August 12, 2010 — The novel epilepsy drug ezogabine (Potiga, Valeant Pharmaceuticals North America) won a hearty endorsement by the US Food and Drug Administration's (FDA's) Peripheral and Central Nervous System Drugs Advisory Committee, who unanimously agreed that the sponsor had provided substantial evidence for the drug's efficacy as adjunctive treatment in partial-onset seizures.
Ezogabine is a potassium-channel opener, activating certain voltage-gated potassium channels in the brain. However, this unique mechanism of action is also presumed to be responsible for some toxic effects that are not usually seen with other anticonvulsants, particularly urinary retention, which was the FDA's chief concern.
Early in the day, Russel G. Katz, MD, director of the Division of Neurology Products at the FDA, told the panel that the FDA was forgoing their usual formal presentation to give the panel plenty of time to discuss safety concerns. "We've examined the sponsor's presentation. We have no material disagreement with the data, and we felt the purpose of the meeting would best be served if we reserved that time for additional discussion."
As it turned out, the advisory committee was not too worried about ezogabine's safety, telling the FDA, by a vote of 11 to 0, with 2 abstentions, it believed that urinary retention could be mitigated by patient monitoring. They also felt that there was no need to monitor patients for infection and urolithiasis.
However, there was a great deal of discussion about what that monitoring should entail.
Inger L. Rosner, MD, from Walter Reed Army Medical Center, Washington, DC, and 1 of 2 urologists on the advisory committee, told the FDA she felt confident that good patient education coupled with a good physician-patient relationship would bring to light any potential urinary adverse effects in a timely manner.
"It sounds as if there are significant relationships going on with epilepsy patients and their physicians," she noted. "If patients are well educated, then clearly, if they have any voiding dysfunction, I am confident they will present with those complaints. Everyone needs to urinate. It's something we all do every day. An open discussion about urinary symptoms is probably the appropriate place to start."
Dr. Rosner added that some individuals might need prior workup with urodynamic testing if they had any voiding dysfunction related to neurologic or structural issues to begin with. "Perhaps in some patients before starting the medication, evaluation by a urologist may be necessary, but it would be up to the clinician."
Philip M. Hanno, MD, MPH, professor of urology in surgery at the University of Pennsylvania, Philadelphia, said he agreed that the potential for urinary retention can be mitigated by patient monitoring but voiced concern about the lack of urodynamic studies among the data presented by the sponsor.
"I'm surprised that the sponsor has not done a single urodynamic study to show what this drug does to the bladder," he said. "There are a lot of things that might show up on urodynamics that wouldn't necessarily be manifested clinically right away."
This is a new drug that is going to be used in thousands of patients, he added. "It would be very nice to have a study showing, both in normals and in patients with epilepsy, whether there are any urodynamic changes that might signal future problems in certain patients so that we would know whether or not to give them ezogabine or to be extravigilant for possible retention."
He added that patients should be advised to look for any change in their voiding function, either in the number of voids or their perception of how they are voiding.
"It looks like there were some patients who developed silent prostatism, where they suddenly presented with renal failure," he noted. "That is very, very rare, and that makes me worry a little bit about this drug. Something is going on here that we don't really appreciate. It's very rare to have spontaneous episodes of something with no prodrome, out of the blue, and we know this drug does something to the bladder. It would be nice to have more information about exactly what it's doing, and urodynamics would be 1 obvious way to look at that issue."
AUA Symptom Index
Doing an American Urological Association (AUA) Symptom Index would be an appropriate test before using ezogabine, both urologists suggested. They were challenged about this by Norman Hershkowitz, MD, team leader of the FDA's Division of Neurology Products, who said, "Neither we nor the sponsor thought that the AUA was very helpful in identifying these patients."
"I guess perhaps the sponsors or neurologists aren't familiar with using the AUA Symptom Index, and we use it every day on every patient or at least male patients," Dr. Rosner replied. "Perhaps, as neurologists become more familiar with it, they will be able to tease out symptoms."
Claude G. Wasterlain, MD, distinguished professor and vice-chair in the Department of Neurology at Geffen School of Medicine at UCLA, Los Angeles, California, voiced disappointment that more was not done to explain the pathophysiology of urinary retention.
There have been red flags all over the place, and essentially very little has been done to understand the phenomenon...
"Usually if you understand the pathophysiology, you know what to do about it," he said. "There have been red flags all over the place, and essentially very little has been done to understand the phenomenon, so I'm very disappointed on that side. I think we have to have studies to understand the pathophysiology."
Dr. Wasterlain and José E. Cavazos, MD, PhD, from the University of Texas Health Science Center, San Antonio, the other epilepsy expert on the panel, said that they would welcome a list of specific things to look for in their patients to alert them to the potential of urinary problems.
"We have to address the epileptologist's ignorance of bladder mechanisms by a precise set of recommendations," Dr. Cavazos said. He said he was initially concerned that some of these patients would be asymptomatic but was reassured by Dr. Rosner and Dr. Hanno that there would be symptoms.
However, if a patient does have symptoms, "what do we do?" he asked. "I treat patients in the VA hospital, where the overwhelming majority of patients are men over 65 and almost all of them have some urinary symptoms, so how do you tell what sign should ring the alarm bell?"
Monitoring Vulnerable Patients
Samuel Frank, MD, from Boston University in Massachusetts and the acting consumer representative on the panel, also appealed to the urologists for guidance about monitoring for urinary tract symptoms in patients who are not able to adequately communicate with their physicians.
"I do think there is going to have to be some other monitoring, specifically for the urinary dysfunction, whether it's an ultrasound for postvoid residuals, which would be easy and noninvasive," he said. "I would rely on my urology colleagues to give a recommendation. I do feel that there is definitely a population of people that we can't monitor just by asking them some questions."
Dr. Wasterlain added that he would like to see more data on the elderly, who now make up most epilepsy patients.
"When I was in medical school, epilepsy was mostly a disease of children," he said. "Today, epilepsy is mostly a disease of the elderly. We have very little information on that group. We have to be careful with that population, which clearly is at higher risk. We cannot assume, from the benign nature of the complications in a very young population, age 37 on average, from these 3 studies, that the same results would apply to the more vulnerable population, which is now the largest group of epileptic patients."
Asked by Advisory Committee Chair Britt Anderson, MD, PhD, from the University of Waterloo in Canada, whether he would advise that ezogabine not be used in patients older than 65 years, given the lack of clinical data on that group, Dr. Wasterlain replied that he would support a recommendation for caution in that age group.
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Cite this: Epilepsy Drug Ezogabine Gets Green Light From FDA Advisory Panel - Medscape - Aug 12, 2010.