FLUDARABINE PHOSPHATE ACTAVIS

Main information

  • Trade name:
  • FLUDARABINE PHOSPHATE ACTAVIS
  • Dosage:
  • 50 Milligram
  • Pharmaceutical form:
  • Lyophilisate for solution for injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1380/003/001
  • Authorization date:
  • 22-08-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1380/003/001

CaseNo:2064890

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ActavisGroupPTCehf

Reykjavikurvegi76-78,220Hafnarfjordur,Iceland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

FludarabinePhosphateActavis50mgPowderForSolutionForInjectionorInfusion

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom24/07/2009until21/08/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 24/07/2009 CRN 2064890 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FludarabinePhosphateActavis50mgPowderForSolutionForInjectionorInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachvialcontains50mgfludarabinephosphate.

1mlofreconstitutedsolutioncontains25mgfludarabinephosphate.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Powderforsolutionforinjectionorinfusion.

Whiteoralmostwhitelyophilisate.

4CLINICALPARTICULARS

4.1TherapeuticIndications

TreatmentofB-cellchroniclymphocyticleukaemia(CLL)inpatientswithsufficientbonemarrowreserves.

FirstlinetreatmentwithFludarabinePhosphateActavisshouldonlybeinitiatedinpatientswithadvanceddisease,Rai

stagesIII/IV(BinetstageC),orRaistagesI/II(BinetstageA/B)wherethepatienthasdiseaserelatedsymptomsor

evidenceofprogressivedisease.

4.2Posologyandmethodofadministration

FludarabinePhosphateActavisshouldbeadministeredunderthesupervisionofaqualifiedphysicianexperiencedin

theuseofantineoplastictherapy.

ItisstronglyrecommendedthatFludarabinePhosphateActavisshouldbeonlyadministeredintravenously.Nocases

havebeenreportedinwhichparavenouslyadministeredfludarabineledtoseverelocaladversereactions.However,the

unintentionalparavenousadministrationmustbeavoided.

Adults

Therecommendeddoseis25mgfludarabinephosphate/m²bodysurfacegivendailyfor5consecutivedaysevery28

daysbytheintravenousroute.Eachvialistobemadeupin2mlwaterforinjection.Eachmloftheresulting

reconstitutedsolutionwillcontain25mgfludarabinephosphate.Therequireddose(calculatedonthebasisofthe

patient'sbodysurface)ofthereconstitutedsolutionisdrawnupintoasyringe.Forintravenousbolusinjectionthisdose

isfurtherdilutedin10mlof0.9%sodiumchloride.Alternatively,forinfusion,therequireddosemaybedilutedin100

ml0.9%sodiumchlorideandinfusedoverapproximately30minutes(seealsosection6.6).

Theoptimaldurationoftreatmenthasnotbeenclearlyestablished.Thedurationoftreatmentdependsonthetreatment

successandthetolerabilityofthedrug.

ItisrecommendedthatFludarabinePhosphateActavisbeadministereduptotheachievementofresponse(usually6

cycles)andthenthedrugshouldbediscontinued.

Hepaticimpairment

Nodataareavailableconcerningtheuseoffludarabinephosphateinpatientswithhepaticimpairment.Inthisgroupof

patients,FludarabinePhosphateActavisshouldbeusedwithcautionandadministerediftheperceivedbenefit

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Renalimpairment

Thetotalbodyclearanceoftheprincipleplasmametabolite2-F-ara-Ashowsacorrelationwithcreatinineclearance,

indicatingtheimportanceoftherenalexcretionpathwayfortheeliminationofthecompound.Patientswithreduced

kidneyfunctiondemonstratedanincreasedtotalbodyexposure(AUCof2F-ara-A).Limitedclinicaldataareavailable

inpatientswithimpairmentofrenalfunction(creatinineclearancebelow70ml/min).Therefore,ifrenalimpairmentis

clinicallysuspected,orinpatientsovertheageof70years,creatinineclearanceshouldbemeasured.Ifcreatinine

clearanceisbetween30and70ml/min,thedoseshouldbereducedbyupto50%andclosehaematologicalmonitoring

shouldbeusedtoassesstoxicity.FludarabinePhosphateActavistreatmentiscontraindicated,ifcreatinineclearanceis

<30ml/min.

