DOXORUBICIN

Main information

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

Documents

Localization

  • Available in:
  • DOXORUBICIN Concentrate for Soln for Inf 2 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1667/001/001
  • Authorization date:
  • 06-08-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA1667/001/001

CaseNo:2084208

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

TransferredfromPA1312/005/001.

PeseriTradingLtd

20,QueenFrederica,ElGrecoHouse,3rdFloor,flat/office303,Nicosia,Cyprus

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Doxorubicin2mg/mlConcentrateforSolutionforInfusion

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom06/08/2010until28/01/2015.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 06/08/2010 CRN 2084208 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Doxorubicin2mg/mlConcentrateforSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Doxorubicinhydrochloride

1mlcontains2mgDoxorubicinhydrochloride.

Each5mlvialcontains10mgofDoxorubicinhydrochloride.

Each10mlvialcontains20mgofDoxorubicinhydrochloride.

Each25mlvialcontains50mgofDoxorubicinhydrochloride.

Each50mlvialcontains100mgofDoxorubicinhydrochloride.

Each100mlvialcontains200mgofDoxorubicinhydrochloride.

Excipients:Theproductcontainssodiumchloride(3.54mgsodiumper1ml).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion

Redconcentrateforinfusion.pH=2.5–3.5

4CLINICALPARTICULARS

4.1TherapeuticIndications

Breastcancer,sarcoma,small-cellcarcinomaofthelung,Hodgkindiseaseornon-Hodgkinlymphoma,acute

leukaemia,cancerofthethyroid,bladder,ovaries,Paediatrictumours,suchasneuroblastoma.

Doxorubicinisfrequentlyusedincombinationchemotherapyregimenswithothercytotoxicdrugs.

4.2Posologyandmethodofadministration

TreatmentwithDoxorubicinshouldbestartedbyorafterconsulationwithadoctorwithextensiveexperiencefrom

cytostatictreatment.

Theconcentrateisinjectedviathetubingofafreely-runningintravenousinfusion(Sodiumchloride0.9%

intravenousinfusionorDextrose5%intravenousinfusion)over2-15minutes.Thistechniqueminimizestheriskof

thrombophlebitisorperivenousextravasationwhichcanleadtoseverecellulitisandvesication.

Intravenousadministration:Thedosageofdoxorubicindependsondosageregimen,generalstatusandprevious

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Severaldosageregimensexist:Therecommendeddoseis60-75mg/m²bodysurfacei.v.asasingledoseorindivided

doseson2-3consecutivedaysadministeredwith21day’sintervals.Thelowerdoseshouldbegiventopatientswith

bonemarrowdepression.

WhenDoxorubicinisadministeredincombinationwithothercytostatics,thedosageshouldbereducedto30-60

mg/m².

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

20mg/m²bodysurfaceperweek.

Inordertoavoidcardiomyopathy,itisrecommendedthatthecumulativetotallifetimedoseofdoxorubicin(including

relateddrugssuchasdaunorubicin)shouldnotexceed450-550mg/mbodysurfacearea;450mg/m²shouldnotbe

exceededincasesofpreviousradiationofmediastinum,previousorconcomitanttreatmentwithpotentiallycardiotoxic

agents.

Incasesofdecreasedliverfunction,thedosageshouldbereducedaccordingtothefollowingtable:

IncasesofrenalinsufficiencywithaGFRlessthan10ml/min,75%ofthecalculateddoseshouldbeadministered.

Dosageinchildrenmayneedtobereduced,pleaserefertotreatmentprotocolsandthespecialistliterature.

Intravesicaladministration:Doxorubicincanbegivenbyintravesicalinstillationfortreatmentofsuperficialcancerof

thebladderandtopreventrelapseaftertransurethralresection(T.U.R).Therecommendeddoseforintravesical

treatmentofsuperficialcancerofthebladderis30-50mgin25-50mlofphysiologicalsalineperinstillation..The

solutionshouldremaininthebladderfor1-2hours.

