CISPLATIN 'EBEWE'

Main information

  • Trade name:
  • CISPLATIN 'EBEWE'
  • Dosage:
  • 0.5
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CISPLATIN 'EBEWE'
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0789/002/001
  • Authorization date:
  • 25-07-1997
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0789/002/001

CaseNo:2050063

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

EbewePharmaGes.m.b.HNfg.KG

Mondseestrasse11,4866Unterach,Austria

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Cisplatin'Ebewe'0.5mg/ml-Concentrateforsolutionforinfusion

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom30/01/2009.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 30/01/2009 CRN 2050063 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cisplatin‘Ebewe’0.5mg/mlConcentrateforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlcontains0.5mgcisplatin.

1vialof20mlconcentrateforsolutionforinfusioncontains10mgcisplatin.

1vialof50mlconcentrateforsolutionforinfusioncontains25mgcisplatin.

1vialof100mlconcentrateforsolutionforinfusioncontains50mgcisplatin.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion

Theconcentrateisaclearandcolourlesssolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Tobeusedasmono-therapy,oraspartofanexistingchemotherapyforadvancedormetastatictumours:testicular

carcinoma(palliativeandcurativepoly-chemotherapy)andovarycarcinoma(stagesIIIandIV),andheadandneck

squamous-cellepithelioma(palliativetherapy).

Inthetreatmentofsmallcelllungcarcinoma.

Inthetreatmentofadvancednon-smallcelllungcarcinoma.

4.2Posologyandmethodofadministration

Cisplatin"Ebewe"0.5mg/mlconcentrateforsolutionforinfusionistobedilutedbeforeuse(seesection6.6.).

Thedilutedsolutionshouldbeadministeredonlyintravenouslybyinfusion(seebelow).Foradministration,anydevice

containingaluminiumthatmaycomeincontactwithcisplatin(setsforintravenousinfusion,needles,catheters,

syringes)mustbeavoided(seesection6.2.).

Adultsandchildren:

Thecisplatindosagedependsontheprimarydisease,theexpectedreaction,andonwhethercisplatinisusedfor

monotherapyorasacomponentofacombinationchemotherapy.Thedosagedirectionsareapplicableforbothadults

andchildren.Forrecommendationsonthedosageapplicable,basedonthediagnosisandtheclinicalcondition,the

currentmedicalliteratureshouldbeconsulted.

Formonotherapy,thefollowingtwodosageregimensarerecommended:

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15to20mg/m²/dayforfivedays,every3to4weeks.

Ifcisplatinisusedincombinationchemotherapy,thedoseofcisplatinmustbereduced.Atypicaldoseis20mg/m²or

moreonceevery3to4weeksunlessinthecombinationtherapyofsmall-cellandnon-small-celllungcarcinoma,in

whichatypicaldoseof80mg/m²isadministered.

Furtherdosagerecommendationsaretobebaseduponcurrentmedicalinsights,tobeobtainedfromtheliterature

or/andtheappropriateworkingparties.

Forwarningsandprecautionstobeconsideredpriortothestartofthenexttreatmentcycle,seesection4.4.

Inpatientswithrenaldysfunctionorbonemarrowdepression,thedoseshouldbereducedadequately.

Thecisplatinsolutionforinfusionpreparedaccordingtoinstructions(seesection6.6.)shouldbeadministeredby

intravenousinfusionoveraperiodof6to8hours.

Adequatehydrationmustbemaintainedfrom2to12hourspriortoadministrationuntilminimum6hoursafterthe

administrationofcisplatin.Hydratationisnecessarytocausesufficientdiuresisduringandaftertreatmentwith

cisplatin.Itisrealisedbyintravenousinfusionofoneofthefollowingsolutions:

sodiumchloridesolution0.9%;

mixtureofsodiumchloridesolution0.9%andglucosesolution5%(1:1).

Hydrationpriortotreatmentwithcisplatin:

Intravenousinfusionof100to200ml/hourforaperiodof6to12hours.

