EPIRUBICIN MARTINDALE PHARMA

Main information

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

Documents

Localization

  • Available in:
  • EPIRUBICIN MARTINDALE PHARMA
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0361/023/001
  • Authorization date:
  • 02-10-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0361/023/001

CaseNo:2045415

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

MartindalePharmaceuticalsLtd

BamptonRoad,HaroldHill,Romford,RM38UG,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

EpirubicinMartindalePharma2mg/mlSolutionforInjection/Infusion

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom02/10/2009until01/10/2014.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EpirubicinMartindalePharma2mg/mlSolutionforInjection/Infusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmillilitreofsolutionforinjection/infusioncontains2mgEpirubicinhydrochloride.

Each5mlvialcontainsatotalcontentofEpirubicinhydrochlorideof10mg.

Each10mlvialcontainsatotalcontentofEpirubicinhydrochlorideof20mg.

Each25mlvialcontainsatotalcontentofEpirubicinhydrochlorideof50mg.

Each50mlvialcontainsatotalcontentofEpirubicinhydrochlorideof100mg.

Each100mlvialcontainsatotalcontentofEpirubicinhydrochlorideof200mg.

Excipient:containssodium3.54mg/ml(0.154mmol)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

SolutionforInjection/Infusion

Aclearredsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Epirubicinisusedinthetreatmentofarangeofneoplasticconditionsincluding:

Carcinomaofthebreast

Advancedovariancancer

Gastriccancer

Smallcelllungcancer

Whenadministeredintravesically,epirubicinhasbeenshowntobebeneficialinthetreatmentof:

Papillarytransitionalcellcarcinomaofthebladder

Carcinoma-in-situ

Intravesicalprophylaxisofrecurrencesofsuperficialbladdercarcinomafollowingtransurethralresection.

4.2Posologyandmethodofadministration

Epirubicinisforintravenousorintravesicaluseonly.

Thesafetyandefficacyofepirubicininchildrenhasnotbeenestablished.

Intravenousadministration

Itisadvisabletoadministerepirubicinviathetubingofafree-runningintravenoussalineinfusionaftercheckingthat

theneedleisproperlyplacedinthevein.Careshouldbetakentoavoidextravasation(seesection4.4).Incaseof

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Conventionaldose

Whenepirubicinisusedasasingleagent,therecommendeddosageinadultsis60-90mg/m 2

bodysurfacearea.

Epirubicinshouldbeinjectedintravenouslyover3-5minutes.Thedoseshouldberepeatedat21-dayintervals,

dependinguponthepatient’shaematologicalstatusandbonemarrowfunction.

Ifsignsoftoxicity,includingsevereneutropenia/neutropenicfeverandthrombocytopeniaoccur(whichcouldpersistat

day21),dosemodificationorpostponementofthesubsequentdosemayberequired.

Highdose

Epirubicinasasingleagentforthehighdosetreatmentoflungcancershouldbeadministeredaccordingtothe

followingregimens:

Smallcelllungcancer(previouslyuntreated):120mg/m 2

day1,every3weeks.

Forhighdosetreatment,epirubicinmaybegivenasanintravenousbolusover3-5minutesorasaninfusionofupto30

minutesduration.

BreastCancer

Intheadjuvanttreatmentofearlybreastcancerpatientswithpositivelymphnodes,intravenousdosesofepirubicin

rangingfrom100mg/m 2

(asasingledoseonday1)to120mg/m 2

(intwodivideddosesondays1and8)every3-4

weeks,incombinationwithintravenouscyclophosphamideand5-fluorouracilandoraltamoxifen,arerecommended.

Lowerdoses(60-75mg/m 2

forconventionaltreatmentand105-120mg/m 2

forhighdosetreatment)arerecommended

forpatientswhosebonemarrowfunctionhasbeenimpairedbypreviouschemotherapyorradiotherapy,byage,or

neoplasticbonemarrowinfiltration.Thetotaldosepercyclemaybedividedover2-3successivedays.

