DOXORUBICIN MARTINDALE PHARMA

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0361/024/001
  • Authorization date:
  • 04-09-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0361/024/001

CaseNo:2045379

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

MartindalePharmaceuticalsLtd

BamptonRoad,HaroldHill,Romford,RM38UG,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

DoxorubicinMartindalePharma2mg/mlConcentrateforsolutionforinfusion

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom04/09/2009until03/09/2014.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DoxorubicinMartindalePharma2mg/mlConcentrateforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmillilitreofconcentrateforsolutionforinfusioncontains2mgDoxorubicinhydrochloride.

Each5mlvialcontainsatotalcontentofDoxorubicinhydrochlorideof10mg.

Each10mlvialcontainsatotalcontentofDoxorubicinhydrochlorideof20mg.

Each25mlvialcontainsatotalcontentofDoxorubicinhydrochlorideof50mg.

Each75mlvialcontainsatotalcontentofDoxorubicinhydrochlorideof150mg.

Each100mlvialcontainsatotalcontentofDoxorubicinhydrochlorideof200mg.

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

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion

Theproductisaclear,redsolutionwhichispracticallyfreeofparticles.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Doxorubicinisindicatedinneoplasticconditionsincludingacuteleukaemia,lymphomas,soft-tissueandosteogenic

sarcomas,paediatricmalignanciesandadultsolidtumours.

Examplesinclude:

-Small-celllungcancer(SCLC)

-Breastcancer

-Advancedovariancarcinoma

-Intravesicallyforbladdercancer

-Neoadjuvantandadjuvanttherapyofosteosarcoma

-Advancedsoft-tissuesarcomainadults

-Ewing’ssarcoma

-Hodgkin’sdisease

-Non-Hodgkin’slymphoma

-Acutelymphaticleukaemia

-Acutemyeloblasticleukaemia

-Advancedmultiplemyeloma

-Advancedorrecurrentendometrialcarcinoma

-Wilms’tumour

-Advancedpapillary/follicularthyroidcancer

-Anaplasticthyroidcancer

-Advancedneuroblastoma

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Doxorubicinisfrequentlyusedincombinationchemotherapyregimenswithothercytostaticagents.

4.2Posologyandmethodofadministration

TreatmentwithDoxorubicinshouldbestartedbyorafterconsultationwithadoctorwithextensiveexperiencefrom

cytostatictreatment.

Duetotheriskofalethalcardiomyopathy,therisksandbenefitstotheindividualpatientshouldbeweightedbefore

eachapplication.

Thedilutedsolutionisinjectedviathetubingofafreely-runningintravenousinfusionover2-15minutes.This

techniqueminimizestheriskofthrombophlebitisorperivenousextravasationwhichcanleadtoseverecellulitisand

vesication.(Forrecommendeddiluentsseesection6.6)

Intravenousadministration:

Thedosageofdoxorubicindependsondosageregimen,generalstatusandprevioustreatmentofthepatient.

Severaldosageregimensexist:

Therecommendeddoseis60-75mg/m²bodysurfacei.v.asasingledoseorindivideddoseson2-3consecutivedays

administeredwith21day’sintervals.Thelowerdoseshouldbegiventopatientswithbonemarrowdepression.

WhenDoxorubicinisadministeredincombinationwithothercytostatics,thedosageshouldbereducedto30-60mg/m²

incyclesofevery3weeks.

Inpatients,whocannotreceivethefulldose(eg.incaseofimmunosuppression,oldage),analternativedosageis15-

20mg/m²bodysurfaceperweek.

Inordertoavoidcardiomyopathy,itisrecommendedthatthecumulativetotallifetimedoseofdoxorubicin(including

relateddrugssuchasdaunorubicin)shouldnotexceed450-550mg/m 2

bodysurfacearea.Ifpatientswithconcomitant

heartdiseasereceivemediastinaland/orheartirradiation,priortreatmentwithalkylatingagentsorconcomitant

treatmentwithpotentiallycardiotoxicagents,andhigh-riskpatients(witharterialhypertensionsince>5years,with

priorcoronary,valvularormyocardialheartdamage,ageover70years)amaximumtotaldoseof400mg/m 2

body

surfaceareashouldnotbeexceededandthecardiacfunctionofthesepatientsshouldbemonitored(seesection4.4)

Hepaticimpairment

Incasesofdecreasedliverfunction,thedosageshouldbereducedaccordingtothefollowingtable:

Doxorubiciniscontraindicatedinpatientswithsevereliverfunctiondisorder(seesection4.3).

