis after 12 - 18 months of treatment (36 in the TYMLOS group and 35 in the placebo group). Of the biopsies obtained, 55 were adequate for quantitative histomorphometry assessment (27 in the TYMLOS group and 28 in the placebo group). Qualitative and quantitative histology assessment showed normal bone architecture and no evidence of woven bone, marrow fibrosis, or mineralization defects.92017-09-01 11:12:57Abaloparatide InjectionTymlosFDA
782017-12-04 17:37:58Medication Guide92017-09-01 11:12:57Abaloparatide InjectionTymlosFDA
792017-12-04 17:38:00Drug DescriptionPlenaxis&trade; (abarelix) for Injectable Suspension WARNING Immediate-onset systemic allergic reactions, some resulting in hypotension and syncope, have occurred after administration of Plenaxis&trade; . These immediate-onset reactions have been reported to occur following any administration of Plenaxis&trade; , including after the initial dose. The cumulative risk of such a reaction increases with the duration of treatment (see WARNINGS). Following each injection of Plenaxis&trade; , patients should be observed for at least 30 minutes in the office and in the event of an allergic reaction, managed appropriately. Only physicians who have enrolled in the Plenaxis&trade; PLUS Program (Plenaxis&trade; User Safety Program), based on their attestation of qualifications and acceptance of prescribing responsibilities, may prescribe Plenaxis&trade; (See DOSAGE AND ADMINISTRATION and HOW SUPPLIED). Plenaxis&trade; is indicated for the palliative treatment of men with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and have one or more of the following: (1) risk of neurological compromise due to metastases, (2) ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, or (3) severe bone pain from skeletal metastases persisting on narcotic analgesia. The effectiveness of Plenaxis&trade; in suppressing serum testosterone to castrate levels decreases with continued dosing in some patients (see CLINICAL PHARMACOLOGY, Pharmacodynamics). Effectiveness beyond 12 months has not been established. Treatment failure can be detected by measuring serum total testosterone concentrations just prior to administration on Day 29 and every 8 weeks thereafter (see WARNINGS). DESCRIPTION Abarelix for injectable suspension (Plenaxis&trade; ) is a synthetic decapeptide with potent antagonistic activity against naturally occurring gonadotropin releasing-hormone (GnRH). Plenaxis&trade; inhibits gonadotropin and related androgen production by directly and competitively blocking GnRH receptors in the pituitary. Abarelix is chemically described as acetyl-D-&beta;-naphthylalanyl-D-4-chlorophenylalanyl- D-3-pyridylalanyl-L-seryl-L-N-methyl-tyrosyl-D-asparagyl-L-leucyl-L-N(&epsilon;)-isopropyllysyl- L-prolyl-D-alanyl-amide. It is initially manufactured as an acetate water complex and converted to a carboxymethylcellulose (CMC) water complex in manufacturing the drug product. The molecular weight for abarelix anhydrous free base is 1416.06. The structural formula for abarelix peptide is: Abarelix for injectable suspension is supplied as a white to off-white sterile dry powder which, when mixed with the diluent, 0.9% Sodium Chloride Injection, USP, becomes a depot suspension intended for intramuscular (IM) injection. The single-dose vial contains 113 mg of anhydrous free base abarelix peptide (net) supplied in an abarelix CMC complex. This complex also contains 19.1 to 31 mg of CMC. After the vial is reconstituted with 2.2 mL of 0.9% sodium chloride injection, 2 mL is administered to deliver a dose of 100 mg of abarelix (net) as the abarelix CMC complex at a pH of 5&plusmn;1.102017-09-01 11:12:57AbarelixPlenaxisFDA
802017-12-04 17:38:00Indications & DosageINDICATIONS Plenaxis&trade; is indicated for the palliative treatment of men with advanced symptomatic prostate cancer, in whom LHRH agonist therapy is not appropriate and who refuse surgical castration, and have one or more of the following: (1) risk of neurological compromise due to metastases, (2) ureteral or bladder outlet obstruction due to local encroachment or metastatic disease, or (3) severe bone pain from skeletal metastases persisting on narcotic analgesia. DOSAGE AND ADMINISTRATION For safety reasons, Plenaxis&trade; is approved with marketing restrictions. Only physicians who attest to the following qualifications and accept the following responsibilities, and on that basis enroll in PRAECIS PHARMACEUTICALS INCORPORATED's Plenaxis&trade; PLUS Program should prescribe Plenaxis&trade; . PRAECIS PHARMACEUTICALS INCORPORATED and its agents will provide Plenaxis&trade; to physicians enrolled in the Plenaxis&trade; PLUS Program. To enroll, physicians must attest that they are able and willing to: diagnose and manage advanced symptomatic prostate cancer. diagnose and treat allergic reactions, including anaphylaxis. have access to medication and equipment necessary to treat allergic reactions, including anaphylaxis. have patients observed for development of allergic reactions for 30 minutes following each administration of Plenaxis&trade; . understand the risks and benefits of palliative treatment with Plenaxis&trade; , including information from the Package Insert, Patient Information, and the Physician Attestation. educate the patients on the risks and benefits of treatment with Plenaxis&trade; and obtain the patient's signature on the Patient Information signature page, sign it, and place the original signed form in the patient's medical record, and give a copy of the Patient Information leaflet with the signed page to the patient. report serious adverse events, such as any immediate-onset systemic allergic event (including anaphylaxis, hypotension, and syncope) as soon as possible to PRAECIS PHARMACEUTICALS INCORPORATED at 1-866-PLENAXIS (1-866-753-6294) or to the Food and Drug Administration's MedWatch Program at 1-800-FDA-1088. understand that they may withdraw their enrollment in the Plenaxis&trade; Prescribing Program by a written statement submitted to PRAECIS PHARMACEUTICALS INCORPORATED (contact information below) or that PRAECIS PHARMACEUTICALS INCORPORATED may withdraw physicians from the Plenaxis&trade; PLUS Program if they do not meet the agreed upon responsibilities. To enroll in the Plenaxis&trade; Prescribing Program call 1-866-PLENAXIS (1-866-753-6294) or visit www.plenaxisplus.com. Dose: The recommended dose of Plenaxis&trade; is 100 mg administered intramuscularly to the buttock on Day 1, 15, 29 (week 4) and every 4 weeks thereafter. Treatment failure can be detected by measuring serum testosterone concentrations just prior to Plenaxis&trade; administration, beginning on Day 29 and every 8 weeks thereafter. Directions for Reconstituting and Administering Plenaxis&trade; Read the instructions completely before performing reconstitution. The sterile powder for suspension is to be reconstituted in accordance with the following directions: Reconstitution Instructions for 1 Vial of Plenaxis&trade; to Provide a 100 mg (50 mg/mL) Dose as a Single IM Injection Use aseptic technique throughout. Prior to reconstitution, gently shake the vial of Plenaxis&trade; (abarelix for injectable suspension). Hold the vial at an angle (45 degrees) and tap lightly on table to break up any caking. Withdraw 2.2 mL of 0.9% Sodium Chloride Inj., USP using the enclosed 18 G x 1 &frac12;&rdquo; needle and a 3 cc syringe. Discard the remaining diluent. Picture 1 Keeping the vial upright, insert the needle all the way into the vial and inject the diluent quickly. Before withdrawing the needle, remove 2.2 mL of air. Shake immediately. Picture 2 Shake for approximately 15 seconds. Allow the vial to stand for approximately 2 minutes. Tap the vial to reduce foaming and swirl the vial occasionally. Again, shake for approximately 15 seconds. Allow the vial to stand for approximately 2 minutes. Tap the vial to reduce foaming and swirl the vial occasionally. Picture 3 Do not reinject the air into the vial. Locate a second injection spot on the stopper, and then insert the 18 G needle. Invert the vial and draw up some of the suspension into the syringe and without removing the needle from the vial reinject it at any remaining solids in the vial. Repeat the process until all solids are dispersed. Swirl the vial before withdrawal and withdraw the entire contents (at least 2 mL) by positioning the needle at a 45 degree angle as shown in the picture. Picture 4 Pull the plunger back to recover the residual suspension in the 18 G x1&frac12;&rdquo; needle. Exchange the 18 G x 1 &frac12;&rdquo; needle with the enclosed 22 G x 1&frac12;&rdquo; Safety Glide&trade; injection needle. Picture 5 Insert the needle at the desired injection site, pull the plunger back to check for back-flow of blood. If blood flows into the syringe, do not inject at this site. Select another injection site. Deliver the entire reconstituted suspension intramuscularly immediately. Picture 6 Observe the patient after injection for 30 minutes for any sign of an allergic-type response. Plenaxis&trade; does not contain a preservative and should be administered within 1 hour following reconstitution. Storage Store at 25&deg;C (77&deg;F), excursions permitted to 15-30&deg;C (59-86&deg;F), USP Controlled Room Temperature. HOW SUPPLIED The physician must attest to meeting the qualifications and accepting the responsibilities in the DOSAGE AND ADMINISTRATION section of this package insert by submitting the Physician's Attestation form to PRAECIS PHARMACEUTICALS INCORPORATED to be enrolled in the Plenaxis&trade; PLUS Program. PRAECIS PHARMACEUTICALS INCORPORATED and its agents will only provide Plenaxis&trade; to physicians enrolled in the Plenaxis&trade; Prescribing Program. Plenaxis&trade; vials are not to be resold or redistributed. Plenaxis&trade; (abarelix for injectable suspension) is supplied as a single-dose, preservativefree vial containing 113 mg of abarelix (anhydrous free base peptide) as an abarelix CMC complex, a sterile powder (NDC 68158-149-01) which, when reconstituted with 2.2 mL of 0.9% sodium chloride solution, yields a 2 mL delivered dose of 100 mg (50 mg/mL). Each single use dispensing pack also contains: a single-use 10 mL diluent vial of 0.9% Sodium Chloride Injection, USP, one 3 cc syringe with an 18 gauge 1&frac12; inch needle and one 22 gauge 1&frac12; inch Safety Glide&trade; injection needle. Praecis Pharmaceuticals Incorporated, 830 Winter Street, Waltham, MA 02451-1420. 02-01102017-09-01 11:12:57AbarelixPlenaxisFDA
812017-12-04 17:38:00Side Effects & Drug InteractionsSIDE EFFECTS Immediate-Onset Systemic Allergic Reactions: See BOXED WARNINGS and WARNINGS In the single study of Plenaxis&trade; conducted in men with advanced symptomatic prostate cancer, adverse events reported by &ge; 10% of patients are listed in Table 4. Adverse events are listed without regard to causality. Causality is often difficult to assess in elderly patients with multiple co-morbidities and prostate cancer. Table 4: Adverse Events in &ge; 10% of Patients in the Advanced Symptomatic Prostate Cancer Study (without regard for causality). Preferred Term Plenaxis&trade; N=81 n (%) Hot flushes* 64 (79) Sleep disturbance* 36 (44) Pain 25 (31) Breast enlargement* 24 (30) Breast pain/nipple tenderness* 16 (20) Back pain 14 (17) Constipation 12 (15) Peripheral edema 12 (15) Dizziness 10 (12) Headache 10 (12) Upper respiratory tract infection 10 (12) Diarrhea 9 (11) Dysuria 8 (10) Fatigue 8 (10) Micturition frequency 8 (10) Nausea 8 (10) Urinary retention 8 (10) Urinary tract infection 8 (10) * Pharmacological consequence of androgen deprivation Changes in Laboratory Values Clinically meaningful increases in serum transaminases were seen in a small percentage of patients in both treatment groups in each active-controlled Plenaxis&trade; study. In Study 1 and Study 2 combined, the percentage of Plenaxis&trade; patients reporting serum ALT > 2.5 times upper limit of normal or > 200 U./L was 8.2% and 1.8%, respectively. The percentage reporting serum AST > 2.5 times upper limit of normal or > 200 U/L was 3.1% and 0.8%, respectively. Similar results were reported for active comparators. Slight decrease in hemoglobin, a pharmacological consequence of castration, were observed in patients receiving Plenaxis&trade; and active comparator. Mean increases in serum triglycerides of approximately 10% were seen in Plenaxis&trade; -treated patients. DRUG INTERACTIONS No formal drug/drug interaction studies with Plenaxis&trade; were performed. Cytochrome P-450 is not known to be involved in the metabolism of Plenaxis&trade; . Plenaxis&trade; is highly bound to plasma proteins (96 to 99%). Laboratory Tests Response to Plenaxis&trade; should be monitored by measuring serum total testosterone concentrations just prior to administration on Day 29 and every 8 weeks thereafter (see WARNINGS). Serum transaminase levels should be obtained before starting treatment with Plenaxis&trade; and periodically during treatment. Periodic measurement of serum PSA levels may also be considered.102017-09-01 11:12:57AbarelixPlenaxisFDA
822017-12-04 17:38:00Warnings & PrecautionsWARNINGS Immediate-Onset Systemic Allergic Reactions (See BOXED WARNINGS) In the clinical trial of patients with advanced, symptomatic prostate cancer, 3 of 81 (3.7%) patients experienced an immediate-onset systemic allergic reaction within minutes of receiving Plenaxis&trade; . The allergic reactions were urticaria (Day 15), urticaria and pruritis (Day 29), and hypotension and syncope (Day 141). Patients should be monitored for at least 30 minutes after each injection of Plenaxis&trade; . In the event of an allergic reaction associated with hypotension and/or syncope, appropriate supportive measures such as leg elevation, oxygen, IV fluids, antihistamines, corticosteroids, and epinephrine (alone or in combination) should be employed. From all the prostate cancer clinical trials with Plenaxis&trade; (mostly in men without advanced, symptomatic disease), immediate-onset systemic allergic reactions (occurring within 30 minutes of dosing), were observed in 1.1% (15/1397) of patients dosed with Plenaxis&trade; . In 14/15 patients who experienced an allergic reaction, each developed symptoms within 8 minutes of injection. The cumulative risk of such a reaction increased with duration of treatment. The cumulative rates (and 95% confidence intervals) on Days 56, 141, 365 and 676 were 0.51%, (0.13%, 0.88%) 0.80% (0.30%, 1.29%), 1.24% (0.43%, 2.04%) and 2.91% (0.87, 4.95%), respectively. Seven patients experienced hypotension or syncope as part of their allergic reaction, representing 0.5% of all patients. The cumulative rates (and 95% confidence intervals) for these types of reactions on Days 56, 141, 365, and 617 after the initial dose were 0.22% (0.0%, 0.46%), 0.32% (0.0%, 0.64%), 0.61% (0.0%, 1.24%) and 1.67% (0.07, 3.28%), respectively. Decrease in Effectiveness With Continued Dosing A decrease in overall effectiveness with increased duration of treatment, as measured by failure to maintain suppression of serum testosterone below 50 ng/dL, was noted (see CLINICAL PHARMACOLOGY, Pharmacodynamics). Treatment failure can be detected by measuring serum total testosterone concentrations just prior to administration on Day 29 after the initial dose and every 8 weeks thereafter. Prolongation of the QT Interval Because Plenaxis&trade; may prolong the QT interval (see CLINICAL PHARMACOLOGY, Pharmacodynamics), physicians should carefully consider whether the risks of Plenaxis&trade; outweigh the benefits in patients with baseline QTc values > 450 msec (e.g. congenital QT prolongation) and in patients taking Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications. PRECAUTIONS General Decreased effectiveness in patients > 225 pounds: The decrease in overall effectiveness of Plenaxis&trade; with increased duration of treatment is greater in patients who weigh more than 225 pounds. Strict monitoring of serum testosterone in these patients is warranted. Monitoring of liver function: Clinically meaningful transaminase elevations were observed in some patients who received Plenaxis&trade; or comparator drugs. Serum transaminase levels should be obtained before starting treatment with Plenaxis&trade; and periodically during treatment (see ADVERSE REACTIONS). Decrease in bone mineral density: Extended treatment with GnRH antagonists and LHRH agonists may result in a decrease in bone mineral density. Geriatric Use Prostate cancer occurs primarily in an older patient population. Clinical studies with Plenaxis&trade; have been conducted primarily in patients &ge; 65 years of age. No difference in the safety profile, when examined as a function of age, was apparent. Pediatric Use The safety and effectiveness of Plenaxis&trade; in pediatric patients have not been studied. Plenaxis&trade; is not indicated for use in pediatric patients. Carcinogenesis, Mutagenesis, Impairment of Fertility Plenaxis&trade; was not carcinogenic to mice or rats when administered as a subcutaneous depot every 28 days for 2 years at doses up to 300 mg/kg in mice and 100 mg/kg in rats. Systemic drug exposures, as measured by mean Cmax, were approximately 210-278-fold for mice and 21-32-fold for rats the human exposure following subcutaneous depot administration of 100 mg. Plenaxis&trade; was not mutagenic in the in vitro bacterial Ames assay or forward mutation assay in mouse lymphoma, or clastogenic in the in vivo mouse micronucleus assay. No effects on mating or fertility in male and female rats given 1 mg/kg subcutaneous Plenaxis&trade; , a dose 0.114-fold the human therapeutic dose of 100 mg based on body surface area. Mating and fertility were significantly decreased at doses of 3 and 10 mg/kg (0.34-fold and 1.135-fold, respectively, the human therapeutic dose of 100 mg based on body surface area), but the effects were reversible. Pregnancy Category X (see CONTRAINDICATIONS) Embryolethality occurred in pregnant rats administered a single subcutaneous dose of Plenaxis&trade; up to 3 mg/kg (0.228-fold the human therapeutic dose of 100 mg based on body surface area). In rabbits a dose-related increase in fetal resorptions and reduced viability was observed at doses up to 30 mg/kg (6.81-fold the human therapeutic dose of 100 mg based on body surface area). No teratogenic effects were observed in rats or rabbits up to doses of 3 mg/kg or 30 mg/kg, respectively. A no-observable-adverse effect- level (NOAEL) dose was 0.3 mg/kg (approximately 0.034-fold the human therapeutic dose of 100 mg based on body surface area) in rats and < 0.01 mg/kg ( < 0.0023-fold the human therapeutic dose of 100 mg based on body surface area) in rabbits. Nursing Mothers It is not known whether Plenaxis&trade; is excreted in human milk. Because many drugs are excreted in human milk, and because the effects of Plenaxis&trade; on lactation and/or the breastfed child have not been determined, Plenaxis&trade; should not be used by nursing mothers.102017-09-01 11:12:57AbarelixPlenaxisFDA
832017-12-04 17:38:00Overdosage & ContraindicationsOVERDOSE The maximum tolerated dose of Plenaxis&trade; has not been determined. The maximum dose used in clinical studies was 150 mg. There have been no reports of accidental overdose with Plenaxis&trade; . CONTRAINDICATIONS Plenaxis&trade; is contraindicated in those patients with a known hypersensitivity to any of the components in abarelix for injectable suspension. Plenaxis&trade; is not indicated in women or pediatric patients. In addition, Plenaxis&trade; may cause fetal harm if administered to a pregnant woman.102017-09-01 11:12:57AbarelixPlenaxisFDA
842017-12-04 17:38:00Clinical Pharmacology102017-09-01 11:12:57AbarelixPlenaxisFDA
852017-12-04 17:38:00Medication GuidePATIENT INFORMATION Plenaxis&trade; (plen&middot;AK&middot;sis) (abarelix for injectable suspension) Read the Patient Information that comes with PlenaxisTM before you start getting injections. Sign the last page if you agree with treatment with Plenaxis&trade; . (Your signature will be required to start treatment.) What is the most important information I should know about Plenaxis&trade; ? Plenaxis&trade; can cause serious or life threatening allergic reactions that may need emergency medical treatment right away. These serious reactions may include: low blood pressure and fainting (shock) swelling of your face, eyelids, tongue, or throat asthma, wheezing, or other breathing problems such as chest tightness or shortness of breath Your chances of getting a serious or life threatening allergic reaction may increase with each Plenaxis&trade; injection that you get. If a serious or life threatening allergic reaction happens, it is usually soon after getting a Plenaxis&trade; injection. Therefore, you must wait in your doctor's office or health care facility for 30 minutes after each Plenaxis&trade; injection. Tell your doctor right away if you feel any warmth, redness, light-headedness, swelling or thickness in your throat. This could mean you are having a serious allergic reaction. Only doctors signed up with PRAECIS PHARMACEUTICALS INCORPORATED can prescribe PlenaxisTM because they know about treating prostate cancer and allergic reactions from Plenaxis&trade; . Plenaxis&trade; is only for treating advanced prostate cancer when a patient cannot have or refuses other treatments for prostate cancer, such as other hormone treatments or surgery to remove the testicles, and there are serious symptoms from the prostate cancer such as the cancer is near or pressing on the spinal cord, causing problems urinating or blockage of urine from the kidneys or bladder, or there is very bad bone pain even when taking narcotic pain medicines. Plenaxis&trade; may not keep working for everyone over time, so doctors should do blood tests about every 8 weeks to make sure Plenaxis&trade; is working by keeping your testosterone hormone level low. What is Plenaxis&trade; ? Plenaxis&trade; is a type of medicine called a gonadotropin-releasing hormone (GnRH) antagonist that lowers the male hormone testosterone in your blood. Testosterone makes most prostate cancers grow. Other ways to treat your prostate cancer are taking other hormone medicines to lower testosterone or surgery to remove your testicles. Plenaxis&trade; is used when these other ways to treat prostate cancer cannot be used or are refused. Who should not take Plenaxis&trade; ? Do not take Plenaxis&trade; if you are: a woman. There is no approved use of Plenaxis&trade; in women. Plenaxis&trade; can cause serious allergic reactions. Plenaxis&trade; can cause the death of an unborn child in a pregnant woman. Plenaxis&trade; may also pass into breast milk. a child under the age of 18 years. There are no studies that show that Plenaxis&trade; is safe or effective for use in children for any condition. allergic to any of the ingredients in Plenaxis&trade; . The ingredients include abarelix and carboxymethylcellulose. The mixing solution contains sodium chloride. Tell your doctor before taking a Plenaxis&trade; injection: if you or any family members have a rare heart condition known as prolongation of the QTc interval about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Plenaxis&trade; has not been studied with other medicines. Plenaxis&trade; and some of your other medicines may affect each other and could cause side effects. How do I take Plenaxis&trade; ? Plenaxis&trade; is only prescribed by doctors who are part of the Plenaxis&trade; PLUS Program (Plenaxis&trade; User Safety Program) run by PRAECIS PHARMACEUTICALS INCORPORATED. Plenaxis&trade; is given as an injection in your buttocks. Your doctor or nurse gives a Plenaxis&trade; injection every two weeks for the first month, and then every four weeks (every 28 days). It is important that you keep your appointment with your doctor's office for the times when your injection is due. Always wait in your doctor's office for 30 minutes after getting each Plenaxis&trade; injection. (See &ldquo;What is the most important information I should know about Plenaxis&trade; ?&rdquo;) Your doctor should do regular blood tests about every 8 weeks to check your testosterone level to see if Plenaxis&trade; is working for you. If you weigh more than 225 pounds, there may be a greater chance that Plenaxis&trade; may stop working. Your doctor should also do blood tests to check on your liver because Plenaxis&trade; may cause changes in your liver tests. What are the possible side effects of Plenaxis&trade; ? Plenaxis&trade; can cause: serious allergic or life threatening reactions. (See &ldquo;What is the most important information I should know about Plenaxis&trade; ?&rdquo;) allergic skin reactions such as a rash, hives, itching, tingling, and redness (flushing). A skin reaction may happen right away after injection with Plenaxis&trade; or several days later. Tell your doctor right away if you get an allergic skin reaction or rash after a Plenaxis&trade; injection. a change in heart rhythm called prolongation of the QTc interval. This condition may change the way your heart beats, cause fainting and even death in some patients. changes in liver function, which usually go away after you stop taking Plenaxis&trade; . Your doctor should do blood tests to check your liver function before you start getting Plenaxis&trade; and during your treatment with it. loss in bone mineral density with extended treatment. Low bone mineral density can lead to thinning of the bones (osteoporosis). The most common side effects of Plenaxis&trade; are: hot flashes problems sleeping pain, including back pain breast enlargement or breast pain constipation Talk to your doctor if you get a side effect that bothers you. These are not all the possible side effects of Plenaxis&trade; . For more information ask your doctor. General Information about Plenaxis&trade; This leaflet summarizes the most important information about Plenaxis&trade; . If you would like more information, talk with your healthcare provider. You can ask your healthcare provider for information about Plenaxis&trade; that is written for health professionals. Patient Signature for Treatment with Plenaxis&trade; I have read and understood the Patient Information leaflet. My doctor has answered my questions about treatment with Plenaxis&trade; for treating advanced prostate cancer. I cannot have or refuse treatments for my prostate cancer, such as other hormone treatments or surgery to remove my testicles, and my doctor has told me I have serious signs and/or symptoms from my prostate cancer such as the cancer is near or pressing on the spinal cord, or it is causing problems urinating or blockage of urine from the kidneys or bladder, or I have very bad bone pain even when taking narcotic pain medicines. Plenaxis&trade; can cause serious allergic reactions right after an injection. Therefore, after each injection I will wait in my doctor's office or health care facility for 30 minutes so if I have a serious allergic reaction, I can be treated. I know that my doctor should be getting blood tests to check my testosterone level about every 8 weeks to check if Plenaxis&trade; is working for me. I understand that I can only get Plenaxis&trade; from doctors who have signed up with the company that makes Plenaxis&trade; . My signature shows that I have read, understood and agree with all the statements above. I allow my doctor to begin treatment with Plenaxis&trade; . I only need to sign this page one time to start my treatment. Name of Patient (Print):________________________________________________ Signature of Patient:________________________________Date:_______________ Name of Physician (Print):_______________________________________________ Signature of Physician ____________________________Date:_________________ Instructions to Physician: As part of beginning Plenaxis&trade; treatment, give the patient a copy of the entire leaflet with the signed page, and put the original patient signature page in the patient's medical chart. This information leaflet has been approved by the U.S. Food and Drug Administration.102017-09-01 11:12:57AbarelixPlenaxisFDA
862017-12-04 17:38:07Drug DescriptionFind Lowest Prices on ORENCIA (abatacept) Injection DESCRIPTION ORENCIA&reg; (abatacept) is a selective T cell costimulation modulator. ORENCIA is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyteassociated antigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (IgG1). Abatacept is produced by recombinant DNA technology in a mammalian cell expression system. The apparent molecular weight of abatacept is 92 kilodaltons. ORENCIA for Injection is a lyophilized powder for intravenous infusion. ORENCIA for Injection is supplied as a sterile, white, preservative-free, lyophilized powder for reconstitution and dilution prior to intravenous administration. Following reconstitution of the lyophilized powder with 10 mL of Sterile Water for Injection, USP, the solution of ORENCIA is clear, colorless to pale yellow, with a pH range of 7.2 to 7.8. Each single-use vial of ORENCIA for Injection provides 250 mg abatacept, maltose (500 mg), monobasic sodium phosphate (17.2 mg), and sodium chloride (14.6 mg) for administration. ORENCIA Injection is a sterile, preservative-free, clear to slightly opalescent, colorless to paleyellow solution with a pH range of 6.8 to 7.4 for subcutaneous administration. ORENCIA Injection is supplied as a single-dose prefilled syringe or as a single-dose ClickJect autoinjector (see Table 4). Table 4: Contents of ORENCIA Subcutaneous Injection Presentation Active Ingredient Quantity and Label Volume Inactive Ingredient Content ORENCIA Injection 50 mg/0.4 mL Prefilled Syringe 50 mg of abatacept in 0.4 mL of solution dibasic sodium phosphate anhydrous (0.335 mg) monobasic sodium phosphate monohydrate (0.114 mg) poloxamer 188 (3.2 mg) sucrose (68 mg) qs to 0.4 mL water for injection ORENCIA Injection 87.5 mg/0.7 mL Prefilled Syringe 87.5 mg of abatacept in 0.7 mL of solution dibasic sodium phosphate anhydrous (0.587 mg) monobasic sodium phosphate monohydrate (0.200 mg) poloxamer 188 (5.6 mg) sucrose (119 mg) qs to 0.7 mL water for injection Unlike the lyophilized formulation for intravenous use, the ORENCIA solutions for subcutaneous administration contain no maltose.112017-09-01 11:12:57AbataceptOrenciaFDA
872017-12-04 17:38:07Indications & DosageINDICATIONS Adult Rheumatoid Arthritis (RA) ORENCIA&reg; is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. ORENCIA may be used as monotherapy or concomitantly with disease-modifying antirheumatic drugs (DMARDs) other than tumor necrosis factor (TNF) antagonists. Juvenile Idiopathic Arthritis ORENCIA is indicated for reducing signs and symptoms in patients 2 years of age and older with moderately to severely active polyarticular juvenile idiopathic arthritis. ORENCIA may be used as monotherapy or concomitantly with methotrexate (MTX). Adult Psoriatic Arthritis (PsA) ORENCIA is indicated for the treatment of adult patients with active psoriatic arthritis (PsA). Important Limitations Of Use ORENCIA should not be administered concomitantly with TNF antagonists. ORENCIA is not recommended for use concomitantly with other biologic rheumatoid arthritis (RA) therapy, such as anakinra. DOSAGE AND ADMINISTRATION Adult Rheumatoid Arthritis For adult patients with RA, ORENCIA may be administered as an intravenous infusion or as a subcutaneous injection. ORENCIA may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists. Intravenous Dosing Regimen ORENCIA lyophilized powder should be reconstituted and administered after dilution [see Adult Psoriatic Arthritis] as a 30-minute intravenous infusion utilizing the weight rangebased dosing specified in Table 1. Following the initial intravenous administration, an intravenous infusion should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. Table 1: Dose of ORENCIA for Intravenous Infusion in Adult RA Patients Body Weight of Patient Dose Number of Vialsa Less than 60 kg 500 mg 2 60 to 100 kg 750 mg 3 More than 100 kg 1000 mg 4 a Each vial provides 250 mg of abatacept for administration. Subcutaneous Dosing Regimen ORENCIA 125 mg in prefilled syringes or in ORENCIA ClickJectTM autoinjector should be administered by subcutaneous injection once weekly [see Adult Psoriatic Arthritis Infusion] and may be initiated with or without an intravenous loading dose. For patients initiating therapy with an intravenous loading dose, ORENCIA should be initiated with a single intravenous infusion (as per body weight categories listed in Table 1), followed by the first 125 mg subcutaneous injection administered within a day of the intravenous infusion. Patients transitioning from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose. Juvenile Idiopathic Arthritis For patients with juvenile idiopathic arthritis (JIA), ORENCIA may be administered as an intravenous infusion (6 years of age and older) or a subcutaneous injection (2 years of age and older). Intravenous dosing has not been studied in patients younger than 6 years of age. ORENCIA may be used as monotherapy or concomitantly with methotrexate. Intravenous Dosing Regimen ORENCIA should be administered as a 30-minute intravenous infusion based on body weight. Pediatric patients with: body weight less than 75 kg should be administered ORENCIA at a dose of 10 mg/kg [see Adult Psoriatic Arthritis]. body weight of 75 kg or more should be administered ORENCIA following the adult intravenous dosing regimen (see Table 1), not to exceed a maximum dose of 1000 mg. Following the initial administration, ORENCIA should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. Any unused portions in the vials must be immediately discarded. Subcutaneous Dosing Regimen ORENCIA for subcutaneous injection should be initiated without an intravenous loading dose and be administered utilizing the weight range-based dosing as specified in Table 2. Table 2: Dose of ORENCIA for Subcutaneous Administration in Patients 2 Years of Age or Older with JIA Body Weight of Patient Dose (once weekly) 10 to less than 25 kg 50 mg 25 to less than 50 kg 87.5 mg 50 kg or more 125 mg The safety and efficacy of ORENCIA ClickJect autoinjector for subcutaneous injection has not been studied in patients under 18 years of age. Adult Psoriatic Arthritis For adult patients with psoriatic arthritis, ORENCIA may be administered as an intravenous infusion (IV) or a subcutaneous (SC) injection. ORENCIA can be used with or without non-biologic DMARDs. Intravenous Dosing Regimen ORENCIA IV should be administered as a 30-minute intravenous infusion utilizing the weight range-based dosing specified in Table 1. Following the initial intravenous administration, an intravenous infusion should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter. Subcutaneous Dosing Regimen ORENCIA SC 125 mg should be administered by subcutaneous injection once weekly without the need for an intravenous loading dose. Patients switching from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose. Preparation And Administration Instructions For Intravenous Infusion Use aseptic technique. ORENCIA for Injection is provided as a lyophilized powder in preservative-free, single-use vials. Each ORENCIA vial provides 250 mg of abatacept for administration. The ORENCIA powder in each vial must be reconstituted with 10 mL of Sterile Water for Injection, USP, using only the silicone-free disposable syringe provided with each vial and an 18- to 21-gauge needle. After reconstitution, the concentration of abatacept in the vial will be 25 mg/mL. If the ORENCIA powder is accidentally reconstituted using a siliconized syringe, the solution may develop a few translucent particles. Discard any solutions prepared using siliconized syringes. If the silicone-free disposable syringe is dropped or becomes contaminated, use a new siliconefree disposable syringe from inventory. For information on obtaining additional silicone-free disposable syringes, contact Bristol-Myers Squibb 1-800-ORENCIA. Use 10 mL of Sterile Water for Injection, USP to reconstitute the ORENCIA powder. To reconstitute the ORENCIA powder, remove the flip-top from the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injection, USP, to the glass wall of the vial. Do not use the vial if the vacuum is not present. Rotate the vial with gentle swirling to minimize foam formation, until the contents are completely dissolved. Do not shake. Avoid prolonged or vigorous agitation. Upon complete dissolution of the lyophilized powder, the vial should be vented with a needle to dissipate any foam that may be present. After reconstitution, each milliliter will contain 25 mg (250 mg/10 mL). The solution should be clear and colorless to pale yellow. Do not use if opaque particles, discoloration, or other foreign particles are present. The reconstituted ORENCIA solution must be further diluted to 100 mL as follows. From a 100 mL infusion bag or bottle, withdraw a volume of 0.9% Sodium Chloride Injection, USP, equal to the volume of the reconstituted ORENCIA solution required for the patient's dose. Slowly add the reconstituted ORENCIA solution into the infusion bag or bottle using the same silicone-free disposable syringe provided with each vial. Gently mix. Do not shake the bag or bottle. The final concentration of abatacept in the bag or bottle will depend upon the amount of drug added, but will be no more than 10 mg/mL. Any unused portions in the ORENCIA vial must be immediately discarded. Prior to administration, the ORENCIA solution should be inspected visually for particulate matter and discoloration. Discard the solution if any particulate matter or discoloration is observed. The entire, fully diluted ORENCIA solution should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, lowprotein- binding filter (pore size of 0.2 &mu;m to 1.2 &mu;m). The infusion of the fully diluted ORENCIA solution must be completed within 24 hours of reconstitution of the ORENCIA vials. The fully diluted ORENCIA solution may be stored at room temperature or refrigerated at 2&deg;C to 8&deg;C (36&deg;F to 46&deg;F) before use. Discard the fully diluted solution if not administered within 24 hours. ORENCIA should not be infused concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of ORENCIA with other agents. General Considerations For Subcutaneous Administration ORENCIA prefilled syringes and ORENCIA ClickJect autoinjectors are intended for subcutaneous use only and are not intended for intravenous infusion. ORENCIA prefilled syringes and ORENCIA ClickJect autoinjectors are intended for use under the guidance of a physician or healthcare practitioner. After proper training in subcutaneous injection technique, a patient or caregiver may inject with ORENCIA if a physician/healthcare practitioner determines that it is appropriate. Patients and caregivers should be instructed to follow the directions provided in the Instructions for Use for additional details on medication administration. Inspect visually for particulate matter and discoloration prior to administration. Do not use ORENCIA prefilled syringes or ORENCIA ClickJect autoinjectors exhibiting particulate matter or discoloration. ORENCIA should be clear and colorless to pale yellow. Patients using ORENCIA prefilled syringes and ORENCIA ClickJect autoinjectors for subcutaneous administration should be instructed to inject the full amount, which provides the proper dose of ORENCIA, according to the directions provided in the Instructions for Use. Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red, or hard. Dosage Forms And Strengths Intravenous Infusion For Injection: 250 mg lyophilized powder in a single-use vial Subcutaneous Injection Injection: 50 mg/0.4 mL, 87.5 mg/0.7 mL, and 125 mg/mL of a clear to slightly opalescent, colorless to pale-yellow solution in a single-dose prefilled glass syringe. Injection: 125 mg/mL of a clear to slightly opalescent, colorless to pale-yellow solution in a single-dose prefilled ClickJect autoinjector. HOW SUPPLIED Storage And Handling For Intravenous Infusion ORENCIA&reg; (abatacept) for Injection is a lyophilized powder for intravenous infusion after reconstitution and dilution. It is supplied as an individually packaged, single-use vial with a silicone-free disposable syringe, providing 250 mg of abatacept in a 15-mL vial: NDC 0003-2187-10: in a clamshell presentation NDC 0003-2187-13: in a carton presentation For Subcutaneous Injection ORENCIA&reg; (abatacept) Injection and ORENCIA&reg; ClickJect (abatacept) are solutions for subcutaneous administration. Prefilled Syringe ORENCIA Injection, 50 mg/0.4 mL, 87.5 mg/0.7 mL, and 125 mg/mL, is supplied as single-dose disposable prefilled glass syringes with BD UltraSafe Passive&trade; needle guard and flange extenders. The Type I glass syringe has a coated stopper and fixed stainless steel needle (5 bevel, 29-gauge thin wall, &frac12;-inch needle) covered with a rigid needle shield. The prefilled syringe provides abatacept in the following packages: NDC 0003-2814-11 (50 mg/0.4 mL): pack of 4 syringes with a passive needle safety guard NDC 0003-2818-11 (87.5 mg/0.7 mL): pack of 4 syringes with a passive needle safety guard NDC 0003-2188-11 (125 mg/mL): pack of 4 syringes with a passive needle safety guard ClickJect Autoinjector ORENCIA ClickJect, 125 mg/mL, is supplied as a single-dose disposable prefilled autoinjector. The Type I glass syringe contained in the autoinjector has a coated stopper and fixed stainless steel needle (5 bevel, 27-gauge special thin wall, &frac12;-inch needle) covered with a rigid needle shield. The autoinjector provides 125 mg of abatacept in 1 mL and is provided in the following package: NDC 0003-2188-51: pack of 4 autoinjectors Storage ORENCIA lyophilized powder supplied in a vial should be refrigerated at 2&deg;C to 8&deg;C (36&deg;F to 46&deg;F). Do not use beyond the expiration date on the vial. Protect the vials from light by storing in the original package until time of use. ORENCIA solution supplied in a prefilled syringe or ClickJect autoinjector should be refrigerated at 2&deg;C to 8&deg;C (36&deg;F to 46&deg;F). Do not use beyond the expiration date on the prefilled syringe or autoinjector. Protect from light by storing in the original package until time of use. Do not allow the prefilled syringe or autoinjector to freeze. Bristol-Myers Squibb Company, Princeton, NJ 08543 USA. Revised March 2017112017-09-01 11:12:57AbataceptOrenciaFDA
