CARBOPLATIN

Main information

  • Trade name:
  • CARBOPLATIN Solution for Infusion 10 Mg/Ml
  • Dosage:
  • 10 Mg/Ml
  • Pharmaceutical form:
  • Solution for Infusion
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CARBOPLATIN Solution for Infusion 10 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0585/024/001
  • Authorization date:
  • 27-04-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0585/024/001

CaseNo:2045950

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

PlivaPharmaLimited

VisionHouse,BedfordRoad,Petersfield,HampshireGU323QB,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Carboplatin10MicromolSolutionforInfusion

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom30/07/2008until.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Carboplatin10mg/mlConcentrateforSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlcontains10mgcarboplatin.

Each5mlvialcontains50mgcarboplatin.

Each15mlvialcontains150mgcarboplatin.

Each45mlvialcontains450mgcarboplatin.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion.

Acolourlesstopaleyellow,clearsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Carboplatin10mg/mlSolutionforInjectionisindicatedforthetreatmentof:

1.advancedovariancarcinomaofepithelialoriginin:

a)firstlinetherapy

b)secondlinetherapy,afterothertreatmentshavefailed

2.smallcellcarcinomaofthelung.

4.2Posologyandmethodofadministration

DosageandAdministration

Carboplatinshouldbeusedbytheintravenousrouteonly.Therecommendeddosageofcarboplatininpreviously

untreatedadultpatientswithnormalkidneyfunctionis400mg/m²asasinglei.v.doseadministeredbya15to60

minutesinfusion.Alternatively,seeCalvertformulabelow:

Dose(mg)=targetAUC(mg/mlxmin)x[GFRml/min+25]

Note:WiththeCalvertformula,thetotaldoseofcarboplatiniscalculatedinmg,notmg/m 2

TargetAUC PlannedChemotherapy Patienttreatmentstatus

5-7mg/ml.min singleagentcarboplatin Previouslyuntreated

4-6mg/ml.min singleagentcarboplatin Previouslytreated

4-6mg/ml.min Carboplatinplus

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Calvert'sformulashouldnotbeusedinpatientswhohavereceivedextensivepretreatmentwiththefollowingtherapy

regimens:

MitomycinC,

Nitrosourea,

combinationtherapywithdoxorubicin/cyclophosphamide/cisplatin,

combinationtherapywith5ormoreagents,

radiotherapy 4500rad,focussedona20x20cmfieldoronmorethanonefield.

Therapywithcarboplatinshouldbediscontinuedinthecaseofanunresponsivetumour,progressivediseaseand/or

occurrenceofnon-tolerablesideeffects.

Therapyshouldnotberepeateduntilfourweeksafterthepreviouscarboplatincourseand/oruntiltheneutrophilcount

isatleast2,000cells/mm³andtheplateletcountisatleast100,000cells/mm 3

Reductionoftheinitialdosageby20-25%isrecommendedforthosepatientswhopresentwithriskfactorssuchas

priormyelosuppressivetreatmentandlowperformancestatus(ECOG-Zubrod2-4orKarnofskybelow80).

Determinationofthehaematologicalnadirbyweeklybloodcountsduringtheinitialcoursesoftreatmentwith

carboplatinisrecommendedforfuturedosageadjustment.

ImpairedRenalFunction

Patientswithcreatinineclearancevaluesoflessthan60ml/minareatgreaterriskofdevelopingmyelosuppression.

Theoptimaluseofcarboplatininpatientspresentingwithimpairedrenalfunctionrequiresadequatedosage

adjustmentsandfrequentmonitoringofbothhaematologicalnadirsandrenalfunction.

Incaseofaglomerularfiltrationrateof<30ml/mincarboplatinshouldnotbeadministeredatall.

CombinationTherapy

Theoptimaluseofcarboplatinincombinationwithothermyelosuppressiveagentsrequiresdosageadjustments

accordingtotheregimenandscheduletobeadopted.

PaediatricPatients

Thereisinsufficientinformationtosupportadosagerecommendationinthepaediatricpopulation.

Elderly

Dosageadjustment,initiallyorsubsequently,maybenecessary,dependentonthephysicalconditionofthepatient.

