Disproportionality analysis and “perpetrator” or “accomplice” review of Baloxavir marboxil in public FAERS database

BACKGROUND: Baloxavir marboxil (Xofluza™) was initially approved for marketing in Japan and the United States in 2018, which is a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Despite indicating that Baloxavir marboxil is effective and well-tolerated through a series of clinical trials, studies on its safety in real-world settings are scarce. METHODS: We conducted a mining analysis of the FDA Adverse Event Reporting System (FAERS) database from Q4 2018 to Q2 2024 to extract adverse events associated with Baloxavir marboxil. Descriptive statistics were first performed to characterize the included reports, covering demographic variables, clinical outcomes, and concomitant medications. We subsequently employed four disproportionality analysis algorithms—ROR, PRR, BCPNN, and MGPS—for signal detection. To verify the robustness of the identified signals, we performed comprehensive subgroup and sensitivity analyses. RESULTS: A total of 1,765 reports comprising 3,624 adverse events with baloxavir marboxil as the primary suspected drug were identified. Most reports originated from the United States (57.98%), followed by Japan (39.58%) and China (1.82%). Over 65% of reports were submitted by non-consumers. Fatal outcomes were reported in 10.89% of cases. In both the overall study population and the deceased subgroup, hypotensive drugs represented the most frequently reported concomitant medications alongside influenza therapeutics. Eight robust safety signals were ultimately detected: altered state of consciousness, anaphylactic reaction, anaphylactic shock, colitis ischaemic, drug eruption, intentional product use issue, melaena, and no adverse event. Among these, “altered state of consciousness” is not listed in the product label. Several labelled adverse reactions with unestablished causality—rash, urticaria, erythema multiforme, vomiting, delirium, abnormal behavior, and hallucinations—disappeared during subgroup and sensitivity analyses. Additionally, the Ω shrinkage measure for the baloxavir marboxil-warfarin interaction yielded Ω₀₂₅ = 1.42. CONCLUSION: The eight ultimately detected signals represent robust positive findings. Reactions including rash, urticaria, erythema multiforme, vomiting, delirium, abnormal behavior, and hallucinations were determined to be false positives. The most severe outcome, death, primarily reflected the presence of pre-existing cardiovascular conditions. A potential interaction between baloxavir marboxil and warfarin was identified, warranting further investigation.