Included as part of the "PRECAUTIONS" Section
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].
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].
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.
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
||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
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.
Dizziness And Gait Disturbance
FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination [see ADVERSE REACTIONS]. 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
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.
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.
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.
Drug Reaction With Eosinophilia And Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including FYCOMPA. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. FYCOMPA should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Administration Of Oral Suspension
Advise patients who are prescribed the oral suspension to shake the bottle well before every administration and to use the adaptor and oral dosing syringe provided. Advise patients that a household teaspoon or tablespoon is not an adequate measuring device. Instruct patients to discard any unused FYCOMPA oral suspension remaining 90 days after first opening the bottle [see DOSAGE AND ADMINISTRATION].
Serious Psychiatric And Behavioral Reactions
Counsel patients, families, and caregivers of patients of the need to monitor for the emergence of anger, aggression, hostility, hallucinations, delusions, confusion, unusual changes in mood, personality, or behavior, and other behavioral symptoms. Advise them to report any such symptoms immediately to their healthcare providers [see WARNINGS AND PRECAUTIONS].
Suicidal Thinking And Behavior
Counsel patients, their caregivers, and families that AEDs, including FYCOMPA, may increase the risk of suicidal thinking and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self -harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to healthcare providers [see WARNINGS AND PRECAUTIONS].
Dizziness, Gait Disturbance, Somnolence, and Fatigue
Counsel patients that FYCOMPA may cause dizziness, gait disturbance, somnolence, and fatigue. Advise patients taking FYCOMPA not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with FYCOMPA [see WARNINGS AND PRECAUTIONS].
Counsel patients that FYCOMPA may cause falls and injuries [see WARNINGS AND PRECAUTIONS].
Instruct patients that a fever associated with signs of other organ system involvement (e.g., rash, lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately [see WARNINGS AND PRECAUTIONS].
Withdrawal Of Antiepileptic Drugs
Counsel patients that abrupt discontinuation of FYCOMPA may increase seizure frequency [see WARNINGS AND PRECAUTIONS].
Counsel females of reproductive potential that FYCOMPA may decrease efficacy of contraceptives containing levonorgestrel, and advise them to use an additional non-hormonal form of contraception while using FYCOMPA and for a month after discontinuation [see DRUG INTERACTIONS , Use In Specific Populations].
Alcohol And Other CNS Depressants
Counsel patients that FYCOMPA may enhance the impairment effects of alcohol. These effects may also be seen if FYCOMPA is taken with other CNS depressants [see DRUG INTERACTIONS].
Counsel patients that if they miss a dose, they should resume dosing the following day at their prescribed daily dose. Instruct patients to contact their physician if more than one day of dosing is missed.
Counsel patients that FYCOMPA is a controlled substance that can be misused and abused [see Drug Abuse And Dependence].
Advise women who are exposed to FYCOMPA during pregnancy that there is a pregnancy exposure registry that monitors pregnancy outcomes. Encourage these patients to enroll in the NAAED Pregnancy Registry [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, And Impairment Of Fertility
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.
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.
Use In Specific Populations
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.
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.
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).
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.
Females And Males Of Reproductive Potential
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 , CLINICAL PHARMACOLOGY].
Safety and effectiveness of FYCOMPA for the treatment of partial-onset seizures have been established in pediatric patients 4 years of age and older.
The safety and effectiveness of FYCOMPA in patients 12 years of age and older was established by three randomized double-blind, placebo-controlled, multicenter studies, which included 72 pediatric patients between 12 and 16 years of age exposed to FYCOMPA [see CLINICAL PHARMACOLOGY and Clinical Studies]. Use of FYCOMPA for the treatment of partial-onset seizures in pediatric patients 4 years to less than 12 years of age is supported by evidence from adequate and well-controlled studies of FYCOMPA in patients 12 years of age and older with partial onset seizures, pharmacokinetic data from adult and pediatric patients, and safety data in 225 pediatric patients 4 years to less than 12 years of age treated with FYCOMPA [see ADVERSE REACTIONS and CLINICAL PHARMACOLOGY].
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 [see Clinical Studies].
The safety and effectiveness of FYCOMPA for the treatment of partial-onset seizures in pediatric patients less than 4 years of age or for the treatment of primary generalized tonic-clonic seizures in pediatric patients less than 12 years of age have not been established.
Juvenile Animal Data
Oral administration of perampanel (1, 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.
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].
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 , CLINICAL PHARMACOLOGY].
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 , CLINICAL PHARMACOLOGY].