Alosetron, sold under the brand name Lotronex among others, is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in females only. It was patented in 1987 and approved for medical use in 2002. It is currently marketed by Prometheus Laboratories Inc. (San Diego). Alosetron was withdrawn from the market in 2000 owing to the occurrence of serious life-threatening gastrointestinal adverse effects, but was reintroduced in 2002 with availability and use restricted. Medical uses Alosetron is indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS-D) who have: chronic IBS symptoms (generally lasting 6 months or longer), had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and not responded adequately to conventional therapy. Severe IBS-D includes: diarrhea and 1 or more of the following: frequent and severe abdominal pain/discomfort, frequent bowel urgency or fecal incontinence, disability or restriction of daily activities due to IBS. Efficacy The phase III trial for approval was published in 2000 as an industry-funded randomized, placebo-controlled trial (PCT). Its authors found 1 mg alosetron, taken orally twice daily for 12 weeks, was associated with a 12% (CI 4.7-19.2) improvement in relief from abdominal pain and discomfort associated with diarrhea-predominant patients. The prescription of alosetron is currently approved in the U.S. at 0.5 and 1 mg. The FDA Medical Officer's Review, dated November 4, 1999, noted: "Patients considered by investigators to fit the diarrhea-predominant subtype had at baseline... stool consistency values that were neither loose nor watery". The FDA's Gastrointestinal Drugs Advisory Committee referred to the drug's efficacy as "modest", highlighting that the placebo brought relief on the primary outcome measure to 40–50% of women. Contraindications Lotronex's prescribing information brochure states that alosetron should not be initiated in patients with constipation. Other contraindications are: history of chronic or severe constipation or sequelae from constipation; intestinal obstruction, stricture, toxic megacolon, gastrointestinal perforation, and/or adhesions, ischemic colitis, impaired intestinal circulation, thrombophlebitis, or hypercoagulable state; Crohn's disease or ulcerative colitis; diverticulitis; severe hepatic impairment. Concomitant use of fluvoxamine is also contraindicated. Adverse effects Alosetron was withdrawn in 2000 following the association of alosetron with serious life-threatening gastrointestinal adverse effects. The cumulative incidence of ischaemic colitis was 2 in 1000, while serious complications arising from constipation (obstruction, perforation, impaction, toxic megacolon, secondary colonic ischaemia, death) was 1 in 1000. A 1999 review performed by FDA medical officer John Senior, indicated that 27% of patients