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:
  • PA1410/017/001
  • Authorization date:
  • 16-11-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1410/017/001

CaseNo:2051674

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

BayerLimited

TheAtrium,BlackthornRoad,Dublin18,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Fludarabinephosphate50mgpowderforsolutionforinjectionorinfusion

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom30/03/2009until01/02/2012.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Fludarabinephosphate50mgpowderforsolutionforinjectionorinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachvialcontains50mgFludarabinephosphate.

1mlofreconstitutedsolutioncontains25mgfludarabinephosphate.

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinjectionorinfusion.

Whitelyophilisateforreconstitution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

TreatmentofB-cellchroniclymphocyticleukaemia(CLL)inpatientswithsufficientbonemarrowreserves.

FirstlinetreatmentwithFludarashouldonlybeinitiatedinpatientswithadvanceddisease,RaistagesIII/IV(Binet

stageC),orRaistagesI/II(BinetstageA/B)wherethepatienthasdiseaserelatedsymptomsorevidenceofprogressive

disease.

4.2Posologyandmethodofadministration

Fludarashouldbeadministeredunderthesupervisionofaqualifiedphysicianexperiencedintheuseofantineoplastic

therapy.

ItisstronglyrecommendedthatFludarashouldbeonlyadministeredintravenously.Nocaseshavebeenreportedin

whichparavenouslyadministeredFludaraledtoseverelocaladversereactions.

However,unintentionalparavenousadministrationmustbeavoided.

Adults

Therecommendeddoseis25mgfludarabinephosphate/m²bodysurfacegivendailyfor5consecutivedaysevery28

daysbyintravenousroute.Eachvialistobemadeupin2mlwaterforinjection.Eachmloftheresultingsolutionwill

contain25mgfludarabinephosphate(seealsosection6.6).

Therequireddose(calculatedonthebasisofthepatient'sbodysurface)ofthereconstitutedsolutionisdrawnupintoa

syringe.Forintravenousbolusinjectionthisdoseisfurtherdilutedin10mlsodiumchloride9mg/ml(0.9%).

Alternatively,forinfusion,therequireddosedrawnupinasyringemaybedilutedin100mlsodiumchloride9mg/ml

(0.9%)andinfusedoverapproximately30minutes.

Thedurationoftreatmentdependsonthetreatmentsuccessandthetolerabilityofthedrug.

InCLLpatients,Fludarashouldbeadministereduptotheachievementofbestresponse(completeorpartialremission,

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Patientswithrenalimpairment

Dosesshouldbeadjustedforpatientswithreducedkidneyfunction.Ifcreatinineclearanceisbetween30and70

ml/min,thedoseshouldbereducedbyupto50%andclosehaematologicalmonitoringshouldbeusedtoassess

toxicity(seesection4.4).

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

Patientswithhepaticimpairment

NodataareavailableconcerningtheuseofFludarainpatientswithhepaticimpairment.Inthisgroupofpatients,

Fludarashouldbeusedwithcaution.

Children

ThesafetyandeffectivenessofFludarainchildrenhasnotbeenestablished.Therefore,Fludaraisnotrecommended

foruseinchildren.

Elderlypatients

SincetherearelimiteddatafortheuseofFludarainelderlypersons(>75years),cautionshouldbeexercisedwiththe

administrationofFludarainthesepatients.

Inpatientsovertheageof70years,creatinineclearanceshouldbemeasured,see‘Patientswithrenalimpairment’and

section4.4.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Renalimpairmentwithcreatinineclearance<30ml/min.

Decompensatedhaemolyticanaemia.

Lactation

4.4Specialwarningsandprecautionsforuse

Myelosuppresion

Severebonemarrowsuppression,notablyanaemia,thrombocytopeniaandneutropenia,hasbeenreportedinpatients

treatedwithFludara.InaPhaseIintravenousstudyinadultsolidtumourpatients,themediantimetonadircountswas

13days(range3–25days)forgranulocytesand16days(range2-32days)forplatelets.Mostpatientshad

haematologicimpairmentatbaselineeitherasaresultofdiseaseorasaresultofpriormyelosuppressivetherapy.

