FLUDARABINE PHOSPHATE "EBEWE"

Main information

  • Trade name:
  • FLUDARABINE PHOSPHATE "EBEWE"
  • Dosage:
  • 25
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0789/015/001
  • Authorization date:
  • 28-11-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Fludarabinphosphate"Ebewe"25mg/mlconcentrateforsolutionforinjectionorinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Vialof2mlcontains50mgfludarabinephosphate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinjectionorinfusion.

Clear,colourlessoralmostcolourlesssolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

TreatmentofB-cellchroniclymphocyticleukemia(CLL)inpatientswithsufficientbonemarrowreserves.

FirstlinetreatmentwithFludarabin“Ebewe”shouldonlybeinitiatedinpatientswithadvanceddisease,Raistages

III/IV(BinetstagesC),orRaistagesI/II(BinetstagesA/B)wherethepatienthasdiseaserelatedsymptomsorevidence

ofprogressivedisease.

4.2Posologyandmethodofadministration

Fludarabinshouldbeadministeredunderthesupervisionofaqualifiedphysicianexperiencedintheuseof

antineoplastictherapy.

ItisstronglyrecommendedthatFludarabinshouldbeonlyadministeredintravenously.Nocaseshavebeenreportedin

whichparavenouslyadministeredFludarabinledtoseverelocaladversereactions.However,unintentionalparavenous

administrationofFludarabinmustbeavoided.

Adults

TherecommendeddoseofFludarabinis25mg/m 2

bodysurfacegivendailyfor5consecutivedays(=onecycle)

every28daysbytheintravenousroute.

Therequireddose(calculatedonthebasisofthepatient'sbodysurface)isdrawnupintoasyringe.For

intravenousbolusinjectionthisdoseisfurtherdilutedin10mlofsodiumchloride9mg/ml(0.9%)solutionfor

injection.Alternatively,forinfusion,therequireddosemaybedilutedin100mlofsodiumchloride9mg/ml

(0.9%)solutionforinjectionandinfusedintravenouslyoveraperiodofapproximately30minutes(seealso

section6.6).

Theoptimaldurationoftreatmenthasnotbeenclearlyestablished.Thedurationoftreatmentdependsonthe

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ItisrecommendedtoadministerFludarabin“Ebewe”untilresponseisachieved(usuallyafter6cycles)andthen

themedicinalproductshouldbediscontinued.

Hepaticimpairment

NodataareavailableconcerningtheuseofFludarabininpatientswithhepaticimpairment.Inthisgroupof

patients,Fludarabinshouldbeusedwithcautionandadministerediftheperceivedbenefitoutweighsany

potentialrisk.Suchpatientsshouldbemonitoredcloselyforexcessivetoxicityanddosageshouldbemodifiedor

themedicinalproductdiscontinuedaccordingly.Seealsosection4.4.

Renalimpairment

Totalbodyclearanceoftheprincipleplasmametabolite2F-ara-Acorrelateswiththecreatinineclearance,indicating

theimportanceoftherenalexcretionpathwayfortheeliminationofthecompound.Patientswithreducedkidney

functiondemonstratedanincreasedtotalbodyexposure(AUCof2F-ara-A).Limitedclinicaldataareavailablein

patientswithimpairedrenalfunction(creatinineclearancebelow70ml/min).Therefore,ifrenalimpairmentis

clinicallysuspected,orinpatientsovertheageof70years,creatinineclearanceshouldbemeasured.Ifcreatinine

clearanceisbetween30and70ml/min,thedosemustbereducedbyupto50%andclosehaematologicalmonitoring

shouldbeusedtoassesstoxicity.Fludarabin“Ebewe”treatmentiscontraindicated,ifcreatinineclearanceisbelow

30ml/min.

Childrenandadolescents

Fludarabinisnotrecommendedforuseinchildrenandadolescents,duetoalackofdataonsafetyand/or

efficacy.

Elderly

Onlylimiteddataavailableconcerningtheuseoffludarabinephosphateinelderlypersons(>75years),caution

shouldbeexercisedwhenfludarabinephosphateisusedforthesepatients(see4.4).

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients,

Renalimpairmentwithcreatinineclearance<30ml/min,

Decompensatedhaemolyticanaemia,

Lactation.

