Beyond monotherapy: sex- and age-stratified pharmacovigilance of blonanserin adverse events focusing on drug-drug interactions

Background Blonanserin is an atypical antipsychotic that has been marketed in several Asian countries, but the drug-drug interaction (DDI) signals between it and commonly co-prescribed medications have not been systematically evaluated. Objective This study aimed to systematically explore adverse event (AE) signals for blonanserin both as monotherapy and in combination therapies, using the Japanese Adverse Drug Event Report (JADER) database. Methods For monotherapy, disproportionality analysis (Reporting Odds Ratio, Proportional Reporting Ratio, Bayesian Confidence Propagation Neural Network) was used to detect potential signals. Time-to-onset (TTO) analysis was further applied to monotherapy signals using the Weibull distribution and group distribution analyses. For DDI assessment, five disproportionality methods were employed (Ω shrinkage, additive, multiplicative, combination risk ratio, and chi-square statistics model). Subgroup analyses were stratified by sex and age. Firth’s penalized logistic regression was performed for DDI signals, adjusting for sex and age. Two sensitivity analyses were conducted. Results Monotherapy analysis identified 87 positive AE signals for blonanserin, including rhabdomyolysis, neuroleptic malignant syndrome, falls, and sedation complications. TTO analysis suggested an early-onset pattern for the reported AEs. DDI analysis identified 268 positive drug-drug-AE disproportionality signals, predominantly involving combinations with benzodiazepines, antipsychotics, and antiepileptics. The strongest disproportionality DDI signals were blonanserin + noradrenaline (n = 10, Ω 0.25 = 3.12, AE = drug interaction). The most frequently observed DDI signals involved blonanserin + estazolam (n = 18, Ω 0.25 = 1.50, AE = rhabdomyolysis). Subgroup analyses revealed significant differences in DDI reporting signals between sexes and between patients aged <60 and ≥60 years. Regression analyses showed that 97.01% of the identified DDI signals remained statistically significant, even after adjusting for sex and age. Sex and age were independently associated with the reporting of specific DDI signals. Both sensitivity analyses indicated that 81.54% of the DDI signals were robust across both scenarios. Conclusion This study identified potential safety signals associated with the concomitant use of blonanserin, particularly when used in combination with benzodiazepines, antipsychotics, and antiepileptic drugs. Sex- and age-related differences were observed in the reporting patterns of specific DDI signals, suggesting that demographic factors may warrant consideration when monitoring the safety of blonanserin combination therapies. Given the inherent limitations of spontaneous reporting databases, further pharmacoepidemiological studies are warranted to validate these signals and investigate potential causality.