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It's well known that sex is a risk factor for the occurrence of adverse events (AEs), most of which have found sex differences. Real-world data studies on the sex differences of fall-risk-increasing drugs (FRIDs) are few and far between, with most small-scale retrospective studies based on FRID classes. To establish a list of FRIDs and describe their sex differences, we used preferred terms from the Medical Dictionary for Regulatory Activities to search for AEs in the FDA Adverse Event Reporting System (FAERS), and then perform disproportionality analyses and female/male ratio analyses. During January 2004 to March 2023, 101,746 fall-related AEs were reported in FAERS from patients aged 50 to 100, with 68,492 (67.3%) females and 32,547 (32.0%) males. We found 261 signals for females while 284 for males. For females, the top 3 signals with the highest reporting odds ratio (ROR) were anethole trithione, clopenthixol, nikethamide (ROR: 388.88, 212.10, 113.94), while the top 3 signals with the highest lower limit of information component (IC025) were nikethamide, anethole trithione, benzbromarone (IC025: 3.91, 3.15, 2.49). For males, the top 3 signals with the highest ROR were fluprednidene acetate, potassium hydroxide, ketazolam (ROR: 216.86, 108.43, 108.43), while the top 3 signals with the highest IC025 were clomethiazole, piribedil, melperone (IC025: 3.31, 3.24, 2.99). Moreover, among the 119 shared signals found between males and females, 33 were positively correlated with falls in females and 38 with falls in males. Signals showing significant sex differences were mainly concentrated on agents of the immune, nervous, musculo-skeletal, and cardiovascular systems. We offered a series of FRIDs and suggested their sex differences in falls through the FAERS. In the future, it is essential to balance the inclusion of women and men, and analyse sex-stratified for FRIDs. [ABSTRACT FROM AUTHOR]

Abstract It’s well known that sex is a risk factor for the occurrence of adverse events (AEs), most of which have found sex differences. Real-world data studies on the sex differences of fall-risk-increasing drugs (FRIDs) are few and far between, with most small-scale retrospective studies based on FRID classes. To establish a list of FRIDs and describe their sex differences, we used preferred terms from the Medical Dictionary for Regulatory Activities to search for AEs in the FDA Adverse Event Reporting System (FAERS), and then perform disproportionality analyses and female/male ratio analyses. During January 2004 to March 2023, 101,746 fall-related AEs were reported in FAERS from patients aged 50 to 100, with 68,492 (67.3%) females and 32,547 (32.0%) males. We found 261 signals for females while 284 for males. For females, the top 3 signals with the highest reporting odds ratio (ROR) were anethole trithione, clopenthixol, nikethamide (ROR: 388.88, 212.10, 113.94), while the top 3 signals with the highest lower limit of information component (IC025) were nikethamide, anethole trithione, benzbromarone (IC025: 3.91, 3.15, 2.49). For males, the top 3 signals with the highest ROR were fluprednidene acetate, potassium hydroxide, ketazolam (ROR: 216.86, 108.43, 108.43), while the top 3 signals with the highest IC025 were clomethiazole, piribedil, melperone (IC025: 3.31, 3.24, 2.99). Moreover, among the 119 shared signals found between males and females, 33 were positively correlated with falls in females and 38 with falls in males. Signals showing significant sex differences were mainly concentrated on agents of the immune, nervous, musculo-skeletal, and cardiovascular systems. We offered a series of FRIDs and suggested their sex differences in falls through the FAERS. In the future, it is essential to balance the inclusion of women and men, and analyse sex-stratified for FRIDs.

Mariko Kozaru, Hiroko Kambara, Akari Higuchi, Tatsuki Kagatsume, Keiko Hosohata Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-1094, JapanCorrespondence: Keiko Hosohata, Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan, Tel +81-72-690-1271, Fax +81-72-690-362, Email keiko.hosohata@ompu.ac.jpBackground: The P2Y12 receptor inhibitors clopidogrel and prasugrel are widely used. Clopidogrel and prasugrel have different metabolic pathways, but whether their adverse event (AE) profiles differ significantly is unclear.Objective: This study aimed to compare the possible AEs induced by clopidogrel and prasugrel and to assess the rank-order of their AEs submitted to a spontaneous reporting database.Materials and Methods: Data were extracted from the Japanese Adverse Drug Event Report database (JADER). Reports of AEs associated with clopidogrel and prasugrel were analyzed to calculate the reporting odds ratios (RORs) and 95% confidence intervals (CIs).Results: Based on 5869 reports for clopidogrel (69.6%, men) and 513 reports for prasugrel (74.1%, men), 703 and 135 different AEs were identified, respectively. Bleeding complications including hemorrhage were commonly reported for both clopidogrel and prasugrel. As for AEs related to clopidogrel, unexpected AEs such as interstitial lung disease (227 reports; ROR, 1.77; 95% CI, 1.49– 2.10), abnormal hepatic function (137 reports; ROR, 1.27; 95% CI, 1.07– 1.51), and hepatocellular injury (96 reports; ROR, 120.0; 95% CI, 94.9– 151.8) ranked at relatively high positions based on the number of occurrences, unlike prasugrel.Conclusion: This analysis of the national pharmacovigilance database highlights distinct AE profiles for clopidogrel and prasugrel. Unexpected AEs associated with clopidogrel were identified, providing valuable insights for clinical monitoring and patient safety.Keywords: P2Y12 platelet inhibitor, pharmacovigilance, adverse events, reporting odds ratio, signal detection, spontaneous reporting system

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. [ABSTRACT FROM AUTHOR]

Abstract Lacosamide was the first approved third-generation antiepileptic drug. However, real-world data regarding its adverse cardiac reactions in large samples still need to be completed. We evaluated the cardiac safety profile of lacosamide using the Food and Drug Administration Adverse Event Reporting System (FAERS). We performed disproportionality analysis computing reporting odds ratio (ROR) as a quantitative metric to assess the signal of lacosamide-related cardiac adverse events (AEs) from 2013 Q1 to 2022 Q4. The signal was considered significant when the lower limit of the 95% confidence interval (CI) of the ROR exceeded 1, and ≥ 5 AEs were reported. Serious and nonserious cases were compared by statistical analysis, and signals were further prioritized using a rating scale. A total of 812 cardiac AEs associated with lacosamide were identified, and 92 signals were detected, of which 17 AEs were significantly associated signals. The median time-to-onset (TTO) for moderate priority signals was 10 days, whereas for weak priority signals, it was 54 days. Notably, all cardiac AEs exhibited an early failing pattern, indicating the risk gradually decreasing. Based on the comprehensive analysis of the FAERS database and prioritization of cardiac AE signals, our research enhances the awareness among healthcare professionals regarding cardiac AEs associated with lacosamide.

