拉米夫定胶囊（拉米夫定说明书）

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MICROBIOLOGY:

MechanismofAction:Lamivudineisasyntheticnucleosideanalogue.Intracellularly,

lamivudineisphosphorylatedtoitsactive5-triphosphatemetabolite,lamivudinetriphosphate(L-TP).TheprincipalmodeofactionofL-TPisinhibitionofreversetranscriptase(RT)viaDNAchainterminationafterincorporationofthenucleosideanalogue.L-TPisaweakinhibitorofmammalianDNApolymerasesáandâ,andmitochondrialDNApolymerase.

AntiviralActivityInVitro:TherelationshipbetweeninvitrosusceptibilityofHIVtolamivudineandtheinhibitionofHIVreplicationinhumanshasnotbeenestablished.InvitroactivityoflamivudineagainstHIV-1wasassessedinanumberofcelllines(includingmonocytesandfreshhumanperipheralbloodlymphocytes)usingstandardsusceptibilityassays.IC50values(50%inhibitoryconcentrations)wereintherangeof2nMto15µM.LamivudinehadantiŒHIV-1activityinallacutevirus-cellinfectionstested.InHIV-1ŒinfectedMT-4cells,lamivudineincombinationwithzidovudinehadsynergisticantiretroviralactivity.Synergisticactivityof?lamivudine/zidovudinewasalsoshowninavariable-ratiostudy.PleaseseetheEPIVIR-HBVpackageinsertforinformationregardingactivityoflamivudineinstudiesusinginvitromodelsystemssuchastransfectedcellsforstudyofHBVreplication.

DrugResistance:Lamivudine-resistantisolatesofHIV-1havebeenselectedinvitro.TheresistantisolatesshowedreducedsusceptibilitytolamivudineandgenotypicanalysisshowedthattheresistancewasduetospecificsubstitutionmutationsintheHIV-1reversetranscriptaseatcodon184frommethioninetoeitherisoleucineorvaline.HIV-1strainsresistanttobothlamivudineandzidovudinehavebeenisolated.

Susceptibilityofclinicalisolatestolamivudineandzidovudinewasmonitoredincontrolledclinicaltrials.Inpatientsreceivinglamivudinemonotherapyorcombinationtherapywithlamivudinepluszidovudine,HIV-1isolatesfrommostpatientsbecamephenotypicallyandgenotypicallyresistanttolamivudinewithin12weeks.Insomepatientsharboringzidovudine-resistantvirusatbaseline,phenotypicsensitivitytozidovudinewasrestoredby12weeksoftreatmentwithlamivudineandzidovudine.Combinationtherapywithlamivudinepluszidovudinedelayedtheemergenceofmutationsconferringresistancetozidovudine.MutationsintheHBVpolymeraseYMDDmotifhavebeenassociatedwithreducedsusceptibilityofHBVtolamivudineinvitro.Instudiesofnon-HIV-infectedpatientswithchronichepatitisB,HBVisolateswithYMDDmutationsweredetectedinsomepatientswhoreceivedlamivudinedailyfor6monthsormore,andwereassociatedwithevidenceofdiminishedtreatmentresponse;similarHBVmutantshavebeenreportedinHIV-infectedpatientswhoreceivedlamivudine-containingantiretroviralregimensinthepresenceofconcurrentinfectionwithhepatitisBvirus(seePRECAUTIONS).[page]

Cross-Resistance:Cross-resistanceamongcertainreversetranscriptaseinhibitorshasbeenobserved.Cross-resistancebetweenlamivudineandzidovudinehasnotbeenreported.Insomeatientstreatedwithlamivudinealoneorincombinationwithzidovudine,isolateshaveemergedithamutationatcodon184,whichconfersresistancetolamivudine.Inthepresenceofthe184utation,cross-resistancetodidanosineandzalcitabinehasbeenseeninsomepatients;thelinicalsignificanceisunknown.Insomepatientstreatedwithzidovudineplusdidanosineoralcitabine,isolatesresistanttomultiplereversetranscriptaseinhibitors,includinglamivudine,haveemerged.

EPIVIR®Tablets(lamivudinetablets)

EPIVIR®OralSolution(lamivudineoralsolution)

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CLINICALPHARMACOLOGY:

PharmacokineticsinAdults:Thepharmacokineticpropertiesoflamivudinehavebeenstudiednasymptomatic,HIV-infectedadultpatientsafteradministrationofsingleintravenous(IV)osesrangingfrom0.25to8mg/kg,aswellassingleandmultiple(twice-dailyregimen)oralosesrangingfrom0.25to10mg/kg.Thepharmacokineticpropertiesoflamivudinehavealsobeenstudiedassingleandmultipleraldosesrangingfrom5mgto600mgperdayadministeredtoHBV-infectedpatients.