Children

Fludarabineisnotrecommendedforuseinchildren,duetoalackofdataonsafetyandefficacy.

4.3Contraindications

FludarabinePhosphateActavisiscontraindicated

-inthosepatientswhoarehypersensitivetotheactivesubstanceoranyoftheexcipients

-inrenallyimpairedpatientswithcreatinineclearance<30ml/min

-inpatientswithdecompensatedhaemolyticanaemia

-duringpregnancyandlactation.

4.4Specialwarningsandprecautionsforuse

Whenusedathighdosesindose-rangingstudiesinpatientswithacuteleukaemia,fludarabinephosphatewas

associatedwithsevereneurologicaleffects,includingblindness,comaanddeath.Thisseverecentralnervoussystem

toxicityoccurredin36%ofpatientstreatedwithdosesapproximatelyfourtimesgreater(96mg/m²/dayfor5-7days)

thanthedoserecommendedfortreatmentofCLL.Inpatientstreatedatdosesintherangeofthedoserecommendedfor

CLL,severecentralnervoussystemtoxicityoccurredrarely(coma,seizuresandagitation)oruncommonly(confusion).

Patientsshouldbecloselyobservedforsignsofneurologicalsideeffects.

Theeffectofchronicadministrationoffludarabinephosphateonthecentralnervoussystemisunknown.However,

patientstoleratedtherecommendeddose,insomestudiesforrelativelylongtermtreatmenttimes,wherebyupto26

coursesoftherapywereadministered.

Inpatientswithimpairedstateofhealth,FludarabinePhosphateActavisshouldbegivenwithcautionandaftercareful

risk/benefitconsideration.Thisappliesespeciallyforpatientswithsevereimpairmentofbonemarrowfunction

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

Severebonemarrowsuppression,notablyanaemia,thrombocytopeniaandneutropenia,hasbeenreportedinpatients

treatedwithfludarabinephosphate.InaPhaseIstudyinsolidtumourpatients,themediantimetonadircountswas13

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

impairmentatbaselineeitherasaresultofdiseaseorasaresultofpriormyelosuppressivetherapy.Cumulative

myelosuppressionmaybeseen.Whilechemotherapy-inducedmyelosuppressionisoftenreversible,administrationof

fludarabinephosphaterequirescarefulhaematologicalmonitoring.

FludarabinePhosphateActavisisapotentantineoplasticagentwithpotentiallysignificanttoxicsideeffects.Patients

undergoingtherapyshouldbecloselyobservedforsignsofhaematologicalandnon-haematologicaltoxicity.Periodic

assessmentofperipheralbloodcountsisrecommendedtodetectthedevelopmentofanaemia,neutropeniaand

thrombocytopenia.

Aswithothercytotoxics,cautionshouldbeexercisedwithfludarabinephosphate,whenfurtherhaematopoieticstem

samplingisconsidered.

Transfusion-associatedgraft-versus-hostdisease(reactionbythetransfusedimmunocompetentlymphocytestothe

host)hasbeenobservedaftertransfusionofnon-irradiatedbloodinpatientstreatedwithfludarabinephosphate.Fatal

outcomeasaconsequenceofthisdiseasehasbeenreportedwithahighfrequency.Therefore,patientswhorequire

bloodtransfusionandwhoareundergoing,orwhohavereceived,treatmentwithFludarabinePhosphateActavisshould

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Reversibleworseningorflareupofpre-existingskincancerlesionshasbeenreportedinsomepatientstooccurduring

orafterfludarabinephosphatetherapy.

