基于FAERS数据库万古霉素在老年患者中的不良事件信号挖掘

目的 通过分析美国食品药品监督管理局不良事件报告系统（FAERS）数据库,挖掘万古霉素在老年患者的不良事件（ADE）,为临床用药监护提供参考。方法 收集FAERS数据库从2004年至2022年第1季度的ADE报告,使用Open Vigil 2.1数据平台,对65岁以上患者使用万古霉素的ADE进行预处理。采用报告比值比（ROR）法和比例报告比值比（PRR）法对ADE进行挖掘与分析,获得发生频次及信号强度前10位的ADE,并分析前10位的联合用药情况。结果 以万古霉素为首要怀疑药品在65岁以上人群中的ADE报告共2221份,检测到ADE信号2194个,其中445个属于药物的不良反应。按照发生频次排序,ADE分别为药物超敏反应（313例）、急性肾损伤（301例）及发热（296例）等。按照信号强度排序,ADE分别为禽流感（ROR＝4312.79）、细菌性心包炎（ROR＝2985.78）及假丝酵母菌脑膜炎（ROR＝1658.77）。联合用药中,前3位的药物分别为哌拉西林/他唑巴坦151例,庆大霉素119例及美罗培南112例。结论 万古霉素在老年人应用时,应警惕肾毒性、超敏反应及谷浓度,同时应注意联合用药对万古霉素不良反应发生的影响。     

Reporting of Thromboembolic Events with JAK Inhibitors: Analysis of the FAERS Database 2010–2019

Introduction

A potentially elevated risk for pulmonary thrombosis with Janus kinase inhibitors (JAKinibs) was identified, as well as an increased risk for portal vein thrombosis, in ruxolitinib patients. Consequently, the objective of this investigation was to repeat a comprehensive analysis of the US FDA’s Adverse Event Reporting System (FAERS) database to assess postmarketing reporting rates of thromboembolic events (TEs) in patients treated with JAKinibs.

Methods

FAERS data (1 January 2010 to 30 September 2019) were searched for reports of all FDA-approved JAKinibs across all indications. For each drug–adverse drug reaction (ADR) pair, the reporting odds ratio (ROR) [two-sided 95% confidence interval (CI)] and empirical Bayesian geometric mean (EBGM) [one-sided 95% lower bound] were calculated to detect drug–ADR pairs with higher-than-expected reporting rates within the FAERS. Significance was declared when both lower 95% CI bounds were > 1.

Results

Significantly elevated reporting rates of pulmonary thrombosis were evident with tofacitinib (ROR 2.36 [1.69–3.31]; EBGM 2.01 [1.53]), as was pulmonary embolism with baricitinib (ROR 12.23 [8.35–17.89]; EBGM 7.72 [3.82]) and portal vein thrombosis with ruxolitinib (ROR 4.16 [2.70–6.40]; EBGM 4.52 [3.11]). Deep vein thrombosis reports were increased with baricitinib (ROR 14.84 [9.64–22.84]; EBGM 9.49 [5.91]), as was thrombosis with ruxolitinib (ROR 1.40 [1.20–1.63]; EBGM 1.72 [1.52]). The relationship between the time of treatment initiation and event occurrence indicated that time to events occurred randomly.

Conclusions

This study found significant reporting rates for TEs in patients treated with JAKinibs across brands and indications, providing additional evidence that JAKinibs may be contraindicated in patients at risk of TEs.

     

Existence of Notoriety Bias in FDA Adverse Event Reporting System Database and Its Impact on Signal Strength

