Abstracts

Rationale: Clinically significant hyponatremia has been associated with the use of carbamazepine (CBZ) and oxcarbazepine (OXC). Eslicarbazepine acetate (ESL) is a novel once-daily voltage-gated sodium channel (VGSC) blocker chemically related to carbamazepine. To gain an understanding of the nature and risks of hyponatremia in association with the use of ESL as an adjunctive antiepileptic drug (AED), adverse events (AEs), laboratory trends, and concomitant AEDs use were analyzed in subjects taking ESL compared with placebo as adjunctive therapy to 1-3 concomitant AEDs (OXC was not allowed) in the pooled data of 3 Phase III studies. Methods: The Safety population (n=1049) was defined as all subjects who received at least 1 dose of study medication (400 mg, 800 mg or 1200 mg of ESL or placebo) during the 14-week double-blind treatment phase of the Phase 3 studies. The incidence of hyponatremia Treatment Emergent Adverse Events (TEAEs) was summarized by treatment group, and analyzed for the combined ESL groups by type of concomitant AED. Descriptive analysis of mean change from baseline, and categorical analysis of serum sodium levels was conducted. Results: The overall risk of hyponatremia TEAEs was low (0.9%) in ESL versus 0% in placebo. Based on measured serum sodium levels, the incidence of hyponatremia among subjects taking ESL with CBZ, lamotrigine (LTG) or both increased to 1.4%, 2.5% and 6.1%, respectively, versus no increase in the placebo group. After 14 weeks, a small decrease in mean serum sodium values of 0, -0.7, -1.3, and -1.5 mEq/L was seen in the placebo and ESL 400 mg, 800 mg and 1200 mg groups, respectively. Decreases in sodium levels of >10 mEq/L were seen in the ESL groups with a clear dose response (0, 0.5, 2.5, and 3.7% in placebo, 400 mg, 800 mg and 1200 mg, respectively), which reverted with ESL discontinuation. Overall, more subjects receiving ESL (13.6%) had a serum sodium level <135 mEq/L at any time during the study compared to placebo (7.4%). In the pooled Phase III studies, 0.5% of ESL-treated patients (4/760) had at least one serum sodium value <125 mEq/L during treatment, compared to none of the patients receiving placebo. All 4 subjects were receiving concomitant CBZ, of which 1 subject was also treated with LTG. A trend toward a higher incidence of low sodium levels was observed for the subset of subjects taking ESL in addition to CBZ (18.3% and 4.5% of subjects for the <135 and <130 mEq/L cut points, respectively) versus subjects on ESL not using CBZ (7.4% and 1.9%, respectively). Conclusions: In this pooled analysis of 3 Phase III studies, clinically significant hyponatremia resulting in a TEAE occurred at a low frequency in association with ESL. The risk of a hyponatremia TEAE was increased in subjects taking ESL in combination with CBZ or LTG. Overall, there appeared to be a trend towards a small dose proportional decrease in mean serum sodium levels for all ESL treatment groups.