TumourlysissyndromeassociatedwithfludarabinephosphatetreatmenthasbeenreportedinCLLpatientswithlarge

tumourburdens.Sincefludarabinephosphatecaninducearesponseasearlyasthefirstweekoftreatment,precautions

shouldbetakeninthosepatientsatriskofdevelopingthiscomplication.

IrrespectiveofanyprevioushistoryofautoimmuneprocessesorCoombsteststatus,life-threateningandsometimes

fatalautoimmunephenomena(e.g.autoimmunehaemolyticanaemia,autoimmunethrombocytopenia,

thrombocytopenicpurpura,pemphigus,Evans'syndrome)havebeenreportedtooccurduringoraftertreatmentwith

fludarabinephosphate.Themajorityofpatientsexperiencinghaemolyticanaemiadevelopedarecurrenceinthe

haemolyticprocessafterrechallengewithfludarabinephosphate.PatientstreatedwithFludarabinePhosphateActavis

shouldbecloselymonitoredforhaemolysis.

PatientsundergoingtreatmentwithFludarabinePhosphateActavisshouldbecloselymonitoredforsignsof

autoimmunehaemolyticanaemia(declineinhaemoglobinlinkedwithhaemolysisandpositiveCoombstest).

DiscontinuationoftherapywithFludarabinePhosphateActavisisrecommendedincaseofhaemolysis.Blood

transfusion(irradiated,seeabove)andadrenocorticoidpreparationsarethemostcommontreatmentmeasuresfor

autoimmunehaemolyticanaemia.

Sincetherearelimiteddatafortheuseoffludarabinephoshpateinelderlypersons(>75years),cautionshouldbe

exercisedwiththeadministrationofFludarabinePhosphateActavisinthesepatients.

Nodataareavailableconcerningtheuseoffludarabinephosphateinchildren.Therefore,treatmentwithFludarabine

PhosphateActavisinchildrenisnotrecommended.

Femalesofchild-bearingpotentialormalesmusttakecontraceptivemeasuresduringandatleastfor6monthsafter

cessationoftherapy.

DuringandaftertreatmentwithFludarabinePhosphateActavisvaccinationwithlivevaccinesshouldbeavoided.

AcrossoverfrominitialtreatmentwithFludarabinePhosphatetochlorambucilfornonresponderstofludarabine

phosphateshouldbeavoidedbecausemostpatientswhohavebeenresistanttofludarabinephosphatehaveshown

resistancetochlorambucil.

Thismedicinalproductcontainslessthan1mmolsodium(23mg)permlafterreconstitution,i.e.essentiallysodium

free.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Inaclinicalinvestigationusingfludarabinephosphateincombinationwithpentostatin(deoxycoformycin)forthe

treatmentofrefractorychroniclymphocyticleukaemia(CLL),therewasanunacceptablyhighincidenceoffatal

pulmonarytoxicity.Therefore,theuseofFludarabinePhosphateActavisincombinationwithpentostatinisnot

recommended.

Thetherapeuticefficacyoffludarabinephosphatemaybereducedbydipyridamoleandotherinhibitorsofadenosine

uptake.

ApharmacokineticdruginteractionwasobservedinCLLandAMLpatientsduringcombinationtherapywith

fludarabinephosphateandAra-C.Clinicalstudiesandinvitroexperimentswithcancercelllinesdemonstratedelevated

intracellularAra-CTPlevelsinleukaemiccellsintermsofintracellularpeakconcentrationsaswellasofintracellular

exposure(AUC)incombinationoffludarabinephosphateandsubsequentAra-Ctreatment.Plasmaconcentrationsof

Ara-CandtheeliminationrateofAra-CTPwerenotaffected.

4.6Pregnancyandlactation

Pregnancy

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Womenofchild-bearingpotentialshouldbeadvisedtoavoidbecomingpregnantandtoinformthetreatingphysician

immediatelyshouldthisoccur.

Verylimitedhumanexperiencesupportsthefindingsofembryotoxicitystudiesinanimalsdemonstratingan

embryotoxicand/orteratogenicpotentialatthetherapeuticdose.Preclinicaldatainratsdemonstratedatransferof

fludarabinephosphateand/ormetabolitesthroughthefoeto-placentalbarrier.

