FYCOMPA(perampanel)tablet/suspension,吡仑帕奈片/口服悬液与吡仑帕奈试剂盒-获美国批准扩大治疗癫痫的新适应症 近日，美国食品和药物管理局已批准扩大抗癫痫药物（AED）吡仑帕奈水合物（Fycompa）的适应症，作为12岁及以上癫痫患者原发性全面强直-阵挛（PGTC）癫痫发作的辅助治疗。 吡仑帕奈是一种新型高选择性AMPA受体拮抗剂，于2012年首次批准用于12岁及以上癫痫患者部分性癫痫发作（有或无继发性全身性癫痫发作）的辅助治疗。 FDA的药物评价和研究中心神经学产品部主任Russell Katz，M.D.说“某些有癫痫人从当前所用治疗没有实现满意癫痫控制，”“对癫痫患者重要是得到各种各样治疗选择。” 扩大PGTC新适应症是基于一项3期研究结果，涉及经1-3种AEDs药物治疗但仍伴有PGTC发作的164例12岁及以上患者。患者接受吡仑帕奈口服片剂治疗，每日一次。 研究显示，相比于安慰剂，吡仑帕奈可显著降低PGTC发作频率（–76.5% vs -38.4%; P< .0001）。 此外，吡仑帕奈的治疗应答率显著高于安慰剂（64.2% vs 39.5%; P = .0019）。在13周的维持期内，约31%接受吡仑帕奈治疗的患者未发生PGTC发作，而安慰剂组只有12%。 吡仑帕奈最常见的不良反应事件包括头晕（32%）、疲劳（15%）、头痛（12%）、困倦（11%)）和烦躁不安（11%）。 Eisai公司在一次新闻发布会上称，癫痫影响着约290万例美国人，且约30%的癫痫患者使用当前市售的AEDs无法控制病情。 该公司指出，PGTC发作是癫痫最严重的症状之一，会导致因突然跌倒而造成的重大损伤，是突发癫痫死亡（SUDEP）的最重要危险因素。“通过扩大这一适应症，Fycompa现在可以作为原发性（继发性除外）全面强直-阵挛发作的辅助治疗。” 批准日期：2015年6月22日；公司：Eisai Inc.公司 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FYCOMPA ®safely and effectively. See full prescribing information for FYCOMPA ® . FYCOMPA ®   (perampanel) t ablets , for oral use ,   CIII FYCOMPA ® (perampanel) o ral s uspension , CIII Initial U.S. Approval: 20 12 WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS See full prescribing information for complete boxed warning. Serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats have been reported in patients taking FYCOMPA (5.1) Monitor patients for these reactions as well as for changes in mood, behavior, or personality that are not typical for the patient, particularly during the titration period and at higher doses (5.1) FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening (5.1) RECENT MAJOR CHANGES Indications and Usage (1.2)                  06/2015 Dosage and Administration (2.7)         04/2016 INDICATIONS AND USAGE FYCOMPA, a non-competitive AMPA glutamate receptor antagonist, is indicated as adjunctive therapy for the treatment of:  Partial-Onset Seizures with or without secondarily generalized seizures in patients with epilepsy 12 years of age and older (1.1) Primary Generalized Tonic-Clonic Seizures in patients with epilepsy 12 years of age and older (1.2) DOSAGE AND ADMINISTRATION Dosing in the absence of enzyme-inducing antiepileptic drugs (AEDs) 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: Partial-Onset Seizures – 8 to 12 mg once daily at bedtime; Primary Generalized Tonic-Clonic Seizures – 8 mg once daily at bedtime (2.1, 2.2) Individual dosing should be adjusted based on clinical response and tolerability Measure oral suspension using provided adaptor and dosing syringe (2.7) Dosing in the presence of concomitant enzyme-inducing AEDs: 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) DOSAGE FORMS AND STRENGTHS Tablets: 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg (3) Oral Suspension: 0.5 mg/mL (3) CONTRAINDICATIONS None (4) 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) Withdrawal of Antiepileptic Drugs: In patients with epilepsy, there may be an increase in seizure frequency (5.5) ADVERSE REACTIONS 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 Eisai at 1-888-274-2378 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS Contraceptives: 12 mg once daily may decrease the effectiveness of hormonal contraceptives containing levonorgestrel (7.1) Cytochrome P450 Inducers: Carbamazepine, oxcarbazepine, and phenytoin increase clearance of perampanel and decrease perampanel plasma concentrations and decrease FYCOMPA’s effectiveness. When these or related enzyme-inducing AEDs are introduced or withdrawn, patients should be closely monitored. Dose adjustment of FYCOMPA may be necessary (7.2) Strong CYP3A Inducers Other than AEDs (e.g., rifampin, St. John’s wort): concomitant use is not recommended (7.2) USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 4/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Partial-Onset Seizures FYCOMPA is indicated as adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy 12 years of age and older. 1.2 Primary Generalized Tonic-Clonic Seizures FYCOMPA is 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 2.1 Dosage for Partial-Onset Seizures In patients not receiving concomitant enzyme-inducing antiepileptic drugs (AEDs), the recommended starting dosage of FYCOMPA is 2 mg once daily taken orally at bedtime. Increase dosage by increments of 2 mg once daily no more frequently than at weekly intervals. The recommended maintenance dose range is 8 mg to 12 mg once daily in the absence of enzyme-inducing AEDs, 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. Individual dosing should be adjusted based on clinical response and tolerability [see Clinical Studies (14.1)]. 