四川地区新型抗癫痫药物超说明书规定用药分析:一项对儿童患者的多中心调查研究
摘要
目的调查四川地区左乙拉西坦、托吡酯、奥卡西平和拉莫三嗪等新型抗癫癎药物在儿童癫癎患者中超说明书规定用药(超说明书用药)的现状及安全性,以为临床制定相关用药指南提供数据,并为临床用药提供参考。方法收集2010年7月-2011年11月于四川大学华西第二医院、成都市妇女儿童中心医院和四川省人民医院门诊接受抗癫癎药物治疗的儿童癫癎患者资料,统计此间应用抗癫癎药物的总病例数和服用4种新型抗癫癎药物的病例数。依据药品说明书适应证,判断使用新型抗癫癎药物的医嘱是否属于超说明书用药及其药物类型,并计算和分析超说明书用药发生率及药物不良反应。结果共854例癫癎患儿接受抗癫癎药物治疗,其中670例患儿服用4种新型抗癫癎药物中的一种或多种,超说明书用药者406例,占抗癫癎药物治疗总病例数的47.54%(406/854),约占新型抗癫癎药物治疗总病例数的60.60%(406/670)。与按说明书用药患儿相比,超说明书用药患儿年龄更小、单药使用比例更高、全面性发作和癫癎综合征患儿比例更高,其病例数比例分别为左乙拉西坦78.50%(157/200)、托吡酯79.81%(253/317)、奥卡西平21.32%(42/197)和拉莫三嗪33.33%(21/63);不同年龄、单药使用和各种发作类型中以左乙拉西坦和托吡酯超说明书用药现象更为突出。除失访病例外,超说明书用药组患儿以奥卡西平[16.67%(7/42)]不良反应发生率最高,其次分别为托吡酯[14.81%(36/243)]、左乙拉西坦[10.60%(16/151)]和拉莫三嗪[9.52%(2/21)],但是与按说明书用药组之间差异无统计学意义(χ~2=0.375、0.448、0.014、0.109,P=0.540、0.503、0.906、0.742)。结论在四川地区儿童癫癎患者中超说明书应用新型抗癫癎药物的发生率较高,其中以托吡酯和左乙拉西坦尤为突出,但新型抗癫癎药物在一定范围内超说明书用药仍具有较好的安全性和耐受性。
Objective To investigate current status and safety about off-label use of levetiracetam, topiramate,oxcarbazepine,lamotrigine among pediatric patients in Sichuan area,so as to provide baseline data for formulating guidelines of off-label drug use.Methods Medical records of pediatric epileptic patients receiving antiepileptic drugs(AEDs) from July 2010 to November 2011 were collected at the following hospitals:West China Second University Hospital of Sichuan University,Chengdu Women's and Children's Central Hospital and Sichuan Provincial People's Hospital.The numbers of patients receiving AEDs and novel AEDs were calculated.Off-label drug use and the category of off-label drug use were judged according to the indications listed in drug instructions.The incidence of off-label drug use was calculated.The patients receiving novel AEDs were devided into on-label and off-label use groups;the clinical characteristics of these two groups were summarized and adverse reactions of two groups were compared by usingχ.2 test.Results During the study period,there were totally 854 patients receiving AEDs including 670 patients receiving novel AEDs.Among 670 patients 406 patients off-label use group received off-label use of novel AEDs,accounting for 47.54%(406/854) of the total patients receiving AEDs and 60.60%(406/670) of patients receiving novel AEDs.When compared with on-label use group,offlabel use group had more younger patients,more patients with single-drug use and more patients with generalized epilepsy or epileptic syndrome.The rates of off-label using drug were levetiracetam 78.50% (157/200),topiramate 79.81%(253/317),oxcarbazepine 21.32%(42/197) and lamotrigine 33.33%(21/63). The off-label use of levetiracetam and topiramate occured in all three aspects:age,single-drug use and seizure type.The adverse reaction rates of off-label use were oxcarbazepine 16.67%(7/42),topiramate 14.81%(36/243),levetiracetam 10.60%(16/151),lamotrigine 9.52%(2/21).When compared with the adverse reaction rates of on-label use group,the difference was not statistically significant(the values ofχ.2 were 0.375,0.448,0.014,0.109 respectively and the values of P were 0.540,0.503,0.906,0.742 respectively).Conclusion Among pediatric patients in Sichuan area,the rate of off-label use of novel AEDs was very high,especially for topiramate and levetiracetam.The follow-up data of this survey suggested that off-label use of novel AEDs with careful observation for adverse reactions had good safety and tolerance.
