氟达拉滨药理Word格式文档下载.docx

氟达拉滨药理Word格式文档下载.docx

《氟达拉滨药理Word格式文档下载.docx》由会员分享，可在线阅读，更多相关《氟达拉滨药理Word格式文档下载.docx（33页珍藏版）》请在冰豆网上搜索。

COMMONTRADENAME（S）:

FLUDARA

CLASSIFICATION:

antimetabolite

Specialpediatricconsiderationsarenotedwhenapplicable,otherwiseadultprovisionsapply.

MECHANISMOFACTION:

Fludarabinephosphateisasyntheticfluorinatedanalogofthepurinenucleosideantiviralagentvidarabine（ara-A）.1,4

Unlikevidarabine,fludarabinephosphateisresistanttodeaminationbyadenosinedeaminase.Fludarabine

phosphateisawater-solubleprodrugthatisrapidlydephosphorylatedto2-fluoro-vidarabine（2F-ara-A）.2F-ara-Ais

activelytransportedintocellsandisthenrephosphorylatedviadeoxycytidinekinasetotheactivetriphosphate

derivative2F-ara-ATP.2F-ara-ATPcompetitivelyinhibitsDNAsynthesisviainhibitionofDNApolymerase,

1,5

ribonucleotidereductase,DNAprimase,andDNAligase.2F-ara-ATPpreventselongationofDNAstrandsthrough

1,2

directincorporationintoDNAasafalsenucleotide.PartialinhibitionofRNApolymeraseIIandresultantreduction

4

inproteinsynthesismayalsooccur.CytotoxicityoccursprimarilyintheS-phaseofcelldivision;

fludarabineisalso

activeagainstnon-proliferatingcells.Fludarabinehasbeenshowntoinduceapoptosisinvitro.

1,6

PHARMACOKINETICS:

IVandoraldosingprovidesimilarsystemicexposure

6

OralAbsorption

Distribution

50-75%2,6,7;

dose-independant,unaffectedbyfood8

widelydistributed3

crossbloodbrainbarrier?

volumeofdistribution3

noinformationfound

2

83-98L/m;

suggestssignificantdegreeoftissue

binding

plasmaproteinbinding

noinvivoinformationfound

Metabolism

Excretion

rapidlyandcompletelydephosphorylatedinplasmato2-F-ara-A;

pharmacokineticdatais

basedon2F-ara-A

activemetabolite（s）

2F-ara-ATP

inactivemetabolite（s）2,9

2F-ara-A,2-F-ara-adenosinediphosphate

minor:

2F-ara-hypoxanthine,2-fluoro-vidarabine

40-60%,23%as2-fluoro-vidarabinewithin24hours;

urine2

renaleliminationisdose-related:

24%at25mg/m/d,

3,10

40-60%athigherdoses

feces

terminalhalflife3

15-23h

children3,10:

10.5-19h

79mL/min/m;

directlycorrelateswithcreatinine

clearance

Adaptedfromstandardreferenceunlessspecifiedotherwise.

BCCancerAgencyCancerDrugManual©

Developed:

September1994

Page1of10

Revised:

February2007,1June2013,1September2013

USES:

Primaryuses:

*Leukemia,chroniclymphocytic

Leukemia,prolymphocytic

*Lymphoma,non-Hodgkin’s

Otheruses:

Conditioningregimenpre-allogeneicbonemarrowtransplant2

5

Leukemia,acutemyeloid

Leukemia,hairycell

3,7

Lymphoma,cutaneousT-cell3,7

Waldenstrom’smacroglobulinemia3,7

*HealthCanadaapprovedindication

SPECIALPRECAUTIONS:

Contraindicatedinpatientswhohaveahistoryofhypersensitivityreactionstofludarabineoranycomponentsofthe

formulation,inrenallyimpairedpatientswithacreatinineclearancelessthan30mL/minute,andinpatientswith

decompensatedhemolyticanemia.

Caution:

Usefludarabinewithcautioninpatientswithsevereimpairmentofbonemarrowfunction,immunodeficiency,or

ahistoryofopportunisticinfections.

Potentiallylife-threateningtransfusion-relatedgraft-versus-host-diseasecanoccurinpatientswithsevere

lymphopenia;

patientsreceivingfludarabineshouldreceiveirradiatedbloodproducts,effectivelyeliminatingthis

risk.

Concomitanttherapywithcorticosteroidsandfludarabineincreasestheriskofinfectionswithopportunistic

7,11

pathogenssuchasPneumocystis,Listeria,andcytomegalovirus;

thecombinationshouldbeavoided.

Highdosesoffludarabine（>

96mg/m/dayfor5-7days）havebeenassociatedwithsevereirreversiblecentral

nervoussystemtoxicitycharacterizedbydelayedprogressiveencephalopathywithseizures,blindness,

1,121

paralysis,coma,anddeath;

severeneurotoxicityhasrarelyoccurredatrecommendeddoses.

HepatitisB（HBV）reactivation:

AlllymphomapatientsshouldbetestedforbothHBsAgandHBcAb.Ifeithertestis

positive,suchpatientsshouldbetreatedwithlamivudine100mg/dayorally,fortheentiredurationofchemotherapy

andforsixmonthsafterwards.SuchpatientsshouldalsobemonitoredwithfrequentliverfunctiontestsandHBV

DNAatleasteverytwomonths.IfthehepatitisBvirusDNAlevelrisesduringthismonitoring,managementshouldbe

reviewedwithanappropriatespecialistwithexperiencemanaginghepatitisandconsiderationgiventohalting

13,14

chemotherapy.

Specialpopulations:

Becausegeriatricpatientsmayhavedecreasedrenalfunction,andpatientswithrenal

impairmentmaybeatincreasedriskoffludarabine-induc