2.2 Dosage for Primary Generalized Tonic-Clonic Seizures In patients not receiving concomitant enzyme-inducing AEDs, the recommended starting dosage of FYCOMPA is 2 mg once daily taken orally at bedtime. Increase dosage by increments of 2 mg once daily no more frequently than at weekly intervals. In patients not taking enzyme-inducing AEDs, the recommended maintenance dose is 8 mg once daily taken at bedtime. Patients who are tolerating FYCOMPA 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. Individual dosing should be adjusted based on clinical response and tolerability [see Clinical Studies (14.2)]. 2.3 Dosing in the Presence of Concomitant Enzyme-Inducing Antiepileptic Drugs (AEDs) Enzyme-inducing AEDs, including phenytoin, carbamazepine, and oxcarbazepine, cause a 50-67% reduction in FYCOMPA plasma levels [see Drug Interactions (7.2), Clinical Pharmacology (12.3)]. In patients receiving concomitant enzyme-inducing AEDs, the recommended starting dosage of FYCOMPA is 4 mg once daily taken orally at bedtime. Increase dosage by increments of 2 mg once daily 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. Individual dosing should be adjusted based on clinical response and tolerability. When enzyme-inducing AEDs are introduced or withdrawn from a patient’s treatment regimen, the patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary.   2.4 Dosage Adjustment in Patients with Hepatic Impairment In patients with mild and moderate hepatic impairment, the starting dose of FYCOMPA 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. FYCOMPA 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 FYCOMPA can be used in patients with moderate renal impairment with close monitoring. A slower titration may be considered, based on clinical response and tolerability. FYCOMPA is 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)]. 2.7 Administration of Oral Suspension FYCOMPA oral suspension, 0.5 mg/mL, should be shaken well before every administration.  The provided adapter and graduated oral dosing syringe should be used to administer the oral suspension. A household teaspoon or tablespoon is not an adequate measuring device. The adapter, which is supplied in the product carton, should be inserted firmly into the neck of the bottle before use and remain in place for the duration of the usage of the bottle. The dosing syringe should be inserted into the adapter and the dose withdrawn from the inverted bottle. The cap should be replaced after each use. The cap fits properly when the adapter is in place [see Instructions for Use]. Discard any unused FYCOMPA oral suspension remaining 90 days after first opening the bottle. 3 DOSAGE FORMS AND STRENGTHS Tablets 2 mg tablets: orange, round, debossed with “2” on one side and “Є 275” on the other. 4 mg tablets: red, round, debossed with “4” on one side and “Є 277” on the other. 6 mg tablets: pink, round, debossed with “6” on one side and “Є 294” on the other. 8 mg tablets: purple, round, debossed with “8” on one side and “Є 295” on the other. 10 mg tablets: green, round, debossed with “10” on one side and “Є 296” on the other. 12 mg tablets: blue, round, debossed with “12” on one side and “Є 297” on the other.  Oral Suspension 0.5 mg/mL white to off-white opaque liquid suspension for oral administration. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 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 FYCOMPA 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. FYCOMPA-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 FYCOMPA than in patients taking placebo. These events included irritability, aggression, anger, and anxiety, which occurred in 2% or greater of FYCOMPA-treated patients and twice as frequently as in placebo-treated patients. Other symptoms that occurred with FYCOMPA 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 FYCOMPA-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 FYCOMPA. 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 FYCOMPA significantly worsened mood and increased anger. Patients taking FYCOMPA 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 FYCOMPA, 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 FYCOMPA [see Adverse Reactions (6.2)].  Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least 1 month after the last dose of FYCOMPA, 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 FYCOMPA should be reduced if these symptoms occur. Permanently discontinue FYCOMPA for persistent severe or worsening psychiatric symptoms or behaviors and refer for psychiatric evaluation. 