Background: Notoriety bias is defined as “a selection bias in which a case has a greater chance of being reported if the subject is exposed to the studied factor known to cause, thought to cause, or likely to cause the event of interest.” This study aimed to determine the existence of notoriety bias in the FDA Adverse Event Reporting System (FAERS) database and estimate the impact of potential notoriety bias induced by safety alerts on signal estimation using disproportionality analysis. Methods: Publicly available FAERS data were downloaded and used for analysis. Thirty-one drugs which had label change/safety alert issued by FDA from 2009 to 2013 were considered. These drugs were reviewed 4 quarters before and after the safety alert notification for the existence of notoriety bias. The impact of notoriety bias induced by safety alerts was analyzed by comparing the signal strength using reporting odds ratio (ROR) and proportional reporting ratio (PRR), 2 years before and after the safety alert. Wilcoxon signed rank test was used to determine whether there were a statistically significant difference before and after the safety alert. Results: There was increased reporting for 11 drugs after the safety alert/label change by the FDA. The reporting of 20 drugs decreased or remained unchanged after the safety alert/label change by the FDA. Wilcoxon signed rank test showed that there is no statistically significant difference with respect to the number of reports before and after the safety alert (P = .330, Z = −0.974). Fourteen (45.16%) drugs had an increase in ROR, while 17 (54.83%) drugs had a decrease in ROR after safety alert issued by FDA (P = .953, Z = −0.059). Fourteen (45.16%) drugs had an increase in PRR, while 17 (54.83%) drugs had a decrease in PRR after safety alert issued by the FDA (P = .914, Z = −0.108). Conclusion: Although few FDA safety alert/warnings had a strong and immediate impact, many had no impact on reporting of AE and signal strength. This study found that overreporting due to notoriety bias does not exist in the FAERS database and the overall disproportionality in signal estimates is not altered by the safety alert.     

奥氮平安全警戒信号的大数据挖掘与分析

目的:基于大数据挖掘分析奥氮平上市后安全警戒信号,为临床合理用药提供参考.方法:利用美国FDA公共数据开放项目(openFDA)调取FDA不良事件报告系统(FAERS)数据库自2004年1月以来收集的奥氮平药物不良事件(ADE)报告,采用报告比值比法(ROR)检测信号,以其95％置信区间下限(ROR 95％CILowe...     

A signal of increased risk of hypoglycaemia with angiotensin receptor blockers caused by confounding

AIMS

To study reporting of hypoglycaemia in angiotensin receptor blocker (ARB) users, and to investigate the possibility of confounding.

METHODS

The French pharmacovigilance database was examined for an association between hypoglycaemia and ARBs or other drugs using reports notified between 1996 and 2005. This association was also tested in patients taking or not taking antidiabetic agents (ADAs) using reporting odds ratios (ROR).

RESULTS

Hypoglycaemia was mentioned in 807 of the 174 595 reports entered during the study period. Overall hypoglycaemia was associated with the use of ARBs [ROR 2, 95% confidence interval (CI) 1, 3] and with the use of ADAs (ROR 32, 95% CI 27, 37). Moreover, the use of ARBs was associated with the use of ADAs (OR 7, 95% CI 6, 8). Considering separately reports with and without ADA, the association of ARB use with a higher risk of hypoglycaemia disappeared (OR 0.4, 95% CI 0.2, 0.8 and OR 2, 95% CI 1, 3, respectively).

CONCLUSION

A signal indicating an association between ARB use and hypoglycaemia was found in the French pharmacovigilance database. This signal disappeared after stratification on ADA use, thus suggesting confounding by indication. Moreover, the association between ARB use and hypoglycaemia was negative in ADA users.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Spontaneous reporting is a valuable way to provide early detection for safety signals related to drug use.
• Due to the increasing size of pharmacovigilance databases, data-mining and other automated methods for signal generation are more and more often used.
• Even if these methods are very useful, they do not allow, for every particular association, an automated exploration of the multiple sources of confounding.

WHAT THIS STUDY ADDS

• An association between angiotensin receptor blockers use and hypoglycaemia was found in the French pharmacovigilance database.
• This signal disappeared after stratification on antidiabetic drug use, suggesting confounding by indication.
• The association between hypoglycaemia and angiotensin receptor blocker use was actually less than expected in concomitant antidiabetic drug users.

     

基于美国FAERS数据库的恩美曲妥珠单抗不良事件信号挖掘与分析

目的:采用美国FDA不良事件报告系统(FAERS)挖掘恩美曲妥珠单抗的不良事件信号,为其安全风险控制和临床合理用药提供参考.方法:采用报告比值比(ROR)法和综合标准(MHRA)法对美国FAERS数据库中2015年第一季度至2020年第四季度共20个季度的恩美曲妥珠单抗相关不良事件报告进行数据挖掘.结果:获得恩美曲妥珠...     