Introduction: Recently, the rise of antibiotic resistance has prompted a reconsideration of tetracyclines. However, existing studies are inadequate in assessing the pediatric safety of this class of antibiotics. To address the gap, our study aims to comprehensively assess the safety of tetracyclines in children. Methods: Adverse event (AE) reports from January 2005 to September 2023 were obtained from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, and reporting odds ratio (ROR) was performed to identify potential risk signals in children under 18 years old who were administered any of the three tetracyclines: doxycycline, minocycline, and tigecycline. Results: A total of 1903 AE cases were included in our study: 782 for doxycycline, 981 for minocycline, and 140 for tigecycline. Doxycycline and tigecycline were predominantly associated with “general disorders and administration site conditions” and “gastrointestinal disorders,” while minocycline was more frequently linked to “skin and subcutaneous tissue disorders” and “gastrointestinal disorders.” Psychiatric risks predominantly included depression, suicidal ideation, and suicide attempt. In the category of skin and subcutaneous tissues, 30.88% of the minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) cases resulted in death, alongside a high occurrence of co-occurring AEs such as multiple organ dysfunction syndrome, Type 1 Diabetes Mellitus (T1DM), and autoimmune thyroiditis. As for the endocrine system, both doxycycline and minocycline were found to potentially increase the risk of thyroid dysfunction. For children under the age of 8, doxycycline was associated with tooth discoloration (N = 7, ROR = 20.11%, 95% CI: 9.48–42.67), although it remained unclear whether the discoloration was permanent. Conclusion: Our findings indicated that for pediatric patients, the majority of results were in line with the prescribing information and previous studies, and minocycline tended to cause more frequent and severe AEs than doxycyclineHowever, it is noteworthy that exceptions were found for psychiatric disorders and thyroid dysfunction associated with doxycycline, which are not mentioned in its FDA prescribing information. Additionally, further safety studies on tigecycline are still needed for children. When prescribing tetracyclines to pediatric patients, a careful risk-benefit assessment is crucial. [ABSTRACT FROM AUTHOR]

Lacosamide was the first approved third-generation antiepileptic drug. However, real-world data regarding its adverse cardiac reactions in large samples still need to be completed. We evaluated the cardiac safety profile of lacosamide using the Food and Drug Administration Adverse Event Reporting System (FAERS). We performed disproportionality analysis computing reporting odds ratio (ROR) as a quantitative metric to assess the signal of lacosamide-related cardiac adverse events (AEs) from 2013 Q1 to 2022 Q4. The signal was considered significant when the lower limit of the 95% confidence interval (CI) of the ROR exceeded 1, and ≥ 5 AEs were reported. Serious and nonserious cases were compared by statistical analysis, and signals were further prioritized using a rating scale. A total of 812 cardiac AEs associated with lacosamide were identified, and 92 signals were detected, of which 17 AEs were significantly associated signals. The median time-to-onset (TTO) for moderate priority signals was 10 days, whereas for weak priority signals, it was 54 days. Notably, all cardiac AEs exhibited an early failing pattern, indicating the risk gradually decreasing. Based on the comprehensive analysis of the FAERS database and prioritization of cardiac AE signals, our research enhances the awareness among healthcare professionals regarding cardiac AEs associated with lacosamide. [ABSTRACT FROM AUTHOR]

Drug‐induced thrombocytopenia (DIT) deserves both clinical and research attention for the serious clinical consequences and high prevalence of the condition. The current study aimed to perform a comprehensive pharmacovigilance analysis of DIT reported in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, with a particular focus on drugs associated with thrombocytopenia events. A disproportionality analysis of DIT was conducted using reports submitted to FARES from January 2004 to December 2022. Both the information component (IC) and reporting odds ratio (ROR) algorithms were applied to identify an association between target drugs and DIT events. A total of 15,940,383 cases were gathered in FAERS, 168,657 of which were related to DIT events. The top 50 drugs ranked by number of cases and ranked by signal strength were documented. The top 5 drugs ranked by number of cases were lenalidomide (10,601 cases), niraparib (3726 cases), ruxolitinib (3624 cases), eltrombopag (3483 cases), and heparin (3478 cases). The top 5 drugs ranked by signal strength were danaparoid (ROR 37.61, 95%CI 30.46‐46.45), eptifibatide (ROR 34.75, 95%CI 30.65‐39.4), inotersen (ROR 34.00, 95%CI 29.47‐39.23), niraparib (ROR 30.53, 95%CI 29.42‐31.69), and heparin (ROR 28.84, 95%CI 27.76‐29.97). The top 3 involved drug groups were protein kinase inhibitors, antimetabolites, and monoclonal antibodies and antibody‐drug conjugates. The current comprehensive pharmacovigilance study identified more drugs associated with thrombocytopenia. Although the mechanisms of DIT have been elucidated for some drugs, others still require further investigation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

PurposeTo identify the most commonly reported drugs associated with QT interval prolongation in the FDA Adverse Event Reporting System (FAERS) and evaluate their risk for QT interval prolongation.MethodsWe employed the preferred term (PT) “electrocardiogram QT prolonged” from the Medical Dictionary for Regulatory Activities (MedDRA) 26.0 to identify adverse drug events (ADEs) of QT interval prolongation in the FAERS database from the period 2004–2022. Reporting odds ratio (ROR) was performed to quantify the signals of ADEs.ResultsWe listed the top 40 drugs that caused QT interval prolongation. Among them, the 3 drugs with the highest number of cases were quetiapine (1,151 cases, ROR = 7.62), olanzapine (754 cases, ROR = 7.92), and citalopram (720 cases, ROR = 13.63). The two most frequently reported first-level Anatomical Therapeutic Chemical (ATC) groups were the drugs for the nervous system (n = 19, 47.50%) and antiinfectives for systemic use (n = 7, 17.50%). Patients with missing gender (n = 3,482, 23.68%) aside, there were more females (7,536, 51.24%) than males (5,158, 35.07%) were involved. 3,720 patients (25.29%) suffered serious clinical outcomes resulting in deaths or life-threatening conditions. Overall, most drugs that caused QT interval prolongation had early failure types according to the assessment of the Weibull's shape parameter (WSP) analysis.ConclusionsOur study offered a list of drugs that frequently caused QT interval prolongation based on the FAERS system, along with a description of some risk profiles for QT interval prolongation brought on by these drugs. When prescribing these drugs in clinical practice, we should closely monitor the occurrence of ADE for QT interval prolongation.

Mariko Kozaru, Tatsuya Iida, Keiko Hosohata Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Takatsuki, Osaka, 569-1094, JapanCorrespondence: Keiko Hosohata, Education and Research Center for Clinical Pharmacy, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan, Tel +81-72-690-1271, Fax +81-72-690-362, Email hosohata@gly.oups.ac.jpPurpose: Clinically, glaucoma is a serious problem because it is asymptomatic until a relatively late stage in most cases, 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 glaucoma with the causative drugs using a spontaneous reporting system database.Methods: Data were extracted from the Japanese Adverse Drug Event Report database of the Pharmaceuticals and Medical Devices Agency (Japan). Based on reports of glaucoma caused by all drugs, we calculated the reporting odds ratio (ROR) and 95% confidence interval (CI) for glaucoma.Results: Among 609 reports of adverse events corresponding to glaucoma (46%, women), the most frequently implicated drug were steroids (prednisolone, betamethasone sodium phosphate, triamcinolone acetonide, and fluorometholone), pregabalin, ranibizumab, crizotinib, tacrolimus hydrate, darbepoetin alfa, and foscarnet sodium hydrate. Among 207 reports involved in angle-closure glaucoma (86%, women), anticholinergic drug and antidepressants ranked high and showed signals. Signals were also detected in bromazepam (ROR, 69.7; 95% CI, 30.9– 157.5), oral brotizolam (ROR, 16.6; 95% CI, 6.18– 44.8), and oral milnacipran hydrochloride (ROR, 22.8; 95% CI, 8.46– 61.4) for angle-closure glaucoma.Conclusion: A national pharmacovigilance database enabled us to identify the drugs that frequently induce glaucoma. The likelihood of the reporting of glaucoma varied among the drugs, which should be used carefully in clinical practice to avoid it.Keywords: glaucoma, pharmacovigilance, adverse drug reactions, reporting odds ratio, spontaneous reporting system

