Japanese Adverse Drug Event Report Database Research Articles

Analysis of the Time-To-Onset and Factors Affecting Clinical Outcomes of Immune Reconstitution Inflammatory Syndrome in People Living with HIV Using Data from the Japanese Spontaneous Reporting Database.

Data on immune reconstitution inflammatory syndrome (IRIS), despite being a widely recognized complication of antiretroviral therapy, remain limited. The objective of the present study was to evaluate the time-to-onset and factors affecting clinical outcomes of IRIS in people living with HIV (PLWH) using data from the Japanese Adverse Drug Event Report (JADER) database. Data of PLWH who developed IRIS as an adverse event were extracted from the JADER database. Cases with the data of both the start date of anti-HIV drug therapy and date of IRIS onset were included in the study. The survey items included sex, age, anti-HIV drug use, IRIS-compatible events, time-to-onset of IRIS, and clinical outcome. The time-to-onset of IRIS was evaluated in relation to anchor drug use. Overall, 79 cases were included in the analysis. The median (range) time-to-onset of IRIS was 29 (1-365) days, and it differed significantly between IRIS-compatible events (P = 0.029). In particular, the time-to-onset of Pneumocystis pneumonia-IRIS was the shortest among the IRIS-compatible events (median [range]: 12 [5-301] days). Age ≥ 50 years at IRIS onset appeared to be related to the poor clinical outcomes of IRIS in PLWH (P = 0.048). The use of integrase strand transfer inhibitors did not affect the time-to-onset of IRIS or clinical outcome of IRIS in PLWH. This analysis based on the data from the JADER database revealed that IRIS-compatible events were related to the time-to-onset of IRIS and that patients older than 50 years had poorer clinical outcomes of IRIS. This finding will be useful for healthcare professionals when considering medications for patients with HIV infection/AIDS and for the management of IRIS.

Pharmacovigilance Evaluation of Bendamustine-related Skin Disorders using the Japanese Adverse Drug Event Report Database.

Bendamustine is used in hematologic malignancies such as non-Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma. This study evaluated the association of bendamustine-related skin disorders using the Japanese Adverse Drug Event Report (JADER) database. We identified and analyzed reports of skin disorders between April 2004 and November 2019 from the JADER database and calculated the reported odds ratios (RORs) using disproportionality analysis. Additionally, we analyzed the relationship between skin disorders related to bendamustine use and patient information (age and sex). The symptoms, ranked in order of decreasing strength of association with skin disorders, were infusion-related reaction (ROR=5.708), herpes zoster (ROR=4.658), hypersensitivity (ROR=3.271), and rash (ROR=1.472). Additionally, analysis of the relationships between rash related to bendamustine and sex or age showed significant relationships for female sex and age younger than 70 years (ROR=2.247 and 2.176, respectively). Meanwhile, analysis of the relationship between herpes zoster and sex showed a significantly stronger association for male than female sex (ROR=2.887). Our analysis of skin disorders related to bendamustine use reported in the spontaneous reporting system databases showed that the association of rash with bendamustine use was affected by sex (female) and age (younger than 70 years). Additionally, the association of herpes zoster with bendamustine was affected by sex (male). Bendamustine is an outpatient chemotherapy regimen, and so we recommend close monitoring of female patients or those younger than 70 years who experience rash-like symptoms and male patients who experience herpes zoster-like symptoms.

In Silico Approach to Predict Severe Cutaneous Adverse Reactions Using the Japanese Adverse Drug Event Report Database.

Severe cutaneous adverse reactions (SCARs), such as Stevens–Johnson syndrome/toxic epidermal necrolysis and drug‐induced hypersensitivity syndrome, are rare and occasionally fatal. However, it is difficult to detect SCARs at the drug development stage, necessitating a new approach for prediction. Therefore, in this study, using the chemical structure information of SCAR‐causative drugs from the Japanese Adverse Drug Event Report (JADER) database, we tried to develop a predictive classification model of SCAR through deep learning. In the JADER database from 2004 to 2017, we defined 185 SCAR‐positive drugs and 195 SCAR‐negative drugs using proportional reporting ratios as the signal detection method, and the total number of reports. These SCAR‐positive and SCAR‐negative drugs were randomly divided into the training dataset for model construction and the test dataset for evaluation. The model performance was evaluated in the independent test dataset inside the applicability domain (AD), which is the chemical space for reliable prediction results. Using the deep learning model with molecular descriptors as the drug structure information, the area under the curve was 0.76 for the 148 drugs of the test dataset inside the AD. The method developed in the present study allows for utilizing the JADER database for SCAR classification, with potential to improve screening efficiency in the development of new drugs. This method may also help to noninvasively identify the causative drug, and help assess the causality between drugs and SCARs in postmarketing surveillance.

