EPIRUBICIN

Main information

  • Trade name:
  • EPIRUBICIN Solution for Injection 2 Mg/Ml
  • Dosage:
  • 2 Mg/Ml
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EPIRUBICIN Solution for Injection 2 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1658/002/001
  • Authorization date:
  • 20-08-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA1658/002/001

CaseNo:2085779

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

TransferredfromPA0585/035/001.

Genepharm(Europe)TradingLtd

ElGrecoHouse,20QueenFredericaSt.,1066Nicosia,Cyprus

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Epirubicin2mg/mlSolutionforInjection

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom20/08/2010until02/04/2014.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Epirubicin2mg/mlSolutionforInjection

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmillilitreofsolutionforinjectioncontains2mgepirubicinhydrochloride.

Thecontentofsodiumis3.54mgpermlandpervialisasfollows:

5mlvial17.71mg,10mlvial35.42mg,25mlvial88.55mg,50mlvial177.1mgand100mlvial354.2mg

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

SolutionforInjection.

Aclearredsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Epirubicinisusedinthetreatmentofarangeofneoplasticconditionsincluding:

Carcinomaofthebreast

Advancedovariancancer

Gastriccancer

Smallcelllungcancer

Whenadministeredintravesically,epirubicinhasbeenshowntobebeneficialinthetreatmentof:

Papillarytransitionalcellcarcinomaofthebladder

Carcinoma-in-situofthebladder

Intravesicalprophylaxisofrecurrencesofsuperficialbladdercarcinomafollowingtransurethralresection

4.2Posologyandmethodofadministration

Epirubicinisforintravenousorintravesicaluseonly.

Thesafetyandefficacyofepirubicininchildrenhasnotbeenestablished.

Epirubicin2mg/mlSolutionforInjectioniscompatiblewithbothdextrose5%andsodiumchloride0.9%.

Pleaserefertosection6.6forinstructionsonthepreparationandhandlingofthedrugproduct.

Intravenousadministration

Itisadvisabletoadministerepirubicinviathetubingofafree-runningintravenoussodiumchloride0.9%infusionafter

checkingthattheneedleisproperlyplacedinthevein.Careshouldbetakentoavoidextravasation(seesection4.4).In

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Conventionaldose

Whenepirubicinisusedasasingleagent,therecommendeddosageinadultsis60-90mg/m²bodyarea.Epirubicin

shouldbeinjectedintravenouslyover3-5minutes.Thedoseshouldberepeatedat21-dayintervals,dependinguponthe

patient'shaematologicalstatusandbonemarrowfunction.

Ifsignsoftoxicity,includingsevereneutropenia/neutropenicfeverandthrombocytopeniaoccur(whichcouldpersistat

day21),dosemodificationorpostponementofthesubsequentdosemayberequired.

Highdose

Epirubicinasasingleagentforthehighdosetreatmentoflungcancershouldbeadministeredaccordingtothe

followingregimens:

Smallcelllungcancer(previouslyuntreated):120mg/m²day1,every3weeks.

Forhighdosetreatment,epirubicinmaybegivenasanintravenousbolusover3-5minutesorasaninfusionofupto30

minutesduration.

BreastCancer

Intheadjuvanttreatmentofearlybreastcancerpatientswithpositivelymphnodes,intravenousdosesofepirubicin

rangingfrom100mg/m²(asasingledoseonday1)to120mg/m²(intwodivideddosesondays1and8)every3-4

weeks,incombinationwithintravenouscyclophosphamideand5-fluorouracilandoraltamoxifen,arerecommended.

Lowerdoses(60-75mg/m²forconventionaltreatmentand105-120mg/m²forhighdosetreatment)arerecommended

forpatientswhosebonemarrowfunctionhasbeenimpairedbypreviouschemotherapyorradiotherapy,byage,or

neoplasticbonemarrowinfiltration.Thetotaldosepercyclemaybedividedover2-3successivedays.

Thefollowingdosesofepirubicinarecommonlyusedinmonotherapyandcombinationchemotherapyforvarious

tumours,asshown:

ª DosesgenerallygivenDay1orDay1,2and3at21-dayintervals

Combinationtherapy

Ifepirubicinisusedincombinationwithothercytotoxicproducts,thedoseshouldbereducedaccordingly.

Commonlyuseddosesareshowninthetableabove.

