EPREX

Main information

  • Trade name:
  • EPREX Solution for Injection 2000IU/ml Units/ml
  • Dosage:
  • 2000IU/ml Units/ml
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EPREX Solution for Injection 2000IU/ml Units/ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0748/025/001
  • Authorization date:
  • 01-11-1994
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0748/025/001

CaseNo:2057376

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

Janssen-CilagLtd

50-100HolmersFarmWay,HighWycombe,Buckinghamshire,HP124EG,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

EPREX2,000IU/ml,solutionforinjection

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom04/02/2009.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EPREX2,000IU/ml,solutionforinjection.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Epoetinalfa*………………………………………2000IU/ml(16.8microgramsperml)

Avialof1.0mlcontains2000IU(16.8micrograms)ofepoetinalfa

*producedinChineseHamsterOvary(CHO)cellsbyrecombinantDNAtechnology

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinjection.

Clear,colourlesssolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofsymptomaticanaemiaassociatedwithchronicrenalfailure(CRF)inadultandpaediatricpatients:

Treatmentofanaemiaassociatedwithchronicrenalfailureinpaediatricandadultpatientsonhaemodialysisand

adultpatientsonperitonealdialysis.

Treatmentofsevereanaemiaofrenaloriginaccompaniedbyclinicalsymptomsinadultpatientswithrenal

insufficiencynotyetundergoingdialysis.

Treatmentofanaemiaandreductionoftransfusionrequirementsinadultpatientsreceivingchemotherapyforsolid

tumours,malignantlymphomaormultiplemyeloma,andatriskoftransfusionasassessedbythepatient’sgeneral

status(e.g.cardiovascularstatus,pre-existinganaemiaatthestartofchemotherapy).

EPREXcanbeusedtoincreasetheyieldofautologousbloodfrompatientsinapredonationprogramme.Itsuseinthis

indicationmustbebalancedagainstthereportedriskofthromboembolicevents.Treatmentshouldonlybegivento

patientswithmoderateanaemia(Hb10-13g/dl[6.2-8.1mmol/l],noirondeficiency)ifbloodsavingproceduresarenot

availableorinsufficientwhenthescheduledmajorelectivesurgeryrequiresalargevolumeofblood(4ormoreunitsof

bloodforfemalesor5ormoreunitsformales).

EPREXcanbeusedtoreduceexposuretoallogeneicbloodtransfusionsinadultnon-irondeficientpatientspriorto

majorelectiveorthopaedicsurgery,havingahighperceivedriskfortransfusioncomplications.Useshouldberestricted

topatientswithmoderateanaemia(e.g.Hb10-13g/dl)whodonothaveanautologouspredonationprogramme

availableandwithexpectedmoderatebloodloss(900to1800ml).

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4.2Posologyandmethodofadministration

Methodofadministration

Aswithanyotherinjectableproduct,checkthattherearenoparticlesinthesolutionorchangeincolour.

intravenousinjection:overatleastonetofiveminutes,dependingonthetotaldose.Inhaemodialysedpatients,

abolusinjectionmaybegivenduringthedialysissessionthroughasuitablevenousportinthedialysisline.

Alternatively,theinjectioncanbegivenattheendofthedialysissessionviathefistulaneedletubing,followedby10

mlofisotonicsalinetorinsethetubingandensuresatisfactoryinjectionoftheproductintothecirculation.

Aslowerinjectionispreferableinpatientswhoreacttothetreatmentwith“flu-like”symptoms.

Donotadministerbyintravenousinfusionormixedwithotherdrugs.

subcutaneousinjection:amaximumvolumeof1mlatoneinjectionsiteshouldgenerallynotbeexceeded.In

caseoflargervolumes,morethanonesiteshouldbechosenfortheinjection.

Theinjectionsaregiveninthelimbsortheanteriorabdominalwall.

Inthosesituationsinwhichthephysiciandeterminesthatapatientorcaregivercansafelyandeffectivelyadminister

EPREXsubcutaneously,instructionastotheproperdosageandadministrationshouldbeprovided.

Refertosection3.HowtouseEPREX(instructionsonhowtoinjectEPREX)ofthepackageleaflet.

Treatmentofsymptomaticanaemiainadultandpaediatricchronicrenalfailurepatients:

Inpatientswithchronicrenalfailurewhereintravenousaccessisroutinelyavailable(haemodialysispatients)

administrationbytheintravenousrouteispreferable.Whereintravenousaccessisnotreadilyavailable(patientsnotyet

undergoingdialysisandperitonealdialysispatients)EPREXmaybeadministeredsubcutaneously.

Anaemiasymptomsandsequelaemayvarywithage,gender,andco-morbidmedicalconditions;aphysician’s

evaluationoftheindividualpatient’sclinicalcourseandconditionisnecessary.

EPREXshouldbeadministeredinordertoincreasehaemoglobintonotgreaterthan12g/dl(7.5mmol/l).Arisein

haemoglobinofgreaterthan2g/dl(1.25mmol/l)overafourweekperiodshouldbeavoided.Ifitoccurs,appropriate

doseadjustmentshouldbemadeasprovided.

Duetointra-patientvariability,occasionalindividualhaemoglobinvaluesforapatientaboveandbelowthedesired

haemoglobinlevelmaybeobserved.Haemoglobinvariabilityshouldbeaddressedthroughdosemanagement,with

considerationforthehaemoglobintargetrangeof10g/dl(6.2mmol/l)to12g/dl(7.5mmol/l).Inpaediatricpatientsthe

recommendedtargethaemoglobinrangeisbetween9.5and11g/dl(5.9-6.8mmol/l).

