CARBOPLATIN "EBEWE"

Main information

  • Trade name:
  • CARBOPLATIN "EBEWE"
  • Dosage:
  • 10 Mg/ Ml
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CARBOPLATIN "EBEWE"
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0789/003/001
  • Authorization date:
  • 23-08-1999
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Carboplatin"Ebewe"10mg/mlConcentrateforSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmloftheconcentratecontains10mgCarboplatin.

Eachvialof5mloftheconcentratecontains50mgCarboplatin.

Eachvialof15mloftheconcentratecontains150mgCarboplatin.

Eachvialof45mloftheconcentratecontains450mgCarboplatin.

Eachvialof60mloftheconcentratecontains600mgCarboplatin.

Eachvialof100mloftheconcentratecontains1000mgCarboplatin.

Forafulllistofexcipients,see6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion.

Aclear,colourlessoralmostcolourlesssolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Carboplatinisusedaloneorincombinationwithotherantineoplasticagentsinthetreatmentofadvancedovarian

carcinoma.

4.2Posologyandmethodofadministration

Dosage

Previouslyuntreatedadultpatientswithnormalrenalfunctionreceive400mgcarboplatin/m²bodysurfacesasi.v.

short,terminfusion(15-60min)therapycyclescanberepeatedafter4weekstherapyfreeinterval.Patientswithrisks

(previouslytreatedwithmyelosuppressiveactivedrugsand/or

radiationtherapyorgeneralbadconditions)shouldbetreatedwithaninitialdoseof300-320mg/m².Inpatientswith

impairedrenalfunctionthe

carboplatindosemustbereducedandadaptedtotheglomerularfiltrationrate.

Acommonformularforcalculatingdosage,baseduponthepatientglomerularfiltrationrate(GFRinml/min)andthe

carboplatintargetareaunderthe

concentrationversustimecurve(AUCinmg/mlxmin)seebelow(Calvertformula):

Note:withtheCalvertformula,thetotaldoseofcarboplatiniscalculatedinmg,notmg/m². Dose(mg)=targetAUC(mg/mlxmin)x[GFRml/min+25]

TargetAUC PlannedChemotherapy Patienttreatmentstatus

5-7mg/ml.min Singleagentcarboplatin Previouslyuntreated

4-6mg/ml.min Singleagentcarboplatin Previouslytreated

4-6mg/ml.min Carboplatin plus

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Forchildrennospecificdosagerecommendationscanbemadebecauseoflackofexperienceinthisfield.

Forpatientsagedmorethan65yearsduringthefirstinthefollowingtreatmentcyclestheCarboplatin-dosehastobe

adjustedtothegeneralcondition

ofthepatient.

RouteofAdministration

Carboplatinisadministeredafterpreparationofthesolutionasi.v.short-timeinfusionoveraperiodof15-60min.

Dilution

Theproductmaybedilutedwith5%GlucoseforInjectionBPtoconcentrationsaslowas0.4mg/ml

(400microgram/ml).

Sincenoantibacterialpreservativesarecontainedintheformulation,itisrecommendedthatanyCarboplatinsolution

bediscardedafter24hoursfromdilutionifstoredatroomtemperatureorifstoredrefrigerated.

4.3Contraindications

Hypersensitivitytodrugcomponentsorotherplatinumcontainingagents.

Pregnancyandlactationperiod.

SevereMyelosuppression.

Renalimpairment(glomerularfiltrationrate<30ml/min).

Patientswithcreatinineclearanceof15ml/minorless:Thedataavailablearetoolimitedtopermita

recommendationfortreatment

Patientswithbleedingcancer

Hearingimpairment.

4.4Specialwarningsandprecautionsforuse

Warnings:

Thisagentshouldonlybeadministeredunderthedirectionofanoncologist,inspecialistunitsunderconditions

permittingadequatemonitoringand

surveillance.

Carboplatinmyelosuppressioniscloselyrelatedtoitsrenalclearance.Patientswithabnormalkidneyfunctionor

receivingconcomitanttherapywithotherdrugswithnephrotoxicpotentialarelikelytoexperiencemoresevereand

prolongedmyelotoxicity.Renalfunctionparametersshouldthereforebecarefullyassessedbeforeandduringtherapy.

Carboplatincoursesshouldnotberepeatedmorefrequentlythanmonthlyundernormalcircumstances.

Thrombocytopenia,leucopeniaandanaemiaoccurafteradministrationofCarboplatin.Weeklymonitoringof

peripheralbloodcountsisrecommendedduringtheinitialcourseoftherapywithregularmonitoringduringand

followingtherapywithCarboplatin.Carboplatincombinationtherapywithothermyelosuppressivecompoundsmustbe

plannedverycarefullywithrespecttodosagesandtiminginordertominimiseadditiveeffects.Supportive

transfusionaltherapyandhaematopoieticgrowthfactorssupportmayberequiredinpatientswhosuffersevere

myelosuppression.

