CARDIOXANE 500MG POWDER FOR CONCENTRATE FOR SOLUTI

Main information

  • Trade name:
  • CARDIOXANE 500MG POWDER FOR CONCENTRATE FOR SOLUTI
  • Dosage:
  • 500mg/ vial Milligram
  • Pharmaceutical form:
  • Pdr/Conc/Soln for Infus
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CARDIOXANE 500MG POWDER FOR CONCENTRATE FOR SOLUTI
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0013/121/001
  • Authorization date:
  • 29-09-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cardioxane500mgPowderforConcentrateforSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Cardioxanecontains500mglyophilizeddexrazoxane,asitshydrochloricsalt.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

PowderforConcentrateforSolutionforInfusion.

Sterile,pyrogen-free,whitetooff-white,lyophilizedpowderforsolutionforinfusion.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Preventionofchroniccumulativecardiotoxicitycausedbydoxorubicinorepirubicinuseinadvancedand/ormetastatic

adultbreastcancerpatientswhohavereceivedapriorcumulativedoseof300mg/m2ofdoxorubicinoraprior

cumulativedoseof540mg/m2ofepirubicinwhenfurtheranthracyclinetreatmentisrequired.

4.2Posologyandmethodofadministration

Posology

Cardioxaneisadministeredbyashortintravenousinfusion(15minutes),approximately30minutespriorto

anthracyclineadministrationatadoseequalto10timesthedoxorubicin-equivalentdoseand10timestheepirubicin-

equivalentdose.

ThusitisrecommendedthatCardioxaneisgivenatadoseof500mg/m 2

whenthecommonlyuseddosageschedulefor

doxorubicinof50mg/m 2

isemployedor600mg/m 2

whenthecommonlyuseddosagescheduleforepirubicinof

60mg/m 2

isemployed.

Paediatricpopulation

Cardioxaneiscontraindicatedinchildrenandadolescentsupto18yearsofage(seesection4.3).

Renalimpairment

Inpatientswithmoderatetosevererenaldysfunction(creatinineclearance<40ml/min)thedexrazoxanedoseshould

bereducedby50%.

Hepaticimpairment

Thedosageratioshouldbekept,i.e.iftheanthracyclinedoseisreducedthedexrazoxanedoseshouldbereduced

accordingly.

Methodofadministration

Intravenoususe

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4.3Contraindications

-Childrenandadolescentsupto18yearsofage(seesections4.4and4.8)

-Patientswhoarehypersensitivetodexrazoxane

-Breast-feeding(seesection4.6)

4.4Specialwarningsandprecautionsforuse

MyelosuppressiveeffectsthatmaybeadditivetothoseofchemotherapywerereportedwithCardioxane(seesection

4.8).Cellcountsatnadirmaybelowerinpatientstreatedwithdexrazoxane.Haematologicalmonitoringisthus

necessary.LeucopeniaandthrombocytopeniagenerallyreversequicklyuponcessationoftreatmentwithCardioxane.

Athigherdosesofchemotherapy,wheretheCardioxanedoseexceeds1000mg/m 2

,myelosuppressionmayincrease

significantly.

Sincedexrazoxaneisacytotoxicagent,withtopoisomeraseIIinhibitionactivity,combinationofdexrazoxanewith

chemotherapymayleadtoanincreasedriskofsecondprimarymalignancy.

Inclinicaltrials,secondprimarymalignancies,inparticularacutemyeloidleukaemia(AML)andmyelodysplastic

syndrome(MDS),havebeenreportedinpaediatricpatientswithHodgkin’sdiseaseandacutelymphoblasticleukaemia

receivingchemotherapyregimesincludingseveralcytotoxics(e.g.etoposide,doxorubicin,cyclophosphamide)(see

section4.8).

AMLhasbeenreporteduncommonlyinadultbreastcancerpatientspost-marketing(seesection4.8).

Insomestudies,ahigherincidenceofdeathhasbeenobservedinthegroupstreatedwithdexrazoxaneplus

chemotherapycomparedtothosetreatedwithchemotherapyalone.Thepossibilitythatdexrazoxanewasacontributing

factortotheimbalancecannotberuledout(seesection5.1).

