Once-Daily Epilepsy Drug Equivalent to Twice-Daily Drug

Pauline Anderson

April 21, 2016

VANCOUVER — A relatively new once-a-day antiepileptic drug (AED) is as effective as an older standard one given twice daily, according to a randomized trial.

Results of the blinded phase 3 study showed eslicarbazepine acetate to be noninferior to controlled-release carbamazepine given as monotherapy.

Eslicarbazepine "may be the better drug because it's given only once a day," which can lead to better adherence, and "it has a slightly broader mechanism of action," said lead researcher Elinor Ben-Menachem, MD, PhD, professor, neurology and epilepsy, University of Gothenburg, Sweden, and member, Council on Education, American Epilepsy Society.

She added that eslicarbazepine is less likely than carbamazepine to induce liver enzymes and to lead to a sometimes fatal skin reaction. This reaction is significantly more common in patients with a particular HLA allele that occurs almost exclusively in patients with Asian ancestry.

According to the US Food and Drug Administration, such patients should be screened before starting treatment with carbamazepine.

Dr Ben-Menachem presented her findings at the American Academy of Neurology (AAN) 2016 Annual Meeting.

Carbamazepine, which has been around since the 1960s, is a mood stabilizer and an anticonvulsant that has been "a very good, probably our best" AED for focal, or new-onset, seizures, said Dr Ben-Menachem. She added that this "gold standard" drug is one of the most frequently used AEDs.

After carbamazepine, another anticonvulsant drug, oxcarbazepine, was developed to reduce side effects of carbamazepine. Now, a molecule that has a slightly different mechanism of action than oxcarbazepine, eslicarbazepine acetate, has come on the market.

Eslicarbazepine acetate (Aptiom, Sunovion) is approved in the United States for the treatment of partial-onset seizures (POS) as monotherapy or adjunctive therapy. It is approved in Europe as adjunctive therapy for POS and will likely soon also be approved for monotherapy, said Dr Ben-Menachem.

Three-Step Design

The new dose-escalation study randomly assigned 815 adult patients with new-onset seizures to first receive eslicarbazepine 800 mg once daily (QD) or carbamazepine 200 mg twice a day (BID).

Patients who experienced a seizure got an increased dose of their drug: 1200 mg QD for eslicarbazepine and 400 mg BID for carbamazepine. If they had another seizure, they got an even higher dose: 1600 QD for eslicarbazepine and 600 mg BID for carbamazepine.

The primary endpoint was the proportion of patients with seizure freedom at 26 weeks. In the per protocol (PP) population, the noninferiority margin was –12%.

The study showed that 71.1% of patients receiving eslicarbazepine and 75.6% receiving carbamazepine were seizure-free for 6 or more months. The average risk difference was –4.28% (95% confidence interval [CI], –10.3% to 1.74%).

After 1 year, the seizure-free rate in the PP population was 64.7% in the eslicarbazepine group and 70.3% in the carbamazepine group. The average risk difference was –5.46% (95% CI, –11.88% to 0.97%).

Being able to take an AED just once in a day is a real advantage because there's less chance that patients will forget to take their medicine, said Dr Ben-Menachem. "They can take it at night when they go to bed."

And because this newer drug has a relatively long half-life, if patients forget this dose, "they won't get in trouble; they can take it the next day," she added.

Dr Ben-Menachem noted that the study included only patients with partial-onset seizures. "We don't know if it's good for the primary generalized or idiopathic epilepsies."

Safety Profile

During the meeting, Pedro Andre Kowacs, MD, Neurology Division, Internal Medicine Department, Hospital de Clínicas, Universidade Federal do Paraná, Brazil, presented results of the safety and tolerability of eslicarbazepine in 813 patients.

"Eslicarbazepine monotherapy demonstrated a safety profile that was similar or more favorable than that of controlled-release carbamazepine in the study population," Dr Kowacs reported.

"There were no real or unexpected safety findings as compared to previous studies."

Incidence rates for headache, dizziness, nausea fatigue, and somnolence were similar between the two groups.

However, the rate of γ-glutamyltransferase was quite a bit higher in the carbamazepine group — 12.6% vs 2.7% — "possibly due to different metabolic pathways," said Dr Kowacs.

Slightly fewer patients taking eslicarbazepine (n = 54) discontinued the study compared with carbamazepine (n = 74).

Four patients died during the study, but only one death was deemed possibly related to the study drug. One patient who was taking carbamazepine committed suicide.

Approached for a comment, Andres M. Kanner, MD, professor, clinical neurology, University of Miami Miller School of Medicine, and director, Comprehensive Epilepsy Center, University of Miami, Florida, said the findings aren't especially unexpected.

"The fact that the two drugs have a comparable efficacy is not going to come as a surprise to anybody."

As for the comparison of toxicity and tolerability, Dr Kanner agreed that the two AEDs seem to yield similar profiles.

The main difference between the two drugs appears to be the fact that eslicarbazepine can be taken once a day, which can be an advantage over carbamazepine, said Dr Kanner.

One disadvantage of carbamazepine, said Dr Kanner, is that as an "enzyme inducing" AED it accelerates the metabolism of other drugs that are metabolized through the same system.

"If you're taking carbamazepine and other medications that are metabolized in the liver, for example, an antidepressant or statin, or certain antibiotics, the interaction requires that you adjust the dose of the other medications because you are eliminating them at a faster rate."

Carbamazepine may also be associated with an increased risk for osteopenia and osteoporosis and increased cholesterol levels, said Dr Kanner.

Because eslicarbazepine appears to have a milder enzyme-inducing effect than carbamazepine, it would be expected to have a lesser effect on the metabolism of concomitant drugs, a lower risk for osteopenia and osteoporosis, and a lesser effect on atherogenesis than those reported for carbamazepine, said Dr Kanner.

"I would have hoped that the authors took advantage of this study to collect such data."

Finally, cost is another issue to consider, he said. Carbamazepine is likely to be less expensive because it's available in generic form. In the United States, eslicarbazepine is available only as a branded product, said Dr Kanner, adding that not all insurance companies will reimburse for it unless patients have tried and not responded to other drugs.

The study was supported by Bial-Portela & Ca. Dr Ben-Menachem has consulted for Elsai, UCB, Electrocore, Astella. Dr Kowacs has received personal compensation for activities with Abbott Laboratories Inc, GlaxoSmithKline Inc, and Cyberonics.

American Academy of Neurology (AAN) 2016 Annual Meeting. Abstract 9132. Presented April 19, 2016.


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