基于FARES数据库的贝利尤单抗ADE风险信号挖掘

ADE Risk Signal Mining Related to Belimumab Based on the FARES Database

目的:挖掘贝利尤单抗相关不良事件(ADE)的风险信号,为该药的安全合理使用提供参考。方法:收集美国FDA不良事件报告系统(FAERS)中2015年第1季度至2021年第1季度的贝利尤单抗相关ADE报告。利用报告比值比(ROR)法和英国药品和保健品管理局的综合标准法(以下简称"MHRA法"),设定阈值为报告数>3且ROR值的95%CI下限>1(ROR法)和比例报告比值(PRR)>2且χ2>4(MHRA法),挖掘贝利尤单抗相关的ADE风险信号。采用《国际医学用语词典》的首选系统器官分类(SOC)和首选术语(PT)对ADE报告进行归纳、分析。结果与结论:共筛选出以贝利尤单抗单药为首要怀疑药物的ADE报告3 529份,其中女性患者(90.31%)远远多于男性(6.15%);患者年龄集中于18~59岁(41.80%);严重ADE报告有1 234份(34.97%),以住院或住院时间延长为主;报告者大部分为消费者或其他非医疗专业人员(81.84%);上报地区主要为北美洲(70.39%),主要上报国家为美国(2 029份)。从3 529份报告中共挖掘出180个PT,除与原发疾病相关PT(系统性红斑狼疮、疼痛、关节痛、发热、体质量降低、肿胀、口咽疼痛等)外,报告数较多的为用药错误相关PT(产品漏用/漏服、产品给予时间表不当、用药剂量不足、产品可获性问题等)和感染相关PT(流行性感冒、尿路感染、感染、鼻窦炎等);涉及26个SOC,报告数排序前10位的SOC为各类损伤、中毒及手术并发症(2 225份),感染及侵染类疾病(1 247份),全身性疾病及给药部位各种反应(1 196份),各种肌肉骨骼及结缔组织疾病(1 195份),各种手术及医疗操作(515份)等。ADE报告数排序第1位的SOC(各类损伤、中毒及手术并发症)中的PT均与用药错误相关,ADE报告数排序第2位的SOC(感染及侵染类疾病)中的带状疱疹、肾脏感染和蜂窝织炎均未被贝利尤单抗药品说明书收录,临床关注的各类神经系统疾病、免疫系统疾病、精神疾病和良性、恶性及性质不明(包括囊状和息肉状)的肿瘤等SOC中的大部分PT亦未被贝利尤单抗药品说明书收录。建议临床在使用贝利尤单抗时应尽量避免用药错误,警惕患者出现带状疱疹、肾脏感染、蜂窝织炎以及各类神经系统疾病、免疫系统疾病、精神疾病等相关不良反应;此外,恶性肿瘤或有相关病史的患者应谨慎使用贝利尤单抗。

OBJECTIVE:To provide reference for clinical safe and rational use of belimumab by mining the risk signals of adverse drug event(ADE).METHODS:ADE reports related to belimumab were collected from FDA adverse event reporting system(FAERS) from the first quarter of 2015 to the first quarter of 2021.The reporting odds ratio(ROR) method and the Medicines and Healthcare Products Regulatory Agency(MHRA) method were adopted to mine the ADE risk signals related to belimumab,setting the threshold as the number of reports >3 and the lower limit of 95% CI >1(ROR method) and the proportional reporting ratio(PRR)>2,and χ2>4(MHRA method).ADEs were counted and classified by using the preferred system organ class(SOC) and preferred term(PT) of Medical Dictionary for Regulatory Activities(MedDRA).RESULTS &CONCLUSIONS:A total of 3 529 ADE reports with belimumab as the primary suspicious drug were screened,in which female patients(90.31%)were much more than male patients(6.15%);age distribution was concentrated in 18-59 years old(41.80%).There were 1 234 cases(34.97%)of severe ADE reports,mainly involving hospital or prolonged hospital stay.Most of the reporters were consumers or other non-medical professionals(81.84%).North America reported the most(70.39%)and the main reporting country was the United States(2 029 reports).A total of 180 PTs were mined from 3 529 reports,in addition to PTs associated with primary disease(systemic lupus erythematosus,pain,arthralgia,pyrexia,weight decreased,swelling,oropharyngeal pain,etc.),PTs related to medication error(product dose omission,inappropriate schedule of product administration,underdose,product availability issue,etc.) and PTs related to infection(influenza,urinary tract infection,infection,sinusitis,etc.) were reported in a large number of cases.Twenty-six SOCs were involved,the top 10 SOC in ADE reports were all kinds of injuries,poisoning and surgical complications(2 225 reports),infections and infectious diseases(1 247 reports),general disorders and administration site conditions(1 196 reports),musculoskeletal and connective tissue disorders(1 195 reports),surgical and medical procedures(515 reports),etc.PTs in SOC in the first place(all kinds of injuries,poisoning and surgical complications)of ADE reports were all related to medication error;herpes zoster,kidney infection and cellulitis in SOC in the second place(infections and infectious diseases)of ADE reports were not included in the drug instruction of belimumab;most PTs in SOCs such as various nervous system diseases,immune system diseases,mental diseases,benign,malignant and unknown tumors(including cystic and polypoid) which were taken attention in clinic were not included in the drug instruction of belimumab.It is suggested to avoid medication errors as far as possible in clinical use of belimumab,and to guard against adverse reactions such as herpes zoster,kidney infection,cellulitis and various nervous system diseases,immune system diseases and mental diseases.In addition,the patients with malignant tumor or related history should use belizumab carefully.