Drug Profile

Alosetron (LOTRONEX) was approved by the Food and Drug Administration (FDA) in 2000 for the management of irritable bowel syndrome (IBS) in women with severe diarrhea as their predominant symptom. The drug is not approved for men.

IBS itself is not a life-threatening condition, although it can be debilitating. If the major symptom is diarrhea, the condition is known as diarrhea-predominant IBS; if it is characterized by constipation, it is called constipation-predominant IBS. The diagnosis of IBS should be based on a set of internationally recognized symptoms known as the Rome II Criteria[1] (see box above) and requires exclusion of treatable causes of the patient’s symptoms, such as ulcerative colitis. This is especially important if the following signs of ulcerative colitis are present: onset after age 50, rectal bleeding, fever, weight loss or anemia. There are no abnormal laboratory tests or changes in the cells of the gastrointestinal (GI) tract on biopsy that can objectively establish the diagnosis of IBS. In fact, the diagnosis of IBS can be made only if the reuslts of all tests for other diseases that might explain the patient’s symptoms are negative and the patient continues to have recurrent abdominal discomfort or pain associated with diarrhea, constipation or both.

Alosetron was inexplicably granted a priority or “fast track” review by the FDA. The justification for granting such a review was that the agency considered alosetron “a significant therapeutic advance” over existing therapies. In fact, alosetron was required to be compared only to a placebo, not to the alternative treatments available.

In truth, the drug is not much better than a placebo. In clinical trials, only 12 to 15 percent of patients actually benefited from the drug. Patients on alosetron improved their abdominal pain/discomfort scores by 0.12 to 0.14 points on a 4-point scale[2],[3] — a trivial benefit. Most patients whose symptoms improve while taking the drug are exhibiting the “placebo effect.”

In late 2000 — only nine months after initial approval — alosetron was withdrawn from the U.S. market. The reason for withdrawal was a life-threatening adverse reaction known as ischemic colitis, a decrease in blood flow to the GI tract that can lead to bleeding, inflammation and perforation of the intestines, sometimes leading to surgery. The condition can result in infection of the abdominal cavity that can be fatal.

Four cases of ischemic colitis had been identified in patients participating in clinical trials even before alosetron was approved. This was “gold standard” evidence that the drug caused a life-threatening adverse drug reaction. But the FDA chose to overlook it. In August 2000, Public Citizen petitioned to ban the drug; there had already been 26 cases of ischemic colitis.[3] We argued that the drug should be available only in a research setting. By April 2002, the FDA had received 84 reports of ischemic colitis and 113 of severe constipation in patients using the drug.[4]

Unfortunately, alosetron returned to the market under restricted conditions in June 2002 after patient groups, some funded by the pharmaceutical industry, demanded the drug’s return. Patients are supposed to be female (there is no evidence alosetron is effective in men); have severe, chronic (lasting longer than six months) diarrhea-predominant IBS; and have failed to respond to other therapies. Among the restrictions imposed in 2002, was the requirement that physicians “self-attest” that they are qualified to diagnose and treat IBS. In addition, both physicians and patients were required to sign consent forms, which were probably intended to protect the manufacturer in product-liability lawsuits.

Public Citizen's Health Research Group argued that even such a highly restricted distribution system was likely to prove inadequate because there are no known factors to predict which women are at the greatest risk of developing ischemic colitis.[5] Therefore, there is no way to adequately warn them which symptoms may lead to this serious adverse reaction or to adequately monitor them, which would be more feasible in the research setting.

With the drug back on the market, cases of ischemic colitis and severe constipation resumed. After a little over a year back on the market, with dramatically decreased sales, alosetron had already been associated with eight cases of ischemic colitis and eight serious complications of constipation.[6]

In 2016, the FDA recklessly decided to ease many of the restrictions on alosetron prescribing that had been imposed in 2002.[7] One of the few remaining restrictions is the requirement that patients prescribed the drug receive an FDA-approved Medication Guide when the prescription is filled.