DOXORUBICIN EBEWE

Main information

  • Trade name:
  • DOXORUBICIN EBEWE
  • Dosage:
  • 2 Mg/Ml
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DOXORUBICIN EBEWE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0789/001/001
  • Authorization date:
  • 22-01-1999
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0789/001/001

CaseNo:2068686

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

EbewePharmaGes.m.b.HNfg.KG

Mondseestrasse11,A-4866Unterach,Austria

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Doxorubicin"Ebewe"2mg/ml,Concentrateforsolutionforinfusion.

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom14/07/2009.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Doxorubicin"Ebewe"2mg/ml,Concentrateforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlcontains2mgdoxorubicinhydrochloride.

Each5mlvialcontains10mgofdoxorubicinhydrochloride.

Each25mlvialcontains50mgofdoxorubicinhydrochloride

Each50mlvialcontains100mgofdoxorubicinhydrochloride

Each100mlvialcontains200mgofdoxorubicinhydrochloride

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion.

Clear,redcolouredsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Doxorubicinisusedinthefollowingindications:softtissueandosteogenicsarcomas,Hodgkin`sdiseaseandnon-

Hodgkin`slymphoma,acutelymphoblasticleukaemia,acutemyeloblasticleukaemia,carcinomasofthethyroid,breast,

ovary,bladder,smallcellbronchogeniccarcinomaandneuroblastoma.

Doxorubicinisusedintravesically forthetreatmentoftransitionalcellcarcinoma,papillarybladdertumoursandcarcinomain

situ.Itshouldnotbeusedforinvasivetumoursofthebladderwhichhavepenetratedthebladderwall,patientswith urinarytract

infectionsorinflammatoryconditionsofthebladder.

4.2Posologyandmethodofadministration

Doxorubicinmaybegivenby

intravenous(bolus)injectionover2-5minutesorascontinuousinfusionintoarunninginfusionofsodiumchloride

0.9%w/vintravenousinjection,dextroseintravenousinjection5%w/vorsodiumchlorideanddextroseintravenous

injection.

Bolusinjectioncauseshigherpeakplasma-concentrationsandthereforeisprobablymorecardiotoxic.

Adultdosage

Monotherapy

Dosagedependsontumortype,cardiacorhepaticfunction,andconcurrentchemotherapy.

Therecommendeddoseassingleagent:Thecommonlyrecommendeddosagescheduleassingleagentis60-75mg/m²

byintravenousinjection,onceeverythreeweeks.Analternativedosescheduleis20mg/m²intravenously,forthree

consecutivedays,onceeverythreeweeks.

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Administrationofdoxorubicininaweeklyregimenhasbeenshowntobeaseffectiveasthe3-weeklyregimenwhilst

reducingcardiactoxicity.Therecommendeddosageis20mg/m²weekly,althoughobjectiveresponseshavebeenseen

withdosesbetween6and12mg/m².

Combinationtherapy

Dosageshouldbedecreasedwhencombinationwithothercytostaticdrugswithanysimilartoxicityisused.

Themaximumcumulativedoseshouldbereducedfrom450mg/m 2

to400mg/m 2

ifapatientreceivedmediastinal

irradiation,hasconcomitantheartdisease,orisalsotreatedwithothercardiotoxic,non-anthracyclineoncolytics.

Dosageadjustmentsinspecificpatientgroups:

Hepaticdysfunction:Dosageshouldbereducedinpatientswithimpairedhepaticfunction.Doxorubicindosageshould

bereducedifthebilirubiniselevatedasfollows:serumbilirubin12to30mg–give½ofthenormaldose,bilirubin>

30mg–give¼ofthenormaldose.

Renaldysfunction:

Ingeneral,impairedrenalfunctiondoesnotrequiredosereduction.

Patientswithcardiacrisk:

Patientsatincreasedriskforcardiotoxicityshouldbeconsideredfortreatmentwitha24hourscontinuousinfusion,

ratherthanbolusinjection.Inthisway,cardiotoxicitymaybelessfrequent,withoutareductionintherapeuticefficacy.

Inthesepatients,theejectionfractionshouldbemeasuredbeforeeachcourse.

Theriskofdevelopmentofcardiomyopathygraduallyincreaseswiththedosage.Acumulativelifetimedoseof450-

550mg/m²shouldnotbeexceeded.