Cumulativemyelosuppressionmaybeseen.Whilechemotherapy-inducedmyelosuppresionisoftenreversible,

administrationoffludarabinephosphaterequirescarefulhaematologicmonitoring.Fludarabinephosphateisapotent

antineoplasticagentwithpotentiallysignificanttoxicsideeffects.Patientsundergoingtherapyshouldbeclosely

observedforsignsofhaematologicandnonhaematologictoxicity.Periodicassessmentofperipheralbloodcountsis

recommendedtodetectthedevelopmentofanaemia,neutropeniaandthrombocytopenia.

Severalinstancesoftrilineagebonemarrowhypoplasiaoraplasiaresultinginpancytopenia,sometimesresultingin

death,havebeenreportedinadultpatients.Thedurationofclinicallysignificantcytopeniainthereportedcaseshas

rangefromapproximately2monthstoapproximately1year.Theseepisodeshaveoccurredbothinpreviouslytreated

oruntreatedpatients.

Aswithothercytotoxics,cautionshouldbeexercisedwithfludarabinephosphate,whenfurtherhaematopoieticstem

cellsamplingisconsidered.

Autoimmunedisorder

IrrespectiveofanyprevioushistoryofautoimmuneprocessesorCoombsteststatus,life-threateningandsometimes

fatalautoimmunedisorder(seesection4.8)havebeenreportedtooccurduringoraftertreatmentwithFludara.The

majorityofpatientsexperiencinghaemolyticanaemiadevelopedarecurrenceinthehaemolyticprocessafter

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DiscontinuationoftherapywithFludaraisrecommendedincaseofhaemolysis.Bloodtransfusion(irradiated,see

above)andadrenocorticoidpreparationsarethemostcommontreatmentmeasuresforautoimmunehaemolytic

anaemia.

Neurotoxicity

TheeffectofchronicadministrationofFludaraonthecentralnervoussystemisunknown.However,patientstolerated

therecommendeddose,insomestudiesforrelativelylongtreatmenttimes(forupto26coursesoftherapy).

Patientsshouldbecloselyobservedforsignsofneurologiceffects.

Whenusedathighdosesindose-rangingstudiesinpatientswithacuteleukaemia,intravenousFludarawasassociated

withsevereneurologicaleffects,includingblindness,comaanddeath.Symptomsappearedfrom21to60daysfrom

lastdose.Thisseverecentralnervoussystemtoxicityoccurredin36%ofpatientstreatedintravenouslywithdoses

approximatelyfourtimesgreater(96mg/m²/dayfor5–7days)thanthedoserecommendedfortreatmentofCLL.In

patientstreatedatdosesintherangeofthedoserecommendedforCLL,severecentralnervoussystemtoxicity

occurredrarely(coma,seizuresandagitation)oruncommonly(confusion).

Inpost-marketingexperienceneurotoxicityhasbeenreportedtooccurearlierorlaterthaninclinicaltrials.

Tumourlysissyndrome

TumourlysissyndromehasbeenreportedinCLLpatientswithlargetumourburdens.SinceFludaracaninducea

responseasearlyasthefirstweekoftreatment,precautionsshouldbetakeninthosepatientsatriskofdevelopingthis

complication.

Transfusion-associatedgraft-versus-hostdisease

Transfusion-associatedgraft-versus-hostdisease(reactionbythetransfusedimmunocompetentlymphocytestothe

host)hasbeenobservedaftertransfusionofnon-irradiatedbloodinFludara-treatedpatients.Fataloutcomeasa

consequenceofthisdiseasehasbeenreportedwithahighfrequency.Therefore,tominimisetheriskoftransfusion-

associatedgraft-versus-hostdisease,patientswhorequirebloodtransfusionandwhoareundergoing,orwhohave

receivedtreatmentwithFludarashouldreceiveirradiatedbloodonly.

