更昔洛韦注射说明书

1CYTOVENE-IV1(ganciclovirsodiumforinjection)2FORINTRAVENOUSINFUSIONONLY34Rxonly5WARNING6THECLINICALTOXICITYOFCYTOVENE-IVINCLUDES7GRANULOCYTOPENIA,ANEMIAANDTHROMBOCYTOPENIA.INANIMAL8STUDIESGANCICLOVIRWASCARCINOGENIC,TERATOGENICAND9CAUSEDASPERMATOGENESIS.10CYTOVENE-IVISINDICATEDFORUSEONLYINTHETREATMENTOF11CYTOMEGALOVIRUS(CMV)RETINITISINIMMUNOCOMPROMISED12PATIENTSANDFORTHEPREVENTIONOFCMVDISEASEINTRANSPLANT13PATIENTSATRISKFORCMVDISEASE(seeINDICATIONSANDUSAGE).14DESCRIPTION15Ganciclovirisasyntheticguaninederivativeactiveagainstcytomegalovirus(CMV).16CYTOVENE-IVisthebrandnameforganciclovirsodiumforinjection.17CYTOVENE-IVisavailableassterilelyophilizedpowderinstrengthof500mgpervial18forintravenousadministrationonly.EachvialofCYTOVENE-IVcontainstheequivalent19of500mgganciclovirasthesodiumsalt(46mgsodium).Reconstitutionwith10mLof20SterileWaterforInjection,USP,yieldsasolutionwithpH11andaganciclovir21concentrationofapproximately50mg/mL.Furtherdilutioninanappropriateintravenous22solutionmustbeperformedbeforeinfusion(seeDOSAGEANDADMINISTRATION).23Ganciclovirisawhitetooff-whitecrystallinepowderwithamolecularformulaof24C9H13N504andamolecularweightof255.23.Thechemicalnameforgancicloviris9-[[2-25hydroxy-1-(hydroxymethyl)-ethoxy]methyl]guanine.Ganciclovirisapolarhydrophilic26compoundwithasolubilityof2.6mg/mLinwaterat25°Candann-octanol/waterpartition27coefficientof0.022.ThepKasforganciclovirare2.2and9.4.28Ganciclovir,whenformulatedasmonosodiumsaltintheIVdosageform,isawhitetooff-29whitelyophilizedpowderwiththemolecularformulaofC9H12N5Na04,andamolecular30weightof277.22.Thechemicalnameforganciclovirsodiumis9-[[2-hydroxy-1-31(hydroxymethyl)-ethoxy]methyl]guanine,monosodiumsalt.Thelyophilizedpowderhasan32aqueoussolubilityofgreaterthan50mg/mLat25°C.AtphysiologicalpH,ganciclovir33sodiumexistsastheun-ionizedformwithasolubilityofapproximately6mg/mLat37°C.34Thechemicalstructuresofganciclovirsodiumandganciclovirare:3536ganciclovirsodiumganciclovir372Alldosesinthisinsertarespecifiedintermsofganciclovir.38VIROLOGY39MechanismofAction40Ganciclovirisanacyclicnucleosideanalogueof2'-deoxyguanosinethatinhibitsreplication41ofherpesviruses.Ganciclovirhasbeenshowntobeactiveagainstcytomegalovirus(CMV)42andherpessimplexvirus(HSV)inhumanclinicalstudies.43Toachieveanti-CMVactivity,ganciclovirisphosphorylatedfirsttothemonophosphate44formbyaCMV-encoded(UL97gene)proteinkinasehomologue,thentothedi-and45triphosphateformsbycellularkinases.Ganciclovirtriphosphateconcentrationsmaybe46100-foldgreaterinCMV-infectedthaninuninfectedcells,indicatingpreferential47phosphorylationininfectedcells.Ganciclovirtriphosphate,onceformed,persistsfordays48intheCMV-infectedcell.GanciclovirtriphosphateisbelievedtoinhibitviralDNA49synthesisby(1)competitiveinhibitionofviralDNApolymerases;and(2)incorporation50intoviralDNA,resultingineventualterminationofviralDNAelongation.51AntiviralActivity52ThemedianconcentrationofganciclovirthatinhibitsCMVreplication(IC50)invitro53(laboratorystrainsorclinicalisolates)hasrangedfrom0.02to3.48g/mL.Ganciclovir54inhibitsmammaliancellproliferation(CIC50)invitroathigherconcentrationsrangingfrom5530to725g/mL.Bonemarrow-derivedcolony-formingcellsaremoresensitive(CIC50560.028to0.7g/mL).TherelationshipofinvitrosensitivityofCMVtoganciclovirand57clinicalresponsehasnotbeenestablished.58ClinicalAntiviralEffectofCYTOVENE-IVandGanciclovirCapsules59CYTOVENE-IV60InastudyofCYTOVENE-IVtreatmentoflife-orsight-threateningCMVdiseasein61immunocompromisedpatients,121of314patientshadCMVculturedwithin7daysprior62totreatmentandsequentialposttreatmentviralculturesofurine,blood,throatand/or63semen.Asjudgedbyconversiontoculturenegativity,oragreaterthan100-folddecreasein64invitroCMVtiter,atleast83%ofpatientshadavirologicresponsewithamedianresponse65timeof7to15days.66AntiviralactivityofCYTOVENE-IVwasdemonstratedintworandomizedstudiesforthe67preventionofCMVdiseaseintransplantrecipients(seeTable1).683Table1PatientsWithPositiveCMVCultures69HeartAllograft*(n=147)BoneMarrowAllograft(n=72)TimeCYTOVENE-IV†PlaceboCYTOVENE-IV‡PlaceboPretreatment1/67(2%)5/64(8%)37/37(100%)35/35(100%)Week22/75(3%)11/67(16%)2/31(6%)19/28(68%)Week43/66(5%)28/66(43%)0/24(0%)16/20(80%)*CMVseropositiveorreceivinggraftfromseropositivedonor70†5mg/kgbidfor14daysfollowedby6mg/kgqdfor5days/weekfor14days71‡5mg/kgbidfor7daysfollowedby5mg/kgqduntilday100posttransplant72GanciclovirCapsules73IntrialscomparingCYTOVENE-IVwithGanciclovircapsulesforthemaintenance74treatmentofCMVretinitisinpatientswithAIDS,serialurineculturesandotheravailable75cultures(semen,biopsyspecimens,bloodandothers)showedthatasmallproportionof76patientsremainedculture-positiveduringmaintenancetherapywithnostatistically77significantdifferencesinCMVisolationratesbetweentreatmentgroups.78ViralResistance79ThecurrentworkingdefinitionofCMVresistancetoganciclovirininvitroassaysisIC50803.0g/mL(12.0M).CMVresistancetoganciclovirhasbeenobservedinindividuals81withAIDSandCMVretinitiswhohaveneverreceivedganciclovirtherapy.Viralresistance82hasalsobeenobservedinpati