Asustainedhaemoglobinlevelofgreaterthan12g/dl(7.5mmol/l)shouldbeavoided.Ifthehaemoglobinisrisingby

morethan2g/dl(1.25mmol/l)permonth,orifthesustainedhaemoglobinexceeds12g/dl(7.5mmol/l)reducethe

epoetinalfadoseby25%.Ifthehaemoglobinexceeds13g/dl(8.1mmol/l),discontinuetherapyuntilitfallsbelow12

g/dl(7.5mmol/l)andthenreinstituteepoetinalfatherapyatadose25%belowthepreviousdose.

PatientsshouldbemonitoredcloselytoensurethatthelowestapproveddoseofEPREXisusedtoprovideadequate

controlofanaemiaandofthesymptomsofanaemia.

Ironstatusshouldbeevaluatedpriortoandduringtreatmentandironsupplementationadministeredifnecessary.In

addition,othercausesofanaemia,suchasB

orfolatedeficiency,shouldbeexcludedbeforeinstitutingtherapywith

epoetinalfa.Nonresponsetoepoetinalfatherapyshouldpromptasearchforcausativefactors.Theseinclude:iron,

folate,orVitaminB

deficiency;aluminiumintoxication;intercurrentinfections;inflammatoryortraumaticepisodes;

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Adulthaemodialysispatients:

Inpatientsonhaemodialysiswhereintravenousaccessisreadilyavailable,administrationbytheintravenousrouteis

preferable.

Thetreatmentisdividedintotwostages:

Correctionphase:

50IU/kg,3timesperweek.

Whenadoseadjustmentisnecessary,thisshouldbedoneinstepsofatleastfourweeks.Ateachstep,theincreaseor

reductionindoseshouldbeof25IU/kg,3timesperweek.

Maintenancephase:

Dosageadjustmentinordertomaintainhaemoglobinvaluesatthedesiredlevel:Hbbetween10and12g/dl(6.2-7.5

mmol/l).

Therecommendedtotalweeklydoseisbetween75and300IU/kg.

Theclinicaldataavailablesuggestthatthosepatientswhoseinitialhaemoglobinisverylow(<6g/dlor<3.75mmol/l)

mayrequirehighermaintenancedosesthanthosewhoseinitialanaemiaislesssevere(>8g/dlor>5mmol/l).

Paediatrichaemodialysispatients:

Thetreatmentisdividedintotwostages:

Correctionphase:

50IU/kg,3timesperweekbytheintravenousroute.Whenadoseadjustmentisnecessary,thisshouldbedoneinsteps

of25IU/kg,3timesperweekatintervalsofatleast4weeksuntilthedesiredgoalisachieved.

Maintenancephase:

Dosageadjustmentinordertomaintainhaemoglobinvaluesatthedesiredlevel:Hbbetween9.5and11g/dl(5.9-6.8

mmol/l).

Generally,childrenunder30kgrequirehighermaintenancedosesthanchildrenover30kgandadults.Forexample,

thefollowingmaintenancedoseswereobservedinclinicaltrialsafter6monthsoftreatment.

Theclinicaldataavailablesuggestthatthosepatientswhoseinitialhaemoglobinisverylow(<6.8g/dlor<4.25

mmol/l)mayrequirehighermaintenancedosesthanthosewhoseinitialhaemoglobinishigher(>6.8g/dlor>4.25

mmol/l).

Adultpatientswithrenalinsufficiencynotyetundergoingdialysis:

Dose(IU/kggiven3xweek)

Weight(kg) Median Usualmaintenancedose

<10 100 75-150

10-30 75 60-150

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Thetreatmentisdividedintotwostages:

Correctionphase:

Startingdoseof50IU/kg,3timesperweek,followedifnecessarybyadosageincreasewith25IU/kgincrements(3

timesperweek)untilthedesiredgoalisachieved(thisshouldbedoneinstepsofatleastfourweeks).

Maintenancephase

Dosageadjustmentinordertomaintainhaemoglobinvaluesatthedesiredlevel:Hbbetween10and12g/dl(6.2-7.5

mmol/l)(maintenancedosebetween17and33IU/kg,3timesperweek).

Themaximumdosageshouldnotexceed200IU/kg,3timesperweek.

Adultperitonealdialysispatients:

WhereintravenousaccessisnotreadilyavailableEPREXmaybeadministeredsubcutaneously.

Thetreatmentisdividedintotwostages:

Correctionphase

Startingdoseof50IU/kg,2timesperweek.

Maintenancephase

Dosageadjustmentinordertomaintainhaemoglobinvaluesatthedesiredlevel:(Hbbetween10and12g/dl(6.2-7.5

mmol/l)(maintenancedosebetween25and50IU/kg2timesperweekinto2equalinjections).

Treatmentofpatientswithchemotherapyinducedanaemia:

EPREXshouldbeadministeredbythesubcutaneousroutetopatientswithanaemia(e.g.haemoglobinconcentration ≤

10g/dl(6.2mmol/l)).Anaemiasymptomsandsequelaemayvarywithage,gender,andoverallburdenofdisease;a

physician’sevaluationoftheindividualpatient’sclinicalcourseandconditionisnecessary.

Duetointra-patientvariability,occasionalindividualhaemoglobinvaluesforapatientaboveandbelowthedesired

haemoglobinlevelmaybeobserved.Haemoglobinvariabilityshouldbeaddressedthroughdosemanagement,with

considerationforthehaemoglobintargetrangeof10g/dl(6.2mmol/l)to12g/dl(7.5mmol/l).Asustainedhaemoglobin

levelofgreaterthan12g/dl(7.5mmol/l)shouldbeavoided;guidanceforappropriatedoseadjustmentforwhen

haemoglobinvaluesexceed12g/dl(7.5mmol/l)aredescribedbelow.

Epoetinalfatherapyshouldcontinueuntilonemonthaftertheendofchemotherapy.