Renalimpairment

IncasesofrenalinsufficiencywithaGFRlessthan10ml/min,75%ofthecalculateddoseshouldbeadministered.

Children

Dosageinchildren

Dosageforchildrenshouldbereduced,sincetheyhaveanincreasedriskforcardiactoxicityespeciallylatetoxicity.

Myelotoxicityshouldbeanticipated,withnadirsat10to14daysafterstartoftreatment.Maximalcumulativedosein

childrenis400mg/m².

Obesepatients

Areducedstartingdoseorprolongeddoseintervalmightneedtobeconsideredinobesepatients(see4.4Special

Serumbilirubin Recommendeddose

20-50micromole/L ½normaldose

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Intravesicaladministration:

Doxorubicincanbegivenbyintravesicalinstillationfortreatmentofsuperficialcancerofthebladderandtoprevent

relapseaftertransurethralresection(T.U.R).Therecommendeddoseforintravesicaltreatmentofsuperficialcancerof

thebladderis30-50mgin25-50mlofphysiologicalsalineperinstillation.Theoptimalconcentrationisabout1

mg/ml.Thesolutionshouldremaininthebladderfor1-2hours.Duringthisperiodthepatientshouldbeturned90 o

every15minutes.Toavoidundesireddilutionwithurinethepatientshouldbeinformednottodrinkanythingfora

periodof12hoursbeforetheinstillation(thisshouldreducetheproductionofurinetoabout50ml/h).Theinstillation

mayberepeatedwithanintervalof1weekto1month,dependentonwhetherthetreatmentistherapeuticor

prophylactic.

4.3Contraindications

Hypersensitivitytodoxorubicinorotheranthracyclines,tomethylparahydroxybenzoateoranthracendiones

Contraindicationsforintravenousadministration:

Persistentmyelosuppressionorseverestomatitiswhichappearedduringpreviouscytotoxictreatmentand/or

radiation

generalinfection

severeimpairedliverfunction

severearrhythmia,heartfailure,previouscardiacinfarct,acuteinflammatoryheartdisease

previoustreatmentwithanthracyclineswithmaximumcumulativedoses

increasedhaemorrhagictendency

Contraindicationsofintravesicaladministration:

invasivetumorsthathavepenetratedthebladder(beyondT1)

urinarytractinfections

inflammationofthebladder

problemswithcatheterizatione.g.urethralstenosis

haematuria

Doxorubicinmaynotbegivenduringpregnancyandlactation(seesection4.6).

4.4Specialwarningsandprecautionsforuse

Doxorubicinshouldbeadministeredonlyunderthesupervisionofaphysicianwhoisexperiencedintheuseofcancer

chemotherapeuticagents.

Patientsshouldrecoverfromtheacutetoxicitiesofpriorcytotoxictreatment(suchasstomatitis,neutropenia,

thrombocytopenia,andgeneralizedinfections)beforebeginningtreatmentwithdoxorubicin.

BeforeorduringtreatmentwithDoxorubicinthefollowingmonitoringexaminationsarerecommended(howoften

theseexaminationsaredonewilldependonthegeneralcondition,thedoseandtheconcomitantmedication):

radiographsofthelungsandchestandECG

regularmonitoringofheartfunction(LVEFbye.g.ECG,UCGandMUGAscan)

dailyinspectionoftheoralcavityandpharynxformucosalchanges

Bloodtests:haematocrit,platelets,differentialwhitecellcount,SGPT,SGOT,LDH,bilirubin,uricacid.

Treatmentcontrol

PriortostartofthetreatmentitisrecommendedtomeasuretheliverfunctionbyusingconventionaltestssuchasAST,

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Controloftheleftventricularfunction

AnalysisofLVEFusingultrasoundorheartscintigraphyshouldbeperformedinordertooptimisetheheartcondition

ofthepatient.Thiscontrolshouldbemadepriortothestartofthetreatmentandaftereachaccumulateddoseof

approximately100mg/m²

CardiacFunction

Cardiotoxicityisariskofanthracyclinetreatmentthatmaybemanifestedbyearly(i.e.acute)orlate(i.e.delayed)

events.