Skincancer

Theworseningorflareupofpre-existingskincancerlesionsaswellasnewonsetofskincancerhasbeenreportedin

somepatientstooccurduringorafterFludaratherapy.

Impariedstateofhealth

Inpatientswithimpairedstateofhealth,Fludarashouldbegivenwithcautionandaftercarefulrisk/benefit

consideration.Thisappliesespeciallyforpatientswithsevereimpairmentofbonemarrowfunction(thrombocytopenia,

anaemia,and/orgranulocytopenia),immunodeficiencyorwithahistoryofopportunisticinfection.

Renalimpairment

Thetotalbodyclearanceoftheprincipleplasmametabolite2-F-ara-Ashowsacorrelationwithcreatinineclearance,

indicatingtheimportanceoftherenalexcretionpathwayfortheeliminationofthecompound.Patientswithreduced

renalfunctiondemonstratedanincreasedtotalbodyexposure(AUCof2F-ara-A).Therearelimitedclinicaldata

availableinpatientswithimpairmentofrenalfunction(creatinineclearance<70ml/min).

Fludaramustbeadministeredcautiouslyinpatientswithrenalinsufficiency.Inpatientswithmoderateimpairmentof

renalfunction(creatinineclearancebetween30and70ml/min),thedoseshouldbereducedbyupto50%andthe

patientshouldbemonitoredclosely(seesection4.2).Fludaratreatmentiscontraindicatedifcreatinineclearanceis<

30ml/min(seesection4.3).

Theelderly

SincetherearelimiteddatafortheuseofFludarainelderlypersons(>75years),cautionshouldbeexercisedwiththe

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Pregnancy

Fludarashouldnotbeusedduringpregnancyunlessclearlynecessary(e.g.life-threateningsituation,noalternative

safertreatmentavailablewithoutcompromisingthetherapeuticbenefit,treatmentcannotbeavoided).Womenshould

avoidbecomingpregnantwhileonFludaratherapy.Ithasthepotentialtocausefoetalharm.(Seesections4.6and5.3).

Womenofchildbearingpotentialmustbeapprisedofthepotentialhazardtothefetus.Prescribersmayonlyconsiderit

tobeused,ifthepotentialbenefitsjustifythepotentialriskstothefoetus.

Contraception

Womenofchild-bearingpotentialorfertilemalesmusttakeeffectivecontraceptivemeasuresduringandatleastfor6

monthsaftercessationoftherapy(seesection4.6).

Vaccination

DuringandaftertreatmentwithFludaravaccinationwithlivevaccinesshouldbeavoided.

RetreatmentoptionsafterinitialFludaratreatment

AcrossoverfrominitialtreatmentwithFludaratochlorambucilfornonresponderstoFludarashouldbeavoided

becausemostpatientswhohavebeenresistanttoFludarahaveshownresistancetochlorambucil.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

InaclinicalinvestigationusingintravenousFludaraincombinationwithpentostatin(deoxycoformycin)forthe

treatmentofrefractorychroniclymphocyticleukaemia(CLL),therewasanunacceptablyhighincidenceoffatal

pulmonarytoxicity.Therefore,theuseofFludaraincombinationwithpentostatinisnotrecommended.

DipyridamoleandotherinhibitorsofadenosineuptakemayreducethetherapeuticefficacyofFludara.Clinicalstudies

andinvitroexperimentsshowedthatduringuseofFludaraincombinationwithcytarabinetheintracellularpeak

concentrationandintracellularexposureofAra-CTP(activemetaboliteofcytarabine)increasedinleukaemiccells.

PlasmaconcentrationsofAra-CandtheeliminationrateofAra-CTPwerenotaffected.