4.4Specialwarningsandprecautionsforuse

Neurotoxicity

Whenusedathighdosesindose-rangingstudiesinpatientswithacuteleukaemia,intravenousfludarabinephosphate

wasassociatedwithsevereneurologiceffectsincludingblindness,coma,anddeath.Symptomsappearedfrom21to60

daysfromlastdose.Thisseverecentralnervoussystemtoxicityoccuredin36%ofpatientstreatedintravenouslywith

dosesapproximatelyfourtimesgreater(96mg/m²/dayfor5-7days)thantherecommendeddose.Inpatientstreatedat

dosesintherangeofthedoserecommendedforchroniclymphocyticleukaemia,severecentralnervoussystemtoxicity

occurredrarely(coma,seizures,andagitation)oruncommonly(confusion).Patientsshouldbecloselyobservedfor

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Theeffectofchronicadministrationoffludarabinephosphateonthecentralnervoussystemisunknown.However,

patientstoleratedtherecommendeddose,insomestudiesforrelativelylongtreatmenttimes(forupto26coursesof

therapy).

Inpostmarketingexperienceneurotoxicityhasbeenreportedtooccurearlierorlaterthaninclinicaltrials.

Impairedstateofhealth

Inpatientswithimpairedstateofhealth,fludarabinephosphateshouldbegivenwithcautionandaftercareful

risk/benefitconsideration.Thisappliesespeciallyforpatientswithsevereimpairmentofbonemarrowfunction

(thrombocytopenia,anaemia,and/orgranulocytopenia),immunodeficiencyorwithahistoryofopportunisticinfection.

Hepaticimpairment

Inpatientswithhepaticimpairmentfludarabinephosphateshouldbeusedwithcautionbecauseitcancausehepatic

toxicity.Fludarabinephosphateshouldonlybeadministerediftheperceivedbenefitoutweighsanypotentialrisk.Such

patientsshouldbemonitoredcloselyforexcessivetoxicityanddosagemodifiedorthemedicinalproductdiscontinued

accordingly.Seealsosection4.2.

Renalimpairment

Thetotalbodyclearanceoftheprincipleplasmametabolite2-F-ara-Ashowsacorrelationwithcreatinineclearance,

indicatingtheimportanceoftherenalexcretionpathwayfortheeliminationofthecompound.Patientswithreduced

renalfunctiondemonstratedanincreasedtotalbodyexposure(AUCof2F-ara-A).Therearelimitedclinicaldata

availableinpatientswithimpairmentofrenalfunction(creatinineclearance<70ml/min).

Fludarabinephosphatemustbeadministeredcautiouslyinpatientswithrenalinsufficiency.Inpatientswithmoderate

impairmentofrenalfunction(creatinineclearancebetween30and70ml/min),thedoseshouldbereducedbyupto50

%andthepatientshouldbemonitoredclosely(seesection4.2).Fludarabinephosphatetreatmentiscontraindicatedif

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

Myelosuppression

Severebonemarrowsuppression,notablyanaemia,thrombocytopeniaandneutropenia,hasbeenreportedinpatients

treatedwithfludarabinephosphate.InaPhaseIintravenousstudyinadultsolidtumourpatients,themediantimeto

nadircountswas13days(range:3-25days)forgranulocytesand16days(range:2-32)forplatelets.Mostpatientshad

haematologicimpairmentatbaselineeitherasaresultofdiseaseorasaresultofpriormyelosuppressivetherapy.

Cumulativemyelosuppressionmaybeseen.Whilechemotherapy-inducedmyelosuppressionisoftenreversible,

administrationoffludarabinephosphaterequirescarefulhaematologicmonitoring.

Fludarabinephosphateisapotentantineoplasticagentwithpotentiallysignificanttoxicsideeffects.Patients

undergoingtherapyshouldbecloselyobservedforsignsofhaematologicandnon-haematologictoxicity.Periodic

assessmentofperipheralbloodcountsisrecommendedtodetectthedevelopmentofanaemia,neutropenia,and

thrombocytopenia.

Severalinstancesoftrilineagebonemarrowhypoplasiaoraplasiaresultinginpancytopenia,sometimesresultingin

death,havebeenreportedinadultpatients.Thedurationofclinicallysignificantcytopeniainthereportedcaseshas

rangedfromapproximately2monthstoapproximately1year.Theseepisodeshaveoccurredbothinpreviouslytreated

oruntreatedpatients.

Aswithothercytotoxics,cautionshouldbeexercisedwithfludarabinephosphatewhenfurtherhematopoieticstemcell

samplingisconsidered.