Dilution&Reconstitution

See6.6InstructionsforUse/Handling.

4.3Contraindications

Carboplatiniscontra-indicatedinpatientswithseverepre-existingrenalimpairment(creatinineclearanceatorbelow

20ml/minute).

Carboplatiniscontra-indicatedinseverelymyelosuppressedpatients.Itisalsocontra-indicatedinpatientswitha

historyofsevereallergicreactionstocarboplatinorotherplatinumcontainingcompounds.

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4.4Specialwarningsandprecautionsforuse

Warnings

Carboplatinshouldbeadministeredbyindividualsexperiencedintheuseofanti-neoplastictherapy.

Carboplatinmyelosuppressioniscloselyrelatedtoitsrenalclearance.Patientswithabnormalkidneyfunctionor

receivingconcomitanttherapywithotherdrugswithnephrotoxicpotentialarelikelytoexperiencemoresevereand

prolongedmyelotoxicity.Renalfunctionparametersshouldthereforebecarefullyassessedbeforeandduringtherapy.

Carboplatincoursesshouldnotberepeatedmorefrequentlythanmonthlyundernormalcircumstances.

Thrombocytopenia,leukopeniaandanaemiaoccurafteradministrationofcarboplatin.Frequentmonitoringof

peripheralbloodcountsisrecommendedthroughoutandfollowingtherapywithcarboplatin.Carboplatincombination

therapywithothermyelosuppressivecompoundsmustbeplannedverycarefullywithrespecttodosagesandtimingin

ordertominimiseadditiveeffects.Supportivetransfusionaltherapymayberequiredinpatientswhosuffersevere

myelosuppression.

Carboplatincancausenauseaandvomiting.Premedicationwithanti-emeticshasbeenreportedtobeusefulinreducing

theincidenceandintensityoftheseeffects.

Renalandhepaticfunctionimpairmentmaybeencounteredwithcarboplatin.Veryhighdosesofcarboplatin(>5times

singleagentrecommendeddose)haveresultedinsevereabnormalitiesinhepaticandrenalfunction.Althoughno

clinicalevidenceoncompoundingnephrotoxicityhasbeenaccumulated,itisrecommendednottocombinecarboplatin

withaminoglycosidesorothernephrotoxiccompounds.

Infrequentallergicreactionstocarboplatinhavebeenreported,e.g.erythematousrash,feverwithnoapparentcauseor

pruritus.Rarelyanaphylaxis,angio-oedemaandanaphylactoidreactionsincludingbronchospasm,urticariaandfacial

oedemahaveoccurred.Thesereactionsaresimilartothoseobservedafteradministrationofotherplatinumcontaining

compoundsandmayoccurwithinminutes.Theincidenceofallergicreactionsmayincreasewithpreviousexposureto

platinumtherapy;however,allergicreactionshavebeenobserveduponinitialexposuretocarboplatin.Patientsshould

beobservedcarefullyforpossibleallergicreactionsandmanagedwithappropriatesupportivetherapy.

Thecarcinogenicpotentialofcarboplatinhasnotbeenstudiedbutcompoundswithsimilarmechanismsofactionand

mutagenicityhavebeenreportedtobecarcinogenic.

Safetyandeffectivenessofcarboplatinadministrationinchildrenarenotproven.

Precautions

Peripheralbloodcountsandrenalandhepaticfunctiontestsshouldbemonitoredclosely.Bloodcountsatthebeginning

ofthetherapyandweeklytoassesshaematologicalnadirforsubsequentdoseadjustmentarerecommended.

Neurologicalevaluationsshouldalsobeperformedonaregularbasis.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Patientsreceivingconcomitanttherapywithothernephrotoxicagentsarelikelytoexperiencemoresevereand

prolongedmyelotoxicity.Theuseofcarboplatinwithaminoglycosidesorothernephrotoxiccompoundsisnot

recommended.

Theconcurrentadministrationofcarboplatinandchelatingagentsshouldbeavoidedasitcantheoreticallyleadtoa

decreaseoftheantineoplasticeffectofcarboplatin.However,theantineoplasticeffectofcarboplatinwasnot

influencedbydiethyl-dithiocarbamateinanimalexperimentsorinclinicaluse.

