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 have been used for refractory LGS, many clinicians are interested in converting existing 1,4-benzodiazepines, especially clonazepam (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 with or without secondary generalization were recruited for a prospective, open-label conversion study conducted at the Barrow Neurological Institute from 2013 to 2014. Patients who were taking a stable dosing regimen of CLN (0.5 to 4 mg 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 is achieved safely, CLB was then titrated up to 40 mg per day as tolerated. Efficacy was determined by measuring mean seizure frequency changes per 28 days over the first 6 month compared to baseline. Safety of CLN conversion to CLB was measured by reported adverse effects and potential increase of seizure frequency. Retention rate was also determined at the end of the first six months of study participation. 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%) and 76% had documented abnormal MRI findings (i.e. heterotopia, cortical dysplasia, stroke and schizencephaly). The average number of concomitant AED's taken was 2 with levetiracetam being the most common. Mean percent seizure reduction during the conversion phase was 51.7%, followed by 31.5% and 39.8% at 3 and 6 months respectively. 95% of patients were able to complete the conversion, and the 6-month retention rate was 81%. The most commonly reported adverse effects were somnolence (33%), dizziness (33%), fatigue (24%), aggression (19%) and headache (19%). There were no reported cases of significant seizure frequency increase or status epilepticus during the study. Conclusions: CLN can be safely converted to CLB at a 1:10 conversion rate typically within 2 weeks for the treatment of epilepsy. The transition from CLN to CLB was very well tolerated and resulted in significant seizure reduction. High retention rate of CLB also suggests the lack of developing tolerance to its therapeutic effects. Support: This research was funded by Lundbeck LLC.