Chain Drug Review, April 29, 2019

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 In two studies in pediatric patients 4 to 12 years with epilepsy a total of 225 patients received FYCOMPA 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 were similar to those seen in patients 12 years 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 tonicclonic 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 11 kg 25 lbs compared to an average of 03 kg 07 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 91 and 09 respectively as compared to 45 and 02 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 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 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 DRUG INTERACTIONS Contraceptives With concomitant use FYCOMPA at a dose of 12 mg per day reduced levonorgestrel exposure by approximately 40 Use of FYCOMPA with contraceptives containing levonorgestrel may render them less effective Additional non hormonal forms of contraception are recommended Moderate and Strong CYP3A4 Inducers The concomitant use of known moderate and strong CYP3A4 inducers including carbamazepine phenytoin or oxcarbazepine with FYCOMPA decreased the plasma levels of perampanel by approximately 50 67 The starting doses for FYCOMPA should be increased in the presence of moderate or strong CYP3A4 inducers When these moderate or strong CYP3A4 inducers are introduced or withdrawn from a patients treatment regimen the patient should be closely monitored for clinical response and tolerability Dose adjustment of FYCOMPA may be necessary 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 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 USE IN SPECIFIC POPULATIONS 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 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 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 lowes tdose tested 1mg 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 1mg kg day is approximately 2 times a human dose of 8mg 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 per day based on body surface area mg m2 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 excreted 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 mothers clinical need for FYCOMPA and any potential adverse effects on the breastfed child from FYCOMPA or from the underlying maternal condition 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 Pediatric Use Safety and effectiveness of FYCOMPA for the treatment of partial onset seizures have been established in pediatric patients 4 years The safety and effectiveness of FYCOMPA in patients 12 years was established by three randomized double blind placebo controlled multicenter studies which included 72 pediatric patients between 12 and 16 years exposed to FYCOMPA Use of FYCOMPA for the treatment of partial onset seizures in pediatric patients 4 to 12 years is supported by evidence from adequate and well controlled studies of FYCOMPA in patients aged 12 years with partial onset seizures pharmacokinetic data from adult and pediatric patients and safety data in 225 pediatric patients 4 to 12 years treated with FYCOMPA The safety and efficacy of FYCOMPA for the adjunctive therapy of primary generalized tonic clonic seizures in pediatric patients 12 years was established in a single randomized double blind placebo controlled multicenter trial n 164 which included 11 pediatric patients 12 to 16 years 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 for the treatment of partial onset seizures in pediatric patients 4 years or for the treatment of primary generalized tonicclonic seizures in pediatric patients 12 years have not been established 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 55 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 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 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 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 DRUG ABUSE AND DEPENDENCE Controlled Substance FYCOMPA contains perampanel and is listed as a Schedule III controlled substance 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 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 15 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 FYCOMPAs 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 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 FYCOMPA may cause dependence and withdrawal symptoms that may include anxiety nervousness irritability fatigue lethargy asthenia mood swings and insomnia 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 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 FYCOMPA Dose 12 mg Group and More Frequent than Placebo cont FYCOMPA is a registered trademark of Eisai R D Management CO Ltd licensed to Eisai Inc 2018 Eisai Inc FYCO US2484 October 2018