EPIRUBICINE HCL

Main information

  • Trade name:
  • EPIRUBICINE HCL
  • Dosage:
  • 2
  • Pharmaceutical form:
  • Solution for Inj/Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EPIRUBICINE HCL
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0937/010/001
  • Authorization date:
  • 16-01-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Epirubicinhydrochloride2mg/ml,solutionforinjectionorinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Activesubstance:

1mlofsolutionforinjectionorinfusioncontains2mgEpirubicinhydrochloride

1vialof5mlsolutioncontains10mgEpirubicinhydrochloride

1vialof10mlsolutioncontains20mgEpirubicinhydrochloride

1vialof25mlsolutioncontains50mgEpirubicinhydrochloride.

1vialof75mlsolutioncontains150mgEpirubicinhydrochloride.

1vialof100mlsolutioncontains200mgEpirubicinhydrochloride

Excipient:

1mlofsolutionforinjectionorinfusioncontains3.5mgsodium

1vialof5mlsolutioncontains17.7mgsodium

1vialof10mlsolutioncontains35.4mgsodium

1vialof25mlsolutioncontains88.5mgsodium.

1vialof75mlsolutioncontains265.5mgsodium.

1vialof100mlsolutioncontains354.1mgsodium

Forfulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinjectionorinfusion.

Aclearredsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Epirubicinisusedinthetreatmentofarangeofneoplasticconditionsincluding;

Breastcarcinoma

Gastriccarcinoma

Whenadministeredintravesically,epirubicinhasbeenshowntobebeneficialinthetreatmentof:

Papillarytransitionalcellcarcinomacarcinomaofthebladder

Carcinomain-situ

Intravesicalprophylaxisofrecurrenceofsuperficialbladdercarcinomafollowingtransurethralresection.

Forintravesicaluseapositivebenefit-riskratiocouldonlybeestablishedinpatientsinwhomliveattenuatedBCGis

contra-indicatedorinappropriate.

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4.2Posologyandmethodofadministration

Epirubicinisonlyintendedforintravenousorintravesicaluse.

Intravenoususe

Itisadvisablethattheredsolution,whichshouldbeclearandtransparent,isinjectedviathecatheterofafreerunning

intravenousinfusionofaphysiologicalsaltsolutionorglucose5%overaperiodofuptoadurationof30minutes

(dependingonthedoseandthevolumeoftheinfusion).Theneedleshouldbeproperlyplacedinthevein.Thismethod

reducestheriskofthrombosisandextravasationthatcouldleadtoseverecellulitisandnecrosis.

Incaseofextravasation,administrationshouldbestoppedimmediately.Injectioninsmallveinsandrepeatedinjection

inthesameveincanleadtovenoussclerosis.

Usualdose

Ifepirubicinisusedasmonotherapy,therecommendeddoseinadultsis60-90mg/m 2

ofbodysurfacearea.Epirubicin

shouldbeinjectedintravenouslyover3-5minutes.Thesamedoseisrepeatedwithanintervalof21days.

Withthedosingschedulethehaematolo-medullarstateofthepatientshouldbetakenintoaccount.

Ifsignsoftoxicity,includingneutropenia/neutropenicfeverandthrombocytopeniaoccur(whichcouldpersistatday

21),dosemodificationorpostponementofthesubsequentdosemayberequired.

Highdose

Epirubicinasmonotherapyforthetreatmentofbreastcarcinomawithahighdoseshouldbeadministeredin

accordancetothefollowingregimen:

Forthetreatmentwithahighdoseepirubicincanbeadministeredasanintravenousbolusover3-5minutesorasan

infusionupto30minutesduration.

Breastcarcinoma

Intheadjuvanttreatmentofearlybreastcancerpatientswithpositivelymphnodesintravenousdosesofepirubicin

goingfrom100mg/m 2

(asasingledoseonday1)to120mg/m 2

(intwodivideddosesondays1and8)every3-4

weeksincombinationwithintravenouscyclophosphamideand5-fluorouracilandoraltamoxifenisrecommended.

Lowerdose(60-75mg/m 2

forusualtreatmentand105-120mg/m 2

fortreatmentwithhighdose)orpostponementof

thenextdosearerecommendedforpatientswithreducedbonemarrowfunctionduetopriorchemotherapyor

radiotherapy,duetoageorneoplasticbonemarrowinfiltration.Thecompletedosepercyclecanbedistributedover2-

3consecutivedays.

Thefollowingdosesofepirubicinarecommonlyusedinmonotherapyandcombinationtherapyforvarioustumours,as

shown:

*DosesgenerallygivenDay1orDay1,2and3at21-dayintervals

Combinationchemotherapy

WhenEpirubicinhydrochloride2mg/mlisusedincombinationwithotherantitumouralproducts,thedoseisreduced

Cancerindication

Epirubicindose(mg/m 2

)*

Monotherapapy Combinationtherapy

Gastriccancer 60-90 50

Bladdercancer 50mg/50mlor80mg/50ml

(carcinomainsitu)

Prophylaxis:50mg/50mlweekly

for4weeksthenmonthlyfor11

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Specialpatientgroups

Elderlypatients

Itisrecommendedtoreducethedoseinelderlypatients.

