Abstracts

Rationale: To examine the long-term safety of lacosamide (LCM) for partial-onset seizures based on all available data from Phase II-III double-blind and open-label extension trials. Methods: Pooled data for patients treated with LCM in completed double-blind trials and corresponding ongoing open-label extension trials were analyzed. For patients who received LCM in double-blind trials, data from the double-blind and open-label trials were included. For patients who received placebo in double-blind trials, data from the transition period at the end of the double-blind trials and from open-label trials were used. Lacosamide exposure was relative to the first dose and was based on all available data (double-blind and open-label extension) from visits completed as of an interim analysis cut-off of April 7, 2008. Safety analyses included treatment-emergent adverse events (TEAEs), ECGs, vital signs, body weight and clinical laboratory data. Results: 1,327 patients received at least one dose of LCM and were included in the analysis, representing 2,663patient-years exposure. The median duration of LCM exposure was 700 days (min 1.0, max 2437) The most common modal dose (dose used for the longest duration of time) was 400mg/day (n=347, 26.1%), with 85.7% of patients (n=1137) having a modal dose of 200-600mg/day and 8.4% (n=111) having a modal dose of >600 to ≤800mg/day. At the time of this interim analysis, 526 patients were still enrolled in LCM clinical trials. 1211 patients (91.3%) had reported at least 1 TEAE as of the interim analysis cut-off. The most common TEAEs (≥10%) were dizziness (45.6), headache (20.6%), diplopia (18.5%), nausea (15.3%), nasopharyngitis (14.3%), vomiting (14.1%), fatigue (13.8%), coordination abnormal (12.5%), vision blurred (12.0%), tremor (11.5%), somnolence (11.5%) convulsion (11.4%), and contusion (10.4%). The overall incidence of TEAEs increased with dose, although the increase was not remarkable. In general, there were no new types of TEAEs thought to be related to the drug that emerged with chronic therapy. Most TEAEs were mild or moderate in intensity. The only AE for which maximum intensity was reported as ‘severe’ in >1% of subjects was dizziness (4.7%). The most common TEAEs leading to discontinuation (>1%) were dizziness (5.3%) followed by vomiting (1.6%), nausea (1.5%), diplopia (1.5%) and coordination abnormal (1.5%). Long-term LCM treatment was not associated with any pattern of change in median or mean measurements for hematology, clinical chemistry, vital sign or body weight. A small increase in mean PR interval of 5 to 9 ms was observed on ECGs acquired at various times during LCM exposure. This did not appear to be clinically relevant, and there were no reports of higher (second or third) degree heart block. Conclusions: Long-term treatment with lacosamide was generally well tolerated, with the incidence of TEAEs, vital signs and clinical laboratory and ECG findings similar to those reported with short-term, double-blind use.