Add-on perampanel is effective at reducing seizure frequency and may maintain seizure freedom for people with drug-resistant focal epilepsy. Perampanel is well-tolerated at doses of 8 mg/day or less.
What is epilepsy?
Epilepsy is one of the most common brain disorders. Approximately 30% of people with epilepsy continue to have seizures (sudden bursts of electrical activity in the brain that change how it works for a short time) despite adequate therapy with antiepileptic medicines. These people are regarded as having drug-resistant epilepsy and usually need treatment with a combination of antiepileptic medicines. Perampanel is a newer antiepileptic medicine that has been investigated as an add-on therapy for drug-resistant focal epilepsy (when seizures originate from one area of the brain).
What did we want to find out?
We wanted to know whether perampanel was effective and tolerable when used as an add-on therapy for people with drug-resistant focal epilepsy.
What did we do?
We searched medical databases for studies investigating the effects of perampanel as add-on therapy in people with drug-resistant focal epilepsy of any age.
What did we find?
We found seven studies that met our criteria. The studies involved 2524 people, who were all aged 12 years and over. During the studies, people received a dose of perampanel (2 mg per day, 4 mg per day, 8 mg per day, or 12 mg per day) or placebo (dummy treatment) as an add-on therapy. The people in the studies received their treatment for 12 to 19 weeks.
People who received perampanel were more likely to have a 50% or more reduction in the number of seizures that they normally experience. A greater number of people who received perampanel became free from all seizures, but they were also more likely to withdraw from treatment. The results indicated that perampanel 8 mg per day or 12 mg per day were most effective at controlling seizures; however, perampanel 12 mg per day also led to more people withdrawing from treatment.
People taking perampanel were more likely to experience side effects than those taking placebo. The most common side effects included dizziness and sleepiness.
What are the limitations of the evidence?
We judged that most studies were at low risk of bias. When a study has low risk of bias, it means that the effect that the study reports should be reliable. We also assessed the evidence used in this review for certainty. We found high-certainty evidence that perampanel was more likely to reduce the number of seizures by 50% or more. This means that we are confident that this finding is accurate. There was low-certainty evidence that more people became free of all seizures, withdrew from treatment, and experienced problems with co-ordination, balance, and speech (known as ataxia) or dizziness, meaning that the findings for these measures may be inaccurate.
How up to date is this evidence?
The evidence is current to October 2022.
Add-on perampanel is effective at reducing seizure frequency and may be effective at maintaining seizure freedom for people with drug-resistant focal epilepsy. Although perampanel was well-tolerated, there was a higher proportion of treatment withdrawals with perampanel compared with placebo. Subgroup analysis suggested that 8 mg/day and 12 mg/day are the most efficacious perampanel doses; however, the use of 12 mg/day would likely increase the number of treatment withdrawals.
Future research should focus on investigating the efficacy and tolerability of perampanel with longer-term follow-up, as well as exploring an optimal dose.
Epilepsy is one of the most common neurological disorders. Approximately 30% of people with epilepsy are considered to be drug-resistant, and usually need treatment with a combination of other antiepileptic drugs. Perampanel is a newer antiepileptic drug that has been investigated as add-on therapy for drug-resistant focal epilepsy.
To evaluate the benefits and harms of perampanel as add-on therapy for people with drug-resistant focal epilepsy.
We used standard, extensive Cochrane search methods. The latest search date was 20 October 2022.
We included randomised controlled trials comparing add-on perampanel with placebo.
We used standard Cochrane methods. Our primary outcome was 1. 50% or greater reduction in seizure frequency. Our secondary outcomes were 2. seizure freedom, 3. treatment withdrawal due to any reason, 4. treatment withdrawal due to adverse effects, and 5. adverse effects. We used an intention-to-treat population for all primary analyses. We presented the results as risk ratios (RR) with 95% confidence intervals (CIs), except for individual adverse effects, which we reported with 99% CIs to compensate for multiple testing. We used GRADE to assess certainty of evidence for each outcome.
We included seven trials involving 2524 participants, all aged over 12 years. The trials were double-blind, randomised, placebo-controlled trials with treatment duration of 12 to 19 weeks. We assessed four trials at overall low risk of bias, and three trials at overall unclear risk of bias, due to risk of detection, reporting, and other biases.
Compared with placebo, participants receiving perampanel were more likely to achieve a 50% or greater reduction in seizure frequency (RR 1.67, 95% CI 1.43 to 1.95; 7 trials, 2524 participants; high-certainty evidence). Compared to placebo, perampanel increased seizure freedom (RR 2.50, 95% CI 1.38 to 4.54; 5 trials, 2323 participants; low-certainty evidence) and treatment withdrawal (RR 1.30, 95% CI 1.03 to 1.63; 7 trials, 2524 participants; low-certainty evidence). Participants treated with perampanel were more likely to withdraw from treatment due to adverse effects compared to those receiving placebo (RR 2.36, 95% CI 1.59 to 3.51; 7 trials, 2524 participants; low-certainty evidence). A higher proportion of participants receiving perampanel reported one or more adverse effects when compared to participants who received placebo (RR 1.17, 95% CI 1.10 to 1.24; 7 trials, 2524 participants; high-certainty evidence). Compared with placebo, participants receiving perampanel were more likely to experience ataxia (RR 14.32, 99% CI 1.09 to 188.31; 2 trials, 1098 participants; low-certainty evidence), dizziness (RR 2.87, 99% CI 1.45 to 5.70; 7 trials, 2524 participants; low-certainty evidence), and somnolence (RR 1.76, 99% CI 1.02 to 3.04; 7 trials, 2524 participants).
Subgroup analysis indicated that a larger proportion of participants who received perampanel at a dose of 4 mg/day (RR 1.38, 95% CI 1.05 to 1.83; 2 trials, 710 participants), 8 mg/day (RR 1.83, 95% CI 1.51 to 2.22; 4 trials, 1227 participants), or 12 mg/day (RR 2.38, 95% CI 1.86 to 3.04; 3 trials, 869 participants) achieved a 50% or greater reduction in seizure frequency compared to placebo; however, treatment with perampanel 12 mg/day also increased treatment withdrawal (RR 1.77, 95% CI 1.31 to 2.40; 3 trials, 869 participants).