A Review of Irritable Bowel Syndrome Drug Tegaserod (ZELNORM) Now Approved for Chronic Constipation

Novartis Pharma announced on August 24, 2004 that its drug tegaserod (ZELNORM) had been approved by the Food and Drug Administration (FDA) to treat chronic constipation in both males and females less than 65 years old. Tegaserod’s approval was granted despite the fact that on July 14, 2004 the FDA’s Gastrointestinal Drugs Advisory Committee of outside experts recommended that there was not enough evidence to support the use of the drug by men of any age. Separately, the committee voted unanimously against approval in adults 65 or older.

Chronic constipation is a common, benign, functional disorder of the lower gastrointestinal tract, affecting mainly people in Western countries.

The FDA originally approved tegaserod in July 2002 for the short-term treatment, four to six weeks, of women, only, with constipation-predominant irritable bowel syndrome. We opposed the approval of the drug based on its extremely marginal efficacy and concerns about the induction of cysts in the ovaries.

On April 28, 2004, the FDA announced that from the time of tegaserod’s initial marketing through March 2004, the agency had received reports of patients taking the drug who experienced significant adverse drug reactions. These reports included 21 patients taking tegaserod who experienced the serious consequences of diarrhea, 20 patients who have been diagnosed with ischemic colitis (lack of blood flow to the large intestine), and 3 patients diagnosed with other types of intestinal ischemia. In some patients, these adverse events led to hospitalization, surgery, and even death.

• Severe diarrhea can lead to dehydration, low blood pressure, and fainting. In some of the reported cases in patients taking tegaserod, these complications have required hospitalization for rehydration.
• Ischemic colitis can cause serious intestinal damage, and death. Some of the signs and symptoms of ischemic colitis are new or worsening abdominal pain, fever, vomiting, bloody diarrhea, rectal bleeding, and low back pain.
• Intestinal ischemia is a condition resulting from reduced blood flow to the intestines that can lead to ischemic colitis or to more severe forms of intestinal damage that may require surgery or result in death.

The remainder of this article is based on publicly available reviews conducted by FDA scientists of data submitted by Novartis Pharma to support the approval of tegaserod for chronic constipation. These reviews were posted on the FDA’s web site prior to the July 14, 2004 Gastrointestinal Drugs Advisory Committee meeting at www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4056b1.htm.

Novartis Pharma submitted two clinical trials to the FDA in support of tegaserod’s approval for chronic constipation. Neither of these trials had been published in a peer reviewed medical journal at the time this article was written.

Both trials measured the average number of complete spontaneous bowel movements (CSBM) per week in patients taking tegaserod or placebo. Patients were classified as responders if there was an average increase of one or more CSBM per week. This is called the trials’ primary efficacy endpoint. The FDA medical officer reviewing the drug pointed out that an increase in just one bowel movement per week did not necessarily offer relief of constipation for many people.

In the first trial, in patients treated with 12 milligrams of tegaserod per day, 40 percent of patients responded. Thirty-six percent of those taking four milligrams of the drug per day also responded, and 27 percent of the group given a placebo responded. The therapeutic gain with tegaserod relative to placebo was 13 percent for the 12 milligram per day dose and nine percent for those receiving four milligrams of the drug per day. Both results were statistically significant.

In the second trial, in patients receiving 12 milligrams of tegaserod per day; 43 percent responded; 41 percent of those taking two milligrams of the drug per day also responded; and 25 percent of the placebo group responded. The therapeutic gain with tegaserod relative to placebo was 17 percent for the 12 milligram dose and 15 percent at a dose of four milligrams per day.

In the two trials, only nine to 16 percent of the patients were 65 years of age or older and the response to tegaserod was significantly smaller in older patients. Even Novartis was forced to state in the labeling for the drug, that “... patients 65 and older showed no significant treatment effects for Zelnorm over placebo.” The Gastrointestinal Drugs Advisory Committee voted 13 to zero not to recommend tegaserod’s approval in older adults. The FDA followed this recommendation.

Only nine to 14 percent of the patients in the two trials were male, and the response to tegaserod was smaller in males than females. The advisory committee voted eight to five not to recommend the drug be approved for use in men. The FDA unfortunately did not accept this recommendation.

The FDA medical officer who wrote the review for the Gastrointestinal Drugs Advisory Committee meeting summed up the effectiveness of the drug in less than glowing terms:

In acknowledging the favorable statistics toward tegaserod, this reviewer ponders about the clinical significance of these efficacy results, in the lifelong treatment of chronic constipation ....

Chronic constipation is a benign condition. Tegaserod is not a benign drug and it is overpriced. A one month supply of the drug at a dose of 12 milligrams per day retails for $153.91.

What You Can Do

You should not use tegaserod for irritable bowel syndrome or chronic constipation. The effectiveness of the drug for both of these conditions is marginal and its potential risks are serious.