Many drugs can cause hearing loss, leading to sensorineural deafness. The aim of this study was to evaluate the risk of drug-induced hearing loss (DIHL) by using the Japanese Adverse Drug Event Report (JADER) database and to obtain profiles of DIHL onset in clinical settings. We relied on the Medical Dictionary for Regulatory Activities preferred terms and standardized queries, and calculated the reporting odds ratios (RORs). Furthermore, we applied multivariate logistic regression analysis, association rule mining, and time-to-onset analysis using Weibull proportional hazard models. Of 534688 reports recorded in the JADER database from April 2004 to June 2018, adverse event signals were detected for platinum compounds, sulfonamides (plain) (loop diuretics), interferons, ribavirin, other aminoglycosides, papillomavirus vaccines, drugs used in erectile dysfunction, vancomycin, erythromycin, and pancuronium by determining RORs. The RORs of other aminoglycosides, other quaternary ammonium compounds, drugs used in erectile dysfunction, and sulfonamides (plain) were 29.4 (22.4–38.6), 18.5 (11.2–30.6), 15.4 (10.6–22.5), and 12.6 (10.0–16.0), respectively. High lift score was observed for patients with congenital diaphragmatic hernia treated with pancuronium using association rule mining. The median durations (interquartile range) for DIHL due to platinum compounds, sulfonamides (plain), interferons, antivirals for treatment of hepatitis C virus (HCV) infections, other aminoglycosides, carboxamide derivatives, macrolides, and pneumococcal vaccines were 25.5 (7.5–111.3), 80.5 (4.5–143.0), 64.0 (14.0–132.0), 53.0 (9.0–121.0), 11.0 (3.0–26.8), 1.5 (0.3–11.5), 3.5 (1.3–6.8), and 2.0 (1.0–4.5), respectively. Our results demonstrated potential risks associated with several drugs based on their RORs. We recommend to closely monitor patients treated with aminoglycosides for DIHL for at least two weeks. Moreover, individuals receiving platinum compounds, sulfonamides (plain), interferons, and antivirals for HCV infection therapy should be carefully observed for DIHL for at least several months.

Direct oral anticoagulants (DOACs) are used in anticoagulant therapy. The purpose of this study was to evaluate the association of DOAC-induced gastrointestinal (GI) and nervous system hemorrhage using the FDA's Adverse Event Reporting System (FAERS) database and the Japanese Adverse Drug Event Report (JADER) database.We identified and analyzed the reports of hemorrhagic reactions between 2004 and 2016 from the FAERS and JADER databases, and calculated the adjusted reported odds ratio (ROR) using the multiple logistic regression method. Additionally, we used the time-to-onset analysis.In the FAERS database, the adjusted ROR of apixaban, rivaroxaban, and dabigatran for GI hemorrhage was 6.79 (5.84-7.91), 19.58 (18.85-20.34), and 14.51 (13.58-15.51), respectively. In the JADER database, the adjusted ROR of apixaban, rivaroxaban, edoxaban, and dabigatran for GI hemorrhage was 11.80 (9.50-14.64), 11.03 (9.18-13.26), 10.17 (6.95-14.88), and 9.85 (7.23-13.42), respectively. We found that the association of GI hemorrhage with DOACs was affected by sex (female). Additionally, 30% of GI hemorrhage was observed after 30 days.Hemorrhagic reactions of both GI and nervous systems were observed in both the spontaneous reporting system databases. We recommend that female patients who experience symptoms related to GI hemorrhage should be closely monitored and advised to adhere to an appropriate care plan. Additionally, our results show that patients should be closely monitored for hemorrhage even after a month.

The aim of our study was to characterize the clinical features of immunerelated adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) in a real-world setting using the Japanese Adverse Drug Event Report (JADER) database. Methods: The irAEs were defined using the preferred terms of the Medical Dictionary for Regulatory Activities. irAEs were categorized as follows: adrenal insufficiency, colitis, eye diseases, hematological disorder, hepatitis, hyperthyroidism, hypopituitarism, hypothyroidism, myasthenia gravis, myocarditis, nephritis/renal dysfunction, pneumonitis, rash, and type 1 diabetes mellitus. We used several indices such as reporting odds ratio (ROR) to assess disproportionality in pharmacovigilance data, time-to-onset analysis using Weibull shape parameters, and the association rule mining technique to evaluate possible risk factors between variables in the spontaneous reporting system 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-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.

BackgroundFalls are a common but serious problem in older adults, and may lead to fractures and bleeding. As many factors, such as medication, aging, and comorbid diseases may simultaneously affect fall-related adverse events (AEs) in older adults, we evaluated the association between fall-related AEs and the use of medication, aging, and comorbid diseases using the Japanese Adverse Drug Event Report (JADER) database.MethodsWe analyzed reports of fall-related AEs associated with α-blockers, diuretics, calcium channel blockers, central nervous system (CNS)-active drugs (opioids, benzodiazepines, hypnotics and sedatives, non-selective monoamine reuptake inhibitors, and selective serotonin reuptake inhibitors (SSRI)) in the JADER database using the reporting odds ratio (ROR). For the definition of falls, we used the Preferred Terms of The Medical Dictionary for Regulatory Activities (MedDRA). We used the association rule mining technique to discover undetected associations, such as potential risk factors.ResultsThe JADER database comprised 430,587 reports between April 2004 and November 2016. The RORs (95% CI) of α-blockers, diuretics, calcium channel blockers, opioids, benzodiazepines, hypnotics and sedatives, non-selective monoamine reuptake inhibitors, and SSRIs were 1.63 (1.27–2.09), 0.74 (0.63–0.86), 1.26 (1.15–1.38), 0.93 (0.80–1.07), 1.83 (1.68–2.01), 1.55 (1.12–2.14), 2.31 (1.82–2.95), and 2.86 (2.49–3.29), respectively. From the lift value in the association rule mining, the number of administered CNS-active drugs and patient age were associated with fall-related AEs. Furthermore, the scores of lift for patients with herpes zoster administered calcium channel blockers or benzodiazepines and patients with dementia administered benzodiazepines were high.ConclusionOur results suggest that the number of administered CNS-active drugs and patient age are both associated with fall-related AEs. We recommend that patients with herpes zoster treated with calcium channel blockers and benzodiazepines be closely monitored for fall-related AEs.