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

PurposeThe 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.MethodsThe 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.ResultsThe 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.ConclusionOur 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.

Identification of target small molecule tyrosine kinase inhibitors that need monitoring and clinical application of protocol for early detection of cancer therapeutics-related cardiac dysfunction using signal detection: An investigation of real world data.

In order to detect cancer therapeutics-related cardiac dysfunction (CTRCD) early, we identified which drugs were to be monitored using signal detection and the package insert, and created and applied a protocol to address this. Adverse event data recorded in the Japanese Adverse Drug Event Report (JADER) database between April 2004 and January 2018 were used. Among small molecule tyrosine kinase inhibitors that are not described in the serious side-effects section of the package insert despite signal detection, tyrosine kinase inhibitors with severe side-effects in the background of cases reported by JADER database were selected to be monitored in clinical practice. We applied our findings clinically by creating a protocol to detect CTRCD early. All cases at Tosei General Hospital where the target tyrosine kinase inhibitors were administered from when they were first released in November 2019 were included. We compared the results from before and after we began the protocol to clarify its effects. We found that CTRCD was not described in the serious side-effect section of the package inserts for Bosutinib, Alectinib, and Osimertinib even though CTRCD signals were detected for them. Therefore, it is possible that we may have previously overlooked CTRCD. When we applied our protocol using Osimertinib as the target drug, we were able to detect CTRCD early in 5/21 (24%) patients. It was clarified that the drug identification method used in this study for early detection of adverse events leads to early detection of adverse events when applied clinically.

Polypharmacy in elderly patients in Japan: Analysis of Japanese real-world databases.

Polypharmacy is associated with an increased risk of adverse drug reactions (ADRs) and drug interactions, decreased adherence to medication and increased medical cost. Recently, polypharmacy has become a major problem in medical care in Japan as a result of the increase in the ageing population. The purpose of this study was to investigate the current situation of polypharmacy and the association between polypharmacy and adverse events. A retrospective data analysis was performed using two different real-world data from 2007 to 2015 in Japan. The Japanese Adverse Drug Event Report (JADER), a public spontaneous adverse drug reaction database constructed by the Pharmaceuticals and Medical Devices Agency (PMDA), and a large prescription database constructed by a database vendor (Japan Medical Information Research Institute, Inc Japan [JMIRI]) were analysed. Trends of polypharmacy during the study period were investigated. The mean number of drugs per report in the JADER database and per prescription in the JMIRI databases during the study period ranged from 4.8 to 5.6 and 3.5 to 3.7, respectively. The mean number of drugs increased with age in both the JADER and JMIRI databases, and the peak of the mean number of drugs was at 80-89years (5.74 drugs) in the JADER database and at 90-99years (4.97 drugs) in the JMIRI database. The number of drugs increased until age 90years or more, even though adverse events are more likely to occur after the age of 80 in Japan. Therefore, polypharmacy in the elderly should be focused on the patients aged ≥80years rather than patients aged ≥65years from the viewpoint of the prevention of adverse events.

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.

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. 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. 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 ≥ 60year group (p = 0.00094; vs. < 60year group) and ≥ 2000mg/m2 dosage group (p = 0.00045; vs. < 2000mg/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 ± 703.2mg/m2, respectively (p < 0.05). Encephalopathy within the first 7days of ifosfamide administration was 94.1% for encephalopathy (PT) and 87.7% for encephalopathy (SMQ), respectively. The present analysis demonstrated that the incidence of encephalopathy with ifosfamide should be closely monitored for a short onset (within 7days). The patients who are administered a high dose of ifosfamide or co-administrated aprepitant should be carefully monitored for the development of encephalopathy.

Pharmacovigilance Assessment of Drug-Induced Acute Pancreatitis Using a Spontaneous Reporting Database.

Acute pancreatitis (AP) is associated with risks of morbidity and mortality. The incidence of AP recently increased compared to that traditionally reported in the literature. The purpose of this study was to evaluate the possible association between AP and drugs using the Japanese Adverse Drug Event Report (JADER) database, which is a spontaneous reporting database of adverse drug events. Adverse event reports submitted to the JADER database between 2004 and 2017 were analyzed. Disproportionality analysis was performed by calculating the reporting odds ratio (ROR) with 95% confidence intervals for signal detection. A total of 3,443 reports (0.17% of all adverse events) were identified as drug-induced AP, in which 431 different drugs were involved. Acute pancreatitis was frequently reported in men (58.5%) in their 60s (19.1%); 40.6% developed AP within 4 weeks after the treatment. Among the most frequently reported drugs, signals were detected for prednisolone, ribavirin, sitagliptin, mesalazine, tacrolimus, and l-asparaginase, which are well-known causes of AP. Telaprevir, donepezil, and ustekinumab also generated signals. As for drugs with high RORs, l-asparaginase and alogliptin were noteworthy. Most of the identified drugs were already known to induce AP, but the likelihood of the reporting of AP varied among the drugs. Our results should raise physicians' awareness of drugs associated with AP, but further investigation of these medications is warranted.

