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Excavation and Analysis of ADR Signals of Fluconazole，Ketoconazole，Itraconazole and Voriconazole
after Marketing
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LIU Hailin ，YUAN Hongmei ，WANG Hu ，DIAO Junlin ，ZHOU Chunqiao ，DING Xiaoli ，ZHANG Xuelin ，
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DONG Zhi ，WANG Song（1. Dept. of Pharmacy，the First People’s Hospital of Chongqing Liangjiang New
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District，Chongqing 401121，China；2. Dept. of Pharmacy，Yunyang County People’s Hospital，Chongqing
404506，China；3. College of Pharmacy，Chongqing Medical University，Chongqing 400046，China）
ABSTRACT OBJECTIVE：To excavate the safety warning signals induced by azole antifungal agents，including fluconazole，
ketoconazole，itraconazole and voriconazole after marketing，and to provide references for rational drug use in the clinic.
METHODS：Reporting odds ratio（ROR）data mining algorithm was used to investigate signals of adverse drug event（ADE）for
fluconazole，ketoconazole，itraconazole and voriconazole from FDA Adverse Event Reporting System （FAERS） during January
1st，2004 to March 30th，2019. ROR data mining method was used to excavate the ADR signals of the drugs，and main ADR
involved in the safety information of azole antifungal agents instructions were analyzed. RESULTS：A total of 27 831，5 712，
5 381 and 11 333 reports were picked out for fluconazole，ketoconazole，itraconazole and voriconazole，respectively. All of these
drugs had exhibited high-risk signals detection by ROR，including medical examination，blood and lymphatic system disorders，
renal and urinary disorders， endocrine diseases， hepatobiliary disorders. The hepatotoxic-related ADR signals were mainly
concentrated in fluconazole and voriconazole （fluconazole ROR＝6.51，voriconazole ROR＝14.65）；ADR detection results of
Cushing’s-like syndrome （ROR＝24.86） and adrenal suppression （ROR＝44.06） by itraconazole showed high-risk signals；
ketoconazole and itraconazole had showed a strong ADR signal in adrenocortical dysfunction （ketoconazole ROR＝15.64，
itraconazole ROR＝23.26），and the signal intensity of ketoconazole （ROR＝2.81）in skin and subcutaneous tissue disorders was
significantly higher than that of other drugs. In addition，hemorrhagic cystitis caused by fluconazole，itraconazole and voriconazole
were not included in the drug instructions （fluconazole ROR＝17.73，itraconazole ROR＝31.43，voriconazole ROR＝17.06）；
netted green spot caused by fluconazole （ROR＝10.50）were not included in the drug instructions. CONCLUSIONS：Clinical staff
should pay more attention to the differences in serious ADR related to fluconazole，ketoconazole，itraconazole and voriconazole；
particularly some ADRs not mentioned in the drug instructions but have high incidence such as hemorrhagic cystitis caused by
fluconazole，itraconazole，voriconazole and netted green spot caused by fluconazole，as well as ADRs mentioned in the drug
instructions but have abnormally high signal，such as Cushing’s-like syndrome and adrenal suppression caused by itraconazole .
KEYWORDS Fluconazole；Ketoconazole；Itraconazole；Voriconazole；ADR；Signal mining；Reporting odds ratio

近年来，随着器官移植、恶性肿瘤以及免疫缺陷患 的ADR及更新信息，运用信号挖掘技术对上述4种唑类
者的增多，真菌感染在临床中也愈发常见 [1-2] 。随着抗真 抗真菌药品涉及的主要 ADR 进行信号分析，以期为临
菌药物的广泛应用，该类药品不良反应（ADR）越来越受 床合理用药提供参考。
到临床的关注，而临床上以唑类抗真菌药物的应用最为 1 资料与方法
[3]
广泛，其上市后的ADR发生率亦最高 。唑类抗真菌药 1.1 数据来源
物主要包括咪唑类和三唑类，咪唑类药物在临床常用的 本研究以美国FDA公众健康项目（open FDA）数据
为酮康唑，而三唑类药物主要包括氟康唑、伊曲康唑和 库作为数据来源，其 ADE 原始数据由 FAERS 导入。
伏立康唑，均为广谱抗真菌药。其中，酮康唑为首个用 FAERS 收集了发生在美国境内外用药相关的自发性安
于治疗真菌感染的口服唑类药物，但因其肝毒性，现主 全报告及上市后临床研究报告，且所有ADE数据以《国
要作为浅表部真菌感染的首选治疗药物；而氟康唑、伊 际医学用语词典》（Medical Dictionary for Drug Regula-
曲康唑和伏立康唑为治疗深部真菌感染的一线用药。 tory Activities，MedDRA）的首选语（Preferred terms）进行
[5]
唑类药物在抗真菌治疗中占有重要地位，但关于其用药 编码 。本研究提取 FAERS 数据库 2004 年 1 月 1 日－
安全性尚未有文献系统阐明。 2019 年 3 月 30 日期间接收的氟康唑、酮康唑、伊曲康唑
基于自发呈报系统进行 ADR 的信号检测和分析， 和伏立康唑的ADE报告进行信号挖掘分析。
是目前主要的 ADR 监测手段和信号来源，常用于发现 1.2 数据处理
新的、潜在的ADR及评估药物风险，可为用药决策提供 本研究数据提取采用 open FDA 分析工具，通过对
数据参考 。本研究拟通过对美国 FDA 药品不良事件 接应用程序接口直接提取 FAERS 数据库中结构化的
[4]
（ADE）报 告 系 统（FDA Adverse Events Reporting Sys- ADE 报告信息。选择“药品不良事件（Drug adverse
tem，FAERS）的相关数据进行挖掘分析，并结合中美两 events，ADE）”模块，为了保证数据提取的完整性，限定
国氟康唑、酮康唑、伊曲康唑和伏立康唑药品说明书中 目标药物通用名（Generic name）为“Fluconazole”“Keto-

中国药房 2020年第31卷第9期 China Pharmacy 2020 Vol. 31 No. 9 ·1119 ·