FLUDARABINE PHOSPHATE

Main information

  • Trade name:
  • FLUDARABINE PHOSPHATE
  • Dosage:
  • 50 Milligram
  • Pharmaceutical form:
  • Pdr for Soln Inj/Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FLUDARABINE PHOSPHATE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0437/061/001
  • Authorization date:
  • 15-08-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FludarabinePhosphate50mgPowderforSolutionforInjectionorInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachvialcontains50mgoffludarabinephosphate.

1mlofreconstitutedsolutionscontains25mgoffludarabinephosphate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinjectionorinfusion.

Awhiteplug.

4CLINICALPARTICULARS

4.1TherapeuticIndications

TreatmentofB-cellchroniclymphocyticleukaemia(CLL)inpatientswithsufficientbonemarrowreserves.

FirstlinetreatmentwithFludarabinePhosphate50mgPowderforSolutionforInjectionorInfusionshouldonlybe

initiatedinpatientswithadvanceddisease,RaistagesIII/IV(binetstageC),orRaistagesI/II(BinetstageA/B)where

thepatienthasdiseaserelatedsymptomsorevidenceofprogressivedisease.

4.2Posologyandmethodofadministration

FludarabinePhosphate50mgPowderforSolutionforInjectionorInfusionshouldbeadministeredunderthe

supervisionofaqualifiedphysicianexperiencedintheuseofantineoplastictherapy.

Intravenousadministration

FludarabinePhosphate50mgPowderforSolutionforInjectionorInfusionisforintravenoususeonly.

Nocaseshavebeenreportedinwhichparavenouslyadministeredfludarabinephosphateledtoseverelocaladverse

reactions.However,paravenousadministrationmustbeavoided.

Adults

Therecommendeddoseoffludarabinephosphateis25mg/m 2

bodysurfaceareagivendailyfor5consecutivedays,

every28daysbytheintravenousroute.

Eachvialistobemadeupin2mlwaterforinjection.Eachmloftheresultingsolutionwillcontain25mgfludarabine

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Therequireddose(calculatedonthebasisofthepatient’sbodysurface)isdrawnupintoasyringe.Forintravenous

bolusinjectionthisdoseisfurtherdilutedinto10mlof0.9%sodiumchloride.Alternatively,forinfusiontherequired

dosedrawnupinasyringemaybedilutedinto100mlsodiumchloride9mg/ml(0.9%)andinfusedoverapproximately

30minutes(seealsosection6.6).

Theoptimaldurationoftreatmenthasnotbeenclearlyestablished.Thedurationoftreatmentdependsonthetreatment

successandthetolerabilityofthedrug.

ItisrecommendedthatFludarabinePhosphate50mgPowderforSolutionforInjectionorInfusionbeadministeredup

totheachievementofresponse(completeorpartialremission,usually6cycles).Treatmentshouldthenbe

discontinued.

HepaticImpairment

Nodataareavailableconcerningtheuseof

FludarabinePhosphate50mgPowderforSolutionforInjectionorInfusioninpatientswithhepaticimpairment.Inthis

groupofpatients,

FludarabinePhosphate50mgPowderforSolutionforInjectionorInfusionshouldbeusedwithcautionand

administerediftheperceivedbenefitoutweighsanypotentialrisk.

RenalImpairment

Thetotalbodyclearanceoftheprincipleplasmametabolite,fludarabine(2-F-ara-A),showsacorrelationwith

creatinineclearance,indicatingtheimportanceoftherenalexcretionpathwayfortheeliminationofthecompound.

Patientswithreducedkidneyfunctiondemonstratedanincreasedtotalbodyexposure(AUCof2F-ara-A).Limited

clinicaldataareavailableinpatientswithimpairmentofrenalfunction(creatinineclearancebelow70ml/min).

Therefore,ifrenalimpairmentisclinicallysuspected,orinpatientsovertheageof70years,creatinineclearance

shouldbemeasured.Ifcreatinineclearanceisbetween30and70ml/min,thedoseshouldbereducedbyupto50%and

closehaematologicalmonitoringshouldbeusedtoassesstoxicity.FludarabinePhosphate50mgPowderforSolution

forInjectionorInfusiontreatmentiscontraindicated,ifcreatinineclearanceis<30ml/min(seesection4.3).