Introduction: For assessing drug safety using spontaneous reporting system databases, quantitative measurements, such as proportional reporting rate (PRR) and reporting odds ratio (ROR), are widely employed to assess the relationship between a drug and a suspected adverse drug reaction (ADR). The databases contain numerous ADRs, and the quantitative measurements need to be calculated by performing the analysis multiple times for each ADR. We proposed a novel, simple, and easy-to-implement method to estimate the PRR and ROR of multiple ADRs in a single analysis using a generalized mixedeffects model for signal detection. Methods: The proposed method simultaneously analyzed the association between any drug and numerous ADRs, as well as estimated the PRR and ROR for a specific combination of drugs and suspected ADRs. Furthermore, the proposed method was applied to detect drug-drug interactions associated with the concurrent use of two or more drugs. Results and discussion: In our simulation studies, the false-positive rate and sensitivity of the proposed method were similar to those of the traditional PRR and ROR. The proposed method detected known ADRs when applied to the Food and Drug Administration Adverse Event Reporting System database. As an important advantage, the proposed method allowed the simultaneous evaluation of several ADRs using multiple drugs. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To analyze the reports of adverse drug events of lactic acidosis, and to summarize the drugs categories that may cause lactic acidosis, so as to provide references for clinical decision-making. METHODS: Adverse drug event reports in the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database were extracted by using OpenVigil 2. 1 software for the drugs from the first quarter of 2004 to the fourth quarter of 2022, the data were analyzed by using reporting odd ratio (ROR) method and proportional reporting ratio (PRR) method, so that the drugs were finally classified according to different systems. RESULTS: A total of 18 114 reports of adverse events of lactic acidosis with drugs as the first suspicion were collected, and 31 adverse reaction signals were finally obtained after analysis, the top 5 drugs ranked by the frequency of lactic acidosis adverse reaction signals were metformin, linezolid, sitagliptin, linagliptin and empagliflozin, and the drug categories involved were mainly digestive and metabolic drugs, cardiovascular system drugs, systemic use anti-infective drugs and neurologic drugs. CONCLUSIONS: Various drugs can cause lactic acidosis, mainly including digestive and metabolic drugs, and systemic anti-infective drugs. [ABSTRACT FROM AUTHOR]

Adverse events associated with opioid use in palliative care have been extensively studied. However, predicting the occurrence of adverse events based on the specific opioid used remains difficult. This study aimed to comprehensively analyze the adverse events related to µ-opioid receptor stimulation of opioids approved in Japan and investigate the tendencies of adverse event occurrence among different opioids. We utilized the FDA Adverse Event Reporting System database to extract reported adverse events for opioids approved in Japan. Cluster analysis was performed on reporting odds ratios (RORs) of adverse event names among opioids to visualize relationships between opioids and adverse events, facilitating a comparative study of their classifications. We calculated the RORs of adverse events for the target opioids. Cluster analysis based on these RORs resulted in five broad clusters based on the reported adverse events: i.e., strong opioids, weak opioids, loperamide, tapentadol, and remifentanil. This study provides a comprehensive classification of the association between μ-opioid-receptor-stimulating opioids and adverse events. [ABSTRACT FROM AUTHOR]

ObjectiveTo systematically evaluate the safety of interferon β-1a for treatment of corona virus disease 2019 （COVID-19）， and to provide references for interferon β-1a's clinical application.MethodsThis study was conducted with the database from US Food and Drug Administration adverse event reporting system （FAERS） from January 1， 2015 to March 31， 2021. Information component （IC） and reporting odds ratio （ROR） methods were applied for signal mining.ResultsA total of 463 700 records of COVID-19 were selected for analysis， and 45 positive drug adverse event signals were detected. Headache （IC025=1.09， ROR025=2.28）， pyrexia （IC025=0.51， ROR025=1.51） and multiple sclerosis relapse （IC025=3.67， ROR025=14.71） were positive adverse events with higher frequency. Autoimmune disorder （IC025=4.42， ROR025=24.03）， streptococcal infection （IC025=4.12， ROR025=19.82）， and multiple sclerosis relapse （IC025=3.67， ROR025=14.71） were positive adverse events. Acute lung injury， cardio-respiratory arrest and metabolic acidosis were associated with a higher proportion and frequency of death.ConclusionThere are certain safety issues with interferon β-1a in the treatment of COVID-19， and some adverse events with high frequency and high death rate deserve further attention by medical staffs.

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OBJECTIVE: To mine the risk signals of three new oral anticoagulants such as dabigatran etexilate, rivaroxaban and apixaban based on big data sample analysis, so as to provide reference for rational clinical drug use. METHODS: Based on the FDA Adverse Event Reporting System ( FAERS) database, OpenVigil 2. 1 platform was used to extract reports from the 1st quarter of 2004 to the 3rd quarter of 2021. Reporting odds ratio (ROR) and proportional reporting ratio ( PRR) were used for signal mining. The risk signals were described and classified according to the preferred terms (PT) and systematic organ classification ( SOC) in the MedDRA (Edition 25. 0). RESULTS: A total of 54 932, 112 642, and 108 850 adverse drug event reports were retrieved for dabigatran etexilate, rivaroxaban and apixaban, respectively. Adverse drug reactions with the first number of cases of dabigatran etexilate, rivaroxaban and apixaban were respectively gastrointestinal haemorrhage ( PRR = 28. 31, ROR = 32. 01), gastrointestinal haemorrhage (PRR= 46. 45, ROR= 54. 47), and haemorrhage (PRR= 6. 09, ROR= 6. 25). Adverse drug reactions with the first signal intensity were gastric occult blood positive ( PRR = 66. 55, ROR = 66. 56), haemorrhagic arteriovenous malformation ( PRR = 689. 45, ROR = 692. 06), and spinal subarachnoid haemorrhage (PRR = 50. 58, ROR = 50. 59). Meanwhile, rivaroxaban may lead to acute kidney injury ( the 10th ranked by occurrence), apixaban may lead to renal impairment (the 9th ranked by occurrence) and hypoacusis (the 10th ranked by occurrence) and auditory disorder ( the 7th ranked by signal strength), which were not mentioned in the drug instructions and should be taken into account. The overall incidence of bleeding risk for the three new oral anticoagulants was rivaroxaban > dabigatran etexilate > apixaban. CONCLUSIONS: Dabigatran etexilate, rivaroxaban and apixaban need to be used with a focus on bleeding risk, and new risk signals for rivaroxaban and apixaban need to be followed. [ABSTRACT FROM AUTHOR]

