Alosetron

ROCKVILLE, MD. -- The manufacturer of the irritable bowel syndrome drug alosetron has issued a warning about the risks of ischemic colitis and severe constipation with the drug.

The manufacturer's warning is a response to continued reports of these complications in people treated with the druge since it came on the market.

These warnings and an expanded list of contraindications to the drug are included in revised labeling of alosetron, which are outlined in a "Dear Health Care Professional" letter issued to physicians by Glaxo Wellcome, which markets the drug under the trade name Lotronex. And to ensure that patients are adequately informed of these risks, the Food and Drug Administration has required that a "patient medication guide" be provided with every dispensed prescription of alosetron, a procedure that began in September.

The medication guide includes information on what patients should do if they become severely constipated while on the drug or if they develop new or worsening abdominal pain or bloody diarrhea or blood in the stool, signs of ischemic colitis.

The drug has "a demonstrated benefit in the treatment of diarrhea-predominant IBS, which can be severely incapacitating," the FDA said in a statement. The agency "believes that the benefits of Lotronex outweigh its risks when it is used according to the instructions in the Medication Guide, which reflect the revised professional labeling."

These labeling changes and the publication of the guide, the first such guide to be required by the FDA, resulted from a review of the adverse event reports and risk management recommendations made by the FDA's gastrointestinal drugs advisory committee meeting.

Alosetron, a serotonin 5-HT3 antagonist, was approved to treat women with diarrhea-predominant IBS in February It is thought to work by blocking the action of serotonin at 5-HT3 receptor sites in the enteric nervous system, reducing sensitivity to colonic distension and slowing colonic transport. The drug has not been extensively studied in men and is therefore not considered effective in men with diarrhea-predominant IBS.

At the time of approval, 4 cases of ischemic colitis had been reported among 3,000 treated women. The drug was approved in February; by June 1, there were 8 more cases reported, for a total of 12 cases. All 12 patients recovered "without serious consequences" once the drug was discontinued, the FDA said in a statement announcing the warnings.

In clinical trials, 25%-30% of subjects on alosetron experienced constipation, the drug's most common side effect, but no serious complications related to constipation had been reported before approval. But between February and June 1, seven reports of serious cases of constipation in women on alosetron were reported to the FDA. Of these patients, six were hospitalized, including three who needed surgery, including one colectomy.

The list of contraindications now includes women with a history of ischemic colitis or a history of chronic or severe constipation or "with a history of sequelae from constipation." Some patients with severe constipation had a history of constipation, according to Glaxo Wellcome.

Soon after the announcement regarding the revised labeling, the national consumer group Public Citizen filed a citizen's petition with the FDA, calling for the withdrawal of the drug from the market. In a letter to the FDA, Public

Citizen argues that the efficacy of alosetron in clinical trials was "limited" and that because IBS is a "poorly defined" disease that is "neither progressive nor life threatening," reports of serious adverse reactions "tip the risk-benefit equation against using the drug."

The letter also says that the medication guide for alosetron "shifts too much responsibility into the hands of patients to promptly diagnose what could be, for them, a serious or life-threatening situation."

Public Citizen said that based on information obtained from the FDA, at least 26 cases of ischemic colitis had been associated with the drug, as of August 28th. These include the 7 cases reported in trials and 19 cases in the first 6 months of marketing.

An FDA spokesperson could not confirm that 11 more cases had been reported but said that additional reports of ischemic colitis and severe constipation-related complications in people on alosetron had been reported to the FDA since June. The FDA is in the process of reviewing these cases.

A spokesperson for Glaxo Wellcome responded that the company continues to believe that alosetron is an important drug that meets a medical need for women with diarrhea-predominant IBS and that the data support a favorable risk-benefit profile. Since the drug was launched in February "tens of thousands of women" have used it successfully, she said, adding that the cases of ischemic colitis reported since February are comparable in terms of frequency and severity with those reported in clinical trials.

A copy of the "Dear Health Care Professional" letter is available on the FDA Web site at: wwwfda.gov/ cder/drug/ infopage/lotronex/lotronex.htm. For questions and copies of the medication guide, call Glaxo Wellcome at 888-825-5249.

The FDA encouraged physicians to report adverse reactions to alosetron to its MedWatch program at 800-332-1088 (phone); 800-332-0178 (fax); via the Internet at www.fda.gov/ medwatch; or by mail (MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, Md. 20857).

More Medication Guides Likely

Physicians can expect to see more medication guides created for outpatient drug products in the future.

Under regulations that became effective in 1999, the FDA can now require a company to create a medication guide for outpatient products that the FDA has determined pose a serious risk "for which patient labeling can help prevent that risk." The guide is written for patients, drafted by the company, and approved by the FDA, which describes these guides as "FDA-approved patient labeling."

At the FDA's gastrointestinal drugs advisory panel meeting in June, Nancy Ostrove, Ph.D., branch chief of the FDA's division of drug marketing, advertising, and communications, estimated that medication guides will be issued for about 5-10 products a year. Some products have already been designated as needing guides, she said, but could not disclose which ones they were.

The first of these guides, created for alosetron, prompted a statement from FDA commissioner Dr. Jane Henney "Today's actions are an important milestone in enabling consumers as well as health care professionals to better manage the risks that are inherent in even very beneficial drug treatments." The FDA required a medication guide for alosetron because "patients play a very critical role in managing the risks of the product."

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