Drug Safety and Polypharmacy Signals in Ibrutinib-Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Age- and Sex-Specific FAERS Analysis of CYP3A Modifier and Antithrombotic Co-Exposure

Background/Objectives: Ibrutinib is an established treatment for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but its use commonly occurs in older patients with polypharmacy, cardiovascular comorbidity and infection vulnerability. CYP3A-modifying drugs and antithrombotic agents are clinically actionable co-exposure domains because they may alter ibrutinib exposure, bleeding risk or the management of atrial arrhythmia. This study evaluated post-marketing reporting patterns for these co-exposures in FAERS. Methods: Adult FAERS reports through 25Q2 with ibrutinib exposure and CLL/SLL-compatible indications were analyzed after false-positive indication captures were removed. Co-exposures were defined at report level using prespecified drug dictionaries, and grouped adverse-event reporting was evaluated using reporting odds ratio, proportional reporting ratio, chi-square and an information-component-style two-by-two metric. Results: The final cohort comprised 20,878 adult CLL/SLL + ibrutinib reports. CYP3A modifier co-exposure was present in 1373 reports (6.6%), and antithrombotic co-exposure in 3701 reports (17.7%). Antithrombotic exposure increased with age, from 9.8% in reports aged 18–64 years to 23.2% in reports aged ≥75 years. CYP3A modifier exposure was associated with enriched reporting of infection and cytopenia phenotypes, particularly severe infection-like events with CYP3A inhibitors and inducers. Antithrombotic exposure showed consistent reporting enrichment for atrial arrhythmia, bleeding and major bleeding-like events, with the strongest grouped signals among anticoagulant-exposed reports. Overlap analyses showed that the co-exposure domains were not mutually exclusive. Conclusions: These findings should be interpreted as reporting disproportionality rather than incidence or causal risk, but they support prioritizing CYP3A-modifying drugs and antithrombotic therapy during medication reconciliation, interaction screening and risk mitigation in older patients receiving ibrutinib.