Vigabatrin

1 INDICATIONS AND USAGE Vigabatrin tablets are indicated for the treatment of: • Refractory Complex Partial Seizures as adjunctive therapy in patients 2 years of age and older who have responded inadequately to several alternative treatments; Vigabatrin tablets are not indicated as a first line agent ( 1.1 ) • Infantile Spasms - monotherapy in infants 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss ( 1.2 ) 1.1 Refractory Complex Partial Seizures (CPS) Vigabatrin tablets are indicated as adjunctive therapy for adults and pediatric patients 2 years of age and older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss [see Warnings and Precautions ( 5.1 ) ]. Vigabatrin tablets are not indicated as a first line agent for complex partial seizures. 1.2 Infantile Spasms (IS) Vigabatrin tablets are indicated as monotherapy for pediatric patients with infantile spasms 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss [ see Warnings and Precautions ( 5.1 ) ]

2 DOSAGE AND ADMINISTRATION Refractory Complex Partial Seizures • Adults (17 years of age and older): Initiate at 1000 mg/day (500 mg twice daily); increase total daily dose weekly in 500 mg/day increments, to the recommended dose of 3000 mg/day (1500 mg twice daily) ( 2.2 ) • Pediatric (2 to 16 years of age): The recommended dosage is based on body weight and administered as two divided doses ( 2.2 ) • The dosage may be increased in weekly intervals, depending on response ( 2.2 ) • Dose patients weighing more than 60 kg according to adult recommendations ( 2.2 ) Infantile Spasms • Initiate at a daily dose of 50 mg/kg (25 mg/kg twice daily); increase total daily dose every 3 days, in increments of 25 mg/kg/day to 50 mg/kg/day, up to a maximum daily dose of 150 mg/kg (75 mg/kg twice daily) ( 2.3 ) Renal Impairment: Dose adjustment recommended ( 2.4 , 8.5 , 8.6 ) 2.1 Important Dosing and Administration Instructions Dosing Use the lowest dosage and shortest exposure to vigabatrin tablets consistent with clinical objectives [ see Warnings and Precautions ( 5.1 ) ]. The vigabatrin tablets dosing regimen depends on the indication, age group, weight, and dosage form (tablets or for oral solution) [ see Dosage and Administration ( 2.2 , 2.3 ) ]. Patients with impaired renal function require dose adjustment [ see Dosage and Administration ( 2.4 ) ]. Monitoring of vigabatrin tablets plasma concentrations to optimize therapy is not helpful. Administration Vigabatrin tablets are given orally with or without food. If a decision is made to discontinue vigabatrin tablets, the dose should be gradually reduced [ see Dosage and Administration ( 2.2 , 2.3 ) and Warnings and Precautions ( 5.6 ) ]. 2.2 Refractory Complex Partial Seizures Adults (Patients 17 Years of Age and Older) Treatment should be initiated at 1000 mg/day (500 mg twice daily). Total daily dose may be increased in 500 mg increments at weekly intervals depending on response. The recommended dose of vigabatrin tablets in adults is 3000 mg/day (1500 mg twice daily). A 6000 mg/day dose has not been shown to confer additional benefit compared to the 3000 mg/day dose and is associated with an increased incidence of adverse events. In controlled clinical studies in adults with complex partial seizures, vigabatrin was tapered by decreasing the daily dose 1000 mg/day on a weekly basis until discontinued [ see Warnings and Precautions ( 5.6 ) ]. Pediatric (Patients 2 to 16 Years of Age) The recommended dosage is based on body weight and administered as two divided doses, as shown in Table 1. The dosage may be increased in weekly intervals to the total daily maintenance dosage, depending on response. Pediatric patients weighing more than 60 kg should be dosed according to adult recommendations. T a bl e 1. CPS Dosing Recommendations for Pediatric Patients Weighing 10 kg up to 60 kg †† Body Weight [kg] Total Daily* S tarting Dose [mg/day] Total Daily* Maintenance Dose † [mg/day] 10 kg to 15 kg 350 mg 1050 mg Greater than 15 kg to 20 kg 450 mg 1300 mg Greater than 20 kg to 25 kg 500 mg 1500 mg Greater than 25 kg to 60 kg 500 mg 2000 mg * Administered in two divided doses † Maintenance dose is based on 3000 mg/day adult-equivalent dose †† Patients weighing more than 60 kg should be dosed according to adult recommendations In patients with refractory complex partial seizures, vigabatrin tablets should be withdrawn if a substantial clinical benefit is not observed within 3 months of initiating treatment. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 3 months, treatment should be discontinued at that time [ see Warnings and Precautions ( 5.1 ) ]. In a controlled study in pediatric patients with complex partial seizures, vigabatrin was tapered by decreasing the daily dose by one third every week for three weeks [ see Warnings and Precautions ( 5.6 ) ]. 2.3 Infantile Spasms The initial daily dosing is 50 mg/kg/day given in two divided do …

