Tegaserod maleate (Zelnorm), a 5-HT4 receptor partial agonist that increases gastrointestinal (GI) motility, was approved by the FDA in 2002 for short-term treatment of irritable bowel syndrome with constipation (IBS-C) in women and in 2004 for treatment of chronic idiopathic constipation (CIC) in adults <65 years old.
In 2007, the manufacturer (Novartis) complied with an FDA request to stop marketing the drug based on an unpublished retrospective analysis of clinical trials in IBS-C and other GI motility disorders that showed a higher rate of ischemic cardiovascular events (including cardiovascular death, nonfatal myocardial infarction [MI], and nonfatal stroke) in patients who took tegaserod than in those who took placebo. Among more than 11,600 patients treated with tegaserod for 1-3 months, 13 (0.11%) had a confirmed ischemic event compared to only 1 (0.01%) of more than 7000 patients who received placebo.1
The mechanism by which tegaserod could cause cardiovascular ischemia is unknown; 5-HT1 receptor agonists used to treat migraine, such as sumatriptan (Imitrex, and others), can constrict coronary arteries, and tegaserod has some affinity for 5-HT1 receptors.1
Based on a re-examination of the data that led to withdrawal of tegaserod and the continued need for a drug with this mechanism of action to treat IBS-C, an FDA advisory committee recommended approval of a supplemental new drug application from a new sponsor (Sloan). The drug is now approved only for treatment of IBS-C in women <65 years old and is contraindicated in patients with a history of MI, stroke, transient ischemic attack, or angina.
Prucalopride (Motegrity), a selective 5-HT4 receptor agonist recently approved by the FDA for treatment of CIC, will be reviewed in a future issue. It has less affinity for 5-HT1 receptors than tegaserod.2