Early(i.e.Acute)Events:Earlycardiotoxicityofdoxorubicinconsistsmainlyofsinustachycardiaand/orECG

abnormalitiessuchasnon-specificST-Twavechanges. Tachyarrhythmias,includingprematureventricular

contractionsandventriculartachycardia,bradycardia,aswellasatrioventricularandbundle-branchblockhavealso

beenreported.Thesesymptomsgenerallyindicateacutetransienttoxicity.FlatteningandwideningoftheQRS-

complexbeyondnormallimitsmayindicatedoxorubicinhydrochloride-inducedcardiomyopathy.Asarule,inpatients

withanormalLVEFbaselinevalue(=50%),a10%decreaseofabsolutevalueordroppingbelowthe50%threshold

indicatescardiacdysfunctionandinsuchsituationtreatmentwithdoxorubicinhydrochlorideshouldbecarefully

considered.

Late(i.e.Delayed)Events:Delayedcardiotoxicityusuallydevelopslateinthecourseoftherapywithdoxorubicinor

within2to3monthsaftertreatmenttermination,butlaterevents,severalmonthstoyearsaftercompletionoftreatment,

havealsobeenreported.Delayedcardiomyopathyismanifestedbyreducedleftventricularejectionfraction(LVEF)

and/orsignsandsymptomsofcongestiveheartfailure(CHF)suchasdyspnoea,pulmonaryoedema,dependent

oedema,cardiomegalyandhepatomegaly,oliguria,ascites,pleuraleffusionandgalloprhythm.Subacuteeffectssuch

aspericarditis/myocarditishavealsobeenreported.Life-threateningCHFisthemostsevereformofanthracycline-

inducedcardiomyopathyandrepresentsthecumulativedose-limitingtoxicityofthedrug.

Cardiacfunctionshouldbeassessedbeforepatientsundergotreatmentwithdoxorubicinandmustbemonitored

throughouttherapytominimizetheriskofincurringseverecardiacimpairment.Theriskmaybedecreasedthrough

regularmonitoringofLVEFduringthecourseoftreatmentwithpromptdiscontinuationofdoxorubicinatthefirstsign

ofimpairedfunction.Theappropriatequantitativemethodforrepeatedassessmentofcardiacfunction(evaluationof

LVEF)includesmulti-gatedradionuclideangiography(MUGA)orechocardiography(ECHO).Abaselinecardiac

evaluationwithanECGandeitheraMUGAscanoranECHOisrecommended,especiallyinpatientswithriskfactors

forincreasedcardiotoxicity.RepeatedMUGAorECHOdeterminationsofLVEFshouldbeperformed,particularly

withhigher,cumulativeanthracyclinedoses.Thetechniqueusedforassessmentshouldbeconsistentthroughout

follow-up.

TheprobabilityofdevelopingCHF,estimatedaround1%to2%atacumulativedoseof300mg/m 2

slowlyincreases

uptothetotalcumulativedoseof450-550mg/m 2

.Thereafter,theriskofdevelopingCHFincreasessteeplyanditis

recommendednottoexceedamaximumcumulativedoseof550mg/m 2

.Ifthepatienthasotherpotentialriskfactorsof

cardiotoxicity(historyofcardiovasculardisease,previoustherapywithotheranthracyclinesoranthracenediones,prior

orconcomitantradiotherapytothemediastinal/pericardialarea,andconcomitantuseofmedicinalproductswiththe

abilitytosuppresscardiaccontractility,includingcyclophosphamideand5-fluoruracil),cardiotoxicitywith

doxorubicinmayoccuratlowercumulativedosesandcardiacfunctionshouldbecarefullymonitored.

Itisprobablethatthetoxicityofdoxorubicinandotheranthracyclinesoranthracenedionesisadditive.

Liverfunction

Themajorrouteofeliminationofdoxorubicinisthehepatobiliarysystem.Serumtotalbilirubinshouldbeevaluated

beforeandduringtreatmentwithdoxorubicin.Patientswithelevatedbilirubinmayexperienceslowerclearanceofthe

drugwithanincreaseinoveralltoxicity.Lowerdosesarerecommendedinthesepatients(seesection4.2Posologyand

MethodofAdministration).Patientswithseverehepaticimpairmentshouldnotreceivedoxorubicin(seesection4.3

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HaematologicToxicity

Doxorubicinmayproducemyelosuppression(SeeSection4.8)Haematologicprofilesshouldbeassessedbeforeand

duringeachcycleoftherapywithdoxorubicin,includingdifferentialwhitebloodcell(WBC)counts.Adose-

dependent,reversibleleucopeniaand/orgranulocytopenia(neutropenia)isthepredominantmanifestationof

doxorubicinhaematologictoxicityandisthemostcommonacutedose-limitingtoxicityofthisdrug.Leucopeniaand

neutropeniagenerallyreachthenadirbetweendays10and14afterdrugadministration;theWBC/neutrophilcounts

returntonormalvaluesinmostcasesbyday21.Dosereductionorincreaseofthedoseintervalshouldbeconsideredif

thebloodvaluesarenotnormalised.Thrombocytopeniaandanaemiamayalsooccur.Clinicalconsequencesofsevere

myelosuppressionincludefever,infections,sepsis/septicaemia,septicshock,haemorrhage,tissuehypoxiaordeath.

