WASHINGTON--The
Food and Drug Administration said Tuesday that the popular diabetes
pill Rezulin--a drug that won "fast-track" government
approval but was linked to scores of liver failures and deaths--will
be withdrawn promptly from the U.S. market.
Compared
to alternative diabetes treatments, "continued use of Rezulin now
poses an unacceptable risk to patients," said Dr. Janet Woodcock,
director of the FDA's drug evaluation center.
The
end for Rezulin, a Wall Street blockbuster that generated more than
$1.8 billion in sales and was promoted as free of serious side
effects, came Tuesday evening when Woodcock telephoned representatives
of the drug's manufacturer, New Jersey-based Warner-Lambert Co.
"FDA today asked the manufacturer of Rezulin . . . to remove the
product from the market," the agency said in a prepared
statement. "The drug's manufacturer . . . has agreed to FDA's
request. "The action came 29 months after the first acknowledged
death of a Rezulin patient in October 1997. The FDA has concluded that
Rezulin use has "possibly or probably" resulted in 90 liver
failures, including 63 deaths and seven nonfatal organ transplants.
About
300,000 Rezulin prescriptions are sold each month. "Patients
taking Rezulin should consult with their physicians as soon as
possible to discuss alternative therapies," Warner-Lambert said
late Tuesday. "Warner-Lambert will work closely with the Food and
Drug Administration . . . to assure a safe and efficient transition
for patients."
Rezulin
becomes the eighth prescription drug to be withdrawn from the U.S.
market in the last 2 years. Among the recent withdrawals were Pondimin
and Redux, ingredients in the "fen-phen" weight-reduction
cocktail, found to cause heart and lung maladies, and Duract, a
nonaddictive painkiller that the FDA associated with four
liver-failure deaths.
More
Toxic Than Two Other Drugs
The
FDA noted that Rezulin is more toxic to the liver than two other
similar drugs, Avandia and Actos, that also lower blood-sugar levels
for adult-onset diabetics.
The
drugs, approved in the last year, "offer the same benefits as
Rezulin without the same risk," the FDA said. Added Woodcock:
"We are now confident that patients have safer
alternatives."
The
FDA sought the withdrawal of Rezulin within two hours of a meeting
that included agency physicians, lawyers and other specialists.
According to people familiar with the private session, Dr. David J.
Graham, the FDA's senior epidemiologist, said he estimated that 20
Rezulin patients a month are suffering liver failure. Graham compared
Rezulin's tendency to cause fatal liver failure with the worst side
effects associated with the other diabetes drugs.
He
concluded that Rezulin, by far, is the most dangerous. Graham was one
of at least five FDA physicians who challenged top agency officials,
beginning at a staff meeting on Jan. 6, by saying that Rezulin's risks
outweighed its benefits and that it should be withdrawn.
The
removal of Rezulin comes after Warner-Lambert and senior FDA officials
had supported its continued use in the face of mounting deaths and
recent repudiation of the pill by numerous health insurers and
hospitals.
On
four occasions after Rezulin was made available for sale in March
1997, the FDA and Warner-Lambert agreed to safety changes in the
drug's labeling, instead of pulling the pill off the market.
The
FDA's stance stood in stark contrast to that of its counterpart in
Britain, the Medicines Control Agency, which oversaw another company's
voluntary withdrawal of Rezulin in December 1997. Citing safety
concerns, the British authority refused to allow the reintroduction of
Rezulin in March 1999.
But
within a week, officials at the FDA, on March 26, 1999, convened an
advisory committee meeting, dominated by supporters of Rezulin,
including paid consultants to Warner-Lambert. At the conclusion of the
meeting, Woodcock indicated in an interview that she did not share the
concern voiced by Graham, the senior agency epidemiologist, who
presented a chilling picture of Rezulin's danger.
Graham
told the committee that Rezulin was one of the most dangerous
prescription drugs on the market, that every patient taking the pill
was at risk of liver failure and that there was no reliable way to
safeguard them.
This
flew in the face of repeated assurances from Warner-Lambert and others
at the FDA, who said that patients would be adequately protected by
monthly blood tests, intended to monitor their liver functions.
In
June 1999, the FDA announced that it would follow the advisory
committee's advice and keep Rezulin on the market. In fact, while the
FDA said that Rezulin should no longer be used as a stand-alone
diabetes treatment, the agency endorsed its expanded use, in
"triple combination" with two other diabetes pills.
The
FDA's reassessment of Rezulin's safety was in direct response to a
December 1998 investigative series by The Times and subsequent
articles published by the newspaper focusing on deaths related to the
drug and the actions of the agency and Warner-Lambert.
The
Times reported that the FDA ignored explicit signs of danger while
examining Rezulin in January 1997, after a six-month review, the
fastest approval granted a diabetes pill.
Complaints
About Intemperate Language
The
FDA approved Rezulin despite a recommendation to reject the drug by a
veteran agency medical officer, Dr. John L. Gueriguian, who cited its
potential danger to the liver and the heart.
Woodcock's
deputy, Dr. Murray Lumpkin, stripped Gueriguian of his role in
reviewing Rezulin in the fall of 1996, following complaints from
Warner-Lambert about his use of intemperate language. Reached Tuesday
night at his home in Rockville, Md., Gueriguian said he was pleased to
hear of Rezulin's withdrawal.
"It
is the right thing to do. But it is too late. Too many people have
already died and suffered." Gueriguian stood alone when he
opposed Rezulin in 1996. No fewer than four other FDA physicians who
examined the drug endorsed its approval. They were persuaded, they
said in hindsight, by Warner-Lambert's claims of safety and the pill's
supposed breakthrough effectiveness.
Indeed,
as recently as Feb. 24, Woodcock told reporters in a prepared
statement that Rezulin "provides an effective treatment to
control blood glucose and in many patients it has proven to be very
effective despite the failure of other therapies."
At
least three federal investigations related to Rezulin have been
initiated: an inspector general's inquiry into a senior National
Institutes of Health physician's acceptance of consulting fees from
Warner-Lambert, an FDA inquiry into allegations that the company
omitted findings of liver toxicity from a 1994 clinical trial and an
FDA internal-affairs investigation into how certain agency e-mails
came into the possession of The Times.
Company's
Troubles Are Not Over
Having
failed to hold support for Rezulin at the FDA, Warner-Lambert on
Tuesday night issued this statement:
"The
company has always believed that it is essential for patients and
physicians to receive accurate and objective information regarding the
benefits and risks of Rezulin. . . . 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."
The
withdrawal, however, will not end the company's troubles. Over the
last year, product-liability cases have been filed in state and
federal courts on behalf of patients or their survivors. One of them,
Ismael "Milo" Valenzuela, whose wife, Rosa Delia Valenzuela,
died in Los Angeles on Dec. 18, 1998, of liver failure after taking
Rezulin, welcomed news of the withdrawal.
"That's
the main thing I wanted to see, to get those pills off the
market," said Valenzuela, a retired jockey who twice won the
Kentucky Derby. "They killed my wife--that's the way I feel about
it."
---Times
researcher Janet Lundblad in Los Angeles contributed to this story.
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