5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including FYCOMPA, 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 (5-100 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 FYCOMPA 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  FYCOMPA 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 FYCOMPA 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 FYCOMPA 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 FYCOMPA-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 FYCOMPA 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 FYCOMPA 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 FYCOMPA 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 FYCOMPA-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 FYCOMPA is known. 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 FYCOMPA (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 FYCOMPA 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 FYCOMPA-treated patients than placebo-treated patients. Elderly patients had an increased risk of falls compared to younger adults and pediatric patients. 5.5 Withdrawal of Antiepileptic Drugs There is the potential of increased seizure frequency in patients with seizure disorders when antiepileptic drugs are withdrawn abruptly. FYCOMPA has a half-life of approximately 105 hours so that even after abrupt cessation, blood levels fall gradually. In epilepsy clinical trials FYCOMPA 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)] 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 A total of 1,038 patients receiving FYCOMPA (2, 4, 8, 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 FYCOMPA 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 FYCOMPA 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 FYCOMPA 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 FYCOMPA 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 Patients with Partial-Onset Seizures (Studies 1, 2, and 3) (Reactions ≥ 2% of Patients in Highest FYCOMPA Dose (12 mg) Group and More Frequent than Placebo) Placebo n=442 % FYCOMPA 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 Primary Generalized Tonic-Clonic Seizures A total of 81 patients receiving FYCOMPA 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 FYCOMPA 8 mg (≥4% and higher than in the placebo group) in Study 4. The most common adverse reactions in patients receiving FYCOMPA (≥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 FYCOMPA 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 FYCOMPA Group and More Frequent than Placebo) Placebo n=82 % FYCOMPA 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 FYCOMPA.   In controlled partial-onset seizure clinical trials, FYCOMPA-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 FYCOMPA-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 pediatric patients treated with FYCOMPA in the primary generalized tonic-clonic seizure clinical trial. Elevated triglycerides Increases in triglycerides have occurred with FYCOMPA 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 FYCOMPA. 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) Psychiatric: Acute psychosis, hallucinations, delusions, paranoia, delirium, confusional state, disorientation, memory impairment [see Warnings and Precautions (5.1)].  7 DRUG INTERACTIONS 7.1 Contraceptives With concomitant use, FYCOMPA at a dose of 12 mg per day reduced levonorgestrel exposure by approximately 40% [see Clinical Pharmacology (12.3)]. Use of FYCOMPA 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 Cytochrome P450 Inducers The concomitant use of known cytochrome P450 (CYP) enzyme inducers including carbamazepine, phenytoin, or oxcarbazepine with FYCOMPA decreased the plasma levels of perampanel by approximately 50-67% [see Clinical Pharmacology (12.3)]. The starting doses for FYCOMPA should be increased in the presence of enzyme-inducing AEDs [see Dosage and Administration (2.3)]. When these enzyme-inducing AEDs are introduced or withdrawn from a patient’s treatment regimen, the patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary [see Dosage and Administration (2.3)]. Concomitant use of FYCOMPA with other strong CYP3A inducers (e.g., rifampin, St. John’s wort) is not recommended. 7.3 Alcohol and Other CNS Depressants The concomitant use of FYCOMPA and CNS depressants including alcohol may increase CNS depression. A pharmacodynamic interaction study in healthy subjects found that the effects of FYCOMPA 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 FYCOMPA 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 FYCOMPA is used in combination with other CNS depressants. Care should be taken when administering FYCOMPA 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 FYCOMPA to gauge whether it adversely affects these activities. 