基于FDA不良事件数据库和指定医疗事件对氯喹和羟氯喹不良反应信号的检测与评价

目的： 挖掘和评价新型冠状病毒肺炎治疗方案（试行第七版）中加入的药物"磷酸氯喹"和《上海市2019冠状病毒病综合救治专家共识》中推荐加入的"硫酸羟氯喹"上市后的安全信号，为临床合理用药提供参考。方法： 检索美国FDA不良事件报告系统（FDA adverse event reporting system，FAERS）数据库2004年1月1日-2019年12月31日收录以"氯喹"及"羟氯喹"为怀疑对象的不良事件（adverse drug events，ADEs）报告，提取排名前200位药物不良反应（adverse drug reaction，ADR）报告进行指定医疗事件（designated medical event，DME）筛选，采用报告比值比法（ROR）和比例报告比值比法（PRR）检测ADR信号，重点评估和比较出现DME的系统器官分类（SOC）中的安全信号，并对DME进行分析。结果： 提取FAERS数据库得到氯喹与羟氯喹ADEs报告数量分别为1 128例和29 639例；氯喹严重不良事件（serious adverse event，SAE）占比57.89%，羟氯喹占比26.60%。经DME筛选，共涉及7种SOC，其中眼部疾病与呼吸系统相关ADR中，羟氯喹检出的信号较多；皮肤和皮下组织类疾病，2种药物信号检出数量大致相等；心脏、血液及肝胆系统相关ADR中，信号主要集中在氯喹；耳部系统相关ADR中，信号检出较少。另外，氯喹检出的7种DME中尖端扭转型室速信号值最高，羟氯喹检出的4种DME中中毒性表皮坏死松解症信号值最高。结论： 基于真实世界的ADR信号检测有助于新冠疫情中氯喹与羟氯喹的安全性评价，降低临床用药风险。

Detection and evaluation of adverse drug reaction signals of chloroquine and hydroxychloroquine based on FDA adverse event database and designated medical event

OBJECTIVE Toexcavate and evaluate the postmarketing safety signals of chloroquine phosphate that recommended for trial in the COVID-19 treatment plan(The seventh trial version)and hydroxychloroquine sulfate that recommended by "Expert consensus on comprehensive treatment of 2019 coronavirus disease in Shanghai",to provide reference for clinical rational drug use.METHODS The FDA adverse event reporting system(FAERS)database was searched from January 1,2004 to December 31,2019 to include adverse event(ADEs)reports with "chloroquine" and "hydroxychloroquine" as suspected objects.The top 200 adverse drug reaction(ADR)reports were extracted for designated medical event(DME)screening.The ADR signals were detected by reporting odds ratio(ROR)and proportional reporting odds ratio(PRR).The safety signals in the system organ class(SOC)with DME were evaluated and compared emphatically,and the DME was analyzed.RESULTS The number of ADEs reported by chloroquine and hydroxychloroquine was 1 128 and 29 639,respectively,by extracting the FAERS database;chloroquine accounted for 57.89% of serious adverse events(SAEs)and hydroxychloroquine accounted for 26.60%.After DME screening,a total of 7 SOCs were involved,of which the signals detected by hydroxychloroquine were more in the ADRs related to eye diseases and respiratory system;the signals detected by the two drugs were approximately equal in the skin and subcutaneous tissue diseases;the signals were mainly concentrated in chloroquine in the ADRs related to heart,blood and hepatobiliary system;and the signals were less detected in the ADRs related to ear system.In addition,torsades de pointes had the highest signal value among the seven DMEs detected by chloroquine and toxic epidermal necrolysis had the highest signal value among the four DMEs detected by hydroxychloroquine.CONCLUSION The detection of ADR signal based on real world is helpful for the safety evaluation of chloroquine and hydroxychloroquine in the new crown epidemic situation and reducing the risk of clinical medication.