Thefollowingdosesofepirubicinarecommonlyusedinmonotherapyandcombinationchemotherapyforvarious

tumours,asshown:

DosesgenerallygivenDay1orDay1,2and3at21-dayintervals

Combinationtherapy

Ifepirubicinisusedincombinationwithothercytotoxicproducts,thedoseshouldbereducedaccordingly.Commonly

useddosesareshowninthetableabove.

Impairedliverfunction

Themajorrouteofeliminationofepirubicinisthehepatobiliarysystem.Inpatientswithimpairedliverfunctionthe

doseshouldbereducedbasedonserumbilirubinlevelsasfollows:

SerumBilirubin DoseReduction

24-51µmol/l 50%

CancerIndication EpirubicinDose(mg/m 2

Monotherapy CombinationTherapy

Advancedovariancancer 60-90 50-100

Gastriccancer 60-90 50

SCLC 120 120

Bladdercancer 50mg/50mlor80mg/50ml

(carcinomainsitu)Prophylaxiz:

50mg/50mlweeklyfor4weeks

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Impairedrenalfunction

Moderaterenalimpairmentdoesnotappeartorequireadosereductioninviewofthelimitedamountofepirubicin

excretedbythisroute.However,dosageadjustmentmaybenecessaryinpatientswithserumcreatinine>5mg/dL.

Intravesicaladministration

Epirubicincanbegivenbyintravesicaladministrationforthetreatmentofsuperficialbladdercancerandcarcinoma-in-

situ.Itshouldnotbegivenintravesicallyforthetreatmentofinvasivetumoursthathavepenetratedthebladderwall,

systemictherapyorsurgeryismoreappropriateinthesesituations(seesection4.3).Epirubicinhasalsobeen

successfullyusedintravesicallyasaprophylacticagentaftertransurethralresectionofsuperficialtumourstoprevent

recurrence.

Forthetreatmentofsuperficialbladdercancerthefollowingregimenisrecommended,usingthedilutiontablebelow:

8weeklyinstillationsof50mg/50ml(dilutedwithsalineorwaterforinjection).

Iflocaltoxicityisobserved:Adosereductionto30mg/50mlisadvised.

Carcinoma-in-situ:Upto80mg/50ml(dependingonindividualtolerabilityofthepatient)

Forprophylaxis:4weeklyadministrationsof50mg/50mlfollowedby11monthlyinstillationsatthesamedose.

DILUTIONTABLEFORBLADDERINSTILLATIONSOLUTIONS

Thesolutionshouldberetainedintravesicallyfor1-2hours.Toavoidunduedilutionwithurine,thepatientshouldbe

instructednottodrinkanyfluidinthe12hourspriortoinstillation.Duringtheinstillation,thepatientshouldberotated

occasionallyandshouldbeinstructedtovoidurineattheendoftheinstillationtime.

Forinstructionsondilutionoftheproductbeforeadministrationseesection6.6.

4.3Contraindications

Epirubiciniscontraindicatedin:

Patientswhohavedemonstratedhypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Patientswithmarkedmyelosuppressioninducedbyprevioustreatmentwitheitherotheranti-neoplasticagentsor

radiotherapy.

Patientstreatedwithmaximalcumulativedosesofotheranthracyclinessuchasdoxorubicinordaunorubicin.

Patientswithcurrentorprevioushistoryofcardiacimpairment(including4 th

degreemuscularheartfailure,acute

heartattackandpreviousheartattackwhichledto3 rd

and4 th

degreemuscularheartfailure,acuteinflammatory

heartdiseases,arrhythmiawithserioushaemodynamicconsequences).

Patientswithacutesystemicinfections

Lactation.

Forintravesicaladministration,epirubiciniscontraindicatedin:

Urinarytractinfections

Invasivetumourspenetratingthebladder

Catheterisationproblems

Vesicalinflammation

Largevolumeofresidualurine

Doseepirubicin

required Volumeof2mg/ml

epirubicininjection Volumeofdiluent

waterforinjectionor

0.9%sterilesaline Totalvolumefor

bladderinstallation

30mg 15ml 35ml 50ml

50mg 25ml 25ml 50ml

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4.4Specialwarningsandprecautionsforuse

Epirubicinshouldonlybeadministeredunderthesupervisionofaqualifiedphysicianwhoisexperiencedintheuseof

chemotherapeuticagents.Diagnosticandtreatmentfacilitiesshouldbereadilyavailableformanagementoftherapyand

possiblecomplicationsduetomyelosuppression,especiallyfollowingtreatmentwithhigherdosesofepirubicin.

