Severe Diarrhea-predominant Irritable Bowel Syndrome in Women
Alosetron is used only for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in women with chronic symptoms (generally lasting 6 months or longer) who have had anatomic or biochemical GI abnormalities excluded and who have failed to respond to conventional therapy. Diarrhea-predominant IBS is considered severe if diarrhea is accompanied by one or more of the following manifestations: frequent and severe abdominal pain and/or discomfort, frequent bowel urgency or fecal incontinence, or disability or restriction of daily activities because of IBS. Because of the potential for serious adverse GI effects, use of alosetron is restricted to patients for whom the benefit-to-risk balance is considered to be most favorable.
(See Warnings under Cautions: Warnings/Precautions.)Efficacy of alosetron in men has not been adequately demonstrated in clinical studies.
Efficacy of alosetron in the management of diarrhea-predominant IBS in women was established in 2 placebo-controlled studies in nonconstipated women with IBS for at least 6 months and in 3 separate placebo-controlled studies in women with severe diarrhea-predominant IBS. Approximately two-thirds of the women in the first 2 studies had diarrhea-predominant IBS. Adequate relief of IBS abdominal pain and discomfort was experienced by 10-19% more of these women receiving alosetron 1 mg twice daily than those receiving placebo. Retrospective analysis of the subset of women with severe diarrhea-predominant IBS in these 2 studies indicated that alosetron was more effective than placebo in providing adequate relief of pain and discomfort. In additional retrospective analyses of the 57% of women who had bowel urgency 5 or more days each week at the beginning of these studies, 32% of those receiving alosetron had bowel urgency no more than 1 day in the last week of the studies compared with 19% of those receiving placebo. Patients with severe diarrhea-predominant IBS who received alosetron in these studies also reported improvements in several outcomes related to IBS; such improvements included less difficulty sleeping, less fatigue, fewer eating problems, and less interference with social and work activities.
Among the 3 studies in women with severe diarrhea-predominant IBS, 2 of the studies included patients who had bowel urgency on at least 50% of days prior to study entry; such patients were randomized to receive alosetron 1 mg twice daily or placebo for 12 weeks. In these studies, women receiving alosetron experienced a substantial (13-16%) increase in the median percentage of days with control of bowel urgency compared with those receiving placebo. Retrospective analysis of the subset of patients who had bowel urgency 5 or more days each week at the beginning of the studies (66% of the study population) indicated that 50% of those receiving alosetron had bowel urgency no more than 1 day during the last week of the studies compared with 29% of those receiving placebo. In addition, bowel urgency occurred in this group no more than 2 days per week in any of the 12 weeks of the study in 12% of those receiving alosetron versus 1% of those receiving placebo. Response to alosetron also was evaluated in these studies by patient daily reports of stool frequency, stool consistency, and sense of incomplete evacuation. After 12 weeks of treatment, improvements were noted in average stool consistency (i.e., from loose to formed) and stool frequency in patients receiving alosetron compared with placebo; however, sense of incomplete evacuation was not consistently different between the treatment groups. In one of the studies, satisfactory control of urgency was reported on 73 or 57% of days by women receiving alosetron or placebo, respectively, over the 12 weeks of the study. In the same study, patients were also asked to evaluate their IBS symptoms over the preceding 4 weeks using a 7-point global improvement scale (ranging from substantially worse to substantially improved); at 4, 8, and 12 weeks, 67, 69, and 76% of women receiving alosetron or 41, 43, and 44% of those receiving placebo, respectively, reported moderate or substantial improvement in IBS symptoms and were considered responders.
In the remaining study in women with severe diarrhea-predominant IBS, patients with abdominal pain of at least moderate severity, bowel urgency on at least 50% of days, and/or restriction of daily activities on at least 25% of days were randomized to receive alosetron (0.5 mg once daily, 1 mg once daily, or 1 mg twice daily) or placebo for 12 weeks. Patients were asked to evaluate their IBS symptoms every 4 weeks using a 7-point global improvement scale (ranging from substantially worse to substantially improved), and were considered responders to therapy if they reported moderate or substantial improvement from baseline. At 12 weeks, the proportion of responders was substantially greater in all 3 alosetron groups compared with placebo (43-51 versus 31%, respectively). Patients in the alosetron groups also had greater relief of IBS pain and discomfort, decreased sense of urgency and stool frequency, and more formed stools compared with those who received placebo.
Long-term efficacy and safety of alosetron 1 mg twice daily was evaluated in a 48-week double-blind, placebo-controlled study in women with diarrhea-predominant (nonconstipated) IBS. In the subset of women with severe diarrhea-predominant IBS who had more frequent urgency (defined as those with urgency on at least 10 days during a 2-week baseline screening period), higher rates of adequate relief of IBS pain and discomfort (52 versus 41%, respectively) and satisfactory control of bowel urgency (60 versus 48%, respectively) were observed with alosetron compared with placebo. Such improvements were observed within 2 weeks and were maintained throughout the 48-week treatment period.