Analysis of drug-induced interstitial lung disease caused by herbal medicine using the Japanese Adverse Drug Event Report database.

BACKGROUND: Drug-induced interstitial lung disease (DIILD) is a severe adverse event leading to morbidity and mortality. This study evaluated the adverse event indicators of DIILD and time-to-onset profiles following the daily intake of herbal drugs (Scutellariae radix ["ogon" in Japanese], Bupleuri radix ["saiko" in Japanese], and Pinelliae tuber ["hange" in Japanese]) using the Japanese Adverse Drug Event Report database. DIILD was defined in accordance with the Medical Dictionary for Regulatory Activities. METHODS: The Japanese Adverse Drug Event Report database contained 830,079 reports published between April 2004 and April 2023. The association between herbal medicines and DILLD was evaluated using the pharmacovigilance index as the reporting odds ratio (ROR), logistic regression models, propensity score-matching techniques, and Weibull shape parameters. RESULTS: The adjusted RORs using multivariate logistic regression models for Scutellariae radix (daily intake), Pinelliae tuber (daily intake), sex (male), age (≥ 60 years), Scutellariae radix (daily intake)*age (≥ 60 years), and Scutellariae radix (daily intake)* Pinelliae tuber (daily intake) were 1.47 (1.36 - 1.59), 1.05 (1.01 - 1.10), 1.45 (1.34 - 1.57), 1.92 (1.74 - 2.11), 3.35 (3.12 - 3.60), and 1.49 (1.46 - 1.53), respectively. DIILD onset profiles were evaluated using the Weibull shape parameter. A logistic plot of daily intake and onset of DIILD was drawn. ROR signals were detected in 32 of 54 herbal medicines, including Scutellariae radix, Bupleuri radix, and Pinelliae tuber. The median duration (days) (interquartile range) to DIILD onset was 36.0 (27.0-63.0) for Saikokaryukotsuboreito, 35.0 (21.0-55.0) for Saireito, and 31.0 (13.5-67.5) for Shosaikoto. The Weibull shape parameter beta (95% confidence interval) values for Saikokaryukotsuboreito, Saireito, and Shosaikoto were 1.36 (1.08-1.67), 1.36 (1.20-1.52), and 1.31 (0.98-1.68), respectively. CONCLUSIONS: DIILD demonstrated a dose-dependent to crude drugs. Clinicians should strive for the early detection of DIILD and avoid the inadvertent administration of herbal medicines.

Study of Factors to Increase the Usage Rate of Generic Drugs in Platelet Aggregation Inhibitors.

To reduce pharmacy-related medical expenses, it is necessary to reduce drug costs. One way to achieve this is by increasing the usage rate of generic drugs. The purpose of this study was to identify platelet aggregation inhibitors (PAIs) that contribute to high drug costs and are sold as brand-name drugs in order to increase the usage rate of generic drugs, and to analyze the factors that affect the usage rate of generic drug. We conducted a cross-sectional study based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data Japan (NODJ) of the Ministry of Health, Labor and Welfare and datasets containing related medical information from official statistical surveys such as the Basic Survey on Wage Structure. Monthly personal income in each prefecture were negatively correlated with outpatient out-of-hospital and outpatient in-hospital prescriptions of the PAIs clopidogrel (75 mg), cilostazol (50 mg), cilostazol (100 mg), and ticlopidine (100 mg), but not between monthly personal income and outpatient out-of-hospital prescription of ticlopidine (100 mg). For outpatient out-of-hospital prescriptions and outpatient in-hospital prescriptions, negative correlation was generally observed between the usage rate of generic drug and monthly personal income, except for ticlopidine (100 mg), which has the lowest price among the brand-name drugs. The usage rate of generic PAIs is negatively correlated with monthly personal income. Promoting the use of generic drugs among high-income earners might be necessary to further increase the usage rate of generic drug.

Osteonecrosis of the Jaw Caused by Denosumab in Treatment-Naïve and Pre-Treatment with Zoledronic Acid Groups: A Time-to-Onset Study Using the Japanese Adverse Drug Event Report (JADER) Database.

