With demise of Rezulin, FDA says there are safe alternatives

Avandia, Actos offer same benefits without same risks

Three-quarters of a million patients who used the insulin-sensitizing drug troglitazone (sold by Warner-Lambert Parke-Davis under the brand name Rezulin) have viable options in two other drugs in the same class that have not displayed the liver toxicity associated with Rezulin, according to the U.S. Food and Drug Administration (FDA).

At the recommendation of the FDA, The Morris Plains, NJ-based pharmaceutical giant withdrew Rezulin from the market on March 21 amid a firestorm of controversy over increasing evidence of liver toxicity in patients taking the drug.

On March 8, the FDA said it had received 88 reports of liver failure "possibly or probably related to use of the drug [Rezulin]" 61 patients died and 10 required liver transplants. Three of the liver-transplant patients died. On March 21, the FDA said in a written statement: "FDA took this action after its review of recent safety data on Rezulin and two similar drugs, rosiglitazone [Avandia] and pioglitazone [Actos], showed that Rezulin is more toxic to the liver than the other two drugs. Data to date show that Avandia and Actos, both approved in the past year, offer the same benefits as Rezulin without the same risk."

"When considered as a whole, the pre-marketing clinical data and post-marketing safety data from Rezulin as compared to similar, alternative diabetes drugs indicate that continued use of Rezulin now poses an unacceptable risk to patients," said Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, in a written statement released several days after the withdrawal of Rezulin from the market. "We are now confident that patients have safer alternatives in this important class of diabetes drugs."

Rezulin also has been pulled from the market in Japan, the only other country where the drug was sold. After the drug was withdrawn from the U.S. market, the Japanese pharmaceutical firm, Sankyo Company Ltd., said it would halt sales of troglitazone, sold there under the brand name Noscal.

In the March 8 statement, the FDA also acknowledged it had received two reports of liver failure in patients taking Avandia, including one death, that FDA medical staff consider "possibly or probably related to use of the drug." The official statement said there have been no reports of liver failure linked to Actos.

The FDA announced it will publicly present the Rezulin data and the rationale for its decision at a meeting of the Endocrine and Metabolic Drugs Advisory Committee, tentatively scheduled for May 18 and 19.

Warner-Lambert, in announcing it was voluntarily discontinuing the sale of Rezulin, said in a written statement, "The company has always believed that it is essential for patients and physicians to receive accurate and objective information regarding benefits and risks of Rezulin. It was for that reason that Warner-Lambert requested a public meeting with the FDA’s expert advisory committee. However, repeated media reports sensationalizing the risks associated with Rezulin therapy have created an environment in which patients and physicians are simply unable to make well-informed decisions regarding the safety and efficacy of Rezulin."

In a "Dear Doctor" letter posted on the Rezulin Web site, Warner-Lambert officials said they were making arrangements for wholesale and pharmacy returns of existing stock of the drug. Patients are instructed to contact the company to receive information about reimbursement for unused supplies of Rezulin. A company spokesman said 1.9 million prescriptions had been written for the drug. Its 1999 sales were reported at $625 million.

Many managed care organizations removed Rezulin from their formularies when reports of liver toxicity escalated. Endocrinologists at the Mayo Clinic in Rochester, MN, decided in October to stop prescribing Rezulin because of concerns about the risks, according to Bruce Zimmerman, MD, a Mayo endocrinologist and president of the Alexandria, VA-based American Diabetes Association.

Public Citizen calls for revised labeling

The latest round of controversy surfaced in early March after the Washington, DC-based public interest group Public Citizen, which had called for Rezulin’s withdrawal from the market in 1998, submitted a petition to the FDA calling for revised labeling on all three drugs in the thiazolidenedione class. "Studies have shown that adverse effects of all three drugs can include liver damage, heart damage, weight gain, fluid retention, low blood pressure, anemia, and possible changes in hormone levels," Public Citizen said in a written statement.

In addition, the organization alleged the class of drugs commonly known as the "glitazones" is not as effective as metformin and sulfonylureas. The FDA has not responded to allegations of toxicities other than liver damage linked to thiazolidenediones. "We’re not happy about these results," said Sidney Wolfe, MD, director of Public Citizen’s Health Research Group, after Rezulin was withdrawn. "Sixty-one people are dead who would be alive if the FDA had acted when they should have."

The group charged that the problems were well known to FDA medical officers who reviewed the drugs before they were approved. Rezulin entered the market in March 1997, Avandia in June 1999, and Actos in August 1999.

Public Citizen is not calling for the withdrawal of Actos and Avandia, but is requesting labeling revisions to warn of possible liver toxicity and advise liver monitoring for patients on the drugs.