4.6Pregnancyandlactation

Pregnancy

PreclinicaldatainratsdemonstratedatransferofFludaraand/ormetabolitesthroughtheplacenta.Theresultsfrom

intravenousembryotoxicitystudiesinratsandrabbitsindicatedanembryolethalandteratogenicpotentialatthe

therapeuticdoses(seesection5.3).

ThereareverylimiteddataofFludarauseinpregnantwomeninthefirsttrimester:

Fludarashouldnotbeusedduringpregnancyunlessclearlynecessary(e.g.lifethreateningsituation,noalternative

saftertreatmentavailablewithoutcompromisingthetherapeuticbenefit,treatmentcannotbeavoided).Ithasthe

potentialtocausefoetalharm.

Womenofchildbearingpotentialmustbeapprisedofthepotentialhazardtothefoetus.Prescribersmayonlyconsider

ittobeused,ifthepotentialbenefitsjustifythepotentialriskstothefoetus.

Bothsexuallyactivemenandwomenshoulduseeffectivemethodsofcontraceptionduring(andupto6monthsafter)

treatment(seesection4.4).

4.7Effectsonabilitytodriveandusemachines

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

agitation,seizureshavebeenobserved.

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BasedontheexperiencewiththeuseofFludara,themostcommonadverseeventsincludemyelosuppression

(neutropenia,thrombocytopeniaandanaemia),infectionincludingpneumonia,cough,fever,fatigue,weakness,nausea,

vomitinganddiarrhoea.Othercommonlyreportedeventsincludechills,edema,malaise,peripheralneuropathy,visual

disturbance,anorexia,mucositis,stomatitis,andskinrash.Seriousopportunisticinfectionshaveoccurredinpatients

treatedwithFludara.Fatalitiesasaconsequenceofseriousadverseeventshavebeenreported.

ThetablebelowreportsadverseeventsbyMedDRAsystemorganclasses(MedDRASOCs).Thefrequenciesarebased

onclinicaltrialdataregardlessofthecausalrelationshipwithFludara.Therareadversereactionsweremainly

identifiedfromthepost-marketingexperience.

SystemOrgan

Class VeryCommon

≥1/10 Common

≥1/100to<1/10 Uncommon

≥1/1000to<1/100 Rare

≥1/10,000to

<1/1000

Infectionsand

infestations Infections/

Opportunistic

infections

(likelatentviral

reactivation,

e.g.Progressive

multifocal

leukoencephalopathy,

Herpeszostervirus

Epstein-Barr-virus),

Pneumonia Lymphoproliferative

disorder

(EBVassociated)

Neoplasms

benign,

malignant

andunspecified

(inclcystsand

polyps) Myelodysplastic

syndromeand

AcuteMyeloid

Leukaemia

(associatedwith

prior,

concomitantor

subsequent

treatmentwith

alkylatingagents

orirradiation)*

Bloodand

lymphaticsystem

disorders Neutropenia,

Anaemia,

Thrombocytopenia Myelosuppression

Immunesystem

disorders Autoimmunedisorder

(including

Autoimmune

haemolyticanaemia,

Evan’ssyndrome,

Thrombocytopenic

purpura,

Acquired

haemophilia,Pemphig

Metabolismand

nutrition

disorders Anorexia Tumourlysis

syndrome

(including

Renalfailure,

Metabolicacidosis,

Hyperkalaemia,

Hypocalcaemia,

Hyperuricaemia,

Haematuria,

Uratecrystalluria,

Hyperphosphataemia)

Nervoussystem

disorders Peripheral

Neuropathy Confusion Coma,

Seizures,

Agitation

Eyedisorders Visualdisturbance Blindness,

Opticneuritis,

Optic

neuropathy

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ThemostappropriateMedDRAtermtodescribeacertainreactionislisted.Synonymsorrelatedconditionsarenot

listed,butshouldbetakenintoaccountaswell.

