The Gastrointestinal Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted overwhelmingly (11 yes, 1 no) to recommend reintroducing tegaserod maleate (Zelnorm, Sloan Pharma) for the treatment of irritable bowel syndrome with constipation (IBS-C) in women without a history of cardiovascular (CV) ischemic disease and who have no more than one risk factor for CV disease.
Women without CV disease include those without myocardial infarction, stroke, transient ischemic attack, or angina, and risk factors for CV disease include hypertension, tobacco use, diabetes, hypercholesterolemia, age ≥ 55 years, or obesity.
The panel voted unanimously that "the therapeutic gain (treatment difference between tegaserod and placebo) is generally similar in magnitude between the severely symptomatic and originally approved population."
Regarding which patient populations would be most likely to experience greater benefits compared with risks for treatment with tegaserod, seven panel members said females with IBS-C and low CV risk, three voted for severely symptomatic females with IBS-C and low CV risk, and one each voted for females with IBS-C and severely symptomatic females with IBS-C.
"I was convinced by the data regarding the benefits of stratifying patients by cardiovascular risk and I was also convinced that there would be a lot of disagreement about determining whether patients did or didn't have severe IBS-C, and that it should be left up to the patient and the practitioner to make that determination regarding benefit," committee chairperson Jean-Pierre Raufman, MD, professor and head, division of gastroenterology and hepatology, University of Maryland School of Medicine, VA Maryland Health Care System, Baltimore, Maryland, said at the meeting.
"I understand the rationale behind perhaps restricting the population to those who are severe, and the FDA shows compelling data suggesting that it is just as efficacious in that context, but it strikes me as just not workable in practice because the definition of severe can be difficult," said voting committee member Benjamin Lebwohl, MD, MS, assistant professor of medicine and epidemiology and director of clinical research, Celiac Disease Center, Columbia University College of Physicians and Surgeons, New York City.
Somewhat Checkered Past
Tegaserod is a 5-HT4 agonist that stimulates peristalsis and intestinal secretion and inhibits visceral sensitivity. Its mechanism of action differs from those currently on the market.
The FDA first approved tegaserod oral tablets (Zelnorm, Novartis) on July 24, 2002, for the short-term treatment of women with IBS-C. Safety and efficacy were not demonstrated in males, as they were not included in clinical trials.
On August 21, 2004, the FDA approved tegaserod for the treatment of patients less than 65 years of age with chronic idiopathic constipation; the applicant did not establish effectiveness in patients aged 65 years or older.
In 2005, the FDA asked Novartis to provide data on suicidal ideation and behavior (SI/B) events that occurred during the premarketing clinical trials, following a routine review of Adverse Event Reporting System reports that showed a potential postmarketing signal for suicidal behaviors with the drug. These data demonstrated an imbalance in the overall frequency of such events associated with tegaserod use.
On February 2, 2007, the FDA issued a letter to Novartis recommending the inclusion of language warning of this potential risk in the prescribing information's Warnings and Precautions section. Novartis did not incorporate this language into the labeling because the company removed the drug from the market for CV safety concerns. The FDA proposes including this language in the proposed labeling by the current applicant.
On March 30, 2007, Novartis suspended its US marketing and sales of tegaserod maleate in compliance with a request from the FDA after data in its clinical databases showed a higher incidence of myocardial infarction, stroke, and unstable angina among patients who took the medication when compared with those who took placebo.
Pooled data from 29 clinical trials showed a statistically nonsignificant trend toward increased angina among those who took the drug in the clinical trial on which the drug's approval was based in 2002; however, a recent analysis of 18,000 participants in the entire clinical database found adverse cardiovascular events in 13 of 11,614 patients (0.11%) taking tegaserod, compared with only one patient (0.01%) out of 7031 in the placebo group, a difference that was statistically significant, according to information in an FDA briefing document.
"While an imbalance in CV safety events associated with tegaserod was noted, the strength of the signal was difficult to interpret due to limitations of the meta-analysis — for example, the trials were not designed to specifically evaluate CV safety, were of short duration, included a low CV-risk population, and involved retrospective assessment of CV information. In addition, the etiology of [CV ischemic] events related to the use of tegaserod is not well understood," the FDA explained in the briefing document.
"Additionally, the results of studies assessing potential effects of tegaserod on platelet aggregation have not been consistent. Further, it is difficult to determine potential clinical characteristics that identify patients who may be at higher risk when using tegaserod given the small number of CV [adverse events; AEs]," the FDA continued.
Later that year, on July 27, 2007, the FDA announced it would allow the restricted use of tegaserod maleate under a new investigational new drug protocol program, saying that it might still benefit certain patients in emergency situations who have no other treatment options, Medscape Medical News reported.
Tegaserod is currently sold in foreign markets including Brazil, Ecuador, and Mexico, the FDA notes.
The panel's vote today follows consideration of data from the 29 placebo-controlled trials and a noninterventional epidemiologic study that further characterized potential CV safety concerns. The advisory committee was not asked to reanalyze the efficacy of tegaserod, but rather to conduct post hoc, exploratory analyses to provide additional information regarding the benefits and risks of reintroducing tegaserod.
"Given the potential for reintroduction of tegaserod in various subpopulations of interest, elucidating the benefits and risks in the presence of a potential CV and SI/B safety signal is of particular clinical importance, as patients with IBS-C may have need for additional treatment options but may also be at risk of AEs," the FDA explains in its briefing document.
"I do think that the CV signal is real, but I think the magnitude of the signal is small," said temporary voting committee member John Teerlink, MD, professor of medicine, University of California San Francisco; director, Heart Failure, and director, Echocardiography, Section of Cardiology, San Francisco Veterans Affairs Medical Center, California.
Medscape Medical News © 2018
Cite this: FDA Panel OKs Tegaserod for IBS With Constipation in Women With Low CV Risk - Medscape - Oct 17, 2018.