10注射用阿尼芬净Word格式.docx
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10注射用阿尼芬净Word格式.docx
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轻度腹泻,肝酶的实验室测试水平轻微上升,以及头痛。
一些病人经历了与输液相关的反应,其中多数为轻度。
在具有重大的潜在医学状况的且正伴服多重药物的少数病人中,有严重肝异常的报道。
Eraxis由纽约州的Pfizer公司生产。
ERAXIS-anidulafungin
injection,powder,lyophilized,forsolution
Roerig
ERAXIS™(anidulafungin)FORINJECTION
[INTRAVENOUSINFUSION,DILUTEDWITHSTERILEWATERFORINJECTION](notforIVBolusInjection)
DESCRIPTION
ERAXISforInjectionisasterile,lyophilizedproductforintravenous(IV)infusionthatcontainsanidulafungin.ERAXIS(anidulafungin)isasemi-syntheticlipopeptidesynthesizedfromafermentationproductof
Aspergillusnidulans.Anidulafunginisanechinocandin,aclassofantifungaldrugsthatinhibitsthesynthesisof1,3-β-D-glucan,anessentialcomponentoffungalcellwalls.
ERAXIS(anidulafungin)is1-[(4R,5R)-4,5-dihydroxy-N2-[[4"
-(pentyloxy)[1,1'
:
4'
1"
-terphenyl]-4-yl]carbonyl]-L-ornithine]echinocandinB.
Anidulafunginisawhitetooff-whitepowderthatispracticallyinsolubleinwaterandslightlysolubleinethanol.Inadditiontotheactiveingredient,anidulafungin,ERAXISforInjectioncontainsthefollowinginactiveingredients:
50mg/vial
-fructose(50mg),mannitol(250mg),polysorbate80(125mg),tartaricacid(5.6mg),andsodiumhydroxideand/orhydrochloricacidforpHadjustment.
100mg/vial
-fructose(100mg),mannitol(500mg),polysorbate80(250mg),tartaricacid(11.2mg),andsodiumhydroxideand/orhydrochloricacidforpHadjustment.
TheempiricalformulaofanidulafunginisC58H73N7O17
andtheformulaweightis1140.3.
Thestructuralformulais:
Priortoadministration,ERAXISforInjectionrequiresreconstitutionwithsterileWaterforInjectionandsubsequentdilutionwitheither5%DextroseInjection,USPor0.9%SodiumChlorideInjection,USP(normalsaline).
DONOTdilutewithothersolutionsorco-infusewithothermedicationsorelectrolytes(see
DOSAGEANDADMINISTRATION).
CLINICALPHARMACOLOGY
Pharmacokinetics
ThepharmacokineticsofanidulafunginfollowingIVadministrationhavebeencharacterizedinhealthysubjects,specialpopulationsandpatients.Systemicexposuresofanidulafunginaredose-proportionalandhavelowintersubjectvariability(coefficientofvariation<
25%)asshowninTable1.Thesteadystatewasachievedonthefirstdayafteraloadingdose(twicethedailymaintenancedose)andtheestimatedplasmaaccumulationfactoratsteadystateisapproximately2.
Table1.Mean(%CV)SteadyStatePharmacokineticParametersofAnidulafunginFollowingIVAdministrationofAnidulafunginOnceDailyfor10DaysinHealthyAdultSubjects
AnidulafunginIVDosingRegimen(LD/MD,mg)
PKParameter
70/35
(N=6)
200/100
(N=10)
260/130
(N
=10)
Cmax,ss
=thesteadystatepeakconcentration
AUCss
=thesteadystateareaunderconcentrationvs.timecurve
CL=clearance
t1/2
=theterminaleliminationhalf-life
LD/MD:
loadingdose/maintenancedoseoncedaily
Parameterswereobtainedfromseparatestudies
DatawerecollectedonDay7
Safetyandefficacyofthesedoseshasnotbeenestablished
SeeOVERDOSAGE
[mg/L]
3.55(13.2)
8.6(16.2)
10.9(11.7)
[mg∙h/L]
42.3(14.5)
111.8(24.9)
168.9(10.8)
CL[L/h]
0.84(13.5)
0.94(24.0)
0.78(11.3)
[h]
43.2(17.7)
52.0(11.7)
50.3(9.7)
Theclearanceofanidulafunginisabout1L/handanidulafunginhasaterminaleliminationhalf-lifeof40–50hours.
Distribution
ThepharmacokineticsofanidulafunginfollowingIVadministrationarecharacterizedbyashortdistributionhalf-life(0.5–1hour)andavolumeofdistributionof30–50Lthatissimilartototalbodyfluidvolume.Anidulafunginisextensivelybound(>
99%)tohumanplasmaproteins.
Metabolism
Hepaticmetabolismofanidulafunginhasnotbeenobserved.Anidulafunginisnotaclinicallyrelevantsubstrate,inducer,orinhibitorofcytochromeP450(CYP450)isoenzymes.ItisunlikelythatanidulafunginwillhaveclinicallyrelevanteffectsonthemetabolismofdrugsmetabolizedbyCYP450isoenzymes.
AnidulafunginundergoesslowchemicaldegradationatphysiologictemperatureandpHtoaring-openedpeptidethatlacksantifungalactivity.The
invitro
degradationhalf-lifeofanidulafunginunderphysiologicconditionsisabout24hours.
Invivo,thering-openedproductissubsequentlyconvertedtopeptidicdegradantsandeliminated.