Incaseofpreexistingheartdiseaseorpriorradiotherapytotheheartorthemediastinum,cumulativedosesofmore

than400mgshouldbeavoided(Monitoringofthecardiacfunction–seesection4.4.SpecialWarnings).

Incombinationwithotheroncolyticsdosesof50-75mg/m²areadministered.Myelosuppressionmaybemore

pronouncedbecauseoftheadditiveeffectsofthedrugs.

Dosageinchildren

Dosageforchildrenshouldbeloweredsincetheyhaveanincreasedriskofcardiotoxicityespeciallydelayed

cardiotoxicityandthereforefollow-upcardiacevaluationisrecommended.

Myelotoxicityshouldbeanticipated,withnadirsat10to14daysafterstartoftreatment,butisusuallyfollowedbya

rapidrecoveryduetothelargebonemarrowreserveofchildrenascomparedtoadults.

Superficialbladdercarcinomaandbladdercarcinomainsitu

Therecommendeddosageis50mgin50mlnormalsaline,administeredviaasterilecatheter.Initially,thisdoseis

givenweekly,lateronmonthly.Theoptimaldurationoftreatmenthasnotyetbeendetermined;itrangesfrom6to

12months.

Restrictionsregardingthemaximalcumulativedose,aswithintravenousadministration,donotapplytointravesical

administration,becausesystemicabsorptionofdoxorubicinisnegligible.

Takecareintheadministrationtoavoidthepossiblityofperivenousinfiltrationresultinginlocalnecrosisand

thrombophlebitis.

Doxorubicinmustnotbegivenintrathecallyorintramuscularly,subcutanorbylongterminfusion.(Sincedoxorubicin

isreportedtoformprecipitatesincombinationwithheparinand5-fluorouracil,itshouldnotbemixedwithanyother

drug.)

4.3Contraindications

Doxorubiciniscontra-indicatedinpatientswhohaveamarkedmyelosuppression(e.g.inducedbypreviousanti-

tumourtreatment),inpre-existingoracutecardiacinsufficiencyorinpatientswhohavepreviouslyreceivedthe

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Thepresenceofbucccalulceration;thismaybeprecededbypremonitorybuccalburningsensationsandrepetitionof

treatmentinthepresenceofthissymptomisnotadvised.

Duringpregnancyandbreastfeeding.

Hypersensitivitytodoxorubicin,chemicallyrelatedproductsoranyotherexcipient.

4.4Specialwarningsandprecautionsforuse

Generalprecautions:

Doxorubicinshouldonlybeadministeredunderthesupervisionofaphysicianexperiencedintheuseofchemotherapy.

Itisrecommendedthatthepatientbehospitalisedduringatleastthefirstphaseoftreatmentsincecloseobservationand

laboratorymonitoringisnecessary.Priortotreatmentwithdoxorubicin,cardiacandhepaticfunctionandhaematology

baselinetestsshouldbecarriedout.

Nausea,vomitingandmucositisareoftenextremelysevereandshouldbetreatedappropriately.Doxorubicinshould

notbeadministeredintramuscularlyorsubcutaneously.

Extravasation:

Extravasationresultsinasevereandprogressivetissuenecrosis.Extravasationissignifiedbypainand/oraburning

sensationatthesiteofintravenousadministrationofdoxorubicin.Ifextravasationoccurs,theinjectionshouldbe

terminatedimmediatelyandrestartedinanothervein.Icepacksshouldbeappliedtothesiteofextravasation.Flooding

withnormalsaline,localinfiltrationwithcorticosteroids,orsodiumhydrogencarbonatesolution(8.4%),and

applicationofdimethylsulfoxidehavebeenreportedwithvaryingsuccess.Localapplicationofhydrocortisonecream

1%maybebeneficial.Theadviceoftheplasticsurgeryconsultantshouldbeaskedfor,andwideexcisionofthe

involvedareashouldbeconsidered.

Cardiotoxicity:

Thereisanestablishedriskofdevelopmentofanthracyclineinducedcumulativedosedependentcardiomyopathy,

thereforecumulativedoseof450-550mg/m²shouldnotbeexceeded.Atdosesabovethistheriskofdevelopmentof

cardiacfailureincreasesconsiderably.Reductionofthecumulativedoseisthemostimportantmeansofavoiding

doxorubicincardiotoxicity.Thecardiotoxicityofdoxorubicinmaymanifestastachycardia,ECGchangesorcardiac

failurewhichmayoccursuddenlyuptoseveralmonths/yearsafterdiscontinuationoftreatmentwithoutprecedingECG

changes.Theriskofdevelopingheartfailureincancerpatientstreatedwithdoxorubicinpersiststhroughoutlife.

