Sex Differences in Levodopa‐Sparing Effect of Safinamide: Post‐hoc Findings from a Multicenter, Longitudinal, Case‐Control Study

Background: Female sex increases the risk of levodopa-induced dyskinesias in Parkinson's disease (PD). While levodopa-sparing effects of monoamine oxidase-B inhibitors (iMAO-B) are established, sex differences in response to safinamide remain unexplored. Objectives: To evaluate sex differences in longitudinal (9 ± 3 months) changes in levodopa dose and total levodopa-equivalent daily dose (LEDD) with safinamide 100 mg. Methods: We included 259 PD patients treated with safinamide 100 mg (cases, n = 130) or never exposed to iMAO-B (controls, n = 129). The primary outcome was the sex × treatment interaction on the change in levodopa daily dose adjusted for body weight. Results: Safinamide 100 mg improved UPDRS-III scores and reduced OFF-time independently of sex. A significant sex × treatment interaction emerged for change in weight-adjusted levodopa dose and total LEDD, with greater reduction in women (p = 0.025 and 0.045, respectively). Conclusions: Safinamide 100 mg provides a larger levodopa-sparing effect in women, supporting sex-specific optimization of dopaminergic therapy in PD management.