Hydrationafterterminationoftheadministrationofcisplatin:

Intravenousinfusionofanother2litresatarateof100to200mlperhourforaperiodof6to12hours.

Forceddiuresismayberequiredshouldtheurinesecretionbelessthan100to200ml/hourafterhydration.Forced

diuresismayberealisedbyintravenouslyadministering37.5gmannitolasa10%solution(375mlmannitolsolution

10%),orbyadministrationofadiureticifthekidneyfunctionsarenormal.Theadministrationofmannitoloradiuretic

isalsorequiredwhentheadministratedcisplatindoseishigherthan60mg/m 2

ofbodysurface.

Itisnecessarythatthepatientdrinkslargequantitiesofliquidsfor24hoursafterthecisplatininfusiontoensure

adequateurinesecretion.

4.3Contraindications

Cisplatiniscontraindicatedinpatients

-withhypersensitivitytotheactivesubstanceorotherplatinumcontainingmedicinalproducts;

-withrenaldysfunction;

-indehydratedcondition(pre-andpost-hydrationisrequiredtopreventseriousrenaldysfunction);

-withmyelosuppression;

-withahearingimpairment;

-withneuropathycausedbycisplatinand

-whoarepregnantorbreastfeeding(seesection4.6.Pregnancyandlactation)

-incombinationwithyellowfevervaccineandphenytoininprophylacticuse(Seesection4.5.Interactionswithother

medicamentsandotherformsofinteraction).

4.4Specialwarningsandprecautionsforuse

Cisplatinmayonlybeadministeredunderthesupervisionofaphysicianqualifiedinoncologywithexperienceinthe

useofantineoplasticchemotherapy.

Cisplatinisproventobecumulativeototoxic,nephrotoxic,andneurotoxic.Thetoxicitycausedbycisplatinmaybe

amplifiedbythecombinedusewithothermedicinalproducts,whicharetoxicforthesaidorgansorsystems.

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(seesection4.8).

Nephrotoxicitycanbepreventedbymaintainingadequatehydrationbefore,duringandaftertheintravenousinfusionof

cisplatin.

Forceddiuresisbyhydrationorbyhydrationandsuitablediureticsbeforeandafterthecisplatinadministration

decreasestheriskofnephrotoxicity.Hyperuricaemiaandhyperalbuminaemiamaypredisposetocisplatin-induced

nephrotoxicity.

Before,duringandafteradministrationofcisplatin,thefollowingparametersresp.organfunctionsmustbedetermined:

Renalfunction;

hepaticfunction;

hematopoiesisfunctions(numberofredandwhitebloodcellsandbloodplatelets);

serumelectrolytes(calcium,sodium,potassium,magnesium).

Theseexaminationsmustberepeatedeveryweekovertheentiredurationofthetreatmentwithcisplatin.

Repeatingadministrationofcisplatinmustbedelayeduntilnormalvaluesareachievedforthefollowingparameters:

Serumcreatinine<130µmol/lrsp.1.5mg/dl

Urea<25mg/dl

Whitebloodcells>4.000/µlresp.>4.0x10 9

Bloodplatelets>100.000/µlresp.>100x10 9

Audiogram:resultswithinthenormalrange.

Specialcautionmustbeexercisedforpatientswithperipheralneuropathynotcausedbycisplatin.

Specialcareisrequiredforpatientswithacutebacterialorviralinfections.

Incasesofextravasation:

immediatelyendtheinfusionofcisplatin;

donotmovetheneedle,aspiratetheextravasatefromthetissue,andrinsewithsodiumchloridesolution0.9%(if

solutionswithcisplatinconcentrationshigherthanrecommendedwereused;seesection6.6.).

Nausea,vomitinganddiarrhoeaoftenoccurafteradministrationofcisplatin(seesection4.8).Thesesymptoms

disappearinmostpatientsafter24hours.Lessseriousnauseaandanorexiamaycontinueuptosevendaysafterthe

treatment.