基于FAERS数据库的托法替尼不良事件信号挖掘研究

目的 基于美国食品药品监督管理局（FDA）不良事件报告系统（FDA adverse event reporting system,FAERS）数据库对托法替尼的不良事件信息进行对比分析,挖掘其潜在的药品不良反应信号,以期为临床安全合理用药提供参考依据。方法 从FAERS数据库中提取2011—2022年托法替尼的不良事件报告数据,利用报告比值比法（report the odds ratio,ROR）和比例报告比值法（proportional report ratio,PRR）对托法替尼的报告进行数据挖掘。利用国际医学用语词典术语集进行汉化及系统/器官（system organ class,SOC）归类得到有效信号。结果 纳入的65 535份报告中,女性患者多于男性,年龄主要集中在50～75岁,上报国家主要为美国;利用ROR和PRR法筛选后共得到545个信号,经系统器官分类后主要集中在各类肌肉骨骼及结缔组织病、各类神经系统疾病、全身性疾病及给药部位反应、感染及侵染类疾病、呼吸系统、胸及纵膈疾病等,其中报告数较多的依次为疼痛、关节痛、状态恶化、类风湿性关节炎等,信号强度依次为硫嘌呤甲基转移酶...     

伊伐布雷定的不良反应信号挖掘与评价

目的 利用美国食品药品管理局公共数据开放项目(openFDA)检索伊伐布雷定的不良反应信号并进行评价,为临床用药提供参考.方法 采用比例失衡法中的报告比值比法(ROR)与比例报告比值法(PRR)对美国FDA不良事件报告系统(FAERS)中自2015年4月15日至2020年11月17日的报告进行关于伊伐布雷定的数据挖掘.结果 使用ROR法和PRR法共得到63个信号,其中35个信号的不良反应未在伊伐布雷定的说明书中出现.结论 挖掘和评价基于FAERS数据库获得的伊伐布雷定不良反应相关信号,可为其临床的合理应用提供依据.     

基于美国FDA不良事件报告系统数据库的洛匹那韦/利托那韦风险信号挖掘研究

目的挖掘洛匹那韦/利托那韦(LPV/r)不良事件(AE)的风险信号,探讨LPV/r的临床安全性,为该药在新型冠状病毒肺炎(COVID-19)治疗中的安全应用提供参考。方法采用报告比值比法(ROR)对美国食品药品管理局不良事件报告系统(FAERS)2010年第1季度至2019年第3季度AE报告数据中LPV/r相关的风险信号进行挖掘,检测阈值为报告数大于3且ROR的95%置信区间(CI)下限大于1的AE,并对AE采用国际医学用语词典(MedDRA)的首选系统器官分类(SOC)和首选术语(PT)进行统计和分类,选取AE报告数和信号强度排名前50位的PT进行分析。结果2010年第1季度至2019年第3季度FAERS数据库共收到LPV/r为首要可疑药物的AE报告13335例,检测出报告数>3且ROR的95%CI下限>1的AE风险信号455个,涉及AE报告7718例。涉及AE报告数占比居前2位的系统器官依次为"各类损伤、中毒及手术并发症"[13.6%(1051/7718)]和"妊娠期、产褥期及围产期状况"[11.7%(899/7718)],但在"各类损伤、中毒及手术并发症"所涉及的1051例AE报告中与妊娠期药物暴露有关者为998例,占95.0%;信号数占比居首位的系统器官为"各种先天性家族遗传性疾病"[16.3%(74/455)]。另外,药物相互作用所致AE共144例,在AE报告数中排第7位。结论检测出LPV/r妊娠期用药相关胎儿、新生儿和婴儿异常等风险信号,提示应关注孕妇和婴幼儿使用LPV/r的风险。LPV/r与其他药物联用时的相互作用也值得关注。     