Epirubicincanhavegenotoxiceffects.Therefore,malepatientstreatedwithepirubicinareadvisednottofatherachild

duringandupto6monthsaftertreatmentandtoseekadviceonconservationofspermpriortotreatmentbecauseofthe

possibilityofinfertilityduetotherapywithepirubicin.

Womenshouldnotbecomepregnantduringtreatmentwithepirubicin.Menandwomenshoulduseaneffectivemethod

ofcontraceptionduringtreatmentandforsixmonthsthereafter.

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/mm 3

)is

experiencedinveryfewpatients,evenfollowinghighdosesofepirubicin.

Patientsmusthaveadequatelyrecoveredfromseverestomatitisormucositisbeforestartingtreatmentwithepirubicin.

Inestablishingthemaximalcumulativedoseofepirubicin,considerationshouldbegiventoanyconcomitanttherapy

withpotentiallycardiotoxicmedicinalproducts.Acumulativedoseof900-1000mg/m 2

shouldonlybeexceededwith

extremecautionwithbothconventionalandhighdosesofepirubicin.Abovethisleveltheriskofirreversible

congestiveheartfailureincreasesgreatly.AnECGisrecommendedbeforeandaftereachtreatmentcycle.Alterations

intheECGtracing,suchasflatteningorinversionoftheT-wave,depressionoftheS-Tsegment,ortheonsetof

arrhythmias,generallytransientandreversible,neednotnecessarilybetakenasindicationstodiscontinuetreatment.

Withcumulativedoses<900mg/m 2

,thereisevidencethatcardiactoxicityrarelyoccurs.However,cardiacfunction

mustbecarefullymonitoredduringtreatmenttominimisetheriskofheartfailureofthetypedescribedforother

anthracyclines.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,especiallyinpatientswithriskfactorsforincreasedcardiactoxicity.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

ItisnotrecommendedthatEpirubicinhydrochloridebemixedwithothermedicinalproducts.However,epirubicincan

beusedincombinationwithotheranti-canceragents.

Druginteractionswithepirubicinhavebeenobservedwithcimetidine,dexverapamil,dexrazoxane,docetaxel,

interferon

,paclitaxelandquinine.

Dexverapamilmayalterthepharmacokineticsofepirubicinandpossiblyincreaseitsbonemarrowdepressanteffects.

Prioradministrationofhigherdoses(900mg/m 2

and1200mg/m 2

)ofdexrazoxanemayincreasethesystemicclearance

ofepirubicinandresultinadecreaseinAUC.

Onestudyfoundthatdocetaxelmayincreasetheplasmaconcentrationsofepirubicinmetaboliteswhenadministered

immediatelyafterepirubicin.

Theco-administrationofinterferon

maycauseareductioninboththeterminaleliminationhalf-lifeandthetotal

clearanceofepirubicin.

Paclitaxelmayaffectthepharmacokineticsofepirubicinanditsmetabolite,epirubicinol.Inonestudy,haematological

toxicitywasgreaterwhenpaclitaxelwasadministeredbeforeepirubicincomparedwithafterepirubicin.

Onestudyhasshownthatpaclitaxelclearanceisreducedbyepirubicin.

Quininemayacceleratetheinitialdistributionofepirubicinfrombloodintothetissuesandmayhaveaninfluenceon

theredbloodcellspartitioningofepirubicin.

Cimetidine400mgb.i.dgivenpriortoepirubicin100mg/m 2

every3weeksledtoa50%increaseinepirubicinAUC

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

bloodflowwerenotreduced,soresultsarenotexplainedbyreducedcytochromeP-450activity.

Epirubicinusedincombinationwithothercytotoxicagentsmayresultinadditivemyelotoxicity.

Thepossibilityofamarkeddisturbanceofhaematopoiesisneedstobekeptinmindwitha(pre-)treatmentwith

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

diphenylhydantoin,amidopyrine-derivate,antiretroviralagents).