Prophylacticadministrationofananti-emeticmaybeeffectiveinalleviatingorpreventingnauseaandvomiting.

Theliquidlosscausedbyvomitinganddiarrhoeamustbecompensated.

Maleandfemalepatientsduringandforatleast6monthsafterthetreatmentwithcisplatin:seesection4.6.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Simultaneoususeofmyelosuppressivesorradiationwillboosttheeffectsofcisplatin’smyelosuppressiveactivity.

Theoccurrenceofnephrotoxicitycausedbycisplatinmaybeintensifiedbyconcomitanttreatmentwith

antihypertensivescontainingfurosemide,hydralazine,diazoxide,andpropranolol.

Concomitantadministrationofnephrotoxic(e.g.cephalosporins,aminoglycosidesorAmphotericinBorcontrast

media)orototoxic(e.g.aminoglycosides)medicinalproductswillpotentiatethetoxiceffectofcisplatinonthese

organs.Duringoraftertreatmentwithcisplatincautionisadvisedwithpredominantlyrenallyeliminatedsubstances,

e.g.cytostaticagentssuchasbleomycinandmethotrexate,becauseofpotentiallyreducedrenalelimination.

Itmayberequiredtoadjustthedosageofallopurinol,colchicine,probenecid,orsulfinpyrazoneifusedtogetherwith

cisplatin,sincecisplatincausesanincreaseinserumuricacidconcentration.

Exceptforpatientsreceivingdosesofcisplatinexceeding60mg/m 2

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hours,noforceddiuresiswithloopdiureticsshouldbeappliedinviewofpossibledamagetothekidneytractand

ototoxicity.

Simultaneoususeofantihistamines,buclizine,cyclizine,loxapine,meclozine,phenothiazines,thioxanthenesor

trimethobenzamidesmaymaskototoxicitysymptoms(suchasdizzinessandtinnitus).

Simultaneoususeofifosphamidecausesincreasedproteinexcretion.

Theototoxicityofcisplatinwasreportedlyenhancedbyconcomitantuseofifosfamide,anagentwhichisnotototoxic

whengivenalone.

Inarandomisedtrialinpatientswithadvancedovariancarcinomatheresponsetotherapywasinfluencednegativelyby

concomitantadministrationofpyridoxineandhexamethylmelamine.

CisplatingivenincombinationwithbleomycinandvinblastincanleadtoaRaynaud-phenomenon.

Evidencehasbeenestablishedthatthetreatmentwithcisplatinpriortoaninfusionwithpaclitaxelmayreducethe

clearanceofpaclitaxelby70-75%andthereforecanintensifyneurotoxicity(in70%ofpatientsormore).

Inastudyofcancerpatientswithmetastaticoradvancedtumors,docetaxelincombinationwithCisplatininducedmore

severeneurotoxiceffects(dose-relatedandsensoric)thaneitherdrugasasingleagentinsimilardoses.

Reductionoftheblood’slithiumvalueswasnoticedinafewcasesaftertreatmentwithcisplatincombinedwith

bleomycinandetoposide.Itisthereforerecommendedtomonitorthelithiumvalues.

Cisplatinmayreducetheabsorptionofphenytoinresultinginreducedepilepsycontrolwhenphenytoinisgivenas

currenttreatment.Duringcisplatintherapystartinganewanticonvulsivanttreatmentwithphenytoinisstrictly

contraindicated(seesection4.3.).

Chelatingagentslikepenicillaminemaydiminishtheeffectivenessofcisplatin.

Thehighintra-individualvariabilityofthecoagulabilityduringdiseases,andthepossibilityofinteractionbetweenoral

anticoagulantsandanticancerchemotherapyrequiresanincreasedfrequencyoftheINR(prothrombintime)

monitoring.

Inconcomitantuseofcisplatinandciclosporintheexcessiveimmunosuppressionwithriskoflymphoproliferationisto

betakenintoconsideration.

Useoflivingvirusvaccinationsisnotrecommendedgivenwithinthreemonthsfollowingtheendofthecisplatin

treatment.

