Alosetron irritable bowel syndrome

There have been several reviews of the pharmacology and use of alosetron (1-5). In patients with irritable bowel syndrome, alosetron increases colonic transit time and colonic compliance. It produces significant improvement in abdominal pain, stool consistency, and frequency and... 

In a randomized, double-blind, placebo-controlled, crossover trial, alosetron (2 mg bd) delayed left colonic transit in both patients with irritable bowel syndrome (n = 13) and healthy volunteers (n = 12) (28). In another double-blind, placebo-controlled trial in 25 non-constipated patients with irritable bowel syndrome, alosetron (1 and 4 mg bd) had no significant effect on gastrointestinal transit or rectal sensory and motor mechanisms (29). 

Women had significantly greater responses than men. Constipation was the most commonly reported adverse effect of alosetron (49% compared with 13% in the placebo group). In a randomized, double-blind, placebo-controlled trial in 626 women with diarrhea-predominant irritable bowel syndrome, alosetron 1 mg bd was significantly more effective than placebo in controlling symptoms... 

Alosetron (Lotronex) Irritable bowel syndrome Serious gastrointestinal events, especially ischemic colitis and constipation 2000 [53]... 

Mayer, E.A. and Bradesi, S., Alosetron and irritable bowel syndrome, Expert Opin. Pharmacother., 4,2089-2098,2003. 

Only physicians who have enrolled in GlaxoSmithKline s Prescribing Program for Lotronex, based on their attestation of qualifications and acceptance of responsibilities, should prescribe alosetron (see Administration and Dosage). Alosetron is indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have failed to respond to conventional... 

Inhibition of 5-HT3 receptors in the gastrointestinal tract results in modulation of visceral afferent pain sensation and intestinal motility. Alosetron is a 5-HT3 antagonist that has been approved for the treatment of patients with severe irritable bowel syndrome with diarrhea (Figure 63-5). Three other 5-HT3 antagonists (ondansetron, granisetron, dolasetron) have been approved for the prevention and treatment of nausea and vomiting (see Antiemetics) however, their efficacy in the treatment of irritable bowel syndrome has not been determined. The relative differences between these 5-HT3 antagonists that determine their pharmacodynamic effects have not been well studied. 

Alosetron currently is approved for the treatment of women with severe irritable bowel syndrome in whom diarrhea is the predominant symptom ("diarrhea-predominant IBS"). Efficacy in men has not been established. In a dosage of 1 mg once or twice daily, it reduces IBS-related lower abdominal pain, cramps, urgency, and diarrhea. Approximately 50-60% of patients report adequate relief of pain and discomfort compared with 30-40% of patients treated with placebo. It also leads to a reduction in the mean number of bowel movements per day and improvement in stool consistency. This agent has not been evaluated for the treatment of other causes of diarrhea. 

Alosetron (1 mg bd) was well tolerated and effective in alleviating abdominal pain, urgency, and stool frequency in a randomized, double-blind, placebo-controlled trial in 647 women with irritable bowel syndrome (26). Constipation occurred in 30% of patients taking alosetron and 3% of those taking placebo. Laboratory values, including liver function tests, were unchanged by alosetron. 

A 55-year-old man with irritable bowel syndrome who took alosetron 1 mg bd for 4 days developed symptoms of ischemic colitis, including rectal bleeding, and the diagnosis was confirmed macroscopically and histologically at colonoscopy. The symptoms suggestive of colitis abated on withdrawal of alosetron, but the symptoms of irritable bowel syndrome returned. Colonoscopy 2 weeks later showed a normal colon and biopsies showed normal colonic histology. 

Reddy P. Alosetron A 5-HT3 receptor antagonist for treatment of irritable bowel syndrome. Formulary 2000 35 404-11. 

Mangel AW, Northeutt AR. Review article the safety and efficacy of alosetron, a 5-HT3 receptor antagonist, in female irritable bowel syndrome patients. Aliment Pharmacol Ther 1999 13(Suppl 2) 77-82. 

Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. Efficacy and safety of alosetron in women with irritable bowel syndrome a randomised, placebo-controlled trial. Lancet 2000 355(9209) 1035 0. 

Bardhan KD, Bodemar G, Geldof H, Schutz E, Heath A, Mills JG, Jacques LA. A double-blind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome. Ahment Pharmacol Ther 2000 14(l) 23-34. 

Houghton LA, Foster JM, Whorwell PJ. Alosetron, a 5-HT3 receptor antagonist, delays colonic transit in patients with irritable bowel syndrome and healthy volunteers. Aliment Pharmacol Ther 2000 14(6) 775-82. 

Thumshirn M, Coulie B, Camilleri M, Zinsmeister AR, Burton DD, Van Dyke C. Effects of alosetron on gastrointestinal transit time and rectal sensation in patients with irritable bowel syndrome. Ahment Pharmacol Ther 2000 14(7) 869-78. 

Wolfe SG, Chey WY, Washington MK, Harding J, Heath AT, McSorley DJ, Dukes GE, Hunt CM. Tolerability and safety of alosetron during long-term administration in female and male irritable bowel syndrome patients. Am J Gastroenterol 2001 96(3) 803-11. 

Camilleri M, Chey WY, Mayer EA, Northcutt AR, Heath A, Dukes GE, McSorley D, Mangel AM. A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome. Arch Intern Med 2001 161(14) 1733-40. 

Alosetron was approved for U. S. use in February 2000 for the treatment of irritable bowel syndrome (IBS) in women whose predominant bowel symptom is diarrhea, although the product was withdrawn in November 2001 because of serious side effects, particularly ischemic colitis. Earlier studies in men for anxiety disorder and schizophrenia, and Phase II studies for nonulcer dyspepsia, have also been discontinued. 

Alosetron (Lotfonex) is effective in certain variants of irritable bowel syndrome (IBS), but was withdrawn from use because it may cause serious side-effects. However, it was later re-instated for restficted use following petitions from patients. 

The FDA has reapproved alosetron for diarrhea-predominant irritable bowel syndrome under a limited distribution system. The manufacturer requires a prescription program that includes physician certification and an elaborate patient education and consent before dispensing. 

Ondansetron and its congeners are extremely useful in the control of vomiting associated with cancer chemotherapy and postoperative vomiting. Alosetron, another 5-HTj antagonist, was used in irritable bowel syndrome in women but has been withdrawn. 

Study and classification of serotonin receptors has resulted in the design and synthesis of highly selective medicines such as Sumatriptan, for the treatment of migraine, Ondansetron for the suppression of the nausea and vomiting caused by cancer chemotherapy and radiotherapy, and Alosetron for treatment of irritable bowel syndrome. 

Two drugs initially withdrawn were allowed back by the FDA in U.S. markets. Lotronex (Alosetron, Glaxo Smith Kline) for irritable bowel syndrome was approved in early 2000 and withdrawn 9 months later due to serious gastrointestinal problems. It was reapproved with restrictions in 2002. Tysabri (Natalizumab, Biogen Idee, Elan) for multiple sclerosis was approved in late 2004 and withdrawn in 2005 due to rare fatal brain lesions and was allowed back in mid-2006. 

Alosetron, another 5-HT3 antagonist, has been used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in women only. Unlike ondansetron, it is not approved as an antiemetic. As 5-HT3 receptor stimulation enhances gastrointestinal motility, 5-HT3 antagonism with alosetron reduces the movement of fecal matter through the large intestine, thus relieving IBS. 

A quantitative benefit-harm balance analysis of alosetron for the treatment of irritable bowel syndrome from the patient s perspective has been reported pS "]. There was greater than 99% chance that both the incremental benefit and the incremental risk associated with alosetron are greater than with placebo. The incremental net benefit of alosetron was greatest in patients with the worst quality of life at baseline. 

Alosetron hydrochloride. Adult dose 0.5-1 mg twice daily (severe diarrhoea, predominant irritable bowel syndrome in women). 

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