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REEVALUATION OF THE CARDIOVASCULAR SAFETY PROFILE OF TEGASEROD: A REVIEW OF THE CLINICAL DATA Author(s): Brian E. Lacy2, Darren M. Brenner3, William D. Chey1 Introduction Tegaserod is a 5-HT4 agonist that stimulates gastrointestinal motility and secretion while inhibiting visceral hypersensitivity. It is currently the only FDA-approved 5-HT4 receptor agonist for the treatment of irritable bowel syndrome with constipation (IBS-C) in adult females <65 years of age. However, it is contraindicated in patients with known cardiovascular (CV) risk factors. In 2007, tegaserod was voluntarily removed from the US market, when a pooled analysis revealed an imbalance in CV ischemic events in patients treated with tegaserod versus placebo. We present an integrated CV safety analysis conducted by the Gastrointestinal Drugs Advisory Committee in 2018, which resulted in the reintroduction of tegaserod to the US market. Methods Two external adjudications were performed on a pooled database of 29 tegaserod placebo-controlled clinical trials in patients with functional GI disorders including IBS, chronic idiopathic constipation and dyspepsia. Ischemic events were categorized as cardiac, vascular, or cerebrovascular in nature. The first adjudication was conducted by Mount Sinai Hospital, NY, and the second by the Duke Clinical Research Institute in NC, which further investigated the CV safety profile of tegaserod by using a broader search including MedDRA search terms for “cardiac disorders.” Additional searches were conducted on PubMed/Medline and Google Scholar for articles relevant to the CV risk of tegaserod. Results Of 18,645 patients evaluated, 11,614 received tegaserod and 7,031 received placebo. The most common CV risk factors were age ≥55 years (20.6%), active smoking (20.6%), obesity (17.9%), hypertension (17.7%) and hyperlipidemia (17.3%). In the first adjudication, 13 (0.11%) patients in the tegaserod group and 1 (0.01%) patient in the placebo group had confirmed CV ischemic events (Table 1). All 14 patients had at least one CV risk factor and 11 had a minimum of 2 risk factors. There were 7 (0.06%) major cardiovascular events (MACE); 4 in females <65 years of age and 1 in a male >65 years of age. In the second adjudication, there were 7 (0.06%) confirmed CV ischemic events (P=0.3) and 4 (0.03%) MACE (P=0.3) in the tegaserod group versus none in the placebo group. In females <65 years of age without a history of CV ischemic disease and ≤1 CV risk factor, only 1 (0.01%) CV ischemic event and no MACE were reported in the tegaserod group versus none in placebo in the first and second adjudications. Additional analyses found no evidence of increased proarrhythmic risk or platelet aggregation within these studies. Conclusions Nearly all CV ischemic events and MACE occurred in patients >65 years of age with other cardiac risk factors. Tegaserod was safe in women <65 years of age without CV risk factors. These findings align with current FDA recommendations for use of tegaserod in individuals with IBS-C. Disclosure: B. E. Lacy: Ironwood: Advisory Committees or Review Panels; D. M. Brenner: Allergan: Speaking and Teaching; Alnylam: Advisory Committees or Review Panels; AlphaSigma: Board Membership; GI Health Foundation: Consulting; Ironwood: Speaking and Teaching; Salix: Speaking and Teaching; Takeda/Shire: Speaking and Teaching; W. D. Chey: Allergan: Consulting; alnylam: Consulting; biomerica: Consulting; im health: Consulting; ironwood: Consulting; Phathom: Consulting; QOL Medical: Consulting; Ritter: Consulting; Salix/Valeant: Consulting; Urovant: Consulting;

Last month the US Food and Drug Administration advisory committee voted to recommend reintroduction of Zelnorm for IBS-C and for the new medication Prucalopride for chronic constipation. The IBS Patient Group provided in-person testimony at the committee meetings. Read our testimonies at https://www.ibspatient.org/advocacy

We are heading to the US FDA in Washington DC/Bethesda on Wednesday and Thursday to testify on behalf of patients for IBS and constipation medications that could help some patients. Zelnorm was well loved by IBS-C patients. Prucalopride is widely used outside the US for constipation. Our presentations are posted. Thank you to those people that helped with some of the quotes and for completing the survey. Zelnorm: https://www.regulations.gov/document?D=FDA-2018-N-3223-0009 Prucalopride: https://www.regulations.gov/document?D=FDA-2018-N-0055-0013