AHFS Class:

• Anticonvulsants, Miscellaneous 28:12.92

Generic Name(s):

• Perampanel

Chemical Name:

• 2-(1',6'-Dihydro-6'-oxo-1'-phenyl[2,3'-bipyridin]-5'-yl)-benzonitrile

Molecular Formula:

• C₂₃H₁₅N₃O

Perampanel, a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor antagonist, is an anticonvulsant.1,2,3,4,14,15,16,19,22,23

Seizure Disorders

Partial Seizures

Perampanel is used as monotherapy or adjunctive therapy (i.e., in combination with other anticonvulsants) in the management of partial-onset seizures with or without secondary generalization in adults and adolescents 12 years of age or older with epilepsy.1,2,3,4,5,6,17,23,29,32

Efficacy of perampanel as adjunctive therapy for partial-onset seizures has been established in 3 randomized, double-blind, placebo-controlled, multicenter studies of similar design in patients 12 years of age and older with refractory partial-onset seizures.1,2,3,4,6,14,15,17 Efficacy of the drug as monotherapy has been extrapolated from the data obtained with adjunctive use.29,32 Patients enrolled in these studies had refractory partial-onset seizures (with or without secondary generalization) that were not adequately controlled while receiving 1-3 concomitant anticonvulsant agents; patients were required to have experienced more than 5 partial-onset seizures during a 6-week baseline period in order to be randomized.1,2,3,4 The average duration of epilepsy was approximately 21 years and the median baseline seizure frequency was 9-14 seizures per 28 days; more than 85% of the patients were receiving 2-3 concomitantly administered anticonvulsants (e.g., carbamazepine, lamotrigine, levetiracetam, valproic acid) with or without concurrent vagal nerve stimulation, and approximately 50% were receiving at least one concomitant anticonvulsant (i.e., carbamazepine, oxcarbazepine, phenytoin) known to induce cytochrome P-450 (CYP) 3A4, the principal enzyme involved in the metabolism of perampanel.1,2,3,4,6 Patients subsequently entered into the double-blind portions of these studies during which they received either placebo or perampanel (2, 4, 8, or 12 mg daily) in addition to their existing anticonvulsant regimen; treatment was continued for a total of 19 weeks (6-week titration phase followed by a 13-week maintenance phase).1,2,3,4,6

Efficacy of perampanel in these studies was evaluated principally by the percent change in 28-day seizure frequency from baseline to the end of the double-blind treatment periods.1 In all 3 studies, perampanel was more effective than placebo in reducing seizure frequency, including the frequency of secondarily generalized seizures; statistical significance was established for dosages of 4, 8, and 12 mg daily.1,2,3,4,6,17 In a pooled analysis of the studies, the median percent reduction in seizure frequency was 23.3, 28.8, or 27.2% for patients receiving perampanel 4, 8, or 12 mg daily, respectively, compared with 12.8% for those receiving placebo.6 In addition, perampanel was associated with higher responder rates (defined as the proportion of patients experiencing a reduction in seizure frequency of 50% or greater) relative to placebo (29, 35, or 35% with perampanel 4, 8, or 12 mg daily, respectively, compared with 19% with placebo).1,6 Patients who were receiving a concomitant CYP-inducing anticonvulsant agent in these studies had a substantially reduced response to perampanel compared with those not receiving such concomitant therapy.1,6,8 (See Drug Interactions: Anticonvulsants.) In addition, patients receiving 3 additional anticonvulsant drugs at baseline were more likely to have a reduced response to adjunctive perampanel therapy than those receiving only one additional anticonvulsant, which may be attributed to a higher prevalence of CYP-inducing anticonvulsant use in the former group.28

Patients who completed one of the placebo-controlled studies were eligible to participate in an extension study which consisted of a 16-week blinded conversion period, during which all patients who were previously randomized to placebo were switched to perampanel, followed by a long-term open-label treatment period.5,30 Dosage of perampanel was further titrated up to 12 mg daily or the highest tolerated dosage.5,30 Results of the extension study suggest that seizure control is maintained with continued perampanel therapy (up to 3 years evaluated at a median dosage of 10.6 mg daily).5 The drug was well tolerated during long-term therapy and no new major safety issues were identified.5,30

Primary Generalized Tonic-Clonic Seizures

Perampanel is used as adjunctive therapy (i.e., in combination with other anticonvulsants) in the management of primary generalized tonic-clonic seizures in adults and adolescents 12 years of age or older with epilepsy.1

Efficacy of perampanel as adjunctive therapy for primary generalized tonic-clonic seizures has been established in a randomized, double-blind, placebo-controlled, multicenter study in patients 12 years of age and older with idiopathic generalized epilepsy.1,27 Patients enrolled in this study were receiving stable dosages of 1-3 concomitant anticonvulsant agents (e.g., lamotrigine, levetiracetam, topiramate, valproic acid) and had experienced at least 3 primary generalized tonic-clonic seizures during an 8-week baseline period.1,27 Perampanel dosage was titrated over 4 weeks up to a target dosage of 8 mg once daily or the highest tolerated dosage, and patients were then treated for 13 additional weeks on the last dosage level achieved at the end of the titration period (total treatment period of 17 weeks).1,27 Efficacy of perampanel was principally evaluated by the percent change in 28-day primary generalized tonic-clonic seizure frequency from baseline to the end of the double-blind treatment period.1,27 Perampanel was found to substantially reduce seizure frequency compared with placebo in this study; the median percent reduction from baseline in primary generalized tonic-clonic seizure frequency was approximately 76% in perampanel-treated patients compared with 38% in placebo recipients.1,27 In addition, perampanel was associated with a higher responder rate (i.e., the proportion of patients experiencing a reduction in seizure frequency of 50% or greater) than placebo (64.2 versus 39.5%).1,27 Approximately 30.9% of patients receiving perampanel were seizure free during the maintenance period compared with 12.3% of those receiving placebo.27