Yellowfevervaccinearestrictlycontra-indicatedbecauseoftheriskoffatalsystemicvaccinaldisease(seesection

4.3.).

4.6Pregnancyandlactation

Therearenoadequatedatafromtheuseofcisplatininpregnantwomen,butbasedonitspharmacologicalproperties

Cisplatinissuspectedtocauseseriousbirthdefects.Studiesinanimalshaveshownreproductivetoxicityand

transplacentalcarcinogenicity(seesection5.3.).Cisplatiniscontraindicatedduringthepregnancyperiod.

Femalesofchild-bearingpotentialshoulduseeffectivecontraceptionduringandatleast6monthsaftertreatmentwith

cisplatin.Geneticconsultationisrecommendedifthepatientwishestohavechildrenafterendingthetreatment.Both

maleandfemalepatientsmustusecontraceptivemethodstopreventconceptionand/orreproductionduringandforat

least6monthsaftertreatmentwithcisplatin.Geneticconsultationisrecommendedifthepatientwishestohave

childrenafterendingthetreatment.Sinceatreatmentwithcisplatinmaycauseirreversibleinfertility,itis

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spermpriortothetreatment.

Cisplatinisexcretedinhumanmilk.Breastfeedingduringthetherapyiscontraindicated.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.

However,theprofilesofundesirableeffects(centralnervoussystemandspecialsenses)mayleadtominorormoderate

influenceontheabilitytodriveandusemachines.Patientswhosufferfromtheseeffects(egsleepyorvomiting)must

avoiddrivingandoperatingmachinery.

4.8Undesirableeffects

Undesirableeffectsdependontheuseddoseandmayhavecumulativeeffects.

Themostfrequentlyreportedadverseevents(>10%)ofCisplatinwerehaematological(leukopenia,thrombocytopenia

andanaemia),gastrointestinal(anorexia,nausea,vomitinganddiarrhoea),eardisorders(hearingimpairment),renal

disorders(renalfailure,nephrotoxicity,hyperuricaemia)andfever.

Serioustoxiceffectsonthekidneys,bonemarrowandearshavebeenreportedinuptoaboutonethirdofpatientsgiven

asingledoseofcisplatin;theeffectsaregenerallydose-relatedandcumulative.Ototoxicitymaybemoreseverein

children.

Frequenciesaredefinedusingthefollowingconvention:

Verycommon(1/10);common(1/100to<1/10);uncommon(1/1,000to<1/100);rare(1/10,000to1/1,000);

veryrare(1/10,000),notknown(cannotbeestimatedfromtheavailabledata).

Infectionsandinfestations

Common:

Infections.Sepsis.

Neoplasmsbenign,malignantandunspecified(inclcystsandpolyps)

Rare:

Cisplatinincreasestheriskofsecondaryleukaemia.Theriskofsecondaryleukaemiaisdose-dependentandnotage-

andsex-related.

Carcinogenicityistheoreticallypossible(basedoncisplatin'smechanismofaction).

Bloodandlymphaticsystemdisorders

Verycommon:

Dosedependent,cumulativeandmostlyreversibleleukopenia,thrombocytopeniaandanaemiaareobservedin25-30%

ofpatientstreatedwithcisplatin.

Common:

Aconsiderabledecreaseinthenumberofwhitebloodcellsoftenoccursapproximately14daysaftertheuse(lessthan

1.5×10 9

/lin5%ofthepatients).Adecreaseofthenumberofplateletsisobservedafterapproximately21days(less

than10%ofthepatientsshowedatotallessthan50×10 9

/l)(therecoveryperiodisapproximately39days).Anaemia

(decreasesofgreaterthan2ghaemoglobin)occursatapproximatelythesamefrequency,butgenerallywithalater

onsetthanleukopeniaandthrombocytopenia.

Rare:

Coombspositivehaemolyticanaemiawasreportedandwasreversibleiftheuseofcisplatinwasterminated.Literature

hasbeenpublishedregardinghemolysispossiblycausedbycisplatin.Seriousbonemarrowfailure(including

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Veryrare:

Thromboticmicroangiopathycombinedwithhaemolyticuraemicsyndrome.