AbsorptionandBioavailability:LamivudinewasrapidlyabsorbedafteroraladministrationinIV-infectedpatients.Absolutebioavailabilityin12adultpatientswas86%±16%(mean±SD)orthetabletand87%±13%fortheoralsolution.Afteroraladministrationof2mg/kgtwiceaayto9adultswithHIV,thepeakserumlamivudineconcentration(Cmax)was1.5±0.5mcg/mLmean±SD).Theareaundertheplasmaconcentrationversustimecurve(AUC)andCmaxncreasedinproportiontooraldoseovertherangefrom0.25to10mg/kg.ninvestigational25-mgdosageformoflamivudinewasadministeredorallyto2asymptomatic,HIV-infectedpatientson2occasions,onceinthefastedstateandoncewithood(1099kcal;75gramsfat,34gramsprotein,72gramscarbohydrate).Absorptionofamivudinewasslowerinthefedstate(Tmax:3.2±1.3hours)comparedwiththefastedstateTmax:0.9±0.3hours);Cmaxinthefedstatewas40%±23%(mean±SD)lowerthaninthe?fastedstate.Therewasnosignificantdifferenceinsystemicexposure(AUC)inthefedandfastedstates;therefore,EPIVIRTabletsandOralSolutionmaybeadministeredwithorwithoutfood.TheaccumulationratiooflamivudineinHIV-positiveasymptomaticadultswithnormalrenalfunctionwas1.50following15daysoforaladministrationof2mg/kgb.i.d.

Distribution:TheapparentvolumeofdistributionafterIVadministrationoflamivudineto20patientswas1.3±0.4L/kg,suggestingthatlamivudinedistributesintoextravascularspaces.Volumeofdistributionwasindependentofdoseanddidnotcorrelatewithbodyweight.

Bindingoflamivudinetohumanplasmaproteinsislow(<36%).Invitrostudiesshowedthat,overtheconcentrationrangeof0.1to100mcg/mL,theamountoflamivudineassociatedwitherythrocytesrangedfrom53%to57%andwasindependentofconcentration.

Metabolism:Metabolismoflamivudineisaminorrouteofelimination.Inman,theonlyknownmetaboliteoflamivudineisthetrans-sulfoxidemetabolite.Within12hoursafterasingleoraldoseoflamivudinein6HIV-infectedadults,5.2%±1.4%(mean±SD)ofthedosewasexcretedasthetrans-sulfoxidemetaboliteintheurine.Serumconcentrationsofthismetabolitehavenotbeendetermined.

Elimination:Themajorityoflamivudineiseliminatedunchangedinurine.In9healthysubjectsgivenasingle300-mgoraldoseoflamivudine,renalclearancewas

199.7±56.9mL/min(mean±SD).In20HIV-infectedpatientsgivenasingleIVdose,renalclearancewas280.4±75.2mL/min(mean±SD),representing71%±16%(mean±SD)oftotalclearanceoflamivudine.Inmostsingle-dosestudiesinHIVŒinfectedpatients,HBV-infectedpatients,orhealthysubjectswithserumsamplingfor24hoursafterdosing,theobservedmeaneliminationhalf-life?(t½)rangedfrom5to7hours.InHIV-infectedpatients,totalclearancewas398.5±69.1mL/min(mean±SD).Oralclearanceandeliminationhalf-lifewereindependentofdoseandbodyweightoveranoraldosingrangefrom0.25to10mg/kg.

EPIVIR®Tablets(lamivudinetablets)

EPIVIR®OralSolution(lamivudineoralsolution)

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SpecialPopulations:AdultswithImpairedRenalFunction:ThepharmacokineticpropertiesoflamivudinehavebeendeterminedinasmallgroupofHIV-infectedadultswithimpairedrenalfunction(Table1).

Table1:PharmacokineticParameters(Mean±SD)AfteraSingle300-mgOralDoseofLamivudinein3GroupsofAdultsWithVaryingDegreesofRenalFunction

Exposure(AUC),Cmax,andhalf-lifeincreasedwithdiminishingrenalfunction(asexpressedbycreatinineclearance).Apparenttotaloralclearance(Cl/F)oflamivudinedecreasedascreatinineclearancedecreased.Tmaxwasnotsignificantlyaffectedbyrenalfunction.Basedontheseobservations,itisrecommendedthatthedosageoflamivudinebemodifiedinpatientswithrenalimpairment(seeDOSAGEANDADMINISTRATION).Basedonastudyinotherwisehealthysubjectswithimpairedrenalfunction,hemodialysisincreasedlamivudineclearancefromameanof64to88mL/min;however,thelengthoftimeofhemodialysis(4hours)wasinsufficienttosignificantlyaltermeanlamivudineexposureafterasingle-doseadministration.Therefore,itisrecommended,followingcorrectionofdoseforcreatinineclearance,thatnoadditionaldosemodificationbemadeafterroutinehemodialysis.Itisnotknownwhetherlamivudinecanberemovedbyperitonealdialysisorcontinuous[page]

(24-hour)hemodialysis.Theeffectsofrenalimpairmentonlamivudinepharmacokineticsinpediatricpatientsarenotknown.