Children

Thesafetyandefficacyofepirubicininchildrenhasnotbeenestablished.

Impairedliverfunction

Theexcretionofepirubicinoccursprimarilyviatheliver.Inpatientswithaliverfunctiondisorderthedoseshouldbe

reducedasfollows,inordertoavoidanincreaseofgeneraltoxicity:

Impairedrenalfunction

Moderaterenalinsufficiencyisnotareasonfordosereduction,consideringthelimitedamountofepirubicinthatis

excretedviathisroute.However,inpatientswithsevererenalinsufficiency(serumcreatinine>450µmol/l)adose

reductionisrecommended.

Intravesicaluse

Forinstructionsondilutionoftheproductbeforeadministrationalsoseesection6.6.

Epirubicincanbeadministeredbyintravesicalrouteforthetreatmentofsuperficialbladdercarcinoma,carcinomain

situandprophylactictopreventrecurrenceaftertransurethralresection.Itshouldnotbeadministeredbyintravesical

routeforthetreatmentofinvasivetumoursthathavepenetratedthebladderwall,systemictherapyorsurgeryismore

suitableinthesesituations.

Variousdosingschedulesareused.Thefollowingcanbeusedasaguideline:

Superficialbladdercarcinoma:weeklybladderlavagewith50mg/50ml(dilutedwithaphysiologicalsaltsolutionor

sterilewater)for8weeks.Adosereductionof30mgper50mlisadvisedincaseoflocaltoxicity(chemicalcystitis).

Carcinomainsitu:Upto80mg/50ml(dependingonthetolerabilityofthepatient).

Prophylaxisofrecurrenceaftertransurethralresection:4timesaweeklyadministrationof50mg/50mlfollowedby11

timesamonthlyinstillationofthesamedose.

DILUTIONTABLEFORBLADDERINSTILLATIONSOLUTIONS

Thesolutionshouldbemaintainedintravesicalfor1-2hours.Toavoidexcessivedilutionwithurinethepatientshould

beinstructednottodrinkanyfluidswithin12hoursbeforetheinstillation.Duringtheinstillationthepatientshouldbe

Serumbilirubin AST (aspartate

aminotransferase) Dosereduction

1.4–3mg/100ml 2-4timesthenormalupper

limit Dose reduction of

>3mg/100ml >4timesthenormallimit Dose reduction of

Doseepirubicin

required Volumeof2mg/ml

epirubicininjection Volume of diluent

sterile water for

injectionor0.9%sterile

saline Total volume

bladder

instillation

30mg 15ml 35ml 50ml

50mg 25ml 25ml 50ml

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4.3Contraindications

Hypersensitivitytoepirubicinoranyothercomponentoftheproduct,otheranthracyclinesoranthracenediones.

Lactation

Intravenoususe

-persistentmyelosuppression

-severehepaticimpairment

-severemyocardialinsufficiency(including4thdegreemuscularheartfailure,acuteheartattackandpreviousheart

attackwhichledto3rdand4thdegreemuscularheartfailure,acuteinflammatoryheartdiseases)

-recentmyocardialinfarction

-severearrhythmias

-previoustreatmentswithmaximumcumulativedosesofepirubicinand/orotheranthracyclinesandanthracenediones

(seesection4.4)

-patientswithacutesystemicinfections

-unstableanginapectoris

-myocardiopathy

Intravesicaluse:

-urinarytractinfections

-inflammationofthebladder

-hematuria

-invasivetumourspenetratingthebladder

-catheterisationproblems

-largevolumeofresidualurine

-contractedbladder.

4.4Specialwarningsandprecautionsforuse

General-Epirubicinshouldbeadministeredonlyunderthesupervisionofqualifiedphysiciansexperiencedintheuse

ofcytotoxictherapy.

Epirubicinmustnotbeadministeredsubcutaneouslyorintramuscularly.

Initialtreatmentcallsforcarefulbaselinemonitoringofvariouslaboratoryparametersandcardiacfunction.

Ifepirubicinisadministeredasacontinuousinfusion,thisshouldpreferablytakeplaceviaacentralvenouscatheter.

Patientsshouldrecoverfromacutetoxicities(suchasstomatitis,mucositis,neutropenia,thrombocytopenia,and

generalizedinfections)ofpriorcytotoxictreatmentbeforebeginningtreatmentwithepirubicin.

Whiletreatmentwithhighdosesofepirubicin(e.g., 90mg/m2every3to4weeks)causesadverseeventsgenerally

similartothoseseenatstandarddoses(<90mg/m2every3to4weeks),theseverityoftheneutropeniaand

stomatitis/mucositismaybeincreased.Treatmentwithhighdosesofepirubicindoesrequirespecialattentionfor

possibleclinicalcomplicationsduetoprofoundmyelosuppression.

CardiacFunction-Cardiotoxicityisariskofanthracyclinetreatmentthatmaybemanifestedbyearly(i.e.,acute)or

late(i.e.,delayed)events.