8 USE IN SPECIFIC POPULATIONS 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 FYCOMPA, during pregnancy. Encourage women who are taking FYCOMPA 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 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of perampanel (1, 3, 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, 30, 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/m2). Upon oral administration of perampanel (1, 3, 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/m2). Oral administration of perampanel (1, 3, 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/m2). 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 FYCOMPA and any potential adverse effects on the breastfed child from FYCOMPA or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Contraception Use of FYCOMPA may reduce the efficacy of hormonal contraceptives containing levonorgestrel. Advise women taking FYCOMPA who are using a levonorgestrel-containing contraceptive to use an additional non-hormonal form of contraception while using FYCOMPA and for a month after discontinuation [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and efficacy of FYCOMPA for the adjunctive therapy of partial-onset seizures in pediatric 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 FYCOMPA. The safety and efficacy of FYCOMPA 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 FYCOMPA; an additional 6 patients were treated with FYCOMPA in the open label extension of the study. The safety and effectiveness of FYCOMPA in pediatric patients less than 12 years of age have not been established [see Clinical Pharmacology (12.3), Clinical Studies (14.1)]. Juvenile Animal Data Oral administration of perampanel (1, 3, 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, 5, 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 FYCOMPA did not include sufficient numbers of patients aged 65 and over to determine the safety and efficacy of FYCOMPA 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 FYCOMPA 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. FYCOMPA 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)]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance FYCOMPA contains perampanel and is listed as a Schedule III controlled substance. 9.2 Abuse Prescription drug abuse is the intentional non-therapeutic use of a drug, even once, for its rewarding psychological or physiological effects. Drug addiction, which develops after repeated drug abuse, is characterized by a strong desire to take a drug despite harmful consequences, difficulty in controlling its use, giving a higher priority to drug use than to obligations, increased tolerance, and sometimes physical withdrawal. Drug abuse and drug addiction are separate and distinct from physical dependence (for example, abuse may not be accompanied by physical dependence) [see Drug Abuse and Dependence (9.3)]. Studies of human abuse potential were performed to evaluate the abuse potential of FYCOMPA (8 mg, 24 mg, and 36 mg) as compared to alprazolam C-IV (1.5 mg and 3 mg), and oral ketamine C-III (100 mg) in recreational polydrug users. Supra-therapeutic doses of FYCOMPA 24 and 36 mg produced responses for “Euphoria” that were similar to ketamine 100 mg and alprazolam 3 mg. For “High,” FYCOMPA 24 mg and 36 mg produced responses comparable to ketamine 100 mg and significantly higher than both doses of alprazolam on a visual analog scale (VAS). “Drug Liking,” “Overall Drug Liking,” and “Take Drug Again” for FYCOMPA were each statistically lower than ketamine 100 mg. In addition, for “Bad Drug Effects,” FYCOMPA 24 mg and 36 mg produced responses significantly higher than ketamine 100 mg. For “Sedation,” FYCOMPA 24 and 36 mg produced responses similar to alprazolam 3 mg and higher than ketamine 100 mg. Additionally, on VAS measures related to dissociative phenomena such as “Floating,” “Spaced Out,” and “Detached,” FYCOMPA at supra-therapeutic doses produced responses similar to ketamine 100 mg and greater than both doses of alprazolam tested. Of note, due to somnolence a number of subjects had missing data around Tmax of FYCOMPA. The above described data might represent an underestimate of FYCOMPA’s effects. The duration of effects of higher doses of FYCOMPA on the majority of measures was much greater than alprazolam 3 mg and ketamine 100 mg. In this study, the incidence of euphoria following FYCOMPA administration 8 mg, 24 mg, and 36 mg was 37%, 46%, 46%, respectively, which was higher than alprazolam 3 mg (13%) but lower than ketamine 100 mg (89%). 