Abstracts

Rationale: To examine the safety and tolerability of lacosamide, a new drug candidate under investigation as adjunctive therapy for partial-onset seizures, in double-blind clinical trials. Methods: Subjects receiving at least 1 dose of placebo or lacosamide in three Phase II/III randomized, double-blind, placebo-controlled, fixed-dose clinical trials (SP667, SP754, SP755) were pooled. Adverse events (AEs), laboratory parameters, ECGs, vital signs, and body weight were evaluated. Results: In these trials, 944 subjects were randomized to lacosamide 200 mg/day (n=270), 400 mg/day (n=471), or 600 mg/day (n=203) and 364 subjects were randomized to placebo. Most subjects (78%) were exposed to lacosamide for at least 85 days. All subjects were receiving 1-3 concomitant antiepileptic drugs (AEDs); 85% of subjects randomized to lacosamide were receiving 2-3 concomitant AEDs. Overall, the most commonly used AEDs were carbamazepine (35%), lamotrigine (31%), levetiracetam (29%), valproate (24%), topiramate (22%), oxcarbazepine (18%) and phenytoin (14%). The percentage of patients discontinuing treatment for AEs was 5.2%, 9.6%, 17.2%, and 28.6% for the placebo, 200, 400, and 600 mg/day lacosamide groups, respectively. The most common AE leading to withdrawal was dizziness (5.9%) for those randomized to lacosamide. Frequently reported treatment emergent AEs (occurring in ≥10% of the pooled lacosamide group) versus placebo were dizziness (31% vs 8%), headache (13% vs 9%), nausea (11% vs 4%), and diplopia (11% vs 2%). Dizziness, nausea and diplopia appeared to be dose-related, with the highest incidence in the 600mg/day group. The overall incidence of common TEAEs (occurring in ≥1% of any lacosamide group) increased with increasing fixed doses of lacosamide (63%, 76%, and 90% for 200mg/day, 400mg/day, and 600mg/day groups, respectively, compared to 56% placebo) and were highest during titration. In the titration phase, only dizziness (25%) occurred at an incidence ≥10% for those randomized to lacosamide; in the maintenance phase, the incidence of dizziness was notably lower (8%). The incidences of other AEs of relevance- peripheral edema (1%), weight gain (1%), memory impairment (2%), pancreatitis (0.1%) and psychotic disorders (0.2%) were low and generally similar to placebo. Across all lacosamide groups, no clinically relevant concerns were observed on laboratory parameters, ECGs, vital signs, or body weight measurements. A small, dose-related increase in PR interval was observed. Conclusions: Although a dose relationship was seen for frequently reported nervous system and gastrointestinal AEs, lacosamide was generally well tolerated when combined with up to three concomitant AEDs.