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

4.9Overdose

HighdosesofFludarahavebeenassociatedwithirreversiblecentralnervoussystemtoxicitycharacterisedbydelayed

blindness,coma,anddeath.Highdosesarealsoassociatedwithseverethrombocytopeniaandneutropeniaduetobone

marrowsuppression.ThereisnoknownspecificantidoteforFludaraoverdosage.Treatmentconsistsofdrug

discontinuationandsupportivetherapy.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antineoplasticagents,purineanalogues

ATC-codeL01BB05

Fludaracontainsfludarabinephosphate,awater-solublefluorinatednucleotideanalogueoftheantiviralagent

vidarabine,9-ß-D-arabinofuranosyladenine(ara-A)thatisrelativelyresistanttodeaminationbyadenosinedeaminase.

Fludarabinephosphateisrapidlydephosphorylatedto2F-ara-Awhichistakenupbycellsandthenphosphorylated

intracellularlybydeoxycytidinekinasetotheactivetriphosphate,2F-ara-ATP.Thismetabolitehasbeenshownto

inhibitribonucleotidereductase,DNApolymerase __and ,DNAprimaseandDNAligasetherebyinhibiting

DNAsynthesis.Furthermore,partialinhibitionofRNApolymeraseIIandconsequentreductioninproteinsynthesis

occur.

Whilesomeaspectsofthemechanismofactionof2F-ara-ATPareasyetunclear,itisassumedthateffectsonDNA,

RNAandproteinsynthesisallcontributetoinhibitionofcellgrowthwithinhibitionofDNAsynthesisbeingthe

dominantfactor.Inaddition,invitrostudieshaveshownthatexposureofCLLlymphocytesto2F-ara-Atriggers

disorders Arrhythmia

Respiratory,

thoracicand

mediastinal

disorders Cough Pulmonarytoxicity

(including

Pulmonaryfibrosis,

Pneumonitis,

Dyspnea)

Gastrointestinal

disorders Vomiting,

Diarrhoea,

Nausea Stomatitis Gastrointestinal

haemorrhage,

Pancreaticenzymes

abnormal

Hepatobiliary

disorders Hepaticenzymes

abnormal

Skinand

subcutaneous

tissuedisorders Rash SkinCancer

Necrolysis

epidermaltoxic

(Lyelltype),

Stevens-

Johnson

syndrome

Renaland

urinarydisorder Haemorrhagic

cystitis

General

disordersand

administration

siteconditions Fever,

Fatigue,

Weakness Edema,

Mucositis,

Chills,

Malaise

*MonotherapywithFludarahasnotbeenassociatedwithanincreasedriskforthedevelopmentof

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AphaseIIItrialinpatientswithpreviouslyuntreatedB-chroniclymphocyticleukaemiacomparingtreatmentwith

Fludaravs.chlorambucil(40mg/m²q4weeks)in195and199patientsrespectivelyshowedthefollowingoutcome:

statisticallysignificanthigheroverallresponseratesandcompleteresponseratesafter1stlinetreatmentwithFludara

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

ofresponse(19vs.12.2months)andtimetoprogression(17vs.13.2months)forthepatientsintheFludaragroup.The

mediansurvivalofthetwopatientgroupswas56.1monthsforFludaraand55.1monthsforchlorambucil,a

nonsignificantdifferencewasalsoshownwithperformancestatus.Theproportionofpatientsreportedtohave

toxicitieswerecomparablebetweenFludarapatients(89.7%)andchlorambucilpatients(89.9%).Whilethedifference

intheoverallincidenceofhaematologicaltoxicitieswasnotsignificantbetweenthetwotreatmentgroups,significantly

greaterproportionsofFludarapatientsexperiencedwhitebloodcell(p=0.0054)andlymphocyte(p=0.0240)toxicities

thanchlorambucilpatients.Theproportionsofpatientswhoexperiencednausea,vomiting,anddiarrhoeawere

significantlylowerforFludarapatients(p<0.0001,p<0.0001,andp=0.0489,respectively)thanchlorambucilpatients.

Toxicitiesoftheliverwerealsoreportedforsignificantly(p=0.0487)lessproportionsofpatientsintheFludaragroup

thaninthechlorambucilgroup.

