Abstract
Background
Epilepsy is a central nervous system disorder (neurological disorder). Epileptic seizures are the result of excessive and abnormal cortical nerve cell electrical activity in the brain. Despite the development of more than 10 new antiepileptic drugs (AEDs) since the early 2000s, approximately a third of people with epilepsy remain resistant to pharmacotherapy, often requiring treatment with a combination of AEDs. In this review, we summarised the current evidence regarding rufinamide, a novel anticonvulsant medication, which, as a triazole derivative, is structurally unrelated to any other currently used anticonvulsant medication when used as an add‐on treatment for drug‐resistant epilepsy. In January 2009, rufinamide was approved by the US Food and Drug Administration for the treatment of children four years of age and older with Lennox‐Gastaut syndrome. It is also approved as an add‐on treatment for adults and adolescents with focal seizures.
This is an updated version of the original Cochrane Review published in 2018.
Objectives
To evaluate the efficacy and tolerability of rufinamide when used as an add‐on treatment for people with drug‐resistant epilepsy.
Search methods
We imposed no language restrictions. We contacted the manufacturers of rufinamide and authors in the field to identify any relevant unpublished studies.
Selection criteria
Randomised, double‐blind, placebo‐controlled, add‐on trials of rufinamide, recruiting people (of any age or gender) with drug‐resistant epilepsy.
Data collection and analysis
Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: 50% or greater reduction in seizure frequency (primary outcome); seizure freedom; treatment withdrawal; and adverse effects (secondary outcomes). Primary analyses were intention‐to‐treat (ITT) and we presented summary risk ratios (RRs) with 95% confidence intervals (CIs). We evaluated dose response in regression models. We carried out a risk of bias assessment for each included study using the Cochrane ‘Risk of bias’ tool and assessed the overall certainty of evidence using the GRADE approach.
Main results
The review included six trials, representing 1759 participants. Four trials (1563 participants) included people with uncontrolled focal seizures. Two trials (196 participants) included individuals with established Lennox‐Gastaut syndrome. Overall, the age of adults ranged from 18 to 80 years and the age of children ranged from 4 to 16 years. Baseline phases ranged from 28 to 56 days and double‐blind phases from 84 to 96 days. Five of the six included trials described adequate methods of concealment of randomisation, and only three described adequate blinding. All analyses were by ITT. Overall, five studies were at low risk of bias and one had unclear risk of bias due to lack of reported information around study design. All trials were sponsored by the manufacturer of rufinamide and therefore were at high risk of funding bias.
The overall RR for 50% or greater reduction in seizure frequency was 1.79 (95% CI 1.44 to 2.22; 6 randomised controlled trials (RCTs), 1759 participants; moderate‐certainty evidence), indicating that rufinamide (plus conventional AED) was significantly more effective than placebo (plus conventional AED) in reducing seizure frequency by at least 50% when added to conventionally used AEDs in people with drug‐resistant focal epilepsy. Data from only one study (73 participants) reported seizure freedom: RR 1.32 (95% CI 0.36 to 4.86; 1 RCT, 73 participants; moderate‐certainty evidence). The overall RR for treatment withdrawal (for any reason and due to AED) was 1.83 (95% CI 1.45 to 2.31; 6 RCTs, 1759 participants; moderate‐certainty evidence), showing that rufinamide was significantly more likely to be withdrawn than placebo. Most adverse effects were significantly more likely to occur in the rufinamide‐treated group. Adverse events significantly associated with rufinamide were headache, dizziness, somnolence, vomiting, nausea, fatigue, and diplopia. The RRs for these adverse effects were as follows: headache 1.36 (95% Cl 1.08 to 1.69; 3 RCTs, 1228 participants; high‐certainty evidence); dizziness 2.52 (95% Cl 1.90 to 3.34; 3 RCTs, 1295 participants; moderate‐certainty evidence); somnolence 1.94 (95% Cl 1.44 to 2.61; 6 RCTs, 1759 participants; moderate‐certainty evidence); vomiting 2.95 (95% Cl 1.80 to 4.82; 4 RCTs, 777 participants; low‐certainty evidence); nausea 1.87 (95% Cl 1.33 to 2.64; 3 RCTs, 1295 participants; moderate‐certainty evidence); fatigue 1.46 (95% Cl 1.08 to 1.97; 3 RCTs, 1295 participants; moderate‐certainty evidence); and diplopia 4.60 (95% Cl 2.53 to 8.38; 3 RCTs, 1295 participants; low‐certainty evidence). There was no important heterogeneity between studies for any outcomes. Overall, we assessed the evidence as moderate to low certainty due to wide CIs and potential risk of bias from some studies contributing to the analysis.