Children

ThesafetyandeffectivenessofFludarabinePhosphate50mgPowderforSolutionforInjectionorInfusioninchildren

hasnotbeenestablished

Elderlypatients

Sincetherearelimiteddatafortheuseoffludarabinephosphateinelderlypersons(>75years),cautionshouldbe

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4.3Contraindications

FludarabinePhosphatePowderforSolutionforInjectionorInfusioniscontraindicated

Inpatientswhohavedemonstratedhypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Inrenallyimpairedpatientswithcreatinineclearance<30ml/min.

Inpatientswithdecompensatedhaemolyticanaemia.

Lactation

4.4Specialwarningsandprecautionsforuse

Mylosuppression

Severebonemarrowsuppression,notablyanaemia,thrombocytopeniaandneutropenia,hasbeenreportedinpatientstreatedwith

fludarabinephosphate.InaPhaseIintravenousstudyinadultsolidtumourpatients,themediantimetonadircountswas13days

(range,3-25days)forgranulocytesand16days(range,2-32)forplatelets.Mostpatientshadhaematologicimpairmentatbaseline

eitherasaresultofdiseaseorasaresultofpriormyelosuppressivetherapy.

Cumulativemyelosuppressionmaybeseen.Whilechemotherapy-inducedmyelosuppressionisoftenreversible,administrationof

fludarabinephosphaterequirescarefulhaematologicalmonitoring.

FludarabinePhosphatePowderforSolutionforInjectionorInfusionisapotentantineoplasticagentwithpotentiallysignificant

toxicsideeffects.Patientsundergoingtherapyshouldbecloselyobservedforsignsofhaematologicandnon-haematologic

toxicity.Periodicassessmentofperipheralbloodcountsisrecommendedtodetectthedevelopmentofanaemia,neutropeniaand

thrombocytopenia.

Severalinstancesoftrilineagebonemarrowhypoplasiaoraplasiaresultinginpancytopenia,sometimesresultingindeath,have

beenreportedinadultpatients.Thedurationofclinicallysignificantcytopeniainthereportedcaseshasrangedfrom

approximately2monthstoapproximately1year.Theseepisodeshaveoccurredbothinpreviouslytreatedoruntreatedpatients.

Aswithothercytotoxics,cautionshouldbeexercisedwithfludarabinephosphate,whenfurtherhaematopoieticstemsamplingis

considered.

Autoimmunedisorders

IrrespectiveofanyprevioushistoryofautoimmuneprocessesorCoombsteststatus,life-threateningandsometimesfatal

autoimmunephenomenahavebeenreportedtooccurduringoraftertreatmentwithfludarabinephosphate.Themajorityof

patientsexperiencinghaemolyticanaemiadevelopedarecurrenceinthehaemolyticprocessafterrechallengewithfludarabine

phosphate.PatientstreatedwithFludarabinePhosphatePowderforSolutionforInjectionorInfusionshouldbecloselymonitored

forhaemolysis.

DiscontinuationoftherapywithFludarabinePhosphatePowderforSolutionforInjectionorInfusionisrecommendedincaseof

haemolysis.Bloodtransfusion(irradiated,seeabove)andadrenocorticoidpreparationsarethemostcommontreatmentmeasures

forautoimmunehaemolyticanaemia.

Neurotoxicity

Whenusedathighdosesindose-rangingstudiesinpatientswithacuteleukaemia,intravenousfludarabinephosphatewas

associatedwithsevereneurologicaleffects,includingblindness,comaanddeath.Symptomsappearedfrom21to60daysfrom

lastdose.Thisseverecentralnervoussystemtoxicityoccurredin36%ofpatientstreatedintravenouslywithdosesapproximately

fourtimesgreater(96mg/m2/dayfor5-7days)thantherecommendeddose.Inpatientstreatedatdosesintherangeofthedose

recommendedforCLL,severecentralnervoussystemtoxicityhasoccurredrarely(coma,seizuresandagitation)oruncommonly

(confusion).

TheeffectofchronicadministrationofFludarabinePhosphatePowderforSolutionforInjectionorInfusiononthecentralnervous

systemisunknown.However,patientstoleratedtherecommendeddose,insomestudiesforrelativelylongtermtreatmenttimes,

(forupto26coursesoftherapy).Patientsshouldbecloselyobservedforsignsofneurologicalsideeffects.

Inpostmarketingexperienceneurotoxicityhasbeenreportedtooccurearlierorlaterthaninclinicaltrials.