Impairedliverfunction

Themajorrouteofeliminationofepirubicinisthehepatobiliarysystem.Inpatientswithimpairedliverfunctionthe

doseshouldbereducedbasedonserumbilirubinlevelsasfollows:

SerumBilirubin DoseReduction

24-51µmol/l 50%

CancerIndication EpirubicinDose(mg/m²)ª

Monotherapy CombinationTherapy

Advancedovariancancer 60-90 50-100

Gastriccancer 60-90 50

SCLC 120 120

Bladdercancer 50mg/50mlor80mg/50ml

(carcinomainsitu)

Prophylaxis:

50mg/50mlweeklyfor4weeks

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Impairedrenalfunction

Moderaterenalimpairmentdoesnotappeartorequireadosereductioninviewofthelimitedamountofepirubicin

execretedbythisroute.However,dosageadjustmentmaybenecessaryinpatientswithserumcreatinine>5mg/dL.

Intravesicaladministration

Epirubicincanbegivenbyintravesicaladministrationforthetreatmentofsuperficialbladdercancerandcarcinom-in-

situ.Itshouldnotbegivenintravesicallyforthetreatmentofinvasivetumoursthathavepenetratedthebladderwall,

systemictherapyorsurgeryismoreappropriateinthesesituations(seesection4.3).Epirubicinhasalsobeen

successfullyusedintravesicallyasaprophylacticagentaftertransurethralresectionofsuperficialtumourstoprevent

recurrence.

Forthetreatmentofsuperficialbladdercancerthefollowingregimenisrecommended,usingthedilutiontablebelow:

8weeklyinstillationsof50mg/50ml(dilutedwithsodiumchloride0.9%).

Iflocaltoxicityisobserved:Adosereductionto30mg/50mlisadvised.

Carcinomainsituofthebladder:Upto80mg/50ml(dependingonindividualtolerabilityofthepatient).

Forprophylaxis:4weeklyadministrationsof50mg/50mlfollowedby11monthlyinstillationsatthesamedose.

DILUTIONTABLEFORBLADDERINSTILLATIONSOLUTIONS

Thesolutionshouldberetainedintravesicallyfor1-2hours.Toavoidunduedilutionwithurine,thepatientshouldbe

instructednottodrinkanyfluidinthe12hourspriortoinstillation.Duringtheinstillation,thepatientshouldberotated

occasionallyandshouldbeinstructedtovoidurineattheendoftheinstillationtime.

4.3Contraindications

Epirubicinisconstraindicatedin:

Patientswhohavedemonstratedhypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Patientswithmarkedmyelosuppressioninducedbyprevioustreatmentwitheitherotheranti-neoplasticagentsor

radiotherapy.

Patientstreatedwithmaximalcumulativedosesofotheranthracyclinessuchasdoxorubicinordaunorubicin.

Patientswithcurrentorprevioushistoryofcardiacimpairment(includingNewYorkHeartAssociation(NYHA)

classIVheartfailure,acutemyocardialinfarctionandpreviousinfarctionwithresidualNYHAclassIIIorclass

IVheartfailure,acuteinflammatoryheartdiseases,arrhythmiawithserioushaemodynamicconsequences).

Patientswithaccutesystemicinfections

Severeliverimpairment

Severemucositisofthemouth,pharynx,oeasophagus,andgastro-intestinaltract.

Lactation

Forintravesicaladministration,epirubiciniscontraindicatedin:

-Urinarytractinfections

-Invasivetumourspenetratingthebladder

-Catheterisationproblems

-Vesicalinflammation

-Largevolumeofresidualurine

DoseEpirubicin

required Volumeof2mg/ml

epirubicininjection Volumeofdiluent

sterilesodium

chloride0.9% Totalvolumefor

bladderinstallation

30mg 15ml 35ml 50ml

50mg 25ml 25ml 50ml

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4.4Specialwarningsandprecautionsforuse

Epirubicinshouldonlybeadministeredunderthesupervisionofaqualifiedphysicianwhoisexperiencedintheuseof

chemotherapeuticagents.Diagnosticandtreatmentfacilitiesshouldbereadilyavailableformanagementoftherapyand

possiblecomplicationsduetomyelosuppression,especiallyfollowingtreatmentwithhigherdosesofepirubicin.

"Menandwomenshoulduseaneffectivemethodofcontraceptionduringtreatmentandforsixmonthsthereafter(see

4.6)".

