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Deaths Climb Since FDA Got Rezulin Warning

TIMES STAFF WRITER

Top officials of the Food and Drug Administration were publicly warned by their own expert epidemiologist nine months ago that every patient taking the diabetes pill Rezulin was at risk of sudden liver failure and no reliable way existed to protect them.

But agency officials decided to keep Rezulin on the market.

Now, newly obtained FDA records show, the number of deaths associated with use of Rezulin has climbed. Since the March 26 warning, Rezulin has been reported as the “primary suspect” drug in the deaths of 53 patients. This raises to 215 the total of reported fatalities linked to the drug since it was introduced in March 1997.

The government’s handling of Rezulin resonates beyond the 15 million Americans who have adult-onset diabetes. It provides a stark measure of how the FDA has shifted the approval and supervision of new drugs.

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The FDA made Rezulin among the fastest-approved prescription drugs in this decade. From 1993 to 1998, Rezulin was one of 556 new drugs approved by the agency under a revamped review process designed to get promising medications to the market sooner. Rezulin has generated sales of roughly $1.7 billion.

Several medical experts said in interviews that they believe it is time for the FDA to remove Rezulin from the market. Since 1997, the agency has overseen the withdrawal of seven drugs, including the painkiller Duract and the diet pill Redux.

‘Rezulin Should Be Pulled’

“There’s no doubt in my mind: Rezulin should be pulled off the market,” said Dr. William B. Applegate, chairman of internal medicine at Wake Forest University. “I am convinced that it greatly increases the chance of liver failure.”

The volume of reported deaths has varied widely for withdrawn drugs: The FDA attributed just four liver-failure deaths to Duract in overseeing its demise in 1998. The death totals have ranged far higher with other drugs. When considering drug withdrawals, the FDA typically weighs benefits and risks, the severity of the disease being treated and the availability of other medicines.

Senior FDA officials were not available for comment. “The agency is continuing to actively evaluate the risks and benefits of [Rezulin] . . . to determine whether any further regulatory actions are warranted,” the agency said in a written statement.

The FDA added that since March 26 it has confirmed nine new deaths from liver failure alone that are “possibly or probably” related to Rezulin. The FDA did not cite its basis for excluding the other reported fatalities.

The reports show that liver failure was present in 21 of the 53 new deaths.

The FDA has not disclosed the latest fatalities to physicians or the public. They are documented in medical reports obtained by The Times through the Freedom of Information Act. The reports, often filed by health care professionals, note that patients died after taking Rezulin. The reports can reflect a physician’s suspicion that a prescription drug caused a death but do not amount to proof.

Moreover, four of the nation’s largest health care insurers said they are now denying or restricting coverage for Rezulin prescriptions because of safety concerns.

The manufacturer of Rezulin, Warner-Lambert Co. of New Jersey, introduced the drug as a “breakthrough” in the treatment of diabetes. The drug was the first to be marketed from a new chemical class of agents that lower blood-sugar levels by boosting the body’s absorption of insulin.

Records show that doctors continue to prescribe the drug to new patients. During the week ending Nov. 5 alone, more than 24,000 new Rezulin prescriptions were written, according to data collected by IMS Health, a health care information company. In September, 370,000 prescriptions of Rezulin were sold, down from 488,000 in January.

Critics Question FDA’s Actions

The FDA is required to ensure that prescription drugs are safe and effective for their intended use. For decades, the agency enjoyed a worldwide reputation as a rigorous regulator of the pharmaceutical industry, although it sometimes was criticized for acting too slowly. But critics question whether the FDA recently has become too responsive to drug manufacturers by rushing to approve risky, nonessential medications.

Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, conceded to colleagues in September that, generally, the agency’s medical reviews need better “quality assurance.” She is among the officials who have kept Rezulin on the market.

The deaths of Rezulin patients have persisted despite four FDA-sanctioned changes in the recommended use of the drug. Each labeling change encouraged patients to submit to more rigorous monitoring of their liver functions--precautions that the FDA epidemiologist, Dr. David J. Graham, found ineffective. He also concluded that Rezulin patients are 1,200 times more likely to suffer liver failure than those who take other medications.

The FDA announced a reassessment of Rezulin in January, prompted by a Times investigative series. In March, after hearing Graham’s warnings, an agency advisory committee recommended narrowing the use of Rezulin but keeping it on the market.

