FDA makes labeling changes for Rezulin
Agency tightens guidelines, considers other drugs
The U.S. Food and Drug Administration (FDA) has tightened the recommendations for Rezulin (troglitazone) and released new safety information that warns of potential liver damage. Within days of this action, the FDA then approved another drug in the same class, Avandia (rosiglitazone), as a monotherapy and to use with metformin to treat insulin resistance.
Avandia (produced by SmithKline Beecham, Philadelphia) may stand to replace a substantial portion of the insulin-resistant Type 2 diabetic market niche carved out by the problem-plagued Rezulin. But Avandia is expected to have some competition soon.
FDA approval for Actos (pioglitazone, produced by Takeda Pharmaceuticals America and to be marketed in the United States by Eli Lilly and Co. in Indianapolis), a third drug in the thiazolidinedione class, is expected very soon.
"[Rosiglitazone] is really exciting if the pre-marketing data are borne out by widespread use, because it doesn’t appear to cause any of the liver problems that have been associated with troglitazone," says Richard Dickey, MD, president of the American Association of Clinical Endocrinologists and an endocrinologist practicing in Hickory, NC.
However, Dickey says, "We need to be cautious and monitor closely."
The "significant" changes in safety information regarding Rezulin were agreed upon in June by the FDA and the drug’s manufacturer, Parke-Davis Pharmaceuticals of Morris Plains, NJ. The FDA slightly softened the blow to Rezulin manufacturers by widening its approval to include combination therapy with metformin and sulfonylureas. Previously, it was recommended only with sulfonylureas.
Physicians and patients are warned of the need for extensive liver monitoring and cautioned against the use of Rezulin as a monotherapy through product labeling, patient package inserts, a patient information sheet to be distributed with each prescription, and a "Dear Health Care Professional" letter scheduled to be mailed soon.
The revisions came in response to reports of the deaths of at least 28 patients from liver failure associated with the use of Rezulin. An FDA expert committee considered the evidence in March and made recommendations similar to the FDA’s final decision.
Safety information now recommends a baseline liver function test before a patient begins Rezulin therapy and then monthly serum transaminase levels during the first year of therapy and quarterly afterward. The original guidelines called for 10 tests during the first year of therapy and "periodic" monitoring afterward.
Rezulin is not recommended as a single agent therapy, although the "Dear Health Care Professional" letter says physicians "may consider it appropriate, based on your clinical judgment of the risk benefit profile in an individual patient, to continue Rezulin in some patients who are currently receiving Rezulin as single agent therapy."
"In all cases, the risk of hepatotoxicity that may be associated with the continuation of Rezulin therapy in an individual patient should be weighed carefully against the expected benefits of continued therapy in that individual patient and the risk benefit profile of other available therapies." (For more on Rezulin, see Diabetes Management, April 1999, p. 37.)
On May 26, the FDA issued a Talk Paper recommending liver monitoring for patients taking Avandia: "Because of the liver toxicity associated with Rezulin, the FDA is recommending . . . liver enzymes should be checked at the start of rosiglitazone therapy and quarterly during the first year. After the first year, testing should continue periodically."
Clinical trials of 4,000 patients showed no cases of Avandia-related jaundice or liver failure.
"Rosiglitazone has pretty clear advantages as far as we know it now," says Barry Goldstein, MD, PhD, professor of medicine and director of the division of endocrinology, diabetes, and metabolism at Jefferson Medical College of Thomas Jefferson University in Philadelphia.
Goldstein, who participated in clinical trials for both Rezulin and Avandia, says that the possibility of liver function problems had already begun to emerge with Rezulin during clinical trials and none as yet have been associated with Avandia.
SmithKline also got a wrist slap from the FDA in April for jumping the gun with promotions before the drug was approved.
In an April 28 letter to the company, FDA regulatory review officer, Mark Askine, RPh, directed the company to discontinue use of a press release that promoted Avandia as safe and effective before it was approved.
Rezulin and Avandia are not recommended for pregnant women because of inadequate research in the area. The Rezulin package liners say insulin is usually the therapy of choice for pregnant women to maintain blood glucose as close to normal as possible.
Both drugs may also be connected with a moderate weight gain, according to Goldstein. Parke-Davis’ package literature for Rezulin says improved glycemic control was accompanied by weigh gains ranging from 5 pounds to 13 pounds over a year. Figures were not available for Avandia.
Yet, despite its problems, Rezulin is effective in normalizing blood glucose and its benefits outweigh its risks within the prescribed precautions, the FDA’s expert panel said in March.
Clinical studies show a mean 1.9% decrease in HbA1c values for patients taking Rezulin over a one-year period. Avandia trials showed a mean decrease of 1.5% in HbA1c.
[For more information, contact Barry Goldstein at (215) 503-1272 and Richard Dickey at (828) 322-7338.]
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