Drug Lotronex Pulled Over Safety Fears
Another drug launched with “fast-track” government approval was withdrawn on Tuesday, marking the 10th time in three years that a prescription medicine has been banished in the United States for safety reasons.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“Lotronex is only the latest ‘fast-track’ drug to be withdrawn by the FDA,” said Rep.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In addition to Lotronex and Rezulin, the other prescription drugs withdrawn since fall 1997 are the diet pills Redux and Pondimin; the painkiller Duract; the allergy pills Seldane and Hismanal; the blood-pressure pill Posicor; the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 2 1/2-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.