Carboplatincancausenauseaandvomiting.Premedicationwithanti-emeticshasbeenreportedtobeusefulinreducing

theincidenceandintensityoftheseeffects.

RenalfunctionimpairmentmaybeencounteredwithCarboplatin.Althoughnoclinicalevidenceoncompounding

nephrotoxicityhasbeenaccumulated,itisrecommendednottocombineCarboplatinwithaminoglycosidesorother

nephrotoxiccompounds.

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Thesemayoccurwithinminutesofadministrationandshouldbemanagedwithappropriatesupportivetherapy.

Anaphylactic-likereactionsmayalsooccuraswithotherplatinumco-ordinationcompounds.

Itscarcinogenicpotentialhasnotbeenstudiedbutcompoundswithsimilarmechanismsofactionandmutagenicity

havebeenreportedtobe

carcinogenic.

Precautions:

Peripheralbloodcounts,renalandhepaticfunctiontestsshouldbemonitoredclosely.Bloodcountsatthebeginningof

thetherapyandweeklytoassesshaematologicalnadirforsubsequentdoseadjustmentarerecommended.Neurological

evaluationsshouldalsobeperformedonaregularbasis.

CasesofhepatictoxicityassociatedwithrenaltoxicityhavebeenreportedwithveryhighdosesofCarboplatin.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

MyelosuppressionisworsenedbytherapycombiningCarboplatinwithothercompoundsthataremyelosuppressive.

Renalfunctionimpairmentmayoccurwithcarboplatin.Therefore,carboplatinshouldnotbecombinedwith

aminoglycosidesorotheragentswithsimilartoxicity.

4.6Fertility,pregnancyandlactation

Carboplatinissuspectedtocauseseriousbirthdefectswhenadministeredduringpregnancy.

AnimalstudieshaveshownCarboplatintobeembryotoxicandteratogenicinrats.Carboplatiniscontraindicated(see

4.3)inpregnancy.

Lactation:

ItisnotknownwhetherCarboplatinisexcretedinhumanmilk.Thereforeitshouldnotbeadministeredtowomenwho

arebreastfeedinginfants.

4.7Effectsonabilitytodriveandusemachines

Carboplatinmayimpairconcentrationandabilityindrivingandhandlingwithmachines.

4.8Undesirableeffects

Incidencesofadversereactionsreportedhereunderarebasedoncumulativedataobtainedinalargegroupofpatients

withvariouspretreatment

prognosticfeatures.

Haematologicaltoxicity:

Verycommon(10%)

Myelosuppressionisthedose-limitingtoxicityofCarboplatin.AtmaximumtolerateddosagesofCarboplatin

administeredasasingleagent,thrombocytopenia,withnadirplateletcountsoflessthan50x10 9

/L,occursinabouta

quarterofthepatients.

Thenadirusuallyoccursbetweendays14and21,withrecoverywithin35daysfromthestartoftherapy.

Leukopeniahasalsooccurredinapproximately14%ofpatientsbutitsrecoveryfromthedaynadir(day14-28)maybe

slowerandusuallyoccurswithin42daysfromthestartoftherapy.Ahaemoglobindecreasemaybeobservedinsome

patients.Neutropeniawithgranulocytecountsbelow1x10 9

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withhaemoglobinvaluesbelow11g/dlhasbeenobservedinmorethantwo-thirdsofpatientswithnormalbase-line

values.

Myelosuppressionmaybemoresevereandprolongedinpatientswithimpairedrenalfunction,extensiveprior

treatment,poorperformancestatusandageabove65.Myelosuppressionisusuallyreversibleandnotcumulativewhen

Carboplatinisusedasasingleagentandattherecommendeddosagesandfrequencies

ofadministration.

Uncommon(0.1%-<1%)

Infectiouscomplicationshaveoccasionallybeenreported.

Haemorrhagiccomplications,usuallyminor,havealsobeenreported.

Nephrotoxicity:

Verycommon(10%)

Renaltoxicityisusuallynotdose-limitinginpatientsreceivingCarboplatin,nordoesitrequirepreventivemeasures

suchashighvolumefluidhydrationorforceddiuresis.Nevertheless,increasingbloodureaorserumcreatininelevels

canoccur.Renalfunctionimpairment,asdefinedbyadecreaseinthecreatinineclearancebelow60ml/min,mayalso

beobserved.Theincidenceandseverityofnephrotoxicitymayincreaseinpatientswhohaveimpairedkidneyfunction

beforeCarboplatintreatment.Itisnotclearwhetheranappropriatehydrationprogrammemightovercomesucheffect,

butdosagereductionordiscontinuationoftherapyisrequiredinthepresenceofseverealterationofrenalfunction

tests.

