DAUNOXOME 2 MG/ ML CONCENTRATE FOR SOLUTION FOR INF

Main information

  • Trade name:
  • DAUNOXOME 2 MG/ ML CONCENTRATE FOR SOLUTION FOR INF
  • Dosage:
  • 2 Mg/ Ml
  • Pharmaceutical form:
  • Concentrate for Susp for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DAUNOXOME 2 MG/ML CONCENTRATE FOR SOLUTION FOR INF
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1329/009/001
  • Authorization date:
  • 30-03-2012
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DaunoXome2mg/mLconcentrateforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Daunorubicinpresentascitratesalt,equivalenttodaunorubicinbase,2mg/ml,encapsulatedinliposomes.

EachsingledosevialofDaunoXomecontains50mgdaunorubicin.

Forexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion.

Eachvialcontainsatranslucentredliposomaldispersionfreefromvisibleparticles.

4CLINICALPARTICULARS

4.1TherapeuticIndications

AIDS-relatedKaposi’sSarcomainpatientswithlowCD4cellcounts(<200cells/mm 3

)andextensivemucocutaneous

orvisceraldisease.

DaunoXomeshouldnotbeusedtotreatAIDS-relatedKSthatmaybeeffectivelytreatedwithlocaltherapy.

4.2Posologyandmethodofadministration

DaunoXomeshouldbeadministeredbyintravenousinfusion.TherecommendedinitialdoseofDaunoXomeinpatients

withAIDS-relatedKaposi’ssarcomais40mg/m 2

everytwoweeks.ThedosageofDaunoXomemustbeadjustedfor

eachpatient.Therapyshouldbecontinuedaslongasdiseasecontrolcanbemaintained.

DaunoXomeshouldbedilutedwith5%dextroseforinfusionbeforeadministration.Therecommendedconcentration

afterdilutionisbetween0.2mgand1mgdaunorubicin/mlofsolution.DaunoXomeshouldbeadministered

intravenouslyoveraminimumperiodof30-60minutes(seealsoSections6.2,6.3and6.6.).

DaunoXomemustnotbegivenbytheintramuscularorsubcutaneousrouteorasabolusinjection.

DaunoXomeisaliposomalpreparationandshouldnotbeusedinterchangeablywithconventionaldaunorubicin.

Pediatricpatients:DaunoXomeisnotrecommendedforuseinchildrenbelow18yearsofageduetoinsufficientdata

onsafetyandefficacy.

Elderly:ThesafetyandeffectivenessofDaunoXomeinpatientsover65yearsofagehavenotbeenestablished.

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Hepaticimpairmentandrenalimpairment:

DaunoXomehasnotbeenstudiedinpatientswithimpairedliverorrenalfunction,thereforeDaunoXomeisnot

recommendedinsuchsituations.

4.3Contraindications

HypersensitivitytoDaunoXome,anyofitsexcipientsorotheranthracyclines/anthracenediones.

Breastfeeding.

4.4Specialwarningsandprecautionsforuse

Cardiotoxicity

DaunoXomeandotheranthracyclinescancausecardiotoxicity,notablycongestiveheartfailureduetocardiomyopathy.

Theonsetofsymptomscanbesuddenandmaynotoccuruntilweeksormonthsafterdiscontinuationoftherapy.

Cardiacdamagemaybeirreversibleandtherehavebeenrarereportsoffatalities,usuallyinpatientswithriskfactors.

Theriskofcardiotoxicityincreaseswithtotalcumulativedosageofanthracyclines.Cautionmustthereforebeexercised

inpatientspreviouslytreatedwithanthracyclines,orthosewithprevious(orconcomitant)therapywithother

cardiotoxiccompoundssuchas5-fluorouracil(5-FU).

Theriskofcardiotoxicityappearstobehigherinthosewithpre-existingcardiovasculardisease,ahistoryof

mediastinalradiationandtheelderly.CautionmustthereforebeexercisedwhenDaunoXomeisgiventothesepatients.

DaunoXomeshouldonlybegiventopatientswithcardiovasculardiseasewhenthebenefitoutweighstherisks.