Tumourlysissyndrome

TumourlysissyndromeassociatedwithfludarabinephosphatetreatmenthasbeenreportedinCLLpatientswithlargetumour

burdens.SinceFludarabinePhosphatePowderforSolutionforInjectionorInfusioncaninducearesponseasearlyasthefirst

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Transfusionassociatedgraft-versus-hostdisease

Transfusion-associatedgraft-versus-hostdisease(reactionbythetransfusedimmunocompetentlymphocytestothehost)hasbeen

observedaftertransfusionofnon-irradiatedbloodinfludarabinephosphatetreatedpatients.Fataloutcomeasaconsequenceof

thisdiseasehasbeenreportedwithahighfrequency.Therefore,tominimisetheriskoftransfusion-associatedgraft-versus-host

disease,patientswhorequirebloodtransfusionandwhoareundergoing,orhavereceived,treatmentwithFludarabinePhosphate

PowderforSolutionforInjectionorInfusionshouldreceiveirradiatedbloodonly.

Skincancer

Theworseningorflareupofpre-existingskincancerlesionsaswellasnewonsetofskincancerhasbeenreportedinsome

patientstooccurduringorafterfludarabinephosphatetherapy.

Impairedstateofhealth

Inpatientswithimpairedstateofhealth,FludarabinePhosphatePowderforSolutionforInjectionorInfusionshouldbegiven

withcautionandaftercarefulrisk/benefitconsideration.Thisappliesespeciallyforpatientswithsevereimpairmentofbone

marrowfunction(thrombocytopenia,anaemia,and/orgranulocytopenia),immunodeficiencyorwithahistoryofopportunistic

infection.

RenalImpairment:

Thetotalbodyclearanceoftheprinciplemetabolite2-F-ara-Ashowsacorrelationwithcreatinine,indicatingtheimportanceof

therenalexcretionpathwayfortheeliminationofthecompound.Patientswithreducedrenalfunctiondemonstratedanincreased

totalbodyexposure(AUCof2F-ara-A).Therearelimitedclinicaldataavailableinpatientswithimpairmentofrenalfunction

(creatinineclearance<70ml/min).

FludarabinePhosphatePowderforSolutionforInjectionorInfusionmustbeadministeredcautiouslyinpatientswithrenal

insufficiency.Inpatientswithmoderateimpairmentofrenalfunction(creatinineclearancebetween30and70ml/min),thedose

shouldbereducedbyupto50%andthepatientshouldbemonitoredclosely(seesection4.2).FludarabinePhosphatePowderfor

SolutionforInjectionorInfusiontreatmentiscontraindicatedifcreatinineclearanceis<30ml/min(seesection4.3).

Theelderly

SincetherearelimiteddatafortheuseofFludarabinePhosphatePowderforSolutionforInjectionorInfusioninelderlypersons

(>75years),cautionshouldbeexercisedwiththeadministrationinthesepatients.

Inpatientsaged65yearsorolder,creatinineclearanceshouldbemeasuredbeforestartoftreatment,see‘RenalImpairment’and

section4.2.

Pregnancy

Fludarabinephosphateshouldnotbeusedduringpregnancyunlessclearlynecessary(e.g.life-threateningsituation,noalternative

safertreatmentavailablewithoutcompromisingthetherapeuticbenefit,treatmentcannotbeavoided).Ithasthepotentialtocause

fetalharm(seesections4.6and5.3).Prescribersmayonlyconsidertheuseoffludarabinephosphate,ifthepotentialbenefits

justifythepotentialriskstothefoetus.

Womenshouldavoidbecomingpregnantwhileonfludarabinephosphatetherapy.

Womenofchildbearingpotentialmustbeapprisedofthepotentialhazardtothefoetus.

Contraception

Womenofchild-bearingpotentialorfertilemalesmusttakecontraceptivemeasuresduringandforatleast6monthsafter

cessationoftherapy(seesection4.6).

Vaccination

DuringandaftertreatmentwithFludarabinePhosphatePowderforSolutionforInjectionorInfusion,vaccinationwithlive

vaccinesshouldbeavoided.

Retreatmentoptionsafterinitialfludarabinephosphatetreatment

AcrossoverfrominitialtreatmentwithFludarabinePhosphatePowderforSolutionforInjectionorInfusiontochlorambucilfor

nonresponderstoFludarabinePhosphatePowderforSolutionforInjectionorInfusionshouldbeavoidedbecausemostpatients

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Inaclinicalinvestigationusingintravenousfludarabinephosphateincombinationwithpentostatin(deoxycoformycin)forthe

treatmentofrefractorychroniclymphocyticleukaemia(CLL),therewasanunacceptablyhighincidenceoffatalpulmonary

toxicity.Therefore,theuseofFludarabinePhosphatePowderforSolutionforInjectionorInfusionincombinationwith

pentostatinisnotrecommended.

