Post-marketing safety evaluation of mirogabalin using the JADER database

Background: Mirogabalin, a novel third-generation α2-δ calcium channel ligand, is approved for diabetic peripheral neuropathic pain (DPNP). However, its post-marketing safety profile remains insufficiently characterized, particularly regarding novel signals and comparative safety profiles with established therapies. Objectives: This study aimed to identify and characterize adverse event (AE) signals associated with mirogabalin, evaluate demographic differences, and compare signal strength with pregabalin and gabapentin. Methods: We conducted a pharmacovigilance analysis using the Japanese Adverse Drug Event Report (JADER) database (January 2019-June 2025). Disproportionality analysis was performed using the Reporting Odds Ratio (ROR) and Information Component (IC) methods. Subgroup analyses by sex and age, sensitivity analyses restricted to monotherapy reports, and time-to-onset (TTO) analysis using Weibull modeling were conducted. Results: Among 463 healthcare professional-reported AE reports, 33 positive signals were identified. Beyond known AEs (e.g., dizziness, somnolence), six novel potential signals were detected: pleural effusion (n = 6), contusion (n = 4), toxic encephalopathy (n = 4), Cardiac failure congestive (n = 4), deafness (n = 3), and angioedema (n = 3). Head-to-head comparisons revealed that mirogabalin exhibited significantly higher reporting odds ratios (RORs) than pregabalin for pleural effusion (ROR = 2.39, 95%CI: 1.01-5.65), toxic encephalopathy (ROR = 6.37, 95%CI: 1.99-20.36), contusion (ROR = 3.35, 95%CI: 1.14-9.87), and deafness (ROR = 3.67, 95%CI: 1.04-12.91), and significantly higher RORs than gabapentin for cardiac failure congestive (ROR = 6.05, 95%CI: 1.78-20.54). Subgroup analysis revealed sex- and age-related differences: male patients showed higher reporting proportions of muscle weakness, myoclonus, erythema multiforme, urinary retention, and elevated liver enzymes, whereas females exhibited higher proportions of renal impairment and falls; elderly patients (≥65 years) showed higher reporting frequencies of dizziness and rhabdomyolysis, whereas the 18-65 age group showed higher proportions of hepatic and cardiovascular events. Sensitivity analysis partially supported the stability of some signals, with rhabdomyolysis identified exclusively in monotherapy reports. The median TTO was 6 days (IQR: 2-42), indicating an early-clustering pattern (β = 0.55, 95% CI: 0.50-0.60). Sensitivity analysis after excluding outliers yielded a median TTO of 5 days (IQR: 2-28) with β = 0.72 (95% CI: 0.65-0.80). Conclusion: This study extends the understanding of mirogabalin's post-marketing safety profile by identifying six novel signals and revealing distinct safety signal profiles compared with established α2-δ ligands. Demographic-stratified monitoring strategies are warranted to optimize patient safety.