儿童口服尼美舒利安全性的系统评价

Safety of oral use of nimesulide in children:a systematic review

目的评价儿童口服尼美舒利的安全性。方法计算机检索PubMed、EMBASE、Cochrane图书馆(2011年第3期)、Cochrance临床对照试验数据库、中国生物医学文献光盘数据库、中国期刊全文数据库、中国维普科技期刊数据库和万方数据库,检索时间均从建库至2011年3月。手工检索中国《药品不良反应信息通报》、WHO Pharmaceuticals Newsletter、MHRA Drug Safety Update和FDA Drug Safety Newsletter。获得儿童尼美舒利安全性评价的队列研究、病例对照研究、RCT研究、非随机分组的对照研究和病例报告,此外还获取上市后药物不良反应监测,各国药物监督和管理机构对尼美舒利的风险利益评估、适应证修改等资料。按纳入和排除标准筛选文献,评价文献质量,提取资料。RCT文献采用RevMan 5.0软件进行Meta分析,余文献采用描述性分析,采用WHO-UMC评价体系评价病例报告中不良反应与尼美舒利的关联性。结果未检出儿童尼美舒利安全性评价的队列研究和病例对照研究。检出符合纳入标准的RCT文献43篇,病例报告9篇,尼美舒利上市后不良反应监测1篇。①RCT文献结果:儿童口服尼美舒利不良反应包括胃肠道反应、体温过低、皮疹,肝酶升高和神经系统不良反应(嗜睡或烦躁)。胃肠道反应发生率低于布洛芬(P<0.000 01)和对乙酰氨基酚(P=0.000 9);体温过低(P=0.01)和神经系统不良反应(P=0.03)发生率高于布洛芬;ALT和(或)AST升高发生率与布洛芬、对乙酰氨基酚差异均无统计学意义。②病例报告分析结果:报道3例严重肝脏不良反应,其中2例死亡;1例很可能由尼美舒利引起,2例可能由尼美舒利引起;报道5例血尿,均很可能由尼美舒利引起。③上市后不良反应监测结果:未检索到中国尼美舒利不良反应监测数据;印度监测4 092例患儿,报告肾脏不良反应13例,未报告肝脏不良反应。④中国食品药品监督管理局于2008年6月修改尼美舒利说明书,仅用于1岁以上儿童,用于退热疗程不超过3 d;欧洲药品管理局于2007年评估尼美舒利风险和效益后,限制其适应证仅为止痛,不用于退热,且疗程不超过15 d,12岁以下儿童禁用;2011年2月印度卫生部禁止12岁以下儿童使用尼美舒利。结论儿童口服尼美舒利胃肠道反应发生率可能低于布洛芬和对乙酰氨基酚,体温过低和神经系统不良反应发生率可能高于布洛芬,肝酶升高发生率可能与布洛芬和对乙酰氨基酚相似,严重肝脏不良反应有待进一步研究明确其与尼美舒利的因果关系。

Objective To evaluate the safety of oral use of nimesulide in children.Methods Clinical studies involving nimesulide orally used in children were identified from PubMed,EMBASE,Cochrane Library（Issue 3th,2011）,Cochrance Clinical Trials Database（CENTRAL）,CBM,CNKI,VIP and Wanfang Database.Other resources were searched manually,including State Food and Drug Administration（SFDA） Drug Adverse Event Report,WHO Pharmaceuticals Newsletter,MHRA Drug Safety Update and FDA Drug safety Newsletter.Data were extracted and evaluated with a specifically data extraction form,the tool recommended by Cochrane was used for risk of bias assessment and RevMan 5.0 software was used for meta-analysis.Casuality of case reports was assessed with WHO-UMC system.Results Cohort study and case controlled study on safety of oral use of nimesulide were not retrieved.A total of 53 clinical studies were included,involving 43 prospective controlled studies,9 case reports and 1 countrywide post-marketing surveillance report.Results of randomized controlled trials showed that adverse events reported in children using nimesulide included gastrointestinal reaction,hypothermia,skin rash,nervous system reaction（somnolence and irritability） and hepatic enzyme elevation.Nimesulide group had statistically lower incidence of gastrointestinal events,higher incidence of hypothermia and nervous system reaction and similar enzyme elevation compared with that using ibuprofen and paracetamol.② Two out of 3 cases reported severe hepatotoxicity died,2/3 were probably and 1/3 was possiblely caused by nimesulide.③ Surveillance of nimesulide in China had not been published by（SFDA）.The countrywide post-marketing surveillance in India,involing 4 092 children,reported 13 cases with renal reaction,but no hepatotoxicity was reported.④ China SFDA modified the instructions of nimesulide in 2008,baned its using in children under 1 year old and used not for more than 3 d for the fever.European Medicines Agency（EMA） assessed the risks and benefits of nimesulide in 2007,limited nimesulide using only for pain,not used for fever,the treatment not more than 15 d,and baned the using in children under 12 years old.Indian Health Ministry baned children aged under 12 years to use nimesulide in February 2011.Conclusions The incidence of gastrointestinal reaction of nimesulide by oral use in children may be less than that of ibuprofen and paracetamol,while the incidence of hypothermia and nervous system reaction may be more than that of ibuprofen.The incidence of hepatic enzyme elevation of nimesulide may be similar with that of ibuprofen and paracetamol.Further study on severe hepatotoxity is needed to understand its relation to nimesulide.