Alosetron

The recent withdrawal of alosetron (Lotronex) from the marketplace will be a setback for a sizable number of patients with irritable bowel syndrome, gastroenterologists told FAMILY PRACTICE NEWS.

"Alosetron definitely had its place. For a lot of patients who had bad diarrhea, it was tremendously helpful. There were some patients who responded well to it and didn't respond to any other therapies. They are definitely going to be more symptomatic," said Dr. Howard R. Mertz of Vanderbilt University, Nashville, Tenn.

Glaxo Wellcome Inc. withdrew alosetron following a Food and Drug Administration review of 70 serious postmarketing adverse events. The agency classified the events, which included 49 cases of ischemic colitis, 21 cases of severe constipation, and 5 deaths, as probably caused by the drug.

Alosetron generated considerable excitement as the first drug designed specifically for irritable bowel syndrome (IBS), the most common GI disorder.

Roughly 150,000 patients were taking the drug. But the complications were cause for great concern, said Dr. Harris R. Clearfield, professor of medicine at the Allegheny University of the Health Sciences, Philadelphia.

"Nobody dies from IBS," he told this newspaper. "It has a quality-of-life impact, but it's not a dangerous disease."

Still, nobody dies from osteoarthritis or psoriasis, yet these patients routinely receive therapies with rare, life-threatening side effects, Dr. Kevin W. Olden countered.

Alosetron was "a silver bullet" targeted at the irritable bowel, and it had fewer side effects than older therapies. Whether the drug was causally related to the reported deaths remains unsettled, he added.

Alosetron's withdrawal highlights a dilemma: Should a highly promising path toward specific therapy for an extremely common and debilitating nonfatal condition be closed off due to a zero-tolerance approach to serious side effects? asked Dr. Olden, a gastroenterologist and psychiatrist at the Mayo Clinic, Scottsdale, Ariz.

Alosetron was approved by the FDA last February, but only for treating women with the diarrhea-predominant form of IBS. It was a niche drug, but IBS is so common that this was a substantial niche. It's estimated that at least 1 in 10 Americans has IBS, with women outnumbering men by a three-to-one margin. Probably one-quarter of affected women have the diarrhea-plus-cramping-predominant form.

Alosetron's absence doesn't leave physicians without recourse. Loperamide and cholestyramine can symptomatically control diarrhea, coupled with off-label use of very-low-dose tricyclic antidepressants to address cramping and abdominal pain.

Dr. Olden said the use of tricyclic antidepressants to reset IBS patients' pain threshold is "reasonably well supported" by small studies. The gut is the target organ, so they're effective in far lower doses than required to pass through the liver and cross the blood-brain barrier to treat depression. He uses them at one-tenth to three-quarters of the minimum antidepressant dose.

Yet the visceral hypersensitivity that's central to IBS tends to render patients quite sensitive to antidepressant side effects, even at the low doses used. "It's not uncommon to have to use two or sometimes three agents before you find one with a good fit side effect--wise and efficacy-wise for a particular patient," he said.

Well along in development are a number of drugs that, like alosetron, target enteric neurotransmitters. Cilansetron, like alosetron, blocks serotonin activity at 5-HT3 receptors. The Solvay drug is in phase-III testing for diarrhea-predominant IBS. Tegaserod, a Novartis drug, is a 5-HT4 agonist for the constipation-predominant form of IBS. Prucalopride, a Janssen 5-HT4 agonist, is earlier in development and also targets constipation-predominant IBS.

COPYRIGHT 2000 International Medical News Group
COPYRIGHT 2001 Gale Group