Adecreaseinphenytoinserumlevelshasbeenobservedincaseofconcurrentadministrationofcarboplatinand

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4.6Pregnancyandlactation

Thesafeuseofcarboplatinduringpregnancyhasnotbeenestablished:carboplatinhasbeenshowntobean

embryotoxinandteratogeninrats.Ifcarboplatinisusedduringpregnancythepatientshouldbeapprisedofthe

potentialhazardtothefoetus.Womenofchild-bearingpotentialshouldbeadvisedtoavoidbecomingpregnant.

Carboplatinhasbeenshowntobemutagenicinvivoandinvitro.

Forwomenwhoarepregnantorbecomepregnantduringtherapy,geneticcounsellingshouldbeprovided.

Fertility

Carboplatinisgenotoxic.Therefore,menbeingtreatedwithcarboplatinareadvisednottofatherachildduringandup

to6monthsaftertreatmentandtoseekadviceonconservationofspermpriortotreatmentbecauseofthepossibilityof

irreversibleinfertilityduetotherapywithcarboplatin.

Lactation

Itisunknownwhethercarboplatinisexcretedinhumanbreastmilk.Breastfeedingshouldbediscontinuedduring

carboplatintherapy.

4.7Effectsonabilitytodriveandusemachines

Carboplatinhasnoornegligibleinfluenceontheabilitytodriveandusemachines.However,Carboplatinmaycause

nauseaandvomiting,indirectlyimpairingtheabilitytodriveandusemachines.

4.8Undesirableeffects

Incidencesofadversereactionsreportedhereunderarebasedoncumulativedataobtainedinalargegroupofpatients

withvariouspretreatmentprognosticfeatures.

Thefollowingfrequencieshavebeenused:

Verycommon( ≥1/10)

Common( ≥1/100,<1/10)

Uncommon( ≥1/1,000,≤1/100)

Rare( ≥1/10,000,≤1/1,000)

Veryrare( ≤1/10,000)includingisolatedreports

Neoplasmsbenign,malignantandunspecified(includingcystsandpolyps)

Uncommon:Secondarymalignancies(includingpromyelocyticleukaemiawhichoccurred6yearsaftermonotherapy

withcarboplatinandpreceedingirradiation)havebeenreportedfollowingadministrationofcarboplatinasasingle

agentorincombinationtherapy(causalrelationshipnotestablished).

Bloodandlymphaticsystemdisorders

Verycommon:Myelosuppressionisthedose-limitingtoxicityofcarboplatin.

Myelosuppressionmaybemoresevereandprolongedinpatientswithimpairedrenalfunction,extensiveprior

treatment,poorperformancestatusandageabove65.Myelosuppressionisalsoworsenedbytherapycombining

carboplatinwithothercompoundsthataremyelosuppressive.

Myelosuppressionisusuallyreversibleandnotcumulativewhencarboplatinisusedasasingleagentandatthe

recommendeddosagesandfrequenciesofadministration.

Atmaximumtolerateddosagesofcarboplatinadministeredasasingleagent,thrombocytopenia,withnadirplatelet

countsoflessthan50x10 9

/l,occursinaboutathirdofthepatients.Thenadirusuallyoccursbetweendays14and21,

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Leukopeniahasalsooccurredinapproximately20%ofpatientsbutitsrecoveryfromthedayofnadir(day14-28)may

beslowerandusuallyoccurswithin42daysfromthestartoftherapy.Neutropeniawithgranulocytecountsbelow1x

/loccursinapproximatelyonefifthofpatients.Haemoglobinvaluesbelow9.5mg/100mlhasbeenobservedin

48%ofpatientswithnormalbase-linevalues.Anaemiaoccursfrequentlyandmaybecumulative.

Common:Haemorrhagiccomplications,usuallyminor,havealsobeenreported.

Uncommon:Infectiouscomplicationshaveoccasionallybeenreported.

Rare:Casesoffebrileneutropeniahavebeenreported.Singlecasesoflife-threateninginfectionsandbleedinghave

occurred.

Renalandurinarydisorders

Verycommon:Renaltoxicityisusuallynotdose-limitinginpatientsreceivingcarboplatin,nordoesitrequire

preventivemeasuressuchashighvolumefluidhydrationorforceddiuresis.Nevertheless,increasingbloodureaor

serumcreatininelevelscanoccur.

