Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system

Aim

We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS).

Methods

We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications.

Results

DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (<1 week) was detected in 46% of patients (47% and 44%, respectively).

Conclusions

The disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury.     

Hematological toxicities in immune checkpoint inhibitors: A pharmacovigilance study from 2014 to 2019

Immune checkpoint inhibitors (ICIs) have shown remarkable clinical effects in many cancer types. However, ICIs could also induce severe organ system toxicities, including those of the hematological system. The present study aimed to extensively characterize the hematological toxicities of ICIs immunotherapy. Data were extracted from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 1, 2014, to March 31, 2019. Disproportionality analysis, including information component (IC) and reporting odds ratio (ROR), was used to detect potential disproportionality signal. The lower boundary of the 95% confidence interval of IC (IC₀₂₅) exceeding zero or that of ROR (ROR₀₂₅) exceeding one was considered statistically significant for detecting disproportionality signal. A total of 29 294 335 records were extracted from the database, with 132 573 related to ICIs. Overall, hematological adverse events (AEs) were more frequently reported in ICIs (IC₀₂₅: 0.81; ROR₀₂₅: 1.80). On further analysis, hematological AEs were overreported in female patients (female vs male, ROR₀₂₅: 1.04) and anti-CTLA-4 monotherapy groups (anti-CTLA-4 vs anti-PD-1, ROR₀₂₅: 1.33) and polytherapy groups (polytherapy vs monotherapy, ROR: 1.20, ROR₀₂₅: 1.11). Moreover, class-specific hematological AEs were also detected and differed in unique ICI regimens. Notably, disseminated intravascular coagulation had the highest proportion of death outcomes among the top 10 most frequently reported ICI-associated hematological AEs. Our study shows a high reporting frequency of hematological AEs induced by ICI monotherapy (especially by anti-CTLA-4 therapy) and reinforced by polytherapy. A spectrum of class-specific disproportionality signal was also detected; some were fatal and reported for the first time. The heterogeneous clinical spectrum of hematological toxicities, including the non-negligible proportion of death as reported outcome, are warranted to be reminded by clinicians. Early recognition and management of ICI-related hematological AEs are highly important and further studies are needed to confirm the results of our study.     

Hepatotoxicity reports in the FDA adverse event reporting system database: A comparison of drugs that cause injury via mitochondrial or other mechanisms

Drug-induced liver injury (DILI) is a leading reason for preclinical safety attrition and post-market drug withdrawals. Drug-induced mitochondrial toxicity has been shown to play an essential role in various forms of DILI, especially in idiosyncratic liver injury. This study examined liver injury reports submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) for drugs associated with hepatotoxicity via mitochondrial mechanisms compared with non-mitochondrial mechanisms of toxicity. The frequency of hepatotoxicity was determined at a group level and individual drug level. A reporting odds ratio (ROR) was calculated as the measure of effect. Between the two DILI groups, reports for DILI involving mitochondrial mechanisms of toxicity had a 1.43 (95% CI 1.42–1.45; P < 0.0001) times higher odds compared to drugs associated with non-mitochondrial mechanisms of toxicity. Antineoplastic, antiviral, analgesic, antibiotic, and antimycobacterial drugs were the top five drug classes with the highest ROR values. Although the top 20 drugs with the highest ROR values included drugs with both mitochondrial and non-mitochondrial injury mechanisms, the top four drugs (ROR values > 18: benzbromarone, troglitazone, isoniazid, rifampin) were associated with mitochondrial mechanisms of toxicity. The major demographic influence for DILI risk was also examined. There was a higher mean patient age among reports for drugs that were associated with mitochondrial mechanisms of toxicity [56.1 ± 18.33 (SD)] compared to non-mitochondrial mechanisms [48 ± 19.53 (SD)] (P < 0.0001), suggesting that age may play a role in susceptibility to DILI via mitochondrial mechanisms of toxicity. Univariate logistic regression analysis showed that reports of liver injury were 2.2 (odds ratio: 2.2, 95% CI 2.12–2.26) times more likely to be associated with older patient age, as compared with reports involving patients less than 65 years of age. Compared to males, female patients were 37% less likely (odds ratio: 0.63, 95% CI 0.61–0.64) to be subjects of liver injury reports for drugs associated with mitochondrial toxicity mechanisms. Given the higher proportion of severe liver injury reports among drugs associated with mitochondrial mechanisms of toxicity, it is essential to understand if a drug causes mitochondrial toxicity during preclinical drug development when drug design alternatives, more clinically relevant animal models, and better clinical biomarkers may provide a better translation of drug-induced mitochondrial toxicity risk assessment from animals to humans. Our findings from this study align with mitochondrial mechanisms of toxicity being an important cause of DILI, and this should be further investigated in real-world studies with robust designs.     

