Pharmacology Update

Perampanel Tablets (Fycompa™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved the first in class α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist for the treatment of seizures. Perampanel is an orally active noncompetitive AMPA antagonist. The drug is marketed by Eisai Inc. as Fycompa.

Indications

Perampanel is indicated as adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in epileptic patients 12 years of age and older.1

Dosage

The recommended starting dose is 2 mg once daily at bedtime.1 For patients on enzyme-inducing drugs (e.g., phenytoin, carbamazepine, oxcarbazepine), the dose is 4 mg once daily. The dose may be increased at 2 mg increments weekly to a range of 4-12 mg daily based on response and tolerability. For elderly patients, dosing increase should occur every 2 weeks. Patients with mild and moderate hepatic dysfunction should start with 2 mg and titrate every 2 weeks up to a maximum of 6 mg daily in those with mild dysfunction and 4 mg with moderate dysfunction.

Perampanel is available as 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg tablets.

Potential Advantages

Perampanel provides a drug with a new mechanism of action for the management of patients with refractory partial-onset seizures. It has a long half-life (70-120 hours) permitting once-daily dosing.

Potential Disadvantages

Perampanel carries a box warning for serious or life-threatening psychiatric and behavioral adverse events, including homicidal ideation.1 As with other antiepileptic drugs (AEDs), perampanel may increase the risk of suicidal thoughts or behavior. Other adverse events at the most common dose in the clinical trials (8 mg) include dizziness (32%), somnolence (16%), headache (11%), fatigue (8%), irritability (7%), nausea (6%), falls (5%), balance disorder (5%), weight gain (4%), and gait disturbance (4%).1

Comments

Perampanel is believed to exert its pharmacological effect by selectively inhibiting the class of ionotropic glutamine (AMPA) receptors that are localized at excitatory synapses in the central nervous system and are important in propagation of epileptic activity.2 The efficacy and safety of perampanel was evaluated in three randomized, double-blind, placebo-controlled studies.1,3-5 Subjects were 12 years of age and older, had partial-onset seizures with or without secondary generalization, had at least five partial seizures in the 6-week baseline phase without a 25-day seizure-free period, failed at least two AEDs in the previous 2 years, and were taking stable doses of up to three AEDs. After the baseline phase, subjects were randomized to placebo, 2 mg, 4 mg, or 8 mg in one study and 8 mg or 12 mg in the other two studies. There was a 6-week titration phase (to randomized dose) and a 13-week maintenance phase. The primary endpoint was the percent change in seizure frequency per 28 days during the maintenance phase as compared to the baseline period. The 2 mg dose was not statistically different than placebo. The median difference from placebo (95% confidence interval [CI]) was -13.7% (-23.3, -4.5) for the 4 mg, -20.1% (-29.7, -10.4), -19.1% (-29.2, -8.4), and -13.5% (-26.2, -1.9) for 8 mg dose in the three studies. For the 12 mg dose, the results were -14.2% (-25.0, -2.7) and -13.7% (-25.2, -2.3). The percent of patients with a 50% or greater reduction in seizure frequency was 28.5%, 35.3%, and 35.0% for 4 mg, 8 mg, and 12 mg, respectively, compared to 19.3% for placebo.1 For those who completed the maintenance phase, roughly 15-19% had 75-100% reduction in seizure frequency compared to 4-5% with placebo.3,4 There was little added benefit in increasing the drug from 8 mg to 12 mg, but there was a higher frequency of adverse events — the discontinuation rate due to adverse events increased from 8% to 19%.1 In a subanalysis by geographic region, benefits compared to placebo were seen in North American subjects but not in Central and South American subjects.3 The response to placebo was substantially higher in the later study population. In an open-label study, subjects (n = 53) who were exposed to perampanel for up to 4 years at a dose of 7.3 mg (± 3.3) maintained improved seizure control with no evidence of new safety signals.6

Clinical Implications

Partial seizures are the most common form of epilepsy. Approximately 25-30% are not controlled with currently available AEDs. Perampanel provides a new option for patients who have failed two or more AEDs. The long-term safety and geographic difference in efficacy will need to be determined.

References

1. Fycompa Prescribing Information. Woodcliff Lake, NJ: Eisai Inc.; October 2012.

2. Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Curr 2011;11:56-63.

3. French JA, et al. Adjunctive perampanel for refractory partial-onset seizures: Randomized phase III study 304. Neurology 2012;79:589-596.

4. French JA, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305. Epilepsia 2012; Aug 20. doi: 10.1111/j.1528-1167.2012.03638.x.

5. Krauss GL, et al. Randomized phase III study 306: Adjunctive perampanel for refractory partial-onset seizures. Neurology 2012;78:1408-1415.

6. Rektor I, et al. Perampanel Study 207: Long-term open-label evaluation in patients with epilepsy. Acta Neurol Scand 2012;126:263-269.