EPREX

Main information

  • Trade name:
  • EPREX Solution for Injection 4000 iu/ml Units/ml
  • Dosage:
  • 4000 iu/ml Units/ml
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EPREX Solution for Injection 4000 iu/ml Units/ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0748/025/002
  • 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)

PA0748/025/002

CaseNo:2046681

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

Janssen-CilagLtd

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

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

EPREX4,000IU/ml,solutionforinjection

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom04/08/2008.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EPREX4,000IU/ml,solutionforinjection.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Epoetinalfa*………………………………………4000IU/ml(33.6microgramsperml)

Avialof1.0mlcontains4000IU(33.6micrograms)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

cells/µlabovebaseline,responseisunlikelyandtreatmentshouldbediscontinued.Therecommendeddosingregimen

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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

tosurgeryandonthedayofsurgery.Incaseswherethereisamedicalneedtoshortentheleadtimebeforesurgeryto

lessthanthreeweeks,300IU/kgepoetinalfashouldbegivendailyfor10consecutivedayspriortosurgery,ontheday

ofsurgeryandforfourdaysimmediatelythereafter.Whenperforminghaematologicassessmentsduringthe

preoperativeperiod,ifthehaemoglobinlevelreaches15g/dl,orhigher,administrationofepoetinalfashouldbe

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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

consideredandtreatedpriortoinitiatingtherapywithepoetinalfa.Inmostcases,theferritinvaluesintheserumfall

simultaneouslywiththeriseinpackedcellvolume.Inordertoensureoptimumresponsetoepoetinalfa,adequateiron

storesshouldbeassured:

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

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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

prophylaxisbyadministrationofacetylsalicylicacid,forexample,isrecommendedinthesepatients.

Hyperkalaemiahasbeenobservedinisolatedcases.Inchronicrenalfailurepatients,correctionforanaemiamayleadto

increasedappetite,andpotassiumandproteinintake.Dialysisprescriptionsmayhavetobeadjustedperiodicallyto

maintainurea,creatinineandpotassiuminthedesiredrange.Serumelectrolytesshouldbemonitoredinchronicrenal

failurepatients.Ifanelevated(orrising)serumpotassiumlevelisdetectedthenconsiderationshouldbegivento

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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

possibilityshouldbecarefullyweighedagainstthebenefittobederivedfromthetreatmentinthispatientgroup.

Patientsscheduledformajorelectiveorthopaedicsurgeryshouldreceiveadequateantithromboticprophylaxis,as

thromboticandvasculareventsmayoccurinsurgicalpatients,especiallyinthosewithunderlyingcardiovascular

disease.Inaddition,specialprecautionshouldbetakeninpatientswithpredispositionfordevelopmentofDVTs.

Moreover,inpatientswithabaselinehaemoglobinof>13g/dl,thepossibilitythatepoetinalfatreatmentmaybe

associatedwithanincreasedriskofpostoperativethrombotic/vasculareventscannotbeexcluded.Therefore,itshould

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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.

Aneurysmshavebeenreported.

Hypersensitivityreactions,includingcasesofrash,urticaria,anaphylacticreaction,andangioneuroticoedemahave

beenreported.

Hypertensivecrisiswithencephalopathyandseizures,requiringtheimmediateattentionofaphysicianandintensive

medicalcare,haveoccurredalsoduringepoetinalfatreatmentinpatientswithpreviouslynormalorlowblood

pressure.Particularattentionshouldbepaidtosuddenstabbingmigraine-likeheadachesasapossiblewarningsignal.

Antibody-mediatedpureredcellaplasiahasbeenveryrarelyreportedin<1/10,000casesperpatientyearaftermonths

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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

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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

EyeDisorders Frequencynotknown Retinalthrombosis

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

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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

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

Anti-erythropoietinantibodypositive 1

Injury,Poisoning,and

ProceduralComplications Common Shuntthrombosesincludingdialysis

equipment(chronicrenalfailure

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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

lineusedfortheproductionaredetectableattheconcentrationsoftheactiveingredientthatareusedinhumans.

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

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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

inthedatareviewed.

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:

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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

Sodiumchloride

6.2Incompatibilities

Intheabsenceofcompatibilitystudies,thismedicinalproductmustnotbemixedwithothermedicinalproducts.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Storeinarefrigerator(2 °

Cto8 °

C).Thistemperaturerangeshouldbecloselymaintaineduntiladministrationtothe

patient.Storeintheoriginalpackageinordertoprotectfromlight.Donotfreezeorshake.

Forthepurposeofambulatoryuse,thepatientmayremoveEPREXfromtherefrigeratorandstoreitnotabove25 °

foronesingleperiodofupto3days.

6.5Natureandcontentsofcontainer

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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

PA0748/025/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 02November1989

Dateoflastrenewal: 04August2008

10DATEOFREVISIONOFTHETEXT

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