Drug Profile

Tegaserod (ZELNORM) was removed from the market in early 2007 due to serious heart safety concerns. It has subsequently been made available on an experimental basis.

Although this drug is no longer officially marketed in the U.S., we continue to provide information about it because people may have access through an experimental drug program, may have supplies in their homes that they may otherwise continue to use or they may obtain these drugs via the Internet.

Tegaserod was originally approved by the Food and Drug Administration (FDA) to treat women with irritable bowel syndrome (IBS) in whom constipation is the predominant symptom. The drug is not approved for IBS in men. The drug works by stimulating the 5-HT4 receptor, one of a family of serotonin receptors. In 2004, tegaserod was approved by the FDA to also treat chronic constipation in both males and females younger than 65 years old.

Public Citizen opposed the approval of the drug based on its marginal efficacy and concerns about the induction of cysts in the ovaries.[2]

IBS itself is not a life-threatening condition, although it can be debilitating. The proper diagnosis of IBS is based on a set of internationally recognized symptoms known as the Rome II Criteria[1] (see box). According to these criteria, IBS should be diagnosed only if a patient’s symptoms are not the result of treatable causes, such as ulcerative colitis. This is especially important if the signs of ulcerative colitis are present: onset after age 50, rectal bleeding, fever, weight loss or anemia. There are no abnormal laboratory tests or changes in the cells of the gastrointestinal (GI) tract on biopsy that can objectively establish the diagnosis of IBS. In fact, the diagnosis of IBS can only be made if all tests for other diseases that might explain the patient’s symptoms are negative and the patient continues to have recurrent abdominal discomfort or pain associated with diarrhea, constipation or both.

Tegaserod is a potentially dangerous drug of minimal efficacy used in the treatment of non-life-threatening conditions. We recommend that you not use it and try the measures outlined in the box above instead.

Studies say…

Tegaserod is associated with many side effects, including ovarian cysts, diarrhea and ischemic colitis (inflammation of the colon). This is especially concerning because tegaserod has questionable efficacy: none of the three pivotal clinical trials used by the FDA for approval demonstrated effectiveness, as judged by the original, predetermined primary clinical outcome measures.[2] Researchers saw that there was no significant improvement for either of the two original outcome measures in the first completed trial. In an attempt to make the drug seem effective so it would gain FDA approval, Novartis (the manufacturer of the drug) altered the endpoints for the other two ongoing (but still blinded) trials, eliminating one measure and redefining the other in a manner that created a lower threshold for declaring improvement. However, even this manipulation produced only one pivotal trial with a statistically significant result, and that result was only half of what Novartis had expected.

Ovarian cysts occurred more frequently in women taking tegaserod than in those taking a placebo during clinical trials. Tegaserod manufacturer Novartis ultimately convinced the FDA that these cases were not related to the drug, however Public Citizen remains concerned. Two reasons for our concern are that tegaserod also induced ovarian cysts in rats; and 5-HT4 receptors, the serotonin receptors that the drug stimulates, are present in human ovaries.[3] In addition, there was an increase in abdominal surgeries in patients taking tegaserod during clinical trials compared to placebo-treated patients. The increase was attributed primarily to an increase in gallbladder removals.

After the drug came on the market, new safety concerns with tegaserod arose. In October 2004, Public Citizen published a Worst Pills, Best Pills News article addressing the use of tegaserod for chronic constipation, arguing against use of the drug.

Regulatory actions surrounding tegaserod

2004: In April 2004, the FDA announced that the drug would be relabeled because of multiple cases of serious diarrhea, ischemic colitis and closely related diseases.[4]

The following statement was also added to the warning section of the product label for tegaserod in April 2004:

Serious consequences of diarrhea, including hypovolemia [a decrease in the volume of circulating blood], hypotension [low blood pressure], and syncope [fainting] have been reported in the clinical studies and during marketed use of Zelnorm. In some cases, these complications have required hospitalization for rehydration. Zelnorm should be discontinued immediately in patients who develop hypotension or syncope. Zelnorm should not be initiated in patients who are currently experiencing or frequently experience diarrhea.[5]

Tegaserod’s approval in men 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.[6]

2007: In 2007, tegaserod's labeling was updated to include the addition of elevations in ALT, AST and bilirubin (liver enzymes); hepatitis; and alopecia (hair loss) in tegaserod users.[7]

On March 30, 2007, the FDA requested that Novartis Pharmaceuticals Corporation voluntarily discontinue marketing of tegaserod based on findings of an increased risk of serious cardiovascular (heart) side effects associated with use of the drug. Novartis has agreed to voluntarily suspend marketing of the drug in the United States.[8]

Later that year, on July 27, the FDA announced that restricted use of tegaserod would be permitted under a treatment investigational new drug (IND) protocol to treat IBS with constipation and chronic idiopathic constipation in women younger than 55 who meet specific guidelines. (An IND treatment within guidelines is when a patient has a serious or life-threatening disease or condition and when no comparable or satisfactory alternative drug or therapy is available. Patients must sign consent materials to ensure they are fully informed of the potential risks and benefits of the drug.[9])