Perampanel

5 WARNINGS AND PRECAUTIONS Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behavior ( 5.2 ) Neurologic Effects: Monitor for dizziness, gait disturbance, somnolence, and fatigue ( 5.3 ) Patients should use caution when driving or operating machinery ( 5.3 ) Falls: Monitor for falls and injuries ( 5.4 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: Discontinue if no alternate etiology ( 5.5 ) Withdrawal of Antiepileptic Drugs: In patients with epilepsy, there may be an increase in seizure frequency ( 5.6 ) 5.1 Serious Psychiatric and Behavioral Reactions In the controlled partial-onset seizure clinical trials, hostility- and aggression-related adverse reactions occurred in 12% and 20% of patients randomized to receive perampanel at doses of 8 mg and 12 mg per day, respectively, compared to 6% of patients in the placebo group. These effects were dose-related and generally appeared within the first 6 weeks of treatment, although new events continued to be observed through more than 37 weeks. Perampanel-treated patients experienced more hostility- and aggression-related adverse reactions that were serious, severe, and led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients. In general, in placebo-controlled partial-onset seizure clinical trials, neuropsychiatric events were reported more frequently in patients being treated with perampanel than in patients taking placebo. These events included irritability, aggression, anger, and anxiety, which occurred in 2% or greater of perampanel-treated patients and twice as frequently as in placebo-treated patients. Other symptoms that occurred with perampanel and were more common than with placebo included belligerence, affect lability, agitation, and physical assault. Some of these events were reported as serious and life-threatening. Homicidal ideation and/or threat were exhibited in 0.1% of 4,368 perampanel-treated patients in controlled and open label trials, including non-epilepsy trials. Homicidal ideation and/or threat have also been reported postmarketing in patients treated with perampanel. In the partial-onset seizure clinical trials, these events occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression. Some patients experienced worsening of their pre-existing psychiatric conditions. Patients with active psychotic disorders and unstable recurrent affective disorders were excluded from the clinical trials. The combination of alcohol and perampanel significantly worsened mood and increased anger. Patients taking perampanel should avoid the use of alcohol [see Drug Interactions (7.3) ]. Similar serious psychiatric and behavioral events were observed in the primary generalized tonic-clonic seizure clinical trial. In healthy volunteers taking perampanel, observed psychiatric events included paranoia, euphoric mood, agitation, anger, mental status changes, and disorientation/confusional state. In the non-epilepsy trials, psychiatric events that occurred in perampanel-treated patients more often than placebo-treated patients included disorientation, delusion, and paranoia. In the postmarketing setting, there have been reports of psychosis (acute psychosis, hallucinations, delusions, paranoia) and delirium (delirium, confusional state, disorientation, memory impairment) in patients treated with perampanel [see Adverse Reactions (6.2) ] . Patients, their caregivers, and families should be informed that perampanel may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least 1 month after the last dose of perampanel, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period) or at other times of dose increases. Dose of perampanel should be reduced if these symptoms occur. Permanently discontinue perampanel for persistent severe or worsening psychiatric symptoms or behaviors and refer for psychiatric evaluation. 5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including perampanel, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1. Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients with Events per 1000 Patients Drug Patients with Events per 1000 patients Relative Risk: Incidence of Events in drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing perampanel or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. 5.3 Neurologic Effects Dizziness and Gait Disturbance Perampanel caused dose-related increases in events related to dizziness and disturbance in gait or coordination [see Adverse Reactions (6.1) ]. In the controlled partial-onset seizure clinical trials, dizziness and vertigo were reported in 35% and 47% of patients randomized to receive perampanel at doses of 8 mg and 12 mg per day, respectively, compared to 10% of placebo-treated patients. The gait disturbance related events (including ataxia, gait disturbance, balance disorder, and abnormal coordination) were reported in 12% and 16% of patients randomized to receive perampanel at doses of 8 mg and 12 mg per day, respectively, compared to 2% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and pediatric patients. These adverse reactions occurred mostly during the titration phase and led to discontinuation in 3% of perampanel-treated patients compared to 1% of placebo-treated patients. These adverse reactions were also observed in the primary generalized tonic-clonic seizure clinical trial. Somnolence and Fatigue Perampanel caused dose-dependent increases in somnolence and fatigue-related events (including fatigue, asthenia, and lethargy). In the controlled partial-onset seizure clinical trials, 16% and 18% of patients randomized to receive perampanel at doses of 8 mg and 12 mg per day, respectively, reported somnolence compared to 7% of placebo patients. In the controlled partial-onset seizure clinical trials, 12% and 15% of patients randomized to receive perampanel at doses of 8 mg and 12 mg per day, respectively, reported fatigue-related events compared to 5% of placebo patients. Somnolence or fatigue-related events led to discontinuation in 2% of perampanel-treated patients and 0.5% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and pediatric patients. In the controlled partial-onset seizure clinical trials, these adverse reactions occurred mostly during the titration phase. These adverse reactions were also observed in the primary generalized tonic-clonic seizure clinical trial. Risk Amelioration Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of perampanel is known. Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when perampanel is used with other drugs with sedative properties because of potential additive effects. 5.4 Falls An increased risk of falls, in some cases leading to serious injuries including head injuries and bone fracture, occurred in patients being treated with perampanel (with and without concurrent seizures). In the controlled partial-onset seizure clinical trials, falls were reported in 5% and 10% of patients randomized to receive perampanel at doses of 8 mg and 12 mg per day, respectively, compared to 3% of placebo-treated patients. Falls were reported as serious and led to discontinuation more frequently in perampanel-treated patients than placebo-treated patients. Elderly patients had an increased risk of falls compared to younger adults and pediatric patients. 5.5 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including perampanel. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Perampanel should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 5.6 Withdrawal of Antiepileptic Drugs There is the potential of increased seizure frequency in patients with seizure disorders when antiepileptic drugs are withdrawn abruptly. Perampanel has a half-life of approximately 105 hours so that even after abrupt cessation, blood levels fall gradually. In epilepsy clinical trials perampanel was withdrawn without down-titration. Although a small number of patients exhibited seizures following discontinuation, the data were not sufficient to allow any recommendations regarding appropriate withdrawal regimens. A gradual withdrawal is generally recommended with antiepileptic drugs, but if withdrawal is a response to adverse events, prompt withdrawal can be considered.