Duringthisperiodthepatientshouldbeturned90every15minutes.Toavoidundesireddilutionwithurinethepatient

shouldbeinformednottodrinkanythingforaperiodof12hoursbeforetheinstillation(thisshouldreducethe

productionofurinetoabout50ml/h).Theinstillationmayberepeatedwithanintervalof1weekto1month,

dependentonwhetherthetreatmentistherapeuticorprophylactic.

Treatmentcontrol

PriortostartofthetreatmentitisrecommendedtomeasuretheliverfunctionbyusingconventionaltestssuchasAST,

ALT,ALPandbilirubinaswellastherenalfunction(seesection4.4).

ControloftheleftventricularfunctionAnalysisofLVEFusingultrasoundorheartscintigraphyshouldbeperformedin

ordertooptimisetheheartconditionofthepatient.Thiscontrolshouldbemadepriortothestartofthetreatmentand

aftereachaccumulateddoseofapproximately100mg/m²(seesection4.4).

Adirectpushinjectionisnotrecommendedduetotheriskofextravasation,whichmayoccureveninthepresenceof

adequatebloodreturnuponneedleaspiration.

Intravesicalinstillationiscontraindicatedininvasivebladdertumours.

4.3Contraindications

Hypersensitivitytodoxorubicin,otheranthracyclinesoranthracenediones

Contraindicationsforintravenousadministration:

-remainingmyelosuppressionorseverestomatitiswhichappearedduringprevious

cytotoxictreatment

-generalinfection

Serumbilirubin Recommendeddose

20-50micromole/L 50%normaldose

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-severearrhythmia,impairedheartfunction,previouscardiacinfarct

-previoustreatmentwithanthracyclineswithmaximalcumulativedoses

Contraindicationsforintravesicaladministration:

-invasivetumoursthathavepenetratedthebladder(beyondT1)

-urinarytractinfections

-inflammationofthebladder

-problemswithcatheterisation

Doxorubicinmaynotbegivenduringpregnancyandlactation(seesection4.6).

4.4Specialwarningsandprecautionsforuse

Acarefulcontrolofpossibleclinicalcomplicationsshouldbeperformed,particularlyinelderlypatients,inpatients

withahistoryofheartdisease,orwithbone-marrowsuppression,orpatientswhopreviouslyhavebeentreatedwith

anthracyclines,ortreatedwithradiationinthemediastinum.

Controlofbloodvalues:Beforeeverytreatmentcycletotalanddifferentialleukocytecount,erythrocyteand

thrombocytecountsshouldbeperformed.Bone-marrowsuppressioninducedbyDoxorubicin,primarilyaffectingthe

leukocytes,requiresathoroughhaematologicalmonitoringsinceseveremyelosuppressionmayleadtosuperinfections

andbleedings.Severeleucopoeniamayappearatdosesrecommendedfortreatmentofsolidtumours(anumberof

leukocytesof1000/mm3orlowerisexpectedduringfulldosetreatmentwithDoxorubicin).Theleucopoeniaismost

pronounced10–14daysafterthetreatmentandleukocyteshaveinmostcasesreturnedtonormalatday21.

Controlofheartfunction:Thereisaknownriskofdevelopmentofanthracyclineinducedcumulativedose-dependent

cardiomyopathy.Thereforeacumulativedoseof(450-)550mg/mshouldnotbeexceeded.Atdosesabovethis,the

riskofdevelopmentofheartfailureconsiderablyincreases.Theheartfunctionshouldthereforebeassessedbeforestart

ofthetreatmentandcarefullymonitoredduringthewholetreatment.Electrocardiographybeforeandaftereach

treatmentcycleisrecommended.ChangesinECGsuchasdepressionornegativeT-wave,decreaseintheST-segment

orarrhythmiasareusuallysignsofanacutebuttransient(reversible)toxiceffectandarenotconsideredindicationsfor

suspensionofdoxorubicintherapy.However,areductionintheamplitudeoftheQRS-waveandaprolongationofthe