Uncommon(0.1%-<1%)

Decreasesinserumelectrolytes(sodium,magnesium,potassiumandcalcium)havebeenreportedaftertreatmentwith

Carboplatinbuthavenotbeen

reportedtobesevereenoughtocausetheappearanceofclinicalsignsorsymptoms.

Rare(0.01%-<0.1%)

Casesofhyponatraemiahavebeenreported.

Gastrointestinaltoxicity:

Verycommon(10%)

Nauseawithoutvomitingoccursinabout15%ofthepatientsreceivingCarboplatin;vomitinghasbeenreportedinover

halfofthepatientsandabout

one-fifthofthesesuffersevereemesis.

Nauseaandvomitingusuallydisappearwithin24hoursaftertreatmentandareusuallyresponsiveto(andmaybe

preventedby)anti-emeticmedication.

Afifthofpatientsexperiencenonauseaorvomiting.

Allergicreactions:

Common(1%-<10%)

InfrequentallergicreactionstoCarboplatinhavebeenreported.Thesereactionsaresimilartothoseobservedafter

administrationofotherplatinum-containingcompounds,i.e.erythematousrash,feverwithnootherapparentcauseand

pruritusandshouldbemanagedwithappropriatesupportive

therapy.

Ototoxicity:

Verycommon(10%)

Subclinicaldecreaseinhearingacuity,consistingofhigh-frequency(4000-8000Hz)hearinglossdeterminedby

audiogram,hasbeenreportedin15%ofthepatientstreatedwithCarboplatin.However,only1%ofpatientspresent

withclinicalsymptoms,manifestedinthemajorityofcasesbytinnitus.

Inpatientswhohavebeenpreviouslytreatedwithcisplatinandhavedevelopedhearinglossrelatedtosuchtreatment,

thehearingimpairmentmay

persistorworsen.

Neurotoxicity:

Common(1%-<10%)

TheincidenceofperipheralneuropathiesaftertreatmentwithCarboplatinis4%.Inthemajorityofthepatients

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anddecreaseddeeptendonreflexes.Thefrequencyandintensityofthesideeffectincreasesinelderlypatientsand

thosepreviouslytreatedwith

cisplatin.

ParaesthesiapresentbeforecommencingCarboplatintherapy,particularlyifrelatedtopriorcisplatintreatment,may

persistorworsenduringtreatment

withCarboplatin.

Oculartoxicity:

Rare(0.01%-<0.1%)

Transientvisualdisturbances,sometimesincludingtransientsightloss,havebeenreportedrarelywithplatinum

therapy.Thisisusuallyassociatedwith

highdosetherapyinrenallyimpairedpatients.

Other:

Verycommon(10%)

Abnormalitiesofliverfunctiontests(usuallymildtomoderate)havebeenreportedwithCarboplatininaboutone-third

ofthepatientswithnormalbaselinevalues.ThealkalinephosphataselevelisincreasedmorefrequentlythanSGOT,

SGPTortotalbilirubin.

Themajorityoftheseabnormalitiesregressspontaneouslyduringthecourseoftreatment.

Common(1%-<10%)

Infrequenteventsconsistingoftastealteration,asthenia,alopecia,feverandchillswithoutevidenceofinfectionor

allergicreactionhaveoccurredinless

than2%ofthepatientsreceivingCarboplatin.

Rare(0.01%-<0.1%)

Haemolytic-uraemicsyndromehasbeenreportedrarely.

4.9Overdose

Aspecificantidoteforoverdosageisnotavailable.

ThereisnoknownantidoteforCarboplatinoverdosage.Theanticipatedcomplicationsofoverdosagewouldberelated

tomyelosuppressionaswellasimpairmentofhepaticandrenalfunction.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antineoplasticagent,ATC-Code:L01XA02

Carboplatinisanantineoplasticagent.Itsactivityhasbeendemonstratedagainstseveralmurineandhumancelllines.

Carboplatinexhibitedcomparableactivitytocisplatinagainstawiderangeoftumoursregardlessofimplantsite.

AlkalineelutiontechniquesandDNAbindingstudieshavedemonstratedthequalitativelysimilarmodesofactionof

carboplatinandcisplatin.Carboplatin,likecisplatin,induceschangesinthesuperhelicalconformationofDNAwhich

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5.2Pharmacokineticproperties

Carboplatinhasbiochemicalpropertiessimilartothatofcisplatin,thusproducingpredominantlyinterstrandand

intrastrandDNAcrosslinks.