Common:Renalfunctionimpairment,asdefinedbyadecreaseinthecreatinineclearancebelow60ml/min,mayalso

beobserved.Theincidenceandseverityofnephrotoxicitymayincreaseinpatientswhohaveimpairedkidneyfunction

beforecarboplatintreatment.

Itisnotclearwhetheranappropriatehydrationprogrammemightovercomesuchaneffect,butdosagereductionor

discontinuationoftherapyisrequiredinthepresenceofmoderatealterationofrenalfunction(creatinineclearance41-

59ml/min)orsevererenalimpairment(creatinineclearance21-40ml/min).Carboplatiniscontra-indicatedinpatients

withacreatinineclearanceatorbelow20ml/min.

Metabolismandnutritiondisorders

Verycommon:Decreasesinserumelectrolytes(sodium,magnesium,potassiumandcalcium)havebeenreportedafter

treatmentwithcarboplatinbuthavenotbeenreportedtobesevereenoughtocausetheappearanceofclinicalsignsor

symptoms.

Rare:Casesofhyponatraemiahavebeenreported.

Gastrointestinaldisorders

Verycommon:Nauseawithoutvomitingoccursinaboutaquarterofpatientsreceivingcarboplatin;vomitinghasbeen

reportedinoverhalfofthepatientsandaboutone-thirdofthesesuffersevereemesis.Nauseaandvomitingusually

disappearwithin24hoursaftertreatmentandareusuallyresponsiveto(andmaybepreventedby)anti-emetic

medication.Aquarterofpatientsexperiencenonauseaorvomiting.Vomitingthatcouldnotbecontrolledbydrugs

wasobservedinonly1%ofpatients.Vomitingseemstooccurmorefrequentlyinpreviouslytreatedpatients,

particularlyinpatientspre-treatedwithcisplatin.

Painfulgastro-intestinaldisordersoccurredin17%ofpatients.

Common:Diarrhoea(6%),constipation(4%),mucositis.

Rare:Tastealteration.Casesofanorexiahavebeenreported.

Immunesystemdisorders

Common:Allergicreactionstocarboplatinhavebeenreportedinlessthan2%ofpatients,e.g.,skinrash,urticaria,

erythema,feverwithnoapparentcauseorpruritus.

Rare:Anaphylaxis,anaphylacticshock,angio-oedemaandanaphylactoidreactions,includingbronchospasm,urticaria

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Earandlabyrinthdisorders

Verycommon:Subclinicaldecreaseinhearingacuity,consistingofhigh-frequency(4000-8000Hz)hearingloss

determinedbyaudiogram,hasbeenreportedin15%ofthepatientstreatedwithcarboplatin.

Common:Only1%ofpatientspresentwithclinicalsymptoms,manifestedinthemajorityofcasesbytinnitus.In

patientswhohavebeenpreviouslytreatedwithcisplatinandhavedevelopedhearinglossrelatedtosuchtreatment,the

hearingimpairmentmaypersistorworsen.

Athigherthanrecommendeddosesincombinationwithotherototoxicagents,clinicallysignificanthearinglosshas

beenreportedtooccurinpaediatricpatientswhencarboplatinwasadministered.

Nervoussystemdisorders

Common:Theincidenceofperipheralneuropathiesaftertreatmentwithcarboplatinis6%.Inthemajorityofthe

patientsneurotoxicityislimitedtoparaesthesiaanddecreaseddeeptendonreflexes.Thefrequencyandintensityofthis

sideeffectincreasesinelderlypatientsandthosepreviouslytreatedwithcisplatin.Paraesthesiapresentbefore

commencingcarboplatintherapy,particularlyifrelatedtopriorcisplatintreatment,maypersistorworsenduring

treatmentwithcarboplatin.

Uncommon:Centralnervoussymptomshavebeenreported,however,theyseemtobefrequentlyattributedto

concomitantantiemetictherapy.

Eyedisorders

Rare:Transientvisualdisturbances,sometimesincludingtransientsightloss,havebeenreportedrarelywithplatinum

therapy.Thisisusuallyassociatedwithhighdosetherapyinrenallyimpairedpatients.

