FDA Panel Recommends Drug to Compete With Rezulin
BETHESDA, Md. — A Food and Drug Administration advisory committee Thursday unanimously recommended approval of a new pill to treat adult-onset diabetes that would compete with the controversial compound Rezulin.
The action by the FDA panel is a victory for Britain-based SmithKline Beecham, maker of the new pill, called Avandia. The drug still must be approved by senior FDA officials before SmithKline can market Avandia in the United States.
The endorsement from the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee followed repeated assurances from SmithKline representatives that their drug--unlike Rezulin, which has been linked by the FDA to 43 confirmed cases of liver failure--will not damage the organ. Avandia and Rezulin are of the same chemical class.
“It appears that the risk for liver damage is probably less, or none at all, compared to [Rezulin],” said Dr. Mark E. Molitch, a committee member who is a professor of medicine at Northwestern University.
Despite the enthusiasm voiced for the safety of Avandia, caution was raised on at least four fronts. SmithKline’s clinical studies have found that, although the drug reliably lowered blood-sugar levels, it also was associated with weight gain, upper-respiratory-tract infections, anemia and abnormal accumulation of fluid (known medically as edema).
Several of the eight voting members of the advisory committee recommended that the drug not be used by patients with severe preexisting heart problems. The panelists also urged SmithKline to conduct various safety studies after Avandia is on the market, assuming that the drug wins final approval.
The committee’s recommendations are not binding on the FDA, but the agency usually follows the advice.
Throughout the eight-hour meeting, the issue of liver toxicity, and particularly the FDA’s experience with Rezulin, was a repeatedly cited concern.
SmithKline’s studies of humans showed dramatically fewer instances of liver injury than occurred during testing of Rezulin, made by Warner-Lambert Co. Yet an FDA pharmacologist, Ronald W. Steigerwalt, said responses of dogs to high doses of Avandia “provide a signal for liver toxicity.”
On the other hand, two liver consultants to the FDA told the advisory committee that they saw no “signal” that Avandia, known chemically as rosiglitazone, would damage humans.
The two consultants, Dr. Leonard B. Seef of the National Institutes of Health and Dr. James H. Lewis of Georgetown University Medical Center, disagreed over whether Avandia patients should be regularly monitored to guard against liver failure.
When the FDA approved Rezulin in 1997, scant attention was paid to the drug’s potential to cause liver damage, and patients and their doctors were not advised of any need to conduct liver-related monitoring. Such monitoring was called for by the FDA eight months after Rezulin went on the market in March 1997.
Lewis, referring to troglitazone, the chemical name for Rezulin, said that those who now want to monitor the liver functions of Avandia patients are misguided. “I think we’re suffering from troglitazone-nervosa,” Lewis said, adding that the clinical studies of Rezulin did, indeed, find a clear “signal” of liver toxicity.
Avandia, he said, “is not [Rezulin]. From what I can tell, it’s completely different.”
Seef, the other liver specialist, said: “I think [Avandia] is far safer with respect to the liver than [Rezulin].” He nonetheless recommended monthly monitoring for Avandia patients, due to the liver damage that has been caused by Rezulin.
“Because of the history of the past drug, we need to do something about it,” Seef said.
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A series of Times stories on the FDA approval of Rezulin and deaths related to its use is on The Times’ Web site: http://161.35.110.226/rezulin
