Perampanel

1 INDICATIONS AND USAGE Perampanel tablets, a non-competitive AMPA glutamate receptor antagonist, is 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 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 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 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 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 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 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 is 2 mg once daily. Increase dosage by increments of 2 mg once daily no more frequently than every 2 weeks. The maximum recommended daily dose is 6 mg for patients with mild hepatic impairment and 4 mg for patients with moderate hepatic impairment. Perampanel is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. 2.5 Dosage Information for Patients with Renal Impairment Perampanel tablets can be used in patients with moderate renal impairment with close monitoring. A slower titration may be considered, based on clinical response and tolerability. Perampanel tablets are not recommended in patients with severe renal impairment or patients undergoing hemodialysis [see Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ]. 2.6 Dosage Information for Elderly Patients In elderly patients, increase dosage no more frequently than every 2 weeks during titration [see Use in Specific Populations (8.5) ].

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 <1 1 1 2 Hyponatremia <1 0 0 2 Limb injury <1 1 1 2 Mood altered <1 1 <1 2 Arthralgia 1 0 3 2 Asthenia 1 1 2 2 Contusion 1 0 2 2 Memory impairment 1 0 1 2 Musculoskeletal pain 1 1 1 2 Oropharyngeal pain 1 2 2 2 Paraesthesia 1 0 1 2 Peripheral edema 1 1 1 2 Skin laceration 1 0 2 2 Pediatric Patients (4 to <12 years of age) In two studies in pediatric patients 4 to <12 years of age with epilepsy, a total of 225 patients received perampanel, with 110 patients exposed for at least 6 months, and 21 patients for at least 1 year. Adverse reactions in pediatric patients 4 to <12 years of age were similar to those seen in patients 12 years of age and older. Primary Generalized Tonic-Clonic Seizures A total of 81 patients receiving perampanel 8 mg once daily constituted the safety population in the placebo-controlled trial in patients with primary generalized tonic-clonic seizures (Study 4). Approximately 57% of patients were female, and the mean age was 27 years. In the controlled primary generalized tonic-clonic seizure clinical trial (Study 4), the adverse reaction profile was similar to that noted for the controlled partial-onset seizure clinical trials (Studies 1, 2, and 3). Table 3 gives the incidence of adverse reactions in patients receiving perampanel 8 mg (≥4% and higher than in the placebo group) in Study 4. The most common adverse reactions in patients receiving perampanel (≥10% and greater than placebo) were dizziness (32%), fatigue (15%), headache (12%), somnolence (11%), and irritability (11%). The adverse reactions most commonly leading to discontinuation in patients receiving perampanel 8 mg (≥2% and greater than placebo) were vomiting (2%) and dizziness (2%). Table 3. Adverse Reactions in a Placebo-Controlled Trial in Patients with Primary Generalized Tonic-Clonic Seizures (Study 4) (Reactions ≥4% of Patients in Perampanel Group and More Frequent than Placebo) Placebo n=82 % Perampanel 8 mg n=81 % Dizziness 6 32 Fatigue 6 15 Headache 10 12 Somnolence 4 11 Irritability 2 11 Vertigo 2 9 Vomiting 2 9 Weight gain 4 7 Contusion 4 6 Nausea 5 6 Abdominal pain 1 5 Anxiety 4 5 Urinary tract infection 1 4 Ligament sprain 0 4 Balance disorder 1 4 Rash 1 4 Weight Gain Weight gain has occurred with perampanel. In controlled partial-onset seizure clinical trials, perampanel-treated adults gained an average of 1.1 kg (2.5 lbs) compared to an average of 0.3 kg (0.7 lbs) in placebo-treated adults with a median exposure of 19 weeks. The percentages of adults who gained at least 7% and 15% of their baseline body weight in perampanel-treated patients were 9.1% and 0.9%, respectively, as compared to 4.5% and 0.2% of placebo-treated patients, respectively. Clinical monitoring of weight is recommended. Similar increases in weight were also observed in adult and adolescent patients treated with perampanel in the primary generalized tonic-clonic seizure clinical trial. Elevated triglycerides Increases in triglycerides have occurred with perampanel use. Comparison of Sex and Race No significant sex differences were noted in the incidence of adverse reactions. Although there were few non-Caucasian patients, no differences in the incidence of adverse reactions compared to Caucasian patients were observed. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of perampanel. 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. Dermatologic : Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.5) ] Psychiatric : Acute psychosis, hallucinations, delusions, paranoia, delirium, confusional state, disorientation, memory impairment [see Warnings and Precautions (5.1) ] .