Theinitialdoseis150IU/kggivensubcutaneously3timesperweek.Alternatively,EPREXcanbeadministeredatan

initialdoseof450IU/kgsubcutaneouslyonceweekly.Ifthehaemoglobinhasincreasedbyatleast1g/dl(0.62mmol/l)

orthereticulocytecounthasincreased ≥40,000cells/µlabovebaselineafter4weeksoftreatment,thedoseshould

remainat150IU/kg3timesperweekor450IU/kgonceweekly.Ifthehaemoglobinincreaseis<1g/dl(<0.62mmol/l)

andthereticulocytecounthasincreased<40,000cells/µlabovebaseline,increasethedoseto300IU/kg

3timesperweek.Ifafteranadditional4weeksoftherapyat300IU/kg3timesperweek,thehaemoglobinhas

increased ≥1g/dl(≥0.62mmol/l)orthereticulocytecounthasincreased≥40,000cells/µl,thedoseshouldremainat

300IU/kg3timesperweek.

However,ifthehaemoglobinhasincreased<1g/dl(<0.62mmol/l)andthereticulocytecounthasincreased<40,000

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Therecommendeddosingregimenisdescribedinthefollowingdiagram:

Patientsshouldbemonitoredcloselytoensurethatthelowestapproveddoseoferythropoiesis-stimulatingagent(ESA)

isusedtoprovideadequatecontrolofthesymptomsofanaemia.

Doseadjustmenttomaintainhaemoglobinconcentrationsbetween10g/dl–12g/dl:

Ifthehaemoglobinisrisingbymorethan2g/dl(1.25mmol/l)permonth,orifthehaemoglobinexceeds12g/dl(7.5

mmol/l),reducetheepoetinalfadosebyabout25-50%.Ifthehaemoglobinexceeds13g/dl(8.1mmol/l),discontinue

therapyuntilitfallsbelow12g/dl(7.5mmol/l)andthenreinstituteepoetinalfatherapyatadose25%belowthe

previousdose.

Adultsurgerypatientsinanautologouspredonationprogramme:

Theintravenousrouteofadministrationshouldbeused.Atthetimeofdonatingblood,epoetinalfashouldbe

administeredafterthecompletionoftheblooddonationprocedure.

Mildlyanaemicpatients(haematocritof33-39%)requiringpredepositof ≥4unitsofbloodshouldbetreatedwith

epoetinalfaat600IU/kg,2timesweeklyfor3weekspriortosurgery.Usingthisregimen,itwaspossibletowithdraw

≥4unitsofbloodfrom81%ofepoetinalfa-treatedpatientscomparedto37%ofplacebo-treatedpatients.Epoetinalfa

therapyreducedtheriskofexposuretohomologousbloodby50%comparedtopatientsnotreceivingepoetinalfa.

Allpatientsbeingtreatedwithepoetinalfashouldreceiveadequateironsupplementation(e.g.200mgoralelemental

irondaily)throughoutthecourseofepoetinalfatreatment.Ironsupplementationshouldbestartedassoonaspossible,

evenseveralweekspriortoinitiatingtheautologouspredeposit,inordertoachievehighironstorespriortostarting

epoetinalfatherapy.

Adultpatientsscheduledformajorelectiveorthopaedicsurgery:

Thesubcutaneousrouteofadministrationshouldbeused.

Therecommendeddoseregimenis600IU/kgofepoetinalfa,givenweeklyforthreeweeks(days-21,-14and-7)prior

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Incaseswherethereisamedicalneedtoshortentheleadtimebeforesurgerytolessthanthreeweeks,300IU/kg

epoetinalfashouldbegivendailyfor10consecutivedayspriortosurgery,onthedayofsurgeryandforfourdays

immediatelythereafter.

Whenperforminghaematologicassessmentsduringthepreoperativeperiod,ifthehaemoglobinlevelreaches15g/dl,

orhigher,administrationofepoetinalfashouldbestoppedandfurtherdosagesshouldnotbegiven.

Careshouldbetakentoensurethatattheoutsetofthetreatmentpatientsarenotirondeficient.Allpatientsbeing

treatedwithepoetinalfashouldreceiveadequateironsupplementation(e.g.200mgoralelementalirondaily)

throughoutthecourseofepoetinalfatreatment.Ifpossible,ironsupplementationshouldbestartedpriortoepoetinalfa

therapy,toachieveadequateironstores.

4.3Contraindications

Patientswhodeveloppureredcellaplasia(PRCA)followingtreatmentwithanyerythropoietinshouldnotreceive

EPREXoranyothererythropoietin(seesection4.4,Specialwarningsandprecautionsforuse).

Uncontrolledhypertension.

Allcontraindicationsassociatedwithautologousbloodpredonationprogrammesshouldberespectedinpatientsbeing

supplementedwithepoetinalfa.

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Theuseofepoetinalfainpatientsscheduledformajorelectiveorthopaedicsurgeryandnotparticipatinginan

autologousbloodpredonationprogrammeiscontraindicatedinpatientswithseverecoronary,peripheralarterial,

carotidorcerebralvasculardisease,includingpatientswithrecentmyocardialinfarctionorcerebralvascularaccident.

Surgerypatientswhoforanyreasoncannotreceiveadequateantithromboticprophylaxis.

4.4Specialwarningsandprecautionsforuse

General

Inallpatientsreceivingepoetinalfa,bloodpressureshouldbecloselymonitoredandcontrolledasnecessary.Epoetin

alfashouldbeusedwithcautioninthepresenceofuntreated,inadequatelytreatedorpoorlycontrollablehypertension.

Itmaybenecessarytoaddorincreaseanti-hypertensivetreatment.Ifbloodpressurecannotbecontrolled,epoetinalfa

treatmentshouldbediscontinued.