Immunesystemdisorders

Uncommon:

Hypersensitivitymaypresentasrash,urticaria,erythema,orpruritusallergic.

Rare:

Anaphylacticreactionshavebeenreported;hypotension,tachycardia,dyspnoea,bronchospasm,faceoedemaandfever

havebeenreported.

Treatmentwithantihistamines,epinephrine(adrenaline)andsteroidsmayberequired.

Immunosuppressionhasbeendocumented.

Endocrinedisorders

Veryrare:

Inappropriateantiduretichormonesecretion.

Metabolismandnutritiondisorders

Rare:

Hypomagnaesaemia,hypocalcaemia,hyponatraemia,hypophosphataemiaandhypokalaemiawithmusclespasms

and/orelectrocardiogramchangesoccurasaresultofdamagetothekidneycausedbycisplatin,thusreducingthe

tubularresorptionofcations.

Hypercholesterolaemia.

Increasedbloodamylase.

Veryrare:

Increasedbloodiron.

Nervoussystemdisorders

Common:

Neurotoxicitycausedbycisplatinischaracterisedbyperipheralneuropathy(typicallybilateralandsensory),andrarely

bythelossoftasteortactilefunction,orbyopticretrobulbarneuritiswithreducedvisualacuityandcerebral

dysfunction(confusion,disarthria,individualcasesofcorticalblindness,lossofmemory,paralysis).Lhermitte'ssign,

autonomousneuropathyandmyelopathyofthespinalcordhavebeenreported.

Rare:

Cerebraldisorders(includingacutecerebrovascularcomplications,cerebralarteritis,occlusionofthecaroticartery,and

encephalopathy).

Veryrare:

Seizures.

Theuseofcisplatinmustbeterminatedimmediatelyifoneoftheabovementionedcerebralsymptomsoccurs.

Neurotoxicitycausedbycisplatinmaybereversible.However,theprocessisirreversiblefor30-50%ofthepatients,

evenafterdiscontinuationofthetreatment.Neurotoxicitymayoccurafterthefirstdoseofcisplatin,orafteralong-term

therapy.Severeneurotoxicitymayoccurinpatientswhohavereceivedcisplatinathighconcentrationsorfora

prolongedperiod.

Eyedisorders

Rare:

Blindnessduringacombinationtreatmentwithcisplatin.Followinghigh-dosecisplatinapplicationimpairmentof

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Veryrare:

Papilloedema,opticneuritisandcorticalblindnesshavebeenreportedfollowingtreatmentwithcisplatin.Onecaseof

unilateralopticneuritisretrobulbarwithreducedvisualacuityhasbeenreportedaftercombinationchemotherapy

followedbycisplatintreatment.

Earandlabyrinthdisorders

Verycommon:

Hearingimpairmenthasbeendocumentedinapproximately31%ofpatientstreatedwith50mg/m 2

cisplatin.The

defectiscumulative,maybeirreversible,andissometimeslimitedtooneear.Ototoxicitymanifestsitselfastinnitus

and/orhearingimpairmentathigherfrequencies(4,000-8,000Hz).Hearingimpairmentatfrequenciesof250-2000Hz

(normalhearingrange)wasnoticedfor10to15%ofthepatients.

Common:

Deafnessandvestibulartoxicitycombinedwithvertigomayoccur.Priororsimultaneouscranialradiationincreasesthe

riskofhearingloss.

Rare:

Patientsmaylosetheabilitytoconductanormalconversation.Cisplatin-inducedhearingimpairmentmaybeserious

forchildrenandelderlypatients.(Seesection4.4.)

Cardiacdisorders

Common:

Arrythmiaincludingbradycardia,tachycardiaandotherelectrocardiogramchangese.g.ST-segmentchanges,signsof

myocardialischemiahavebeenobservedparticularlyincombinationwithothercytotoxics.

