Withdrawal-related adverse events from clinical trials of clobazam in Lennox-Gastaut syndrome

To assess withdrawal-related adverse event (AE) rates following abrupt clobazam discontinuation in Phase I trials and gradual clobazam tapering (2-3 weeks) following discontinuation from III trials met the criteria for potential/III trials, we evaluated AE data from four multiple-dosage Phase I trials (duration: 8-34 days). Therapeutic (20 and 40 mg/day) and supratherapeutic clobazam dosages (120 and 160 mg/day) were administered. Adverse events (AEs) were also assessed for patients with Lennox-Gastaut syndrome enrolled in Phase II (OV-1002) and Phase III (OV-1012) studies (duration ≤15 weeks) and in the open-label extension (OLE) trial OV-1004 (≤5 years). Potential withdrawal-related AEs were identified by preferred terms, provided that the AEs occurred ≥1 day following and ≤30 days after the last clobazam doses, or were deemed withdrawal symptoms by investigators. Clinical Institute Withdrawal Assessment for Benzodiazepines (CIWA-B) scale was used to evaluate withdrawal intensity in three of the four Phase I trials. A total of 207 participants in Phase I trials received steady-state clobazam dosages of 20-160 mg/day, 182 received clobazam dosages of ≥40 mg/day, and 94 received clobazam dosages of ≥120 mg/day. Abrupt clobazam discontinuation led to 193 withdrawal-related AEs for 68 Phase I participants. Nearly 50% of AEs occurred after discontinuation of clobazam dosages of ≥120 mg/day. Adverse events were mild or moderate and included headache (14% of Phase I participants), insomnia (12.6%), tremor (10.1%), and anxiety (8.7%). The CIWA-B scores varied (range: 0-59). Most scores were <30, indicating possible mild benzodiazepine withdrawal. III trials met the criteria for potential/III patients received clobazam dosages of ≤40 mg/day, and those in the OLE trial received clobazam dosages of ≤80 mg/day. Eighty-seven patients discontinued clobazam and were gradually tapered. No withdrawal-related AEs or incidences of status epilepticus were reported. Withdrawal-related AEs observed in Phase I studies following abrupt clobazam discontinuation at therapeutic and supratherapeutic dosages were generally mild. No withdrawal-related AEs occurred when dosages were tapered over 3 weeks, after short- or long-term clobazam use (≤5 years).