Cardiacfailureduetodoxorubicinmaybeunresponsivetoconventionaltreatment.

Theriskofcardiotoxicityincreasesinpatientspreviouslytreatedwithmediastinalorpericardialirradiation,inpatients

treatedwithotherorpreviousanthracyclinesand/oranthracenediones,inpatientswithahistoryofcardiacdisease,in

elderlypatients(age>70years)aswellasinchildrenbelow15years.Cardiotoxicitymayoccuratdoseslowerthan

therecommendedcumulativelimit.Thetotalcumulativedoseofdoxorubicintoanindividualpatientshouldtherefore

takeintoaccountanypreviousorconcomitanttreatmentwithotherpotentiallycardiotoxicdrugsortherapysuchas

highdoseIVcyclophosphamide,mitomycinCordacarbazine,otheranthracyclinessuchasdaunorubicin,or

mediastinalorpericardialirradiation.

Acuteseverearrhythmiashavebeenreportedtooccurduringorwithinafewhoursafterdoxorubicinadministration.

ECGchangesmayoccurincludingareductioninthevoltageoftheQRSwave,andaprolongationofthesystolictime

interval,andtheejectionfractionmaybereduced.

Extremecareshouldbetakeninpatientswithexistingheartdisease,suchasarecentmyocardialinfarction,heart

failure,cardiomyopathy,pericarditisordysrhythmias,orinpatientswhohavereceivedothercardiotoxicagentssuchas

cyclophosphamide(seesection4.5).

Monitoringofthecardiacfunction:

Cardiacfunctionshouldbeassessedpriortothestartoftreatmentandshouldbecarefullymonitoredthroughout

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ChangesinECGsuchasdepressionornegativeT-wave,decreaseintheST-segmentorarrhythmiasareusuallysigns

ofanacutebuttransient(reversible)toxiceffectandarenotconsideredindicationsforsuspensionofdoxorubicin

therapy.HoweverapersistentreductionintheamplitudeofQRS-waveandaprolongationofthesystolicintervalare

consideredmoreindicativeofanthracyclineinducedcardiotoxicity.

WhenthevoltageoftheQRSwavedecreasesby30%oratafractionalshorteningof5%itisrecommendedthat

treatmentbestopped.

Theoptimummethodofpredictionofcardiomyopathyisdetectionofareductionoftheleftventricularejection

fraction(LVEF),determinedbyultrasoundoraheartscintigraphy.LVEFinvestigationshouldbeperformedpriorto

treatmentandrepeatedaftereachcumulativedoseof100mg/m²andatanyclinicalsignsofcardiacfailure.Asarule

anabsolutedecreaseof>10%oradecreasebelow50%inpatientswithnormalinitialLVEF-valuesisasignof

impairmentofcardiacfunction.Continuedtreatmentwithdoxorubicininsuchpatientsmustbecarefullyevaluated.

Myelosuppression:

Thehighincidenceofbonemarrowdepressionrequirescarefulhaematologicalmonitoring.Thereisasignificantrisk

ofneutropenia,thrombocytopenia,andanaemiaoccurringlessfrequently.Thenadirisreachedbetween10-14days

afteradministration.Bloodvaluesusuallyreturntonormalwithin21daysafteradministration.Doxorubicintherapy

shouldnotbestartedorcontinuedwhenpolynucleargranulocytecountsarebelow2000/mm 3

.Inthetreatmentofacute

leukaemiasthislimitmaybesetlower,dependingonthecircumstances.

Severemyelosuppressionmayresultinhaemorrhageorsuperinfectionandisanindicationforthereductionor

suspensionofdoxorubicintreatment.

Becauseofthepotentialforimmunosuppression,measuresshouldbetakentopreventsecondaryinfection.

Hyperuricaemia:

Aswithothercancerchemotherapeuticagents,thereisariskofhyperuricaemiaresultinginacutegoutorurate

nephropathyfollowingtumorlysiswithregimenscontainingdoxorubicin.

