FDA panel says Rezulin should not be used as monotherapy
Experts say benefits to patients outweigh risks
Rezulin remains on the market, but with some new restrictions and many caveats — after a Food and Drug Administration (FDA) advisory panel decided March 26 the benefits of the controversial insulin-sensitizing drug outweigh the risks of liver failure.
The recommendations of the Endocrinologic and Metabolic Drugs Advisory Committee, expected to be taken up by the full FDA in April, warn against the use of Rezulin as a monotherapy, but acknowledge its effectiveness when used for patients with particularly stubborn insulin resistance.
"This is not to be used ever as a first-line drug for diabetes," says panel member Jules Hirsch, MD, senior physician at the Laboratory for Human Behavior and Metabolism at The Rockefeller University in New York City.
Rezulin, marketed by Warner-Lambert, has been linked to at least 28 deaths from acute liver failure.
The panel’s recommendation was greeted as a "good decision" by Richard Kahn, PhD, chief scientific and medical officer of the American Diabetic Association (ADA) in Alexandria, VA. "Monotherapy and the risk of adverse events are a concern. The use of monotherapy suggests that other therapies haven’t been tried," he says.
In conjunction with either insulin, metformins, or sulfonylureas, Kahn says he believes the benefits to hundreds of thousands of patients who are particularly insulin-resistant outweigh the risks of liver damage.
Testimony from FDA epidemiologist David Graham, PhD, showed that at least 28 people have died from liver failure connected with the use of Rezulin since the drug was approved in January 1997. Seven others survived only with liver transplants, and five recovered without a transplant.
However, Graham told the panel he believes the incidence of adverse liver reactions due to the use of Rezulin has been underreported. He conservatively estimates that only about 10% of the liver side effects have been reported, suggesting the incidence of acute liver failure is as high as one in 1,800 patients using the drug. Reports in the Los Angeles Times alleged 155 deaths might be tied to Rezulin. Approximately 750,000 patients have used it.
Last July, Warner Lambert inserted package liners alerting physicians to perform liver function tests at the beginning of Rezulin therapy and repeat them monthly for the first eight months of using the drug. With the start of month nine, liver tests should be done every two months for the remainder of the first year of Rezulin therapy, then performed periodically thereafter.
Rapid failures can’t be detected early
However, Graham told the panel it took less than a month for patients to experience the most dramatic reactions to Rezulin, and as many as 75% of liver failures would be missed by monthly monitoring because of extremely rapid deterioration. He called these patients "rapid risers," who went into sudden acute liver failure in as little as four days after beginning Rezulin therapy.
"For most of these patients, jaundice was the first sign of trouble, and by then, the horse is out of the barn," he said, adding that encephalopathy rapidly follows jaundice.
Some panel members suggested that patients need additional education when they begin taking Rezulin, and they should be advised to contact their physicians immediately if they experience nausea, vomiting, or jaundice.
Graham said the risk of complications increases the longer patients stay on troglitazone, and patients taking the drug have a risk of acute liver failure that is 50 times greater than that of the general population.
However, Warner Lambert argued that the risk seemed to diminish as patients take Rezulin for longer periods of time. The company said no cases of acute liver failure have appeared beyond 11 months of using the drug.
Stephen Clement, MD, an endocrinologist at the Georgetown University Medical Center in Washington, DC, argued on behalf of the ADA that "the benefits of Rezulin may outweigh its risks.
"Rezulin is a drug whose mechanism of action is not shared by any other approved glucose-lowering agent, and because of that fact, it has offered health care professionals an important advance in pharmacotherapy," Clement told the panel.
He said Rezulin has been "invaluable for countless individuals who, for many reasons, cannot achieve good glycemic control with the other drugs available."
Clement said the ADA trusts the FDA’s expertise, not only in the matter of Rezulin, but in approving and reviewing new drugs, weighing benefits and risks in diabetes treatment.
March 23, the British equivalent of the FDA, the UK Medicines Control Agency, rejected an application by Glaxo Wellcome to reintroduce troglitazone to the British market. Glaxo voluntarily withdrew the drug from that market in December 1997 after reports of liver toxicity emerged in the United States and Japan. Glaxo applied for the reintroduction with recommendations of increased liver monitoring.
[For more information, contact the American Diabetes Association at (703) 549-1500. Contact the FDA’s Center for Drug Evaluation and Research Endocrinologic and Metabolic Drugs Advisory Committee at (301) 827-7001.]
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