Systemic Drugs Associated With Maculopathy

Importance: Systemic medications may have unrecognized macular toxic effects; early identification might be important for vision preservation. Objectives: To identify systemic drugs potentially associated with maculopathy via pharmacovigilance reporting and to evaluate their macular adverse effects in a nationwide encounter database. Design, Setting, and Participants: This 2-part study included (1) disproportionality analysis for candidate identification, using 15 748 maculopathy-related individual case safety reports from the US Food and Drug Administration Adverse Event Reporting System (FAERS) between July 2014 and December 2023, and (2) a population-based cohort study for association evaluation, using the South Korean Health Insurance Review and Assessment Service (HIRA) database among users of the candidate drugs, covering approximately 50 million individuals. Data were analyzed from January 1, 2015, to December 31, 2023. Exposure: Use of systemic drugs identified as candidate signals in FAERS. Main Outcomes and Measures: Reporting odds ratios for signal detection in FAERS and incidence rate ratios, hazard ratios, and cumulative incidence of maculopathy in HIRA. Results: Five systemic drugs with underrecognized macular toxic effects-fingolimod, apixaban, paclitaxel, ibrutinib, and sildenafil-were identified among the top 30 maculopathy signals in FAERS. In HIRA, the incidence rate ratios for maculopathy following exposure (vs preexposure) were 1.92 (95% CI, 0.62-5.96) for fingolimod, 3.08 (95% CI, 2.68-3.54) for apixaban, 2.85 (95% CI, 1.62-5.02) for paclitaxel, 3.71 (95% CI, 2.58-5.34) for ibrutinib, and 2.75 (95% CI, 2.17-3.48) for sildenafil. The cumulative incidence rates ranged from 4.4% (fingolimod) to 15.7% (apixaban). Dose-response relationships were observed for paclitaxel (hazard ratio, 2.01 [95% CI, 1.77-2.29] for third vs first quartile) and ibrutinib (hazard ratio, 4.82 [95% CI, 1.39-16.81] for fourth vs first quartile). Conclusions and Relevance: These findings suggest that the integration of pharmacovigilance signal detection and nationwide health claims analysis identified associations of maculopathy with apixaban, paclitaxel, ibrutinib, and sildenafil. This combined approach offers a potentially cost-effective, robust method for identifying systemic drugs with possibly underrecognized macular adverse effects.