Vigabatrin

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.

1 INDICATIONS AND USAGE VIGADRONE is 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; VIGADRONE is 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) VIGADRONE is 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) ]. VIGADRONE is not indicated as a first line agent for complex partial seizures. 1.2 Infantile Spasms (IS) VIGADRONE is 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 1,000 mg/day (500 mg twice daily); increase total daily dose weekly in 500 mg/day increments, to the recommended dose of 3,000 mg/day (1,500 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 VIGADRONE consistent with clinical objectives [see Warnings and Precautions (5.1) ]. The VIGADRONE dosing regimen depends on the indication, age group, weight, and dosage form (tablets or powder 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 VIGADRONE plasma concentrations to optimize therapy is not helpful. Administration VIGADRONE tablets are given orally with or without food. If a decision is made to discontinue VIGADRONE, the dose should be gradually reduced [see Dosage and Administration (2.2 , 2.3) , Warnings and Precautions (5.6) ]. 2.2 Refractory Complex Partial Seizures Adults (Patients 17 Years of Age and Older) Treatment should be initiated at 1,000 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 VIGADRONE in adults is 3,000 mg/day (1,500 mg twice daily). A 6,000 mg/day dose has not been shown to confer additional benefit compared to the 3,000 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 1,000 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. Table 1. CPS Dosing Recommendations for Pediatric Patients Weighing 10 kg up to 60 kg Patients weighing more than 60 kg should be dosed according to adult recommendations Body Weight [kg] Total Daily Administered in two divided doses. Starting Dose [mg/day] Total Daily Maintenance Dose Maintenance dose is based on 3,000 mg/day adult-equivalent dose [mg/day] 10 kg to 15 kg 350 mg 1,050 mg Greater than 15 kg to 20 kg 450 mg 1,300 mg Greater than 20 kg to 25 kg 500 mg 1,500 mg Greater than 25 kg to 60 kg 500 mg 2,000 mg In patients with refractory complex partial seizures, VIGADRONE 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 doses (25 mg/kg twice daily); subsequent dosing can be titrated by 25 mg/kg/day to 50 mg/kg/day increments every 3 days, up to a maximum of 150 mg/kg/day given in 2 divided doses (75 mg/kg twice daily) [see Use in Specific Populations (8.4) ]. Table 2 provides the volume of the 50 mg/mL dosing solution of vigabatrin for oral solution that should be administered as individual doses in infants of various weights. Table 2. Infant Dosing Table Weight [kg] Starting Dose 50 mg/kg/day Maximum Dose 150 mg/kg/day 3 1.5 mL twice daily 4.5 mL twice daily 4 2 mL twice daily 6 mL twice daily 5 2.5 mL twice daily 7.5 mL twice daily 6 3 mL twice daily 9 mL twice daily 7 3.5 mL twice daily 10.5 mL twice daily 8 4 mL twice daily 12 mL twice daily 9 4.5 mL twice daily 13.5 mL twice daily 10 5 mL twice daily 15 mL twice daily 11 5.5 mL twice daily 16.5 mL twice daily 12 6 mL twice daily 18 mL twice daily 13 6.5 mL twice daily 19.5 mL twice daily 14 7 mL twice daily 21 mL twice daily 15 7.5 mL twice daily 22.5 mL twice daily 16 8 mL twice daily 24 mL twice daily In patients with infantile

6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are described elsewhere in labeling: Permanent Vision Loss [see BOXED WARNING , 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 Upsher-Smith Laboratories, LLC at 1-855-899-9180 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 2 0 1 Vertigo 2 5 1 Eye Disorders Blurred vision 13 16 5 Diplopia 7 16 3 Asthenopia 2 2 0 Eye pain 0 5 0 Gastrointestinal Disorders Diarrhea 10 16 7 Nausea 10 2 8 Vomiting 7 9 6 Constipation 8 5 3 Upper abdominal pain 5 5 1 Dyspepsia 4 5 3 Stomach discomfort 4 2 1 Abdominal pain 3 2 1 Toothache 2 5 2 Abdominal distension 2 0 1 General Disorders Fatigue 23 40 16 Gait disturbance 6 12 7 Asthenia 5 7 1 Edema peripheral 5 7 1 Fever 4 7 3 Chest pain 1 5 1 Thirst 2 0 0 Malaise 0 5 0 Infections Nasopharyngitis 14 9 10 Upper respiratory tract infection 7 9 6 Influenza 5 7 4 Urinary tract infection 4 5 0 Bronchitis 0 5 1 Injury Contusion 3 5 2 Joint sprain 1 2 1 Muscle strain 1 2 1 Wound secretion 0 2 0 Metabolism and Nutrition Disorders Increased appetite 1 5 1 Weight gain 6 14 3 Musculoskeletal Disorders Arthralgia 10 5 3 Back pain 4 7 2 Pain in extremity 6 2 4 Myalgia 3 5 1 Muscle twitching 1 9 1 Muscle spasms 3 0 1 Nervous System Disorders Headache 33 26 31 Somnolence 22 26 13 Dizziness 24 26 17 Nystagmus 13 19 9 Tremor 15 16 8 Memory impairment 7 16 3 Abnormal coordination 7 16 2 Disturbance in attention 9 0 1 Sensory disturbance 4 7 2 Hyporeflexia 4 5 1 Paraesthesia 7 2 1 Lethargy 4 7 2 Hyperreflexia 4 2 3 Hypoaesthesia 4 5 1 Sedation 4 0 0 Status epilepticus 2 5 0 Dysarthria 2 2 1 Postictal state 2 0 1 Sensory loss 0 5 0 Psychiatric Disorders Irritability 7 23 7 Depression 6 14 3 Confusional state 4 14 1 Anxiety 4 0 3 Depressed mood 5 0 1 Abnormal thinking 3 7 0 Abnormal behavior 3 5 1 Expressive language disorder 1 7 1 Nervousness 2 5 2 Abnormal dreams 1 5 1 Reproductive System Dysmenorrhea 9 5 3 Erectile dysfunction 0 5 0 Respiratory and Thoracic Disorders Pharyngolaryngeal pain 7 14 5 Cough 2 14 7 Pulmonary congestion 0 5 1 Sinus headache 6 2 1 Skin and Subcutaneous Tissue Disorders Rash 4 5 4 Pediatrics 2 to 16 years of age Table 6 lists adverse reactions from controlled clinical studies of pediatr

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 VIGADRONE may cause a moderate reduction in total phenytoin plasma levels [see Clinical Pharmacology (12.3) ]. Clonazepam VIGADRONE may moderately increase the C max 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 VIGADRONE is unlikely to affect the efficacy of steroid oral contraceptives [see Clinical Pharmacology (12.3) ]. 7.3 Drug-Laboratory Test Interactions VIGADRONE 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 VIGADRONE may preclude the use of these markers, especially ALT, to detect early hepatic injury. VIGADRONE 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).