The FDA has approved the sodium/hydrogen exchanger 3 (NHE3) inhibitor tenapanor (Xphozah – Ardelyx) to reduce serum phosphorus in adults with chronic kidney disease (CKD) on dialysis as add-on therapy when phosphate binders are ineffective or as monotherapy when phosphate binders cannot be tolerated. Tenapanor is the first NHE3 inhibitor to be approved in the US for hyperphosphatemia. It was previously approved as Ibsrela to treat irritable bowel syndrome with constipation (IBS-C).

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

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In 2007, the manufacturer (Novartis) complied with an FDA request to stop marketing the drug based on an unpublished retrospective analysis of clinical trials in IBS-C and other GI motility disorders that showed a higher rate of ischemic cardiovascular events (including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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The FDA has approved plecanatide (Trulance – Synergy), a guanylate cyclase-C receptor agonist, for treatment of chronic idiopathic constipation (CIC) in adults. Linaclotide (Linzess), another guanylate cyclase-C receptor agonist, and lubiprostone (Amitiza), a chloride channel activator, were approved earlier for treatment of CIC in adults.

The FDA has warned that eluxadoline (Viberzi – Allergan), a mu-opioid receptor agonist and delta-opioid receptor antagonist approved in 2015 for treatment of irritable bowel syndrome with diarrhea (IBS-D),1 should not be used in patients without a gallbladder because of an increased risk of serious pancreatitis.2

As of February 2017, the FDA had received reports of 118 cases of serious, nonfatal pancreatitis and 2 deaths associated with use of eluxadoline. Both deaths occurred in patients without a gallbladder who developed severe abdominal pain and vomiting shortly after taking the first dose. At least 48 of the cases occurred after only 1 or 2 doses of eluxadoline. Of the 68 patients whose gallbladder status was reported, 56 did not have a gallbladder. Most of the patients without a gallbladder (44/56) were taking the reduced dosage of eluxadoline recommended for such patients (75 mg once/day).

Patients considered at risk for pancreatitis were excluded from the two trials that led to approval of eluxadoline. One case of pancreatitis and 8 cases of abdominal pain with hepatic enzyme elevation associated with sphincter of Oddi spasm occurred with use of eluxadoline in the trials, all in patients without a gallbladder.3

According to the current label, eluxadoline is contraindicated in patients who abuse alcohol (including those who consume >3 servings of alcohol per day) and in those with known or suspected biliary duct, pancreatic duct, or GI tract obstruction, sphincter of Oddi disease or dysfunction, or severe hepatic impairment (Child-Pugh C). It is also contraindicated in those with a history of pancreatitis, structural pancreatic disease, or chronic or severe constipation.

Some alternatives to eluxadoline, which is only modestly more effective than placebo in relieving IBS-D symptoms, are the antidiarrheal loperamide (Imodium, and generics), the non-absorbed antibiotic rifaximin (Xifaxan), and the 5-HT₃ receptor antagonist alosetron (Lotronex, and generics). Taken as needed, loperamide can reduce postprandial urgency and stool frequency, but it does not improve global symptoms of IBS-D. Like eluxadoline, rifaximin has only been modestly effective in relieving symptoms. Because of concerns about severe constipation and ischemic colitis, alosetron should be used only in women with severe, chronic IBS-D that is unresponsive to other drugs.4

1. Eluxadoline (Viberzi) for irritable bowel syndrome with diarrhea. Med Lett Drugs Ther 2016; 58:4.
2. FDA Drug Safety Communication: FDA warns about increased risk of serious pancreatitis with irritable bowel drug Viberzi (eluxadoline) in patients without a gallbladder. Available at: www.fda.gov. Accessed April 13, 2017.
3. AJ Lembo et al. Eluxadoline for irritable bowel syndrome with diarrhea. N Engl J Med 2016; 374:242.
4. Drugs for irritable bowel syndrome. Med Lett Drugs Ther 2016; 58:121.

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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.

The FDA has approved eluxadoline (Viberzi – Actavis), a mu-opioid receptor agonist and delta-opioid receptor antagonist, for oral treatment of adults with irritable bowel syndrome with diarrhea (IBS-D).

Rifaximin (Xifaxan – Salix), a minimally absorbed oral antibiotic approved previously to treat travelers' diarrhea and to reduce the risk of recurrent hepatic encephalopathy, has now been approved by the FDA for treatment of irritable bowel syndrome with diarrhea (IBS-D). Eluxadoline (Viberzi – Actavis), a mu-opioid receptor agonist, was also recently approved for IBS-D and will be reviewed in a future issue.

Linaclotide (lin´´ a kloe´ tide; Linzess – Ironwood/Forest), a guanylate cyclase-C receptor agonist, was recently approved by the FDA for oral treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) in adults. It is the second drug approved for this indication; lubiprostone (Amitiza), a metabolite of prostaglandin E1, was the first.

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.

(Vol. 49, p. 66, August 13, 2007) A reader has pointed out that Saccharomyces boulardii is not a separate species, but a strain of Saccharomyces cerevisiae. S. cerevisiae (including S. boulardii) has been reported to cause systemic infection after oral ingestion in both immunocompromised patients and healthy hosts (MJ McCullough et al. J Clin Microbiol 1998; 36:2613).

Probiotics are live, nonpathogenic microorganisms (usually bacteria or yeasts) that have been used for centuries for their potential health benefits. They are currently marketed for prevention and treatment of a variety of disorders, including diarrhea, irritable bowel syndrome and inflammatory bowel disease.

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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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).

The FDA recently announced that it will permit reintroduction of alosetron hydrochloride (Lotronex - GlaxoSmithKline) for treatment of irritable bowel syndrome (IBS). The drug was previously withdrawn from the market because of severe gastrointestinal toxicity. The reintroduced drug will have a 50% lower starting dose, a narrower indication and some other marketing restrictions (www.fda.gov/cder/drug/infopage/lotronex/lotronex.htm).