AvastinBevacizumab商品名Avastin.docx
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AvastinBevacizumab商品名Avastin
Genentech公司的抗癌新药Bevacizumab（商品名Avastin）于2004年2月26日获得美国食品和药品管理局（FDA）的批准上市用于一线治疗晚期结直肠癌，这是世界上首个批准上市的血管内皮生长因子（VEGF）抑制剂。
Bevacizumab（商品名Avastin）中文说明书
【性状】剂型：
水剂。
剂量：
两种，100mg/4ml或400mg/16ml。
【作用机制】Bevacizumab（商品名Avastin）是一种重组的人类单克隆IgG1抗体，通过抑制人类血管内皮生长因子的生物学活性而起作用。
药理毒理】药物代谢动力学特性：
静脉给药后，平均清除半衰期为20天（范围11－50天），预测达到稳态的时间为100天。
特殊人群：
根据人群用药资料，没有发现稳态血药浓度与患者的年龄、性别之间有相关性。
与处方者有关的临床前安全资料,在兔子中使用超过两倍Avastin人类推荐剂量，出现致畸性。
目前无Avastin在人类和动物致癌性资料。
【适应症】Avastin适用于联合以5－FU为基础的化疗方案一线治疗转移性结直肠癌。
【禁忌症】目前不知Avastin的禁忌症。
【用法与用量】推荐剂量为5mg/kg，每2周静脉注射1次直至疾病进展。
Avastin应在术后28天以后使用，且伤口完全愈合。
Avastin需用100ml0.9%的生理盐水稀释，不能用葡萄糖溶解。
Avastin不能静脉推注，第一次静脉滴注应在化疗后，滴注时间应超过90分钟。
第一次滴注耐受性好，第二次静脉滴注时间应超过60分钟，仍然耐受好，以后滴注时间超过30分钟即可。
【不良反应】最严重的不良反应为胃肠穿孔/伤口并发症、出血、高血压危象、肾病综合症、充血性心力衰竭。
最常见的严重不良反应（NCI-CTC3-4级）为：
无力、疼痛、高血压、腹泻、白细胞减少。
最常见不良反应为：
无力、疼痛、腹痛、头痛、高血压、腹泻、恶心、呕吐、食欲下降、口腔炎、便秘、上呼吸道感染、鼻衄、呼吸困难、剥脱性皮炎、蛋白尿。
【贮藏】Avastin必须储存在原包装内，冷藏于2～8℃，避光保存。
不能冷冻，不能摇动。
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DESCRIPTIONAVASTIN®（Bevacizumab）isarecombinanthumanizedmonoclonalIgG1antibodythatbindstoandinhibitsthebiologicactivityofhumanvascularendothelialgrowthfactor（VEGF）ininvitroandinvivoassaysystems.Bevacizumabcontainshumanframeworkregionsandthecomplementarity-determiningregionsofamurineantibodythatbindstoVEGF
（1）.BevacizumabisproducedinaChineseHamsterOvarymammaliancellexpressionsysteminanutrientmediumcontainingtheantibioticgentamicinandhasamolecularweightofapproximately149kilodaltons.AVASTINisacleartoslightlyopalescent,colorlesstopalebrown,sterile,pH6.2solutionforintravenous（IV）infusion.AVASTINissuppliedin100mgand400mgpreservative-free,single-usevialstodeliver4mLor16mLofAVASTIN（25mg/mL）.The100mgproductisformulatedin240mg
-trehalosedihydrate,23.2mgsodiumphosphate（monobasic,monohydrate）,4.8mgsodiumphosphate（dibasic,anhydrous）,1.6mgpolysorbate20,andWaterforInjection,USP.The400mgproductisformulatedin960mg
-trehalosedihydrate,92.8mgsodiumphosphate（monobasic,monohydrate）,19.2mgsodiumphosphate（dibasic,anhydrous）,6.4mgpolysorbate20,andWaterforInjection,USP.
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CLINICALPHARMACOLOGYMechanismofActionBevacizumabbindsVEGFandpreventstheinteractionofVEGFtoitsreceptors（Flt-1andKDR）onthesurfaceofendothelialcells.TheinteractionofVEGFwithitsreceptorsleadstoendothelialcellproliferationandnewbloodvesselformationininvitromodelsofangiogenesis.AdministrationofBevacizumabtoxenotransplantmodelsofcoloncancerinnude（athymic）micecausedreductionofmicrovasculargrowthandinhibitionofmetastaticdiseaseprogression.