882017-12-04 17:38:07Side Effects & Drug InteractionsSIDE EFFECTS Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to abatacept in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Clinical Studies Experience In Adult RA Patients Treated With Intravenous ORENCIA The data described herein reflect exposure to ORENCIA administered intravenously in patients with active RA in placebo-controlled studies (1955 patients with ORENCIA, 989 with placebo). The studies had either a double-blind, placebo-controlled period of 6 months (258 patients with ORENCIA, 133 with placebo) or 1 year (1697 patients with ORENCIA, 856 with placebo). A subset of these patients received concomitant biologic DMARD therapy, such as a TNF blocking agent (204 patients with ORENCIA, 134 with placebo). The majority of patients in RA clinical studies received one or more of the following concomitant medications with ORENCIA: methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, TNF blocking agents, azathioprine, chloroquine, gold, hydroxychloroquine, leflunomide, sulfasalazine, and anakinra. The most serious adverse reactions were serious infections and malignancies. The most commonly reported adverse events (occurring in &ge; 10% of patients treated with ORENCIA) were headache, upper respiratory tract infection, nasopharyngitis, and nausea. The adverse events most frequently resulting in clinical intervention (interruption or discontinuation of ORENCIA) were due to infection. The most frequently reported infections resulting in dose interruption were upper respiratory tract infection (1.0%), bronchitis (0.7%), and herpes zoster (0.7%). The most frequent infections resulting in discontinuation were pneumonia (0.2%), localized infection (0.2%), and bronchitis (0.1%). Infections In the placebo-controlled trials, infections were reported in 54% of ORENCIA-treated patients and 48% of placebo-treated patients. The most commonly reported infections (reported in 5%-13% of patients) were upper respiratory tract infection, nasopharyngitis, sinusitis, urinary tract infection, influenza, and bronchitis. Other infections reported in fewer than 5% of patients at a higher frequency ( > 0.5%) with ORENCIA compared to placebo, were rhinitis, herpes simplex, and pneumonia [see WARNINGS AND PRECAUTIONS]. Serious infections were reported in 3.0% of patients treated with ORENCIA and 1.9% of patients treated with placebo. The most common (0.2%-0.5%) serious infections reported with ORENCIA were pneumonia, cellulitis, urinary tract infection, bronchitis, diverticulitis, and acute pyelonephritis [see WARNINGS AND PRECAUTIONS]. Malignancies In the placebo-controlled portions of the clinical trials (1955 patients treated with ORENCIA for a median of 12 months), the overall frequencies of malignancies were similar in the ORENCIA and placebo-treated patients (1.3% and 1.1%, respectively). However, more cases of lung cancer were observed in ORENCIA-treated patients (4, 0.2%) than placebo-treated patients (0). In the cumulative ORENCIA clinical trials (placebo-controlled and uncontrolled, open-label) a total of 8 cases of lung cancer (0.21 cases per 100 patient-years) and 4 lymphomas (0.10 cases per 100 patient-years) were observed in 2688 patients (3827 patient-years). The rate observed for lymphoma is approximately 3.5-fold higher than expected in an age- and gender-matched general population based on the National Cancer Institute's Surveillance, Epidemiology, and End Results Database. Patients with RA, particularly those with highly active disease, are at a higher risk for the development of lymphoma. Other malignancies included skin, breast, bile duct, bladder, cervical, endometrial, lymphoma, melanoma, myelodysplastic syndrome, ovarian, prostate, renal, thyroid, and uterine cancers [see WARNINGS AND PRECAUTIONS]. The potential role of ORENCIA in the development of malignancies in humans is unknown. Infusion-Related Reactions And Hypersensitivity Reactions Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies III, IV, and V [see Clinical Studies] were more common in the ORENCIA-treated patients than the placebo patients (9% for ORENCIA, 6% for placebo). The most frequently reported events (1%-2%) were dizziness, headache, and hypertension. Acute infusion-related events that were reported in > 0.1% and &le; 1% of patients treated with ORENCIA included cardiopulmonary symptoms, such as hypotension, increased blood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, and wheezing. Most of these reactions were mild (68%) to moderate (28%). Fewer than 1% of ORENCIA-treated patients discontinued due to an acute infusion-related event. In controlled trials, 6 ORENCIA-treated patients compared to 2 placebo-treated patients discontinued study treatment due to acute infusion-related events. In clinical trials of 2688 adult RA patients treated with intravenous ORENCIA, there were two cases ( < 0.1%) of anaphylaxis or anaphylactoid reactions. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients and generally occurred within 24 hours of ORENCIA infusion. Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see WARNINGS AND PRECAUTIONS]. Adverse Reactions In Patients With COPD In Study V [see Clinical Studies], there were 37 patients with chronic obstructive pulmonary disease (COPD) who were treated with ORENCIA and 17 COPD patients who were treated with placebo. The COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo (97% vs 88%, respectively). Respiratory disorders occurred more frequently in ORENCIA-treated patients compared to placebo-treated patients (43% vs 24%, respectively) including COPD exacerbation, cough, rhonchi, and dyspnea. A greater percentage of ORENCIA-treated patients developed a serious adverse event compared to placebo-treated patients (27% vs 6%), including COPD exacerbation (3 of 37 patients [8%]) and pneumonia (1 of 37 patients [3%]) [see WARNINGS AND PRECAUTIONS]. Other Adverse Reactions Adverse events occurring in 3% or more of patients and at least 1% more frequently in ORENCIA-treated patients during placebo-controlled RA studies are summarized in Table 3. Table 3: Adverse Events Occurring in 3% or More of Patients and at Least 1% More Frequently in ORENCIA-Treated Patients During Placebo-Controlled RA Studies Adverse Event (Preferred Term) ORENCIA (n=1955)a Percentage Placebo (n=989)b Percentage Headache 18 13 Nasopharyngitis 12 9 Dizziness 9 7 Cough 8 7 Back pain 7 6 Hypertension 7 4 Dyspepsia 6 4 Urinary tract infection 6 5 Rash 4 3 Pain in extremity 3 2 a Includes 204 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab). b Includes 134 patients on concomitant biologic DMARDs (adalimumab, anakinra, etanercept, or infliximab). Immunogenicity Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in RA patients for up to 2 years following repeated treatment with ORENCIA. Thirty-four of 1993 (1.7%) patients developed binding antibodies to the entire abatacept molecule or to the CTLA-4 portion of abatacept. Because trough levels of abatacept can interfere with assay results, a subset analysis was performed. In this analysis it was observed that 9 of 154 (5.8%) patients that had discontinued treatment with ORENCIA for over 56 days developed antibodies. Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies in a cell-based luciferase reporter assay. Six of 9 (67%) evaluable patients were shown to possess neutralizing antibodies. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity. No correlation of antibody development to clinical response or adverse events was observed. The data reflect the percentage of patients whose test results were positive for antibodies to abatacept in specific assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to abatacept with the incidence of antibodies to other products may be misleading. Clinical Experience In Methotrexate-Naive Patients Study VI was an active-controlled clinical trial in methotrexate-naive patients [see Clinical Studies]. The safety experience in these patients was consistent with Studies I-V. Clinical Studies Experience In Adult RA Patients Treated With Subcutaneous ORENCIA Study SC-1 was a randomized, double-blind, double-dummy, non-inferiority study that compared the efficacy and safety of abatacept administered subcutaneously (SC) and intravenously (IV) in 1457 subjects with rheumatoid arthritis, receiving background methotrexate, and experiencing an inadequate response to methotrexate (MTX-IR) [see Clinical Studies]. The safety experience and immunogenicity for ORENCIA administered subcutaneously was consistent with intravenous Studies I-VI. Due to the route of administration, injection site reactions and immunogenicity were evaluated in Study SC-1 and two other smaller studies discussed in the sections below. Injection Site Reactions In Adult RA Patients Treated With Subcutaneous ORENCIA Study SC-1 compared the safety of abatacept including injection site reactions following subcutaneous or intravenous administration. The overall frequency of injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous abatacept group and the intravenous abatacept group (subcutaneous placebo), respectively. All these injection site reactions (including hematoma, pruritus, and erythema) were mild (83%) to moderate (17%) in severity, and none necessitated drug discontinuation. Immunogenicity In Adult RA Patients Treated With Subcutaneous ORENCIA Study SC-1 compared the immunogenicity to abatacept following subcutaneous or intravenous administration. The overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no correlation of immunogenicity with effects on pharmacokinetics, safety, or efficacy. Immunogenicity And Safety Of Subcutaneous ORENCIA Administration As Monotherapy Without An Intravenous Loading Dose Study SC-2 was conducted to determine the effect of monotherapy use of ORENCIA on immunogenicity following subcutaneous administration without an intravenous load in 100 RA patients, who had not previously received abatacept or other CTLA4Ig, who received either subcutaneous ORENCIA plus methotrexate (n=51) or subcutaneous ORENCIA monotherapy (n=49). No patients in either group developed anti-product antibodies after 4 months of treatment. The safety observed in this study was consistent with that observed in the other subcutaneous studies. Immunogenicity And Safety Of Subcutaneous ORENCIA Upon Withdrawal (Three Months) And Restart Of Treatment Study SC-3 in the subcutaneous program was conducted to investigate the effect of withdrawal (three months) and restart of ORENCIA subcutaneous treatment on immunogenicity in RA patients treated concomitantly with methotrexate. One hundred sixty-seven patients were enrolled in the first 3-month treatment period and responders (n=120) were randomized to either subcutaneous ORENCIA or placebo for the second 3-month period (withdrawal period). Patients from this period then received open-label ORENCIA treatment in the final 3-month period of the study (period 3). At the end of the withdrawal period, 0/38 patients who continued to receive subcutaneous ORENCIA developed anti-product antibodies compared to 7/73 (9.6%) of patients who had subcutaneous ORENCIA withdrawn during this period. Half of the patients receiving subcutaneous placebo during the withdrawal period received a single intravenous infusion of ORENCIA at the start of period 3 and half received intravenous placebo. At the end of period 3, when all patients again received subcutaneous ORENCIA, the immunogenicity rates were 1/38 (2.6%) in the group receiving subcutaneous ORENCIA throughout, and 2/73 (2.7%) in the group that had received placebo during the withdrawal period. Upon reinitiating therapy, there were no injection reactions and no differences in response to therapy in patients who were withdrawn from subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous therapy, whether therapy was reintroduced with or without an intravenous loading dose. The safety observed in this study was consistent with that observed in the other studies. Clinical Studies Experience In Juvenile Idiopathic Arthritis Patients Treated With Intravenous ORENCIA In general, the adverse events in pediatric patients were similar in frequency and type to those seen in adult patients [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]. Study JIA-1 was a three-part study including an open-label extension that assessed the safety and efficacy of intravenous ORENCIA in 190 pediatric patients, 6 to 17 years of age, with polyarticular juvenile idiopathic arthritis. Overall frequency of adverse events in the 4-month, lead-in, open-label period of the study was 70%; infections occurred at a frequency of 36% [see Clinical Studies]. The most common infections were upper respiratory tract infection and nasopharyngitis. The infections resolved without sequelae, and the types of infections were consistent with those commonly seen in outpatient pediatric populations. Other events that occurred at a prevalence of at least 5% were headache, nausea, diarrhea, cough, pyrexia, and abdominal pain. A total of 6 serious adverse events (acute lymphocytic leukemia, ovarian cyst, varicella infection, disease flare [2], and joint wear) were reported during the initial 4 months of treatment with ORENCIA. Of the 190 patients with juvenile idiopathic arthritis treated with ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of events reported in adults. Upon continued treatment in the open-label extension period, the types of adverse events were similar in frequency and type to those seen in adult patients, except for a single patient diagnosed with multiple sclerosis while on open-label treatment. Immunogenicity Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with juvenile idiopathic arthritis following repeated treatment with ORENCIA throughout the open-label period. For patients who were withdrawn from therapy for up to 6 months during the double-blind period, the rate of antibody formation to the CTLA-4 portion of the molecule was 41% (22/54), while for those who remained on therapy the rate was 13% (7/54). Twenty of these patients had samples that could be tested for antibodies with neutralizing activity; of these, 8 (40%) patients were shown to possess neutralizing antibodies. The presence of antibodies was generally transient and titers were low. The presence of antibodies was not associated with adverse events, changes in efficacy, or an effect on serum concentrations of abatacept. For patients who were withdrawn from ORENCIA during the double-blind period for up to 6 months, no serious acute infusion-related events were observed upon re-initiation of ORENCIA therapy. Clinical Studies Experience In Juvenile Idiopathic Arthritis Patients Treated With Subcutaneous ORENCIA Study JIA-2 was an open-label study with a 4-month short-term period and a long-term extension period that assessed the pharmacokinetics (PK), safety, and efficacy of subcutaneous ORENCIA in 205 pediatric patients, 2 to 17 years of age with juvenile idiopathic arthritis. The safety experience and immunogenicity for ORENCIA administered subcutaneously were consistent with the intravenous Study JIA-1. There were no reported cases of hypersensitivity reactions. Local injection-site reactions occurred at a frequency of 4.4%. Clinical Studies Experience In Adult PsA Patients The safety of ORENCIA was evaluated in 594 patients with psoriatic arthritis (341 patients on ORENCIA and 253 patients on placebo), in two randomized, double-blind, placebo-controlled trials. Of the 341 patients who received ORENCIA, 128 patients received intravenous ORENCIA (PsA-I) and 213 patients received subcutaneous ORENCIA (PsA-II). The safety profile was comparable between studies PsA-I and PsA-II and consistent with the safety profile in rheumatoid arthritis [see WARNINGS AND PRECAUTIONS, Clinical Studies Experience in Adult RA Patients Treated with Intravenous ORENCIA and Clinical Studies Experience in Adult RA Patients Treated with Subcutaneous ORENCIA]. Postmarketing Experience Adverse reactions have been reported during the postapproval use of ORENCIA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to ORENCIA. Based on the postmarketing experience in adult RA patients, the following adverse reaction has been identified during postapproval use with ORENCIA. Vasculitis (including cutaneous vasculitis and leukocytoclastic vasculitis) DRUG INTERACTIONS TNF Antagonists Concurrent administration of a TNF antagonist with ORENCIA has been associated with an increased risk of serious infections and no significant additional efficacy over use of the TNF antagonists alone. Concurrent therapy with ORENCIA and TNF antagonists is not recommended [see WARNINGS AND PRECAUTIONS]. Other Biologic RA Therapy There is insufficient experience to assess the safety and efficacy of ORENCIA administered concurrently with other biologic RA therapy, such as anakinra, and therefore such use is not recommended. Blood Glucose Testing Parenteral drug products containing maltose can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA for intravenous administration, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving ORENCIA through intravenous administration, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods. ORENCIA for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring.112017-09-01 11:12:57AbataceptOrenciaFDA
892017-12-04 17:38:07Warnings & PrecautionsWARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Concomitant Use With TNF Antagonists In controlled clinical trials in patients with adult RA, patients receiving concomitant intravenous ORENCIA and TNF antagonist therapy experienced more infections (63%) and serious infections (4.4%) compared to patients treated with only TNF antagonists (43% and 0.8%, respectively) [see ADVERSE REACTIONS]. These trials failed to demonstrate an important enhancement of efficacy with concomitant administration of ORENCIA with TNF antagonist; therefore, concurrent therapy with ORENCIA and a TNF antagonist is not recommended. While transitioning from TNF antagonist therapy to ORENCIA therapy, patients should be monitored for signs of infection. Hypersensitivity In clinical trials of 2688 adult RA patients treated with intravenous ORENCIA, there were two cases ( < 0.1%) of anaphylaxis or anaphylactoid reactions. Other reactions potentially associated with drug hypersensitivity, such as hypotension, urticaria, and dyspnea, each occurred in less than 0.9% of ORENCIA-treated patients. Of the 190 patients with juvenile idiopathic arthritis treated with ORENCIA in clinical trials, there was one case of a hypersensitivity reaction (0.5%). Appropriate medical support measures for the treatment of hypersensitivity reactions should be available for immediate use in the event of a reaction [see ADVERSE REACTIONS]. Anaphylaxis or anaphylactoid reactions can occur after the first infusion and can be life threatening. In postmarketing experience, a case of fatal anaphylaxis following the first infusion of ORENCIA has been reported. If an anaphylactic or other serious allergic reaction occurs, administration of ORENCIA should be stopped immediately with appropriate therapy instituted, and the use of ORENCIA should be permanently discontinued. Infections Serious infections, including sepsis and pneumonia, have been reported in patients receiving ORENCIA. Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy which in addition to their underlying disease, could further predispose them to infection. Physicians should exercise caution when considering the use of ORENCIA in patients with a history of recurrent infections, underlying conditions which may predispose them to infections, or chronic, latent, or localized infections. Patients who develop a new infection while undergoing treatment with ORENCIA should be monitored closely. Administration of ORENCIA should be discontinued if a patient develops a serious infection [see ADVERSE REACTIONS]. A higher rate of serious infections has been observed in adult RA patients treated with concurrent TNF antagonists and ORENCIA [see Concomitant Use with TNF Antagonists]. Prior to initiating immunomodulatory therapies, including ORENCIA, patients should be screened for latent tuberculosis infection with a tuberculin skin test. ORENCIA has not been studied in patients with a positive tuberculosis screen, and the safety of ORENCIA in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated by standard medical practice prior to therapy with ORENCIA. Antirheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines before starting therapy with ORENCIA. In clinical studies with ORENCIA, patients who screened positive for hepatitis were excluded from study. Immunizations Live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. The efficacy of vaccination in patients receiving ORENCIA is not known. Based on its mechanism of action, ORENCIA may blunt the effectiveness of some immunizations. It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ORENCIA therapy. Use In Patients With Chronic Obstructive Pulmonary Disease (COPD) Adult COPD patients treated with ORENCIA developed adverse events more frequently than those treated with placebo, including COPD exacerbations, cough, rhonchi, and dyspnea. Use of ORENCIA in patients with RA and COPD should be undertaken with caution and such patients should be monitored for worsening of their respiratory status [see ADVERSE REACTIONS]. Immunosuppression The possibility exists for drugs inhibiting T cell activation, including ORENCIA, to affect host defenses against infections and malignancies since T cells mediate cellular immune responses. The impact of treatment with ORENCIA on the development and course of malignancies is not fully understood [see ADVERSE REACTIONS]. In clinical trials in patients with adult RA, a higher rate of infections was seen in ORENCIA-treated patients compared to placebo [see ADVERSE REACTIONS]. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use). Concomitant Use With Biologic Medications For RA Inform patients that they should not receive ORENCIA treatment concomitantly with a TNF antagonist, such as adalimumab, etanercept, and infliximab because such combination therapy may increase their risk for infections [see INDICATIONS AND USAGE, WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS], and that they should not receive ORENCIA concomitantly with other biologic RA therapy, such as anakinra because there is not enough information to assess the safety and efficacy of such combination therapy [see INDICATIONS AND USAGE, DRUG INTERACTIONS]. Hypersensitivity Instruct patients to immediately tell their healthcare professional if they experience symptoms of an allergic reaction during or for the first day after the administration of ORENCIA [see WARNINGS AND PRECAUTIONS]. Infections Ask patients if they have a history of recurrent infections, have underlying conditions which may predispose them to infections, or have chronic, latent, or localized infections. Ask patients if they have had tuberculosis (TB), a positive skin test for TB, or recently have been in close contact with someone who has had TB. Instruct patients that they may be tested for TB before they receive ORENCIA. Inform patients to tell their healthcare professional if they develop an infection during therapy with ORENCIA [see WARNINGS AND PRECAUTIONS]. Immunizations Inform patients that live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation. Inform caregivers of patients with juvenile idiopathic arthritis that the patient should be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ORENCIA therapy and to discuss with their healthcare provider how best to handle future immunizations once ORENCIA therapy has been initiated [see WARNINGS AND PRECAUTIONS]. Pregnancy And Nursing Mothers Inform patients that ORENCIA has not been studied in pregnant women or nursing mothers so the effects of ORENCIA on pregnant women or nursing infants are not known. Instruct patients to tell their healthcare professional if they are pregnant, become pregnant, or are thinking about becoming pregnant [see Use in Specific Populations]. Instruct patients to tell their healthcare professional if they plan to breastfeed their infant [see Use in Specific Populations]. Blood Glucose Testing Intravenous Administration Ask patients if they have diabetes. Maltose is contained in ORENCIA for intravenous administration and can give falsely elevated blood glucose readings with certain blood glucose monitors on the day of ORENCIA infusion. If a patient is using such a monitor, advise the patient to discuss with their healthcare professional methods that do not react with maltose [see DRUG INTERACTIONS]. Subcutaneous Administration ORENCIA for subcutaneous administration does not contain maltose; therefore, patients do not need to alter their glucose monitoring. Disposal Of Prefilled Syringes And ClickJect Autoinjectors Advise patients to follow disposal instructions in the Instructions for Use. A puncture-resistant container for disposal of needles and syringes should be used. Instruct patients that they will need to follow their community guidelines for the correct way to dispose of their sharps disposal container. Instruct patients not to recycle their used sharps disposal container. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility In a mouse carcinogenicity study, weekly subcutaneous injections of 20, 65, or 200 mg/kg of abatacept administered for up to 84 weeks in males and 88 weeks in females were associated with increases in the incidence of malignant lymphomas (all doses) and mammary gland tumors (intermediate- and high-dose in females). The mice from this study were infected with murine leukemia virus and mouse mammary tumor virus. These viruses are associated with an increased incidence of lymphomas and mammary gland tumors, respectively, in immunosuppressed mice. The doses used in these studies produced exposures 0.8, 2.0, and 3.0 times higher, respectively, than the exposure associated with the maximum recommended human dose (MRHD) of 10 mg/kg based on AUC (area under the time-concentration curve). The relevance of these findings to the clinical use of ORENCIA is unknown. In a one-year toxicity study in cynomolgus monkeys, abatacept was administered intravenously once weekly at doses up to 50 mg/kg (producing 9 times the MRHD exposure based on AUC). Abatacept was not associated with any significant drug-related toxicity. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centers in the spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphologic changes was observed, despite the presence of a virus (lymphocryptovirus) known to cause these lesions in immunosuppressed monkeys within the time frame of this study. The relevance of these findings to the clinical use of ORENCIA is unknown. No mutagenic potential of abatacept was observed in the in vitro bacterial reverse mutation (Ames) or Chinese hamster ovary/hypoxanthine guanine phosphoribosyl-transferase (CHO/HGPRT) forward point mutation assays with or without metabolic activation, and no chromosomal aberrations were observed in human lymphocytes treated with abatacept with or without metabolic activation. Abatacept had no adverse effects on male or female fertility in rats at doses up to 200 mg/kg every three days (11 times the MRHD exposure based on AUC). Use In Specific Populations Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ORENCIA during pregnancy. Healthcare professionals are encouraged to register patients and pregnant women are encouraged to enroll themselves by calling 1-877-311-8972. Risk Summary The data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk. In reproductive toxicology studies in rats and rabbits, no fetal malformations were observed with intravenous administration of ORENCIA during organogenesis at doses that produced exposures approximately 29 times the exposure at the maximum recommended human dose (MRHD) of 10 mg/kg/month on an AUC basis. However, in a pre- and postnatal development study in rats, ORENCIA altered immune function in female rats at 11 times the MRHD on an AUC basis. Data Human Data There are no adequate and well-controlled studies of ORENCIA use in pregnant women. The data with ORENCIA use in pregnant women are insufficient to inform on drug-associated risk. Animal Data Intravenous administration of abatacept during organogenesis to mice (10, 55, or 300 mg/kg/day), rats (10, 45, or 200 mg/kg/day), and rabbits (10, 45, or 200 mg/kg every 3 days) produced exposures in rats and rabbits that were approximately 29 times the MRHD on an AUC basis (at maternal doses of 200 mg/kg/day in rats and rabbits), and no embryotoxicity or fetal malformations were observed in any species. In a study of pre- and postnatal development in rats (10, 45, or 200 mg/kg every 3 days from gestation day 6 through lactation day 21), alterations in immune function in female offspring, consisting of a 9-fold increase in T-cell-dependent antibody response relative to controls on postnatal day (PND) 56 and thyroiditis in a single female pup on PND 112, occurred at approximately 11 times the MRHD on an AUC basis (at a maternal dose of 200 mg/kg). No adverse effects were observed at approximately 3 times the MRHD (a maternal dose of 45 mg/kg). It is not known if immunologic perturbations in rats are relevant indicators of a risk for development of autoimmune diseases in humans exposed in utero to abatacept. Exposure to abatacept in the juvenile rat, which may be more representative of the fetal immune system state in the human, resulted in immune system abnormalities including inflammation of the thyroid and pancreas [see Nonclinical Toxicology]. Lactation Risk Summary There is no information regarding the presence of abatacept in human milk, the effects on the breastfed infant, or the effects on milk production. However, abatacept was present in the milk of lactating rats dosed with abatacept. Pediatric Use In Study JIA-1, ORENCIA with intravenous administration was shown to reduce signs and symptoms of active polyarticular JIA in patients 6 to 17 years of age [see Clinical Studies]. ORENCIA with intravenous administration has not been studied in patients younger than 6 years of age. In Study JIA-2, the PK and safety of ORENCIA prefilled syringe for subcutaneous injection have been studied in patients 2 to 17 years of age. The efficacy of ORENCIA for subcutaneous injection in children 2 to 17 years of age is based on pharmacokinetic exposure and extrapolation of established efficacy of intravenous ORENCIA in polyarticular JIA patients and subcutaneous ORENCIA in patients with RA [see CLINICAL PHARMACOLOGY and Clinical Studies]. The safety and immunogenicity of ORENCIA for subcutaneous injection in children 2 to 17 years of age were assessed descriptively [see ADVERSE REACTIONS]. ORENCIA may be used as monotherapy or concomitantly with methotrexate. The safety and efficacy of ORENCIA ClickJect autoinjector for subcutaneous injection have not been studied in patients under 18 years of age. Studies in juvenile rats exposed to ORENCIA prior to immune system maturity have shown immune system abnormalities including an increase in the incidence of infections leading to death as well as inflammation of the thyroid and pancreas [see Nonclinical Toxicology]. Studies in adult mice and monkeys have not demonstrated similar findings. As the immune system of the rat is undeveloped in the first few weeks after birth, the relevance of these results to humans is unknown. The safety and efficacy of ORENCIA in pediatric patients for uses other than juvenile idiopathic arthritis have not been established. It is unknown if abatacept can cross the placenta into the fetus when the woman is treated with abatacept during pregnancy. Since abatacept is an immunomodulatory agent, the safety of administering live vaccines in infants exposed in utero to abatacept is unknown. Risk and benefits should be considered prior to vaccinating such infants. Geriatric Use A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received ORENCIA in clinical studies. No overall differences in safety or effectiveness were observed between these patients and younger patients, but these numbers are too low to rule out differences. The frequency of serious infection and malignancy among ORENCIA-treated patients over age 65 was higher than for those under age 65. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.112017-09-01 11:12:57AbataceptOrenciaFDA
902017-12-04 17:38:07Overdosage & ContraindicationsOVERDOSE Doses up to 50 mg/kg have been administered intravenously without apparent toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted. CONTRAINDICATIONS None.112017-09-01 11:12:57AbataceptOrenciaFDA
912017-12-04 17:38:07Clinical PharmacologyCLINICAL PHARMACOLOGY Mechanism Of Action Abatacept, a selective costimulation modulator, inhibits T cell (T lymphocyte) activation by binding to CD80 and CD86, thereby blocking interaction with CD28. This interaction provides a costimulatory signal necessary for full activation of T lymphocytes. Activated T lymphocytes are implicated in the pathogenesis of RA and PsA and are found in the synovium of patients with RA and PsA. In vitro, abatacept decreases T cell proliferation and inhibits the production of the cytokines TNF alpha (TNF&alpha;), interferon-&gamma;, and interleukin-2. In a rat collagen-induced arthritis model, abatacept suppresses inflammation, decreases anti-collagen antibody production, and reduces antigen specific production of interferon-&gamma;. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its clinical effects is unknown. Pharmacodynamics In clinical trials with ORENCIA at doses approximating 10 mg/kg, decreases were observed in serum levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), rheumatoid factor (RF), C-reactive protein (CRP), matrix metalloproteinase-3 (MMP3), and TNF&alpha;. The relationship of these biological response markers to the mechanisms by which ORENCIA exerts its clinical effects is unknown. Pharmacokinetics Healthy Adults And Adult RA - Intravenous Administration The pharmacokinetics of abatacept were studied in healthy adult subjects after a single 10 mg/kg intravenous infusion and in RA patients after multiple 10 mg/kg intravenous infusions (see Table 5). Table 5: Pharmacokinetic Parameters (Mean, Range) in Healthy Subjects and RA Patients After 10 mg/kg Intravenous Infusion(s) PK Parameter Healthy Subjects (After 10 mg/kg Single Dose) n=13 RA Patients (After 10 mg/kg Multiple Dosesa) n=14 Peak Concentration (Cmax) [mcg/mL] 292 (175-427) 295 (171-398) Terminal half-life (t1/2) [days] 16.7 (12-23) 13.1 (8-25) Systemic clearance (CL) [mL/h/kg] 0.23 (0.16-0.30) 0.22 (0.13-0.47) Volume of distribution (Vss) [L/kg] 0.09 (0.06-0.13) 0.07 (0.02-0.13) a Multiple intravenous infusions were administered at days 1, 15, 30, and monthly thereafter. The pharmacokinetics of abatacept in RA patients and healthy subjects appeared to be comparable. In RA patients, after multiple intravenous infusions, the pharmacokinetics of abatacept showed proportional increases of Cmax and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady state by day 60 with a mean (range) trough concentration of 24 mcg/mL (1 to 66 mcg/mL). No systemic accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at monthly intervals in RA patients. Population pharmacokinetic analyses in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect clearance. Concomitant methotrexate, NSAIDs, corticosteroids, and TNF blocking agents did not influence abatacept clearance. No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of abatacept. Adult RA - Subcutaneous Administration Abatacept exhibited linear pharmacokinetics following subcutaneous administration. The mean (range) for Cmin and Cmax at steady state observed after 85 days of treatment was 32.5 mcg/mL (6.6 to 113.8 mcg/mL) and 48.1 mcg/mL (9.8 to 132.4 mcg/mL), respectively. The bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6%. Mean estimates for systemic clearance (0.28 mL/h/kg), volume of distribution (0.11 L/kg), and terminal half-life (14.3 days) were comparable between subcutaneous and intravenous administration. Study SC-2 was conducted to determine the effect of monotherapy use of ORENCIA on immunogenicity following subcutaneous administration without an intravenous load. When the intravenous loading dose was not administered, a mean trough concentration of 12.6 mcg/mL was achieved after 2 weeks of dosing. Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous abatacept in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent clearance. Juvenile Idiopathic Arthritis - Intravenous Administration In Study JIA-1 among patients 6 to 17 years of age, the mean (range) steady state serum peak and trough concentrations of abatacept were 217 mcg/mL (57 to 700 mcg/mL) and 11.9 mcg/mL (0.15 to 44.6 mcg/mL). Population pharmacokinetic analyses of the serum concentration data showed that clearance of abatacept increased with baseline body weight. The estimated mean (range) clearance of abatacept in the juvenile idiopathic arthritis patients was 0.4 mL/h/kg (0.20 to 1.12 mL/h/kg). After accounting for the effect of body weight, the clearance of abatacept was not related to age and gender. Concomitant methotrexate, corticosteroids, and NSAIDs were also shown not to influence abatacept clearance. Juvenile Idiopathic Arthritis - Subcutaneous Administration In Study JIA-2 among patients 2 to 17 years of age, steady state of abatacept was achieved by Day 85 following the weekly body-weight-tiered subcutaneous abatacept dosing. Comparable trough concentrations across weight tiers and age groups were achieved by the body-weight- tiered subcutaneous dosing regimen. The mean (range) trough concentration of abatacept at Day 113 was 44.4 mcg/mL (13.4 to 88.1 mcg/mL), 46.6 mcg/mL (22.4 to 97.0 mcg/mL), and 38.5 mcg/mL (9.3 to 73.2 mcg/mL) in pediatric JIA patients weighing 10 to < 25 kg, 25 to < 50 kg, and &ge; 50 kg, respectively. Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous abatacept in JIA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant medication, such as methotrexate, corticosteroids, and NSAIDs, did not influence abatacept apparent clearance. Adult Psoriatic Arthritis - Intravenous And Subcutaneous Administration In Study PsA-I, a dose ranging study, IV abatacept was administered at 3 mg/kg, 10 mg/kg (weight range-based dosing: 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100 kg), or two doses of 30 mg/kg followed by weight range-based dose of 10 mg/kg. Following monthly IV administration, abatacept showed linear PK over the dose range of 3 mg/kg to 10 mg/kg. At 10 mg/kg, the steady state of abatacept was reached by Day 57 and the geometric mean (CV%) trough concentration (Cmin) was 24.3 mcg/mL (40.8%) at Day 169. In Study PsA-II following weekly SC administration of abatacept at 125 mg, the steady state of abatacept was reached at Day 57 and the geometric mean (CV%) Cmin was 25.6 mcg/mL (47.7%) at Day 169. Consistent with the RA results, population pharmacokinetic analyses for abatacept in psoriatic arthritis patients revealed that there was a trend toward higher clearance (L/h) of abatacept with increasing body weight. In addition, relative to the RA patients with the same body weight, abatacept clearance in psoriatic arthritis patients was approximately 8% lower, resulting in higher abatacept exposures in patients with PsA. This slight difference in exposures, however, is not considered to be clinically meaningful. Animal Toxicology And/Or Pharmacology A juvenile animal study was conducted in rats dosed with abatacept from 4 to 94 days of age in which an increase in the incidence of infections leading to death occurred at all doses compared with controls. Altered T-cell subsets including increased T-helper cells and reduced T-regulatory cells were observed. In addition, inhibition of T-cell-dependent antibody responses (TDAR) was observed. Upon following these animals into adulthood, lymphocytic inflammation of the thyroid and pancreatic islets was observed. In studies of adult mice and monkeys, inhibition of TDAR was apparent. However, infection and mortality, altered T-helper cells, and inflammation of thyroid and pancreas were not observed. Clinical Studies Adult Rheumatoid Arthritis The efficacy and safety of ORENCIA for intravenous administration were assessed in six randomized, double-blind, controlled studies (five placebo-controlled and one active-controlled) in patients &ge; 18 years of age with active RA diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, IV, and VI required patients to have at least 12 tender and 10 swollen joints at randomization. Study V did not require any specific number of tender or swollen joints. ORENCIA or placebo treatment was given intravenously at weeks 0, 2, and 4 and then every 4 weeks thereafter in intravenous Studies I, II, III, IV, and VI. The safety and efficacy of ORENCIA for subcutaneous administration were assessed in Study SC-1, which was a randomized, double-blind, double-dummy, non-inferiority study that compared abatacept administered subcutaneously and intravenously in 1457 subjects with rheumatoid arthritis (RA), receiving background methotrexate (MTX), and experiencing an inadequate response to methotrexate (MTX-IR). Study I evaluated ORENCIA as monotherapy in 122 patients with active RA who had failed at least one non-biologic DMARD or etanercept. In Study II and Study III, the efficacy and safety of ORENCIA were assessed in patients with an inadequate response to methotrexate and who were continued on their stable dose of methotrexate. In Study IV, the efficacy and safety of ORENCIA were assessed in patients with an inadequate response to a TNF blocking agent, with the TNF blocking agent discontinued prior to randomization; other DMARDs were permitted. Study V primarily assessed safety in patients with active RA requiring additional intervention in spite of current therapy with DMARDs; all DMARDs used at enrollment were continued. Patients in Study V were not excluded for comorbid medical conditions. In Study VI, the efficacy and safety of ORENCIA were assessed in methotrexate-naive patients with RA of less than 2 years disease duration. In Study VI, patients previously naive to methotrexate were randomized to receive ORENCIA plus methotrexate or methotrexate plus placebo. In Study SC-1, the goal was to demonstrate the efficacy and safety of ORENCIA subcutaneous relative to ORENCIA intravenous administration in subjects with moderate to severely active RA and experiencing inadequate response to methotrexate, using a non-inferiority study design. Study I patients were randomized to receive one of three doses of ORENCIA (0.5, 2, or 10 mg/kg) or placebo ending at week 8. Study II patients were randomized to receive ORENCIA 2 or 10 mg/kg or placebo for 12 months. Study III, IV, V, and VI patients were randomized to receive a dose of ORENCIA based on weight range or placebo for 12 months (Studies III, V, and VI) or 6 months (Study IV). The dose of ORENCIA was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100 kg. In Study SC-1, patients were randomized with stratification by body weight ( < 60 kg, 60 to 100 kg, > 100 kg) to receive ORENCIA 125 mg subcutaneous injections weekly, after a single intravenous loading dose of ORENCIA based on body weight or ORENCIA intravenously on Days 1, 15, 29, and every four weeks thereafter. Subjects continued taking their current dose of methotrexate from the day of randomization. Clinical Response The percent of ORENCIA-treated patients achieving ACR 20, 50, and 70 responses and major clinical response in Studies I, III, IV, and VI are shown in Table 6. ORENCIA-treated patients had higher ACR 20, 50, and 70 response rates at 6 months compared to placebo-treated patients. Month 6 ACR response rates in Study II for the 10 mg/kg group were similar to the ORENCIA group in Study III. In Studies III and IV, improvement in the ACR 20 response rate versus placebo was observed within 15 days in some patients and within 29 days versus methotrexate in Study VI. In Studies II, III, and VI, ACR response rates were maintained to 12 months in ORENCIA-treated patients. ACR responses were maintained up to three years in the open-label extension of Study II. In Study III, ORENCIA-treated patients experienced greater improvement than placebo-treated patients in morning stiffness. In Study VI, a greater proportion of patients treated with ORENCIA plus methotrexate achieved a low level of disease activity as measured by a DAS28-CRP less than 2.6 at 12 months compared to those treated with methotrexate plus placebo (Table 6). Of patients treated with ORENCIA plus methotrexate who achieved DAS28-CRP less than 2.6, 54% had no active joints, 17% had one active joint, 7% had two active joints, and 22% had three or more active joints, where an active joint was a joint that was rated as tender or swollen or both. In Study SC-1, the main outcome measure was ACR 20 at 6 months. The pre-specified noninferiority margin was a treatment difference of -7.5%. As shown in Table 6, the study demonstrated non-inferiority of ORENCIA administered subcutaneously to intravenous infusions of ORENCIA with respect to ACR 20 responses up to 6 months of treatment. ACR 50 and 70 responses are also shown in Table 6. No major differences in ACR responses were observed between intravenous and subcutaneous treatment groups in subgroups based on weight categories (less than 60 kg, 60 to 100 kg, and more than 100 kg; data not shown). Table 6: Clinical Responses in Controlled Trials Response Rate Percent of Patients Intravenous Administration Subcutaneous Administration Inadequate Response to DMARDs Inadequate Response to Methotrexate (MTX) Inadequate Response to TNF Blocking Agent MTX-Naive Inadequate Response to MTX Study I Study III Study IV Study VI Study SC-1 ORNa n=32 PBO n=32 ORNb +MTX n=424 PBO +MTX n=214 ORNb + DMARDs n=256 PBO + DMARDs n=133 ORNb +MTX n=256 PBO +MTX n=253 ORNe SC +MTX n=693 ORNe IV +MTX n=678 ACR 20 Month 3 53% 31% 62%&Dagger; 37% 46%&Dagger; 18% 64%* 53% 68% 69% Month 6 NA NA 68%&Dagger; 40% 50%&Dagger; 20% 75%&dagger; 62% 76%&sect; 76% Month 12 NA NA 73%&Dagger; 40% NA NA 76%&Dagger; 62% NA NA ACR 50 Month 3 16% 6% 32%&Dagger; 8% 18%&dagger; 6% 40%&Dagger; 23% 33% 39% Month 6 NA NA 40%&Dagger; 17% 20%&Dagger; 4% 53%&Dagger; 38% 52% 50% Month 12 NA NA 48%&Dagger; 18% NA NA % 7 5 42% NA NA ACR 70 Month 3 6% 0 13%&Dagger; 3% 6%* 1% 19%&dagger; 10% 13% 16% Month 6 NA NA 20%&Dagger; 7% 10%&dagger; 2% 32%&dagger; 20% 26% 25% Month 12 NA NA 29%&Dagger; 6% NA NA 43%&Dagger; 27% NA NA Major Clinical Responsec NA NA 14%&Dagger; 2% NA NA 27%&Dagger; 12% NA NA DAS28-CRP < 2.6d Month 12 NA NA NA NA NA NA 41%&Dagger; 23% NA NA * p < 0.05, ORENCIA (ORN) vs placebo (PBO) or MTX. &dagger; p < 0.01, ORENCIA vs placebo or MTX. &Dagger; p < 0.001, ORENCIA vs placebo or MTX. &sect; 95% CI: -4.2, 4.8 (based on prespecified margin for non-inferiority of -7.5%). a 10 mg/kg. b Dosing based on weight range [see DOSAGE AND ADMINISTRATION]. c Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period. d Refer to text for additional description of remaining joint activity. e Per protocol data is presented in table. For ITT; n=736, 721 for SC and IV ORENCIA, respectively. The results of the components of the ACR response criteria for Studies III, IV, and SC-1 are shown in Table 7 (results at Baseline [BL] and 6 months [6 M]). In ORENCIA-treated patients, greater improvement was seen in all ACR response criteria components through 6 and 12 months than in placebo-treated patients. Table 7: Components of ACR Responses at 6 Months Component (median) Intravenous Administration Subcutaneous Administration Inadequate Response to Methotrexate (MTX) Inadequate Response to TNF Blocking Agent Inadequate Response to MTX Study III Study IV Study SC-1c ORN +MTX n=424 PBO +MTX n=214 ORN +DMARDs n=256 PBO +DMARDs n=133 ORN SC +MTX n=693 ORN IV +MTX n=678 BL 6 M BL 6 M BL 6 M BL 6 M BL 6 M BL 6 M Number of tender joints (0-68) 28 7&Dagger; 31 14 30 13&Dagger; 31 24 27 5 27 6 Number of swollen joints (0-66) 19 5&Dagger; 20 11 21 10&Dagger; 20 14 18 4 18 3 Paina 67 27&Dagger; 70 50 73 43&dagger; 74 64 71 25 70 28 Patient global assessmenta 66 29&Dagger; 64 48 71 44&Dagger; 73 63 70 26 68 27 Disability indexb 1.75 1.13&Dagger; 1.75 1.38 1.88 1.38&Dagger; 2.00 1.75 1.88 1.00 1.75 1.00 Physician global assessmenta 69 21&Dagger; 68 40 71 32&Dagger; 69 54 65 16 65 15 CRP (mg/dL) 2.2 0.9&Dagger; 2.1 1.8 3.4 1.3&Dagger; 2.8 2.3 1.6 0.7 1.8 0.7 &dagger; p < 0.01, ORENCIA (ORN) vs placebo (PBO), based on mean percent change from baseline. &Dagger; p < 0.001, ORENCIA vs placebo, based on mean percent change from baseline. a Visual analog scale: 0 = best, 100 = worst. b Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. c SC-1 is a non-inferiority study. Per protocol data is presented in table. The percent of patients achieving the ACR 50 response for Study III by visit is shown in Figure 1. The time course for the ORENCIA group in Study VI was similar to that in Study III. Figure 1: Percent of Patients Achieving ACR 50 Response by Visit* (Study III) The percent of patients achieving the ACR 50 response for Study SC-1 in the ORENCIA subcutaneous (SC) and intravenous (IV) treatment arms at each treatment visit was as follows: Day 15-SC 3%, IV 5%; Day 29-SC 11%, IV 14%; Day 57-SC 24%, IV 30%; Day 85- SC 33%, IV 38%; Day 113-SC 39%, IV 41%; Day 141-SC 46%, IV 47%; Day 169-SC 51%, IV 50%. Radiographic Response In Study III and Study VI, structural joint damage was assessed radiographically and expressed as change from baseline in the Genant-modified Total Sharp Score (TSS) and its components, the Erosion Score (ES) and Joint Space Narrowing (JSN) score. ORENCIA/methotrexate slowed the progression of structural damage compared to placebo/methotrexate after 12 months of treatment as shown in Table 8. Table 8: Mean Radiographic Changes in Study IIIa and Study VIb Parameter ORENCIA/ MTX Placebo/ MTX Differences P-valued Study III First Year TSS 1.07 2.43 1.36 < 0.01 ES 0.61 1.47 0.86 < 0.01 JSN score 0.46 0.97 0.51 < 0.01 Second Year TSS 0.48 0.74c - - ES 0.23 0.22c - - JSN score 0.25 0.51c - - Study VI First Year TSS 0.6 1.1 0.5 0.04 a Patients with an inadequate response to MTX. b MTX-naive patients. c Patients received 1 year of placebo/MTX followed by 1 year of ORENCIA/MTX. d Based on a nonparametric ANCOVA model. In the open-label extension of Study III, 75% of patients initially randomized to ORENCIA/methotrexate and 65% of patients initially randomized to placebo/methotrexate were evaluated radiographically at Year 2. As shown in Table 8, progression of structural damage in ORENCIA/methotrexate-treated patients was further reduced in the second year of treatment. Following 2 years of treatment with ORENCIA/methotrexate, 51% of patients had no progression of structural damage as defined by a change in the TSS of zero or less compared with baseline. Fifty-six percent (56%) of ORENCIA/methotrexate-treated patients had no progression during the first year compared to 45% of placebo/methotrexate-treated patients. In their second year of treatment with ORENCIA/methotrexate, more patients had no progression than in the first year (65% vs 56%). Physical Function Response And Health-Related Outcomes Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). In the HAQ-DI, ORENCIA demonstrated greater improvement from baseline versus placebo in Studies II-V and versus methotrexate in Study VI. In Study SC-1, improvement from baseline as measured by HAQ-DI at 6 months and over time was similar between subcutaneous and intravenous administration. The results from Studies II and III are shown in Table 9. Similar results were observed in Study V compared to placebo and in Study VI compared to methotrexate. During the open-label period of Study II, the improvement in physical function has been maintained for up to 3 years. Table 9: Mean Improvement from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) HAQ Disability Index Inadequate Response to Methotrexate Study II Study III ORENCIAa +MTX (n=115) Placebo +MTX (n=119) ORENCIAb +MTX (n=422) Placebo+ MTX (n=212) Baseline (Mean) 0.98c 0.97c 1.69d 1.69d Mean Improvement Year 1 0 40c*** 0.15c 0.66d*** 0.3 7d *** p < 0.001, ORENCIA vs placebo. a 10 mg/kg. b Dosing based on weight range [see DOSAGE AND ADMINISTRATION]. c Modified Health Assessment Questionnaire: 0 = best, 3 = worst; 8 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. d Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in Studies II, III, and IV and at 12 months in Studies II and III. In these studies, improvement was observed in the ORENCIA group as compared with the placebo group in all 8 domains of the SF-36 as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS). Juvenile Idiopathic Arthritis Juvenile Idiopathic Arthritis - Intravenous Administration The safety and efficacy of ORENCIA with intravenous administration were assessed in Study JIA-1, a three-part study including an open-label extension in children with polyarticular juvenile idiopathic arthritis (JIA). Patients 6 to 17 years of age (n=190) with moderately to severely active polyarticular JIA who had an inadequate response to one or more DMARDs, such as methotrexate or TNF antagonists, were treated. Patients had a disease duration of approximately 4 years with moderately to severely active disease at study entry, as determined by baseline counts of active joints (mean, 16) and joints with loss of motion (mean, 16); patients had elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dL) and ESR (mean, 32 mm/h). The patients enrolled had subtypes of JIA that at disease onset included Oligoarticular (16%), Polyarticular (64%; 20% were rheumatoid factor positive), and Systemic (20%). At study entry, 74% of patients were receiving methotrexate (mean dose, 13.2 mg/m&sup2; per week) and remained on a stable dose of methotrexate (those not receiving methotrexate did not initiate methotrexate treatment during the study). In Period A (open-label, lead-in), patients received 10 mg/kg (maximum 1000 mg per dose) intravenously on days 1, 15, 29, and monthly thereafter. Response was assessed utilizing the ACR Pediatric 30 definition of improvement, defined as &ge; 30% improvement in at least 3 of the 6 JIA core set variables and &ge; 30% worsening in not more than 1 of the 6 JIA core set variables. Patients demonstrating an ACR Pedi 30 response at the end of Period A were randomized into the double-blind phase (Period B) and received either ORENCIA or placebo for 6 months or until disease flare. Disease flare was defined as a &ge; 30% worsening in at least 3 of the 6 JIA core set variables with &ge; 30% improvement in not more than 1 of the 6 JIA core set variables; &ge; 2 cm of worsening of the Physician or Parent Global Assessment was necessary if used as 1 of the 3 JIA core set variables used to define flare, and worsening in &ge; 2 joints was necessary if the number of active joints or joints with limitation of motion was used as 1 of the 3 JIA core set variables used to define flare. At the conclusion of Period A, pediatric ACR 30/50/70 responses were 65%, 50%, and 28%, respectively. Pediatric ACR 30 responses were similar in all subtypes of JIA studied. During the double-blind randomized withdrawal phase (Period B), ORENCIA-treated patients experienced significantly fewer disease flares compared to placebo-treated patients (20% vs 53%); 95% CI of the difference (15%, 52%). The risk of disease flare among patients continuing on ORENCIA was less than one-third than that for patients withdrawn from ORENCIA treatment (hazard ratio=0.31, 95% CI [0.16, 0.59]). Among patients who received ORENCIA throughout the study (Period A, Period B, and the open-label extension Period C), the proportion of pediatric ACR 30/50/70 responders has remained consistent for 1 year. Juvenile Idiopathic Arthritis - Subcutaneous Administration ORENCIA for subcutaneous administration without an intravenous loading dose was assessed in Study JIA-2, a 2-period, open-label study that included children 2 to 17 years of age (n=205). Patients had active polyarticular disease at the time of the study and had inadequate response to at least one nonbiologic or biologic DMARD. The patient subtypes at study entry included Polyarticular (79%; 22% were rheumatoid factor positive), Extended and Persistent Oligoarticular (14%), Enthesitis-Related Arthritis (1%), and Systemic (2%). Patients had a mean disease duration of 2.5 years with active joints (mean, 11.9), joints with loss of motion (mean, 10.4), and elevated C-reactive protein (CRP) levels (mean, 1.2 mg/dL). At study entry, 80% of patients were receiving methotrexate and remained on a stable dose of methotrexate. Patients received weekly open-label ORENCIA subcutaneously by a weight-tiered dosing regimen. The primary objective of the study was evaluation of PK in order to support the extrapolation of efficacy based on exposure to ORENCIA supported by descriptive efficacy [see CLINICAL PHARMACOLOGY]. JIA ACR 30/50/70 responses assessed at 4 months in the 2- to 17-year-old patients were consistent with the results from the intravenous study, JIA-1. Adult Psoriatic Arthritis The efficacy of ORENCIA was assessed in 594 patients with psoriatic arthritis, in two randomized, double-blind, placebo-controlled studies (Studies PsA-I and PsA-II) in adult patients, age 18 years and older. Patients had active psoriatic arthritis ( &ge; 3 swollen joints and &ge; 3 tender joints) despite prior treatment with DMARD therapy and had one qualifying psoriatic skin lesion of at least 2 cm in diameter. In PsA-I and PsA-II, 37% and 61% of patients, respectively, were treated with TNFi previously. In PsA-I, a dose-ranging study, 170 patients received study drug IV at Day 1, 15, 29, and then every 28 days thereafter in a double blind manner for 24 weeks, followed by open-label ORENCIA every 28 days. Patients were randomized to receive placebo or ORENCIA 3 mg/kg, 10 mg/kg (weight range-based dosing: 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1000 mg for patients weighing greater than 100 kg), or two doses of 30 mg/kg followed by weight range-based dosing of 10 mg/kg without escape for 24 weeks. Patients were allowed to receive stable doses of concomitant methotrexate, low dose corticosteroids (equivalent to &le; 10 mg of prednisone) and/or NSAIDs during the trial. At enrollment, approximately 60% of patients were receiving methotrexate. At baseline, the mean (SD) CRP for ORENCIA IV was 17 mg/L (33.0) and mean number (SD) of tender joints and swollen joints was 22.2 (14.3) and 10.9 (7.6), respectively. In PsA-II, 424 patients were randomized 1:1 to receive weekly doses of SC placebo or ORENCIA 125 mg without a loading dose for 24 weeks-in a double-blind manner, followed by open-label ORENCIA 125 mg SC weekly. Patients were allowed to receive stable doses of concomitant methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, low dose corticosteroids (equivalent to &le; 10 mg of prednisone) and/or NSAIDs during the trial. At randomization, 60.4% of patients were receiving methotrexate. The baseline disease characteristics included presence of joint erosion on X-rays in 84% (341/424) with a mean (SD) PsA-modified Sharp van der Heijde erosion score (SHS) of 10.8 (24.2), elevated serum C reactive protein (CRP) in 66% [277/424]) with a mean (SD) of 14.1 mg/L (25.9), and polyarticular disease in 98% (416/424) of patients with a mean number (SD) of tender joints and swollen joints of 20.2 (13.3) and 11.6 (7.5), respectively. Patients who had not achieved at least a 20% improvement from baseline in their swollen and tender joint counts by Week 16 escaped to open-label ORENCIA 125 mg SC weekly. The primary endpoint for both PsA-I and PsA-II was the proportion of patients achieving ACR 20 response at Week 24 (Day 169). Clinical Response A higher proportion of patients achieved an ACR20 response after treatment with ORENCIA 10 mg/kg IV (weight range-based dosing as described above) or 125 mg SC compared to placebo at Week 24. Responses were seen regardless of prior TNFi treatment and regardless of concomitant non-biologic DMARD treatment. The percent of patients achieving ACR 20, 50, or 70 responses in Studies PsA-I and PsA-II are presented in Table 10 below. Table 10: Proportion of Patients With ACR Responses at Week 24 in Studies PsA-I and PsA-IIa PsA-I PsA-II ORENCIA 10mg/kg IVb N=40 Placebo N=42 ORENCIA 125 mg SC N=213 Placebo N=211 ACR 20 47.5%* 19.0% * 39.4% 22.3% ACR 50 25.0% 2.4% 19.2% 12.3% ACR 70 12.5% 0% 10.3% 6.6% * p < 0.05 versus placebo a Patients who had less than 20% improvement in tender or swollen joint counts at Week 16 met escape criteria and were considered non-responders. b Weight range-based dosing (as described above). The percentage of patients in PsA-II achieving ACR20 response through Week 24 is shown below in Figure 2. Figure 2: Percent of Patients Achieving ACR20 Responsea in PsA-II Study Through Week 24 (Day 169) Results were generally consistent across the ACR components in Study PsA-I and PsA-II. Improvements in enthesitis and dactylitis were seen with ORENCIA treatment at Week 24 in both PsA-I and PsA-II. Physical Function Response In study PsA-I, there was a higher proportion of patients with at least a 0.30 decrease from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 24, with an estimated difference for ORENCIA 10 mg/kg (weight range-based dosing as described above) (45.0%) vs. placebo (19.0%) of 26.1 (95% confidence interval: 6.8, 45.5). In study PsA-II, the proportion of patients with at least a 0.35 decrease from baseline in HAQ-DI on ORENCIA was 31%, as compared to 24% on placebo (estimated difference: 7%; 95% confidence interval: -1%, 16%). There was a higher adjusted mean change from baseline in HAQ-DI on ORENCIA (-0.33) vs. placebo (-0.20) at Week 24, with an estimated difference of -0.13 (95% confidence interval: -0.25, -0.01).112017-09-01 11:12:57AbataceptOrenciaFDA
922017-12-04 17:38:07Medication GuidePATIENT INFORMATION ORENCIA&reg; (oh-REN-see-ah) (abatacept) for Injection, for Intravenous Use ORENCIA&reg; (oh-REN-see-ah) (abatacept) Injection, for Subcutaneous Use What is ORENCIA? ORENCIA is a prescription medicine that reduces signs and symptoms in: adults with moderate to severe rheumatoid arthritis (RA), including those who have not been helped enough by other medicines for RA. ORENCIA may prevent further damage to your bones and joints and may help your ability to perform daily activities. In adults, ORENCIA may be used alone or with other RA treatments other than tumor necrosis factor (TNF) antagonists. patients 2 years of age and older with moderate to severe polyarticular juvenile idiopathic arthritis (JIA). ORENCIA may be used alone or with methotrexate. adults with active psoriatic arthritis (PsA). In adults, ORENCIA can be used alone or with other PsA treatments. It is not known if ORENCIA is safe and effective in children under 2 years of age. It is not known if ORENCIA is safe and effective in children for uses other than juvenile idiopathic arthritis. Before you use ORENCIA, tell your healthcare provider about all of your medical conditions, including if you: have any kind of infection even if it is small (such as an open cut or sore), or an infection that is in your whole body (such as the flu). If you have an infection when taking ORENCIA, you may have a higher chance for getting serious side effects. have an infection that will not go away or an infection that keeps coming back. are allergic to abatacept or any of the ingredients in ORENCIA. See the end of this Patient Information leaflet for a complete list of ingredients in ORENCIA. have or have had inflammation of your liver due to an infection (viral hepatitis). Before you use ORENCIA, your healthcare provider may examine you for hepatitis. have had a lung infection called tuberculosis (TB), a positive skin test for TB, or you recently have been in close contact with someone who has had TB. Before you use ORENCIA, your healthcare provider may examine you for TB or perform a skin test. Symptoms of TB may include: a cough that does not go away weight loss fever night sweats are scheduled to have surgery. recently received a vaccination or are scheduled for a vaccination. If you are receiving ORENCIA, and for 3 months after you stop receiving ORENCIA, you should not receive live vaccines. have a history of a breathing problem called chronic obstructive pulmonary disease (COPD). have diabetes and use a blood glucose monitor to check your blood sugar (blood glucose) levels. ORENCIA for intravenous infusion (given through a needle placed in a vein) contains maltose, a type of sugar, that can give false high blood sugar readings with certain types of blood glucose monitors on the day of ORENCIA infusion. Your healthcare provider may tell you to use a different way to monitor your blood sugar levels. ORENCIA for subcutaneous injection (injected under the skin) does not contain maltose. You do not need to change your blood sugar monitoring if you are taking ORENCIA subcutaneously. are pregnant or plan to become pregnant. It is not known if ORENCIA can harm your unborn baby. If you took ORENCIA during pregnancy, talk to your healthcare provider before your baby receives any vaccines. Bristol-Myers Squibb Company has a registry for pregnant women exposed to ORENCIA. The purpose of this registry is to check the health of the pregnant mother and her child. Women are encouraged to call the registry themselves or ask their healthcare provider to contact the registry for them by calling 1-877-311-8972. are breastfeeding or plan to breastfeed. It is not known if ORENCIA passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use ORENCIA. Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. ORENCIA may affect the way other medicines work, and other medicines may affect the way ORENCIA works causing serious side effects. Especially tell your healthcare provider if you take other biologic medicines to treat RA, JIA or PsA that may affect your immune system, such as: Enbrel&reg; (etanercept) Humira&reg; (adalimumab) Remicade&reg; (infliximab) Kineret&reg; (anakinra) Rituxan&reg; (rituximab) Simponi&reg; (golimumab) Cimzia&reg; (certolizumab pegol) Actemra&reg; (tocilizumab) You may have a higher chance of getting a serious infection if you take ORENCIA with other biologic medicines for your RA, JIA, or PsA. Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new prescription. How should I use ORENCIA? You may receive ORENCIA given by a healthcare provider through a vein in your arm (IV or intravenous infusion). It takes about 30 minutes to give you the full dose of medicine. You will then receive ORENCIA 2 weeks and 4 weeks after the first dose and then every 4 weeks. You may also receive ORENCIA as an injection under your skin (subcutaneous). For home use, ORENCIA comes in a prefilled syringe or prefilled ClickJect autoinjector. Your healthcare provider will prescribe the type that is best for you. If your healthcare provider decides that you or a caregiver can give your injections of ORENCIA prefilled syringes or ORENCIA ClickJect autoinjectors at home, you or your caregiver should receive training on the right way to prepare and inject ORENCIA. Do not try to inject ORENCIA until you have been shown the right way to give the injections by your healthcare provider. Your healthcare provider will tell you how much ORENCIA to use and when to use it. See the Instructions for Use at the end of this Patient Information leaflet for instructions about the right way to prepare and give your ORENCIA injections at home. What are the possible side effects of ORENCIA? ORENCIA can cause serious side effects including: infections. ORENCIA can make you more likely to get infections or make the infection that you have get worse. Some people have died from these infections. Call your healthcare provider right away if you have any symptoms of an infection. Symptoms of an infection may include: fever feel very tired have a cough have flu-like symptoms warm, red, or painful skin allergic reactions. Allergic reactions can happen to people who use ORENCIA. Call your healthcare provider or go to the emergency room right away if you have any symptoms of an allergic reaction. Symptoms of an allergic reaction may include: hives swollen face, eyelids, lips, or tongue trouble breathing hepatitis B infection in people who carry the virus in their blood. If you are a carrier of the hepatitis B virus (a virus that affects the liver), the virus can become active while you use ORENCIA. Your healthcare provider may do a blood test before you start treatment with ORENCIA. vaccinations. You should not receive ORENCIA with certain types of vaccines (live vaccines). ORENCIA may also cause some vaccinations to be less effective. Talk with your healthcare provider about your vaccination plans. breathing problems in people with Chronic Obstructive Pulmonary Disease (COPD). Some people may get certain respiratory problems more often if they receive ORENCIA and have COPD. Symptoms of respiratory problems include: COPD that becomes worse cough trouble breathing cancer (malignancies). Certain kinds of cancer have been reported in people using ORENCIA. It is not known if ORENCIA increases your chance of getting certain kinds of cancer. Common side effects of ORENCIA include:  headache upper respiratory tract infection throat nausea In children and adolescents, other side effects may include: diarrhea cough fever abdominal pain These are not all the possible side effects of ORENCIA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA- 1088. How should I store ORENCIA? Store ORENCIA in the refrigerator at 36&deg;F to 46&deg;F (2&deg;C to 8&deg;C). Keep ORENCIA in the original package and out of the light. Do not freeze ORENCIA. Safely throw away medicine that is out of date or no longer needed. Keep ORENCIA and all medicines out of the reach of children. General information about the safe and effective use of ORENCIA Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ORENCIA for a condition for which it was not prescribed. Do not give ORENCIA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ORENCIA that is written for health professionals. What are the ingredients in ORENCIA? Active ingredient: abatacept Intravenous inactive ingredients: maltose, monobasic sodium phosphate, sodium chloride for administration Subcutaneous inactive ingredients: sucrose, poloxamer 188, monobasic sodium phosphate monohydrate, dibasic sodium phosphate anhydrous, water for injection INSTRUCTIONS FOR USE ORENCIA&reg; (oh-REN-see-ah) (abatacept) Prefilled Syringe with BD UltraSafe Passive&trade; Needle Guard ORENCIA&reg; Prefilled Syringe with BD UltraSafe Passive&trade; Needle Guard (abatacept) Injection Read these instructions before you start using your ORENCIA Prefilled Syringe and each time you get a refill. There may be new information. Before you use the prefilled syringe for the first time, make sure your healthcare provider shows you the right way to use it and decides that you or a caregiver may be able to give your injections of ORENCIA at home. Important: Keep the Prefilled Syringe in the refrigerator until ready to use. Do not freeze. Before You Begin: Get to Know Your Prefilled Syringe There are 3 types of prefilled syringes: The type of prefilled syringe you receive depends on the dose prescribed by your healthcare provider. The 125 mg/mL prefilled syringe is shown below. The prefilled syringe has a flange extender that makes it easier to hold and inject, and a needle guard that automatically covers the needle after a complete injection. DO NOT remove the needle cover until you are ready to inject. DONOT PULL back on the plunger at any time. DO NOT RECAP the prefilled syringe at any time, as this may damage, bend, or break the needle. Step 1: Preparing for an ORENCIA Injection Gather and place supplies for your injection on a clean, flat surface. Only the prefilled syringe is included in the package: Let your Prefilled Syringe warm up. Remove one prefilled syringe from the refrigerator and wait 30 minutes to allow it to reach room temperature. Do not speed up the warming process in any way, such as using the microwave or placing the syringe in warm water. Do not remove the needle cover while allowing the prefilled syringe to reach room temperature. Wash your hands well with soap and water. Step 2: Examine the Prefilled Syringe Hold the prefilled syringe by the body with the needle cover pointing down as shown. Check the expiration date printed on the label. Do not use if the expiration date has passed. Check the prefilled syringe for damage. Do not use if it is cracked or broken. Check the Liquid. Check the liquid in the prefilled syringe through the viewing window. It should be clear and colorless to pale yellow. Do not inject if the liquid is cloudy, discolored, or has particles in it. *Note: the 50 mg prefilled syringe is shown. Note: It is normal to see an air bubble. Do not attempt to remove it. Step 3: Check the Dose on the Prefilled Syringe Hold the syringe at eye level. Look closely to make sure that the amount of liquid in the prefilled syringe is at or just above the fill line for your prescribed dose: Do not use if your prefilled syringe does not have the correct amount of liquid. Call your pharmacist immediately. Step 4: Choose and Prepare an Injection Site Choose your injection site. Choose your injection site in either the stomach (abdomen), front of the thighs, or outer area of upper arm (only if caregiver administered). Rotate injection site. Each week you can use the same area of your body, but use a different injection site in that area. Do not inject into an area where the skin is tender, bruised, red, scaly, or hard. Do not give the injection in any areas with scars or stretch marks. Record the date, time, and site where you inject. Gently clean injection site. Wipe the injection site with an alcohol swab and let it air dry. Do not touch the injection site again before giving the injection. Do not fan or blow on the clean area. Remove the needle cover by holding the body of the prefilled syringe with one hand and pulling the cover straight off with your other hand. Do not put the needle cover back on the needle after you remove it. Throw away the needle cover in your household trash. Do not use the prefilled syringe if it is dropped after the needle cover is removed. Do not use the prefilled syringe if the needle is damaged or bent. Note: It is normal to see a drop of fluid leaving the needle. DO NOT RECAP the Prefilled Syringe, as this may damage the needle. Step 5: Inject Your Dose of ORENCIA Hold the body of the prefilled syringe in your hand using your thumb and index finger. With your other hand, pinch the area of skin you cleaned. Insert the needle. Gently insert the needle into the pinched skin at a 45&deg; angle. Complete all steps to deliver your full dose of the medicine. Inject: push the plunger with your thumb as far as it will go. Release Needle Guard: slowly lift your thumb from the plunger to activate the needle guard Confirm: after a complete injection, the needle guard will cover the needle and you may hear a click. Remove the prefilled syringe and let go of the pinched skin. Step 6: After the Injection Care of injection site: There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site. Do not rub the injection site. If needed, you may cover the injection site with an adhesive bandage. Disposing of used Prefilled Syringes: Put your used ORENCIA prefilled syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and prefilled syringes in your household trash. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. Do not throw away (dispose of) your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. See Frequently Asked Questions for additional disposal information. If your injection is administered by a caregiver, this person must also be careful handling the syringe to prevent accidental needle stick injury and possibly spreading infection. Keep ORENCIA prefilled syringes and the disposal container out of the reach of children. How to store ORENCIA Prefilled Syringe Store ORENCIA in the refrigerator at 36&deg;F to 46&deg;F (2&deg;C to 8&deg;C). Keep ORENCIA in the original package and out of the light. Do not freeze ORENCIA. Safely throw away medicine that is out of date or no longer needed. Frequently Asked Questions Q. Why do I need to allow the prefilled syringe to warm up at room temperature for 30 minutes prior to injecting? A. This step is primarily for your comfort. Never try to speed up the warming process in any way, like using the microwave or placing the syringe in warm water. Q. Is it necessary to hold the skin pinch during the entire time I inject the dose? A. You must pinch the skin during needle insertion however, for your comfort you may release the skin pinch as you deliver the injection. Q. What if my prefilled syringe appears to be broken or damaged? A. Do not use the prefilled syringe. Contact your healthcare provider or pharmacist for further instructions. Q. What if I cannot clearly see the liquid inside the syringe? A. Look at the syringe closely by holding at eye level and up to the light. You may tilt the syringe slowly to get a better view of the drug fluid. If you still have trouble, contact your healthcare provider or pharmacist for further instructions. Q. Is it normal to feel a little bit of burning or pain during injection? A. You may feel a prick from the needle. Sometimes, the medicine can cause slight irritation near the injection site. Discomfort should be mild to moderate. If you have any side effects, including pain, swelling, or discoloration near the injection site, contact your healthcare provider. Frequently Asked Questions Q. How should I dispose of a used prefilled syringe? A. Place the used prefilled syringe into an FDA-cleared sharps disposal container. If you do not have one you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and injector pens. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. Q. How should I keep my prefilled syringes cool while traveling? A. Store them in a cool carrier between 36&deg;F to 46&deg;F (2&deg;C to 8&deg;C). Do not freeze them. Keep them in the original carton and protected from light. Your healthcare provider may know about special carrying cases. Q. Can I take my prefilled syringes on an airplane? A. Generally you are allowed to carry your prefilled syringes with you on an airplane. Do not put them in your checked luggage. You should carry your prefilled syringes with you in your travel cooler at a temperature of 36&deg;F to 46&deg;F (2&deg;C to 8&deg;C). Keep your prefilled syringes in the original carton, and with its original preprinted labels and protected from light. Q. What if my prefilled syringe does not stay cool for an extended period of time? Is it dangerous to use? A. Contact 1-800-673-6242 for more information. If you have questions or concerns about your prefilled syringe, please contact your healthcare provider or call our toll-free help line at 1-800-673-6242. Bristol-Myers Squibb Company, Princeton, NJ 08543 USA, U.S. License Number 1713 INSTRUCTIONS FOR USE ORENCIA&reg; ClickJect&trade; (oh-REN-see-ah) (abatacept) Prefilled Autoinjector ORENCIA&reg; ClickJect&trade; (abatacept) Injection Prefilled Autoinjector 125 mg/mL, Single-Dose Autoinjector, For Subcutaneous Use Only Read these instructions before you use the ClickJect Autoinjector and each time you get a refill. There may be new information. Before you use the Autoinjector for the first time, make sure your healthcare provider shows you the right way to use it. Important: Keep the ClickJect Autoinjector in the refrigerator until ready to use. Do not freeze. Before You Begin Get to know the ClickJect Autoinjector The Autoinjector automatically delivers the medicine. The transparent tip locks over the needle once the injection is complete and the Autoinjector is removed from the skin. Do not remove the orange needle cover until you are ready to inject. Gather supplies for your injection on a clean, flat surface (only the ClickJect Autoinjector is included in the package): Step 1: Prepare Your Autoinjector Let your ClickJect Autoinjector warm up. Remove one Autoinjector from the refrigerator and let it rest at room temperature for 30 minutes. Do not remove the Autoinjector needle cover while allowing it to reach room temperature. Wash your hands well with soap and water. Examine the ClickJect Autoinjector: Check expiration date printed on the label. Do not use if past the expiration date. Check the Autoinjector for damage. Do not use if it is cracked or broken. Check the liquid through the viewing window. It should be clear and colorless to pale yellow. You may see a small air bubble. You do not need to remove it. Do not inject if the liquid is cloudy, discolored, or has particles in it. Step 2: Prepare for Injection Choose your injection site in either the stomach (abdomen), front of the thighs, or outer area of upper arm (only if caregiver administered). Rotate injection site. Each week you can use the same area of your body, but use a different injection site in that area. Do not inject into an area where the skin is tender, bruised, red, scaly, or hard. Do not give the injection in any areas with scars or stretch marks. Record the date, time, and site where you inject. Gently clean injection site: Wipe the injection site with an alcohol swab and let it air dry. Do not touch the injection site again before giving the injection. Do not fan or blow on the clean area. Pull orange needle cover STRAIGHT off. DO NOT RECAP the Autoinjector. Throw away (discard) the needle cover in your household trash. Do not use the Autoinjector if it is dropped after the needle cover is removed. Note: It is normal to see a drop of fluid leaving the needle. Step 3: Inject Your Dose Position the Autoinjector so you can see the viewing window and it is at a 90&deg; angle to the injection site. With your other hand, gently pinch the cleaned skin. Complete all steps to deliver your full dose of medicine: Push DOWN on the skin to unlock the Autoinjector. Press button, HOLD for 15 seconds AND watch window. You will hear a click as the injection begins. To deliver the full dose of medicine, hold the Autoinjector in place for 15 seconds AND wait until the blue indicator stops moving in window. Remove the ClickJect Autoinjector from the injection site by lifting it straight up. After you remove it from your skin, the transparent tip will lock over the needle. Release skin pinch. Step 4: After the Injection Care of injection site: There may be a little bleeding at the injection site. You can press a cotton ball or gauze over the injection site. Do not rub the injection site. If needed, you may cover the injection site with an adhesive bandage. Disposing of used ClickJect Autoinjectors: Put your used ClickJect Autoinjector in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and prefilled syringes in your household trash. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. See Frequently Asked Questions for additional disposal information. If your injection is administered by a caregiver, this person must also handle the Autoinjector carefully to prevent accidental needle stick injury and possibly spreading infection. Keep Autoinjector and the disposal container out of the reach of children. How to store ORENCIA ClickJect Autoinjector Store ORENCIA in the refrigerator at 36&deg;F to 46&deg;F (2&deg;C to 8&deg;C). Keep ORENCIA in the original package and out of the light. Do not freeze ORENCIA. Safely throw away medicine that is out of date or no longer needed Frequently Asked Questions Q. Why do I need to allow the Autoinjector to warm up at room temperature for 30 minutes prior to injecting? A. This step is primarily for your comfort. If the medicine is cold, the injection may take longer than 15 seconds. Never try to speed the warming process in any way, like using the microwave or placing the Autoinjector in warm water. Q. What if I accidentally remove the needle cover (orange cap) before I'm ready to use the Autoinjector? A. If you remove the cover before you are ready to use the Autoinjector, be careful. Do not try to replace it. Use the Autoinjector as soon as possible. While you prepare for the injection, carefully place the Autoinjector on its side on a clean, flat surface. Be sure to keep the Autoinjector away from children. Q. What if the Autoinjector appears to be broken or damaged? A. Do not use the Autoinjector. Contact your healthcare provider or pharmacist for further instructions. Q. What if the injection was not triggered? A. Before the injection can be triggered, the device must be unlocked. To unlock, firmly push the Autoinjector down on the skin without touching the button. Once the stop-point is felt, the device is unlocked and can be triggered by pushing the button. Q. I feel a little bit of burning or pain during injection. Is this normal? A. When giving an injection, you may feel a prick from the needle. Sometimes, the medicine can cause slight irritation near the injection site. If this occurs, the discomfort should be mild to moderate. If you experience any side effects, including pain, swelling, or discoloration near the injection site, contact your healthcare provider or pharmacist immediately. You are encouraged to report side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. Q. How do I know I received my full dose? A. Before lifting the Autoinjector from the injection site, check to ensure that the blue indicator has stopped moving. Then, before disposing of the Autoinjector, check the bottom of the transparent viewing window to make sure there is no liquid left inside. If the medicine has not been completely injected, consult your healthcare provider or pharmacist. Frequently Asked Questions Q. How should I dispose of a used Autoinjector? A. Place used Autoinjector into an FDA-cleared sharps disposal container right away after use. If you do not have one, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and Autoinjectors. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal. Do not recycle your used sharps disposal container. Q. How should I keep my Autoinjector cool while traveling? A. Your healthcare provider or pharmacist may be familiar with special carrying cases for injectable medicines. Store at 36&deg;F to 46&deg;F (2&deg;C to 8&deg;C). Do not freeze. Protect from light. Q. Can I take my Autoinjector on board an aircraft? A. Generally, this is allowed. Be sure to pack your Autoinjector in your carry-on, and do not put it in your checked luggage. You should carry it with you in your travel cooler at a temperature of 36&deg;F to 46&deg;F (2&deg;C to 8&deg;C) until you are ready to use it. Airport security procedures and airline policies change from time to time, so it's best to check with airport authorities and the airline for any special rules. Prior to flying, get a letter from your healthcare provider to explain that you are traveling with prescription medicine that uses a device with a needle; if you are carrying a sharps container in your carry-on baggage, notify the screener at the airport. Q. What if my Autoinjector does not stay cool for an extended period of time? Is it dangerous to use? A. Contact 1-800-673-6242 for details. If you have questions or concerns about your Autoinjector, please contact a healthcare provider or call our toll-free help line at 1-800-673-6242.112017-09-01 11:12:57AbataceptOrenciaFDA