Epoetinalfashouldalsobeusedwithcautioninthepresenceofepilepsyandchronicliverfailure.

Chronicrenalfailureandcancerpatientsonepoetinalfashouldhavehaemoglobinlevelsmeasuredonaregularbasis

untilastablelevelisachieved,andperiodicallythereafter.

Inallpatients,haemoglobinlevelsshouldbecloselymonitoredduetoapotentialincreasedriskofthromboembolic

eventsandfataloutcomeswhenpatientsaretreatedathaemoglobinlevelsabovethetargetfortheindicationofuse.

Theremaybeamoderatedose-dependentriseintheplateletcountwithinthenormalrangeduringtreatmentwith

epoetinalfa.Thisregressesduringthecourseofcontinuedtherapy.Inaddition,thrombocythaemiaabovethenormal

rangehasbeenreported.Itisrecommendedthattheplateletcountisregularlymonitoredduringthefirst8weeksof

therapy.

Allothercausesofanaemia(irondeficiency,haemolysis,bloodloss,vitaminB12orfolatedeficiencies)shouldbe

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Inmostcases,theferritinvaluesintheserumfallsimultaneouslywiththeriseinpackedcellvolume.Inordertoensure

optimumresponsetoepoetinalfa,adequateironstoresshouldbeassured:

ironsupplementation,e.g.200-300mg/dayorally(100-200mg/dayforpaediatricpatients)isrecommendedfor

chronicrenalfailurepatientswhoseserumferritinlevelsarebelow100ng/ml.

oralironsubstitutionof200-300mg/dayisrecommendedforallcancerpatientswhosetransferrinsaturationis

below20%.

Alloftheseadditivefactorsofanaemiashouldalsobecarefullyconsideredwhendecidingtoincreasethedoseof

epoetinalfaincancerpatients.

InordertoimprovethetraceabilityoftheESAallmeasuresnecessaryandpossibletoensureitshouldbetaken(e.g.

exactinformationontheproductusedshouldbedocumentedinanappropriateway).

Furthermore,patientsshouldonlybeswitchedfromoneESAtoanotherunderappropriatesupervision.

PureRedCellAplasia

Antibody-mediatedpureredcellaplasia(PRCA)hasbeenveryrarelyreportedaftermonthstoyearsofsubcutaneous

Epoetintreatment.Inpatientsdevelopingsuddenlackofefficacydefinedbyadecreaseinhaemoglobin(1to2g/dlper

month)withincreasedneedfortransfusions,areticulocytecountshouldbeobtainedandtypicalcausesofnon-response

(e.g.iron,folateorVitaminB12deficiency,aluminiumintoxication,infectionorinflammation,bloodlossand

haemolysis)shouldbeinvestigated.

Ifthereticulocytecountcorrectedforanaemia(i.e.,thereticulocyte‘index’)islow(<20,000/mm3or<

20,000/microlitreor<0.5%),plateletandwhitebloodcellcountsarenormal,andifnoothercauseoflossofeffecthas

beenfound,anti-erythropoietinantibodiesshouldbedeterminedandabonemarrowexaminationshouldbeconsidered

fordiagnosisofPRCA.

Ifanti-erythropoietin,antibody-mediatedPRCAissuspected,therapywithEPREX shouldbediscontinued

immediately.Noothererythropoietictherapyshouldbecommencedbecauseoftheriskofcross-reaction.Appropriate

therapysuchasbloodtransfusionsmaybegiventopatientswhenindicated.

Treatmentofsymptomaticanaemiainadultandpaediatricchronicrenalfailurepatients

Inchronicrenalfailurepatientstherateofincreaseinhaemoglobinshouldbeapproximately1g/dl(0.62mmol/l)per

monthandshouldnotexceed2g/dl(1.25mmol/l)permonthtominimiserisksofanincreaseinhypertension.

Inpatientswithchronicrenalfailuremaintenancehaemoglobinconcentrationshouldnotexceedtheupperlimitofthe

targethaemoglobinconcentrationasrecommendedinsection4.2.Inclinicaltrials,anincreasedriskofdeathand

seriouscardiovasculareventswasobservedwhenESAswereadministeredtotargetahaemoglobinofgreaterthan

12g/dl(7.5mmol/l).

Controlledclinicaltrialshavenotshownsignificantbenefitsattributabletotheadministrationofepoetinswhen

haemoglobinconcentrationisincreasedbeyondthelevelnecessarytocontrolsymptomsofanaemiaandtoavoidblood

transfusion.

ChronicrenalfailurepatientstreatedwithEPREXbythesubcutaneousrouteshouldbemonitoredregularlyforlossof

efficacy,definedasabsentordecreasedresponsetoEPREXtreatmentinpatientswhopreviouslyrespondedtosuch

therapy.ThisischaracterisedbyasustaineddecreaseinhaemoglobindespiteanincreaseinEPREXdosage.

Shuntthromboseshaveoccurredinhaemodialysispatients,especiallyinthosewhohaveatendencytohypotensionor

whosearteriovenousfistulaeexhibitcomplications(e.g.stenoses,aneurysms,etc.).Earlyshuntrevisionandthrombosis

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Hyperkalaemiahasbeenobservedinisolatedcases.Inchronicrenalfailurepatients,correctionforanaemiamayleadto

increasedappetite,andpotassiumandproteinintake.Dialysisprescriptionsmayhavetobeadjustedperiodicallyto

maintainurea,creatinineandpotassiuminthedesiredrange.

Serumelectrolytesshouldbemonitoredinchronicrenalfailurepatients.Ifanelevated(orrising)serumpotassium

levelisdetectedthenconsiderationshouldbegiventoceasingepoetinalfaadministrationuntilhyperkalaemiahasbeen

corrected.