Transfusion-associatedgraft-versus-hostdisease

Transfusion-associatedgraft-versus-hostdisease(reactionbythetransfusedimmunocompetentlymphocytestothe

host)hasbeenobservedaftertransfusionofnon-irradiatedbloodinfludarabinephosphatetreatedpatients.Fatal

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transfusion-associatedgraft-versus-hostdisease,patientswhorequirebloodtransfusionandwhoareundergoing,or

whohavereceived,treatmentwithfludarabinephosphateshouldreceiveirradiatedbloodonly.

Skincancer

Theworseningorflareupofpre-existingskincancerlesionsaswellasnewonsetofskincancerhasbeenreportedin

somepatientsduringorafterfludarabinephosphatetherapy.

Tumourlysissyndrome

Tumourlysissyndromehasbeenreportedinpatientswithlargetumourburdens.Sincefludarabinephosphatecan

inducearesponseasearlyaswithinthefirstweekoftreatment,precautionsshouldbetakeninthosepatientsatriskof

developingthiscomplication.

Autoimmunedisorders

IrrespectiveofanyprevioushistoryofautoimmuneprocessesorCoombsteststatus,life-threateningandsometimes

fatalautoimmunephenomena(e.g.autoimmunehaemolyticanaemia,autoimmunethrombocytopenia,

thrombocytopenicpurpura,pemphigus,Evans'syndrome)havebeenreportedtooccurduringoraftertreatmentwith

fludarabinephosphate.Themajorityofpatientsexperiencinghaemolyticanaemiadevelopedarecurrenceinthe

haemolyticprocessafterrechallengewithfludarabinephosphate.Patientstreatedwithfludarabinephosphateshouldbe

closelymonitoredforsignsofhaemolysis.

Patientsundergoingtreatmentwithfludarabinephosphateshouldbecloselymonitoredforsignsofautoimmune

haemolyticanaemia(declineinhaemoglobinlinkedwithhaemolysisandpositiveCoombstest).Discontinuationof

therapywithfludarabinephosphateisrecommendedincaseofhaemolysis.Bloodtransfusions(irradiated,seeabove)

andadrenocorticoidpreparationsarethemostcommontreatmentmeasuresforautoimmunehaemolyticanaemia.

Theelderly

Sincetherearelimiteddatafortheuseoffludarabinephosphateinelderlypersons(>75years),cautionshouldbe

exercisedwiththeadministrationoffludarabinephosphateinthesepatients.

Inpatientsaged65yearsorolder,creatinineclearanceshouldbemeasuredbeforestartoftreatment,seeRenal

impairmentandsection4.2

Childrenandadolescents

Nodataareavailableconcerningtheuseoffludarabinephosphateinchildrenandadolescents.Therefore,treatment

withfludarabinephosphateinchildrenandadolescentsisnotrecommended.

Pregnancy

Fludarashouldnotbeusedduringpregnancyunlessclearlynecessary(e.g.life-threateningsituation,noalternative

safertreatmentavailablewithoutcompromisingthetherapeuticbenefit,treatmentcannotbeavoided).Ithasthe

potentialtocausefetalharm(seesections4.6and5.3).PrescribersmayonlyconsidertheuseofFludara,ifthe

potentialbenefitsjustifythepotentialriskstothefoetus.

WomenshouldavoidbecomingpregnantwhileonFludaratherapy.

Womenofchildbearingpotentialmustbeapprisedofthepotentialhazardtothefoetus.

Contraception

Womenofchild-bearingpotentialorfertilemalesmusttakeeffectivecontraceptivemeasuresduringandatleastfor6

monthsaftercessationoftherapy(seesection4.6).

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Duringandaftertreatmentwithfludarabinephosphatevaccinationwithlivevaccinesshouldbeavoided.

Retreatmentoptionsafterinitialfludarabinetreatment

Acrossoverfrominitialtreatmentwithfludarabinephosphatetochlorambucilfornonresponderstofludarabine

phosphateshouldbeavoidedbecausemostpatientswhohavebeenresistanttofludarabinephosphatehaveshown

resistancetochlorambucil.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Inaclinicalinvestigationusingintravenousfludarabinephosphateincombinationwithpentostatin(deoxycoformycin)

forthetreatmentofrefractorychroniclymphocyticleukaemia(CLL),therewasanunacceptablyhighincidenceoffatal

pulmonarytoxicity.Therefore,theuseoffludarabinephosphateincombinationwithpentostatinisnotrecommended.

