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FDA panel votes against recommendation for tedisamil
An inadequate safety profile drew tough questions and a negative vote from the panel.
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The Cardiovascular and Renal Drugs Advisory Panel voted unanimously against recommending approval of an antiarrhythmic potassium channel blocker because of concerns about safety.
The eight-member panel evaluated the premarket application of tedisamil (Pulzium, Solvay Pharmaceuticals Inc.) at a recent meeting. The drug, originally designed as a compound to treat angina, was found to have antiarrhythmic properties and developed for the rapid conversion of atrial fibrillation to normal sinus pressure.
The panel’s decision came a day after it had voted to recommend for approval vernakalant hydrochloride, another antiarrhythmic drug designed to convert AF to sinus rhythm.
“Tedisamil does have some potential value, but I’m concerned about the representative nature of the patient population, which included some issues with the drug treatment,” panel member Robert A. Harrington, MD, professor of medicine at the Duke University Medical School and director of the Duke Clinical Research Institute said at the meeting. “I’m not entirely convinced that we’ve well characterized the safety. The dosing and the monitoring have not been completely worked out and is quite complex. More information is warranted before approval.”
Problems with data sets
Another concern of the panel was the representativeness of the sample population. According to the integrated safety data set for the trials that comprised the tedisamil clinical program, 98% of those enrolled in the tedisamil arm were white, and there were more men (n=759) than women (n=642).
The tedisamil clinical program consisted of two phase-2 and seven phase-3 studies. The pooled safety data for tedisamil showed a disproportionate increase in adverse events among women, including elevated rates of torsade de pointe, hypotension, tachycardia and bradycardia. During one of the randomized phase-3 trials, a significant number of women experienced arrhythmic events, forcing the sponsor to halt the trial and amend the procedure. The program’s safety monitoring board revised the trial protocols to adjust the size of the dose given to the remaining enrolled women. The monitoring board also outlined protocols for the implementation of additional follow-up studies designed to evaluate men and women exclusively.
Solvay Pharmaceuticals responded to the panel’s vote by pledging to cooperate and comply with the panel’s requests for more robust data sets and safety data.
“Although we are disappointed with today’s vote, we remain committed to working with the FDA to determine the appropriate next steps in the review of this drug application,” Laurence Downey, MD, president and CEO of Solvay Pharmaceuticals Inc., said in a press release. - by Eric Raible
Currently available medications for acute conversion of AF to sinus rhythm have the issues of incomplete efficacy and occasional adverse effects, notably proarrhythmia. Thus, a key requirement for new medications for this indication is not simply efficacy but also lack of risk, especially risk for proarrhythmia or other serious adverse effects like bradyarrhythmias or hypotension.
—Dan Roden, MD