Seizures Associated with Lennox-Gastaut Syndrome

Perampanel is designated an orphan drug by the FDA for the treatment of seizures associated with Lennox-Gastaut syndrome†; however, the drug is not labeled by the FDA for this orphan indication.24

Administration

Perampanel is administered orally as tablets or oral suspension.1 The drug usually is administered once daily at bedtime and may be given without regard to food.1,25 (See Description.) Bioavailability of the commercially available oral suspension is comparable to that of the tablets, and the dosage forms may be used interchangeably.1

When discontinuing any anticonvulsant therapy, gradual withdrawal is recommended to minimize the potential for increased seizure frequency in patients with seizure disorders.1 However, the manufacturer states that there are insufficient data to make specific recommendations regarding withdrawing perampanel.1 Because of its prolonged half-life (approximately 105 hours), plasma concentrations are expected to decline gradually even after abrupt discontinuance.1 If discontinuance of perampanel is necessary because of adverse effects, prompt withdrawal of the drug may be considered.1 (See Discontinuance of Anticonvulsants under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Patients currently receiving or beginning therapy with perampanel and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1,10,12 (See Suicidality Risk under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Monitoring for adverse neuropsychiatric effects is recommended in patients receiving perampanel, especially during the initial titration period (or any other time dosage is increased) and when high dosages (e.g., 12 mg daily) of the drug are used.1 If any neuropsychiatric manifestations occur, dosage of perampanel should be reduced or therapy discontinued, depending on the severity of the reaction.1 (See Serious Psychiatric and Behavioral Reactions under Warnings/Precautions: Warnings, in Cautions.)

Oral Suspension

Perampanel oral suspension should be administered using the oral dosing syringe and bottle adapter supplied by the manufacturer; a household teaspoon or tablespoon is not an adequate measuring device.1 The oral suspension is a white to off-white opaque suspension that should be shaken well prior to each administration.1 The oral suspension should be stored at temperatures below 30°C and not frozen, and should be used within 90 days of first opening the bottle; any remaining unused portions should be discarded.1

Dosage

Initial dosage recommendations for perampanel vary based on whether a moderate or potent cytochrome P-450 (CYP) 3A4 enzyme-inducing drug (e.g., carbamazepine, oxcarbazepine, phenytoin) is used concomitantly.1,6 Such CYP3A4-inducing drugs can reduce plasma concentrations, and thus efficacy, of perampanel.1,6,8 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Partial Seizures

In the Absence of Moderate or Potent CYP3A4 Inducers

The recommended initial dosage of perampanel as monotherapy or adjunctive therapy for partial-onset seizures in adults and adolescents 12 years of age or older who are not concomitantly receiving a moderate or potent CYP3A4 inducer (e.g., carbamazepine, oxcarbazepine, phenytoin) is 2 mg once daily at bedtime.1 Dosage should be increased by increments of 2 mg daily no more frequently than once a week based on individual clinical response and tolerability; the recommended maintenance dosage range is 8-12 mg once daily, but some patients may respond to a dosage of 4 mg daily.1 While a clear dose-response relationship has been established between perampanel dosages of 4 and 8 mg daily, a dosage of 12 mg daily appeared to provide little additional benefit over a dosage of 8 mg daily in the principal efficacy studies, but was associated with a substantial increase in the incidence of adverse effects (e.g., neuropsychiatric effects).1,3,4,6,8,15,16,18,23 (See Serious Psychiatric and Behavioral Reactions under Warnings/Precautions: Warnings, in Cautions.) In contrast, data from a pharmacokinetic modeling study demonstrated a linear exposure-response relationship across a perampanel dosage range of 2-12 mg daily, suggesting that some patients who can tolerate a dosage of 12 mg daily may achieve some greater benefit from this higher dosage.21 Clinicians generally recommend that perampanel dosage be increased to the maximum recommended dosage of 12 mg daily only if tolerated and clinically indicated (i.e., satisfactory response not achieved with the lower 8-mg daily dosage).2,3,6,15

Dosage adjustment of perampanel may be necessary when moderate or potent CYP3A4-inducing drugs are added to the patient's anticonvulsant regimen, and the patient should be monitored closely for clinical response and tolerability in these situations.1 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