Copyright of Evaluation & Analysis of Drug-Use in Hospitals of China is the property of Evaluation & Analysis of Drug-Use in Hospitals of China Editorial Board and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

OBJECTIVE: To mine the risk signals of three new oral anticoagulants such as dabigatran etexilate, rivaroxaban and apixaban based on big data sample analysis, so as to provide reference for rational clinical drug use. METHODS: Based on the FDA Adverse Event Reporting System ( FAERS) database, OpenVigil 2. 1 platform was used to extract reports from the 1st quarter of 2004 to the 3rd quarter of 2021. Reporting odds ratio (ROR) and proportional reporting ratio ( PRR) were used for signal mining. The risk signals were described and classified according to the preferred terms (PT) and systematic organ classification ( SOC) in the MedDRA (Edition 25. 0). RESULTS: A total of 54 932, 112 642, and 108 850 adverse drug event reports were retrieved for dabigatran etexilate, rivaroxaban and apixaban, respectively. Adverse drug reactions with the first number of cases of dabigatran etexilate, rivaroxaban and apixaban were respectively gastrointestinal haemorrhage ( PRR = 28. 31, ROR = 32. 01), gastrointestinal haemorrhage (PRR= 46. 45, ROR= 54. 47), and haemorrhage (PRR= 6. 09, ROR= 6. 25). Adverse drug reactions with the first signal intensity were gastric occult blood positive ( PRR = 66. 55, ROR = 66. 56), haemorrhagic arteriovenous malformation ( PRR = 689. 45, ROR = 692. 06), and spinal subarachnoid haemorrhage (PRR = 50. 58, ROR = 50. 59). Meanwhile, rivaroxaban may lead to acute kidney injury ( the 10th ranked by occurrence), apixaban may lead to renal impairment (the 9th ranked by occurrence) and hypoacusis (the 10th ranked by occurrence) and auditory disorder ( the 7th ranked by signal strength), which were not mentioned in the drug instructions and should be taken into account. The overall incidence of bleeding risk for the three new oral anticoagulants was rivaroxaban > dabigatran etexilate > apixaban. CONCLUSIONS: Dabigatran etexilate, rivaroxaban and apixaban need to be used with a focus on bleeding risk, and new risk signals for rivaroxaban and apixaban need to be followed. [ABSTRACT FROM AUTHOR]

Copyright of Practical Pharmacy & Clinical Remedies is the property of Editorial Department of Practical Pharmacy & Clinical Remedies and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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. [ABSTRACT FROM AUTHOR]

Background/Aim: Interstitial lung disease (ILD) is a serious adverse event (AE) associated with the use of immune checkpoint inhibitors (ICIs). However, the risk factors for developing ICI-related ILD remain poorly understood. Therefore, this study investigated the effect of concomitant analgesics on developing ICI-related ILD using the Japanese Adverse Drug Event Report (JADER) database. Patients and Methods: All the reported AE data were downloaded from the Pharmaceuticals and Medical Devices Agency website, and the JADER data between January 2014 and March 2021 were analysed. The relationship between ICI-related ILD and concomitant use of analgesics was assessed using reporting odds ratio (ROR) and 95% confidence interval. We investigated whether the effect of developing ILD varied according to the type of analgesics used during ICI treatment. Results: Positive signals for ICI-related ILD development were detected for the concomitant use of the narcotic analgesics codeine, fentanyl and oxycodone, but not with morphine. In contrast, there were no positive signals for the concomitant use of the non-narcotic analgesics celecoxib, acetaminophen, loxoprofen and tramadol. An increased ROR for ICI-related ILD in cases with concomitant use of narcotic analgesics was observed in a multivariate logistic analysis adjusted by sex and age. Conclusion: These results suggest that the concomitant use of narcotic analgesics is involved in the development of ICI-related ILD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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 β 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.

Adverse events associated with opioid use in palliative care have been extensively studied. However, predicting the occurrence of adverse events based on the specific opioid used remains difficult. This study aimed to comprehensively analyze the adverse events related to µ-opioid receptor stimulation of opioids approved in Japan and investigate the tendencies of adverse event occurrence among different opioids. We utilized the FDA Adverse Event Reporting System database to extract reported adverse events for opioids approved in Japan. Cluster analysis was performed on reporting odds ratios (RORs) of adverse event names among opioids to visualize relationships between opioids and adverse events, facilitating a comparative study of their classifications. We calculated the RORs of adverse events for the target opioids. Cluster analysis based on these RORs resulted in five broad clusters based on the reported adverse events: i.e., strong opioids, weak opioids, loperamide, tapentadol, and remifentanil. This study provides a comprehensive classification of the association between μ-opioid-receptor-stimulating opioids and adverse events.

BACKGROUND: Antimuscarinics are the backbone of the pharmacological management of overactive bladder. Still, concerns have been raised over the nervous system (NS) adverse drug events (AEs) due to their dissimilarities to muscarinic receptor-subtype affinities. OBJECTIVE: This study aimed to identify the nervous system and gastrointestinal adverse drug events (ADEs) associated with solifenacin use in older adults (≥65 years). METHODS: A case/non-case analysis was performed on the reports submitted to the FDA Adverse Event Reporting System (FAERS) between 01/01/2004 and 30/06/2020. Cases were reports for solifenacin with ≥1 ADEs as preferred terms included in the Medical Dictionary of Regulatory Activities (MedDRA) system organ classes 'nervous system' or 'gastrointestinal' disorders. Non-cases were all other remaining reports for solifenacin. The case/non-cases was compared between solifenacin and other bladder antimuscarinics. Frequentist approaches, including the proportional reporting ratio (PRR) and reporting odds ratio (ROR), were used to measure disproportionality. The empirical Bayesian Geometric Mean (EBGM) score and information component (IC) value were calculated using a Bayesian approach. A signal was defined as the lower limit of 95% confidence intervals of ROR ≥ 2, PRR ≥ 2, IC > 0, EBGM > 1, for ADEs with ≥4 reports. RESULTS: 107 MedDRA preferred terms (PTs) comprising 970 ADE reports were retrieved for nervous system disorders associated with solifenacin. For gastrointestinal disorders, 129 MedDRA PTs comprising 1817 ADE reports were retrieved. Statistically significant results were found for 'altered state of consciousness': ROR = 9.71 (2.13–44.35), PRR = 9.69 (2.12–44.2) and IC = 1.29 (0.93–1.66). CONCLUSIONS: The disproportionality reporting of 'altered state of consciousness', a previously unidentified ADE, was unexpected. Further monitoring of this ADE is needed to ensure patient safety, as this could be linked to poor balance and falls in older adults. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Urinary tract infection (UTI) and pyelonephritis cause urosepsis, which can become life threating. Sodium‐dependent glucose cotransporter 2 (SGLT2) inhibitors, a class of oral anti‐diabetic drugs, may increase the risk of UTI and pyelonephritis, as observed from their mechanism of action. Patients with diabetes receiving SGLT2 inhibitors are often concomitantly administered other antidiabetic, antidyslipidemic, or antihypertensive drugs. To determine if drug–drug interactions (DDIs) between SGLT2 inhibitors and these medications increased the risk of UTI and pyelonephritis, we analyzed the Food and Drug Administration Adverse Event Reporting System (FAERS) database. We applied Norén's and Gosho's methods for detecting DDIs. FAERS contains records describing 14 526 398 patient characteristics, 54 290 663 drug properties, and 47 252 416 reactions/events. We found 23 drug combinations that could induce UTI and pyelonephritis, such as SGLT2 inhibitors administered with dipeptidyl peptidase‐4 inhibitors, thiazolidinediones, glinides, statins, angiotensin II receptor blockers, and calcium channel blockers. Combination therapy with the drugs detected in our analyses would show potential interactions that could result in UTI and pyelonephritis in patients with diabetes mellitus. However, owing to various limitations, these results must be confirmed by additional analyses. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Isavuconazole is a novel second-generation triazole antifungal agent.We conducted a retrospective investigation to analyze the occurrence of adverse events (AEs) associated with isavuconazole in real-world clinical use by data-mining self-reporting databases, aiming to provide comprehensive data for its safe and effective clinical application., Research Design and Methods: All data obtained from the VigiBase, the EudraVigilance and the FAERS database. In the FAERS database, data mining algorithms, including reporting odds ratio (ROR) and proportional reporting ratio (PRR), were utilized to detect adverse event (AE) signals., Results: A total of 4,105 AE reports related to isavuconazole were retrieved from these databases. The highest proportion of AE reports was observed in individuals aged between 18-64 years old. The general disorders and administration site conditions system organ class accounted for the largest number of reported cases. The system organ classes with most signals and reports included general disorders and administration site conditions, blood and lymphatic system disorders as well as investigations related to hepatobiliary disorders. Notably high ROR and PRR values were observed for AE signals associated with hepatobiliary disorders., Conclusion: Isavuconazole has fewer interactions and less liver, kidney and cardiac toxicity than other triazole antibiotics. The identification of novel AEs necessitates meticulous attention and further investigation and analysis.