抗MRSA药物性别差异性药品不良反应信号的检测和分析

目的:挖掘和评价抗MRSA抗生素性别差异性药品不良反应信号(ADR),为不同性别患者临床合理用药提供参考。方法:调取美国FDA不良事件报告系统(FAERS)数据库2004年1月1日-2016年12月31日接收的万古霉素、利奈唑胺、达托霉素、替考拉宁药品不良事件(ADE)报告,采用报告比值比(ROR)数据挖掘方法对前述药品进行性别差异性ADR信号挖掘。结果:提取FAERS数据库信息得到ADE报告万古霉素3827例、利奈唑胺6 372例、达托霉素3 454例、替考拉宁1 413例,经ROR法检测,分别得到性别差异性ADR信号3,11,6,9个。统计学分析发现,女性患者各药品ADE上报数均小于男性患者,但女性ADR信号数量及强度均高于男性。对于女性患者,万古霉素、利奈唑胺、替考拉宁易发重症药疹及其相关ADR,如万古霉素(ROR=3.12;P=2.21×10_-17)与利奈唑胺(ROR=2.62;P=8.28×10_-5)诱发的药物超敏反应,替考拉宁诱发的毒性表皮坏死松解症(ROR=5.21;P=1.46×10(-6))、史-约综合征(ROR=4.54;P=6.80×10^-6)等。对于男性患者,万古霉素未见ADR信号,利奈唑胺与达托霉素出现肾功能受损信号。结论:万古霉素、利奈唑胺、达托霉素、替考拉宁存在性别差异性ADR信号,临床医务人员应提高对抗MRSA抗生素不良反应性别差异性的认识,避免发生严重不良反应。     

Paraesthesia after Local Anaesthetics: An Analysis of Reports to the FDA Adverse Event Reporting System

This study was aimed to evaluate the possible alert signals of paraesthesia by local anaesthetics, focusing on those used in dentistry. A case/non‐case study of spontaneous adverse events recorded in FAERS (FDA Adverse Event Reporting System) between 2004 and 2011 was performed. Cases were represented by the reports of reactions grouped under the term ‘Paraesthesias and dysaesthesias’ involving local anaesthetics (ATC: N01B*); non‐cases were all other reports of the same drugs. Reporting odds ratios (ROR) with the relevant 95% confidence intervals (95CI) were calculated. Alert signal was considered when number of cases >3 and lower limit of ROR 95CI > 1. To estimate the specificity of signals for dentistry, the analysis was restricted to the specific term “Oral Paraesthesia” and to reports concerning dental practice. Overall, 528 reports of ‘Paraesthesias and dysaesthesias’ were retrieved, corresponding to 573 drug–reaction pairs (247 lidocaine, 99 bupivacaine, 85 articaine, 30 prilocaine, 112 others). The signal was significant only for articaine (ROR=18.38; 95CI = 13.95–24.21) and prilocaine (2.66; 1.82–3.90). The analysis of the specific term “Oral Paraesthesia” retrieved 82 reports corresponding to 90 drug–reaction pairs (37 articaine, 19 lidocaine, 14 prilocaine, 7 bupivacaine, 13 others) and confirmed the signal for articaine (58.77; 37.82–91.31) and prilocaine (8.73; 4.89–15.57). The analysis of reports concerning dental procedures retrieved a signal for articaine, both for any procedures (8.84; 2.79–27.97) and for non‐surgical ones (15.79; 1.87–133.46). In conclusion, among local anaesthetics, only articaine and prilocaine generated a signal of paraesthesia, especially when used in dentistry.     

Signal detection for Thai traditional medicine: Examination of national pharmacovigilance data using reporting odds ratio and reported population attributable risk

Herbal containing medicine consumption has increased while the awareness of adverse drug reaction (ADR) was less than conventional medicine. Early detection of unexpected numbers of ADRs from herbal medicines’ reports which are abnormal from the whole database needs quantification. Disproportionality analysis has been performed for signal detection by using reporting odds ratio (ROR) as measurement. The impact of having medicine as exposures in each ADR should be measured by using reported population attributable risks (RPAR). This study aimed to quantify the contribution of Thai traditional medicine (TTM) to ADR reports and to assess the association between TTMs and serious adverse drug reactions. Data were retrieved from the adverse drug reaction surveillance database, Thai-Food and Drug Administration from 2002 to 2013. Crude and adjusted RORs for each drug–ADR pair and RPARs were computed. TTM contributed only 0.001% of all serious ADRs reported. Out of 4208 TTM-ADR pairs were examined, three had the statistically significant RORs, namely Andrographis paniculata and anaphylactic shock (ROR 2.32, 95% CI 1.03, 5.21); green traditional medicine and Stevens-Johnson syndrome (ROR 13.04, 95% CI 5.4–31.51) and Derris scandens Benth and angioedema (ROR 2.71, 95% CI 1.05–6.95). Their RPARs ranged from 0.05% to 0.16%. We conclude that TTMs need more intensive surveillance.     

