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Emerging Drug List — Tegaserod Hydrogen Maleate

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Emerging Drug List — Tegaserod Hydrogen Maleate Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH TEGASEROD HYDROGEN MALEATE TECHNOLOGY ASSESSMENT NO. 32 MAY 2002 Generic (Trade Name): Tegaserod hydrogen maleate (Zelnorm™) Manufacturer: Novartis Pharmaceuticals Indication: For the symptomatic treatment of irritable bowel syndrome with constipation (IBS-C) in female patients whose main symptoms are constipation and abdominal pain and/or discomfort. The maximum duration of treatment should be no longer than 12 weeks and the treatment should be discontinued if there has been no response after four weeks. Current Regulatory Zelnorm™ was approved by Health Canada's Therapeutic Products Directorate on Status: March 12, 2002. Launch in Canada is impending1. Description: Tegaserod is a partial agonist of 5-HT4 receptors, a new chemical class of proki- netic medications. This subclass of receptors is found throughout the gastroin- testinal tract, and it is postulated that when activated, they minimize the percep- tion of discomfort, pain and constipation associated with IBS. Tegaserod exhibits a low absolute bioavailablity after oral dosing (11%), and the time to achieve a peak concentration ranges from one to 1.3 hours.2 It is highly protein bound (98% to α1-acid glycoprotein) and its terminal half-life is 11± 5 hours. Diarrhea, abdominal pain, headache, flatulence and fatigue are the most frequently report- ed adverse events. Compared to placebo, no differences in QTc interval prolon- gations have been reported in clinical trials, although syncope (an effect seen with cisapride) has been observed at a greater frequency in tegaserod users. The recommended dosage of Zelnorm™ is 6 mg twice daily, administered prior to a meal with water. Current Treatments: Avoidance of foods that trigger difficulties should be the first step in managing IBS. Agents such as lactose, caffeine, high-fat content, alcohol and gas-producing vegetables may aggravate the disease. The choice of therapy would depend on the symptoms of the condition.3 Should the patient be experiencing constipa- tion predominant disease, fibre agents such as psyllium (Metamucil® - P&G) or osmotic agents (e.g. lactulose) are usually recommended. For those with diar- rhea-predominant disease, loperamide (Imodium® - McNeil) or diphenoxylate (Lomotil® - Pharmacia) are suggested for treatment. When pain is a common complaint, antispasmodics such as dicyclomine (Bentylol® - Aventis), or pinaveri- um (Dicetel® - Solvay) are therapeutic options. Inconclusive evidence is available surrounding the use of psychotropic agents in IBS. Cost: At the time of preparing this review, a cost for this agent was not available. The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca) Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH TEGASEROD HYDROGEN MALEATE TECHNOLOGY ASSESSMENT Evidence: Several double-blind studies have either been published or presented at conferences regarding the efficacy and safety of tegaserod in the treatment of IBS.4,5 The largest was conducted by Lefkowitz and colleagues where female patients (n=1,519) with constipation-predominant disease were randomized to placebo or tegaserod 6 mg twice daily. Over the 12-week treatment period, patients reported significant improvement (p<0.05) in their disease as determined by the Subject's Global Assessment of Relief scale. Bowel-related assessments (including stool frequency, consistency and straining) improved (p<0.05) within the first week of enrollment, and this improvement was sustained throughout the study. Discontinuations occurred in 6.4 and 4.7 per cent of tegaserod and placebo treated patients. Although randomized trials have been conducted in males and females, no evidence of effica- cy has been found in males. Commentary: Irritable bowel syndrome is a prevalent condition, particularly in the western world where it is estimated 10 to 20 per cent of the population suffer from this difficulty. It affects the quality of life of those who are afflicted, and has a pro- found effect on the workforce, accounting for a significant percentage of work- place absenteeism. Most agents used in this condition are aimed at managing spe- cific symptoms (e.g. bloating, pain, diarrhea), but have only shown limited, if any, success. Compared to placebo, tegaserod has shown statistically significant short-term effica- cy in females in large clinical trials, and the community with IBS will likely wel- come new drugs. A point that should still be borne in mind is that the approved length of treatment with tegaserod is short considering the chronicity of the condi- tion. With further long-term studies, this question may be answered, and will also elucidate the long-term safety profile. Concerns about the questionable efficacy and safety profile of tegaserod have been raised by the Washington-based FDA watchdog, Public Citizen.6 Another agonist for 5-HT4 receptors, cisparide, has been recently withdrawn from the Canadian market. In addition, alosetron, which was marketed for IBS-related diarrhea-pre- dominate disease, was withdrawn after reports of serious adverse events. Together, these concerns may create hesitancy on the part of prescribers until further practi- cal experience has been realized. References: 1. Therapeutics Products Programme, Health Canada. Drug Product Database [database online]. Available: http://www.hc-sc.gc.ca/hpb/drugs-dpd/index.html (accessed 2002 Apr 20). 2. Scott LJ, Perry CM. Tegaserod. Drugs 1999;58(3):491-6. 3. Levine M, Lexchin J, Pellizzari R, editors. Drugs of choice: a formulary for general practice. Ottawa: Canadian Medical Association;1998. The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca) Emerging Drug List CANADIAN COORDINATING OFFICE FOR HEALTH TEGASEROD HYDROGEN MALEATE TECHNOLOGY ASSESSMENT 4. Camilleri M. Review article: tegaserod. Aliment Pharmacol Ther 2001;15(3):277-89. 5. Abdominal pain and constipation significantly reduced by Zelnorm™ (tegaserod maleate) in women with irritable bowel syndrome [press release]. New York: Bristol-Myers Squibb; 2002. Available: http:// www.bms.com/news/other/data/fg_other_news.1640.html (accessed 2002 Apr 24). 6. Letter to the Food and Drug Administration urging that it not approve tegaserod (Zelmac) because of its highly questionable efficacy and its potential to cause ovarian cysts (HRG Publication #1561). In: Health Research Group [database online]. Washington: Public Citizen; 2002. Available: http://www.citizen.org/publications/release.cfm?ID=6764 (accessed 2002 May 15). This series highlights medical technologies that are not yet in widespread use in Canada and that may have a significant impact on health care. The contents are based on information from early experience with the technology; however, further evidence may become available in the future. These summaries are not intended to replace professional medical advice. They are compiled as an information service for those involved in planning and providing health care in Canada. Emerging Drug List ISSN 1496-8398 (online only) The Canadian Coordinating Office for Health Technology Assessment (CCOHTA) is a non-profit organization funded by the federal, provincial and territorial governments. (www.ccohta.ca).
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