Abstracts

Rationale: Eslicarbazepine acetate (ESL) is a once-daily oral antiepileptic drug (AED) for partial-onset (focal) seizures (POS). ESL is not FDA-approved for use in children. The putative mechanism of action of ESL (a dibenzazepine carboxamide AED) is sodium channel blockade; other dibenzazepine carboxamides have been found to be associated with hyponatremia. Also, reductions in sodium levels (from baseline) and clinically significant hyponatremia have been observed in some adults taking ESL. Here, we evaluate the effect of ESL on plasma sodium levels and incidence of hyponatremia treatment-emergent adverse events (TEAEs) in clinical trials of ESL in children. Methods: A subset of data (ages 4–17 years) pooled from studies 2093-208 and -305 were analyzed to address specific FDA requests for pediatric registration in the US. Both trials were randomized, double-blind, placebo-controlled studies of once-daily adjunctive ESL in children with POS refractory to treatment with 1–2 AEDs. Study 208 (part 1) was a 12-week, Phase II study in patients aged 6–16 years, with a target dose of 30 mg/kg/day. Study 305 (part 1) was an 18-week, Phase III study in patients aged 2–17 years, with a target dose of 20 mg/kg/day. All patients could continue into uncontrolled, open-label extensions (OLEs). Plasma sodium levels and TEAEs were assessed during the studies. Results: The safety populations of the pooled controlled studies, 1-year OLEs and post 1-year OLEs comprised 362, 337 and 177 patients, respectively (Table 1). Baseline demographics and clinical characteristics were comparable between treatment groups: the majority of patients were Caucasian and enrolled in European centers; gender distribution was approximately equal; mean (SD) ages were 11.1 (3.4) and 10.3 (3.5) years for ESL and placebo, respectively. Few patients taking ESL had a >10 mEq/L decrease in plasma sodium level from baseline (n = 3, 5, 1) and/or potentially clinically significant (=125 mEq/L) minimum post-dose sodium levels (n = 1, 0, 1) during the controlled, 1-year OLE and post 1-year OLE periods, respectively; indeed, minimum post-dose sodium levels were >135 mEq/L in >90% of patients in all periods (Table 2). There were no reports of hyponatremia-related TEAEs during the controlled or post 1-year OLE periods. However, hyponatremia was reported for one patient (0.3%) during the 1-year OLE period. In addition, during the post-marketing reporting period (September 23, 2014–July 8, 2016), a single, non-serious case of hyponatremia (lab values not provided) occurred in a pediatric patient (using ESL off-label). Conclusions: There were few incidences of potentially clinically significant minimum post-dose sodium levels/reductions in sodium levels from baseline and hyponatremia-related TEAEs in clinical trials of ESL in children (aged 4–17 years). Too few patients had medically significant hyponatremia to draw conclusions regarding differences across age groups or weight categories. Funding: Studies sponsored by BIAL; analyses sponsored by Sunovion Pharmaceuticals Inc.