Analysis of drug-induced interstitial lung disease using the Japanese Adverse Drug Event Report database

Objectives: Drug-induced interstitial lung disease occurs when exposure to a drug causes inflammation and, eventually, fibrosis of the lung interstitium. Drug-induced interstitial lung disease is associated with substantial morbidity and mortality. The aim of this retrospective study was to obtain new information on the time-to-onset profiles of drug-induced interstitial lung disease by consideration of other associated clinical factors using the Japanese Adverse Drug Event Report database. Methods: We identified and analyzed reports of drug-induced interstitial lung disease between 2004 and 2018 from the Japanese Adverse Drug Event Report database. The reporting odds ratio and 95% confidence interval was used to detect the signal for each drug-induced interstitial lung disease incidence. We evaluated the time-to-onset profile of drug-induced interstitial lung disease and used the applied association rule mining technique to uncover undetected relationships, such as possible risk factors. Results: The reporting odds ratios (95% confidence intervals) of drug-induced interstitial lung disease due to temsirolimus, gefitinib, sho-saiko-to, sai-rei-to, osimertinib, amiodarone, alectinib, erlotinib, everolimus, and bicalutamide were 18.3 (15.6-21.3), 17.8 (16.5-19.2), 16.3 (11.8-22.4), 14.5 (11.7-18.2), 12.5 (10.7-14.7), 10.9 (9.9-11.9), 10.6 (8.1-13.9), 9.6 (8.8-10.4), 9.4 (8.7-10.0), and 9.2 (7.9-10.6), respectively. The median durations (day (interquartile range)) for drug-induced interstitial lung disease were as follows: amiodarone (123.0 (27.0-400.5)), methotrexate (145.5 (67.8-475.8)), fluorouracil (86.0 (35.5-181.3)), gemcitabine (53.0 (20.0-83.0)), paclitaxel (52.0 (28.5-77.5)), docetaxel (47.0 (18.8-78.3)), bleomycin (92.0 (38.0-130.5)), oxaliplatin (45.0 (11.0-180.0)), nivolumab (56.0 (21.0-135.0)), gefitinib (24.0 (11.0-55.0)), erlotinib (21.0 (9.0-49.0)), temsirolimus (38.0 (14.0-68.5)), everolimus (56.0 (35.0-90.0)), osimertinib (51.5 (21.0-84.8)), alectinib (78.5 (44.3-145.8)), bicalutamide (50.0 (28.0-147.0)), pegylated interferon-2 alpha (140.0 (75.8-233.0)), sai-rei-to (35.0 (20.0-54.5)), and sho-saiko-to (33.0 (13.5-74.0)) days. Association rule mining suggested that the risk of drug-induced interstitial lung disease was increased by a combination of amiodarone or sho-saiko-to and aging. Conclusion: Our results showed that patients who receive gefitinib or erlotinib should be closely monitored for the development of drug-induced interstitial lung disease within a short duration (4 weeks). In addition, elderly people who receive amiodarone or sho-saiko-to should be carefully monitored for the development of drug-induced interstitial lung disease.