9.3 Dependence Physical dependence is characterized by withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. A nonclinical dependence study in rats demonstrated withdrawal symptoms, including hyperreactivity to handling, muscle rigidity, and decreases in food consumption and body weights. The potential for FYCOMPA to produce withdrawal symptoms in humans has not been adequately evaluated. 10 OVERDOSAGE There is limited clinical experience with FYCOMPA overdose. The highest reported overdose (approximately 264 mg) was intentional. This patient experienced serious adverse reactions of altered mental status, agitation, and aggressive behavior and recovered without sequelae. In general, the adverse reactions associated with overdoses were similar to the reactions at therapeutic doses with dizziness reported most frequently. There were no reported sequelae. There is no available specific antidote to the overdose reactions of FYCOMPA. 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 FYCOMPA. Due to its long half-life, the reactions caused by FYCOMPA could be prolonged.  11 DESCRIPTION FYCOMPA tablets and oral suspension contain perampanel a non-competitive AMPA receptor antagonist as a 4:3 hydrate. The chemical name of the active ingredient is 2-(1′,6′-dihydro-6′-oxo-1′-phenyl[2,3′-bipyridin]-5′-yl)-benzonitrile, hydrate (4:3). The molecular formula is C23H15N3O • ¾H2O 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 1-methyl-2-pyrrolidinone, sparingly soluble in acetonitrile and acetone, slightly soluble in methanol, ethanol and ethyl acetate, very slightly soluble in 1-octanol and diethyl ether, and practically insoluble in heptane and water. The chemical structure is: Tablets FYCOMPA 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, povidone, microcrystalline cellulose, magnesium stearate, hypromellose, polyethylene glycol, talc, and titanium dioxide. Tablets of different strengths may contain yellow ferric oxide (10 mg and 2 mg), red ferric oxide (2 mg, 4 mg, 6 mg, 8 mg), black ferric oxide (8 mg), and FD&C Blue No. 2 (indigo carmine) aluminum lake (10 mg and 12 mg). Oral Suspension FYCOMPA oral suspension is a white to off-white opaque liquid providing perampanel in a concentration of 0.5 mg/mL. The oral suspension contains the following inactive ingredients: sorbitol, microcrystalline cellulose, carboxymethyl-cellulose sodium, poloxamer, simethicone, citric acid, sodium benzoate and purified water. 12 CLINICAL PHARMACOLOGY 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 FYCOMPA exerts its antiepileptic effects in humans is unknown. 12.2 Pharmacodynamics Psychomotor Performance In a healthy volunteer study to assess the effects of FYCOMPA tablets on psychomotor performance using a standard battery of assessments including simulated driving, single and multiple daily doses of FYCOMPA 4 mg did not impair simple psychomotor tasks, driving performance, or sensorimotor coordination. Single and multiple doses of 8 mg and 12 mg impaired psychomotor performance in a dose-related manner. Car handling ability was impaired after dosing of FYCOMPA 12 mg, but postural stability was not significantly impaired. Performance testing returned to baseline within 2 weeks of cessation of FYCOMPA dosing. Interactions with Alcohol In the above study (see Psychomotor Performance), when administered to healthy subjects receiving alcohol to achieve a blood concentration of 80-100 mg/100 mL, FYCOMPA consistently impaired simple psychomotor performance after single doses of 4 to 12 mg, and after 21 days of multiple 12 mg/day doses. The effects of FYCOMPA on complex tasks such as driving ability were additive or supra-additive to the impairment effects of alcohol. FYCOMPA enhanced the effects of alcohol on vigilance and alertness, and increased levels of anger, confusion, and depression. Potential to Prolong QT Interval In a placebo-controlled thorough QT study of perampanel in healthy subjects, there was no evidence that perampanel caused QT interval prolongation of clinical significance at doses of 6 or 12 mg (i.e., the upper bound of the 95% confidence interval for the largest placebo-adjusted baseline-corrected QTc was below 10 msec). The exposures observed with the 12 mg dose in this study will not cover the exposures expected in patients with hepatic impairment taking doses over 6 mg/day. At the highest recommended dose (12 mg), perampanel did not prolong the QTc interval to any clinically relevant extent. 