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) ] .

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) and Clinical Studies (14.1) ] . Use of perampanel for the treatment of partial-onset seizures in pediatric patients 4 years to less than 12 years of age is supported by evidence from adequate and well-controlled studies of perampanel in patients 12 years of age and older with partial onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data in 225 pediatric patients 4 years to less than 12 years of age treated with perampanel [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] . The safety and efficacy of perampanel for the adjunctive therapy of primary generalized tonic-clonic seizures in pediatric patients 12 years of age and older was established in a single randomized double-blind, placebo-controlled, multicenter trial (n=164), which included 11 pediatric patients 12 to 16 years of age exposed to perampanel; an additional 6 patients were treated with perampanel in the open-label extension of the study [see Clinical Studies (14.2) ] . The safety and effectiveness of perampanel for the treatment of partial-onset seizures in pediatric patients less than 4 years of age or for the treatment of primary generalized tonic-clonic seizures in pediatric patients less than 12 years of age have not been established. Juvenile Animal Data Oral administration of perampanel (1 mg/kg/day, 3 mg/kg/day, 3/10/30 mg/kg/day; high dose increased on postnatal days [PND] 28 and 56) to young rats for 12 weeks starting on PND 7 resulted in reduced body weight, reduced growth, neurobehavioral impairment (water maze performance and auditory startle habituation) at the mid and high doses, and delayed sexual maturation at the high doses. CNS signs (reduced activity, incoordination, excessive grooming/scratching), pup death, decreased hindlimb splay, and decreased hindlimb grip strength were observed at all doses. Effects on pup body weight, pup growth, hindlimb splay, impairment in the water maze performance, and auditory startle persisted after dosing was stopped. A no-effect dose for postnatal developmental toxicity was not identified in this study. Oral administration of perampanel (1 mg/kg/day, 5 mg/kg/day, 5/10 mg/kg/day; high dose increased on PND 56) to juvenile dogs for 33 weeks, starting on PND 42, resulted in CNS signs (incoordination, excessive grooming/licking/scratching, spatial disorientation, and/or ataxic gait) at all doses tested. 8.5 Geriatric Use Clinical studies of perampanel did not include sufficient numbers of patients aged 65 and over to determine the safety and efficacy of perampanel in the elderly population. Because of increased likelihood for adverse reactions in the elderly, dosing titration should proceed slowly in patients aged 65 years and older [see Dosage and Administration (2.5) ]. 8.6 Hepatic Impairment Use of perampanel in patients with severe hepatic impairment is not recommended, and dosage adjustments are recommended in patients with mild or moderate hepatic impairment [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ]. 8.7 Renal Impairment Dose adjustment is not required in patients with mild renal impairment. Perampanel should be used with caution in patients with moderate renal impairment, and slower titration may be considered. Use in patients with severe renal impairment or patients undergoing hemodialysis is not recommended [see Dosage and Administration (2.5) , Clinical Pharmacology (12.3) ].

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 ).

8.4 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) and Clinical Studies (14.1) ] . Use of perampanel for the treatment of partial-onset seizures in pediatric patients 4 years to less than 12 years of age is supported by evidence from adequate and well-controlled studies of perampanel in patients 12 years of age and older with partial onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data in 225 pediatric patients 4 years to less than 12 years of age treated with perampanel [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] . The safety and efficacy of perampanel for the adjunctive therapy of primary generalized tonic-clonic seizures in pediatric patients 12 years of age and older was established in a single randomized double-blind, placebo-controlled, multicenter trial (n=164), which included 11 pediatric patients 12 to 16 years of age exposed to perampanel; an additional 6 patients were treated with perampanel in the open-label extension of the study [see Clinical Studies (14.2) ] . The safety and effectiveness of perampanel for the treatment of partial-onset seizures in pediatric patients less than 4 years of age or for the treatment of primary generalized tonic-clonic seizures in pediatric patients less than 12 years of age have not been established. Juvenile Animal Data Oral administration of perampanel (1 mg/kg/day, 3 mg/kg/day, 3/10/30 mg/kg/day; high dose increased on postnatal days [PND] 28 and 56) to young rats for 12 weeks starting on PND 7 resulted in reduced body weight, reduced growth, neurobehavioral impairment (water maze performance and auditory startle habituation) at the mid and high doses, and delayed sexual maturation at the high doses. CNS signs (reduced activity, incoordination, excessive grooming/scratching), pup death, decreased hindlimb splay, and decreased hindlimb grip strength were observed at all doses. Effects on pup body weight, pup growth, hindlimb splay, impairment in the water maze performance, and auditory startle persisted after dosing was stopped. A no-effect dose for postnatal developmental toxicity was not identified in this study. Oral administration of perampanel (1 mg/kg/day, 5 mg/kg/day, 5/10 mg/kg/day; high dose increased on PND 56) to juvenile dogs for 33 weeks, starting on PND 42, resulted in CNS signs (incoordination, excessive grooming/licking/scratching, spatial disorientation, and/or ataxic gait) at all doses tested.