ExperienceinpatientstreatedwithhighdoseDaunoXome(above60mg/m2)formalignanciesotherthanKaposi’s

sarcomaindicatesthattheriskofcardiotoxicitymaybehigherinthesepatients.

Cardiacmonitoring

CarefulmonitoringofcardiacfunctionisessentialinpatientstreatedwithDaunoXome.

Cardiomyopathyinducedbyanthracyclinesisusuallyassociatedwithadecreasedleftventricularejectionfraction

(LVEF)measuredbyechocardiographyorbyMUGA(MultipleGatedAcquisition)scan.MeasurementofLVEF

providesamorespecificmethodformonitoringcardiacfunctionthanECG.

AllpatientsshouldundergobaselineECGs,echocardiographyandmeasurementofLVEFpriortostarting

DaunoXome.Thesetestsshouldberepeatedregularlyduringtreatment.Furthermore,inallpatients,LVEFmustbe

determinedwhenacumulativedoseof320mg/m2hasbeenreached,thenevery160mg/m2thereafter,inorderto

identifyatanearlystageanychangesinLVEFthatmaybeaprecursortocardiomyopathyifDaunoXometherapyis

continued.

InpatientswithriskfactorsforcardiotoxicitywithDaunoXome,orthosereceivinghighdoseDaunoXomepercycle

(e.g.120mg/m2orabove),decreasesincardiacfunctionmayoccuratlowercumulativedosesofDaunoXome,

thereforeconsiderationshouldbegiventodeterminationofLVEFaftereachtreatmentcycleandbeforeanyadditional

DaunoXomeis

administered.

TransientECGchangessuchasT-waveflattening,S-Tsegmentdepressionandbenignarrhythmiasarenotconsidered

mandatoryindicationsforcessationofDaunoXome.AreductionoftheQRSwaveisconsideredmoreindicativeof

cardiactoxicity.

Whenevercardiomyopathyissuspected,and/orLVEFhasdecreasedsignificantlyascomparedtopre-treatmentvalues

(e.g.20%decline)and/oriftheLVEFislowerthanwouldbeexpected(e.g.<45%),thebenefitofcontinuedtherapy

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ItisrecommendedthattreatmentwithDaunoXomeisstoppedifclinicalsignsofcardiotoxicityappear.

Haematologicaltoxicity

DaunoXomeisabonemarrowsuppressant.Themostsignificanteffectisusuallyneutropenia,whichmaybesevere

andresultinfeverandinfection.Anemiaandthrombocytopeniamayalsooccur,butareusuallylessmarked.Persistent

severemyelosuppressionmayresultinsepsis,orhaemorrhage.Completebloodcountsmustbeperformedpriortoeach

doseandmonitored,asmedicallyappropriate,duringthecourseofDaunoXometherapy.

Patientsmustbeobservedcarefullyforevidenceofintercurrentoropportunisticinfections.

HaematologicaltoxicitymayrequiredosereductionofDaunoXomeorsuspensionordelayoftherapy.Thecolony

stimulatingfactorGCSFhasbeenusedtomanagepatientswithneutropenia.

CautioniswarrantedwhencombiningDaunoXomewithotheragentswhichsuppressbonemarrowfunction.

Injectionsitereactions

CareshouldbetakentoensurethatthereisnoextravasationofDaunoXomeduringadministration.Paravenous

administrationhasresultedinerythema,painandswellingaroundthesiteoftissueinfiltration.Thesechangesare

generallytransitory,resolvingwithin6months.However,localisedtissuenecrosismuststillberegardedasapossible

consequenceofextravasation.

Ifanysignsorsymptomsofextravasationoccur(e.g.stinging,erythema),theinfusionshouldbestoppedimmediately

andre-startedinanothervein.Itmaybeinappropriatetoprovideanymeasurethatmightcausereleaseofthedrug

fromtheliposome(suchasapplicationoficeorcorticosteroids,instillationoflocalantidotes,localcompression,etc.)

Acuteinfusionassociatedreactions

Acuteinfusion-relatedreactionshavebeenreportedinpatientstreatedwithDaunoXome.

