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Lacosamide is an antiepileptic drug (AED) available in multiple formulations that was first approved in 2008 as adjunctive therapy for partial-onset seizures (POS) in adults. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing, and reduction in long-term channel availability without affecting physiological function. Lacosamide has a well-characterized and favorable pharmacokinetic profile, including a fast absorption rate, minimal or no interaction with cytochrome P-450 izoenzymes, and a low potential for drug-drug interactions. Lacosamide clinical development included three placebo-controlled, double-blind, randomized trials conducted in more than 1300 patients, each demonstrating safety and efficacy of lacosamide compared to placebo as adjunctive therapy for adults with POS. The clinical use of lacosamide may broaden, pending results of trials evaluating its use as monotherapy for POS in adults, as treatment for epilepsy in pediatric subjects, and as adjunctive treatment for uncontrolled primary generalized tonic-clonic seizures in those with idiopathic generalized epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. Methods: This open-label, multicenter trial, enrolled patients with epilepsy who were taking 1-2 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12-lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. Key Findings: A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence ≥10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical laboratory parameters, or vital signs were observed. Trough plasma concentrations suggested that near steady-state lacosamide concentrations were achieved with a single intravenous loading dose. Significance: Intravenous loading doses of 200 and 300 mg lacosamide administered over 15 min followed by oral lacosamide were well tolerated in lacosamide-naive patients. The 400-mg loading dose was less well tolerated due to a higher frequency of dose-related TEAEs. These results support the feasibility of rapid initiation of adjunctive lacosamide treatment. [ABSTRACT FROM AUTHOR]

Summary Purpose: To evaluate the long-term (up to 5 years exposure) safety and efficacy of lacosamide as adjunctive therapy in patients with uncontrolled partial-onset seizures taking one to three concomitant antiepileptic drugs (AEDs) in open-label extension trial SP756 (NCT00522275). Methods: Patients who completed the double-blind trial SP754 (NCT00136019) were eligible to participate in this open-label extension trial (SP756). At the conclusion of trial SP754, patients had transitioned to lacosamide 200 mg/day. Subsequent dosage adjustments of lacosamide (100-800 mg/day) and/or concomitant AEDs were allowed to optimize tolerability and seizure reduction. Treatment-emergent adverse events (TEAEs), vital signs, body weight, clinical laboratory data, electrocardiography studies, and seizure frequency were evaluated. Key Findings: A total of 308 patients received open-label lacosamide and 138 patients (44.8%) completed the long-term trial. The median modal dose (defined as the daily lacosamide dose a patient received for the longest duration during the treatment period) was 500 mg/day. The percentages of patients with lacosamide exposure >1, >2, >3, or >4 years were 75%, 63%, 54%, and 29%, respectively. Primary reasons for discontinuation were lack of efficacy (26%) and adverse events (11%). Common TEAEs (≥15%) were dizziness, headache, contusion, nausea, convulsion, nasopharyngitis, fall, vomiting, and diplopia. TEAEs that led to discontinuation in ≥1.0% of patients were dizziness (1.6%) and convulsion (1.0%). The median percent reductions from baseline of trial SP754 in 28-day seizure frequency were 53.4%, 55.2%, 58.1%, and 62.5%, respectively, for 1-, 2-, 3-, and 4-year completers. The ≥50% responder rates were 52.8%, 56.5%, 58.7%, and 62.5% for 1-, 2-, 3-, and 4-year completers, respectively. Seven of eight patients on lacosamide monotherapy for ≥12 months were deemed 50% responders. Of patients exposed to lacosamide ≥2 years, 3.1% remained seizure-free for a period ≥2 years. Significance: Long-term (up to 5 years) lacosamide treatment was generally well tolerated. The safety profile of lacosamide observed in this trial is consistent with that established in previous double-blind, placebo-controlled trials. Although the open-label trial design limits the analysis of efficacy, long-term reduction in seizure frequency and maintenance of efficacy was observed. [ABSTRACT FROM AUTHOR]

