EPIRUBICIN "EBEWE"

Main information

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

Documents

Localization

  • Available in:
  • EPIRUBICIN "EBEWE"
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0754/008/001
  • Authorization date:
  • 17-02-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0754/008/001

CaseNo:2044953

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

Techno-PharmLimited

Pharmapark,Chapelizod,Dublin20,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Epirubicin"EBEWE"2mg/mlconcentrateforsolutionforinfusion

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom24/01/2008until16/02/2011.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

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Date Printed 25/01/2008 CRN 2044953 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Epirubicin"EBEWE"2mg/mlconcentrateforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each1mlconcentrateforsolutionforinfusionandinjectioncontains2mgEpirubicinhydrochloride

Each5mlconcentrateforsolutionforinfusionandinjectioncontains10mgEpirubicinhydrochloride

Each25mlconcentrateforsolutionforinfusionandinjectioncontains50mgEpirubicinhydrochloride

Each50mlconcentrateforsolutionforinfusionandinjectioncontains100mgEpirubicinhydrochloride

Each100mlconcentrateforsolutionforinfusionandinjectioncontains200mgEpirubicinhydrochloride

Forexcipientssee6.1

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion

Theconcentrateisaclearredsolution

4CLINICALPARTICULARS

4.1TherapeuticIndications

Malignantneoplasticdiseases:

Epirubicinhasshownefficacyinbreastcancer.

Thereissomeevidencethatindicateobjectiveresponseinnon-Hodgkin'slymphoma,breast-,ovarian-,gastric-,

lungcancerandleukemias.

IntravesicaladministrationofEpirubicinhasbeenshowntobebeneficialinsuperficialbladdercancer.

4.2Posologyandmethodofadministration

Epirubicinisnotactivewhengivenorallyandshouldnotbeinjectedintramuscularlyorintrathecally.

Itisadvisabletogivethedrugviathetubingofafreely-runningi.v.salineinfusionaftercheckingthattheneedleis

wellplacedinthevein.Thismethodminimisestheriskofdrugextravasationandmakessurethattheveinisflushed

withsalineaftertheadministrationofthedrug.Extravasationofepirubicinfromtheveinduringinjectionmaygive

risetoseveretissuelesions,evennecrosis.Venoussclerosismayresultfrominjectionintosmallvesselsorrepeated

injectionsintothesamevein.Infusionpreparationsaretobepreparedeitherwith0.9%sodiumchlorideorwith5%

glucose.

Thedoselevelusedinmoststudies:WhenEpirubicin"EBEWE"isusedasasingleagent,therecommendeddosagein

adultsis60-90mg/m 2

bodyarea;thedrugshouldbeinjectedi.v.over3-5minutesanddependingonthepatient's

haematomedullarystatus,thedoseshouldberepeatedat21-dayintervals.

Meanwhileepirubicinispreferentiallygivenincombinationwithothercytotoxicdrugs.Inthesecasesthedoseof

epirubicinshouldbeadjustedtothetoxicityoftheothercombinationpartners.Adiminisheddoseofepirubicinof60-

75mg/m2(or105-120mg/m2indoseintensifiedregimens)isgenerallygivenincombinationregimens.

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themajorrouteofeliminationofEpirubicinisthehepatobiliarysystem,thedosageshouldbereducedinpatientswith

impairedliverfunction,inordertoavoidanincreaseofoveralltoxicity.Moderateliverimpairment(bilirubin:1.4-3

mg/100ml)requiresa50%reductionofdose,whilesevereimpairment>3mg/100ml)necessitatesadosereductionof

75%.

Intravesicaladministration:Asaguide50mg/50mlEpirubicindilutedwithsalineordistilledsterilewater.The

solutionshouldberetainedintravesicallyforonehour.Incaseoflocaltoxicity(chemicalcystitis)adosereductionis

advised(30mg/50ml).

4.3Contraindications

Epirubicin"EBEWE"iscontra-indicatedinpatientswithhypersensitivitytotheactivesubstanceandwithmarked

myelosuppressioninducedbyprevioustreatmentwithotherantitumouragentsorbyradiotherapyandinpatients

alreadytreatedwithmaximalcumulativedosesofotheranthracyclinessuchasdoxorubicinordaunorubicin.Thedrug

iscontra-indicatedinpatientswithseveremucositisandinpatientswithacurrentorprevioushistoryofcardiac

impairment(cardiacfailuregradeIV).