In the Presence of Moderate or Potent CYP3A4 Inducers

The recommended initial dosage of perampanel as monotherapy or adjunctive therapy for partial-onset seizures in adults and adolescents 12 years of age or older who are concomitantly receiving a moderate or potent CYP3A4 inducer (e.g., carbamazepine, oxcarbazepine, phenytoin) is 4 mg once daily at bedtime.1 Dosage should be increased by increments of 2 mg daily no more frequently than once a week based on individual clinical response and tolerability.1 A maintenance dosage in patients receiving concomitant CYP3A4 inducers has not been established; in clinical studies, the highest dosage studied in patients receiving concomitant enzyme-inducing anticonvulsants was 12 mg once daily.1 Since clinical trials have demonstrated a substantially reduced effect of perampanel on seizures in patients concurrently receiving CYP3A4-inducing drugs, including enzyme-inducing anticonvulsant agents (e.g., carbamazepine, oxcarbazepine, phenytoin), such patients should be closely monitored for response.1 While a clear dose-response relationship has been established between perampanel dosages of 4 and 8 mg daily, a dosage of 12 mg daily appeared to provide little additional benefit over a dosage of 8 mg daily in the principal efficacy studies and was associated with a substantial increase in the incidence of adverse effects (e.g., neuropsychiatric effects).1,3,4,6,8,15,16,18,23 (See Serious Psychiatric and Behavioral Reactions under Warnings/Precautions: Warnings, in Cautions.) In contrast, data from a pharmacokinetic modeling study demonstrated a linear exposure-response relationship across a perampanel dosage range of 2-12 mg daily, suggesting that some patients who can tolerate a dosage of 12 mg daily may achieve some greater benefit from this higher dosage.21 Clinicians generally recommend that perampanel dosage be increased to the maximum recommended dosage of 12 mg daily only if tolerated and clinically indicated (i.e., satisfactory response not achieved with the lower 8-mg daily dosage).2,3,6,15

Dosage adjustment of perampanel may be necessary when moderate or potent CYP3A4-inducing drugs are added to, or discontinued from, the patient's anticonvulsant regimen; patients should be monitored closely for clinical response and tolerability in these situations.1 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Primary Generalized Tonic-Clonic Seizures

In the Absence of Moderate or Potent CYP3A4 Inducers

The recommended initial dosage of perampanel as adjunctive therapy for primary generalized tonic-clonic seizures in adults and adolescents 12 years of age or older who are not concomitantly receiving a moderate or potent CYP3A4 inducer (e.g., carbamazepine, oxcarbazepine, phenytoin) is 2 mg once daily at bedtime.1 Dosage should be increased in increments of 2 mg daily no more frequently than once a week based on individual clinical response and tolerability; the recommended maintenance dosage is 8 mg once daily.1 Patients tolerating the drug well at a dosage of 8 mg daily and who require further seizure control may benefit from a dosage increase to 12 mg once daily if tolerated.1

Dosage adjustment of perampanel may be necessary when moderate or potent CYP3A4-inducing drugs are added to the patient's anticonvulsant regimen, and the patient should be monitored closely for clinical response and tolerability in these situations.1 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

In the Presence of Moderate or Potent CYP3A4 Inducers

The recommended initial dosage of perampanel as adjunctive therapy for primary generalized tonic-clonic seizures in adults and adolescents 12 years of age or older who are concomitantly receiving a moderate or potent CYP3A4-inducing drug (e.g., carbamazepine, oxcarbazepine, phenytoin) is 4 mg once daily at bedtime.1 Dosage should be increased in increments of 2 mg daily no more frequently than once a week based on individual clinical response and tolerability.1 A maintenance dosage in patients receiving concomitant CYP3A4 inducers has not been established; in clinical studies, the highest dosage studied in patients receiving concomitant enzyme-inducing anticonvulsants was 12 mg once daily.1 Patients should be monitored closely for response since a substantially decreased effect on seizures may occur in these patients.1

Dosage adjustment of perampanel may be necessary when moderate or potent CYP3A4-inducing drugs are added to, or discontinued from, the patient's anticonvulsant regimen; patients should be monitored closely for clinical response and tolerability in these situations.1 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Special Populations

In patients with mild or moderate hepatic impairment, perampanel therapy should be initiated at a dosage of 2 mg once daily; dosage may be increased by increments of 2 mg daily no more frequently than every 2 weeks up to a maximum dosage of 6 mg once daily for patients with mild hepatic impairment or 4 mg once daily for those with moderate hepatic impairment.1 As with all patients, dosage should be individualized based on patient response and tolerability.1 Perampanel has not been studied in patients with severe hepatic impairment, and use of the drug in such patients is not recommended.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustment of perampanel is necessary for patients with mild renal impairment.1 The manufacturer states that perampanel may be used in patients with moderate renal impairment with close monitoring.1 A slower titration schedule may be considered in such patients based on clinical response and tolerability.1 Perampanel has not been studied in patients with severe renal impairment and patients undergoing hemodialysis; use of the drug in such patients is not recommended.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

In geriatric patients, dosage increases of perampanel during titration are recommended no more frequently than once every 2 weeks.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

No dosage adjustments are required based on gender or race/ethnicity.1

Contraindications

The manufacturer states that there are no known contraindications to the use of perampanel.1

