Perampanel (Fycompa®)
Perampanel is a first-in-class, selective, non-competitive AMPA receptor antagonist approved for adjunctive treatment of focal-onset seizures (with or without secondary generalization) in patients ≥4 years and primary generalized tonic-clonic seizures in patients ≥12 years, with monotherapy approval for focal seizures in the US. 1, 2, 3
Indications
FDA-approved indications include:
- Focal-onset seizures (with or without focal to bilateral tonic-clonic seizures): adjunctive therapy in patients ≥4 years; monotherapy in patients ≥4 years (US only) 1, 4
- Primary generalized tonic-clonic seizures: adjunctive therapy in patients ≥12 years 1, 3
Real-world evidence suggests broader utility in Lennox-Gastaut syndrome (46.5% responder rate) and other drug-resistant epilepsy syndromes, though these remain off-label uses 5, 6.
Dosing
Initial Dosing and Titration
Start at 2 mg once daily at bedtime and titrate slowly by 2 mg increments every 1-2 weeks based on clinical response and tolerability. 1, 2
- Target maintenance dose: 8-12 mg once daily
- Maximum dose: 12 mg/day
- Optimal dose for refractory partial-onset seizures: 8 mg/day is first-line; 12 mg/day is second-line based on network meta-analysis 7
Critical dosing principle: Slow titration (2 mg every 2-4 weeks) significantly improves tolerability and reduces behavioral adverse events in real-world practice 2. Bedtime administration mitigates somnolence and dizziness 2.
Special Populations
Pediatric patients (≥4 years): Weight-based dosing may be considered, though specific weight-based recommendations are not established in the FDA label. Real-world data in children shows retention rates of 79% at 12 months with doses ranging 1.5-12 mg/day 8.
Elderly patients: No dose adjustment required based on age alone, though start low and titrate slowly 1.
Renal impairment: No dose adjustment needed for mild-to-moderate impairment. Not recommended in severe renal impairment or hemodialysis 1, 9.
Hepatic impairment:
- Mild impairment: No adjustment
- Moderate impairment: Maximum 6 mg/day
- Severe impairment: Maximum 4 mg/day 1
Drug Interactions Requiring Dose Adjustment
Strong CYP3A inducers (carbamazepine, phenytoin, oxcarbazepine, rifampin): Increase perampanel dose by 50-100% to maintain therapeutic effect 1, 10. Perampanel clearance increases 2-3 fold with enzyme inducers 10.
Weak/moderate CYP3A inducers: Consider 25-50% dose increase 10.
CYP3A inhibitors: No routine dose adjustment, but monitor closely for adverse effects 1.
Hormonal contraceptives: Perampanel may reduce levonorgestrel exposure by 40%; use additional non-hormonal contraception 1.
Contraindications
There are no absolute contraindications listed in the FDA label. 1
Relative contraindications/strong cautions:
- Severe hepatic impairment (use maximum 4 mg/day only if benefits outweigh risks)
- Severe renal impairment including hemodialysis (not recommended)
- History of serious psychiatric disorders (requires intensive monitoring due to boxed warning) 1, 9
Boxed Warning: Serious psychiatric and behavioral reactions including aggression, hostility, irritability, anger, and homicidal ideation have occurred. Monitor closely, especially during titration 1, 9.
Monitoring Recommendations
Pre-Treatment Assessment
- Baseline psychiatric evaluation: Document mood, behavior, and any history of psychiatric disorders 1, 2
- Liver function tests: If hepatic impairment suspected
- Pregnancy test: If applicable (pregnancy category C)
- Medication review: Identify CYP3A inducers/inhibitors 1, 10
Ongoing Monitoring
Behavioral monitoring is the most critical safety parameter. Counsel patients and caregivers to immediately report:
- Aggression, hostility, irritability
- Mood changes, depression, suicidal ideation
- Homicidal ideation or violent behavior 1, 2
Clinical monitoring:
- Seizure frequency: Document at each visit
- Adverse effects: Particularly dizziness, somnolence, fatigue, ataxia (most common CNS effects) 2, 3
- Weight: Monitor regularly; weight loss reported in some patients
- Falls risk: Especially in elderly due to dizziness/ataxia 2
Therapeutic drug monitoring (TDM):
- Not routinely required but can be valuable for:
- Suspected non-adherence
- Drug-drug interactions with CYP3A inducers
- Suboptimal response despite adequate dosing
- Suspected toxicity
- Target concentration range: 180-1000 ng/mL (though not formally established) 10
Pharmacogenetic testing: CYP3A5*3 polymorphism may inform initial dosing but is not routinely recommended 10.
Laboratory Monitoring
No routine laboratory monitoring is required (unlike many other antiepileptics). This is a significant advantage over agents requiring regular CBC, LFTs, or renal function monitoring 2, 9.
Consider periodic LFTs only if:
- Baseline hepatic impairment
- Concurrent hepatotoxic medications
- Clinical signs of liver dysfunction
Common Pitfalls and Caveats
Titration too rapid: The most common cause of treatment discontinuation. Always titrate by 2 mg every 1-2 weeks minimum 2.
Ignoring drug interactions: Failure to increase dose with enzyme inducers leads to therapeutic failure. Conversely, stopping an inducer without reducing perampanel dose causes toxicity 10.
Inadequate behavioral counseling: Patients and families must understand the psychiatric risks before starting therapy. Document this discussion 1, 2.
Daytime administration: Giving perampanel in the morning increases daytime somnolence and dizziness. Always dose at bedtime 2.
Premature discontinuation: Many adverse effects (especially GI and CNS) are transient and resolve with continued therapy. Consider dose reduction before stopping 2.
Pregnancy considerations: Limited human data. Use only if seizure control benefits clearly outweigh fetal risks. Encourage enrollment in pregnancy registries 1.
Half-life considerations: With a 105-hour half-life, steady state takes 2-3 weeks. Clinical effects of dose changes are delayed 9, 3.