Abstracts

Rationale: Eslicarbazepine acetate (ESL) is a once-daily oral antiepileptic drug (AED) approved as adjunctive treatment for partial-onset seizures (POS) in the USA, Europe, and Canada, and as monotherapy for POS in the USA. ESL is a member of the dibenzazepine carboxamide class of putative voltage-gated sodium channel blockers, use of which has been associated with development of hyponatremia. This analysis examines the effect of ESL on plasma sodium levels and on the incidence of hyponatremia-related treatment emergent adverse events (TEAEs) in Phase III clinical trials of ESL. Methods: Plasma sodium levels and TEAEs were assessed during Phase III trials of ESL for treatment-refractory POS: three 14-week studies (2093-301, -302, -304) of double-blind adjunctive ESL or placebo (both taken with baseline AEDs); two dose-blind, 18-week conversion-to-monotherapy studies (093-045, -046); and open-label extensions (OLEs; studies 301/302, and 045/046 [093-050]) which allowed flexible dosing. 'True monotherapy' patients received ESL monotherapy during study 045/046 and did not re-introduce baseline AEDs during the OLE. Results: The controlled study analysis population comprised 1812 patients; 913 continued into the OLEs. Changes in sodium levels between baseline and end of study are reported in Table 1; small reductions in sodium levels occurred in the ESL treatment groups, but not in the placebo group. In the controlled trials, clinically meaningful minimum post-dose sodium levels (=125 mEq/L) were reported for 11 (1.1%) and 12 (3.3%) patients taking adjunctive ESL and ESL monotherapy, respectively (Table 1). In the uncontrolled OLE trials, sodium levels =125 mEq/L were reported for 17 (1.9%) patients (Table 1). Plasma sodium levels decreased by >10 mEq/L between baseline and end of study for < 10% of patients taking adjunctive ESL or ESL monotherapy in the controlled and uncontrolled trials. Incidences of hyponatremia-related TEAEs are reported in Table 2. In the controlled trials, the TEAE of 'hyponatremia' was reported for 17 (1.7%) and 15 (4.1%) patients taking adjunctive ESL and ESL monotherapy, respectively; incidences appeared to be dose-related (Table 2). Symptoms of hyponatremia were more frequent in patients with sodium levels < 130 mEq/L. Conclusions: Reductions in sodium levels and hyponatremia-related TEAEs were reported for some patients taking ESL. Monitoring of plasma sodium levels should therefore be considered during ESL treatment, particularly for patients with symptoms of hyponatremia, or for those receiving other medications known to reduce plasma sodium. Funding: Studies sponsored by Sunovion Pharmaceuticals Inc.