932017-12-04 17:38:16Orencia Patient Information Including Side EffectsFind Lowest Prices on Brand Names: Orencia Generic Name: abatacept (Pronunciation: a BAY ta sept) What is abatacept (Orencia)? What are the possible side effects of abatacept (Orencia)? What is the most important information I should know about abatacept (Orencia)? What should I discuss with my healthcare provider before using abatacept (Orencia)? How should I use abatacept (Orencia)? What happens if I miss a dose (Orencia)? What happens if I overdose (Orencia)? What should I avoid while using abatacept (Orencia)? What other drugs will affect abatacept (Orencia)? Where can I get more information? What is abatacept (Orencia)? Abatacept is a man-made protein that prevents your body's immune system from attacking healthy tissues such as joints. The immune system helps your body fight infections. In people with autoimmune disorders, the immune system mistakes the body's own cells for invaders and attacks them.Abatacept is used to treat the symptoms of rheumatoid arthritis, and to prevent joint damage caused by these conditions. It is also used to treat arthritis in children who are at least 6 years old.Abatacept is not a cure for any autoimmune disorder and will only treat the symptoms of your condition.Abatacept may also be used for purposes not listed in this medication guide. What are the possible side effects of abatacept (Orencia)? Some people receiving an abatacept injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you feel dizzy, light-headed, itchy, or have a severe headache or trouble breathing within 1 hour after receiving the injection.Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.Serious infections may occur during treatment with abatacept. Stop using abatacept and call your doctor right away if you have signs of infection such as:fever, chills, night sweats, flu symptoms, weight loss;feeling very tired;dry cough, sore throat; orwarmth, pain, or redness of your skin.Call your doctor at once if you have any of these other serious side effects:trouble breathing;stabbing chest pain, wheezing, cough with yellow or green mucus;pain or burning when you urinate; orsigns of skin infection such as itching, swelling, warmth, redness, or oozing.Less serious side effects may include:nausea, diarrhea, stomach pain, indigestion; orheadache, dizziness;cold symptoms such as stuffy nose, sneezing, sore throat, cough;back pain.This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What is the most important information I should know about abatacept (Orencia)? You should not use abatacept if you are allergic to it, or if you are also using anakinra (Kineret), etanercept (Enbrel), adalimumab (Humira), certolizumab (Cimzia), golimumab (Simponi), infliximab (Remicade), natalizumab (Tysabri), rituximab (Rituxan), or tocilizumab (Actemra).Before using abatacept, tell your doctor if you have ever had tuberculosis, if anyone in your household has tuberculosis, or if you have recently traveled to an area where tuberculosis is common.Also tell your doctor if you have a weak immune system, any type of infection (including skin infection or open sores), COPD, diabetes, a history of hepatitis, or if you have scheduled to receive any vaccinations.Children using this medication should be current on all childhood immunizations before starting treatment with abatacept.Serious infections may occur during treatment with abatacept. Contact your doctor right away if you have signs of infection such as: fever, chills, dry cough, sore throat, night sweats, tired feeling, weight loss, or painful warmth or redness of your skin.Using abatacept may increase your risk of developing certain types of cancer such as lymphoma (cancer of the lymph nodes). This risk may be greater in older adults. Talk to your doctor about your specific risk.122017-09-01 11:12:57AbataceptOrenciaMultum
942017-12-04 17:38:16Orencia Patient Information including How Should I TakeWhat should I discuss with my healthcare provider before using abatacept (Orencia)? You should not use abatacept if you are allergic to it, or if you are also using anakinra (Kineret), etanercept (Enbrel), adalimumab (Humira), certolizumab (Cimzia), golimumab (Simponi), infliximab (Remicade), natalizumab (Tysabri), rituximab (Rituxan), or tocilizumab (Actemra).Before using abatacept, tell your doctor if you have ever had tuberculosis, if anyone in your household has tuberculosis, or if you have recently traveled to an area where tuberculosis is common.To make sure you can safely use abatacept, tell your doctor if you have any of these other conditions:a weak immune system;any type of infection including a skin infection or open sores;COPD (chronic obstructive pulmonary disease);diabetes;if you have ever had hepatitis; orif you are scheduled to receive any vaccines.FDA pregnancy category C. It is not known whether abatacept will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.If you are pregnant, your name may be listed on a pregnancy registry. This is to track the outcome of the pregnancy and to evaluate any effects of abatacept on the baby.It is not known whether abatacept passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using abatacept.Children using this medication should be current on all childhood immunizations before starting treatment with abatacept.Using abatacept may increase your risk of developing certain types of cancer such as lymphoma (cancer of the lymph nodes). This risk may be greater in older adults. Talk to your doctor about your specific risk. How should I use abatacept (Orencia)? Before you start treatment with abatacept, your doctor may perform tests to make sure you do not have tuberculosis or other infections.Abatacept is injected under the skin, or into a vein through an IV. You may be shown how to use injections at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, syringes, IV tubing, and other items used to inject the medicine.Abatacept must be given slowly when infected into a vein, and the IV infusion can take at least 30 minutes to complete. This medication is usually given every 1 to 4 weeks. Follow your doctor's instructions.You may need to mix abatacept with a liquid (diluent) before using it. If you are using the injections at home, be sure you understand how to properly mix and store the medication.Do not shake the medication bottle or you may ruin the medicine. Prepare your dose in a syringe only when you are ready to give yourself an injection. Do not use the medication if it has changed colors or has particles in it. Call your doctor for a new prescription.Each single-use vial (bottle) or prefilled syringe of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.Use a disposable needle only once. Throw away used needles in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.If you need surgery, tell the surgeon ahead of time that you are using abatacept.If you have hepatitis B you may develop liver symptoms after you stop taking this medication, even months after stopping. Your doctor may want to check your liver function for several months after you stop using abatacept. Visit your doctor regularly.This medication can cause false results with certain blood glucose tests, showing high blood sugar readings. If you have diabetes, talk to your doctor about the best way to check your blood sugar while you are using abatacept.Autoimmune disorders are often treated with a combination of different drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.Store this medication in the refrigerator. Do not freeze and protect from light. Keep the medicine in original carton to protect it from light. Do not use abatacept if the expiration date on the medicine label has passed.Abatacept that has been mixed with a diluent may be stored in a refrigerator or at room temperature and used within 24 hours.122017-09-01 11:12:57AbataceptOrenciaMultum
952017-12-04 17:38:16Orencia Patient Information including If I Miss a Dose122017-09-01 11:12:57AbataceptOrenciaMultum
962017-12-04 17:38:20Drug DescriptionFind Lowest Prices on ReoPro&reg; (abciximab) for Intravenous Administration DESCRIPTION Abciximab, ReoPro&reg;, is the Fab fragment of the chimeric human-murine monoclonal antibody 7E3. Abciximab binds to the glycoprotein (GP) IIb/IIIa receptor of human platelets and inhibits platelet aggregation. Abciximab also binds to the vitronectin (&alpha;v&beta;3) receptor found on platelets and vessel wall endothelial and smooth muscle cells. The chimeric 7E3 antibody is produced by continuous perfusion in mammalian cell culture. The 47,615 dalton Fab fragment is purified from cell culture supernatant by a series of steps involving specific viral inactivation and removal procedures, digestion with papain and column chromatography. ReoPro&reg; is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use. Each single use vial contains 2 mg/mL of Abciximab in a buffered solution (pH 7.2) of 0.01 M sodium phosphate, 0.15 M sodium chloride and 0.001% polysorbate 80 in Water for Injection. No preservatives are added.132017-09-01 11:12:57AbciximabReoProFDA
972017-12-04 17:38:20Indications & DosageINDICATIONS Abciximab is indicated as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours Safety and efficacy of Abciximab use in patients not undergoing percutaneous coronary intervention have not been established. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting, as described in Clinical Studies. DOSAGE AND ADMINISTRATION The safety and efficacy of Abciximab have only been investigated with concomitant administration of heparin and aspirin as described in Clinical Studies. In patients with failed PCIs, the continuous infusion of Abciximab should be stopped because there is no evidence for Abciximab efficacy in that setting. In the event of serious bleeding that cannot be controlled by compression, Abciximab and heparin should be discontinued immediately. The recommended dosage of Abciximab in adults is a 0.25 mg/kg intravenous bolus administered 10-60 minutes before the start of PCI, followed by a continuous intravenous infusion of 0.125 &mu;g/kg/min (to a maximum of 10 &mu;g/min) for 12 hours. Patients with unstable angina not responding to conventional medical therapy and who are planned to undergo PCI within 24 hours may be treated with an Abciximab 0.25.mg/kg intravenous bolus followed by an 18- to 24-hour intravenous infusion of 10 &mu;g/min, concluding one hour after the PCI. Instructions For Administration Parenteral drug products should be inspected visually for particulate matter prior to administration. Preparations of Abciximab containing visibly opaque particles should NOT be used. Hypersensitivity reactions should be anticipated whenever protein solutions such as Abciximab are administered. Epinephrine, dopamine, theophylline, antihistamines and corticosteroids should be available for immediate use. If symptoms of an allergic reaction or anaphylaxis appear, the infusion should be stopped and appropriate treatment given (see WARNINGS: Allergic Reactions). As with all parenteral drug products, aseptic procedures should be used during the administration of Abciximab. Withdraw the necessary amount of Abciximab for bolus injection into a syringe. Filter the bolus injection using a sterile, non-pyrogenic, low protein-binding 0.2 or 5 &mu;m syringe filter (Millipore SLGV025LS or SLSV025LS or equivalent). Withdraw the necessary amount of Abciximab for the continuous infusion into a syringe. Inject into an appropriate container of sterile 0.9% saline or 5% dextrose and infuse at the calculated rate via a continuous infusion pump. The continuous infusion should be filtered either upon admixture using a sterile, non-pyrogenic, low protein-binding 0.2 or 5 &mu;m syringe filter (Millipore SLGV025LS or SLSV025LS or equivalent) or upon administration using an in-line, sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 &mu;m filter (Abbott #4524 or equivalent). Discard the unused portion at the end of the infusion. No incompatibilities have been shown with intravenous infusion fluids or commonly used cardiovascular drugs. Nevertheless, Abciximab should be administered in a separate intravenous line whenever possible and not mixed with other medications. No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets. HOW SUPPLIED Abciximab (ReoPro&reg;) 2 mg/mL is supplied in 5 mL vials containing 10 mg (NDC 0002-7140-01). Vials should be stored at 2 to 8 &deg;C (36 to 46 &deg;F). Do not freeze. Do not shake. Do not use beyond the expiration date. Discard any unused portion left in the vial. Manufactured by: Janssen Biologics B.V. Leiden, The Netherlands, U.S. License Number: 1865. Distributed by: Eli Lilly and Company, Indianapolis, IN 46285. Revision Date: November 2013132017-09-01 11:12:57AbciximabReoProFDA
982017-12-04 17:38:20Side Effects & Drug InteractionsSIDE EFFECTS Bleeding Abciximab has the potential to increase the risk of bleeding, particularly in the presence of anticoagulation, e.g., from heparin, other anticoagulants or thrombolytics. Bleeding in the Phase 3 trials was classified as major, minor or insignificant by the criteria of the Thrombolysis in Myocardial Infarction study group (16). Major bleeding events were defined as either an intracranial hemorrhage or a decrease in hemoglobin greater than 5 g/dL. Minor bleeding events included spontaneous gross hematuria, spontaneous hematemesis, observed blood loss with a hemoglobin decrease of more than 3 g/dL, or a decrease in hemoglobin of at least 4 g/dL without an identified bleeding site. Insignificant bleeding events were defined as a decrease in hemoglobin of less than 3 g/dL or a decrease in hemoglobin between 3-4 g/dL without observed bleeding. In patients who received transfusions, the number of units of blood lost was estimated through an adaptation of the method of Landefeld, et al. (17). In the EPIC trial, in which a non-weight-adjusted, longer-duration heparin dose regimen was used, the most common complication during Abciximab therapy was bleeding during the first 36 hours. The incidences of major bleeding, minor bleeding and transfusion of blood products were significantly increased. Major bleeding occurred in 10.6% of patients in the Abciximab bolus plus infusion arm compared with 3.3% of patients in the placebo arm. Minor bleeding was seen in 16.8% of Abciximab bolus plus infusion patients and 9.2% of placebo patients (7). Approximately 70% of Abciximab-treated patients with major bleeding had bleeding at the arterial access site in the groin. Abciximab-treated patients also had a higher incidence of major bleeding events from gastrointestinal, genitourinary, retroperitoneal, and other sites. Bleeding rates were reduced in the CAPTURE trial, and further reduced in the EPILOG and EPISTENT trials by use of modified dosing regimens and specific patient management techniques. In EPILOG and EPISTENT, using the heparin and Abciximab dosing, sheath removal and arterial access site guidelines described under PRECAUTIONS, the incidence of major bleeding in patients treated with Abciximab and low-dose, weight-adjusted heparin was not significantly different from that in patients receiving placebo. Subgroup analyses in the EPIC and CAPTURE trials showed that non-CABG major bleeding was more common in Abciximab patients weighing &le; 75 kg. In the EPILOG and EPISTENT trials, which used weight-adjusted heparin dosing, the non-CABG major bleeding rates for Abciximab-treated patients did not differ substantially by weight subgroup. Although data are limited, Abciximab treatment was not associated with excess major bleeding in patients who underwent CABG surgery. (The range among all treatment arms was 3-5% in EPIC, and 1-2% in the CAPTURE, EPILOG, and EPISTENT trials.) Some patients with prolonged bleeding times received platelet transfusions to correct the bleeding time prior to surgery. (see PRECAUTIONS: Restoration of Platelet Function) The rates of major bleeding, minor bleeding and bleeding events requiring transfusions in the CAPTURE, EPILOG, and EPISTENT trials are shown in Table 4. The rates of insignificant bleeding events are not included in Table 4. Cases of fatal bleeding have been reported rarely during post-marketing use of Abciximab (see WARNINGS: Bleeding Events). Pulmonary alveolar hemorrhage has been rarely reported during use of Abciximab. This can present with any or all of the following in close association with ReoPro administration: hypoxemia, alveolar infiltrates on chest x-ray, hemoptysis, or an unexplained drop in hemoglobin. Table 4: NON-CABG BLEEDING IN TRIALS OF PERCUTANEOUS CORONARY INTERVENTION (EPILOG, EPISTENT and CAPTURE) Number of Patients with Bleeds (%) Placeboc (n= 1748) Abciximab + Low-dose Heparind (n=2525) Abciximab + Standard-dose Heparine (n=918) EPILOG and EPISTENT: Majora 18 (1.0) 21 (0.8) 17 (1.9) Minor 46 (2.6) 82 (3.2) 70 (7.6) Requiring transfusionb 15 (0.9) 13 (0.5) 7 (0.8) CAPTURE: Placebof (n=635) Abciximabf (n=630) Majora 12 (1.9) 24 (3.8) Minor 13 (2.0) 30 (4.8) Requiring transfusionb 9 (1.4) 15 (2.4) a Patients who had bleeding in more than one classification are counted only once according to the most severe classification. Patients with multiple bleeding events of the same classification are also counted once within that classification. b Patients with major non-CABG bleeding who received packed red blood cells or whole blood transfusion. c Standard-dose heparin with or without stent (EPILOG and EPISTENT) d Low-dose heparin with or without stent (EPILOG and EPISTENT) e Standard-dose heparin (EPILOG) f Standard-dose heparin (CAPTURE) Intracranial Hemorrhage And Stroke The total incidence of intracranial hemorrhage and non-hemorrhagic stroke across all four trials was not significantly different, 9/3023 for placebo patients and 15/4680 for Abciximab-treated patients. The incidence of intracranial hemorrhage was 3/3023 for placebo patients and 7/4680 for Abciximab patients. Thrombocytopenia In the clinical trials, patients treated with Abciximab were more likely than patients treated with placebo to experience decreases in platelet counts. Among patients in the EPILOG and EPISTENT trials who were treated with Abciximab plus low-dose heparin, the proportion of patients with any thrombocytopenia (platelets less than 100,000 cells/&mu;L) ranged from 2.5 to 3.0%. The incidence of severe thrombocytopenia (platelets less than 50,000 cells/&mu;L) ranged from 0.4 to 1.0% and platelet transfusions were required in 0.9 to 1.1%, respectively. Modestly lower rates were observed among patients treated with placebo plus standard-dose heparin. Overall higher rates were observed among patients in the EPIC and CAPTURE trials treated with Abciximab plus longer duration heparin: 2.6 to 5.2% were found to have any thrombocytopenia, 0.9 to 1.7% had severe thrombocytopenia, and 2.1 to 5.5% required platelet transfusion, respectively. In a readministration registry study of patients receiving a second or subsequent exposure to Abciximab (see PRECAUTIONS: Readministration) the incidence of any degree of thrombocytopenia was 5%, with an incidence of profound thrombocytopenia of 2% ( < 20,000 cell/&mu;L). Factors associated with an increased risk of thrombocytopenia were a history of thrombocytopenia on previous Abciximab exposure, readministration within 30 days, and a positive HACA assay prior to the readministration. Among 14 patients who had thrombocytopenia associated with a prior exposure to Abciximab, 7 (50%) had recurrent thrombocytopenia. In 130 patients with a readministration interval of 30 days or less, 25 (19%) developed thrombocytopenia. Severe thrombocytopenia occurred in 19 of these patients. Among the 71 patients who had a positive HACA assay at baseline, 11 (15%) developed thrombocytopenia, 7 of which were severe. Allergic Reactions There have been rare reports of allergic reactions, some of which were anaphylaxis (see WARNINGS: Allergic Reactions). Other Adverse Reactions Table 5 shows adverse events other than bleeding and thrombocytopenia from the combined EPIC, EPILOG and CAPTURE trials which occurred in patients in the bolus plus infusion arm at an incidence of more than 0.5% higher than in those treated with placebo. Table 5 : ADVERSE EVENTS AMONG TREATED PATIENTS IN THE EPIC, EPILOG, AND CAPTURE TRIALS Event Placebo (n=2226) Bolus + Infusion (n=3111) Number of Patients (%) Cardiovascular system Hypotension 230 (10.3) 447 (14.4) Bradycardia 79 (3.5) 140 (4.5) Gastrointestinal system Nausea 255 (11.5) 423 (13.6) Vomiting 152 ( 6.8) 226 (7.3) Abdominal pain 49 ( 2.2) 97 (3.1) Miscellaneous Back pain 304 (13.7) 546 (17.6) Chest pain 208 (9.3) 356 (11.4) Headache 122 (5.5) 200 (6.4) Puncture site pain 58 (2.6) 113 (3.6) Peripheral edema 25 (1.1) 49 (1.6) The following additional adverse events from the EPIC, EPILOG and CAPTURE trials were reported by investigators for patients treated with a bolus plus infusion of Abciximab at incidences which were less than 0.5% higher than for patients in the placebo arm. Cardiovascular System: ventricular tachycardia (1.4%), pseudoaneurysm (0.8%), palpitation (0.5%), arteriovenous fistula (0.4%), incomplete AV block (0.3%), nodal arrhythmia (0.2%), complete AV block (0.1%), embolism (limb)(0.1%); thrombophlebitis (0.1%); Gastrointestinal System: dyspepsia (2.1%), diarrhea (1.1%), ileus (0.1%), gastroesophogeal reflux (0.1%); Hemic and Lymphatic System: anemia (1.3%), leukocytosis (0.5%), petechiae (0.2%); Nervous System: dizziness (2.9%), anxiety (1.7%), abnormal thinking (1.3%), agitation (0.7%), hypesthesia (0.6%), confusion (0.5%) muscle contractions (0.4%), coma (0.2%), hypertonia (0.2%), diplopia (0.1%); Respiratory System: pneumonia (0.4%), rales (0.4%), pleural effusion (0.3%), bronchitis (0.3%) bronchospasm (0.3%), pleurisy (0.2%), pulmonary embolism (0.2%), rhonchi (0.1%); Musculoskeletal System: myalgia (0.2%); Urogenital System: urinary retention (0.7%), dysuria (0.4%), abnormal renal function (0.4%), frequent micturition (0.1%), cystalgia (0.1%), urinary incontinence (0.1%), prostatitis (0.1%); Miscellaneous: pain (5.4%), sweating increased (1.0%), asthenia (0.7%), incisional pain (0.6%), pruritus (0.5%), abnormal vision (0.3%), edema (0.3%), wound (0.2%), abscess (0.2%), cellulitis (0.2%), peripheral coldness (0.2%), injection site pain (0.1%), dry mouth (0.1%), pallor (0.1%), diabetes mellitus (0.1%), hyperkalemia (0.1%), enlarged abdomen (0.1%), bullous eruption (0.1%), inflammation (0.1%), drug toxicity (0.1%). Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. In the EPIC, EPILOG, and CAPTURE trials, positive HACA responses occurred in approximately 5.8% of these patients receiving a first exposure to Abciximab. No increase in hypersensitivity or allergic reactions was observed with Abciximab treatment (see WARNINGS: Allergic Reactions). In a study of readministration of Abciximab to patients (see PRECAUTIONS: Readministration) the overall rate of HACA positivity prior to the readministration was 6% and increased post-readministration to 27%. Among the 36 subjects receiving a fourth or greater Abciximab exposure, HACA positive assays were observed postreadministration in 16 subjects (44%). There were no reports of serious allergic reactions or anaphylaxis (see WARNINGS: Allergic Reactions). HACA positive status was associated with an increased risk of thrombocytopenia (see PRECAUTIONS: Thrombocytopenia). The data reflect the percentage of patients whose test results were considered positive for antibodies to Abciximab using an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Abciximab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS Formal drug interaction studies with Abciximab have not been conducted. Abciximab has been administered to patients with ischemic heart disease treated concomitantly with a broad range of medications used in the treatment of angina, myocardial infarction and hypertension. These medications have included heparin, warfarin, beta-adrenergic receptor blockers, calcium channel antagonists, angiotensin converting enzyme inhibitors, intravenous and oral nitrates, ticlopidine, and aspirin. Heparin, other anticoagulants, thrombolytics, and antiplatelet agents are associated with an increase in bleeding. Patients with HACA titers may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies. REFERENCES 16. Rao, AK, Pratt C, Berke A, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial - Phase I: Hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol. 1988;11:1-11. 17. Landefeld, CS, Cook EF, Flatley M, et al. Identification and preliminary validation of predictors of major bleeding in hospitalized patients starting anticoagulant therapy. Am J Med. 1987;82:703-713.132017-09-01 11:12:57AbciximabReoProFDA
992017-12-04 17:38:20Warnings & PrecautionsWARNINGS Bleeding Events Abciximab has the potential to increase the risk of bleeding events, rarely including those with a fatal outcome, particularly in the presence of anticoagulation, e.g., from heparin, other anticoagulants, or thrombolytics (see ADVERSE REACTIONS: Bleeding). The risk of major bleeds due to Abciximab therapy is increased in patients receiving thrombolytics and should be weighed against the anticipated benefits. Should serious bleeding occur that is not controllable with pressure, the infusion of Abciximab and any concomitant heparin should be stopped. Allergic Reactions (including anaphylaxis) Allergic reactions, some of which were anaphylaxis (sometimes fatal), have been reported rarely in patients treated with ReoPro. Patients with allergic reactions should receive appropriate treatment. Treatment of anaphylaxis should include immediate discontinuation of ReoPro administration and initiation of resuscitative measures. PRECAUTIONS Bleeding Precautions To minimize the risk of bleeding with Abciximab, it is important to use a low-dose, weight-adjusted heparin regimen, a weight-adjusted Abciximab bolus and infusion, strict anticoagulation guidelines, careful vascular access site management, discontinuation of heparin after the procedure and early femoral arterial sheath removal. Therapy with Abciximab requires careful attention to all potential bleeding sites including catheter insertion sites, arterial and venous puncture sites, cutdown sites, needle puncture sites, and gastrointestinal, genitourinary, pulmonary (alveolar), and retroperitoneal sites. Arterial and venous punctures, intramuscular injections, and use of urinary catheters, nasotracheal intubation, nasogastric tubes and automatic blood pressure cuffs should be minimized. When obtaining intravenous access, non-compressible sites (e.g., subclavian or jugular veins) should be avoided. Saline or heparin locks should be considered for blood drawing. Vascular puncture sites should be documented and monitored. Gentle care should be provided when removing dressings. Femoral artery access site Arterial access site care is important to prevent bleeding. Care should be taken when attempting vascular access that only the anterior wall of the femoral artery is punctured, avoiding a Seldinger (through and through) technique for obtaining sheath access. Femoral vein sheath placement should be avoided unless needed. While the vascular sheath is in place, patients should be maintained on complete bed rest with the head of the bed &le; 30&deg; and the affected limb restrained in a straight position. Patients may be medicated for back/groin pain as necessary. Discontinuation of heparin immediately upon completion of the procedure and removal of the arterial sheath within six hours is strongly recommended if APTT &le; 50 sec or ACT &le; 175 sec (see PRECAUTIONS: Laboratory Tests). In all circumstances, heparin should be discontinued at least two hours prior to arterial sheath removal. Following sheath removal, pressure should be applied to the femoral artery for at least 30 minutes using either manual compression or a mechanical device for hemostasis. A pressure dressing should be applied following hemostasis. The patient should be maintained on bed rest for six to eight hours following sheath removal or discontinuation of Abciximab, or four hours following discontinuation of heparin, whichever is later. The pressure dressing should be removed prior to ambulation. The sheath insertion site and distal pulses of affected leg(s) should be frequently checked while the femoral artery sheath is in place and for six hours after femoral artery sheath removal. Any hematoma should be measured and monitored for enlargement. The following conditions have been associated with an increased risk of bleeding and may be additive with the effect of Abciximab in the angioplasty setting: PCI within 12 hours of the onset of symptoms for acute myocardial infarction, prolonged PCI (lasting more than 70 minutes) and failed PCI. Use Of Thrombolytics, Anticoagulants And Other Antiplatelet Agents In the EPIC, EPILOG, CAPTURE, and EPISTENT trials, Abciximab was used concomitantly with heparin and aspirin. For details of the anticoagulation algorithms used in these clinical trials, see Clinical Studies: Anticoagulation. Because Abciximab inhibits platelet aggregation, caution should be employed when it is used with other drugs that affect hemostasis, including thrombolytics, oral anticoagulants, non-steroidal anti-inflammatory drugs, dipyridamole, and ticlopidine. In the EPIC trial, there was limited experience with the administration of Abciximab with low molecular weight dextran. Low molecular weight dextran was usually given for the deployment of a coronary stent, for which oral anticoagulants were also given. In the 11 patients who received low molecular weight dextran with Abciximab, five had major bleeding events and four had minor bleeding events. None of the five placebo patients treated with low molecular weight dextran had a major or minor bleeding event (see CONTRAINDICATIONS). Because of observed synergistic effects on bleeding, Abciximab therapy should be used judiciously in patients who have received systemic thrombolytic therapy. The GUSTO V trial randomized patients with acute myocardial infarction to treatment with combined Abciximab and half-dose Reteplase, or full-dose Reteplase alone (15). In this trial, the incidence of moderate or severe nonintracranial bleeding was increased in those patients receiving Abciximab and half-dose Reteplase versus those receiving Reteplase alone (4.6% versus 2.3%, respectively). Thrombocytopenia Thrombocytopenia, including severe thrombocytopenia, has been observed with Abciximab administration (see ADVERSE REACTIONS: Thrombocytopenia). Platelet counts should be monitored prior to, during, and after treatment with Abciximab. Acute decreases in platelet count should be differentiated between true thrombocytopenia and pseudothrombocytopenia (see PRECAUTIONS: Laboratory Tests). If true thrombocytopenia is verified, Abciximab should be immediately discontinued and the condition appropriately monitored and treated. In clinical trials, patients who developed thrombocytopenia were followed with daily platelet counts until their platelet count returned to normal. Heparin and aspirin were discontinued for platelet counts below 60,000 cells/&mu;L and platelets were transfused for a platelet count below 50,000 cells/&mu;L. Most cases of severe thrombocytopenia ( < 50,000 cells/&mu;L) occurred within the first 24 hours of Abciximab administration. In a registry study of Abciximab readministration, a history of thrombocytopenia associated with prior use of Abciximab was predictive of an increased risk of recurrent thrombocytopenia (see ADVERSE REACTIONS: Thrombocytopenia). Readministration within 30 days was associated with an increased incidence and severity of thrombocytopenia, as was a positive human anti-chimeric antibody (HACA) test at baseline, compared to the rates seen in studies with first administration. Restoration Of Platelet Function In the event of serious uncontrolled bleeding or the need for emergency surgery, Abciximab should be discontinued. If platelet function does not return to normal, it may be restored, at least in part, with platelet transfusions. Laboratory Tests Before infusion of Abciximab, prothrombin time, ACT, APTT, and platelet count should be measured to identify pre-existing hemostatic abnormalities. Based on an integrated analysis of data from all studies, the following guidelines may be utilized to minimize the risk for bleeding: When Abciximab is initiated 18 to 24 hours before PCI, the APTT should be maintained between 60 and 85 seconds during the Abciximab and heparin infusion period. During PCI the ACT should be maintained between 200 and 300 seconds. If anticoagulation is continued in these patients following PCI, the APTT should be maintained between 55 and 75 seconds. The APTT or ACT should be checked prior to arterial sheath removal. The sheath should not be removed unless APTT &le; 50 seconds or ACT &le; 175 seconds. Platelet counts should be monitored prior to treatment, two to four hours following the bolus dose of Abciximab and at 24 hours or prior to discharge, whichever is first. If a patient experiences an acute platelet decrease (e.g., a platelet decrease to less than 100,000 cells/&mu;L and a decrease of at least 25% from pre-treatment value), additional platelet counts should be determined. Platelet monitoring should continue until platelet counts return to normal. To exclude pseudothrombocytopenia, a laboratory artifact due to in vitro anticoagulant interaction, blood samples should be drawn in three separate tubes containing ethylenediaminetetraacetic acid (EDTA), citrate and heparin, respectively. A low platelet count in EDTA but not in heparin and/or citrate is supportive of a diagnosis of pseudothrombocytopenia. Readministration Administration of Abciximab may result in the formation of HACA that could potentially cause allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia or diminished benefit upon readministration of Abciximab (see WARNINGS: Allergic Reactions; see ADVERSE REACTIONS: Immunogenicity). Readministration of Abciximab to patients undergoing PCI was assessed in a registry that included 1342 treatments in 1286 patients. Most patients were receiving their second Abciximab exposure; 15% were receiving the third or subsequent exposure. The overall rate of HACA positivity prior to the readministration was 6% and increased to 27% postreadministration. There were no reports of serious allergic reactions or anaphylaxis (see WARNINGS: Allergic Reactions). Thrombocytopenia was observed at higher rates in the readministration study than in the phase 3 studies of first-time administration (see PRECAUTIONS: Thrombocytopenia and ADVERSE REACTIONS: Thrombocytopenia), suggesting that readministration may be associated with an increased incidence and severity of thrombocytopenia. Carcinogenesis, Mutagenesis And Impairment Of Fertility In vitro and in vivo mutagenicity studies have not demonstrated any mutagenic effect. Long-term studies in animals have not been performed to evaluate the carcinogenic potential or effects on fertility in male or female animals. Pregnancy Category C Animal reproduction studies have not been conducted with Abciximab. It is also not known whether Abciximab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Abciximab should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, caution should be exercised when Abciximab is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been studied. Geriatric Use Of the total number of 7860 patients in the four Phase 3 trials, 2933 (37%) were 65 and over, while 653 (8%) were 75 and over. No overall differences in safety or efficacy were observed between patients of age 65 to less than 75 as compared to younger patients. The clinical experience is not adequate to determine whether patients of age 75 or greater respond differently than younger patients. REFERENCES 15. Data on file.132017-09-01 11:12:57AbciximabReoProFDA
1002017-12-04 17:38:20Overdosage & ContraindicationsOVERDOSE There has been no experience of overdosage in human clinical trials. CONTRAINDICATIONS Because Abciximab may increase the risk of bleeding, Abciximab is contraindicated in the following clinical situations: Active internal bleeding Recent (within six weeks) gastrointestinal (GI) or genitourinary (GU) bleeding of clinical significance. History of cerebrovascular accident (CVA) within two years, or CVA with a significant residual neurological deficit Bleeding diathesis Administration of oral anticoagulants within seven days unless prothrombin time is &le; 1.2 times control Thrombocytopenia ( < 100,000 cells/&mu;L) Recent (within six weeks) major surgery or trauma Intracranial neoplasm, arteriovenous malformation, or aneurysm Severe uncontrolled hypertension Presumed or documented history of vasculitis Use of intravenous dextran before PCI, or intent to use it during an intervention Abciximab is also contraindicated in patients with known hypersensitivity to any component of this product or to murine proteins.132017-09-01 11:12:57AbciximabReoProFDA