ItinvolvesapermanentreductionoftheQRS-voltage,aprolongationoutsidethenormallimitsofthesystolictime

interval(PEP/LVET)andareductionoftheleftventricularejectionfraction.Earlyclinicaldiagnosisofheartfailure

inducedbycytostaticagentsappearsessentialtoasuccessfultreatmentwithdigitalis,diuretics,peripheralvasodilators,

adietwithalowsodiumcontentandsufficientbedrest.Therefore,cardiacmonitoringofpatientsreceivingepirubicin

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Early(i.e.,Acute)Events. Earlycardiotoxicityofepirubicinconsistsmainlyofsinustachycardiaand/or

electrocardiogram(ECG)abnormalitiessuchasnon-specificST-Twavechanges.Tachyarrhythmias,including

prematureventricularcontractions,ventriculartachycardia,andbradycardia,aswellasatrioventricularandbundle-

branchblockhavealsobeenreported.Theseeffectsdonotusuallypredictsubsequentdevelopmentofdelayed

cardiotoxicity,arerarelyofclinicalimportance,andaregenerallynotaconsiderationforthediscontinuationof

epirubicintreatment.

Late(i.e.,Delayed)Events.Delayedcardiotoxicityusuallydevelopslateinthecourseoftherapywithepirubicinor

within2to3monthsaftertreatmenttermination,butlaterevents(severalmonthstoyearsaftercompletionof

treatment)havealsobeenreported.Delayedcardiomyopathyismanifestedbyreducedleftventricularejectionfraction

(LVEF)and/orsignsandsymptomsofcongestiveheartfailure(CHF)suchasdyspnea,pulmonaryedema,dependent

edema,cardiomegalyandhepatomegaly,oliguria,ascites,pleuraleffusion,andgalloprhythm.Life-threateningCHFis

themostsevereformofanthracycline-inducedcardiomyopathyandrepresentsthecumulativedose-limitingtoxicityof

thedrug.

TheriskofdevelopingCHFincreasesrapidlywithincreasingtotalcumulativedosesofepirubicininexcessof900

mg/m2oralowercumulativedoseinpatientswhoreceivedradiationofthemediastenalarea;thiscumulativedose

shouldonlybeexceededwithextremecaution(seesection5.1).

Cardiacfunctionshouldbeassessedbeforepatientsundergotreatmentwithepirubicinandmustbemonitored(by

meansofanECG,echocardiographyornuclearmeasuringoftheejectionfraction(bymeansofaradionuclide

angiography))throughouttherapytominimizetheriskofincurringseverecardiacimpairment.Theriskmaybe

decreasedthroughregularmonitoringofLVEFduringthecourseoftreatmentwithpromptdiscontinuationof

epirubicinatthefirstsignofimpairedfunction.Theappropriatequantitativemethodforrepeatedassessmentof

cardiacfunction(evaluationofLVEF)includesmulti-gatedradionuclideangiography(MUGA)orechocardiography

(ECHO).AbaselinecardiacevaluationwithanECGandeitheraMUGAscanoranECHOisrecommended,

especiallyinpatientswithriskfactorsforincreasedcardiotoxicity.RepeatedMUGAorECHOdeterminationsof

LVEFshouldbeperformed,particularlywithhigher,cumulativeanthracyclinedoses.Thetechniqueusedfor

assessmentshouldbeconsistentthroughoutfollow-up.

Giventheriskofcardiomyopathy,acumulativedoseof900mg/m2epirubicinshouldbeexceededonlywithextreme

caution.

Inestablishingthemaximalcumulativedoseofepirubicin,considerationshouldbegiventoanyconcomitanttherapy

withpotentiallycardiotoxicdrugs.Acumulativedoseof900-1000mg/m2shouldonlybeexceededwithextreme

cautionwithbothusualandhighdosesofepirubicin.Abovethisleveltheriskofirreversiblecongestiveheartfailure

increasesgreatly.

Riskfactorsforcardiactoxicityincludeactiveordormantcardiovasculardisease,priororconcomitantradiotherapyto

themediastinal/pericardialarea,previoustherapywithotheranthracyclinesoranthracenediones,andconcomitantuse

ofotherdrugswiththeabilitytosuppresscardiaccontractilityorcardiotoxicdrugs(e.g.,trastuzumab)(seesection

4.5).

Cardiacfunctionmonitoringmustbeparticularlystrictinpatientsreceivinghighcumulativedosesandinthosewith

riskfactors.Elderlypatients,childrenandpatientswithahistoryofheartdiseasealsohaveagreaterriskof

cardiotoxicity.

However,cardiotoxicitywithepirubicinmayoccuratlowercumulativedoseswhetherornotcardiacriskfactorsare

present.

Itisprobablethatthetoxicityofepirubicinandotheranthracyclinesoranthracenedionesisadditive.