SecondaryLeukaemia

Secondaryleukaemia,withorwithoutapreleukaemicphase,hasbeenreportedinpatientstreatedwithanthracyclines.

SecondaryleukaemiaismorecommonwhensuchdrugsaregivenincombinationwithDNA-damagingantineoplastic

agents,whenpatientshavebeenheavilypretreatedwithcytotoxicdrugsorwhendosesoftheanthracyclineshavebeen

escalated.Theseleukaemiascanhavea1to3yearlatencyperiod.

Carcinogenesis,MutagenesisandImpairmentofFertility

Doxorubicinwasgenotoxicandmutagenicinvitroandinvivotests.

Inwomen,doxorubicinmaycauseinfertilityduringthetimeofdrugadministration.Doxorubicinmaycause

amenorrhoea(seesection4.8).Ovulationandmenstruationappeartoreturnafterterminationoftherapy,although

prematuremenopausecanoccur.

Doxorubicinismutagenicandcaninducechromosomaldamageinhumanspermatozoa.Oligospermiaorazoospermia

maybepermanent;however,spermcountshavebeenreportedtoreturntonormospermiclevelsinsomeinstances.

Thismayoccurseveralyearsaftertheendoftherapy.Menundergoingdoxorubicintreatmentshoulduseeffective

contraceptivemethods.

Menandwomanwhoaresexuallyactiveandundergoingdoxorubicintreatmentshoulduseeffectivecontraceptive

methods.

Intravesicaladministration

Intravesicaladministrationofdoxorubicinmaycausesymptomsofchemicalcystitis(i.e.dysuria,urinaryfrequency,

nocturia,stranguria,haematuria,necrosisofthebladderwall).

Specialattentionisneededincaseofcatheterproblems(i.e.urethralobstructioncausedbyinvasionofintravesical

tumour).

Intravesicaladministrationiscontraindicatedfortumoursthathavepenetratedthebladder(beyondT1).

Theintravesicalrouteofadministrationshouldnotbeattemptedinpatientswith,invasivetumoursthathavepenetrated

thebladderwall,urinarytractinfections,inflammatoryconditionsofthebladder.

Radiotherapy

Specialcautionismandatoryforpatientswhohavehadradiotherapypreviously,arehavingradiotherapyconcurrently

orareplanningtohaveradiotherapy.Thesepatientsareatspecialriskoflocalreactionsintheradiationfield(recall

phenomenon)ifDoxorubicinMartindalePharmaisused.Severe,sometimesfatal,hepatotoxicity(liverdamage)has

beenreportedinthisconnection.Priorradiationtothemediastinumincreasesthecardiotoxicityofdoxorubicin.The

cumulativedoseof400mg/m²mustnotbeexceededespeciallyinthiscase.

Anticancertherapies:

Doxorubicinmaypotentiatethetoxicityofotheranticancertherapies.Exacerbationofcyclophosphamide-induced

haemorrhagiccystitisandenhancedhepatotoxicityof6-mercaptopurinehavebeenreported.

Aswithothercytotoxicagents,thrombophlebitisandthromboembolicphenomenaincludingpulmonaryembolism(in

somecasesfatal)havebeencoincidentallyreportedwiththeuseofdoxorubicin(seesection4.8‘Undesirableeffects’).

Vaccines

Thismedicinalproductisgenerallynotrecommendedincombinationwithlive,attenuatedvaccines.Contacttopersons

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Other:

Thesystemicclearanceofdoxorubicinisreducedinobesepatients(i.e.>130%idealbodyweight)(seesection4.2

PosologyandMethodofAdministration).

Doxorubicinmayinducehyperuricaemiaasaconsequenceoftheextensivepurinecatabolismthataccompaniesdrug-

inducedrapidlysisofneoplasticcells(tumour-lysissyndrome)(seesection4.8‘Undesirableeffects’).Blooduricacid

levels,potassium,calciumphosphateandcreatinineshouldbeevaluatedafterinitialtreatment.Hydration,urine

alkalinization,andprophylaxiswithallopurinoltopreventhyperuricaemiamayminimizepotentialcomplicationsof

tumourlysissyndrome.