Warnings/Precautions

Warnings

Serious Psychiatric and Behavioral Reactions

Serious, sometimes life-threatening, psychiatric and behavioral reactions have occurred in patients receiving perampanel.1,5,6,8,20,31 Such events have ranged from irritability, anger, agitation, anxiety, and labile affect to more severe behaviors such as belligerence, hostility, aggression, homicidal ideation and/or threats, and physical assaults.1,5,6,8,20 In the placebo-controlled studies in patients with partial-onset seizures, adverse neuropsychiatric events generally were reported more frequently in patients receiving perampanel than in those receiving placebo and occurred in patients with and without underlying risk factors (e.g., prior psychiatric history, prior aggressive behavior, concomitant use of other drugs associated with hostility and aggression).1,6,8 In these studies, some patients experienced worsening of their preexisting psychiatric condition.1 Among adverse neuropsychiatric events, hostility- and aggression-related adverse reactions were reported in 12 and 20% of patients who received perampanel 8 and 12 mg daily, respectively, compared with 6% of placebo recipients; perampanel-treated patients experienced more of these reactions that were serious, severe, and led to dosage reduction, interruption, and discontinuance than the placebo recipients.1,6 These effects were dose related and generally occurred within the first 6 weeks of therapy (i.e., titration phase), although new reactions continued to be reported for longer than 37 weeks.1,5,8,31 Similar serious psychiatric and behavioral events were observed in the placebo-controlled study in patients with primary generalized tonic-clonic seizures.1 Homicidal ideation and/or threat were observed in 0.1% of patients receiving perampanel in controlled and open-label studies, including non-epilepsy studies, and also reported during postmarketing experience with the drug.1,31 Neuropsychiatric effects such as disorientation/confusional state, delusion, paranoia, euphoric mood, agitation, anger, and mental status changes also have been observed in patients with other (nonepileptic) indications as well as in healthy individuals receiving perampanel.1,6,31 (See Abuse Potential and Dependence under Warnings/Precautions: Other Warnings and Precautions, in Cautions.) In addition, suicidal ideation and suicide attempts have been reported in patients receiving the drug.2,4,6,8,26 (See Suicidality Risk under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Patients should be monitored for psychiatric and behavioral reactions as well as for changes in mood, behavior, or personality that are not typical for the patients during perampanel therapy and for at least 1 month following discontinuance of the drug.1 Because these effects appear to be dose related, monitoring is particularly important during the first few weeks of therapy (titration period), following dosage increases, and when higher dosages of the drug are used.1 If any psychiatric manifestations occur, dosage of perampanel should be reduced; if symptoms are persistently severe or worsening, the drug should be immediately and permanently discontinued and the patient referred for psychiatric evaluation.1 (See Advice to Patients.)

Concomitant use of alcohol may substantially worsen mood and increase anger; therefore, alcohol should be avoided during perampanel therapy.1 (See Drug Interactions: Alcohol and Other CNS Depressants.)

Sensitivity Reactions

Multi-organ Hypersensitivity Reactions

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) has been reported with anticonvulsants, including perampanel.1 DRESS can be fatal or life-threatening and typically, but not exclusively, presents with eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, and myositis.1 However, such reactions are variable in their clinical presentation, and signs and symptoms associated with other organ systems also may occur.1 If manifestations of a multi-organ hypersensitivity reaction occur, patients should be evaluated immediately; if an alternative cause cannot be identified, perampanel should be discontinued.1

Other Warnings and Precautions

Suicidality Risk

Suicidal behavior and ideation have been reported in patients receiving anticonvulsants, including perampanel.1,2,4,6,10,12,26 An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of studies using various anticonvulsants compared with placebo.1,10,12 The analysis of suicidality reports from 199 placebo-controlled studies involving 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1,10,12 This increased suicidality risk was observed as early as 1 week after beginning therapy and continued through 24 weeks.1,10 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative risk for suicidality was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1,10

Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy.1 All patients currently receiving or beginning therapy with any anticonvulsant should be closely monitored for the emergence or worsening of suicidal thoughts or behavior or depression.1,10,12

Clinicians who prescribe perampanel or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness.1,10 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.1,12 If suicidal thoughts or behaviors emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.1,12 (See Advice to Patients.)

Neurologic Effects

Perampanel can cause a variety of adverse neurologic effects, including dizziness, disturbances in gait or coordination (including ataxia, balance disorder, and abnormal coordination), somnolence, and fatigue; these effects are dose related and generally occur during the dosage titration phase.1,4,13,20 Geriatric patients appear to be at increased risk of these adverse effects.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

CNS-related events were among the most common adverse effects associated with perampanel in clinical studies.1,2,3,4,13,20 In the placebo-controlled studies in patients with partial-onset seizures, dizziness and vertigo were reported in 35% of patients receiving perampanel 8 mg daily and in 47% of those receiving the 12-mg daily dosage of the drug compared with 10% of those receiving placebo.1 Somnolence occurred in 16 or 18% of patients receiving perampanel 8 or 12 mg daily, respectively, compared with 7% of those receiving placebo.1 Other gait-related disturbances (e.g., ataxia, balance disorder, abnormal coordination) and fatigue-related effects (e.g., asthenia, lethargy) were reported in about 12-16% and 12-15% of patients, respectively, in the perampanel treatment groups of these studies.1 Similar CNS-related events were observed in the placebo-controlled study in patients with primary generalized tonic-clonic seizures.1 In addition, perampanel can cause psychomotor impairment when used at higher dosages (e.g., 8 or 12 mg daily).1

Patients should be cautioned about the possibility of somnolence, fatigue, dizziness, and other CNS-related effects with perampanel therapy and advised not to operate a motor vehicle or other dangerous machinery until the effects of the drug are known.1 The risk of adverse neurologic effects appears to be greater with concomitant use of alcohol and/or other CNS depressants.1 (See Drug Interactions: Alcohol and Other CNS Depressants and also see Advice to Patients.)