Extravasationofepirubicinfromtheveinduringinjectionmaycauseseveretissuelesionsandnecrosis.Venous

sclerosismayresultfrominjectionintosmallvesselsorrepeatedinjectionsintothesamevein.

Carefulbaselinemonitoringofvariouslaboratoryparametersandcardiacfunctionshouldprecedeinitialtreatmentwith

epirubicin.

Duringtreatmentwithepirubicin,redbloodcell,whitebloodcell,neutrophilandplateletcountsshouldbecarefully

monitoredbothbeforeandduringeachcycleoftherapy.Leucopeniaandneutropeniaareusuallytransientwith

conventionalandhigh-doseschedulesreachinganadirbetweenthe10 th

and14 th

day,valuesshouldreturntonormal

bythe21 st

day;theyaremoreseverewithhighdoseschedules.Thrombocytopenia(<100,000platelets/mm³)is

experiencedinveryfewpatients,evenfollowinghighdosesofepirubicin.

Patientsmusthaveadequatelyrecoveredfromseverestomatitisormucositisbeforestartingtreatmentwithepirubicin.

Inestablishingthemaximalcumulativedoseofepirubicin,considerationshouldbegiventoanyconcomitanttherapy

withpotentiallycardiotoxicdrugs.Acumulativedoseof900-1000mg/m²shouldonlybeexceededwithextreme

cautionwithbothconventionalandhighdosesofepirubicin.Abovethisleveltheriskofirreversiblecongestiveheart

failureincreasesgreatly.AnECGisrecommendedbeforeandaftereachtreatmentcycle.AlterationsintheECG

tracing,suchasflatteningorinversionoftheT-wave,depressionoftheS-Tsegment,ortheonsetofarrhythmias,

generallytransientandreversibleneednotnecessarilybetakenasindicationstodiscontinuetreatment.With

cumulativedoses<900mg/m²,thereisevidencethatcardiactoxicityrarelyoccurs.However,cardiacfunctionmustbe

carefullymonitoredduringtreatmenttominimisetheriskofheartfailureofthetypedescribedforotheranthracyclines.

Incaseofcardiacinsufficiency,treatmentwithepirubicinshouldbediscontinued.

CardiomyopathyinducedbyanthracyclinesisassociatedwithpersistentreductionoftheQRSvoltage,prolongation

beyondnormallimitsofthesystolicinterval(PEP/LVET)andareductionoftheejectionfraction.Cardiacmonitoring

ofpatientsreceivingepirubicintreatmentishighlyimportantanditisadvisabletoassesscardiacfunctionbynon-

invasivetechniques.Electrocardiogram(ECG)changesmaybeindicativeofanthracycline-inducedcardiomyopathy,

butECGisnotasensitiveorspecificmethodforfollowinganthracycline-relatedcardiotoxicity.Theriskofserious

cardiacimpairmentmaybedecreasedthroughregularmonitoringofleftventricularejectionfraction(LVEF)during

thecourseoftreatmentwithpromptdiscontinuationofepirubicinatthefirstsignofimpairedfunction.Thepreferred

methodforrepeatedassessmentofcardiacfunctionisevaluationofLVEFmeasurebymulti-gatedradionuclide

angiography(MUGA)orechocardiography(ECHO).AbaselinecardiacevaluationwithanECGandaMUGAscanor

anECHOisrecommended,especiallyinpatientswithriskfactorsforincreasecardiatoxicity.RepeatedMUGAor

ECHOdeterminationsofLVEFshouldbeperformed,particularlywithhigher,cumulativeanthracyclinedoses.The

techniqueusedforassessmentshouldbeconsistentthroughfollow-up.Inpatientswithriskfactors,particularlyprior

anthracyclineoranthracenedioneuse,themonitoringofcardiacfunctionmustbeparticularlystrict.

Aswithothercytotoxicagents,epirubicinmayinducehyperuricaemiaasaresultofrapidlysisofneoplasticcells.

Blooduricacidlevelsshouldthereforebecheckedsothatthisphenomenonmayberecognisedandproperlymanaged.

Hydration,urinealkalinisationandprophylaxiswithallopurinoltopreventhyperuricaemiamayminimizepotential

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Heartfailuremayappearseveralweeksafterdiscontinuingtherapywithepirubicinandmaybeunresponsivetospecific

medicaltreatment.Thepotentialriskofcardiotoxicitymayincreaseinpatientswhohavereceivedconcomitant,or

prior,radiotherapytothemediastinalpericardialareaand/orwhoareundermedicaltreatmentwithpotentially

cardiotoxicmedicinalproducts(seesection4.5).