Asignificantdecreaseintumourresponseratehasbeenreportedinonestudyinadvancedbreastcancerpatientstreated

withdoxorubicinanddexrazoxanecomparedtopatientstreatedwithdoxorubicinandplacebo.Sincebothdexrazoxane

anddoxorubicinaretopoisomeraseinhibitors,itispossiblethatdexrazoxanemayinterferewiththeanti-tumour

efficacyofdoxorubicin.Useofdexrazoxaneincombinationwithadjuvantbreastcancertherapyorchemotherapy

intendedascurativeisthereforenotrecommended.

Clearanceofdexrazoxaneanditsactivemetabolitesmaybereducedinpatientswithdecreasedcreatinineclearance.

LiverdysfunctionwasoccasionallyobservedinpatientstreatedwithCardioxane(seesection4.8).

Standardcardiacmonitoringassociatedwithdoxorubicinorepirubicintreatmentshouldbecontinued.

Therearenodatathatsupporttheuseofdexrazoxaneinpatientswithmyocardialinfarctionwithinthepast12months,

pre-existingheartfailure(includingclinicalheartfailuresecondarytoanthracyclinetreatment),uncontrolledanginaor

symptomaticvalvularheartdisease.

Combinationofdexrazoxanewithchemotherapymayleadtoanincreasedriskofthromboembolism(seesection4.8).

Sincedexrazoxaneisacytotoxicagent,sexuallyactivemenshouldcontinueusingeffectivemethodsofcontraception

foratleast3monthsaftercessationoftreatmentwithdexrazoxane(seesection4.6).

Anaphylacticreactionincludingangioedema,skinreactions,bronchospasm,respiratorydistress,hypotensionandloss

ofconsciousnesshavebeenobservedinpatientstreatedwithCardioxaneandanthracyclines(seesection4.8).Previous

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Cardioxanemayincreasehaematologicaltoxicityinducedbychemotherapyorradiation,requiringcarefulmonitoring

ofhaematologicalparametersduringthefirsttwotreatmentcycles(seesection4.4).

Interactionstudieswithdexrazoxanearelimited.EffectsonCYP450enzymesordrugtransportershavenotbeen

studied.

Cardioxaneshouldnotbemixedwithanyothermedicinalproductsduringinfusion.

4.6Fertility,pregnancyandlactation

Womenofchildbearingpotential/contraceptioninmalesandfemales

Bothsexuallyactivemenandwomenshoulduseeffectivemethodsofcontraceptionduringtreatment.Formenthe

contraceptionshouldbecontinuedforatleast3monthsaftercessationoftreatmentwithCardioxane(seesection4.4).

Pregnancy

Therearenoadequatedatafromtheuseofdexrazoxaneinpregnantwomen.Animalstudiesshowedembryotoxicand

teratogeniceffects(seesection5.3).Thepotentialriskforhumansisunknown.Cardioxaneshouldnotbeusedduring

pregnancyunlessclearlynecessary.

Breast-feeding

Therearenoanimalstudiesonthetransferoftheactivesubstanceand/oritsmetabolitesintomilk.Itisunknown

whetherdexrazoxaneand/oritsmetabolitesareexcretedinhumanmilk.Becauseofthepotentialforseriousadverse

reactionsininfantsexposedtoCardioxane,mothersshoulddiscontinuebreast-feedingduringCardioxanetherapy(see

section4.3).

Fertility

TheeffectsofCardioxaneonthefertilityofhumansandanimalshavenotbeenstudied.

4.7Effectsonabilitytodriveandusemachines

Patientsshouldbeadvisedtobecautiouswhendrivingorusingmachinesiftheyexperiencefatigueduringtreatment

withCardioxane.