Falls and Injuries

Perampanel therapy is associated with an increased risk of falls (both with and without concurrent seizures), which have resulted in serious injuries in some cases (including head injuries, bone fractures, and lacerations).1,3 In the principal efficacy studies in patients with partial-onset seizures, falls were reported in 5% of patients receiving perampanel 8 mg daily and in 10% of those receiving perampanel 12 mg daily, compared with 3% of those receiving placebo.1 Falls also were reported as serious and led to drug discontinuance more frequently with perampanel therapy compared with placebo.1 In some cases, falls occurred in association with other CNS-related effects (e.g., gait disturbance, ataxia, dizziness, slurred speech).3

Risk of falls appears to be greater in geriatric patients.1,8 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Discontinuance of Anticonvulsants

As with all anticonvulsant agents, there is a potential for increased seizure frequency when perampanel therapy is withdrawn abruptly.1 In clinical studies of perampanel in patients with seizure disorders, a few patients experienced seizures when perampanel was discontinued without downward dosage titration.1

In general, gradual withdrawal is recommended whenever any anticonvulsant agent is discontinued; however, the manufacturer states that insufficient data are available to make specific recommendations regarding an appropriate withdrawal regimen for perampanel.1 Because of the prolonged half-life of perampanel (approximately 105 hours), plasma concentrations are expected to decline gradually even after abrupt cessation of therapy.1 If discontinuance of therapy is necessary because of adverse effects, the manufacturer states that prompt withdrawal may be considered.1

Abuse Potential and Dependence

Perampanel is subject to control as a schedule III (C-III) drug.1,7 In abuse-potential studies in recreational multiple-drug abusers, supratherapeutic doses (24 and 36 mg) of perampanel produced euphoric-type responses similar to those produced by alprazolam, a schedule IV benzodiazepine, and oral ketamine, a schedule III drug.1 “High” and dissociative (e.g., floating, spaced out, detached) responses with perampanel were comparable to those with ketamine, but greater than those with alprazolam.1 Based on currently available data, the Drug Enforcement Administration (DEA) states that the abuse potential of perampanel may lead to moderate to low physical dependence or high psychological dependence, but is expected to be less than that of drugs in schedules I and II.7

The potential for perampanel to produce withdrawal symptoms has not been adequately evaluated to date.1

Specific Populations

Pregnancy

There are no adequate data in humans to determine if there is any risk associated with the use of perampanel during pregnancy; in animal reproductive studies, developmental toxicity (e.g., visceral abnormalities, decreased fetal weight gain, delayed sexual maturation) was observed at clinically relevant doses.1

Women who are taking perampanel during pregnancy should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or [Web].1

Lactation

Perampanel and/or its metabolites are distributed into milk in rats at concentrations higher than those in maternal plasma; it is not known whether the drug is distributed into human milk.1 The effects of perampanel on the nursing infant or on milk production also are not known.1 The known benefits of breast-feeding should be considered along with the mother's clinical need for perampanel and any potential adverse effects on the infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of perampanel have not been established in pediatric patients younger than 12 years of age.1 A total of 72 adolescents 12-16 years of age were included in the controlled partial-onset seizure trials and 11 adolescents 12-16 years of age were included in the study evaluating primary generalized tonic-clonic seizures with an additional 6 pediatric patients in the open-label extension of the study.1 In the 3 placebo-controlled studies of perampanel in patients with partial seizures, aggression was observed more frequently in adolescents than in adults receiving the drug.31 (See Serious Psychiatric and Behavioral Reactions under Warnings/Precautions: Warnings, in Cautions.)

Geriatric Use

There is insufficient experience in patients 65 years of age and older to establish efficacy and safety of perampanel in this population.1 Geriatric patients treated with the drug appear to be at increased risk of adverse neurologic effects (e.g., dizziness, gait disturbances, somnolence, fatigue) compared with younger adults and adolescents.1 In addition, the risk of falls appears to be greater in geriatric patients.1,8 Because of a greater likelihood of such adverse reactions in geriatric patients, dosage of perampanel should be titrated gradually in patients 65 years of age and older.1

Hepatic Impairment

Systemic exposure and half-life of perampanel are increased in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment; dosage adjustments are recommended in such patients.1 (See Dosage and Administration: Special Populations.)

In a study evaluating the pharmacokinetics of perampanel in individuals with various degrees of hepatic impairment (normal, mild, or moderate), the area under the plasma concentration-time curve (AUC) of free (unbound) perampanel was increased by 1.8- or 3.3-fold in those with mild or moderate hepatic impairment, respectively; half-life of the drug was prolonged by more than twofold in both groups of hepatically impaired individuals compared with those with normal hepatic function.1

Perampanel has not been studied in patients with severe hepatic impairment; use of the drug is not recommended in such patients.1

Renal Impairment

Perampanel has not been specifically evaluated to date in patients with renal impairment.1 In a population pharmacokinetic analysis in patients with partial-onset seizures, clearance of perampanel was reduced by 27% in patients with mild renal impairment (creatinine clearance of 50-80 mL/minute) compared with those with normal renal function (creatinine clearance greater than 80 mL/minute); however, there was substantial overlap in perampanel exposure between the 2 groups.1 In a population pharmacokinetic analysis in patients with primary generalized tonic-clonic seizures, clearance of perampanel was not influenced by baseline creatinine clearance.1 Therefore, the manufacturer states that dosage adjustment is not necessary in patients with mild renal impairment.1

Perampanel may be used in patients with moderate renal impairment with close monitoring; more gradual dosage titration may be considered in these patients based on clinical response and tolerability.1

Perampanel has not been studied in patients with severe renal impairment and in those undergoing hemodialysis; use of the drug is not recommended in such patients.1 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects reported in at least 4% of patients with partial-onset seizures receiving perampanel in 3 controlled clinical trials and more frequently with the drug than with placebo include dizziness,1,2,3,4 somnolence,1,2,3,4 fatigue,1,3,4 irritability,1,2,3 falls,1,2,3 nausea,1,3 weight gain,1,3 vertigo,1 ataxia,1,2 gait disturbance,1,4 and balance disorder.1

Adverse effects reported in at least 10% of patients with primary generalized tonic-clonic seizures receiving perampanel in a controlled clinical trial and more frequently with the drug than with placebo include dizziness,1 fatigue,1 headache,1 somnolence,1 and irritability.1