Excretion
Inasingle-doseclinicalstudy,radiolabeled(14C)anidulafunginwasadministeredtohealthysubjects.Approximately30%oftheadministeredradioactivedosewaseliminatedinthefecesover9days,ofwhichlessthan10%wasintactdrug.Lessthan1%oftheadministeredradioactivedosewasexcretedintheurine.Anidulafunginconcentrationsfellbelowthelowerlimitsofquantitation6dayspost-dose.Negligibleamountsofdrug-derivedradioactivitywererecoveredinblood,urine,andfeces8weekspost-dose.
SpecialPopulations
Patientswithfungalinfections
PopulationpharmacokineticanalysesfromfourPhase2/3clinicalstudiesincluding107maleand118femalepatientswithfungalinfectionsshowedthatthepharmacokineticparametersofanidulafunginarenotaffectedbyage,race,orthepresenceofconcomitantmedicationswhichareknownmetabolicsubstrates,inhibitorsorinducers.
Thepharmacokineticsofanidulafungininpatientswithfungalinfectionsaresimilartothoseobservedinhealthysubjects.ThepharmacokineticparametersofanidulafunginestimatedusingpopulationpharmacokineticmodelingfollowingIVadministrationofamaintenancedoseof50mg/dayor100mg/day(followingaloadingdose)arepresentedinTable2.
Table2.Mean(%CV)SteadyStatePharmacokineticParametersofAnidulafunginFollowingIVAdministrationofAnidulafungininPatientswithFungalInfectionsEstimatedUsingPopulationPharmacokineticModeling
100/50
Alltheparameterswereestimatedbypopulationmodelingusingatwo-compartmentmodelwithfirstorderelimination;
AUCss,Cmax,ss
andCmin,ss
(steadystatetroughplasmaconcentration)wereestimatedusingindividualPKparametersandinfusionrateof1mg/mintoadministerrecommendeddosesof50and100mg/day.
loadingdose/dailymaintenancedose
t1/2,β
isthepredominanteliminationhalf-lifethatcharacterizesthemajorityoftheconcentration-timeprofile.
4.2(22.4)
7.2(23.3)
Cmin,ss
1.6(42.1)
3.3(41.8)
55.2(32.5)
110.3(32.5)
1.0(33.5)
26.5(28.5)
Gender
Dosageadjustmentsarenotrequiredbasedongender.Plasmaconcentrationsofanidulafungininhealthymenandwomenweresimilar.Inmultiple-dosepatientstudies,drugclearancewasslightlyfaster(approximately22%)inmen.
Geriatric
Dosageadjustmentsarenotrequiredforgeriatricpatients.Thepopulationpharmacokineticanalysisshowedthatmedianclearancedifferedslightlybetweentheelderlygroup(patients≥65,medianCL=1.07L/h)andthenon-elderlygroup(patients<
65,medianCL=1.22L/h)andtherangeofclearancewassimilar.
Race
Dosageadjustmentsarenotrequiredbasedonrace.AnidulafunginpharmacokineticsweresimilaramongWhites,Blacks,Asians,andHispanics.
HIVStatus
DosageadjustmentsarenotrequiredbasedonHIVstatus,irrespectiveofconcomitantanti-retroviraltherapy.
HepaticInsufficiency
Dosageadjustmentsarenotrequiredonthebasisofmild,moderateorseverehepaticinsufficiency.Anidulafunginisnothepaticallymetabolized.AnidulafunginpharmacokineticswereexaminedinsubjectswithChild-PughclassA,BorChepaticinsufficiency.Anidulafunginconcentrationswerenotincreasedinsubjectswithanydegreeofhepaticinsufficiency.ThoughaslightdecreaseinAUCwasobservedinpatientswithChild-PughChepaticinsufficiency,itwaswithintherangeofpopulationestimatesnotedforhealthysubjects.
RenalInsufficiency
Dosageadjustmentsarenotrequiredforpatientswithanydegreeofrenalinsufficiencyincludingthoseonhemodialysis.Anidulafunginhasnegligiblerenalclearance.Inaclinicalstudyofsubjectswithmild,moderate,severeorendstage(dialysis-dependent)renalinsufficiency,anidulafunginpharmacokineticsweresimilartothoseobservedinsubjectswithnormalrenalfunction.Anidulafunginisnotdialyzableandmaybeadministeredwithoutregardtothetimingofhemodialysis.
Pediatric
Thepharmacokineticsofanidulafunginafterdailydoseswereinvestigatedinimmunocompromisedpediatric(2through11years)andadolescent(12through17years)patientswithneutropenia.Thesteadystatewasachievedonthefirstdayafteradministrationoftheloadingdose(twicethemaintenancedose),andtheCmax
andAUCss
increasedinadose-proportionalmanner.Concentrationsandexposuresfollowingadministrationofmaintenancedosesof0.75and1.5mg/kg/dayinthispopulationweresimilartothoseobservedinadultsfollowingmaintenancedosesof50and100mg/day,respectively(asshowninTable3)(see
PRECAUTIONS,PediatricUse).
Table3.Mean(%CV)SteadyStatePharmacokineticParametersofAnidulafunginFollowingIVAdministrationofAnidulafunginOnceDailyinPediatricSubjects
PKParameter
AnidulafunginIVDosingRegimen
(LD/MD,mg/kg)
1.5/0.75
3.0/1.5
DatawerecollectedonDay5
loadingdose/dailymaintenan
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