Thepatientshouldbeinformedthattheurinemightbereddish,particularlyinthefirstspecimenafteradministration,

butthatthisisnocauseforalarm.

Astingingorburningsensationatthesiteofadministrationmaysignifyasmalldegreeofextravasation.If

extravasationissuspectedoroccurs,theinjectionshouldbediscontinuedandrestartedinadifferentbloodvessel.

Coolingtheareafor24hourscanreducethediscomfort.Thepatientshouldbecarefullymonitoredforseveralweeks.

Surgicalmeasuresmightbenecessary(seesection4.8‘Undesirableeffects’)

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Doxorubicincardiotoxicityisenhancedbypreviousorconcurrentuseofotheranthracyclines,orotherpotentially

cardiotoxicdrugs(e.g.5-fluorouracile,cyclophosphamideorpaclitaxel)orwithproductsaffectingcardiacfunction

(likecalciumantagonists).Whendoxorubicinisusedtogetherwiththeabovementionedagents,cardiacfunctionmust

befollowedcarefully.

Theuseoftrastuzumabincombinationwithanthracyclines(suchasdoxorubicin)isassociatedwithahighcardiotoxic

risk.Trastuzumabandanthracyclinesshouldnotbeusedincombinationforthetimebeing,exceptinwellcontrolled

clinicalstudieswherethecardiacfunctionismonitored.Whenanthracyclinesareusedaftertheendofatherapywith

trastuzumab,anelevatedriskofcardiotoxicitymayresult.Ifpossible,thereshouldbeasufficientlylonginterval(upto

22weeks)betweentheendofatherapywithtrastuzumabandthebeginningoftheanthracyclinetherapy.Careful

monitoringofthecardiacfunctionisimperative.

Doxorubicinhepatotoxicitymaybeenhancedbyotherhepatotoxictreatmentmodalities(e.g.6-mercaptopurine).

DoxorubicinundergoesmetabolismviaCytochromeP450(CYP450)andisasubstrateforthePgptransporter.

ConcomitantadministrationofinhibitorsofCYP450and/orPgpmightleadtoincreasedplasmaconcentrationsof

doxorubicinandtherebyincreasedtoxicity.Conversely,concomitantadministrationofinducersofCYP450,suchas

rifampicinandbarbiturates,mightdecreaseplasmaconcentrationsofdoxorubicinandreduceefficacy.

Ciclosporin,aninhibitorofCYP3A4andPgp,increasedtheAUCofdoxorubicinanddoxorubicinolby55%and

350%,respectively.Thecombinationmightrequiredoseadjustment.Cimetidinehasalsobeenshowntoreducethe

plasmaclearanceandincreasetheAUCofdoxorubicin.

Paclitaxeladministeredshortlybeforedoxorubicinmaydecreaseclearanceandincreaseplasmaconcentrationsof

doxorubicin.Somedataindicatethatthisinteractionislesspronouncedwhendoxorubicinisadministeredbefore

paclitaxel.

Barbituratesmayleadtoanacceleratedplasmaclearanceofdoxorubicin,whiletheconcomitantadministrationof

phenytoinmayresultinlowerplasmaphenytoinlevels.

Elevatedserumdoxorubicinconcentrationswerereportedaftertheconcomitantadministrationofdoxorubicinand

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Thetoxiceffectsofadoxorubicintherapymaybeincreasedinacombinationwithothercytostatics(e.g.cytarabine,

cisplatin,cyclophosphamide).Necrosesofthelargeintestinewithmassivehaemorrhageandsevereinfectionsin

connectionwithcombinationtherapieswithcytarabine.

Clozapinemayincreasetheriskandseverityofthehematologictoxicity ofDoxorubicin

MarkednephrotoxicityofAmphotericinBcanoccurduringdoxorubicintherapy.

Asdoxorubicinisrapidlymetabolisedandpredominantlyeliminatedbythebiliarysystem,theconcomitant

administrationofknownhepatotoxicchemotherapeuticagents(e.g.mercaptopurine,methotrexate,streptozocin)could

potentiallyincreasethetoxicityofdoxorubicinasaresultofreducedhepaticclearanceofthedrug.Dosingof

doxorubicinmustbemodifiedifconcomitanttherapywithhepatotoxicdrugsismandatory.