systolicintervalareconsideredmoreindicativeofanthracycline-inducedcardiactoxicity.Thebestsigntopredict

cardiomyopathyisareductionintheleftventricularejectionfraction(LVEF),determinedbyultrasoundorheart

scintigraphy.LVEF-investigationsshouldbeperformedbeforetreatmentandberepeatedaftereachaccumulateddose

ofabout100mg/m,andatclinicalsignsofheartfailure.Asarule,anabsolutedecreasewith>10%oradecrease

below50%,inpatientswithnormalinitialLVEF-values,isasignofanimpairmentoftheheartfunction.Continued

treatmentwithdoxorubicinmustinthesecasesbecarefullyevaluated.Theriskforcardiotoxicitymayincreasein

patientspreviouslyonradiotherapytowardsthemediastinalpericardium,inpatientspreviouslytreatedwithother

anthracyclinesand/oranthracenediones,orinpatientswithahistoryofheartdiseases.Thetotaldoseofdoxorubicin

administeredtotheindividualpatientshouldalsotakeintoaccountanyprevious

orconcomitanttherapywithotherpotentiallycardiotoxicagentssuchashigh-dosei.v.cyclophosphamide,

mediastinalirradiationorrelatedanthracyclinecompoundssuchasdaunorubicin.

Controlofliverfunction:Doxorubicinismainlyeliminatedviathehepatobiliarysystem.Theeliminationofthedrug

canthereforebeprolongedwithsubsequentgeneraltoxicityiftheliverfunctionisimpairedorbiliarysecretionis

obstructed.Beforestartandduringtreatment,controloftheliverfunctionwithconventionaltestssuchasAST,ALT,

ALPandbilirubinisrecommended.Dosereductionmaybenecessary(see4.2).

Controlofserumuricacid:Duringtherapyserumuricacidmayincrease.Incaseofhyperuricemiaantihyperuricemic

therapyshouldbeinitiated.

Inpatientswithseverelyimpairedrenalfunctiondosereductionsmaybenecessary(seesection4.2).

Doxorubicinmaypotentiatethetoxicityofotheranticancerchemotherapies(seesection4.5).Doxorubicin

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Astingingorburningsensationatthesiteofadministrationmaysignifyasmalldegreeofextravasation.If

extravasationissuspectedoroccurs,theinjectionshouldbediscontinuedandrestartedinadifferentbloodvessel.

Coolingtheareafor24hourscanreducethediscomfort.Thepatientshouldbecarefullymonitoredforseveralweeks.

Surgicalmeasuresmightbenecessary.

Thepatientshouldbeinformedthattheurinemightbereddishafteradministration.

Thismedicinalproductcontains3.54mgsodiumper1mlofdoxorubicinhydrochlorideconcentrateforsolutionfor

infusion.Thisshouldbetakenintoconsiderationbypatientsonacontrolledsodiumdiet.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Doxorubicincardiotoxicityisenhancedbypreviousorconcurrentuseofotheranthracyclines,orotherpotentially

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

(likecalciumantagonists).Whendoxorubicinisusedtogetherwiththeabovementionedagents,cardiacfunctionmust

befollowedcarefully.

Doxorubicinhepatotoxicitymaybeenhancedbyotherhepatotoxictreatmentmodalities(e.g.6-mercaptopurine).

Doxorubicinusedincombinationwithciclosporinmightrequiredose-adjustment.Atconcomitantadministrationof

ciclosporin,theclearanceofdoxorubicinisreducedbyapproximate50%.ThedoxorubicinAUCisincreasedby55%

andAUCofdoxorubicinolby350%.Withthiscombinationa40%dosereductionofdoxorubicinissuggested.

Ciclosporininhibits,similartoverapamil,bothCYP3A4andP-glycoprotein,whichmightexplaintheinteractionand

resultinginanincreaseinadverseeffects.