Beforecommencingtherapywithepirubicin,andifpossibleduringtreatment,liverfunctionshouldbeevaluated

(SGOT,SGT,alkalinephosphatase,bilirubin),(seesection4.2).

Epirubicinmayimpartaredcolourtotheurineforoneortwodaysafteradministration.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ItisnotrecommendedthatEpirubicin2mg/mlSolutionforInjectionbemixedwithothermedicinalproducts.

However,epirubicincanbeusedincombinationwithotheranti-canceragentsbutpatientsshouldbemonitoredfor

additivetoxicity,especiallymyelotoxicityandgastrointestinaltoxicity.

Druginteractionswithepirubicinhavebeenobservedwithcimetidine,dexverapamil,dexrazoxane,docetaxel,

interferon

bpaclitaxelandquinine.

Dexverapamilmayalterthepharmacokineticsofepirubicinandpossiblyincreaseitsbonemarrowdepressanteffects.

Prioradministrationofhigherdoses(900mg/m²and1200mg/m²)ofdexrazoxanemayincreasethesystemicclearance

ofepirubicinandresultinadecreaseinAUC.

Onestudyfoundthatdocetaxelmayincreasetheplasmaconcentrationsofepirubicinmetaboliteswhenadministered

immediatelyafterepirubicin.

Theco-administrationofinterferon

bmaycauseareductioninboththeterminaleliminationhalf-lifeandthetotal

clearanceofepirubicin.

Paclitaxelmayaffectthepharmacokineticsofepirubicinanditsmetabolite,epirubicinol.Inonestudy,haematological

toxicitywasgreaterwhenpaclitaxelwasadministeredbeforeepirubicincomparedwithafterepirubicin.

Onestudyhasshownthatpaclitaxelclearanceisreducedbyepirubicin.

Quininemayacceleratetheinitialdistributionofepirubicinfrombloodintothetissuesandmayhaveaninfluenceon

theredbloodcellspartitioningofepirubicin.

Cimetidine400mgb.i.dgivenpriortoepirubicin100mg/m²every3weeksledtoa50%increaseinepirubicinAUC

anda41%increaseinepirubicinolAUC(latterp<0.05).TheAUCofthe7-deoxy-doxorubicinolaglyconeandliver

bloodflowwerenotreduced,soresultsarenotexplainedbyreducedcytochromeP-450activity.

Thepossibilityofamarkeddisturbanceofhaematopoiesisneedstobekeptinmindwitha(pre-)treatmentwith

medicationswhichinfluencethebonemarrow(i.e.cytostaticagents,sulphonamide,chloramphenicol,

diphenylhydantoin,amidopyrine-derivate,antiretroviralagents).

Thepotentialriskofcardiotoxicitymayincreaseinpatientswhohavereceivedconcomitantcardiotoxicagents(e.g.5-

fluorouracil,cyclophosphamide,cisplatin,taxanes),orconcomitant(orprior)radiotheraphytothemediastinalarea.

Ifepirubicinisusedconcomitantlywithotherdrugsthatmaycauseheartfailure,e.g.calciumchannelblockers,then

cardiacfunctionmustbemonitoredthroughoutthecourseoftreatment.

Epirubicinismainlymetabolizedintheliver;eachconcomitantmedicationwhichaffectshepaticfunctioncanalso

affectthemetabolisationofthepharmacokineticsofepirubicinand,consequently,itsefficacyand/ortoxicity.

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4.6Pregnancyandlactation

Thereisnoconclusiveinformationastowhetherepirubicinmayadverselyaffecthumanfertilityorcauseteratogenesis.