Doxorubicinisapotent,radiosensitizingagent(“radiosensitizer”),andrecallphenomenainducedbyitmaybelife-

threatening.Anypreceding,concomitantorsubsequentradiationtherapymayincreasethecardiotoxicityor

hepatotoxicityofdoxorubicin.Thisappliesalsotoconcomitanttherapieswithcardiotoxicorhepatotoxicdrugs.

Doxorubicinmaycauseexacerbationsofhemorrhagiccystitiscausedbypreviouscyclophosphamidetherapy.

Doxorubicintherapymayleadtoincreasedserumuricacid,thereforedoseadjustmentofuricacidloweringagentsmay

benecessary.

Doxorubicinmayreduceoralbioavailabilityofdigoxin.

DuringtreatmentwithDoxorubicinpatientsshouldnotbeactivelyvaccinatedandalsoavoidcontactwithrecently

poliovaccinatedpersons.

4.6Pregnancyandlactation

Pregnancy:

Doxorubicinshouldnotbegivenduringpregnancy.Ingeneralcytostaticsshouldonlybeadministeredduring

pregnancyonstrictindication,andthebenefittothemotherweighedagainstpossiblehazardstothefoetus.Inanimal

studies,doxorubicinhasshownembryo-,foeto-andteratogeniceffects(see5.3Preclinicalsafetydata).

Menandwomenshoulduseeffectivecontraceptionduringandupto6monthsaftertreatment.

Lactation:

Doxorubicinhasbeenreportedtobeexcretedinhumanbreastmilk.Arisktothesucklingchildcannotbeexcluded.

Breast-feedingshouldbediscontinuedduringtreatmentwithdoxorubicin.

4.7Effectsonabilitytodriveandusemachines

Duetothefrequentoccurrenceofnauseaandvomiting,drivingcarsandoperationofmachineryshouldbediscouraged.

4.8Undesirableeffects

Treatmentwithdoxorubicinoftencausesundesirableeffects,andsomeoftheseeffectsareseriousenoughtoentail

carefulmonitoringofthepatient.Thefrequencyandkindofundesirableeffectsareinfluencedbythespeedof

administrationandthedosage.Bone-marrowsuppressionisanacutedoselimitingadverseeffect,butismostly

transient.Clinicalconsequencesofdoxorubicinbonemarrow/haematologicaltoxicitymaybefever,infections,

sepsis/septicaemia,septicshock,haemorrhages,tissuehypoxiaordeath.Nauseaandvomitingaswellasalopeciaare

seeninalmostallpatients.

Theestimationoffrequency:Verycommon( ≥1/10);common(≥1/100,<1/10);uncommon(≥1/1,000,<1/100);rare(≥

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Common Uncommon Rare Notknown

Infectionsand

infestations Sepsis,septiciaemia

Neoplasms

benignand

malignant Secondaryleukaemia

whenincombination

withanti-neoplastic

drugswhichdamage

theDNA.(seesection

4.4),tumourlysis

syndrome

Bloodand

lymphatic

system

disorders: bone-marrow

suppression,

leucopeniaand

neutropenia Thrombocytopenia,

anaemia

ImmuneSystem

disorders Anaphylactic

reactions

Endocrine

disorders Hotflushes

Eyedisorders conjunctivitis

Cardiac

disorders cardiomyopathy

(2%;e.g.decrease

ofLVEF,

dyspnoea);

ECGchanges(e.g.

sinustachycardia,

tachyarythmia,

ventricular

tachycardia,

bradycardia,bundle

arrhythmia,

heartfailure

Vascular

disorders phlebitis Thrombophlebitis;

thromboembolism

Gastrointestinal

disorders: nausea;vomiting;

mucositis;anorexia;

diarrhoea Gastrointestinal

haemorrhage,

abdominalpain;

ulcerationofthe

mucousmembranesin

themouth,pharynx,

oesophagusand

gastrointestinaltract

mayappear;in

combinationwith

cytarabine,ulceration

andnecrosisofthe

colon,inparticularthe

caecum,havebeen

reported(seesection

4.5)

Respiratory,

thoracicand

mediastinal

disorders Bronchospasm,radiat

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4.9Overdose

Acuteoverdosageofdoxorubicinmayleadtomyelosuppression(particularlyleucopeniaandthrombocytopenia),

generally10–14daysfollowingoverdose,gastrointestinaltoxiceffects(particularlymucositis)andacutecardiac

alterations,whichmayoccurwithin24hours.Treatmentincludesintravenousantibiotics,transfusionofgranulocytes

andthrombocytesandtreatmentofthegastrointestinalsymptomsandhearteffects.Movingthepatienttoasterileroom

andtheuseofahaemopoieticgrowthfactorshouldbeconsidered.

