Alosetron Tablets (Lotronex—Glaxo Wellcome)
By William T. Elliott, MD, FACP and James Chan, PharmD, PhD
Glaxo wellcome has received fda approval to market alosetron for the treatment of irritable bowel syndrome (IBS) in women. The drug is the first in a new class of drugs for this indication—the selective 5HT3 antagonists. Alosetron will be marketed under the trade name Lotronex. Other pharmaceutical manufacturers are rushing to develop similar drugs for this indication, which affects as many as 20% of Americans and for which no current treatment provides consistent relief. The drug is only approved for use in women who are twice as likely as men to suffer from IBS.
Indications
Alosetron is indicated for the treatment of IBS in women whose predominant bowel symptom is diarrhea.1
Dosage
The recommended dose is 1 mg taken twice daily. The drug may be taken without regard to meals.
Potential Advantages
In multicenter, double-blind, placebo-controlled clinical trials, alosetron was reported to be more effective than placebo in improving symptoms of IBS in women. Treatment with alosetron resulted in more effective relief of pain and discomfort, decreased the proportion of days with urgency, decreased stool frequency, and produced firmer stools.1 Previously available agents have produced varying degrees of success for relieving these symptoms.
Potential Disadvantages
Alosetron does not appear to be effective in men at any dose.1 In clinical trials, about 40% of women reported inadequate relief of IBS pain and discomfort with the drug. Alosetron was not studied in patients with severe pain. Constipation is the most common side effect and is dose related. Approximately 25-30% of patients experienced constipation and about 9% required interruption of therapy. About 10% of patients could not tolerate the usual daily dose of 1 mg twice daily on a continuing basis.1
Other side effects include nausea and gastrointestinal (GI) discomfort. Acute ischemic colitis has been reported infrequently (i.e., incidence of 1/100 to 1/1000).1
Comments
Alosetron is the first member of a new class of drugs for the treatment of IBS. It is a 5HT3 receptor antagonist. These receptors are believed to regulate visceral pain, colonic transit, and gastrointestinal secretions.
Alosetron reduces pain, hypersensitivity, and hyperactivity of the GI tract.1 Efficacy was demonstrated in two, yet-to-be-published, U.S. multicenter, double-blind, placebo-controlled trials in nonconstipated women (n = 1273). The primary end point was the women’s weekly assessment of adequate relief of pain and discomfort. Adequate response has been strongly associated with improvement in abdominal pain and urgency to defecate.4 Secondary end points include percentage of days with urgency and daily assessment of stool frequency and consistency. The percent of patients with adequate relief ranged from 42-61% compared to 30-48% for placebo over a 12-week period in one study and 30-55% compared to 30-40% in the second study. Statistical difference was evident from week 1 through week 12 in the first study and week 4 through week 12 in the second study. Upon discontinuation of treatment, symptoms returned within one week.1 The drug is generally well tolerated, with constipation being the most common side effect. Improvement of symptoms may be evident within the first week but may take 2-4 weeks.1 Alosetron costs about $4.75 per day.
Clinical Implications
IBS or "spastic colon" is a common disorder and is believed to account for about 12% of primary care visits and 20-50% of referrals to gastroenterologists. About 20% of the population in the United States with twice as many women than men are believed to have IBS symptoms.2 It is a waxing and waning disorder with a high response rate to placebo (40-70%). The Rome Criteria for the diagnosis of IBS are continuous or recurrent symptoms for at least three months with the following symptoms: abdominal pain relieved with defecation or associated with a change in frequency and consistency of stool; and irregular pattern of defecation at least 25% of the time characterized by altered stool frequency, altered stool form, altered stool passage, passage of mucus or bloating or feeling of abdominal distention.3 Traditional treatment has included anticholinergics, barbiturates, antidepressants, benzodiazepines, fiber supplements, and opioids. These treatments may help with specific symptoms, but they are not effective for the overall symptoms.3
Abdominal pain appears to be more difficult to treat. Alosetron appears to relieve pain more effectively than placebo although about 40% of patients still did not report adequate relief. It is only effective in women and in diarrhea-predominant IBS.
References
1. Lotronex Product Information. Glaxo Wellcome Inc. February 2000.
2. Damianos AJ. Irritable bowel syndrome. In: Rakel RE, ed. Conn’s Current Therapy. Philadelphia, Pa: W.B. Saunders Company; 1996.
3. Thompson WG, et al. Gastroenterol Int 1992;5:75-91.
4. Camilleri M, et al. Aliment Pharmacol Ther 1999;13: 1149-1159.
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