DipyridamoleandotherinhibitorsofadenosineuptakemayreducethetherapeuticefficacyofFludarabinePhosphatePowderfor

SolutionforInjectionorInfusion.

Clinicalstudiesandinvitroexperimentsshowedthatduringuseoffludarabineincombinationwithcytarabinetheintracellular

exposureofAra-CTP(activemetaboliteofcytarabine)increasedinleukaemiccells.PlasmaconcentrationsofAra-Candthe

eliminationrateofAra-CTPwerenotaffected.

4.6Fertility,pregnancyandlactation

PREGNANCY

Preclinicaldatainratsdemonstratedatransferoffludarabineand/ormetabolitesthroughtheplacenta.Theresultsfrom

intravenousembryotoxicitystudiesinratsandrabbitsindicatedanembyrolethalandteratogenicpotentialatthetherapeuticdoses

(seesection5.3).

Thereareverylimiteddataoffludarabineuseinpregnantwomeninthefirsttrimester.

Fludarabineshouldnotbeusedduringpregnancyunlessclearlynecessary(e.g.life-threateningsituation,noalternativesafer

treatmentavailablewithoutcompromisingthetherapeuticbenefit,treatmentcannotbeavoided).Fludarabinehasthepotentialto

causefetalharm.Prescribersmayonlyconsidertheuseoffludarabine,ifthepotentialbenefitsjustifythepotentialriskstothe

foetus.

Womenofchildbearingpotentialmustbeapprisedofthepotentialhazardtothefoetus.

Bothsexuallyactivemenandwomenofchildbearingpotentialmusttakeeffectivecontraceptivemeasuresduringandatleastfor6

monthsaftercessationoftherapy(seesection4.4).

LACTATION

Itisnotknownwhetherthisdrugoritsmetabolitesareexcretedinhumanmilk.

However,thereisevidencefrompreclinicaldatathatfludarabinephosphateand/ormetabolitestransferfrommaternalbloodto

milk.

Becauseofthepotentialforseriousadversereactionstofludarabineinbreast-fedinfants.Fludarabineiscontraindicatedinnursing

mothers(seesection4.3).

4.7Effectsonabilitytodriveandusemachines

Fludarabinemayreducetheabilitytodriveandusemachines,sincee.g.fatigue,weakness,visualdisturbances,confusion,

agitationandseizureshavebeenobserved.

4.8Undesirableeffects

Themostcommonadverseeventsincludemyelosuppression(neutropenia,thrombocytopeniaandanaemia),infectionincluding

pneumonia,cough,fever,fatigue,weakness,nausea,vomitinganddiarrhoea.Othercommonlyreportedeventsincludechills,

oedema,malaise,peripheralneuropathy,visualdisturbance,anorexia,mucositis,stomatitisandskinrashes.Seriousopportunistic

infectionshaveoccurredinpatientstreatedwithFludarabinePhosphatePowderforSolutionforInjectionorInfusion.Fatalitiesas

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ThetablebelowreportsadverseeventsbyMedDRAsystemorganclasses(MedDRASOCs).Thefrequenciesarebasedon

clinicaltrialdataregardlessofthecausalrelationshipwithfludarabine.Therareadversereactionsweremainlyidentifiedfromthe

post-marketingexperience.

SystemOrgan

Class

MedDRA VeryCommon

1/10 Common

≥1/100to<1/10 Uncommon

≥1/1000to

<1/100 Rare

1/10,000to

<1/1000 Notknown

Infectionsand

infestations Infections/

Opportunistic

infections

(likelatentviral

reactivation,

e.g.Progressive

multifocal

leucoencephalopathy,

Herpeszoster

virus

Epstein-Barr-

virus),

Lymphoproliferative

disorder(EBV-

associated)

Neoplasms

benign,

malignant

andunspecified

(inclcystsand

polyps) Myelodysplastic

syndromeand

Acutemyeloid

leukaemia

(mainly

associatedwith

prior,

concomitantor

subsequent

treatmentwith

alkylatingagents,

topoisomerase

inhibitorsor

irradiation)

Bloodand

lymphatic

system

disorders Neutropenia,

Anaemia,

Thrombocytopenia Myelosuppression

Immunesystem

disorders Autoimmune

disorder

(including

Autoimmune

haemolytic

anaemia,

Evans

syndrome,

Thrombocytopenic

purpura,

Acquired

haemophilia,

Pemphigus)