12.3 Pharmacokinetics Pharmacokinetics of perampanel are similar in healthy subjects, patients with partial-onset seizures, and patients with primary generalized tonic-clonic seizures. The half-life of perampanel is about 105 hours, so that steady state is reached in about 2 to 3 weeks. AUC of perampanel increased in a dose-proportional manner after single-dose administration of 0.2 mg to 12 mg tablets and after multiple-dose administration of 1 mg to 12 mg tablets once daily. Perampanel oral suspension has comparable bioavailability to perampanel tablets under steady state. Both formulations may be used interchangeably. The pharmacokinetics of perampanel are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures (in the absence of concomitant moderate or strong CYP3A4 inducers). Absorption Perampanel is rapidly and completely absorbed after oral administration with negligible first-pass metabolism. Median time to reach peak concentration (t max ) ranged from 0.5 to 2.5 hours under fasted condition. Co-administration of perampanel tablet with a high fat meal had no impact on the total exposure (AUC 0-inf ) of perampanel and reduced the peak plasma concentration (C max ) of perampanel by 11% to 40%. The t max was delayed by approximately 1 to 3 hours in fed state compared to that under fasted conditions. Distribution Data from in vitro studies indicate that, in the concentration range of 20 ng/mL to 2000 ng/mL, perampanel is approximately 95 to 96% bound to plasma proteins, mainly bound to albumin and α1-acid glycoprotein. Blood to plasma ratio of perampanel is 0.55 to 0.59. Metabolism Perampanel is extensively metabolized via primary oxidation and sequential glucuronidation. Oxidative metabolism is primarily mediated by CYP3A4/5 and to a lesser extent by CYP1A2 and CYP2B6, based on results of in vitro studies using recombinant human CYPs and human liver microsomes. Other CYP enzymes may also be involved. Following administration of radiolabeled perampanel, unchanged perampanel accounted for 74% to 80% of total radioactivity in systemic circulation, whereas only trace amounts of individual perampanel metabolites were detected in plasma. Elimination Following administration of a radiolabeled perampanel tablet dose to 8 healthy elderly subjects, 22% of administered radioactivity was recovered in the urine and 48% in the feces. In urine and feces, recovered radioactivity was primarily composed of a mixture of oxidative and conjugated metabolites. Population pharmacokinetic analysis of pooled data from 19 Phase 1 studies reported that t ½ of perampanel was 105 hours on average. Apparent clearance of perampanel in healthy subjects and patients was approximately 12 mL/min. Specific Populations Hepatic Impairment The pharmacokinetics of perampanel following a single 1 mg tablet dose were evaluated in 12 subjects with mild and moderate hepatic impairment (Child-Pugh A and B, respectively) compared with 12 demographically matched healthy subjects. The total (free and protein bound) exposure (AUC 0-inf ) of perampanel was 50% greater in subjects with mild hepatic impairment and more than doubled (2.55-fold) in subjects with moderate hepatic impairment compared to their healthy controls. The AUC 0-inf of free perampanel in subjects with mild and moderate hepatic impairment was 1.8-fold and 3.3-fold, respectively, of those in matched healthy controls. The t ½ was prolonged in subjects with mild impairment (306 vs. 125 hours) and moderate impairment (295 vs. 139 hours). Perampanel has not been studied in subjects with severe hepatic impairment [see Dosage and Administration (2.4) , Use in Specific Populations (8.6) ]. Renal Impairment A dedicated study has not been conducted to evaluate the pharmacokinetics of perampanel in patients with renal impairment. Population pharmacokinetic analysis was performed on pooled data from patients with partial-onset seizures and receiving perampanel tablets up to 12 mg/day in placebo-controlled clinical trials. Results showed that perampanel apparent clearance was decreased by 27% in patients with mild renal