Abstracts

Rationale: Clobazam (CLB), a 1,-5 benzodiazepine, was approved by the United States Food and Drug Administration in October 2011 for adjunctive treatment of seizures associated with Lennox-Gastaut Syndrome (LGS). As various types of 1,4-benzodiazepines, such as clonazepam (CLN) have been used for refractory LGS, many clinicians are interested in converting existing 1,4-benzodiazepines, especially CLN, to CLB to improve seizure control and improve overall long-term tolerability. However, the safety of such conversion therapy or conversion dosing ratio has not been established. We conducted a CLN to CLB conversion study in order to provide practical information in regards to safety, efficacy, and dosing ranges.Methods: Patients with a current diagnosis of medically refractory epilepsy were recruited for a prospective, open-label conversion study conducted in a single epilepsy center. Patients taking a stable dosing regimen of CLN (0.5 to 4mg daily) for seizures with at least one additional AED, and experiencing at least 2 seizures during the 8-weeks prior to entry were recruited to the study. The initial targeted conversion ratio was 1 to 10 (CLN to CLB). Patient’s CLN dose was reduced by 50% each week while CLB was increased based on the conversion ratio (Table 1). Once full conversion was safely achieved, CLB was then titrated up to 40 mg per day as tolerated. The primary outcome of the study was to measure the safety and tolerability of CLN to CLB conversion. Efficacy was evaluated by mean seizure frequency changes and 50% responder rates at 3, 6 and 12 month intervals.Results: A total of 21 patients were enrolled in the study. Fifty seven percent were female and the median age was 34 years (21 to 69 years). Patients had predominately partial onset seizures (95%) taking on average 2 concomitant AED’s. Conversion was very well tolerated and none reported status epileptics or significantly worsening of seizure frequency or severity. Of the most commonly reported adverse effects (AE’s) (somnolence [33%], dizziness [33%], fatigue [24%], aggression [19%] and headache [19%]), only 11.5% were reported during the conversion phase. Mean percent seizure reduction during conversion was 43.6%, followed by 41.0%, 42.6% and 59.1% at 3, 6 and 12 months, respectively. Responder rates were 38.1% during conversion, 47.1% at 3 and 6 months, and 64.3% at 12 months. Following conversion, 95% of patients required an increase in CLB dose to obtain seizure control. 47.6% of patients also required adjustment of their concomitant AED’s to obtain optimal seizure control. Of the 21 patients initially enrolled, 5 discontinued CLB due to reported AE’s. CLN was re-started in 2 of these patients.Conclusions: CLN can be safely converted to CLB at a 1:10 conversion rate typically within 2 weeks (range 1 to 4 weeks) for the treatment of refractory epilepsy. The transition from CLN to CLB was well tolerated and resulted in moderate seizure reduction. Support: This research was funded by Lundbeck LLC.