Experimentaldata,however,suggestthatepirubicinmayharmthefoetus.Likemostotheranti-canceragents,

epirubicinhasshownmutagenicandcarcinogenicpropertiesinanimals.Bothmenandwomenreceivingepirubicin

shouldbeinformedofthepotentialriskofadverseeffectsonreproductionandshoulduseaneffectivemethodof

contraceptionduringtreatmentandforsixmonthsthereafter.Malepatientstreatedwithepirubicinareadvisednotto

fatherachildduringandupto6monthsaftertreatmentandtoseekadviceonconservationofspermpriortotreatment

becauseofthepossibilityofinfertilityduetotherapywithepirubicin.Womenofchildbearingpotentialshouldbefully

informedofthepotentialhazardtothefoetusandthepossibilityofgeneticcounsellingshouldbeconsideredifthey

becomepregnantduringepirubicintherapy.Incancerchemotherapy,epirubicinshouldnotbeusedinpregnantwomen

orwomenofchildbearingpotentialwhomightbecomepregnantunlessthepotentialbenefitstothemotheroutweigh

thepossiblyriskstothefoetus.

Itisunknownwhetherepirubicinisexcretedinhumanbreastmilk.Arisktothesucklingchildcannotbeexcluded.

BreastfeedingmustbediscontinuedbeforeandduringtherapywithEpirubicin.

4.7Effectsonabilitytodriveandusemachines

Therehavebeennoreportsofparticularadverseeventsrelatingtotheeffectsonabilitytodriveandtousemachines.

Epirubicinmaycauseepisodesofnauseaandvomiting,whichcantemporarilyleadtoanimpairmentofabilitytodrive

oroperatemachines.

4.8Undesirableeffects

Adverseeventfrequencieshavebeencategorizedasfollows:Verycommon( ≥1/10);common(≥1/100to<1/10);

uncommon( ≥1/1,000to<1/100);rare(≥1/10,000to<1/1,000);veryrare(<1/10,000),notknown(cannotbe

estimatedfromtheavailabledata).

Verycommon

≥1/10) Bloodandlymphatic

systemdisorder Myelosuppression(leucopenia,

granulocytopenia,neutropenia,febrile

neutropenia,thrombocytopenia,anaemia).

Haemorrhageandtissuehypoxia(asa

resultofmyelosuppression)mayoccur.

Highdosesofepirubicinhavebeensafely

administeredinalargenumberof

untreatedpatientshavingvarioussolid

tumoursandhascausedadverseevents

whicharenodifferentfromthoseseenat

conventionaldoseswiththeexceptionof

reversibleservereneutropenia(<500

neutrophils/mm³for<7days)which

occurredinthemajorityofpatients.Only

fewpatientsrequiredhospitalisationand

supportivetherapyforsevereinfectious

complicationsathighdoses.

Renalandurinary

disorders Chromaturie(urineredcoloured)

Skinandsubcutaneous

tissuedisorders Alopecia,normallyreversible,appearsin

60-90%oftreatedcases;itisaccompanied

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Common

≥1/100to

≤1/10) Gastrointestinaldisorders Nausea,vomiting,diarrhoea,whichcan

resultindehydration,lossofappetiteand

abdominalpain.Oesophagitisand

hyperpigmentationoftheoralmucosamay

alsooccur.

Skinandsubcutaneous

tissuedisorders Hotflushes

Injury,poisoningand

proceduralcomplications Chemicalcystitis,sometimes

haemorrhagic,hasbeenobserved

followingintravesicaladministration.

Generaldisordersand

administrationsite

conditions Mucositis–mayappear5-10daysafter

thestartoftreatment,andusuallyinvolves

stomatitiswithareasofpainfulerosions,

ulcerationandbleeding,mainlyalongthe

sideofthetongueandthesublingual

mucosa.

Rednessalongtheinfusionvein.Local

phlebitis,phlebosclerosis.Localpainand

tissuenecrosis(followingaccidental

paravenousinjection)mayoccur.

Immunesystemdisorders Allergicreactionsfollowingintravesical

administration.

Uncommon( ≥

1/1,000to

<1/100) Skinandsubcutaneous

tissuedisorders Hyperpigmentationoftheskinandnails.

Skinreddening.

Vasculardisorders Thrombophlebitis

Generaldisordersand

administrationsite

conditions Headache

Immunesystemdisorders Sensitivitytolightorhypersensitivityin

thecaseofradiotherapy(“recall

phenomenon”).

Rare(<1/10,000

to<1/1,000) Investigations Increasedtransaminaselevels

Cardiacdisorders Cardiotoxicity(ECGchanges,tachycardia,

arrhythmia,cardiomyopathy,congestive

heartfailure(dyspnoea,oedema,

enlargementoftheliver,ascites,

pulmonaryoedema,pleuraleffusions,

galloprhythm),ventriculartachycardia,

bradycardia,AVblock,bundle-branch

block(seesection4.4).

