Drug-associated insomnia and sex-specific disproportionality in the FDA adverse event reporting system (2019-Q1 2025)

Insomnia is a frequent and clinically relevant adverse drug reaction that can impair quality of life, treatment adherence and long-term outcomes. Evidence on drug-associated insomnia has largely been derived from selected clinical trial populations or focused on individual drug classes, while comprehensive post-marketing assessments-particularly those considering potential sex-related heterogeneity-remain limited. Using the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), we conducted a large-scale pharmacovigilance analysis to identify and characterise drug-insomnia signals of disproportionate reporting (SDRs) and to explore potential sex-related heterogeneity in reporting patterns. Individual case safety reports from January 2019 to March 2025 were analysed using a transparent, multi-step preprocessing pipeline, including removal of deleted cases, consolidation by case identifier and case version, and additional rule-based deduplication across case identifiers. Insomnia cases were identified using a narrow set of MedDRA Preferred Terms (PTs)-insomnia, initial insomnia, middle insomnia, terminal insomnia, and early morning awakening-and analyses were restricted to parent systemic drugs. Disproportionality was assessed using reporting odds ratios (RORs) in primary-suspect and any-suspect analyses. Sex-stratified RORs were estimated for female and male reports, and formal heterogeneity was evaluated using interaction-based metrics with false discovery rate control. The final analytic cohort comprised 2,935,560 unique reports, of which 74,444 contained insomnia reactions after exclusion of sleep-related indications. A broad spectrum of psychotropic and non-psychotropic agents showed SDRs for insomnia, spanning hypnotics, antineoplastic therapies, immunomodulators, endocrine agents and commonly used anti-infectives. Sex-stratified analyses revealed largely overlapping signal profiles between females and males, and formal heterogeneity testing identified few drug-insomnia pairs with robust evidence of sex-related heterogeneity after multiple-testing correction. These findings represent signals of disproportionate reporting rather than estimates of incidence or causal risk. Observed sex-related heterogeneity should therefore be interpreted as hypothesis-generating and may reflect heterogeneity in exposure prevalence, prescribing indications and reporting context rather than intrinsic biological susceptibility. Overall, this study provides a contemporary overview of drug-associated insomnia reporting in FAERS and highlights drug-sex combinations that may warrant further investigation in analytically adjusted pharmacoepidemiologic studies.