Abstracts

Rationale: Antiepileptic drugs (AEDs) should not ordinarily be withdrawn abruptly, but there are instances where this is necessary. The potential for eslicarbazepine acetate (ESL) to produce withdrawal symptoms has not previously been evaluated. With any centrally-acting drug, it is important to examine the potential for physical dependence, but no specific physical dependence/withdrawal scales are available for AEDs. This analysis evaluated the risk of physical dependence during treatment with ESL, according to the incidence of emergent adverse events (AEs) following abrupt discontinuation. Methods: For patients who discontinued ESL abruptly (contrary to the study protocols), data were pooled from 10 placebo-controlled trials (which included healthy volunteers and patients with epilepsy or other conditions). For inclusion in the analysis, patients must have had ≥7 days ESL exposure and a follow-up AE assessment, and must have discontinued ESL or placebo abruptly. Bipolar disorder trials were not included because recurrence of bipolar symptoms after withdrawal of ESL could have interfered with detection of AEs potentially related to dependence. AEs were obtained from patient reports (not by using a prospectively and systematically applied questionnaire); autonomic measures were not recorded. Results were analyzed by ESL mean daily dose, using the following categories: placebo (PBO); <800mg; 800 ̶ 1200mg; >1200mg. AEs with onset or increase in severity within 7 or 30 days of abrupt ESL/PBO discontinuation were assessed. Concomitant medication use prior to ESL/PBO discontinuation, or initiated within 7 or 30 days of discontinuation, was also evaluated. Results: This pooled analysis included 577 patients taking PBO and 1725 taking ESL (<800mg, n=563; 800 ̶ 1200mg, n=1053; >1200mg, n=109). Incidence of AEs within 7 days after abrupt ESL discontinuation was low, and similar to that after discontinuation of PBO (PBO, 2.6%; <800mg, 4.3%; 800 ̶ 1200mg, 4.6%; >1200mg, 2.8%). The most frequently reported AEs are shown in Table 1. AE incidence within 30 days of ESL/PBO discontinuation showed a similar pattern. There were no reports of hallucinations, autonomic hyperactivity, or perceptual disturbances (the presence of which might suggest development of physical dependence). Following abrupt discontinuation of ESL, analgesics and anti-inflammatory/anti-rheumatic drugs were the most frequently used concomitant medications, although use was less frequent after discontinuation of ESL (6.8% and 3.0%, respectively) versus PBO (10.1% and 4.5%, respectively). Medication use appeared to be related to symptoms of underlying disease states and not withdrawal-related symptoms. Conclusions: In this pooled analysis of AEs from ten PBO-controlled trials, abrupt discontinuation of ESL did not appear to be associated with AEs suggestive of physical dependence. There was no evidence of a withdrawal-emergent syndrome and patients did not exhibit a specific pattern of withdrawal-related AEs.