Skinandsubcutaneous

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4.9Overdose

Veryhighsingledosesofepirubicinmaybeexpectedtocauseacutemyocardialdegenerationwithin24hoursand

severemyelosuppressionwithin10-14days.Treatmentshouldaimtosupportthepatientduringthisperiodandshould

utilisesuchmeasuresasantibiotics,bloodtransfusionandreversebarriernursing.Delayedcardiacfailurehasbeen

seenwiththeanthracyclinesupto6monthsaftertheoverdose.Patientsshouldbeobservedcarefullyandshould,if

signsofcardiacfailurearise,betreatedalongconventionallines.Epirubicinisnotdialyzable.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antineoplasticagent.ATCcode:L01DB03

Epirubicinisacytotoxicactiveantibioticfromtheanthracyclinegroup.

ThemechanismofactionofepirubicinisrelatedtoitsabilitytobindtoDNA.Cellculturestudieshaveshownrapid

cellpenetration,localisationinthenucleusandinhibitionofnucleicacidsynthesisandmitosis.Epirubicinhasproven

tobeactiveonawidespectrumofexperimentaltumoursincludingL1210andP388leukaemias,sarcomasSA180

(solidandasciticforms),B16melanoma,mammarycarcinoma,Lewislungcarcinomaandcoloncarcinoma38.Ithas

alsoshownactivityagainsthumantumourstransplantedintoathymicnudemice(melanoma,mammary,lung,prostatic

andovariancarcinomas).

5.2Pharmacokineticproperties

Inpatientswithnormalandhepaticandrenalfunction,plasmalevelsafterintravenousinjectionof60-150mg/m²ofthe

drugfollowatri-exponentialdecreasingpatternwithaveryfastfirstphaseandaslowterminalphasewithameanhalf-

lifeofabout40hours.Thesedosesarewithinthelimitsofpharmacokineticlinearitybothintermsofplasmaclearance

valuesandmetabolicpathway.Between60and120mg/m²thereisanextensivelinearpharmacokinetic,150mg/m²is

atthemarginofdoselinearity.Themajormetabolitesthathavebeenidentifiedareepirubicinol(13-OHepirubicin)and

Neoplasmsbenign,

malignantandunspecified

(includingcystsand

polyps) Secondaryactuemyeloidleukaemiawith

orwithoutapre-leukaemicphase,in

patientstreatedwithepirubicinin

combinationwithDNA-damaging

antineoplasticagents.Theseleukaemias

haveashort(1-3year)latency.

Immunesystemdisorders Anaphylaxis(anaphylactic/anaphylactiod

reactionswithorwithoutshockincluding

skinrash,pruritus,feverandchills)

Generaldisordersand

administrationsite

conditions Fever,chills,dizziness,hyperuricaemia(as

aresultofrapidlysisofneoplasticcells).

Hyperpyrexia,malaise,weaknesshave

alsobeenreported.

Reproductivesystemand

breastdisorders Amenorrhea,azoospermia

Frequency

Unknown Infectionsandinfestations Fever,infections,pneumonia,sepsisand

septicshockmayoccurasaresultof

myelosuppression.

Vasculardisorders Coincidentalcasesofthromboembolic

events(includingpulmonaryembolism[in

isolatedcaseswithfataloutcome])have

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Inpharmacokineticstudiesofpatientswithcarcinomainsituofthebladdertheplasmalevelsofepirubicinafter

intravesicalinstillationaretypicallylow(<10mg/ml).Asignificantsystemicresorptioncanthereforenotbeassumed.

Inpatientswithlesionsofthemucosaofthebladder(e.g.tumour,cystitis,operations),ahigherresorptionratecanbe

expected.

The4’-O-glucuronidationdistinguishesepirubicinfromdoxorubicinandmayaccountforthefastereliminationof

epirubicinanditsreducedtoxicity.Plasmalevelsofthemainmetabolite,the13-OHderivative(epirubicinol)are

consistentlylowerandvirtuallyparallelthoseoftheunchangeddrug.

Epirubiciniseliminatedmainlythroughtheliver,highplasmaclearancevalues(0.91/min)indicatethatthisslow

eliminationisduetoextensivetissuedistribution.Urinaryexcretionaccountsforapproximately9-10%ofthe

administereddosein48hours.