AdultswithImpairedHepaticFunction:Thepharmacokineticpropertiesoflamivudinehaveeendeterminedinadultswithimpairedhepaticfunction.Pharmacokineticparameterswerenotlteredbydiminishinghepaticfunction;therefore,nodoseadjustmentforlamivudineisrequiredforpatientswithimpairedhepaticfunction.Safetyandefficacyoflamivudinehavenotbeenestablishedinthepresenceofdecompensatedliverdisease.

PediatricPatients:Forpharmacokineticpropertiesoflamivudineinpediatricpatients,seePRECAUTIONS:PediatricUse.

Gender:Therearenosignificantgenderdifferencesinlamivudinepharmacokinetics.

Race:Therearenosignificantracialdifferencesinlamivudinepharmacokinetics.

DrugInteractions:Noclinicallysignificantalterationsinlamivudineorzidovudine

pharmacokineticswereobservedin12asymptomaticHIV-infectedadultpatientsgivenasingledoseofzidovudine(200mg)incombinationwithmultipledosesoflamivudine(300mgq12h).Lamivudineandtrimethoprim/sulfamethoxazole(TMP/SMX)werecoadministeredto14HIV-positivepatientsinasingle-center,open-label,randomized,crossoverstudy.Eachpatientreceivedtreatmentwithasingle300-mgdoseoflamivudineandTMP160mg/SMX800mgonceadayfor5dayswithconcomitantadministrationoflamivudine300mgwiththefifthdose.

EPIVIR®Tablets(lamivudinetablets)

EPIVIR®OralSolution(lamivudineoralsolution)

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inacrossoverdesign.CoadministrationofTMP/SMXwithlamivudineresultedinanincreaseof44%±23%(mean±SD)inlamivudineAUC,adecreaseof29%±13%inlamivudineoralclearance,andadecreaseof30%±36%inlamivudinerenalclearance.ThepharmacokineticpropertiesofTMPandSMXwerenotalteredbycoadministrationwithlamivudine.Lamivudineandzalcitabinemayinhibittheintracellularphosphorylationofoneanother.Therefore,useoflamivudineincombinationwithzalcitabineisnotrecommended.Therewasnosignificantpharmacokineticinteractionbetweenlamivudineandinterferonalfanastudyof19healthymalesubjects.

INDICATIONSANDUSAGE:EPIVIRincombinationwithotherantiretroviralagentsis

indicatedforthetreatmentofHIVinfection(seeDescriptionofClinicalStudies).

DescriptionofClinicalStudies:ClinicalEndpointStudyinAdults:B3007(CAESAR)wasaulticenter,double-blind,placebo-controlledstudycomparingcontinuedcurrenttherapyz[vudinealone(62%ofpatients)orzidovudinewithdidanosineorzalcitabine(38%ofpatients)]totheadditionofEPIVIRorEPIVIRplusaninvestigationalnon-nucleosidereversetranscriptaseinhibitor(NNRTI),randomized1:2:1.Atotalof1816HIV-infectedadultswith25to250CD4cells/mm3(median=122cells/mm3)atbaselinewereenrolled:medianagewas36years,87%weremale,84%werenucleoside-experienced,and16%weretherapy-naive.The?mediandurationonstudywas12months.ResultsaresummarizedinTable2.

Table2:NumberofPatients(%)WithAtLeastOneHIVDiseaseProgressionEventorDeath

ClinicalEndpointStudyinPediatricPatients:ACTG300wasamulticenter,randomized,double-blindstudythatprovidedforcomparisonofEPIVIRplusRETROVIR®(zidovudine)todidanosinemonotherapy.Atotalof471symptomatic,HIV-infectedtherapy-naive(56daysofantiretroviraltherapy)pediatricpatientswereenrolledinthese2treatmentarms.Themedianagewas2.7years(range6weeksto14years),58%werefemale,and86%werenon-Caucasian.ThemeanbaselineCD4cellcountwas868cells/mm3(mean:1060cells/mm3andrange:0to4650cells/mm3forpatients.5yearsofage;mean419cells/mm3andrange:0to1555cells/mm3?forpatients>5yearsofage)andthemeanbaselineplasmaHIVRNAwas5.0log10copies/mL.Themediandurationonstudywas10.1monthsforthepatientsreceivingEPIVIRplusRETROVIRand9.2monthsforpatientsreceivingdidanosinemonotherapy.ResultsaresummarizedinTable3.

EPIVIR®Tablets(lamivudinetablets)

EPIVIR®OralSolution(lamivudineoralsolution)

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Table3:NumberofPatients(%)ReachingaPrimaryClinicalEndpoint

(DiseaseProgressionorDeath)

SurrogateEndpointStudies:Therapy-NaiveAdults:A3001wasarandomized,double-blindstudycomparingEPIVIR150mgb.i.d.plusRETROVIR200mgt.i.d.;EPIVIR300mgb.i.d.plusRETROVIR;EPIVIR300mgb.i.d.;andRETROVIR.Threehundredsixty-sixadultsenrolled:male(87%),Caucasian(61%),medianageof34years,asymptomaticHIVinfection(80%),baselineCD4cellcountsof200to500cells/mm3(median=352cells/mm3),andmeanbaselineplasmaHIVRNAof4.47(log10copies/mL).B3001wasarandomized,double-blindstudycomparingEPIVIR300mgb.i.d.plusRETROVIR200mgt.i.d.versusRETROVIR.Onehundredtwenty-nineadultsenrolled:male(74%),Caucasian(82%),medianageof33years,[page]

asymptomaticHIVinfection(64%),andbaselineCD4cellcountsof100to400cells/mm3(median=260cells/mm3).MeanchangesinCD4cellcountandHIVRNAthrough24weeksoftreatmentforStudyA3001aresummarizedinFigures1and2,respectively.MeanchangeinCD4cellcountthrough24weeksoftreatmentforStudyB3001issummarizedinFigure3.