Reports of Rezulin’s liver toxicity began to emerge a few months after it entered the U.S. market. The drug was pulled from the British market by medical authorities in December 1998 after reports of 130 cases of liver damage worldwide, including six deaths.

Benefits outweigh risks

In March 1999, an FDA expert panel said Rezulin’s benefits outweighed the risks associated with the drug. During hearings before the panel, Stephen Clement, MD, an endocrinologist with Georgetown University in Washington, DC, testified as a spokesman for the American Diabetes Association. "The American Diabetes Association believes that Rezulin has been a very useful drug for many patients, and its unique mechanism of action has been invaluable for countless individuals who, for many reasons, cannot achieve good glycemic control with the other drugs available."

Clement noted at the time that, despite its "risk of serious adverse events," Rezulin was the only drug available that offered help to certain patients with severe insulin resistance. He added that new therapies and new drugs would soon become available. "At that time, the FDA may need to reassess the benefits of Rezulin as it should all drugs previously approved to treat diabetes. . . ."

In response to the panel’s March recommendation, in June 1999, the FDA ordered labeling changes for Rezulin that warned of liver toxicity and recommended close monitoring of liver function for the first year a patient was using the drug. It also said Rezulin should be used only as a combination therapy with other oral agents.

In the interim, the FDA granted priority review status to Avandia, manufactured by SmithKline Beecham, and Actos, manufactured by Takeda Pharmaceuticals American and Eli Lilly and Co., and approved both drugs within a few months.

The day after Rezulin was withdrawn from the market, Public Citizen presented additional allegations in a letter to Donna Shalala, secretary of the U.S. Department of Health and Human Services. The organization wrote that FDA officials harassed FDA physicians "in the context of the recent controversy over Rezulin," and that the FDA had "lowered safety standards" in 1997 when Rezulin and several other controversial drugs were approved.

"The number of drugs already pulled off the market [Posicor, Duract, Raxar, and Rezulin] from those approved in 1997 is twice as many as in any other previous year of approval," wrote Wolfe in his March 22 letter to Shalala. He also mentioned the withdrawal of the weight loss aid Redux in 1996. "In many of these cases, there was either opposition by FDA employees to the approval of these drugs [Redux and Rezulin], unsuccessful urging of stronger product warnings on approval [Duract], or inadequately heeded opposition from several FDA advisory committee members [Posicor]."

Wolfe said a Public Citizen survey of medical officers at the FDA’s Center for Drug Evaluation and Research in late 1998 found 27 instances in which a drug was approved over a medical officer’s objection and 14 instances in which FDA officers were told not to present adverse information at FDA advisory committee hearings.

At press time, the FDA declined to comment on Public Citizen’s demands for a criminal investigation of alleged irregularities in Warner-Lambert’s reporting of evidence of hepatotoxicity that emerged in clinical trials on troglitazone.

Two physicians involved in Rezulin clinical trials say their conclusions were not properly reported by Warner-Lambert.

Janet McGill, MD, an endocrinologist, principal researcher and associate professor of medicine at Washington University in St. Louis, says she reported atypical elevated liver enzymes in two of 10 patients in her part of the 1994 Rezulin trials and that a third patient experienced an allergic reaction to the drug. These were downplayed in the data the company submitted to the FDA, she charges.

One patient, McGill says, had liver enzymes five times the normal amount, although none of her patients suffered liver failure. "What does this mean? It means that the FDA is looking only at cases of complete liver failure, and not considering sick livers.’ I saw two cases of liver problems in patients who had no problem before that. Behind the liver failure, there may be 10 times as many cases of people who were made ill by the drug."

Another physician, Mohammed Saad, MD, deputy chief of endocrinology and diabetes at the University of California at Los Angeles told CBS television that a patient in his study on Rezulin died of liver failure during the trial, but when he cautioned medical students about Rezulin’s risks, Warner-Lambert complained.

Saad, who could not be reached for comment, told CBS, "I have been teaching young doctors for 20 years now. This never happened before. I thought they were using pressure tactics that were inappropriate."

In May 1997, the FDA’s principal Rezulin investigator, Robert Misbin, MD, investigated Warner-Lambert’s data, according to reports on CBS News, and found patients with liver enzymes up to 30 times normal. An FDA internal document shows Warner-Lambert privately admitted its report to the FDA was "not correct," according to CBS. Another draft document "shows the FDA allowed the company to cross out mention of the most severe cases," said the news report.

Before Rezulin was withdrawn from the market, Misbin took the unusual step of sending a letter to Congress saying he was "frustrated" in his efforts to persuade his superiors to remove Rezulin from the market. Once a supporter of the drug, Misbin told legislators there are now safer drugs available.