Background: Adverse cutaneous drug reactions have been reported with most drugs, including antidepressants (ADs) and second-generation antipsychotics (SGAs). The lack of extensive research on the relationship between ADs and SGAs, and cutaneous toxicity remains troubling. Our study aimed to assess the cutaneous toxicity of ADs and SGAs and provide valuable insights for clinical applications and scientific investigations., Research Design and Methods: We conduct a pharmacovigilance study based of the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database to analysis the relationship of ADs and SGAs and cutaneous adverse events. Reporting odds ratios (ROR) and information components (IC) were presented using statistical shrinkage transformation., Results: Comparing ACDRs to other ADRs, each AD (fluoxetine (ROR 025  = 1.49), fluvoxamine (ROR 025  = 1.14), paroxetine (ROR 025  = 1.49), escitalopram (ROR 025  = 1.79), sertraline (ROR 025  = 1.44), venlafaxine (ROR 025  = 1.46) and duloxetine (ROR 025  = 1.69)) showed significantly more cases. There was no association between SGA and cutaneous toxicity. The spectrum displayed strong signals in duloxetine-induced genital ulceration (IC 025  = 2.75) and amisulpride-induced conjunctivitis (IC 025  = 2.56)., Discussion: This study provides a valuable foundation for clinical practice and medication monitoring by thoroughly analyzing, methodically evaluating, and quantifying the potential dermal toxicity of ADs and SGAs.

Introduction: β-Blockers are essential for cardiovascular disease management but can induce respiratory issues, particularly with non-selective β-blockers. Their safety in asthmatic patients is debated., Objective: This study investigates the link between different classes of β-blockers and the risk of asthma and asthma-like adverse events (AEs) using data from the Food and Drug Administration's Adverse Event Reporting System (FAERS)., Methods: β-Blockers were first reviewed according to European Society of Cardiology classification and then using the Vashistha and Kumar classification. The risk associated with different β-blocker classes was evaluated through disproportionality analysis using the reporting odds ratio (ROR)., Results: Among 251,145 AEs reported for β-blockers, 4104 were asthma-related. Selective β 1 -blockers had a higher asthma risk signal (ROR: 1.15) compared to non-selective β-blockers (ROR: 0.90). α- and β-Blockers showed the lowest risk (ROR: 0.51). The Vashistha and Kumar classification detailed risk profiles for various β-blockers, highlighting differences even within the same class. Dual α- and β-blockers, hydrophilic, and lipophilic β-blockers posed lower asthma risks, while selective β 1 -blockers had higher risks regardless of intrinsic sympathomimetic activity., Conclusion: Although the signals detected by disproportionality analysis are only candidate risks, the risk stratification resulting from our analysis highlights the need for cautious β-blocker selection in asthmatic patients or those predisposed to asthma. Furthermore, despite the limitations associated with the FAERS data, the study reveals significant variability in risk among different β-blocker classes, crucial for clinical decisions and patient management. Drugs like esmolol, metoprolol, nebivolol, and nadolol may be safer for asthmatic patients, whereas betaxolol, bisoprolol, timolol, and propranolol should be avoided., Competing Interests: Declaration of competing interest We have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Furthermore, we declare that this manuscript was not funded/sponsored, and no writing assistance was utilised in its production., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and purpose: Serious adverse events following immunization (AEFI) associated with the COVID-19 vaccines, including BNT162b2 (Pfizer-BioNTech), Ad26.COV2.S (Janssen), and mRNA-1273 (Moderna), have not yet been fully investigated. This study was designed to evaluate the serious AEFI associated with these three vaccines.Methods: A disproportionality study was performed to analyze data acquired from the Vaccine Adverse Event-Reporting System (VAERS) between 1 January 2010 and 30 April 2021. The reporting odds ratio (ROR) method was used to identify the association between the COVID-19 vaccines BNT162b2, Ad26.COV2.S, and mRNA-1273 and each adverse event reported. Moreover, the ratio of the ROR value to the 95% CI span was applied to improve the credibility of the ROR. The median values of time from vaccination to onset (TTO) for the three vaccines were analyzed.Results: Compared with BNT162b2 and mRNA-1273, Ad26.COV2.S vaccination was associated with a lower death frequency (p < 0.05). Ad26.COV2.S vaccination was associated with a lower birth defect and emergency room visit frequency than BNT162b2 (p < 0.05). There were 6,605, 830, and 2,292 vaccine recipients who suffered from COVID-19-related symptoms after vaccination with BNT162b2, Ad26.COV2.S, and mRNA-1273, respectively, including people who were infected by COVID-19, demonstrated a positive SARS-CoV-2 test, and were asymptomatic. Serious AEFI, including thromboembolism, hemorrhage, thrombocytopenia, cardiac arrhythmia, hypertension, and hepatotoxicity, were associated with all three vaccines. Cardiac failure and acute renal impairment events were associated with BNT162b2 and mRNA-1273, while seizure events were associated with BNT162b2 and Ad26.COV2.S. The median values of TTO associated with the three vaccinations were similar.Conclusion: These findings may be useful for health workers and the general public prior to inoculation, especially for patients with underlying diseases; however, the risk/benefit profile of these vaccines remains unchanged. The exact mechanism of SARS-CoV-2 vaccine-induced AEFI remains unknown, and further studies are required to explore these phenomena.