PatientswhoinitiallyrespondtoFludarahaveachanceofrespondingagaintoFludaramonotherapy.Arandomised

trialofFludaravs.cyclophosphamide,adriamycinandprednisone(CAP)in208patientswithCLLBinetstageBorC

revealedthefollowingresultsinthesubgroupof103previouslytreatedpatients:theoverallresponserateandthe

completeresponseratewerehigherwithFludaracomparedtoCAP(45%vs.26%and13%vs.6%,respectively);

responsedurationandoverallsurvivalweresimilarwithFludaraandCAP.Withinthestipulatedtreatmentperiodof6

monthsthenumberofdeathswas9(Fludara)vs.4(CAP).

Post-hocanalysesusingonlydataofupto6monthsafterstartoftreatmentrevealedadifferencebetweensurvival

curvesofFludaraandCAPinfavourofCAPinthesubgroupofpretreatedBinetstageCpatients.

5.2Pharmacokineticproperties

Plasmaandurinarypharmacokineticsoffludarabine(2F-ara-A)

Thepharmacokineticsoffludarabine(2F-ara-A)havebeenstudiedafterintravenousadministrationbyrapidbolus

injectionandshort-terminfusionaswellasfollowingcontinuousinfusionandafterperoraldosingoffludarabine

phosphate(Fludara,2F-ara-AMP).

Noclearcorrelationwasfoundbetween2F-ara-Apharmacokineticsandtreatmentefficacyincancerpatients.

However,occurrenceofneutropeniaandhaematocritchangesindicatedthatthecytotoxicityoffludarabinephosphate

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Distributionandmetabolism

2F-ara-AMPisawater-solubleprodrugoffludarabine(2Fara-A),whichisrapidlyandquantitativelydephosphorylated

inthehumanorganismtothenucleosidefludarabine(2F-ara-A).

Anothermetabolite,2F-ara-hypoxanthine,whichrepresentsthemajormetaboliteinthedog,wasobservedinhumans

onlytoaminorextent.

Aftersingledoseinfusionof25mg2F-ara-AMPperm²toCLLpatientsfor30minutes2F-ara-Areachedmean

maximumconcentrationsintheplasmaof3.5-3.7µMattheendoftheinfusion.Corresponding2F-ara-Alevelsafter

thefifthdoseshowedamoderateaccumulationwithmeanmaximumlevelsof4.4-4.8µMattheendofinfusion.

Duringa5-daytreatmentschedule2F-ara-Aplasmatroughlevelsincreasedbyafactorofabout2.Anaccumulationof

2F-ara-Aoverseveraltreatmentcyclescanbeexcluded.Postmaximumlevelsdecayedinthreedispositionphaseswith

aninitialhalf-lifeofapproximately5minutes,anintermediatehalf-lifeof1-2hoursandaterminalhalflifeof

approximately20hours.

Aninterstudycomparisonof2F-ara-Apharmacokineticsresultedinameantotalplasmaclearance(CL)of79±40

ml/min/m²(2.2±1.2ml/min/kg)andameanvolumeofdistribution(Vss)of83±55l/m²(2.4±1.6l/kg).Datashowed

ahighinterindividualvariability.Afterintravenousandperoraladministrationoffludarabinephosphateplasmalevels

of2F-ara-Aandareasundertheplasmaleveltimecurvesincreasedlinearlywiththedose,whereashalf-lives,plasma

clearanceandvolumesofdistributionremainedconstantindependentofthedoseindicatingadoselinearbehaviour.

Elimination

2F-ara-Aeliminationislargelybyrenalexcretion.40to60%oftheadministeredintravenousdosewasexcretedinthe

urine.Massbalancestudiesinlaboratoryanimalswith³H-2F-ara-AMPshowedacompleterecoveryofradio-labelled

substancesintheurine.