BACKGROUND: Medication-related osteonecrosis of the jaw is a serious adverse event associated with bone-modifying agents, such as injectable bisphosphonate (zoledronic acid) and the anti-receptor activator of nuclear factor-κB ligand antibody (denosumab). OBJECTIVE: This study aims to evaluate and compare the time-to-onset profile for medication-related osteonecrosis of the jaw associated with denosumab between treatment-naïve (naïve group) and pre-treatment with zoledronic acid (post-zoledronic acid group) patients using the Japanese Adverse Drug Event Report database. METHODS: Medication-related osteonecrosis of the jaw was defined according to the Medical Dictionary for Regulatory Activities. The medication-related osteonecrosis of the jaw onset profiles were evaluated using the Weibull shape parameter and the log-rank test. RESULTS: The Japanese Adverse Drug Event Report database contains 632,409 reports published between April 2004 and March 2020. In the time-to-onset analysis, after extracting the combinations with complete information for the treatment start date and the medication-related osteonecrosis of the jaw onset date, 272 reports of the naïve group and 86 reports of the post-zoledronic acid group were analyzed. The median onset in the naïve and post-zoledronic acid groups was 487.0 (25-75%: 274.0-690.8) and 305.5 (25-75%: 158.3-508.5) days, respectively. Medication-related osteonecrosis of the jaw occurred earlier in the post-zoledronic acid group than in the naïve group, and the log-rank test demonstrated a significant difference in their time transitions (p < 0.0001). CONCLUSIONS: The results indicated a risk of medication-related osteonecrosis of the jaw in naïve and post-zoledronic acid groups and a shorter onset time in the latter than in the former. Thus, healthcare professionals should take the early risk of medication-related osteonecrosis of the jaw into account when switching patients from zoledronic acid to denosumab treatment.

Analysis of drug-induced hand-foot syndrome using a spontaneous reporting system database.

Purpose: The aim of our study was to assess the clinical features of hand-foot syndrome (HFS) associated with certain systemic chemotherapeutic drugs in a real-world setting using the Japanese Adverse Drug Event Report (JADER) database. Methods: HFS was defined using the preferred terms from the Medical Dictionary for Regulatory Activities. We used several indices, such as the reporting odds ratios (RORs) at 95% confidence interval (CI), the time-to-onset profile of HFS, and cluster analysis. Results: Of 646,779 reports (submission period: April 2004 to September 2020), 1814 reported HFS events. The RORs (95% CI) for axitinib, capecitabine, lapatinib, regorafenib, sorafenib, and sunitinib were 14.9 (11.1-20.1), 54.6 (49.2-60.6), 130.4 (110.7-153.6), 63.3 (55.2-72.6), 29.0 (25.8-32.7), and 13.9 (11.7-16.5), respectively. The analysis of time-to-onset profiles revealed that the median values (interquartile range: 25.0-75.0%) of drug-induced HFS caused by capecitabine, cisplatin, docetaxel, everolimus, regorafenib, sorafenib, and trastuzumab were 21.0 (13.0-42.0), 15.0 (10.0-82.0), 6.0 (3.0-25.0), 86.5 (67.0-90.5), 9.0 (6.0-14.0), 9.0 (6.0-14.0), and 70.0 (15.0-189.0) days, respectively. The number of clusters was set to 4. Among these, one cluster, which included capecitabine, regorafenib, and lapatinib, exhibited a higher reporting ratio and ROR of drug-induced HFS than other drugs. Conclusions: The RORs and results of time-to-onset analysis obtained in this study indicated the potential risk of HFS associated with chemotherapeutic drugs. Our results suggest that health care professionals must be aware of the potential onset of drug-induced HFS with docetaxel, regorafenib, and sorafenib for at least 4 weeks; therefore, careful observation is recommended. Plain Language Summary: Elucidation of the relationship between cancer drugs and risk of hand-foot syndrome: Purpose: Hand-foot syndrome (HFS) is an adverse effect of some cancer drugs, which is characterized by symptoms such as redness, swelling, blistering, and pain in the area of palms and soles. HFS reduces the quality of life of patients and can sometimes interfere with anticancer treatment plans. It is important to understand the clinical manifestations of HFS and gain knowledge that will allow for early intervention by clinicians.Methods: In this study, we used a large-scale side effect database of real-world cases for a comprehensive investigation of anticancer-drug-induced HFS. The database contained 646,779 adverse event reports from April 2004 to September 2020; among which, we identified 1814 HFS events. Using these data, we could obtain information on the relationship between 19 types of anticancer drugs and HFS, and the onset time of HFS and HFS prognosis related to each anticancer drug. Results: Our results suggest that clinicians should monitor the risk of HFS with docetaxel, regorafenib, and sorafenib for at least the first 4 weeks after drug administration. Conclusion: These findings are crucial for improving the management of the adverse effects caused by anticancer drugs.

