The FDA has approved tenapanor (Ibsrela - Ardelyx), a sodium/hydrogen exchanger 3 (NHE3) inhibitor, for twice-daily oral treatment of irritable bowel syndrome with constipation (IBS-C) in adults. Tenapanor is the first NHE3 inhibitor to become available in the US.

Irritable bowel syndrome (IBS) is a common disorder characterized by recurrent abdominal pain and altered bowel habits, often accompanied by bloating.IBS is classified according to the predominant bowel symptom as IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed type (IBS-M), or unclassified (IBS-U). Alterations in the microbiome, stress responses, sensory and motor function of the gut, and host genetic factors may be contributing factors. Since the exact cause of IBS is unknown, the goal of treatment is symptom control.

View the Table: Safety of Drugs for IBS in Pregnancy and Lactation

The FDA has approved the 5-HT4 receptor agonist prucalopride (Motegrity – Shire) for treatment of chronic idiopathic constipation (CIC) in adults. Prucalopride is the only drug currently approved in the US for treatment of CIC that stimulates colonic peristalsis. It has been available in Europe and Canada for several years.

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In 2007, the manufacturer (Novartis) complied with an FDA request to stop marketing the drug based on an unpublished retrospective analysis of clinical trials in IBS-C and other GI motility disorders that showed a higher rate of ischemic cardiovascular events (including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

1. In brief: tegaserod withdrawn. Med Lett Drugs Ther 2007; 49:40.
2. J Tack et al. Systematic review: cardiovascular safety profile of 5-HT₄ agonists developed for gastrointestinal disorders. Aliment Pharmacol Ther 2012; 35:745.

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Irritable bowel syndrome (IBS) is a common disorder characterized by chronic, intermittent abdominal pain or discomfort and altered bowel habits. It is subtyped according to the predominant bowel symptom as IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed type (IBS-M), or unclassified (IBS-U). Since the exact cause of IBS is unknown, the goal of treatment is symptom control.

Irritable bowel syndrome (IBS) is a common disorder, occurring in up to 15% of the US population; it is 2-2.5 times more frequent in women than in men. IBS is characterized by chronic, intermittent abdominal pain or discomfort accompanied by altered bowel habits. Since the underlying mechanisms of disease remain unclear, management of IBS focuses on symptom control.

Lubiprostone (Amitiza), which was previously approved for treatment of chronic idiopathic constipation in adults, has now also been approved in a lower dose for use in women with irritable bowel syndrome with constipation (IBS-C). Since tegaserod (Zelnorm) has been withdrawn from the market,2 lubiprostone is the only drug approved by the FDA for treatment of this common condition.

Tegaserod maleate (Zelnorm – Novartis), a partial serotonin 5-HT4 receptor agonist that increases gastrointestinal motility, was approved by the FDA in 2002 for short-term treatment of constipation-predominant irritable bowel syndrome in women,1 and in 2004 for treatment of chronic constipation in adults ≤65 years old. Its efficacy has not been impressive statistically, but according to Medical Letter consultants some patients with slow-transit constipation have benefited from taking the drug. Diarrhea has been its main adverse effect.2

The FDA now has requested that the manufacturer stop marketing the drug based on an unpublished postmarketing analysis of earlier clinical trials that showed a higher rate of serious cardiovascular events (including angina, myocardial infarction and stroke) in patients who took tegaserod compared to 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 patient (0.01%) among more than 7000 treated with placebo. The mechanism by which tegaserod would cause cardiovascular ischemia is unknown; serotonin 5-HT₁ receptor agonists used to treat migraine, such as sumatriptan (Imitrex), can constrict coronary arteries, and tegaserod has some affinity for 5-HT₁ receptors.3

Tegaserod may still be available, possibly through a special access program, for patients who do not have other treatment options.

1. Tegaserod maleate (Zelnorm) for IBS with constipation. Med Lett Drugs Ther 2002; 44:79.

2. Drugs for irritable bowel syndrome. Treat Guidel Med Lett 2006; 4:11.

3. AJ Busti et al. Tegaserod-induced myocardial infarction: case report and hypothesis. Pharmacotherapy 2004; 24:526.

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The FDA has approved lubiprostone (Amitiza - Sucampo/Takeda), a chloride channel activator, for treatment of chronic idiopathic constipation in adults. The only other prescription drug approved by the FDA for this indication (in 2004 for adults <= 65 years old) is tegaserod (Zelnorm), a partial agonist of serotonin that is also approved for constipation-predominant irritable bowel syndrome in women. Of course, numerous over-the-counter products are available for treatment of constipation.

Irritable bowel syndrome (IBS) is a common disorder, occuring in about 15% of the US population; it is 2-3 times more frequent in women than in men. IBS is characterized by chronic abdominal pain or discomfort and altered bowel habits.

Tegaserod maleate (teg a ser' od; Zelnorm - Novartis), a serotonin derivative, has received FDA approval for short-term treatment of women with irritable bowel syndrome (IBS) whose primary symptom is constipation. Alosetron (Lotronex), which was withdrawn previously because of toxicity, will soon be available again for women with severe diarrhea-predominant IBS (Medical Letter 2002; 44:67).