Objective To investigate current status and safety about off-label use of levetiracetam, topiramate,oxcarbazepine,lamotrigine among pediatric patients in Sichuan area,so as to provide baseline data for formulating guidelines of off-label drug use.Methods Medical records of pediatric epileptic patients receiving antiepileptic drugs(AEDs) from July 2010 to November 2011 were collected at the following hospitals:West China Second University Hospital of Sichuan University,Chengdu Women's and Children's Central Hospital and Sichuan Provincial People's Hospital.The numbers of patients receiving AEDs and novel AEDs were calculated.Off-label drug use and the category of off-label drug use were judged according to the indications listed in drug instructions.The incidence of off-label drug use was calculated.The patients receiving novel AEDs were devided into on-label and off-label use groups;the clinical characteristics of these two groups were summarized and adverse reactions of two groups were compared by usingχ.2 test.Results During the study period,there were totally 854 patients receiving AEDs including 670 patients receiving novel AEDs.Among 670 patients 406 patients off-label use group received off-label use of novel AEDs,accounting for 47.54%(406/854) of the total patients receiving AEDs and 60.60%(406/670) of patients receiving novel AEDs.When compared with on-label use group,offlabel use group had more younger patients,more patients with single-drug use and more patients with generalized epilepsy or epileptic syndrome.The rates of off-label using drug were levetiracetam 78.50% (157/200),topiramate 79.81%(253/317),oxcarbazepine 21.32%(42/197) and lamotrigine 33.33%(21/63). The off-label use of levetiracetam and topiramate occured in all three aspects:age,single-drug use and seizure type.The adverse reaction rates of off-label use were oxcarbazepine 16.67%(7/42),topiramate 14.81%(36/243),levetiracetam 10.60%(16/151),lamotrigine 9.52%(2/21).When compared with the adverse reaction rates of on-label use group,the difference was not statistically significant(the values ofχ.2 were 0.375,0.448,0.014,0.109 respectively and the values of P were 0.540,0.503,0.906,0.742 respectively).Conclusion Among pediatric patients in Sichuan area,the rate of off-label use of novel AEDs was very high,especially for topiramate and levetiracetam.The follow-up data of this survey suggested that off-label use of novel AEDs with careful observation for adverse reactions had good safety and tolerance.
引文
[1]Banerjee PN,Fi1ippi D,A11en Hauser W.The descriptive epidemio1ogy of epi1epsy:a review.Epi1epsy Res,2009,85:31- 45.
[2]Huang SP.Se1ection of antiepi1eptic drugs.Shi Yong Er Ke Lin Chuang Za Zhi,2011,26:1845-1847.[黄绍平.抗癫癎药物的选择.实用儿科临床杂志,2011,26:1845-1847.]
[3]Kothare SV,Ka1eyias J.The adverse effects of antiepi1eptic drugs in chi1dren.Expert Opin Drag Saf,2007,6:251-265.
[4]LaRoche SM,He1mers SL.The new antiepi1eptic drugs.JAMA, 2004,291:605-614.
[5]Chen H,Deshpande AD,Jiang R,et a1.An epidemio1ogica1 investigation of off-1abe1 anticonvu1sant drug use in the Georgia Medicaid popu1ation.Pharmacoepidemio1 Drug Saf,2005,14: 629-638.
[6]Wi1ton LV,Pearce G,Mann RD.The use of new1y marketed drugs in chi1dren and ado1escents prescribed in genera1 practice,Pharmacoepidemio1 Drug Saf,1999,8 Supp1 1:37-45.