Lactation

Breast-feedingmustbediscontinuedforthedurationofFludarabinePhosphateActavistherapy.Itisnotknown

whetherthisdrugisexcretedinhumanmilk.However,thereisevidencefrompreclinicaldatathatfludarabine

phosphateand/ormetabolitestransferfrommaternalbloodtomilk.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.

FludarabinePhosphateActavismayinfluencetheabilitytodriveandusemachinessincefatigue,weakness,agitation,

seizuresandvisualdisturbanceshasbeenobserved.

4.8Undesirableeffects

AdversereactionsarepresentedbelowaccordingtotheMedDRAsystemorganclassandrankedunderheadingof

frequency:Verycommon( ≥1/10);common(≥1/100to<1/10);uncommon(≥1/1,000to≤1/100);rare(≥1/10,000to≤

1/1,000);veryrare( ≤1/10,000),notknown(cannotbeestimatedformtheavailabledata).

Thefrequencyofthecommonlyanduncommonlyreportedadverseeventsandthosereactionswhicharemoreclearly

relatedtothedrugarebasedonclinicaltrialdataregardlessofthecausalrelationshipwithfludarabinephosphate.The

rareeventsweremainlyidentifiedfromthepost-marketingexperience.Fatalitiesasaconsequenceofseriousadverse

eventshavebeenreported.

Themostcommonadverseeventsincludemyelosuppression(neutropenia,thrombocytopeniaandanaemia),infection

includingpneumonia,fever,nausea,vomitinganddiarrhoea.Othercommonlyreportedeventsincludefatigue,

weakness,stomatitis,malaise,anorexia,oedema,chills,peripheralneuropathy,visualdisturbancesandskinrashes.

Seriousopportunisticinfectionshaveoccurredinpatientstreatedwithfludarabinephosphate.Fatalitiesasa

consequenceofseriousadverseeventshavebeenreported.

Cardiacdisorders

Rare:Heartfailureandarrhythmia.

Bloodandlymphaticsystemdisorders

Haematologicalevents(neutropenia,thrombocytopenia,andanaemia)havebeenreportedinthemajorityofpatients

treatedwithfludarabinephosphate.Myelosuppressionmaybesevereandcumulative.Themedicinalproduct´s

prolongednegativeeffectonthedecreaseinthenumbersofT-lymphocytesmayleadtoanincreasedriskof

opportunisticinfections,includingthoseduetolatentviralreactivation,e.g.Herpeszoster,Epstein-BarrVirus(EBV)

orprogressivemultifocalleucoencephalopathy(seesection4.4).EvolutionofEBV-infection/reactivationintoEBV-

associatedlymphoproliferativedisordershasbeenobservedinimmunocompromisedpatients.

Uncommon:Clinicallysignificantautoimmunephenomena(seesection4.4).

Rare:Myelodysplasticsyndrome(MDS)hasbeendescribedinpatientstreatedwithfludarabinephosphate.The

majorityofthesepatientsalsoreceivedprior,concomitantorsubsequenttreatmentwithalkylatingagentsorirradiation.

MonotherapywithfludarabinephosphatehasnotbeenassociatedwithanincreasedriskforthedevelopmentofMDS.

Nervoussystem

Common:Peripheralneuropathy.

Uncommon:Confusion.

Rare:Coma,agitationandseizures.

Eyedisorders

Common:Visualdisturbances

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Respiratory,thoracicandmediastinaldisorders

Common:Pneumonia.

Uncommon:Pulmonaryhypersensitivityreactions(pulmonaryinfiltrates/pneumonitis/fibrosis)associatedwith

dyspnoeaandcough.

Gastrointestinaldisorders

Common:Gastrointestinaldisturbancessuchasnauseaandvomiting,diarrhoea,stomatitis,andanorexia.

Uncommon:Gastrointestinalbleeding,mainlyrelatedtothrombocytopenia.