Clinical Pharmacology of Entacapone (Comtan) From the FDA Reviewer

This new drug application was first submitted to the US Food and Drug Administration (FDA) by the Orion Corporation from Finland on January 2, 1998. The final clinical pharmacology review was completed on September 3, 1999. Entacapone is a potent and specific peripheral catechol-O-methyltransferase inhibitor. It has been shown to improve the clinical benefits of levodopa plus an aromatic L-amino acid decarboxylase inhibitor when given to patients with Parkinson’s disease and end-of-dose deterioration in the response to levodopa (the “wearing-off” phenomenon). The drug indication is for Parkinson’s disease as an adjunct therapy to levodopa/carbidopa. This is a combination drug with carbidopa (aromatic amino acid decarboxylation inhibitor) and entacapone. It is rapidly absorbed after oral administration of a single dose, with peak time generally reached within 1 hour. It is noted that no accumulation of plasma entacapone was detected after 8 daily doses. The maximum daily dose is 2000 mg. In this paper, the clinical pharmacology review of the drug is presented from the perspective of a clinical pharmacologist who reviewed this new drug application at the FDA. It should be noted that all the information in this paper is publicly available on the FDA website and in its literature.     

A comparative clinical investigation of the therapeutic effect of levodopa alone and in combination with a decarboxylase inhibitor (carbidopa) in cases of Parkinson's disease

Summary

The therapeutic effect of the combination of levodopa and carbidopa (‘Sinemet’) was compared with that of levodopa alone in 21 patients with Parkinson's disease. Eighteen parameters of the clinical condition and of functional impairment were determined quantitatively and the results statistically evaluated. Changing over from levodopa to the combination preparation resulted in an average improvement of 51.9% within 2 weeks. No relationship was found to exist between the degree of improvement and the severity or the progression of the disease. By the use of the combination preparation, the daily dosage of levodopa could be reduced by 77 %. Side-effects connected with the gastro-intestinal tract occurred much less frequently, while hyperkinesia increased. No arrhythmogenic effect was found with the combination product. From the clinical standpoint, combination therapy appeared to be qualitatively superior. By selective maintenance of freshly formed dopamine, it should be possible to assure a directed influence on the disturbed equilibrium of the functional systems of the brain.     

基于FAERS数据库的奥司他韦神经精神不良事件数据挖掘研究

目的:通过美国FDA不良事件报告系统(FAERS)数据库,挖掘奥司他韦神经精神学不良事件(neuropsychiatric ad-verse events,NPAEs)信号,为用药监护提供依据.方法:采用报告比值比(reporting odds ration,ROR)法对FAERS数据库中于2004-2020年上报的奥...     

基于FAERS数据库的丁苯那嗪与氘丁苯那嗪安全性对比研究

目的 基于美国食品药品监督管理局（FDA）公共数据开放项目（openFDA）中丁苯那嗪和氘丁苯那嗪不良事件的数据,分析2个药物的安全性,为临床用药提供参考。方法 收集2017年1月1日—2022年12月31日FDA不良事件报告系统（FAERS）中丁苯那嗪与氘丁苯那嗪相关的不良事件报告,提取报告数排名前50位不良事件报告,采用报告比值比法（ROR）挖掘不良反应风险信号。结果 共得到丁苯那嗪相关的不良事件报告1 468例,氘丁苯那嗪相关的不良事件报告3 097例,对报告数排名前50位不良事件进行药物不良反应风险信号分析,分别检测出丁苯那嗪39个不良反应风险信号,氘丁苯那嗪35个不良反应信号。按照不良事件报告数进行排名,丁苯那嗪前5位的不良事件依次为超说明书使用、死亡、药物无效、抑郁、治疗不服从;氘丁苯那嗪前5位的不良事件依次为药物无效、运动障碍、抑郁、嗜睡、失眠。结论 氘丁苯那嗪通过结构改造,优化了药动学参数,减少了给药剂量和频次,从而明显提高了患者的用药依从性,检测到的不良反应风险信号与原型药物相比有所减少,但需注意其自杀风险,提示临床予以进一步的安全性评价。     

