Perampanel

1 INDICATIONS AND USAGE Perampanel tablets, a non-competitive AMPA glutamate receptor antagonist, are indicated for: Treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy 4 years of age and older ( 1.1 ) Adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in patients with epilepsy 12 years of age and older ( 1.2 ) 1.1 Partial-Onset Seizures Perampanel tablets are indicated for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy 4 years of age and older. 1.2 Primary Generalized Tonic-Clonic Seizures Perampanel tablets are indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients with epilepsy 12 years of age and older.

2 DOSAGE AND ADMINISTRATION Dosing in the absence of moderate or strong CYP3A4 inducers Starting dose: 2 mg once daily orally at bedtime ( 2.1 , 2.2 ) May increase dose based on clinical response and tolerability by increments of 2 mg once daily no more frequently than at weekly intervals ( 2.1 , 2.2 ) Recommended maintenance dose in monotherapy or adjunctive therapy for partial-onset seizures: 8 mg to 12 mg once daily at bedtime ( 2.1 ) Recommended maintenance dose in adjunctive therapy for primary generalized tonic-clonic seizures: 8 mg once daily at bedtime ( 2.2 ) Dosing in the presence of concomitant moderate or strong CYP3A4 inducers : see section 2.3 Specific Populations Mild and Moderate Hepatic Impairment: Maximum recommended daily dose is 6 mg (mild) and 4 mg (moderate) once daily at bedtime ( 2.4 ) Severe Hepatic Impairment: Not recommended ( 2.4 ) Severe Renal Impairment or on Hemodialysis: Not recommended ( 2.5 ) Elderly: Increase dose no more frequently than every 2 weeks ( 2.6 ) 2.1 Dosage for Partial-Onset Seizures Monotherapy or Adjunctive Therapy The recommended starting dosage of perampanel tablets in adults and pediatric patients 4 years of age and older is 2 mg once daily taken orally at bedtime. Increase dosage no more frequently than at weekly intervals by increments of 2 mg once daily based on individual clinical response and tolerability. The recommended maintenance dose range is 8 mg to 12 mg once daily, although some patients may respond to a dose of 4 mg daily. A dose of 12 mg once daily resulted in somewhat greater reductions in seizure rates than the dose of 8 mg once daily, but with a substantial increase in adverse reactions. Dosage adjustment is recommended with concomitant use of moderate or strong CYP3A4 enzyme inducing drugs, which include certain antiepileptic drugs (AEDs) [ see Dosage and Administration (2.3) ]. 2.2 Dosage for Primary Generalized Tonic-Clonic Seizures Adjunctive Therapy The recommended starting dosage of perampanel tablets in adults and pediatric patients 12 years of age and older is 2 mg once daily taken orally at bedtime. Increase dosage no more frequently than at weekly intervals by increments of 2 mg once daily based on individual clinical response and tolerability. The recommended maintenance dose is 8 mg once daily taken at bedtime. Patients who are tolerating perampanel tablets at 8 mg once daily and require further reduction of seizures may benefit from a dose increase up to 12 mg once daily if tolerated. Dosage adjustment is recommended with concomitant use of moderate or strong CYP3A4 enzyme inducing drugs, which include certain AEDs [ see Dosage and Administration (2.3) ]. 2.3 Dosage Modifications with Concomitant Use of Moderate or Strong CYP3A4 Enzyme Inducers Moderate and strong CYP3A4 inducers, including enzyme-inducing AEDs such as phenytoin, carbamazepine, and oxcarbazepine, cause a reduction in perampanel tablets plasma levels [ see Drug Interactions (7.2) , Clinical Pharmacology (12.3) ]. Therefore, in adults and pediatric patients 4 years of age and older receiving these concomitant enzyme-inducing drugs, the recommended starting dosage of perampanel tablets is 4 mg once daily taken orally at bedtime. Increase dosage by increments of 2 mg once daily based on individual clinical response and tolerability, no more frequently than at weekly intervals. A maintenance dose has not been established in clinical trials. The highest dose studied in patients on concomitant enzyme-inducing AEDs was 12 mg once daily. When moderate or strong CYP3A4 inducers are introduced or withdrawn from a patient’s treatment regimen, the patient should be closely monitored for clinical response and tolerability. Dose adjustment of perampanel tablets may be necessary. 2.4 Dosage Adjustment in Patients with Hepatic Impairment In patients with mild and moderate hepatic impairment, the starting dose of perampanel tablets is 2 mg once daily. Increase dosage by increments of 2 mg once d …