Renalandurinarydisorders

Rare:Haemorrhagiccystitis.

Skinandsubcutaneoustissuedisorders

Common:Skinrashes.

Rare:Stevens-Johnsonsyndromeoratoxicepidermalnecrolysis(Lyell'ssyndrome).

Metabolismandnutritiondisorders

Common:Oedema.

Uncommon:Tumourlysissyndrome.Thiscomplicationmayincludehyperuricaemia,hyperphosphataemia,

hypocalcaemia,metabolicacidosis,hyperkalaemia,haematuria,uratecrystalluria,andrenalfailure.Theonsetofthis

syndromemaybeheraldedbyflankpainandhaematuria.Changesinhepaticandpancreaticenzymelevels.

Generaldisordersandadministrationsiteconditions

Common:Infection,fever,fatigue,weakness,malaise,andchills.

4.9Overdose

Highdosesoffludarabinephosphatehavebeenassociatedwithanirreversiblecentralnervoussystemtoxicity

characterisedbydelayedblindness,coma,anddeath.Highdosesarealsoassociatedwithseverethrombocytopeniaand

neutropeniaduetobonemarrowsuppression.Thereisnoknownspecificantidoteforfludarabinephosphate

overdosage.Treatmentconsistsofdrugdiscontinuationandsupportivetherapy.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:AntineoplasticagentsATC-codeL01BB05

FludarabinePhosphateActaviscontainsfludarabinephosphate,awater-solublefluorinatednucleotideanalogueofthe

antiviralagentvidarabine,"9ß-D-"arabinofuranosyladenine(ara-A)thatisrelativelyresistanttodeaminationby

adenosinedeaminase.

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

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AphaseIIItrialinpatientswithpreviouslyuntreatedB-chroniclymphocyticleukaemiacomparingtreatmentwith

fludarabinephosphatevs.chlorambucil(40mg/m²q4weeks)in195and199patientsrespectivelyshowedthe

followingoutcome:statisticallysignificanthigheroverallresponseratesandcompleteresponseratesafter1stline

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

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

forthepatientsinthefludarabinephosphategroup.

Themediansurvivalofthetwopatientgroupswas56.1monthsforfludarabinephosphateand55.1monthsfor

chlorambucil,anon-significantdifferencewasalsoshownwithperformancestatus.Theproportionofpatientsreported

tohavetoxicitieswerecomparablebetweenfludarabinephosphatepatients(89.7%)andchlorambucilpatients(89.9%).

Whilethedifferenceintheoverallincidenceofhaematologicaltoxicitieswasnotsignificantbetweenthetwotreatment

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.

Patientswhoinitiallyrespondtofludarabinephosphatehaveachanceofrespondingagaintofludarabinephosphate

monotherapy.

Arandomisedtrialoffludarabinephosphatevs.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(fludarabine

phosphate,2F-ara-AMP).

2F-ara-AMPisawater-solubleprodrug,whichisrapidlyandquantitativelydephosphorylatedinthehumanorganism

tothenucleosidefludarabine(2F-ara-A).Aftersingledoseinfusionof25mg2F-ara-AMPperm²tocancerpatients

for30minutes2F-ara-Areachedmeanmaximumconcentrationsintheplasmaof3.5-3.7µMattheendofthe

infusion.Corresponding2F-ara-Alevelsafterthefifthdoseshowedamoderateaccumulationwithmeanmaximum

levelsof4.4-4.8µMattheendofinfusion.Duringa5-daytreatmentschedule2F-ara-Aplasmatroughlevels

increasedbyafactorofabout2.Anaccumulationof2F-ara-Aoverseveraltreatmentcyclescanbeexcluded.