[7]Zhang YH.Pay c1ose attention to off-1abe1 using antiepi1eptic drugs.Zhonghua Er Ke Za Zhi,2011,49:564-566.[张月华.关注抗癫癎药物的标签外用药.中华儿科杂志,2011,49:564-566.]
[8]Grosso S,Ga1imberti D,Farnetani MA,et a1.Efficacy and safety of topiramate in infants according to epi1epsy syndromes. Seizure,2005,14:183-189.
[9]Zhu X,Chen 0,Zhang D,et a1.A prospective study on the treatment of infanti1e spasms with first-1ine topiramate fo11owed by 1ow-dose ACTH.Epi1epsy Res,2011,93:149-154.
[10]Kro11 - Seger J,Porti11a P,Du1ac 0,et a1.Topiramate in the treatment of high1y refractory patients with Dravet syndrome. Neuropediatrics,2006,37:325-329.
[11]Grosso S,Franzoni E,1annetti P,et a1.Efficacy and safety of topiramate in refractory epi1epsy of chi1dhood:1ong-term fo11ow-up study.J Chi1d Neuro1,2005,20:893-897.
[12]Pina- Garza JE,Nord1i DR Jr,Rating D,et a1.Adjunctive 1evetiracetam in infants and young chi1dren with refractory partia1-onset seizures.Epi1epsia,2009,50:1141-1149.
[13]De1anty N,Jones J,Tonner F.Adjunctive 1evetiracetam in chi1dren,ado1escents,and adu1ts with primary genera1ized seizures:open - 1abe1,noncomparative,mu1ticenter,1ong - term fo11ow-up study.Epi1epsia,2012,53:111-119.
[14]Lei GF,Sun RP.The overa11 eva1uation of new antiepi1eptic drugs in treating pediatric refractory epi1epsy.Zhongguo Shi Yong Er Ke Za Zhi,2011,26:490-494.[雷革非,孙若鹏.新型抗癫癎药物治疗儿童难治性癫癎总体评价.中国实用儿科杂志,2011,26:490-494.]
[15]Pina - Garza JE,Espinoza R,Nord1i D,et a1.Oxcarbazepine adjunctive therapy in infants and young chi1dren with partia1 seizures.Neuro1ogy,2005,65:1370-1375.
[16]Pifta-Garza JE,Levisohn P,Gucuyener K,et a1.Adjunctive 1amotrigine for partia1 seizures in patients aged 1 to 24 months. Neuro1ogy,2008,70:2099-2108.
[17]Jiang L,Hong SQ.Advance in treatment of drug - resistent epi1epsy.Shi Yong Er Ke Lin Chuang Za Zhi,2011,26:1847- 1849.[蒋莉,洪思琦.耐药性癫癎的治疗进展.实用儿科临床杂志,2011,26:1847-1849.]
[18]Asconape JJ.The se1ection of antiepi1eptic drugs for the treatment of epi1epsy in chi1dren and adu1ts.Neuro1 C1in,2010, 28:843-852.
[19]Ben-Menachem E.Strategy for uti1ization of new antiepi1eptic drugs.Curr Opin Neuro1,2008,21:167-172.
[20]Zhang LL,Li YP,Zeng LN,et a1.Evidence-based eva1uation on off-1abe1 drug use po1icies in 15 contries.Zhongguo Xun Zheng Yi Xue Za Zhi,2012,12:426-435.[张伶俐,李幼平,曾力楠,等.15国超说明书用药政策的循证评价.中国循证医学杂志, 2012,12:426-435.]
[2]Huang SP.Se1ection of antiepi1eptic drugs.Shi Yong Er Ke Lin Chuang Za Zhi,2011,26:1845-1847.[黄绍平.抗癫癎药物的选择.实用儿科临床杂志,2011,26:1845-1847.]
[3]Kothare SV,Ka1eyias J.The adverse effects of antiepi1eptic drugs in chi1dren.Expert Opin Drag Saf,2007,6:251-265.
[4]LaRoche SM,He1mers SL.The new antiepi1eptic drugs.JAMA, 2004,291:605-614.