HematologicToxicity-Aswithothercytotoxicagents,epirubicinmayproducemyelosuppression.Hematologic

profilesshouldbeassessedbeforeandduringeachcycleoftherapywithepirubicin,includingdifferentialwhiteblood

cell(WBC)counts.Adose-dependent,reversibleleukopeniaand/orgranulocytopenia(neutropenia)isthepredominant

manifestationofepirubicinhematologictoxicityandisthemostcommonacutedose-limitingtoxicityofthisdrug.

Leukopeniaandneutropeniaaregenerallymoreseverewithhigh-doseschedules,reachingthenadirinmostcases

betweendays10and14afterdrugadministration;thisisusuallytransientwiththeWBC/neutrophilcountsreturningto

normalvaluesinmostcasesbyday21.Thrombocytopeniaandanemiamayalsooccur.Clinicalconsequencesof

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SecondaryLeukemia-Secondaryleukemia,withorwithoutapreleukemicphase,hasbeenreportedinpatientstreated

withanthracyclines,includingepirubicin.Secondaryleukemiaismorecommonwhensuchdrugsaregivenin

combinationwithDNA-damagingantineoplasticagents,incombinationwithradiationtreatment,whenpatientshave

beenheavilypre-treatedwithcytotoxicdrugs,orwhendosesoftheanthracyclineshavebeenescalated.These

leukemiascanhavea1-to3 -yearlatencyperiod.(Seesection5.1).

Gastrointestinal-Epirubicinisemetigenic.Mucositis/stomatitisgenerallyappearsearlyafterdrugadministrationand,

ifsevere,mayprogressoverafewdaystomucosalulcerations.Mostpatientsrecoverfromthisadverseeventbythe

thirdweekoftherapy.

LiverFunction-Themajorrouteofeliminationofepirubicinisthehepatobiliarysystem.Serumtotalbilirubin,

alkalinephosphatase,ALTandASTlevelsshouldbeevaluatedbeforeandduringtreatmentwithepirubicin.Patients

withelevatedbilirubinorASTmayexperienceslowerclearanceofdrugwithanincreaseinoveralltoxicity.Lower

dosesarerecommendedinthesepatients(seesections4.2and5.2).Patientswithseverehepaticimpairmentshouldnot

receiveepirubicin(seesection4.3).

RenalFunction-Serumcreatinineshouldbeassessedbeforeandduringtherapy.Dosageadjustmentisnecessaryin

patientswithserumcreatinine>5mg/dL(seesection4.2).

EffectsatSiteofInjection-Phlebosclerosismayresultfromaninjectionintoasmallvesselorfromrepeated

injectionsintothesamevein.Followingtherecommendedadministrationproceduresmayminimizetheriskof

phlebitis/thrombophlebitisattheinjectionsite(seesection4.2).

Extravasation-Extravasationofepirubicinduringintravenousinjectionmayproducelocalpain,severetissuelesions

(vesication,severecellulitis)andnecrosis.Shouldsignsorsymptomsofextravasationoccurduringintravenous

administrationofepirubicin,thedruginfusionshouldbeimmediatelydiscontinued.Thepatient’spainmayberelieved

bycoolingdowntheareaandkeepingitcoolfor24hours.Localinfiltrationwithcorticosteroids,withorwithoutthe

combinationofasodiumbicarbonatesolution(8.4%)andlocalapplicationofdimethylsulfoxideandcoldpackshave

beenusedwithvariousdegreesofsuccess.Thepatientshouldbemonitoredcloselyduringthesubsequentperiodof

time,asnecrosismayoccurafterseveralweeksafterextravasationoccurs,aplasticsurgeonshouldbeconsultedwitha

viewtopossibleexcision

Other-Aswithothercytotoxicagents,thrombophlebitisandthromboembolicphenomena,includingpulmonary

embolism(insomecasesfatal),havebeencoincidentallyreportedwiththeuseofepirubicin

Tumor-LysisSyndrome-Epirubicinmayinducehyperuricemiabecauseoftheextensivepurinecatabolismthat

accompaniesrapiddrug-inducedlysisofneoplasticcells(tumor-lysissyndrome).Blooduricacidlevels,potassium,

calciumphosphate,andcreatinineshouldbeevaluatedafterinitialtreatment.Hydration,urinealkalinization,and

prophylaxiswithallopurinoltopreventhyperuricemiamayminimizepotentialcomplicationsoftumor-lysissyndrome.

ImmunosuppressantEffects/IncreasedSusceptibilitytoInfections-Administrationofliveorlive-attenuatedvaccines

inpatientsimmunocompromisedbychemotherapeuticagentsincludingepirubicin,mayresultinseriousorfatal

infections.(seesection4.5)

Reproductivesystem:Epirubicincancausegenotoxicity.Menandwomentreatedwithepirubicinshouldadopt

appropriatecontraceptivesPatientsdesiringtohavechildrenaftercompletionoftherapyshouldbeadvisedtoobtain

geneticcounsellingifappropriateandavailable(seesection4.6).

AdditionalWarningsandPrecautionsforOtherRoutesofAdministration

Intravesicalroute-Administrationofepirubicinmayproducesymptomsofchemicalcystitis(suchasdysuria,

polyuria,nocturia,stranguria,hematuria,bladderdiscomfort,necrosisofthebladderwall)andbladderconstriction.