Thepotentialriskofcardiotoxicitymayincreaseinpatientswhohavereceivedconcomitantcardiotoxicagents(e.g.5-

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

Ifepirubicinisusedconcomitantlywithothermedicinalproductsthatmaycauseheartfailure,e.g.calciumchannel

blockers,thencardiacfunctionmustbemonitoredthroughoutthecourseoftreatment.

Epirubicinismainlymetabolisedintheliver;eachconcomitantmedicationwhichaffectshepaticfunctioncanalso

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Thisproductisgenerallynotrecommendedincombinationwithliveattenuatedvaccines.

4.6Pregnancyandlactation

Thereisnoconclusiveinformationastowhetherepirubicinmayadverselyaffecthumanfertilityorcauseteratogenesis.

Experimentaldata,however,suggestthatepirubicinmayharmthefoetus.Likemostotheranti-canceragents,

epirubicinhasshownmutagenicandcarcinogenicpropertiesinanimals.Bothmenandwomenreceivingepirubicin

shouldbeinformedofthepotentialriskofadverseeffectsonreproduction.Womenofchildbearingpotentialshouldbe

fullyinformedofthepotentialhazardtothefoetusandthepossibilityofgeneticcounsellingshouldbeconsideredif

theybecomepregnantduringepirubicintherapy.Incancerchemotherapy,epirubicinshouldnotbeusedinpregnant

womenorwomenofchildbearingpotentialwhomightbecomepregnantunlessthepotentialbenefitstothemother

outweighthepossibleriskstothefoetus.

Breastfeedingmustbediscontinuedbeforeandduringtherapywithepirubicin.

4.7Effectsonabilitytodriveandusemachines

Therehavebeennoreportsofparticularadverseeventsrelatingtotheeffectsonabilitytodriveandtousemachines.

Epirubicinmaycauseepisodesofnauseaandvomiting,whichcantemporarilyleadtoanimpairmentofabilitytodrive

oroperatemachines.

4.8Undesirableeffects

Theestimationoffrequency: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);notknown(cannotbeestimatedfromtheavailabledata).

Investigations

Rare:Increasedtransaminaselevels.

Cardiacdisorders

Rare:Cardiotoxicity(ECGchanges,tachycardia,arrhythmia,cardiomyopathy,congestiveheartfailure(dyspnoea,

oedema,enlargementoftheliver,ascites,pulmonaryoedema,pleuraleffusion,galloprhythm),ventriculartachycardia,

bradycardia,AVblock,bundle-branchblock)(seesection4.4).

Bloodandlymphaticsystemdisorder

Frequency unknown: Myelosuppression (leukopenia, granulcytopenia, neutropenia, febril neutropenia,

thrombocytopenia,anaemia),Hemorrhagiaandtissuehypoxia(asaresultofmyelosuppression)mayoccur.Highdoses

ofepirubicinhavebeensafelyadministeredinalargenumberofuntreatedpatientshavingvarioussolidtumoursand

havecausedadverseeventswhicharenodifferentfromthoseseenatconventionaldoseswiththeexceptionof

reversiblesevereneutropenia(<500neutrophils/mm 3

for<7days)whichoccurredinthemajorityofpatients.Only

fewpatientsrequiredhospitalisationandsupportivetherapyforsevereinfectiouscomplicationsathighdoses.

Gastrointestinaldisorders

Common:Nausea,vomiting,diarrhoea,whichcanresultindehydration,lossofappetiteandabdominalpain.

Oesophagitisandhyperpigmentationoftheoralmucosamayalsooccur.

Skinandsubcutaneoustissuedisorders

Verycommon:Alopecia,normallyreversible,appearsin60-90%oftreatedcases;itisaccompaniedbylackofbeard

growthinmales.

Common:Hotflushes.

Uncommon:Hyperpigmentationofskinandnails.Skinreddening.

Rare:Urticaria.

Metabolismandnutritiondisorders

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Infectionsandinfestations

Frequencyunknown:Fever,infections,pneumonia,sepsisandsepticshockmayoccurasaresultofmyelosuppression.