[5]Chen H,Deshpande AD,Jiang R,et a1.An epidemio1ogica1 investigation of off-1abe1 anticonvu1sant drug use in the Georgia Medicaid popu1ation.Pharmacoepidemio1 Drug Saf,2005,14: 629-638.
[6]Wi1ton LV,Pearce G,Mann RD.The use of new1y marketed drugs in chi1dren and ado1escents prescribed in genera1 practice,Pharmacoepidemio1 Drug Saf,1999,8 Supp1 1:37-45.
[7]Zhang YH.Pay c1ose attention to off-1abe1 using antiepi1eptic drugs.Zhonghua Er Ke Za Zhi,2011,49:564-566.[张月华.关注抗癫癎药物的标签外用药.中华儿科杂志,2011,49:564-566.]
[8]Grosso S,Ga1imberti D,Farnetani MA,et a1.Efficacy and safety of topiramate in infants according to epi1epsy syndromes. Seizure,2005,14:183-189.
[9]Zhu X,Chen 0,Zhang D,et a1.A prospective study on the treatment of infanti1e spasms with first-1ine topiramate fo11owed by 1ow-dose ACTH.Epi1epsy Res,2011,93:149-154.
[10]Kro11 - Seger J,Porti11a P,Du1ac 0,et a1.Topiramate in the treatment of high1y refractory patients with Dravet syndrome. Neuropediatrics,2006,37:325-329.
[11]Grosso S,Franzoni E,1annetti P,et a1.Efficacy and safety of topiramate in refractory epi1epsy of chi1dhood:1ong-term fo11ow-up study.J Chi1d Neuro1,2005,20:893-897.
[12]Pina- Garza JE,Nord1i DR Jr,Rating D,et a1.Adjunctive 1evetiracetam in infants and young chi1dren with refractory partia1-onset seizures.Epi1epsia,2009,50:1141-1149.
[13]De1anty N,Jones J,Tonner F.Adjunctive 1evetiracetam in chi1dren,ado1escents,and adu1ts with primary genera1ized seizures:open - 1abe1,noncomparative,mu1ticenter,1ong - term fo11ow-up study.Epi1epsia,2012,53:111-119.
[14]Lei GF,Sun RP.The overa11 eva1uation of new antiepi1eptic drugs in treating pediatric refractory epi1epsy.Zhongguo Shi Yong Er Ke Za Zhi,2011,26:490-494.[雷革非,孙若鹏.新型抗癫癎药物治疗儿童难治性癫癎总体评价.中国实用儿科杂志,2011,26:490-494.]
[15]Pina - Garza JE,Espinoza R,Nord1i D,et a1.Oxcarbazepine adjunctive therapy in infants and young chi1dren with partia1 seizures.Neuro1ogy,2005,65:1370-1375.
[16]Pifta-Garza JE,Levisohn P,Gucuyener K,et a1.Adjunctive 1amotrigine for partia1 seizures in patients aged 1 to 24 months. Neuro1ogy,2008,70:2099-2108.
[17]Jiang L,Hong SQ.Advance in treatment of drug - resistent epi1epsy.Shi Yong Er Ke Lin Chuang Za Zhi,2011,26:1847- 1849.[蒋莉,洪思琦.耐药性癫癎的治疗进展.实用儿科临床杂志,2011,26:1847-1849.]
[18]Asconape JJ.The se1ection of antiepi1eptic drugs for the treatment of epi1epsy in chi1dren and adu1ts.Neuro1 C1in,2010, 28:843-852.
[19]Ben-Menachem E.Strategy for uti1ization of new antiepi1eptic drugs.Curr Opin Neuro1,2008,21:167-172.
[20]Zhang LL,Li YP,Zeng LN,et a1.Evidence-based eva1uation on off-1abe1 drug use po1icies in 15 contries.Zhongguo Xun Zheng Yi Xue Za Zhi,2012,12:426-435.[张伶俐,李幼平,曾力楠,等.15国超说明书用药政策的循证评价.中国循证医学杂志, 2012,12:426-435.]
目录