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 2-3 weeks. AUC of perampanel increased in a dose-proportional manner after single-dose administration of 0.2-12 mg tablets and after multiple-dose administration of 1-12 mg tablets once daily. FYCOMPA oral suspension has comparable bioavailability to FYCOMPA tablets under steady state. Both formulations may be used interchangeably. Absorption Perampanel is rapidly and completely absorbed after oral administration with negligible first-pass metabolism. Median time to reach peak concentration (tmax) ranged from 0.5 to 2.5 hours under fasted condition. Co-administration of FYCOMPA tablet with a high fat meal had no impact on the total exposure (AUC0-inf) of perampanel and reduced the peak plasma concentration (Cmax) of perampanel by 11%-40%. The tmax was delayed by approximately 1-3 hours in fed state compared to that under fasted conditions. Distribution Data from in vitro studies indicate that, in the concentration range of 20 to 2000 ng/mL, perampanel is approximately 95-96% bound to plasma proteins, mainly bound to albumin and α1-acid glycoprotein. Blood to plasma ratio of perampanel is 0.55-0.59. 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 74-80% 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 t1/2 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 (AUC0-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 AUC0-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 t1/2 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 FYCOMPA 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 50-80 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 FYCOMPA 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 FYCOMPA has not been studied in patients less than 12 years of age. In a population pharmacokinetic analysis of pediatric patients 12 to 17 years of age with partial-onset seizures receiving FYCOMPA tablets in placebo-controlled trials, apparent clearance of perampanel was 0.729 L/hr, slightly higher than that in adults. Pediatric patients 12 years of age and older can be dosed similarly to adults. 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 FYCOMPA 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 FYCOMPA 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 Cmax 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 FYCOMPA: 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 Cmax and AUC0-inf of a single 2 mg tablet dose of perampanel by 26% and 67%, respectively. The t1/2 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 FYCOMPA on Concomitant AEDs: FYCOMPA 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. FYCOMPA 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). FYCOMPA 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 FYCOMPA 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 t1/2 by 15% (67.8 vs. 58.4 hours) and increased AUC0-inf by 20%. Contraceptives. Perampanel Cmax and AUC0-72h 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 FYCOMPA on Other Drugs Midazolam. Perampanel administered as 6 mg tablet once daily doses for 20 days decreased AUC0-inf and Cmax 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 Cmax or AUC0-24h 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 FYCOMPA 12 mg or 8 mg tablets in healthy females. FYCOMPA at 12 mg did not alter AUC0-24h of ethinylestradiol but decreased its Cmax by 18%, and also decreased Cmax and AUC0-24h of levonorgestrel by 42% and 40%, respectively. FYCOMPA at 8 mg did not have significant effect on Cmax or AUC0-24h of either ethinylestradiol or levonorgestrel, with a decrease in AUC0-24h 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 Cmax and AUC0-inf of levodopa in healthy subjects. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Perampanel was administered orally to mice (1, 3, 10, or 30 mg/kg/day) and rats (10, 30, or 100 mg/kg/day in males; 3, 10, or 30 mg/kg/day in females) for up to 104 weeks. There was no evidence of drug-related tumors in either species. Plasma perampanel exposures (AUC) at the highest doses tested were less than that in humans dosed at 8 mg/day. Mutagenesis Perampanel was negative in the in vitro Ames and mouse lymphoma tk assays, and in the in vivo rat micronucleus assay. Impairment of Fertility In male and female rats administered perampanel (oral doses of 1, 10, or 30 mg/kg/day) prior to and throughout mating and continuing in females to gestation day 6, there were no clear effects on fertility. Prolonged and/or irregular estrus cycles were observed at all doses but particularly at the highest dose tested. Plasma perampanel exposures (AUC) at all doses were lower than that in humans dosed at 8 mg/day.     