Anincreaseinheparindoseduringhaemodialysisisfrequentlyrequiredduringthecourseoftherapywithepoetinalfa

asaresultoftheincreasedpackedcellvolume.Occlusionofthedialysissystemispossibleifheparinisationisnot

optimum.

Basedoninformationavailabletodate,correctionofanaemiawithepoetinalfainadultpatientswithrenal

insufficiencynotyetundergoingdialysisdoesnotacceleratetherateofprogressionofrenalinsufficiency.

Treatmentofpatientswithchemotherapyinducedanaemia

Epoetinsaregrowthfactorsthatprimarilystimulateredbloodcellproduction.Erythropoietinreceptorsmaybe

expressedonthesurfaceofavarietyoftumourcells.Aswithallgrowthfactors,thereisaconcernthatepoetinscould

stimulatethegrowthoftumours.Inseveralcontrolledstudies,epoetinshavenotbeenshowntoimproveoverall

survivalordecreasetheriskoftumourprogressioninpatientswithanaemiaassociatedwithcancer.

Incontrolledclinicalstudies,useofEPREXandotherESAshaveshown:

decreasedlocoregionalcontrolinpatientswithadvancedheadandneckcancerreceivingradiationtherapywhen

administeredtotargetahaemoglobinofgreaterthan14g/dl(8.7mmol/l),

shortenedoverallsurvivalandincreaseddeathsattributedtodiseaseprogressionat4monthsinpatientswith

metastaticbreastcancerreceivingchemotherapywhenadministeredtotargetahaemoglobinof12-14g/dl(7.5-

8.7mmol/l),

increasedriskofdeathwhenadministeredtotargetahaemoglobinof12g/dl(7.5mmol/l)inpatientswithactive

malignantdiseasereceivingneitherchemotherapynorradiationtherapy.ESAsarenotindicatedforuseinthis

patientpopulation.

Incancerpatientsreceivingchemotherapy,the2-3weekdelaybetweenESAadministrationandtheappearanceof

erythropoietin-inducedredcellsshouldbetakenintoaccountwhenassessingifepoetinalfatherapyisappropriate

(patientatriskofbeingtransfused).

Asanincreasedincidenceofthromboticvascularevents(TVEs)hasbeenobservedincancerpatientsreceivingESAs

(seesection4.8,Undesirableeffects),thisriskshouldbecarefullyweighedagainstthebenefittobederivedfrom

treatmentwithepoetinalfaparticularlyincancerpatientswithanincreasedriskofthromboticvascularevents,suchas

obesityandpatientswithapriorhistoryofTVEs(e.g.deepvenousthrombosisorpulmonaryembolism).

Aninvestigationalstudy(BESTstudy)inwomenwithmetastaticbreastcancerwasdesignedtodeterminewhether

epoetinalfatreatmentthatextendedbeyondthecorrectionofanaemiacouldimprovetreatmentoutcomes.Inthatstudy

theincidenceoffatalthromboemboliceventswashigherinpatientsreceivingepoetinalfathaninthosereceiving

placebo.

Surgerypatientsinautologouspredonationprogrammes

Allspecialwarningsandspecialprecautionsassociatedwithautologouspredonationprogrammes,especiallyroutine

volumereplacement,shouldberespected.

Patientsscheduledformajorelectiveorthopaedicsurgery

Inpatientsscheduledformajorelectiveorthopaedicsurgerythecauseofanaemiashouldbeestablishedandtreated,if

possible,beforethestartofepoetinalfatreatment.Thromboticeventscanbeariskinthispopulationandthis

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Patientsscheduledformajorelectiveorthopaedicsurgeryshouldreceiveadequateantithromboticprophylaxis,as

thromboticandvasculareventsmayoccurinsurgicalpatients,especiallyinthosewithunderlyingcardiovascular

disease.Inaddition,specialprecautionshouldbetakeninpatientswithpredispositionfordevelopmentofDVTs.

Moreover,inpatientswithabaselinehaemoglobinof>13g/dl,thepossibilitythatepoetinalfatreatmentmaybe

associatedwithanincreasedriskofpostoperativethrombotic/vasculareventscannotbeexcluded.Therefore,itshould

notbeusedinpatientswithbaselinehaemoglobin>13g/dl.

Thismedicinalproductcontainslessthan1mmolsodium(23mg)perdosei.e.essentially“sodiumfree”.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Noevidenceexiststhatindicatesthattreatmentwithepoetinalfaaltersthemetabolismofotherdrugs.However,since

cyclosporinisboundbyRBCsthereispotentialforadruginteraction.Ifepoetinalfaisgivenconcomitantlywith

cyclosporin,bloodlevelsofcyclosporinshouldbemonitoredandthedoseofcyclosporinadjustedasthehaematocrit

rises.

NoevidenceexiststhatindicatesaninteractionbetweenepoetinalfaandG-CSForGM-CSFwithregardto

haematologicaldifferentiationorproliferationoftumourbiopsyspecimensinvitro.

4.6Pregnancyandlactation

Therearenoadequateandwell-controlledstudiesinpregnantwomen.Studiesinanimalshaveshownreproduction

toxicity(seesection5.3,Preclinicalsafetydata).Consequently:

Inchronicrenalfailurepatients,epoetinalfashouldbeusedinpregnancyonlyifthepotentialbenefitoutweighs

thepotentialrisktothefoetus.

Inpregnantorlactatingsurgicalpatientsparticipatinginanautologousbloodpredonationprogramme,theuseof

epoetinalfaisnotrecommended.

4.7Effectsonabilitytodriveandusemachines

None.