Dipyridamoleandotherinhibitorsofadenosineuptakemayreducethetherapeuticefficacyoffludarabinephosphate.

ApharmacokineticmedicinalproductinteractionwasobservedinCLLandAML(acutemyeloidleukaemia)patients

duringcombinationtherapywithfludarabinephosphateandAra-C.Clinicalstudiesandinvitroexperimentsshowed

thatduringuseoffludarabinephosphateincombinationwithcytarabinetheintracellularpeakconcentrationand

intracellularexposureofAra-CTP(activemetaboliteofcytarabine)increasedinleukaemiccells.Plasma

concentrationsofAra-CandtheeliminationrateofAra-CTPwerenotaffected.

4.6Fertility,pregnancyandlactation

Pregnancy

PreclinicaldatainratsdemonstratedatransferofFludaraand/ormetabolitesthroughtheplacenta.Theresultsfrom

intravenousembryotoxicitystudiesinratsandrabbitsindicatedanembyrolethalandteratogenicpotentialatthe

therapeuticdoses(seesection5.3).

ThereareverylimiteddataofFludarauseinpregnantwomeninthefirsttrimester.

Fludarashouldnotbeusedduringpregnancyunlessclearlynecessary(e.g.life-threateningsituation,noalternative

safertreatmentavailablewithoutcompromisingthetherapeuticbenefit,treatmentcannotbeavoided).Fludarahasthe

potentialtocausefetalharm.PrescribersmayonlyconsidertheuseofFludara,ifthepotentialbenefitsjustifythe

potentialriskstothefoetus.

Womenofchildbearingpotentialmustbeapprisedofthepotentialhazardtothefoetus.

Bothsexuallyactivemenandwomenofchildbearingpotentialmusttakeeffectivecontraceptivemeasuresduringand

atleastfor6monthsaftercessationoftherapy(seesection4.4).

Lactation

Itisnotknownwhetherthisdrugoritsmetabolitesareexcretedinhumanmilk.

However,thereisevidencefrompreclinicaldatathatfludarabinephosphateand/ormetabolitestransferfrommaternal

bloodtomilk.

BecauseofthepotentialforseriousadversereactionstoFludarainbreast-fedinfants,Fludaraiscontraindicatedin

nursingmothers(seesection4.3).

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,fludarabine

phosphatemayreducetheabilitytodriveandusemachines,sincee.g.fatigue,weakness,visualdisturbances,

confusion,agitationandseizureshavebeenobserved.

4.8Undesirableeffects

Basedontheexperiencewiththeuseoffludarabine,themostcommonadverseeventsincludemyelosuppression

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

vomitinganddiarrhoea.Othercommonlyreportedeventsincludechills,oedema,malaise,peripheralneuropathy,visual

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Seriousopportunisticinfectionshaveoccurredinpatientstreatedwithfludarabine.Fatalitiesasaconsequenceof

seriousadverseeventshavebeenreported.

ThetablebelowreportsadverseeventsbyMedDRAsystemorganclasses(MedDRASOCs).Thefrequenciesarebased

onclinicaltrialdataregardlessofthecausalrelationshipwithfludarabine.Therareadversereactionsweremainly

identifiedfromthepost-marketingexperience.

System

OrganClass

MedDRA VeryCommon

1/10 Common

1/100to<

1/10 Uncommon

1/1000to<1/100 Rare

1/10,000

to<1/1000 Notknown

Infectionsand

infestations Infections/

Opportunistic

infections(like

latentviral

reactivation,

e.g.progressive

multifocal

leucoencephalopathy,

herpeszoster

virus,Epstein-

Barr-virus),

Lymphoproliferative

disorder

(EBV-

associated)

Neoplasms

benign,

malignant

unspecified

(inclcystsand

polyps) Myelodysplastic

syndromeand

acutemyeloid

leukaemia

(mainly

associatedwith

prior,

concomitantor

subsequent

treatmentwith

alkylating

agents,

topoisomerase

inhibitorsor

irradiation)

Bloodand

lymphatic

system

disorders Neutropenia,

anaemia,

thrombo-

cytopenia Myelo-

suppression

Immune

system

disorders Autoimmune

disorder(including

autoimmune

haemolytic

anaemia,Evans

syndrome,

thrombocytopenic

purpura,acquired

haemophilia,

pemphigus)

Metabolism

andnutrition

disorders Anorexia Tumourlysis

syndrome

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ThemostappropriateMedDRAtermtodescribeacertainadverseeventislisted.Synonymsorrelatedconditionsare

notlisted,butshouldbetakenintoaccountaswell.AdverseeventtermrepresentationisbasedonMedDRAversion

12.0.