Analysis of Prednisolone-Induced Osteoporosis Using the Japanese Adverse Drug Event Report Database.

PURPOSE: Osteoporosis is an adverse event of prednisolone. This study aimed to assess prednisolone-induced osteoporosis (PIO) profiles and patient backgrounds by analyzing data from the Japanese Adverse Drug Event Report (JADER) database. METHODS: The current study focused only on orally administered prednisolone. PIO was defined using preferred terms from the Medical Dictionary for Regulatory Activities. Reporting odds ratio (ROR) at 95% confidence interval (CI) and the time-to-onset profile of PIO were used to evaluate adverse events. RESULTS: The RORs (95% CI) of the female and male subgroups were 4.73 (4.17-5.38) and 2.49 (2.06-3.00), respectively. The analysis of time-to-onset profiles demonstrated that the median values (interquartile range: 25.0-75.0%) of PIO were 136 (74.0-294.0). The prednisolone treatment duration was significantly longer in the PIO patient group than in the non-PIO patient group. The findings suggest that patients with rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome receiving prednisolone have different age-related PIO profiles. CONCLUSIONS: Our results suggest that longer prednisolone treatment duration and larger cumulative dose might be risk factors of PIO. The potential risk for PIO should not be overlooked, and careful observation is recommended.

Analysis of Drug-Induced Gastrointestinal Obstruction and Perforation Using the Japanese Adverse Drug Event Report Database.

Drug-induced gastrointestinal obstruction (DIGO) and gastrointestinal perforation (DIGP) may be the result of gastrointestinal hypomotility and severe constipation, which may lead to potentially fatal complications of bowel ischemia, sepsis and perforation. We evaluated the onset profile of DIGs (DIGO and DIGP) associated with prescription drugs by analyzing data in the Japanese Adverse Drug Event Report (JADER) database. We selected 161 DIG-related drugs and categorized them into 19 classes based on the Anatomical Therapeutic Chemical (ATC) Classification System. Finally, we focused on 58 drugs and conducted subsequent analyses for the time-to-onset and outcomes. We extracted 79 preferred terms (PTs) with the strings "ileus," "stenosis," "obstruction," "obstructive," "impaction," "perforation," "perforated," "hypomotility," and "intussusception" from the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) of SMQ20000104: gastrointestinal perforation, ulcer, hemorrhage, obstruction non-specific findings/procedures; SMQ20000105: gastrointestinal obstruction; and SMQ20000107: gastrointestinal perforation. Among the 667, 729 reports in the JADER database submitted between April 2004 and November 2020, we identified 11,351 occurrences of DIGs. The reporting odds ratios (RORs) (95% confidence interval) of "barium sulfate containing X-ray media," "drugs for treatment of hyperkalemia and hyperphosphatemia," and "oral bowel cleanser" were 142.0 (127.1-158.6), 25.8 (23.1-28.8), and 29.7 (24.8-35.6), respectively. The median number of days (interquartile range) until the onset of an adverse event caused by each drug category was as follows: barium sulfate containing X-ray contrast media [2.0 (1.0-3.0)], diazepines, oxazepines, thiazepines, and oxepines [8.0 (8.0-18.5)], drugs for treatment of hyperkalemia and hyperphosphatemia [29.0 (8.0-55.0)], non-selective monoamine reuptake inhibitors [19.0 (7.0-47.5)], and oral bowel cleanser [0.0 (0.0-0.0)]. Depending on the drug, the time to onset of side effects ranged from days to several months. Our results highlighted the need to perform detailed monitoring of each drug for possible association with DIGs, which might otherwise have fatal consequences.