4.4Specialwarningsandprecautionsforuse

Epirubicin"EBEWE"shouldbeadministeredonlyunderthesupervisionofaqualifiedphysicianexperiencedin

antiblasticandcytotoxictherapy.

Treatmentwithhighdoseepirubicininparticularrequirestheavailabilityoffacilitiesforthecareofpatientswith

possibleclinicalcomplicationsduetomyelosuppression.

Simultaneoususeofradiationshouldbeavoided.

Initialtreatmentcallsforcarefulbaselinemonitoringofvariouslaboratoryparametersandcardiacfunction.

DuringeachcycleoftreatmentwithEpirubicin"EBEWE",patientsmustbecarefullyandfrequentlymonitored.Red

andwhitebloodcells,neutrophilsandplateletcountsshouldbecarefullyassessedbothbeforeandduringeachcycleof

therapy.Leukopeniaandneutropeniaareusuallytransientbothwithconventionalandhighdoses,reachinganadir

betweenthe10thand14thdayandreturningtonormalvaluesbythe21stday:theyaremoreseverewithhighdose

schedules.Veryfewpatients,evenreceivinghighdoses,experiencethrombocytopenia(<100,000platelets/mm 3

Beforestartingtherapyandifpossibleduringtreatmentliverfunctionshouldbeevaluated(AST,ALT,alkaline

phosphatase,bilirubin).Acumulativedoseof900-1000mg/m 2

shouldnotbeexceeded.Abovethisleveltheriskof

irreversiblecongestivecardiacfailureincreasesgreatly.Thereisobjectiveevidencethatcardiactoxicitymayrarely

occurbelowthisrange.However,cardiacfunctionmustbecarefullymonitoredduringtreatmenttominimisetherisk

ofheartfailureofthetypedescribedforotheranthracyclines.

Heartfailurecanappearevenseveralweeksafterdiscontinuingtreatmentandmayproveunresponsivetospecific

medicaltreatment.Thepotentialriskofcardiotoxicitymayincreaseinpatientswhohavereceivedconcomitant,or

prior,radiotherapytothemediastinalpericardialarea.

Inestablishingthemaximalcumulativedosesofepirubicinanyconcomitanttherapywithpotentiallycardiotoxicdrugs

shouldbetakenintoaccount.

ItisrecommendedthatanECGbeforeandaftertreatmentcycleshouldbecarriedout.AlterationsintheECGtracing,

suchasflatteningorinversionoftheTwave,depressionoftheS-Tsegment,ortheonsetofarrhythmias,generally

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CardiomyopathyinducedbyanthracyclinesisassociatedwithapersistentreductionoftheQRSvoltage,prolongation

beyondnormallimitsofthesystolicinterval(PEP/LVET)andareductionoftheejectionfraction.Cardiacmonitoring

ofpatientsreceivingEpirubicin"EBEWE"treatmentishighlyimportantanditisadvisabletoassesscardiacfunction

bynon-invasivetechniquessuchasECG,echocardiographyand,ifnecessary,measurementofejectionfractionby

radionuclideangiography.

Likeothercytotoxicagents,epirubicinmayinducehyperuricemiaasaresultofrapidlysisofneoplasticcells.Blood

uricacidlevelsshouldthereforebecarefullycheckedsothatthisphenomenonmaybecontrolledpharmacologically.

Epirubicin"EBEWE"mayimpartaredcolourtotheurinefor1-2daysafteradministration.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Epirubicinshouldnotbemixedwithotherdrugs.ButEpirubicincanbeusedincombinationwithotheranti-cancer

drugs.

Cimetidineincreasestheformationoftheactivemetaboliteofebirubicinandtheexposureoftheunchangedepirubicin

bypharmacokineticinteraction.

Epirubicinmustnotbedilutedinalcalineinfusionsolutions(e.g.hydrogencarbonate-solutions).

4.6Pregnancyandlactation

Thereisnoconclusiveinformationastowhetherepirubicinmayadverselyaffecthumanfertilityorcause

teratogenesis.Experimentaldata,however,suggestthatepirubicinmayharmthefoetus.Likemostotheranticancer

agents,epirubicinhasshownmutagenicandcarcinogenicpropertiesinanimals.Thisproductshouldnotnormallybe

administeredtopatientswhoarepregnantortomotherswhoarebreast-feeding.Womenofchild-bearingageshould

takecontraceptivestopreventconceptionand/orreproductionduringandforatleast6monthsaftertreatmentwith

cisplatin.