基于FAERS数据库的双膦酸盐类药物不良事件信号挖掘研究

目的 基于FDA不良事件报告系统(FDA adverse event reporting system,FAERS)数据库对双膦酸盐类药物(bisphosphonate,BPS)的不良事件信息进行分析对比,挖掘其潜在的药品不良反应(adverse drug reaction,ADR)信号,以期优化患者治疗方案,为临床安全合理用药提供参考。方法 从FAERS提取2004年第1季度—2020年第4季度的不良事件报告数据,利用比值比(report odds ratio,ROR)法和比例报告比值(proportional report ratio,PRR)法对BPS的报告进行数据挖掘。得到有效信号后,利用国际医学用语词典术语集进行汉化及系统、器官归类。结果 经过筛选后,结果显示：阿仑膦酸钠累及19个系统,共1 072种信号;唑来膦酸共累及20个系统,共709种信号;利塞膦酸累及20个系统,共638种信号;帕米膦酸累及18个系统,共456种信号;伊班膦酸累及19个系统,共361种信号。结论 该研究有效利用ROR法和PRR法挖掘出5种BPS的ADR信号,5种BPS之间ADR具有一定的差异性,可为临床用药提供一定的参考,有利于促进临床合理用药。     

基于FDA不良事件报告系统的氯喹及羟氯喹不良反应分析与评价

目的：氯喹及羟氯喹是新型冠状病毒肺炎的推荐试用治疗药物,但存在较多安全性问题。研究利用FDA不良事件报告系统（FAERS）数据库挖掘和综合评价分析氯喹及羟氯喹相关事件,为新型冠状病毒肺炎患者提供安全用药信息。方法：从FAERS数据库中提取氯喹及羟氯喹相关不良事件个案报告,对患者基本信息、报告者信息、报告时间、常见不良事件等进行分析,采用比值比法（reporting odds ratio,ROR）和综合标准法（medicines and healthcare products regulatory agency,MHRA）两种比值失衡分析法检测氯喹及羟氯喹相关信号,进而通过病例分析和文献报道对ROR法和MHRA法均有检出的信号进行药品相关性评估分析。结果：2014年7月至2019年3月FAERS数据库中以氯喹和羟氯喹为主要和次要怀疑药物的初次上报报告分别为383例和11 169例,其中导致死亡的报告51例（13.3%）和310例（2.8%）,致死事件包括药物中毒、自杀、胎儿死亡、心脏骤停等。ROR法和MHRA法分别检出氯喹相关信号105个和100个,羟氯喹相关728个和650个。经筛选,相关的不良反应主要为心肌病、房室传导阻滞、视网膜病变、感音神经性耳聋、肌病、药物性精神病、转氨酶异常和溶血等。其中心肌病、房室传导阻滞、心室肥大、视神经萎缩、反射消失、肌无力综合征、血脂异常等和尖端扭转型室速、长QT综合征、限制性心肌病、颅神经损伤、低血糖等分别未在氯喹和羟氯喹说明书中提及。结论：在氯喹和羟氯喹的临床应用中,应关注心脏毒性、视网膜毒性和耳毒性等不良反应,并加强反射消失、肌无力综合征、血脂异常（氯喹）,及低血糖（羟氯喹）等新的不良反应信号的监测。     

基于FAERS数据库的左乙拉西坦不良事件信号挖掘与分析

目的 通过对抗癫痫药物左乙拉西坦不良事件（ADE）信号的挖掘分析,以期为临床安全合理用药提供参考。方法 采用比例失衡法中的报告比值比法（ROR）和综合标准法（MHRA）对2017年1季度至2021年3季度美国食品药品监督管理局（FDA）不良事件报告系统（FAERS）中左乙拉西坦的ADE报告进行数据挖掘及分析。结果 分析处理数据后共得到622个有效信号,涉及24个系统器官,主要集中在各类神经系统疾病、精神病类、妊娠期及产褥期及围产期状况等方面,发现说明书中未出现的信号累及器官系统有6个。结论 基于FAERS数据库对左乙拉西坦ADE信号挖掘可促进左乙拉西坦的安全、合理使用。