CimetidinealsoreducedtheplasmaclearanceandincreasedtheAUCofDoxorubicin,possiblybysimilarmechanisms

assuggestedforciclosporin,andmaythusleadtoanincreaseinadverseeffects.Conversely,phenobarbitaldecreased

Doxorubicinplasmalevelsandmaythusleadtoadecreaseinefficacy.

Doxorubicinpotentiatestheeffectofradiationtherapyandcan,evenifadministeredsomeconsiderabletimeafter

discontinuationoftheradiationtherapy,causeseveresymptomsintheareaconcerned.

Doxorubicinmaycauseexacerbationsofhemorrhagiccystitiscausedbypreviouscyclophosphamide

therapy.

Doxorubicintherapymayleadtoincreasedserumuricacid,thereforedoseadjustmentofuricacidloweringagents

maybenecessary.

Doxorubicinmayreduceoralbioavailabilityofdigoxin.

DuringtreatmentwithDoxorubicinpatientsshouldnotbeactivelyvaccinatedandalsoavoidcontactwithrecently

poliovaccinatedpersons.

4.6Pregnancyandlactation

Pregnancy:

Doxorubicinshouldnotbegivenduringpregnancy.Ingeneralcytostaticsshouldonlybeadministeredduring

pregnancyonstrictindication,andthebenefittothemotherweighedagainstpossiblehazardstothefoetus.

Inanimalstudies,doxorubicinhasshownembryo-,foeto-andteratogeniceffects(see5.3Preclinicalsafetydata).Men

andwomenshoulduseeffectivecontraceptionduringandupto6monthsaftertreatment.

Lactation:

Doxorubicinhasbeenreportedtobeexcretedinhumanbreastmilk.Arisktothesucklingchildcannotbeexcluded.

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4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.

4.8Undesirableeffects

Treatmentwithdoxorubicinoftencausesundesirableeffects,andsomeoftheseeffectsareseriousenoughtoentail

carefulmonitoringofthepatient.Thefrequencyandkindofundesirableeffectsareinfluencedbythespeedof

administrationandthedosage.Bone-marrowsuppressionisanacutedoselimitingadverseeffect,butismostly

transient.Clinicalconsequencesofdoxorubicinbonemarrow/haematologicaltoxicitymaybefever,infections,

sepsis/septicaemia,septicshock,haemorrhages,tissuehypoxiaordeath.Nauseaandvomitingaswellasalopeciaare

seeninalmostallpatients.

Common

Cardiacdisorders:Cardiomyopathy(2%;e.g.decreaseofLVEF,( ≥1/100todyspnoea),ECGchanges(e.g.

sinustachycardia,tachyarythmia,<1/10)ventriculartachycardia,bradycardia,bundlebranchblock)

Bloodandlymphaticsystemdisorders:Bone-marrowsuppression

Gastrointestinaldisorders:Nausea,vomiting,mucositis,anorexia,

diarrhoea

Renalandurinarydisorders:Localreactions(chemicalcystitis)might

occuratintravesicaltreatment

Skinandsubcutaneoustissuedisorders:Alopecia

Uncommon

Gastrointestinaldisorders:Incombinationwithcytarabineulceration( ≥1/1,000toandnecrosisofthecolon,in

particularthecaecum,havebeen<1/100)reported.

Rare

Eyedisorders:Conjunctivitis( ≥1/10,000to<1/1,000)

Skinandsubcutaneoustissuedisorders:

Urticaria,exanthema,localerythematousreactionsalongtheveinwhichwasusedfortheinjection,

hyperpigmentationofskinandnails,onycholysisGeneraldisordersandadministrationsiteconditions:

Anaphylacticreactions,shivering,fever,dizziness

Bloodandlymphaticsystemdisorders:

