Disproportionate reporting of seizures with histamine H1 receptor antagonists: The role of drug generation and brain H1 receptor occupancy assessed using the Japanese Adverse Drug Event Report database

BACKGROUND: Histamine H1 receptor antagonists are widely used as antiallergic agents. However, seizure reporting patterns across individual drugs, drug generation, and brain H1 receptor occupancy (H1RO)-based classification have not been comprehensively evaluated. OBJECTIVE: To evaluate seizure signals for H1 receptor antagonists by drug generation and H1RO-based classification using the Japanese Adverse Drug Event Report (JADER) database. MATERIALS AND METHODS: Reports included in the JADER database from April 2004 to December 2024 were analyzed. Seizure signals for H1 receptor antagonists were evaluated using the reporting odds ratio (ROR). Analyses included all reports and a subgroup of patients under 10 years of age. RESULTS: Overall, seizure signals were detected for selected individual H1 receptor antagonists in both generations, and the observed patterns were not consistently explained by drug generation or H1RO-based classification. As supporting findings, aggregated analyses showed signals for first-generation (ROR: 1.68, 95% CI: 1.46 - 1.93) and second-generation agents (ROR: 1.47, 95% CI: 1.34 - 1.61). In patients under 10 years of age, seizure signals were detected across both drug generations and different H1RO-based categories and were not consistently explained by either classification. CONCLUSION: These findings suggest that seizure signals differ across individual drugs, with similar patterns observed in children under 10 years of age. Individual drug characteristics and patient age may warrant consideration in drug selection rather than relying solely on drug generation or H1RO-based classification.