Ischemic colitis and complications of constipation associated with the use of alosetron under a risk management plan: clinical characteristics, outcomes, and incidences.
OBJECTIVE
Alosetron is a potent, selective 5-HT(3) receptor antagonist prescribed for women with severe diarrhea-predominant irritable bowel syndrome (IBS-D) under a risk management plan (RMP). The RMP was implemented following cases of ischemic colitis (IC) and complications of constipation (CoC) associated with the use of alosetron. The objectives of this study were to characterize IC and CoC clinical features, outcomes, and incidence rates in the new restricted patient population to evaluate the effectiveness of the RMP in the prevention of serious outcomes.


METHODS
Safety data from adverse event reporting from November 2002 through June 2008 were reviewed for probable and possible IC and CoC using the US Food and Drug Administration/sponsor-defined criteria and definitions. Evidence for IC included medical documentation, colonoscopy, and sigmoidoscopy+/-biopsy. Evidence for CoC included medical history and confirmation from health-care professionals.


RESULTS
Within the inclusion dates, 29,072 patients received 203,939 alosetron prescriptions. Although the absolute numbers of IC and CoC cases have declined, the incidence rates for IC and CoC (0.95 and 0.36 cases per 1,000 patient-years, respectively) were similar to rates during the postmarketing cycle before alosetron withdrawal. In patients with severe IBS-D receiving alosetron (n=998) or placebo (n=411) in clinical trials since reintroduction, incidence rates for IC were 4 and 2 cases per 1,000 patients, respectively. Rates for CoC were 2 and 0 cases per 1,000 patients in the alosetron and placebo groups, respectively. No mesenteric ischemia, surgeries, transfusions, or deaths occurred in patients with IC and no cases of CoC were associated with toxic megacolon, perforation, surgeries, transfusions, or deaths. IC and CoC cases were typically of short duration and all improved on prompt withdrawal of alosetron.


CONCLUSIONS
Serious outcomes associated with IC and CoC appear to be mitigated since introduction of alosetron under the RMP.
Chang
Lin
L
Center for Neurobiology Stress, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Tong
Kenneth
K
Ameen
Vanessa
V
D016907:Adverse Drug Reaction Reporting Systems; D002243:Carbolines / Q000009:adverse effects*; D017091:Colitis, Ischemic / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology; D003248:Constipation / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology; D005260:Female; D006801:Humans; D015994:Incidence; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011358:Product Surveillance, Postmarketing; D012308:Risk Management; D012702:Serotonin Antagonists / Q000009:adverse effects*; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology
D002243:Carbolines; D012702:Serotonin Antagonists; C090840:alosetron