ARTICLE IN BRIEF
On the basis of new data showing that zonisamide was non-inferior to carbamazepine for newly diagnosed partial epilepsy, the European Medicines Agency approved zonisamide as an initial monotherapy.
Zonisamide is non-inferior to carbamazepine and is well tolerated as an initial monotherapy for partial seizures in adults with newly diagnosed epilepsy, investigators reported in the July edition of the Lancet Neurology.
Until now zonisamide (Zonegran) had been limited for use in the European Union as well as in the United States as an add-on therapy only. On the basis of the new data, however, the European Medicines Agency (EMA) approved the drug as a monotherapy for partial seizures. Zonisamide is manufactured by Eisai, which funded the study.
“Zonisamide will be on the list for first-line monotherapy in Europe,” said co-author Martin J. Brodie, MD, director of the Epilepsy Unit at the Western Infirmary in Glasgow, Scotland. “It's arguably a little more expensive than the standard of care, but it's taken once daily, and doesn't cause drug interactions [with other antiepileptic drugs]. Whether physicians will choose it for their patients is another kettle of fish.”
Dr. Brodie said the study was done to support approval of the drug as a monotherapy.
“Zonisamide probably won't be approved as a monotherapy in the United States, where 75 percent of the world's antiepileptic drugs are sold, because the FDA demands that a drug demonstrate superiority, not just non-inferiority,” Dr. Brodie said. “You have to show that the drug definitely works,” he said, “and no drug company is going to do a huge, expensive study if they don't have a pretty good chance of getting a license.”
ABOUT THE STUDY
The primary outcome of the double-blind, randomized study was the proportion of patients who achieved seizure freedom for 26 weeks or more; 583 adults newly diagnosed with partial seizures were randomized to receive once-daily zonisamide or twice-daily controlled-release carbamazepine (Tegretol) as monotherapy. At the end of 26 weeks 79.4 percent in the zonisamide group were seizure free, and 83.7 percent in the carbamazepine group.
The incidence of adverse events — the most frequent being headache, decreased appetite, somnolence, dizziness, and weight loss — were almost identical, with 60 percent in the zonisamide group reporting at least one adverse event, and 62 percent in the carbamazepine group.
EXPERTS: OTHER CONCERNS ABOUT APPROVAL
Several epileptologists, who were not involved with the study, raised other issues about the findings. Among them, the 26-week study was not long enough to determine the long-term impact of the drugs on the human body, which is always a concern, Jacqueline French, MD, professor of neurology at New York University and co-director of Epilepsy Research and Epilepsy Clinical Trials at the NYU Comprehensive Epilepsy Center, told Neurology Today, for which she serves on the editorial advisory board.
“Carbamazepine is in a class of strong hepatic enzyme-inducing antiepileptic drugs,” Dr. French said. “Zonisamide is not. Carbamazepine produces a lot of changes in internal milieu of body. For example, you hypermetabolize vitamin D, so you need vitamin D supplementation or you may get bone changes. Carbamazepine also produces hypermetabolism of 60 percent of other drugs, so people taking drugs such as antidepressants or statins often need to start taking double doses. Carbamazepine elevates cholesterol levels and makes the use of oral contraceptive pill very problematic. There are lots of things that are not measured in studies like this.”
One side-effect of zonisamide — weight loss — may enhance its popularity, several experts pointed out. “Zonisamide is chemically and clinically similar to topiramate (Topamax), which is under very active consideration by the FDA as a weight loss drug,” said Robert Fisher, MD, PhD, Maslah Saul MD Professor of Neurology at Stanford University, and director of the Stanford Comprehensive Epilepsy Center. “The mechanisms are unclear, but they have been hypothesized to depend on effects on neurotransmitter systems. My own clinic experience is that weight loss is more often welcomed than weight gain, but not always.”
Dr. French has encountered the same phenomenon. “Tell patients, I have two drugs — one makes you lose weight, the other makes you gain weight, and they're pretty much the same otherwise,” she said. “Pick which you want. What do you think they're going to say?”
• Baulac M, Brodie MJ, Giorgi L, et al. Efficacy and tolerability of zonisamide versus controlled release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurology
• Brodie MJ, Barry SJE, Kwan P, et al. Patterns of treatment response in newly diagnosed epilepsy. Neurology 2012;78(20):1548–1554.
©2012 American Academy of Neurology