14 CLINICAL STUDIES 14.1 Partial-Onset Seizures The efficacy of FYCOMPA in partial-onset seizures, with or without secondary generalization, was studied in patients who were not adequately controlled with 1 to 3 concomitant AEDs in 3 randomized, double-blind, placebo-controlled, multicenter trials (Studies 1, 2, and 3) in adult and pediatric patients (12 years of age and older). All trials had an initial 6-week Baseline Period, during which patients were required to have more than five seizures in order to be randomized. The Baseline Period was followed by a 19-week Treatment Period consisting of a 6-week Titration Phase and a 13-week Maintenance Phase. Patients in these 3 trials had a mean duration of epilepsy of approximately 21 years and a median baseline seizure frequency ranging from 9 to 14 seizures per 28 days. During the trials, more than 85% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation, and approximately 50% were on at least one AED known to induce CYP3A4, an enzyme critical to the metabolism of FYCOMPA (i.e., carbamazepine, oxcarbazepine, or phenytoin), resulting in a significant reduction in FYCOMPA’s serum concentration [see Drug Interactions (7.2), Clinical Pharmacology (12.3)]. Each study evaluated placebo and multiple FYCOMPA dosages (see Figure 1). During the Titration period in all 3 trials, patients on FYCOMPA received an initial 2 mg once daily dose, which was subsequently increased in weekly increments of 2 mg per day to the final dose. Patients experiencing intolerable adverse reactions were permitted to have their dose reduced to the previously tolerated dose. The primary endpoint in Studies 1, 2, and 3 was the percent change in seizure frequency per 28 days during the Treatment Period as compared to the Baseline Period. The criterion for statistical significance was p<0.05. A statistically significant decrease in seizure rate was observed at doses of 4 to 12 mg per day. Dose response was apparent at 4 to 8 mg with little additional reduction in frequency at 12 mg per day.  Figure 1. Median Percent Reduction in Seizure Frequency per 28 Days from Baseline to Treatment Period Tables 4 and 5 present an analysis combining data from all 3 studies, grouping patients based upon whether or not concomitant enzyme-inducing AEDs (carbamazepine, oxcarbazepine, or phenytoin) were used. The analysis revealed a substantially reduced effect in the presence of inducers. Table 4. Median Percent Reduction for Combined Studies (Study 1, 2 and 3) Based on the Presence or Absence of Concomitant Enzyme-Inducing AEDs (carbamazepine, oxcarbazepine, phenytoin)a Without Enzyme-Inducing AEDs With Enzyme-Inducing AEDs   Placebo % FYCOMPA % Placebo % FYCOMPA % 2 mg/day 16 23 14 16 4 mg/day 16 22 14 33 8 mg/day 19 45 12 24 12 mg/day 19 54 9 22 Patients from Latin American region are excluded because of a significant treatment-by-region interaction due to high placebo response Table 5. Responder Rate for Combined Studies (Study 1, 2 and 3) Based on the Presence or Absence of Concomitant Enzyme-Inducing AEDs (carbamazepine, oxcarbazepine, phenytoin) a,b Without Enzyme-Inducing AEDs With Enzyme-Inducing AEDs   Placebo % FYCOMPA % Placebo % FYCOMPA % 2 mg/day 19 26 18 20 4 mg/day 19 35 18 26 8 mg/day 17 45 19 32 12 mg/day 15 54 21 33 aPatients from Latin American region are excluded because of a significant treatment-by-region interaction due to high placebo response bThe proportion of patients with at least a 50% decrease in seizure frequency Figure 2 shows the proportion of patients with different percent reductions during the maintenance phase over baseline across all three trials. Patients in whom the seizure frequency increased are shown at left as “worse.” Patients in whom the seizure frequency decreased are shown in the remaining four categories. Figure 2. Proportion of Patients Exhibiting Different Percent Reductions During the Maintenance Phase Over Baseline Across All Three Trials. The percentages of patients with a 50% or greater reduction in seizure frequency were 19%, 29%, 35%, 35% for placebo, 4, 8, and 12 mg, respectively. 