Abstracts

Rationale: Eslicarbazepine acetate (ESL) is an antiepileptic that was approved in 2009 by the European Medicines Agency as adjunctive therapy in adults with partial-onset seizures (POS), with or without secondary generalization. ESL is not approved in the US. Safety data from the titration phase of 3 randomized, double-blind, placebo-controlled trials (BIA-2093-301, -302 and -304) were analyzed to investigate the influence of initial ESL dose on adverse events (AEs). Methods: Patients aged 16yrs (only study BIA-2093-304), or 18yrs who had 4 POS/month and were taking 1 3 anti-epileptic drugs were randomized 1:1:1:1 to once-daily (QD) placebo (PBO), ESL 400mg (2 studies), 800mg, or 1200mg. Different 2-wk titration schedules were followed in each study, followed by a 12-wk maintenance phase at the final target dose. Schedules for wk 1/2 during titration were as follows: FINAL DOSE: WEEK 1/2 DOSES 400mg: 400mg/400mg 800mg: 400mg/800mg or 800mg/800mg 1200mg: 400mg/800mg or 800mg/800mg. Treatment-emergent AEs (TEAEs) were monitored throughout.Results: 1447 patients received 1 dose of ESL or PBO. Mean age was ~38yrs (range 16 75yrs). Most patients were Caucasian. The double-blind period was completed by 86.2% (PBO), 88.8% (400mg), 81.7% (800mg), and 68.5% (1200mg) of patients. During wk 1, 31.5% (PBO; n=426), 35.1% (400mg; n=612), and 61.9% (800mg; n=409) of patients experienced 1 TEAE. The following TEAEs occurred at 5% higher frequency with ESL 800mg vs 400mg: dizziness (23.0% vs 7.5%), somnolence (14.7% vs 5.6%), headache (10.0% vs 3.1%) and nausea (11.5% vs 2.9%). During titration, the 800mg/800mg scheme was associated with a markedly higher incidence of TEAEs vs PBO (Table 1). Patients on the 400mg/800mg scheme had a similar incidence of TEAEs as PBO. TEAEs tended to be more frequent in the first wk of a new dose (Table 2). Escalation by 400mg increments was associated with a minimally increased incidence of TEAEs vs PBO. Patients on the 400mg/800mg scheme experienced fewer TEAEs in the first wk at 800mg than those who initiated at 800mg. During the second wk on dose, incidence of TEAEs for those who escalated by 400mg increments was comparable to PBO. Incidence of TEAEs in the second week on dose for those starting at 800mg remained higher than PBO, but lower than the first wk at 800mg. During maintenance, incidence of TEAEs was 48.3% (PBO; N=410), 48.4% (400mg; N=192), 56.7% (800mg; N=383), and 61.0% (1200mg; N=364).The incidence of TEAEs during tapering was 14.0% (PBO; N=93), 19.4% (400mg; N=93), 17.4% (800mg; N=92), and 19.0% (1200mg; N=84). Conclusions: ESL 800mg and 1200mg QD were generally well tolerated. Dose escalation to 800mg in increments of 400mg was associated with a more favorable AE profile than a starting dose of 800mg. TEAEs were more frequent in the first wk at a new dose level. By the second wk, patients receiving 400mg, or who had escalated to 800mg or 1200mg in 400mg increments, showed an incidence of new TEAEs comparable with PBO.