Metabolism

andnutrition

disorders Anorexia Tumourlysis

syndrome

(including

Renalfailure,

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ThemostappropriateMedDRAtermtodescribeacertainadverseeventislisted.Synonymsorrelatedconditionsarenotlisted,

butshouldbetakenintoaccountaswell.AdverseeventtermrepresentationisbasedonMedDRAversion12.0.

acidosis,

Hyperkalaemia,

Hypocalcemia,

Hyperuricemia,

Haematuria,

Urate

crystalluria,

Hyperphosphatemia)

Nervoussystem

disorders Neuropathy

peripheral Confusion Coma,

Seizures,

Agitation Cerebral

haemorrhage

Eyedisorders Visual

disturbance Blindness,

Opticneuritis,

Opticneuropathy

Cardiac

disorders Heartfailure,

Arrhythmia

Respiratory,

thoracicand

mediastinal

disorders Cough Pulmonary

toxicity

(including

Pulmonary

fibrosis,

Pneumonitis,

Dyspnoea) Pulmonary

haemorrhage

Gastrointestinal

disorders Vomiting,

Diarrhoea,

Nausea Stomatitis Gastrointestinal

haemorrhage,

Pancreatic

enzymes

abnormal

Hepatobiliary

disorders Hepaticenzyme

abnormal

Skinand

subcutaneous

tissuedisorders Rash Skincancer,

Necrolysis

epidermaltoxic

(Lyelltype),

Stevens-Johnson

syndrome

Renaland

urinary

disorder Haemorrhagic

cystitis

General

disordersand

administration

siteconditions Fever,

Fatigue,

Weakness Oedema,

Mucositis,

Chills,

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4.9Overdose

Highdosesoffludarabinephosphatehavebeenassociatedwithanirreversiblecentralnervoussystemtoxicitycharacterizedby

delayedblindness,coma,anddeath.Highdosesarealsoassociatedwithseverethrombocytopeniaandneutropeniaduetobone

marrowsuppression.

ThereisnoknownspecificantidoteforFludarabinePhosphatePowderforSolutionforInjectionorInfusionoverdose.Treatment

consistsofdrugdiscontinuationandsupportivetherapy.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antineoplasticagentsantimetabolites,purineanalogues . .

ATCcode:L01BB05

FludarabinePhosphate50mgPowderforSolutionforInjectionorInfusionisawater-solublefluorinatednucleotide

analogueoftheantiviralagentvidarabine,9-ß-D-arabinofuranosyladenine(ara-A)thatisrelativelyresistantto

deaminationbyadenosinedeaminase.

Fludarabinephosphateisrapidlydephosphorylatedto2F-ara-Awhichistakenupbycellsandthenphosphorylated

intracellularlybydeoxycytidinekinasetotheactivetriphosphate,2F-ara-ATP.Thismetabolitehasbeenshownto

inhibitribonucleotidereductase,DNApolymerase/and,DNAprimaseandDNAligasetherebyinhibitingDNA

synthesis.Furthermore,partialinhibitionofRNApolymeraseIIandconsequentreductioninproteinsynthesisoccur.

Whilesomeaspectsofthemechanismofactionof2F-ara-ATPareasyetunclear,itisassumedthateffectsonDNA,

RNAandproteinsynthesisallcontributetoinhibitionofcellgrowthwithinhibitionofDNAsynthesisbeingthe

dominantfactor.Inaddition,invitrostudieshaveshownthatexposureofCLLlymphocytesto2F-ara-Atriggers

extensiveDNAfragmentationandcelldeathcharacteristicofapoptosis.

AphaseIIItrialinpatientswithpreviouslyuntreatedB-chroniclymphocyticleukaemiacomparingtreatmentwith

fludarabinephosphatevs.chlorambucil(40mg/m 2

q4weeks)in195and199patientsrespectivelyshowedthe

followingoutcome:statisticallysignificanthigheroverallresponseratesandcompleteresponseratesafter1 st

line

treatmentwithfludarabinephosphatecomparedtochlorambucil(61.1%vs.37.6%and14.9%vs.3.4%,respectively);

statisticallysignificantlongerdurationofresponse(19vs.12.2months)andtimetoprogression(17vs.13.2months)

forthepatientsinthefludarabinephosphategroup.Themediansurvivalofthetwopatientgroupswas56.1monthsfor

fludarabinephosphateand55.1monthsforchlorambucil,anon-significantdifferencewasalsoshownwith

performancestatus.Theproportionofpatientsreportedtohavetoxicitieswerecomparablebetweenfludarabine