Cardiacdisorders

Veryrare:Cardiovascularevents(cardiacfailure,embolism)aswellascerebrovascularevents(apoplexy)havebeen

reportedinsinglecases(causalrelationshipwithcarboplatinnotestablished).Singlecasesofhypertensionhavebeen

reported.

Hepato-biliarydisorders

Verycommon:Abnormalitiesofliverfunctiontests(usuallymildtomoderate)havebeenreportedwithcarboplatinin

aboutone-thirdofthepatientswithnormalbaselinevalues.Thealkalinephosphataselevelisincreasedmorefrequently

thanSGOT,SGPTortotalbilirubin.Themajorityoftheseabnormalitiesregressspontaneouslyduringthecourseof

treatment.

Rare:Severehepaticdysfunction(includingacutelivernecrosis)hasbeenreportedafteradministrationofhigherthan

recommendedcarboplatindosages.

Skinandsubcutaneoustissuedisorders

Common:Alopecia.

Generaldisordersandadministrationsiteconditions

Verycommon:Hyperuricaemiaisobservedinaboutonequarterofpatients.Serumlevelsofuricacidcanbedecreased

byallopurinol.Asthenia.

Common:Malaise

Uncommon:Feverandchillswithoutevidenceofinfection;injectionsitereactionssuchaspain,erythema,swelling,

urticariaandnecrosis

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4.9Overdose

Symptomsofoverdose

CarboplatinwasadministeredinPhaseIstudiesatadosageofupto1600mg/m2i.v.percourse.Atthisdosage,life-

threateninghaematologicalsideeffectswithgranulocytopenia,thrombocytopeniaandanaemiawereobserved.

Thegranulocyte,thrombocyteandhaemoglobinnadirwereobservedbetweendays9-25(median:days12-17).The

granulocyteshadreachedvaluesof 500/µlafter8-14days(median:11)andthethrombocytesvaluesof 25.000/µl

after3-8days(median:7).

Thefollowingnon-haematologicalsideeffectsalsooccurred:renalfunctiondisturbanceswitha50%dropinthe

glomerularfiltrationrate,neuropathy,ototoxicity,sightloss,hyperbilirubinaemia,mucositis,diarrhoea,nauseaand

vomitingwithheadache,erythema,andsevereinfection.Inthemajorityofcases,hearingdisturbancesweretransient

andreversible.

Treatmentofoverdose

Thereisnoknownantidoteforcarboplatinoverdosage.Theanticipatedcomplicationsofoverdosagewouldberelated

tomyelosuppressionaswellasimpairmentofhepaticandrenalfunction.Bonemarrowtransplantationandtransfusions

(thrombocytes,blood)canbeeffectivemeasuresofmanaginghaematologicalsideeffects.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Carboplatinisanantineoplasticagent.Itsactivityhasbeendemonstratedagainstseveralmurineandhumancelllines.

ATCcode:L01XA02.

Carboplatinexhibitedcomparableactivitytocisplatinagainstawiderangeoftumoursregardlessofimplantsite.

AlkalineelutiontechniquesandDNAbindingstudieshavedemonstratedthequalitativelysimilarmodesofactionof

carboplatinandcisplatin.Carboplatin,likecisplatin,induceschangesinthesuperhelicalconformationofDNAwhich

isconsistentwitha"DNAshorteningeffect".

Paediatricpatients:safetyandefficacyinchildrenhavenotbeenestablished.

5.2Pharmacokineticproperties

Carboplatinhasbiochemicalpropertiessimilartothatofcisplatin,thusproducingpredominantlyinterstrandand

intrastrandDNAcrosslinks.Followingadministrationofcarboplatininman,linearrelationshipsexistbetweendose

andplasmaconcentrationsoftotalandfreeultrafilterableplatinum.Theareaundertheplasmaconcentrationversus

timecurvefortotalplatinumalsoshowsalinearrelationshipwiththedosewhencreatinineclearance ≥60ml/min.