Injury,poisoningandproceduralcomplications

Common:Chemicalcystitis,insomecaseshaemorrhagic,isobservedfollowingintravesicaladministration.

Neoplasmsbenign,malignantandunspecified(includingcystsandpolyps)

Rare:Secondaryacutemyeloidleukaemiawithorwithoutapre-leukaemicphaseinpatientstreatedwithepirubicinin

combinationwithDNA-damagingantineoplasticagents.Theseleukaemia’shaveshort(1-3years)latency.

Vasculardisorders

Uncommon:Thrombophlebitis.

Frequencyunknown:Coincidentalcasesofthromboembolicevents(includingpulmonaryembolism(inisolatedcases

withfataloutcome))haveoccurred.

Generaldisordersandadministrationsiteconditions

Common:Mucositis,mayappear5-10daysafterthestartoftreatmentandusuallyinvolvesstomatitiswithareasof

painfulerosions,ulcerationandbleedings,mainlyalongthesideofthetongueandthesublingualmucosa.Redness

alongtheinfusionvein.Localphlebitis,phlebosclerosis,Localpainandtissuenecrosismayoccur(following

accidentalparavenousinjection).

Uncommon:Headache.

Rare:Fever,chills,dizziness,hyperpyrexia,malaise,weakness.

Immunesystemdisorders

Common:Allergicreactionsafterintravesicaladministration.

Uncommon:Photosensitivityorhypersensitivityincaseofradiotherapy(“recallphenomenon”).

Rare:Anaphylaxis(anaphylaxis/anaphylactoidreactionswithorwithoutshockincludingskinrash,pruritus,feverand

chills).

Reproductivesystemandbreastdisorders

Rare:Amenorrhea,azoospermi.

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.Epirubicinhasproved

tobeactiveonawidespectrumofexperimentaltumoursincludingL1210andP388leukaemias,sarcomasSA180

(solidandasciticforms),B16melanoma,mammarycarcinoma,Lewislungcarcinomaandcoloncarcinoma38.Ithas

alsoshownactivityagainsthumantumourstransplantedintoathymicnudemice(melanoma,mammary,lung,prostatic

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5.2Pharmacokineticproperties

Inpatientswithnormalhepaticandrenalfunction,plasmalevelsafterintravenousinjectionof60-150mg/m 2

ofthe

medicinalproductfollowatri-exponentialdecreasingpatternwithaveryfastfirstphaseandaslowterminalphasewith

ameanhalf-lifeofabout40hours.Thesedosesarewithinthelimitsofpharmacokineticlinearitybothintermsof

plasmaclearancevaluesandmetabolicpathway.Between60and120mg/m 2

thereisanextensivelinear

pharmacokinetic,150mg/m 2

isatthemarginofdoselinearity.Themajormetabolitesthathavebeenidentifiedare

epirubicinol(13-OHepirubicin)andglucuronidesofepirubicinandepirubicinol.

Inpharmacokineticstudiesofpatientswithcarcinomainsituofthebladdertheplasmalevelsofepirubicinafter

intravesicalinstillationaretypicallylow(<10ng/ml).Asignificantsystemicresorptioncanthereforenotbeassumed.

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

expected.

The4’-O-glucuronidationdistinguishesepirubicinfromdoxorubicinandmayaccountforthefastereliminationof

epirubicinanditsreducedtoxicity.Plasmalevelsofthemainmetabolite,the13-OHderivative(epirubicinol)are

consistentlylowerandvirtuallyparallelthoseoftheunchangedactivesubstance.

Epirubiciniseliminatedmainlythroughtheliver;highplasmaclearancevalues(0.9l/min)indicatethatthisslow

eliminationisduetoextensivetissuedistribution.Urinaryexcretionaccountsforapproximately9-10%ofthe

administereddosein48hours.

Biliaryexcretionrepresentsthemajorrouteofelimination,about40%oftheadministereddosebeingrecoveredinthe

bilein72hours.Theactivesubstancedoesnotcrossthebloodbrainbarrier.