4.8Undesirableeffects

Cardioxaneisadministeredtogetherwithanthracyclinechemotherapyand,consequently,therelativecontributionsof

anthracyclineandCardioxanetotheadversereactionprofilemaybeunclear.Themostcommonadversereactionsare

haematologicalandgastroenterologicalreactions,primarilyanaemia,leukopenia,nausea,vomitingandstomatitis,as

wellasastheniaandalopecia.MyelosuppressiveeffectsofCardioxanemaybeadditivetothoseofchemotherapy(see

section4.4).Anincreasedriskofthedevelopmentofsecondprimarymalignancies,particularlyAML,hasbeen

reported.

Adversereactions

Thefollowingtableincludesreactionsfromclinicaltrialsandfrompost-marketinguse.Duetothespontaneousnature

ofpost-marketingreporting,sucheventsarelistedwithfrequency“notknown”iftheywerenotalreadyidentifiedas

reactionsfromclinicaltrials.

Adversereactionsarerankedunderheadingsoffrequency,themostfrequentfirst,usingthefollowingconvention:very

common(1/10);common(1/100to <

1/10);uncommon(1/1,000to <

1/100);notknown(cannotbeestimated

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Table1

Clinicaltrialdata

Theabovetableshowsadversereactionsreportedinclinicalstudiesandhavingareasonablepossibilityofacausal

relationshipwithCardioxane.ThesedataarederivedfromclinicaltrialsincancerpatientswhereCardioxanewasused

incombinationwithanthracycline-basedchemotherapy,andwhereinsomecasesacontrolgroupofpatientsreceiving

chemotherapyalonecanbereferredto.

Infectionsandinfestations

Uncommon Infection,sepsis

Neoplasmsbenign,malignantandunspecified(includingcystsandpolyps)

Uncommon Acutemyeloidleukaemia

Bloodandlymphaticsystemdisorders

Verycommon Anaemia,leukopenia

Common Neutropenia,thrombocytopenia,febrileneutropenia,granulocytopenia

Uncommon Febrilebonemarrowaplasia,eosinophilcountincreased,neutrophil

countincreased,plateletcountincreased,whitebloodcellcount

increased,lymphocytecountdecreased,monocytecountdecreased

Immunesystemdisorders

Notknown Anaphylacticreaction,hypersensitivity

Metabolismandnutritiondisorders

Common Anorexia

Nervoussystemdisorders

Common Paraesthesia,dizziness,headache,peripheralneuropathy

Uncommon Syncope

Eyedisorders

Common Conjunctivitis

Earandlabyrinthdisorders

Uncommon Vertigo,earinfection

Cardiacdisorders

Common Ejectionfractiondecreased,tachycardia

Vasculardisorders

Common Phlebitis

Uncommon Venousthrombosis,lymphoedema

Notknown Embolism

Respiratory,thoracicandmediastinaldisorders

Common Dyspnoea,cough,pharyngitis

Uncommon Respiratorytractinfection

Notknown Pulmonaryembolism

Gastrointestinaldisorders

Verycommon Nausea,vomiting,stomatitis

Common Diarrhoea,constipation,abdominalpain,dyspepsia

Uncommon Gingivitis,oralcandidiasis

Hepatobiliarydisorders

Common Transaminasesincreased

Skinandsubcutaneoustissuedisorders

Verycommon Alopecia

Common Naildisorder,erythema

Generaldisordersandadministrationsiteconditions

Verycommon Asthenia

Common Mucosalinflammation,pyrexia,fatigue,malaise,injectionsitereaction

(includingpain,swelling,burningsensation,erythema,pruritus,

thrombosis)

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Ofthese76%weretreatedforbreastcancerand24%foravarietyofadvancedcancers.

Cardioxanetreatment:ameandoseof1010mg/m²(median:1000mg/m²)incombinationwithdoxorubicin,and

ameandoseof941mg/m²(median:997mg/m²)incombinationwithepirubicin.

Chemotherapytreatmentreceivedbypatientstreatedforbreastcancer:45%combinationtherapywith

doxorubicin50mg/m²(mainlywith5-fluorouracilandcyclophosphamide):17%withepirubicinalone;14%

combinationtherapywithepirubicin60or90mg/m²(mainlywith5-fluorouracilandcyclophosphamide).