3 DOSAGE FORMS AND STRENGTHS Tablets 2 mg tablets: Orange colored, round shaped, biconvex, film-coated tablets, debossed with “P” on one side and “21” on other side. 4 mg tablets: Brick red colored, round shaped, biconvex, film-coated tablets, debossed with “P” on one side and “22” on other side. 6 mg tablets: Pink colored, round shaped, biconvex, film-coated tablets, debossed with “P” on one side and “23” on other side. 8 mg tablets: Beige colored, round shaped, biconvex, film-coated tablets, debossed with “P” on one side and “24” on other side. 10 mg tablets: Green colored, round shaped, biconvex, film-coated tablets, debossed with “P” on one side and “25” on other side. 12 mg tablets: Blue colored, round shaped, biconvex, film-coated tablets, debossed with “P” on one side and “26” on other side. Tablets: 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg ( 3 )

4 CONTRAINDICATIONS None. None ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Serious Psychiatric and Behavioral Reactions [see Warnings and Precautions (5.1) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.2) ] Neurologic Effects [see Warnings and Precautions (5.3) ] Falls [see Warnings and Precautions (5.4) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.5) ] Most common adverse reactions (≥5% and ≥1% higher than placebo) include dizziness, somnolence, fatigue, irritability, falls, nausea, weight gain, vertigo, ataxia, headache, vomiting, contusion, abdominal pain, and anxiety ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Partial-Onset Seizures Adult and Adolescent Patients (12 years of age and older) A total of 1,038 patients receiving perampanel (2 mg, 4 mg, 8 mg, or 12 mg once daily) constituted the safety population in the pooled analysis of the placebo-controlled trials (Studies 1, 2, and 3) in patients with partial-onset seizures. Approximately 51% of patients were female, and the mean age was 35 years. Adverse Reactions Leading to Discontinuation In controlled clinical trials (Studies 1, 2, and 3), the rate of discontinuation as a result of an adverse reaction was 3%, 8%, and 19% in patients randomized to receive perampanel at the recommended doses of 4 mg, 8 mg, and 12 mg per day, respectively, and 5% in patients randomized to receive placebo [see Clinical Studies (14) ]. The adverse reactions most commonly leading to discontinuation (≥1% in the 8 mg or 12 mg perampanel group and greater than placebo) were dizziness, somnolence, vertigo, aggression, anger, ataxia, blurred vision, irritability, and dysarthria [see Warnings and Precautions (5.1 , 5.3) ]. Most Common Adverse Reactions Table 2 gives the incidence in the controlled clinical trials (Studies 1, 2, and 3) of the adverse reactions that occurred in ≥2% of patients with partial-onset seizures in the perampanel 12 mg dose group and more frequent than placebo (in order of decreasing frequency for the 12 mg dose group). The most common dose-related adverse reactions in patients receiving perampanel at doses of 8 mg or 12 mg (≥4% and occurring at least 1% higher than the placebo group) included dizziness (36%), somnolence (16%), fatigue (10%), irritability (9%), falls (7%), nausea (7%), ataxia (5%), balance disorder (4%), gait disturbance (4%), vertigo (4%), and weight gain (4%). For almost every adverse reaction, rates were higher on 12 mg and more often led to dose reduction or discontinuation. Table 2. Adverse Reactions in Pooled Placebo-Controlled Trials in Adult and Adolescent Patients with Partial-Onset Seizures (Studies 1, 2, and 3) (Reactions ≥ 2% of Patients in Highest Perampanel Dose (12 mg) Group and More Frequent than Placebo) Placebo n=442 % Perampanel Tablets 4 mg n=172 % 8 mg n=431 % 12 mg n=255 % Dizziness 9 16 32 43 Somnolence 7 9 16 18 Headache 11 11 11 13 Irritability 3 4 7 12 Fatigue 5 8 8 12 Falls 3 2 5 10 Ataxia 0 1 3 8 Nausea 5 3 6 8 Vertigo 1 4 3 5 Back pain 2 2 2 5 Dysarthria 0 1 3 4 Anxiety 1 2 3 4 Blurred vision 1 1 3 4 Gait disturbance 1 1 4 4 Weight gain 1 4 4 4 Cough 3 1 1 4 Upper respiratory tract infection 3 3 3 4 Vomiting 3 2 3 4 Hypersomnia 0 1 2 3 Anger <1 0 1 3 Aggression 1 1 2 3 Balance disorder 1 0 5 3 Diplopia 1 1 1 3 Head injury 1 1 1 3 Hypoaesthesia 1 0 0 3 Pain in extremity 1 0 2 3 Constipation 2 2 2 3 Myalgia 2 1 1 3 Coordination abnormal 0 1 <1 2 Euphoric mood 0 0 <1 2 Confusional state < …

