Background: Tegaserod, a serotonin (5-HT4) agonist initially approved for constipation but withdrawn from use in 2007 because of concerns about cardiovascular adverse effects, was resubmitted to the Food and Drug Administration (FDA) in 2018 for use in a restricted population.
Areas of uncertainty: Despite an 18-year regulatory history, there remain pharmacology and clinical trial concerns that have not been addressed but are critical for proper assessment of the drug safety and efficacy profile.
Sources: Original FDA reviews, FDA and developer advisory committee briefing documents, and published literature.
Results: The major pharmacology concern is that the fate and effects of half of the molecule, the pentylaminoguanidine moiety, are unknown. There is evidence that pentylaminoguanidine may contribute to both efficacy and safety. There are other metabolites that are poorly characterized, and potential receptor interactions that suggest cardiovascular effects are possible. The major clinical trial concern is that, while the trial data support a low but definite cardiovascular risk, both subject follow-up and cardiovascular event descriptions were incomplete such that an accurate estimate of cardiovascular risk is not possible.
Conclusions: The uncertainties and lack of reliable evidence regarding tegaserod metabolism and cardiovascular risk estimates may discourage clinical use. Signals for cardiovascular toxicity in typical drug development programs are subtle and must be pursued aggressively, with complete case follow-up and cardiovascular event capture in the clinical trials.