4.8Undesirableeffects

General

Incancerpatientsandinchronicrenalfailurepatientsthemostfrequentadversedrugreactionduringtreatmentwith

epoetinalfaisadose-dependentincreaseinbloodpressureoraggravationofexistinghypertension.Monitoringofthe

bloodpressureshouldbeperformed,particularlyatthestartoftherapy(seesection4.4,Specialwarningsand

precautionsforuse).Othercommonadversedrugreactionsobservedinclinicaltrialsofepoetinalfaaredeepvein

thrombosis,pulmonaryembolism,seizures,diarrhoea,nausea,headache,influenza-likeillness,pyrexia,rash,and

vomiting.Influenza-likeillnessincludingheadaches,arthralgia,myalgia,andpyrexiamayoccurespeciallyatthestart

oftreatment.Frequenciesmayvarydependingontheindication(seetablebelow).

Seriousadversedrugreactionsincludevenousandarterialthrombosesandembolism(includingsomewithfatal

outcomes),suchasdeepvenousthrombosis,pulmonaryemboli,arterialthrombosis(includingmyocardialinfarction

andmyocardialischaemia),retinalthrombosis,andshuntthrombosis(includingdialysisequipment).Additionally,

cerebrovascularaccidents(includingcerebralinfarctionandcerebralhaemorrhage)andtransientischaemicattacks

havebeenreportedinclinicaltrialsofepoetinalfa.

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Hypersensitivityreactions,includingcasesofrash,urticaria,anaphylacticreaction,andangioneuroticoedemahave

beenreported.

Hypertensivecrisiswithencephalopathyandseizures,requiringtheimmediateattentionofaphysicianandintensive

medicalcare,haveoccurredalsoduringepoetinalfatreatmentinpatientswithpreviouslynormalorlowblood

pressure.Particularattentionshouldbepaidtosuddenstabbingmigraine-likeheadachesasapossiblewarningsignal.

Antibody-mediatedpureredcellaplasiahasbeenveryrarelyreportedin<1/10,000casesperpatientyearaftermonths

toyearsoftreatmentwithEPREX(seesection4.4,Specialwarningsandprecautionsforuse).

TheoverallsafetyprofileofEPREXwasevaluatedin142subjectswithchronicrenalfailureandin765subjectswith

cancerwhoparticipatedinplacebo-controlled,double-blindclinicalregistrationtrials.Adversedrugreactionsreported

≥0.2%ofEPREX-treatedsubjectsfromthesetrials,additionalclinicaltrialsandfrompost-marketingexperience

arelistedbelowbysystemorganclassandfrequency.

Frequenciesaredefinedas:Verycommon(1/10);common(1/100,<1/10);uncommon(1/1,000,<1/100);rare

(1/10,000,<1/1,000);veryrare(<1/10,000).Afrequencyisdefinedasnotknowniftheadversedrugreactionwasnot

reportedintheplacebo-controlled,double-blindclinicalregistrationtrialsorwhenthefrequencycannotbeestimated

fromotheravailabledata.

Withineachfrequencygrouping,adversedrugreactionsarepresentedinorderofdecreasingseriousness.

SystemOrganClass Frequency AdverseDrugReaction

Blood&LymphaticSystem

Disorders Uncommon Thrombocythaemia(cancerpatients)

Frequencynotknown Erythropoeitinantibody-mediatedpure

redcellaplasia 1

Thrombocythaemia(chronicrenal

failurepatients)

ImmuneSystemDisorders Frequencynotknown Anaphylacticreaction

Hypersensitivity

NervousSystemDisorders Verycommon Headache(cancerpatients)

Common Seizures(chronicrenalfailure

patients)

Headache(chronicrenalfailure

patients)

Uncommon Cerebralhaemorrhage 2

Seizures(cancerpatients)

Frequencynotknown

Cerebrovascularaccident 2

Hypertensiveencephalopathy

Transientischaemicattacks

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VascularDisorders Common

Deepveinthrombosis 2

(cancer

patients)

Hypertension

Frequencynotknown Deepveinthrombosis 2

(chronicrenal

failurepatients)

Arterialthrombosis

Hypertensivecrisis

Respiratory,Thoracic,and

MediastinalDisorders Common

Pulmonaryembolism 2

(cancer

patients)

Frequencynotknown

Pulmonaryembolism 2

(chronicrenal

failurepatients)

GastrointestinalDisorders Verycommon Nausea

Common Diarrhoea(cancerpatients)

Vomiting

Uncommon Diarrhoea(chronicrenalfailure

patients)

SkinandSubcutaneousTissue

Disorders Common Rash

Frequencynotknown Angioneuroticoedema

Urticaria

Musculoskeletal,Connective

Tissue,andBoneDisorders Verycommon Arthralgia(chronicrenalfailure

patients)

Common Arthralgia(cancerpatients)

Uncommon Myalgia(cancerpatients)

Frequencynotknown Myalgia(chronicrenalfailurepatients)

Congenitaland

Familial/GeneticDisorders Frequencynotknown Porphyria

GeneralDisordersand

AdministrationSiteConditions Verycommon Pyrexia(cancerpatients)

Influenza-likeillness(chronicrenal

failurepatients)

Common Influenza-likeillness(cancerpatients)

Frequencynotknown Drugineffective

Peripheraloedema

Pyrexia(chronicrenalfailurepatients)

Injectionsitereaction

Investigations Frequencynotknown

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Thefrequencycannotbeestimatedfromclinicaltrials.

Includingcaseswithafataloutcome.

Chronicrenalfailurepatients

Inchronicrenalfailurepatients,haemoglobinlevelsgreaterthan12g/dlmaybeassociatedwithahigherriskof

cardiovascularevents,includingdeath(seesection4.4,Specialwarningsandprecautionsforuse).

Shuntthromboseshaveoccurredinhaemodialysispatients,especiallyinthosewhohaveatendencytohypotensionor

whosearteriovenousfistulaeexhibitcomplications(e.g.stenoses,aneurysms,etc)(seesection4.4,Specialwarnings

andprecautionsforuse).

