Sex-specific adverse event profiles of PDE4 inhibitors: a comparative big-data pharmacovigilance study of apremilast, crisaborole, and roflumilast in FAERS (2004–2025)

Introduction: Phosphodiesterase-4 (PDE4) inhibitors, including apremilast, crisaborole and roflumilast, are widely prescribed for chronic inflammatory diseases. However, sex-specific safety profiles of these agents in routine clinical practice remain poorly characterized. Methods: We conducted a retrospective pharmacovigilance study using the US Food and Drug Administration Adverse Event Reporting System (FAERS) from Q1-2004 to Q1-2025. Data cleaning and deduplication were performed following the FDA Guidance for Industry: Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (FDA, 2005). Specifically, deduplication was executed by retaining only the most recent FDA_DT for each unique CASEID, and demographic (DEMO), drug (DRUG), and reaction (REAC) files were merged. Reports listing apremilast, crisaborole, or roflumilast as primary suspect drugs formed three target cohorts. Disproportionality analyses were performed using reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN, information component), and multi-item gamma Poisson shrinker (MGPS, empirical Bayes geometric mean). Positive signals required meeting all four algorithmic thresholds. Signals were summarised at Preferred Term (PT) and System Organ Class (SOC) levels, stratified by sex, and visualised with volcano plots, forest plots, and SOC-level heatmaps. Time-to-onset (TTO) was calculated as the interval between treatment start and event onset. Results: A total of 127,516 Apremilast, 7,562 Crisaborole, and 2,142 Roflumilast reports were included. Clear sex-specific disproportionality patterns emerged across the three agents. For Apremilast, females exhibited higher reporting of dizziness, palpitations, and infection-related adverse events, whereas Crisaborole showed a modest male predominance for "product use issue," and Roflumilast demonstrated male-skewed signals, particularly for malignancy- and metabolism-related events. System Organ Class (SOC) analyses further revealed distinct organ-system involvement for each agent. Time-to-onset profiles showed substantially delayed onset for Apremilast compared with the more immediate onset observed for Crisaborole and Roflumilast. The median TTO (IQR) was 24 (7-86) days for Apremilast, 4 (1-15) days for Crisaborole, and 42 (14-128) days for Roflumilast. Discussion/Conclusion: This large-scale real-world analysis reveals pronounced sex-specific and drug-specific heterogeneity in the safety profiles of PDE4 inhibitors. These findings highlight the need for sex-stratified risk communication, individualized monitoring strategies, and further mechanistic investigations.