Specialattentionisrequiredforcatheterizationproblems(e.g.,uretheralobstructionduetomassiveintravesical

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Intra-arterialroute-Intra-arterialadministrationofepirubicin(transcatheterarterialembolizationforthelocalizedor

regionaltherapiesofprimaryhepatocellularcarcinomaorlivermetastases)mayproduce(inadditiontosystemic

toxicityqualitativelysimilartothatobservedfollowingintravenousadministrationofepirubicin)localizedorregional

eventswhichincludegastro-duodenalulcers(probablyduetorefluxofthedrugsintothegastricartery)andnarrowing

ofbileductsduetodrug-inducedsclerosingcholangitis.Thisrouteofadministrationcanleadtowidespreadnecrosis

oftheperfusedtissue.

Thismedicinalproductcontains3.5mgsodiumpermlsolutionforinjectionorinfusion.Tobetakenintoconsideration

bypatientsonacontrolledsodiumdiet.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Epirubicinismainlyusedincombinationwithothercytotoxicdrugs.Additivetoxicitymayoccurespeciallywith

regardtobonemarrow/hematologicandgastro-intestinaleffects(seesection4.4).Theuseofepirubicinincombination

chemotherapywithotherpotentiallycardiotoxicdrugs,aswellastheconcomitantuseofothercardioactivecompounds

(e.g.,calciumchannelblockers),requiresmonitoringofcardiacfunctionthroughouttreatment.

Epirubicinisextensivelymetabolizedbytheliver.Changesinhepaticfunctioninducedbyconcomitanttherapiesmay

affectepirubicinmetabolism,pharmacokinetics,therapeuticefficacyand/ortoxicity(seesection4.4Specialwarnings

andprecautionsforuse).

Anthracyclinesincludingepirubicinshouldnotbeadministeredincombinationwithothercardiotoxicagentsunlessthe

patient’scardiacfunctioniscloselymonitored.Patientsreceivinganthracyclinesafterstoppingtreatmentwithother

cardiotoxicagents,especiallythosewithlonghalf-livessuchastrastuzumab,mayalsobeatanincreasedriskof

developingcardiotoxicity.Thehalf-lifeoftrastuzumabisapproximately28.5daysandmaypersistinthecirculationfor

upto24weeks.Therefore,physiciansshouldavoidanthracycline-basedtherapyforupto24weeksafterstopping

trastuzumabwhenpossible.Ifanthracyclinesareusedbeforethistime,carefulmonitoringofcardiacfunctionis

recommended.

Vaccinationwithalivevaccineshouldbeavoidedinpatientsreceivingepirubicin.Killedorinactivatedvaccinesmay

beadministered;however,theresponsetosuchvaccinesmaybediminished.

MedicinalproductsthatinducetheenzymecytochromeP-450(suchasrifampicinandbarbiturates)canincreasethe

metabolismofepirubicin,resultinginareductionoftheefficacy.

Cimetidine400mgtwotimesdailygivenpriortoepirubicin100mg/m2every3weeksledtoa50%increasein

epirubicinAUCanda41%increaseinepirubicinolAUC(latterp<0.05).TheAUCofthe7-deoxy-doxorubicinol

aglyconeandliverbloodflowwerenotreduced,soresultsarenotexplainedbyreducedcytochromeP-450activity.

Cimetidineshouldbediscontinuedduringtreatmentwithepirubicin

Whengivenpriortoepirubicin,paclitaxelcancauseincreasedplasmaconcentrationsofunchangedepirubicinandits

metabolites,thelatterbeing,however,neithertoxicnoractive.Inonestudy,haematologicaltoxicitywasgreaterwhen

paclitaxelwasadministeredbeforeepirubicincomparedwithafterepirubicin.

Coadministrationofpaclitaxelordocetaxeldidnotaffectthepharmacokineticsofepirubicinwhenepirubicinwas

administeredpriortothetaxane.

Thiscombinationmaybeusedifusingstaggeredadministrationbetweenthetwoagents.Infusionofepirubicinand

paclitaxelshouldbeperformedwithatleasta24hourintervalbetweenthe2agents.

Dexverapamilmayalterthepharmacokineticsofepirubicinandpossiblyincreaseitsbonemarrowdepressanteffects.

Onestudyfoundthatdocetaxelmayincreasetheplasmaconcentrationsofepirubicinmetaboliteswhenadministered

immediatelyafterepirubicin

Quininemayacceleratetheinitialdistributionofepirubicinfrombloodintothetissuesandmayhaveaninfluenceon

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Theco-administrationofinterferon2bmaycauseareductioninboththeterminaleliminationhalf-lifeandthetotal

clearanceofepirubicin.

Thepossibilityofamarkeddisturbanceofhaematopoiesisneedstobekeptinmindwitha(pre)treatmentwith

medications which influences the bone marrow (i.e. cytostatic agents, sulphonamide, chloramphenicol,

diphenylhydantoin,amidopyrine-derivate,antiretroviralagents).