Hepaticimpairment:

Sincedoxorubicinisexcretedmainlyviatheliver,reducedhepaticfunctionorfailuremaydelayeliminationand

increaseoveralltoxicity.Thereforeitisrecommendedthathepaticfunctiontests(SGOT,SGPT,alkalicphosphatase

andbilirubin)becarriedoutpriortoandduringthetreatment.

Theblooduricacidlevelshouldbemonitored;sufficientfluidintakeshouldbeascertained(withadailyminimumof

3l/m²).Ifnecessary,axanthine-oxidaseinhibitor(allopurinol)maybeadministered.

Menaswellaswomenshouldtakeeffectivecontraceptivemeasuresduringandforatleastthreemonthsafter

doxorubicintherapy.

Discolorationofurine:

Patientsshouldbewarnedthatdoxorubicinmayimpartaredcolourtotheurine,particularlyinthefirstspecimen

followingadministration,butthatthisisnocauseforalarm.

Intravesicalroute:

Theintravesicalrouteofadministrationshouldnotbeattemptedinpatientswith,invasivetumoursthathavepenetrated

thebladderwall,urinarytractinfections,inflammatoryconditionsofthebladder.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Cautionshouldbeexercisedwhenadministeringdoxorubicinafterortogetherwithothercardiotoxicoranticancer

(especiallymyelotoxic)agentsascardiotoxicityisenhanced.

Doxorubicinpeaklevels,terminalhalf-lifeandvolumeofdistributionmaybeincreasedfollowingtheco-

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Doxorubicinmaycauseexacerbationsofhemorragiccystitiscausedbypreviouscyclophosphamidetherapy.

Asdoxorubicinisrapidlymetabolisedandpredominantlyeliminatedbythebiliarysystem,theconcomitant

administrationofknownhepatotoxicchemotherapeuticagents(e.g.methotrexate)couldpotentiallyincreasethe

toxicityofdoxorubicinasaresultofreducedhepaticclearanceofthedrug.

HighdoseCyclosporinandDoxorubicinincreasestheserumlevelsofboth.Thismaycauseanincreasemyelotoxicity

andexcessiveimmunsuppression.

InhibitorsofcytochromeP-450(e.g.cimetidineandranitidine)maydecreasethemetabolismofdoxorubicin,witha

possibleincreaseintoxiceffects.InducersofenzymecytochromeP-450(e.g.rifampicinandbarbiturates)may

stimulatethemetabolismofdoxorubicin,withapossibledecreaseinefficacy.

Doxorubicinpotentiatestheeffectofradiationtherapyandcan,evenifadministeredsomeconsiderabletimeafter

discontinuationoftheradiationtherapy,causeseveresymptomsintheareaconcerned.

4.6Pregnancyandlactation

Reproductivestudiesinanimals,showedthatdoxorubicinwasteratogenicandembryotoxic(seesection5.3).

Doxorubicinissecretedintobreastmilk.Doxorubicinshouldnotbeusedduringpregnancyorbreastfeeding(see

section4.3.).

Doxorubicinisexcretedinbreastmilk.Usageduringlactationisthereforenotrecommended.

4.7Effectsonabilitytodriveandusemachines

Patientswhosufferfromanyeffectsthatmayimpairdrivingperformance(drowsiness,nauseaorvomiting)should

avoiddrivingandoperatingmachinery.

4.8Undesirableeffects

Frequenciesaredefinedusingthefollowingconvention: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).

ADRareverycommon.Doselimitingtoxicitiesoftherapyaremyelosuppressionandcardiotoxicitywhichoccurin

upto>10%and1-10%ofpatientsrespectively.

Doxorubicinmaypotentiatethetoxicityofradiotherapyandotheranticarcinogenictherapies(streptozocin,

methotrexate,cyclophosphamide).

Neoplasmsbenignandmalignant(includingcystsandpolys):

Uncommon:Paediatricpatientsmaybeatincreasedriskoflaterneoplasticdisease,particularlyacutemyeloid

leukaemia(AML).

Rare:Theoccurrenceofsecondaryacutemyeloidleukaemia,withorwithoutapreleukaemicphase,hasbeen

reportedrarelyinpatientstreatedwithdoxorubicininassociationwithDNA-damaginganti-neoplasticagents.Such

casesmayalsohaveashort(1-3year)latencyperiod.

Bloodandthelymphaticsystemdisorders

Verycommon:

Myelosuppressionincludesatransientleukopenia,anemiaandthrombocytopenia,reachingitsnadirat10-14days

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Eyedisorders

Rare

Conjunctivitis,lacrimation.