Symptomstypicallyincludebackpain,flushing,chesttightnessanddyspnoea.Theseinfusionreactionsmayoccur

duringthepatient’sfirstexposuretoDaunoXome,orduringre-exposureinapatientwhohadpreviouslyreceived

DaunoXomewithoutincident.Infusion-relatedreactionsgenerallyoccurwithinthefirst10minutesoftheinfusionand

subsidewhentheinfusionisslowedorhalted.Acuteallergic/anaphylacticreactions,sometimesassociatedwith

hypotension,havealsobeenreported.

CautionshouldbeexercisedwhenDaunoXomeisusedconcomitantlywithothermyelosuppressiveorcardiotoxic

agents(seealsosection4.5).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ProteaseInhibitorsandNonNucleosideReverseTranscriptaseInhibitorsareknowninhibitorsofCytochromeP450

IIIA(CYP-3A)andmayalsohavearoleintheinhibitionofthedrugtransportingprotein,P-glycoprotein(P-gp).

DaunorubicinandotheranthracyclinesmayundergosomemetabolismbyCYP-3AandareknownsubstratesofP-gp.

ThereisthereforeatheoreticalpossibilityofinteractionbetweenDaunoXomeandthesetwogroupsofantiviral

therapy.Todatehowever,asinglestudyhasindicatedthatthereisnoeffectofPI’sorNNRTI’sonDaunoXome’s

pharmacokineticproperties.Limiteddatafromonesmallstudywherepatientsweretreatedwithandwithoutprotease

inhibitorsindicatethattherewerenomajorchangesinDaunoXomeassociatedtoxicity.

CautionshouldbeexercisedwhenDaunoXomeisusedconcomitantlywithothermyelosuppressiveorcardiotoxic

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4.6Fertility,pregnancyandlactation

Womenofchildbearingpotential/Contraceptioninmalesandfemales

Womenofchildbearingpotentialmustuseeffectivecontraceptionwhiletheyortheirmalepartnerisreceiving

DaunoXome,andfor24weeksfollowingdiscontinuationoftreatmentwithDaunoXome.

Pregnancy

TheactiveingredientofDaunoXome,daunorubicin,hasbeenshowntobemutagenic,teratogenicandcarcinogenicin

invitroandinvivoexperiments(seesection5.3).

DaunoXomemaycauseseriousbirthdefectsandshouldnotbeusedduringpregnancyunlessclearlynecessaryandthe

mothershouldbeinformedabouttherisktothefetus

Breastfeeding

BreastfeedingiscontraindicatedduringtreatmentwithDaunoXome(seesection4.3).

Fertility

Noclinicaldataareavailable.Nonclinicalfertilitystudieshavebeenperformed,howeverundesirableeffectsonthe

testiswereobservedinastudyindogs(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

NostudieshavebeenperformedontheeffectsofDaunoXomeontheabilitytodriveandusemachines.However,

patientsshouldbeinformedthatdizzinesshasbeenreportedduringtreatmentwithDaunoXome.

4.8Undesirableeffects

TheadversereactionsconsideredatleastpossiblyrelatedtotreatmentwithDaunoXomearelistedbelow,bybody

systemorganclassandabsolutefrequency.Frequenciesaredefinedasfollows:verycommon 10%;common 1%

and<10%;uncommon 0.1%and<1%;rare 0.01%and<0.1%,veryrare<0.01%.

INFECTIONSANDINFESTATIONS

Verycommon:infections

Uncommon:sepsis,septicshock(seeSection4.4)

BLOODANDLYMPHATICSYSTEMDISORDERS

Verycommon:bonemarrowsuppression,agranulocytosis,neutropenia,febrileneutropenia,leucopenia,pancytopenia,

thrombocytopeniaandanemia(seeSection4.4)

IMMUNESYSTEMDISORDERS

Verycommon:allergicreactions

Rare:anaphylacticreaction

METABOLISMANDNUTRITIONALDISORDERS

Common:dehydration

PSYCHIATRICDISORDERS

Common:depression

NERVOUSSYSTEMDISORDERS

Verycommon:headache

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CARDIACDISORDERS(seeSection4.4):