7 DRUG INTERACTIONS Contraceptives: 12 mg once daily may decrease the effectiveness of hormonal contraceptives containing levonorgestrel ( 7.1 ) Moderate and Strong CYP3A4 Inducers (including carbamazepine, oxcarbazepine, and phenytoin): increase clearance of perampanel and decrease perampanel plasma concentrations. When moderate or strong CYP3A4 inducers are introduced or withdrawn, monitor patients closely. Dose adjustment of perampanel tablets may be necessary ( 2.3 , 7.2 ) 7.1 Contraceptives With concomitant use, perampanel at a dose of 12 mg per day reduced levonorgestrel exposure by approximately 40% [see Clinical Pharmacology (12.3) ] . Use of perampanel with contraceptives containing levonorgestrel may render them less effective. Additional non-hormonal forms of contraception are recommended [see Use in Specific Populations (8.3) ] . 7.2 Moderate and Strong CYP3A4 Inducers The concomitant use of known moderate and strong CYP3A4 inducers including carbamazepine, phenytoin, or oxcarbazepine with perampanel decreased the plasma levels of perampanel by approximately 50% to 67% [see Clinical Pharmacology (12.3) ] . The starting doses for perampanel should be increased in the presence of moderate or strong CYP3A4 inducers [see Dosage and Administration (2.3) ] . When these moderate or strong CYP3A4 inducers are introduced or withdrawn from a patient's treatment regimen, the patient should be closely monitored for clinical response and tolerability. Dose adjustment of perampanel may be necessary [see Dosage and Administration (2.3) ]. 7.3 Alcohol and Other CNS Depressants The concomitant use of perampanel and CNS depressants including alcohol may increase CNS depression. A pharmacodynamic interaction study in healthy subjects found that the effects of perampanel on complex tasks such as driving ability were additive or supra-additive to the impairment effects of alcohol [see Clinical Pharmacology (12.3) ]. Multiple dosing of perampanel 12 mg per day also enhanced the effects of alcohol to interfere with vigilance and alertness, and increased levels of anger, confusion, and depression. These effects may also be seen when perampanel is used in combination with other CNS depressants. Care should be taken when administering perampanel with these agents. Patients should limit activity until they have experience with concomitant use of CNS depressants (e.g., benzodiazepines, narcotics, barbiturates, sedating antihistamines). Advise patients not to drive or operate machinery until they have gained sufficient experience on perampanel to gauge whether it adversely affects these activities.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), such as perampanel, during pregnancy. Encourage women who are taking perampanel during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org. Risk Summary There are no adequate data on the developmental risk associated with use in pregnant women. In animal studies, perampanel induced developmental toxicity in pregnant rat and rabbit at clinically relevant doses [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 Oral administration of perampanel (1 mg/kg/day, 3 mg/kg/day, or 10 mg/kg/day) to pregnant rats throughout organogenesis resulted in an increase in visceral abnormalities (diverticulum of the intestine) at all doses tested; maternal toxicity was observed at the mid and high doses. In a dose-ranging study at higher oral doses (10 mg/kg/day, 30 mg/kg/day, or 60 mg/kg/day), embryo lethality and reduced fetal body weight were observed at the mid and high doses tested. The lowest dose tested (1 mg/kg/day) is similar to a human dose of 8 mg/day based on body surface area (mg/m 2 ). Upon oral administration of perampanel (1 mg/kg/day, 3 mg/kg/day, or 10 mg/kg/day) to pregnant rabbits throughout organogenesis, embryo lethality and maternal toxicity were observed at the mid and high doses tested; the no-effect dose for embryo-fetal developmental toxicity in rabbit (1 mg/kg/day) is approximately 2 times a human dose of 8 mg/day based on body surface area (mg/m 2 ). Oral administration of perampanel (1 mg/kg/day, 3 mg/kg/day or 10 mg/kg/day) to rats throughout gestation and lactation resulted in fetal and pup deaths at the mid and high doses (associated with maternal toxicity) and delayed sexual maturation in males and females at the highest dose tested. No effects were observed on measures of neurobehavioral or reproductive function in the offspring. The no-effect dose for pre- and postnatal developmental toxicity in rat (1 mg/kg/day) is similar to a human dose of 8 mg/day based on body surface area (mg/m 2 ). 8.2 Lactation Risk Summary There are no data on the presence of perampanel in human milk, the effects on the breastfed child, or the effects of the drug on milk production. Perampanel and/or its metabolites are present in rat milk, and are detected at concentrations higher than that in maternal plasma. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for perampanel and any potential adverse effects on the breastfed child from perampanel or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception Use of perampanel may reduce the efficacy of hormonal contraceptives containing levonorgestrel. Advise women taking perampanel who are using a levonorgestrel-containing contraceptive to use an additional non-hormonal form of contraception while using perampanel and for a month after discontinuation [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . 8.4 Pediatric Use Safety and effectiveness of perampanel for the treatment of partial-onset seizures have been established in pediatric patients 4 years of age and older. The safety and effectiveness of perampanel in patients 12 years of age and older was established by three randomized double-blind, placebo-controlled, multicenter studies, which included 72 pediatric patients between 12 and 16 years of age exposed to perampanel [see Clinical Pharmacology (12.3) …