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

failure,metabolic

acidosis,

hyperkalaemia,

hypocalcemia,

hyperuricemia,

haematuria,urate

crystalluria,

hyperphosphatemia)

Nervous

system

disorders Neuropathy

peripheral Confusion Coma,

seizures,

agitation Cerebral

haemorrhage

Eyedisorders Visual

disturbance Blindness,

optic

neuritis,

optic

neuropathy

Cardiac

disorders Heart

failure,

arrhythmia

Respiratory,

thoracicand

mediastinal

disorders Cough Pulmonarytoxicity

(including

pulmonaryfibrosis,

pneumonitis,

dyspnoea) Pulmonary

haemorrhage

Gastro-

intestinal

disorders Vomiting,

diarrhoea,

nausea Stomatitis Gastrointestinal

haemorrhage,

pancreaticenzymes

abnormal

Hepatobiliary

disorders Hepaticenzyme

abnormal

Skinand

subcutaneous

tissue

disorders Rash Skin

cancer,

necrolysis

epidermal

toxic(Lyell

type),

Stevens-

Johnson

Syndrome

Renaland

urinary

disorder Haemorrhagic

cystitis

General

disordersand

administration

site

conditions Fever,fatigue,

weakness Oedema,

mucositis,

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Highdosesoffludarabinephosphatehavebeenassociatedwithirreversiblecentralnervoussystemtoxicity

characterisedbydelayedblindness,coma,anddeath.Highdosesarealsoassociatedwithseverethrombocytopeniaand

neutropeniaduetobonemarrowsuppression.Thereisnospecificantidoteforfludarabinephosphateoverdosage.

Treatmentconsistsofdrugdiscontinuationandsupportivetherapy.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antineoplasticagents,ATCcode:L01BB05

Fludarabinephosphatecontainsfludarabinephosphate(2F-Ara-AMP),awater-solublefluorinatednucleotideanalogue

oftheantiviralagentvidarabine(Ara-A,9-ß-D-arabinofuranosyladenine)thatisrelativelyresistanttodeaminationby

adenosinedeaminase.

Fludarabinephosphateisrapidlydephosphorylatedto2F-ara-A,whichistakenupbycellsandthenintracellularly

phosphorylatedbydeoxycytidinekinasetoactivetriphosphate,2F-ara-ATP.Thismetaboliteinhibitsribonucleotide

reductase,DNApolymerase/and,DNAprimaseandDNAligasetherebypreventingDNAsynthesis.

Furthermore,partialinhibitionofRNApolymeraseIIandconsequentreductioninproteinsynthesisoccur.

Whilesomeaspectsofthemechanismofactionof2F-ara-ATPareasyetunclearitisbelievedthateffectsonDNA,

RNAandproteinsynthesisallcontributetotheinhibitionofcellgrowth,withinhibitionofDNAsynthesisbeingthe

dominantfactor.Inaddition,invitrostudieshaveshownthatexposureofCLLlymphocytesto2F-ara-Atriggers

apoptosiswithextensiveDNAfragmentation.

Inaphase-III-studyincludingpatientswithpreviouslyuntreatedB-cell-CLL,195patientsweretreatedwith

fludarabineand199patientswithchlorambucil(40mg/m 2

,repeatedevery4weeks).

Theoverallremissionrateandtherateofcompleteremissionswasstatisticallysignificanthigherafterfirstline

treatmentwithfludarabineincomparisontochlorambucil61%versus37.6%and19%versus3.4%,respectively.

Thedurationofremission(19monthsversus12.2months)andtimetoprogression(17versus13.2months)were

statisticallysignificantlongerwithfludarabinetreatmentthanwithchlorambucil.Mediansurvivalwas56.1months

withfludarabinephosphateand55.1monthswithchlorambucil,anon-significantdifferencewasalsoshownwith

performancestatus.Theincidenceoftoxicitieswascomparable(89.7%withfludarabinephosphate,89.9%with

chlorambucil).Overallhematologicaltoxicitieswereequallyfrequent,butadecreaseofthecountsofleucocytesand

oflymphocyteswassignificantlymorefrequentwithfludarabinephosphatethanwithchloramucil(p=0.0054and

0.0240,respectively).Nausea,vomitinganddiarhoeawassignificantlylessfrequentwithfludarabinephosphatethan

withchlorambucil(p<0.0001,p<0.0001,p=0.0489,respectively).