1012017-12-04 17:38:20Clinical PharmacologyCLINICAL PHARMACOLOGY General Abciximab binds to the intact platelet GPIIb/IIIa receptor, which is a member of the integrin family of adhesion receptors and the major platelet surface receptor involved in platelet aggregation. Abciximab inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa receptor sites on activated platelets. The mechanism of action is thought to involve steric hindrance and/or conformational effects to block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa. Abciximab binds with similar affinity to the vitronectin receptor, also known as the &alpha;v&beta;3 integrin. The vitronectin receptor mediates the procoagulant properties of platelets and the proliferative properties of vascular endothelial and smooth muscle cells. In in vitro studies using a model cell line derived from melanoma cells, Abciximab blocked &alpha;v&beta;3-mediated effects including cell adhesion (IC50 = 0.34 &mu;g/mL). At concentrations which, in vitro, provide > 80% GPIIb/IIIa receptor blockade, but above the in vivo therapeutic range, Abciximab more effectively blocked the burst of thrombin generation that followed platelet activation than select comparator antibodies which inhibit GPIIb/IIIa alone (1). The relationship of these in vitro data to clinical efficacy is unknown. Abciximab also binds to the activated Mac-1 receptor on monocytes and neutrophils (2). In in vitro studies, Abciximab and 7E3 IgG blocked Mac-1 receptor function as evidenced by inhibition of monocyte adhesion (3). In addition, the degree of activated Mac-1 expression on circulating leukocytes and the numbers of circulating leukocyteplatelet complexes has been shown to be reduced in patients treated with Abciximab compared to control patients (4). The relationship of these in vitro data to clinical efficacy is uncertain. Pre-Clinical Experience Maximal inhibition of platelet aggregation was observed when &ge; 80% of GPIIb/IIIa receptors were blocked by Abciximab. In non-human primates, Abciximab bolus doses of 0.25 mg/kg generally achieved a blockade of at least 80% of platelet receptors and fully inhibited platelet aggregation. Inhibition of platelet function was temporary following a bolus dose, but receptor blockade could be sustained at &ge; 80% by continuous intravenous infusion. The inhibitory effects of Abciximab were substantially reversed by the transfusion of platelets in monkeys. The antithrombotic efficacy of prototype antibodies [murine 7E3 Fab and F(ab')2] and Abciximab was evaluated in dog, monkey and baboon models of coronary, carotid, and femoral artery thrombosis. Doses of the murine version of 7E3 or Abciximab sufficient to produce high-grade ( &ge; 80%) GPIIb/IIIa receptor blockade prevented acute thrombosis and yielded lower rates of thrombosis compared with aspirin and/or heparin. Pharmacokinetics Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. Platelet function generally recovers over the course of 48 hours (5,6), although Abciximab remains in the circulation for 15 days or more in a platelet-bound state. Intravenous administration of a 0.25 mg/kg bolus dose of Abciximab followed by continuous infusion of 10 &mu;g/min (or a weight-adjusted infusion of 0.125 &mu;g/kg/min to a maximum of 10 &mu;g/min) produces approximately constant free plasma concentrations throughout the infusion. At the termination of the infusion period, free plasma concentrations fall rapidly for approximately six hours then decline at a slower rate. Pharmacodynamics Intravenous administration in humans of single bolus doses of Abciximab from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function as measured by ex vivo platelet aggregation in response to adenosine diphosphate (ADP) or by prolongation of bleeding time. At the two highest doses (0.25 and 0.30 mg/kg) at two hours post injection (the first time point evaluated), over 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20 &mu;M ADP was almost abolished. The median bleeding time increased to over 30 minutes at both doses compared with a baseline value of approximately five minutes. Intravenous administration in humans of a single bolus dose of 0.25 mg/kg followed by a continuous infusion of 10 &mu;g/min for periods of 12 to 96 hours produced sustained high-grade GPIIb/IIIa receptor blockade ( &ge; 80%) and inhibition of platelet unction (ex vivo platelet aggregation in response to 5 &mu;M or 20 &mu;M ADP less than 20% of baseline and bleeding time greater than 30 minutes) for the duration of the infusion in most patients. Similar results were obtained when a weight-adjusted infusion dose (0.125 &mu;g/kg/min to a maximum of 10 &mu;g/min) was used in patients weighing up to 80 kg. Results in patients who received the 0.25 mg/kg bolus followed by a 5 &mu;g/min infusion for 24 hours showed a similar initial receptor blockade and inhibition of platelet aggregation, but the response was not maintained throughout the infusion period. The onset of Abciximab-mediated platelet inhibition following a 0.25 mg/kg bolus and 0.125 &mu;g/kg/min infusion was rapid and platelet aggregation was reduced to less than 20% of baseline in 8 of 10 patients at 10 minutes after treatment initiation. Low levels of GPIIb/IIIa receptor blockade are present for more than 10 days following cessation of the infusion. After discontinuation of Abciximab infusion, platelet function returns gradually to normal. Bleeding time returned to &le; 12 minutes within 12 hours following the end of infusion in 15 of 20 patients (75%), and within 24 hours in 18 of 20 patients (90%). Ex vivo platelet aggregation in response to 5 ADP returned to &ge; 50% of baseline within 24 hours following the end of infusion in 11 of 32 patients (34%) and within 48 hours in 23 of 32 patients (72%). In response to 20 ADP, ex vivo platelet aggregation returned to &ge; 50% of baseline within 24 hours in 20 of 32 patients (62%) and within 48 hours in 28 of 32 patients (88%). Clinical Studies Abciximab has been studied in four Phase 3 clinical trials, all of which evaluated the effect of Abciximab in patients undergoing percutaneous coronary intervention (PCI): in patients at high risk for abrupt closure of the treated coronary vessel (EPIC), in a broader group of patients (EPILOG), in unstable angina patients not responding to conventional medical therapy (CAPTURE), and in patients suitable for either conventional angioplasty/atherectomy or primary stent implantation (EPILOG Stent; EPISTENT). Percutaneous intervention included balloon angioplasty, atherectomy, or stent placement. All trials involved the use of various, concomitant heparin dose regimens and, unless contraindicated, aspirin (325 mg) was administered orally two hours prior to the planned procedure and then once daily. EPIC was a multicenter, double-blind, placebo-controlled trial of Abciximab in patients undergoing percutaneous transluminal coronary angioplasty or atherectomy (PTCA) who were at high risk for abrupt closure of the treated coronary vessel (7). Patients were allocated to treatment with: 1) Abciximab bolus plus infusion for 12 hours; 2) Abciximab bolus plus placebo infusion, or; 3) placebo bolus plus infusion. All patients received concomitant heparin (10,000 to 12,000 U bolus followed by an infusion for 12 hours). The primary endpoint was the composite of death, myocardial infarction (MI), or urgent intervention for recurrent ischemia within 30 days of randomization. The primary endpoint event rates in the Abciximab bolus plus infusion group were reduced mostly in the first 48 hours and this benefit was sustained through 30 days (7), 6 months (8), and three years (9). EPILOG was a randomized, double-blind, multicenter, placebo-controlled trial which evaluated Abciximab in a broad population of patients undergoing PCI (excluding patients with myocardial infarction and unstable angina meeting the EPIC high risk criteria) (10). Study procedures emphasized discontinuation of heparin after the procedure with early femoral arterial sheath removal and careful access site management (see PRECAUTIONS). EPILOG was a three-arm trial comparing Abciximab plus standard-dose heparin, Abciximab plus low-dose heparin, and placebo plus standard-dose heparin. Abciximab and heparin infusions were weight-adjusted in all arms. The Abciximab bolus plus infusion regimen was: 0.25 mg/kg bolus followed by a 0.125 &mu;g/kg/min infusion (to a maximum of 10 &mu;g/min) for 12 hours. The heparin regimen was either a standard-dose regimen (initial 100 U/kg bolus, target ACT &ge; 300 seconds) or a low-dose regimen (initial 70 U/kg bolus, target ACT &ge; 200 seconds). The primary endpoint of the EPILOG trial was the composite of death or MI occurring within 30 days of PCI. The composite of death, MI, or urgent intervention was an important secondary endpoint. The endpoint events in the Abciximab treatment group were reduced mostly in the first 48 hours and this benefit was sustained through 30 days and six months (10) and one year (11). The (Kaplan-Meier) endpoint event rates at 30 days are shown in Table 1. Table 1: ENDPOINT EVENT RATES AT 30 DAYS - EPILOG TRIAL Placebo + Standard Dose Heparin (n=939) Abciximab + Standard Dose Heparin (n=918) Abciximab + Low Dose Heparin (n=935) Number of Patients (%) Death or MIa 85 (9.1) 38 (4.2) 35 (3.8) p-value vs. placebo < 0.001 < 0.001 Death, MI, or urgent interventiona 109 (11.7) 49 (5.4) 48 (5.2) p-value vs. placebo < 0.001 < 0.001 Components of Composite Endpointsb Death 7 (0.8) 4 (0.4) 3 (0.3) Acute myocardial infarctions in surviving patients 78 (8.4) 34 (3.7) 32 (3.4) Urgent interventions in surviving patients without an acute myocardial infarction 24 (2.6) 11 (12) 13 (1.4) a Patients who experienced more than one event in the first 30 days are counted only once. b Patients are counted only once under the most serious component (death > acute MI > urgent intervention). At the six-month follow up visit, the event rate for death, MI, or repeat (urgent or non-urgent) intervention remained lower in the Abciximab treatment arms (22.3% and 22.8%, respectively, for the standard- and low-dose heparin arms) than in the placebo arm (25.8%) and the event rate for death, MI, or urgent intervention was substantially lower in the Abciximab treatment arms (8.3% and 8.4%, respectively, for the standardand low-dose heparin arms) than in the placebo arm (14.7%). The treatment associated effects continued to persist at the one-year follow up visit. The proportionate reductions in endpoint event rates were similar irrespective of the type of coronary intervention used (balloon angioplasty, atherectomy, or stent placement). Risk assessment using the American College of Cardiology/American Heart Association clinical/morphological criteria had large inter-observer variability. Consequently, a low risk subgroup could not be reproducibly identified in which to evaluate efficacy. The EPISTENT trial was a randomized, multicenter trial evaluating three different treatment strategies in patients undergoing PCI: conventional PTCA with Abciximab plus low-dose heparin, primary intracoronary stent implantation with Abciximab plus lowdose heparin, and primary intracoronary stent implantation with placebo plus standarddose heparin (12). The heparin dose was weight-adjusted in all arms. The JJIS Palmaz- Schatz stent was used in over 90% of the patients receiving stents. The two stent arms were blinded with respect to study agent (Abciximab or placebo) and heparin dose; the PCI arm with Abciximab was open-label. The Abciximab bolus plus infusion regimen was the same as that used in the EPILOG trial. The standard-dose and low-dose heparin regimens were the same as those used in the EPILOG trial. All patients were to receive aspirin; ticlopidine, if given, was to be started prior to study agent. Patient and access site management guidelines were the same as those for EPILOG, including a strong recommendation for early sheath removal. The results demonstrated benefit in both Abciximab arms (i.e., with and without stents) compared with stenting alone on the composite of death, MI, or urgent intervention (repeat PCI or CABG) within 30 days of PCI (12). The (Kaplan-Meier) endpoint event rates at 30 days are shown in Table 2. Table 2 : PRIMARY ENDPOINT EVENT RATE AT 30 DAYS - EPISTENT TRIAL Placebo + Stent (n=809) Abciximab + Stent (n=794) Abciximab + PTCA (n=796) Number of Patients (%) Death, MI, or urgent interventiona 87 (10.8%) 42 (5.3%) 55 (6.9%) p-value vs. placebo < 0.001 0.007 Components of Composite Endpointb Death 5 (0.6%) 2 (0.3%) 6 (0.8%) Acute myocardial infarctions in surviving patients 77 (9.6%) 35 (4.4%) 40 (5.0%) Urgent interventions in surviving patients without an acute myocardial infarction 5 (0.6%) 5 (0.6%) 9 (1.1%) a Patients who experienced more than one event in the first 30 days are counted only once. b Patients are counted only once under the most serious component (death > acute MI > urgent intervention). This benefit was maintained at 6 months: 12.1% of patients in the placebo/stent group experienced death, MI, or urgent revascularization compared with 6.4% of patients in the Abciximab/stent group (p < 0.001 vs placebo/stent) and 9.2% in the Abciximab/PTCA group (p=0.051 vs placebo/stent). At 6 months, a reduction in the composite of death, MI, or all repeat (urgent or non-urgent) intervention was observed in the Abciximab/stent group compared with the placebo/stent group (15.4% vs 20.4%, p=0.006); the rate of this composite endpoint was similar in the Abciximab/PTCA and placebo/stent groups (22.4% vs 20.4%, p=0.467). (13) CAPTURE was a randomized, double-blind, multicenter, placebo-controlled trial of the use of Abciximab in unstable angina patients not responding to conventional medical therapy for whom PCI was planned, but not immediately performed (14). The CAPTURE trial involved the administration of placebo or Abciximab starting 18 to 24 hours prior to PCI and continuing until one hour after completion of the intervention. Patients were assessed as having unstable angina not responding to conventional medical therapy if they had at least one episode of myocardial ischemia despite bed rest and at least two hours of therapy with intravenous heparin and oral or intravenous nitrates. These patients were enrolled into the CAPTURE trial, if during a screening angiogram, they were determined to have a coronary lesion amenable to PCI. Patients received a bolus dose and intravenous infusion of placebo or Abciximab for 18 to 24 hours. At the end of the infusion period, the intervention was performed. The Abciximab or placebo infusion was discontinued one hour following the intervention. Patients were treated with intravenous heparin and oral or intravenous nitrates throughout the 18- to 24-hour Abciximab infusion period prior to the PCI. The Abciximab dose was a 0.25 mg/kg bolus followed by a continuous infusion at a rate o f 10 &mu;g/min. The CAPTURE trial incorporated weight adjustment of the standard heparin dose only during the performance of the intervention, but did not investigate the effect of a lower heparin dose, and arterial sheaths were left in place for approximately 40 hours. The primary endpoint of the CAPTURE trial was the occurrence of any of the following events within 30 days of PCI: death, MI, or urgent intervention. The 30-day (Kaplan-Meier) primary endpoint event rates are shown in Table 3. Table 3: PRIMARY ENDPOINT EVENT RATE AT 30 DAYS - CAPTURE TRIAL Placebo (n=635) Abciximab (n=630) Number of Patients (%) Death, MI, or urgent interventiona 101 (15.9) 71 (11.3) p-value vs. placebo 0.012 Components of Primary Endpointb Death 8 (1.3) 6 (1.0) MI in surviving patients 49 (7.7) 24 (3.8) Urgent intervention in surviving patients without an acute MI 44 (6.9) 41 (6.6) a Patients who experienced more than one event in the first 30 days are counted only once. Urgent interventions included any unplanned PCI after the planned intervention, as well as any stent placement for immediate patency and any unplanned CABG or use of an intra-aortic balloon pump. b Patients are counted only once under the most serious component (death > acute MI > urgent intervention). The 30-day results are consistent with the results of the other three trials, with the greatest effects on the myocardial infarction and urgent intervention components of the composite endpoint. As secondary endpoints, the components of the composite endpoint were analyzed separately for the period prior to the PCI and the period from the beginning of the intervention through Day 30. The greatest difference in MI occurred in the post-intervention period: the rates of MI were lower in the Abciximab group compared with placebo (Abciximab 3.6%, placebo 6.1%). There was also a reduction in MI occurring prior to the PCI (Abciximab 0.6%, placebo 2.0%). An Abciximab-associated reduction in the incidence of urgent intervention occurred in the post-intervention period. No effect on mortality was observed in either period. At six months of follow up, the composite endpoint of death, MI, or all repeat intervention (urgent or non-urgent) was not different between the Abciximab and placebo groups (Abciximab 31.0%, placebo 30.8%, p=0.77). Mortality was uncommon in all four trials. Similar mortality rates were observed in all arms within each trial. Patient follow-up through one year of the EPISTENT trial suggested decreased mortality among patients treated with Abciximab and stent placement compared to patients treated with stent alone (8/794 vs. 19/809, p=0.037). Data from earlier studies with balloon angioplasty were not suggestive of the same benefit. In all four trials, the rates of acute MI were significantly lower in the groups treated with Abciximab. Most of the Abciximab treatment effect was seen in reduction in the rate of acute non-Q-wave MI. Urgent intervention rates were also lower in Abciximab-treated groups in these trials. Anticoagulation EPILOG and EPISTENT: Weight-adjusted low dose heparin, weight-adjusted Abciximab, careful vascular access site management and discontinuation of heparin after the procedure with early femoral arterial sheath removal were used. The initial heparin bolus was based upon the results of the baseline ACT, according to the following regimen: ACT < 150 seconds: administer 70 U/kg heparin ACT 150 - 199 seconds: administer 50 U/kg heparin ACT &ge; 200 seconds: administer no heparin Additional 20 U/kg heparin boluses were given to achieve and maintain an ACT of &ge; 200 seconds during the procedure. Discontinuation of heparin immediately after the procedure and removal of the arterial sheath within six hours were strongly recommended in the trials. If prolonged heparin therapy or delayed sheath removal was clinically indicated, heparin was adjusted to keep the APTT at a target of 60 to 85 seconds (EPILOG) or 55 to 75 seconds (EPISTENT). CAPTURE trial: Anticoagulation was initiated prior to the administration of Abciximab. Anticoagulation was initiated with an intravenous heparin infusion to achieve a target APTT of 60 to 85 seconds. The heparin infusion was not uniformly weight adjusted in this trial. The heparin infusion was maintained during the Abciximab infusion and was adjusted to achieve an ACT of 300 seconds or an APTT of 70 seconds during the PCI. Following the intervention, heparin management was as outlined above for the EPILOG trial. REFERENCES 1. Reverter JC, Beguin S, Kessels H, Kumar R, Hemmer HC, Coller BS. Inhibition of platelet-mediated, tissue-factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody; potential implications for the effect of c7E3 Fab treatment on acute thrombosis and &ldquo;clinical restenosis&rdquo;. J Clin Invest. 1996;98:863-874. 2 Alteri D, Edgington T, A monoclonal antibody reacting with distinct adhesion molecules defines a transition in the functional state of the receptor CD11b/CD18 (Mac- 1). The Journal of Immunology. 1988;141:2656-2660. 3. Simon DI, Xu H, Ortlepp S, Rogers C, Rao NK. 7E3 monoclonal antibody directed against the platelet glycoprotein IIb/IIIa cross-reacts with the leukocyte integrin Mac-1 and blocks adhesion to fibrinogen and ICAM-1. Arterioscler Thromb Vasc Biol. 1997;17:528-535. 4. Mickelson JK, Ali MN, Kleiman NS, Lakkis NM, Chow TW, Hughes BJ. Chimeric 7E3 Fab (ReoPro) decreases detectable CD11b on neutrophils from patients undergoing coronary angioplasty. J Am Coll Cardiol. 1999;33:97-106. 5. Tcheng J, Ellis SG, George BS. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high risk coronary angioplasty. Circulation. 1994;90:1757- 1764. 6. Simoons ML, de Boer MJ, van der Brand MJBM, et al. Randomized trial of a GPIIb/IIIa platelet receptor blocker in refractory unstable angina. Circulation. 1994;89:596-603. 7. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med. 1994;330:956-961. 8. Topol EJ, Califf RM, Weisman HF, et al. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet. 1994;343:881-886. 9. Topol EJ, Ferguson JJ, Weisman HF, et al. for the EPIC Investigators. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin blockade with percutaneous coronary intervention. JAMA. 1997;278:479-484. 10. EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low dose heparin during percutaneous coronary revascularization. N Eng J Med. 1997;336:1689-1696. 11. Lincoff AM, Tcheng JE, Califf RM, et al. for the EPILOG Investigators. Sustained suppression of ischemic complications of coronary intervention by platelet GP IIb/IIIa blockade with abciximab. Circ. 1999; 99:1951-1958. 12. EPISTENT Investigators. Randomised placebo-controlled and balloon angioplastycontrolled trial to assess safety of coronary stenting with use of platelet glycoprotein- IIb/IIIa blockade. Lancet. 1998;352:87-92. 13. Lincoff AM, Califf RM, Moliterno DJ, et al. for the EPISTENT Investigator. Complementary clinical benefits of coronary stenting and blockade of platelet glycoprotein IIb/IIIa receptors. N Engl J Med 1999; 341:319-327. 14. CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before, during and after coronary intervention in refractory unstable angina: the CAPTURE study. Lancet. 1997; 349:1429-1435.132017-09-01 11:12:57AbciximabReoProFDA
1022017-12-04 17:38:20Medication GuidePATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.132017-09-01 11:12:57AbciximabReoProFDA
1032017-12-04 17:38:29Drug DescriptionFind Lowest Prices on ABELCET&reg; (amphotericin B lipid complex) Injection DESCRIPTION ABELCET&reg; (amphotericin b) is a sterile, pyrogen-free suspension for intravenous infusion. ABELCET&reg; consists of amphotericin B complexed with two phospholipids in a 1:1 drug-to-lipid molar ratio. The two phospholipids, L-&alpha;-dimyristoylphosphatidylcholine (DMPC) and L-&alpha;-dimyristoylphosphatidylglycerol (DMPG), are present in a 7:3 molar ratio. ABELCET&reg; (amphotericin b) is yellow and opaque in appearance, with a pH of 5 - 7. NOTE: Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug's functional properties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipid-complexed products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect functional properties of these drug products. Amphotericin B is a polyene, antifungal antibiotic produced from a strain of Streptomyces nodosus. Amphotericin B is designated chemically as [1R-(1R*, 3S*, 5R*, 6R*, 9R*, 11R*, 15S*, 16R*, 17R*, 18S*, 19E, 21E, 23E, 25E, 27E, 29E, 31E, 33R*, 35S*, 36R*, 37S*)]-33-[(3-Amino-3, 6-dideoxy-&beta;-D-mannopyranosyl) oxy]-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicy-clo[33.3.1] nonatriaconta-19, 21, 23, 25, 27, 29, 31-heptaene-36-carboxylic acid. It has a molecular weight of 924.09 and a molecular formula of C47H73NO17. The structural formula is: ABELCET&reg; (amphotericin b) is provided as a sterile, opaque suspension in 20 mL glass, single-use vials. Each 20 mL vial contains 100 mg of amphotericin B (see DOSAGE AND ADMINISTRATION), and each mL of ABELCET&reg; contains: Amphotericin B USP.......................................5 mgL-&alpha;-dimyristoylphosphatidylcholine (DMPC).......................................3.4 mg L-&alpha;-dimyristoylphosphatidylglycerol (DMPG).......................................1.5 mg Sodium Chloride USP.......................................9 mg Water for Injection USP, q.s. 1 mL142017-09-01 11:12:57AbelcetAmphotericin B InjectionFDA
1042017-12-04 17:38:29Indications & DosageINDICATIONS ABELCET&reg; (amphotericin b) is indicated for the treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B therapy. This is based on open-label treatment of patients judged by their physicians to be intolerant to or failing conventional amphotericin B therapy (See Description Of Clinical Studies). DOSAGE AND ADMINISTRATION The recommended daily dosage for adults and children is 5 mg/kg given as a single infusion. ABELCET&reg; (amphotericin b) should be administered by intravenous infusion at a rate of 2.5 mg/kg/h. If the infusion time exceeds 2 hours, mix the contents by shaking the infusion bag every 2 hours. Renal toxicity of ABELCET&reg; (amphotericin b) , as measured by serum creatinine levels, has been shown to be dose dependent. Decisions about dose adjustments should be made only after taking into account the overall clinical condition of the patient. Preparation of Admixture for Infusion: Shake the vial gently until there is no evidence of any yellow sediment at the bottom. Withdraw the appropriate dose of ABELCET&reg; (amphotericin b) from the required number of vials into one or more sterile syringes using an 18-gauge needle. Remove the needle from each syringe filled with ABELCET&reg; (amphotericin b) and replace with the 5-micron filter needle supplied with each vial. Each filter needle may be used to filter the contents of up to four 100 mg vials. Insert the filter needle of the syringe into an IV bag containing 5% Dextrose Injection USP, and empty the contents of the syringe into the bag. The final infusion concentration should be 1 mg/mL. For pediatric patients and patients with cardiovascular disease the drug may be diluted with 5% Dextrose Injection to a final infusion concentration of 2 mg/mL. Before infusion, shake the bag until the contents are thoroughly mixed. Do not use the admixture after dilution with 5% Dextrose Injection if there is any evidence of foreign matter. Vials are for single use. Unused material should be discarded. Aseptic technique must be strictly observed throughout handling of ABELCET&reg; (amphotericin b) , since no bacteriostatic agent or preservative is present. DO NOT DILUTE WITH SALINE SOLUTIONS OR MIX WITH OTHER DRUGS OR ELECTROLYTES as the compatibility of ABELCET&reg; (amphotericin b) with these materials has not been established. An existing intravenous line should be flushed with 5% Dextrose Injection before infusion of ABELCET&reg; (amphotericin b) , or a separate infusion line should be used. DO NOT USE AN IN-LINE FILTER. The diluted ready-for-use admixture is stable for up to 48 hours at 2&deg; to 8&deg;C (36&deg; to 46&deg;F) and an additional 6 hours at room temperature. HOW SUPPLIED Single-use vials along with 5-micron filter needles are individually packaged. 100 mg of ABELCET&reg; (amphotericin b) in 20 mL of suspension NDC 57665-101-41 Storage Prior to admixture, ABELCET&reg; (amphotericin b) should be stored at 2&deg; to 8&deg;C (36&deg; to 46&deg;F) and protected from exposure to light. Do not freeze. ABELCET&reg; (amphotericin b) should be retained in the carton until time of use. The admixed ABELCET&reg; (amphotericin b) and 5% Dextrose Injection may be stored for up to 48 hours at 2&deg; to 8&deg;C (36&deg; to 46&deg;F) and an additional 6 hours at room temperature. Do not freeze. Any unused material should be discarded. Distributed by: ENZON Pharmaceuticals Inc., Bridgewater, NJ 08807.142017-09-01 11:12:57AbelcetAmphotericin B InjectionFDA
1052017-12-04 17:38:29Side Effects & Drug InteractionsSIDE EFFECTS The total safety data base is composed of 921 patients treated with ABELCET&reg; (amphotericin b) (5 patients were enrolled twice and counted as separate patients), of whom 775 were treated with 5 mg/kg/day. Of these 775 patients, 194 patients were treated in four comparative studies; 25 were treated in open-label, non-comparative studies; and 556 patients were treated in an open-label, emergency-use program. Most had underlying hematologic neoplasms, and many were receiving multiple concomitant medications. Of the 556 patients treated with ABELCET&reg; (amphotericin b) , 9% discontinued treatment due to adverse events regardless of presumed relationship to study drug. In general, the adverse events most commonly reported with ABELCET&reg; (amphotericin b) were transient chills and/or fever during infusion of the drug. Adverse Eventsa with an Incidence of &ge; 3% (N=556) Adverse Event Percentage (%) of Patients Chills 18 Fever 14 Increased Serum Creatinine 11 Multiple Organ Failure 11 Nausea 9 Hypotension 8 Respiratory Failure 8 Vomiting 8 Dyspnea 7 Sepsis 7 Diarrhea 6 Headache 6 Heart Arrest 6 Hypertension 5 Hypokalemia 5 Infection 5 Kidney Failure 5 Pain 5 Thrombocytopenia 5 Abdominal Pain 4 Anemia 4 Bilirubinemia 4 Gastrointestinal Hemorrhage 4 Leukopenia 4 Rash 4 Respiratory Disorder 4 Chest Pain 3 Nausea and Vomiting 3 a The causal association between these adverse events and ABELCET&reg; is uncertain. The following adverse events have also been reported in patients using ABELCET&reg; (amphotericin b) in open-label, uncontrolled clinical studies. The causal association between these adverse events and ABELCET&reg; (amphotericin b) is uncertain. Body as a whole: malaise, weight loss, deafness, injection site reaction including inflammation Allergic: bronchospasm, wheezing, asthma, anaphylactoid and other allergic reactions Cardiopulmonary:cardiac failure, pulmonary edema, shock, myocardial infarction, hemoptysis, tachypnea, thrombophlebitis, pulmonary embolus, cardiomyopathy, pleural effusion, arrhythmias including ventricular fibrillation. Dermatological: maculopapular rash, pruritus, exfoliative dermatitis, erythema multiforme Gastrointestinal:acute liver failure, hepatitis, jaundice, melena, anorexia, dyspepsia, cramping, epigastric pain, veno-occlusive liver disease, diarrhea, hepatomegaly, cholangitis, cholecystitis Hematologic:coagulation defects, leukocytosis, blood dyscrasias including eosinophilia Musculoskeletal: myasthenia, including bone, muscle, and joint pains Neurologic: convulsions, tinnitus, visual impairment, hearing loss, peripheral neuropathy, transient vertigo, diplopia, encephalopathy, cerebral vascular accident, extrapyramidal syndrome and other neurologic symptoms Urogenital: oliguria, decreased renal function, anuria, renal tubular acidosis, impotence, dysuria Serum electrolyte abnormalities: hypomagnesemia, hyperkalemia, hypocalcemia, hypercalcemia Liver function test abnormalities: increased AST, ALT, alkaline phosphatase, LDH Renal function test abnormalities: increased BUN Other test abnormalities: acidosis, hyperamylasemia, hypoglycemia, hyperglycemia, hyperuricemia, hypophosphatemia DRUG INTERACTIONS No formal clinical studies of drug interactions have been conducted with ABELCET&reg; (amphotericin b) . However, when administered concomitantly, the following drugs are known to interact with amphotericin B; therefore, the following drugs may interact with ABELCET&reg; (amphotericin b) : Antineoplastic agents: Concurrent use of antineoplastic agents and amphotericin B may enhance the potential for renal toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given concomitantly with ABELCET&reg; (amphotericin b) with great caution. Corticosteroids and corticotropin (ACTH): Concurrent use of corticosteroids and corticotropin (ACTH) with amphotericin B may potentiate hypokalemia which could predispose the patient to cardiac dysfunction. If used concomitantly with ABELCET&reg; (amphotericin b) , serum electrolytes and cardiac function should be closely monitored. Cyclosporin A: Data from a prospective study of prophylactic ABELCET&reg; (amphotericin b) in 22 patients undergoing bone marrow transplantation suggested that concurrent initiation of cyclosporin A and ABELCET&reg; (amphotericin b) within several days of bone marrow ablation may be associated with increased nephrotoxicity. Digitalis glycosides: Concurrent use of amphotericin B may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly with ABELCET&reg; (amphotericin b) , serum potassium levels should be closely monitored. Flucytosine: Concurrent use of flucytosine with amphotericin B-containing preparations may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Flucytosine should be given concomitantly with ABELCET&reg; (amphotericin b) with caution. Imidazoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.): Antagonism between amphotericin B and imidazole derivatives such as miconazole and ketoconazole, which inhibit ergosterol synthesis, has been reported in both in vitro and in vivo animal studies. The clinical significance of these findings has not been determined. Leukocyte transfusions: Acute pulmonary toxicity has been reported in patients receiving intravenous amphotericin B and leukocyte transfusions. Leukocyte transfusions and ABELCET&reg; (amphotericin b) should not be given concurrently. Other nephrotoxic medications: Concurrent use of amphotericin B and agents such as aminoglcosides and pentamidine may enhance the potential for drug-induced renal toxicity. Aminoglycosides and pentamidine should be used concomitantly with ABELCET&reg; (amphotericin b) only with great caution. Intensive monitoring of renal function is recommended in patients requiring any combination of nephrotoxic medications. Skeletal muscle relaxants: Amphotericin B-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g., tubocurarine) due to hypokalemia. When administered concomitantly with ABELCET&reg; (amphotericin b) , serum potassium levels should be closely monitored. Zidovudine: Increased myelotoxicity and nephrotoxicity were observed in dogs when either ABELCET&reg; (amphotericin b) (at doses 0.16 or 0.5 times the recommended human dose) or amphotericin B desoxycholate (at 0.5 times the recommended human dose) were administered concomitantly with zidovudine for 30 days. If zidovudine is used concomitantly with ABELCET&reg; (amphotericin b) , renal and hematologic function should be closely monitored.142017-09-01 11:12:57AbelcetAmphotericin B InjectionFDA
1062017-12-04 17:38:29Warnings & PrecautionsWARNINGS Anaphylaxis has been reported with amphotericin B desoxycholate and other amphotericin B-containing drugs. Anaphylaxis has been reported with ABELCET&reg; (amphotericin b) with an incidence rate of < 0.1%. If severe respiratory distress occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of ABELCET&reg; (amphotericin b) . PRECAUTIONS General As with any amphotericin B-containing product, during the initial dosing of ABELCET&reg; (amphotericin b) , the drug should be administered under close clinical observation by medically trained personnel. Acute reactions including fever and chills may occur 1 to 2 hours after starting an intravenous infusion of ABELCET&reg; (amphotericin b) . These reactions are usually more common with the first few doses of ABELCET&reg; (amphotericin b) and generally diminish with subsequent doses. Infusion has been rarely associated with hypotension, bronchospasm, arrhythmias, and shock. Laboratory Tests Serum creatinine should be monitored frequently during ABELCET&reg; therapy (see ADVERSE REACTIONS). It is also advisable to regularly monitor liver function, serum electrolytes (particularly magnesium and potassium), and complete blood counts. Carcinogenesis, Mutagenesis, and Impairment of Fertility No long-term studies in animals have been performed to evaluate the carcinogenic potential of ABELCET&reg; (amphotericin b) . The following in vitro (with and without metabolic activation) and in vivo studies to assess ABELCET&reg; (amphotericin b) for mutagenic potential were conducted: bacterial reverse mutation assay, mouse lymphoma forward mutation assay, chromosomal aberration assay in CHO cells, and in vivo mouse micronucleus assay. ABELCET&reg; (amphotericin b) was found to be without mutagenic effects in all assay systems. Studies demonstrated that ABELCET&reg; (amphotericin b) had no impact on fertility in male and female rats at doses up to 0.32 times the recommended human dose (based on body surface area considerations). Pregnancy There are no reports of pregnant women having been treated with ABELCET&reg; (amphotericin b) . Teratogenic Effects. Pregnancy Category B: Reproductive studies in rats and rabbits at doses of ABELCET&reg; (amphotericin b) up to 0.64 times the human dose revealed no harm to the fetus. Because animal reproductive studies are not always predictive of human response, and adequate and well-controlled studies have not been conducted in pregnant women, ABELCET&reg; (amphotericin b) should be used during pregnancy only after taking into account the importance of the drug to the mother. Nursing Mothers It is not known whether ABELCET&reg; (amphotericin b) is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in breast-fed infants from ABELCET&reg; (amphotericin b) , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use One hundred eleven children (2 were enrolled twice and counted as separate patients), age 16 years and under, of whom 11 were less than 1 year, have been treated with ABELCET&reg; (amphotericin b) at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. In one single-center study, 5 children with hepatosplenic candidiasis were effectively treated with 2.5 mg/kg/day of ABELCET&reg; (amphotericin b) . No serious unexpected adverse events have been reported. Geriatric Use Forty-nine elderly patients, age 65 years or over, have been treated with ABELCET&reg; (amphotericin b) at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. No serious unexpected adverse events have been reported.142017-09-01 11:12:57AbelcetAmphotericin B InjectionFDA
1072017-12-04 17:38:29Overdosage & ContraindicationsOVERDOSE Amphotericin B desoxycholate overdose has been reported to result in cardio-respiratory arrest. Fifteen patients have been reported to have received one or more doses of ABELCET&reg; (amphotericin b) between 7-13 mg/kg. None of these patients had a serious acute reaction to ABELCET&reg; (amphotericin b) . If an overdose is suspected, discontinue therapy, monitor the patient's clinical status, and administer supportive therapy as required. ABELCET&reg; (amphotericin b) is not hemodialyzable. CONTRAINDICATIONS ABELCET&reg; (amphotericin b) is contraindicated in patients who have shown hypersensitivity to amphotericin B or any other component in the formulation.142017-09-01 11:12:57AbelcetAmphotericin B InjectionFDA
1082017-12-04 17:38:29Clinical PharmacologyCLINICAL PHARMACOLOGY Microbiology Mechanism of Action The active component of ABELCET&reg;, amphotericin B, acts by binding to sterols in the cell membrane of susceptible fungi, with a resultant change in the permeability of the membrane. Mammalian cell membranes also contain sterols, and damage to human cells is believed to occur through the same mechanism of action. Activity in vitro and in vivo ABELCET&reg; (amphotericin b) shows in vitro activity against Aspergillus sp. (n=3) and Candida sp. (n=10), with MICs generally < 1 &micro;g/mL. Depending upon the species and strain of Aspergillus and Candida tested, significant in vitro differences in susceptibility to amphotericin B have been reported (MICs ranging from 0.1 to > 10 &micro;g/mL). However, standardized techniques for susceptibility testing for antifungal agents have not been established, and results of susceptibility studies do not necessarily correlate with clinical outcome. ABELCET&reg; (amphotericin b) is active in animal models against Aspergillus fumigatus, Candida albicans, C. guillermondii, C. stellatoideae, and C. tropicalis, Cryptococcus sp., Coccidioidomyces sp., Histoplasma sp., and Blastomyces sp. in which end-points were clearance of microorganisms from target organ(s) and/or prolonged survival of infected animals. Drug Resistance Fungal species with decreased susceptibility to amphotericin B have been isolated after serial passage in culture media containing the drug, and from some patients receiving prolonged therapy. Although the relevance of drug resistance to clinical outcome has not been established, fungal species which are resistant to amphotericin B may also be resistant to ABELCET&reg; (amphotericin b) . Pharmacokinetics The assay used to measure amphotericin B in the blood after the administration of ABELCET&reg; does not distinguish amphotericin B that is complexed with the phospholipids of ABELCET&reg; from amphotericin B that is uncomplexed. The pharmacokinetics of amphotericin B after the administration of ABELCET&reg; (amphotericin b) are nonlinear. Volume of distribution and clearance from blood increase with increasing dose of ABELCET&reg; (amphotericin b) , resulting in less than proportional increases in blood concentrations of amphotericin B over a dose range of 0.6-5 mg/kg/day. The pharmacokinetics of amphotericin B in whole blood after the administration of ABELCET&reg; and amphotericin B desoxycholate are: Pharmacokinetic Parameters of Amphotericin B in Whole Blood in Patients Administered Multiple Doses of ABELCET&reg; or Amphotericin B Desoxycholate Pharmacokinetic Parameter ABELCET&reg; (amphotericin b) 5 mg/kg/day for 5-7 days Mean &plusmn; SD Amphotericin B 0.6 mg/kg/day for 42 daysa Mean &plusmn; SD Peak Concentration (&micro;g/mL) 1.7 &plusmn; 0.8 (n=10)b 1.1 &plusmn; 0.2 (n=5) Concentration at End of Dosing Interval (&micro;g/mL) 0.6 &plusmn; 0.3 (n=10)b 0.4 &plusmn; 0.2 (n=5) Area Under Blood Concentration-Time Curve (AUC0-24h) (ng*h/mL) 14 &plusmn; 7 (n=14)b,c 17.1 &plusmn; 5 (n=5) Clearance (mL/h*kg) 436 &plusmn; 188.5 (n=14)b,c 38 &plusmn;15 (n=5) Apparent Volume of Distribution (Vdarea) (L/kg) 131 &plusmn; 57.7 (n=8)c 5 &plusmn; 2.8 (n=5) Terminal Elimination Half-Life (h) 173.4 &plusmn; 78 (n=8)c 91.1 &plusmn; 40.9 (n=5) Amount Excreted in Urine Over 24 h After Last Dose (% of dose)d 0.9 &plusmn; 0.4 (n=8)c 9.6 &plusmn; 2.5 (n=8) a Data from patients with mucocutaneous leishmaniasis. Infusion rate was 0.25 mg/kg/h. b Data from studies in patients with cytologically proven cancer being treated with chemotherapy or neutropenic patients with presumed or proven fungal infection. Infusion rate was 2.5 mg/kg/h. c Data from patients with mucocutaneous leishmaniasis. Infusion rate was 4 mg/kg/h. d Percentage of dose excreted in 24 hours after last dose. The large volume of distribution and high clearance from blood of amphotericin B after the admistration of ABELCET&reg; (amphotericin b) probably reflect uptake by tissues. The long terminal elimination half-life probably reflects a slow redistribution from tissues. Although amphotericin B is excreted slowly, there is little accumulation in the blood after repeated dosing. AUC of amphotericin B increased approximately 34% from day 1 after the administration of ABELCET&reg; (amphotericin b) 5 mg/kg/day for 7 days. The effect of gender or ethnicity on the pharmacokinetics of ABELCET&reg; (amphotericin b) has not been studied. Tissue concentrations of amphotericin B have been obtained at autopsy from one heart transplant patient who received three doses of ABELCET&reg; (amphotericin b) at 5.3 mg/kg/day: Concentration in Human Tissues Organ Amphotericin B Tissue Concentration (&micro;g/g) Spleen 290 Lung 222 Liver 196 Lymph Node 7.6 Kidney 6.9 Heart 5 Brain 1.6 This pattern of distribution is consistent with that observed in preclinical studies in dogs in which greatest concentrations of amphotericin B after ABELCET&reg; (amphotericin b) administration were observed in the liver, spleen, and lung; however, the relationship of tissue concentrations of amphotericin B to its biological activity when administered as ABELCET&reg; (amphotericin b) is unknown. Special Populations Hepatic Impairment: The effect of hepatic impairment on the disposition of ABELCET&reg; (amphotericin b) is not known. Renal Impairment: The effect of renal impairment on the disposition of ABELCET&reg; (amphotericin b) is not known. The effect of dialysis on the elimination of ABELCET&reg; has not been studied; however, amphotericin B is not removed by hemodialysis when administered as amphotericin B desoxycholate. Pediatric and Elderly Patients: The pharmacokinetics and pharmacodynamics of pediatric patients ( &le; 16 years of age) and elderly patients ( &ge; 65 years of age) have not been studied. Description Of Clinical Studies Fungal Infections Data from 473 patients were pooled from three open-label studies in which ABELCET&reg; (amphotericin b) was provided for the treatment of patients with invasive fungal infections who were judged by their physicians to be refractory to or intolerant of conventional amphotericin B, or who had preexisting nephrotoxicity. Results of these studies demonstrated effectiveness of ABELCET&reg; (amphotericin b) in the treatment of invasive fungal infections as a second line therapy. Patients were defined by their individual physician as being refractory to or failing conventional amphotericin B therapy based on overall clinical judgement after receiving a minimum total dose of 500 mg of amphotericin B. Nephrotoxicity was defined as a serum creatinine that had increased to > 2.5 mg/dL in adults and > 1.5 mg/dL in pediatric patients, or a creatinine clearance of < 25 mL/min while receiving conventional amphotericin B therapy. Of the 473 patients, four were enrolled more than once; each enrollment contributed separately to the denominator. The median age was 39 years (range of < 1 to 93 years); 307 patients were male and 166 female. Patients were Caucasian (381, 81%), African-American (41, 9%), Hispanic (27, 6%), Asian (10, 2%), and various other races (14, 3%). The median baseline neutrophil count was 4,000 PMN/mm3; of these, 101 (21%) had a baseline neutrophil count < 500/mm3. Two-hundred eighty-two patients of the 473 patients were considered evaluable for response to therapy; the other 191 patients were excluded on the basis of unconfirmed diagnosis, confounding factors, concomitant systemic antifungal therapy, or receiving 4 doses or less of ABELCET&reg; (amphotericin b) . For evaluable patients, the following fungal infections were treated (n=282): aspergillosis (n=111), candidiasis (n=87), zygomycosis (n=25), cryptococcosis (n=16), and fusariosis (n=11). There were fewer than 10 evaluable patients for each of several other fungal species treated. For each type of fungal infection listed above there were some patients successfully treated. However, in the absence of controlled studies it is unknown how response would have compared to either continuing conventional amphotericin B therapy or the use of alternative antifungal agents. Renal Function: Patients with aspergillosis who initiated treatment with ABELCET&reg; (amphotericin b) when serum creatinine was above 2.5 mg/dL experienced a decline in serum creatinine during treatment (Figure 1). Serum creatinine levels were also lower during treatment with ABELCET&reg; (amphotericin b) when compared to the serum creatinine levels of patients treated with conventional amphotericin B in a retrospective historical control study. Meaningful statistical testing of the differences between these two groups is precluded since these data were obtained from two separate studies. Figure 1: Changes in Mean Serum Creatinine Over Time Patients with Aspergillosis and Serum Creatinine > 2.5 mg/dL at Baseline [ ]= Number of patients at each time point. Note: These curves do not represent the clinical course of a given patient, but that of an open-label cohort of patients. Figure 2: Changes in Mean Serum Creatinine Over Time Patients with Fungal Infections and Serum Creatinine > 2.5 mg/dL at Baseline [ ]= Number of patients at each time point. Note: These curves do not represent the clinical course of a given patient, but that of an open-label cohort of patients. In a randomized study of ABELCET&reg; (amphotericin b) for the treatment of invasive candidiasis in patients with normal baseline renal function, the incidence of nephrotoxicity was significantly less for ABELCET (amphotericin b) &reg; at a dose of 5 mg/kg/day than for conventional amphotericin B at a dose of 0.7 mg/kg/day. Despite generally less nephrotoxicity of ABELCET&reg; (amphotericin b) observed at a dose of 5 mg/kg/day compared with conventional amphotericin B therapy at a dose range of 0.6-1 mg/kg/day, dose-limiting renal toxicity may still be observed with ABELCET&reg; (amphotericin b) . Renal toxicity of doses greater than 5 mg/kg/day of ABELCET&reg; (amphotericin b) has not been formally studied.142017-09-01 11:12:57AbelcetAmphotericin B InjectionFDA