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A well-known problem in pharmacotherapy is an increased risk of adverse drug reactions (ADRs) in older as compared to younger patients. The Russian pharmacovigilance database includes a significant number of spontaneous reports of suspected ADRs in patients aged 65 and older. An increase in ADRs reporting makes it difficult to identify potential safety signals based on qualitative approaches only, which necessitates the use of statistical methods for signal detection based on disproportionality.The aim of the study was to assess the applicability of quantitative methods for signal detection and analysis of ADR risks in the elderly using the Russian spontaneous report database.Materials and methods: the study covered the reports on patients 65 years of age and older, which were submitted to the spontaneous report database from January 2008 until June 2018. The procedure recommended by the European Medicines Agency was used to identify potential statistical safety signals which were determined based on the following criteria: Reporting Odds Ratio, ROR—lower bound of the 95% confidence interval >1, number of cases ≥2; Proportional Reporting Ratio, PRR ≥ 2, Chi-square value χ2 ≥ 4, number of cases ≥3, lower bound of the 95% confidence interval >1, number of cases ≥3.Results: 2231 potential statistical signals were identified. Of these, the vast majority of combinations of suspected drugs and ADRs were associated with known drug risks, and were not new safety signals for these drugs. The largest proportion of statistical signals was attributed to the following pharmacological groups: antiplatelet agents, cephalosporins, non-steroidal anti-inflammatory drugs, fluoroquinolones, angiotensin-converting enzyme inhibitors, metabolic agents, and indirect anticoagulants.Conclusion: the results obtained indicate the applicability and effectiveness of statistical methods based on disproportionality of reporting for the analysis of the Russian spontaneous report database in order to identify potential drug safety issues.

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 β 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: CAR-T-associated neurotoxicity is extremely frequent with highly variable clinical presentation., Research Design and Methods: Disproportionality analysis was conducted leveraging the FDA Adverse Event Reporting System (FAERS), covering the period from 1 January 2017, through 31 March 2023. The reporting odds ratio (ROR) and the information component (IC) were utilized to assess the adverse signals in total/individual CAR-T product. The lower limit of the ROR and IC 95% confidence interval (ROR 025 and IC 025 ) both exceeding threshold value (1 and 0, respectively) was considered a significant signal., Results: Of the 60, 730 records associated with CAR-T, 11, 037 (18.17%) pertained to neurological events. Tisagenlecleucel exhibited the highest percentage of death (38.02%) and life-threatening (12.90%) outcomes. Notably, it also displayed the broadest distribution of neurotoxicity. Additionally, distinct adverse signals unique to individual CAR-T products were identified. For instance, paraparesis, cerebral hemorrhage, impaired pupillary reflex, Guillain-Barre syndrome, brain death following tisagenlecleucel; dysarthria, orthostatic hypotension, and spinal cord edema after axicabtagene; parkinsonism, Bell's palsy, and cranial nerve paralysis post ciltacabtagene., Conclusions: Axicabtagene ciloleucel, tisagenlecleucel, brexucabtagene autoleucel, lisocabtagene maraleucel, idecabtagene vicleucel, and ciltacabtagene autoleucel exhibited increased odds of neurotoxicity, with some discrepancies in their characteristics, profiles, and severity.

BackgroundAlthough several metabolic and nutritional disorders (MNDs) have been reported in the recipients of immune checkpoint inhibitors (ICIs), these events have not been fully captured and comprehensively characterized in real-world population.ObjectivesTo provide complete metabolic and nutritional toxicity profiles after ICIs (single and combined) initiation through an integrated big database.MethodsReporting odds ratios (ROR) and information component (IC) based on statistical shrinkage transformation were utilized to perform disproportionality analysis using the US Food and Drug Administration Adverse Events Reporting System. Both ROR and IC were used to calculate disproportionality when compared with the whole database, but only ROR was used when comparison was made for different ICI strategies. Only when both the lower limits of 95% confidence intervals (CIs) for ROR (ROR025) and IC (IC025) exceeded specified threshold values (1 and 0, respectively) was regarded as a signal.ResultsA total of 29,294,335 records were involved and 8,662 records were for MNDs in patients exposed to ICIs. Statistically significant association was detected between ICIs use and total MNDs (IC025/ROR025 = 1.06/2.19). For monotherapy, three ICI monotherapies (anti-PD-1, anti-PDL-1, and anti-CTLA-4) were all disproportionately associated with MNDs. Statistically significant differences in reporting frequencies also emerged when comparing anti-PD-1 with anti-PD-L1/anti-CTLA-4 monotherapy, with RORs of 1.11 (95%CI 1.01-1.21), and 1.35 (95%CI 1.23-1.48), respectively. Notably, combination therapy was associated with a higher reporting frequency of theses toxicities compared to monotherapy with a ROR of 1.56 (95%CI 1.48-1.64). Additionally, disproportionality analysis at High-level Group Term level highlighted eight broad entities of MNDs. Further disproportionality analysis at Preferred Term level indicated a wide range and varied strength of signals. For ICI monotherapy, nivolumab and pembrolizumab showed the broadest spectrum of MNDs. For combination therapy, a variety of signals were detected for nivolumab + ipilimumab therapy even comparable to two PD-1 monotherapies.ConclusionMetabolic and nutritional complications could be provoked by ICI monotherapy (especially anti-PD-1) and further reinforced by combination therapy. Clinicians and patients should be informed about these potential risks that might be encountered in real-world practice. Aforehand education and regular monitoring of related biochemical parameters (calcium, sodium, potassium, protein) are recommended to ensure better cancer survivorship.

Background: Due to the embryotoxicity found in animal studies and scarce clinical data in pregnant women, it is still controversial whether entecavir (ETV) and adefovir dipivoxil (ADV) are safe during human pregnancy. This is of paramount importance when counseling pregnant women with hepatitis B virus (HBV) on risks and benefits to their offspring.Objective: To quantify the association between administration of ETV and ADV in pregnant women and occurrence of adverse events (AEs) during pregnancy (AEDP).Methods: Pregnancy reports from the FDA Adverse Event Reporting System (FAERS) were used to perform a retrospective analysis of AEDP associated with ETV or ADV. Disproportionality analysis estimating the reporting odds ratio (ROR) was conducted to identify the risk signals. A signal was defined as ROR value >2, and lower limit of 95% confidence interval (CI)> 1.Results: A total of 1,286,367 reports involving AEDP were submitted to FAERS by healthcare professionals. Of these, there were 547 cases reporting ETV and 242 cases reporting ADV as primary suspected drugs. We found a moderate or strong signal for increased risk of spontaneous abortion when comparing ETV with tenofovir disoproxil fumarate (TDF) and telbivudine (LdT), with RORs equal to 1.58 (95% CI, 1.09–2.30) and 2.13 (95% CI, 1.04–4.36), respectively. However, when the included reports were limited to indication containing HBV infection, no signals for increased AEDP were detected. Futhermore, a strong signal for increased risk of spontaneous abortion was identified in patients with HBV infection when comparing ETV or ADV with lamivudine (LAM), with RORs of 3.55 (95% CI, 1.54–8.18) and 2.85 (95% CI, 1.15–7.08), respectively.Conclusion: We found a strong signal for increased risk of spontaneous abortion in patients with HBV infection taking ETV or ADV, in comparison with those prescribed with LAM. Moreover, no obvious signal association of human teratogenicity with exposure to ETV or ADV was identified in fetuses during pregnancy. Nevertheless, owing to the limitations of a spontaneous reporting database, which inevitably contains potential biases, there is a pressing need for well-designed comparative safety studies to validate these results in clinical practice.

