experienced constipation. The phase III trial reported constipation occurred in 30% and 3% of patients in the alosetron and placebo groups, respectively. It was cited as the most important reason for patients dropping out of the study. Mechanism of action Alosetron has an antagonist action on the 5-HT3 receptors of the enteric nervous system of the gastrointestinal tract. While being a 5-HT3 antagonist like ondansetron, it is not classified or approved as an antiemetic. Since stimulation of 5-HT3 receptors is positively correlated with gastrointestinal motility, alosetron's 5-HT3 antagonism slows the movement of fecal matter through the large intestine, increasing the extent to which water is absorbed, and decreasing the moisture and volume of the remaining waste products. History Alosetron was originally approved by the U.S. Food and Drug Administration (FDA) on February 9, 2000, after a seven-month review. At the time of the initial approval U.S. Food and Drug Administration (FDA) reviewers found that alosetron improved symptoms in 10% to 20% of patients. Shipment to pharmacies started in March, 2000. On July 17, a health professional filed a report with the FDA on the death of a 50-year-old woman who suffered mesenteric ischemia. The report identified alosetron as the "primary suspect" in the death. Alosetron was withdrawn from the market voluntarily by GlaxoWellcome on November 28, 2000 owing to the occurrence of serious life-threatening gastrointestinal adverse effects, including 5 deaths and additional bowel surgeries. The FDA said it had reports of 49 cases of ischemic colitis and 21 cases of "severe constipation" and that ten of the 70 patients underwent surgeries and 34 others were examined at hospitals and released without surgery. Through November 17, 2000, pharmacists had filled 474,115 prescriptions for alosetron. Severe adverse events continued to be reported, with a final total of 84 instances of ischaemic colitis, 113 of severe constipation, 143 admissions to hospital, and 7 deaths. Patient advocacy groups, most notably the Lotronex Action Group and the International Foundation for Functional Gastrointestinal Disorders (IFFGD) lobbied for the drug's return. Public Citizen Health Research Group, another patient advocacy group, opposed the reintroduction. On June 7, 2002, the FDA announced the approval of a supplemental New Drug Application (sNDA) that allows restricted marketing of Lotronex (alosetron hydrochloride), to treat only women with severe diarrhea-predominant irritable bowel syndrome (IBS). The strict prescribing guidelines initially introduced in 2002 were relaxed slightly in 2016, enabling electronic prescriptions among other benefits.