PharmacokineticsThepharmacokineticprofileofBevacizumabwasassessedusinganassaythatmeasurestotalserumBevacizumabconcentrations（i.e.,theassaydidnotdistinguishbetweenfreeBevacizumabandBevacizumabboundtoVEGFligand）.Basedonapopulationpharmacokineticanalysisof491patientswhoreceived1to20mg/kgofAVASTINweekly,every2weeks,orevery3weeks,theestimatedhalf-lifeofBevacizumabwasapproximately20days（range11-50days）.Thepredictedtimetoreachsteadystatewas100days.Theaccumulationratiofollowingadoseof10mg/kgofBevacizumabevery2weekswas2.8.
TheclearanceofBevacizumabvariedbybodyweight,bygender,andbytumorburden.Aftercorrectingforbodyweight,maleshadahigherBevacizumabclearance（0.262L/dayvs.0.207L/day）andalargerVc（3.25Lvs.2.66L）thanfemales.Patientswithhighertumorburden（atorabovemedianvalueoftumorsurfacearea）hadahigherBevacizumabclearance（0.249L/dayvs.0.199L/day）thanpatientswithtumorburdensbelowthemedian.Inarandomizedstudyof813patients（Study1）,therewasnoevidenceoflesserefficacy（hazardratioforoverallsurvival）inmalesorpatientswithhighertumorburdentreatedwithAVASTINascomparedtofemalesandpatientswithlowtumorburden.TherelationshipbetweenBevacizumabexposureandclinicaloutcomeshasnotbeenexplored.
SpecialPopulationsAnalysesofdemographicdatasuggestthatnodoseadjustmentsarenecessaryforageorsex.
Patientswithrenalimpairment.NostudieshavebeenconductedtoexaminethepharmacokineticsofBevacizumabinpatientswithrenalimpairment.
Patientswithhepaticdysfunction.NostudieshavebeenconductedtoexaminethepharmacokineticsofBevacizumabinpatientswithhepaticimpairment..
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CLINICALSTUDIESThesafetyandefficacyofAVASTINinthetreatmentofpatientswithmetastaticcarcinomaofthecolonorrectumwerestudiedinthreerandomized,controlledclinicaltrialsincombinationwithintravenous5-fluorouracil-basedchemotherapy.TheactivityofAVASTINinpatientswithmetastaticcolorectalcancerthatprogressedonorafterreceivingbothirinotecanbased-andoxaliplatinbased-chemotherapyregimenswasevaluatedinanopen-accesstrialincombinationwithintravenous5-fluorouracil-basedchemotherapy.
AVASTINinCombinationwithBolus-IFLStudy1wasarandomized,double-blind,active-controlledclinicaltrialevaluatingAVASTINasfirst-linetreatmentofmetastaticcarcinomaofthecolonorrectum.Patientswererandomizedtobolus-IFL（irinotecan125mg/m2IV,5-fluorouracil500mg/m2IV,andleucovorin20mg/m2IVgivenonceweeklyfor4weeksevery6weeks）plusplacebo（Arm1）,bolus-IFLplusAVASTIN（5mg/kgevery2weeks）（Arm2）,or5-FU/LVplusAVASTIN（5mg/kgevery2weeks）（Arm3）.EnrollmentinArm3wasdiscontinued,aspre-specified,whenthetoxicityofAVASTINincombinationwiththebolus-IFLregimenwasdeemedacceptable.
Ofthe813patientsrandomizedtoArms1and2,themedianagewas60,40%werefemale,and79%wereCaucasian.Fifty-sevenpercenthadanECOGperformancestatusof0.Twenty-onepercenthadarectalprimaryand28%receivedprioradjuvantchemotherapy.Inthemajorityofpatients,56%,thedominantsiteofdiseasewasextra-abdominal,whiletheliverwasthedominantsitein38%ofpatients.ResultsarepresentedinTable1andFigure1.
