Disproportionality analysis of safety signals for milnacipran and levomilnacipran: a pharmacovigilance study using the FDA adverse event reporting system

Background Major depressive disorder (MDD) is a global health concern, with serotonin-norepinephrine reuptake inhibitors (SNRIs) constituting a mainstay of the psychopharmacological approach to its clinical management. Milnacipran and levomilnacipran are SNRIs with distinct serotonin/norepinephrine reuptake ratios. Their real-world adverse event (AE) profiles and sex-specific patterns remain incompletely characterized owing to limitations of small-scale clinical trials. Methods Utilizing the FAERS database, adverse event signals were identified for milnacipran (2,752 cases) and levomilnacipran (715 cases) through the methods of Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS). Sex-stratified analyses were also conducted, employing a modified ROR approach. Results Female patients predominated in AE reports (milnacipran: 79.61%; levomilnacipran: 64.48%). At the level of System Organ Class, milnacipran exhibited significant signals in vascular disorders (EBGM05 = 2.16), while levomilnacipran demonstrated stronger signals in psychiatric (EBGM05 = 3.45), reproductive (EBGM05 = 8.65), and renal/urinary systems (EBGM05 = 2.39). Out of 26 shared Preferred Terms, painful ejaculation and urinary retention showed the largest disparities (levomilnacipran risk higher). Sex-specific signals included female-predominant nausea (milnacipran) and suicidal ideation (levomilnacipran), and male-predominant urinary retention (both agents). Conclusion This real-world pharmacovigilance study has highlighted the distinct adverse event profiles of milnacipran and levomilnacipran, with a particular emphasis on sex-specific reactions. This differentiation supports the adoption of precision prescribing strategies and addresses the limitations often encountered in traditional clinical trial data.