3 DOSAGE FORMS AND STRENGTHS Tablet: 500 mg: White to off-white in color, convex, oval shaped film-coated tablets debossed with “VI” and “GT” on either side of the score line on one side of the tablet and “500” on the other side. Tablet: 500 mg ( 3 )

4 CONTRAINDICATIONS None. None ( 4 )

6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are described elsewhere in labeling: Permanent Vision Loss [see BOXED WARNING and Warnings and Precautions (5.1) ] Magnetic Resonance Imaging (MRI) Abnormalities in Infants [see Warnings and Precautions (5.3) ] Neurotoxicity [see Warnings and Precautions (5.4) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.5) ] Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions (5.6) ] Anemia [see Warnings and Precautions (5.7) ] Somnolence and Fatigue [see Warnings and Precautions (5.8) ] Peripheral Neuropathy [see Warnings and Precautions (5.9) ] Weight Gain [see Warnings and Precautions (5.10) ] Edema [see Warnings and Precautions (5.11) ] Refractory Complex Partial Seizures Most common adverse reactions in controlled studies include (incidence ≥5% over placebo): Adults: blurred vision, somnolence, dizziness, abnormal coordination, tremor, and fatigue (6.1) Pediatric patients (3 to 16 years of age): weight gain (6.1) Infantile Spasms (incidence >5% and greater than on placebo) Somnolence, bronchitis, ear infection, and acute otitis media (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In U.S. and primary non-U.S. clinical studies of 4,079 vigabatrin-treated patients, the most common (≥5%) adverse reactions associated with the use of vigabatrin in combination with other AEDs were headache, somnolence, fatigue, dizziness, convulsion, nasopharyngitis, weight gain, upper respiratory tract infection, visual field defect, depression, tremor, nystagmus, nausea, diarrhea, memory impairment, insomnia, irritability, abnormal coordination, blurred vision, diplopia, vomiting, influenza, pyrexia, and rash. The adverse reactions most commonly associated with vigabatrin treatment discontinuation in ≥1% of patients were convulsion and depression. In patients with infantile spasms, the adverse reactions most commonly associated with vigabatrin treatment discontinuation in ≥1% of patients were infections, status epilepticus, developmental coordination disorder, dystonia, hypotonia, hypertonia, weight gain, and insomnia. Refractory Complex Partial Seizures Adults Table 5 lists the adverse reactions that occurred in ≥2% and more than one patient per vigabatrin-treated group and that occurred more frequently than in placebo patients from 2 U.S. adjunctive clinical studies of refractory CPS in adults. Table 5. Adverse Reactions in Pooled, Adjunctive Trials in Adults with Refractory Complex Partial Seizures Vigabatrin dosage (mg/day) Body System Adverse Reaction 3,000 [N=134] % 6,000 [N=43] % Placebo [N=135] % Ear Disorders Tinnitus Vertigo 2 2 0 5 1 1 Eye Disorders Blurred vision Diplopia Asthenopia Eye pain 13 7 2 0 16 16 2 5 5 3 0 0 Gastrointestinal Disorders Diarrhea Nausea Vomiting Constipation Upper abdominal pain Dyspepsia Stomach discomfort Abdominal pain Toothache Abdominal distension 10 10 7 8 5 4 4 3 2 2 16 2 9 5 5 5 2 2 5 0 7 8 6 3 1 3 1 1 2 1 General Disorders Fatigue Gait disturbance Asthenia Edema peripheral Fever Chest pain Thirst Malaise 23 6 5 5 4 1 2 0 40 12 7 7 7 5 0 5 16 7 1 1 3 1 0 0 Infections Nasopharyngitis Upper respiratory tract infection Influenza Urinary tract infection Bronchitis 14 7 5 4 0 9 9 7 5 5 10 6 4 0 1 Injury Contusion Joint sprain Muscle strain Wound secretion 3 1 1 0 5 2 2 2 2 1 1 0 Metabolism and Nutrition Disorders Increased appetite Weight gain 1 6 5 14 1 3 Musculoskeletal Disorders Arthralgia Back pain Pain in extremity Myalgia Muscle twitching Muscle spasms 10 4 6 3 1 3 5 7 2 5 9 0 3 2 4 1 1 1 Nervous System Disord …

