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Painkiller Posed Risk of Damage to Liver

Dec 20, 2000 | LA Times The FDA medical officers who reviewed a proposed painkiller called Duract saw the problem from the outset: Too many patients who took the pill in clinical trials suffered liver injury.

"It seems imprudent to open the doors to extensive use when there have been early warning signs," an FDA medical officer, Dr. John E. Hyde, wrote on July 31, 1996. He said the specialists reviewing Duract "were concerned about the frequency and severity" of the injuries reflected in patients' blood tests.

Hyde and a colleague, Dr. Rudolph M. Widmark, concluded in another report: "The [liver] toxicity is a significant concern with this drug."

Believing that the risk increased the longer a patient remained on Duract, they sought to rid the label of any reference to long-term use. They also proposed a prominent black box warning regarding Duract's liver toxicity.

This was not what the manufacturer, Wyeth-Ayerst Laboratories, had in mind.

"They were unhappy with my review," Widmark said in an interview.

In a market already stocked with more than 20 prescription and over-the-counter painkillers, a black box warning could turn off doctors and cripple sales.

Wyeth-Ayerst took its case to Widmark's superiors. Widmark responded, in a memo dated Nov. 14, 1996, to the FDA drug center's No. 2 administrator, Dr. Murray M. "Mac" Lumpkin:

"The company would like a label that actually puts the onus on the prescribing physician because if severe and maybe fatal liver toxicity [occurs], the physician will be sued and will be found liable if he/she did not 'monitor' for liver damage. Wyeth-Ayerst will be in the clear, because 'it is in the label.' "

Widmark added, "I hope that this short memo will help you to make the right decision in this dispute."

When the company rolled out Duract following the FDA's approval on July 15, 1997, there was no black box on the label. Securities analysts predicted that in four years Duract could yield annual sales topping $500 million.

Beginning on the 135th line, the label's fine print informed doctors that Duract was recommended for "generally less than 10 days." The label also advised that, "if a physician chooses to administer Duract for a longer duration," patients' liver functions should be checked after a month.

Seven months after Duract's market launch, the FDA and Wyeth-Ayerst responded to reports of severe liver damage: A black box was added.

The revised labeling also flatly warned doctors for the first time "not" to prescribe the drug for longer than 10 days.

"Patients using Duract for more than 10 days have developed jaundice, fulminant hepatitis and liver failure requiring transplants," the FDA said, announcing the label change.

By the time Wyeth-Ayerst announced Duract's withdrawal on June 22, 1998, the FDA had received 13 voluntarily filed reports of liver failure. The agency said that "almost all" of the cases occurred among patients who took the drug longer than 10 days.

Widmark, an Austrian immigrant, said he believes that lives would have been saved if FDA administrators had stood behind his original recommendation for a black box warning.

"I personally think yes," Widmark said. "They were more impressed with the company's consultants than they had confidence in their own reviewers. . . .

"Something is wrong and something should be done to avoid this in the future."

Now 75, Widmark retired in December 1997 after spending 11 years with the FDA. He still works as a consultant to the pharmaceutical industry.

The spokesman for Wyeth-Ayerst, Petkus, said the company's consultants "made a case that there was no need for a black box," believing the recommendation to use Duract generally less than 10 days was sufficient. The FDA's management, he said, agreed.

In their May 1999 medical journal article, Woodcock and Lumpkin said the problems that emerged with Duract were "unexpected," adding: "Given the availability of other analgesics with a wider margin of safety than [Duract], the FDA believed that the risk from this product outweighed its benefits."

In a written response to questions, Woodcock said, that if used short term, "it was felt that Duract would not cause liver damage more often than" certain other painkillers. She said the findings of potential danger, identified in advance by the agency's two medical officers, involved tests that "do not always signal clinically important [liver] toxicity."

By late 1998, the FDA had received voluntary reports citing Duract as a suspect in 68 deaths, including 17 that involved liver failure. During its one year on the market, Duract generated sales totaling $89.7 million for Wyeth-Ayerst.

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