Datasheet1_Disproportionality analysis of quinolone safety in children using data from the FDA adverse event reporting system (FAERS).docx

BackgroundQuinolones are widely prescribed for the treatment or prevention of infectious diseases in children. To gain further insight into quinolone-associated adverse event (AE) in children and better protect pediatric patients, continued surveillance of safety data is essential. The purpose of this study was to characterize the safety profiles of quinolone-associated AEs in children by mining the FDA adverse event reporting system (FAERS).
MethodsFAERS reports from quarter 1 of 2004 to quarter 1 of 2022 were included in the study. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify adverse events. Reporting odds ratios (ROR) corresponding 95% confidence intervals (CIs) and information component (IC) along with 95% CIs were calculated to detect drug–AE pairs with higher-than-expected reporting rates within the FAERS from System Organ Classes (SOCs) to Preferred Terms (PTs). Reports were considered as signals if the 95% confidence interval did not contain the null value.
ResultsAfter inclusion criteria were applied, a total of 4,704 reports associated with quinolones were considered. Most FAERS reports associated with ciprofloxacin (N = 2,706) followed by levofloxacin (N = 1,191), moxifloxacin (N = 375), oflaxacin (N = 245) and ozenoxacin (N = 187). The most common age group was 12–18 years. The median weight was 39.0 kilogram. The adverse effects of quinolones emerging for SOCs primarily included Infections and infestations, gastrointestinal symptoms, blood and lymphatic system disorders, cardiac disorders, nervous system disorders, musculoskeletal and connective tissue disorders and psychiatric disorders. The most frequently AE signals at the PT level were pyrexia (N = 236), febrile neutropenia (N = 120), off label use (N = 48), drug resistance (N = 18) and cardiac arrest (N = 22) following the use of ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, and ozenoxacin, respectively. Serious oznoxacin-associated AE signals were found and have not been documented in the package insert. They included cardiac arrest (N = 22; ROR = 19.83; IC = 3.68), overdose (N = 21; ROR = 4.98; IC = 2.07), seizure (N = 16; ROR = 6.01; IC = 2.29), small for dates baby (N = 9; ROR = 14.7; IC = 3.05), completed suicide (N = 15, ROR = 18.87; IC = 3.51), asthma (N = 9; ROR = 6.69; IC = 2.24;) and hypotension (N = 9; ROR = 3.83; IC = 1.68).
ConclusionThis study provided additional evidence with respect to quinolones-related AEs for children. Generally, the findings of this study are compatible with AEs recorded in package inserts. The unexpected signals of ozenoxacin justify active vigilance by clinicians and timely monitoring by pharmacovigilance experts.

研究背景
喹诺酮类（quinolones）药物被广泛用于儿童感染性疾病的治疗与预防。为深入了解儿童喹诺酮类相关不良事件（adverse event, AE），并更好地保护儿科患者，持续开展安全性数据监测至关重要。本研究旨在通过挖掘美国食品药品监督管理局不良事件报告系统（FDA Adverse Event Reporting System, FAERS）的数据，阐明儿童喹诺酮类相关不良事件的安全性特征。

研究方法
本研究纳入了2004年第一季度至2022年第一季度的FAERS报告。本研究采用监管活动医学词典（Medical Dictionary for Regulatory Activities, MedDRA）识别不良事件。本研究计算了报告比值比（Reporting Odds Ratios, ROR）及其对应的95%置信区间（95% confidence intervals, CIs），以及信息成分（IC）及其95%置信区间，以在FAERS数据库中从系统器官分类（System Organ Classes, SOCs）到首选术语（Preferred Terms, PTs）层面，识别报告率高于预期的药物-不良事件配对。若95%置信区间未包含无效值，则将相关报告视为信号。

研究结果
经纳入标准筛选后，本研究共纳入4704份与喹诺酮类药物相关的报告。其中环丙沙星相关报告最多（N=2706），其次为左氧氟沙星（N=1191）、莫西沙星（N=375）、氧氟沙星（N=245）及奥泽沙星（N=187）。最常见的年龄组为12~18岁，受试者中位体重为39.0千克。从系统器官分类层面来看，喹诺酮类药物相关不良事件主要包括感染与侵袭、胃肠道症状、血液及淋巴系统疾病、心脏疾病、神经系统疾病、肌肉骨骼与结缔组织疾病以及精神疾病。在首选术语层面，最常见的不良事件信号分别为：使用环丙沙星后的发热（N=236）、使用左氧氟沙星后的发热性中性粒细胞减少症（N=120）、使用莫西沙星后的超说明书用药（N=48）、使用氧氟沙星后的耐药性（N=18），以及使用奥泽沙星后的心搏骤停（N=22）。本研究发现了奥泽沙星相关的严重不良事件信号，这些信号未在药品说明书中记载，包括心搏骤停（N=22；报告比值比ROR=19.83；信息成分IC=3.68）、药物过量（N=21；ROR=4.98；IC=2.07）、癫痫发作（N=16；ROR=6.01；IC=2.29）、足月小样儿（N=9；ROR=14.7；IC=3.05）、自杀完成（N=15；ROR=18.87；IC=3.51）、哮喘（N=9；ROR=6.69；IC=2.24）及低血压（N=9；ROR=3.83；IC=1.68）。

研究结论
本研究为儿童喹诺酮类相关不良事件提供了新增证据。总体而言，本研究结果与药品说明书中记载的不良事件相符。奥泽沙星相关的未预期不良事件信号，提示临床医师应提高警惕，药物警戒专家需及时开展监测。