1092017-12-04 17:38:29Medication GuidePATIENT INFORMATION See WARNINGS, CONTRAINDICATIONS, and PRECAUTIONS.142017-09-01 11:12:57AbelcetAmphotericin B InjectionFDA
1102017-12-04 17:38:40Drug DescriptionFind Lowest Prices on ABILIFY&reg; (aripiprazole) Tablets WARNING INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS and SUICIDAL THOUGHTS AND BEHAVIORS WITH ANTIDEPRESSANT DRUGS Elderly pati ents with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ABILIFY is not approved for the treatment of patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS]. Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see WARNINGS AND PRECAUTIONS]. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see WARNINGS AND PRECAUTIONS]. DESCRIPTION Aripiprazole is a psychotropic drug that is available as ABILIFY&reg; (aripiprazole) Tablets, ABILIFY DISCMELT&reg; (aripiprazole) Orally Disintegrating Tablets, ABILIFY&reg; (aripiprazole) Oral Solution, and ABILIFY&reg; (aripiprazole) Injection, a solution for intramuscular injection. Aripiprazole is 7-[4-[4-(2,3dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril. The empirical formula is C23H27Cl2N3O2 and its molecular weight is 448.38. The chemical structure is: ABILIFY Tablets are available in 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg strengths. Inactive ingredients include cornstarch, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. Colorants include ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake. ABILIFY DISCMELT Orally Disintegrating Tablets are available in 10 mg and 15 mg strengths. Inactive ingredients include acesulfame potassium, aspartame, calcium silicate, croscarmellose sodium, crospovidone, crème de vanilla (natural and artificial flavors), magnesium stearate, microcrystalline cellulose, silicon dioxide, tartaric acid, and xylitol. Colorants include ferric oxide (yellow or red) and FD&C Blue No. 2 Aluminum Lake. ABILIFY Oral Solution is a clear, colorless to light-yellow solution available in a concentration of 1 mg/mL. The inactive ingredients for this solution include disodium edetate, fructose, glycerin, dl-lactic acid, methylparaben, propylene glycol, propylparaben, sodium hydroxide, sucrose, and purified water. The oral solution is flavored with natural orange cream and other natural flavors. ABILIFY Injection is available in single-dose vials as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) clear, colorless, sterile, aqueous solution for intramuscular use only. Inactive ingredients for this solution include 199.5mg of sulfobutylether &beta;-cyclodextrin (SBECD), 10.4 mg of tartaric acid, qs to pH 4.3 of sodium hydroxide, and qs to 1.33 mL of water for injection.152017-09-01 11:12:57AbilifyAripiprazoleFDA
1112017-12-04 17:38:40Indications & DosageINDICATIONS ABILIFY Oral Tablets, Orally-Disintegrating Tablets, and Oral Solution are indicated for the treatment of: Schizophrenia [see Clinical Studies] Acute Treatment of Manic and Mixed Episodes associated with Bipolar I Disorder [see Clinical Studies] Adjunctive Treatment of Major Depressive Disorder [see Clinical Studies] Irritability Associated with Autistic Disorder [see Clinical Studies] Treatment of Tourette's Disorder [see Clinical Studies] ABILIFY Injection is indicated for the treatment of: Agitation associated with schizophrenia or bipolar mania [see Clinical Studies] DOSAGE AND ADMINISTRATION Schizophrenia Adults The recommended starting and target dose for ABILIFY is 10 or 15 mg/day administered on a once-a-day schedule without regard to meals. ABILIFY has been systematically evaluated and shown to be effective in a dose range of 10 to 30 mg/day, when administered as the tablet formulation; however, doses higher than 10 or 15 mg/day were not more effective than 10 or 15 mg/day. Dosage increases should generally not be made before 2 weeks, the time needed to achieve steady-state [see Clinical Studies]. Maintenance Treatment: Maintenance of efficacy in schizophrenia was demonstrated in a trial involving patients with schizophrenia who had been symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from those medications and randomized to either ABILIFY 15 mg/day or placebo, and observed for relapse [see Clinical Studies]. Patients should be periodically reassessed to determine the continued need for maintenance treatment. Adolescents The recommended target dose of ABILIFY is 10 mg/day. Aripiprazole was studied in adolescent patients 13 to 17 years of age with schizophrenia at daily doses of 10 mg and 30 mg. The starting daily dose of the tablet formulation in these patients was 2 mg, which was titrated to 5 mg after 2 days and to the target dose of 10 mg after 2 additional days. Subsequent dose increases should be administered in 5 mg increments. The 30 mg/day dose was not shown to be more efficacious than the 10 mg/day dose. ABILIFY can be administered without regard to meals [see Clinical Studies]. Patients should be periodically reassessed to determine the need for maintenance treatment. Switching From Other Antipsychotics There are no systematically collected data to specifically address switching patients with schizophrenia from other antipsychotics to ABILIFY or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the period of overlapping antipsychotic administration should be minimized. Bipolar I Disorder Acute Treatment Of Manic And Mixed Episodes Adults: The recommended starting dose in adults is 15 mg given once daily as monotherapy and 10 mg to 15 mg given once daily as adjunctive therapy with lithium or valproate. ABILIFY can be given without regard to meals. The recommended target dose of ABILIFY is 15 mg/day, as monotherapy or as adjunctive therapy with lithium or valproate. The dose may be increased to 30 mg/day based on clinical response. The safety of doses above 30 mg/day has not been evaluated in clinical trials. Pediatrics: The recommended starting dose in pediatric patients (10 to 17 years) as monotherapy is 2 mg/day, with titration to 5 mg/day after 2 days, and a target dose of 10 mg/day after 2 additional days. Recommended dosing as adjunctive therapy to lithium or valproate is the same. Subsequent dose increases, if needed, should be administered in 5 mg/day increments. ABILIFY can be given without regard to meals [see Clinical Studies]. Adjunctive Treatment Of Major Depressive Disorder Adults The recommended starting dose for ABILIFY as adjunctive treatment for patients already taking an antidepressant is 2 to 5 mg/day. The recommended dosage range is 2 to 15 mg/day. Dosage adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week [see Clinical Studies]. Patients should be periodically reassessed to determine the continued need for maintenance treatment. Irritability Associated With Autistic Disorder Pediatric Patients (6 to 17 years) The recommended dosage range for the treatment of pediatric patients with irritability associated with autistic disorder is 5 to 15 mg/day. Dosing should be initiated at 2 mg/day. The dose should be increased to 5 mg/day, with subsequent increases to 10 or 15 mg/day if needed. Dose adjustments of up to 5 mg/day should occur gradually, at intervals of no less than 1 week [see Clinical Studies]. Patients should be periodically reassessed to determine the continued need for maintenance treatment. Tourette's Disorder Pediatric Patients (6 to 18 years) The recommended dosage range for Tourette's Disorder is 5 to 20 mg/day. For patients weighing less than 50 kg, dosing should be initiated at 2 mg/day with a target dose of 5 mg/day after 2 days. The dose can be increased to 10 mg/day in patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually at intervals of no less than 1 week. For patients weighing 50 kg or more, dosing should be initiated at 2 mg/day for 2 days, and then increased to 5 mg/day for 5 days, with a target dose of 10 mg/day on day 8. The dose can be increased up to 20 mg/day for patients who do not achieve optimal control of tics. Dosage adjustments should occur gradually in increments of 5 mg/day at intervals of no less than 1 week. [see Clinical Studies]. Patients should be periodically reassessed to determine the continued need for maintenance treatment. Agitation Associated With Schizophrenia Or Bipolar Mania (Intramuscular Injection) Adults The recommended dose in these patients is 9.75 mg. The recommended dosage range is 5.25 to 15 mg. No additional benefit was demonstrated for 15 mg compared to 9.75 mg. A lower dose of 5.25 mg may be considered when clinical factors warrant. If agitation warranting a second dose persists following the initial dose, cumulative doses up to a total of 30 mg/day may be given. However, the efficacy of repeated doses of ABILIFY injection in agitated patients has not been systematically evaluated in controlled clinical trials. The safety of total daily doses greater than 30 mg or injections given more frequently than every 2 hours have not been adequately evaluated in clinical trials [see Clinical Studies]. If ongoing ABILIFY therapy is clinically indicated, oral ABILIFY in a range of 10 to 30 mg/day should replace ABILIFY injection as soon as possible [see Schizophrenia and Bipolar I Disorder sections above]. Administration Of ABILIFY Injection To administer ABILIFY Injection, draw up the required volume of solution into the syringe as shown in Table 1. Discard any unused portion. Table 1: ABILIFY Injection Dosing Recommendations Single-Dose Required Volume of Solution 5.25 mg 0.7 mL 9.75 mg 1.3 mL 15 mg 2 mL ABILIFY Injection is intended for intramuscular use only. Do not administer intravenously or subcutaneously. Inject slowly, deep into the muscle mass. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Dosage Adjustments For Cytochrome P450 Considerations Dosage adjustments are recommended in patients who are known CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers (see Table 2). When the coadministered drug is withdrawn from the combination therapy, ABILIFY dosage should then be adjusted to its original level. When the coadministered CYP3A4 inducer is withdrawn, ABILIFY dosage should be reduced to the original level over 1 to 2 weeks. Patients who may be receiving a combination of strong, moderate, and weak inhibitors of CYP3A4 and CYP2D6 (e.g., a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor or a moderate CYP3A4 inhibitor with a moderate CYP2D6 inhibitor), the dosing may be reduced to one-quarter (25%) of the usual dose initially and then adjusted to achieve a favorable clinical response. Table 2: Dose Adjustments for ABILIFY in Patients who are known CYP2D6 Poor Metabolizers and Patients Taking Concomitant CYP2D6 Inhibitors, 3A4 Inhibitors, and/or CYP3A4 Inducers Factors Dosage Adjustments for ABILIFY Known CYP2D6 Poor Metabolizers Administer half of usual dose Known CYP2D6 Poor Metabolizers taking concomitant strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) Administer a quarter of usual dose Strong CYP2D6 (e.g., quinidine, fluoxetine, paroxetine) or CYP3A4 inhibitors (e.g., itraconazole, clarithromycin) Administer half of usual dose Strong CYP2D6 and CYP3A4 inhibitors Administer a quarter of usual dose Strong CYP3A4 inducers (e.g., carbamazepine, rifampin) Double usual dose over 1 to 2 weeks When adjunctive ABILIFY is administered to patients with major depressive disorder, ABILIFY should be administered without dosage adjustment as specified in sections above. Dosing Of Oral Solution The oral solution can be substituted for tablets on a mg-per-mg basis up to the 25 mg dose level. Patients receiving 30 mg tablets should receive 25 mg of the solution [see CLINICAL PHARMACOLOGY]. Dosing Of Orally Disintegrating Tablets The dosing for ABILIFY Orally Disintegrating Tablets is the same as for the oral tablets [see sections above]. HOW SUPPLIED Dosage Forms And Strengths ABILIFY&reg; (aripiprazole) Tablets are available as described in Table 3. Table 3: ABILIFY Tablet Presentations Tablet Strength Tablet Color/Shape Tablet Markings 2 mg green &ldquo;A-006&rdquo; modified rectangle and &ldquo;2&rdquo; 5 mg blue &ldquo;A-007&rdquo; modified rectangle and &ldquo;5&rdquo; 10 mg pink &ldquo;A-008&rdquo; modified rectangle and &ldquo;10&rdquo; 15 mg yellow &ldquo;A-009&rdquo; round and &ldquo;15&rdquo; 20 mg white &ldquo;A-010&rdquo; round and &ldquo;20&rdquo; 30 mg pink &ldquo;A-011&rdquo; round and &ldquo;30&rdquo; ABILIFY DISCMELT&reg; (aripiprazole) Orally Disintegrating Tablets are available as described in Table 4. Table 4: ABILIFY DISCMELT Orally Disintegrating Tablet Presentations Tablet Strength Tablet Color/Shape Tablet Markings 10 mg pink (with scattered specks) &ldquo;A&rdquo; and &ldquo;640&rdquo; round &ldquo;10&rdquo; 15 mg yellow (with scattered specks) &ldquo;A&rdquo; and &ldquo;641&rdquo; round &ldquo;15&rdquo; ABILIFY&reg; (aripiprazole) Oral Solution (1 mg/mL) is a clear, colorless to light-yellow solution, supplied in child-resistant bottles along with a calibrated oral dosing cup. ABILIFY&reg; (aripiprazole) Injection for Intramuscular Use is a clear, colorless solution available as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) solution in clear, Type 1 glass vials. Storage And Handling ABILIFY&reg; (aripiprazole) Tablets have markings on one side and are available in the strengths and packages listed in Table 32. Table 32: ABILIFY Tablet Presentations Tablet Strength Tablet Color/Shape Tablet Markings Pack Size NDC Code 2 mg green modified rectangle &ldquo;A-006&rdquo; and &ldquo;2&rdquo; Bottle of 30 59148-006-13 5 mg blue &ldquo;A-007&rdquo; Bottle of 30 59148-007-13 modified rectangle and &ldquo;5&rdquo; Blister of 100 59148-007-35 10 mg pink &ldquo;A-008&rdquo; Bottle of 30 59148-008-13 modified rectangle and &ldquo;10&rdquo; Blister of 100 59148-008-35 15 mg yellow &ldquo;A-009&rdquo; Bottle of 30 59148-009-13 round and &ldquo;15&rdquo; Blister of 100 59148-009-35 20 mg white &ldquo;A-010&rdquo; Bottle of 30 59148-010-13 round and &ldquo;20&rdquo; Blister of 100 59148-010-35 30 mg pink &ldquo;A-011&rdquo; Bottle of 30 59148-011-13 round and &ldquo;30&rdquo; Blister of 100 59148-011-35 ABILIFY DISCMELT&reg; (aripiprazole) Orally Disintegrating Tablets are round tablets with markings on either side. ABILIFY DISCMELT is available in the strengths and packages listed in Table 33. Table 33: ABILIFY DISCMELT Orally Disintegrating Tablet Presentations Tablet Strength Tablet Color Tablet Markings Pack Size NDC Code 10 mg pink (with scattered specks) &ldquo;A&rdquo; and &ldquo;640&rdquo; &ldquo;10&rdquo; Blister of 30 59148-640-23 15 mg yellow (with scattered specks) &ldquo;A&rdquo; and &ldquo;641&rdquo; &ldquo;15&rdquo; Blister of 30 59148-641-23 ABILIFY&reg; (aripiprazole) Oral Solution (1 mg/mL) is supplied in child-resistant bottles along with a calibrated oral dosing cup. ABILIFY Oral Solution is available as follows: 150 mL bottle NDC 59148-013-15 ABILIFY&reg; (aripiprazole) Injection for intramuscular use is available as a ready-to-use, 9.75 mg/1.3 mL (7.5 mg/mL) solution in clear, Type 1 glass vials as follows: 9.75 mg/1.3 mL single-dose vial NDC 59148-016-65 Storage Tablets Store at 25&deg;C (77&deg;F); excursions permitted between 15&deg;C to 30&deg;C (59&deg;F to 86&deg;F) [see USP Controlled Room Temperature] . Oral Solution Store at 25&deg;C (77&deg;F); excursions permitted between 15&deg;C to 30&deg;C (59&deg;F to 86&deg;F) [see USP Controlled Room Temperature]. Opened bottles of ABILIFY Oral Solution can be used for up to 6 months after opening, but not beyond the expiration date on the bottle. The bottle and its contents should be discarded after the expiration date. Injection Store at 25&deg;C (77&deg;F); excursions permitted between 15&deg;C to 30&deg;C (59&deg;F to 86&deg;F) [see USP Controlled Room Temperature]. Protect from light by storing in the original container. Retain in carton until time of use. Tablets manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Orally Disintegrating Tablets, Oral Solution, and Injection manufactured by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850 USA. Revised: Aug 2016152017-09-01 11:12:57AbilifyAripiprazoleFDA
1122017-12-04 17:38:40Side Effects & Drug InteractionsSIDE EFFECTS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following adverse reactions are discussed in more detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see BOXED WARNING and WARNINGS AND PRECAUTIONS] Cerebrovascular Adverse Events, Including Stroke [see WARNINGS AND PRECAUTIONS] Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see BOXED WARNING and WARNINGS AND PRECAUTIONS] Neuroleptic Malignant Syndrome (NMS) [see WARNINGS AND PRECAUTIONS] Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS] Metabolic Changes [see WARNINGS AND PRECAUTIONS] Pathological Gambling and Other Compulsive Behaviors [see WARNINGS AND PRECAUTIONS] Orthostatic Hypotension [see WARNINGS AND PRECAUTIONS] Leukopenia, Neutropenia, and Agranulocytosis [see WARNINGS AND PRECAUTIONS] Seizures/Convulsions [see WARNINGS AND PRECAUTIONS] Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS] Body Temperature Regulation [see WARNINGS AND PRECAUTIONS] Suicide [see WARNINGS AND PRECAUTIONS] Dysphagia [see WARNINGS AND PRECAUTIONS] The most common adverse reactions in adult patients in clinical trials ( &ge; 10%) were nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness. The most common adverse reactions in the pediatric clinical trials ( &ge; 10%) were somnolence, headache, vomiting, extrapyramidal disorder, fatigue, increased appetite, insomnia, nausea, nasopharyngitis, and weight increased. ABILIFY has been evaluated for safety in 13,543 adult patients who participated in multiple-dose, clinical trials in schizophrenia, bipolar disorder, major depressive disorder, Dementia of the Alzheimer's type, Parkinson's disease, and alcoholism, and who had approximately 7619 patient-years of exposure to oral ABILIFY and 749 patients with exposure to ABILIFY injection. A total of 3390 patients were treated with oral ABILIFY for at least 180 days and 1933 patients treated with oral ABILIFY had at least 1 year of exposure. ABILIFY has been evaluated for safety in 1,686 patients (6 to 18 years) who participated in multiple-dose, clinical trials in schizophrenia, bipolar mania, autistic disorder, or Tourette's disorder and who had approximately 1,342 patient-years of exposure to oral ABILIFY. A total of 959 pediatric patients were treated with oral ABILIFY for at least 180 days and 556 pediatric patients treated with oral ABILIFY had at least 1 year of exposure. The conditions and duration of treatment with ABILIFY (monotherapy and adjunctive therapy with antidepressants or mood stabilizers) included (in overlapping categories) double-blind, comparative and noncomparative open-label studies, inpatient and outpatient studies, fixed-and flexible-dose studies, and short-and longer-term exposure. Clinical Trials Experience Adult Patients With Schizophrenia The following findings are based on a pool of five placebo-controlled trials (four 4-week and one 6-week) in which oral ABILIFY was administered in doses ranging from 2 to 30 mg/day. Commonly Observed Adverse Reactions The only commonly observed adverse reaction associated with the use of ABILIFY in patients with schizophrenia (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) was akathisia (ABILIFY 8%; placebo 4%). Adult Patients With Bipolar Mania Monotherapy The following findings are based on a pool of 3-week, placebo-controlled, bipolar mania trials in which oral ABILIFY was administered at doses of 15 or 30 mg/day. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of ABILIFY in patients with bipolar mania (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) are shown in Table 16. Table 16: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Adult Patients with Bipolar Mania Treated with Oral ABILIFY Monotherapy Preferred Term Percentage of Patients Reporting Reaction ABILIFY (n=917) Placebo (n=753) Akathisia 13 4 Sedation 8 3 Restlessness 6 3 Tremor 6 3 Extrapyramidal Disorder 5 2 Less Common Adverse Reactions In Adults Table 17 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia and up to 3 weeks in bipolar mania), including only those reactions that occurred in 2% or more of patients treated with ABILIFY (doses &ge; 2 mg/day) and for which the incidence in patients treated with ABILIFY was greater than the incidence in patients treated with placebo in the combined dataset. Table 17: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Adult Patients Treated with Oral ABILIFY System Organ Class Preferred Term Percentage of Patients Reporting Reactiona ABILIFY (n=1843) Placebo (n=1166) Eye Disorders Blurred Vision 3 1 Gastrointestinal Disorders Nausea 15 11 Constipation 11 7 Vomiting 11 6 Dyspepsia 9 7 Dry Mouth 5 4 Toothache 4 3 Abdominal Discomfort 3 2 Stomach Discomfort 3 2 General Disorders and Administration Site Conditions Fatigue 6 4 Pain 3 2 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Stiffness 4 3 Pain in Extremity 4 2 Myalgia 2 1 Muscle Spasms 2 1 Nervous System Disorders Headache 27 23 Dizziness 10 7 Akathisia 10 4 Sedation 7 4 Extrapyramidal Disorder 5 3 Tremor 5 3 Somnolence 5 3 Psychiatric Disorders Agitation 19 17 Insomnia 18 13 Anxiety 17 13 Restlessness 5 3 Respiratory, Thoracic, and Mediastinal Disorders Pharyngolaryngeal Pain 3 2 Cough 3 2 a Adverse reactions reported by at least 2% of patients treated with oral ABILIFY, except adverse reactions which had an incidence equal to or less than placebo. An examination of population subgroups did not reveal any clear evidence of differential adverse reaction incidence on the basis of age, gender, or race. Adult Patients With Adjunctive Therapy With Bipolar Mania The following findings are based on a placebo-controlled trial of adult patients with bipolar disorder in which ABILIFY was administered at doses of 15 or 30 mg/day as adjunctive therapy with lithium or valproate. Adverse Reactions Associated with Discontinuation of Treatment In a study of patients who were already tolerating either lithium or valproate as monotherapy, discontinuation rates due to adverse reactions were 12% for patients treated with adjunctive ABILIFY compared to 6% for patients treated with adjunctive placebo. The most common adverse drug reactions associated with discontinuation in the adjunctive ABILIFY-treated compared to placebo-treated patients were akathisia (5% and 1%, respectively) and tremor (2% and 1%, respectively). Commonly Observed Adverse Reactions The commonly observed adverse reactions associated with adjunctive ABILIFY and lithium or valproate in patients with bipolar mania (incidence of 5% or greater and incidence at least twice that for adjunctive placebo) were: akathisia, insomnia, and extrapyramidal disorder. Less Common Adverse Reactions In Adult Patients With Adjunctive Therapy In Bipolar Mania Table 18 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred during acute treatment (up to 6 weeks), including only those reactions that occurred in 2% or more of patients treated with adjunctive ABILIFY (doses of 15 or 30 mg/day) and lithium or valproate and for which the incidence in patients treated with this combination was greater than the incidence in patients treated with placebo plus lithium or valproate. Table 18: Adverse Reactions in a Short-Term, Placebo-Controlled Trial of Adjunctive Therapy in Patients with Bipolar Disorder System Organ Class Preferred Term Percentage of Patients Reporting Reactiona ABILIFY + Li or Val* (n=253) Placebo + Li or Val* (n=130) Gastrointestinal Disorders Nausea 8 5 Vomiting 4 0 Salivary Hypersecretion 4 2 Dry Mouth 2 1 Infections and Infestations Nasopharyngitis 3 2 Investigations Weight Increased 2 1 Nervous System Disorders Akathisia 19 5 Tremor 9 6 Extrapyramidal Disorder 5 1 Dizziness 4 1 Sedation 4 2 Psychiatric Disorders Insomnia 8 4 Anxiety 4 1 Restlessness 2 1 a Adverse reactions reported by at least 2% of patients treated with oral ABILIFY, except adverse reactions which had an incidence equal to or less than placebo. * Lithium or Valproate Pediatric Patients (13 to 17 years) With Schizophrenia The following findings are based on one 6-week, placebo-controlled trial in which oral ABILIFY was administered in doses ranging from 2 to 30 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between ABILIFY-treated and placebo-treated pediatric patients (13 to 17 years) was 5% and 2%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of ABILIFY in adolescent patients with schizophrenia (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) were extrapyramidal disorder, somnolence, and tremor. Pediatric Patients (10 to 17 years) With Bipolar Mania The following findings are based on one 4-week, placebo-controlled trial in which oral ABILIFY was administered in doses of 10 or 30 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between ABILIFY-treated and placebo-treated pediatric patients (10 to 17 years) was 7% and 2%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of ABILIFY in pediatric patients with bipolar mania (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) are shown in Table 19. Table 19: Commonly Observed Adverse Reactions in Short- Term, Placebo-Controlled Trials of Pediatric Patients(10 to 17 years) with Bipolar Mania Treated with Oral ABILIFY Preferred Term Percentage of Patients Reporting Reaction ABILIFY (n=197) Placebo (n=97) Somnolence 23 3 Extrapyramidal Disorder 20 3 Fatigue 11 4 Nausea 11 4 Akathisia 10 2 Blurred Vision 8 0 Salivary Hypersecretion 6 0 Dizziness 5 1 Pediatric Patients (6 to 17 years) With Autistic Disorder The following findings are based on two 8-week, placebo-controlled trials in which oral ABILIFY was administered in doses of 2 to 15 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between ABILIFY-treated and placebo-treated pediatric patients (6 to 17 years) was 10% and 8%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of ABILIFY in pediatric patients with autistic disorder (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) are shown in Table 20. Table 20: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 17 years) with Autistic Disorder Treated with Oral ABILIFY Preferred Term Percentage of Patients Reporting Reaction ABILIFY (n=212) Placebo (n=101) Sedation 21 4 Fatigue 17 2 Vomiting 14 7 Somnolence 10 4 Tremor 10 0 Pyrexia 9 1 Drooling 9 0 Decreased Appetite 7 2 Salivary Hypersecretion 6 1 Extrapyramidal Disorder 6 0 Lethargy 5 0 Pediatric Patients (6 to 18 years) With Tourette's Disorder The following findings are based on one 8-week and one 10-week, placebo-controlled trials in which oral ABILIFY was administered in doses of 2 to 20 mg/day. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions between ABILIFY-treated and placebo-treated pediatric patients (6 to 18 years) was 7% and 1%, respectively. Commonly Observed Adverse Reactions Commonly observed adverse reactions associated with the use of ABILIFY in pediatric patients with Tourette's disorder (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) are shown in Table 21. Table 21: Commonly Observed Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) with Tourette's Disorder Treated with Oral ABILIFY Preferred Term Percentage of Patients Reporting Reaction ABILIFY (n=121) Placebo (n=72) Sedation 13 6 Somnolence 13 1 Nausea 11 4 Headache 10 3 Nasopharyngitis 9 0 Fatigue 8 0 Increased Appetite 7 1 Less Common Adverse Reactions In Pediatric Patients (6 to 18 years) With Schizophrenia, Bipolar Mania, Autistic Disorder, Or Tourette's Disorder Table 22 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks in schizophrenia, up to 4 weeks in bipolar mania, up to 8 weeks in autistic disorder, and up to 10 weeks in Tourette's disorder), including only those reactions that occurred in 2% or more of pediatric patients treated with ABILIFY (doses &ge; 2 mg/day) and for which the incidence in patients treated with ABILIFY was greater than the incidence in patients treated with placebo. Table 22: Adverse Reactions in Short-Term, Placebo-Controlled Trials of Pediatric Patients (6 to 18 years) Treated with Oral ABILIFY System Organ Class Preferred Term Percentage of Patients Reporting Reactiona ABILIFY (n=732) Placebo (n=370) Eye Disorders Blurred Vision 3 0 Gastrointestinal Disorders Abdominal Discomfort 2 1 Vomiting 8 7 Nausea 8 4 Diarrhea 4 3 Salivary Hypersecretion 4 1 Abdominal Pain Upper 3 2 Constipation 2 2 General Disorders and Administration Site Conditions Fatigue 10 2 Pyrexia 4 1 Irritability 2 1 Asthenia 2 1 Infections and Infestations Nasopharyngitis 6 3 Investigations Weight Increased 3 1 Metabolism and Nutrition Disorders Increased Appetite 7 3 Decreased Appetite 5 4 Musculoskeletal and Connective Tissue Disorders Musculoskeletal Stiffness 2 1 Muscle Rigidity 2 1 Nervous System Disorders Somnolence 16 4 Headache 12 10 Sedation 9 2 Tremor 9 1 Extrapyramidal Disorder 6 1 Akathisia 6 4 Drooling 3 0 Lethargy 3 0 Dizziness 3 2 Dystonia 2 1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 2 1 Skin and Subcutaneous Tissue Disorders Rash 2 1 a Adverse reactions reported by at least 2% of pediatric patients treated with oral ABILIFY, except adverse reactions which had an incidence equal to or less than placebo. Adult Patients Receiving ABILIFY As Adjunctive Treatment Of Major Depressive Disorder The following findings are based on a pool of two placebo-controlled trials of patients with major depressive disorder in which ABILIFY was administered at doses of 2 mg to 20 mg as adjunctive treatment to continued antidepressant therapy. Adverse Reactions Associated with Discontinuation of Treatment The incidence of discontinuation due to adverse reactions was 6% for adjunctive ABILIFY-treated patients and 2% for adjunctive placebo-treated patients. Commonly Observed Adverse Reactions The commonly observed adverse reactions associated with the use of adjunctive ABILIFY in patients with major depressive disorder (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo) were: akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision. Less Common Adverse Reactions in Adult Patients with Major Depressive Disorder Table 23 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (up to 6 weeks), including only those adverse reactions that occurred in 2% or more of patients treated with adjunctive ABILIFY (doses &ge; 2 mg/day) and for which the incidence in patients treated with adjunctive ABILIFY was greater than the incidence in patients treated with adjunctive placebo in the combined dataset. Table 23: Adverse Reactions in Short-Term, Placebo-Controlled Adjunctive Trials in Patients with Major Depressive Disorder System Organ Class Preferred Term Percentage of Patients Reporting Reactiona ABILIFY + ADT* (n=371) Placebo + ADT* (n=366) Eye Disorders Blurred Vision 6 1 Gastrointestinal Disorders Constipation 5 2 General Disorders and Administration Site Conditions Fatigue 8 4 Feeling Jittery 3 1 Infections and Infestations Upper Respiratory Tract Infection 6 4 Investigations Weight Increased 3 2 Metabolism and Nutrition Disorders Increased Appetite 3 2 Musculoskeletal and Connective Tissue Disorders Arthralgia 4 3 Myalgia 3 1 Nervous System Disorders Akathisia 25 4 Somnolence 6 4 Tremor 5 4 Sedation 4 2 Dizziness 4 2 Disturbance in Attention 3 1 Extrapyramidal Disorder 2 0 Psychiatric Disorders Restlessness 12 2 Insomnia 8 2 a Adverse reactions reported by at least 2% of patients treated with adjunctive ABILIFY, except adverse reactions which had an incidence equal to or less than placebo. * Antidepressant Therapy Patients With Agitation Associated With Schizophrenia Or Bipolar Mania (Intramuscular Injection) The following findings are based on a pool of three placebo-controlled trials of patients with agitation associated with schizophrenia or bipolar mania in which ABILIFY injection was administered at doses of 5.25 mg to 15 mg. Commonly Observed Adverse Reactions There was one commonly observed adverse reaction (nausea) associated with the use of ABILIFY injection in patients with agitation associated with schizophrenia and bipolar mania (incidence of 5% or greater and ABILIFY incidence at least twice that for placebo). Less Common Adverse Reactions in Patients with Agitation Associated with Schizophrenia or Bipolar Mania Table 24 enumerates the pooled incidence, rounded to the nearest percent, of adverse reactions that occurred during acute therapy (24-hour), including only those adverse reactions that occurred in 2% or more of patients treated with ABILIFY injection (doses &ge; 5.25 mg/day) and for which the incidence in patients treated with ABILIFY injection was greater than the incidence in patients treated with placebo in the combined dataset. Table 24: Adverse Reactions in Short-Term, Placebo-Controlled Trials in Patients Treated with ABILIFY Injection System Organ Class Preferred Term Percentage of Patients Reporting Reactiona ABILIFY (n=501) Placebo (n=220) Cardiac Disorders Tachycardia 2 < 1 Gastrointestinal Disorders Nausea 9 3 Vomiting 3 1 General Disorders and Administration Site Conditions Fatigue 2 1 Nervous System Disorders Headache 12 7 Dizziness 8 5 Somnolence 7 4 Sedation 3 2 Akathisia 2 0 a Adverse reactions reported by at least 2% of patients treated with ABILIFY injection, except adverse reactions which had an incidence equal to or less than placebo. Dose-Related Adverse Reactions Schizophrenia Dose response relationships for the incidence of treatment-emergent adverse events were evaluated from four trials in adult patients with schizophrenia comparing various fixed doses (2, 5, 10, 15, 20, and 30 mg/day) of oral ABILIFY to placebo. This analysis, stratified by study, indicated that the only adverse reaction to have a possible dose response relationship, and then most prominent only with 30 mg, was somnolence [including sedation]; (incidences were placebo, 7.1%; 10 mg, 8.5%; 15 mg, 8.7%; 20 mg, 7.5%; 30 mg, 12.6%). In the study of pediatric patients (13 to 17 years of age) with schizophrenia, three common adverse reactions appeared to have a possible dose response relationship: extrapyramidal disorder (incidences were placebo, 5.0%; 10 mg, 13.0%; 30 mg, 21.6%); somnolence (incidences were placebo, 6.0%; 10 mg, 11.0%; 30 mg, 21.6%); and tremor (incidences were placebo, 2.0%; 10 mg, 2.0%; 30 mg, 11.8%). Bipolar Mania In the study of pediatric patients (10 to 17 years of age) with bipolar mania, four common adverse reactions had a possible dose response relationship at 4 weeks; extrapyramidal disorder (incidences were placebo, 3.1%; 10 mg, 12.2%; 30 mg, 27.3%); somnolence (incidences were placebo, 3.1%; 10 mg, 19.4%; 30 mg, 26.3%); akathisia (incidences were placebo, 2.1%; 10 mg, 8.2%; 30 mg, 11.1%); and salivary hypersecretion (incidences were placebo, 0%; 10 mg, 3.1%; 30 mg, 8.1%). Autistic Disorder In a study of pediatric patients (6 to 17 years of age) with autistic disorder, one common adverse reaction had a possible dose response relationship: fatigue (incidences were placebo, 0%; 5 mg, 3.8%; 10 mg, 22.0%; 15 mg, 18.5%). Tourette's Disorder In a study of pediatric patients (7 to 17 years of age) with Tourette's disorder, no common adverse reaction(s) had a dose response relationship. Extrapyramidal Symptoms Schizophrenia In short-term, placebo-controlled trials in schizophrenia in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for ABILIFY-treated patients was 13% vs. 12% for placebo; and the incidence of akathisia-related events for ABILIFY-treated patients was 8% vs. 4% for placebo. In the short-term, placebo-controlled trial of schizophrenia in pediatric patients (13 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for ABILIFY-treated patients was 25% vs. 7% for placebo; and the incidence of akathisia-related events for ABILIFY-treated patients was 9% vs. 6% for placebo. Objectively collected data from those trials was collected on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias). In the adult schizophrenia trials, the objectively collected data did not show a difference between ABILIFY and placebo, with the exception of the Barnes Akathisia Scale (ABILIFY, 0.08; placebo, -0.05). In the pediatric (13 to 17 years) schizophrenia trial, the objectively collected data did not show a difference between ABILIFY and placebo, with the exception of the Simpson Angus Rating Scale (ABILIFY, 0.24; placebo, -0.29). Similarly, in a long-term (26-week), placebo-controlled trial of schizophrenia in adults, objectively collected data on the Simpson Angus Rating Scale (for EPS), the Barnes Akathisia Scale (for akathisia), and the Assessments of Involuntary Movement Scales (for dyskinesias) did not show a difference between ABILIFY and placebo. Bipolar Mania In the short-term, placebo-controlled trials in bipolar mania in adults, the incidence of reported EPS-related events, excluding events related to akathisia, for monotherapy ABILIFY-treated patients was 16% vs. 8% for placebo and the incidence of akathisia-related events for monotherapy ABILIFY-treated patients was 13% vs. 4% for placebo. In the 6-week, placebo-controlled trial in bipolar mania for adjunctive therapy with lithium or valproate, the incidence of reported EPS-related events, excluding events related to akathisia for adjunctive ABILIFY-treated patients was 15% vs. 8% for adjunctive placebo and the incidence of akathisia-related events for adjunctive ABILIFY-treated patients was 19% vs. 5% for adjunctive placebo. In the short-term, placebo-controlled trial in bipolar mania in pediatric (10 to 17 years) patients, the incidence of reported EPS-related events, excluding events related to akathisia, for ABILIFY-treated patients was 26% vs. 5% for placebo and the incidence of akathisia-related events for ABILIFY-treated patients was 10% vs. 2% for placebo. In the adult bipolar mania trials with monotherapy ABILIFY, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between ABILIFY and placebo (ABILIFY, 0.50; placebo, -0.01 and ABILIFY, 0.21; placebo, -0.05). Changes in the Assessments of Involuntary Movement Scales were similar for the ABILIFY and placebo groups. In the bipolar mania trials with ABILIFY as adjunctive therapy with either lithium or valproate, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive ABILIFY and adjunctive placebo (ABILIFY, 0.73; placebo, 0.07 and ABILIFY, 0.30; placebo, 0.11). Changes in the Assessments of Involuntary Movement Scales were similar for adjunctive ABILIFY and adjunctive placebo. In the pediatric (10 to 17 years), short-term, bipolar mania trial, the Simpson Angus Rating Scale showed a significant difference between ABILIFY and placebo (ABILIFY, 0.90; placebo, -0.05). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the ABILIFY and placebo groups. Major Depressive Disorder In the short-term, placebo-controlled trials in major depressive disorder, the incidence of reported EPS-related events, excluding events related to akathisia, for adjunctive ABILIFY-treated patients was 8% vs. 5% for adjunctive placebo-treated patients; and the incidence of akathisia-related events for adjunctive ABILIFY-treated patients was 25% vs. 4% for adjunctive placebo-treated patients. In the major depressive disorder trials, the Simpson Angus Rating Scale and the Barnes Akathisia Scale showed a significant difference between adjunctive ABILIFY and adjunctive placebo (ABILIFY, 0.31; placebo, 0.03 and ABILIFY, 0.22; placebo, 0.02). Changes in the Assessments of Involuntary Movement Scales were similar for the adjunctive ABILIFY and adjunctive placebo groups. Autistic Disorder In the short-term, placebo-controlled trials in autistic disorder in pediatric patients (6 to 17 years), the incidence of reported EPS-related events, excluding events related to akathisia, for ABILIFY-treated patients was 18% vs. 2% for placebo and the incidence of akathisia-related events for ABILIFY-treated patients was 3% vs. 9% for placebo. In the pediatric (6 to 17 years) short-term autistic disorder trials, the Simpson Angus Rating Scale showed a significant difference between ABILIFY and placebo (ABILIFY, 0.1; placebo, 0.4). Changes in the Barnes Akathisia Scale and the Assessments of Involuntary Movement Scales were similar for the ABILIFY and placebo groups. Tourette's Disorder In the short-term, placebo-controlled trials in Tourette's disorder in pediatric patients (6 to 18 years), the incidence of reported EPS-related events, excluding events related to akathisia, for ABILIFY-treated patients was 7% vs. 6% for placebo and the incidence of akathisia-related events for ABILIFY-treated patients was 4% vs. 6% for placebo. In the pediatric (6 to 18 years) short-term Tourette's disorder trials, changes in the Simpson Angus Rating Scale, Barnes Akathisia Scale and Assessments of Involuntary Movement Scale were not clinically meaningfully different for ABILIFY and placebo. Agitation Associated with Schizophrenia or Bipolar Mania In the placebo-controlled trials in patients with agitation associated with schizophrenia or bipolar mania, the incidence of reported EPS-related events excluding events related to akathisia for ABILIFY-treated patients was 2% vs. 2% for placebo and the incidence of akathisia-related events for ABILIFY-treated patients was 2% vs. 0% for placebo. Objectively collected data on the Simpson Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) for all treatment groups did not show a difference between ABILIFY and placebo. Dystonia Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Additional Findings Observed In Clinical Trials Adverse Reactions in Long-Term, Double-Blind, Placebo-Controlled Trials The adverse reactions reported in a 26-week, double-blind trial comparing oral ABILIFY and placebo in patients with schizophrenia were generally consistent with those reported in the short-term, placebo-controlled trials, except for a higher incidence of tremor [8% (12/153) for ABILIFY vs. 2% (3/153) for placebo]. In this study, the majority of the cases of tremor were of mild intensity (8/12 mild and 4/12 moderate), occurred early in therapy (9/12 &le; 49 days), and were of limited duration (7/12 &le; 10 days). Tremor infrequently led to discontinuation ( < 1%) of ABILIFY. In addition, in a long-term (52 week), active-controlled study, the incidence of tremor was 5% (40/859) for ABILIFY. A similar profile was observed in a long-term monotherapy study and a long-term adjunctive study with lithium and valproate in bipolar disorder. Other Adverse Reactions Observed During the Premarketing Evaluation Of ABILIFY The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients: Adults -Oral Administration Blood and Lymphatic System Disorders: rare -thrombocytopenia Cardiac Disorders: infrequent - bradycardia, palpitations, rare - atrial flutter, cardiorespiratory arrest, atrioventricular block, atrial fibrillation, angina pectoris, myocardial ischemia, myocardial infarction, cardiopulmonary failure Eye Disorders: infrequent - photophobia; rare -diplopia Gastrointestinal Disorders: infrequent -gastroesophageal reflux disease General Disorders and Administration Site Conditions: frequent -asthenia; infrequent - peripheral edema, chest pain; rare - face edema Hepatobiliary Disorders: rare -hepatitis, jaundice Immune System Disorders: rare -hypersensitivity Injury, Poisoning, and Procedural Complications: infrequent fall; rare heat stroke Investigations: frequent -weight decreased, infrequent -hepatic enzyme increased, blood glucose increased, blood lactate dehydrogenase increased, gamma glutamyl transferase increased; rare - blood prolactin increased, blood urea increased, blood creatinine increased, blood bilirubin increased, electrocardiogram QT prolonged, glycosylated hemoglobin increased Metabolism and Nutrition Disorders: frequent - anorexia; infrequent -rare - hypokalemia, hyponatremia, hypoglycemia Musculoskeletal and Connective Tissue Disorders: infrequent -muscular weakness, muscle tightness; rare - rhabdomyolysis, mobility decreased Nervous System Disorders: infrequent -parkinsonism, memory impairment, cogwheel rigidity, hypokinesia, myoclonus, bradykinesia; rare akinesia, myoclonus, coordination abnormal, speech disorder, Grand Mal convulsion; < 1/10,000 patients -choreoathetosis Psychiatric Disorders: infrequent - aggression, loss of libido, delirium; rare - libido increased, anorgasmia, tic, homicidal ideation, catatonia, sleep walking Renal and Urinary Disorders: rare -urinary retention, nocturia Reproductive System and Breast Disorders: infrequent -erectile dysfunction; rare - gynaecomastia, menstruation irregular, amenorrhea, breast pain, priapism Respiratory, Thoracic, and Mediastinal Disorders: infrequent -nasal congestion, dyspnea Skin and Subcutaneous Tissue Disorders: infrequent -rash, hyperhidrosis, pruritus, photosensitivity reaction, alopecia; rare -urticaria Vascular Disorders: infrequent hypotension, hypertension Pediatric Patients -Oral Administration Most adverse events observed in the pooled database of 1,686 pediatric patients, aged 6 to 18 years, were also observed in the adult population. Additional adverse reactions observed in the pediatric population are listed below. Eye Disorders :infrequent -oculogyric crisis Gastrointestinal Disorders: infrequent -tongue dry, tongue spasm Investigations: frequent -blood insulin increased Nervous System Disorders: infrequent -sleep talking Renal and Urinary Disorders frequent - enuresis Skin and Subcutaneous Tissue Disorders: infrequent -hirsutism Adults -Intramuscular Injection Most adverse reactions observed in the pooled database of 749 adult patients treated with ABILIFY injection, were also observed in the adult population treated with oral ABILIFY. Additional adverse reactions observed in the ABILIFY injection population are listed below. General Disorders and Administration Site Conditions: &ge; 1/100 patients -injection site reaction; &ge; 1/1000 patients and < 1/100 patients -venipuncture site bruise Postmarketing Experience The following adverse reactions have been identified during post-approval use of ABILIFY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure: occurrences of allergic reaction (anaphylactic reaction, angioedema, laryngospasm, pruritus/urticaria, or oropharyngeal spasm), pathological gambling, hiccups and blood glucose fluctuation. DRUG INTERACTIONS Drugs Having Clinically Important Interactions With ABILIFY Table 25: Clinically Important Drug Interactions with ABILIFY: Concomitant Drug Name or Drug Class Clinical Rationale Clinical Recommendation Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) The concomitant use of ABILIFY with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY]. With concomitant use of ABILIFY with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the ABILIFY dosaae [see DOSAGE AND ADMINISTRATION ]. Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin) The concomitant use of ABILIFY and carbamazepine decreased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY]. With concomitant use of ABILIFY with a strong CYP3A4 inducer, consider increasing the ABILIFY dosage [see DOSAGE AND ADMINISTRATION ]. Antihypertensive Drugs Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents. Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS]. Benzodiazepines (e.g., lorazepam) The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS] Monitor sedation and blood pressure. Adjust dose accordingly. Drugs Having No Clinically Important Interactions With ABILIFY Based on pharmacokinetic studies, no dosage adjustment of ABILIFY is required when administered concomitantly with famotidine, valproate, lithium, lorazepam. In addition, no dosage adjustment is necessary for substrates of CYP2D6 (e.g., dextromethorphan, fluoxetine, paroxetine, or venlafaxine), CYP2C9 (e.g., warfarin), CYP2C19 (e.g., omeprazole, warfarin, escitalopram), or CYP3A4 (e.g., dextromethorphan) when co-administered with ABILIFY. Additionally, no dosage adjustment is necessary for valproate, lithium, lamotrigine, lorazepam, or sertraline when co-administered with ABILIFY. [see CLINICAL PHARMACOLOGY]. Drug Abuse And Dependence Controlled Substance ABILIFY is not a controlled substance. Abuse ABILIFY has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of ABILIFY misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior). Dependence In physical dependence studies in monkeys, withdrawal symptoms were observed upon abrupt cessation of dosing. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed.152017-09-01 11:12:57AbilifyAripiprazoleFDA
1132017-12-04 17:38:40Warnings & PrecautionsWARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Increased Mortality In Elderly Patients With Dementia-Related Psychosis Increased Mortality Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ABILIFY (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING]. Safety Experience In Elderly Patients With Psychosis Associated With Alzheimer's Disease In three, 10-week, placebo-controlled studies of ABILIFY in elderly patients with psychosis associated with Alzheimer's disease (n=938; mean age: 82.4 years; range: 56-99 years), the adverse reactions that were reported at an incidence of &ge; 3% and ABILIFY incidence at least twice that for placebo were lethargy [placebo 2%, ABILIFY 5%], somnolence (including sedation) [placebo 3%, ABILIFY 8%], and incontinence (primarily, urinary incontinence) [placebo 1%, ABILIFY 5%], excessive salivation [placebo 0%, ABILIFY 4%], and lightheadedness [placebo 1%, ABILIFY 4%]. The safety and efficacy of ABILIFY in the treatment of patients with psychosis associated with dementia have not been established. If the prescriber elects to treat such patients with ABILIFY, assess for the emergence of difficulty swallowing or excessive somnolence, which could predispose to accidental injury or aspiration [see BOXED WARNING]. Cerebrovascular Adverse Events, Including Stroke In placebo-controlled clinical studies (two flexible dose and one fixed dose study) of dementia-related psychosis, there was an increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, in ABILIFY-treated patients (mean age: 84 years; range: 7888 years). In the fixed-dose study, there was a statistically significant dose response relationship for cerebrovascular adverse events in patients treated with ABILIFY. ABILIFY is not approved for the treatment of patients with dementia-related psychosis [see BOXED WARNING]. Suicidal Thoughts And Behaviors In Children, Adolescents, And Young Adults Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 1824) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 5. Table 5 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case &ge; 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, ie, beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for ABILIFY should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients For Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that ABILIFY is not approved for use in treating depression in the pediatric population. Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) may occur with administration of antipsychotic drugs, including ABILIFY. Rare cases of NMS occurred during ABILIFY treatment in the worldwide clinical database. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and, thereby, may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, ABILIFY should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on ABILIFY, drug discontinuation should be considered. However, some patients may require treatment with ABILIFY despite the presence of the syndrome. Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Hyperglycemia/Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with ABILIFY [see ADVERSE REACTIONS]. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Because ABILIFY was not marketed at the time these studies were performed, it is not known if ABILIFY is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Adults In an analysis of 13 placebo-controlled monotherapy trials in adults, primarily with schizophrenia or bipolar disorder, the mean change in fasting glucose in ABILIFY-treated patients (+4.4 mg/dL; median exposure 25 days; N=1057) was not significantly different than in placebo-treated patients (+2.5 mg/dL; median exposure 22 days; N=799). Table 6 shows the proportion of ABILIFY-treated patients with normal and borderline fasting glucose at baseline (median exposure 25 days) that had treatment-emergent high fasting glucose measurements compared to placebo-treated patients (median exposure 22 days). Table 6: Changes in Fasting Glucose From Placebo-Controlled Monotherapy Trials in Adult Patients Category Change (at least once) from Baseline Treatment Arm n/N % Glucose Normal to High ( < 100 mg/dL to &ge; 126 mg/dL) ABILIFY 31/822 3.8 Placebo 22/605 3.6 Borderline to High ( &ge; 100 mg/dL and < 126 mg/dL to &ge; 126 mg/dL) ABILIFY 31/176 17.6 Placebo 13/142 9.2 At 24 weeks, the mean change in fasting glucose in ABILIFY-treated patients was not significantly different than in placebo-treated patients [+2.2 mg/dL (n=42) and +9.6 mg/dL (n=28), respectively]. The mean change in fasting glucose in adjunctive ABILIFY-treated patients with major depressive disorder (+0.7 mg/dL; median exposure 42 days; N=241) was not significantly different than in placebo-treated patients (+0.8 mg/dL; median exposure 42 days; N=246). Table 7 shows the proportion of adult patients with changes in fasting glucose levels from two placebo-controlled, adjunctive trials (median exposure 42 days) in patients with major depressive disorder. Table 7: Changes in Fasting Glucose From Placebo-Controlled Adjunctive Trials in Adult Patients with Major Depressive Disorder Category Change (at least once) from Baseline Treatment Arm n/N % Glucose Normal to High ( < 100 mg/dL to &ge; 126 mg/dL) ABILIFY 2/201 1.0 Placebo 2/204 1.0 Borderline to High ( &ge; 100 mg/dL and < 126 mg/dL to &ge; 126 mg/dL) ABILIFY 4/34 11.8 Placebo 3/37 8.1 Pediatric Patients And Adolescents In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years), the mean change in fasting glucose in ABILIFY-treated patients (+4.8 mg/dL; with a median exposure of 43 days; N=259) was not significantly different than in placebo-treated patients (+1.7 mg/dL; with a median exposure of 42 days; N=123). In an analysis of two placebo-controlled trials in pediatric and adolescent patients with irritability associated with autistic disorder (6 to 17 years) with median exposure of 56 days, the mean change in fasting glucose in ABILIFY-treated patients (-0.2 mg/dL; N=83) was not significantly different than in placebo-treated patients (-0.6 mg/dL; N=33). In an analysis of two placebo-controlled trials in pediatric and adolescent patients with Tourette's disorder (6 to 18 years) with median exposure of 57 days, the mean change in fasting glucose in ABILIFY-treated patients (0.79 mg/dL; N=90) was not significantly different than in placebo-treated patients (-1.66 mg/dL; N=58). Table 8 shows the proportion of patients with changes in fasting glucose levels from the pooled adolescent schizophrenia and pediatric bipolar patients (median exposure of 42-43 days), from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder (median exposure of 56 days), and from the two placebo-controlled trials in pediatric patients (6 to 18 year) with Tourette's Disorder (median exposure 57 days). Table 8: Changes in Fasting Glucose From Placebo-Controlled Trials in Pediatric and Adolescent Patients Category Change (at least once) from Baseline Indication Treatment Arm n/N % Fasting Glucose Normal to High ( < 100 mg/dL to &ge; 126 mg/dL) Pooled Schizophrenia and Bipolar Disorder ABILIFY 2/236 0.8 Placebo 2/110 1.8 Irritability Associated with Autistic Disorder ABILIFY 0/73 0 Placebo 0/32 0 Tourette's Disorder ABILIFY 3/88 3.4 Placebo 1/58 1.7 Fasting Glucose Borderline to High ( &ge; 100 mg/dL and < 126 mg/dL to &ge; 126 mg/dL) Pooled Schizophrenia and Bipolar Disorder ABILIFY 1/22 4.5 Placebo 0/12 0 Irritability Associated with Autistic Disorder ABILIFY 0/9 0 Placebo 0/1 0 Tourette's Disorder ABILIFY 0/11 0 Placebo 0/4 0 At 12 weeks in the pooled adolescent schizophrenia and pediatric bipolar disorder trials, the mean change in fasting glucose in ABILIFY-treated patients was not significantly different than in placebo-treated patients [+2.4 mg/dL (n=81) and +0.1 mg/dL (n=15), respectively]. Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. There were no significant differences between ABILIFY-and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting LDLs, and fasting/nonfasting HDLs. Analyses of patients with at least 12 or 24 weeks of exposure were limited by small numbers of patients. Adults Table 9 shows the proportion of adult patients, primarily from pooled schizophrenia and bipolar disorder monotherapy placebo-controlled trials, with changes in total cholesterol (pooled from 17 trials; median exposure 21 to 25 days), fasting triglycerides (pooled from eight trials; median exposure 42 days), fasting LDL cholesterol (pooled from eight trials; median exposure 39 to 45 days, except for placebo-treated patients with baseline normal fasting LDL measurements, who had median treatment exposure of 24 days) and HDL cholesterol (pooled from nine trials; median exposure 40 to 42 days). Table 9: Changes in Blood Lipid Parameters From Placebo-Controlled Monotherapy Trials in Adults Treatment Arm n/N % Total Cholesterol ABILIFY 34/1357 2.5 Normal to High ( < 200 mg/dL to &ge; 240 mg/dL) Placebo 27/973 2.8 Fasting Triglycerides ABILIFY 40/539 7.4 Normal to High ( < 150 mg/dL to &ge; 200 mg/dL) Placebo 30/431 7.0 Fasting LDL Cholesterol ABILIFY 2/332 0.6 Normal to High ( < 100 mg/dL to &ge; 160 mg/dL) Placebo 2/268 0.7 HDL Cholesterol ABILIFY 121/1066 11.4 Normal to Low ( &ge; 40 mg/dL to < 40 mg/dL) Placebo 99/794 12.5 In monotherapy trials in adults, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between ABILIFY-and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 1/71 (1.4%) vs. 3/74 (4.1%); Fasting Triglycerides, 8/62 (12.9%) vs. 5/37 (13.5%); Fasting LDL Cholesterol, 0/34 (0%) vs. 1/25 (4.0%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 1/42 (2.4%) vs. 3/37 (8.1%); Fasting Triglycerides, 5/34 (14.7%) vs. 5/20 (25%); Fasting LDL Cholesterol, 0/22 (0%) vs. 1/18 (5.6%), respectively. Table 10 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting), fasting triglycerides, fasting LDL cholesterol, and HDL cholesterol from two placebo-controlled adjunctive trials in adult patients with major depressive disorder (median exposure 42 days). Table 10: Changes in Blood Lipid Parameters From Placebo-Controlled Adjunctive Trials in Adult Patients with Major Depressive Disorder Treatment Arm n/N % Total Cholesterol ABILIFY 3/139 2.2 Normal to High ( < 200 mg/dL to &ge; 240 mg/dL) Placebo 7/135 5.2 Fasting Triglycerides ABILIFY 14/145 9.7 Normal to High ( < 150 mg/dL to &ge; 200 mg/dL) Placebo 6/147 4.1 Fasting LDL Cholesterol ABILIFY 0/54 0 Normal to High ( < 100 mg/dL to &ge; 160 mg/dL) Placebo 0/73 0 HDL Cholesterol ABILIFY 17/318 5.3 Normal to Low ( &ge; 40 mg/dL to < 40 mg/dL) Placebo 10/286 3.5 Pediatric Patients And Adolescents Table 11 shows the proportion of adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years) with changes in total cholesterol and HDL cholesterol (pooled from two placebo-controlled trials; median exposure 42 to 43 days) and fasting triglycerides (pooled from two placebo-controlled trials; median exposure 42 to 44 days). Table 11: Changes in Blood Lipid Parameters From Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients in Schizophrenia and Bipolar Disorder Treatment Arm n/N % Total Cholesterol ABILIFY 3/220 1.4 Normal to High ( < 170 mg/dL to &ge; 200 mg/dL) Placebo 0/116 0 Fasting Triglycerides ABILIFY 7/187 3.7 Normal to High ( < 150 mg/dL to &ge; 200 mg/dL) Placebo 4/85 4.7 HDL Cholesterol ABILIFY 27/236 11.4 Normal to Low ( &ge; 40 mg/dL to < 40 mg/dL) Placebo 22/109 20.2 In monotherapy trials of adolescents with schizophrenia and pediatric patients with bipolar disorder, the proportion of patients at 12 weeks and 24 weeks with changes from Normal to High in total cholesterol (fasting/nonfasting), fasting triglycerides, and fasting LDL cholesterol were similar between ABILIFY-and placebo-treated patients: at 12 weeks, Total Cholesterol (fasting/nonfasting), 0/57 (0%) vs. 0/15 (0%); Fasting Triglycerides, 2/72 (2.8%) vs. 1/14 (7.1%), respectively; and at 24 weeks, Total Cholesterol (fasting/nonfasting), 0/36 (0%) vs. 0/12 (0%); Fasting Triglycerides, 1/47 (2.1%) vs. 1/10 (10.0%), respectively. Table 12 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 56 days) and HDL cholesterol (median exposure 55 to 56 days) from two placebo-controlled trials in pediatric patients (6 to 17 years) with irritability associated with autistic disorder. Table 12: Changes in Blood Lipid Parameters From Placebo-Controlled Trials in Pediatric Patients with Autistic Disorder Treatment Arm n/N % Total Cholesterol ABIUFY 1/95 1.1 Normal to High ( < 170 mg/dL to &ge; 200 mg/dL) Placebo 0/34 0 Fasting Triglycerides ABIUFY 0/75 0 Normal to High ( < 150 mg/dL to &ge; 200 mg/dL) Placebo 0/30 0 HDL Cholesterol ABILIFY 9/107 8.4 Normal to Low ( &ge; 40 mg/dL to < 40 mg/dL) Placebo 5/49 10.2 Table 13 shows the proportion of patients with changes in total cholesterol (fasting/nonfasting) and fasting triglycerides (median exposure 57 days) and HDL cholesterol (median exposure 57 days) from two placebo-controlled trials in pediatric patients (6 to 18 years) with Tourette's Disorder. Table 13: Changes in Blood Lipid Parameters From Placebo-Controlled Trials in Pediatric Patients with Tourette's Disorder Treatment Arm n/N % Total Cholesterol ABILIFY 1/85 1.2 Normal to High ( < 170 mg/dL to &ge; 200 mg/dL) Placebo 0/46 0 Fasting Triglycerides ABILIFY 5/94 5.3 Normal to High ( < 150 mg/dL to &ge; 200 mg/dL) Placebo 2/55 3.6 HDL Cholesterol ABILIFY 4/108 3.7 Normal to Low ( &ge; 40 mg/dL to < 40 mg/dL) Placebo 2/67 3.0 Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Adults In an analysis of 13 placebo-controlled monotherapy trials, primarily from pooled schizophrenia and bipolar disorder, with a median exposure of 21 to 25 days, the mean change in body weight in ABILIFY-treated patients was +0.3 kg (N=1673) compared to -0.1 kg (N=1100) in placebo-controlled patients. At 24 weeks, the mean change from baseline in body weight in ABILIFY-treated patients was -1.5 kg (n=73) compared to -0.2 kg (n=46) in placebo-treated patients. In the trials adding ABILIFY to antidepressants, patients first received 8 weeks of antidepressant treatment followed by 6 weeks of adjunctive ABILIFY or placebo in addition to their ongoing antidepressant treatment. The mean change in body weight in patients receiving adjunctive ABILIFY was +1.7 kg (N=347) compared to +0.4 kg (N=330) in patients receiving adjunctive placebo. Table 14 shows the percentage of adult patients with weight gain &ge; 7% of body weight by indication. Table 14: Percentage of Patients From Placebo-Controlled Trials in Adult Patients with Weight Gain &ge; 7% of Body Weight Indication Treatment Arm N Patients n (%) Weight gain &ge; 7% of body weight Schizophreniaa ABILIFY 852 69 (8.1) Placebo 379 12 (3.2) Bipolar Maniab ABILIFY 719 16 (2.2) Placebo 598 16 (2.7) Major Depressive Disorder (Adjunctive Therapy)c ABILIFY 347 18 (5.2) Placebo 330 2 (0.6) a 4-6 weeks duration. b 3 weeks duration. c 6 weeks duration Pediatric Patients And Adolescents In an analysis of two placebo-controlled trials in adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years) with median exposure of 42 to 43 days, the mean change in body weight in ABILIFY-treated patients was +1.6 kg (N=381) compared to +0.3 kg (N=187) in placebo-treated patients. At 24 weeks, the mean change from baseline in body weight in ABILIFY-treated patients was +5.8 kg (n=62) compared to +1.4 kg (n=13) in placebo-treated patients. In two short-term, placebo-controlled trials in patients (6 to 17 years) with irritability associated with autistic disorder with median exposure of 56 days, the mean change in body weight in ABILIFY-treated patients was +1.6 kg (n=209) compared to +0.4 kg (n=98) in placebo-treated patients. In two short-term, placebo-controlled trials in patients (6 to 18 years) with Tourette's Disorder with median exposure of 57 days, the mean change in body weight in ABILIFY-treated patients was +1.5 kg (n=105) compared to +0.4 kg (n=66) in placebo-treated patients. Table 15 shows the percentage of pediatric and adolescent patients with weight gain &ge; 7% of body weight by indication. Table 15: Percentage of Patients From Placebo-Controlled Monotherapy Trials in Pediatric and Adolescent Patients with Weight Gain &ge; 7% of Body Weight Indication Treatment Arm N Patients n (%) Weight gain &ge; 7% of body weight Pooled Schizophrenia and Bipolar Maniaa ABILIFY 381 20 (5.2) Placebo 187 3 (1.6) Irritability Associated with Autistic Disorderb ABILIFY 209 55 (26.3) Placebo 98 7 (7.1) Tourette's Disorderc ABILIFY 105 21 (20.0) Placebo 66 5 (7.6) a 4-6 weeks duration. b 8 weeks duration. c 8-10 weeks duration. In an open-label trial that enrolled patients from the two placebo-controlled trials of adolescents with schizophrenia (13 to 17 years) and pediatric patients with bipolar disorder (10 to 17 years), 73.2% of patients (238/325) completed 26 weeks of therapy with ABILIFY. After 26 weeks, 32.8% of patients gained &ge; 7% of their body weight, not adjusted for normal growth. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of pediatric patients and adolescents by comparisons to age-and gender-matched population standards. A z-score change < 0.5 SD is considered not clinically significant. After 26 weeks, the mean change in z-score was 0.09 SD. In an open-label trial that enrolled patients from two short-term, placebo-controlled trials, patients (6 to 17 years) with irritability associated with autistic disorder, as well as de novo patients, 60.3% (199/330) completed one year of therapy with ABILIFY. The mean change in weight z-score was 0.26 SDs for patients receiving > 9 months of treatment. When treating pediatric patients for any indication, weight gain should be monitored and assessed against that expected for normal growth. Pathological Gambling And Other Compulsive Behaviors Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other compulsive urges, reported less frequently include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges. Orthostatic Hypotension ABILIFY may cause orthostatic hypotension, perhaps due to its &alpha;1-adrenergic receptor antagonism. The incidence of orthostatic hypotension-associated events from short-term, placebo-controlled trials of adult patients on oral ABILIFY (n=2467) included (ABILIFY incidence, placebo incidence) orthostatic hypotension (1%, 0.3%), postural dizziness (0.5%, 0.3%), and syncope (0.5%, 0.4%); of pediatric patients 6 to 18 years of age (n=732) on oral ABILIFY included orthostatic hypotension (0.5%, 0%), postural dizziness (0.4%, 0 %), and syncope (0.2%, 0%); and of patients on ABILIFY Injection (n=501) included orthostatic hypotension (0.6%, 0%), postural dizziness (0.2%, 0.5%), and syncope (0.4%, 0%). [see ADVERSE REACTIONS] The incidence of a significant orthostatic change in blood pressure (defined as a decrease in systolic blood pressure &ge; 20 mmHg accompanied by an increase in heart rate &ge; 25 bpm when comparing standing to supine values) for ABILIFY was not meaningfully different from placebo (ABILIFY incidence, placebo incidence): in adult oral ABILIFY-treated patients (4%, 2%), in pediatric oral ABILIFY-treated patients aged 6 to 18 years (0.4%, 1%), or in ABILIFY injection-treated patients (3%, 2%). ABILIFY should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease, or conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) [see DRUG INTERACTIONS]. If parenteral benzodiazepine therapy is deemed necessary in addition to ABILIFY injection treatment, patients should be monitored for excessive sedation and for orthostatic hypotension [see DRUG INTERACTIONS]. Leukopenia, Neutropenia, And Agranulocytosis In clinical trials and/or postmarketing experience, events of leukopenia and neutropenia have been reported temporally related to antipsychotic agents, including ABILIFY. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of ABILIFY at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue ABILIFY in patients with severe neutropenia (absolute neutrophil count < 1000/mm&sup3;) and follow their WBC counts until recovery. Seizures/Convulsions In short-term, placebo-controlled trials, patients with a history of seizures excluded seizures/convulsions occurred in 0.1% (3/2467) of undiagnosed adult patients treated with oral ABILIFY, in 0.1% (1/732) of pediatric patients (6 to 18 years), and in 0.2% (1/501) of adult ABILIFY injection-treated patients. As with other antipsychotic drugs, ABILIFY should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older. Potential For Cognitive And Motor Impairment ABILIFY, like other antipsychotics, may have the potential to impair judgment, thinking, or motor skills. For example, in short-term, placebo-controlled trials, somnolence (including sedation) was reported as follows (ABILIFY incidence, placebo incidence): in adult patients (n=2467) treated with oral ABILIFY (11%, 6%), in pediatric patients ages 6 to 17 (n=611) (24%, 6%), and in adult patients (n=501) on ABILIFY Injection (9%, 6%). Somnolence (including sedation) led to discontinuation in 0.3% (8/2467) of adult patients and 3% (20/732) of pediatric patients (6 to 18 years) on oral ABILIFY in short-term, placebo-controlled trials, but did not lead to discontinuation of any adult patients on ABILIFY Injection. Despite the relatively modest increased incidence of these events compared to placebo, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with ABILIFY does not affect them adversely. Body Temperature Regulation Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ABILIFY for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration) [see ADVERSE REACTIONS]. Suicide The possibility of a suicide attempt is inherent in psychotic illnesses, bipolar disorder, and major depressive disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for ABILIFY should be written for the smallest quantity consistent with good patient management in order to reduce the risk of overdose [see ADVERSE REACTIONS]. Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use, including ABILIFY. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. ABILIFY and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Increased Mortality in Elderly Patients with Dementia-Related Psychosis and ADVERSE REACTIONS]. Patient Counseling Information See Medication Guide Discuss the following issues with patients prescribed ABILIFY: Clinical Worsening of Depression and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see WARNINGS AND PRECAUTIONS]. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with ABILIFY and should counsel them in its appropriate use. A patient Medication Guide including information about &ldquo;Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions&rdquo; is available for ABILIFY. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. It should be noted that ABILIFY is not approved as a single agent for treatment of depression and has not been evaluated in pediatric major depressive disorder. Pathological Gambling and Other Compulsive Behaviors Advise patients and their caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges while taking aripiprazole. In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see WARNINGS AND PRECAUTIONS]. Use of Orally Disintegrating Tablet Do not open the blister until ready to administer. For single tablet removal, open the package and peel back the foil on the blister to expose the tablet. Do not push the tablet through the foil because this could damage the tablet. Immediately upon opening the blister, using dry hands, remove the tablet and place the entire ABILIFY DISCMELT Orally Disintegrating Tablet on the tongue. Tablet disintegration occurs rapidly in saliva. It is recommended that ABILIFY DISCMELT be taken without liquid. However, if needed, it can be taken with liquid. Do not attempt to split the tablet. Interference with Cognitive and Motor Performance Because ABILIFY may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that ABILIFY therapy does not affect them adversely [see WARNINGS AND PRECAUTIONS]. Nursing Advise patients that breastfeeding is not recommended with ABILIFY treatment because of the potential for serious adverse reactions in a nursing infant [see Use in Specific Populations]. Concomitant Medication Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see DRUG INTERACTIONS]. Heat Exposure and Dehydration Patients should be advised regarding appropriate care in avoiding overheating and dehydration [see WARNINGS AND PRECAUTIONS]. Sugar Content Patients should be advised that each mL of ABILIFY Oral Solution contains 400 mg of sucrose and 200 mg of fructose. Phenylketonurics Phenylalanine is a component of aspartame. Each ABILIFY DISCMELT Orally Disintegrating Tablet contains the following amounts: 10 mg, 1.12 mg phenylalanine and 15 mg, 1.68 mg phenylalanine. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility Carcinogenesis Lifetime carcinogenicity studies were conducted in ICR mice, Sprague-Dawley (SD) rats, and F344 rats. Aripiprazole was administered for 2 years in the diet at doses of 1, 3, 10, and 30 mg/kg/day to ICR mice and 1, 3, and 10 mg/kg/day to F344 rats (0.2 to 5 times and 0.3 to 3 times the maximum recommended human dose [MRHD] based on mg/m&sup2; , respectively). In addition, SD rats were dosed orally for 2 years at 10, 20, 40, and 60 mg/kg/day (3 to 19 times the MRHD based on mg/m&sup2; ). Aripiprazole did not induce tumors in male mice or male rats. In female mice, the incidences of pituitary gland adenomas and mammary gland adenocarcinomas and adenoacanthomas were increased at dietary doses of 3 to 30 mg/kg/day (0.1 to 0.9 times human exposure at MRHD based on AUC and 0.5 to 5 times the MRHD based on mg/m&sup2; ). In female rats, the incidence of mammary gland fibroadenomas was increased at a dietary dose of 10 mg/kg/day (0.1 times human exposure at MRHD based on AUC and 3 times the MRHD based on mg/m&sup2; ); and the incidences of adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas were increased at an oral dose of 60 mg/kg/day (14 times human exposure at MRHD based on AUC and 19 times the MRHD based on mg/m&sup2; ). Proliferative changes in the pituitary and mammary gland of rodents have been observed following chronic administration of other antipsychotic agents and are considered prolactin-mediated. Serum prolactin was not measured in the aripiprazole carcinogenicity studies. However, increases in serum prolactin levels were observed in female mice in a 13-week dietary study at the doses associated with mammary gland and pituitary tumors. Serum prolactin was not increased in female rats in 4-week and 13-week dietary studies at the dose associated with mammary gland tumors. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown. Mutagenesis The mutagenic potential of aripiprazole was tested in the in vitro bacterial reverse-mutation assay, the in vitro bacterial DNA repair assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster lung (CHL) cells, the in vivo micronucleus assay in mice, and the unscheduled DNA synthesis assay in rats. Aripiprazole and a metabolite (2,3-DCPP) were clastogenic in the in vitro chromosomal aberration assay in CHL cells with and without metabolic activation. The metabolite, 2,3-DCPP, produced increases in numerical aberrations in the in vitro assay in CHL cells in the absence of metabolic activation. A positive response was obtained in the in vivo micronucleus assay in mice; however, the response was due to a mechanism not considered relevant to humans. Impairment Of Fertility Female rats were treated with oral doses of 2, 6, and 20 mg/kg/day (0.6, 2, and 6 times the maximum recommended human dose [MRHD] on a mg/m&sup2;basis) of aripiprazole from 2 weeks prior to mating through day 7 of gestation. Estrus cycle irregularities and increased corpora lutea were seen at all doses, but no impairment of fertility was seen. Increased pre-implantation loss was seen at 6 and 20 mg/kg/day and decreased fetal weight was seen at 20 mg/kg/day. Male rats were treated with oral doses of 20, 40, and 60 mg/kg/day (6, 13, and 19 times the MRHD on a mg/m&sup2;basis) of aripiprazole from 9 weeks prior to mating through mating. Disturbances in spermatogenesis were seen at 60 mg/kg and prostate atrophy was seen at 40 and 60 mg/kg, but no impairment of fertility was seen. Use In Specific Populations Pregnancy Pregnancy Category C Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ABILIFY during pregnancy. For more information contact the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or visit http://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/. Risk Summary Neonates exposed to antipsychotic drugs (including ABILIFY) during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. Adequate and well controlled studies with ABILIFY have not been conducted in pregnant women. Animal reproduction studies were conducted with aripiprazole in rats and rabbits during organogenesis, and in rats during the pre-and post-natal period. Oral and intravenous aripiprazole administration during organogenesis in rats and/or rabbits at doses higher than the maximum recommended human dose (MRHD) produced fetal death, decreased fetal weight, undescended testicles, delayed skeletal ossification, skeletal abnormalities, and diaphragmatic hernia. Oral and intravenous aripiprazole administration during the pre-and post-natal period in rats at doses higher than the maximum recommended human dose (MRHD) produced prolonged gestation, stillbirths, decreased pup weight, and decreased pup survival. Administer ABILIFY during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs (including ABILIFY) during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms. Data Animal Data In animal studies, aripiprazole demonstrated developmental toxicity, including possible teratogenic effects in rats and rabbits. Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the maximum recommended human dose [MRHD] on a mg/m&sup2;basis) of aripiprazole during the period of organogenesis. Gestation was slightly prolonged at 30 mg/kg/day. Treatment at the high dose of 30 mg/kg/day caused a slight delay in fetal development (decreased fetal weight), undescended testes, and delayed skeletal ossification (also seen at 10 mg/kg/day). There were no adverse effects on embryofetal or pup survival. Delivered offspring had decreased body weights (10 and 30 mg/kg/day), and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia at 30 mg/kg (the other dose groups were not examined for these findings). Postnatally, delayed vaginal opening was seen at 10 and 30 mg/kg/day and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, live fetuses, and increased post-implantation loss, likely mediated through effects on female offspring) was seen at 30 mg/kg/day. Some maternal toxicity was seen at 30 mg/kg/day however, there was no evidence to suggest that these developmental effects were secondary to maternal toxicity. In pregnant rats receiving aripiprazole injection intravenously (3, 9, and 27 mg/kg/day) during the period of organogenesis, decreased fetal weight and delayed skeletal ossification were seen at the highest dose where it also caused maternal toxicity. Pregnant rabbits were treated with oral doses of 10, 30 , and 100 mg/kg/day (2 , 3, and 11 times human exposure at MRHD based on AUC and 6, 19 , and 65 times the MRHD based on mg/m&sup2; ) of aripiprazole during the period of organogenesis. At the high dose of 100 mg/kg/day decreased maternal food consumption, and increased abortions were seen as well as increased fetal mortality, decreased fetal weight (also seen at 30 mg/kg/day), increased incidence of a skeletal abnormality (fused sternebrae) (also seen at 30 mg/kg/day). In pregnant rabbits receiving aripiprazole injection intravenously (3, 10, and 30 mg/kg/day) during the period of organogenesis, the highest dose, which caused pronounced maternal toxicity, resulted in decreased fetal weight, increased fetal abnormalities (primarily skeletal), and decreased fetal skeletal ossification. The fetal no-effect dose was 10 mg/kg/day, which is 5 times the human exposure at the MRHD based on AUC and is 6 times the MRHD based on mg/m&sup2;. In a study in which rats were treated peri-and post-natally with oral doses of 3, 10, and 30 mg/kg/day (1, 3, and 10 times the MRHD on a mg/m&sup2;basis) of aripiprazole from gestation day 17 through day 21 postpartum, slight maternal toxicity, slightly prolonged gestation an increase in stillbirths and, decreases in pup weight (persisting into adulthood) and survival were seen at 30 mg/kg/day. In rats receiving aripiprazole injection intravenously (3, 8, and 20 mg/kg/day) from gestation day 6 through day 20 postpartum, an increase in stillbirths was seen at 8 and 20 mg/kg/day, and decreases in early postnatal pup weights and survival were seen at 20 mg/kg/day; these effects were seen in presence of maternal toxicity. There were no effects on postnatal behavioral and reproductive development. Labor And Delivery The effect of ABILIFY on labor and delivery in humans is unknown. Nursing Mothers ABILIFY is present in human breast milk. Because of the potential for serious adverse reactions in nursing infants from ABILIFY, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients with major depressive disorder or agitation associated with schizophrenia or bipolar mania have not been established. The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric patients, 10 to 17 years of age, were similar to those in adults after correcting for the differences in body weight [see CLINICAL PHARMACOLOGY]. Schizophrenia Safety and effectiveness in pediatric patients with schizophrenia were established in a 6-week, placebo-controlled clinical trial in 202 pediatric patients aged 13 to 17 years [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, and Clinical Studies]. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. Bipolar I Disorder Safety and effectiveness in pediatric patients with bipolar mania were established in a 4-week, placebo-controlled clinical trial in 197 pediatric patients aged 10 to 17 years [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, and Clinical Studies]. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. The efficacy of adjunctive ABILIFY with concomitant lithium or valproate in the treatment of manic or mixed episodes in pediatric patients has not been systematically evaluated. However, such efficacy and lack of pharmacokinetic interaction between aripiprazole and lithium or valproate can be extrapolated from adult data, along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. Irritability Associated With Autistic Disorder Safety and effectiveness in pediatric patients demonstrating irritability associated with autistic disorder were established in two 8-week, placebo-controlled clinical trials in 212 pediatric patients aged 6 to 17 years [see INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, and Clinical Studies]. A maintenance trial was conducted in pediatric patients (6 to 17 years of age) with irritability associated with autistic disorder. The first phase of this trial was an open-label, flexibly dosed (aripiprazole 2 to 15 mg/day) phase in which patients were stabilized (defined as > 25% improvement on the ABC-I subscale, and a CGI-I rating of &ldquo;much improved&rdquo; or &ldquo;very much improved&rdquo;) on ABILIFY for 12 consecutive weeks. Overall, 85 patients were stabilized and entered the second, 16-week, double-blind phase where they were randomized to either continue ABILIFY treatment or switch to placebo. In this trial, the efficacy of ABILIFY for the maintenance treatment of irritability associated with autistic disorder was not established. Tourette's Disorder Safety and effectiveness of aripiprazole in pediatric patients with Tourette's Disorder were established in one 8-week (aged 7 to 17) and one 10-week trial (aged 6 to 18) in 194 pediatric patients [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, and Clinical Studies]. Maintenance efficacy in pediatric patients has not been systematically evaluated. Juvenile Animal Studies Aripiprazole in juvenile rats caused mortality, CNS clinical signs, impaired memory and learning, and delayed sexual maturation when administered at oral doses of 10, 20, 40 mg/kg/day from weaning (21 days old) through maturity (80 days old). At 40 mg/kg/day, mortality, decreased activity, splayed hind limbs, hunched posture, ataxia, tremors and other CNS signs were observed in both genders. In addition, delayed sexual maturation was observed in males. At all doses and in a dose-dependent manner, impaired memory and learning, increased motor activity, and histopathology changes in the pituitary (atrophy), adrenals (adrenocortical hypertrophy), mammary glands (hyperplasia and increased secretion), and female reproductive organs (vaginal mucification, endometrial atrophy, decrease in ovarian corpora lutea) were observed. The changes in female reproductive organs were considered secondary to the increase in prolactin serum levels. A No Observed Adverse Effect Level (NOAEL) could not be determined and, at the lowest tested dose of 10 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period, and most of the drug effects in juvenile rats were also observed in adult rats from previously conducted studies. Aripiprazole in juvenile dogs (2 months old) caused CNS clinical signs of tremors, hypoactivity, ataxia, recumbency and limited use of hind limbs when administered orally for 6 months at 3, 10, 30 mg/kg/day. Mean body weight and weight gain were decreased up to 18% in females in all drug groups relative to control values. A NOAEL could not be determined and, at the lowest tested dose of 3 mg/kg/day, there is no safety margin relative to the systemic exposures (AUC0-24) for aripiprazole or its major active metabolite in adolescents at the maximum recommended pediatric dose of 15 mg/day. All drug-related effects were reversible after a 2-month recovery period. Geriatric Use No dosage adjustment is recommended for elderly patients [see BOXED WARNING, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY]. Of the 13,543 patients treated with oral ABILIFY in clinical trials, 1073 (8%) were &ge; 65 years old and 799 (6%) were &ge; 75 years old. Placebo-controlled studies of oral ABILIFY in schizophrenia, bipolar mania, or major depressive disorder did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 749 patients treated with ABILIFY injection in clinical trials, 99 (13%) were &ge; 65 years old and 78 (10%) were &ge; 75 years old. Placebo-controlled studies of ABILIFY injection in patients with agitation associated with schizophrenia or bipolar mania did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. ABILIFY is not approved for the treatment of patients with psychosis associated with Alzheimer's disease [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. CYP2D6 Poor Metabolizers Dosage adjustment is recommended in known CYP2D6 poor metabolizers due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3-8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Hepatic And Renal Impairment No dosage adjustment for ABILIFY is required on the basis of a patient's hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15), or renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute) [see CLINICAL PHARMACOLOGY]. Other Specific Populations No dosage adjustment for ABILIFY is required on the basis of a patient's sex, race, or smoking status [see CLINICAL PHARMACOLOGY].152017-09-01 11:12:57AbilifyAripiprazoleFDA
