Washington Editor

A panel of federal advisers told the FDA that it should approve Kynapid but reject Pulzium to treat atrial fibrillation, a condition in which the two uppermost chambers of the heart beat irregularly and at an extremely rapid rate.

Kynapid (vernakalant) is being co-developed by Vancouver, Canada-based Cardiome Pharma Corp. and Deerfield, Ill.-based Astellas Pharma U.S. Inc. Cardiome granted exclusive licensing rights to the U.S. affiliate of Tokyo-based Astellas in October 2003 to develop and commercialize Kynapid in North America. Cardiome has retained all rights to the intravenous formulations of the drug outside of the U.S., Canada and Mexico.

Pulzium (tedisamil sesquifumurate) is being developed by Marietta, Ga.-based Solvay Pharmaceuticals Inc.

Regulators are not bound by advisory committee recommendations, but the FDA typically follows the advice of its expert panels.

The agency is expected to take approval action for both drugs by Jan. 19, the Prescription Drug User Fee Act action dates.

While both Kynapid and Pulzium have some degree of effectiveness, at least for atrial fibrillation of short duration, the drugs are "clearly less effective than is electrical conversion," the FDA said in briefing documents.

In addition, the agency said, both products carry risks, specifically proarrhythmic risks.

While Pulzium was found to cause bradycardia and hypotension, which led to at least one study participant death, those adverse effects were less of a concern for Kynapid, the FDA said.

The FDA's Cardiovascular and Renal Drugs Advisory Committee Tuesday voted 6 to 2 in favor of approval of the Kynapid, a mixed potassium and sodium channel blocker intended to be administered in the hospital setting. But the panel Wednesday unanimously agreed that Pulzium's risks outweighed its benefits.

If approved, Kynapid will be the first new therapy for the conversion of atrial fibrillation to normal sinus rhythm in eight years.

While Kynapid was shown to be effective in converting short-term atrial fibrillation, FDA drug reviewers expressed reservations about the drug's safety. Kynapid caused two cases of ventricular fibrillation, one of which was fatal, in the "highly monitored" study environment, agency scientists said.

However, the reviewers noted that it was "very likely" that the fatality was precipitated by the study participant's aortic stenosis and heart failure. But there was not sufficient data available "that would lend support to this hypothesis," the reviewers stated.

In addition, regulators said, because the level of exposure to Kynapid was limited, there is no assurance that other cases of ventricular fibrillation will not occur when exposure to the drug increases and patients with significant structural heart disease are exposed.

In the absence of data, the reviewers said, it can only be assumed that fatal ventricular fibrillation will be observed at a rate of at least one per every 1,000 patients with other risk factors of ventricular arrhythmia administered the drug.

The FDA noted that acute myocardial infarction and advanced heart failure, two of the main causes of atrial fibrillation, were excluded from the Kynapid studies. Therefore, regulators said, the population studied is not representative of the proposed indication for the drug.

Other adverse events associated with Kynapid include third-degree atrioventricular block, life-threatening bradycardia, hypotension and possibly ventricular tachycardia and dyspnea, the FDA said.

The agency reviewers advised that if the drug is approved, a post-marketing surveillance program be established to detect serious adverse events, especially cardiac and respiratory effects.

Pulzium, which was examined in four Phase II and five Phase III clinical trials, was found to be effective in both men and women. However, the drug appears to be relatively less effective in women compared with men when administered the same dosing regimen.

Solvay proposed a lower dose in women, but women have somewhat lower rates of conversion at any given dose than men, the FDA noted. So, regulators said, lowering the dose in women would appear to reduce any net clinical benefit.

There was "no clear rationale for a sex specific dosing regimen, particularly when the dose administered is already adjusted for body weight," the FDA stated.

Having two dose regimens could lead to a drug administration error, the agency said. The panel voted 7-0 against approval.

Because of the complicated dosing regimen of the drug, Solvay is proposing to establish a risk management plan for Pulzium that includes a physician checklist to ensure that the patient is suitable for treatment with the drug, an infusion bag sticker, an arrhythmia diagnostic guide, a dose guide and calculator, a QTc guide and calculator, a health care professional administration and monitoring guide, and a health care professional website.