FDA Okays Lacosamide Monotherapy in Partial-Onset Seizures

Susan Jeffrey

Disclosures

September 02, 2014

The US Food and Drug Administration (FDA) has approved a supplemental new drug application for the antiepileptic drug lacosamide (Vimpat, UCB) as monotherapy in treating partial-onset seizures in epilepsy patients aged 17 years or older.

The drug is already approved in the United States as adjunctive treatment for partial-onset seizures, USB notes in a statement issued September 1. "This new indication means that adults with partial-onset seizures can be initiated on Vimpat monotherapy, and patients already on an anti-epileptic drug can be converted to Vimpat monotherapy," the statement adds.

The FDA also approved a new single-loading-dose administration option for all formulations of the drug used either as monotherapy or adjunctive therapy, the company said. The approval allows initiation of treatment as a single-loading dose of 200 mg (oral or injection) followed approximately 12 hours later by a 100-mg twice-daily dose. The loading dose should be administered with medical supervision, the company notes, considering that the drug's pharmacokinetics and increased incidence of central nervous system adverse reactions and dosage adjustments are recommended for those with mild or moderate hepatic impairment or severe renal impairment.

The most common loading dose adverse events > 5% were dizziness, headache, paraesthesia, and gait disturbance, the statement said. It is not recommended for use in patients with severe hepatic impairment.

Monotherapy Approval

The monotherapy approval is based on a phase 3 historical-control conversion to lacosamide monotherapy study in 425 adult patients with partial-onset seizures, the company said. The study met its primary endpoint, showing that the exit percentage, defined as the estimated percentage of patients meeting predefined exit criteria including increase in seizure frequency and duration or severity, for patients on lacosamide 400 mg per day as monotherapy was significantly lower than the exit percentage seen among a group of historical controls at day 112 of treatment.

For the lacosamide 400 mg/day group, the estimated percentage of patients meeting at least 1 exit criterion by day 112 was 30.0% (95% confidence interval [CI]: 24.6% - 35.5%). "The upper limit of the 2-sided 95% CI (35.5%) was below the threshold of 65.3% derived from the historical control data, meeting the pre-specified criteria for efficacy," the company notes. Lacosamide 300 mg per day also met criteria for efficacy.

Discontinuation due to an adverse event occurred in 16% of patients randomized to receive lacosamide at the recommended doses of 300 and 400 mg/day; the adverse reaction most commonly leading to discontinuation was dizziness (≥ 1% on lacosamide). Adverse reactions were "generally similar" to those observed and attributed to drug in adjunctive placebo-controlled studies, the statement said; "however, one adverse reaction, insomnia, was seen at a rate of > 2% and was not reported at a similar rate in previous studies." Insomnia has also been observed in postmarketing experience, they note, but because the study didn't include a placebo group, "causality could not be established."

Dizziness, headache, nausea, somnolence, and fatigue were all reported at lower incidences during the antiepileptic drug withdrawal phase and monotherapy phase, compared with the titration phase, the statement adds.

Warnings and precautions on the drug in the US include those for suicidal behavior and ideation, dizziness and ataxia, cardiac rhythm and conduction abnormalities, and syncope, among others.

In the European Union, lacosamide is approved as adjunctive therapy for the treatment of partial-onset seizures with or without secondary generalization in adult and adolescent (16 to 18 years) patients with epilepsy, but not as monotherapy. It's also approved in the EU for initiation as a single-loading dose of 200 mg followed 12 hours later by a 100-mg twice-daily maintenance dose regimen.

"A non-inferiority monotherapy study is underway to support the potential monotherapy filing with the European Medicines Agency," the company adds. "The study aims to compare the efficacy and safety of lacosamide to carbamazepine controlled-release as monotherapy in newly or recently newly diagnosed patients (≥ 16 years) with partial-onset seizures."

The drug is a Schedule V controlled substance.Full prescribing information can be found here: http://www.vimpat.com/PDF/vimpat_PI.pdf.

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