Biliaryexcretionrepresentsthemajorrouteofelimination,about40%oftheadministereddosebeingrecoveredinthe

bilein72hours.Thedrugdoesnotcrossthebloodbrainbarrier.

5.3Preclinicalsafetydata

Followingrepeateddosingwithepirubicin,thetargetorgansinrat,rabbitanddogwerethehaemolymphopoietic

system,GItract,kidney,liverandreproductiveorgans.Epirubicinwasalsocardiotoxicintherat,rabbitanddog.

Epirubicin,likeotheranthracyclines,wasmutagenic,genotoxic,embryotoxicandcarcinogenicinrats.

Nomalformationswereseeninratsorrabbits,butlikeotheranthracyclinesandcytotoxicdrugs,epirubicinmustbe

consideredpotentiallyteratogenic.

Alocaltolerancestudyinratsandmiceshowedextravasationofepirubicincausestissuenecrosis.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

SodiumChloride

WaterforInjections

HydrochloricacidforpHadjustment

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3ShelfLife

Shelflifebeforeopening2years.

AfterfirstpenetrationofthestoppertheEpirubicinHydrochloride2mg/mlsolutionmaybestoredupto24hoursat2

to8ºCintheabsenceoflight.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediatelyafterfirstpenetrationoftherubber

stopperand/ordilution.Ifnotusedimmediately,in-usestoragetimesandconditionspriortousearetheresponsibility

oftheuserandwouldnormallynotbemorethan24hoursat2to8ºC,unlesspenetration/dilutionhastakenplacein

controlledandvalidatedasepticconditions.

Fromachemicalandphysicalpointofview,theproductshouldbeusedimmediatelyafterdilution.Anyunusedportion

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6.4Specialprecautionsforstorage

Storeinarefrigerator(2ºC-8ºC).

Keepthevialintheoutercartoninordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Epirubicin2mg/mlsolutionforinjectionsissuppliedinclear,typeIborosilicateglassvials,forparenteraluse,with

chlorobutylfacedstoppersandaluminiumsealswithflip-off,containing5ml,10ml,25ml,50mlor100mlofsterile

solutionofEpirubicinhydrochloride2mg/ml.

Packsizes:

Glassvialscontaining5ml,10ml,25ml,50mland100mlsuppliedinthefollowingpacksizes:

1x5ml,1x10ml,1x25ml,1x50ml,1x100ml.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Theinjectionsolutioncontainsnopreservativeandanyunusedportionofthevialshouldbediscardedimmediately.

Epirubicin2mg/mlSolutionforInjectioniscompatiblewithdextrose5%andsodiumchloride0.9%.

Guidelinesforthesafehandlinganddisposalofantineoplasticagents:

1.Ifaninfusionsolutionistobeprepared,thisshouldbeperformedbytrainedpersonnelunderasepticconditions.

2.Preparationofaninfusionsolutionshouldbeperformedinadesignatedasepticarea.

3.Adequateprotectivedisposablegloves,goggles,gownandmaskshouldbeworn.

4.Precautionsshouldbetakentoavoidthemedicinalproductaccidentallycomingintocontactwiththeeyes,irrigate

withlargeamountsofwaterand/or0.9%sodiumchloridesolution.Thenseekmedicalevaluationbyaphysician.

5.Incaseofskincontact,thoroughlywashtheaffectedareawithsoapandwaterorsodiumbicarbonatesolution.

However,donotabradetheskinbyusingascrubbrush.Alwayswashhandsafterremovinggloves.

6.Spillageorleakageshouldbetreatedwithdilutesodiumhypochlorite(1%availablechlorine)solution,preferablyby

soaking,andthenwater.Allcleaningmaterialsshouldbedisposedofasdetailedbelow.

7.Pregnantstaffshouldnothandlethecytotoxicpreparation.

8.Adequatecareandprecautionsshouldbetakeninthedisposalofitems(syringes,needlesetc)usedtoreconstitute

and/ordilutecytotoxicmedicinalproducts.Anyunusedproductorwastematerialshouldbedisposedofinaccordance

withlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

Genepharm(Europe)TradingLtd

ElGrecoHouse

20QueenFredericaSt.

1066Nicosia

Cyprus

Irish Medicines Board

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Date Printed 20/08/2010 CRN 2085779 page number: 11

PA1658/2/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:3April2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 20/08/2010 CRN 2085779 page number: 12