Pharmacovigilance study of anti-infective-related acute kidney injury using the Japanese adverse drug event report database.

BACKGROUND: Acute kidney injury (AKI) is associated with significant increases in short- and long-term morbidity and mortality. Drug-induced AKI is a major concern in the present healthcare system. Our spontaneous reporting system (SRS) analysis assessed links between AKI, along with patients' age, as healthcare-associated risks and administered anti-infectives. We also generated anti-infective-related AKI-onset profiles. METHOD: We calculated reporting odds ratios (RORs) for reports of anti-infective-related AKI (per Medical Dictionary for Regulatory Activities) in the Japanese Adverse Drug Event Report database and evaluated the effect of anti-infective combination therapy. The background factors of cases with anti-infective monotherapy and combination therapy (≥ 2 anti-infectives) were matched using propensity score. We evaluated time-to-onset data and hazard types using the Weibull parameter. RESULTS: Among 534,688 reports (submission period: April 2004-June 2018), there were 21,727 AKI events. The reported number of AKI associated with glycopeptide antibacterials, fluoroquinolones, third-generation cephalosporins, triazole derivatives, and carbapenems were 596, 494, 341, 315, and 313, respectively. Crude RORs of anti-infective-related AKI increased among older patients and were higher in anti-infective combination therapies [anti-infectives, ≥ 2; ROR, 1.94 (1.80-2.09)] than in monotherapies [ROR, 1.29 (1.22-1.36)]. After propensity score matching, the adjusted RORs of anti-infective monotherapy and combination therapy (≥ 2 anti-infectives) were 0.67 (0.58-0.77) and 1.49 (1.29-1.71), respectively. Moreover, 48.1% of AKI occurred within 5 days (median, 5.0 days) of anti-infective therapy initiation. CONCLUSION: RORs derived from our new SRS analysis indicate potential AKI risks and number of administered anti-infectives.

Gentamicin-induced hearing loss: A retrospective study using the Food and Drug Administration Adverse Event Reporting System and a toxicological study using drug-gene network analysis.

The objectives of the study were to evaluate the relationship between gentamicin (GEN) and hearing loss using the Food and Drug Administration Adverse Event Reporting system (FAERS) database and elucidate the potential toxicological mechanism of GEN-induced hearing loss through a drug-gene network analysis. Using the preferred terms and standardized queries from the Medical Dictionary for Regulatory Activities, we calculated the reporting odds ratios (RORs). We extracted GEN-associated genes (seed genes) and analyzed drug-gene interactions using the ClueGO plug-in in the Cytoscape software and the DIseAse MOdule Detection (DIAMOnD) algorithm. The lower limit of the 95% confidence interval (CI) of the ROR for aminoglycosides (AG) antibacterials was over 1, and the ROR was 5.5 (5.1-6.0). We retrieved 17 seed genes related to GEN from the PharmGKB and Drug Gene Interaction databases. In total, 1018 human genes interacting with GEN were investigated using ClueGO. Through Molecular Complex Detection (MCODE) analysis, we identified 17 local gene clusters. The nodes and edges of the highest-ranked local gene cluster named "Cluster 1" were 30 and 433, respectively. According to the ClueGO analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG), Cluster 1 genes were highly enriched in "oxidative phosphorylation." According to the ClueGO analysis using ClinVar, Cluster 1 genes were highly enriched in "mitochondrial diseases," "mitochondrial complex I deficiency," "hereditary hearing loss and deafness," and "Leigh syndrome." We identified 60 GEN-associated genes using the DIAMOnD algorithm. Several GEN-associated genes in the DIAMOnD algorithm were highly enriched in "PI3K-Akt signaling pathway," "Ras signaling pathway," "focal adhesion," "MAPK signaling pathway," "regulation of actin cytoskeleton," "oxidative phosphorylation," and "ECM-receptor interaction." Our analysis demonstrated an association between several AGs and hearing loss using the FAERS database. Drug-gene network analysis demonstrated that GEN may be associated with oxidative phosphorylation-associated genes and integrin genes, which may be associated with hearing loss.