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Whilethedifferenceinoverallincidenceofhaematologicaltoxicitieswasnotsignificantbetweenthetwotreatment

groups,significantlygreaterproportionsoffludarabinephosphatepatientsexperiencedwhitebloodcell(p=0.0054)and

lymphocyte(p=0.0240)toxicitiesthanchlorambucilpatients.Theproportionsofpatientswhoexperiencednausea,

vomiting,anddiarrhoeaweresignificantlylowerforfludarabinephosphatepatients(p<0.0001,p<0.0001,and

p=0.0489,respectively)thanchlorambucilpatients.Toxicitiesoftheliverwerealsoreportedforsignificantly

(p=0.0487)lessproportionsofpatientsinthefludarabinephosphategroupthaninthechlorambucilgroup.

PatientswhoinitiallyrespondedtoFludarabinePhosphate50mgPowderforSolutionforInjectionorInfusionhavea

chanceofrespondingagaintoFludarabinePhosphate50mgPowderforSolutionforInjectionorInfusion

monotherapy.

Arandomizedtrialoffludarabinephosphatevs.cyclophosphamide,adriamycinandprednisone(CAP)in208patients

withCLLBinetstageBorCrevealedthefollowingresultsinthesubgroupof103previouslytreatedpatients:the

overallresponserateandthecompleteresponseratewerehigherwithfludarabinephosphatecomparedtoCAP(45%

vs.26%and13%vs.6%respectively);responsedurationandoverallsurvivalweresimilarwithfludarabinephosphate

andCAP.Withinthestipulatedtreatmentperiodof6monthsthenumberofdeathswas9(fludarabinephosphate)vs.4

(CAP).

Post-hocanalysesusingonlydataofupto6monthsafterstartoftreatmentrevealedadifferencebetweensurvival

curvesoffludarabinephosphateandCAPinfavourofCAPinthesubgroupofpretreatedBinetstageCpatients.

5.2Pharmacokineticproperties

PlasmaandurinarypharmacokineticsofFludarabine(2F-ara-A)

ThepharmacokineticsofFludarabine(2F-ara-A)havebeenstudiedafterintravenousadministrationbyrapidbolus

injectionandshort-terminfusionaswellasfollowingcontinuousinfusionoffludarabinephosphate(2F-ara-AMP).

2F-ara-AMPisawatersolubleprodrug,whichisrapidlyandquantitativelydephosphorylatedinthehumanorganismto

thenucleosideFludarabine(2F-ara-A).Aftersingledoseinfusionof25mg2F-ara-AMPperm 2

tocancerpatientsfor

30minutes2F-ara-Areachedmeanmaximumconcentrationsintheplasmaof3.5–3.7µMattheendoftheinfusion.

Corresponding2F-ara-Alevelsafterthefifthdoseshowedamoderateaccumulationwithmeanmaximumlevelsof4.4

–4.8µMattheendoftheinfusion.Duringa5-daytreatmentschedule2F-ara-Aplasmatroughlevelsincreasedbya

factorofabout2.Anaccumulationof2F-ara-Aoverseveraltreatmentcyclescanbeexcluded.Postmaximumlevels

decayedinthreedispositionphaseswithaninitialhalf-lifeofapprox.5minutes,anintermediatehalf-lifeof1-2hours

andaterminalhalf-lifeofapprox.20hours.

Aninterstudycomparisonof2F-ara-Apharmacokineticsresultedinameantotalplasmaclearance(CL)of79±40

ml/min/m 2

(2.2±1.2ml/min/kg)andameanvolumeofdistribution(Vss)of83±55l/m 2

(2.4±1.6l/kg).Datashowed

ahighinterindividualvariability.Plasmalevelsof2F-ara-Aandareasundertheplasmaleveltimecurvesincreased

linearlywiththedose,whereashalf-lives,plasmaclearanceandvolumesofdistributionremainedconstantindependent

ofdoseindicatingadoselinearbehaviour.

Occurrenceofneutropeniaandhaematocritchangesindicatedthatacytotoxicityoffludarabinephosphatedepressesthe

haematopoiesisinadosedependentmanner.

2F-ara-Aeliminationislargelybyrenalexcretion.40to60%oftheadministeredi.v.dosewasexcretedintheurine.