Patientsreceivingchemotherapyalone(n=157)

Allweretreatedforbreastcancer

Chemotherapytreatmentreceived:43%singleagentepirubicin120mg/m²;33%combinationtherapywith50

mg/m²doxorubicin(mainlywith5-fluorouracilandcyclophosphamide);24%combinationtherapywith

epirubicinat60or90mg/m²(mainlywith5-fluorouracilandcyclophosphamide).

Secondprimarymalignancies

Secondaryacutemyeloidleukaemia(AML)/myelodysplasticsyndrome(MDS)hasbeenobservedinpaediatric

patientswithHodgkin’sdiseaseoracutelymphoblasticleukaemiareceivingdexrazoxaneincombinationwith

chemotherapy(seesection4.4).AMLhasbeenreporteduncommonlyinadultbreastcancerpatientspost-marketing.

Safetyprofileatmaximumtolerateddose

Dexrazoxane'smaximumtolerateddose(MTD)whengivenasmonotherapybyshortinfusioneverythreeweeksfor

cardioprotectionhasnotbeenspecificallystudied.Instudiesofdexrazoxaneasacytotoxic,itsMTDisshowntobe

dependentonposologyanddosingschedule,andvariesfrom3750mg/m 2

whenshortinfusionsaregivenindivided

dosesover3daysto7420mg/m 2

whengivenweeklyfor4weeks,withmyelosuppressionandabnormalliverfunction

testsbecomingdose-limiting.TheMTDislowerinpatientswhohavebeenheavilypre-treatedwithchemotherapy,and

thosewithpre-existingimmunosuppression(e.g.AIDS).

ThefollowingareadversereactionsreportedwhenCardioxanewasgivenatdosesaroundtheMTD:neutropenia,

thrombocytopenia,nausea,vomiting,andincreaseinhepaticparameters.Othertoxiceffectsweremalaise,lowgrade

fever,increasedurinaryclearanceofironandzinc,anemia,abnormalbloodclotting,transientelevationofserum

triglycerideandamylaselevels,andatransientdecreaseinserumcalciumlevel.

4.9Overdose

Thesignsandsymptomsofoverdosearelikelytoconsistofleucopenia,thrombocytopenia,nausea,vomiting,

diarrhoea,skinreactionsandalopecia.Thereisnospecificantidoteandsymptomatictreatmentshouldbeprovided.

Managementshouldincludeprophylaxisandtreatmentofinfections,fluidregulationandmaintenanceofnutrition.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Detoxifyingagentsforantineoplastictreatment,ATCcode:V03AF02

Theexactmechanismbywhichdexrazoxaneexertsitscardioprotectiveeffecthasnotbeenfullyelucidated,however

basedontheavailableevidencethefollowingmechanismhasbeensuggested.Thedose-dependentcardiotoxicity

observedduringanthracyclineadministrationisduetoanthracycline-inducediron-dependentfreeradicaloxidative

stressontherelativelyunprotectedcardiacmuscle.Dexrazoxane,ananalogueofEDTA(ethylenediaminetetra-acetic

acid),ishydrolysedincardiaccellstothering-openedproductICRF-198.Bothdexrazoxane(ICRF-187)andICRF-

198arecapableofchelatingmetalions.Itisgenerallythoughtthattheycanprovidecardioprotectionbyscavenging

metalionsthuspreventingtheFe3+-anthracyclinecomplexfromredoxcyclingandformingreactiveradicals.

Theevidencefromclinicaltrialstodatesuggestsincreasingcardioprotectivebenefitfromdexrazoxaneasthe

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Dexrazoxanedoesnotprotectagainstnon-cardiactoxicitiesinducedbyanthracyclines.

Themajorityofcontrolledclinicalstudieswereperformedinpatientswithadvancedbreastcancer.Datafromadults

treatedin8controlledrandomisedclinicalstudieshavebeenreviewed,780patientsreceiveddexrazoxaneplus

chemotherapyand789receivedchemotherapyalone.Therateofdeathonstudywashigherwiththecombination

dexrazoxanepluschemotherapy(5.0%)comparedtochemotherapyalone(3.4%).Thedifferencewasnotstatistically

significantandnoconsistentcausewasapparent,howeveracontributionofdexrazoxanetothedifferencecannotbe

ruledout.