Common:decreasedleftventricularejectionfraction

Uncommon:congestiveheartfailure,cardiomyopathy

Rare:atrialfibrillation,myocardialinfarction

RESPIRATORY,THORACICANDMEDIASTINALDISORDERS

Verycommon:dyspnoea

GASTROINTESTINALDISORDERS:

Verycommon:stomatitis,mucousulcerations,nausea,vomiting,diarrhoea,abdominalpain

SKINANDSUBCUTANEOUSTISSUEDISORDERS

Verycommon:alopecia

Rare:palmar-plantarerythrodysaesthesiasyndrome(seebelow)

Palmar-plantarerythrodysaesthesiasyndrome(hand-footsyndrome)hasbeenreportedrarelyinpatientstreatedwith

highdoseDaunoXomeandcytarabineforleukaemia.Theconditionischaracterisedbyswelling,pain,tinglingand

erythemaofthepalmsandsoles,whichmayleadtodesquamationoftheskininsomepatients.Dosereductionor

delayeddosingmayberequiredtomanagethecondition.

GENERALDISORDERSANDADMINISTRATIONSITECONDITIONS:

Verycommon:infusion-associatedreactions(includingbackpain,flushing,chesttightness,anddyspnoea)(SeeSection

4.4),asthenia,fatigue,fever,chills

Common:extravasationattheinjectionsitemayresultinerythema,painandswelling;seeSection4.4)

4.9Overdose

Fromexperiencewithnon-liposomalanthracyclinpreparations,theprimaryanticipatedtoxicityfromsuchan

overdosewouldbemyelosuppression.Furthermoreothersideeffectsmayoccurinmorepronouncedform,like

cardiomyopathy.Intheeventofoverdosebonemarrowfunctionandcardiacfunctionshouldbecarefullymonitored

withappropriatetherapyforanysevereside -effects.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcodeL01DB02,Pharmacotherapeuticgroup:Antineoplasticagent

TheactiveingredientofDaunoXomeisdaunorubicin,acytotoxicanthracyclineantibioticisolatedfrom

Streptomycescoeruleorubidus.Theexactmechanismoftheantitumouractivityofdaunorubicinisnotknown.Itis

generallybelievedthatinhibitionofDNA,RNAandproteinsynthesisisresponsibleforthemajorityofthecytotoxic

effects.ThisisprobablytheresultofintercalationoftheanthracyclinebetweenadjacentbasepairsoftheDNA

doublehelixthuspreventingtheirunwindingforreplication.Daunorubicinalsohasantibacterialand

immunosuppressiveproperties.

DaunoXomeisaliposomalpreparationofdaunorubicinformulatedtoprolongcirculationtimeandtomaximisethe

selectivityofdaunorubicinfortumors.Whileinthecirculation,theDaunoXomeformulationhelpstoprotectthe

entrappeddaunorubicinfromchemicalandenzymaticdegradation,minimisesproteinbinding,andgenerally

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TumourselectivityofDaunoXomehasbeendemonstratedfortransplantedtumoursinanimalmodels.Theexact

mechanismbywhichDaunoXomeisabletodeliverdaunorubicintosolidtumoursinsituisnotknown.However,it

isbelievedtobeafunctionofincreasedpermeabilityofthetumourneovasculaturetosomeparticulatesinthesize

rangeofDaunoXome.Oncewithinthetumourenvironment,DaunoXomevesiclesenterthetumourcellsintact,after

whichliposomaldisruptionoccurswithintracellularreleaseoffreedaunorubicin.Pharmacokineticstudiesalsoshow

measurablelevelsoffreedaunorubicininplasma,whichmayhaveanadditionalanti-tumoureffect.Resultsfromin

vivotherapeuticstudiesinmice,i.e.,antitumouractivitymeasuredasincreasedmediansurvivaltimeandbyreduced

tumoursize,haveshownthatDaunoXomehasimprovedefficacycomparedwithdaunorubicinatoptimaldoses.

Clinicaltrialscomparingliposomalandconventionaldaunorubicinhavenotbeenconducted.

5.2Pharmacokineticproperties

FollowingtheadministrationofDaunoXome,daunorubicinispresentinplasmaboundtoliposomesandasfree

(protein-boundandnon-protein-bound)drug.

