Alosetron for irritable bowel syndrome
Michel Lièvre
BMJ 2002; 325: 555-556.

On 9 February 2000 alosetron (marketed as Lotronex by GlaxoSmithKline), a type 3 serotonin (5-HT3) receptor antagonist, was approved by the US Food and Drug Administration (FDA) for the treatment of patients with irritable bowel syndrome, a benign though unpleasant disorder that affects one in five adults in the industrialised world.1 By November 2000, the FDA had received 49 reports of ischaemic colitis and 21 of severe constipation related to the drug, resulting in 44 admissions to hospital, 10 surgical interventions, and 3 deaths.2 The drug was withdrawn from the market by its sponsor. Severe adverse events continued to be reported for some time, with a final total of 84 instances of ischaemic colitis, 113 of severe constipation, 143 admissions to hospital, and 7 deaths.3 On 7 June 2002, however, the FDA issued a supplemental new drug application that permits marketing of alosetron through a prescribing programme for treating women with irritable bowel syndrome whose main symptom is severe diarrhoea (5% of patients). Doctors will have to sign an attestation of qualification and acceptance of responsibilities. Patients will have to sign a patient-physician agreement attesting that they have been adequately informed of the risks and that they have the form of irritable bowel syndrome that may be treated with alosetron.4 This prescription programme is unlikely to prevent severe adverse reactions due to alosetron. In November 2000, the FDA's office of post-marketing drug risk assessment underlined that ischaemic colitis could not be predicted, some patients were not able to recognise the signs and symptoms of constipation, the reversibility of ischaemic colitis had not been established, and the signs and symptoms of these severe adverse effects were too similar to those of the disease being treated.2 The increasing number of severe adverse experiences reported after the "Dear Doctor" and "Dear Pharmacist" letters issued in June 2000 at the request of the FDA also suggests that a real and effective risk management policy is not possible. The FDA's decision to put alosetron back on the market was made despite strong opposition of an insider (read Paul Stolley's story, p 592), and dissent is now being voiced by members of the advisory committee (see p 561). According to the information given in the patient-physician agreement, severe constipation occurred in about 1 in 1000 patients treated for six months, and ischaemic colitis in 1 in 350. The present prescription plan would theoretically allow up to two million people in the United States to receive alosetron, which might result in 2000 cases of severe constipation, 5714 cases of ischaemic colitis, 1109 surgical interventions, and 329 deaths; 240 000 women would experience some relief of symptoms.5 The price to pay for this benefit looks very high.