Zelnorm

Synopsis: Tegaserod (Zelnorm) is the first treatment approved by the U.S. Food and Drug Administration (FDA) for the short-term management of constipation-predominant irritable bowel syndrome (c-IBS) in women. A partial agonist of serotonin subtype-4 (5-H[T.sub.4]) receptors, tegaserod stimulates peristalsis, increases intestinal secretion, and may alter associated pain. (1) In contrast, alosetron (Lotronex) is available under restricted conditions of use for diarrhea-predominant IBS.

Safety: To date, tegaserod appears generally safe and well tolerated, although the potential for serious adverse effects when use becomes more widespread requires further study and monitoring (as occurred with alosetron). Tegaserod has been associated with a small increase in abdominal surgeries (0.3 versus 0.2 percent with placebo), but review by the FDA has not established a causal relationship. (2) In short-term studies, tegaserod does not prolong the QTc interval, or cause other electrocardiographic changes, like some older prokinetic agents (e.g., cisapride [Propulsid]). Although a weak inhibitor of several liver enzymes, no clinically important drug interactions have been described.1,2 Tegaserod carries a pregnancy rating of B and should not be used in women who are breastfeeding. (2)

Tolerability: The side effects most commonly reported during clinical trials of tegaserod compared with placebo include headache (15 versus 12 percent), abdominal pain (12 versus 11 percent), and diarrhea (9 versus 4 percent). (2) Diarrhea is most often transient (i.e., a single episode) and occurs during the first week of therapy. (1) Adverse effects leading to discontinuation of therapy during studies occurred in 7 percent of patients who received tegaserod compared with 5 percent of those who received placebo. The most frequent reasons given for discontinuation were diarrhea and abdominal pain.

Effectiveness: In three pre-marketing studies, patients were asked to record subjective changes in overall well-being, bowel habits, and abdominal pain or discomfort as the primary outcome. Patients were counted as responders if they experienced either considerable or complete relief at least 50 percent of the time, or if they felt at least somewhat relieved 100 percent of the time. With this composite end point, tegaserod produced a response in 38 to 46 percent of patients, a statistically significant improvement when compared with a response rate of 30 to 39 percent in patients receiving placebo. (3,4,5) Thus, approximately 12 to 21 women would need to be treated with the drug instead of placebo for one additional person to receive this level of benefit (number needed to treat range = 12-21). However, in one study there was no difference between tegaserod and placebo in the percentage of women reporting considerable or complete relief of symptoms. (4) Studies have not been performed comparing tegaserod with diet changes, use of psyllium powder, or other interventions in c-IBS.

Price: A one-month supply of tegaserod (Zelnorm) will cost patients approximately $148. Patients will spend <$15 for a one-month supply of generic psyllium powder (30 g per day).

Simplicity: Compared with some other treatments for c-IBS, tegaserod is arguably easier to use and more palatable to many patients, although data to support these contentions are lacking. While available in both 2-mg and 6-mg tablets, the labeled dosage for adults (women only) is 6 mg, taken shortly before a meal two times a day. If patients experience relief of symptoms after four to six weeks of therapy, they may continue tegaserod for a total of 12 weeks. Tegaserod is contraindicated in patients with severe renal or moderate to severe hepatic impairment; in those with a history of bowel obstruction, symptomatic gallbladder disease, suspected sphincter of Oddi dysfunction, or abdominal adhesions; and in patients with a known hypersensitivity to the drug. (2)

Bottom line: Despite design limitations common to drug therapy trials for c-IBS (e.g., subjective outcomes, high placebo response rate), tegaserod is at least somewhat effective at relieving troublesome symptoms in women. Considering the modest benefits and high cost, tegaserod is best used as a short-term, second-line agent for those women who do not respond adequately to changes in diet, to bulk-forming agents like psyllium, or to other interventions. The safety and effectiveness of tegaserod when used long-term are not known. It is important for physicians to remember that this drug has not been shown to be effective in men or in patients with diarrhea-predominant IBS.

REFERENCES

(1.) Corsetti M, Tack M. Tegaserod: a new 5-HT(4) agonist in the treatment of irritable bowel syndrome. Expert Opin Pharmacother 2002;3:1211-8.

(2.) Zelnorm product monograph. Novartis Pharmaceuticals Corporation. July 2002. Accessed December 17, 2003, at http://www.pharma.us.novartis.com/ product/pi/pdf/zelnorm.pdf.

(3.) Muller-Lissner SA, Fumagalli I, Bardhan KD, Pace F, Pecher E, Nault B, et al. Tegaserod, a 5-HT(4) receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment Pharmacol Ther 2001;14:1655-66.

(4.) Lefkowitz M, Shi Y, Heggland J, Dunger-Baldauf C, Ruegg PC. Tegaserod rapidly improves abdominal pain, bloating and bowel function in patients with c-IBS. Gut 2000;37(Suppl. III):A217/P833.

(5.) Novick J, Miner P, Krause R, Glebas K, Bliesath H, Ligozio G, et al. A randomized, double-blind, placebo-controlled trial of tegaserod in female patients suffering from irritable bowel syndrome with constipation. Aliment Pharmacol Ther 2002; 16:1877-88.

STEPS drug updates cover Safety, Tolerability, Effectiveness, Price, and Simplicity.

The series coordinator of STEPS is Allen F. Shaughnessy, Pharm.D., director of medical education at Pinnacle Health System, Harrisburg, Pa.

G. Robert DeYoung, Pharm.D., BCPS, is a clinical pharmacist at Ambulatory Care in Grand Rapids, Michigan.

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