Lotronex

ROCKVILLE, MD. -- Several members of a Food and Drug Administration advisory panel agreed that the risk management program in place for the irritable bowel syndrome drug alosetron should not be modified--despite some elements that the manufacturer says may deter physicians from prescribing the drug to appropriate patients.

At a meeting of the FDA's drug safety and risk management advisory committee, the drug's manufacturer GlaxoSmithKline (GSK) and the FDA provided an update on the risk management program for alosetron.

The program was instituted at the time of the drug's reintroduction in November 2002 for women with severe diarrhea-predominant irritable bowel syndrome who have failed to respond to conventional therapy. The program aims to make the drug available to appropriate patients and to ensure that alosetron is prescribed by physicians qualified to diagnose and manage not only IBS, but also ischemic colitis and severe complications of constipation--the serious adverse events that were reported in patients taking alosetron during the months following the drug's initial approval in February 2000. Some of these cases were fatal.

Alosetron, marketed as Lotronex, which blocks serotonin activity at 5-HT3 receptor sites in the enteric nervous system, was voluntarily withdrawn by GSK from the market in November 2000. But after the FDA and the manufacturer were contacted by desperate IBS patients who wanted the drug back--the FDA received approximately 5,000 e-mail messages--GSK submitted an approval application in December 2001. In June 2002, the FDA approved the drug's reintroduction with the following caveats: a narrower indication, a lower recommended starting dose, and the risk management program.

A main element of the program is that physicians who meet qualifications for diagnosing and managing IBS and potential side effects enroll in the program and sign a form attesting that they accept certain responsibilities, including educating patients about the risks of the drug and reporting serious adverse events. Other elements include a voluntary patient survey.

The purpose of the FDA meeting was to update the panel, not to seek specific recommendations. But after presentations by the FDA and manufacturer, panel members gave their opinions on the presentation.

Between Nov. 20, 2002, and Feb. 6, 2004, eight cases of ischemic colitis, which resolved without sequelae, and eight cases of constipation complications were reported: there were no reports of drug-associated deaths. The ischemic colitis and constipation cases were similar to those reported in trials, but resulted in less severe outcomes, suggesting that "prompt and appropriate action" is being taken by physicians and patients, said Craig Metz. Ph.D., GSK's vice president of U.S. regulatory affairs. Research Triangle Park, N.C.

During that time, approximately 34,000 prescriptions were written for roughly 10,000 patients: among those patients, 127 postmarketing adverse events were reported. Most prescribing physicians have been gastroenterologists, with ob.gyns., family physicians, and internists composing the rest. Nearly 90% of prescriptions have been written by physicians enrolled in the program, and 80% of the prescribing physicians are enrolled in the program. Results of the patient survey, with a 36% response rate, indicated that 90% of the women and 84% of men met the treatment severity criteria for treatment.

Dr. Metz told the panel that although the number of prescriptions was low, no new safety issues were raised and that the company believes the program has been successfully implemented.

Some features should be modified to improve access to the drug by patients who could benefit "while continuing to effectively manage risk," he added.

There is evidence that physicians don't like the attestation process, possibly because they consider it an affront to their professionalism and they perceive that signing the form transfers liability from the company to the physician, he said. A "disturbing" finding is that 50% of physicians who enroll in the program never write a prescription and only 10% of those enrolled have written more than 15 prescriptions.

Only a small proportion of women who meet the criteria for the drug have used it, he added. There is also evidence that language in the product's labeling, which focuses primarily on the potential risks, tends to frighten patients, he said. In clinical trials, 28% of patients refused to participate once told of these risks.

At the meeting, Dr. Robert Justice, director of the FDA's division of gastrointestinal and coagulation products, said that overall, the FDA believes that the program appears to be managing risk and ensuring proper use. He said that efforts to improve the program could focus on physicians' perceptions of liability and patient labeling that "frightens rather than informs."

But Dr. Brian Strom, professor of biostatistics and epidemiology. University of Pennsylvania, Philadelphia, said he thought the program was working well and shouldn't be changed in any major way, "until we have data on predictors of efficacy and adverse events."

No information is available that would help identify which IBS patients will benefit from the drug or those who are more likely to develop serious side effects. Not all patients benefit from alosetron: In clinical trials, response rates were 13%-21% above placebo.

Modifying the program would be "simply unacceptable in terms of protecting the public health," added the panel's consumer representative. Arthur Levin, who is director of the Center for Medical Consumers, New York. He bristled at the idea that a physician might consider having a conversation with a patient about a drug's benefits and risks and signing a form as "so burdensome that they opt out of the program."

During the open public hearing. Dr. Sidney Wolfe, director of Public Citizen Health Research Group, said that the eight cases of ischemic colitis and eight cases of constipation complications were "alarming." He added that because the drug does not have unique, clinically significant benefits, it should once again be taken off the market and made available only as an investigational new drug.

BY ELIZABETH MECHCATIE

Senior Writer

COPYRIGHT 2004 International Medical News Group
COPYRIGHT 2004 Gale Group