Figure1:MeanAbsoluteCD4CellCountChange(cells/mm3)

FromBaselineinStudyA3001.

EPIVIR®Tablets(lamivudinetablets)

EPIVIR®OralSolution(lamivudineoralsolution)

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Figure2:MeanChangeFromBaseline

inPlasmaHIVRNA(log10copies/mL)inStudyA3001

Figure3:MeanAbsoluteCD4CellCountChange(cells/mm3)

FromBaselineinStudyB3001

Therapy-ExperiencedAdults(....24WeeksofPriorZidovudineTherapy):A3002wasarandomized,double-blindstudycomparingEPIVIR150mgb.i.d.plusRETROVIR200mgt.i.d.;EPIVIR300mgb.i.d.plusRETROVIR;andRETROVIRpluszalcitabine0.75mgt.i.d.Twohundredfifty-fouradultsenrolled:male(83%),Caucasian(63%),medianageof37years,asymptomaticHIVinfection(58%),mediandurationofpriorzidovudineuseof24months,baselineCD4cellcountsof100to300cells/mm3(median=211cells/mm3),andmeanbaselineplasmaHIVRNAof4.60(log10copies/mL).B3002wasarandomized,double-blindstudycomparingEPIVIR150mgb.i.d.plusRETROVIR,EPIVIR300mgb.i.d.plusRETROVIR,and

RETROVIR.Twohundredtwenty-threeadultsenrolled:male(83%),Caucasian(96%),median.

EPIVIR®Tablets(lamivudinetablets)

EPIVIR®OralSolution(lamivudineoralsolution)

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ageof36years,asymptomaticHIVinfection(53%),mediandurationofpriorzidovudineuseof23months,andbaselineCD4cellcountsof100to400cells/mm3(median=241cells/mm3).MeanchangesinCD4cellcountandHIVRNAthrough24weeksoftreatmentinStudyA3002aresummarizedinFigures4and5,respectively.MeanchangeinCD4cellcountthrough24weeksoftreatmentforStudyB3002issummarizedinFigure6.

Figure4:MeanAbsoluteCD4CellCountChange(cells/mm3)

FromBaselineinStudyA3002

Figure5:MeanChangeFromBaseline

inPlasmaHIVRNA(log10copies/mL)inStudyA3002.

EPIVIR®Tablets(lamivudinetablets)

EPIVIR®OralSolution(lamivudineoralsolution)

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Figure6:MeanAbsoluteCD4CellCountChange(cells/mm3)

FromBaselineinStudyB3002

CONTRAINDICATIONS:EPIVIRTabletsandOralSolutionarecontraindicatedinpatientswithpreviouslydemonstratedclinicallysignificanthypersensitivitytoanyofthecomponentsoftheproducts.

WARNINGS:Inpediatricpatientswithahistoryofpriorantiretroviralnucleosideexposure,ahistoryofpancreatitis,orothersignificantriskfactorsforthedevelopmentofpancreatitis,EPIVIRshouldbeusedwithcaution.TreatmentwithEPIVIRshouldbestoppedimmediatelyifclinicalsigns,symptoms,orlaboratoryabnormalitiessuggestiveofpancreatitisoccur(seeADVERSEREACTIONS).LacticAcidosis/SevereHepatomegalywithSteatosis:Lacticacidosisandseverehepatomegalywithsteatosis,includingfatalcases,havebeenreportedwiththeuseofnucleosideanaloguesaloneorincombination,includinglamivudineandotherantiretrovirals.Amajorityofthesecaseshavebeeninwomen.Obesityandprolongednucleosideexposuremayberiskfactors.ParticularcautionshouldbeexercisedwhenadministeringEPIVIRtoanypatientwithknownriskfactorsforliverdisease;however,caseshavealsobeenreportedinpatientswithnoknownriskfactors.TreatmentwithEPIVIRshouldbesuspendedinanypatientwhodevelopsclinicalorlaboratoryfindingssuggestiveoflacticacidosisorpronouncedhepatotoxicity(whichmayincludehepatomegalyandsteatosisevenintheabsenceofmarkedtransaminaseelevations).