Also,livertoxicitieswerereportedforsignificantly(p=0.0487)lesspatientsinthefludarabinephosphatearmthanin

thechlorambucilarm.

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phosphatemonotherapy.

Arandomizedstudycomparingfludarabinephosphatewithacombinationofcyclophosphamideplusadriamycinand

prednisolon(CAP)in208patientswithCLL(BinetstageBandC)showedinasubgroupof103pretreatedpatientsthe

followingresults:Theoverallresponserateandthenumberofcompleteremissionswerehigherwithfludarabine

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

similarwithfludarabinephosphateandCAP.Withinthestipulatedtreatmentperiodof6monthsthenumberofdeaths

was9(fludarabinephosphate)vs.4(CAP).

Post-hocanalysesusingdataofupto6monthsafterstartoftreatmentrevealedadifferencebetweensurvivalcurvesof

fludarabinephosphateandCAPinfavourofCAPinthesubgroupofpre-treatedBinetstageCpatients.

5.2Pharmacokineticproperties

Plasmaandurinepharmacokineticsoffludarabine(2F-ara-A)

Thepharmacokineticpropertiesoffludarabinephosphatewereinvestigatedafterintravenousbolusinjectionandafter

shortandlongtermintravenousinfusionoffludarabinephosphate(2F-ara-AMP)inpatientswithmalignantdiseases.

2F-ara-AMPisawater-solubleprodrug,whichisrapidlyandquantitativelydephosphorylatedinthehumanorganism

tothenucleosidefludarabine(2F-ara-A).Aftercancerpatientshadreceivedasingleinfusionof25mg2F-ara-AMPper

m²toover30minutes,2F-ara-Areachedmeanmaximumconcentrationsintheplasmaof3.5-3.7µMattheendofthe

infusion.Corresponding2F-ara-Alevelsafterthefifthdoseshowedamoderateaccumulationwithmeanmaximum

levelsof4.4-4.8µMattheendoftheinfusion.Duringa5-daytreatmentperiod,2F-ara-Aplasmatroughlevels

increasedbyafactorofabout2.Anaccumulationof2F-ara-Aoverseveraltreatmentcyclescanberuledout.Post

maximumlevelsof2F-ara-Awerereducedinthreedispositionphaseswithaninitialhalf-lifeofapprox.5minutes,an

intermediatehalf-lifeof1-2hoursandaterminalhalf-lifeofapprox.20hours.

Aninter-studycomparisonof2F-ara-Apharmacokineticsresultedinameanoverallplasmaclearance(CL)of79±40

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

ahighinter-individualvariability.Plasmalevelsof2F-ara-Aandareasundertheplasmaleveltimecurvesincreased

linearlywiththedosage,whereashalf-lives,plasmaclearanceandvolumesofdistributionremainedconstantlydose

independent,indicatingadoselinearbehaviour.

Occurrenceofneutropeniaandhaematocritchangesindicatedthatcytotoxicityoffludarabinephosphatecausesdose

dependenthaematopoiesisinhibition.

Themainpathwayof2F-ara-Aeliminationleadsviathekidneys.40to60%oftheadministeredIVdosewasexcreted

intheurine.Massbalancestudiesinlaboratoryanimalswith³H-2F-ara-AMPshowedthattheradio-taggedsubstances

werecompletelyexcretedintheurine.2F-ara-hypoxanthine,whichisthemajormetaboliteindogs,wasobservedin

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ara-A,dosereductionisrequiredinthesecases.Invitrostudieswithhumanplasmaproteinsshowednopronounced

tendencyof2F-ara-Aproteinbinding.