Rare:

Hypertensionandmyocardialinfarctionmayoccur,evensomeyearsafterchemotherapy.

Veryrare:

Cardiacarresthasbeenreportedaftertreatmentwithcisplatincombinedwithothercytotoxics.

Vasculardisorders

Common:

Phlebitismayoccurintheareaoftheinjectionafterintravenousadministration.

Veryrare:

Vasculardisorders(cerebralormyocardialischaemia,impairmentoftheperipheralcirculationrelatedtotheRaynaud's

syndrome)werelinkedtocisplatinchemotherapy.

Respiratory,thoracicandmediastinaldisorders

Common:

Dyspnoea,pneumoniaandrespiratoryfailure.

Gastrointestinaldisorders

Verycommon:

Anorexia,nausea,vomitinganddiarrhoeaoccurbetween1and4hoursaftertheuseofcisplatin.(Seesection4.4.)

Uncommon:

Metallicsettingonthegums.

Rare:

Stomatitis.

Hepatobiliarydisorders

Common:

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Rare:

Reducedbloodalbuminlevelswerenoticedandmaybelinkedtothetreatmentwithcisplatin.

Skinandsubcutaneoustissuedisorders

Common:

Erythemaandskinulcermayoccurintheareaoftheinjectionafterintravenousadministration.

Uncommon:

Alopecia.

Renalandurinarydisorders

Verycommon:

Renalfailureaftersingleormultipledosesofcisplatin.Amild,reversiblerenaldysfunctionmaybeobservedaftera

singleintermediarydoseofcisplatin(20mg/m 2

to<50mg/m 2

).Theuseofasinglehighdose(50-120mg/m 2

),or

repeateddailyuseofcisplatin,maycauserenalfailurewithtubularrenalnecrosispresentingasuraemiaoranuria.

Renalfailuremaybeirreversible.

Thenephrotoxicityiscumulativeandmayoccur2-3days,ortwoweeksafterthefirstdoseofcisplatin.Serum

creatinineandureaconcentrationsmayincrease.Nephrotoxicitywasobservedin28-36%ofpatientswithoutsufficient

hydrationafterasingledoseof50mg/m 2

ofcisplatin.(Seesection4.4.)

Hyperuricaemiaoccursasymptomaticallyorasgout.Hyperuricaemiahasbeenreportedin25-30%ofpatientsin

conjunctionwithnephrotoxicity.Hyperuricaemiaandhyperalbuminaemiamaypredisposetocisplatin-induced

nephrotoxicity.

Reproductivesystemandbreastdisorders:

Uncommon:

Abnormalspermatogenesisandovulation,andpainfulgynaecomastia.

Generaldisordersandadministrationsiteconditions:

Verycommon:

Fever.

Common:

Localisedoedemaandpainmayoccurintheareaoftheinjectionafterintravenousadministration.

4.9Overdose

Overdosesareexpectedtocausethetoxicactivitiesasdescribedhereinbeforetoanexcessiveextent.Efficient

hydrationandosmoticdiuresismaycontributetothereductionofthecisplatintoxicity,ifusedimmediatelyafterthe

overdose.

Anoverdose(>200mg/m 2

)maydirectlyaffecttherespiratorycentre,whichmaycausefatalrespiratorydysfunction

andupsettingoftheacid/basebalanceresultingfrompassingtheblood-brainbarrier.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antineoplasticagents/PlatinumcompoundsATCcode:L01XA01

Cisplatinisananorganicsubstancecontainingaheavymetal[cis-diamminedichloroplatinum(II)].Thissubstance

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RNAsynthesisisinhibitedtoalesserextent.

AlthoughtheprimaryactivityofcisplatinseemstobetheinhibitionofDNAsynthesis,theantineoplasticprocess

includesotheractivities,suchasenlargementofthetumourimmunogenicity.Cisplatin’soncolyticfunctionscanbe

comparedtothefunctionsofalkylatingsubstances.Cisplatinalsooffersimmunosuppressive,radiosensitisingand

antibacterialfeatures.