Massbalancestudiesinlaboratoryanimalswith 3

H-2F-ara-AMPshowedacompleterecoveryofradio-labelled

substancesintheurine.Anothermetabolite,2F-ara-hypoxanthine,whichrepresentsthemajormetaboliteinthedog,

wasobservedinhumansonlytoaminorextent.Individualswithimpairedrenalfunctionexhibitareducedtotalbody

clearance,indicatingtheneedforadosereduction.Invitroinvestigationswithhumanplasmaproteinsrevealedno

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Cellularpharmacokineticsoffludarabinetriphosphate

2F-ara-Aisactivelytransportedintoleukaemiccells,whereuponitisrephosphorylatedtothemonophosphateand

subsequentlytothedi-andtriphosphate.Thetriphosphate2F-ara-ATPisthemajorintracellularmetaboliteandthe

onlymetaboliteknowntohavecytotoxicactivity.Maximum2F-ara-ATPlevelsinleukaemiclymphocytesofCLL

patientswereobservedatamedianof4hoursandexhibitedaconsiderablevariationwithamedianpeakconcentration

ofapprox.20µM.

2F-ara-ATPlevelsinleukaemiccellswerealwaysconsiderablyhigherthanmaximum2F-ara-Alevelsintheplasma

indicatinganaccumulationatthetargetsites.In-vitroincubationofleukaemiclymphocytesshowedalinear

relationshipbetweenextracellular2F-ara-Aexposure(productof2F-ara-Aconcentrationanddurationofincubation)

andintracellular2F-ara-ATPenrichment.2F-ara-ATPeliminationfromtargetcellsshowedmedianhalf-lifevaluesof

15and23hours.

Noclearcorrelationwasfoundbetween2F-ara-Apharmacokineticsandtreatmentefficacyincancerpatients.

Thetotalbodyclearanceoftheprincipleplasmametabolite2-F-ara-Ashowsacorrelationwithcreatinineclearance,

indicatingtheimportanceoftherenalexcretionpathwayfortheeliminationofthecompound.Patientswithreduced

renalfunctiondemonstratedanincreasedtotalbodyexposure(AUCof2F-ara-A).

5.3Preclinicalsafetydata

Inacutetoxicitystudies,singledosesoffludarabinephosphateproducedsevereintoxicationsymptomsordeathat

dosagesabouttwoordersofmagnitudeabovetherapeuticdose.Asexpectedforacytotoxiccompound,thebone

marrow,lymphoidorgans,gastrointestinalmucosa,kidneysandmalegonadswereaffected.Inpatientssevereside

effectswereobservedclosertotherecommendedtherapeuticdose(factor3to4)andincludedsevereneurotoxicity

partlywithlethaloutcome(seeSection4.9).

Systemictoxicitystudiesfollowingrepeatedadministrationoffludarabinephosphateshowedalsotheexpectedeffects

onrapidlyproliferatingtissuesaboveathresholddose.Theseverityofmorphologicalmanifestationsincreasedwith

doselevelsanddurationofdosingandtheobservedchangesweregenerallyconsideredtobereversible.Inprinciple,

theavailableexperiencefromthetherapeuticuseoffludarabinephosphatepointstoacomparabletoxicologicalprofile

inhumans,althoughadditionalundesirableeffectssuchasneurotoxicitywereobservedinpatients.(seeSection4.8).

Theresultsfromanimalembryotoxicitystudiesindicatedateratogenicpotentialoffludarabinephosphate.Inviewof

thesmallsafetymarginbetweentheteratogenicdosesinanimalsandthehumantherapeuticdoseaswellasinanalogy

tootherantimetaboliteswhichareassumedtointerferewiththeprocessofdifferentiation,thetherapeuticuseof

FludarabinePhosphate50mgPowderforSolutionforInjectionorInfusionisassociatedwitharelevantriskof

teratogeniceffectsinhumans(seeSection4.6).

Fludarabinephosphatehasbeenshowntoinducechromosomalaberrationsinaninvitrocytogeneticassay,tocause

DNA-damageinasisterchromatidexchangetestandtoincreasetherateofmicronucleiinthemousemicronucleustest

invivo,butwasnegativeingenemutationassaysandinthedominantlethaltestinmalemice.Thus,themutagenic

potentialwasdemonstratedinsomaticcellsbutcouldnotbeshowningermcells.