Analysis of chemotherapy-induced peripheral neuropathy using the Japanese Adverse Drug Event Report database.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event associated with several antineoplastic drugs; however, the precise risks and time course of reactions of particular drugs are not clearly understood. The aim of this study was to evaluate the relationship between anticancer agents and CIPN development using data from the Japanese Adverse Drug Event Report (JADER) database and to characterize the time-to-onset and outcomes of CIPN. Chemotherapy-induced peripheral neuropathy was defined using the Medical Dictionary for Regulatory Activities preferred terms. Disproportionality analysis was performed by calculating the reporting odds ratio (ROR) with 95% confidence interval for signal detection. Data of nine Anatomical Therapeutic Chemical (ATC) drug categories correlated with CIPN development, in addition to the data of the time-to-onset and outcomes. Among 622,289 reports in the JADER database from April 2004 to March 2020, there were 1883 reports of adverse events corresponding to peripheral neuropathy. The ROR (95% confidence interval) for vinblastine, sorbent-based paclitaxel (sb-PTX), oxaliplatin, and bortezomib was 20.4 (12.5-33.4), 13.6 (11.9-15.7), 26.2 (23.6-29.1), and 30.8 (26.6-35.8), respectively. The median duration (interquartile range) to CIPN development after the administration of vinca alkaloids and analogues, taxanes, platinum compounds, and monoclonal antibodies was 11.0 (5.0-46.5), 22.5 (6.0-82.5), 22.0 (6.0-68.5), and 32.5 (11.3-73.8) days, respectively. The median duration (interquartile range) of sb-PTX and nanoparticle albumin-bound (nab)-PTX was 35.0 (7.0-94.0) and 5.5 (3.0-29.3) days, respectively. Our analysis of records in the JADER database revealed several drugs associated with a high risk for CIPN development. In particular, the development of CIPN after vinca alkaloid administration should be closely monitored for 2 weeks after administration. CIPN caused by nab-PTX showed significantly faster onset than that by sb-PTX. Patients who receive taxanes or monoclonal antibodies often do not show an improvement; accordingly, early treatment is required.

Neuropsychiatric Adverse Events of Montelukast: An Analysis of Real-World Datasets and drug-gene Interaction Network.

Montelukast is a selective leukotriene receptor antagonist that is widely used to treat bronchial asthma and nasal allergy. To clarify the association between montelukast and neuropsychiatric adverse events (AEs), we evaluated case reports recorded between January 2004 and December 2018 in the Food and Drug Administration Adverse Event Reporting System (FAERS). Furthermore, we elucidated the potential toxicological mechanisms of montelukast-associated neuropsychiatric AEs through functional enrichment analysis of human genes interacting with montelukast. The reporting odds ratios of suicidal ideation and depression in the system organ class of psychiatric disorders were 21.5 (95% confidence interval (CI): 20.3-22.9) and 8.2 (95% CI: 7.8-8.7), respectively. We explored 1,144 human genes that directly or indirectly interact with montelukast. The molecular complex detection (MCODE) plug-in of Cytoscape detected 14 clusters. Functional analysis indicated that several genes were significantly enriched in the biological processes of "neuroactive ligand-receptor interaction." "Mood disorders" and "major depressive disorder" were significant disease terms related to montelukast. Our retrospective analysis based on the FAERS demonstrated a significant association between montelukast and neuropsychiatric AEs. Functional enrichment analysis of montelukast-associated genes related to neuropsychiatric symptoms warrant further research on the underlying pharmacological mechanisms.

Trends Associated with Hemorrhoids in Japan: Data Mining of Medical Information Datasets and the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data Japan.

