http://www.latimes.com/news/nation/updates2/lat_fda001129.htm
Wednesday, November 29, 2000
Drug Lotronex Pulled Over Safety Fears
By DAVID WILLMAN, Times Staff Writer
WASHINGTON--Another drug launched with "fast-track" government
approval was withdrawn on Tuesday, marking the 10th time in three
years that a prescription medicine has been banished in the United
States for safety reasons.
The drug, Lotronex, was approved nine months ago for treating
irritable bowel syndrome in women. The withdrawal was announced by
Glaxo Wellcome Inc. after the Food and Drug Administration received
voluntary reports linking the company's drug to five deaths and
additional bowel surgeries.
The withdrawal raised new doubts about the FDA's practice of
conducting accelerated medical reviews of drugs that do not offer
potential lifesaving benefits. On March 21, the FDA announced the
banishment of Rezulin, the adult-onset diabetes pill, which also was
approved in a fast-track review.
"Lotronex is only the latest 'fast-track' drug to be withdrawn
by the FDA," said Rep. Henry A. Waxman (D-Los Angeles), who has
helped shape legislation affecting the regulatory agency. "There's
now a real question of whether the right balance of approval-speed
and safety is being struck."
The FDA began granting the fast-track reviews in 1996 for new
drugs intended to treat "serious" or life-threatening conditions.
In addition to Lotronex and Rezulin, the other prescription
drugs withdrawn since fall 1997 are the diet pills Redux and
Pondimin; the painkiller Duract; the allergy pills Seldane and
Hismanal; the blood-pressure pill Posicor; the antibiotic Raxar; and
the heartburn drug Propulsid.
The agency approved Lotronex on Feb. 9 following a review that
took just seven months, compared to the standard duration of one
year. Senior FDA officials decided to approve Lotronex despite an
agency physician's emphatic warnings that it could cause constipation
and ischemic colitis--a potentially fatal complication that results
from inadequate blood flow to the colon.
In a statement issued Tuesday night, the FDA said it had
received reports of 49 cases of ischemic colitis and 21 cases of
"severe constipation." Ten of those 70 patients underwent surgeries
and 34 others were examined at hospitals and released without
surgery, according to the FDA.
Lotronex sales in the U.S. totaled $50.4 million through
September, according to the research firm IMS Health. Through Nov.
17, pharmacists had filled 474,115 prescriptions for the drug.
Glaxo's stock price dropped 4.4%, to $56.56, in trading Tuesday
on the New York Stock Exchange.
The end for Lotronex came Tuesday during a 212-hour meeting
convened privately at the FDA's headquarters in suburban Rockville,
Md. According to those familiar with the session, Glaxo executives,
led by company Chairman Robert A. Ingram, reiterated their position
that the risks of Lotronex could be managed adequately through
revised labeling and other measures. Agency officials recommended
that Glaxo either withdraw the drug or agree to controls that would
restrict sales of the pill, once regarded by Wall Street as a
potential blockbuster.
"We said to the FDA, 'Look, these [proposed controls] are
no-gos. We believe you're asking us to remove the drug,' " said Dr.
Richard S. Kent, Glaxo's chief medical officer and vice president. "
'So, we are going to remove the drug.' "
Kent estimated that ischemic colitis occurred in one of every
1,000 Lotronex patients and that "about half are managed as
outpatients and half are hospitalized." He contended that Lotronex
offers risks and benefits that are comparable to various other
medications, including popular pain pills sold by prescription and
over the counter.
When the FDA convened a special advisory committee meeting on
June 27 to reassess Lotronex, Kent had argued against the agency
staff's proposal to stiffen the warning of ischemic colitis by
placing a bold, black box around the product labeling. "I think there
is a great duty not to overwarn," Kent said then.
Following the June 27 meeting, the FDA dropped the proposal for
a black-box warning, which signifies for doctors that a drug has
elevated and deadly risk.
In a prepared statement on Tuesday, Glaxo acknowledged "rare
reports of fatalities" but said that "a causal relationship to
Lotronex has not been established." Reports filed with the FDA
through October identified Lotronex as the "primary suspect drug" in
five deaths.
The top FDA official who attended the session Tuesday with
Glaxo, drug-review center director Dr. Janet Woodcock, issued no
public comment. In a 12-paragraph "talk paper," the agency described
the withdrawal of Lotronex as voluntary.
Missing from Tuesday's session with Glaxo was Dr. John
Senior--the FDA medical officer who had warned of Lotronex's severe
risk. Senior pointed out one year ago to the agency's
Gastrointestinal Drugs Advisory Committee that no patient who took an
inert placebo pill in clinical studies had gotten ischemic colitis.
Senior also underscored that irritable bowel syndrome, although it
can result in diarrhea and abdominal pain, is not associated with
either ischemic colitis or death.
Senior, a gastroenterologist who also is an adjunct professor at
the University of Pennsylvania, alleged a year ago in his medical
review that Glaxo had "totally ignored" the drug's capacity to induce
ischemic colitis.
But senior FDA officials were unpersuaded. They followed the
recommendation of the advisory committee and declined to delay
approval of Lotronex until a more sweeping study could be launched to
assess the risk of ischemic colitis.
The FDA approved Lotronex based on a pledge from Glaxo that the
company would then conduct a major new ischemic-colitis study. That
study has never begun. The company now will shut down all testing in
humans of the drug within the U.S., Kent said.
The Glaxo executive also said in an interview that the company
does not believe the earlier "risk-management" measures it undertook
with the FDA were given enough time to work. A leaflet for patients,
called a medication guide, was not distributed to pharmacies until
late September, he said.
Woodcock told The Times on June 30 that she hoped the leaflets
would provide an innovative way to educate doctors and to persuade
patients to use the medication properly. Yet with Lotronex, many if
not most of the patients who were hospitalized appeared to have taken
the medication as directed, according to Dr. Sidney Wolfe of Public
Citizen, a consumer group that had called for an earlier withdrawal
of the drug.
"The larger lesson here is not to approve these kinds of drugs,"
Wolfe said.
A Glaxo executive, Dr. James Palmer, said that "thousands of
women" benefited from Lotronex. "Without this medicine," he said,
"many of these women will have to resort to therapies that did not
adequately treat their symptoms."
---
Times researcher Janet Lundblad in Los Angeles contributed to this report.
Copyright © 2001 Los Angeles Times
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