Sex-stratified pharmacovigilance of gastrointestinal events associated with first-line smoking-cessation medicines: Insights from the FAERS database

Abstract

Background Tobacco smoking is a major global health threat. Pharmacological aids, including nicotine-replacement therapy (NRT), varenicline, and bupropion, improve quit rates but are associated with gastrointestinal (GI) adverse events (AEs) that can compromise adherence. The real-world reporting profiles of these GI AEs, particularly the differences between sexes, have not been comprehensively characterized. Methods We analyzed the FDA Adverse Event Reporting System (FAERS) database from 2004 Q1 to 2024 Q2. After deduplication, reports designating NRT, varenicline, or bupropion as the primary suspect drug were extracted. Disproportionality analyses, including the Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR), were conducted to quantify drug-event associations. The Breslow–Day test was used to assess the homogeneity of RORs between male and female strata. Results Varenicline was associated with the highest proportion of GI reports (36.0% of its total reports). The disproportionality signal was significantly stronger in women than in men (ROR 6.41 vs. 5.10 for nausea, p  < 0.001). NRT was linked to 24.3% of GI reports, with hiccups (PRR = 60.1) being the most prominent signal. In contrast to varenicline, several key GI AE signals for NRT were significantly stronger in men (e.g., nausea, ROR 3.09 in men vs. 2.45 in women, p  < 0.001). Bupropion had the lowest proportion of GI reports (2.1%) but still generated significant disproportionality signals (overall ROR 4.50), particularly for anorexia (PRR = 4.80) and dry mouth (PRR = 4.42), with most signals being stronger in women. Conclusion NRT, varenicline, and bupropion exhibit distinct and statistically significant sex-specific GI AE reporting profiles in a real-world setting. These hypothesis-generating findings underscore the importance of considering sex as a variable in pharmacovigilance studies and may inform future research aimed at personalizing smoking cessation therapy.