What is the maximum recommended dose of perampanel (perampanel) for refractory seizures?

Maximum Dose of Perampanel for Refractory Seizures

The maximum recommended dose of perampanel for refractory seizures is 12 mg/day, administered once daily after careful titration and evaluation of clinical response and tolerability. 1, 2

FDA-Approved Dosing Parameters

The FDA label establishes clear dosing boundaries for perampanel in refractory partial-onset seizures 1:

• Starting dose: 2 mg/day once daily 2
• Recommended maintenance dose: 4-8 mg/day 2
• Maximum dose: 12 mg/day 1, 2
• Titration increments: 2 mg/day 2
• Titration interval: At least 1 week between dose increases, though slower titration may be appropriate 2

Clinical Evidence Supporting 12 mg/day Maximum

Multiple Phase III trials demonstrate that 12 mg/day represents the upper therapeutic threshold 3, 4, 5:

• In the Asia-Pacific Phase III trial, perampanel 12 mg/day achieved a 38.0% median reduction in seizure frequency compared to 10.8% with placebo (P < .0001) 4
• The 12 mg dose showed dose-proportional efficacy superior to both 4 mg and 8 mg doses 4
• In long-term extension studies, 91% of patients were successfully titrated to 10-12 mg/day, with the majority tolerating these higher doses 5

Important Considerations for Maximum Dosing

The 12 mg dose should only be considered after careful evaluation 2:

• Patients must demonstrate inadequate response to lower doses (4-8 mg/day) 2
• Tolerability at intermediate doses must be established before escalation 2
• The half-life of perampanel is approximately 105 hours, meaning steady state is reached in 2-3 weeks, requiring patience during titration 1

Safety Profile at Maximum Dose

At 12 mg/day, perampanel remains generally well tolerated, though CNS-related adverse effects are more common 3, 4:

• Most frequent adverse events include dizziness (43.9%), somnolence (20.2%), headache (16.7%), and fatigue (12.1%) 5
• In Phase III trials, dizziness and irritability occurred at least twice as frequently with perampanel versus placebo 4
• Discontinuation rates due to adverse events were 6.2% across all doses in the Asia-Pacific trial 4
• No serious idiosyncratic adverse effects have been associated with perampanel at any dose 2

Critical Drug Interactions Affecting Maximum Dose

Enzyme-inducing antiepileptic drugs significantly impact perampanel metabolism 1:

• Perampanel is primarily metabolized by CYP3A4/5, with contributions from CYP1A2 and CYP2B6 1
• Concomitant use of strong CYP3A4 inducers (phenytoin, carbamazepine, phenobarbital) may require dose adjustments 1
• Multivariate analysis showed absence of enzyme-inducing medications at baseline predicted better seizure freedom rates (p = 0.0056) 6

Hepatic Impairment Considerations

Doses above 6 mg/day require special caution in hepatic impairment 1:

• The thorough QT study did not cover exposures expected in hepatic impairment patients taking doses over 6 mg/day 1
• Perampanel pharmacokinetics were evaluated only up to 1 mg in patients with mild-moderate hepatic impairment 1
• Maximum doses in hepatically impaired patients should be approached with heightened vigilance 1

Long-Term Efficacy at Maximum Dose

Extension study data demonstrate sustained benefit at higher doses 6, 5:

• Over 40% of patients achieved seizure freedom for at least 6 consecutive months during long-term treatment 6
• Median seizure frequency reduction increased from 39.2% at weeks 14-26 to 58.1% at weeks 92-104 5
• Responder rates (≥50% seizure reduction) increased from 41.4% at weeks 14-26 to 62.7% at weeks 92-104 5

Common Pitfalls to Avoid

• Never exceed 12 mg/day: No evidence supports higher doses, and safety has not been established above this threshold 1, 2
• Avoid rapid titration: The long half-life (105 hours) means steady state takes 2-3 weeks; rushing titration increases adverse event risk 1
• Don't combine with alcohol: Perampanel enhances alcohol's effects on vigilance, alertness, anger, confusion, and depression, with additive or supra-additive impairment on complex tasks like driving 1
• Monitor for psychiatric effects: Aggression and irritability are recognized adverse effects that may emerge at higher doses 2, 4