impairment (creatinine clearance 50 to 80 mL/min) compared to patients with normal renal function (creatinine clearance >80 mL/min), with a corresponding 37% increase in AUC. Considering the substantial overlap in the exposure between normal and mildly impaired patients, no dosage adjustment is necessary for patients with mild renal impairment. Perampanel has not been studied in patients with severe renal impairment and patients undergoing hemodialysis [see Dosage and Administration (2.5) , Use in Specific Populations (8.7) ]. Sex In a population pharmacokinetic analysis of patients with partial-onset and primary generalized tonic-clonic seizures receiving perampanel tablets in placebo-controlled clinical trials, perampanel apparent clearance in females (0.54 L/hr) was 18% lower than in males (0.66 L/hr). No dosage adjustment is necessary based on sex. Pediatrics In a population pharmacokinetic analysis of healthy subjects and pediatric and adult patients with partial-onset seizures, including 123 children 4 years to less than 12 years of age, 226 adolescents 12 years to less than 18 years of age, and 1912 adults 18 years of age and older, no significant effect of age or body weight on perampanel clearance was found. Geriatrics In a population pharmacokinetic analysis of patients with partial-onset seizures and primary generalized tonic-clonic seizures ranging in age from 12 to 74 years receiving perampanel tablets in placebo-controlled trials, no significant effect of age on perampanel apparent clearance was found [see Dosage and Administration (2.6) , Use in Specific Populations (8.5) ]. Race In a population pharmacokinetic analysis of patients with partial-onset seizures and primary generalized tonic-clonic seizures, which included 614 Caucasians, 15 Blacks, 4 Japanese, 4 American Indians/Alaska Natives, 79 Chinese and 108 other Asians receiving perampanel tablets in placebo-controlled trials, no significant effect of race on perampanel apparent clearance was found. No dosage adjustment is necessary. Drug Interaction Studies In Vitro Assessment of Drug Interactions Drug Metabolizing Enzymes In human liver microsomes, perampanel at a concentration of 30 μmol/L, about 10 fold the steady state C max at a 12 mg dose, had a weak inhibitory effect on CYP2C8, CYP3A4, UGT1A9, and UGT2B7. Perampanel did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, UGT1A1, UGT1A4, and UGT1A6 up to a concentration of 30 μmol/L. Compared with positive controls (including phenobarbital and rifampin), perampanel was found to weakly induce CYP2B6 (30 μmol/L) and CYP3A4/5 (≥3 μmol/L) in cultured human hepatocytes. Perampanel also induced UGT1A1 (≥3 μmol/L) and UGT1A4 (30 μmol/L). Perampanel did not induce CYP1A2 at concentrations up to 30 μmol/L. Transporters In vitro studies showed that perampanel is not a substrate or significant inhibitor of the following: organic anion transporting polypeptides 1B1 and 1B3; organic anion transporters 1, 2, 3, and 4; organic cation transporters 1, 2, and 3; efflux transporters P-glycoprotein and Breast Cancer Resistance Protein. In Vivo Assessment of Drug Interactions Drug Interactions with AEDs Effect of Concomitant AEDs on Perampanel: Carbamazepine. As an inducer of CYP enzymes, carbamazepine increases perampanel clearance. Steady state administration of carbamazepine at 300 mg BID in healthy subjects reduced the C max and AUC 0-inf of a single 2 mg tablet dose of perampanel by 26% and 67%, respectively. The t ½ of perampanel was shortened from 56.8 hours to 25 hours. In clinical studies examining partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 64% in patients on carbamazepine compared to the AUC in patients not on enzyme-inducing AEDs [see Dosage and Administration (2.3) , Drug Interactions (7.2) ]. Oxcarbazepine. In clinical studies examining partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 48% in patients on oxcarbazepine compared to patients not on enzyme-inducing AEDs [see Dosage and Administration (2.3) , Drug Interactions (7.2) ]. Eslicarbazepine. Eslicarbazepine is structurally similar to