DURACT: Painkiller Posed Risk of Damage to Liver
Wednesday, December 20, 2000 | Print this story
Drugmaker's lobbying won fine print instead of prominent warning.
By DAVID WILLMAN, Times Staff Writer
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'
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
This was not what the manufacturer, Wyeth-Ayerst Laboratories, had in
"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
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
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
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