Characteristicsinpatients

Individualswithimpairedrenalfunctionexhibitedareducedtotalbodyclearance,indicatingtheneedforadose

reduction.Invitroinvestigationswithhumanplasmaproteinsrevealednopronouncedtendencyof2F-ara-Aprotein

binding.

Cellularpharmacokineticsoffludarabinetriphosphate

2F-ara-Aisactivelytransportedintoleukaemiccells,whereuponitisrephosphorylatedtothemonophosphateand

subsequentlytothedi-andtriphosphate.Thetriphosphate2F-ara-ATPisthemajorintracellularmetaboliteandthe

onlymetaboliteknowntohavecytotoxicactivity.Maximum2F-ara-ATPlevelsinleukaemiclymphocytesofCLL

patientswereobservedatamedianof4hoursandexhibitedaconsiderablevariationwithamedianpeakconcentration

ofapproximately20µM.2F-ara-ATPlevelsinleukaemiccellswerealwaysconsiderablyhigherthanmaximum2F-

ara-Alevelsintheplasmaindicatinganaccumulationatthetargetsites.In-vitroincubationofleukaemiclymphocytes

showedalinearrelationshipbetweenextracellular2F-ara-Aexposure(productof2F-ara-Aconcentrationandduration

ofincubation)andintracellular2F-ara-ATPenrichment.2F-ara-ATPeliminationfromtargetcellsshowedmedianhalf-

lifevaluesof15and23hours.

5.3Preclinicalsafetydata

Systemictoxicity

Inacutetoxicitystudies,singledosesoffludarabinephosphateproducedsevereintoxicationsymptomsordeathat

dosagesabouttwoordersofmagnitudeabovethetherapeuticdose.Asexpectedforacytotoxiccompound,thebone

marrow,lymphoidorgans,gastrointestinalmucosa,kidneysandmalegonadswereaffected.Inpatients,severeside

effectswereobservedclosertotherecommendedtherapeuticdose(factor3to4)andincludedsevereneurotoxicity

partlywithlethaloutcome(seesection4.9).

Systemictoxicitystudiesfollowingrepeatedadministrationoffludarabinephosphateshowedalsotheexpectedeffects

onrapidlyproliferatingtissuesaboveathresholddose.Theseverityofmorphologicalmanifestationsincreasedwith

doselevelsanddurationofdosingandtheobservedchangesweregenerallyconsideredtobereversible.Inprinciple,

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althoughadditionalundesirableeffectssuchasneurotoxicitywereobservedinpatients(seesection4.8).

Embryotoxicity

Theresultsfromintravenousanimalembryotoxicitystudiesinratsandrabbitsindicatedanembryolethaland

teratogenicpotentialoffludarabinephosphateasmanifestedinskeletalmalformations,foetalweightlossandpost

implantationloss.Inviewofthesmallsafetymarginbetweentheteratogenicdosesinanimalsandthehuman

therapeuticdoseaswellasinanalogytootherantimetaboliteswhichareassumedtointerferewiththeprocessof

differentiation,thetherapeuticuseofFludaraisassociatedwitharelevantriskofteratogeniceffectsinhumans(see

section4.6).

Genotoxicpotential,tumorigenicity

FludarabinephosphatehasbeenshowntocauseDNA-damageinasisterchromatidexchangetest,toinduce

chromosomalaberrationsinaninvitrocytogeneticassayandtoincreasetherateofmicronucleiinthemouse

micronucleustestinvivo,butwasnegativeingenemutationassaysandinthedominantlethaltestinmalemice.Thus,

themutagenicpotentialwasdemonstratedinsomaticcellsbutcouldnotbeshowningermcells.

TheknownactivityoffludarabinephosphateattheDNA-levelandthemutagenicitytestresultsformthebasisforthe

suspicionofatumorigenicpotential.Noanimalstudieswhichdirectlyaddressthequestionoftumorigenicityhavebeen

conducted,becausethesuspicionofanincreasedriskofsecondtumoursduetoFludaratherapycanexclusivelybe

verifiedbypidemiologicaldata.

