基于FDA不良事件报告系统的氯喹及羟氯喹不良反应分析与评价

目的：氯喹及羟氯喹是新型冠状病毒肺炎的推荐试用治疗药物，但存在较多安全性问题。研究利用FDA不良事件报告系统（FAERS）数据库挖掘和综合评价分析氯喹及羟氯喹相关事件，为新型冠状病毒肺炎患者提供安全用药信息。方法：从FAERS数据库中提取氯喹及羟氯喹相关不良事件个案报告，对患者基本信息、报告者信息、报告时间、常见不良事件等进行分析，采用比值比法（reporting odds ratio，ROR）和综合标准法（medicines and healthcare products regulatory agency，MHRA）两种比值失衡分析法检测氯喹及羟氯喹相关信号，进而通过病例分析和文献报道对ROR法和MHRA法均有检出的信号进行药品相关性评估分析。结果：2014年7月至2019年3月FAERS数据库中以氯喹和羟氯喹为主要和次要怀疑药物的初次上报报告分别为383例和11 169例，其中导致死亡的报告51例（13.3%）和310例（2.8%），致死事件包括药物中毒、自杀、胎儿死亡、心脏骤停等。ROR法和MHRA法分别检出氯喹相关信号105个和100个，羟氯喹相关728个和650个。经筛选，相关的不良反应主要为心肌病、房室传导阻滞、视网膜病变、感音神经性耳聋、肌病、药物性精神病、转氨酶异常和溶血等。其中心肌病、房室传导阻滞、心室肥大、视神经萎缩、反射消失、肌无力综合征、血脂异常等和尖端扭转型室速、长QT综合征、限制性心肌病、颅神经损伤、低血糖等分别未在氯喹和羟氯喹说明书中提及。结论：在氯喹和羟氯喹的临床应用中，应关注心脏毒性、视网膜毒性和耳毒性等不良反应，并加强反射消失、肌无力综合征、血脂异常（氯喹），及低血糖（羟氯喹）等新的不良反应信号的监测。

Chloroquine and hydroxychloroquine related adverse events based on FDA adverse event reporting system (FAERS) and assessment

OBJECTIVE Chloroquine and hydroxychloroquine are recommended trial agents for novel coronavirus pneumonia, but there are many safety problems.In this study, chloroquine and hydroxychloroquine-related events were analyzed using the FDA Adverse Event Reporting System (FAERS) database mining and comprehensive evaluation to provide safe medication information for patients with novel coronavirus pneumonia.METHODS Reports of chloroquine and hydroxychloroquine-related adverse events were extracted from FAERS database, and the basic information of patients, reports, reporting time, and common adverse events were analyzed. Two disproportionality analysis methods, reporting odds ratio (ROR) and medicines and regulatory healthcare products agency (MHRA) method, were used to detect chloroquine and hydroxychloroquine-related signals, and then the signals detected by ROR and MHRA methods were evaluated and analyzed for drug correlation through case analysis and literature reports.RESULTS From July 2014 to March 2019, 383 and 11 169 cases were initially reported in FAERS database for chloroquine and hydroxychloroquine as primary and secondary suspected drugs, respectively, of which 51 cases (13.3%) and 310 cases (2.8%) led to death. Fatal events included drug poisoning, suicide, fetal death and sudden cardiac arrest.105 and 100 chloroquine-related signals and 728 and 650 hydroxychloroquine-related signals were detected by ROR and MHRA, respectively. After screening, the related adverse reactions were mainly cardiomyopathy, atrioventricular block, retinopathy, sensorineural deafness, myopathy, drug-induced psychosis, transaminase abnormalities and hemolysis. Among them, cardiomyopathy, atrioventricular block, ventricular hypertrophy, optic atrophy, areflexia, myasthenic syndrome, dyslipidemia and torsades de pointes, long QT syndrome, restrictive cardiomyopathy, cranial nerve injury, hypoglycemia are not mentioned in the package inserts of chloroquine and hydroxychloroquine, respectively.CONCLUSION In the clinical application of chloroquine and hydroxychloroquine, attention should be paid to adverse reactions such as cardiotoxicity, retinotoxicity and ototoxicity, and the monitoring of new adverse reaction signals such as areflexia, myasthenic syndrome, dyslipidemia (chloroquine), and hypoglycemia (hydroxychloroquine) should be strengthened.