Abstracts

Rationale: Eslicarbazepine acetate (ESL) is an antiepileptic that is converted to eslicarbazepine after oral administration. ESL 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. Three randomized, double-blind, placebo-controlled phase III trials (BIA-2093-301, -302 and -304) evaluated the safety and efficacy of ESL as adjunctive treatment for adults with POS. This analysis reports pooled safety data from these studies.Methods: Patients with 4 POS/month, receiving 1 3 anti-epileptic drugs (AEDs), were enrolled. All 3 trials comprised an 8-wk baseline period, a 2-wk double-blind titration phase, and a 12-wk double-blind, fixed-dose maintenance phase. Patients were randomized equally to receive placebo (PBO) or ESL, given once-daily (QD) at 400mg (only 2 studies), 800mg, or 1200mg. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, serious AEs (SAEs), and deaths.Results: Only data for the 800mg and 1200mg doses are reported here as the 400mg dose was not statistically significantly more effective than PBO in these trials. The pooled safety population included 825 patients who received 1 dose of ESL 800mg (n=415) or 1200mg (n=410) QD (total exposure, 102 and 90.1 patient-yrs, respectively), and 426 patients who received PBO. Median age was 38.0, 37.0 and 37.0 yrs in the ESL 800mg, 1200mg and PBO groups, respectively. Overall, ~78% of patients were Caucasian, and around 27% were taking a single AED. The most frequent TEAEs, seen in 5% of patients in either ESL group are shown in Table 1. A dose-response relationship was noted for these TEAEs (except blurred vision) and for TEAEs leading to discontinuation. Allergic reactions were not increased with ESL treatment, while rates of hyponatremia events were higher with ESL than PBO. SAEs were observed in 7.0% and 2.7% of ESL 800mg and 1200mg patients, respectively versus 2.8% of PBO-treated patients. SAEs with incidence 0.5% in either ESL group were ataxia, balance disorder, diplopia, fall, hyponatremia, nausea, POS, POS with secondary generalization, vertigo, and vomiting. Serious skin reactions were reported in 2 ESL-treated patients (leukocytoclastic vasculitis, 800mg, n=1; rash, 1200mg, n=1), but not in PBO-treated patients. Two deaths were observed in the PBO group (acute respiratory failure, n=1; possibly SUDEP, n=1) and one in the ESL 800mg group (status epilepticus). ESL had no clinically relevant impact on laboratory parameters (other than occasional decreases in serum sodium and thyroid hormones), vital signs, or electrocardiograms.Conclusions: This pooled analysis showed that ESL 800mg and 1200mg once daily were consistently well tolerated, with a low incidence of SAEs, when used as adjunctive therapy in adult patients with POS. TEAEs, particularly nervous system and gastrointestinal disorders, were more common with ESL than PBO, and increased with dose.