Postmaximumlevelsdecayedinthreedispositionphaseswithaninitialhalf-lifeofapprox.5minutes,anintermediate

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

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.Plasmalevelsof2F-ara-Aandareasundertheplasmaleveltimecurvesincreased

linearlywiththedose,whereashalf-lives,plasmaclearanceandvolumesofdistributionremainedconstantindependent

ofthedoseindicatingadoselinearbehaviour.Occurrenceofneutropeniaandhaematocritchangesindicatedthatthe

cytotoxicityoffludarabinephosphatedepressesthehaematopoiesisinadosedependentmanner.

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Massbalancestudiesinlaboratoryanimalswith³H-2F-ara-AMPshowedacompleterecoveryofradio-labelled

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

wasobservedinhumansonlytoaminorextent.Individualswithimpairedrenalfunctionexhibitareducedtotalbody

clearance,indicatingtheneedforadosereduction.Invitroinvestigationswithhumanplasmaproteinsrevealedno

pronouncedtendencyof2F-ara-Aproteinbinding.

Cellularpharmacokineticsoffludarabinetriphosphate

2F-ara-Aisactivelytransportedintoleukaemiccells,whereuponitisrephosphorylatedtothemonophosphateand

subsequentlytothedi-andtriphosphate.Thetriphosphate2F-ara-ATPisthemajorintracellularmetaboliteandthe

onlymetaboliteknowntohavecytotoxicactivity.Maximum2F-ara-ATPlevelsinleukaemiclymphocytesofCLL

patientswereobservedatamedianof4hoursandexhibitedaconsiderablevariationwithamedianpeakconcentration

ofapprox.20µM.2F-ara-ATPlevelsinleukaemiccellswerealwaysconsiderablyhigherthanmaximum2F-ara-A

levelsintheplasmaindicatinganaccumulationatthetargetsites.Invitroincubationofleukaemiclymphocytes

showedalinearrelationshipbetweenextracellular2F-ara-Aexposure(productof2F-ara-Aconcentrationandduration

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

lifevaluesof15and23hours.

Noclearcorrelationwasfoundbetween2F-ara-Apharmacokineticsandtreatmentefficacyincancerpatients.

5.3Preclinicalsafetydata

Inacutetoxicitystudies,singledosesoffludarabinephosphateproducedsevereintoxicationsymptomsordeathat

dosagesabouttwoordersofmagnitudeabovethetherapeuticdose.Asexpectedforacytotoxiccompound,thebone

marrow,lymphoidorgans,gastrointestinalmucosa,kidneysandmalegonadswereaffected.

Systemictoxicitystudiesfollowingrepeatedadministrationoffludarabinephosphateshowedalsotheexpectedeffects

onrapidlyproliferatingtissuesaboveathresholddose.Theseverityofmorphologicalmanifestationsincreasedwith

doselevelsanddurationofdosingandtheobservedchangesweregenerallyconsideredtobereversible.Inprinciple,

theavailableexperiencefromthetherapeuticuseoffludarabinephosphatepointstoacomparabletoxicologicalprofile

inhumans,althoughadditionalundesirableeffectssuchasneurotoxicitywereobservedinpatients(seesection4.8).

Theresultsfromanimalembryotoxicitystudiesindicatedateratogenicpotentialoffludarabinephosphate.Inviewof

thesmallsafetymarginbetweentheteratogenicdosesinanimalsandthehumantherapeuticdoseaswellasinanalogy

tootherantimetaboliteswhichareassumedtointerferewiththeprocessofdifferentiation,thetherapeuticuseof

fludarabinephosphateisassociatedwitharelevantriskofteratogeniceffectsinhumans(seesection4.6).

Fludarabinephosphatehasbeenshowntoinducechromosomalaberrationsinaninvitrocytogeneticassay,tocause

DNA-damageinasisterchromatidexchangetestandtoincreasetherateofmicronucleiinthemousemicronucleustest

invivo,butwasnegativeingenemutationassaysandinthedominantlethaltestinmalemice.Thus,themutagenic

potentialwasdemonstratedinsomaticcellsbutcouldnotbeshowningermcells.