Cancerpatients

AnincreasedincidenceofthromboemboliceventshasbeenreportedincancerpatientsreceivingESAs,including

epoetinalfa(seesection4.4,Specialwarningsandprecautionsforuse).

Surgerypatients

Inpatientsscheduledformajorelectiveorthopaedicsurgery,withabaselinehaemoglobinof10to13g/dl,the

incidenceofthrombotic/vascularevents(mostofwhichweredeepveinthrombosis)intheoverallpatientpopulationof

theclinicaltrialsappearedtobesimilaracrossthedifferentepoetinalfadosinggroupsandplacebogroup,althoughthe

clinicalexperienceislimited.

Moreover,inpatientswithabaselinehaemoglobinof>13g/dl,thepossibilitythatepoetinalfatreatmentmaybe

associatedwithanincreasedriskofpostoperativethrombotic/vasculareventscannotbeexcluded.

4.9Overdose

Thetherapeuticmarginofepoetinalfaisverywide.Overdosageofepoetinalfamayproduceeffectsthatareextensions

ofthepharmacologicaleffectsofthehormone.Phlebotomymaybeperformedifexcessivelyhighhaemoglobinlevels

occur.Additionalsupportivecareshouldbeprovidedasnecessary.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCClassification:B03XA01

Erythropoietinisaglycoproteinthatstimulates,asamitosis-stimulatingfactoranddifferentiatinghormone,the

formationoferythrocytesfromprecursorsofthestemcellcompartment.

Theapparentmolecularweightoferythropoietinis32,000to40,000dalton.Theproteinfractionofthemolecule

contributesabout58%andconsistsof165aminoacids.ThefourcarbohydratechainsareattachedviathreeN-

glycosidicbondsandoneO-glycosidicbondtotheprotein.Epoetinalfaobtainedbygenetechnologyisglycosylated

andisidenticalinitsaminoacidandcarbohydratecompositiontoendogenoushumanerythropoietinthathasbeen

isolatedfromtheurineofanaemicpatients.

Epoetinalfahasthehighestpossiblepurityaccordingtothepresentstateoftheart.Inparticular,noresiduesofthecell

Injury,Poisoning,and

ProceduralComplications Common Shuntthrombosesincludingdialysis

equipment(chronicrenalfailure

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Thebiologicalefficacyofepoetinalfahasbeendemonstratedinvariousanimalmodelsinvivo(normalandanaemic

rats,polycythaemicmice).Afteradministrationofepoetinalfa,thenumberoferythrocytes,theHbvaluesand

reticulocytecountsincreaseaswellasthe59Fe-incorporationrate.

Anincreased3H-thymidineincorporationintheerythroidnucleatedspleencellshasbeenfoundinvitro(mousespleen

cellculture)afterincubationwithepoetinalfa.

Itcouldbeshownwiththeaidofcellculturesofhumanbonemarrowcellsthatepoetinalfastimulateserythropoiesis

specificallyanddoesnotaffectleucopoiesis.Cytotoxicactionsofepoetinalfaonbonemarrowcellscouldnotbe

detected.

721cancerpatientsreceivingnon-platinumchemotherapywereincludedinthreeplacebo-controlledstudies,389

patientswithhaematologicalmalignancies(221multiplemyeloma,144non-Hodgkin’slymphomaand24other

haematologicalmalignancies)and332withsolidtumours(172breast,64gynaecological,23lung,22prostate,21

gastrointestinal,and30othertumourtypes).Intwolarge,open-labelstudies,2697cancerpatientsreceivingnon-

platinumchemotherapywereincluded,1895withsolidtumours(683breast,260lung,174gynaecological,300

gastrointestinal,and478othertumourtypes)and802withhaematologicalmalignancies.

Inaprospective,randomised,double-blind,placebo-controlledtrialconductedin375anaemicpatientswithvarious

non-myeloidmalignanciesreceivingnon-platinumchemotherapy,therewasasignificantreductionofanaemia-related

sequelae(e.g.fatigue,decreasedenergy,andactivityreduction),asmeasuredbythefollowinginstrumentsandscales:

FunctionalAssessmentofCancerTherapy-Anaemia(FACT-An)generalscale,FACT-Anfatiguescale,andCancer

LinearAnalogueScale(CLAS).Twoothersmaller,randomised,placebo-controlledtrialsfailedtoshowasignificant

improvementinqualityoflifeparametersontheEORTC-QLQ-C30scaleorCLAS,respectively.

Erythropoietinisagrowthfactorthatprimarilystimulatesredcellproduction.Erythropoietinreceptorsmaybe

expressedonthesurfaceofavarietyoftumourcells.

Survivalandtumourprogressionhavebeenexaminedinfivelargecontrolledstudiesinvolvingatotalof2833patients,

ofwhichfourweredouble-blindplacebo-controlledstudiesandonewasanopen-labelstudy.Thestudieseither

recruitedpatientswhowerebeingtreatedwithchemotherapy(twostudies)orusedpatientpopulationsinwhichESAs

arenotindicated:anaemiainpatientswithcancernotreceivingchemotherapy,andheadandneckcancerpatients

receivingradiotherapy.Thetargethaemoglobinconcentrationintwostudieswas>13g/dl;intheremainingthree

studiesitwas12-14g/dl.Intheopen-labelstudytherewasnodifferenceinoverallsurvivalbetweenpatientstreated

withrecombinanthumanerythropoietinandcontrols.Inthefourplacebo-controlledstudiesthehazardratiosfor

overallsurvivalrangedbetween1.25and2.47infavourofcontrols.Thesestudieshaveshownaconsistent

unexplainedstatisticallysignificantexcessmortalityinpatientswhohaveanaemiaassociatedwithvariouscommon

cancerswhoreceivedrecombinanthumanerythropoietincomparedtocontrols.Overallsurvivaloutcomeinthetrials

couldnotbesatisfactorilyexplainedbydifferencesintheincidenceofthrombosisandrelatedcomplicationsbetween

thosegivenrecombinanthumanerythropoietinandthoseinthecontrolgroup.