7 DRUG INTERACTIONS Decreased phenytoin plasma levels: dosage adjustment may be needed ( 7.1 ) 7.1 Antiepileptic Drugs Phenytoin Although phenytoin dose adjustments are not routinely required, dose adjustment of phenytoin should be considered if clinically indicated, since vigabatrin may cause a moderate reduction in total phenytoin plasma levels [ see Clinical Pharmacology ( 12.3 ) ]. Clonazepam Vigabatrin may moderately increase the Cmax of clonazepam resulting in an increase of clonazepam-associated adverse reactions [ see Clinical Pharmacology ( 12.3 ) ]. Other AEDs There are no clinically significant pharmacokinetic interactions between vigabatrin and either phenobarbital or sodium valproate. Based on population pharmacokinetics, carbamazepine, clorazepate, primidone, and sodium valproate appear to have no effect on plasma concentrations of vigabatrin [ see Clinical Pharmacology ( 12.3 ) ]. 7.2 Oral Contraceptives Vigabatrin is unlikely to affect the efficacy of steroid oral contraceptives [ see Clinical Pharmacology ( 12.3 ) ]. 7.3 Drug-Laboratory Test Interactions Vigabatrin decreases alanine transaminase (ALT) and aspartate transaminase (AST) plasma activity in up to 90% of patients. In some patients, these enzymes become undetectable. The suppression of ALT and AST activity by vigabatrin may preclude the use of these markers, especially ALT, to detect early hepatic injury. Vigabatrin may increase the amount of amino acids in the urine, possibly leading to a false positive test for certain rare genetic metabolic diseases (e.g., alpha aminoadipic aciduria).

8 USE IN SPECIFIC POPULATIONS • Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) • Lactation: Vigabatrin is excreted in human milk ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, including vigabatrin, during pregnancy. Encourage women who are taking vigabatrin during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. This must be done by the patient herself. Risk Summary There are no adequate data on the developmental risk associated with the use of vigabatrin in pregnant women. Limited available data from case reports and cohort studies pertaining to vigabatrin use in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, based on animal data, vigabatrin use in pregnant women may result in fetal harm. When administered to pregnant animals, vigabatrin produced developmental toxicity, including an increase in fetal malformations and offspring neurobehavioral and neurohistopathological effects, at clinically relevant doses. In addition, developmental neurotoxicity was observed in rats treated with vigabatrin during a period of postnatal development corresponding to the third trimester of human pregnancy (see Data) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Administration of vigabatrin (oral doses of 50 to 200 mg/kg/day) to pregnant rabbits throughout the period of organogenesis was associated with an increased incidence of malformations (cleft palate) and embryofetal death; these findings were observed in two separate studies. The no-effect dose for adverse effects on embryofetal development in rabbits (100 mg/kg/day) is approximately 1/2 the maximum recommended human dose (MRHD) of 3 g/day on a body surface area (mg/m 2 ) basis. In rats, oral administration of vigabatrin (50, 100, or 150 mg/kg/day) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. The no-effect dose for adverse effects on embryo-fetal development in rats (50 mg/kg/day) is approximately 1/5 the MRHD on a mg/m 2 basis. Oral administration of vigabatrin (50, 100, 150 mg/kg/day) to rats from the latter part of pregnancy through weaning produced long-term neurohistopathological (hippocampal vacuolation) and neurobehavioral (convulsions) abnormalities in the offspring. A no-effect dose for developmental neurotoxicity in rats was not established; the low-effect dose (50 mg/kg/day) is approximately 1/5 the MRHD on a mg/m 2 basis. In a published study, vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to a mutant mouse strain on a single day during organogenesis (day 7, 8, 9, 10, 11, or 12). An increase in fetal malformations (including cleft palate) was observed at both doses. Oral administration of vigabatrin (5, 15, or 50 mg/kg/day) to young rats during the neonatal and juvenile periods of development (postnatal days 4 to 65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg/day) was associated with plasma vigabatrin exposures (AUC) less than 1/30 of those measured in pediatric patients receiving an oral d …