Authors’ conclusions
For people with drug‐resistant focal epilepsy, rufinamide when used as an add‐on treatment was effective in reducing seizure frequency. However, the trials reviewed were of relatively short duration and provided no evidence for long‐term use of rufinamide. In the short term, rufinamide as an add‐on was associated with several adverse events. This review focused on the use of rufinamide in drug‐resistant focal epilepsy, and the results cannot be generalised to add‐on treatment for generalised epilepsies. Likewise, no inference can be made about the effects of rufinamide when used as monotherapy.
Plain language summary
How well does rufinamide treat drug‐resistant epilepsy when given with another antiepileptic medicine?
What is drug‐resistant epilepsy?
Epilepsy is a condition in which sudden bursts of intense electrical activity happen in the brain and cause the brain’s messages to get mixed up, resulting in a seizure. Seizures affect people in different ways: they may cause unusual sensations, movements or feelings, loss of awareness, falls, stiffness or jerking. Epileptic seizures can occur repeatedly and without any triggers. Seizures can happen anytime and anywhere; they can come on suddenly and can happen often.
Treatments for epilepsy focus on stopping or reducing the number of seizures a person has with as few unwanted effects as possible. Most seizures are controlled by taking a single antiepileptic medicine. But some people’s epilepsy does not respond (drug‐resistant epilepsy) and they may need more than one medicine to control the seizures. Drug‐resistant epilepsy is more common if the seizures involve one area of the brain (focal epilepsy) rather than the whole outer area of the brain (generalised epilepsy).
Why we did this review
Rufinamide is an antiepileptic medicine. It is given in addition to other antiepileptic medicines as an ‘add‐on’ treatment for focal epilepsy in adults and adolescents.
We wanted to know how well add‐on rufinamide works to treat drug‐resistant epilepsy, including the potential benefits and any unwanted effects of treatment.
What did we do?
We searched for studies that investigated the use of rufinamide as an add‐on treatment for drug‐resistant epilepsy.
We looked for randomised controlled studies, in which the treatments people received were decided at random, because these studies usually give the most reliable evidence about the effects of a treatment. We assessed the evidence we found by looking at how the studies were conducted, the study sizes, and whether their findings were consistent.
Search date: we included evidence published up to 20 February 2020.
What we found
We found six studies in 1759 people (aged 4 to 80 years). Four studies included people with focal seizures and two studies included children with Lennox‐Gastaut syndrome (a type of epilepsy affecting children). They were short‐term studies: treatments were given for at most 96 days, and assessments continued for up to 3 to 6 months afterwards.
The studies assessed add‐on rufinamide treatment compared with an ‘add‐on’ dummy (placebo) treatment. The doses of rufinamide in the studies ranged from 200 mg to 3200 mg daily.
We were interested in how many seizures people had. We also wanted to find out if adding rufinamide would affect the number and types of unwanted effects.
What are the results of our review?
Adding rufinamide to another antiepileptic medicine probably reduced how often seizures happened more than an add‐on placebo did (6 studies). Add‐on rufinamide probably increased seizure freedom (no seizures) more than an add‐on placebo, although only one study measured this.
More people stopped taking add‐on rufinamide (because of unwanted effects or for any other reason) than stopped taking add‐on placebo treatment (6 studies). Unwanted effects were probably more common in people who received add‐on rufinamide rather than add‐on placebo. Unwanted effects that were reported included: feeling dizzy (3 studies), feeling tired (3 studies), feeling sick (3 studies), headache (3 studies), feeling drowsy or sleepy (6 studies), being sick (vomiting) (4 studies) and double vision (3 studies).
How reliable are these results?
We are moderately confident (certain) about our findings for the effects of add‐on rufinamide on how many seizures people had, and on some of the unwanted effects seen (dizziness, sleepiness, headaches, tiredness and feeling sick). Our results may change if further evidence becomes available.
We are less confident (uncertain) about the unwanted effects of vomiting and double vision seen with add‐on rufinamide, because the results for these effects varied widely. Our results are likely to change if further evidence becomes available.
All studies were conducted or sponsored by a pharmaceutical company that makes rufinamide: this may have affected how the studies were designed, carried out and reported. One study did not fully report its study design.
Conclusions
Adding rufinamide to an antiepileptic medicine probably reduced seizures more than a placebo, but probably caused more unwanted effects (in the short term); more people stopped add‐on rufinamide treatment.
