Felbamate used with other antiepileptic drugs for drug-resistant focal epilepsy

Background

Up to 30% of people with epilepsy still suffer epileptic seizures despite trying multiple antiepileptic drugs, whether separately or in combination. These people are described as having drug-resistant epilepsy. Drug-resistance is most common in people with focal epilepsy (epilepsy that initially begins in one area of the brain, but can progress to affect the whole brain). Felbamate is an antiepileptic drug that might be effective for people with drug-resistant focal epilepsy when used with other antiepileptic drugs.

Aim of the review

This review investigated whether felbamate is effective and tolerable for people with drug-resistant focal epilepsy, when used with other antiepileptic drugs (add-on therapy).

Results

After searching the available literature, we found four trials, involving 236 participants, that investigated the use of felbamate in people with drug-resistant focal epilepsy. We included the four trials in the review.

Although three of the trials reported percentage reduction in seizure frequency, they all reported very different results. One reported a 36% reduction in seizure frequency with felbamate, one reported only a 4% reduction with felbamate, and the other trial reported that there was no difference between felbamate and placebo (an inactive, dummy drug). We therefore found no clear evidence to suggest that felbamate was better than placebo at reducing seizure frequency for people with drug-resistant focal epilepsy. Additionally, there was mixed evidence about whether more people withdraw from treatment with felbamate or placebo. Notably, less than 10% of people in each trial withdrew from treatment when they were receiving felbamate, suggesting that felbamate may have good tolerability. The side effects that were reported by all four trials, suggesting that they are the most common, were headache, dizziness, and nausea.

Quality of evidence

It is important to note that the four trials in this review studied a small number of people, over a short period of time (less than 10 weeks). We are very uncertain about whether the findings of this review are accurate. It is likely that the true effect of felbamate could be very different to that reported here. More large trials, conducted over a longer period of time are necessary to improve the certainty of the findings reported by this review.

The evidence is current to 18 December 2018.

Authors' conclusions: 

In view of the methodological deficiencies, the limited number of included studies and the differences in outcome measures, we have found no reliable evidence to support the use of felbamate as an add-on therapy in people with drug-resistant focal-onset epilepsy. A large-scale, randomised controlled trial conducted over a longer period of time is required to inform clinical practice.

Read the full abstract...
Background: 

This is an updated version of the Cochrane Review previously published in 2017.

Epilepsy is a chronic and disabling neurological disorder, affecting approximately 1% of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available antiepileptic drugs and require treatment with multiple antiepileptic drugs in combination. Felbamate is a second-generation antiepileptic drug that can be used as add-on therapy to standard antiepileptic drugs.

Objectives: 

To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with drug-resistant focal-onset epilepsy.

Search strategy: 

For the latest update we searched the Cochrane Register of Studies (CRS Web), MEDLINE, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP), on 18 December 2018. There were no language or time restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies.

Selection criteria: 

We searched for randomised placebo-controlled add-on studies of people of any age with drug-resistant focal seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel-group or cross-over design.

Data collection and analysis: 

Two review authors independently selected studies for inclusion and extracted information. In the case of disagreements, the third review author arbitrated. Review authors assessed the following outcomes: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life.

Main results: 

We included four randomised controlled trials, representing a total of 236 participants, in the review. Two trials had parallel-group design, the third had a two-period cross-over design, and the fourth had a three-period cross-over design. We judged all four studies to be at an unclear risk of bias overall. Bias arose from the incomplete reporting of methodological details, the incomplete and selective reporting of outcome data, and from participants having unstable drug regimens during experimental treatment in one trial. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the extracted data.

Only one study reported the outcome, 50% or greater reduction in seizure frequency, whilst three studies reported percentage reduction in seizure frequency compared to placebo. One study claimed an average seizure reduction of 35.8% with add-on felbamate while another study claimed a more modest reduction of 4.2%. Both studies reported that seizure frequency increased with add-on placebo and that there was a significant difference in seizure reduction between felbamate and placebo (P = 0.0005 and P = 0.018, respectively). The third study reported a 14% reduction in seizure frequency with add-on felbamate but stated that the difference between treatments was not significant. There were conflicting results regarding treatment withdrawal. One study reported a higher treatment withdrawal for placebo-randomised participants, whereas the other three studies reported higher treatment withdrawal rates for felbamate-randomised participants. Notably, the treatment withdrawal rates for felbamate treatment groups across all four studies remained reasonably low (less than 10%), suggesting that felbamate may be well tolerated. Felbamate-randomised participants most commonly withdrew from treatment due to adverse effects. The adverse effects consistently reported by all four studies were: headache, dizziness and nausea. All three adverse effects were reported by 23% to 40% of felbamate-treated participants versus 3% to 15% of placebo-treated participants.

We assessed the evidence for all outcomes using GRADE and found it as being very-low certainty, meaning that we have little confidence in the findings reported. We mainly downgraded evidence for imprecision due to the narrative synthesis conducted and the low number of events. We stress that the true effect of felbamate could likely be significantly different from that reported in this current review update.

Share/Save