Long-Term Results Show Lacosamide Continues to Reduce Seizures

Allison Gandey

December 08, 2010

December 8, 2010 — Results from a phase 3 open-label extension study show adjunctive lacosamide reduces partial-onset seizures long term.

"These data add to the growing body of support showing that lacosamide reduces seizure frequency and improves patient-reported quality-of-life measures on a long-term basis," investigator Aatif Husain, MD, from Duke University Medical Center in Durham, North Carolina, said in a news release. "These results, combined with the consistent long-term tolerability profile, are important milestones for this antiepileptic drug."

The UCB product marketed as Vimpat has been available in the United States since 2009. These latest findings were presented at the American Epilepsy Society 64th Annual Meeting in San Antonio, Texas.

Half the patients in this trial tried 7 or more previous antiepileptic drugs.

Investigators led by R. Edward Faught, MD, from Emory University in Atlanta, Georgia, presented the final efficacy results for the open-label extension trial evaluating lacosamide through 5 years.

They studied patients who completed the US phase 3 clinical trial and who chose to enter the open-label extension. The primary reasons for trial withdrawal were lack of efficacy (26%) and adverse events (11%).

In all, 75% of patients completed at least 12 months of open-label treatment. This represented 767.4 patient-years of exposure.

Participants transitioned to a lacosamide dose of 200 mg/day. Lacosamide could be decreased to 100 mg/day or increased up to 800 mg/day. Dose changes were made in 100 mg per week increments. Concomitant medications could be increased or decreased on an individual basis.

A small number of patients, 3.1%, remained seizure free from the first dose of open-label lacosamide to at least 2 years. About a quarter of patients experienced a 75% response and just under half had a 50% response.

The maximum recommended daily dose for lacosamide in the US and European Union is 400 mg/day. The median modal dose of lacosamide in this trial was 500 mg/day. In all, 39% of patients had a modal dose of 600 mg/day or more.

Lacosamide is a functionalized amino acid. It is thought to exert its therapeutic effects through a different mechanism of action from other antiepileptic drugs by enhancing slow inactivation of sodium channels.

UCB Pharma warns the product has been linked to suicidal behavior and patients taking the drug should be monitored for the emergence or worsening of depression, suicidal thoughts, and unusual changes in mood or behavior.

Caution is also advised for patients with known conduction problems or cardiac disease such as a history of myocardial infarction or heart failure. Multiorgan hypersensitivity reactions have also been reported. If this reaction is suspected, the company advises that use of lacosamide be discontinued.

In a separate presentation, Dr. Husain reported that 23% of patients in the open-label study experienced a serious adverse event. The most common were convulsion (3.6%), chest pain (1.6%), pneumonia (1.6%), dizziness (1.3%), and vomiting (1.3%). He also outlined the most common treatment-emergent adverse events.

Table. Treatment-Emergent Adverse Events

Event Rate, %
Dizziness 50.0
Headache 21.8
Contusion 18.5
Nausea 18.5
Convulsion 17.2
Nasopharyngitis 17.2
Fall 15.9
Vomiting 15.9
Diplopia 15.3

 

"Long-term, open-label adjunctive treatment with lacosamide up to 800 mg/day was generally well tolerated in this trial of patients with refractory partial-onset seizures," Dr. Husain concluded. "The safety profile was consistent with that of other clinical trials with lacosamide."

In a third presentation from a different group, senior investigator Christopher DeGiorgio, MD, from the University of California at Los Angeles, reported 2 cases of serious cardiac arrhythmias possibly associated with lacosamide treatment for partial-onset seizures.

Serious Cardiac Arrhythmias

One case involved a 37-year-old woman with intractable partial seizures and no cardiac risk factors. While taking 600 mg/day of lacosamide and 300 mg/day of lamotrigine, she experienced sudden onset of rapid heartbeat, palpitations, and lightheadedness. In the hospital, an electrocardiogram detected atrial flutter and fibrillation with a rapid rate of 136 beats per minute. The treating physician initiated treatment with warfarin and a calcium channel blocker.

The patient's lacosamide dose was reduced to 400 mg/day, but on reevaluation 3 weeks later, atrial fibrillation persisted. The physician decided to taper and discontinue lacosamide treatment by 100 mg/week. An electrocardiogram 1 week after cessation showed complete resolution of the atrial fibrillation and flutter. Dr. DeGiorgio reports this has not recurred in the 6 months since discontinuation.

Physicians should remain alert.

The second case involved a 49-year-old man with severe intractable frontal lobe seizures. He was taking 400 mg/day of lacosamide as adjunctive therapy in addition to preexisting carbamazepine, lamotrigine, clonazepam, and valproate. The patient had no prior history of cardiac arrhythmias but had well-controlled hypertension and hypercholesterolemia treated with atorvastatin, valsartan, and triamterene.

A cardiac stress test prior to the addition of lacosamide demonstrated no abnormalities. While undergoing a repeat cardiac stress test, he experienced sustained ventricular tachycardia, which required acute stabilization and hospitalization. The physician tapered the dosage by 100 mg/day until discontinuation. The result of a repeat electrophysiologic study 24 hours after drug use was stopped appeared normal. Surgeons implanted an electrocardiogram loop monitor, and there has been no recurrence of the arrhythmia at 4 months after discontinuation.

"The onset of the arrhythmias while on lacosamide followed by resolution after discontinuation provides evidence of a possible link," Dr. DeGiorgio and his team suggest. "Physicians should remain alert to the potential for cardiac arrhythmias in patients with epilepsy treated with lacosamide."

The open-label extension study was funded by UCB Pharma. The investigators received compensation for their work on the trial. The case report authors have disclosed no relevant financial relationships.

American Epilepsy Society (AES) 64th Annual Meeting: Posters 1.249, 1.263, and 1.265. Presented December 4, 2010.

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