Postmarketing safety of biologics and biological devices

Background contextRegardless of study design, the approval process of biologics and biological devices cannot identify every possible safety concern. Postmarketing safety surveillance can provide information based on real-world use of medical products in heterogeneous populations and is critical for identifying potentially serious adverse events, events that are too rare to be detected during premarketing studies, late complications, and events involving individuals or uses that were not evaluated in clinical trials.PurposeTo review why adverse event reporting is important and how the information is used, with emphasis on the points that are most applicable for surgeons and other spine professionals.MethodsThis is an overview of postmarketing safety surveillance.ResultsReview of adverse event reports has resulted in safety notifications, label changes, and publications regarding the safety of biologics and biological devices, such as the risk of airway compromise after the use of recombinant human bone morphogenetic protein in cervical spine fusion, the occurrence of a fatal air embolism after the use of a fibrin sealant that had been applied with a spray device, and infections after allograft transplantation of human tissues.ConclusionsIn light of the rapid development of new biologics, postmarketing surveillance is imperative for ensuring that these products are as safe as possible. By reporting adverse events, surgeons and other health care professionals play a key role in improving and refining our understanding of the safety of biologics.     

A Survey of the FAERS Database Concerning the Adverse Event Profiles of α1-Adrenoreceptor Blockers for Lower Urinary Tract Symptoms

Purpose: Current guidelines recommend α1-adrenoreceptor blockers (A1Bs) for treating lower urinary tract symptoms suggestive of benign prostatic hyperplasia, but their adverse effects can be problematic. In this study, reports submitted to the US Food and Drug Administration Adverse Event Reporting System (FAERS) between 1997 and 2011 were reviewed to assess the safety profiles of A1Bs.Methods: After deleting duplicated submissions and revising arbitrary drug names, reports involving A1Bs for male patients were analyzed. Data mining algorisms were used for the quantitative detection of signals, where a signal represents an association between a drug and an adverse event or a drug-associated adverse event, including the proportional reporting ratio, reporting odds ratio, information component given by a Bayesian confidence propagation neural network, and empirical Bayes geometric mean.Results: The total number of reports used was 1,260,182. Signal scores suggested the associations of alfuzosin, doxazosin, tamsulosin, and terazosin with dizziness/vertigo, orthostatic hypotension, erectile dysfunction, ejaculation dysfunction (EjD), thirst/dry mouth, and constipation; however, reports on naftopidil, silodosin, and urapidil were not enough to compare with the other 4 A1Bs. Signal scores for EjD were higher for tamsulosin, and those for dizziness/vertigo were lower for doxazosin than for the other 3 drugs.Conclusions: Tamsulosin-associated EjD, which was found in clinical studies, was reproduced in this analysis with markedly higher signal scores, and these results strongly suggest the necessity of well-organized clinical studies on A1B-associated adverse events.     

Adverse drug and device reactions in the oral cavity: Surveillance and reporting

BackgroundAccording to the U.S. Centers for Disease Control and Prevention, 48 percent of Americans (roughly 144 million people) used at least one prescribed medication in the preceding month; 11 percent used five or more. The authors describe the U.S. Food and Drug Administration&apos;s (FDA&apos;s) MedWatch program, the safety surveillance system for drugs and devices in the United States, and the dentist&apos;s role with regard to voluntary reporting of adverse effects (AEs). They also identify the most frequent AEs in the oral cavity as reported in the FDA Adverse Event Reporting System (FAERS).MethodsThe authors reviewed the literature regarding MedWatch, and they mined data in the FAERS public database for the 100 most commonly prescribed medications and their associated AEs.ResultsPharyngitis was the most common AE. Cough, dysgeusia and dysphagia also were common.ConclusionThe MedWatch program and its related databases contain useful information about AEs of pharmaceuticals and devices manifested in the oral cavity. Increased participation in the reporting of suspected adverse reactions will improve the national surveillance system and ultimately will protect patients&apos; safety.Practical ImplicationsAs pharmaceutical consumption increases exponentially for a growing segment of the population, and as innovation in dental technology and devices flourishes, dentists have a distinct role in safeguarding patients&apos; well-being. Promptly reporting AEs in the oral cavity improves quality of care and protects patients&apos; well-being.     

Analysis of the adverse reactions of atezolizumab: A real-world study based on FAERS database

Objective In this study, we aimed to determine the incidence of adverse drug reactions (ADRs) of atezolizumab, identify ADR signals that are significantly related to atezolizumab, and provide a reference for the rational use of atezolizumab in the clinic through the statistical analysis of its adverse drug events (ADEs) reported in the American Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database. Methods In total, 4796 cases of atezolizumab ADEs reported in the American FAERS database from 2017 to 2019 were retrospectively analyzed. Results The top three ADEs were febrile neutropenia (3.7％), anemia (2.9％), and acute renal failure (2.3％). In addition, the incidence rates of some ADEs were significantly different according to sex and age. The systematic organ classification of atezolizumab ADEs involved 32 systems, among which the top three were blood and lymphatic system disorders (585 cases, 12.2％), gastrointestinal disorders (433 cases, 9.0％), and infections and infestations (401 cases, 8.4％). The reporting odds ratio (ROR) method was used to detect the ADR signals of atezolizumab. The ROR (95％ confidence interval) of the top ADE, febrile neutropenia, was 39.236 (33.757–45.604). In addition, we found 121 cases of complications associated with immune-related ADEs. Conclusion The ADRs of atezolizumab reported in the FAERS database were consistent with those mentioned in the instructions for atezolizumab use, suggesting that atezolizumab has an acceptable and controllable drug effect.     

