Abstracts

Rationale: As the pharmacological management of epilepsy often requires long-term treatment with antiepileptic drugs (AEDs), it is necessary to examine the safety of AEDs upon prolonged exposure. The short-term safety and efficacy of the AED lacosamide for adjunctive treatment of partial-onset seizures has been established in three Phase 2/3 double-blind, placebo-controlled trials. The primary goal of this Phase 3 multicenter, uncontrolled open-label extension (OLE) trial (SP756; NCT00522275) was to examine the long-term safety of lacosamide in patients exposed for up to 5 years. Methods: Patients completing the maintenance phase of the US Phase 3 double-blind clinical trial (SP754; NCT00136019; Chung et al., Epilepsia 2010), who elected to enter the open-label extension trial were transitioned to a lacosamide dose of 200 mg/day to begin open-label treatment. This dose could be adjusted as necessary up to a maximum of 800 mg/day (in 100 mg/day per week increments) or decreased to a minimum of 100 mg/day; concomitant AEDs could also be increased or decreased on an individual basis. The safety outcomes included: adverse events (AEs), serious AEs (SAEs), withdrawal due to AEs, and changes in hematology, blood chemistry, urinalysis parameters, 12-lead ECGs, vital signs, body weight, and physical or neurological examination findings. Data were analyzed for all patients who received at least one dose of open-label lacosamide. Results: A total of 308 patients were exposed to open-label lacosamide (median modal dose 500 mg/day) over the trial period, representing 767.4 patient-years exposure. A total of 75% of patients completed at least 12 months of open-label treatment. Of the 138 (45%) patients remaining at trial closure (following commercial availability of lacosamide), 128 (93%) continued lacosamide as part of their post-trial treatment regimen. The primary reasons for trial withdrawal were lack of efficacy (26%) and AEs (11%). The most common treatment-emergent AEs (?15%) occurring at anytime over the duration of the trial included dizziness (50.0%), headache (21.8%), contusion (18.5%), nausea (18.5%), convulsion (17.2%), nasopharyngitis (17.2%), fall (15.9%), vomiting (15.9%), and diplopia (15.3%). The incidences of treatment-emergent AEs that led to discontinuation in ?1.0% of patients were dizziness (1.6%) and convulsion (1.0%). A total of 71 (23%) patients reported an SAE, the most common (>1.0%) being convulsion (3.6%), chest pain (1.6%), pneumonia (1.6%), dizziness (1.3%), and vomiting (1.3%). There was no meaningful pattern of changes from baseline of the previous trial in hematology, blood chemistry, urinalysis, ECG parameters, vital signs, body weight, or physical/neurological exam findings. Conclusions: Long-term, open-label adjunctive treatment with lacosamide up to 800mg/day was generally well tolerated in this trial of patients with refractory partial-onset seizures. The safety profile was consistent with that of other clinical trials with lacosamide.