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MARION MERRELL DOW SELDANE CARDIOVASCULAR SIDE EFFECT FOLLOW- UP STUDIES

Executive Summary

MARION MERRELL DOW SELDANE CARDIOVASCULAR SIDE EFFECT FOLLOW- UP STUDIES show that the "vast majority" of analyzable serious cardiovascular events have been associated with known risk factors, MMD consultant Leonard Bernstein, MD, told a Sept. 15 Rx- to-OTC symposium sponsored by the Nonprescription Drug Manufacturers Association. Those findings are "very reassuring," Bernstein explained, "because if it ever will make OTC, we have to be really sure about those risk factors." Bernstein, a professor of medicine at the University of Cincinnati Medical Center and chairman of FDA's Pulmonary-Allergy Drugs Advisory Committee, noted that he had recently downgraded his expectations for Rx-to-OTC switches of the two nonsedating antihistamines, Marion Merrell Dow's Seldane (terfenadine) and J&J's Hismanal (astemizole), after both prescription drugs were re-labeled in July. A boxed warning is being added to Seldane labeling for serious cardiovascular events associated with high doses of the drug and potentially serious drug-drug interactions with ketoconazole and erythromycin (see story above). Two weeks later, FDA asked Janssen to add a boxed warning for serious cardiovascular events associated with overdosage ("The Pink Sheet" July 27, p. 3). MMD has identified a total of 75 episodes of serious adverse events associated with Seldane use, Bernstein noted. Of those, MMD has been able to analyze 56 events, he said, adding: "The vast majority...were associated with these known risk factors." Other data accumulated by MMD shows that "bioequivalence is excellent" and that terfenadine "is just about totally absorbed" and the pharmacokinetics are "the same" in healthy patients and in elderly patients and patients with heart disease, Bernstein said. The adverse events appear to be dose-dependent without "any ideosyncratic effect," he added. Bernstein indicated that he is a little more optimistic about the chances of an OTC switch for terfenadine after seeing the new adverse reaction data from MMD. The company has enlarged its pharmacokinetic/pharmacodynamic studies of terfenadine and has "also gone to great efforts to do some pharmaco-epidemiologic studies which may very well change how we look upon these adverse events we currently are considering," he noted. "In response specifically to these cardiac events, new use data sources are being used...in a retrospective pharmaco- epidemiologic studies based on Medicaid users and the Harvard Medical Health Plan," Bernstein said. "In both of these studies," he asserted, "the bottom line is: [terfenadine] comes out probably as safe as ibuprofen in terms of these adverse cardiac evens [and] it comes out better than some other antihistamines, namely diphenhydramine." The MMD studies may be open to some criticism "on the basis of being retrospective," Bernstein acknowledged. "But I think they encompass a lot of use data and I think that they have to be considered seriously."
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