5.3Preclinicalsafetydata

Followingrepeateddosingwithepirubicin,thetargetorgansinrat,rabbitanddogwerethehaemolymphopoietic

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

Epirubicin,likeotheranthracyclines,wasmutagenic,genotoxic,embryotoxicandcarcinogenicinrats.

Nomalformationswereseeninratsorrabbits,butlikeotheranthracyclinesandcytotoxicactivesubstances,epirubicin

mustbeconsideredpotentiallyteratogenic.

Alocaltolerancestudyinratsandmiceshowedextravasationofepirubicincausestissuenecrosis.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumchloride

Hydrochloricacid(forpH-adjustment)

Waterforinjections.

6.2Incompatibilities

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6.3ShelfLife

Beforefirstopening:2years

Inuse:

Epirubicinhydrochloridemaybefurtherdiluted,underasepticconditions,inGlucose5%orSodiumChloride0.9%

andadministeredasanintravenousinfusion.Theinfusionsolutionischemicallyandphysicallystableforupto24

hours,whenpreparedunderfullasepticallycontrolledconditionsinpolypropylenesyringesandinPVCinfusionbags

at2to8ºC.

Howeverfromamicrobiologicalpointofview,itisrecommendedthattheproductshouldbeusedimmediately.Ifnot

usedimmediately,in-usestoragetimesandconditionspriortousearetheresponsibilityoftheuserandwouldnormally

notbelongerthan24hoursat2to8ºC.

6.4Specialprecautionsforstorage

Storeinarefrigerator(2 °

C–8 °

Forstorageconditionsafterfirstopeningofthevialandofthedilutedmedicinalproduct,seesection6.3.

Keepthevialintheoutercartoninordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Epirubicinhydrochlorideissuppliedinclearglassvials(TypeIPhEur)withfluoropolymercoatedchlorobutylrubber

stoppers(PhEur).

Packsizes:

1x5mlvial(10mg/5ml)

1x10mlvial(20mg/10ml)

1x25mlvial(50mg/25ml)

1x50mlvial(100mg/50ml)

1x100mlvial(200mg/100ml)

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

EpirubicinhydrochloridemaybefurtherdilutedinGlucose5%orSodiumChloride0.9%andadministeredasan

intravenousinfusion.Forinformationonthestabilityoftheinfusionsolutionspleaserefertosection6.3.

Theinjectionsolutioncontainsnopreservativeandanyunusedportionofthevialshouldbediscardedimmediately.

Guidelinesforthesafehandlinganddisposalofantineoplasticagents:

1.Ifaninfusionsolutionistobeprepared,thisshouldbeperformedbytrainedpersonnelunderasepticconditions.

2.Preparationofaninfusionsolutionshouldbeperformedinadesignatedasepticarea.

3.Adequateprotectivedisposablegloves,goggles,gownandmaskshouldbeworn.

4.Precautionsshouldbetakentoavoidthemedicinalproductaccidentallycomingintocontactwiththeeyes.Inthe

eventofcontactwiththeeyes,irrigatewithlargeamountsofwaterand/or0.9%sodiumchloridesolution.Then

seekmedicalevaluationbyaphysician.

5.Incaseofskincontact,thoroughlywashtheaffectedareawithsoapandwaterorsodiumbicarbonatesolution.

However,donotabradetheskinbyusingascrubbrush.Alwayswashhandsafterremovinggloves.

6.Spillageorleakageshouldbetreatedwithdilutesodiumhypochlorite(1%availablechlorine)solution,

preferablybysoaking,andthenwater.Allcleaningmaterialsshouldbedisposedofasdetailedbelow.

Irish Medicines Board

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Date Printed 05/10/2009 CRN 2045415 page number: 10

8.Adequatecareandprecautionsshouldbetakeninthedisposalofitems(syringes,needlesetc)usedto

reconstituteand/ordilutecytotoxicmedicinalproducts.Anyunusedproductorwastematerialshouldbedisposed

ofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

MartindalePharmaceuticalsLimited

BamptonRoad

HaroldHill

Romford

Essex

RM38UG

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA361/23/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation;2ndOctober2009

Irish Medicines Board

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Date Printed 05/10/2009 CRN 2045415 page number: 11