Prioradministrationofhigherdoses(900mg/m2and1200mg/m2)ofdexrazoxanemayincreasethesystemic

clearanceofepirubicinresultingandresultinadecreaseinAUC.

Thecardiotoxicityofepirubicinispotentiatedbycertainradiotherapeutictreatmentsandbypreviousorconcomitant

useofotheranthracyclinederivatives(e.g.mitomycin-C,dacarbazine,dactinomycinandpossiblycyclophosphamide)

orothercardiotoxicagents(e.g.5-fluorouracil,cyclophosphamide,cisplatin,taxanes).Epirubicincanpotentiatethe

effectofradiationtothemediastinalarea.

Ifepirubicinisusedconcomitantlywithotherdrugsthatmaycauseheartfailure,e.g.calciumchannelblockers,then

cardiacfunctionmustbemonitoredthroughoutthecourseoftreatment.

Concomitantusewithciclosporine,maycauseexcessiveimmunosuppression.

4.6Fertility,pregnancyandlactation

(Seesection5.3)

ImpairmentofFertility

Epirubicincouldinducechromosomaldamageinhumanspermatozoa.Menundergoingtreatmentwithepirubicin

shoulduseeffectivecontraceptivemethodsandifappropriateandavailable,seekadviceonspermpreservationdueto

thepossibilityofirreversibleinfertilitycausedbytherapy.Malepatientstreatedwithepirubicinareadvisednotto

fatherachildduringandupto6monthsaftertreatment

Epirubicinmaycauseamenorrheaorprematuremenopauseinpremenopausalwomen.

Womenshouldnotbecomepregnantduringtreatmentwithepirubicin.Menandwomenshoulduseaneffectivemethod

ofcontraceptionduringtreatmentandfor6monthsthereafter.

Pregnancy

Experimentaldatainanimalssuggestthatepirubicinmaycausefetalharmwhenadministeredtoapregnantwoman.If

epirubicinisusedduringpregnancy(particularlyinthefirsttrimester)orifthepatientbecomespregnantwhiletaking

thisdrug,thepatientshouldbeapprisedofthepotentialhazardtothefetusandthecytostaticdrugsshouldonlybeused

onstrictindicationandwhenthepotentialbenefitstothemotherhavebeenweightagainstpossiblerisksofadverse

effectsonreproduction.

Therearenostudiesinpregnantwomen.Epirubicinshouldbeusedduringpregnancyonlyifthepotentialbenefit

justifiesthepotentialrisktothefetus.

Lactation

Itisnotknownwhetherepirubicinisexcretedinhumanmilk.Becausemanydrugs,includingotheranthracyclines,are

excretedinhumanmilkandbecauseofthepotentialforseriousadversereactionsinnursinginfantsfromepirubicin,

mothersshoulddiscontinuenursingpriortotakingthisdrug.

4.7Effectsonabilitytodriveandusemachines

Theeffectofepirubicinontheabilitytodriveorusemachineryhasnotbeensystematicallyevaluated.

However,epirubicinmaycauseepisodesofnauseaandvomiting,whichcantemporarilyleadtoanimpairmentof

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4.8Undesirableeffects

Thefollowingundesirableeffectshavebeenobservedandreportedduringtreatmentwithepirubicinwiththefollowing

frequencies:Verycommon(1/10);common(1/100to<1/10);uncommon(1/1,000to1/100);rare(1/10,000to

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

Morethan10%oftreatedpatientscanexpecttodevelopundesirableeffects.Themostcommonundesirableeffectsare

myelosuppression,gastrointestinalsideeffects,anorexia,alopecia,infection.

SystemOrganClass Frequency Undesirableeffects

Infectionsandinfestations Common Infection

NotKnown Septicshock(mayoccurasa

resultofmyelosuppression),

sepsis,pneumonia

Neoplasmsbenign,malignant

andunspecified(inclcysts

andpolyps) Rare Acutelymphocytic

leukemia,acutemyelogenous

leukemiawithorwithoutapre-

leukaemicphase,inpatients

treatedwithepirubicinin

combinationwithDNA-

damagingantineoplasticagents.

Theseleukaemiashaveashort

(1-3year)latency.

Bloodandthelymphatic

systemdisorders VeryCommon Myelosuppression(leukopenia,

granucytopeniaand

neutropenia,anemiaandfebrile

neutropenia)

Uncommon Thrombocytopenia

Notknown Haemorrhageandtissue

hypoxiaasresultof

myelosuppression.

Immunesystemdisorders Rare Anaphylaxis

(anaphylactic/anaphylactoid

reactionswithorwithoutshock

includingskinrash,pruritus,

feverandchills).

Metabolismandnutrition

disorders Common Anorexia,dehydration

Rare Hyperuricemia(seesection

4.4)

Nervoussystemdisorders Rare Dizziness

Notknown Peripheralneuropathy(with

highdoses),headache

Eyedisorders Notknown Conjunctivitis,keratitis

Cardiacdisorders Rare Congestiveheartfailure(see

section4.4),(dyspnoea;

oedema,hepatomegaly,ascites,

pulmonaryoedema,

pleuraleffusions,gallop

rhythm)cardiotoxicity(e.g.