Cisplatindoesnotseemtobecellcyclespecific.

ThecytotoxicactivitiesofcisplatinarecausedbybindingallDNAbases,withapreferencefortheN-7positionof

guanineandadenosine.

5.2Pharmacokineticproperties

Afterintravenousadministration,cisplatinisrapidlydistributedamongalltissues.Followingcisplatindosesof20to

120mg/m²,theconcentrationsofplatinumarehighestinliver,prostateandkidney,somewhatlowerinbladder,

muscles,testicle,pancreasandspleenandlowestinbowel,adrenal,heart,lung,cerebrumandcerebellum.Over90%of

thetotalplasmacisplatinisboundedwithproteinaftertwohoursfollowingtheadministration.Thisprocessmaybe

irreversible.Theprotein-boundedpartisnotantineoplasticactive.Cisplatinisnon-linearlypharmacokinetic.Cisplatin

isconvertedbyanon-enzymaticprocessintooneormoremetabolites.Eliminationfromtheplasmaisrealisedintwo

phasesafterintravenousbolusinjectionof50-100mg/m 2

ofcisplatin.Thefollowinghalf-lifeperiodhavebeen

registeredforhumans:

t½(distribution):10-60minutes

t½(terminal):approximately2-5days

Theconsiderableproteinbindingofthetotalplatinumcontentsresultsinanextendedorincompleteexcretionphase

withcumulativeurinesecretionrangingfrom27to45%oftheadministereddoseinaperiodfrom84to120hours.An

extendedinfusionresultsintheurinesecretionofalargerpartofthedose.Thefaecalsecretionisminimal,andsmall

amountsofplatinumcanbetracedinthegallbladderandthelargeintestine.Dysfunctionalkidneysincreasetheplasma

half-lifeperiod,whichmayalsoincreasetheoreticallyinthepresenceofascitescausedbythehighlyproteinbinding

activitiesofcisplatin.

5.3Preclinicalsafetydata

Chronictoxicity:

Chronictoxicitymodelsindicatekidneydamage,bonemarrowdepression,gastro-intestinedisordersandototoxicity.

Mutagenityandcarcinogenity:

Cisplatinismutagenicinnumerousinvitroandinvivotests(bacterialtestsystemsandchromosomedefectsinanimal

cellsandtissuecultures).Longtermstudiesofcisplatinonmiceandratsevidencedthecarcinogeniceffects.

Reproductivetoxicity:

Fertility:Gonadalsuppressionresultinginamenorrhoeaorazoospermiamaybeirreversibleandcausedefinitive

infertility.

Studiesinratsshowedthatexposureduringpregnancyproducestumoursintheadultoffspring.

Pregnancyandlactation:Cisplatinisembryotoxicandteratogenicformiceandrats,anddefectshavebeenreportedfor

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumchloride

Hydrochloricacid,dilute

Waterforinjections

6.2Incompatibilities

Cisplatinreactswithaluminiumwhichresultsinproductionofablackplatinumprecipitate.Thereforeanydevice

containingaluminiumthatmaycomeincontactwithcisplatin(setsforintravenousinfusion,needles,catheters,

syringes)mustbeavoided.

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

Thecisplatin0.5mg/mlconcentratemustnotbedilutedwithglucosesolution5%aloneormannitolsolution5%alone,

butonlywiththemixturescontainingadditionallysodiumchlorideasstatedinsection6.6.

Antioxidants(suchassodiummetabisulphite),bicarbonates(sodiumbicarbonate),sulfates,fluorouracilandpaclitaxel

mayinactivatecisplatinininfusionsystems.

6.3ShelfLife

Medicinalproductaspackagedforsale:

2years

Solutionforinfusionafterdilution(seesection6.6.):

Chemicalandphysicalin-usestabilityhasbeendemonstratedfor48hoursat2to8°C

forsolutionswithafinalcisplatinconcentrationof0.1mg/mlafterdilutionofthecisplatin0.5mg/mlconcentratewith

oneofthefollowingsolutions:

-sodiumchloridesolution0.9%;

-mixtureofsodiumchloridesolution0.9%andglucosesolution5%(1:1);

-mixtureofsodiumchloridesolution0.9%andmannitolsolution5%(1:1).

