Narrative Review
Tegaserod: What’s Old Is New Again

https://doi.org/10.1016/j.cgh.2022.01.024Get rights and content

Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are common gastrointestinal disorders imposing considerable impact on the quality of life and well-being of affected individuals. A paucity of evidence-based treatment options exist for CIC and IBS-C sufferers. Tegaserod, a 5-HT4 agonist, has a substantial body of preclinical and clinical study evidence to support its beneficial role in modulating sensorimotor function of the luminal gastrointestinal tract. Tegaserod was first approved for use by the U.S. Food and Drug Administration for the management of IBS-C and CIC in 2002 and 2004, respectively. Tegaserod enjoyed a successful uptake in the management of these disorders during its first several years of availability in the United States, but was later withdrawn from the market in 2007 over concerns related to adverse cardiovascular events. Since then, additional safety data has been generated, and following a resubmission and review by the Food and Drug Administration, in April 2019, tegaserod was once again approved for use in IBS-C under a more restricted labeling, confining use to women under 65 years of age without heart disease or additional cardiovascular risk factors. This review summarizes the regulatory journey of tegaserod and details the existing pharmacokinetic, physiologic, clinical, and safety data of tegaserod generated over the last 2 decades. The discussion also examines the future of tegaserod in the treatment of these constipation disorders, as well as its potential role in other related disorders of brain-gut interaction.

Section snippets

Irritable Bowel Syndrome With Constipation: Major Impacts And Unmet Needs

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction characterized by recurrent abdominal pain associated with altered bowel habits.1,2 Large population-based studies estimate a worldwide IBS prevalence of 5%–15% in developed countries, with a female predominance, and approximately one-third of IBS patients having IBS with a constipation-predominant bowel pattern (IBS-C).3, 4, 5 IBS imparts a substantial negative impact on the health-related quality of life of affected

5-HT4 Receptor Pharmacology

For 5-HT4 receptor pharmacology, see the Supplementary Materials.

Tegaserod Pharmacokinetics And Metabolism

For tegaserod pharmacokinetics and metabolism, see the Supplementary Materials.

Tegaserod Effects On Gi Function

For tegaserod effects on GI function, see the Supplementary Materials.

Tegaserod Phase II/III IBS-C Trial Summary

The initial studies evaluated a dose range of tegaserod and, based on these findings, the doses of 2 and 6 mg were selected for further evaluation.39 Two pivotal placebo-controlled 12-week studies were conducted in IBS-C patients, one evaluating both 2 and 6 mg twice daily doses in males and females40 and the other only evaluating 6 mg twice daily in females.41 The primary endpoint in these studies was the Subjective Global Assessment (SGA) of relief, assessed using a 5-point ordinal scale.42

Cisapride History

Cisapride was introduced worldwide in the 1990s as a serotonin 5-HT4 agonist with 5-HT3 antagonist activity (Supplementary Table 3) and was approved by the FDA for nocturnal heartburn but was widely used for the treatment of a wide range of motility disorders.21 However, it was eventually recognized that cisapride use could result in prolongation of the QT interval and thereby increase the risk of arrhythmia.47, 48, 49, 50 Because cisapride is metabolized by the cytochrome P450 enzyme system,

“New Again”: The Re-Emergence Of Tegaserod

In light of this constellation of data dispelling concern relating to potential serious adverse events, in 2018 a supplemental new drug application was submitted by Sloan Pharma to the U.S. FDA for tegaserod use in women with IBS-C and low CV risk.66 On October 17, 2018, an FDA and Gastrointestinal Drugs Advisory Committee meeting convened to perform a complete review of the tegaserod resubmission, including the available safety data.67 Members of that committee ultimately voted 11 to 1 in

Conclusions and Expert Opinion

The efficacy of tegaserod in the management of chronic constipation disorders, including the global abdominal symptoms of IBS, has been well established. With careful consideration of the potentially serious adverse events, in this current era the concerns relating to CV events and intestinal ischemia have been sufficiently, and convincingly, addressed to allow FDA reapproval for the use of this agent in IBS-C patients. Tegaserod overall is well tolerated, with treatment-related adverse events

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  • Cited by (4)

    • Tegaserod maleate exhibits antileukemic activity by targeting TRPM8

      2022, Biomedicine and Pharmacotherapy
      Citation Excerpt :

      Our study evaluated the antileukemic activity of 2040 compounds at a single concentration using a large-scale screen in AML cell lines. Tegaserod maleate, a 5-hydroxytryptamine 4 (5-HT4) receptor partial agonist, has been approved for treating irritable bowel syndrome with constipation (IBS-C) [15–17]. None of the other 5-HT4 receptor agonists in the drug screening exhibited anti-AML effects, which prompted us to explore the mechanisms underlying the regulation of AML progression by tegaserod maleate.

    Conflicts of interest The authors disclose the following: Gregory Sayuk has served as a consultant for AbbVie (Allergan), Ironwood, Salix, and Alnylam; and served on the speakers bureau for AbbVie (Allergan), Ironwood, Salix, Alnylam, and the GI Health Foundation. Jan Tack has served as a consultant for Adare, AlfaWassermann, Allergan, Arena, Bayer, Christian Hansen, Clasado, Danone, Devintec, Falk, Grünenthal, Ironwood, Janssen, Kiowa Kirin, Menarini, Mylan, Neurogastrx, Neutec, Novartis, Noventure, Nutricia, Shionogi, Shire, Takeda, Theravance, Tramedico, Truvion, Tsumura, Zealand, and Zeria Pharmaceuticals; received research support from Shire, Sofar, and Tsumura, and served on the speakers bureau for Abbott, Allergan, AstraZeneca, Janssen, Kyowa Kirin, Menarini, Mylan, Novartis, Shire, Takeda, Truvion, and Zeria.

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