Endocrinedisorders

Notknown

Pediatricpatients

Ingeneralintensivechemotherapyregimescanresultinpre-pubertalgrowthfailureandendocrinedysfunction.

Doxorubicincancontributetopre-pubertalgrowthfailure.Doxorubicinhasreportedlynoapparentendocrinelate

effects

Metabolismandnutritiondisorders

Common-verycommon

Hyperuricaemia

Cardiacdisorders

Common-verycommon

Cardiotoxicitymayoccurasarrhythmiadirectlyfollowingdrugadministration;ECGchanges,includingT-wave

flatteningandS-Tdepression,maylastuptotwoweeksafteradministration.Pericarditisandmyocarditismayoccur.

Theriskofadevelopingcardiomyopathygraduallyincreaseswithanincreasingdosage.Acumulativedoseof450-

550mg/m²shouldnotbeexceeded,butirreversiblecongestiveheartfailuremayevenoccurwithdoseof240mg/m².

Ageover70orbelow15yearsshouldberegardedasariskfactor.Also,concomitantorprevioustreatmentwith

mitomycinC, cyclophosphamide or dacarbazine has been reported to potentiate doxorubicin induced

cardiomyopathy(seesection4.4.).

Cardiotoxicitymaybedelayedseveralweeks,monthsorevenyearsafterdiscontinuationofdoxorubicintherapy.

Theriskofdevelopingheartfailureincancerpatientstreatedwithdoxorubicinpersiststhroughoutlife.

Vasculardisorders

Veryrare

Thrombophlebitishasbeenreported.

Respiratory,thoracicandmediastinaldisorders

Veryrare

Somesingularcasesofpulmonarytoxicityhavebeenreported(tachypnoe,dyspnoe/pleuraleffusion,bronchiolitis

obliterans organizing pneumonia, bronchocentric granulomatosis/life-threatening respiratory depression,

postpneumonectomy-likesyndrome,interstitialpneumonits,radiationpneumonitis,pulmonaryembolism).Incases

ofcombinedcytostatictreatment(esp.gemcitabine,bleomycin,taxaneorrituximabcombinations)withorwithout

mediastinalradiotherapyaswellasinpredisposedpatientsthepossibilityofoccurrenceofpulmonarytoxicityshould

beconsidered.

Gastrointestinaldisorders

Verycommon:

Nausea,vomiting,mucositis(asstomatitisandproctitis)anddiarrhoeamayoccur5to10daysafteradministration.

Damageofthegastro-intestinaltractcanleadtoulceration,haemorrhageandperforation.

Mucositiscommonlybeginswithaburningsensationinthemouthandthroat5-10daysaftertreatmentandmay

progresstoulcerationwiththeassociatedriskofsecondaryinfection.Mucositismayalsoaffectthevagina,rectum

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4.9Overdose

Thesymptomsofanoverdosearelikelytobeanexaggeration/extensionofthepharmacologicalaction.Fatalitiesdue

tosingledosesof250mgand500mgdoxorubicinhavebeenreported.Acutemyocardialdegenerationmayoccur

within24hours.Severemyelosuppressionmayoccurwithpeakeffects10to15daysafteradministrationof

doxorubicin.Cardiacfailuremayoccuruptosixmonthsfollowinganoverdose.

Symptomaticsupportivemeasuresshouldbeadoptedincasesofoverdosage.

Assoonaspossibletheappropriatemeasuresshouldbetaken,suchastheadministrationofheartglycosidesand

diuretics.

Treatmentofpossiblehaemorrhageandofinfectionsduetoseveremyelo-orimmuno-suppressionmaybenecessary.

Bloodtransfusionsandreversebarriernursingmayberequired.

Haemodialysisisofnobenefitasdoxorubicinismostlyexcretedinthebiliarytractandbytheintestine.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCclassification:L01DB01

Doxorubicinhasbeenshowntohaveantineoplasticactivityinseveralanimalmodelsandiseffectiveinhumansbut

thereisasyetnoconsensusastohowdoxorubicinandotheranthracyclinesexerttheirantitumouractivity.Three

principalbiochemicalmechanismshavebeenproposed:DNAintercalation,membranebindingandmetabolic

Hepato-biliarydisorders:

Common

Slighttransientincreasesofliverenzymeshavebeenreported.Concomitantirradiationofthelivermaycausesevere

hepatotoxicity,sometimesprogressingtocirrhosis.