Perampanel is principally metabolized by cytochrome P-450 (CYP) isoenzyme 3A4/5 and, to a lesser extent, by CYP1A2 and CYP2B6, although other CYP-mediated pathways may be involved.1

Perampanel is a weak inhibitor of CYP2C8 and 3A4, and a weak inducer of CYP2B6 and 3A4/5 in vitro.1 The drug does not appear to inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, and 2E1 nor induce CYP1A2.1

Perampanel is neither a substrate nor substantial inhibitor of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); organic anion transport proteins (OATP) 1B1 and 1B3; organic anion transporters 1, 2, 3, and 4; and organic cation transporters 1, 2, and 3.1 Perampanel has weak inhibitory effects on uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and 2B7 and does not appear to inhibit UGT1A1, 1A4, and 1A6.1 The drug has been shown to induce UGT1A1 and 1A4.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Concomitant use of perampanel with moderate or potent CYP3A4-inducing drugs (e.g., carbamazepine, oxcarbazepine, phenytoin, rifampin, St. John's wort [ Hypericum perforatum ]) may decrease systemic exposure of perampanel.1,9 Dosage adjustment of perampanel is necessary when the drug is used in the presence of moderate or potent CYP3A4 inducers.1 (See Dosage and Administration: Dosage and also see Drug Interactions: Anticonvulsants.)

Concomitant use of perampanel with potent CYP3A4 inhibitors (e.g., ketoconazole) may increase plasma concentrations of perampanel.1

Pharmacokinetic interactions also are possible when perampanel is used concomitantly with CYP3A4 substrates (e.g., midazolam).1

Alcohol and Other CNS Depressants

Concomitant use of perampanel with alcohol or other CNS depressants (e.g., benzodiazepines, opiate analgesics, barbiturates, sedating antihistamines) can increase the risk of CNS-related adverse effects; caution is advised.1 In a study in healthy individuals, the impairing effects of alcohol (e.g., inability to carry out complex tasks such as driving) were enhanced with concomitant use of perampanel.1 Multiple doses of perampanel (12 mg daily) also enhanced the impairing effects of alcohol on vigilance and alertness, and increased levels of anger, confusion, and depression.1 These enhanced effects also may occur if perampanel is used concurrently with other CNS depressants.1 The manufacturer states that alcohol should be avoided in patients receiving perampanel.1 (See Advice to Patients.)

Anticonvulsants

Concomitant use of known moderate or potent CYP3A4-inducing anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenytoin) reduced plasma concentrations of perampanel by approximately 50-67%.1,9

In healthy individuals, concurrent administration of carbamazepine (300 mg twice daily) and perampanel (single dose of 2 mg) decreased peak plasma concentrations and area under the plasma concentration-time curve (AUC) of perampanel by 26 and 67%, respectively; half-life of perampanel also was substantially decreased.1 In a population pharmacokinetic analysis of data from clinical studies evaluating partial-onset and primary generalized tonic-clonic seizures, carbamazepine, oxcarbazepine, phenytoin, and topiramate decreased systemic exposure of perampanel by approximately 64, 48, 43, and 19%, respectively.1 Because eslicarbazepine is structurally similar to oxcarbazepine, a similar pharmacokinetic interaction may be expected.1 Exposure to perampanel was not substantially altered by phenobarbital and primidone, although a modest effect of these anticonvulsants on perampanel concentrations cannot be excluded.1 The initial dosage of perampanel should be increased in the presence of known moderate or potent CYP3A4-inducing anticonvulsants, including carbamazepine, oxcarbazepine, and phenytoin; close monitoring is recommended and adjustment of perampanel dosage may be required whenever these anticonvulsants are added to or discontinued from therapy.1 (See Dosage and Administration: Dosage.)

Results of the population pharmacokinetic analysis indicated that other anticonvulsants (i.e., clobazam, clonazepam, lamotrigine, levetiracetam, valproic acid, and zonisamide) did not affect the clearance of perampanel.1

Regarding the effect of perampanel on concomitant anticonvulsant agents, perampanel at dosages of up to 12 mg daily had no substantial effect on clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, or zonisamide in a population pharmacokinetic analysis of data from patients with partial-onset seizures.1 Although clearance of carbamazepine, clobazam, lamotrigine, and valproic acid were each increased following concomitant perampanel administration, the degree of change was less than 10%.1 Clearance of oxcarbazepine was decreased by approximately 26%; concentrations of oxcarbazepine's active 10-monohydroxy metabolite were not measured.1

Ketoconazole

Concomitant administration of perampanel (single dose of 1 mg) and ketoconazole (400 mg once daily), a potent CYP3A4 inhibitor, increased systemic exposure of perampanel by 20% and prolonged its half-life by 15%.1

Levodopa

In healthy individuals, concomitant administration of perampanel (4 mg once daily for 19 days) had no effect on peak plasma concentrations or AUC of levodopa.1

Midazolam

Concomitant administration of perampanel 6 mg daily and midazolam, a CYP3A4 substrate, in healthy individuals decreased peak plasma concentrations and AUC of midazolam by 15 and 13%, respectively.1

Hormonal Contraceptives

In healthy females, concomitant use of perampanel 12 mg daily and an oral contraceptive containing ethinyl estradiol and levonorgestrel decreased peak plasma concentrations and systemic exposure of levonorgestrel by approximately 42 and 40%, respectively; systemic exposure of ethinyl estradiol was not altered.1 This interaction appears to be specific to the higher dosage of perampanel; when perampanel dosages of 4 and 8 mg daily were administered concomitantly with the same oral contraceptive, the pharmacokinetics of both hormonal components were not substantially affected.1