Repeateddosingduringfourconsecutivedaysdidnotproduceanaccumulationofplatinuminplasma.Followingthe

administrationofcarboplatinreportedvaluesfortheterminaleliminationofhalf-livesoffreeultrafilterableplatinum

andcarboplatininmanareapproximately6hoursand1.5hoursrespectively.Duringtheinitialphase,mostofthefree

ultrafilterableplatinumispresentascarboplatin.Theterminalhalf-lifefortotalplasmaplatinumis24hours.

Approximately87%ofplasmaplatinumisproteinboundwithin24hoursfollowingadministration.Carboplatinis

excretedprimarilyintheurine,withrecoveryofapproximately70%oftheadministeredplatinumwithin24hours.

Mostofthedrugisexcretedinthefirst6hours.

Totalbodyandrenalclearancesoffreeultrafilterableplatinumcorrelatewiththerateofglomerularfiltrationbutnot

tubularsecretion.

Carboplatinclearancehasbeenreportedtovaryby3-to4-foldinpaediatricpatients.Asforadultpatients,literature

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5.3Preclinicalsafetydata

Carboplatinhasbeenshowntobeembryotoxicandteratogenicinrats.(See4.6,PregnancyandLactation.)Itis

mutagenicinvivoandinvitroandalthoughthecarcinogenicpotentialofcarboplatinhasnotbeenstudied,compounds

withsimilarmechanismsofactionandmutagenicityhavebeenreportedtobecarcinogenic.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

WaterforInjections

Concentratedammoniasolution

6.2Incompatibilities

Needles,syringes,cathetersorintravenoussetscontainingaluminiumpartsthatmaycomeintocontactwithcarboplatin

shouldnotbeusedforpreparationoradministrationofcarboplatin

6.3ShelfLife

Unopenedproduct-18months

Dilutedproduct-Whendilutioniscarriedoutundervalidatedasepticconditions,andifjustified,theproductmaybe

storedforamaximumperiodof24hoursat2-8 °

Cor8hoursatroomtemperature(15-25°C).

6.4Specialprecautionsforstorage

Donotstoreabove25 °

C.Keepvialintheoutercarton.Donotfreeze.

Dilutedproduct:

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor8hoursatroomtemperature(15-25°C).

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat

2to8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

Forstorageconditionsofthedilutedmedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

CardboardcartoncontainingonecolourlessTypeIglassvialwithafluoropolymercoatedbromobutylrubberstopper

andaluminiumclosurewithpolypropylenetop.

Packsizes:

5mlvial,containing50mgofcarboplatin,10mg/ml.

15mlvial,containing150mgofcarboplatin,10mg/ml.

45mlvial,containing450mgcarboplatin,10mg/ml.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Thisproductisforsingledoseuseonly.

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Dilution

Theproductmaybedilutedwith5%GlucoseforInjectionBP,or0.9%SodiumChlorideforInjectionBP,to

concentrationsaslowas0.5mg/ml(500micrograms/ml).

Guidelinesforthesafehandlingofanti-neoplasticagents:

Trainedpersonnelshouldreconstitutethedrug.

Thisshouldbeperformedinadesignatedarea.

Adequateprotectiveglovesshouldbeworn.

Precautionsshouldbetakentoavoidthedrugaccidentallycomingintocontactwiththeeyes.Intheeventofcontact

withtheeyes,washwithwaterand/orsaline.

Thecytotoxicpreparationshouldnotbehandledbypregnantstaff.

Adequatecareandprecautionsshouldbetakeninthedisposalofitems(syringes,needles,etc.)usedtoreconstitute

cytotoxicdrugs.Excessmaterialandbodywastemaybedisposedofbyplacingindoublesealedpolythenebagsand

incineratingatatemperatureof1,000°C.Liquidwastemaybeflushedwithcopiousamountsofwater.

Theworksurfaceshouldbecoveredwithdisposableplastic-backedabsorbentpaper.

UseLuer-Lockfittingsonallsyringesandsets.Largeboreneedlesarerecommendedtominimisepressureandthe

possibleformationofaerosols.Thelattermayalsobereducedbytheuseofaventingneedle.

7MARKETINGAUTHORISATIONHOLDER

PLIVAPharmaLtd.

VisionHouse

BedfordRoad

Petersfield

HampshireGU323QB

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA585/24/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:27thApril2007

10DATEOFREVISIONOFTHETEXT

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