Adverse event profiles of drugs used for treatment of juvenile idiopathic arthritis according to spontaneous reporting system database.

Juvenile idiopathic arthritis (JIA) is a systemic inflammatory disease of childhood onset. The purpose of this study was to clarify the frequency of adverse events caused by drugs used in JIA treatment and characterize their safety profiles using a spontaneous reporting system database. We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports on drugs used for the treatment of JIA and which were submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for reports on each adverse event were calculated. A total of 5,748 reports were identified in the treatment of JIA, in which 35 different drugs were involved. Adverse events by drugs in JIA were frequently reported in females (64.3%) and in those younger than 10 (61.2%). Among the most frequently reported drugs, prednisolone (36.8%) and tocilizumab (36.0%) were predominant. Prednisolone was significantly correlated with hematophagic histiocytosis (ROR, 1.37; 95% CI, 1.18 - 1.61). Tocilizumab was associated with a high ROR for pneumonia (ROR, 8.61: 95% CI, 5.81 - 12.7), a decreased neutrophil count (ROR, 6.1; 95% CI, 4.07 - 9.16), and lymphadenitis (ROR, 8.34; 95% CI, 4.2 - 16.6). Our results revealed the safety profile of drugs for the treatment of JIA patients. It was suggested that there is a diversity in drugs and their strength of association with adverse events in JIA patients. Our results may provide useful information for the treatment of JIA patients, although further research with more data is needed.

Current status of adverse event profile of tacrolimus in patients with solid organ transplantation from a pharmacovigilance study.

OBJECTIVE: The calcineurin inhibitor tacrolimus has been widely used to prevent allograft rejection after transplantation. The purpose of this study was to clarify the adverse events associated with tacrolimus in solid organ transplantation using a spontaneous reporting system database. MATERIALS AND METHODS: We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated. RESULTS: The database comprised 26,620 reports associated with tacrolimus, of which 2,014, 1,988, and 725 reports involved heart, kidney, and liver transplantation, respectively. Infectious disorder was commonly detected in these transplant patients. There was a significant association between tacrolimus use and colon cancer in patients undergoing heart transplantation (ROR: 3.33, 95% CI: 2.18 - 5.08), but not kidney or liver transplantation. Tacrolimus use in those undergoing kidney transplantation is strongly associated with bronchitis (ROR, 8.95; 95% CI, 6.34 - 12.6). A signal for seizure was detected in liver transplant patients with tacrolimus (ROR, 4.12; 95% CI, 1.77 - 9.59). CONCLUSION: It was suggested that there is a diversity in the strength of the association between tacrolimus and adverse events in patients receiving heart, kidney, and liver transplantation. Our results may provide useful information for treatment with tacrolimus, although further research with more data is needed to clarify this.

Safety profiles of new xanthine oxidase inhibitors: A post-marketing study.

INTRODUCTION: The development of new xanthine oxidase (XO) inhibitors, such as febuxostat and topiroxostat, could offer an alternative to treatment with allopurinol. The purpose of this study was to compare safety profiles of new XO inhibitors with allopurinol using a spontaneous reporting system database. MATERIALS AND METHODS: A retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated. RESULTS: Among 7,305 reports of adverse events associated with XO inhibitors, 64.5% involved males, who were frequently in their 70s (25.9%). A large number of skin-related adverse events were detected with the use of allopurinol, but not with febuxostat or topiroxostat. As for individual XO inhibitors, the signal values showing associations between drug reaction with eosinophilia and systemic symptoms (DRESS) and allopurinol, drug-induced liver injury and febuxostat, and blood urea increase and topiroxostat were noteworthy. CONCLUSION: The strength of the associations of XO inhibitors with adverse events is variable, and further studies are required to evaluate the identified signals.

Drug-induced thrombotic microangiopathy using the Japanese pharmacovigilance database.