ImportantDifferencesAmongLamivudine-ContainingProducts:EPIVIRTabletsandOralSolutioncontainahigherdoseofthesameactiveingredient(lamivudine)thaninEPIVIR-HBVTabletsandOralSolution.EPIVIR-HBVwasdevelopedforpatientswithchronichepatitisB.TheformulationanddosageoflamivudineinEPIVIR-HBVarenotappropriateforpatientsduallyinfectedwithHIVandHBV.LamivudinehasnotbeenadequatelystudiedfortreatmentofchronichepatitisBinpatientsduallyinfectedwithHIVandHBV.IftreatmentwithEPIVIR-HBVisprescribedforchronichepatitisBforapatientwithunrecognizedoruntreated?HIVinfection,rapidemergenceofHIVresistanceislikelytoresultbecauseofthesubtherapeutic.

EPIVIR®Tablets(lamivudinetablets)

EPIVIR®OralSolution(lamivudineoralsolution)

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doseandtheinappropriatenessofmonotherapyHIVtreatment.IfadecisionismadetoadministerlamivudinetopatientsduallyinfectedwithHIVandHBV,EPIVIRTablets,EPIVIROralSolution,orCOMBIVIRÚ(lamivudine/zidovudine)Tabletsshouldbeusedaspartofanappropriatecombinationregimen.COMBIVIR(afixed-dosecombinationtabletoflamivudineandzidovudine)shouldnotbeadministeredconcomitantlywithEPIVIR,EPIVIR-HBV,RETROVIR,orTRIZIVIR®.PosttreatmentExacerbationsofHepatitis:Inclinicaltrialsinnon-HIV-infectedpatientstreatedwithlamivudineforchronichepatitisB,clinicalandlaboratoryevidenceofexacerbationsofhepatitishaveoccurredafterdiscontinuationoflamivudine.TheseexacerbationshavebeendetectedprimarilybyserumALTelevationsinadditiontore-emergenceofHBVDNA.Althoughmosteventsappeartohavebeenself-limited,fatalitieshavebeenreportedinsomecases.Similar[page]

eventshavebeenreportedfrompost-marketingexperienceafterchangesfrom

lamivudine-containingHIVtreatmentregimenstonon-lamivudine-containingregimensinpatientsinfectedwithbothHIVandHBV.Thecausalrelationshiptodiscontinuationoflamivudinetreatmentisunknown.Patientsshouldbecloselymonitoredwithbothclinicalandlaboratoryfollowupforatleastseveralmonthsafterstoppingtreatment.Thereisinsufficientevidencetodeterminewhetherre-initiationoflamivudinealtersthecourseofposttreatmentexacerbationsofhepatitis.

PRECAUTIONS:

PatientswithImpairedRenalFunction:ReductionofthedosageofEPIVIRisrecommendedforpatientswithimpairedrenalfunction(seeCLINICALPHARMACOLOGYandDOSAGEANDADMINISTRATION).

PatientswithHIVandHepatitisBVirusCoinfection:SafetyandefficacyoflamivudinehavenotbeenestablishedfortreatmentofchronichepatitisBinpatientsduallyinfectedwithHIVandHBV.Innon-HIV-infectedpatientstreatedwithlamivudineforchronichepatitisB,emergenceoflamivudine-resistantHBVhasbeendetectedandhasbeenassociatedwithdiminishedtreatmentresponse(seeEPIVIR-HBVpackageinsertforadditionalinformation).EmergenceofhepatitisB?virusvariantsassociatedwithresistancetolamivudinehasalsobeenreportedinHIV-infectedpatientswhohavereceivedlamivudine-containingantiretroviralregimensinthepresenceofconcurrentinfectionwithhepatitisBvirus.Posttreatmentexacerbationsofhepatitishavealsobeenreported(seeWARNINGS).

InformationforPatients:EPIVIRisnotacureforHIVinfectionandpatientsmaycontinuetoexperienceillnessesassociatedwithHIVinfection,includingopportunisticinfections.PatientsshouldremainunderthecareofaphysicianwhenusingEPIVIR.PatientsshouldbeadvisedthattheuseofEPIVIRhasnotbeenshowntoreducetheriskoftransmissionofHIVtoothersthroughsexualcontactorbloodcontamination.PatientsshouldbeadvisedthatEPIVIRTabletsandOralSolutioncontainahigherdoseofthesameactiveingredient(lamivudine)asEPIVIR-HBVTabletsandOralSolution.IfadecisionismadetoincludelamivudineintheHIVtreatmentregimenofapatientduallyinfectedwithHIVandHBV,theformulationanddosageoflamivudineinEPIVIR(notEPIVIR-HBV)shouldbeused.Patientsshouldbeadvisedthatthelong-termeffectsofEPIVIRareunknownatthistime.

EPIVIRTabletsandOralSolutionarefororalingestiononly.PatientsshouldbeadvisedoftheimportanceoftakingEPIVIRexactlyasitisprescribed.

EPIVIR®Tablets(lamivudinetablets)

EPIVIR®OralSolution(lamivudineoralsolution)

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Parentsorguardiansshouldbeadvisedtomonitorpediatricpatientsforsignsandsymptomsofpancreatitis.