5.2Pharmacokineticproperties

Afterintravenousadministrationtocancerpatients,serumkineticsofdexrazoxanegenerallyfollowanopentwo-

compartmentmodelwithfirst-orderelimination.Themaximumplasmaconcentrationobservedaftera12-15minute

infusionof1000mg/m 2

isaround80µg/mlwithareaundertheplasmaconcentration-timecurve(AUC)of130±15

mg.h/l.Theplasmaconcentrationsdeclinedthereafterwithanaveragehalf-lifevalueof2.2±1.2hours.Theapparent

volumeofdistributionis44.0±3.9l,suggestingthatdexrazoxanedistributesmainlyinthetotalbodywater.Thetotal

bodyclearanceofdexrazoxaneinadultsisestimatedat14.4±1.6l/h.Cardioxaneanditsmetabolitesweredetectedin

theplasmaandurineofanimalsandman.Themajorityoftheadministereddoseiseliminatedinurinemainlyas

unchangeddexrazoxane.

Thetotalurinaryexcretionofunchangeddexrazoxaneisintheorderof40%.Plasmaproteinbindingofdexrazoxaneis

low(2%)anditdoesnotpenetrateintothecerebrospinalfluidtoaclinicallysignificantextent.Activesubstance

clearancemaybereducedinelderlypatientsandpatientswithlowcreatinineclearance.Thereislimiteddataon

pharmacokineticinteractionswithchemotherapeuticagentsotherthandoxorubicin,epirubicin,cyclophosphamide,5-

fluorouracilandpaclitaxel.Nostudieswereconductedintheelderlyandsubjectswithhepaticorrenalimpairment.

5.3Preclinicalsafetydata

Preclinicalstudiesindicatethatwithrepeateddexrazoxaneadministration,theprimarytargetorgansarethoseofrapid

celldivision:bonemarrow,lymphoidtissue,testesandgastro-intestinalmucosa.TheCardioxanedosingscheduleisa

primaryfactorinthedegreeoftissuetoxicityproduced.Asinglehighdoseisbettertoleratedthanthesamedose

administeredseveraltimesaday.

Dexrazoxanehasbeenshowntopossessmutagenicactivity.Thecarcinogenicpotentialofdexrazoxanehasnotbeen

investigated.Howeverprolongedadministrationofhighdosesofrazoxane,theracemicmixtureofwhichdexrazoxane

istheS(+)-enantiomer,hasbeenassociatedwiththedevelopmentofsecondarymalignancies(primarilyacutemyeloid

leukaemia).Animalreproductionstudiesrevealthatrazoxaneisembryotoxictomice,ratsandrabbitsandalso

teratogenictoratsandmice,althoughadifferentdosingschedulewasusedcomparedtothatusedinman.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Notapplicable

6.2Incompatibilities

Incompatibilitieswithothermedicinalproductsormaterialsarenotknown.HoweverCardioxaneshouldnotbemixed

withothermedicinalproductsduringinfusion,otherthanthediluentsmentionedinsection6.6.

6.3Shelflife

Beforeopening:

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Afterreconstitutionanddilution:

Chemicalandphysicalin-usestabilityofreconstitutedandsubsequentlydilutedCardioxaneis4hoursat25°C.

Fromamicrobiologicalpointofview,reconstitutedandsubsequentlydilutedCardioxaneshouldbeusedimmediately.

Ifnotusedimmediately,storagetimesandconditionspriortousearetheresponsibilityoftheuser,andshouldnotbe

longerthan4hoursat2°Cto8°C(intherefrigerator)withprotectionfromlight.

6.4Specialprecautionsforstorage

Beforeopening:Donotstoreabove25°C.Inordertoprotectfromlightstoreintheoriginalpackage.

