Abstracts

Rationale: Abrupt or rapid discontinuation of benzodiazepines (BZD) commonly results in a range of adverse events (AEs) that may be classified as withdrawal symptoms. Rates of these types of events with clobazam (CLB), a 1,5-BZD under FDA review for LGS in patients 2 years and older, may be different than rates for other BZDs. We assessed rates of withdrawal-related events following abrupt discontinuation and gradual tapering from CLB during Phase I III studies.Methods: Potential withdrawal-related AEs following the abrupt discontinuation of CLB were assessed in 4 multiple-dosage Phase I studies (CLB dosing 8 34 days). These studies were conducted with therapeutic (20 and 40 mg/day) and supratherapeutic dosages (120 and 160 mg/day). These events were also assessed in Phase II/III studies of CLB in LGS (CLB dosing up to 18 weeks) and their open-label extension (OLE) (CLB dosing 5 years). In these studies, gradual tapering over 2 to 3 weeks was conducted. Withdrawal-related AEs identified were consistent with those described in the literature on BZD use^{1 3}, and included sedation, somnolence, insomnia, irritability, anxiety, and seizures. The AE must have occurred 1 day following the last dose of CLB and within 30 days after last dose, or must have been designated as a withdrawal symptom by principal investigators.Results: Phase I participants received dosages at steady state over a range of 20 mg/day to 160 mg/day, with the vast majority receiving 40 mg/day and nearly half receiving 120 mg/day ( 4 times the maximum daily dosage of Phase II/III studies). In contrast, LGS patients received 40 mg/day during Phase II/III and 80 mg/day in the OLE. 87 patients discontinued CLB during Phase II/III and tapered study drug. None reported potential withdrawal-related AEs. As anticipated with BZD use, abrupt CLB discontinuation led to AEs consistent with withdrawal symptoms. Ninety-three AEs were reported for 68 of 207 participants receiving CLB in Phase I studies. Nearly all AEs occurred after abrupt discontinuation of CLB 40 mg/day dosage, with approximately half occurring at 120 mg/day. The majority of AEs following abrupt discontinuation were deemed mild, and included headache, insomnia, anxiety, and tremor. No status epilepticus occurred during withdrawal/tapering.Conclusions: Withdrawal-related AEs did not occur during 2- to 3-week tapering at the conclusion of Phase II/III studies of CLB. This tapering may have been even more rapid than is typically done in clinical practice. Further, no withdrawal-related AEs have been observed with long-term CLB therapy through 5 years in an OLE. In Phase I, abrupt CLB withdrawal led to generally mild AEs at rates comparable to what has been observed for other BZDs. However, the lack of consistency in sample size and dosing duration across studies and dosage groups makes it difficult to fully assess the effect of dosage on withdrawal symptoms. References: ¹Denis C, et al. Cochrane Database Syst Rev. 2006;3:CD005194. ²Petursson H, et al. Br Med J. 1981;282:1931 2. ³Petursson H, et al. Br Med J. 1981;283:643 5.