Cellularpharmacokineticsoffludarabinetriphosphate

2F-ara-Aisactivelyabsorbedintoleukemiccells,whereuponitisrephosphorylatedtomono-anddiphosphateand

subsequentlytotriphosphate.Fludarabinetriphosphate,2F-ara-ATP,isthemajorintracellularmetaboliteandtheonly

oneknowntohavecytotoxicactivity.Maximum2F-ara-ATPlevelsinleukemiclymphocytesofCLLpatientswere

observedapprox.4hoursafterapplicationandexhibitedaconsiderablevariationaroundamedianpeakconcentration

ofapprox.20µM.2F-ara-ATPlevelsinleukemiccellswereconsiderablyhigherthanmaximum2F-ara-Aplasmalevels

indicatinganaccumulationinthetargetcells.Invitroincubationofleukemiclymphocytesshowedalinearrelationship

betweenextracellular2F-ara-Aexposure(productof2F-ara-Aconcentrationandincubationtime)andintracellular2F-

ara-ATPenrichment.2F-ara-ATPeliminationfromtargetcellsshowedmedianhalf-lifevaluesof15and23hours.

Noclearcorrelationwasfoundbetween2F-ara-Apharmacokineticsandtreatmentefficacyincancerpatients.

5.3Preclinicalsafetydata

Acuteandrepeatdosetoxicologystudiesinanimalsshowedthatthebonemarrow,lymphoidorgans,gastrointestinal

mucosa,kidneysandthemalereproductiveorgansweretheprimarytargetorgansoftoxicity.Neurotoxicitywasseen

athighdosages.

Fludarabinephosphatewasteratogenicinanimalsandcausedskeletalmalformationsandexternaldeformitiesat

dosagessimilarorlessthanthetherapeuticdose.

Genotoxicitystudiesdemonstratedthatfludarabinephosphatewasnegativeingenemutationassaysandinthe

dominantlethaltestinmalemice,butdidinduceclastogeniceffectsinthenon-activatedchromosomalaberrationassay

inChineseHamsterOvary(CHO)cellsandintheinvivomousemicronucleustest.

However,basedonthemechanismofactionandtheresultsofthemutagenicitytests,atumorigenicpotentialis

suspectedforfludarabinephosphate.

Nocarcinogenicitystudieshavebeenperformed.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Disodiumphosphatedihydrate,

sodiumhydroxide,

waterforinjection.

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Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3Shelflife

Aspackagedforsale:

3years.

Shelflifeafterdilution:

Infusionsolutionsdetailedinsection6.6arephysicallyandchemicallystableforatleast28dayswhenstoredina

refrigerator(2-8°C)withprotectionfromlightandatroomtemperature(20°C-25°C)withandwithoutprotectionfrom

light.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynobelongerthan24hoursat2°

Cto8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Aspackagedforsale:

Storeinarefrigerator(2ºC– 8ºC).

Forstorageconditionofthedilutedmedicinalproduct,seesection6.3

6.5Natureandcontentsofcontainer

CleartypeIglassvialwithgreyfluoropolymercoatedchlorobutylrubberstopper,withorwithoutaprotectiveplastic

overwrap(ONCO-SAFE).

Packsizes:1vial,5vials,10vials

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Dilution

Therequireddose(calculatedonthebasisofthepatient’sbodysurface)isdrawnupintoasyringe.

Forintravenousbolusinjectionthisdoseisfurtherdilutedin10mlofsodiumchloride9mg/ml(0.9%)solutionfor

injection.Alternatively,forinfusion,therequireddosemaybedilutedin100mlofsodiumchloride9mg/ml(0.9%)

solutionforinjectionandinfusedoverapproximately30minutes.

Inspectionpriortouse

Onlyclearandcolourlesssolutionswithoutparticlesshouldbeused.Theproductshouldnotbeusedincaseofa

Irish Medicines Board

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Date Printed 03/04/2012 CRN 2104419 page number: 11

Handlinganddisposal

Pregnantwomenshouldbeexcludedfromhandlingfludarabinephosphate.TheRegulationsconcerningproper

handlinganddisposalmustbefollowedconsideringguidelinesforproperhandlinganddisposalofcytotoxicmedicinal

products.Anyspilledorunusedmaterialmaybeeliminatedbyincineration.

Cautionshouldbeexercisedduringhandlingandpreparationoffludarabinephosphatesolution.Theuseofprotective

glovesandsafetyglassesisrecommendedtoavoidexposureincaseofbreakageofthevialorotheraccidentalspillage.

Ifthesolutioncomesincontactwithskinormucousmembranes,theaffectedareashouldbecleanedthoroughlywith

soapandwater.

7MARKETINGAUTHORISATIONHOLDER

EBEWEPharmaGes.m.b.H.Nfg.KG

Mondseestrasse11

48866Unterach

Austria

8MARKETINGAUTHORISATIONNUMBER

PA789/15/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28thNovember2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 03/04/2012 CRN 2104419 page number: 12