Background: Although several metabolic and nutritional disorders (MNDs) have been reported in the recipients of immune checkpoint inhibitors (ICIs), these events have not been fully captured and comprehensively characterized in real-world population. Objectives: To provide complete metabolic and nutritional toxicity profiles after ICIs (single and combined) initiation through an integrated big database. Methods: Reporting odds ratios (ROR) and information component (IC) based on statistical shrinkage transformation were utilized to perform disproportionality analysis using the US Food and Drug Administration Adverse Events Reporting System. Both ROR and IC were used to calculate disproportionality when compared with the whole database, but only ROR was used when comparison was made for different ICI strategies. Only when both the lower limits of 95% confidence intervals (CIs) for ROR (ROR025) and IC (IC025) exceeded specified threshold values (1 and 0, respectively) was regarded as a signal. Results: A total of 29,294,335 records were involved and 8,662 records were for MNDs in patients exposed to ICIs. Statistically significant association was detected between ICIs use and total MNDs (IC025/ROR025 = 1.06/2.19). For monotherapy, three ICI monotherapies (anti-PD-1, anti-PDL-1, and anti-CTLA-4) were all disproportionately associated with MNDs. Statistically significant differences in reporting frequencies also emerged when comparing anti-PD-1 with anti-PD-L1/anti-CTLA-4 monotherapy, with RORs of 1.11 (95%CI 1.01-1.21), and 1.35 (95%CI 1.23-1.48), respectively. Notably, combination therapy was associated with a higher reporting frequency of theses toxicities compared to monotherapy with a ROR of 1.56 (95%CI 1.48-1.64). Additionally, disproportionality analysis at High-level Group Term level highlighted eight broad entities of MNDs. Further disproportionality analysis at Preferred Term level indicated a wide range and varied strength of signals. For ICI monotherapy, nivolumab and pembrolizumab showed the broadest spectrum of MNDs. For combination therapy, a variety of signals were detected for nivolumab + ipilimumab therapy even comparable to two PD-1 monotherapies. Conclusion: Metabolic and nutritional complications could be provoked by ICI monotherapy (especially anti-PD-1) and further reinforced by combination therapy. Clinicians and patients should be informed about these potential risks that might be encountered in real-world practice. Aforehand education and regular monitoring of related biochemical parameters (calcium, sodium, potassium, protein) are recommended to ensure better cancer survivorship. [ABSTRACT FROM AUTHOR]

Background: Due to the embryotoxicity found in animal studies and scarce clinical data in pregnant women, it is still controversial whether entecavir (ETV) and adefovir dipivoxil (ADV) are safe during human pregnancy. This is of paramount importance when counseling pregnant women with hepatitis B virus (HBV) on risks and benefits to their offspring. Objective: To quantify the association between administration of ETV and ADV in pregnant women and occurrence of adverse events (AEs) during pregnancy (AEDP). Methods: Pregnancy reports from the FDA Adverse Event Reporting System (FAERS) were used to perform a retrospective analysis of AEDP associated with ETV or ADV. Disproportionality analysis estimating the reporting odds ratio (ROR) was conducted to identify the risk signals. A signal was defined as ROR value >2, and lower limit of 95% confidence interval (CI)> 1. Results: A total of 1,286,367 reports involving AEDP were submitted to FAERS by healthcare professionals. Of these, there were 547 cases reporting ETV and 242 cases reporting ADV as primary suspected drugs. We found a moderate or strong signal for increased risk of spontaneous abortion when comparing ETV with tenofovir disoproxil fumarate (TDF) and telbivudine (LdT), with RORs equal to 1.58 (95% CI, 1.09–2.30) and 2.13 (95% CI, 1.04–4.36), respectively. However, when the included reports were limited to indication containing HBV infection, no signals for increased AEDP were detected. Futhermore, a strong signal for increased risk of spontaneous abortion was identified in patients with HBV infection when comparing ETV or ADV with lamivudine (LAM), with RORs of 3.55 (95% CI, 1.54–8.18) and 2.85 (95% CI, 1.15–7.08), respectively. Conclusion: We found a strong signal for increased risk of spontaneous abortion in patients with HBV infection taking ETV or ADV, in comparison with those prescribed with LAM. Moreover, no obvious signal association of human teratogenicity with exposure to ETV or ADV was identified in fetuses during pregnancy. Nevertheless, owing to the limitations of a spontaneous reporting database, which inevitably contains potential biases, there is a pressing need for well-designed comparative safety studies to validate these results in clinical practice. [ABSTRACT FROM AUTHOR]

BACKGROUND: Between 2012 and 2017, 25 new medications or combination products were approved by the Food and Drug Administration (FDA) for use in treatment of chronic lower respiratory diseases (CLRDs). With limited data on post-marketing patient exposure to these drugs, their safety profiles remain unknown. This study aims to provide post-marketing surveillance of these medications. METHODS: A list of new CLRD medications approved between 2012 and 2017 was generated through searches on Drugs.com (https://www.drugs.com), FDA.gov (https://www.fda.gov), and IBM Micromedex (https://www.micromedexsolutions.com/home/dispatch/ssl/true). Data describing adverse drug reactions (ADRs) were collected from the FDA Adverse Event Reporting System for analysis. Of the 25 identified medications, we selected 4 medications indicated for asthma or COPD with at least 500 reports. Only ADRs catalogued with these medications as the primary suspect were analyzed. Reporting odds ratios were calculated for the top 10 ADRs of each CLRD medication. RESULTS: A total of 61,682 ADR reports were collected for newly approved CLRD medications (n = 27,190 older adults; n = 30,502 male). Reports of COPD medications (umeclidinium and umeclidinium/vilanterol) indicate that umeclidinium/vilanterol yielded a higher reporting odds ratio than umeclidinium alone for reports of pain. Fluticasone furoate/vilanterol had higher reporting odds ratios for cough, pain, and dizziness than budesonide/formoterol and fluticasone propionate/salmeterol. CONCLUSIONS: Our findings suggest that the incidence of different adverse events experienced by patients in post-marketing reports resembles the incidence reported in pre-marketing clinical trials for COPD medications, except for fluticasone furoate/vilanterol, which has several differences. [ABSTRACT FROM AUTHOR]