oxcarbazepine and thus may also reduce perampanel plasma concentrations when used concomitantly. Phenytoin. In clinical studies examining partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 43% in patients on phenytoin compared to patients not on enzyme-inducing AEDs [see Dosage and Administration (2.3) , Drug Interactions (7.2) ]. Phenobarbital and Primidone. In a population pharmacokinetic analysis of patients with partial-onset and primary generalized tonic-clonic seizures in clinical trials (40 patients co-administered phenobarbital and 9 patients co-administered primidone), no significant effect on perampanel AUC was found. A modest effect of phenobarbital and primidone on perampanel concentrations cannot be excluded. Topiramate. Population pharmacokinetic analysis of patients with partial-onset and primary generalized tonic-clonic seizures in clinical trials showed that perampanel AUC was reduced by approximately 19% in patients on topiramate compared to patients not on enzyme-inducing AEDs. Other AEDs. Population pharmacokinetic analysis of patients with partial-onset and primary generalized tonic-clonic seizures in clinical trials showed that clobazam, clonazepam, lamotrigine, levetiracetam, valproate, and zonisamide did not have an effect on perampanel clearance. Other strong CYP3A inducers (e.g., rifampin, St. John's wort) may also greatly increase clearance of perampanel and reduce perampanel plasma concentrations [see Drug Interactions (7.2) ]. Effect of Perampanel on Concomitant AEDs: Perampanel tablets up to 12 mg/day did not significantly affect the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, or zonisamide based on a population pharmacokinetic analysis of patients with partial-onset seizures in clinical trials. Perampanel had a statistically significant effect on the clearance of carbamazepine, clobazam, lamotrigine, and valproic acid, but the increases in clearance of these drugs were each less than 10% at the highest perampanel dose evaluated (12 mg/day). Perampanel co-administration resulted in a 26% decrease in oxcarbazepine clearance and increased its concentrations. The concentrations of 10-monohydroxy metabolite (MHD), the active metabolite of oxcarbazepine, were not measured. Drug-drug Interaction Studies with Other Drugs Effect of Other Drugs on Perampanel Ketoconazole. Co-administration of single 1-mg dose of perampanel tablet with 400 mg once daily doses of ketoconazole, a strong CYP3A4 inhibitor, for 8 days in healthy subjects prolonged perampanel t ½ by 15% (67.8 vs. 58.4 hours) and increased AUC 0-inf by 20%. Contraceptives. Perampanel C max and AUC 0-72h were not altered when a single 6-mg dose of perampanel tablet was administered to healthy female subjects following a 21-day course of oral contraceptives containing ethinylestradiol 30 μg and levonorgestrel 150 μg. Effect of Perampanel on Other Drugs Midazolam. Perampanel administered as 6 mg tablet once daily doses for 20 days decreased AUC 0-inf and C max of midazolam (a CYP3A4 substrate) by 13% and 15%, respectively, in healthy subjects. Contraceptives. Co-administration of perampanel 4 mg tablet once daily with an oral contraceptive containing ethinylestradiol 30 µg and levonorgestrel 150 µg for 21 days did not alter C max or AUC 0-24h of either ethinylestradiol or levonorgestrel in healthy female subjects. In another study, a single dose of the oral contraceptive was administered following 21-day once daily dosing of perampanel 12 mg or 8 mg tablets in healthy females. Perampanel at 12 mg did not alter AUC 0-24h of ethinylestradiol but decreased its C max by 18%, and also decreased C max and AUC 0-24h of levonorgestrel by 42% and 40%, respectively. Perampanel at 8 mg did not have significant effect on C max or AUC 0-24h of either ethinylestradiol or levonorgestrel, with a decrease in AUC 0-24h of levonorgestrel (9% on average) [see Drug Interactions (7.1) , Use in Specific Populations (8.3) ]. Levodopa. Perampanel tablets administered as 4 mg once daily doses for 19 days had no effect on C max and AUC 0-inf of levodopa in healthy subjects.