Innovations In Clinical Neuroscience

Current Trends in Epilepsy 2015

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FYCOMPA ® is a registered trademark of Eisai R&D Management CO., Ltd., licensed to Eisai Inc. Manufactured and marketed by Eisai Inc., 100 Tice Blvd., Woodcliff Lake, NJ 07677 ©2015 Eisai Inc. All rights reserved. FYCO-US0112 July 2015 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 t onic-clonic seizures (Study 4). Approximately 57% of patients were female, and the mean age was 2 7 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 r eceiving 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%) a nd dizziness (2%). Table 3. Adverse Reactions in a Placebo-Controlled Trial in Patients with Primary Generalized T onic-Clonic Seizures (Study 4) (Reactions ≥ 4% of Patients in FYCOMPA Group and More Frequent than Placebo) P lacebo n=82 % FYCOMPA 8 mg n=81 % D izziness 6 32 Fatigue 6 15 Headache 10 12 S omnolence 4 11 Irritability 2 11 Vertigo 2 9 Vomiting 2 9 Weight gain 4 7 C ontusion 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. 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). DRUG INTERACTIONS 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 oral or implant contraceptives containing levonorgestrel may render them less effective. Additional non-hormonal forms of contraception are recommended. 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. 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. U SE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. In a nimal studies, perampanel induced developmental toxicity in pregnant rat and rabbit at clinically relevant d oses. FYCOMPA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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 t ested. 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) i s similar to a human dose of 8 mg per day based on body surface area (mg/m 2 ) . Upon oral administration of perampanel (1, 3, or 10 mg/kg per day) to pregnant rabbits throughout organogenesis, embryo lethality was observed at the mid and high doses tested; the no-effect dose for embryo-fetal developmental toxicity i n rabbit (1 mg/kg/day) is approximately 2 times a human dose of 8 mg per day based on body surface area (mg/m 2 ) . Oral administration of perampanel (1, 3, or 10 mg/kg per day) to rats throughout gestation and lactation resulted in fetal and pup deaths at the mid and high doses and delayed sexual maturation in males and females at the highest dose tested. No effects were observed on measures of neurobehavioral or r eproductive 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/m 2 ) . Pregnancy Registry To provide information regarding the effects of in utero exposure to FYCOMPA, physicians are advised to recommend that pregnant patients taking FYCOMPA enroll in the North American Antiepileptic D rug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website: Nursing Mothers Perampanel and/or its metabolites are excreted in r at milk, and are detected at concentrations higher than that in maternal plasma. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FYCOMPA is administered to a nursing woman. Pediatric Use The safety and efficacy of F YCOMPA 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 7 2 pediatric patients between 12 and 16 years of age exposed to FYCOMPA. The safety and efficacy of F YCOMPA 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 w eeks 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 m aturation at the high doses. CNS signs (reduced activity, incoordination, excessive grooming/scratching), p up 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 a uditory 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 i ncreased 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 [see Dosage and Administration (2.5)]. 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)]. 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)]. 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) [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 T max 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%). Dependence Physical dependence is characterized by withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. The potential for FYCOMPA to produce withdrawal symptoms has not been adequately evaluated. 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 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.)

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