FollowingadministrationofCarboplatininman,linearrelationshipsexistbetweendoseandplasmaconcentrationsof

totalandfreeultrafilterableplatinum.Theareaundertheplasmaconcentrationversustimecurvefortotalplatinumalso

showsalinearrelationshipwiththedose.

Repeateddosingduringfourconsecutivedaysdidnotproduceanaccumulationofplatinuminplasma.Followingthe

administrationofCarboplatinreportedvaluesfortheterminaleliminationhalf-livesoffreeultrafilterableplatinumand

Carboplatininmanareapproximately6hoursand1.5hoursrespectively.Duringtheinitialphase,mostofthefree

ultrafilterableplatinumispresentasCarboplatin.Theterminalhalf-lifefortotalplasmaplatinumis24hours.

Approximately87%ofplasmaplatinumisproteinboundwithin24hoursfollowingadministration.

Carboplatinisexcretedprimarilyintheurine,withrecoveryofapproximately70%oftheadministeredplatinumwithin

24hours.Mostofthedrugisexcretedinthefirst6hours.

Totalbodyandrenalclearancesoffreeultrafilterableplatinumcorrelatewiththerateofglomerularfiltrationbutnot

tubularsecretion.

5.3Preclinicalsafetydata

Carboplatinhasbeenshowntobeembryotoxicandteratogenicinrats.(SeePara.4.6,PregnancyandLactation).Itis

mutagenicinvivoandinvitroandalthoughthecarcinogenicpotentialofCarboplatinhasnotbeenstudied,compounds

withsimilarmechanismsofactionandmutagenicityhavebeenreportedtobecarcinogenic.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Waterforinjections

6.2Incompatibilities

Carboplatinmayformaprecipitateoncontactwithaluminium.

Thismedicinalproductmustnotbemixedwithothermedicinalproductsotherthanthosementionedinsection4.2.

6.3ShelfLife

Aspackagedforsale:18months

Removesolutionfromvialimmediatelybeforeuse.

Shelflifeafterdilution:Chemicalandphysicalinusestabilityhasbeendemonstratedin5%Glucoseatconcentrations

of0.4mg/mland2mg/mlfor

24hoursat2-8°Cand25°C.

In-use:Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-use

storagetimesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24

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6.4Specialprecautionsforstorage

Donotstoreabove25°C.Keepthevialintheoutercartoninordertoprotectfromlight.

Forstorageconditionsofthedilutedmedicinalproduct,seesection6.3

6.5Natureandcontentsofcontainer

VialsofTypeIPh.Eur.glasswithbromobutylstopperandaluminiumcrimpcap.Vialsarepackedwithorwithouta

protectiveplasticoverwrap(ONCO-SAFE)inacarton.

Packagesizes:

5mlCarboplatin“Ebewe”10mg/ml:1,5or10vialsarepackedinonecarton.

15mlCarboplatin“Ebewe”10mg/ml:eachvialispackedinacardboardbox.

45mlCarboplatin“Ebewe”10mg/ml:eachvialispackedinacardboardbox.

60mlCarboplatin“Ebewe”10mg/ml:eachvialispackedinacardboardbox.

100mlCarboplatin“Ebewe”10mg/ml:eachvialispackedinacardboardbox.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Forsingleuseonly.

Carboplatin"Ebewe"shouldonlybepreparedforadministrationbypersonnelwhohavebeentrainedinthesafe

handlingofcytotoxics.

Pregnantpersonnelshouldnothandlecytotoxicagents.

Operationssuchasdilutionoftheconcentrateshouldbecarriedoutonlyinthedesignatedarea.Detailedinstructions

onthedilutionoftheconcentratearelistedinsection4.2.

Personnelhandlingtheproductshouldbeadequatelyprotectedwithappropriatepersonalprotectiveequipment,e.g.

clothing,mask,gloves,eyeshield.

Unusedsolutionshouldbediscarded.

Destructionofdrugorcontaminatedarticles:

Incineration:1000°C

Chemical:Diluteinlargevolumesofwater;allowtostandfor48hours.

Contactwithskin:Washwithwater.

Liquidwastemaybeflushedwithcopiousamountsofwater.

Observeguidelinesforthehandlingofcytotoxicdrugs.

7MARKETINGAUTHORISATIONHOLDER

EBEWEPharmaGes.m.b.H.Nfg.KG

A-4866Unterach

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8MARKETINGAUTHORISATIONNUMBER

PA0789/003/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:23August1999

Dateoflastrenewal:22February2009

10DATEOFREVISIONOFTHETEXT

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