Because of the possibility of reduced efficacy of contraceptives containing levonorgestrel, the manufacturer recommends that an additional nonhormonal contraceptive be used during perampanel therapy and for 1 month following discontinuance of therapy in patients receiving perampanel concurrently with contraceptives containing levonorgestrel.1 Some experts recommend the use of nonhormonal methods of contraception in patients receiving perampanel therapy.23

Description

Perampanel, a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor antagonist, is an anticonvulsant.1,2,3,4,14,15,16,19,22,23 The exact mechanism of action by which perampanel exerts its anticonvulsant effects remains to be fully elucidated; however, the drug is known to inhibit AMPA-type glutamate receptors, a class of ionotropic glutamate receptors that mediate fast excitatory neurotransmission and play an important role in the generation and spread of epileptic seizures.1,14,15,16,22,23 In vitro studies indicate that perampanel selectively and noncompetitively inhibits AMPA receptors on postsynaptic neurons, thereby reducing excessive glutamatergic activity and neuronal excitation.1,5,16 Increased levels of glutamate, the principal excitatory neurotransmitter in the CNS, have been implicated in a variety of neurologic disorders caused by increased excitatory neurotransmission.1,16 Perampanel is highly selective for AMPA glutamate receptors and has little or no inhibitory effect on the N -methyl-d-aspartate (NMDA) and kainate ionotropic glutamate receptors.14,22 The drug has demonstrated a broad spectrum of anticonvulsant activity in various animal models.16,19

Perampanel is rapidly and completely absorbed following oral administration; peak plasma concentrations are attained within approximately 0.5-2.5 hours under fasting conditions.1,19 The bioavailability of the oral suspension is comparable to that of the tablets under steady-state conditions.1 Administration with a high-fat meal delayed time to peak plasma concentration by approximately 1-3 hours and reduced peak plasma concentrations of the drug by 11-40%, but did not affect the extent of absorption.1 Perampanel is extensively metabolized in the liver, primarily by oxidation followed by glucuronidation.1 In vitro studies indicate that the oxidative metabolism of perampanel is principally mediated by cytochrome P-450 (CYP) isoenzymes 3A4/5 and, to a lesser extent, by CYP1A2 and CYP2B6, although other CYP-mediated pathways may be involved.1 Following administration of a radiolabeled dose of perampanel in healthy geriatric individuals, approximately 22% of the dose was recovered in urine and 48% in feces mainly as oxidative and conjugated metabolites.1 Perampanel is approximately 95-96% protein bound (mainly to albumin and α₁-acid glycoprotein).1 The elimination half-life of the drug is approximately 105 hours.1

Advice to Patients

Importance of providing patient with a copy of manufacturer's patient information (medication guide) when perampanel therapy is begun and each time the drug is dispensed.1

Importance of taking perampanel only as prescribed.1 Instruct patients who are prescribed the oral suspension on proper administration of the dosage form.1

Importance of informing patients that perampanel can cause serious psychiatric and behavioral reactions.1 Importance of advising patients and their families and caregivers of the need to monitor for the emergence of anger; aggression; hostility; unusual changes in mood, personality, or behavior; and other behavioral symptoms during perampanel therapy and for at least 1 month following discontinuance of therapy.1 Advise patients, family members, and caregivers to immediately contact the responsible clinician if such symptoms occur.1,10

Importance of patients, family members, and caregivers being aware that anticonvulsants, including perampanel, may increase the risk of having suicidal thoughts or actions in a very small number of people (about 1 in 500).1,10,12 Advise patients, family members, and caregivers to pay close attention to any day-to-day changes in mood, behavior, and actions; these changes can happen very quickly.1,10 They also should be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).1,10 Advise patients, family members, and caregivers to contact the responsible clinician immediately if these or any new and worrisome behaviors occur.1,10

Risk of neurologic effects such as dizziness, gait disturbance, somnolence, and fatigue.1 Importance of advising patients not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects.1 Importance of also advising patients that concomitant use of CNS depressants (e.g., benzodiazepines, opiate analgesics, barbiturates, sedating antihistamines) can increase the risk of CNS-related adverse effects; patients should limit activity until the effects of such concomitant therapy are known.1

Risk of potentiated CNS impairment with concurrent use of alcohol or other CNS depressants.1 Importance of advising patients to avoid alcohol during perampanel therapy.1

Importance of advising patients that perampanel may increase the risk of falls (particularly in elderly patients), which can cause serious injuries.1

Importance of informing patients that sudden discontinuance of perampanel may increase seizure frequency.1

Importance of advising patients that if a dose is missed, to administer the prescribed daily dose at the regularly scheduled time the following day; if more than one day of dosing is missed, patients should contact their clinician.1

Importance of counseling patients that perampanel is a controlled substance that can be misused or abused.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of clinicians informing women about the existence of and encouraging enrollment in the pregnancy registry (see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions).1

Importance of informing women that perampanel may reduce the efficacy of levonorgestrel-containing contraceptives and that an additional nonhormonal method of contraception should be used during perampanel therapy and for 1 month following discontinuance of therapy.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., kidney disease, liver disease, depression or other psychiatric disorders, aggressive or hostile behavior, suicidality) or family history of suicidality or bipolar disorder.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Eisai Inc. Fycompa^® (perampanel) tablets and oral suspension prescribing information. Woodcliff Lake, NJ; 2017 Jul.

