FDA APPROVES RESTRICTED MARKETING OF LOTRONEX

The Food and Drug Administration (FDA) today announced the approval of a supplemental New Drug Application (sNDA) that permits marketing of Lotronex (alosetron hydrochloride) with restrictions. The manufacturer of the drug, GlaxoSmithKline, will be implementing a risk management program including a prescribing program to enroll physicians who wish to prescribe Lotronex. The drug's indication has been narrowed to be only for treatment of women with severe, diarrhea-predominant Irritable Bowel Syndrome (IBS) who have failed to respond to conventional IBS therapy. Limiting the use of Lotronex to this severely affected population is intended to maximize the benefit to risk ratio.

The marketing of Lotronex is being restricted because serious and unpredictable gastrointestinal adverse events, including some that resulted in death, were reported in association with its use when it was previously marketed.

Less than 5% of IBS is considered severe, and only a fraction of severe cases are diarrhea-predominant IBS. Severe IBS is a chronic condition (in this case, generally lasting more than 6 months) with symptoms that disable or significantly curtail the daily activities of patients. Symptoms typically include frequent and severe abdominal pain and fecal incontinence or the uncontrollable urge to have a bowel movement.

The approved sNDA for Lotronex includes a risk management program that the drug's manufacturer, GlaxoSmithKline (GSK), will implement. The program is designed to help ensure not only that patients and physicians are fully informed of the risks and benefits of Lotronex prior to using it but also that only appropriate patients are prescribed the drug. Therefore, the risk management program emphasizes the need for doctors, patients and pharmacists to work together to maximize the benefit of Lotronex and minimize the risk.

"All drugs have risks. It's FDA's job to balance the need for access to effective medications with those risks," said Dr. Lester M. Crawford, FDA Deputy Commissioner.

"Informed decision-making by physicians and patients is critically important in managing the risks of marketed medications. Everyone needs to take an active role," added Dr. Janet Woodcock, Director of FDA's Center for Drug Evaluation and Research.

Specifically, the Lotronex Risk Management Program includes the following components:

• GSK will establish a prescribing program for Lotronex to enroll physicians who plan to prescribe Lotronex. Enrollment will be based on physician self-attestation of qualifications.
• GSK will enroll in the prescribing program physicians who agree to educate patients on the risks and benefits of Lotronex treatment, and to provide patients a copy of the FDA-approved Medication Guide.
• Patients will be asked to read and sign a Patient-Physician Agreement before receiving their initial prescription for Lotronex.
• Pharmacists will be asked to fill only prescriptions that display a prescribing program sticker affixed by an enrolled physician, and to give patients a copy of the FDA-approved Medication Guide every time they dispense the drug.

In addition, enrolled physicians will have agreed to report serious adverse events to GSK at 1-888-825-5249 or to FDA at 1-800-FDA-1088.

GSK will conduct an ongoing assessment of the Risk Management Program, including a study of the prescribing and actual use of Lotronex.

Today's action follows an April 23, 2002, recommendation by FDA's Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Advisory Committee for Pharmaceutical Science to restore access to Lotronex through a restricted distribution and use program.

As of March 8, 2002, there had been 84 cases of ischemic colitis and 113 cases of serious complications of constipation reported to FDA through its Adverse Event Reporting System (AERS). The 84 cases of ischemic colitis resulted in 54 patients requiring hospitalization, two receiving blood transfusions, 11 requiring surgery and two deaths. The 113 cases of serious complications of constipation resulted in 83 patients requiring hospitalization, 34 undergoing surgery, two receiving blood tr-ansfusions and two deaths.

FDA first approved Lotronex in February 2000. Following post-marketing reports of, and a public advisory committee meeting about, serious and life-threatening cases of ischemic colitis and complications of constipation, including deaths, GlaxoSmithKline voluntarily withdrew Lotronex from the market in November 2000. Although constipation and ischemic colitis were observed in the pre-approval clinical trials of Lotronex, serious complications of constipation and consequences of ischemic colitis were not seen until after marketing when many more people were exposed to the drug.

Additional information on Lotronex, including the revised professional and patient labels and physician and patient agreement documents, can be found on FDA's website at http://www.fda.gov/cder/drug/infopage/lotronex/lotronex.htm.

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