Epileptologist Ochsner Neuroscience Institute New Orleans, Louisiana
Rationale: Clobazam is a benzodiazepine that was approved by the U.S. Food and Drug Administration in year 2011 for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients ≥2 years of age based on results from two randomized, controlled trials of clobazam at fixed dosages of a maximum of 10-40 mg/d. During a subsequent open-label study, enrolled patients were started at 0.5 mg/kg/d, not to exceed 40 mg/d. This dosage was maintained for 48 hours; then dosages could be adjusted up to 2.0 mg/kg/d (maximum allowed dosage 80 mg/d) based on efficacy and tolerability. In clinical practice, clobazam has been widely used for seizure control in both focal and generalized epilepsies. However, there are few reports of tolerability at doses > 40 mg/d. Methods: We conducted a retrospective review of charts of adult patients who were maintained on 60-160 mg/day of clobazam for the management of epilepsy from January 1, 2019-January 1, 2020. We reviewed the demographic information in addition to patient reported dose related side effects related to clobazam. We also reviewed potential drug interactions impacting tolerability. All patients were on oral tablet formulation. Efficacy assessments and percent change in seizure frequency were not quantified in this study. The dose of clobazam was titrated by treating neurologists based on clinical judgement with the goal of optimizing seizure control. Results: We identified 32 patients, 16 females and 16 males, mean age was 40 years, 19 (59%) had focal onset epilepsy, none had generalized onset epilepsy, and 13 (40%) had LGS. The mean body weight was 75.8 kg. No patient had hepatic or renal dysfunction. No patients reported the use of marijuana products. One patient who reported increased sedation while on concurrent omeprazole was switched to pantoprazole with resolution of symptoms. The number of concurrent antiseizure drugs (ASD) ranged from one to five. 12 (38%) patients had vagal nerve stimulator placement.
In this cohort, the maximum tolerated maintenance dose of clobazam was 60 mg/d in 9 patients, 80 mg/d in 11 patients, 90 mg/d in one patient, 100 mg/d in two patients, 120 mg/d in six patients, 140 mg/d in one patient, and 160 mg/d in two patients. Three patients reported dose dependent side effects; lethargy at 160mg/d, insomnia at 80 mg/d, and headache at 120 mg/d. Two cases of Sudden Unexplained Death in Epilepsy (SUDEP) were reported: one patient with LGS (80 mg/d) and one patient with focal-onset epilepsy (120 mg/d). Both patients were also maintained on two additional ASDs. Conclusions: In our cohort study, we describe characteristics of 32 patients who tolerated clobazam at a dose range of 60-160 mg/d with no identifiable confounding drug interactions. Interestingly these patients were also maintained on one to five concurrent ASDs. Three patients who reported dose dependent side effects were eventually maintained at a minimum of 80 mg/d. In this study we provide data on the favorable safety profile at doses up to four times greater than the standard 40 mg/d in the control of seizures in adult patients with epilepsy. Funding: Please list any funding that was received in support of this abstract.: None