2. French JA, Krauss GL, Biton V et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology . 2012; 79:589-96. [PubMedCentral][PubMed 22843280]

3. French JA, Krauss GL, Steinhoff BJ et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia . 2013; 54:117-25. [PubMed 22905857]

4. Krauss GL, Serratosa JM, Villanueva V et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology . 2012; 78:1408-15. [PubMed 22517103]

5. Krauss GL, Perucca E, Ben-Menachem E et al. Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307. Epilepsia . 2014; 55:1058-68. [PubMedCentral][PubMed 24867391]

6. Steinhoff BJ, Ben-Menachem E, Ryvlin P et al. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia . 2013; 54:1481-9. [PubMed 23663001]

7. Drug Enforcement Administration (DEA), Department of Justice. Schedules of controlled substances: placement of perampanel into schedule III. 21 CFR Part 1308. Final Rule. [Docket No. DEA-374]. Fed Regist. 2013; 78 (231): 72013-16.

8. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 202834Orig1s000: Summary Review. From FDA website. [Web]

9. Eisai, Woodcliff Lake, NJ: Personal communication.

10. Food and Drug Administration. FDA Alert: Information for healthcare professionals: suicidal behavior and ideation and antiepileptic drugs. Rockville, MD; 2008 Jan 31; updated 2008 Dec 16. From the FDA website.

12. Food and Drug Administration. Suicidal behavior and ideation and antiepileptic drugs: update 5/5/2009. Rockville, MD; 2009 May 5. From the FDA website. Accessed 2012 May 4.

13. Krauss GL, Bar M, Biton V et al. Tolerability and safety of perampanel: two randomized dose-escalation studies. Acta Neurol Scand . 2012; 125:8-15. [PubMed 21883097]

14. Plosker GL. Perampanel: as adjunctive therapy in patients with partial-onset seizures. CNS Drugs . 2012; 26:1085-96. [PubMed 23179642]

15. Zaccara G, Giovannelli F, Cincotta M et al. AMPA receptor inhibitors for the treatment of epilepsy: the role of perampanel. Expert Rev Neurother . 2013; 13:647-55. [PubMed 23739002]

16. Shih JJ, Tatum WO, Rudzinski LA. New drug classes for the treatment of partial onset epilepsy: focus on perampanel. Ther Clin Risk Manag . 2013; 9:285-93. [PubMedCentral][PubMed 23874099]

17. Ko D, Ramsay RE. Perampanel: expanding therapeutic options for patients with medically refractory secondary generalized convulsive seizures. Acta Neurol Scand Suppl . 2013; :36-43. [PubMed 23480155]

18. Hsu WW, Sing CW, He Y et al. Systematic review and meta-analysis of the efficacy and safety of perampanel in the treatment of partial-onset epilepsy. CNS Drugs . 2013; 27:817-27. [PubMedCentral][PubMed 23918722]

19. Rogawski MA, Hanada T. Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol Scand Suppl . 2013; :19-24. [PubMedCentral][PubMed 23480152]

20. Zaccara G, Giovannelli F, Cincotta M et al. The adverse event profile of perampanel: meta-analysis of randomized controlled trials. Eur J Neurol . 2013; 20:1204-11. [PubMed 23607817]

21. Gidal BE, Ferry J, Majid O et al. Concentration-effect relationships with perampanel in patients with pharmacoresistant partial-onset seizures. Epilepsia . 2013; 54:1490-7. [PubMed 23772853]

22. Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Curr . 2011; 11:56-63. [PubMedCentral][PubMed 21686307]

23. . Perampanel (Fycompa) for epilepsy. Med Lett Drugs Ther . 2014; 56:9-10. [PubMed 24662975]

24. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Rockville, MD. From FDA website. Accessed 2014 Nov 9. [Web]

25. US Food and Drug Administration. Center for Drug Evaluation and Research. NDA number 202834: Clinical pharmacology review. From FDA website. Accessed 2014 Oct 24. [Web]

26. Hoppner AC, Fauser S, Kerling F. Clinical course of intoxication with the new anticonvulsant drug perampanel. Epileptic Disord . 2013; 15:362-4. [PubMed 24001596]

27. French JA, Krauss GL, Wechsler RT et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy A randomized trial. Neurology . 2015; 85:950-7. [PubMed 26296511]

28. Glauser T, Laurenza A, Yang H et al. Efficacy and tolerability of adjunct perampanel based on number of antiepileptic drugs at baseline and baseline predictors of efficacy: A phase III post-hoc analysis. Epilepsy Res . 2016; 119:34-40. [PubMed 26656783]

29. Faulkner MA. Spotlight on perampanel in the management of seizures: design, development and an update on place in therapy. Drug Des Devel Ther . 2017; 11:2921-2930. [PubMed 29042752]

30. Montouris G, Yang H, Williams B et al. Efficacy and safety of perampanel in patients with drug-resistant partial seizures after conversion from double-blind placebo to open-label perampanel. Epilepsy Res . 2015; 114:131-40. [PubMed 26088896]

31. Ettinger AB, LoPresti A, Yang H et al. Psychiatric and behavioral adverse events in randomized clinical studies of the noncompetitive AMPA receptor antagonist perampanel. Epilepsia . 2015; 56:1252-63. [PubMed 26140524]

32. Eisai. FDA approves Eisai's Fycompa^® (perampanel) for use as monotherapy for the treatment of partial-onset seizures. Woodcliff Lake, NJ; 2017 July 26. Press release. [Web]