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Safety Profile of Tegaserod, a 5-HT4 Receptor Agonist, for the Treatment of Irritable Bowel Syndrome

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Abstract

This article reviews the safety and tolerability profile of tegaserod, a novel selective partial agonist of the serotonin 5-HT4 receptor. Tegaserod was recently approved for the treatment of women with irritable bowel syndrome (IBS) with constipation.

Tegaserod exhibits rapid absorption from the small intestine, and is excreted unchanged in the faeces and as metabolites in the urine. Meal ingestion decreases its bioavailability. There is little effect of age or gender on pharmacokinetics, although plasma levels may be slightly higher in the elderly. Tegaserod has no effect on plasma levels of other drugs metabolised by cytochrome P450 enzyme systems.

Gastrointestinal symptoms are the most common adverse effects of tegaserod therapy. In data pooled from phase III randomised controlled trials (RCTs) in IBS with constipation patients, diarrhoea was reported by 8.8% of patients treated with tegaserod 6mg twice daily versus 3.8% of patients receiving placebo. Similar rates have been observed in international post-US marketing RCTs. In most patients, tegaserod-induced diarrhoea was mild and transient. In RCTs, it did not elicit fluid or electrolyte disturbances, and fewer than 3% of IBS patients discontinued tegaserod due to diarrhoea. Since its release, rare cases of more severe diarrhoea and ischaemic colitis have been reported. The incidence of other gastrointestinal symptoms (e.g. abdominal pain, nausea, and flatulence) has been similar among tegaserod-treated patients and placebo-treated patients. Pooled analysis of phase III RCTs and post-US marketing RCTs have not demonstrated significant differences between tegaserod-treated patients and placebo-treated patients in the incidence of abdominal-pelvic surgery. There is no convincing evidence that rebound gastrointestinal symptoms occur upon termination of tegaserod therapy.

Pooled analysis of phase III RCTs demonstrated an increase in the incidence of headaches among tegaserod-treated patients (6mg twice daily) compared with placebo-treated patients (15% vs 12.3%, respectively, p < 0.05), although post-US marketing RCTs have not observed this increase. Other extra-gastrointestinal adverse events occur with similar frequency among tegaserod-treated patients and placebo-treated patients. Tegaserod-treated patients in RCTs have not demonstrated significant prolongation of the QTc interval or cardiac arrhythmias compared with placebo-treated patients. Supra-therapeutic doses in healthy volunteers did not effect electrocardiographic parameters. Laboratory parameters are mostly unaffected by tegaserod, although several individuals have exhibited increased eosinophil counts.

In summary, tegaserod exhibits a favourable safety and tolerability profile in IBS patients based on data from clinical trials. Diarrhoea is the most common adverse event associated with tegaserod use. Continued post-US marketing surveillance will further define the safety and tolerability profile of tegaserod.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

The opinions and assertions contained herein are the sole views of the authors and are not to be construed as official or as reflecting the views of the Department of Veterans Affairs.

This study was supported by an unrestricted educational grant from Novartis Pharmaceuticals Corporation.

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Authors and Affiliations

  1. Division of Gastroenterology, University of Michigan School of Medicine, 3912 Taubman Center, Box 0362, Ann Arbor, Michigan, 48109, USA

    William L. Hasler & Philip Schoenfeld

  2. Veterans Affairs Center for Excellence in Health Services Research, Ann Arbor, Michigan, USA

    Philip Schoenfeld

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  1. William L. Hasler
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  2. Philip Schoenfeld
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Correspondence to William L. Hasler.

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Hasler, W.L., Schoenfeld, P. Safety Profile of Tegaserod, a 5-HT4 Receptor Agonist, for the Treatment of Irritable Bowel Syndrome. Drug-Safety 27, 619–631 (2004). https://doi.org/10.2165/00002018-200427090-00001

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