Real-world safety profile of roflumilast: a pharmacovigilance analysis using FDA adverse event reporting system and Canada vigilance database

Background: Roflumilast, a highly selective phosphodiesterase 4 inhibitor, is used to treat with chronic obstructive pulmonary disease and psoriasis. We aim to determine potential roflumilast-associated adverse events (AEs) and the differences in AE signals among diverse populations. Methods: Roflumilast's AE reports between the first quarter of 2011 and the fourth quarter of 2024 were obtained from the FDA Adverse Event Reporting System (FAERS) and Canada Vigilance Adverse Reaction Database (CVARD). The signal strength was measured by four disproportionality analysis methods, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS). Results: In FAERS, population aged ≥65 years and oral medication users accounted for a predominant proportion in the reported cases. FDA-unlabeled respiratory, thoracic and mediastinal disorders was the only one signal categorized by system organ class met all four algorithms. Newly identified AEs such as dyspnea, condition aggravated, cough, and tachycardia could contribute valuable safety considerations for clinical practice. The analysis of the available time-to-onset data suggested that cases often occurred within the first 30 days post-treatment. These results were externally validated in CVARD, suggesting consistent findings. Notably, headache was more frequently reported among users of topical formulations and female patients, while suicidal ideation and weight loss were more commonly reported in male patients and oral medications, respectively. Conclusion: This study confirmed established adverse reactions and identified novel AEs in real-world clinical practice by dual-database pharmacovigilance analysis. Clinicians should remain vigilant for AEs that differ by gender and route to enable early intervention and improve prognosis. The findings highlight personalized safety management, while underscoring the necessity of prospective studies to validate results and further characterize roflumilast's safety profile.