Thepharmacokineticdataoffreedaunorubicinissparseandalsosomewhatdeficientasanalyticalmethodscouldnot

distinguishbetweendaunorubicinanddaunorubicinol.Followingadministrationofconventionaldaunorubicin(80

mg/m 2

)asanintravenousbolus,plasmalevelswereapproximately0.4+0.6µg/mlafter15minutes.Thelevelsfell

below0.1µg/mlwithinapproximately24-36hours.Thevolumeofdistributionwas1055 ±

235l;daunorubicinexhibits

extensivetissuebinding.Clearancewasapproximately223ml/min,AUCapproximately10.3µg.hr/ml.Theplasma

concentration-timecurveshowsabiphasicprocess;thesloweliminationisprobablyduetoslowreleasefromthetissue

bindingsites.Asmallamountwasexcretedthroughtheurine;Daunorubicinisprobablylargelyexcretedthrougha

biliarypathway.

DaunoXomewasadministeredasanintravenousinfusionover30minutesindosesfrom10to80mg/m 2

.Theincrease

inAUCoftotaldaunorubicinlevelswassomewhatgreaterthanproportionaltodose.Averagemaximumlevelsoftotal

daunorubicinfollowing40mg/m 2

were18µg/ml(range15-22µg/ml).Clearancefortotallevelswasapproximately10

ml/min(range7-15).Thesteady-statevolumeofdistributionwasaround4l(range2-6l).Meanterminalhalf-lifewas

4hours(range3-6hours).Maximumdaunorubicinollevelswerebelow0.3µg/mlfollowingtheIVadministrationof

40mg/m 2

DaunoXome.

Theexposure,expressedastheAUCoftotaldaunorubicinlevels,followingadministrationof80mg/m 2

DaunoXomewasapproximately36-foldincreasedascomparedwiththeAUCafteradministrationof80mg/m 2

conventionaldaunorubicin.

5.3Preclinicalsafetydata

Daunorubicinismutagenicbothinvitroandinvivo,andcarcinogenicinvivo.Ahighincidenceofmammarytumours

wasobservedinratstreatedwithdaunorubicin.AlthoughnosuchstudieshavebeenconductedwithDaunoXome,itis

mostlikelythatDaunoXomewillhaveasimilarmutagenicpotential.

Inexperimentsinrats,DaunoXomeanddaunorubicinhaveshownsomerenaltoxicity;however,renaldamageisnot

documentedintheclinicaluseofdaunorubicin.Inexperimentswithmice,acardiotoxiceffectofDaunoXomewas

documented;inclinicalpracticehoweverDaunoXomehassofarprovenlesscardiotoxicthandaunorubicin.

Inmice,singleIVdosesofDaunoXomedidnotincreasethemyelosuppressiveactivitycomparedwithequivalentdoses

offreedaunorubicin.

Studiestoevaluatetheeffectsofliposomaldaunorubicinonfertilityhavenotbeenperformed;however,theactive

ingredient,daunorubicin,causedtesticularatrophyandtotalaplasiaofspermatocytesintheseminiferoustubulesin

maledogsadministered0.25mg/kgperday(approximatelyeighttimestherecommendedhumandoseonamg/m2

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Listofexcipients

Liposome:

Colfoscerilstearate

Cholesterol

Citricacid

Buffer:

Sucrose

Glycine

Calciumchloridedihydrate

Hydrochloricacid

Sodiumhydroxide

Waterforinjection

6.2Incompatibilities

DaunoXomemayonlybemixedwith5%dextroseforinfusion.IfDaunoXomeismixedwithsaline,aggregationofthe

liposomesmayresult.Admixturescontainingbacteriostaticagentssuchasbenzylalcoholorotherdetergent -like

moleculesshouldbeavoidedaswellbecausesuchcompoundscanrupturethebilayerwalloftheliposomescausing

prematureleakageoftheactivedrug.