Risk Evaluation for Acute Kidney Injury Induced by the Concomitant Use of Valacyclovir, Analgesics, and Renin-Angiotensin System Inhibitors: The Detection of Signals of Drug-Drug Interactions.

Background: Drug-related acute kidney disease is a common side effect of valacyclovir (VACV) treatment. Although analgesics are frequently administered concomitantly with VACV to treat the pain of herpes zoster, the differences between nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen in relation to VACV-related acute kidney injury (AKI) are unclear. The risk for AKI with concomitant use of VACV and renin–angiotensin system (RAS) inhibitors that can cause AKI via a similar mechanism to NSAIDs is also unknown. We therefore evaluated the association between concomitant use of these drugs and VACV-related AKI, which was characterized according to the Japanese Adverse Drug Event Report (JADER) database. Methods: We analyzed data from the JADER database, which is a spontaneous reporting system. The reporting odds ratio was used to evaluate the signals of AKI. Results: A high proportion of VACV-related AKI cases occurred in summer. There was an increase in AKI signal in cases with concomitant use of VACV and NSAIDs, while no increase was detected in cases with concomitant use of VACV and acetaminophen. AKI events in cases with concomitant use of VACV and NSAIDs were more frequent in older and female patients and those with hypertension. Additionally, a signal increase for VACV-related AKI was observed with concomitant use of RAS inhibitors, with or without NSAIDs. Conclusions: We identified a seasonal variation in VACV-related AKI. Additionally, our findings indicate that acetaminophen might represent a safer analgesic than NSAIDs with respect to VACV-related AKI. We also identified candidate risk factors for AKI with concomitant use of NSAIDs, such as older age, female sex, and hypertension. Although further studies are warranted, our findings highlight the need to consider concomitant drug use and seasonal factors that lead to urinary output loss so that VACV-related AKI can be avoided.

Analyses of Respiratory Depression Associated with Opioids in Cancer Patients Based on the Japanese Adverse Drug Event Report Database.

Opioid-induced respiratory depression is a potentially life-threatening adverse drug event. The purpose of this study was to evaluate the incidence of respiratory depression using the Japanese Adverse Drug Event Report (JADER) Database to obtain data to promote proper use of opioids. The JADER database from April 2004 to March 2017 was obtained from the Pharmaceuticals and Medical Devices Agency. We calculated the reporting odds ratios (RORs) of suspected opioids (morphine, fentanyl, oxycodone, tapentadol, methadone, tramadol, pentazocine, buprenorphine, and codeine phosphate hydrate), analyzed the daily dose at first appearance and the time-to-onset profile, and assessed the hazard type using the Weibull shape parameter. ROR analysis detected adverse event signals for all opioids. Morphine showed a large ROR value with statistical significance in elderly (≥70 years old) patients. The median daily doses of oral morphine and oxycodone for inducing respiratory depression were comparably low (30 mg/d as oral morphine equivalent dose), while that of transdermal fentanyl was 120 mg/d (oral morphine equivalent dose). On time-to-onset analysis using the Weibull distribution, those opioids were classified as the early failure type. The median time-to-onset of oral morphine, oral oxycodone and transdermal fentanyl was 5.5, 11 and 12.5 d, respectively, and almost 50% of cases were reported within 30 d. Taken together, our results suggest that it is important to monitor patients carefully for at least the first one week to one month, even if opioids are administered at a relatively low dose, especially in elderly patients administered morphine.

Association of Stevens-Johnson syndrome and toxic epidermal necrolysis with antiepileptic drugs in pediatric patients: Subgroup analysis based on a Japanese spontaneous database.