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2

to8°C,unlessreconstitution/dilution(etc)hastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Medicinalproductaspackagedforsale:

Donotstoreabove25°C.Donotrefrigerateorfreeze.Keepthevialintheoutercarton.

Forstorageconditionsofthedilutedmedicinalproduct,seesection6.3.

6.5Natureandcontentsofcontainer

AmbertypeIglassvialwithchlorobutylrubberstopperwithaluminiumoverseal.

Packsof

1vialcontaining20ml(10mg)concentrateforsolutionforinfusioneach.

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1vialcontaining100ml(50mg)concentrateforsolutionforinfusioneach.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Cisplatin"Ebewe"0.5mg/mlconcentrateforsolutionforinfusionistobedilutedbeforeuse.Forpreparationof

solutionforinfusion,anydevicecontainingaluminiumthatmaycomeincontactwithcisplatin(setsforintravenous

infusion,needles,catheters,syringes)mustbeavoided(seesection6.2.).

Preparationofsolutionforinfusionmusttakeplaceinasepticconditions.

Fordilutionoftheconcentrate,oneofthefollowingsolutionsshouldbeused:

sodiumchloridesolution0.9%;

mixtureofsodiumchloridesolution0.9%andglucosesolution5%(1:1)(resultingfinalconcentrations:sodium

chloride0.45%,glucose2.5%).

Shouldhydrationpriortothetreatmentwithcisplatinbeimpossible,theconcentratemaybedilutedwith:

mixtureofsodiumchloridesolution0.9%andmannitolsolution5%(1:1)(resultingfinalconcentrations:sodium

chloride0.45%,mannitol2.5%).

Preparationofcisplatinsolutionforinfusion:

Therequiredamount(dose)ofthecisplatinconcentrate0.5mg/mlcalculatedaccordingtotheinstructionsinsection

4.2.shouldbedilutedin1-2litresofoneoftheabovementionedsolutions.

Thedilutedsolutionshouldbeadministeredonlybyintravenousinfusion(seesection4.2.).

Onlyclearandcolourlesssolutionswithoutvisibleparticlesshouldbeused.

Forsingleuseonly.

Cytotoxicagentsshouldbepreparedforadministrationonlybypersonnelwhohavebeentrainedinthesafehandlingof

thepreparation.

Refertolocalcytotoxichandlingguidelines.

Asanyothercytotoxicagent,cisplatinshouldbeusedwithextremecaution:gloves,facemasksandprotectiveclothing

arerequiredandvital.Cisplatinshouldbeprocessedunderaprotectivehood,ifpossible.Contactwithskinand/or

mucousmembranesmustbeavoided.Pregnanthospitalemployeesshouldnotworkwithcisplatin.

Skincontact:Rinsewithlargequantitiesofwater.Applyanointmentifyouhaveatemporaryburningfeeling.(Note:

Somepersonsaresensitivetoplatinumandmayexperienceaskinreaction).

Intheeventofspillage,operatorsshouldputonglovesandmopupthespilledmaterialwithaspongekeptinthearea

forthatpurpose.Rinsetheareatwicewithwater.Putallsolutionsandspongesintoaplasticbagandsealit.Inthecase

ofspillageallitemscomingintocontactwithCisplatinshouldbehandledanddisposedinaccordancetolocalcytotoxic

guidelines.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

EbewePharmaGes.m.b.HNfg.KG

Mondseestrasse11

A-4866Unterach

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8MARKETINGAUTHORISATIONNUMBER

PA789/2/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 25 th

July1997

Dateoflastrenewal: 14 th

May2007

10DATEOFREVISIONOFTHETEXT

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Date Printed 30/01/2009 CRN 2050063 page number: 13