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approval was withdrawn on Tuesday, marking the 10th time in three 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     "Lotronex is only the latest 'fast-track' drug to be withdrawn 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drugs withdrawn since fall 1997 are the diet pills Redux and 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 21Ž2-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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