Singledosesof250mgand500mgofdoxorubicinhaveprovedfatal.

Chronicoverdosage,withacumulativedoseexceeding550mg/m 2

increasestheriskforcardiomyopathyandmaylead

toheartfailure,whichshouldbetreatedalongconventionallines.Delayedcardiacfailuremayoccuruptosixmonths

Skinand

subcutaneous

tissuedisorders: alopecia Itching,local

hypersensitivity

reactionofthefieldof

radiation(recall

phenomenon) urticaria,exanthema,

localerythematous

reactionsalongthe

veinwhichwasused

fortheinjection,

hyperpigmentationof

skinandnails,

onycholysis tissuehypoxia

Renaland

urinary

disorders: localreactions

(chemicalcystitis)

mightoccurat

intravesical

treatment(i.e.

dysuria,urinary

frequency,nocturia,

stranguria,

haematuria,necrosis

acuterenalfailure,

hyperuricaemia(see

section4.4)

Reproductive

systemand

breastdisorders Amenorrhoea,

oligospermia,

azoospermia(see

section4.4)

General

disordersand

administration

siteconditions: dehydration anaphylactic

reactions,shivering,

fever,

dizziness Astingingorburning

sensationatthe

administrationsite(see

section4.4)

Malaise/weakness

Hepatobiliar

disorders Hepatotoxicity,

transientincreaseof

liverenzymes

Surgicaland

medical

procedure Extravasationcanlead

toseverecellulitis,

vesicationandlocal

tissuenecrosiswhich

mayrequiresurgical

measures(including

skingrafts)(see

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Cytotoxicagents(anthracyclinesandrelatedsubstances)

ATCcode:L01DB01

Doxorubicinisananthracyclineantibiotic.Themechanismofactionisnotcompletelyelucidated.Itispostulatedthat

DoxorubicinMartindalePharmaexertsitsantineoplasticeffectviacytotoxicmechanismsofaction,especially

intercalationintoDNA,inhibitionoftheenzymetopoisomeraseII,andformationofreactiveoxygenspecies(ROS).

AllofthesehaveadeleteriouseffectonDNAsynthesis:Intercalationofthedoxorubicinmoleculeleadstoan

inhibitionofRNAandDNApolymerasesbywayofdisturbancesinbaserecognitionandsequencespecificity.The

inhibitionoftopoisomeraseIIproducessingleanddoublestrandbreaksoftheDNAhelix.ScissionofDNAalso

originatesfromthechemicalreactionwithhighlyreactiveoxygenspecieslikethehydroxylradicalOH h

.Mutagenesis

andchromosomalaberrationsaretheconsequences.

Thespecificityofdoxorubicintoxicityappearstoberelatedprimarilytoproliferativeactivityofnormaltissue.Thus,

bonemarrow,gastro-intestinaltractandgonadsarethemainnormaltissuesdamaged.

Animportantcauseoftreatmentfailurewithdoxorubicinandotheranthracyclinesisthedevelopmentofresistance.In

anattempttoovercomecellularresistancetodoxorubicin,theuseofcalciumantagonistssuchasverapamilhasbeen

consideredsincetheprimarytargetisthecellmembrane.Verapamilinhibitstheslowchannelofcalciumtransportand

canenhancecellularuptakeofdoxorubicin.Acombinationofdoxorubicinandverapamilisassociatedwithsevere

cardiotoxiceffects.

5.2Pharmacokineticproperties

Distribution

Followingintravenousinjection,doxorubicinisrapidlyclearedfromtheblood,andwidelydistributedintotissues

includinglungs,liver,heart,spleen,lymphnodes,bonemarrowandkidneys.Thevolumeofdistributionisabout25

litres.Thedegreeofproteinbindingis60-70%.

Doxorubicindoesnotcrosstheblood-brainbarrier,althoughhigherlevelsinliquormaybereachedinthepresenceof

brainmetastasesorleukemiccerebraldissemination.Doxorubicinisrapidlydistributedintotheascites,whereit

reacheshigherconcentrationsthaninplasma.Doxorubicinissecretedintobreastmilk.