Hemorrhoids are a common anorectal disease. Epidemiological studies on medication trends and risk factors using information from real-world databases are rare. Our objective was to analyze the relationship between hemorrhoid treatment prescription trends and several risk factors using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data Japan and related medical information datasets. We calculated the standardized prescription ratio (SPR) based on the 2nd NDB Open Data Japan from 2015. The correlation coefficients between the SPR of antihemorrhoidals and those of "antispasmodics," "antiarrhythmic agents," "antidiarrheals, intestinal regulators," "purgatives and clysters," "hypnotics and sedatives, antianxietics," "psychotropic agents," and "opium alkaloids preparations" were 0.7474, 0.7366, 0.7184, 0.6501, 0.6320, 0.4571, and 0.4542, respectively. The correlation coefficient between the SPR of antihemorrhoidals and those of "average annual temperature," "percentage of people who were smokers," and "percentage of people who drank regularly" were -0.7204, 0.6002, and 0.3537, respectively. The results of cluster analysis revealed that Hokkaido and Tohoku regions tended to have low average annual temperature values and high percentage of people who were smokers and had comparatively high SPRs of "antispasmodics," "antiarrhythmic agents," "antidiarrheals, intestinal regulators," "purgatives and clysters," "hypnotics and sedatives, antianxietics," "psychotropic agents," and "opium alkaloids preparations." Antihemorrhoidals are frequently used in Hokkaido and Tohoku, Japan; thus, it is important for these prefectural governments to focus on these factors when taking measures regarding health promotion.

Assessment of Reye's syndrome profile with data from the US Food and Drug Administration Adverse Event Reporting System and the Japanese Adverse Drug Event Report databases using the disproportionality analysis.

OBJECTIVES: Reye's syndrome is a rare and potentially fatal illness that is defined as encephalopathy accompanied by liver failure. The aim of this study was to assess Reye's syndrome profiles by analyzing data from the spontaneous reporting system database. METHODS: We analyzed reports of Reye's syndrome using the US Food and Drug Administration Adverse Event Reporting System and the Japanese Adverse Drug Event Report databases. The reporting odds ratio and proportional reporting rate were used to detect the pharmacovigilance signal. RESULTS: The US Food and Drug Administration Adverse Event Reporting System contains 12,201,620 reports from January 2004 to June 2020, of which 186 are on Reye's syndrome. The Japanese Adverse Drug Event Report contains 646,779 reports from April 2004 to September 2020, of which 30 are on Reye's syndrome. In the US Food and Drug Administration Adverse Event Reporting System database, the reporting odds ratios (95% confidence interval, number of cases) of aspirin, diclofenac, ibuprofen, acetaminophen, and valproate sodium were 404.6 (302.6-541.0, n = 80), 15.1 (6.7-34.1, n = 6), 26.2 (16.1-42.6, n = 18), 10.7 (5.5-20.9, n = 9), and 47.1 (26.2-84.6, n = 12), respectively. In the Japanese Adverse Drug Event Report database, the reporting odds ratios (95% confidence interval, number of cases) of aspirin, diclofenac, ibuprofen, loxoprofen, acetaminophen, and valproate sodium were 14.1 (5.4-36.8, n = 5), 51.7 (22.2-120.5, n = 7), 135.0 (40.8-446.2, n = 3), 17.6 (6.7-46.0, n = 5), 24.0 (9.2-62.6, n = 5), and 13.8 (3.3-57.9, n = 2), respectively. The reported number of female patients aged 30-39 years was the highest in the Japanese Adverse Drug Event Report. CONCLUSION: Although the frequency of the occurrence of Reye's syndrome is low, the possible risk of the disease occurring in adult females should be considered.

Analysis of immune-related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database.

PURPOSE: The aim of our study was to characterize the clinical features of immune-related 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. RESULTS: The JADER database contained 534 688 reports from April 2004 to June 2018. The RORs of pneumonitis including interstitial lung disease for nivolumab, pembrolizumab, and ipilimumab were 7.02 (95% confidence interval: 6.55-7.52), 9.08 (8.28-9.97), and 1.74 (1.27-2.38), respectively. The median onsets (quartiles, 25-75%) of myocarditis caused by nivolumab and pembrolizumab were 28.0 (15.5-60.5) and 18.0 (13.0-44.5) days, respectively. Co-therapy with nivolumab and ipilimumab may be associated with irAEs in several categories as per the association rule mining analysis. CONCLUSION: Our results demonstrated a potential risk of irAEs associated with ICIs, based on RORs and time-to-onset analysis. Furthermore, our findings indicated that patients receiving nivolumab and ipilimumab as co-therapy should be carefully monitored.

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-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.

Evaluation of anti-infective-related Clostridium difficile-associated colitis using the Japanese Adverse Drug Event Report database.

