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

Abstract

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-2α (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.