DrugInteractions:TMP160mg/SMX800mgoncedailyhasbeenshowntoincreaselamivudineexposure(AUC)by44%(seeCLINICALPHARMACOLOGY).Nochangeindoseofeitherdrugisrecommended.ThereisnoinformationregardingtheeffectonlamivudinepharmacokineticsofhigherdosesofTMP/SMXsuchasthoseusedtotreatPneumocystiscariniipneumonia.Nodataareavailableregardingthepotentialforinteractionwithotherdrugsthathaverenalclearancemechanismssimilartothatoflamivudine.Lamivudineandzalcitabinemayinhibittheintracellularphosphorylationofoneanother.Therefore,useoflamivudineincombinationwithzalcitabineisnotrecommended.

Carcinogenesis,Mutagenesis,andImpairmentofFertility:Long-termcarcinogenicitystudieswithlamivudineinmiceandratsshowednoevidenceofcarcinogenicpotentialatexposuresupto10times(mice)and58times(rats)thoseobservedinhumansattherecommendedtherapeuticdoseforHIVinfection.Lamivudinewasnotactiveinamicrobialmutagenicityscreenoraninvitrocelltransformationassay,butshowedweakinvitromutagenicactivityinacytogenetic?assayusingculturedhumanlymphocytesandinthemouselymphomaassay.However,?lamivudineshowednoevidenceofinvivogenotoxicactivityintheratatoraldosesofupto2000mg/kg,producingplasmalevelsof35to45timesthoseinhumansattherecommendeddoseforHIVinfection.Inastudyofreproductiveperformance,lamivudineadministeredtoratsatdosesupto4000mg/kgperday,producingplasmalevels47to70timesthoseinhumans,revealednoevidenceofimpairedfertilityandnoeffectonthesurvival,growth,anddevelopmenttoweaningoftheoffspring.

Pregnancy:PregnancyCategoryC.Reproductionstudieshavebeenperformedinratsandrabbitsatorallyadministereddosesupto4000mg/kgperdayand1000mg/kgperdayrespectively,producingplasmalevelsuptoapproximately35timesthatfortheadultHIVdose.Noevidenceofteratogenicityduetolamivudinewasobserved.Evidenceofearlyembryolethalitywasseenintherabbitatexposurelevelssimilartothoseobservedinhumans,buttherewasnoindicationofthiseffectintheratatexposurelevelsupto35timesthatinhumans.Studiesinpregnantratsandrabbitsshowedthatlamivudineistransferredtothefetusthroughtheplacenta.Therearenoadequateandwell-controlledstudiesinpregnantwomen.Becauseanimalreproductivetoxicitystudiesarenotalwayspredictiveofhumanresponse,lamivudineshouldbeusedduringpregnancyonlyifthepotentialbenefitsoutweightherisks.[page]

AntiretroviralPregnancyRegistry:Tomonitormaternal-fetaloutcomesofpregnantwomenexposedtolamivudine,aPregnancyRegistryhasbeenestablished.Physiciansareencouragedtoregisterpatientsbycalling1-800-258-4263.

NursingMothers:TheCentersforDiseaseControlandPreventionrecommendthatHIV-infectedmothersnotbreastfeedtheirinfantstoavoidriskingpostnataltransmissionofHIVinfection.?Astudyinwhichlactatingratswereadministered45mg/kgoflamivudineshowedthatlamivudineconcentrationsinmilkwereslightlygreaterthanthoseinplasma.Althoughitisnotknowniflamivudineisexcretedinhumanmilk,thereisthepotentialforadverseeffectsfromlamivudineinnursinginfants.Mothersshouldbeinstructednottobreastfeediftheyarereceivinglamivudine.

PediatricUse:HIV:ThesafetyandeffectivenessofEPIVIRincombinationwithotherantiretroviralagentshavebeenestablishedinpediatricpatients3monthsofageandolder.

EPIVIR®Tablets(lamivudinetablets)

EPIVIR®OralSolution(lamivudineoralsolution)

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InStudyA2002,pharmacokineticpropertiesoflamivudinewereassessedinasubsetof57HIV-infectedpediatricpatients(agerange:4.8monthsto16years,weightrange:5to66kg)afteroralandIVadministrationof1,2,4,8,12,and20mg/kgperday.Inthe9infantsandchildren(range:5monthsto12yearsofage)receivingoralsolution4mg/kgtwicedaily(theusualrecommendedpediatricdose),absolutebioavailabilitywas66%±26%(mean±SD),whichwaslessthanthe86%±16%(mean±SD)observedinadults.Themechanismforthediminishedabsolutebioavailabilityoflamivudineininfantsandchildrenisunknown.Systemicclearancedecreasedwithincreasingageinpediatricpatients,asshowninFigure7.