Antiepileptic drugs (AEDs) are known to cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are severe cutaneous disorders; however, real-world data remain limited, especially on pediatric patients. The objective of this study was to investigate the association of AEDs with SJS and TEN in pediatric patients based on the Japanese Adverse Drug Event Report (JADER) database, which is a spontaneous reporting database. Adverse event reports submitted to the JADER database between 2004 and 2017 were analysed. We performed a retrospective pharmacovigilance disproportionality analysis, calculating the reporting odds ratio (ROR) with a 95% confidence interval (CI). A total of 159605 adverse events were reported in pediatric patients. Significant SJS signals were detected for ethosuximide, phenytoin, phenobarbital, gabapentin, carbamazepine, zonisamide, clonazepam and lamotrigine. TEN signals were detected for ethosuximide, phenytoin, phenobarbital, gabapentin, carbamazepine and zonisamide, but the signal was strongest for gabapentin (ROR, 24.76; 95% CI, 11.4-53.9). Severe cutaneous disorders were associated with multiple AEDs, but individual AEDs were associated with variable signals. These results may be useful for minimizing the risk of SJS or TEN during treatment of children with AEDs.

Granulocyte colony-stimulating factor-associated aortitis in the Japanese Adverse Drug Event Report database

BackgroundGranulocyte colony-stimulating factor (G-CSF) is the standard-of-care therapy for chemotherapy-associated neutropenia in patients with malignancies. Recent case reports have implied that G-CSF treatment may be associated with the development of aortitis, but the precise nature of the relationship is unclear. We investigated the association between G-CSF and risk for aortitis in patients with various malignancies. MethodsWe performed an observational study of 102,014 subjects with malignant neoplasms documented in the Japanese Adverse Drug Event Report (JADER) database between April 2004 and February 2018. The adjusted odds ratio (OR) and 95% confidence interval (CI) for aortitis in patients treated and not treated with G-CSF were estimated using multivariate logistic regression with R software. ResultsAmong the 102,014 subjects, 25 developed aortitis. Of the 3409 and 98,630 subjects treated and not treated with G-CSF, 16 (0.47% [95% CI; 0.27, 0.76]) and 9 (0.01% [0.00, 0.02]) developed aortitis, respectively. Multivariate logistic regression indicated an association between G-CSF and aortitis (adjusted OR 45.87 [19.16, 109.8], p < 0.001). The values for filgrastim, pegfilgrastim, and lenograstim were 0.25% (0.07, 0.63), 1.58% (0.79, 2.81), and 0.24% (0.05, 0.69), respectively. ConclusionG-CSF treatment was associated with a signal of increased risk for aortitis among patients with malignant neoplasms. Three different G-CSF agents were associated with such risk, implying that it is a class effect. However, we do not recommend changing G-CSF prescriptions, because our results may have been influenced by the limitations of the JADER database and because the benefit of G-CSF treatment outweighs the potential risk.

Adverse reaction profiles of hemorrhagic adverse reactions caused by direct oral anticoagulants analyzed using the Food and Drug Administration Adverse Event Reporting System (FAERS) database and the Japanese Adverse Drug Event Report (JADER) database.

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.

Drug-induced hyperglycemia in the Japanese Adverse Drug Event Report database: association of evelolimus use with diabetes.

Some categories of drugs are known for causing hyperglycemia or diabetes such as steroids, antipsychotics, and immunosuppressant. However, there has been little evidence from studies about the proportion of each drug in the context of drug-induced diabetes. In this study, we used data from the Japanese Adverse Drug Event Report (JADER) database, a spontaneous reporting system database maintained at the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan, reported between April 2004 and June 2017. Among 459,250 reports of adverse drug reactions in JADER database, reported instances of the adverse event of hyperglycemia or diabetes were extracted. After the exclusion of anti-diabetes drugs, the drugs frequently implicated in the development of hyperglycemia or diabetes, including prednisolone, tacrolimus, everolimus, ribavirin, quetiapine, aripiprazole, interferon alfa-2b, risperidone, atorvastatin, dexamethasone, ciclosporin, nilotinib, methylprednisolone, or nivolumab, were identified. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, was manifested as the third most frequently associated drug with hyperglycemia or diabetes (340 cases), following prednisolone (694 cases) and tacrolimus (393 cases), and the reporting odds ratio (ROR 8.56, 95% CI 7.65-9.57) of this drug was higher than that of the two aforementioned drugs (ROR 3.96, 95% CI 3.66-4.28 and ROR 3.51, 95% CI 3.17-3.89). These results suggest that there is a potent association of evelolimus with hyperglycemia in clinical practice in Japan.

Evaluation of pregabalin-induced adverse events related to falls using the FDA adverse event reporting system and Japanese Adverse Drug Event Report databases.

Pregabalin is used for neuropathic and postherpetic pain and generalized anxiety. The aim of this study was to obtain the onset profiles of adverse events (AE) related to falls (AEFs) such as "somnolence," "dizziness," "loss of consciousness" and "fall" onset and several clinical factor combinations such as age and administered dose, using spontaneous reporting system (SRS) analysis such as the US Food and Drug Administration Adverse Event Reporting System (FAERS) database and the Japanese Adverse Drug Event Report (JADER) database. We used the reporting odds ratio (ROR) to analyse the association between pregabalin and AEFs. Additionally, we used the time-to-onset analysis. The crude RORs of AEFs such as somnolence and dizziness were higher than one for both the databases. The adjusted RORs for AEFs in the ≥60years age group compared to those in the <60years age group for the FAERS and JADER databases were 1.46 (95% CI=1.39-1.53; P<0.0001) and 2.58 (95% CI=2.06-3.27; P<0.0001), respectively. In the JADER database, the median and quartile range for AEFs with pregabalin, at ≤75 and ≥100mg/d, were 2.0 (0.0-5.0) and 2.0 (1.0-4.3)days, respectively. Additionally, 57.2% of AEFs (four preferred terms) were observed within 2days after administration. This study is the first to evaluate the relationship between pregabalin and AEFs using the SRS analysis strategy. The risk of AEFs in the ≥60years age group might increase compared to that in the <60years age group. AEFs occurred almost within 1week after pregabalin administration, and the median for AEF onset was 2days. Our results show that patients should be closely monitored for AEFs for 1week from the start of pregabalin administration.

Evaluation of medication-related osteonecrosis of the jaw using the Japanese Adverse Drug Event Report database.

BackgroundBisphosphonates (BPs) and denosumab are widely used to treat osteoporosis and complications associated with bone metastases. However, medication-related osteonecrosis of the jaw (MRONJ) is a serious problem.ObjectiveThe objective of this study was to evaluate the frequency, outcome, and characteristics of patients with drug-induced MRONJ.MethodsRetrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database from the Pharmaceuticals and Medical Devices Agency. Adverse event reports submitted to JADER between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) was calculated.ResultsAmong the BPs that cause MRONJ, zoledronate was the most common; therefore, we compared the characteristics of cases of MRONJ induced by zoledronate with those induced by denosumab. Among the 3,875 (68.1% women) cases of MRONJ, zoledronate-related MRONJ accounted for 1,283 (56.0% women) and denosumab-related MRONJ accounted for 322 (55.3% women). MRONJ was more frequent after 70 years of age regardless of the use of either zoledronate or denosumab; onset occurred after 1 year from the denosumab treatment, but it is unknown when onset occurred after zoledronate treatment. The outcomes for MRONJ were poor, with 406 reports on zoledronate (31.6%) and 152 reports on denosumab (47.2%) demonstrating nonrecovery. Zoledronate (ROR: 319.3, 95% CI: 296.0–344.4) had the highest ROR among BP agents. Denosumab had a high ROR (ROR: 155.2, 95% CI: 136.5–176.3). Zoledronate and denosumab were used in similar patient backgrounds, and their use resulted in a similar frequency of MRONJ.ConclusionThe findings of this comprehensive evaluation of MRONJ using the JADER database will be helpful for prescribing medications to elderly patients.

Analysis of fall-related adverse events among older adults using the Japanese Adverse Drug Event Report (JADER) database

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.

Assessment of the Relationship between Hypnotics and Delirium Using the Japanese Adverse Drug Event Report (JADER) Database

The Japanese Adverse Drug Event Report (JADER) database was used to examine the risk of delirium and the time of its onset with various hypnotics, including 10 benzodiazepines (BZDs), 3 non-benzodiazepines (non-BZDs), 1 melatonin receptor agonist (MRTA), and 1 orexin receptor inhibitor (OXRI). Data entered in the JADER database between April 1, 2004 and February 1, 2016 were analyzed. The index for safety signal detection, the reporting odds ratio (ROR), was the odds ratio for adverse drug reaction reporting. The ROR for each drug was calculated; a signal was considered present if the lower bound of the 95% confidence interval of the ROR was greater than 1. The time to onset of delirium was calculated for drugs for which the number of days from the start of drug administration to delirium onset was reported. During the period examined in the analysis, a total of 621114 adverse drug reaction reports were seen, and the total number of delirium reports was 1417 after redundant cases were excluded. A signal was detected for 5 of the 10 BZDs and all 3 non-BZDs, with no signal for the MRTA and the OXRI. The time of delirium onset varied widely even for drugs classified as being in the same action duration group, and no correlation was seen for delirium onset time. The results of this study suggested that delirium risk varies depending on the hypnotic. Thus, hypnotics can be selected according to their delirium risk.