How should perampanel be initiated and titrated in adults, including elderly (≥65 years) or frail patients, those with moderate hepatic impairment (Child‑Pugh B), and patients taking strong cytochrome P450 3A4 (CYP3A4) inducers or inhibitors?

Perampanel Dose Initiation and Titration

Initiate perampanel at 2 mg once daily at bedtime, titrate by 2 mg increments every 1-2 weeks (or every 2-4 weeks in elderly/frail patients) to a target maintenance dose of 4-8 mg/day, with maximum doses of 12 mg/day in most adults, 8 mg/day in elderly patients, and 6 mg/day in patients with moderate hepatic impairment. 1, 2, 3

Standard Adult Initiation and Titration

• Start at 2 mg once daily at bedtime to minimize CNS adverse effects including somnolence and dizziness 1, 3
• Increase by 2 mg increments every 1-2 weeks based on clinical response and tolerability 1, 2
• Target maintenance dose is 4-8 mg/day, with 8 mg/day being the most commonly used effective dose 2, 4
• Maximum dose is 12 mg/day for standard adult patients 2, 3, 4
• Bedtime administration specifically mitigates somnolence and dizziness that occur with perampanel 1

Elderly Patients (≥65 years) and Frail Patients

• Use slower titration: increase by 2 mg every 2-4 weeks rather than the standard 1-2 week intervals 1
• Maximum recommended dose is 8 mg/day in elderly patients, as clearance values are similar (~10.5 ml/min in elderly vs 10.9 ml/min in adults) but tolerability may be reduced 3
• Monitor closely for CNS effects including dizziness and sedation, which increase fall risk in this population 1
• Real-world evidence demonstrates ≥50% responder rates of 22.2%-42.9% in elderly patients, with seizure frequency reduction of 12.5%-16.9% 1

Moderate Hepatic Impairment (Child-Pugh B)

• Maximum dose is 6 mg/day in patients with moderate hepatic impairment 3
• Perampanel is extensively metabolized (>90%) in the liver, primarily by CYP3A4, necessitating dose reduction 3
• Perampanel is contraindicated in severe hepatic disease (Child-Pugh C) 5
• No clinically important effects on liver function tests have been observed at approved doses, indicating low hepatotoxicity potential 6

Patients Taking Strong CYP3A4 Inducers

• Faster titration is appropriate: increase by 2 mg every week when co-administered with carbamazepine, phenytoin, or other strong CYP3A4 inducers 3
• CYP3A4-inducing AEDs (such as carbamazepine) reduce perampanel half-life from 105 hours to 25 hours, requiring more frequent dose adjustments 3
• Higher maintenance doses may be required due to enhanced clearance, though specific dose recommendations are not established 3
• Optimum therapeutic outcome can be achieved sooner with faster titration in this population 3

Patients Taking Strong CYP3A4 Inhibitors

• Avoid concomitant use with strong CYP3A4 inhibitors (boceprevir, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, telaprevir, posaconazole, voriconazole) 5
• If co-administration is unavoidable, use slower titration and lower maximum doses due to significantly increased perampanel exposure 5
• Monitor closely for dose-related adverse events including CNS effects and behavioral changes 1, 2

Critical Monitoring and Counseling

• Counsel patients about potential behavioral changes including irritability and aggression before initiating therapy 1, 2
• Monitor for psychiatric symptoms, which can be decreased by starting at low doses and titrating slowly 2
• Watch for seizure aggravation, particularly in pediatric and adolescent populations 2
• Perampanel 12 mg enhances metabolism of progesterone in oral contraceptives, requiring additional reliable contraceptive methods 3

Common Pitfalls to Avoid

• Avoid rapid titration, which increases the rate and severity of adverse events including somnolence, dizziness, and behavioral problems 1, 2
• Do not administer perampanel in the morning, as bedtime dosing specifically reduces CNS adverse effects 1
• Do not exceed 8 mg/day in elderly patients or 6 mg/day in moderate hepatic impairment, as higher doses increase toxicity risk without proportional benefit 3
• Do not combine with strong CYP3A4 inhibitors without dose adjustment, as this significantly increases perampanel exposure 5, 3