Alosetron Hydrochloride Tablets (Lotronex — GlaxoSmithKline) Reintroduction
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA has approved restricted marketing of alosetron (Lotronex) for the treatment of women with diarrhea-predominant irritable bowel syndrome (IBS). The drug was originally approved in February 2000 and withdrawn in November 2000 due to serious and unpredictable gastrointestinal side effects. At least 7 deaths were associated with use of the drug. The approval includes a risk management program intended to ensure that both physicians and patients are fully informed about the risks and benefits of the drug.
Alosetron is only indicated for women with severe diarrhea-predominant IBS who have chronic IBS (> 6 months), failed to respond to conventional therapy, and severe diarrhea-predominant IBS with no anatomic or biochemical abnormalities. Severe diarrhea is defined as frequent and severe abdominal pain/discomfort, frequent bowel urgency or fecal incontinence, or disability or restriction of daily activity due to IBS.1
The starting dose is 1 mg daily for 4 weeks. The dose may be increased to 1 mg twice daily if symptoms are not controlled. Alosetron should be discontinued if adequate symptom control has not been achieved after 4 weeks with twice daily dosing.
Alosetron is available as 1 mg tablets.
Studies have indicated that alosetron was modestly effective compared to placebo in women with diarrhea-predominant IBS. In 2 reports with similar study design (n = 626,647) between 41-43% of patients treated with alosetron reported relief of IBS pain and discomfort compared to 26-29% for placebo (P < 0.001) for 3 months.2,3 The primary end point was adequate relief of IBS pain and discomfort for at least 2 weeks per month. In another, (n = 801) using satisfactory control of bowel urgency as an end point, 73% of alosetron-treated patients had a satisfactory control of urgency compared to 57% for placebo (P < 0.001).4 These studies were analyzed based on intent-to-treat and last observation carried forward.
Serious adverse events have been reported with alosetron. These include ischemic colitis and serious complications of constipation.1 Since December 31, 2001, 352 hospitalizations have been associated with alosetron. There were 85 cases of ischemic colitis and 13 deaths. Seven of these were strongly associated with the drug.5 Constipation occurred in 25-30% of patients compared to 3-5% for placebo.2,3 The risks of serious problems resulting from constipation and ischemic colitis are about 0.1% and 0.3%, respectively.1
Alosetron is a 5HT3 receptor antagonist. These receptors are believed to regulate visceral pain, colonic transit, and gastrointestinal secretions. The manufacturer voluntarily withdrew the drug in November 2000 due to serious side effects. The FDA has now decided to approve a restricted marketing of alosetron. This approval was at least due to compelling testimony by patients who have benefited from the drug. The conditions of the marketing are that GSK will establish a prescribing program to enroll physicians who plan to prescribe the drug. These physicians will self-attest to his or her qualification and agree to educate patients on the risk and benefit of the drug. The physician will provide the patient with a copy of the FDA-approved Medication Guide and the patients will be asked to read and sign a Patient-Physician Agreement before receiving the initial prescription. The pharmacist will only be asked to fill prescriptions that display the prescribing program sticker affixed by an enrolled physician.6 Patients will be started on a lower dose and titrated up to 1 mg twice daily as tolerated. GSK has committed to post-marketing studies and monitoring of the risk management program.
IBS is a common, non-life threatening disorder affecting about 20% of the population and twice as many women than men. It is a waxing and waning disorder with a high response rate to placebo. However, less than 5% is considered severe and only a fraction of the severe cases are diarrhea-predominant. It has been estimated that about 10% of severe patients would have a lasting effect with alosetron (about 0.5% or less).7 This compares to the risk of ischemic colitis of 0.3% and the risk of serious problems resulting from constipation of 0.1%.
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.
1. Lotronex Product Information. GlaxoSmithKline. May 2002.
2. Camilleri M, et al. Arch Intern Med. 2001;161:1733-1740.
3. Camilleri M, et al. Lancet. 2000;355:1035-1040.
4. Lembo R, et al. Am J Gastroenterol. 2001;96(9):2662-2670.
5. Charatan F. BMJ. 2002;324:1053.
6. FDA News. June 7, 2002.
7. FDC Report. The Pink Sheet. 2002; 64(17):8.