基于FAERS数据库的氟尿嘧啶和卡培他滨不良事件信号挖掘研究

目的 挖掘氟尿嘧啶和卡培他滨的药物不良事件（ADE）信号,为安全用药提供参考。方法 提取FAERS数据库2017年第1季度至2021年第3季度共19个季度内上述药物的不良反应报告数据,采用报告比值比法（ROR）和综合标准法（MHRA）进行信号挖掘。结果 去重后共检出654个ADE信号,累及27个系统器官分类,其中氟尿嘧啶的ADE信号主要集中在血液及淋巴系统疾病、全身性疾病及给药部位各种反应、胃肠系统疾病和各类神经系统疾病等;卡培他滨的ADE信号主要集中在胃肠系统疾病、皮肤及皮下组织类疾病、全身性疾病及给药部位各种反应和血液及淋巴系统疾病等。在消化系统毒性方面,两种药物均显示出较强的相关性,区别在于氟尿嘧啶与血液系统毒性、心脏相关毒性关联性更强,而卡培他滨与皮肤相关毒性关联性更强。结论 检出的氟尿嘧啶和卡培他滨ADE信号中,大多数与药品说明书重合性较好,证明了本研究的可靠性。本研究还发现了药品说明书未记载的ADE,可供临床参考。     

基于FAERS数据库的蒽环类药物不良事件信号挖掘研究

目的 通过挖掘美国食品药品监督管理局不良事件呈报系统（FAERS）数据库中关于蒽环类药物（多柔比星、多柔比星脂质体,表柔比星、伊达比星、柔红霉素、米托蒽醌）的相关数据,探讨该药潜在的不良反应（ADR）,为临床安全用药提供依据。方法 提取FAERS数据库中2017年第一季度至2021年第四季度共20个季度6种蒽环类药物的不良事件（ADE）数据,采用报告比值比法（ROR）和综合标准法（MHRA）进行信号挖掘。结果 共得到16 334例次以6种蒽环类药物为首要怀疑药物的ADE报告,检测得到1 654个有效ADR信号。其中,多柔比星（非脂质体,DOX）有效信号637个,多柔比星脂质体（PLD）有效信号441个,表柔比星（EPC）有效信号247个,柔红霉素（DAC）有效信号183个,伊达比星（IDC）有效信号87个,米托蒽醌（MT）有效信号59个。信号累及23个不同的系统器官分类（SOC）,不同蒽环类药物的ADE主要累及血液及淋巴系统疾病、感染及侵染类疾病、心脏器官疾病等SOC。结论 蒽环类药物常见ADR累及的主要系统具有差异性,且不同药物之间与各系统ADR的关联强度不同。临床应用蒽环类药物时需关注血液及淋巴系统、心脏器官系统及神经系统相关指标的监测,以保证临床合理用药。     

基于FAERS的地舒单抗安全警戒信号挖掘与评价

基于FAERS数据库挖掘安全警戒信号,分析评估地舒单抗潜在不良反应信号,为其临床使用提供一定参考依据。方法 通过Openvigil 2.1访问 FAERS 数据库,将地舒单抗作为主要药物,检索自该药首次上市时间（2010年5月—2021年9月）的数据,获得与地舒单抗相关的不良事件报告记录。使用报告比值比法（ROR）和贝叶斯置信度递进神经网络法（BCPNN）筛选地舒单抗安全警戒信号,挖掘潜在的不良反应,并通过工具BioPortal对不良事件信号挖掘结果进行系统分类,通过判断信号间置信区间的变化,发现与药物不良事件关联性较大的信号。结果 从FAERS数据库中收集到270503份不良反应事件（ADE）报告,根据ROR法和BCPNN法共得到343个不良事件信号,通过信号间同义合并、剔除与药物无关的信号后,得到316个不良事件信号。地舒单抗的不良事件系统分类主要为肌肉骨骼和结缔组织疾病、医学检查、胃肠道疾病。FAERS数据库的信号挖掘结果发现,高风险且说明书中未收录的安全警戒信号包括颞下颌关节综合征、下颌脓肿、雌激素缺乏症、血液甲状旁腺激素增加,计算高风险信号的置信区间显示颞下关节综合征较有可能发展成为新的不良反应;另外,也发现种植体周围炎为具有临床意义的可疑警戒信号,但有待进一步观察研究。结论 基于FAERS数据库的信号挖掘结果提示临床应规范使用地舒单抗,治疗期间需警惕患者是否出现颞下颌关节综合征、下颌脓肿、雌激素缺乏症、血液甲状旁腺激素增加等不良反应事件,以便尽早发现尽早处理,从而有效降低临床用药风险