In June, the FDA advised doctors to no longer prescribe Rezulin as a first choice for patients. But at the same time, the agency endorsed a new use for Rezulin, in combination with two other diabetes pills. This recommendation was sought by Warner-Lambert and is being cited by the firm in its ongoing promotions of Rezulin.

Warner-Lambert said in a prepared statement Monday that it “will continue to make this important therapy available.” The company declined to identify how many new deaths can be attributed to Rezulin.

“The appropriate individuals to evaluate the safety of Rezulin are the highly qualified scientists at both Warner-Lambert and the FDA, together with the FDA’s independent scientific advisors,” Warner-Lambert said.

Current and former FDA officials said that the reported deaths--filed voluntarily by doctors and others--can provide a sign of problems with a drug. Prescription-drug experts say research has found that the deaths reported to the FDA typically represent just 1% to 10% of all fatalities.

38 Deaths Include Liver-Related Findings

Of the 53 deaths reported since March 26, 38 included liver-related findings, such as swelling of the liver, jaundice and liver failure. The patients who died ranged in age from 35 to 86, with roughly an even split of women and men.

An additional 10 deaths in which cancer was cited as part of the patient’s condition were not counted among the 53 reported fatalities since March 26.

The Times examined each report by hand and computer to exclude duplicate filings. The methods used in analyzing the data were overseen by a consultant to The Times, Sheila R. Weiss, a former FDA epidemiologist who is an assistant professor at the University of Maryland’s department of pharmacy practice and science.

Health insurers and hospitals are reacting to Rezulin’s liver-failure danger by removing the drug from preferred lists of prescription drugs, meaning that the pills will be more difficult and more expensive for patients to obtain.

Representatives of the major health care organizations contacted by The Times--Cigna Healthcare, UnitedHealthcare, Kaiser Permanente and Aetna Inc.--said that their groups either have removed Rezulin or are requiring doctors to justify prescribing the drug.

James Harris, a Cigna spokesman, said that Rezulin was removed in August because of “increasing reports of [liver] toxicity coupled with the fact that other alternatives” are available. He added, “No new starts will be approved.”

At the Mayo Clinic, diabetes specialists have also recommended removal of Rezulin, according to Dr. Bruce Zimmerman, an endocrinologist there who is president of the American Diabetes Assn.

Zimmerman noted that the FDA over the last seven months has approved two newer diabetes pills, similar chemically to Rezulin but with virtually no liver toxicity shown in clinical trials.

One of the newer drugs, Avandia, has been prescribed by doctors since June. Its use since then has been associated with one death, according to reports filed with the FDA. The other drug, Actos, has been for sale since August. Records filed with the FDA through late November showed no fatalities.

Yet through September, twice as many patients took Rezulin than Avandia and Actos combined, records show.

“If there’s an alternative medication that, for all other purposes, has the same [method of] action and benefits, then why do you maintain one that has this extra risk that the others don’t have?” Zimmerman asked.

Doctors who continue to prescribe Rezulin say that they find it effective at lowering blood-sugar levels.

“I am still using Rezulin,” said Dr. Jose Luis Bautista, a Fresno area diabetes specialist. “In case a patient doesn’t want to use Rezulin, I can use Avandia or Actos.”

A dozen diabetes pills are on the market. These agents lower blood-sugar levels by varying means. Adult-onset diabetics can control their blood sugar through diet and exercise or medication. Juvenile-onset diabetics face certain death without daily injections of insulin.

The liver-monitoring guidelines embraced by the FDA and Warner-Lambert recommend that patients undergo monthly checks only through the first year, reflecting an assumption that the risk of organ failure falls with longer use.

That assumption was challenged during an agency advisory committee meeting in March by the FDA’s Graham, who said that Rezulin patients incur more risk of liver failure the longer they stay on the drug.

According to interviews with physicians, Rezulin patients have died of liver failure after taking the drug for durations that vary from three weeks to 18 months.

Graham also warned that even those monitored monthly would not be reliably shielded because Rezulin-induced liver failure can strike so suddenly. More than 99% of the patients evaluated by Graham did not fully comply with the monitoring recommendations.

Prescription records suggest that 1.5 million or more patients have taken Rezulin at least once.

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Researchers Janet Lundblad in Los Angeles and Sunny Kaplan in Washington contributed to this story.

A series of investigative reports on the FDA’s fast-track approval of Rezulin is available on The Times’ Web site: https://www.latimes.com/rezulin


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