Introduction: Recently, the rise of antibiotic resistance has prompted a reconsideration of tetracyclines. However, existing studies are inadequate in assessing the pediatric safety of this class of antibiotics. To address the gap, our study aims to comprehensively assess the safety of tetracyclines in children., Methods: Adverse event (AE) reports from January 2005 to September 2023 were obtained from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database, and reporting odds ratio (ROR) was performed to identify potential risk signals in children under 18 years old who were administered any of the three tetracyclines: doxycycline, minocycline, and tigecycline., Results: A total of 1903 AE cases were included in our study: 782 for doxycycline, 981 for minocycline, and 140 for tigecycline. Doxycycline and tigecycline were predominantly associated with "general disorders and administration site conditions" and "gastrointestinal disorders," while minocycline was more frequently linked to "skin and subcutaneous tissue disorders" and "gastrointestinal disorders." Psychiatric risks predominantly included depression, suicidal ideation, and suicide attempt. In the category of skin and subcutaneous tissues, 30.88% of the minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) cases resulted in death, alongside a high occurrence of co-occurring AEs such as multiple organ dysfunction syndrome, Type 1 Diabetes Mellitus (T1DM), and autoimmune thyroiditis. As for the endocrine system, both doxycycline and minocycline were found to potentially increase the risk of thyroid dysfunction. For children under the age of 8, doxycycline was associated with tooth discoloration (N = 7, ROR = 20.11%, 95% CI: 9.48-42.67), although it remained unclear whether the discoloration was permanent., Conclusion: Our findings indicated that for pediatric patients, the majority of results were in line with the prescribing information and previous studies, and minocycline tended to cause more frequent and severe AEs than doxycycline. However, it is noteworthy that exceptions were found for psychiatric disorders and thyroid dysfunction associated with doxycycline, which are not mentioned in its FDA prescribing information. Additionally, further safety studies on tigecycline are still needed for children. When prescribing tetracyclines to pediatric patients, a careful risk-benefit assessment is crucial., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qiao, Chen, Wang, Liu, Guo, Gu, Ding, Zhang and Mei.)

Background Immunosuppressants are administered in various combinations to prevent immune-induced transplant rejection in patients with liver transplant, as each immunosuppressant acts on different cellular sites. However, the use of multiple immunosuppressants also increases the risk for adverse events. Therefore, it is desirable to reduce the types of immunosuppressants administered without increasing the incidence of transplant rejection. The effectiveness of prednisone avoidance has been suggested, although this was not based on statistical significance in many instances. To definitively establish the effectiveness of prednisone avoidance, a statistically significant difference from a prednisone-use group should be demonstrated. Additionally, the effectiveness of prednisone avoidance might vary depending on the combination of other immunosuppressants administered. It has therefore been considered necessary to investigate, for various immunosuppressant combinations, the administration patterns in which prednisone avoidance is effective. Objectives This study aimed to investigate the effectiveness of prednisone avoidance in patients with liver transplant and discuss the results based on statistically significant differences. Methods Data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) were obtained. In studying immunosuppressant combinations, it was essential to control for confounding. Thus, the immunosuppressant combinations, excluding prednisone, were kept the same in the two groups being compared (prednisone-use and prednisone-avoidance groups). The large sample from FAERS allowed for those various immunosuppressant combinations to be compared. Comparisons of transplant rejection in the prednisone-use and prednisone-avoidance groups used the reporting odds ratio (ROR) and the adjusted ROR (aROR), which controlled for differences in patient background. Results With the prednisone-use groups being set as the reference, ROR and aROR were calculated for the prednisone-avoidance groups. Various immunosuppressant combinations were evaluated, and in four patterns - (1) the combination of prednisone and tacrolimus, (2) the combination of prednisone, cyclosporine, and tacrolimus, (3) the combination of prednisone, tacrolimus, and basiliximab, and (4) the combination of prednisone and everolimus) - both the ROR and the aROR for transplant rejection in the prednisone-avoidance group were significantly <1.000. Conclusions This study identified effective immunosuppressant combinations for prednisone avoidance that were not associated with increased transplant rejection. The evidence supporting the effectiveness of prednisone avoidance is strengthened when combined with results from previous studies., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Ogura et al.)

Purpose: To identify the most commonly reported drugs associated with QT interval prolongation in the FDA Adverse Event Reporting System (FAERS) and evaluate their risk for QT interval prolongation., Methods: We employed the preferred term (PT) "electrocardiogram QT prolonged" from the Medical Dictionary for Regulatory Activities (MedDRA) 26.0 to identify adverse drug events (ADEs) of QT interval prolongation in the FAERS database from the period 2004-2022. Reporting odds ratio (ROR) was performed to quantify the signals of ADEs., Results: We listed the top 40 drugs that caused QT interval prolongation. Among them, the 3 drugs with the highest number of cases were quetiapine (1,151 cases, ROR = 7.62), olanzapine (754 cases, ROR = 7.92), and citalopram (720 cases, ROR = 13.63). The two most frequently reported first-level Anatomical Therapeutic Chemical (ATC) groups were the drugs for the nervous system ( n  = 19, 47.50%) and antiinfectives for systemic use ( n  = 7, 17.50%). Patients with missing gender ( n  = 3,482, 23.68%) aside, there were more females (7,536, 51.24%) than males (5,158, 35.07%) were involved. 3,720 patients (25.29%) suffered serious clinical outcomes resulting in deaths or life-threatening conditions. Overall, most drugs that caused QT interval prolongation had early failure types according to the assessment of the Weibull's shape parameter (WSP) analysis., Conclusions: Our study offered a list of drugs that frequently caused QT interval prolongation based on the FAERS system, along with a description of some risk profiles for QT interval prolongation brought on by these drugs. When prescribing these drugs in clinical practice, we should closely monitor the occurrence of ADE for QT interval prolongation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Tan, Yan, Chen, Huang, Luo, Li, Lan, Chen and Xi.)

Saki Oyama, Keiko Hosohata, Ayaka Inada, Iku Niinomi, Yasuhiro Mori, Yuki Yamaguchi, Mayako Uchida, Kazunori Iwanaga Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan 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. Keywords: tubulointerstitial nephritis, pharmacovigilance, spontaneous reporting system, reporting odds ratio, Japanese Adverse Drug Event Report database, JADER

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. [ABSTRACT FROM AUTHOR]

Purpose: Small-molecule protein kinase inhibitors (PKIs) have substantially improved clinical outcomes of various diseases. However, some studies suggested these agents might induce acute kidney injury (AKI). This study was designed to comprehensively assess the adverse events of AKI in real-world patients receiving small-molecule PKIs using the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).Methods: The FAERS data between 2004 and 2019 were extracted to describe the characteristics of AKI cases after the use of small-molecule PKIs approved by the FDA. The reporting odds ratio (ROR) with 95% confidence interval (CI) for AKI was calculated for each small-molecule PKI agent. A disproportionality signal was defined when the lower limit of 95% CI > 1.Results: Among the 462,020 adverse event reports for small-molecule PKIs, 9970 (2.16%) were identified as AKI cases. The median AKI onset time was 32 (interquartile range 11-124) days after the initiation of small-molecule PKI treatment. A total of 61.38% and 26.04% of AKI cases resulted in hospitalization and death, respectively. Based on RORs, 14 of 52 small-molecule PKIs yielded disproportionality signals for AKI, including six VEGFR inhibitors, three mTOR inhibitors and five small-molecule PKIs with other targets. The agents with the highest AKI RORs were entrectinib (ROR 6.40, 95% CI 2.23, 18.34), sirolimus (ROR 3.76, 95% CI 3.45, 4.09), and cobimetinib (ROR 3.40, 95% CI 2.69, 4.28).Conclusion: Analysis of the FAERS data helped identify the small-molecule PKIs that were most frequently reported for AKI. Further investigations are needed to confirm these potential risks. [ABSTRACT FROM AUTHOR]