NoincompatibilitiesofDaunoXomewithotherdrugshavebeenreported.However,itisknownthattheactive

componentdaunorubicinisphysicallyincompatiblewithheparinsodiumandwithdexamethasonephosphatewhen

directlyadmixed.Aprecipitateisproducedwitheitherdrug.Additionally,becauseofthechemicalinstabilityofthe

glycosidicbondofdaunorubicin,admixtureintoahighlyalkalinemedia(pH>8.0)isnotrecommended.

6.3Shelflife

Theshelflifeis12monthswhenstoredat2 -8ºC.

Chemicalandphysicalin-usestabilityhasbeendemonstratedforDaunoXomedilutedwith5%dextrose,seetable

belowfordetails.

Fromamicrobialpointofview,dilutedDaunoXomeshouldbeusedimmediately.Ifnotusedimmediately,in-use

storagetimesandconditionspriortousearetheresponsibilityoftheuserandshouldnotbelongerthan24hoursat2-

8ºCforthe5%dextrosedilutions.Thisrecommendationismadeontheassumptionthatdilutionhastakenplacein

controlledandvalidatedasepticconditions.

Diluent DilutionRatio,

mLtomL FinalConcentration

Daunorubicinmg/mL DurationofChemical

Stabilityat25 o

5%Dextrose 1:2 1.0 24hours

24hours

0.25 6hours

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6.4Specialprecautionsforstorage

Storeconcentrateinarefrigerator(at2 -8ºC).Donotfreeze.Keepthevialintheoutercartoninordertoprotectfrom

light.

6.5Natureandcontentsofcontainer

DaunoXomeispresentedin50 -mlsterileType1glassPh.Eur.vial.Eachvialcontains25mlliquidforinfusion.The

closureconsistsofabutylrubberstopperandaluminumringsealfittedwitharemovableplasticcap.Eachsingle -dose

vialispackedinawhitechipboardcarton.Includedineachcartonaredirectionsforuse.

Packsize1x25mL.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Donotstorepartiallyusedvialsforfuturepatientuse.Vialsareforsingleuseonly.Discardanyunusedproduct.

Visuallyexaminethevialforevidenceofdeterioration.Evidenceofdeteriorationincludeprecipitationorcrystals

formingintheproduct,changeincolorfromotherthanatranslucentredcolor.Ifthevialshowsevidenceofdamage

includingleakageordeterioration,donotusetheproductanddiscardproductinamannerconsistentwiththehandling

ofanti-cancerdrugs.

Proceduresforproperhandlinganddisposalofanticancerdrugsshouldbefollowed.

UseAsepticTechnique.Aseptictechniquemustbestrictlyobservedinallhandling,sincenopreservativeor

bacteriostaticagentispresentinDaunoXomeorinthematerialsrecommendedfordilution.

WithdrawthecalculatedvolumeofDaunoXomeintoasterilesyringe.InstiltheDaunoXomepreparationintoasterile

containerwiththecorrectamountof5%dextroseforinfusion.Therecommendedconcentrationafterdilutionis

between0.2mgand1mgdaunorubicin/mlofsolution.Infuseovera30-60minuteperiod.Aswithallparenteraldrug

products,inspectthesolutionvisuallyforparticulatematterpriortoadministration.

Caution:TheonlyfluidwhichmaybemixedwithDaunoXome5%dextroseforinfusion;DaunoXomeshouldnotbe

mixedwithsaline,bacteriostaticagentssuchasbenzylalcohol,oranyothersolution.

Anin-linefilterisnotrecommendedfortheintravenousinfusionofDaunoXome.However,ifsuchafilterisused,the

meanporediameterofthefiltershouldnotbelessthan5micron.

IfDaunoXomecomesincontactwithskinorcornea,washimmediatelywithcopiousamountsofcoldwater.The

patientshouldseekmedicalattentionifsignsofinflammationshouldoccur.

DaunoXomeshouldbehandled,andanyremaindershouldbedisposedofinamannerconsistentwiththehandlingof

anti-cancerdrugs.Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

GalenLimited

SeagoeIndustrialEstate

Craigavon

BT635UA

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8MARKETINGAUTHORISATIONNUMBER

PA1329/9/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:01May1996

Dateoflastrenewal:24May2010

10DATEOFREVISIONOFTHETEXT

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