Background: Lacosamide, a new antiepileptic drug (AED) with a different pharmacological action that enhances sodium channel slow inactivation, is approved for the adjunctive treatment of partial-onset seizures in adults. Previous analyses of pooled phase II/III trials have demonstrated that lacosamide provides additional efficacy when added to a broad range of AEDs. Objective: To further evaluate the efficacy and safety of lacosamide by grouping patients based upon the sodium channel-blocking properties of their concomitant AEDs. Study Design: Post hoc exploratory analyses were performed on pooled data in which patients were grouped based upon inclusion or non-inclusion of at least one `traditional' sodium channel-blocking AED (defined as carbamazepine, lamotrigine, oxcarbazepine and phenytoin derivatives) as part of their concomitant AED regimen. Setting: Data pooled from previously conducted phase II/III clinical trials of lacosamide. Patients: Adult patients with partial-onset seizures with or without secondary generalization (N = 1308). Intervention: Four- to six-week Titration Phase followed by 12-week maintenance treatment with adjunctive lacosamide (Vimpat®) [200, 400 or 600 mg/day] or placebo. Main Outcome Measure: Efficacy variables included change in seizure frequency per 28 days and the proportion of patients experiencing a ≥50% reduction in seizure frequency (50% responder rate) from Baseline to the Maintenance Phase. The proportion of patients experiencing a ≥75% reduction in seizure frequency from Baseline to the Maintenance Phase (75% responder rate) was also assessed. Safety parameters assessed were treatment-emergent adverse events (TEAEs) and discontinuation due to TEAEs. Additional safety assessments were changes in ECG and laboratory parameters as well as vital signs (including bodyweight). Results: Of 1308 patients in the pooled phase II/III population, the majority (82%) were using at least one 'traditional' sodium channel-blocking concomitant AED. In this subgroup of patients, adjunctive lacosamide showed significant reductions in seizure frequency (p<0.01, all dosages) and significantly greater 50% and 75% responder rates (p<0.01 for 400 mg/day; p<0.01 [50% responder rate] and p<0.05 [75% responder rate] for 600mg/day) compared with placebo; these effects were similar to the results seen in the pooled phase 11/Ill population. TEAEs and discontinuations due to TEAEs in this subgroup were dose related and similar to the pooled phase II/III population. In the remaining subgroup of patients, i.e. those not taking `traditional' sodium channel-blocking AEDs as part of their concomitant AED regimen (n = 231; 18%), a pronounced, dose-related seizure reduction was observed with lacosamide (p<0.01, 400 and 600mg/day for median percent seizure reduction and 50% or 75% responder rates). Also in this group, incidences of TEAEs were low, and discontinuations due to TEAEs did not appear to increase with dose. Analyses of ECG, laboratory and vital signs (including bodyweight) assessments did not identify abnormalities in either subgroup that were outside of the known safety profile of lacosamide observed in the pooled phase II/III population. Conclusion: In this post hoc exploratory analysis, adjunctive lacosamide demonstrated significant seizure reduction over placebo regardless of the inclusion of 'traditional' sodium channel blockers in the concomitant AED regimen. Future prospective studies evaluating single AED combinations (e.g. lacosamide plus one other drug) are needed to better evaluate the potential for additive or synergistic effects of lacosamide in combination with AEDs not considered 'traditional' sodium channel blockers. [ABSTRACT FROM AUTHOR]

Lacosamide is an antiepileptic drug approved in the USA and Europe as adjunctive therapy for partial-onset seizures. Studies suggest that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels and possibly interacts with collapsin response mediator protein-2. The efficacy of lacosamide has been shown in animal models of epilepsy and Phase II/III clinical trials. Pharmacokinetic studies show that it is renally excreted, minimally bound to plasma proteins and has no known clinically relevant drug-drug interactions. Clinical trials show that lacosamide is well tolerated; the most common adverse events were dizziness, nausea and vomiting. In a Phase II/III pooled analysis, lacosamide 200 and 400 mg/day significantly reduced partial-onset seizure frequency and improved the 50% responder rate compared with placebo. [ABSTRACT FROM AUTHOR]

Summary: Lacosamide is a new chemical entity being investigated as an adjunctive treatment for epilepsy, as well as monotherapy for diabetic neuropathic pain. Lacosamide appears to have a dual mode of action: selective enhancement of sodium channel inactivation and modulation of collapsin response mediator protein-2. Rapidly and completely absorbed after oral administration, lacosamide has an elimination half-life of approximately 13 hours and a low potential for drug interactions. Additionally, lacosamide exhibits linear, dose-proportional pharmacokinetics with low intra- and interpatient variability. Randomized controlled trials of adjunctive lacosamide (200, 400, and 600 mg/day) have demonstrated statistically significant reduction in median seizure frequency compared with placebo. In addition, 50% responder rates for lacosamide (400 and 600 mg/day) were statistically superior to placebo. The most frequently reported adverse events (≥10% of lacosamide-treated patients) included dizziness, headache, and nausea. A double-blind, double-dummy randomized trial of intravenous lacosamide (30- and 60-minute infusion) as replacement for oral lacosamide showed that the safety and tolerability profiles were comparable for intravenous and oral lacosamide. The efficacy and safety results from completed clinical trials, as well as the favorable pharmacokinetic profile, suggest that lacosamide may represent a significant advance in antiepileptic drug therapy. [Copyright &y& Elsevier]