Skinandsubcutaneoustissuedisorders

Verycommon:

Reversiblealopeciainthemajorityofpatients,hyperpigmentationofnailbeds,dermalcreases,onycholysis.

Doxorubicinishighlyirritantandextravasationattheinfusionsitemaycauselocalpain,irritation,inflammation,

thrombophlebitis,evenleadingtoseriousulcerationandskinnecrosis.

Hypersensitivityreactionssuchascutaneousreactions(rashes,pruritus,urticaria,angiooedema,feverand

anaphylaxis)havebeenoccasionallyreported.

Doxorubicininfluencesandpotentiatesnormaltissuereactionstoradiation.Also,late("recall")reactionsmayoccur

whendoxorubicinisadministeredsometimeafterirradiation.

Renalandurinarydisorders

Common:

Intravesicaladministrationmaycausethefollowingadversereactions:hematuria,vesicalandurethralirritation,

stranguriaandpolyuria.Thesereactionsareusuallyofmoderateseverityandofshortduration.Intravesical

administrationofdoxorubicinmaysometimescausehemorrhagiccystitis;thismaycauseadecreaseinbladder

capacity.Doxorubicincausesreddiscolorationoftheurine.

Generaldisordersandadministrationsiteconditions

Rare:

conjunctivitis,lacrimation.

Facialflushingmayoccuriftheinjectionisgiventoorapidly.

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Animportantcauseoftreatmentfailurewithdoxorubicinandotheranthracyclinesisthedevelopmentofresistance.In

anattempttoovercomecellularresistancetodoxorubicintheuseofcalciumantagonistssuchasverapamilhasbeen

consideredsincetheprimarytargetisthecellmembrane;verapamilinhibitstheslowchannelofcalciumtransportand

canenhancecellularuptakeofdoxorubicin.Changetal,1989haveshownthatthecytotoxicityofdoxorubicinis

potentiatedbyverapamilinvitrousingthreepancreaticcancercelllines.

Theyalsoinvestigatedapossibleroleofitsmajorreductionmetabolite,doxorubicinol,whichoccursinhumanplasma,

butconcludedthatitwasnotinvolvedintheintracellularaccumulation/retentionofdoxorubicin.Itshouldbenotedthat

acombinationofdoxorubicinandverapamilhasbeenshowntobeassociatedwithseveretoxiceffectsinanimal

experiments.(Sridharetal,1992).

5.2Pharmacokineticproperties

Theintravenousadministrationofdoxorubicinisfollowedbyarapidplasmaclearance(t½=10min.)andsignificant

tissuebinding.Theterminalhalf-lifeisapproximately30hours.

Doxorubicinispartlymetabolised,mainlytodoxorubicinolandtoalesserextent,totheaglycon,andisconjugatedto

theglucuronideandsulfate.Biliaryandfecalexcretionrepresentsthemajorexcretionroute.About10%ofthedoseis

eliminatedbyrenalexcretion.Plasmaproteinbindingofdoxorubicinrangesfrom50-85%.Thevolumeofdistribution

is800-3500L/m².

Doxorubicinisnotabsorbedafteroraladministration;itdoesnotcrosstheblood-brainbarrier.

Impairmentofliverfunctionmaydecreasetheclearanceofdoxorubicinanditsmetabolites.

5.3Preclinicalsafetydata

TheLD

afterasingleintravenousbolusinjectionofdoxorubicintorats,miceandrabbitswere12.6,9.4and6mg/kg,

respectively.

Reductioninbodyweightsandsurvivaltimeswereseeninoldandyoungratsadministeredasingleintravenousdose

of2.5and5mg/kg,respectively.

Theanimaldatashowanincreasedtoxicityinelderrats.

AsexpectedfromitsinteractionwithDNAandcytotoxicpropertiesdoxorubicinismutagenic,showingchromosome

damageinvitroinhumanlymphocytesandisalsocarcinogenicinanimals.Thecompoundisalsoteratogenicand

embryocidal.Althoughi.v.andi.p.dosagetomiceandratsatdosesupto1mg/kgfromdays7to13ofgestation

producednoevidenceofteratogenicityahigherdoseof2mg/kgi.p.forlongertoratscausedatresiaoftheoesophagus

andintestineandcardiovascularabnormalities.Inrabbitsdosedi.v.atupto0.6mg/kgondays16-18abortionsoccurred

buttherewerenofoetalabnormalities.Post-natalrenaldamagewasproducedinratsdosedwith1or1.5mg/kgof

doxorubicinduringdays6-9or10-12.

