Safety assessment of clomiphene: a real-world pharmacovigilance analysis from the Food and Drug Administration adverse event reporting system

Clomiphene is widely used for the treatment of anovulatory infertility, yet there remain many unrecognized adverse events (AEs). The objective of this study is to provide a comprehensive overview of the safety profile of clomiphene. The data were derived from the first quarter of 2004 to the third quarter of 2023 from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. The detection of new AE signals involved the use of four algorithms: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM). A total of 16,677,289 AE reports were acquired from the FAERS database, and there were 2,620 AEs specifically reported in 720 patients following clomiphene use. The AEs encompassed 102 preferred terms (PTs) across 24 system organ classes (SOCs). Some new AEs were identified, including conjoined twins (0.5%), Potter’s syndrome (0.3%), genitalia external ambiguous (0.3%), esophageal atresia (0.6%), and anal atresia (0.3%). Although the majority of AEs aligned with the drug instruction, some new AE signals such as conjoined twins and genitalia external ambiguous were not captured. Well-designed studies are required to demonstrate the safety of clomiphene.

克罗米芬（Clomiphene）被广泛应用于无排卵性不孕症的治疗，但目前仍存在大量未被认知的不良事件（Adverse Events, AEs）。本研究旨在全面阐明克罗米芬的安全性特征。研究数据取自2004年第一季度至2023年第三季度的美国食品药品监督管理局不良事件报告系统（Food and Drug Administration Adverse Event Reporting System, FAERS）数据库。新型不良事件信号的检测采用了四种算法：报告比值比（reporting odds ratio, ROR）、比例报告比值比（proportional reporting ratio, PRR）、贝叶斯置信传播神经网络（Bayesian confidence propagation neural network, BCPNN）以及经验贝叶斯几何均值（empirical Bayesian geometric mean, EBGM）。本研究从FAERS数据库中共获取16677289份不良事件报告，其中2620例不良事件为720例使用克罗米芬的患者所特有。这些不良事件覆盖了24个系统器官分类（system organ classes, SOCs）下的102个首选术语（preferred terms, PTs）。本研究识别出若干新型不良事件，包括连体双胞胎（0.5%）、波特综合征（0.3%）、外生殖器性别不清（0.3%）、食管闭锁（0.6%）以及肛门闭锁（0.3%）。尽管多数不良事件与药品说明书所载内容一致，但连体双胞胎、外生殖器性别不清等新型不良事件信号未被现有说明书收录。未来需开展设计严谨的研究，以验证克罗米芬的安全性。