Figure7:SystemicClearance(L/h...kg)

ofLamivudineinRelationtoAge

Afteroraladministrationoflamivudine4mg/kgtwicedailyto11pediatricpatientsrangingfrom4monthsto14yearsofage,Cmaxwas1.1±0.6mcg/mLandhalf-lifewas2.0±0.6hours.(Inadultswithsimilarbloodsampling,thehalf-lifewas3.7±1hours.)Totalexposuretolamivudine,asreflectedbymeanAUCvalues,wascomparablebetweenpediatricpatientsreceivingan8-mg/kg-per-daydoseandadultsreceivinga4-mg/kg-per-daydose.Distributionoflamivudineintocerebrospinalfluid(CSF)wasassessedin38pediatricpatientsaftermultipleoraldosingwithlamivudine.CSFsampleswerecollectedbetween2and4hourspostdose.Atthedoseof8mg/kgperday,CSFlamivudineconcentrationsin8patientsrangedfrom5.6%to30.9%(mean±SDof14.2%±7.9%)oftheconcentrationinasimultaneousserum?sample,withCSFlamivudineconcentrationsrangingfrom0.04to0.3mcg/mL.Theeffectofrenalimpairmentonlamivudinepharmacokineticsinpediatricpatientsisnotknown.ThesafetyandpharmacokineticpropertiesofEPIVIRincombinationwithotherantiretroviralagentshavenotbeenestablishedinpediatricpatientslessthan3monthsofage.SeeINDICATIONSANDUSAGE:DescriptionofClinicalStudies,CLINICALPHARMACOLOGY,WARNINGS,ADVERSEREACTIONS,andDOSAGEANDADMINISTRATION.

HBV:SeethecompleteprescribinginformationforEPIVIR-HBVTabletsandOralSolutionforadditionalinformationonthepharmacokineticsoflamivudineinHBV-infectedchildren.

GeriatricUse:ClinicalstudiesofEPIVIRdidnotincludesufficientnumbersofsubjectsaged65andovertodeterminewhethertheyresponddifferentlyfromyoungersubjects.Ingeneral,doseselectionforanelderlypatientshouldbecautious,reflectingthegreaterfrequencyofdecreased.

EPIVIR®Tablets(lamivudinetablets)

EPIVIR®OralSolution(lamivudineoralsolution)

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hepatic,renal,orcardiacfunction,andofconcomitantdiseaseorotherdrugtherapy.Inparticular,becauselamivudineissubstantiallyexcretedbythekidneyandelderlypatientsaremorelikelytohavedecreasedrenalfunction,renalfunctionshouldbemonitoredanddosageadjustmentsshouldbemadeaccordingly(seePRECAUTIONS:PatientswithImpairedRenalFunctionandDOSAGEANDADMINISTRATION).

ADVERSEREACTIONS:

ClinicalTrialsinHIV:Adults:Selectedclinicaladverseeventswitha.5%frequencyduringtherapywithEPIVIR150mgb.i.d.plusRETROVIR200mgt.i.d.comparedwithzidovudinearelistedinTable4.

Table4:SelectedClinicalAdverseEvents(...5%Frequency)inFourControlled

ClinicalTrials(A3001,A3002,B3001,B3002)

EPIVIR®Tablets(lamivudinetablets)

EPIVIR®OralSolution(lamivudineoralsolution)

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SelectedlaboratoryabnormalitiesobservedduringtherapyaresummarizedinTable5.

Table5:FrequenciesofSelectedLaboratoryAbnormalitiesin

AdultsinFour24-WeekSurrogateEndpointStudies(A3001,A3002,B3001,

B3002)andaClinicalEndpointStudy(B3007)

PediatricPatients:Selectedclinicaladverseeventsandphysicalfindingswitha.5%

frequencyduringtherapywithEPIVIR4mg/kgtwicedailyplusRETROVIR160mg/m23timesdailycomparedwithdidanosineintherapy-naive(56daysofantiretroviraltherapy)pediatricpatientsarelistedinTable6.[page]

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Table6:SelectedClinicalAdverseEventsandPhysicalFindings(...5%Frequency)

inPediatricPatientsinStudyACTG300

Selectedlaboratoryabnormalitiesexperiencedbytherapy-naive(56daysofantiretroviraltherapy)pediatricpatientsarelistedinTable7.

Table7:FrequenciesofSelectedLaboratoryAbnormalitiesinPediatricPatients

inStudyACTG300

Pancreatitis,whichhasbeenfatalinsomecases,hasbeenobservedinantiretroviral

nucleoside-experiencedpediatricpatientsreceivingEPIVIRaloneorincombinationwithotherantiretroviralagents.Inanopen-labeldose-escalationstudy(A2002),14patients(14%)developedpancreatitiswhilereceivingmonotherapywithEPIVIR.Threeofthesepatientsdiedof.

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complicationsofpancreatitis.Inasecondopen-labelstudy(A2005),12patients(18%)developedpancreatitis.InStudyACTG300,pancreatitiswasnotobservedin236patientsrandomizedtoEPIVIRplusRETROVIR.Pancreatitiswasobservedin1patientinthisstudywhoreceivedopen-labelEPIVIRincombinationwithRETROVIRandritonavirfollowingdiscontinuationofdidanosinemonotherapy.

Paresthesiasandperipheralneuropathieswerereportedin15patients(15%)inStudyA2002,6patients(9%)inStudyA2005,and2patients(<1%)inStudyACTG300.