OBJECTIVE: Thrombotic microangiopathy (TMA), often described as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), is clinically problematic because it is life-threatening. However, up-to-date information on drugs inducing TMA is limited in the real-world setting. The purpose of this study was to clarify drugs associated with TMA using a spontaneous reporting system database. MATERIAL AND METHODS: We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2004 and 2017 were analyzed. The drug-induced TMA, TTP, and HUS signals were estimated using disproportionality analysis with calculation of the reporting odds ratio (ROR) and 95% confidence interval (CI). RESULTS: A total of 3,292 TMA cases were identified. In the overall analysis, approximately half of the TMA cases involved males, and the most patients were in their 60s. Signal scores of TMA were high for ticlopidine hydrochloride (ROR: 16.2, 95% CI: 12.9 - 20.5), busulfan (ROR: 15.2, 95% CI: 11.5 - 20.3), tacrolimus hydrate (ROR: 10.6, 95% CI: 9.59 - 11.8), gemcitabine hydrochloride (ROR: 10.5, 95% CI: 8.96 - 12.2), and cyclosporine (ROR: 8.70, 95% CI: 7.67 - 9.86). As for TTP or HUS, signal scores of TTP and HUS for tacrolimus and cyclosporine were similar; however, those of TTP for ticlopidine and those of HUS for gemcitabine were noteworthy, and other drugs showed varied likelihoods of reporting TTP and HUS. CONCLUSION: Our results should raise physicians' awareness of drugs associated with TMA, but further investigation of these medications is warranted.

Surveillance of drugs that most frequently induce acute kidney injury: A pharmacovigilance approach.

WHAT IS KNOWN AND OBJECTIVE: Acute kidney injury (AKI) often occurs in hospitalized patients, and it is an increasing problem worldwide. Recently, clinical studies have shown that there is a strong association between drug-induced AKI and poor outcomes, including the progression of chronic kidney disease and end-stage renal disease; however, limited data are available on drug-induced AKI. The purpose of this study was to clarify the rank-order of the association of all drugs with AKI using a spontaneous reporting system database. METHODS: We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to Pharmaceuticals and Medical Devices Agency between April 2004 and January 2017 were analysed. RESULTS AND DISCUSSION: Based on 5 195 890 reports of all adverse events, we obtained 12 964 reports of AKI caused by all drugs and calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) for AKI. The most frequently reported drugs were valaciclovir hydrochloride (ROR, 24.88; 95% CI: 23.1-26.8), eldecalcitol (ROR, 14.23; 95% CI, 11.68-17.33), edaravone (ROR, 14.03; 95% CI, 11.76-16.75), acyclovir (ROR, 11.17; 95% CI, 9.55-13.1), piperacillin-tazobactam (ROR, 9.23; 95% CI, 7.72-11.0), and spironolactone (ROR, 7.36; 95% CI, 6.12-8.86). WHAT IS NEW AND CONCLUSION: A comprehensive study using a pharmacovigilance database enabled us to identify the drugs that most frequently induce AKI, raising physicians' awareness of the drugs in use for patients with potentially decreased renal function.

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

WHAT IS KNOWN AND OBJECTIVE: 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. METHODS: 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). RESULTS AND DISCUSSION: A total of 159 605 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). WHAT IS NEW AND CONCLUSION: 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.

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

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Pattern recognition of forced oscillation technique measurement results using deep learning can identify asthmatic patients more accurately than setting reference ranges.

No official clinical reference values have been established for MostGraph, which measures total respiratory resistance and reactance using the forced oscillation technique, complicating result interpretation. This study aimed to establish a reference range for MostGraph measurements and examine its usefulness in discriminating participants with asthma from controls (participants without any respiratory diseases). The study also aimed to investigate the effectiveness of deep learning in discriminating between the two aforementioned groups. To establish reference ranges, the MostGraph measurements of healthy controls (n = 215) were power-transformed to distribute the data more normally. After inverse transformation, the mean ± standard deviation × 2 of the transformed values were used to establish the reference ranges. The number of measured items outside the reference ranges was evaluated to discriminate patients with asthma (n = 941) from controls. Additionally, MostGraph measurements were evaluated using deep learning. Although reference ranges were established, patients with asthma could not be discriminated from controls. However, with deep learning, we could discriminate between the two groups with 78% accuracy. Therefore, deep learning, which considers multiple measurements as a whole, was more effective in interpreting MostGraph measurement results than use of reference ranges, which considers each result individually.

