ARTICLE IN BRIEF
The FDA approved ezogabine tablets for use as an add-on medication to treat partial seizures in adults — taken three times daily, not exceeding 1200 mg/day.
On June 10, the FDA approved ezogabine (Potiga), the first approved drug in its class of neuronal potassium channel openers developed for the treatment of epilepsy. Ezogabine tablets are recommended for use as an add-on medication to treat partial seizures in adults — taken three times daily, not exceeding 1200 mg/day.
The presumed mechanism for the drug is that it reduces neuronal excitability by keeping potassium channels in an opened position, said Kimford J. Meador, MD, professor of neurology at Emory University and director of the Emory Epilepsy Center in Atlanta, who was not involved with the approval.
According to company prescribing information, ezogabine “can be abused or lead to drug dependence” (http://1.usa.gov/n31LQc); it will be submitted for consideration as a controlled substance by the Drug Enforcement Agency. Ezogabine will not be available in US pharmacies until the end of 2011, after this process is completed. The FDA has also ruled for a Risk Evaluation and Mitigation Strategy, which must be provided by the manufacturers of the drug, for informing health professionals about the treatment‘s associated risks of urinary retention.
The FDA approval was based on three randomized, placebo-controlled trials. These international, 24-26 week studies compared ezogabine (at 600, 900 and/or 1200 mg/day) to placebo, as adjunct therapy, in a total of 1244 patients with a mean age of 35-38 years, who had experienced at least four seizures over a 28-day period, despite other antiepileptic drug treatment.
The investigators reported that the primary endpoint for ezogabine — a significantly greater percent reduction from baseline in frequency of partial seizures over 28 days compared with placebo was achieved. There was a 35-44 percent reduction for those taking the 1,200 mg dose, 29-40 percent for those taking 900 mg/day, and 23-28 percent for those taking the 600 mg dose, compared with 13-18 percent among those taking placebo.
The most commonly recorded adverse reactions were dizziness, somnolence, fatigue, and confusional state, as well as hallucinations and psychosis in some patients. Adverse events relating to urine voiding dysfunction and urinary retention (including: dysuria, urinary hesitation) were reported for 5 percent of the ezogabine-treated patients of all doses, compared with 3 percent of the placebo population.
In August 2010, the FDA Peripheral and Central Nervous System Drugs Advisory Committee agreed unanimously that there was substantial evidence that the drug was effective as an add-on for treating partial seizures, and that urinary retention could be mitigated by monitoring patients.
Carl Bazil, MD, PhD, professor of clinical neurology at Columbia University College of Physicians and Surgeons, who was not involved with the approval studies, said that the approval was a necessary step for the 30-40 percent of epilepsy patients who are still not fully controlled with currently available medications. Although he does not yet have personal experience with ezogabine, he said he would prescribe it initially in patients who have failed other available medications.
Dr. Meador agreed, adding: “When we have more clinical experience and more patients have been exposed, the side effects, safety, and utility of the drug will be clearer.” Then, he said, he will consider prescribing it to other patients.
The drug seems to perform as efficiently in trials as other recently approved antiepileptic medications, Dr. Bazil said, and yet differs in its mechanism of action: “it seems to act primarily on specific potassium channels,” which may be the answer for some uncontrolled patients.
There are, however, some drawbacks to the therapy, he said. “It will require three doses per day — a frequency that many patients find difficult to maintain. The titration is also slower than many other drugs, so it may be weeks before an effect is seen.”
DATA FOR EZOGABINE
* All three trials exhibited statistical significance for the relevant doses (except one arm in one study): the placebo versus 600 mg/day dose arm in one study (p<0.007), the placebo versus 900 mg/day dose arm in two studies (p<0.001 and 0.043) and the placebo versus the 1200 mg/day dose arm in two studies (p<0.001).
* One study failed to demonstrate a significant difference between the placebo and the 600 mg/day dose (p<0.199). (See http://1.usa.gov/nI4JRR.)