Maximalbone-marrowsuppressionoccursafter10-14days,butthewhiteandredbloodcellcounts(bloodvalues)are

oftennormalisedafter21days.Dosereductionorincreaseofthedoseintervalshouldbeconsideredifthebloodvalues

arenotnormalised.Haematologicalmonitoringshouldbeundertakenregularlyinbothhaematologicalandnon-

haematologicalconditions.Secondaryacutemyeloidleukaemia(AML),withorwithoutapre-leukaemicphase,hasin

rarecasesbeenreportedinpatientssimultaneouslytreatedwithdoxorubicinandantineoplasticdrugs,whichdamage

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Cardiacdisorders:CardiotoxicitymaybemanifestedintachycardiaincludingsupraventriculartachycardiaandECG

changes.Cardiomyopathycandevelopevenlongafterdiscontinuationofthetreatment,andisofseriousnature.Itis

oftencharacterisedbyadecreaseinLVEF,adecreaseinamplitudeoftheQRSwave,rapidonsetofcardiacdilatation,

whichoftendoesnotrespondtotreatmentwithmedicinalproductswithinotropiceffect.AcutetransientECGchanges

thatoccurdirectlyinconnectionwith,orafewhoursaftertheadministration,areinmostcasesreversibleandare

usuallyofnoclinicalsignificance.

Gastrointestinaldisorders:Nauseaandvomitingoftenoccurduringthefirst24hoursaftertheadministration.

Mucositis(stomatitisandoesophagitis)mayoccur5-10daysafteradministration,andismorefrequentandserious

whenatherapy,whichinvolvestreatmentduringthreeconsecutivedays,isapplied.Ulcerationandnecrosisofthe

colon,inparticularthecaecum,resultinginbleedingandseriousinfections,sometimesfatal,havebeenreportedin

patientswithacutenonlymphocyticleukaemia,who,duringthreedays,weretreatedwithdoxorubicinincombination

withcytarabine.Hyperpigmentationoforalmucosaalsooccurred.

Skinandsubcutaneoustissuedisorders:Alopeciaisdose-dependentandinmostcasesreversible.Photosensitization,

“radiationrecallreaction”.Extravasationcanleadtoseverecellulitis,vesicationandlocaltissuenecrosiswhichmay

requiresurgicalmeasures(includingskingrafts).

Othersideeffects:

Hyperuricaemia,bronchospasm,amenorrhoea,transientincreaseofliverenzymes.

4.9Overdose

Acuteoverdosageofdoxorubicinmayleadtomyelosuppression(particularlyleucopoeniaandthrombocytopenia),

generally10–14daysfollowingoverdose,gastrointestinaltoxiceffects(particularlymucositis)andacutecardiac

alterations,whichmayoccurwithin24hours.Treatmentincludesintravenousantibiotics,transfusionofgranulocytes

andthrombocytesandtreatmentofthegastrointestinalsymptomsandhearteffects.Movingthepatienttoasterileroom

andtheuseofahaemopoieticgrowthfactorshouldbeconsidered.Singledosesof250mgand500mgofdoxorubicin

haveprovedfatal.

Chronicoverdosage,withacumulativedoseexceeding550mg/mincreasestheriskforcardiomyopathyandmaylead

toheartfailure,whichshouldbetreatedalongconventionallines.Delayedcardiacfailuremayoccuruptosixmonths

aftertheoverdosage.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcode:L01DB01Anthracyclinesandrelatedsubstances

Doxorubicinbelongstothegroupofanthracyclinesandisacytostaticantibioticthathasbeenisolatedfromculturesof

Streptomycespeucetiusvar.caesius.Itisnowpreparedsemi-syntheticallyfromdaunorubicin.Doxorubicinisastrong

tissueirritant.

ThebiologicalactivityofdoxorubicinisattributedtoitsDNA-bindingproperty,whichresultsininhibitionofthe

enzymaticsystem,vitalfortheDNA-replicationandtheDNA-transcription.Theblockingofthecellularcycleseemsto

bemaximalduringSphaseandmitosis,butinhibitionhasalsobeenobservedduringothercellcyclephases.