LamivudineinPatientswithChronicHepatitisB:ClinicaltrialsinchronichepatitisBusedalowerdoseoflamivudine(100mgdaily)thanthedoseusedtotreatHIV.Themostfrequentadverseeventswithlamivudineversusplacebowereear,nose,andthroatinfections(25%versus21%);malaiseandfatigue(24%versus28%);andheadache(21%versus21%),respectively.ThemostfrequentlaboratoryabnormalitiesreportedwithlamivudinewereelevatedALT,elevatedserumlipase,elevatedCPK,andposttreatmentelevationsofliverfunctiontests.Emergenceof

HBVviralmutantsduringlamivudinetreatment,associatedwithreduceddrugsusceptibilityanddiminishedtreatmentresponse,wasalsoreported(alsoseeWARNINGSandPRECAUTIONS).PleaseseethecompleteprescribinginformationforEPIVIR-HBVTabletsandOralSolutionformoreinformation.

ObservedDuringClinicalPractice:Inadditiontoadverseeventsreportedfromclinicaltrials,thefollowingeventshavebeenidentifiedduringpost-approvaluseoflamivudine.Becausetheyarereportedvoluntarilyfromapopulationofunknownsize,estimatesoffrequencycannotbemade.Theseeventshavebeenchosenforinclusionduetoacombinationoftheirseriousness,frequencyofreporting,orpotentialcausalconnectiontolamivudine.

Digestive:Stomatitis.

EndocrineandMetabolic:Hyperglycemia.

General:Weakness.

HemicandLymphatic:Anemia,lymphadenopathy,pureredcellaplasia,splenomegaly.

HepaticandPancreatic:Lacticacidosisandhepaticsteatosis,pancreatitis,posttreatment

exacerbationofhepatitisB(seeWARNINGSandPRECAUTIONS).

Hypersensitivity:Anaphylaxis,urticaria.

Musculoskeletal:Muscleweakness,CPKelevation,rhabdomyolysis.

Nervous:Paresthesia,peripheralneuropathy.

Respiratory:Abnormalbreathsounds/wheezing.

Skin:Alopecia,rash,pruritus.

OVERDOSAGE:ThereisnoknownantidoteforEPIVIR.Onecaseofanadultingesting6gofEPIVIRwasreported;therewerenoclinicalsignsorsymptomsnotedandhematologictestsremainednormal.TwocasesofpediatricoverdosewerereportedinACTG300.Onecasewasasingledoseof7mg/kgofEPIVIR;thesecondcaseinvolveduseof5mg/kgofEPIVIRtwicedailyfor30days.Therewerenoclinicalsignsorsymptomsnotedineithercase.Itisnotknownwhetherlamivudinecanberemovedbyperitonealdialysisorhemodialysis.

DOSAGEANDADMINISTRATION:

Adults:TherecommendedoraldoseofEPIVIRforadultsis150mgtwicedaily,administeredincombinationwithotherantiretroviralagents.Iflamivudineisadministeredtoapatientdually.

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infectedwithHIVandHBV,thedosageindicatedforHIVtherapyshouldbeusedaspartofanappropriatecombinationregimen(seeWARNINGS).

PediatricPatients:TherecommendedoraldoseofEPIVIRforHIV-infectedpediatricpatients3monthsupto16yearsofageis4mg/kgtwicedaily(uptoamaximumof150mgtwiceaday),administeredincombinationwithotherantiretroviralagents.

DoseAdjustment:ItisrecommendedthatdosesofEPIVIRbeadjustedinaccordancewithrenalfunction(seeTable8).(SeeCLINICALPHARMACOLOGYsection.)

Table8:AdjustmentofDosageofEPIVIRinAdultsandAdolescentsinAccordanceWithCreatinineClearance

InsufficientdataareavailabletorecommendadosageofEPIVIRinpatientsundergoingdialysis.AlthoughthereareinsufficientdatatorecommendaspecificdoseadjustmentofEPIVIRinpediatricpatientswithrenalimpairment,areductioninthedoseand/oranincreaseinthedosingintervalshouldbeconsidered.[page]

HOWSUPPLIED:EPIVIRTablets,150mg,arewhite,modifieddiamond-shaped,film-coatedtabletsimprintedwithii150ltononesideandinGXCJ7l0onthereverseside.Theyareavailableinbottlesof60tablets(NDC0173-0470-01)withchild-resistantclosures.

Storeat25°C(77°F),excursionspermittedto15°Cto30°C(59°to86°F)[seeUSPControlledRoomTemperature].

EPIVIROralSolution,aclear,colorlesstopaleyellow,strawberry-bananaflavoredliquid,contains10mgoflamivudineineach1mLinplasticbottlesof240mL(NDC0173-0471-00)withchild-resistantclosures.Thisproductdoesnotrequirereconstitution.

Storeintightlyclosedbottlesat25°C(77°F)[seeUSPControlledRoomTemperature].

GlaxoSmithKline

ResearchTrianglePark,NC27709

Manufacturedunderagreementfrom

ShirePharmaceuticalsGroupplc

Basingstoke,UK

EPIVIRÚOralSolutionManufacturedinEngland.

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