4.7Effectsonabilitytodriveandusemachines

Therehavebeennoreportsofparticularadverseeventsrelatingtoeffectsonabilitytodriveandtousemachines.

4.8Undesirableeffects

Apartfrommyelosuppressionandcardiotoxicity(describedunderPrecautions)thefollowingadversereactionshave

beendescribed).

Bloodandthelymphaticsystemdisorders:

Highdosesofepirubicinhavebeensafelyadministeredinalargenumberofuntreatedpatientshavingvarioussolid

tumoursandhascausedadverseeventswhicharenodifferentfromthoseseenatconventionaldoseswiththeexception

ofreversiblesevereneutropenia(<500neutrophils/mm 3

for<7days)whichoccurredinthemajorityofpatients.Only

afewpatientshaverequiredhospitalisationandsupportivetherapyforsevereinfectiouscomplicationsathighdoses.

verycommon>10%

Myelosuppression,Granulocytopenia,Leucocytopenia,Thrombocytopenia,Neutropenia

common>1%

Anaemia,hemorhagia,

rare

Theoccurrenceofsecondaryacutemyeloidleukaemiawithorwithoutapre-leukaemicphasehasbeenreportedrarely

inpatientsconcurrentlytreatedwithepirubicininassociationwithDNA-damagingantineoplasticagents.Suchcases

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Immunesystemdisorders:

Rare

Asasequelofmyelosuppression,fever,infections,pneumonia,sepsis,septicshock,haemorrhages,tissuehypoxiamay

occurandmayevenleadtodeath.Fever,sepsis,infectionshyperpyrexia,chillsandurticariahavebeenrarelyreported;

anaphylaxismayoccur.

Labyrinthdisorders:

verycommon>10%

Nausea

Cardiacdisorders:

common>1%

Cardiotoxicity

Gastrointestinaldisorders:

verycommon>10%

mucositismayappear5-10daysafterthestartoftreatmentandusuallyinvolvesstomatitiswithareasofpainful

erosions,mainlyalongthesideofthetongueandonthesublingualmucosa

common>1%

nausea,vomitinganddiarrhoea

Skindisorders:

verycommon>10%

alopecia,normallyreversible,appearsin60-90%oftreatedcases;itisaccompaniedbylackofbeardgrowthinmales.

uncommon>0.1%

hypersensitivityoftheskintolight

pigmentationoftheskin

urticariauncommon

Duringintravesicaladministration,asdrugabsorptionisminimal,systemicsideeffectsarerare;morefrequently

chemicalcystitis,sometimeshaemorrhagic,hasbeenobserved.

4.9Overdose

Veryhighsingledosesofepirubicinmaybeexpectedtocauseacutemyocardialdegenerationwithin24hoursand

severemyelosuppressionwithin10-14days.Treatmentshouldaimtosupportthepatientduringthisperiodandshould

utilisesuchmeasuresasbloodtransfusionsandreversebarriernursing.Delayedcardiacfailurehasbeenseenwiththe

anthracyclinesupto6monthsaftertheoverdosage.Patientsshouldbeobservedcarefullyandshould,ifsignsof

cardiacfailurearise,betreatedalongconventionallines.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCCode:L01DB03

Invitrostudiesshowedthatepirubicinpossessescytotoxicityatleastequivalenttothatofdoxorubicinagainstavariety

ofanimalandhumantumourcelllinesincludingthosederivedfrombreast,liver,lung,gastric,colorectal,squamous

cell,cervical,bladder,ovariancarcinomas,neuroblastomaandleukaemia.

Themechanismofantitumouractionforepirubicinhasnotbeencompletelyelucidated;however,anthracyclinesappear

toformacomplexwithDNAbyintercalationbetweentheDNAstrands,thusinhibitingreplicationandtranscription.

Thisactionmaybeattributed,atleastinpart,tointerferencewithtopoisomerase-DNA'cleavablecomplex'andhelicase

activitybyanthracyclines.ReductiontosemiquinonefreeradicalsmaycausedamagetoDNA,cellmembranelipids

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5.2Pharmacokineticproperties

Followingrapidintravenousadministration,epirubicinundergoestriphasicplasmaelimination.Epirubicinexhibitsa

rapidinitial()distributionphase(t

=1.8to4.8minutes),followedbyanintermediate()phase(t

0.5to2.6

hours)andamuchslower()terminaleliminationphase(t

=15to45hours).