Microscopicexaminationoftheheartofpatientsshowsevidenceofaseverecardiomyopathyandavarietyof

alterationshavebeendescribedthemajorityofwhichhavebeenreproducedinanimalmodelsinthemouse,rat,rabbit,

dogandmonkey;thedevelopmentandcharacterofthelesionsintheratandrabbitcloselyresemblethoseinhumans

althoughratsdevelopcardiomyopathyatlowertotaldosesthanrabbits.Thepathogenesisisdifficulttoassesssincea

largenumberofcomplexbiochemicaleffectshavebeenshowntooccurintheheart.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Hydrochloricacid(forpHadjustment)

Sodiumchloride

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6.2Incompatibilities

ContactwithanysolutionofanalkalinepHshouldbeavoidedasitwillresultinhydrolysisofthedrug.Doxorubicin

shouldnotbemixedwithheparinand5-fluororuacilasaprecipitatemayformanditisnotrecommendedthat

doxorubicinbemixedwithotherdrugs.

6.3ShelfLife

Medicinalproductaspackagedforsale:2years.

Removesolutionfromvialimmediatelybeforeuse.

Shelflifeafterdilution:Chemicalandphysicalin-usestabilityhasbeendemonstratedupto24hoursat2-8°C.

InUse:Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-use

storagetimesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24

hoursat2to8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Storeinarefrigerator(at2-8°C).Keepthevialintheoutercartoninordertoprotectfromlight.

Forstorageofthedilutedproduct,seesection6.3.

6.5Natureandcontentsofcontainer

VialsofPh.Eur.TypeIclearglasswithgreyteflon-coatedchlorobutylrubberstopperandaluminiumcrimpcap.Vials

arepackedwithorwithoutaprotectiveplasticoverwrap(ONCO-SAFE),packedinacardboardbox.

Packagesizes:

5mlDoxorubicn“Ebewe”2mg/ml:1,5or10vialsarepackedinonecardboardbox.

25mlDoxorubicn“Ebewe”2mg/ml:Eachvialispackedinonecardboardbox.

50mlDoxorubicn“Ebewe”2mg/ml:Eachvialispackedinonecardboardbox.

100mlDoxorubicn“Ebewe”2mg/ml:Eachvialispackedinonecardboardbox.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Forsingleuseonly.

Observeguidelinesforhandlingcytotoxicdrugs.

Thefollowingprotectiverecommendationsaregivenduetothetoxicnatureofthissubstance:

Personnelshouldbetrainedingoodtechinqueforhandling.

Pregnantstaffshouldbeexcludedfromworkingwiththisdrug.

Personnelhandlingdoxorubicinshouldwearprotectiveclothing:goggles,gownsanddisposableglovesand

masks.

Allitemsusedforadministrationorcleaning,includinggloves,shouldbeplacedinhighriskwastedisposal

bagsforhightemperature(700°C)incineration.

Accidentalcontactwiththeskinoreyesshouldbetreatedimmediatelybycopiouslavagewithwater,orsoapand

Irish Medicines Board

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Date Printed 15/07/2009 CRN 2068686 page number: 10

Spillageorleakageshouldbetreatedwithdilutesodiumhypochlorite(1%availablechlorite)solution,preferably

soakingovernightandthenrinsewithwater.

Allcleaningmaterialsshouldbedisposedofasindicatedpreviously.

RecommendedinfusionsolutionsareSodiumChlorideIntravenousInfusion0.9%w/v,GlucoseIntravenousInfusion

5%w/vorSodiumChlorideandGlucoseIntravenousInfusion(seesection4.2.).

Becauseofthevariousexistingdosageschemestheuseisonlyrecommendedunderthedirectionofthoseexperienced

incytotoxictherapy.

7MARKETINGAUTHORISATIONHOLDER

EBEWEPharmaGes.m.b.H.Nfg.KG

Mondseestrasse11

A-4866Unterach

Austria

8MARKETINGAUTHORISATIONNUMBER

PA789/1/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:22January1999

Dateoflastrenewal:22January2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 15/07/2009 CRN 2068686 page number: 11