Clostridium difficile-associated colitis (CDAC) may cause gastrointestinal illness, ranging in severity from mild diarrhea to fulminant colitis and even mortality. The purpose of this study was to evaluate anti-infective-related CDAC profiles using the Japanese Adverse Drug Event Report (JADER) database. Methods: We selected case reports of adverse events of CDAC as specified in the Medical Dictionary for Regulatory Activities. The association between the number of administered anti-infectives and aging was evaluated using reporting odds ratio (ROR) and adjusted for covariates using multiple-logistic regression. We also evaluated anti-infective-related CDAC-onset profiles using Weibull shape parameter. Results: The JADER database contained 534 688 reports from April 2004 to June 2018. There were 1222 anti-infective related CDAC events. The top five anti-infectives were as follows: third-generation cephalosporins (Anatomical Therapeutic Chemical (ATC) code: J01DD, 313 cases), fluoroquinolones (ATC code: J01MA, 201 cases), macrolides (ATC code: J01FA, 146 cases), carbapenems (ATC code: J01DH, 143 cases), and penicillins with extended spectrum (ATC code: J01CA, 103 cases). The adjusted RORs (95% confidence interval) in individuals using 1, 2, and ≥ 3 anti-infectives were 8.88 (7.05-11.18), 9.77 (6.89-13.86), and 18.39 (11.85-28.54), respectively. Moreover, 47.2% of CDACs occurred within 7 days of anti-infective therapy initiation. The adjusted ROR of interaction terms of ≥ 70 years × 1 drug was 21.81 (14.56-32.68). Conclusion: Our results suggest that the number of administered anti-infectives and patient age are associated with CDAC. These data may be particularly beneficial to prescribers and would contribute to improving the management of CDAC.

Analysis of drug-induced hearing loss by using a spontaneous reporting system database.

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.

Adverse event profiles of ifosfamide-induced encephalopathy analyzed using the Food and Drug Administration Adverse Event Reporting System and the Japanese Adverse Drug Event Report databases.

PURPOSE: Ifosfamide is extensively used to treat several malignant conditions. Administration of ifosfamide can cause encephalopathy and other neurotoxic effects. The aim of this study was to obtain novel information on the onset profiles of ifosfamide-induced encephalopathy (IIE) considering other associated clinical factors using the US Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report (JADER) databases. METHODS: We analyzed the reports of encephalopathy between 2004 and 2018 from the FAERS and JADER databases. To define IIE, we used the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms and standardized queries. The reporting odds ratios (ROR) at 95% confidence interval (CI) was used to detect the signal for IIE and adjusted for covariates using a multivariate logistic regression technique. We evaluated the time-to-onset profile of IIE and used the association rule mining technique to discover undetected associations, such as potential risk factors. RESULTS: In the FAERS database, the ROR (CI) for encephalopathy (preferred term, PT) and encephalopathy (standardized MedDRA queries, SMQ) was 56.58 (51.69-61.93) and 1.57 (1.48-1.67), respectively. In the JADER database, the ROR (95% CI) for encephalopathy (PT) and encephalopathy (SMQ) was 13.54 (9.91-18.50) and 1.24 (1.01-1.53), respectively. The multivariate logistic regression analysis showed a significant contribution in IIE signal in the ≥ 60 year group (p = 0.00094; vs. < 60 year group) and ≥ 2000 mg/m2 dosage group (p = 0.00045; vs. < 2000 mg/m2 dosage group). The association rules of {ifosfamide, aprepitant} → {encephalopathy (SMQ)} demonstrated high lift values. The average dose of ifosfamide in patients with encephalopathy (PT) and without encephalopathy (PT) was 2022.8 ± 592.8 (mean ± standard deviation) and 1568.5 ± 703.2 mg/m2, respectively (p < 0.05). Encephalopathy within the first 7 days of ifosfamide administration was 94.1% for encephalopathy (PT) and 87.7% for encephalopathy (SMQ), respectively. CONCLUSIONS: The present analysis demonstrated that the incidence of encephalopathy with ifosfamide should be closely monitored for a short onset (within 7 days). The patients who are administered a high dose of ifosfamide or co-administrated aprepitant should be carefully monitored for the development of encephalopathy.