ECGabnormalities,

arrhythmias,cardiomyopathy),

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bradycardia,AVblock,bundle-

branchblock.

Vasculardisorders Common Hotflashes,phlebosclerosis

Uncommon Phlebitis,thrombophlebitis

Notknown Shock,thromboembolism,

includingpulmonaryemboli(in

isolatedcaseswithfatal

outcome)

Gastrointestinaldisorders Common Mucositis(canoccur5to10

daysaftertheinitiationofthe

treatment),esophagitis,

stomatitis,vomiting,diarrhea

whichcanresultin

dehydration,nausea(nausea

andvomitingoftenoccur

withinthefirst24hours(in

nearlyallpatients)

Skinandsubcutaneoustissue

disorders VeryCommon Alopecia(in60-90%oftreated

cases.Itinvolvespoorbeard

growthinmen.Alopeciais

dose-dependentandinmost

casesreversible)

Rare Urticaria,pruritis,local

erythematousreactionsalong

theveinthatwasusedforthe

injection.

NotKnown Localtoxicity,rash,itch,skin

changes,erythema,flushes,

changesinskinandnail

(hyperpigmentation),

photosensitivity,

hypersensitivitytoirradiated

skin(radiation-recallreaction)

Renalandurinarydisorders Verycommon Redcolorationofurinefor1to

2daysafteradministration

Notknown Proteinuriainpatientswho

weretreatedwithahighdose

Reproductivesystemand

breastdisorders Rare Amenorrhea,azoospermia

Generaldisordersand

administrationsiteconditions Common Infusionsiteerythema

Rare Malaise,asthenia,fever,chills,

hyperpyrexia

Investigations Rare Changesintransaminaselevels

NotKnown Asymptomaticdropsinleft

ventricularejectionfraction

Injury,poisoningand

proceduralcomplications Common Chemicalcystitis,sometimes

haemorrhagic,hasbeen

observedfollowingintravesical

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Intravesicaladministration:

Asonlyasmallamountofactiveingredientisreabsorbedafterintravesicalinstillation,severesystemicadversedrug

reactionsaswellasallergicreactionsarerare.Commonlyreportedarelocalreactionslikeburningsensationand

frequentvoiding(pollakisuria).Occasionalbacterialorchemicalcystitishavebeenreported(seesection4.4).These

ADRsaremostlyreversible.

4.9Overdose

Acuteoverdosagewithepirubicinwillresultinseveremyelosuppression(mainlyleukopeniaandthrombocytopenia),

gastrointestinaltoxiceffects(mainlymucositis)andacutecardiaccomplications.Duringthisperiodabloodtransfusion

isrequiredaswellasisolationinasterileroom.Latentcardiacfailurehasbeenobservedwithanthracyclinesseveral

monthstoyearsaftercompletionoftreatment(seesection4.4).Patientsmustbecarefullymonitored.Ifsignsof

cardiacfailureoccur,patientsshouldbetreatedaccordingtoconventionalguidelines.

Treatment:

Symptomatic.Epirubicincannotberemovedbydialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticcategory:Anthracyclinesandrelatedsubstances.

ATC-code:L01DB03

TheworkingmechanismofepirubicindependsonitsabilitytoformcomplexeswithDNA.Experimentalstudieswith

cellcultureshaveshownthatepirubicinrapidlypenetratesthecellandisrecoveredinthenucleuswhereitinhibitsthe

nucleicacidsynthesisandthemitosis.

Theactivityofepirubicinwasestablishedonmanyexperimentaltumours,amongstwhichleucaemiasL1210andP388,

thesarcomaSA180(solidandasceticform),theB16melanoma,thebreastcarcinoma,thelungcarcinomaofLewis

andthecoloncarcinoma38,furthermoreaneffectwasalsoshownonhumantumoursthatweretransplantedinathymic

nudemice(melanomaandmammary,lung,prostateandovariancarcinoma).

5.2Pharmacokineticproperties

Inpatientswithanormalliverandkidneyfunctiontheplasmalevelofepirubicindropsafteranintravenousinjectionof

60-150mg/m²inatri-exponentialwaywithaveryrapidfirstphaseandaslowlastphasewithameanhalflifeofabout

40hours.Thesedosesfallwithinthelimitsofthepharmacokineticlinearitybothconcerningtheplasmaclearance

valuesandthemetabolism.Distributionstudiesinratshaveshownthatepirubicindoesnotcrosstheblood-brain

barrier.Thehighplasmaclearancevaluesofepirubicin(0.9l/min)andthesloweliminationmethodsindicatealarge

distributionvolume.

Biotransformation

Themostimportantmetabolitesthatwereidentifiedareepirubicinol(13-OHepirubicin),glucuronidesofepirubicin

andofepirubicinol.The4’-O-glucuronidationdistinguishesepirubicinfromdoxorubicinandcanexplainthefaster

eliminationofepirubicinanditsreducedtoxicity.Plasmalevelsofthemostimportantmetabolite,epirubicinol,are

alwayslowerthanthoseoftheunchangedproductandrunpracticallyparallel.