Effect of a 6-week strengthening program on shoulder and scapular-stabilizer strength and scapular kinematics in division I collegiate swimmers.

CONTEXT: Shoulder injuries are common in swimmers because of the demands of the sport. Muscle imbalances frequently exist due to the biomechanics of the sport, which predispose swimmers to injury. To date, an effective shoulder-injury-prevention program for competitive swimmers has not been established. OBJECTIVE: To assess the effectiveness of a 6-wk strengthening and stretching intervention program on improving glenohumeral and scapular muscle strength and scapular kinematics in collegiate swimmers. DESIGN: Randomized control trial. SETTING: University biomechanics research laboratory. PARTICIPANTS: Forty-four Division I collegiate swimmers. INTERVENTIONS: The intervention program was completed 3 times per week for 6 wk. The program included strengthening exercises completed using resistance tubing-scapular retraction (Ts), scapular retraction with upward rotation (Ys), scapular retraction with downward rotation (Ws), shoulder flexion, low rows, throwing acceleration and deceleration, scapular punches, shoulder internal rotation at 90° abduction, and external rotation at 90° abduction-and 2 stretching exercises: corner stretch and sleeper stretch. MAIN OUTCOME MEASUREMENTS: Scapular kinematics and glenohumeral and scapular muscle strength assessed preintervention and postintervention. RESULTS: There were no significant between-groups differences in strength variables at pre/post tests, although shoulder-extension and internal-rotation strength significantly increased in all subjects regardless of group assignment. Scapular kinematic data revealed increased scapular internal rotation, protraction, and elevation in all subjects at posttesting but no significant effect of group on the individual kinematic variables. CONCLUSIONS: The current strengthening and stretching program was not effective in altering strength and scapular kinematic variables but may serve as a framework for future programs. Adding more stretching exercises, eliminating exercises that overlap with weight-room training and swim training, and timing of implementation may yield a more beneficial program for collegiate swimmers.

Drug-induced Neuropsychiatric Adverse Events Using Post-Marketing Surveillance.

BACKGROUND: Several studies reported that abnormal behavior was noted in pediatric patients receiving several drugs, including neuraminidase inhibitors (NIs). However, the information on drugs associated with abnormal behavior in a real-world setting remains limited. The purpose of this study was to clarify the drugs associated with abnormal behavior using a spontaneous reporting system database. METHODS: We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency were analyzed, and the reporting odds ratio at 95% confidence interval were calculated. RESULTS: A total of 1,144 reports of abnormal behavior were identified. The signals were detected through the association of 4 neuraminidase inhibitors (oseltamivir, zanamivir, laninamivir, and peramivir) with the abnormal behaviour. These signals were stronger for oseltamivir than other neuraminidase inhibitors. The signals were also detected for acetaminophen and montelukast. CONCLUSION: Our results should be able to raise physicians' awareness of drugs associated with abnormal behavior, but further investigation of these medications is warranted.

Current Status of Adverse Event Profile of Cyclosporine in Kidney, Stem Cell, and Heart Transplantations Using the Japanese Pharmacovigilance Database.

BACKGROUND: Cyclosporine is widely used to prevent allograft rejection after transplantation. The purpose of this study was to clarify the adverse events profiles associated with cyclosporine in transplant patients using a spontaneous reporting system database. METHODS: Retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database, with the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event. RESULTS: The database comprised 3,327, 958, and 956 reports associated with cyclosporine in the kidney, stem cell, and heart transplant patients, respectively. Infectious and renal disorders were commonly detected in these transplant patients. The signal scores of cyclosporine for toxic nephropathy were noteworthy in the kidney (ROR: 15.1, 95% CI: 11-20.8) and stem cell (ROR, 216; 95% CI, 29.3-1593) transplantation. Cyclosporine in heart transplantation was strongly associated with gastric cancer (ROR, 39.4; 95% CI, 16.7-93.2), but not kidney or stem cell transplantation. CONCLUSION: It was suggested that there is a diversity in the strength of the association between cyclosporine and adverse events in the kidney, stem cell, and heart transplantation. Our results may provide useful information for treatment with cyclosporine, although further research with more data is needed.

Association between a low dose of proton pump inhibitors and kidney function decline in elderly hypertensive patients: a retrospective observational study.

OBJECTIVES: Proton pump inhibitors (PPIs) are widely used for acid suppression therapy. Recently, PPI use was reported to be associated with chronic kidney disease (CKD); however, whether a low dose of PPIs is associated with CKD remains unknown. METHODS: This retrospective observational study included hypertensive patients who visited Kenwakai Hospital between 2017 and 2019. Renal parameters, such as the estimated glomerular filtration rate (eGFR) and serum creatinine (Scr), were extracted from medical records and compared between three years before treatment and the baseline. PPI use was assessed as cumulative exposure for three years. RESULTS: The study population included 152 patients (57.9% men; mean age, 74.5 years). Of those, 35.5% were PPI users (low dose, 17.1%; high dose, 18.4%). A significant decrease in eGFR and an increase in Scr were observed between three years before treatment and the baseline in the high-dose PPI group but not the non-use or low-dose PPI groups. CONCLUSIONS: Our results suggest that a low dose of PPIs may be safe in clinical settings, but further prospective studies are needed to clarify our findings.

Comparison of Adverse Event Profiles of Tumor Necrosis Factor-Alfa Inhibitors: Analysis of a Spontaneous Reporting Database.

INTRODUCTION: Concerns over safety profiles of tumor necrosis factor (TNF)-alfa inhibitors have been raised. The purpose of this study was to clarify the adverse events associated with TNF-alfa inhibitors using a spontaneous reporting system database. MATERIALS AND METHODS: A retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated. RESULTS: Among the 34,031 reports of adverse events associated with TNF-alfa inhibitors, 65.8% were women, who were frequently in their 60s (28.2%). Signals were detected for pneumonia (ROR, 5.36; 95% CI, 5.14-5.6), interstitial lung disease (ROR, 2.04; 95% CI, 1.95-2.15), pneumocystis jirovecii pneumonia (ROR, 11.8; 95% CI, 11.1-12.5), and herpes zoster (ROR, 6.4; 95% CI, 5.92-6.91) for TNF-alfa inhibitors as a class. There was variability in their signal strength across individual TNF-alfa inhibitors. CONCLUSION: The strength of the associations of TNF-alfa inhibitors with adverse events is variable, and further studies are required to evaluate the identified signals.

Improvement of Blood Pressure Control by Adherence Check in Patients With Apparent Treatment-Resistant Hypertension: A Case Series.

Adherence to medications is an important challenge while treating chronic disease such as resistant hypertension, which is defined as uncontrolled blood pressure (BP) despite treatment with more than 3 antihypertensive drugs to achieve targets. It is possible that poor adherence is the most significant contributor to rates of pseudo-resistance among treated hypertensive patients. In this report, we describe 4 patients with apparent treatment-resistant hypertension, who received intervention to promote adherence by pharmacists who set the prescribed medicines in a weekly medication calendar and conducted a weekly pill count. The results showed that the intervention of pharmacists to medication adherence improved systolic BP in patients with apparent treatment-resistant hypertension; however, further controlled trials are required to strengthen supporting evidence.

Novel variants in outer protein surface of flavin-containing monooxygenase 3 found in an Argentinian case with impaired capacity for trimethylamine N-oxygenation.

Flavin-containing monooxygenase 3 (FMO3) is a polymorphic drug metabolizing enzyme associated with the genetic disorder trimethylaminuria. We phenotyped a white Argentinian 11-year-old girl by medical sensory evaluation. After pedigree analysis with her brother and parents, this proband showed to harbor a new allele p.(P73L; E158K; E308G) FMO3 in trans configuration with the second new one p.(F140S) FMO3. Recombinant FMO3 proteins of the wild-type and the novel two variants underwent kinetic analyses of their trimethylamine N-oxygenation activities. P73L; E158K; E308G and F140S FMO3 proteins exhibited moderately and severely decreased trimethylamine N-oxygenation capacities (~50% and ~10% of wild-type FMO3, respectively). Amino acids P73 and F140 were located on the outer surface region in a crystallographic structure recently reported of a FMO3 analog. Changes in these positions would indirectly impact on key FAD-binding residues. This is the first report and characterization of a patient of fish odor syndrome caused by genetic aberrations leading to impaired FMO3-dependent N-oxygenation of trimethylamine found in the Argentinian population. We found novel structural determinants of FAD-binding domains, expanding the list of known disease-causing mutations of FMO3. Our results suggest that individuals homozygous for any of these new variants would develop a severe form of this disorder.

Comparison of Safety Profiles of New Oral Anticoagulants with Warfarin Using the Japanese Spontaneous Reporting Database.

BACKGROUND: The development of new oral anticoagulants (NOACs) has led to an alternative to treatment with warfarin. However, real-world data on comparing safety profiles of NOACs and warfarin are insufficient. PURPOSE: The purpose of this study was to compare safety profiles of warfarin and NOACs using a spontaneous reporting system database. PATIENTS AND METHODS: Adverse event reports spontaneously submitted to the Pharmaceuticals and Medical Devices Agency (Japan) between April 2011 and January 2017 were analysed. We performed disproportionality analyses, calculating the reporting odds ratio (ROR) with 95% confidence interval (CI). RESULTS: The database comprised 3445 reports associated with warfarin, and 14,269 reports with NOACs. A large number of bleeding complications were detected with the use of both warfarin and NOACs. As for cerebral haemorrhage, the signal scores were greater for NOACs as a class (ROR 25.1, 95% CI 23.3-27) and individual agents (edoxaban: ROR 23.6, 95% CI 18.6-29.9; rivaroxaban ROR 23.9, 95% CI 21.4-26.8; apixaban ROR 28.1, 95% CI 25.4-31.1) than for warfarin (ROR 18.9, 95% CI 16.4-21.7), but showed the lowest value for dabigatran (ROR 9.26, 95% CI 7.76-11). Gastrointestinal haemorrhage had stronger signals for NOACs (ROR 19.4, 95% CI 17.8-21.1) than warfarin (ROR 12.2, 95% CI 10.2-14.6). With respect to calciphylaxis, the association with warfarin was noteworthy (ROR 190; 95% CI, 126-287), but no reports were detected involving NOACs. CONCLUSION: Our results may provide useful information for treatment with oral anticoagulants, although further studies with more data are needed.

Adverse Cutaneous Drug Reactions Associated with Old- and New- Generation Antiepileptic Drugs Using the Japanese Pharmacovigilance Database.

BACKGROUND AND OBJECTIVE: Adverse cutaneous drug reactions associated with antiepileptic drugs (AEDs) are a serious problem in the clinical setting. New-generation AEDs have been reported to be better tolerated than old-generation forms; however, information about the risks of adverse cutaneous drug reactions to new-generation AEDs is limited. OBJECTIVE: The purpose of this study was to clarify the association of AEDs with adverse cutaneous drug reactions using a spontaneous reporting database. METHODS: We performed a retrospective pharmacovigilance disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between April 2004 and January 2017 were analyzed. Based on reports of all adverse events, we obtained 4805 reports of adverse cutaneous drug reactions associated with AEDs, and calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) for drug rash, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). RESULTS: Individual AEDs had variable signals for drug rash, SJS, and TEN. The strongest signals were detected for drug rash caused by lamotrigine (ROR 9.18, 95% CI 8.65-9.74), SJS caused by zonisamide (ROR 9.85, 95% CI 8.23-11.78), and TEN caused by phenobarbital (ROR 14.08, 95% CI 11.28-17.57). CONCLUSION: There are clear differences in the risk of cutaneous reactions among AEDs, and further studies are needed to confirm these findings.

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

BACKGROUND: Bisphosphonates (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. OBJECTIVE: The objective of this study was to evaluate the frequency, outcome, and characteristics of patients with drug-induced MRONJ. METHODS: Retrospective 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. RESULTS: Among 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. CONCLUSION: The findings of this comprehensive evaluation of MRONJ using the JADER database will be helpful for prescribing medications to elderly patients.

Drug-induced tubulointerstitial nephritis in a retrospective study using spontaneous reporting system database.

INTRODUCTION: Tubulointerstitial nephritis (TIN) is a problem in clinical settings because drug therapy is the cause in most cases. Patients often present with nonspecific symptoms, which can lead to delays in the diagnosis and treatment of the disease. The purpose of this study was to clarify the rank-order of the association of TIN with the causative drugs using a spontaneous reporting system database. MATERIALS AND METHODS: Data were extracted from the Japanese Adverse Drug Event Report database of the Pharmaceuticals and Medical Devices Agency (Japan). Based on 5,195,890 reports of all adverse reactions, we obtained 3,088 reports of TIN caused by all drugs and calculated the reporting odds ratio (ROR) and 95% CI for TIN. RESULTS: The 5 drugs with the highest RORs were gliclazide (ROR, 30.5; 95% CI, 17.4-53.2), tosufloxacin tosilate hydrate (ROR, 29.5; 95% CI, 21.3-41.0), piperacillin-tazobactam (ROR, 24.3; 95% CI, 19.4-30.5), cefteram pivoxil (ROR, 23.5; 95% CI, 12.5-44.2), and mefenamic acid (ROR, 22.5; 95% CI, 13.4-37.7). No sex-related difference was observed in drug-induced TIN. Most of the reports about TIN onset following the administration of culprit drugs were recorded within 12 weeks. CONCLUSION: Based on the results, a comprehensive study using a pharmacovigilance database enabled us to identify the dugs that most frequently induced TIN, so these drugs should be used carefully in clinical practice to avoid TIN.

Differential profiles of adverse events associated with mycophenolate mofetil between adult and pediatric renal transplant patients.

OBJECTIVE: Immunosuppressive regimens after renal transplantation usually include a combination of calcineurin inhibitors, corticosteroids, and a proliferation inhibitor, either azathioprine or mycophenolate mofetil (MMF), to prevent rejection and maintain graft function. MMF has a stronger immunosuppressive effect than does azathioprine. This study aimed to examine MMF-associated adverse events in renal transplant patients. METHODS: Retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report database. RESULTS: A total of 11,594 adverse drug events were reported in renal transplant patients; 10,272 (88.6%) involved adults and 1322 (11.4%) involved children. In adult patients, the most frequent adverse events induced by MMF were cytomegalovirus infection (272 reports), urinary tract infection (69 reports), and polyomavirus-associated nephropathy (61 reports). Among adverse events, the highest reporting odds ratio (ROR) was found for cytomegalovirus infection (ROR, 1.58; 95% confidence interval, 1.36-1.83). In pediatric patients, the rank order for MMF-associated adverse events was cytomegalovirus infection (27 reports), bronchitis (23 reports), and cytomegalovirus viremia (19 reports), but these adverse events were not detected as a signal. CONCLUSION: Our results show the safety profile of MMF in pediatric renal transplant patients. These findings can be used to update information used for prescriptions for pediatric patients.