Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857
On March 22, 2001, we wrote urging you not to approve the drug Zelmac (tegaserod) due to concerns about its lack of efficacy and safety. Zelmac is a drug for irritable bowel syndrome that works as an agonist at the 5-HT4 receptor site. The major focus of our safety concerns was the occurrence of symptomatic ovarian cysts in women taking the drug, a risk that was estimated by the Medical Officer to be about three times that for placebo patients. This worry was amplified by the dose-related occurrence of ovarian cysts in rats caused by the drug.
In our letter we argued that, in order to investigate a potential mechanism for the induction of these cysts, Novartis should be required to conduct assays for the 5-HT4 receptor in human ovarian tissue. Absent such studies, we said, Zelmac should not be approved. We have recently learned of a study that has done just that. The authors analyzed 17 human tissues for the presence and relative amounts of the 5-HT4 receptor. They used an electrophoretic gel to compare the DNA generated from the tissues own mRNA to the cloned human 5-HT4 receptor DNA. They discovered that the 5-HT4 receptor was present at intermediate levels in human ovary. This is the first study to document the presence of the 5-HT4 receptor in ovarian tissue. As a result, we now have a plausible biological mechanism for the development of the observed ovarian cysts that occurred in women and rats.
It seems the curtain may be closing on Tegaserod: in a May 31, 2001 press release, Novartis and Bristol-Myers Squibb announced that they were voluntarily withdrawing the marketing application for tegaserod from the European Agency for the Evaluation of Medicinal Products. As explained in the press release, the Committee for Proprietary Medicinal Products expressed concerns regarding the relevance of the observed clinical effect and also questioned the methodological conduct of some preclinical studies. (In our March 22 letter to you, we also emphasized that the purported efficacy of Zelmac had only been demonstrated in one of three clinical trials, was of limited magnitude, and had only been apparent after the company redefined the study endpoints.)
In recent years, there have been a number of instances in which foreign regulatory agencies took actions stronger than the FDA’s, and U.S. patients paid the price. For example, troglitazone was banned in Britain long before it was banned in the U.S.: many other countries did not even approve the drug in the first place. For safety and efficacy reasons, we urge you not approve tegaserod.
Elizabeth Barbehenn, Ph.D.
Peter Lurie, M.D., M.P.H.
Sidney M. Wolfe, M.D.
Public Citizen s Health Research Group
 Bach T, Syversveen T, Kvingedal AM, et al. 5-HT4(a) and 5-HT4(b) receptors have nearly identical pharmacology and are both expressed in human atrium and ventricle. Naunyn-Schmiedeberg s Arch Pharmacol 2001;363:146-160.