TheknownactivityoffludarabinephosphateattheDNA-levelandthemutagenicitytestresultsformthebasisforthe

suspicionofatumorigenicpotential.Noanimalstudieswhichdirectlyaddressthequestionoftumorigenicityhavebeen

conducted,becausethesuspicionofanincreasedriskofsecondtumoursduetofludarabinephosphatetherapycan

exclusivelybeverifiedbyepidemiologicaldata.

Accordingtotheresultsfromanimalexperimentsfollowingintravenousadministrationoffludarabinephosphate,no

remarkablelocalirritationhastobeexpectedattheinjectionsite.Evenincaseofmisplacedinjections,norelevant

localirritationwasobservedafterparavenous,intraarterial,andintramuscularadministrationofanaqueoussolution

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol

Sodiumhydroxide(forpHadjustment).

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3ShelfLife

Vialbeforeopening:

36months

Afterreconstitution:

Thephysicochemicalstabilityofthedrugproductafterreconstitutioninwaterforinjectionshasbeendemonstratedfor

8hoursat25°C±2°C/60%±5%RHandfor7daysat5°C±3°C.Fromamicrobiologicalpointofview,theproduct

shouldbeusedimmediately.Ifnotusedimmediately,in-usestoragetimesandconditionspriortousearethe

responsibilityoftheuser.

6.4Specialprecautionsforstorage

Storebelow25 °

Forstorageafterreconstitutionordilution,seeSection6.3.

6.5Natureandcontentsofcontainer

Colourlessglassvial(typeI)withbromobutylicrubberstopperandmetalliccap(aluminium)withpolypropylenedisk.

Packsizes

1x50mgvial

5x50mgvial

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Reconstitution

FludarabinePhosphateActavisshouldbepreparedforparenteralusebyasepticallyaddingsterilewaterforinjection.

Whenreconstitutedwith2mlofsterilewaterforinjection,thepowdershouldfullydissolvein15secondsorless.Each

mloftheresultingsolutionwillcontain25mgoffludarabinephosphate,25mgofmannitol,andsodiumhydroxideto

adjustthepHto7.7.ThepHrangeforthefinalproductis7.2-8.2.

Dilution

Therequireddose(calculatedonthebasisofthepatient'sbodysurface)isdrawnupintoasyringe.

Forintravenousbolusinjectionthisdoseisfurtherdilutedin10mlof0.9%sodiumchloride.Alternatively,for

infusion,therequireddosemaybedilutedin100mlof0.9%sodiumchloride(seesection4.2).

Inspectionpriortouse

Thereconstitutedsolutionisclearandcolourless.Itshouldbevisuallyinspectedbeforeuse.

Onlyclearandcolourlesssolutionswithoutparticlesshouldbeused.FludarabinePhosphateActavisshouldnotbeused

incaseofadefectivecontainer.

Handlinganddisposal

Irish Medicines Board

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Date Printed 24/07/2009 CRN 2064890 page number: 9

Proceduresforproperhandlingshouldbefollowedaccordingtolocalrequirementsforcytotoxicdrugs.Cautionshould

beexercisedinthehandlingandpreparationoftheFludarabinePhosphateActavissolution.Theuseoflatexglovesand

safetyglassesisrecommendedtoavoidexposureincaseofbreakageofthevialorotheraccidentalspillage.

Ifthesolutioncomesintocontactwiththeskinormucousmembranes,theareashouldbewashedthoroughlywithsoap

andwater.Intheeventofcontactwiththeeyes,rinsethemthoroughlywithcopiousamountsofwater.Exposureby

inhalationshouldbeavoided.

Themedicinalproductisforsingleuseonly.Anyunusedproductorwastematerialshouldbedisposedofin

accordancewithlocalrequirementsforcytotoxicagents.

7MARKETINGAUTHORISATIONHOLDER

ActavisGroupPTCehf

Reykjavikurvegi76-78

220Hafnarfjordur,

Iceland

8MARKETINGAUTHORISATIONNUMBER

PA1380/3/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:22ndAugust2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 24/07/2009 CRN 2064890 page number: 10