Drug-Associated Insomnia and Sex-Specific Disproportionality in the FDA Adverse Event Reporting System (2019–Q1 2025)

Hao Wen^1,2Yuchuan Shen^1,2Hai Li¹Xiangbin Chen¹Yanzhao Lin^1*Wei Bin^1,2*

• ¹Guangzhou University of Chinese Medicine, Guangzhou, China
• ²Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Zhuhai, China

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.