DOCTOR'S VIEW ARCHIVE
NOTE: On March 30, 2007 the FDA notified healthcare professionals and patients that Novartis has agreed to discontinue marketing Zelnorm, a drug used for the short-term treatment of women with irritable bowel syndrome with constipation and for patients younger than 65 years of age with chronic constipation. FDA analysis of safety data pooled from 29 clinical trials involving over 18,000 patients showed an excess number of serious cardiovascular adverse events, including angina, heart attacks, and stroke, in patients taking Zelnorm compared to patients given placebo. Patients taking Zelnorm should contact their healthcare professional to discuss treatment alternatives and seek emergency medical care if they experience severe chest pain, shortness of breath, sudden onset of weakness or difficulty walking or talking, or other symptoms of a heart attack or stroke. Healthcare professionals should assess their patients and transition them to other therapies as appropriate. Click Here to read the entire FDA Press Release.
The United States Food and Drug Administration (FDA) has approved tegaserod (Zelnorm), the first drug for the treatment of abdominal pain and constipation in patients with the irritable bowel syndrome (IBS).
What is IBS?
IBS is a common gastrointestinal condition. Patients with IBS typically complain of recurrent abdominal pain, bloating, and alteration in bowel habit. Some IBS patients are prone to constipation, some are prone to diarrhea, and some have periods of constipation alternating with periods of diarrhea. IBS is a chronic condition; symptoms can come and go over months, years or even decades.
IBS is a functional disorder of the intestines and its nerves; it may be caused by either abnormal motility (abnormal contractions) of the intestinal muscles or abnormally sensitive nerves in the intestines (visceral hyper-sensitivity). IBS is more difficult to diagnose than diseases with structural abnormalities. (Structural abnormalities are abnormalities that can be "seen" by examinations such as x-ray or endoscopy such as ulcers, infections, colitis, and cancers.)
While IBS is not life-threatening, symptoms of IBS can have a significant impact on a person's quality of life and can even be debilitating. For example, a patient with frequent diarrhea and an urgent need to have a bowel movement after meals may avoid eating out; and patients who develop bloating and abdominal pain after meals may develop a fear of eating.
What causes IBS?
The cause of abnormal intestinal motility and visceral hypersensitivity in IBS is not precisely known. Most scientists believe that a chemical called serotonin (also known as 5-hydroxytryptamine or 5-HT) plays an important role in stimulating muscle contractions in the intestines and increasing the sensitivity of the intestines to pain. For a serotonin molecule to exert these influences, it must first attach to it's receptor. These receptors are called 5-HT receptors, and there are several subtypes of the 5-HT receptor, referred to as 5-HT1, 5-HT2, 5-HT3, and 5-HT4. In IBS, it is believed that there may be either abnormal amounts of serotonin or 5-HT receptors or abnormal binding of serotonin to the 5-HT receptors and that these abnormalities cause most of the symptoms.
What is the traditional treatment of IBS?
Traditional treatment of IBS is directed at the symptoms, and not at the underlying molecular or cellular abnormalities that may be responsible for IBS. For example, constipation has been treated with fiber supplements, stool softeners, and laxatives; diarrhea has been treated with anti-diarrhea agents such as loperamide (Imodium) or cholestyramine powder (Questran). Abdominal pain and cramps have been treated with anti-spasmodic agents such as Donnatal or Librax, or anti-depressants in low doses to decrease the sensitivity of the intestines to pain. Unfortunately, most of these traditional treatments usually are ineffective or only partially or temporarily effective in treating the symptoms of IBS.
How does tegaserod work?
In animal studies, tegaserod has been found to bind to one subtype of serotonin receptor, the 5-HT4 receptor, and thereby stimulate contractions of the intestinal muscle. It also reduces the sensitivity of the intestinal pain-sensing nerves. Stimulating intestinal contractions speeds up transit of digesting food through the intestine thereby relieving constipation, while suppressing the pain-sensing nerves reduces abdominal pain.
How effective and safe is tegaserod?
A randomized, double blind, placebo-controlled, multi-center clinical trial evaluating the efficacy and safety of tegaserod has been published (Aliment Pharmocol Ther 200; 15: 1655-1666). More than 1000 patients (80% women) with constipation-predominant IBS were randomly assigned to receive either placebo or tegaserod for twelve weeks.
Tegaserod was found to be more effective than placebo in increasing the frequency of stools, relieving abdominal pain and discomfort, and decreasing the sensations of bloating among women subjects. There was an insufficient number of male participants to draw conclusions about the effectiveness of treatment in men. The beneficial effects of treatment started early (during the first week of treatment) and were sustained throughout the 12-week period of study.
Diarrhea was the only observed side effect. Diarrhea typically occurred early during treatment and quickly resolved even if treatment was continued.
There was no effect of tegaserod on blood counts, liver and kidney tests, EKG, blood pressure, pulse, and body weight. A medication similar to tegaserod, called cisapride (Propulsid), also stimulated intestinal muscle contractions, but cisapride was withdrawn from the market due to rare but potentially fatal effects on the electrical rhythm of the heart. So far, there have been no reports of rhythm disturbances related to Tegaserod.
Based on this study and two additional studies with similar findings, the FDA approved tegaserod for up to 12 weeks of treatment for women with constipation-predominant IBS.
What is the recommended dose of tegaserod?
The recommended dose is of tegaserod is 6 mg twice daily for 12 weeks. For optimal results, it should be taken on an empty stomach half an hour before breakfast and dinner.
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Are there any precautions when taking tegaserod?
Patients with major liver or kidney disease should not take tegaserod. The safety of tegaserod to the fetus or infant in pregnant or nursing women has not been studied and is unknown. Therefore, tegaserod should be avoided by pregnant or nursing women.
Are there other issues to be considered when using tegaserod?
Even though tegaserod has been used in Europe for some time, and the experience in Europe has shown few side effects, doctors in the US have limited experience because the drug has been recently approved. As with every new FDA-approved medication, doctors in the US need longer-term experience before the safety of tegaserod can be confirmed.
Tegaserod has been approved for relieving constipation, abdominal pain, and bloating in patients with IBS, yet there are many other causes of constipation unrelated to IBS. Accurate diagnosis and careful patient selection is vitally important to ensure that problems other than IBS are not missed.
IBS is a chronic disorder, yet tegaserod has been approved for only 12 weeks of treatment at a time. Until long-term (more than 12 weeks in this case) information on safety and efficacy become available, doctors must decide whether or not to extend treatment beyond 12 weeks.
Though less common than women, men also suffer from IBS, yet tegaserod is
approved only for women. Before more data on men become available, doctors must
decide whether or not to offer tegaserod to men. I have prescribed tegaserod for
three patients; one of them is a man. This man has severe, debilitating,
prolonged IBS with constipation that has failed all treatments. I hope it works!
Medical Author: Dennis Lee, M.D.
Medical Editor: Jay W. Marks, M.D.