Table1
Study1EfficacyResults
IFL+Placebo
IFL+AVASTIN
5 mg/kgq2wks
NumberofPatients
411
402
OverallSurvivala
Median（months）
15.6
20.3
Hazardratio
0.66
Progression-FreeSurvivala
Median（months）
6.2
10.6
Hazardratio
0.54
OverallResponseRateb
Rate（percent）
35%
45%
DurationofResponse
Median（months）
7.1
10.4
ap < 0.001bystratifiedlogranktest.
bp < 0.01byx2test.
Figure1
DurationofSurvivalinStudy1
Errorbarsrepresent95%confidenceintervals.
TheclinicalbenefitofAVASTIN,asmeasuredbysurvivalinthetwoprincipalarms,wasseeninthesubgroupsdefinedbyage（<65,>65）andgender.
Amongthe110patientsenrolledinArm3,medianoverallsurvivalwas18.3months,medianprogression-freesurvivalwas8.8months,overallresponseratewas39%,andmediandurationofresponsewas8.5months.
AVASTINinCombinationwith5-FU/LVChemotherapyStudy2wasarandomized,activecontrolledclinicaltrialtestingAVASTINincombinationwith5-FU/LVasfirstlinetreatmentofmetastaticcolorectalcancer.Patientswererandomizedtoreceive5-FU/LV（5fluorouracil500mg/m2,leucovorin500mg/m2weeklyfor6weeksevery8weeks）or5-FU/LVplusAVASTIN（5mg/kgevery2weeks）or5-FU/LVplusAVASTIN（10mg/kgevery2weeks）.Theprimaryendpointsofthetrialwereobjectiveresponserateandprogression-freesurvival.ResultsarepresentedinTable2.
Table2
Study2EfficacyResults
5-FU/LV
5-FU/LV+AVASTIN
5 mg/kg
5-FU/LV+AVASTIN
10 mg/kg
NumberofPatients
36
35
33
OverallSurvival
Median（months）
13.6
17.7
15.2
Progression-FreeSurvival
Median（months）
5.2
9.0
7.2
OverallResponseRate
Rate（percent）
17
40
24
Progression-freesurvivalwassignificantlylongerinpatientsreceiving5-FU/LVplusAVASTINat5mg/kgwhencomparedtothosenotreceivingAVASTIN.However,overallsurvivalandoverallresponseratewerenotsignificantlydifferent.Outcomesforpatientsreceiving5-FU/LVplusAVASTINat10mg/kgwerenotsignificantlydifferentthanforpatientswhodidnotreceiveAVASTIN.
AVASTINinCombinationwith5-FU/LVandOxaliplatinChemotherapyStudy3wasanopen-label,randomized,3-arm,active-controlled,multicenterclinicaltrialevaluatingAVASTINalone,AVASTINincombinationwith5-FU/LVandoxaliplatin（FOLFOX4）,andFOLFOX4aloneinthesecond-linetreatmentofmetastaticcarcinomaofthecolonorrectum.Patientswerepreviouslytreatedwithirinotecanand5-FUforinitialtherapyformetastaticdiseaseorasadjuvanttherapy.PatientswererandomizedtoFOLFOX4（Day1:
oxaliplatin85mg/m2andleucovorin200mg/m2concurrentlyIV,then5-FU400mg/m2IVbolusfollowedby600mg/m2continuouslyIV;Day2:
leucovorin200mg/m2IV,then5-FU400mg/m2IVbolusfollowedby600mg/m2continuouslyIV;repeatedevery2weeks）,FOLFOX4plusAVASTIN,orAVASTINmonotherapy.AVASTINwasadministeredatadoseof10mg/kgevery2weeksandforpatientsintheFOLFOX4plusAVASTINarm,priortotheFOLFOX4chemotherapyonDay1.
Ofthe829patientsrandomizedtothethreearms,themedianagewas61years,40%werefemale,87%wereCaucasian,and49%hadanECOGperformancestatusof0.Twenty-sixpercenthadreceivedpriorradiationtherapy,80%receivedprioradjuvantchemotherapy.Ninety-ninepercentreceivedprioririnotecan,withorwithout5-FUformetastaticcolorectalcancer,and1%receivedprioririnotecanand5-FUasadjuvanttherapy.
TheAVASTINmonotherapyarmofStudy3wasclosedtoaccrualafterenrollmentof244oftheplanned290patientsfollowingaplannedinterimanalysisbythedatamonitoringcommittee（DMC）,basedon
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