Excretion

Approximately9-10%oftheadministereddoseisexcretedviatheurinewithin48hours.Epirubicinisprimarily

excretedviatheliver;approximately40%oftheadministereddoseisrecoveredinthebilewithin72hours.Aliver

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5.3Preclinicalsafetydata

Followingrepeateddosingwithepirubicin,thetargetorgansinrat,rabbitanddogwerethehaemolyphopoieticsystem,

GItract,kidney,liverandreproductiveorgans,Epirubicinwasalsocardiotoxicinrat,rabbitanddog.

Epirubicin,likeotheranthracyclines,wasmutagenic,genotoxic,embryotoxicandcarcinogenicinrats.

Peri/postnatalstudiesinratindicateadverseeffectsontheoffspringatclinicaldoses.Itisnotknownwhether

epirubicinisexcretedinbreastmilk.

Nomalformationswereseeninratsorrabbits,butlikeotheranthracyclinesandcytotoxicdrugs,epirubicinmustbe

consideredpotentiallyteratogenic.

Animalstudiesindicatethatepirubicinhasamorefavourabletherapeuticindexandalowersystemicandcardiac

toxicitythandoxorubicin.

Alocaltolerancestudyinratsandmiceshowedextravasationofepirubicincausestissuenecrosis

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

sodiumchloride

hydrochloricacid,forpHadjustment

waterforinjections

6.2Incompatibilities

Long-termcontactwithalkalinesolutionsshouldbeavoidedasthiscanleadtohydrolysis.Epirubicinhydrochloride2

mg/mlmustnotbemixedwithheparinduetopossibleprecipitation.

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthose

mentionedinsection6.6.

6.3Shelflife

2years.

Epirubicinhydrochloride2mg/mlcanbedilutedinNaCl0.9%orGlucose5%andadministeredintravenously.For

intravesicaladministrationtheproductshouldbedilutedwithNaCl0.9%orsterilewater.

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor28daysat15-25°C±2°Candat2–8°C.Froma

microbiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestoragetimes

andconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2to8°.

6.4Specialprecautionsforstorage

Storeintherefrigerator(2-8°C).

Storeandtransportrefrigerated

Donotfreeze

Forstorageconditionsofthedilutedmedicinalproductandforstorageafteropening,seesection6.3.

Storageofthesolutionforinjectionatrefrigeratedconditionscanresultintheformationofagelledproduct.This

gelledproductwillreturntoaslightlyviscoustoamobilesolutionaftertwotoamaximumoffourhoursequilibration

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6.5Natureandcontentsofcontainer

Epirubicinhydrochloride2mg/mlisdeliveredincolourless,Type1glassvialswithbromobutylrubbercap,aluminium

closingandsnap-cap,withrespectively5ml,10ml,25ml,75mland100mlsolutionforinjectionorinfusion.

Eachcartoncontainsasinglevial.

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposalandotherhandling

Ifaninfusionsolutionistobeprepared,thisshouldbeperformedbytrainedpersonnelunderasepticconditions.

Preparationofaninfusionsolutionshouldbeperformedinadesignatedasepticarea.

PeopleworkingwithEpirubicinhydrochloride2mg/mlarerequiredtowearprotectivegloves,safetygogglesanda

mask.

Epirubicinhydrochloride2mg/mlcanbedilutedinNaCl0.9%orGlucose5%andbeadministeredintravenously.The

solutionmustbepreparedimmediatelypriortouse.

ForintravesicaladministrationtheproductmustbedilutedwithNaCl0.9%orsterilewater.Theconcentrationofthe

dilutionhastobe0.6-1.6mg/ml.

Epirubicinhydrochloride2mg/mlcontainsnopreservativesandisthereforeonlysuitableforsingleuse.Afterusethe

unusedremaindershouldbedestroyedaccordingtotheregulationsforcytostaticagents.Seealso“Disposal”.

Inactivationofspilledorleakedmedicinalproductcanbeobtainedwitha1%sodiumhypochloritesolutionorsimply

withaphosphatebufferingagent(pH>8)untilthesolutionisdecolourised.Allcleaningmaterialsaredisposedofas

mentionedunder“Disposal”.

Pregnantwomenmustavoidcontactwithcytostaticagents.

Excretaandvomitshouldbecleanedupwithcare.

Adamagedvialmustbetreatedwiththesameprecautionsandmustbeconsideredascontaminatedwaste.

Contaminatedwastemustbestoredinappropriatespeciallymarkedwastecontainers.Seeunder“Disposal”.

Disposal

Anyunusedproduct,allmaterialsusedinthepreparationandadministration,orwhichhavecomeincontactwith

epirubicinhydrochlorideinanyway,mustbedestroyedinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

PharmachemieB.V.

Swensweg5

P.O.Box552

Haarlem,2003RN

Netherlands

8MARKETINGAUTHORISATIONNUMBER

PA937/10/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:16 th

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10DATEOFREVISIONOFTHETEXT

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