Fycompa - Drug Monograph

Introduction

Fycompa (perampanel) is a novel antiepileptic drug developed by Eisai Inc. and approved by the FDA in 2012. It represents the first in a new class of antiepileptic medications that selectively targets AMPA-type glutamate receptors. Fycompa is indicated for the treatment of partial-onset seizures and primary generalized tonic-clonic seizures in patients with epilepsy aged 4 years and older.

Mechanism of Action

Fycompa exerts its antiepileptic effects through non-competitive antagonism of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) glutamate receptors on post-synaptic neurons. Glutamate is the primary excitatory neurotransmitter in the central nervous system, and excessive glutamate activity through AMPA receptors is implicated in seizure generation and propagation. By selectively blocking these receptors, perampanel reduces neuronal hyperexcitability and dampens the spread of seizure activity.

Indications

FDA-approved indications:

• Monotherapy or adjunctive therapy for partial-onset seizures with or without secondary generalization in patients ≥4 years
• Adjunctive therapy for primary generalized tonic-clonic seizures in patients ≥12 years

Dosage and Administration

• Partial-onset seizures: 2 mg once daily at bedtime
• Primary generalized tonic-clonic seizures: 2 mg once daily at bedtime

• Increase by 2 mg increments no more frequently than weekly
• Recommended maintenance dose: 8-12 mg daily
• Maximum dose: 12 mg daily

• Hepatic impairment: Reduce dose in mild-moderate impairment; contraindicated in severe impairment
• Renal impairment: Caution advised in severe impairment (CrCl <30 mL/min)
• Elderly: Consider slower titration
• Pediatric: Dosing based on weight for patients 4 to <12 years

• Administer orally once daily at bedtime
• May be taken with or without food
• Tablets should be swallowed whole

Pharmacokinetics

• Oral bioavailability: ~100%
• Tmax: 0.5-2.5 hours (fasting); delayed with high-fat meal
• Food does not affect overall bioavailability

• Protein binding: ~95-96% (primarily to albumin and α1-acid glycoprotein)
• Volume of distribution: ~1.1 L/kg
• Crosses blood-brain barrier effectively

• Primarily metabolized via CYP3A4 and CYP3A5-mediated oxidation
• Subsequent phase II metabolism via glucuronidation
• No active metabolites identified

• Half-life: ~105 hours
• Excretion: Primarily fecal (48%) and renal (22%)
• Time to steady state: 2-3 weeks

Contraindications

• Hypersensitivity to perampanel or any component of the formulation
• Severe hepatic impairment

Warnings and Precautions

• Serious psychiatric and behavioral reactions including aggression, hostility, irritability, anger, and homicidal ideation/threats

• Dizziness, gait disturbance, somnolence, and falls: Patients should be cautioned about operating machinery
• Suicidal behavior and ideation: Monitor for emergence or worsening of depression
• Withdrawal seizures: Avoid abrupt discontinuation (taper gradually)
• Drug reaction with eosinophilia and systemic symptoms (DRESS): Discontinue if suspected
• Cognitive and neuropsychiatric adverse reactions: May impair physical and mental abilities

Drug Interactions

• Carbamazepine, phenytoin, oxcarbazepine: Decrease perampanel concentrations by approximately 50-67%
• Rifampin: Decreases perampanel exposure
• Dose adjustments may be necessary

• Perampanel may decrease efficacy of levonorgestrel-containing contraceptives
• Recommend additional non-hormonal contraception

• Alcohol: Increases impairment of cognitive and motor function
• Benzodiazepines, opioids, other AEDs: Additive CNS depression

• Felbamate: May increase perampanel concentrations

Adverse Effects

• Dizziness (38-43%)
• Somnolence (16-19%)
• Fatigue (9-12%)
• Irritability (7-12%)
• Falls (5-10%)
• Nausea (8-9%)
• Ataxia (5-7%)

• Psychiatric and behavioral reactions (aggression, anger, hostility)
• Suicidal ideation and behavior
• Severe dizziness and gait disturbance
• DRESS/multiorgan hypersensitivity
• Stevens-Johnson syndrome

Monitoring Parameters

• Seizure frequency and characteristics
• Psychiatric symptoms: Aggression, hostility, depression, suicidal ideation
• Cognitive and neurological function
• Gait stability and fall risk
• Complete blood count, liver function tests at baseline and periodically
• Pregnancy testing in women of childbearing potential
• Adherence to therapy

Patient Education

• Take medication exactly as prescribed at bedtime
• Do not stop abruptly due to risk of increased seizures
• Avoid alcohol and other CNS depressants
• Be aware of potential for dizziness, drowsiness, and coordination problems
• Report any new or worsening mood changes, depression, or suicidal thoughts
• Use caution when driving or operating machinery
• Inform all healthcare providers about Fycompa use
• Women of childbearing potential should use effective contraception
• Notify provider if pregnancy is planned or suspected
• Keep all appointments for monitoring

References

1. FDA Prescribing Information: Fycompa (perampanel). Revised 2022. 2. Rogawski MA, et al. Perampanel, a selective AMPA receptor antagonist, as adjunctive therapy for refractory partial-onset seizures. Epilepsy Currents. 2013;13(2):84-87. 3. French JA, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology. 2012;79(6):589-596. 4. Krauss GL, et al. Assessing safety and efficacy of perampanel in patients with epilepsy aged ≥65 years. Neurology. 2020;94(24):e2584-e2595. 5. Patsalos PN, et al. Clinical pharmacokinetics of perampanel. Epilepsia. 2013;54(8):1485-1490. 6. Steinhoff BJ, et al. Perampanel for the treatment of epilepsy: a safety evaluation. Expert Opinion on Drug Safety. 2021;20(3):295-303.