Localtolerance

Accordingtotheresultsfromanimalexperimentsfollowingintravenousadministrationoffludarabinephosphate,no

remarkablelocalirritationistobeexpectedattheinjectionsite.Evenincaseofmisplacedinjections,norelevantlocal

irritationwasobservedafterparavenous,intraarterial,andintramuscularadministrationofanaqueoussolution

containing7.5mgfludarabinephosphate/ml.

Thesimilarityinnatureoftheobservedlesionsinthegastrointestinaltractafterintravenousorintragastricdosingin

animalexperimentssupportstheassumptionthatthefludarabinephosphateinducedenteritisisasystemiceffect.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol,

Sodiumhydroxide(toadjustthepHto7.7).

6.2Incompatibilities

Intheabsenceofcompatibilitystudies,thismedicinalproductmustnotbemixedwithothermedicinalproducts.

6.3ShelfLife

Aspackagedforsale:3years.

Chemicalandphysicalin-usestabilityafterreconstitutionhasbeendemonstratedfor7daysat4 °

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestoragetimes

andconditionspriortousearetheresponsibilityoftheuserandshouldnotbelongerthan24hoursat2to8 °

Cor8hoursat

roomtemperature.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

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6.5Natureandcontentsofcontainer

10mlcolourlessTypeIglassvialscontaining50mgfludarabinephosphate.

Eachpackagecontains5vials.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Reconstitution

FludaraTwoshouldbepreparedforparenteralusebyasepticallyaddingsterilewaterforinjection.Whenreconstituted

with2mlofsterilewaterforinjection,thepowdershouldfullydissolvein15secondsorless.Eachmloftheresulting

solutionwillcontain25mgoffludarabinephosphate,25mgofmannitol,andsodiumhydroxide(toadjustthepHto

7.7).ThepHrangeforthefinalproductis7.2-8.2.

Dilution

Therequireddose(calculatedonthebasisofthepatient'sbodysurface)isdrawnupintoasyringe.

Forintravenousbolusinjectionthisdoseisfurtherdilutedin10mlofsodiumchloride9mg/ml(0.9%).Alternatively,

forinfusion,therequireddosemaybedilutedin100mlofsodiumchloride9mg/ml(0.9%)andinfusedover

approximately30minutes.

Inclinicalstudies,theproducthasbeendilutedin100mlor125mlof5%dextroseinjectionorsodiumchloride

9mg/ml(0.9%).

Instructionpriortouse

Thereconstitutedsolutionisclearandcolourless.Itshouldbevisuallyinspectedbeforeuse.

Onlyclearandcolourlesssolutionswithoutparticlesshouldbeused.FludaraTwoshouldnotbeusedincaseofa

defectivecontainer.

Handlinganddisposal

FludaraTwoshouldnotbehandledbypregnantstaff.

Proceduresforproperhandlingshouldbefollowedaccordingtolocalrequirementsforcytotoxicdrugs.

CautionshouldbeexercisedinthehandlingandpreparationoftheFludaraTwosolution.Theuseoflatexglovesand

safetyglassesisrecommendedtoavoidexposureincaseofbreakageofthevialorotheraccidentalspillage.Ifthe

solutioncomesintocontactwiththeskinormucousmembranes,theareashouldbewashedthoroughlywithsoapand

water.Intheeventofcontactwiththeeyes,rinsethemthoroughlywithcopiousamountsofwater.Exposureby

inhalationshouldbeavoided.

Themedicinalproductisforsingleuseonly.Anyunusedproduct,spillageorwastematerialshouldbedisposedofin

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7MARKETINGAUTHORISATIONHOLDER

BayerLimited

TheAtrium

BlackthornRoad

Dublin18

8MARKETINGAUTHORISATIONNUMBER

PA1410/17/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:2ndFebruary2007

10DATEOFREVISIONOFTHETEXT

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