6.5Natureandcontentsofcontainer

Vials(TypeIbrownglass),containing500mgofpowder,closedwithachlorobutylrubberstopperandanaluminium

capwithpre-cutstrip.Theproductisfurtherenclosedinanoutercarton.Itissuppliedinpacksof1and4vials.Notall

packsizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Recommendationsforsafehandling

PrescribersshouldrefertonationalorrecognisedguidelinesonhandlingcytotoxicagentswhenusingCardioxane.

Reconstitutionshouldonlybecarriedoutbytrainedstaffinacytotoxicdesignatedarea.Thepreparationshouldnotbe

handledbypregnantstaff.

Useofglovesandotherprotectiveclothingtopreventskincontactisrecommended.Skinreactionshavebeenreported

followingcontactwithCardioxane.IfCardioxanepowderorsolutioncomesintocontactwiththeskinormucosal

surfaces,theaffectedareashouldimmediatelyberinsedthoroughlywithwater.

Preparationforintravenousadministration

ReconstitutionofCardioxane

Forreconstitutionthecontentsofeachvialshouldbedissolvedin25mlWaterforInjections.Thevialcontentswill

dissolvewithinafewminuteswithgentleshaking.TheresultantsolutionhasapHofapproximately1.6.Thissolution

shouldbefurtherdilutedbeforeadministrationtothepatient.

DilutionofCardioxane

Toavoidtheriskofthrombophlebitisattheinjectionsite,Cardioxaneshouldbedilutedpriortoinfusionwithoneof

thesolutionsmentionedinthetablebelow.PreferablysolutionswithahigherpHshouldbeused.Thefinalvolumeis

proportionaltothenumberofvialsofCardioxaneusedandtheamountofinfusionfluidfordilution,whichcanbe

between25mland100mlpervial.

ThetablebelowsummarisesthefinalvolumeandtheapproximatepHofreconstitutedanddilutedproductforonevial

andfourvialsofCardioxane.Theminimumandmaximumvolumesofinfusionfluidstobeusedpervialareshown

below.

Infusionfluid

usedfordilution Volumeoffluid

usedtodilute1

vialof

reconstituted

Cardioxane Finalvolume

obtainedfrom1

vial Finalvolume

obtainedfrom4

vials pH

(approximate)

Ringerlactate 25ml

100ml 50ml

125ml 200ml

500ml 2,2

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*SodiumLactate11.2%shouldbedilutedbyafactorof6toreachaconcentrationof0.16M

Theuseoflargerdilutionvolumes(withamaximumof100mlofadditionalinfusionfluidper25mlreconstituted

Cardioxane)isusuallyrecommendedtoincreasethepHofthesolution.Smallerdilutionvolumes(withaminimumof

25mlofadditionalinfusionfluidper25mlreconstitutedCardioxane)canbeusedifneeded,basedonthe

haemodynamicstatusofthepatient.

Cardioxaneisforsingleuseonly.Reconstitutedandsubsequentlydilutedproductshouldbeusedimmediatelyor

within4hoursifstoredbetween2 o

Cand8 o

Parenteraldrugproductsshouldbeinspectedvisuallyforparticulatematterwheneverthesolutionandcontainerpermit.

Cardioxaneisnormallyacolourlesstoyellowsolutionimmediatelyonreconstitution,butsomevariabilityincolour

maybeobservedovertime,whichdoesnotindicatelossofactivityiftheproducthasbeenstoredasrecommended.It

ishoweverrecommendedtodisposeoftheproductifthecolourimmediatelyonreconstitutionisnotcolourlessto

yellow.

Disposal

Anyunusedsolutionshouldbediscardedinaccordancewithlocalrequirements.Adequatecareandprecautionsshould

betakeninthedisposalofitemsusedtoreconstituteanddiluteCardioxane.

7MARKETINGAUTHORISATIONHOLDER

NovartisPharmaceuticalsUKLtd

FrimleyBusinessPark

Frimley,Camberley

SurreyGU167SR

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA13/121/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:22October1993

Dateoflastrenewal:22October2008

10DATEOFREVISIONOFTHETEXT

0.16MSodium

Lactate* 25ml

100ml 50ml

125ml 200ml

500ml 2,9

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