# UCLA Insider Trak Newsletter - Winter 2000



## Jeffrey Roberts (Apr 15, 1987)

http://www.med.ucla.edu/ndp/Winter2000Msg.htm The Inside TrakChronic Gastronintestinal Disorders News from the UCLA/CURE Neuroenteric Disease ProgramWinter 2000 - Vol 4 Issue 1A Message from the Director It has been close to one year since our last edition of the Inside Trak Newsletter. Many things of considerable importance have happened during this time, the most important one being the "rise and fall" of the first true irritable bowel syndrome (IBS) medication, Lotronex. Since the issues around this drug are of great importance to many of our patients (and readers of this Newsletter), I want to dedicate this column primarily to the events involving Lotronex. Lotronex, a 5-HT3 antagonist, had been developed by Glaxo Wellcome, Inc. (GW) for the treatment of diarrhea-predominant IBS. Several large scale national and international studies demonstrated an effectiveness of this drug over placebo, comparable to the effectiveness of many other successful drugs, which treat other conditions such as ulcers, migraine headaches, and pain. Initially, it appeared that the only potential side effect of this drug was the development of constipation (seen in about 25% of patients), a complication easily managed by either decreasing the dose, taking additional fiber or in some cases stopping the drug. Later, a very small number of patients on the drug (approximately 1 per 1000 patients) reported increased abdominal pain and rectal bleeding. In these patients, endoscopic examination of the colon showed changes consistent with decreased blood flow to the inner lining of the colon (the mucosa). This complication is referred to as ischemic colitis. Ten patients (out of a total of 300,000 patients) were reported to have developed serious complications with the drug requiring hospitalization, and surgery, and three patients were thought to have died from such complications. While the relationship of Lotronex with the side effect of constipation was clearly established, the relationship with the rectal bleeding (ischemic colitis) was less clear, and a thorough review of the serious complications showed no causal relationship with the drug. However, under pressure from the consumer advocacy group Public Citizen and its spokesperson Dr. Sidney Wolfe, and from a series of articles in the LA Times, the Food and Drug Administration (FDA) requested additional measures from Glaxo Wellcome to minimize the risk of side effects. Ultimately, and sadly, it appears that the FDA sided with Public Citizen in the assessment of the situation as follows: 1) IBS is not a serious disease and does not warrant a drug with any side effects, 2) Lotronex shows only minimal effectiveness and 3) Lotronex is a dangerous drug. We firmly believe that all 3 assumptions are wrong. Many suggestions by Glaxo Wellcome to improve the regulation of the drug were rejected by the FDA, leaving Glaxo Wellcome no choice other than to withdraw the drug from the market. If you are suffering from diarrhea-predominant IBS and particularly if you suffer from the additional complication of fecal incontinence, this is very bad news. The thousands of patients who have contacted Glaxo Wellcome, or unsuccessfully tried to contact the FDA are a testimony to the fact how valuable a drug Lotronex had become. It will be some time before another drug will make it to the market. The criteria established by the FDA in the case of Lotronex (see above) will make it increasingly difficult to get any drug approved any time soon. It is our firm belief that the decision by the FDA (not to mention the one-sided LA Times coverage and the assessment by Public Citizen) was wrong. Many other options were available to assure maximal protection of patients from rare serious side effects. There are many drugs in common use which have a much higher risk of serious side effects. We believe that Lotronex was a perfectly safe drug, provided it was prescribed by a physician familiar with IBS who took the time to inform patients about the possible side effect of constipation and who was responsive to questions by the patient. Not a single case of a serious complication in connection with Lotronex was observed by physicians at UCLA Medical Center during the 8 months when the drug was available. We hope there will be other drugs for IBS available within the next two years. These medications include Tegaserod (Zelmac) which also acts on the serotonin system but is different from Lotronex. It is a 5-HT4 agonist which has been found to be effective for the treatment of constipation-predominant IBS and will hopefully be available in 4-6 months. There is another 5-HT3 receptor antagonist (Cilansetron) which is presently undergoing clinical investigation for the treatment of diarrhea-predominant IBS. And finally, there is a substance P (neurotransmitter involved in pain transmission) antagonist for the treatment of IBS which is also undergoing investigation through clinical trials. We will keep you informed about the progress in this development. In the current issue, we deal with several other important topics for our patients: We provide you with additional information about our ongoing non-medical treatment option, the IBS Class. We had intended to start a research study, evaluating the likely additional beneficial effect of the IBS class in IBS patients taking Lotronex. Unfortunately, due to the withdrawal of the drug from the market, we will have to go back to the drawing board and redesign the study protocol without the new medication. We also have produced two articles dealing with the stress response. Rapid scientific developments are beginning to shed light on how stresses in our lives can affect our health and cause disease, including functional GI disorders such as IBS. Finally, we will give you some update on the ongoing research program with another 5-HT3 antagonist, Cilansetron. No serious side effects have been reported with this compound in extensive clinical testing and this drug may in the future take the place of Lotronex in clinical management of diarrhea-predominant IBS.[This message has been edited by Jeffrey Roberts (edited 03-27-2001).]


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