Rezulin comes under fire as LA Times alleges more adverse reactions
FDA and manufacturer continue to counter new claims of fatality
The controversy over Rezulin (troglitazone) erupted anew in mid-December when the Los Angeles Times alleged 53 more deaths have been linked to the enormously popular drug used to treat the most stubborn cases of insulin resistance. Countering with a statement of its own, Warner-Lambert, manufacturer of Rezulin, announced the reports were taken out of context and accused the LA Times of bias and distortion.
But even before this newest round of tough press, health care professionals say they have been moving away from Rezulin out of concerns for the safety of their patients.
"It doesn’t really make sense to prescribe troglitazone in light of the safety concerns and that there are two other drugs in the same class that have a similar mode of action and do not have the hepatotoxic effects," says American Diabetes Association (ADA) president Bruce Zimmerman, MD. He is an endocrinologist at the Mayo Clinic in Rochester, MN. Zimmerman says safety concerns about Rezulin prompted him and his endocrinology team to recommend removing the drug from Mayo’s formulary several months ago. The ADA, he says, is discussing its viewpoint on the matter. "It’s not where we can develop a consensus now or put a name on hard scientific evidence. We need to let more facts accumulate."
That cautious viewpoint was echoed by the ADA’s chief scientific and medical officer, Richard Kahn, PhD. "It’s hard for the ADA to make a judgment based on an article in the Los Angeles Times. We certainly assume the FDA is paying close attention to the safety and efficacy issues as they relate to the use of this drug." He says the ADA will most likely present evidence if the FDA decides to conduct another review of Rezulin as it did in March of last year, two years after the drug was introduced.
In practice, health care organizations are voting with their checkbooks when it comes to Rezulin.
The LA Times reported that four major managed care organizations — Aetna Inc., Cigna Healthcare, UnitedHealthcare, and Kaiser Permanente — have either removed Rezulin from their formularies or are requiring doctors to justify the drug’s use. That means patients who want to stay on the drug will find it harder to get and may have to pay the entire cost out of their own pockets. Prudential Healthcare officials removed Rezulin from their formulary last fall because of safety concerns, says Arthur Levin, MD, vice president for technical and clinical practice assessment for Prudential who now holds the same title for the merged company under Aetna’s corporate name.
"This is disturbing," he says. "I don’t think we should have to learn about this from the press. I’d certainly like to see these reports from the FDA. There should be some mechanism for informing physicians and health care organizations about what information they have received. It concerns me greatly that these data seem to be piling up at the FDA and nobody knows anything about it except the people at the FDA."
Rezulin remains on the Aetna formulary with several restrictions. The company’s pharmacy and therapeutics committee is currently considering its position on the matter, Levin said.
The LA Times article reported the 53 cases were found by searching records gained under a federal Freedom of Information request. If these reports are substantiated, it would mean a total of 215 reported fatalities could be attributed to Rezulin use, due to incidences of liver failure occurring since the drug was introduced in March 1997.
In a written statement, the FDA disputed the figures and said it is investigating all reports of adverse effects linked to the drug. FDA spokes-woman Crystal Wyand says nine new cases have been received since March 1999, when the agency’s Metabolic and Endocrine Drugs Advis ory Committee reviewed Rezulin’s status and issued directives for close monitoring of liver function for patients using the drug. She says six of those cases are "probable" Rezulin links, the other three are "possible," and there have been no new cases reported since August 1999.
At the March hearing, FDA epidemiologist David Graham testified that at least 28 people had died of liver failure associated with Rezulin use since the drug came on the market. The report says 21 of the 53 new deaths were from liver failure. During that hearing, Graham also told the panel he believed the number of incidents of liver failure associated with Rezulin had been underreported and suggested the number of adverse liver side effects may be as high as one in 1,800 patients using the drug. Graham also estimated Rezulin patients were 1,200 times more likely to suffer liver failure than those who take other medications.
After that review hearing, the panel said the benefits of Rezulin outweighed the risks associated with its use. However, the panel recommend Rezulin not be used as a monotherapy and said close liver function monitoring is necessary for patients using the drug.
Warner-Lambert accused the LA Times of providing its readers with "a biased and strongly distorted picture of Rezulin," called the reports of additional deaths "absolutely false," and said the article "represents a cynical intent to alarm the public and prescribing physicians."
A written company statement issued shortly after the article was published stated the article cites post-marketing case reports out of context and contends that the recent reports listed in the FDA’s MEDWATCH explicitly warn users that reports of additional liver toxicity events "cannot be interpreted as proof of causality."
Warner-Lambert says that through November 1999, the company received reports of seven deaths or liver transplants, which were considered based on available information to be "possibly or probably related to the drug."
Rezulin use dropped dramatically between January and September, according to figures reported by the Los Angeles Times. In January, 488,000 prescriptions were written for the drug, and in September, 370,000 prescriptions were written. The LA Times reported Rezulin has generated sales of approximately $1.7 billion.
During the intervening months, not only did the FDA review Rezulin, but two other drugs in thiazolidinedione class were approved. Rosiglitazone, marketed under the brand name Avandia by SmithKline Beecham was approved in May, and pioglitazone, marketed by Eli Lilly under the brand name Actos, was approved a few weeks later. Neither of the newer drugs was associated with liver toxicity in clinical trials. Since Avandia entered the market in June, the LA Times reported, one death from undisclosed causes has been reported to the FDA. No deaths have been linked to Actos, which became available in August.
Experts such as Zimmerman have expressed concern that liver toxicity may increase over time with any of the medications because they are intended for long-term use and there is no means of determining their potential effects over years.
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