TheknownactivityoffludarabinephosphateattheDNA-levelandthemutagenicitytestresultsformthebasisforthe

suspicionofatumorigenicpotential.Noanimalstudieswhichdirectlyaddressthequestionoftumorigenicityhavebeen

conducted,becausethesuspicionofanincreasedriskofsecondtumoursduetofludarabinephosphatetherapycan

exclusivelybeverifiedbyepidemiologicaldata.

Accordingtotheresultsfromanimalexperimentsfollowingintravenousadministrationoffludarabinephosphate,no

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Evenincaseofmisplacedinjections,norelevantlocalirritationwasobservedafterparavenous,intraarterial,and

intramuscularadministrationofanaqueoussolutioncontaining7.5mgfludarabinephosphate/ml.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol

SodiumHydroxide(forpHadjustment)

6.2Incompatibilities

Intheabsenceofcombatibilitystudies,thismedicinalproductmustnotbemixedwithothermedicinalproducts.

6.3Shelflife

2years

InUse:

FludarabinePhosphate50mgPowderforSolutionforInjectionorInfusion50mg,followingreconstitutionwithWater

forInjectionto25mg/ml,isstableforupto8hrswhenstoredeitherat2-8ºCwhenprotectedfromlightorat25ºCin

normallightconditions.

TheinfusionsolutionischemicallystablewhenstoredinPVCinfusionbags,preparedunderfullasepticallycontrolled

conditions,for8hourswhenstoredeitherat2-8ºCprotectedfromlightorat25ºCinnormallightconditions.

Fromamicrobiologicalpointofviewhowever,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-

usestoragetimesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan8

hoursat2-8ºCor8hoursatroomtemperature.

6.4Specialprecautionsforstorage

Donotstoreabove25 °

Forstorageafterreconstitutionordilution,seeSection6.3.

6.5Natureandcontentsofcontainer

10mlTypeI(clearglass)vialswitharubberstopperandplasticflip-offtop.

Eachpackcontains5vials.

6.6Specialprecautionsfordisposalandotherhandling

Reconstitution

FludarabinePhosphate50mgPowderforSolutionforInjectionorInfusionshouldbepreparedforparenteraluseby

asepticallyaddingsterilewaterforinjection.Whenreconstitutedwith2mlofsterilewaterforinjection,thepowder

shouldfullydissolvein15secondsorless.Eachmloftheresultingsolutionwillcontain25mgoffludarabine

phosphate,25mgofmannitol,andsodiumhydroxidetoadjustthepHto7.7.ThepHrangeforthefinalproductis7.2–

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Dilution

Therequireddose(calculatedonthebasisofthepatient'sbodysurface)isdrawnupintoasyringe.Forintravenous

bolusinjectionthisdoseisfurtherdilutedin10mlof0.9%sodiumchloride.Alternatively,forinfusion,therequired

dosemaybedilutedin100mlof0.9%sodiumchlorideandinfusedoverapproximately30minutes.

Inclinicalstudies,theproducthasbeendilutedin100mlor125mlof5%dextroseinjectionor0.9%sodium

chloride.

Inspectionpriortouse

FludarabinePhosphate50mgPowderforSolutionforInjectionorInfusionshouldnotbeusedincaseofadefective

container.

Thereconstitutedsolutionisclearandcolourless.Itshouldbevisuallyinspectedbeforeuse.

Onlyclearandcolourlesssolutionswithoutparticlesshouldbeused.

Handlinganddisposal

FludarabinePhosphate50mgPowderforSolutionforInjectionorInfusionshouldnotbehandledbypregnantstaff.

Proceduresforproperhandlingshouldbefollowedaccordingtolocalrequirementsforcytotoxicdrugs.Cautionshould

beexercisedinthehandlingandpreparationofthefludarabinephosphatesolution.Theuseoflatexglovesandsafety

glassesisrecommendedtoavoidexposureincaseofbreakageofthevialorotheraccidentalspillage.

Ifthesolutioncomesintocontactwiththeskinormucousmembranes,theareashouldbewashedthoroughlywithsoap

andwater.Intheeventofcontactwiththeeyes,rinsethemthoroughlywithcopiousamountsofwater.Exposureby

inhalationshouldbeavoided.

Themedicinalproductisforsingleuseonly.Anyunusedproductorwastematerialshouldbedisposedofin

accordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

HospiraUKLimited

Queensway,

RoyalLeamingtonSpa,

Warwickshire,

CV313RW,

8MARKETINGAUTHORISATIONNUMBER

PA437/61/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:15thAugust2008

10DATEOFREVISIONOFTHETEXT

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