12.1 Mechanism of Action The precise mechanism of vigabatrin’s anti-seizure effect is unknown, but it is believed to be the result of its action as an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the metabolism of the inhibitory neurotransmitter GABA. This action results in increased levels of GABA in the central nervous system. No direct correlation between plasma concentration and efficacy has been established. The duration of drug effect is presumed to be dependent on the rate of enzyme re-synthesis rather than on the rate of elimination of the drug from the systemic circulation.

11 DESCRIPTION Vigabatrin tablets, USP are an oral antiepileptic drug and are available as white to off-white film-coated 500 mg tablets. The chemical name of vigabatrin, a racemate consisting of two enantiomers, is (±) 4-amino-5-hexenoic acid. The molecular formula is C 6 H 11 NO 2 and the molecular weight is 129.16. It has the following structural formula: Vigabatrin USP is a white or almost white powder which is freely soluble in water, slightly soluble in methanol, very slightly to practically insoluble in alcohol, practically insoluble in methylene chloride, and insoluble in toluene. The pH of a 1% aqueous solution is about 6.9. The n-octanol/water partition coefficient of vigabatrin is about 0.011 (log P=- 1.96) at physiologic pH. Vigabatrin melts with decomposition in a 3-degree range within the temperature interval of 171°C to 176°C. The dissociation constants (pK a ) of vigabatrin are 4 and 9.7 at room temperature (25°C). Each vigabatrin tablet, USP contains 500 mg of vigabatrin USP. The inactive ingredients are hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate and titanium dioxide. FDA approved dissolution test specifications differ from USP. str

10 OVERDOSAGE 10.1 Signs, Symptoms, and Laboratory Findings of Overdosage Confirmed and/or suspected vigabatrin overdoses have been reported during clinical trials and in post marketing surveillance. No vigabatrin overdoses resulted in death. When reported, the vigabatrin dose ingested ranged from 3 g to 90 g, but most were between 7.5 g and 30 g. Nearly half the cases involved multiple drug ingestions including carbamazepine, barbiturates, benzodiazepines, lamotrigine, valproic acid, acetaminophen, and/or chlorpheniramine. Coma, unconsciousness, and/or drowsiness were described in the majority of cases of vigabatrin overdose. Other less commonly reported symptoms included vertigo, psychosis, apnea or respiratory depression, bradycardia, agitation, irritability, confusion, headache, hypotension, abnormal behavior, increased seizure activity, status epilepticus, and speech disorder. These symptoms resolved with supportive care. 10.2 Management of Overdosage There is no specific antidote for vigabatrin overdose. Standard measures to remove unabsorbed drug should be used, including elimination by emesis or gastric lavage. Supportive measures should be employed, including monitoring of vital signs and observation of the clinical status of the patient. In an in vitro study, activated charcoal did not significantly adsorb vigabatrin. The effectiveness of hemodialysis in the treatment of vigabatrin overdose is unknown. In isolated case reports in renal failure patients receiving therapeutic doses of vigabatrin, hemodialysis reduced vigabatrin plasma concentrations by 40% to 60%.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Vigabatrin Tablets, USP, 500 mg tablets are white film coated, modified oval, bi-convex with “54 444” debossed on one side and scored on the other. They are supplied as bottles of 100 (NDC 0054-0652-25). 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F). See USP controlled room temperature.

16.1 How Supplied Vigabatrin Tablets, USP, 500 mg tablets are white film coated, modified oval, bi-convex with “54 444” debossed on one side and scored on the other. They are supplied as bottles of 100 (NDC 0054-0652-25).