1142017-12-04 17:38:40Overdosage & ContraindicationsOVERDOSE MedDRA terminology has been used to classify the adverse reactions. Human Experience In clinical trials and in postmarketing experience, adverse reactions of deliberate or accidental overdosage with oral ABILIFY have been reported worldwide. These include overdoses with oral ABILIFY alone and in combination with other substances. No fatality was reported with ABILIFY alone. The largest known dose with a known outcome involved acute ingestion of 1260 mg of oral ABILIFY (42 times the maximum recommended daily dose) by a patient who fully recovered. Deliberate or accidental overdosage was also reported in children (age 12 and younger) involving oral ABILIFY ingestions up to 195 mg with no fatalities. Common adverse reactions (reported in at least 5% of all overdose cases) reported with oral ABILIFY overdosage (alone or in combination with other substances) include vomiting, somnolence, and tremor. Other clinically important signs and symptoms observed in one or more patients with ABILIFY overdoses (alone or with other substances) include acidosis, aggression, aspartate aminotransferase increased, atrial fibrillation, bradycardia, coma, confusional state, convulsion, blood creatine phosphokinase increased, depressed level of consciousness, hypertension, hypokalemia, hypotension, lethargy, loss of consciousness, QRS complex prolonged, QT prolonged, pneumonia aspiration, respiratory arrest, status epilepticus, and tachycardia. Management Of Overdosage No specific information is available on the treatment of overdose with ABILIFY. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers. Charcoal: In the event of an overdose of ABILIFY, an early charcoal administration may be useful in partially preventing the absorption of aripiprazole. Administration of 50 g of activated charcoal, one hour after a single 15 mg oral dose of ABILIFY, decreased the mean AUC and Cmax of aripiprazole by 50%. Hemodialysis: Although there is no information on the effect of hemodialysis in treating an overdose with ABILIFY, hemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins. CONTRAINDICATIONS ABILIFY is contraindicated in patients with a history of a hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis [see ADVERSE REACTIONS].152017-09-01 11:12:57AbilifyAripiprazoleFDA
1152017-12-04 17:38:40Clinical PharmacologyCLINICAL PHARMACOLOGY Mechanism Of Action The mechanism of action of aripiprazole in schizophrenia or bipolar mania, is unknown. However, the efficacy of aripiprazole could be mediated through a combination of partial agonist activity at D2 and 5-HT1A receptors and antagonist activity at 5-HT2A receptors. Actions at receptors other than D2, 5HT1A, and 5-HT2A may explain some of the other clinical effects of aripiprazole (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors). Pharmacodynamics Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic and histamine H1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC50 > 1000 nM). [Aripiprazole functions as a partial agonist at the dopamine D2 and the serotonin 5-HT1A receptors, and as an antagonist at serotonin 5-HT2A receptor.] Pharmacokinetics ABILIFY activity is presumably primarily due to the parent drug, aripiprazole, and to a lesser extent, to its major metabolite, dehydro-aripiprazole, which has been shown to have affinities for D2 receptors similar to the parent drug and represents 40% of the parent drug exposure in plasma. The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole and dehydroaripiprazole, respectively. Steady-state concentrations are attained within 14 days of dosing for both active moieties. Aripiprazole accumulation is predictable from single-dose pharmacokinetics. At steady-state, the pharmacokinetics of aripiprazole is dose-proportional. Elimination of aripiprazole is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4. For CYP2D6 poor metabolizers, the mean elimination half-life for aripiprazole is about 146 hours. Pharmacokinetic studies showed that ABILIFY DISCMELT Orally Disintegrating Tablets are bioequivalent to ABILIFY Tablets. Oral Administration Absorption Tablet: Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%. ABILIFY can be administered with or without food. Administration of a 15 mg ABILIFY Tablet with a standard high-fat meal did not significantly affect the Cmax or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed Tmax by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole. Oral Solution: Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher than that from the tablet formulation. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution to tablet ratios of geometric mean Cmax and AUC values were 122% and 114%, respectively [see DOSAGE AND ADMINISTRATION]. The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional between the doses of 5 mg to 30 mg. Distribution The steady-state volume of distribution of aripiprazole following intravenous administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99% bound to serum proteins, primarily to albumin. In healthy human volunteers administered 0.5 to 30 mg/day aripiprazole for 14 days, there was dose-dependent D2 receptor occupancy indicating brain penetration of aripiprazole in humans. Metabolism And Elimination Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in the systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of the oral dose was recovered unchanged in the feces. Drug Interaction Studies Effects of other drugs on the exposures of aripiprazole and dehydro-aripiprazole are summarized in Figure 1 and Figure 2, respectively. Based on simulation, a 4.5-fold increase in mean Cmax and AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. A 3-fold increase in mean Cmax and AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors. Figure 1: The effects of other drugs on aripiprazole pharmacokinetics Figure 2: The effects of other drugs on dehydro-aripiprazole pharmacokinetics The effects of ABILIFY on the exposures of other drugs are summarized in Figure 3. A population PK analysis in patients with major depressive disorder showed no substantial change in plasma concentrations of fluoxetine (20 or 40 mg/day), paroxetine CR (37.5 or 50 mg/day), or sertraline (100 or 150 mg/day) dosed to steady-state. The steady-state plasma concentrations of fluoxetine and norfluoxetine increased by about 18% and 36%, respectively, and concentrations of paroxetine decreased by about 27%. The steady-state plasma concentrations of sertraline and desmethylsertraline were not substantially changed when these antidepressant therapies were coadministered with aripiprazole. Figure 3: The effects of ABILIFY on pharmacokinetics of other drugs Studies In Specific Populations Exposures of aripiprazole and dehydro-aripiprazole in specific populations are summarized in Figure 4 and Figure 5, respectively. In addition, in pediatric patients (10 to 17 years of age) administered with Abilify (20 mg to 30 mg), the body weight corrected aripiprazole clearance was similar to the adults. Figure 4: Effects of intrinsic factors on aripiprazole pharmacokinetics Figure 5: Effects of intrinsic factors on dehydro-aripiprazole pharmacokinetics Intramuscular Administration In two pharmacokinetic studies of aripiprazole injection administered intramuscularly to healthy subjects, the median times to the peak plasma concentrations were at 1 hour and 3 hours. A 5 mg intramuscular injection of aripiprazole had an absolute bioavailability of 100%. The geometric mean maximum concentration achieved after an intramuscular dose was on average 19% higher than the Cmax of the oral tablet. While the systemic exposure over 24 hours was generally similar between aripiprazole injection given intramuscularly and after oral tablet administration, the aripiprazole AUC in the first 2 hours after an intramuscular injection was 90% greater than the AUC after the same dose as a tablet. In stable patients with schizophrenia or schizoaffective disorder, the pharmacokinetics of aripiprazole after intramuscular administration were linear over a dose range of 1 mg to 45 mg. Although the metabolism of aripiprazole injection was not systematically evaluated, the intramuscular route of administration would not be expected to alter the metabolic pathways. Animal Toxicology And/Or Pharmacology Aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg and in a 2-year carcinogenicity study at doses of 40 and 60 mg/kg. The 40 and 60 mg/kg/day doses are 13 and 19 times the maximum recommended human dose (MRHD) based on mg/m&sup2;and 7 to 14 times human exposure at MRHD based on AUC. Evaluation of the retinas of albino mice and of monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown. Clinical Studies Efficacy of the oral formulations of ABILIFY (aripiprazole) was established in the following adequate and well-controlled trials: Four short-term trials and one maintenance trial in adult patients and one short-term trial in adolescents (ages 13-17) with schizophrenia [see Clinical Studies] Four short-term monotherapy trials and one 6-week adjunctive trial in adult patients and one short-term monotherapy trial in pediatric patients (ages 1017) with manic or mixed episodes [see Clinical Studies] One maintenance monotherapy trial and in one maintenance adjunctive trial in adult patients with bipolar I disorder [see Clinical Studies] Two short-term trials in adult patients with MDD who had an inadequate response to antidepressant therapy during the current episode [see Clinical Studies] Two short-term trials in pediatric patients (ages 6-17 years) for the treatment of irritability associated with autistic disorder [see Clinical Studies] Two short-term trials in pediatric patients (ages 6-18 years) with Tourette's disorder [see Clinical Studies] Efficacy of the injectable formulation of ABILIFY (aripiprazole) was established in the following adequate and well-controlled trials: Three 24-hour trials in agitated adult patients with schizophrenia or manic/mixed episodes of bipolar I disorder [see Clinical Studies] Schizophrenia Adults The efficacy of ABILIFY in the treatment of schizophrenia was evaluated in five short-term (4-week and 6-week), placebo-controlled trials of acutely relapsed inpatients who predominantly met DSM-III/IV criteria for schizophrenia. Four of the five trials were able to distinguish ABILIFY from placebo, but one study, the smallest, did not. Three of these studies also included an active control group consisting of either risperidone (one trial) or haloperidol (two trials), but they were not designed to allow for a comparison of ABILIFY and the active comparators. In the four positive trials for ABILIFY, four primary measures were used for assessing psychiatric signs and symptoms. Efficacy was evaluated using the total score on the Positive and Negative Syndrome Scale (PANSS). The PANSS is a 30 item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); total PANSS scores range from 30 to 210. The Clinical Global Impression (CGI) assessment reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In a 4-week trial (n=414) comparing two fixed doses of ABILIFY (15 or 30 mg/day) to placebo, both doses of ABILIFY were superior to placebo in the PANSS total score (Study 1 in Table 26), PANSS positive subscale, and CGI-severity score. In addition, the 15 mg dose was superior to placebo in the PANSS negative subscale. In a 4-week trial (n=404) comparing two fixed doses of ABILIFY (20 or 30 mg/day) to placebo, both doses of ABILIFY were superior to placebo in the PANSS total score (Study 2 in Table 26), PANSS positive subscale, PANSS negative subscale, and CGI-severity score. In a 6-week trial (n=420) comparing three fixed doses of ABILIFY (10, 15, or 20 mg/day) to placebo, all three doses of ABILIFY were superior to placebo in the PANSS total score (Study 3 in Table 26), PANSS positive subscale, and the PANSS negative subscale. In a 6-week trial (n=367) comparing three fixed doses of ABILIFY (2, 5, or 10 mg/day) to placebo, the 10 mg dose of ABILIFY was superior to placebo in the PANSS total score (Study 4 in Table 26), the primary outcome measure of the study. The 2 and 5 mg doses did not demonstrate superiority to placebo on the primary outcome measure. Thus, the efficacy of 10, 15, 20, and 30 mg daily doses was established in two studies for each dose. Among these doses, there was no evidence that the higher dose groups offered any advantage over the lowest dose group of these studies. An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age, gender, or race. A longer-term trial enrolled 310 inpatients or outpatients meeting DSM-IV criteria for schizophrenia who were, by history, symptomatically stable on other antipsychotic medications for periods of 3 months or longer. These patients were discontinued from their antipsychotic medications and randomized to ABILIFY 15 mg/day or placebo for up to 26 weeks of observation for relapse. Relapse during the double-blind phase was defined as CGI-Improvement score of &ge; 5 (minimally worse), scores &ge; 5 (moderately severe) on the hostility or uncooperativeness items of the PANSS, or &ge; 20% increase in the PANSS total score. Patients receiving ABILIFY 15 mg/day experienced a significantly longer time to relapse over the subsequent 26 weeks compared to those receiving placebo (Study 5 in Figure 6). Pediatric Patients The efficacy of ABILIFY (aripiprazole) in the treatment of schizophrenia in pediatric patients (13 to 17 years of age) was evaluated in one 6-week, placebo-controlled trial of outpatients who met DSM-IV criteria for schizophrenia and had a PANSS score &ge; 70 at baseline. In this trial (n=302) comparing two fixed doses of ABILIFY (10 or 30 mg/day) to placebo, ABILIFY was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day treatment arm and in 11 days in the 30 mg/day treatment arm. Both doses of ABILIFY were superior to placebo in the PANSS total score (Study 6 in Table 26), the primary outcome measure of the study. The 30 mg/day dosage was not shown to be more efficacious than the 10 mg/day dose. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients. Table 26: Schizophrenia Studies Study Number Treatment Group Primary Efficacy Measure: PANSS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI) Study 1 ABILIFY (15 mg/day)* 98.5 (17.2) -15.5 (2.40) -12.6 (-18.9, -6.2) ABILIFY (30 mg/day)* 99.0 (19.2) -11.4 (2.39) -8.5 (-14.8, -2.1) Placebo 100.2 (16.5) -2.9 (2.36) -- Study 2 ABILIFY (20 mg/day)* 92.6 (19.5) -14.5 (2.23) -9.6 (-15.4, -3.8) ABILIFY (30 mg/day)* 94.2 (18.5) -13.9 (2.24) -9.0 (-14.8, -3.1) Placebo 94.3 (18.5) -5.0 (2.17) -- Study 3 ABILIFY (10 mg/day)* 92.7 (19.5) -15.0 (2.38) -12.7 (-19.00, -6.41) ABILIFY (15 mg/day)* 93.2 (21.6) -11.7 (2.38) -9.4 (-15.71, -3.08) ABILIFY (20 mg/day)* 92.5 (20.9) -14.4 (2.45) -12.1 (-18.53, -5.68) Placebo 92.3 (21.8) -2.3 (2.35) -- Study 4 ABILIFY (2 mg/day) 90.7 (14.5) -8.2 (1.90) -2.9 (-8.29, 2.47) ABILIFY (5 mg/day) 92.0 (12.6) -10.6 (1.93) -5.2 (-10.7, 0.19) ABILIFY (10 mg/day)* 90.0 (11.9) -11.3 (1.88) -5.9 (-11.3, -0.58) Placebo 90.8 (13.3) -5.3 (1.97) -- Study 6 (Pediatric,13-17 years) ABILIFY (10 mg/day)* 93.6 (15.7) -26.7 (1.91) -5.5 (-10.7, -0.21) ABILIFY (30 mg/day)* 94.0 (16.1) -28.6 (1.92) -7.4 (-12.7, -2.13) Placebo 94.6 (15.6) -21.2 (1.93) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo. Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Schizophrenia Study 5) Bipolar Disorder Acute Treatment of Manic and Mixed Episodes Adults Monotherapy The efficacy of ABILIFY as monotherapy in the acute treatment of manic episodes was established in four 3-week, placebo-controlled trials in hospitalized patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These studies included patients with or without psychotic features and two of the studies also included patients with or without a rapid-cycling course. The primary instrument used for assessing manic symptoms was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score). A key secondary instrument included the Clinical Global Impression-Bipolar (CGI-BP) Scale. In the four positive, 3-week, placebo-controlled trials (n=268; n=248; n=480; n=485) which evaluated ABILIFY in a range of 15 mg to 30 mg, once daily (with a starting dose of 30 mg/day in two studies and 15 mg/day in two studies), ABILIFY was superior to placebo in the reduction of Y-MRS total score (Studies 1-4 in Table 27) and CGI-BP Severity of Illness score (mania). In the two studies with a starting dose of 15 mg/day, 48% and 44% of patients were on 15 mg/day at endpoint. In the two studies with a starting dose of 30 mg/day, 86% and 85% of patients were on 30 mg/day at endpoint. Adjunctive Therapy The efficacy of adjunctive ABILIFY with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in a 6-week, placebo-controlled study (n=384) with a 2-week lead-in mood stabilizer monotherapy phase in adult patients who met DSM-IV criteria for bipolar I disorder. This study included patients with manic or mixed episodes and with or without psychotic features. Patients were initiated on open-label lithium (0.6 to 1.0 mEq/L) or valproate (50 to 125 &mu;g/mL) at therapeutic serum levels, and remained on stable doses for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response (YMRS total score &ge; 16 and &le; 25% improvement on the Y-MRS total score) to lithium or valproate were randomized to receive either ABILIFY (15 mg/day or an increase to 30 mg/day as early as day 7) or placebo as adjunctive therapy with open-label lithium or valproate. In the 6-week, placebo-controlled phase, adjunctive ABILIFY starting at 15 mg/day with concomitant lithium or valproate (in a therapeutic range of 0.6 to 1.0 mEq/L or 50 to 125 &mu;g/mL, respectively) was superior to lithium or valproate with adjunctive placebo in the reduction of the Y-MRS total score (Study 5 in Table 27) and CGI-BP Severity of Illness score (mania). Seventy-one percent of the patients coadministered valproate and 62% of the patients coadministered lithium were on 15 mg/day at 6-week endpoint. Pediatric Patients The efficacy of ABILIFY in the treatment of bipolar I disorder in pediatric patients (10 to 17 years of age) was evaluated in one 4-week, placebo-controlled trial (n=296) of outpatients who met DSM-IV criteria for bipolar I disorder manic or mixed episodes with or without psychotic features and had a Y-MRS score &ge; 20 at baseline. This double-blind, placebo-controlled trial compared two fixed doses of ABILIFY (10 or 30 mg/day) to placebo. The ABILIFY dose was started at 2 mg/day, which was titrated to 5 mg/day after 2 days, and to the target dose in 5 days in the 10 mg/day treatment arm, and in 13 days in the 30 mg/day treatment arm. Both doses of ABILIFY were superior to placebo in change from baseline to week 4 on the Y-MRS total score (Study 6 in Table 27). Table 27: Bipolar Studies Study Number Treatment Group Primary Efficacy Measure: Y-MRS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI) Study 1 ABILIFY (30 / 15 mg/day)* 29.0 (5.9) -12.52 (1.05) -5.33 (-7.90, -2.76) Placebo 28.5 (4.6) -7.19 (1.07) -- Study 2 ABILIFY (30 / 15 mg/day)* 27.8 (5.7) -8.15 (1.23) -4.80 (-7.80, -1.80) Placebo 29.1 (6.9) -3.35(1.22) -- Study 3 ABILIFY (15 - 30 mg/day)* 28.5 (5.6) -12.64 (0.84) -3.63 (-5.75 , -1.51) Placebo 28.9 (5.9) 9.01 (0.81) -- Study 4 ABILIFY (15 -30 mg/day)* 28.0 (5.8) -11.98 (0.80) -2.28 (-4.44 , -0.11) Placebo 28.3 (5.8) -9.70 (0.83) -- Study 5 ABILIFY (15 or 30 mg/day)* + 23.2 (5.7) -13.31 (0.50) -2.62 (-4.29 , -0.95) Lithium/Valproate Placebo + Lithium/Valproate 23.0 (4.9) -10.70 (0.69) -- Study 6 (Pediatric,10-17 years) ABILIFY (10 mg/day)* 29.8 (6.5) -14.2 (0.89) -5.99 (-8.49, -3.50) ABILIFY (30 mg/day)* 29.5 (6.3) -16.5 (0.87) -8.26 (-10.7, -5.77) Placebo 30.7 (6.8) -8.2 (0.91) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo. Maintenance Treatment Of Bipolar I Disorder Monotherapy Maintenance Therapy A maintenance trial was conducted in adult patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode who had been stabilized on open-label ABILIFY and who had maintained a clinical response for at least 6 weeks. The first phase of this trial was an open-label stabilization period in which inpatients and outpatients were clinically stabilized and then maintained on open-label ABILIFY (15 or 30 mg/day, with a starting dose of 30 mg/day) for at least 6 consecutive weeks. One hundred sixty-one outpatients were then randomized in a double-blind fashion, to either the same dose of ABILIFY they were on at the end of the stabilization and maintenance period or placebo and were then monitored for manic or depressive relapse. During the randomization phase, ABILIFY was superior to placebo on time to the number of combined affective relapses (manic plus depressive), the primary outcome measure for this study (Study 7 in Figure 7). A total of 55 mood events were observed during the double-blind treatment phase. Nineteen were from the ABILIFY group and 36 were from the placebo group. The number of observed manic episodes in the ABILIFY group (6) were fewer than that in the placebo group (19), while the number of depressive episodes in the ABILIFY group (9) was similar to that in the placebo group (11). An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age and gender; however, there were insufficient numbers of patients in each of the ethnic groups to adequately assess inter-group differences. Figure 7: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Bipolar Study 7) Adjunctive Maintenance Therapy An adjunctive maintenance trial was conducted in adult patients meeting DSMIV criteria for bipolar I disorder with a recent manic or mixed episode. Patients were initiated on open-label lithium (0.6 to 1.0 mEq/L) or valproate (50 to 125 &mu;g/mL) at therapeutic serum levels, and remained on stable doses for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response (Y-MRS total score &ge; 16 and &le; 35% improvement on the Y-MRS total score) to lithium or valproate received ABILIFY with a starting dose of 15 mg/day with the option to increase to 30 mg or reduce to 10 mg as early as day 4, as adjunctive therapy with open-label lithium or valproate. Prior to randomization, patients on the combination of single-blind ABILIFY and lithium or valproate were required to maintain stability (Y-MRS and MADRS total scores &le; 12) for 12 consecutive weeks. Three hundred thirty-seven patients were then randomized in a double-blind fashion, to either the same dose of ABILIFY they were on at the end of the stabilization period or placebo plus lithium or valproate and were then monitored for manic, mixed, or depressive relapse for a maximum of 52 weeks. ABILIFY was superior to placebo on the primary endpoint, time from randomization to relapse to any mood event (Study 8 in Figure 8). A mood event was defined as hospitalization for a manic, mixed, or depressive episode, study discontinuation due to lack of efficacy accompanied by Y-MRS score > 16 and/or a MADRS > 16, or an SAE of worsening disease accompanied by YMRS score > 16 and/or a MADRS > 16. A total of 68 mood events were observed during the double-blind treatment phase. Twenty-five were from the ABILIFY group and 43 were from the placebo group. The number of observed manic episodes in the ABILIFY group (7) were fewer than that in the placebo group (19), while the number of depressive episodes in the ABILIFY group (14) was similar to that in the placebo group (18). The Kaplan-Meier curves of the time from randomization to relapse to any mood event during the 52-week, double-blind treatment phase for ABILIFY and placebo groups are shown in Figure 8. Figure 8: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse to Any Mood Event (Bipolar Study 8) An examination of population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age and gender; however, there were insufficient numbers of patients in each of the ethnic groups to adequately assess inter-group differences. Adjunctive Treatment Of Major Depressive Disorder Adults The efficacy of ABILIFY in the adjunctive treatment of major depressive disorder (MDD) was demonstrated in two short-term (6-week), placebo-controlled trials of adult patients meeting DSM-IV criteria for MDD who had had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response to 8 weeks of prospective antidepressant therapy (paroxetine controlled-release, venlafaxine extended-release, fluoxetine, escitalopram, or sertraline). Inadequate response for prospective treatment was defined as less than 50% improvement on the 17-item version of the Hamilton Depression Rating Scale (HAMD17), minimal HAMD17 score of 14, and a Clinical Global Impressions Improvement rating of no better than minimal improvement. Inadequate response to prior treatment was defined as less than 50% improvement as perceived by the patient after a minimum of 6 weeks of antidepressant therapy at or above the minimal effective dose. The primary instrument used for assessing depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale used to assess the degree of depressive symptomatology. The key secondary instrument was the Sheehan Disability Scale (SDS), a 3-item self-rated instrument used to assess the impact of depression on three domains of functioning with each item scored from 0 (not at all) to 10 (extreme). In the two trials (n=381, n=362), ABILIFY was superior to placebo in reducing mean MADRS total scores (Studies 1, 2 in Table 28). In one study, ABILIFY was also superior to placebo in reducing the mean SDS score. In both trials, patients received ABILIFY adjunctive to antidepressants at a dose of 5 mg/day. Based on tolerability and efficacy, doses could be adjusted by 5 mg increments, one week apart. Allowable doses were: 2, 5, 10, 15 mg/day, and for patients who were not on potent CYP2D6 inhibitors fluoxetine and paroxetine, 20 mg/day. The mean final dose at the end point for the two trials was 10.7 and 11.4 mg/day. An examination of population subgroups did not reveal evidence of differential response based on age, choice of prospective antidepressant, or race. With regard to gender, a smaller mean reduction on the MADRS total score was seen in males than in females. Table 28: Adjunctive Treatment of Major Depressive Disorder Studies Study Number Treatment Group Primary Efficacy Measure: MADRS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea(95% CI) Study 1 ABILIFY (5-20 mg/day)* + 25.2(6.2) -8.49 (0.66) -2.84 (-4.53 , -1.15) Antidepressant Placebo + Antidepressant 27.0 (5.5) -5.65 (0.64) -- Study 2 ABILIFY (5-20 mg/day)* + 26.0 (6.0) -8.78 (0.63) -3.01 (-4.66 , -1.37) Antidepressant Placebo + Antidepressant 26.0 (6.5) -5.77 (0.67) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo. Irritability Associated With Autistic Disorder Pediatric Patients The efficacy of ABILIFY (aripiprazole) in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in pediatric patients (6 to 17 years of age) who met the DSM-IV criteria for autistic disorder and demonstrated behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these problems. Over 75% of these subjects were under 13 years of age. Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement (CGI-I) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured symptoms of irritability in autistic disorder. The results of these trials are as follows: In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=98), aged 6 to 17 years, received daily doses of placebo or ABILIFY 2 to 15 mg/day. ABILIFY, starting at 2 mg/day with increases allowed up to 15 mg/day based on clinical response, significantly improved scores on the ABC-I subscale and on the CGI-I scale compared with placebo. The mean daily dose of ABILIFY at the end of 8week treatment was 8.6 mg/day (Study 1 in Table 29). In the other 8-week, placebo-controlled trial in children and adolescents with autistic disorder (n=218), aged 6 to 17 years, three fixed doses of ABILIFY (5 mg/day, 10 mg/day, or 15 mg/day) were compared to placebo. ABILIFY dosing started at 2 mg/day and was increased to 5 mg/day after one week. After a second week, it was increased to 10 mg/day for patients in the 10 and 15 mg dose arms, and after a third week, it was increased to 15 mg/day in the 15 mg/day treatment arm (Study 2 in Table 29). All three doses of ABILIFY significantly improved scores on the ABC-I subscale compared with placebo. Table 29: Irritability Associated with Autistic Disorder Studies (Pediatric) Study Number Treatment Group Primary Efficacy Measure: ABC-I Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI) Study 1 ABILIFY (2-15 mg/day)* 29.6 (6.37) -12.9 (1.44) -7.9 (-11.7, -4.1) Placebo 30.2 (6.52) -5.0 (1.43) -- Study 2 ABILIFY (5 mg/day)* 28.6 (7.56) -12.4 (1.36) -4.0 (-7.7, -0.4) ABILIFY (10 mg/day)* 28.2 (7.36) -13.2 (1.25) -4.8 (-8.4, -1.3) ABILIFY (15 mg/day)* 28.9 (6.41) -14.4 (1.31) -6.0 (-9.6, -2.3) Placebo 28.0 (6.89) -8.4 (1.39) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo. Tourette's Disorder Pediatric Patients The efficacy of ABILIFY (aripiprazole) in the treatment of Tourette's disorder was established in one 8-week (7 to 17 years of age) and one 10-week (6 to 18 years of age), placebo-controlled trials in pediatric patients (6 to 18 years of age) who met the DSM-IV criteria for Tourette's disorder and had a Total Tic score (TTS) &ge; 20 -22 on the Yale Global Tic Severity Scale (YGTSS). The YGTSS is a fully validated scale designed to measure current tic severity. Efficacy was evaluated using two assessment scales: 1) the Total Tic score (TTS) of the YGTSS and 2) the Clinical Global Impressions Scale for Tourette's Syndrome (CGI-TS), a clinician-determined summary measure that takes into account all available patient information. Over 65% of these patients were under 13 years of age. The primary outcome measure in both trials was the change from baseline to endpoint in the TTS of the YGTSS. Ratings for the TTS are made along 5 different dimensions on a scale of 0 to 5 for motor and vocal tics each. Summation of these 10 scores provides a TTS (i.e., 0-50). The results of these trials are as follows: In the 8-week, placebo-controlled, fixed-dose trial, children and adolescents with Tourette's disorder (n=133), aged 7 to 17 years, were randomized 1:1:1 to low dose ABILIFY, high dose ABILIFY, or placebo. The target doses for the low and high dose ABILIFY groups were based on weight. Patients < 50 kg in the low dose ABILIFY group started at 2 mg per day with a target dose of 5 mg per day after 2 days. Patients &ge; 50 kg in the low dose ABILIFY group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at day 7. Patients < 50 kg in the high dose ABILIFY group started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at day 7. Patients &ge; 50 kg in the high dose ABILIFY group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a dose of 10 mg per day at day 7 and were allowed weekly increases of 5 mg per day up to a target dose 20 mg per day at Day 21. ABILIFY (both high and low dose groups) demonstrated statistically significantly improved scores on the YGTSS TTS (Study 1 in Table 30) and on the CGI-TS scale compared with placebo. The estimated improvements on the YGTSS TTS over the course of the study are displayed in Figure 9. Figure 9: Least Square Means of Change from Baseline in YGTSS TTS by Week (Tourette's Disorder Study 1) In the 10-week, placebo-controlled, flexible-dose trial in children and adolescents with Tourette's disorder (n=61), aged 6 to 18 years, patients received daily doses of placebo or ABILIFY, starting at 2 mg/day with increases allowed up to 20 mg/day based on clinical response. ABILIFY demonstrated statistically significantly improved scores on the YGTSS TTS scale compared with placebo (Study 2 in Table 30). The mean daily dose of ABILIFY at the end of 10-week treatment was 6.54 mg/day. Table 30: Tourette's Disorder Studies (Pediatric) Study Number Treatment Group Primary Efficacy Measure: YGTSS TTS Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI) Study 1 ABILIFY (low dose)* 29.2 (5.63) -13.4 (1.59) -6.3 (-10.2, -2.3) ABILIFY (high dose)* 31.2 (6.40) -16.9 (1.61) -9.9 (-13.8, -5.9) Placebo 30.7 (5.95) -7.1 (1.55) -- Study 2 ABILIFY (2-20 mg/day)* 28.3 (5.51) -15.0 (1.51) -5.3 (-9.8, -0.9) Placebo 29.5 (5.60) -9.6 (1.64) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo. Agitation Associated With Schizophrenia Or Bipolar Mania The efficacy of intramuscular ABILIFY for injection for the treatment of agitation was established in three short-term (24-hour), placebo-controlled trials in agitated inpatients from two diagnostic groups: schizophrenia and bipolar I disorder (manic or mixed episodes, with or without psychotic features). Each of the trials included a single active comparator treatment arm of either haloperidol injection (schizophrenia studies) or lorazepam injection (bipolar mania study). Patients could receive up to three injections during the 24-hour treatment periods; however, patients could not receive the second injection until after the initial 2-hour period when the primary efficacy measure was assessed. Patients enrolled in the trials needed to be: (1) judged by the clinical investigators as clinically agitated and clinically appropriate candidates for treatment with intramuscular medication, and (2) exhibiting a level of agitation that met or exceeded a threshold score of &ge; 15 on the five items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness, and excitement items) with at least two individual item scores &ge; 4 using a 1-7 scoring system (1 = absent, 4 = moderate, 7 = extreme). In the studies, the mean baseline PANSS Excited Component score was 19, with scores ranging from 15 to 34 (out of a maximum score of 35), thus suggesting predominantly moderate levels of agitation with some patients experiencing mild or severe levels of agitation. The primary efficacy measure used for assessing agitation signs and symptoms in these trials was the change from baseline in the PANSS Excited Component at 2 hours post-injection. A key secondary measure was the Clinical Global Impression of Improvement (CGI-I) Scale. The results of the trials follow: In a placebo-controlled trial in agitated inpatients predominantly meeting DSM-IV criteria for schizophrenia (n=350), four fixed ABILIFY injection doses of 1 mg, 5.25 mg, 9.75 mg, and 15 mg were evaluated. At 2 hours post-injection, the 5.25 mg, 9.75 mg, and 15 mg doses were statistically superior to placebo in the PANSS Excited Component (Study 1 in Table 31) and on the CGI-I Scale. In a second placebo-controlled trial in agitated inpatients predominantly meeting DSM-IV criteria for schizophrenia (n=445), one fixed ABILIFY injection dose of 9.75 mg was evaluated. At 2 hours post-injection, ABILIFY for injection was statistically superior to placebo in the PANSS Excited Component (Study 2 in Table 31) and on the CGI-I Scale. In a placebo-controlled trial in agitated inpatients meeting DSMIV criteria for bipolar I disorder (manic or mixed) (n=291), two fixed ABILIFY injection doses of 9.75 mg and 15 mg were evaluated. At 2 hours post-injection, both doses were statistically superior to placebo in the PANSS Excited Component (Study 3 in Table 31). Examination of population subsets (age, race, and gender) did not reveal any differential responsiveness on the basis of these subgroupings. Table 31: Agitation Associated with Schizophrenia or Bipolar Mania Studies Study Number Treatment Group Primary Efficacy Measure: PANSS Excited Component Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI) Agitation Associated with Schizophrenia Study 1 ABILIFY (1 mg) 19.16 (3.26) -4.47 (0.72) -1.19 (-2.96 , 0.59) ABILIFY (5.25 mg)* 19.41 (3.31) -5.65 (0.68) -2.37 (-4.10 , -0.63) ABILIFY (9.75 mg)* 19.42 (2.80) -6.69 (0.72) -3.40 (-5.18 , -1.62) ABILIFY (15 mg)* 19.34 (2.38) -5.72 (0.72) -2.44 (-4.21 , -0.68) Placebo 19.18 (2.95) -3.28 (0.70) -- Study 2 ABILIFY (9.75 mg)* 18.82 (2.67) -7.27 (0.59) -2.48 (-3.77, -1.19) Placebo 18.74 (2.71) -4.78 (0.69) -- Agitation Associated with Bipolar Mania Study 3 ABILIFY (9.75 mg)* 18.77 (2.45) -8.74 (0.57) -2.99 (-4.53, -1.44) ABILIFY (15 mg)* 18.29 (2.49) -8.67 (0.57) -2.91 (-4.44, -1.38) Placebo 17.95 (2.63) -5.76 (0.58) -- SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. a Difference (drug minus placebo) in least-squares mean change from baseline. * Doses statistically significantly superior to placebo.152017-09-01 11:12:57AbilifyAripiprazoleFDA

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