Elimination

Theeliminationofdoxorubicinfromthebloodistriphasicwithmeanhalf-livesof12minutes(distribution),3.3hours

andabout30hours.Doxorubicinundergoesrapidmetabolismintheliver.Themainmetaboliteisthe

pharmacologicallyactivedoxorubicinol.Othermetabolitesaredeoxyrubicinaglycone,glucuronideandsulphate

conjugate.About40to50%ofadoseisexcretedinbilewithin7days,ofwhichabouthalfisexcretedasunchanged

drugandtherestasmetabolites.Only5-15%oftheadministereddoseiseliminatedinurine.

Specialpopulations

Astheeliminationofdoxorubicinismainlyhepatic,impairmentofliverfunctionresultsinslowerexcretion,and

consequently,increasedretentionandaccumulationinplasmaandtissues.Dosereductionisgenerallyadvised.

Althoughrenalexcretionisaminoreliminationpathwayfordoxorubicin,severerenalimpairmentmightaffecttotal

eliminationandrequiredosereduction.

Inastudyinobesepatients(>130%ofidealbodyweight)thedoxorubicinclearancewasreducedandthehalflife

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5.3Preclinicalsafetydata

Animalstudiesfromliteratureshowthatdoxorubicinaffectsthefertility,isembryo-andfoetotoxicandteratogenic.

Otherdatashowsthatdoxorubicinismutagenic.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Waterforinjections

Sodiumchloride

Hydrochloricacid(forpHadjustment)

6.2Incompatibilities

ContactwithanysolutionofanalkalinepHshouldbeavoidedasitwillresultinhydrolysisofthedrug.Doxorubicin

shouldnotbemixedwithheparinand5-fluorouracilsinceaprecipitatemayform,anditisnotrecommendedthat

doxorubicinbemixedwithotherdrugsuntilspecificcompatibilitydataareavailable.

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.3.

6.3ShelfLife

Unopenedvials:2years

Openedvials:Theproductshouldbeusedimmediatelyafteropeningthevial.

Preparedinfusionsolutions:

Followingdilutionthepreparedsolutionshouldberefrigeratedinordertoprotectfromlight.

Chemicalandphysicalin-usestabilityhasbeendemonstratedinsodiumchloride0.9%orglucose5%forupto48

hoursat2–8°Candforupto24hoursat25°CwhenpreparedinPVCinfusionbagsandpolypropylenesyringes

protectedfromlight.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2°

Cto8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Storeinarefrigerator(2°C-8°C).

Keepthecontainerintheoutercartoninordertoprotectfromlight.

Forstorageconditionsofthereconstitutedproductseesection6.3.

6.5Natureandcontentsofcontainer

Colourlessglassvials(typeIglass)withchlorobutylrubberstopperswithETFE(ethylenetetrafluoroethylene–

fluorocarbon-basedpolymer)layer.

Packsizes:

1x5mlvial(10mg/5ml)

1x10mlvial(20mg/10ml)

1x25mlvial(50mg/25ml)

1x75mlvial(150mg/75ml)

1x100mlvial(200mg/100ml)

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6.6Specialprecautionsfordisposalandotherhandling

Forsingleuseonly.Dilutebeforeuse

Observeguidelinesforhandlingcytotoxicdrugs.

Thefollowingprotectiverecommendationsaregivenduetothetoxicnatureofthissubstance:

Personnelshouldbetrainedingoodtechniqueforhandling.

Pregnantstaffshouldbeexcludedfromworkingwiththisdrug.

Personnelhandlingdoxorubicinshouldwearprotectiveclothing:goggles,gownsanddisposableglovesandmasks.

Allitemsusedforadministrationorcleaning,includinggloves,shouldbeplacedinhighriskwastedisposalbagsfor

hightemperature(700°C)incineration.

Accidentalcontactwiththeskinshouldbetreatedimmediatelybycopiouslavagewithwaterorsoapandwater.Inan

accidentalcontact,theeyesshouldberinsedcopiouslywithwaterorsodiumbicarbonatesolution.Medicalattention

shouldbesought.

Spillageorleakageshouldbetreatedwithdilutesodiumhypochlorite(1%availablechlorine)solution,preferably

soakingovernightandthenrinsewithwater.

Allcleaningmaterialsshouldbedisposedofasindicatedpreviously.

DoxorubicinMartindalePharmashouldbefurtherdilutedinSodiumChloride0.9%orGlucose5%andadministeredas

anintravenousinfusion.Theinfusionsolutionshouldbepreparedimmediatelybeforeuse.

7MARKETINGAUTHORISATIONHOLDER

MartindalePharmaceuticalsLimited

BamptonRoad

HaroldHill

Romford

EssexRM38UG

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA361/24/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:4thSeptember2009

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