Asystematicreviewhasalsobeenperformedinvolvingmorethan9000cancerpatientsparticipatingin57clinical

trials.Meta-analysisofoverallsurvivaldataproducedahazardratiopointestimateof1.08infavourofcontrols(95%

CI:0.99,1.18;42trialsand8167patients).Anincreasedrelativeriskofthromboembolicevents(RR1.67,95%CI:

1.35,2.06,35trialsand6769patients)wasobservedinpatientstreatedwithrecombinanthumanerythropoietin.There

isanincreasedriskforthromboemboliceventsinpatientswithcancertreatedwithrecombinanthumanerythropoietin

andanegativeoverallimpactonsurvivalcannotbeexcluded.Theextenttowhichtheseoutcomesmightapplytothe

administrationofrecombinanthumanerythropoietintopatientswithcancer,treatedwithchemotherapytoachieve

haemoglobinconcentrationslessthan13g/dl,isunclearbecausefewpatientswiththesecharacteristicswereincluded

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5.2Pharmacokineticproperties

I.V.route

Measurementofepoetinalfafollowingmultipledoseintravenousadministrationrevealedahalf-lifeofapproximately4

hoursinnormalvolunteersandasomewhatmoreprolongedhalf-lifeinrenalfailurepatients,approximately5hours.A

half-lifeofapproximately6hourshasbeenreportedinchildren.

S.C.route

Followingsubcutaneousinjection,serumlevelsofepoetinalfaaremuchlowerthanthelevelsachievedfollowingi.v.

injection,thelevelsincreaseslowlyandreachapeakbetween12and18hourspostdose.Thepeakisalwayswellbelow

thepeakachievedusingthei.v.route(approximately1/20thofthevalue).

Thereisnoaccumulation:thelevelsremainthesame,whethertheyaredetermined24hoursafterthefirstinjectionor

24hoursafterthelastinjection.

Thehalf-lifeisdifficulttoevaluateforthesubcutaneousrouteandisestimatedabout24hours.

Thebioavailabilityofsubcutaneousinjectableepoetinalfaismuchlowerthanthatoftheintravenousdrug:

approximately20%.

5.3Preclinicalsafetydata

Insomepre-clinicaltoxicologicalstudiesindogsandrats,butnotinmonkeys,epoetinalfatherapywasassociatedwith

subclinicalbonemarrowfibrosis(bonemarrowfibrosisisaknowncomplicationofchronicrenalfailureinhumansand

mayberelatedtosecondaryhyperparathyroidismorunknownfactors.Theincidenceofbonemarrowfibrosiswasnot

increasedinastudyofhaemodialysispatientswhoweretreatedwithepoetinalfafor3yearscomparedtoamatched

controlgroupofdialysispatientswhohadnotbeentreatedwithepoetinalfa).

Inanimalstudies,epoetinalfahasbeenshowntodecreasefoetalbodyweight,delayossificationandincreasefoetal

mortalitywhengiveninweeklydosesofapproximately20timestherecommendedhumanweeklydose.Thesechanges

areinterpretedasbeingsecondarytodecreasedmaternalbodyweightgain.

Epoetinalfadidnotshowanychangesinbacterialandmammaliancellculturemutagenicitytestsandaninvivo

micronucleustestinmice.

Long-termcarcinogenicitystudieshavenotbeencarriedout.Thereareconflictingreportsintheliteratureregarding

whethererythropoietinsmayplayaroleastumourproliferators.Thesereportsarebasedoninvitrofindingsfrom

humantumoursamples,butareofuncertainsignificanceintheclinicalsituation.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Polysorbate80

Glycine

Waterforinjections

Excipientsknowntohaverecognisedactionoreffect(presentinthisproductat<1mmol):

Sodiumdihydrogenphosphatedihydrate

Disodiumphosphatedihydrate

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6.2Incompatibilities

Intheabsenceofcompatibilitystudies,thismedicinalproductmustnotbemixedwithothermedicinalproducts.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Storeinarefrigerator(2 °

Cto8 °

C).Thistemperaturerangeshouldbecloselymaintaineduntiladministrationtothe

patient.Storeintheoriginalpackageinordertoprotectfromlight.Donotfreezeorshake.

Forthepurposeofambulatoryuse,thepatientmayremoveEPREXfromtherefrigeratorandstoreitnotabove25 °

foronesingleperiodofupto3days.

6.5Natureandcontentsofcontainer

1.0ml(2000IU)ofsolutionforinjectioninavial(typeIglass)withstopper(teflon-lined)-packsizeof6.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Donotadministerbyintravenousinfusionorinconjunctionwithotherdrugsolutions.

Beforeuse,leavetheEPREXvialtostanduntilitreachesroomtemperature.Thisusuallytakesbetween15and30

minutes.

Theproductshouldnotbeused,anddiscarded

ifthesealisbroken,

iftheliquidiscolouredoryoucanseeparticlesfloatinginit,

iftherehasbeenarefrigeratorfailure,or

ifyouknow,orthinkthatitmayhavebeenaccidentallyfrozen.

Theproductisforsingleuseonly.OnlytakeonedoseofEPREXfromeachvial.Refertosection3.Howtouse

EPREX(instructionsonhowtoinjectEPREX)ofthepackageleaflet.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

Janssen-CilagLtd

50-100HolmersFarmWay

HighWycombe

Buckinghamshire

HP124EG

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 02November1989

Dateoflastrenewal: 04August2008

10DATEOFREVISIONOFTHETEXT

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