14.2 Primary Generalized Tonic-Clonic (PGTC) Seizures The efficacy of FYCOMPA as adjunctive therapy in patients 12 years of age and older with idiopathic generalized epilepsy experiencing primary generalized tonic-clonic seizures was established in one multicenter, randomized, double-blind, placebo-controlled study (Study 4), conducted at 78 sites in 16 countries. Eligible patients on a stable dose of 1 to 3 AEDs experiencing at least 3 primary generalized tonic-clonic seizures during the 8-week baseline period were randomized to either FYCOMPA or placebo. Efficacy was analyzed in 162 patients (FYCOMPA N=81, placebo N=81) who received medication and at least one post-treatment seizure assessment. Patients were titrated over 4 weeks up to a dose of 8 mg per day or the highest tolerated dose and treated for an additional 13 weeks on the last dose level achieved at the end of the titration period. The total treatment period was 17 weeks. Study drug was given once per day. The primary endpoint was the percent change from baseline in primary generalized tonic-clonic seizure frequency per 28 days during the treatment period as compared to the baseline period. The criterion for statistical significance was p<0.05. Table 6 shows the results of this study. A statistically significant decrease in seizure rate was observed with FYCOMPA compared to placebo. Table 6. Median Percent Reduction from Baseline in Primary Generalized Tonic-Clonic Seizure Frequency in Study 4 Placebo (N=81) FYCOMPA 8 mg (N=81) Percent Reduction During Treatment 38 76a a P-value compared to placebo: <0.0001. Statistically significant as compared to placebo based on ANCOVA with treatment and pooled country as factors and the ranked baseline seizure frequency per 28 days as a covariate.  Figure 3 shows the proportion of patients with different percent reductions during the maintenance phase over baseline in primary generalized tonic-clonic seizure frequency. Patients in whom the seizure frequency increased are shown at left as “worse.” Patients in whom the seizure frequency decreased are shown in the remaining four categories. Figure 3. Proportion of Patients Exhibiting Different Percent Reductions During the Maintenance Phase Over Baseline in Primary Generalized Tonic-Clonic Seizure Frequency. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied FYCOMPA Tablets 2 mg are orange, round, biconvex, film-coated tablets debossed with “2” on one side and “Є 275” on the other. They are supplied as follows: Bottles of 30       NDC 62856-272-30 Bottles of 90       NDC 62856-272-90 4 mg are red, round, biconvex, film-coated tablets debossed with “4” on one side and “Є 277” on the other. They are supplied as follows: Bottles of 30       NDC 62856-274-30 Bottles of 90       NDC 62856-274-90 6 mg are pink, round, biconvex, film-coated tablets debossed with “6” on one side and “Є 294” on the other. They are supplied as follows: Bottles of 30       NDC 62856-276-30 Bottles of 90       NDC 62856-276-90 8 mg are purple, round, biconvex, film-coated tablets debossed with “8” on one side and “Є 295” on the other. They are supplied as follows: Bottles of 30       NDC 62856-278-30 Bottles of 90       NDC 62856-278-90 10 mg are green, round, biconvex, film-coated tablets debossed with “10” on one side and “Є 296” on the other. They are supplied as follows: Bottles of 30       NDC 62856-280-30 Bottles of 90       NDC 62856-280-90 12 mg are blue, round, biconvex, film-coated tablets debossed with “12” on one side and “Є 297” on the other. They are supplied as follows: Bottles of 30       NDC 62856-282-30 Bottles of 90       NDC 62856-282-90 FYCOMPA Oral Suspension 0.5 mg/mL is a white to off-white opaque liquid. It is supplied in a round amber PET bottle with a child-resistant closure. It is packaged with a dispenser set that provides two 20-mL graduated oral dosing syringes and a push-in bottle adapter. Bottle containing 340 mL       NDC 62856-290-38 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] Oral Suspension: Do not store above 30°C (86°F). Do not freeze. Use within 90 days after the first opening of the bottle. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=71cf3309-e182-473c-8b0b-280cabd0e122 卫材新一代癫痫药物Fycompa口服悬液获FDA批准 2016年5月10日，日本药企卫材(Eisai)获FDA已批准新一代癫痫药物Fycompa(perampanel)口服混悬液，作为一种辅助疗法，用于12岁及以上癫痫患者部分发作性癫痫(有或无继发性全身性癫痫发作)和原发性全面强直阵挛(PGTC)癫痫发作的治疗。Fycompa口服混悬液剂型与Fycompa片剂剂型具有生物等效性和可互换性。卫材已计划在2016年6月将Fycompa口服混悬液推向美国市场，该药将为吞咽片剂可能存在困难或更倾向液体制剂的癫痫患者提供一种新的选择。 Fycompa口服混悬液的获批，是基于一项生物等效性研究的数据。该研究在健康受试者中开展，证实了空腹条件下，单剂量Fycompa口服混悬液和单剂量Fycompa片剂具有生物等效性。 Fycompa是由卫材内部研发的一种首创(first-in-class)的抗癫痫药物(AEDs)，该药是一种高度选择性、非竞争性的AMPA型谷氨酸受体拮抗剂。谷氨酸是介导癫痫发作的主要神经递质。作为AMPA受体拮抗剂，Fycompa能通过靶向突触后AMPA受体-谷氨酸的活动，减少与癫痫发作相关神经元的过度兴奋;这种作用机制与目前市售的抗癫痫药物(AEDs)不同。 目前，已上市Fycompa片剂规格包括2mg、4mg、6mg、8mg、10mg、12mg薄膜衣片，该药适应症为：作为一种辅助药物，用于12岁及以上癫痫患者部分性癫痫发作(有或无继发性全身性癫痫发作)和原发性全面强直阵挛(PGTC)癫痫发作的治疗。 癫痫(epilepsy)是全球最常见的神经系统疾病之一，在美国约有290万例患者，其中大约有30%的患者使用市售抗癫痫药物(AEDs)无法控制病情，因此该领域存在着巨大的医疗需求。原发性全面强直阵挛(PGTC)癫痫发作，即癫痫大发作(grand mal)，是癫痫最严重的症状之一，以意识丧失和全身抽搐为特征。发作可分四期。常见癫痫大发作症状主要有口吐白沫，两眼上翻，四肢抽搐，尖叫等严重会造成大小便失禁，持续发作等。癫痫发作是大脑神经元激发和抑制不平衡的结果，这些不平衡可能通过多种神经化学机制引发，但目前知之甚少。