12.1 Mechanism of Action Perampanel is a non-competitive antagonist of the ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor on post-synaptic neurons. Glutamate is the primary excitatory neurotransmitter in the central nervous system and is implicated in a number of neurological disorders caused by neuronal over excitation. The precise mechanism by which perampanel exerts its antiepileptic effects in humans is unknown.

11 DESCRIPTION Perampanel tablets contain perampanel, a non-competitive AMPA receptor antagonist, as a 4:3 hydrate. The chemical name of the active ingredient is 2-(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3 yl)benzonitrile hydrate (4:3). The molecular formula is C 23 H 15 N 3 O • 3⁄4 H 2 O and the molecular weight is 362.90 (349.39 for anhydrous perampanel). It is a white to yellowish white powder. It is freely soluble in N-Methyl pyrrolidone, sparingly soluble in acetonitrile, slightly soluble in methanol and practically insoluble in water. The chemical structure is: Tablets Perampanel tablets are round, bi-convex, film-coated tablets containing 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, or 12 mg of perampanel. Tablets contain the following inactive ingredients: lactose monohydrate, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, povidone. The 2 mg film-coated tablets contain hypromellose, polyethylene glycol, titanium dioxide, iron oxide red and iron oxide yellow, 4 mg contains hypromellose, polyethylene glycol, titanium dioxide, talc and iron oxide red, 6 mg contains hypromellose, polyethylene glycol, titanium dioxide and iron oxide red, 8 mg contains hypromellose, polyethylene glycol, talc, titanium dioxide, iron oxide red and black iron oxide, 10 mg contains hypromellose, polyethylene glycol, titanium dioxide, iron oxide yellow and FD&C BLUE #2, 12 mg contains hypromellose, polyethylene glycol, titanium dioxide, iron oxide yellow and FD&C BLUE #2. peram-tabs-structure

10 OVERDOSAGE The highest reported overdose of perampanel was 300 mg. Events reported after perampanel overdose include somnolence, stupor, coma, psychiatric or behavioral reactions, altered mental status, and dizziness or gait disturbances. There is no available specific antidote to the overdose reactions of perampanel. In the event of overdose, standard medical practice for the management of any overdose should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of cardiac rhythm and vital sign measurement is recommended. A certified poison control center should be contacted for updated information on the management of overdose with perampanel. Due to its long half-life, the reactions caused by perampanel could be prolonged.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Perampanel Tablets 2 mg are Orange colored, round shaped, biconvex, film-coated tablets, debossed with “P” on one side and “21” on other side. They are supplied as follows: Bottles of 30 NDC 72205-221-30 Bottles of 90 NDC 72205-221-90 4 mg are Brick red colored, round shaped, biconvex, film-coated tablets, debossed with “P” on one side and “22” on other side. They are supplied as follows: Bottles of 30 NDC 72205-222-30 Bottles of 90 NDC 72205-222-90 6 mg are Pink colored, round shaped, biconvex, film-coated tablets, debossed with “P” on one side and “23” on other side. They are supplied as follows: Bottles of 30 NDC 72205-223-30 Bottles of 90 NDC 72205-223-90 8 mg are Beige colored, round shaped, biconvex, film-coated tablets, debossed with “P” on one side and “24” on other side. They are supplied as follows: Bottles of 30 NDC 72205-224-30 Bottles of 90 NDC 72205-224-90 10 mg are Green colored, round shaped, biconvex, film-coated tablets, debossed with “P” on one side and “25” on other side. They are supplied as follows: Bottles of 30 NDC 72205-225-30 Bottles of 90 NDC 72205-225-90 12 mg are Blue colored, round shaped, biconvex, film-coated tablets, debossed with “P” on one side and “26” on other side. They are supplied as follows: Bottles of 30 NDC 72205-226-30 Bottles of 90 NDC 72205-226-90 16.2 Storage Tablets: store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature]