Relationship Between Melatonin Receptor Agonists and Parkinson's Disease.

Parkinson's disease affects millions of people worldwide, and without significant progress in disease prevention and treatment, its incidence and prevalence could increase by more than 30% by 2030. Researchers have focused on targeting sleep and the circadian system as a novel treatment strategy for Parkinson's disease. This study investigated the association between melatonin receptor agonists and Parkinson's disease, using the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS). The target drugs were melatonin receptor agonists including ramelteon, tasimelteon, and agomelatine. Parkinson's disease cases were defined according to the Medical Dictionary for Regulatory Activities (MedDRA) 25.0; Standardized MedDRA Query (SMQ) using both the "narrow" and "broad" preferred terms (PTs) associated with Parkinson's disease. The association between melatonin receptor agonists (ramelteon, tasimelteon, and agomelatine) and Parkinson's disease was evaluated by the reporting odds ratio. Upon analyzing the data from all patients registered in the FAERS, ramelteon (ROR: 0.66, 95% confidence interval [95% CI]: 0.51-0.84) and tasimelteon (ROR: 0.49, 95% CI: 0.38-0.62) showed negative correlations with Parkinson's disease. Conversely, only agomelatine was positively correlated with Parkinson's disease (ROR: 2.63, 95% CI: 2.04-3.40). These results suggest that among the melatonin receptor agonists, ramelteon and tasimelteon are negatively correlated with Parkinson's disease. In contrast, agomelatine was shown to be positively correlated with Parkinson's disease. These results should be used in research to develop drugs for the treatment of Parkinson's disease, fully considering the limitations of the spontaneous reporting system.

Autoimmune disorders reported following COVID-19 vaccination: A disproportionality analysis using the WHO database.

PURPOSE: Owing to adverse event following immunization (AEFI) related to autoimmune disorders and coronavirus disease 2019 (COVID-19) vaccines sharing common biological mechanisms, identifying the risk of AEFIs associated with COVID-19 vaccines remains a critical unmet need. We aimed to assess the potential safety signals for 16 AEFIs and explore co-reported adverse events (AEs) and drugs using the global database of the World Health Organization, VigiBase. METHODS: We assessed the occurrence of 16 AEFIs following COVID-19 vaccination through the Standardized MedDRA Queries group "Immune-mediated/Autoimmune Disorders" from MedDRA and performed a disproportionality analysis using reporting odds ratio (ROR) and information component (IC) with 95% confidence intervals (CIs). RESULTS: We identified 25,219 events associated with COVID-19 vaccines in VigiBase. Although rare, we detected four potential safety signals related to autoimmune disorders following COVID-19 vaccination, including ankylosing spondylitis or psoriatic arthritis (ROR 1.86; 95% CI 1.53-2.27), inflammatory bowel disease (ROR 1.77; 95% CI 1.60-1.96), polymyalgia rheumatica (ROR 1.42; 95% CI 1.30-1.55), and thyroiditis (ROR 1.40; 95% CI 1.30-1.50), with positive IC025 values. The top co-reported AEs were musculoskeletal disorders, and immunosuppressants were the most representative co-reported drugs. CONCLUSION: In addressing the imperative to comprehend AEFI related to autoimmune disorders following COVID-19 vaccination, our study identified four potential safety signals. Thus, our research underscores the importance of proactive safety monitoring for the identification of the four AEFIs following COVID-19 vaccination, considering the associated advantages.

Antipsychotics and obsessive-compulsive disorder/obsessive-compulsive symptoms: A pharmacovigilance study of the FDA adverse event reporting system.

OBJECTIVE: Antipsychotics have conflicting data with respect to obsessive-compulsive disorder/symptoms (OCD/OCS), with some reporting causality and some reporting treatment benefits. This pharmacovigilance study aimed to investigate reporting of OCD/OCS in association with the use of antipsychotics in comparison to one another, as well as treatment failure using data derived from the FDA Adverse Event Reporting System (FAERS). METHODS: Data from January 1st, 2010 to December 31st, 2020 on suspected adverse drug reactions (ADRs) including OCD/OCS was obtained. The information component (IC) was used to determine a disproportionality signal, and reporting odds ratio (ROR) calculations were performed via intra-class analyses to discern differences between the evaluated antipsychotics. RESULTS: A total of 1454 OCD/OCS cases were utilized in IC and ROR calculations and 385,972 suspected ADRs were used as non-cases. A significant disproportionality signal was seen with all second generation antipsychotics. Relative to other antipsychotics, only aripiprazole had a significant ROR of 23.87 (95% CI: 21.01-27.13; p < 0.0001). The ROR for antipsychotic treatment failure in those with OCD/OCS was highest with aripiprazole, and lowest with risperidone and quetiapine. Sensitivity analyses were largely in favor of the primary findings. Our analysis appears to implicate the 5-HT1A receptor or an imbalance between this receptor and the D2 -receptor in antipsychotic treatment-emergent OCD/OCS. CONCLUSIONS: In contrast to prior reports noting clozapine as the antipsychotic most commonly associated with de novo or exacerbated OCD/OCS, this pharmacovigilance study found aripiprazole was most frequently reported for this adverse effect. While these findings from FAERS offer a unique perspective on OCD/OCS with different antipsychotic agents, due to the inherent limitations of pharmacovigilance studies they should ideally be validated through alternative prospective research studies involving direct comparisons of antipsychotic agents.

An exploratory study evaluating the 30 medications most commonly associated with headaches in the FDA Adverse Event Reporting System.

OBJECTIVE: This project seeks to identify the top 30 drugs most commonly associated with headaches in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), as well as their respective reporting odds ratios (RORs). BACKGROUND: Headache secondary to medication use is a well-known entity. However, which medications are most likely to cause headaches on a global scale is unknown. METHODS: We extracted case identifiers, adverse events, and attributed medications for entries in the FAERS database from July 1, 2018, to March 31, 2020. Entries were split into two datasets based on whether or they contained the word "headache(s)." Non-medication words were then excluded. The medications most commonly associated with headaches were then identified. RESULTS: We extracted 2,673,081 entries, of which 86,086 contain the word "headache(s)." The 30 most frequently appearing medications were then ranked by ROR values with associated 95% confidence intervals. The three medications with the greatest association with headaches were selexipag (ROR 16.7, 95% CI 15.8-17.7), epoprostenol (ROR 11.7, 95% CI 10.8-12.7), and glecaprevir (ROR 8.7, 95% CI 8.3-9.2). Immunosuppressants, antivirals, as well as pulmonary hypertension medication classes were most commonly associated with headache. CONCLUSION: Our study offers a potential list of the medication classes commonly associated with iatrogenic headaches.

Analysis of Appendicitis Cases in the Japanese Adverse Drug Event Report (JADER) Database.

Appendicitis is one of the most common abdominal surgical emergencies worldwide; however, its causes remain poorly understood. The Japanese Adverse Drug Event Report (JADER) database is a spontaneous reporting system (SRS) that can be utilized to analyze the safety signals of adverse events. In this study, we investigated the association between drug use and the onset of appendicitis using the JADER database. We first used the reporting odds ratio (ROR) as the signal and found signals for appendicitis, perforated appendicitis, and complicated appendicitis for 23, 9, and 1 drug, respectively. To investigate the level of hazard over time in drug-associated appendicitis, the Weibull shape parameter ß was calculated using a Weibull plot, which revealed drug-dependent patterns for changes in the risk of appendicitis over time for the eight drugs. Furthermore, logistic regression analysis was performed to account for the influence of age, sex, and primary disease, and a significant association was detected between two drugs and appendicitis. Several types of drugs, such as antitumor, antirheumatic, and anti-inflammatory drugs, were included in our analyses; however, only clozapine, which is used for patients with schizophrenia, was commonly identified in these analyses. The resulting data suggest that certain drugs may be associated with appendicitis and may require adequate attention.

COVID-19 mRNA vaccination is associated with IgA nephropathy: an analysis of the Japanese adverse drug event report database.

Purpose: Coronavirus disease 2019 (COVID-19) mRNA vaccines are used worldwide to prevent severe symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. IgA nephropathy (IgAN) is the most common form of glomerular injury after COVID-19 vaccination; however, because of the low frequency of such events, only a few reports have been published. A large pharmacovigilance database of real-world spontaneous adverse event (AE) reports is essential for evaluating the drug-associated safety signals regarding rare AEs. Herein, we aimed to investigate the frequency of IgAN after the COVID-19 vaccination, using the Japanese Adverse Drug Event Report (JADER) database. Methods: Data on drug-associated AEs reported between April 2004 and May 2022 were obtained from the JADER database on the Pharmaceuticals and Medical Devices Agency website. To evaluate the safety signals for the targeted AEs, reporting odds ratios (RORs), information components (ICs), and their 95% confidence intervals (CIs) were calculated using two-by-two contingency tables. Results: A total of 697,885 cases were included in the analysis. Safety signals were detected for IgAN (ROR: 6.49, 95% CI: 4.38-9.61; IC: 2.27, 95% CI: 1.70-2.83). Of 30 cases for IgAN associated with COVID-19 mRNA vaccines, 16 had information available on time to onset. Of the 16 cases, 11 occurred ≤2 days after vaccination, and two occurred >28 days after vaccination. Conclusion: These results suggest that, compared with other drugs, COVID-19 vaccination is associated with a higher frequency of IgAN. Monitoring of gross hematuria following COVID-19 vaccination should be needed.

Numbers of spontaneous reports: How to use and interpret?

Due to the high intensity of the COVID-19 vaccination campaigns and heightened attention for safety issues, the number of spontaneous reports has surged. In the Netherlands, pharmacovigilance centre Lareb has received more than 100 000 reports on adverse events following immunization (AEFI) associated with Covid-19 vaccination. It is tempting to interpret absolute numbers of reports of AEFIs in signal detection. Signal detection of spontaneously reported adverse drug reactions has its origin in case-by-case analysis, where all case reports are assessed by clinically qualified assessors. The concept of clinical review of cases-even if only a few per country-followed by sharing concerns of suspicions of potential adverse reactions again proved the strength of the system. Disproportionality analysis can be useful in signal identification, and comparing reported cases with expected based on background incidence can be useful to support signal detection. However, they cannot be used without an in-depth analysis of the underlying clinical data and pharmacological mechanism. This in-depth analysis has been performed, and is ongoing, for the signal of vaccine-induced immune thrombotic thrombocytopenia (VITT) in relation to the AstraZeneca and Janssen Covid-19 vaccines. Although not frequency or incidence rates, reporting rates can provide an impression of the occurrence of the event. But the unknown underreporting should also be part of this context. To quantify the incidence rates, follow-up epidemiological studies are needed.

Adverse event profiles of PCSK9 inhibitors alirocumab and evolocumab: Data mining of the FDA adverse event reporting system.

BACKGROUND: Proprotein convertase subtilisin/kexin type (PCSK9) inhibitor is a new drug class approved for treating dyslipidemias. Herein, we aimed to investigate the safety profiles of PCSK9 inhibitors (alirocumab and evolocumab) using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: We included adverse event (AE) reports regarding alirocumab and evolocumab submitted to the FAERs between 2015Q3 to 2021Q1. Disproportionality analyses, including reporting odds ratio (ROR), were performed to detect risk signals from the FAERs data to identify potential drug-AE associations. A signal was considered when the lower limit of the 95% confidence interval of ROR exceeded 1 and ≥3 AEs were reported. The definition relied on system organ class and preferred terms established by the Medical Dictionary for Regulatory Activities. RESULTS: The FAERS database documented 31 475 reports regarding PCSK9 inhibitors (alirocumab and evolocumab) from July 1, 2015, to March 31, 2021. Although some differences were detected, alirocumab and evolocumab shared considerably similar safety profiles. The most significant RORs and most common reports were injection-site reactions (eg, injection-site pain, bruising, haemorrhage, erythema), muscle-related AEs (eg, myalgia, back pain, arthralgia, muscle spasms), influenza-like illness, pain and headache. CONCLUSION: Data mining of the FAERs is useful for examining PCSK9 inhibitor-induced AEs. Herein, our findings were largely consistent with clinical experience and could help clinicians improve the safety of PCSK9 inhibitors in clinical practice.

Analysis of adverse drug events in pulmonary Mycobacterium avium complex disease using spontaneous reporting system.

BACKGROUND: In Japan, Mycobacterium avium complex lung disease (MAC-LD) is the most common in nontuberculous mycobacterial lung disease. Patients often experience adverse events, resulting in the discontinuation of treatment, which causes treatment failure. The JADER (Japanese Adverse Drug Event Report) database is a database of adverse events that allows us to collect real-world data on adverse events. We can collect large-scale data cost-effectively and detect signals of potential adverse events such as reporting odds ratio (ROR) by using spontaneous reporting systems. In this study, we aimed to elucidate the adverse events of clarithromycin (CAM), ethambutol (EB), and rifampicin (RFP) using the JADER database. METHODS: We included cases of MAC-LD between April 2004 and June 2017. We investigated sex, age, and medications that may have caused the adverse events, outcomes, and time of onset. We calculated the safety signal index as the ROR. Time-to-event analysis was performed using the Weibull distribution. RESULTS: The total number of adverse events of CAM, EB, and RFP was 2780, with 806 patients. In the overall adverse events, hematologic and lymphatic disorders were the most common adverse events, with 17.3%, followed by eye disorders (16.6%), and hepatobiliary disorders (14.0%). The outcomes were as follows: recovery, 40.0%; remission, 27.1%; non-recovery, 11.2%; and death, 7.1%. Regarding the most common onset time of CAM, EB, and RFP was within 120 days at 40%, 181-300 days at 43.6%, and within 120 days at 88.5%. For CAM, the RORs of infections and infestations, hepatobiliary system disorders, and immune system disorders were 4.13 (95% confidence interval [CI], 2.3-7.44), 2.61 (95% CI, 1.39-4.91), and 2.38 (95% CI, 1.04-5.44). For EB, the ROR of eye disorders was 215.79 (95% CI, 132.62-351.12). For RFP, the RORs of renal and urinary tract disorders and investigations were 7.03 (95% CI, 3.35-14.77) and 6.99 (95% CI, 3.22-15.18). The ß value of EB was 2.07 (95% CI, 1.48-2.76), which was classified as a wear-out failure type. CONCLUSIONS: For MAC-LD, the adverse event which has the highest ROR is infections and infestations in CAM, eye disorders in EB, renal and urinary tract disorders in RFP. Adverse events of EB occur after 180 days, whereas the adverse events of CAM and RFP occur early in the course of treatment.

Antibacterial-associated acute kidney injury among older adults: A post-marketing surveillance study using the FDA adverse events reporting system.

PURPOSE: Antibacterials induce a differential risk of acute kidney injury (AKI) in older adults. This study investigated the reporting risk of AKI associated with antibacterials using the individual case safety reports (ICSRs) submitted to the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: A case/non-case method was used to assess AKI risk associated with antibacterials between 1 January 2000 and 30 September 2021. Cases were ICSRs for antibacterials with AKI as preferred terms included in the Medical Dictionary of Regulatory Activities (MedDRA) system organ classes 'Renal and urinary disorders' disorders. The analyses were completed on a de-duplicated data set containing only the recent version of the ICSR. Signals were defined by a lower 95% confidence interval (CI) of reporting odds ratio (ROR) ≥ 2, proportional reporting ratio (PRR) ≥ 2, information component (IC) > 0, Empirical Bayes Geometric Mean (EBGM) > 1 and reports ≥4. Sensitivity analyses were conducted a priori to assess the robustness of signals. RESULTS: A total of 3 680 621 reports on ADEs were retrieved from FAERS over the study period, of which 92 194 were antibacterial reports. Gentamicin, sulfamethoxazole, trimethoprim and vancomycin consistently gave strong signals of disproportionality on all four disproportionality measures and across the different sensitivity analyses: gentamicin (ROR = 2.95[2.51-3.46]), sulfamethoxazole (ROR = 2.97[2.68-3.29]), trimethoprim (ROR = 2.81[2.29-3.46]) and vancomycin (ROR = 3.35[3.08-3.64]). CONCLUSION: Signals for gentamicin, sulfamethoxazole, trimethoprim and vancomycin were confirmed by using antibacterials as a comparator, adjusting for drug-related competition bias and event-related competition bias.

Signal Detection of Acute Renal Failure Following the Use of SGLT-2 Inhibitors: Stratified Analysis and Time Trend Analysis in Japan and the United States.

The results of previous studies that have used databases to investigate the associations between sodium-glucose-cotransporter-2 (SGLT-2) inhibitors and acute renal failure (ARF) have differed, and the impact of biases such as the Weber effect and stimulated reporting has not been fully examined. This study aimed to determine the associations between SGLT-2 inhibitors and ARF using signal detection, the effects on signals of regulatory agency alerts for ARF, and the publication of prominent studies by measuring changes in signals over time. Data registered in the Food and Drug Administration's Adverse Event Reporting System from January 2013 to March 2020 were downloaded, signals were detected, and reporting odds ratios (RORs) were calculated for each country of occurrence (Japan/the United States). Quarterly changes in the number of reports and RORs were examined. Although an association between SGLT-2 inhibitor use and ARF was suggested in the United States, this study did not suggest such an association in Japan. The number of reports and RORs fluctuated when regulatory alerts and prominent studies were published, and events affecting the number of reports and RORs varied by country. This study revealed the difference in the associations between SGLT-2i and ARF in Japan and the United States. Additionally, the signal was identified to be influenced by alerts and the publication of studies. Therefore, these results should be interpreted cautiously as there could be a possibility of overestimation due to alert biases and publication of studies.

Analysis of the US FDA adverse event reporting system to identify adverse cardiac events associated with hydroxychloroquine in older adults.

PURPOSE: The purpose of this study is to analyze the US FDA Adverse Event Reporting System (FAERS) to identify adverse cardiac events of hydroxychloroquine in older adults. METHOD: A case/non-case method was used to determine adverse events associated with hydroxychloroquine as the primary suspect drug between January 1, 2004, and December 31, 2019, for older adults (≥65 years). Adverse events are preferred terms (PTs) defined in MedDRA. We used frequentist approaches, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR) to measure disproportionality. We used Bayesian approaches to derive information component (IC) value and Empirical Bayesian Geometric Mean (EBGM) score. Signals were defined as the number of reports > 3 and the lower limit of 95% confidence intervals (CI) of ROR ≥ 2, PRR ≥ 2, IC > 0, EBGM > 1. RESULTS: We identified 334 adverse cardiac events comprising 71 different MedDRA PTs from 2004 to 2019 for hydroxychloroquine in older adults. Strong disproportionality signals were noted for "Restrictive cardiomyopathy" (ROR = 272.43 (138.09-537.47); EBGM = 149.78 (77.34-264.67), "Right ventricular hypertrophy" (219.49 (85.32-564.70); 102.74 (39.67-222.81), "Cardiac septal hypertrophy" (226.77 (78.65-653.80); 93.82 (32.19-219.81), "Myocardial fibrosis" (57.29 (21.06-155.85); 42.99 (14.74-100.75), and "Cardiotoxicity" (43.90 (26.66-72.27); 40.28 (24.02-63.72). CONCLUSIONS: The risk of cardiomyopathy and myocardial disorders is high following exposure to hydroxychloroquine in older adults. Due to the current lack of safety data from randomized controlled trials as well as large observational studies to confirm the risk of adverse cardiac events associated with hydroxychloroquine, findings from analyses of post-marketing data may serve as interim guidance.

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.

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.

Adverse drug event profile associated with pregabalin among patients with and without cancer: analysis of a spontaneous reporting database.

WHAT IS KNOWN AND OBJECTIVE: Pregabalin is used for the relief of neuropathic pain in patients with and without cancer. However, no report has examined whether there is a difference in the adverse drug event (ADE) profile of pregabalin in each context. We aimed to establish whether pregabalin's ADE profile was different between patients with and without cancer. This study was based on the Japanese Adverse Drug Event Report (JADER) database, which is a spontaneous reporting database. METHOD: Reports obtained from the JADER database were analysed from April 2004 to December 2016 for ADEs, using reporting odds ratios (RORs), a method of disproportionality analysis. We evaluated the association between the RORs and ADEs of pregabalin and compared the age, dosage and time at which ADEs occurred in patients with and without cancer. The primary outcome was RORs. Secondary outcomes were expression age and time-to-onset of ADE among patients with and without cancer. RESULTS AND DISCUSSION: In total, 426 216 reports from the JADER database were analysed. The major side effects associated with pregabalin among both patient groups were interstitial pneumonia, renal failure, liver failure, altered consciousness, heart failure and rhabdomyolysis. The pregabalin dose was significantly higher in patients with cancer than in those without cancer. Furthermore, the times to reporting of interstitial pneumonia, altered consciousness and liver failure were significantly shorter in patients with cancer than in those without cancer. WHAT IS NEW AND CONCLUSION: The ADE profiles of pregabalin were broadly similar among patients with and without cancer, but time-to-onset and type of some ADEs may be different.

[Case-non case studies: Principles, methods, bias and interpretation]. / Les études cas­non cas : principe, méthodes, biais et interprétations.

Case-non case studies belongs to the methods assessing drug safety by analyzing the disproportionality of notifications of adverse drug reactions in pharmacovigilance databases. Used for the first time in the 1980s, the last few decades have seen a significant increase in the use of this design. The principle of the case-non case study is to compare drug exposure in cases of a studied adverse reaction with that of cases of other reported adverse reactions and called "non cases". Results are presented in the form of a reporting odds ratio (ROR), the interpretation of which makes it possible to identify drug safety signals. This article describes the principle of the case-non case study, the method of calculating the ROR and its confidence interval, the different modalities of analysis and how to interpret its results with regard to the advantages and limitations of this design.

Blood Pressure Elevation Associated with Topical Prostaglandin F2α Analogs: An Analysis of the Different Spontaneous Adverse Event Report Databases.

Topical prostaglandin F2α (PGF2α) analogs are widely used as the first line of therapy for glaucoma. Systemic PGF2α is suggested to increase blood pressure. Some ophthalmic formulations with ß-receptor blocking or α-receptor stimulating actions are reported to cause systemic adverse events such as a decrease in heart rate and blood pressure. The objective of this study was to evaluate the association between topical PGF2α analogs and blood pressure elevation. We analyzed the reports obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database from the first quarter of 2004 until the end of 2015 and the Japanese Adverse Drug Event Report (JADER) database from April 2004 to January 2016 for signal detection using reporting odds ratio (ROR), a method of disproportionality analyses. Signals are considered significant if the ROR estimates and lower bound of the 95% confidence interval (CI) exceed 1. Preferred terms in the Medical Dictionary for Regulatory Activities were utilized to define blood pressure elevation. A total of 6156081 reports from the FAERS and 351226 reports from the JADER were analyzed. The significant RORs with 95% CI were calculated to be 1.82 (95% CI: 1.55-2.13) for bimatoprost, 1.69 (95% CI: 1.53-1.85) for latanoprost, and 2.17 (95% CI: 1.82-2.59) for travoprost from the FAERS. From the JADER, 5.01 (95% CI: 1.59-15.8) was calculated for bimatoprost and 8.02 (95% CI: 2.94-21.9) for tafluprost. The resulting data suggest the necessity for further clinical research on blood pressure elevation associated with topical PGF2α analogs and close monitoring.

Analysis of Adverse Drug Reaction Risk in Elderly Patients Using the Japanese Adverse Drug Event Report (JADER) Database.

In general, the risk of adverse drug reactions (ADRs) is higher in elderly patients than in younger patients. In this study, we performed a comprehensive assessment of the risks of possible drug-ADR combinations in elderly patients using the Japanese Adverse Drug Event Report (JADER) database of the Pharmaceutical and Medical Devices Agency (PMDA, Japan) using the reporting odds ratio (ROR) as an index. Data recorded from April 2004 to September 2015 in the JADER database were downloaded from the PMDA website. The patients were classified into younger (≤69 years old) and elderly (≥70 years old) groups. The ROR and 95% confidence interval (CI) were calculated for all combinations of drugs and ADRs for which there were three or more reports in the database, focusing particularly on the combinations where more than 100 cases had been reported in elderly and younger patients. The most frequently reported drug-ADR combination was methotrexate with interstitial lung disease (646 cases). The combination with the highest ROR was methotrexate with lymphoproliferative disorder (ROR: 484.6, 95% CI: 334.1-702.9). In total, 27 drug-ADR combinations were found to have high risk in elderly patients. In conclusion, the findings of this comprehensive assessment of drug-ADR combinations using the JADER database will be valuable for updating the ADR risks for elderly patients in clinical setting.