Epirubicinundergoesextensivetissuedistribution;volumeofdistributionvalueswerehighandvariable(13to52

L/kg),butsimilartothosereportedfordoxorubicin.Areaundertheplasmaconcentrationversustimecurvevalues

adjustedfordosewere30to70%higherfordoxorubicinthatepirubicinfollowingsingle-doseintravenous

administration.Followingintravenousadministration,epirubicinisrapidlymetabolisedto2glucuronides,plus

epirubicinoland4aglycones.Epirubiciniseliminatedprimarilyviathehepatobiliarysystem,withapproximately11to

15%ofadoseeliminatedintheurineasunchangeddrugandmetabolites.Patientswithmoderatetoseverehepatic

dysfunctionexhibitedreducedclearanceofepirubicinandelevatedplasmadrugconcentrations.

5.3Preclinicalsafetydata

Inanimalstudiesepirubicinhasbeenshowntoharmthefoetusandismutagenicandcarcinogenic

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumchloride

Hydrochloricacid

Waterforinjections

6.2Incompatibilities

ProlongedcontactwithanysolutionofanalkalinepHshouldbeavoidedasitwillresultinhydrolysisofthedrug.

Epirubicinshouldnotbemixedwithheparinduetochemicalincompatibilitywhichmayleadtoprecipitationwhenthe

drugsareincertainproportions.

Epirubicinconcentrateforsolutionforinfusionmustnotbemixedwithotherpreparationsexceptwiththosementioned

in6.6.

6.3ShelfLife

Unopened:2years

Theproductshouldbeusedimmediatelyafteropening.

6.4Specialprecautionsforstorage

Storeat2 °

Cto8 °

Removesolutionfromvialimmediatelybeforeuse.Fromamicrobiologicalpointofview,theproductshouldbeused

immediatelyafterdilution.Ifnotusedimmediately,in-usestoragetimesandconditionspriortousearethe

responsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2to8°C,unlessdilutionhastakenplacein

controlledandvalidatedasepticconditions.Testsofthedilutedsolutionupto96hoursat2-8°Candroomtemperature

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6.5Natureandcontentsofcontainer

ClearvialsofglassTypeIPhEurwithfluoropolymercoatedhalobutylrubberstoppersandcrimpcapofanominal

capacityof5ml,25ml,50ml,and100ml

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

RecommendedinfusionsolutionsareSodiumChlorideIntravenousInfusion0.9%w/v,GlucoseIntravenousInfusion

5%w/vorSodiumChlorideandGlucoseIntravenousInfusion.

Preparationofsolutionforinfusionmusttakeplaceinasepticconditions.

Thefollowingprotectiverecommendationsaregivenduetothetoxicnatureofthissubstance.

-Personnelshouldbetrainedingoodtechniqueforreconstitutionandhandling.

-Pregnantstaffshouldbeexcludedfromworkingwiththisdrug.

-Personnelhandlingepirubicinshouldwearprotectiveclothing:goggles,gownsanddisposableglovesandmasks.

-Adesignatedareashouldbedefinedforreconstitution(preferablyunderalaminarflowsystem).Theworksurface

shouldbeprotectedbydisposable,plastic-backed,absorbentpaper.

-allitemsusedforreconstitution,administrationorcleaning,includinggloves,shouldbeplacedinhigh-risk,waste-

disposalbagsforhightemperatureincineration.

Accidentalcontactwiththeskinoreyesshouldbetreatedimmediatelybycopiouslavagewithwater,orsoapand

water,orsodiumbicarbonatesolution;medicalattentionshouldbesought.

Spillageorleakageshouldbetreatedwithdilutesodiumhypochlorite(1%availablechlorine)solution,preferablyby

soaking,andthenwater.

Allcleaningmaterialsshouldbedisposedofasindicatedpreviously.

Handleaccordingtotheguidelinesforcytostatics

7MARKETINGAUTHORISATIONHOLDER

TechnopharmLtd

Pharmapark

Chapelizod

Dublin20

8MARKETINGAUTHORISATIONNUMBER

PA754/8/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

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