5.2Pharmacokineticproperties

Afterintravenousadministration,doxorubicineliminationischaracterisedbyatri-phasiceliminationfromplasma

withaterminalhalflifeofapproximately30hours.Thedistributionvolumeisapproximately25L/kg.Thedegreeof

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Highestdrugconcentrationsareattainedinthelung,liver,spleen,kidney,heart,smallintestineandbone-marrow.

Doxorubicindoesnotcrosstheblood-brainbarrier.

Doxorubicinisrapidlymetabolised,andthemainmetaboliteisthelessactive13dihydroderivativedoxorubicinol.

Withinfivedaysapproximately5%isrecoveredintheurine,whilst40-50%isexcretedthroughthebilewithin7days.

Reducedliverfunctionresultsinaslowereliminationofthesubstance.

5.3Preclinicalsafetydata

Animalstudiesfromliteratureshowthatdoxorubicinaffectsthefertility,isembryo-andfoetotoxicandteratogenic.

Otherdatashowsthatdoxorubicinismutagenic.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Hydrochloricacid

Sodiumchloride

Waterforinjections

6.2Incompatibilities

Doxorubicinmustnotbemixedwithheparin,asthiswillresultinprecipitation.Untildetailedcompatibility

informationaboutmiscibilityisavailable,Doxorubicinshouldnotbemixedwithanyothermedicinalproducts.

Incompatibilitieswiththefollowingproductshavealsobeenreported:Aminophyllin,cephalotin,dexamethasone,

fluorouracil,hydrocortisone.

6.3ShelfLife

Unopenedvial:2years

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuser

Fromachemicalandphysicalpointofview,theproductshouldbeusedimmediatelyafterfirstopening.Anyunused

portionmustbediscardedafteruse.

6.4Specialprecautionsforstorage

Storeinarefrigerator(2ºC-8ºC)

Keepvialintheoutercartoninordertoprotectfromlight

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6.5Natureandcontentsofcontainer

Colourless,borosilicate,typeIglassvialwithchlorobutylbased,typeIrubberstopperandaluminiumcapwithplastic

flip-offtop,containing5ml,10ml,25ml,50mlor100mlofsterilesolutionofDoxorubicinhydrochloride2mg/ml

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Theinjectionsolutioncontainsnopreservativeandanyunusedportionofthevialshouldbediscardedimmediately.

Doxorubiciniscompatiblewithsodiumchloride0.9%anddextrose5%.

Guidelinesforthesafehandlinganddisposalofantineoplasticagents:

1.Adequateprotectivedisposablegloves,goggles,gownandmaskshouldbeworn.

2.Precautionsshouldbetakentoavoidthemedicinalproductaccidentallycomingintocontactwiththeeyes.Inthe

eventofcontactwiththeeyes,irrigatewithlargeamountsofwaterand/or0.9%sodiumchloridesolution.Then

seekmedicalevaluationbyaphysician.

3.Incaseofskincontact,thoroughlywashtheaffectedareawithsoapandwaterorsodiumbicarbonatesolution.

However,donotabradetheskinbyusingascrubbrush.Alwayswashhandsafterremovinggloves.

4.Spillageorleakageshouldbetreatedwithdilutedsodiumhypochlorite(1%availablechlorine)solution,preferably

bysoaking,andthenwaterormostsimplywithphosphatebuffer(pH>8)untilthesolutionisdestained.All

cleaningmaterialsshouldbedisposedofasdetailedbelow.

5.Pregnantstaffshouldnothandlethecytotoxicpreparation.

6.Adequatecareandprecautionsshouldbetakeninthedisposalofitems(syringes,needlesetc)usedtoreconstitute

and/ordilutecytotoxicmedicinalproducts.Anyunusedproductorwastematerialshouldbedisposedofin

accordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

PeseriTradingLimited

20QueenFrederica

ElGrecoHouse

Floor

Flat/office303

1066Nicosia

Cyprus

8MARKETINGAUTHORISATIONNUMBER

PA1667/1/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:29thJanuary2010

10DATEOFREVISIONOFTHETEXT

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