CISPLATIN TEVA

Main information

  • Trade name:
  • CISPLATIN TEVA
  • Dosage:
  • 0.5 Mg/Ml
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CISPLATIN TEVA
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/119/001
  • Authorization date:
  • 26-02-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CisplatinTeva0.5mg/ml,Concentrateforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

CisplatinTeva0.5mg/mlconcentrateforsolutionforinfusioncontains0.5mg/mlofcisplatin.

Eachmlofsolutioncontains3.5mgofsodium.

Foracompletelistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion.

Clear,lightyellowsolutionfreefromvisibleparticles

4CLINICALPARTICULARS

4.1TherapeuticIndications

CisplatinTevaisintendedforthetreatmentof:

advancedormetastasisedtesticularcancer

advancedormetastasisedovariancancer

advancedormetastasisedbladdercarcinoma

advancedormetastasisedsquamouscellcarcinomaoftheheadandneck

advancedormetastasisednon-smallcelllungcarcinoma

advancedormetastasisedsmallcelllungcarcinoma.

Cisplatinisindicatedincombinationwithradiotherapyinthetreatmentofcervicalcarcinoma.

Cisplatincanbeusedasmonotherapyandincombinationtherapy.

4.2Posologyandmethodofadministration

CisplatinTeva0.5mg/mlconcentrateforsolutionforinfusionistobedilutedbeforeadministration.Forinstructionson

dilutionoftheproductbeforeadministrationseesection6.6.

Thedilutedsolutionshouldbeadministeredonlyintravenouslybyinfusion(seebelow).Foradministration,anydevice

containingaluminiumthatmaycomeincontactwithcisplatin(setsforintravenousinfusion,needles,catheters,

syringes)mustbeavoided(seesection6.2.).

Adultsandchildren:

Thecisplatindosagedependsontheprimarydisease,theexpectedreaction,andonwhethercisplatinisusedfor

monotherapyorasacomponentofacombinationchemotherapy.Thedosagedirectionsareapplicableforbothadults

andchildren.

Formonotherapy,thefollowingtwodosageregimensarerecommended:

Singledoseof50to120mg/m²bodysurfaceevery3to4weeks;

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Ifcisplatinisusedincombinationchemotherapy,thedoseofcisplatinmustbereduced.Atypicaldoseis20mg/m²or

moreonceevery3to4weeks.

Fortreatmentofcervicalcancercisplatinisusedincombinationwithradiotherapy.Atypicaldoseis40mg/m 2

weekly

for6weeks.

Forwarningsandprecautionstobeconsideredpriortothestartofthenexttreatmentcycle,seesection4.4.

Inpatientswithrenaldysfunctionorbonemarrowdepression,thedoseshouldbereducedadequately.

Thecisplatinsolutionforinfusionpreparedaccordingtoinstructions(seesection6.6.)shouldbeadministeredby

intravenousinfusionoveraperiodof6to8hours.

Adequatehydrationmustbemaintainedfrom2to12hourspriortoadministrationuntilminimum6hoursafterthe

administrationofcisplatin.Hydrationisnecessarytocausesufficientdiuresisduringandaftertreatmentwithcisplatin.

Itisrealisedbyintravenousinfusionofoneofthefollowingsolutions:

sodiumchloridesolution0.9%;

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

Hydrationpriortotreatmentwithcisplatin:

Intravenousinfusionof100to200ml/hourforaperiodof6to12hours,withatotalamountofatleast1L.

Hydrationafterterminationoftheadministrationofcisplatin:

Intravenousinfusionofanother2litresatarateof100to200mlperhourforaperiodof6to12hours.

Forceddiuresismayberequiredshouldtheurinesecretionbelessthan100to200ml/hourafterhydration.Forced

diuresismayberealisedbyintravenouslyadministering37.5gmannitolasa10%solution(375mlmannitolsolution

10%),orbyadministrationofadiureticifthekidneyfunctionsarenormal.Theadministrationofmannitoloradiuretic

isalsorequiredwhentheadministratedcisplatindoseishigherthan60mg/m 2

ofbodysurface.

Itisnecessarythatthepatientdrinkslargequantitiesofliquidsfor24hoursafterthecisplatininfusiontoensure

adequateurinesecretion.

4.3Contraindications

Cisplatiniscontraindicatedinpatients

withhypersensitivitytocisplatinorotherplatinumcompoundsortoanyoftheexcipients;

withrenaldysfunction(creatinineclearance<60ml/min);

indehydratedcondition(pre-andpost-hydrationisrequiredtopreventseriousrenaldysfunction);

withmyelosuppression;

withahearingimpairment;

withneuropathycausedbycisplatin

whoarebreastfeeding(seesection4.6.)

incombinationwithyellowfevervaccineandphenytoininprophylacticuse(Seesection4.5.).

4.4Specialwarningsandprecautionsforuse

Cisplatinmayonlybeadministeredunderthesupervisionofaphysicianqualifiedinoncologywithexperienceinthe

useofantineoplasticchemotherapy.

Cisplatinisproventobecumulativeototoxic,nephrotoxic,andneurotoxic.Thetoxicitycausedbycisplatinmaybe

amplifiedbythecombinedusewithothermedicinalproducts,whicharetoxicforthesaidorgansorsystems.

Audiogramsmustbemadebeforestartingtreatmentwithcisplatinandalwaysbeforestartinganothertreatmentcycle

(seesection4.8).

Nephrotoxicitycanbepreventedbymaintainingadequatehydrationbefore,duringandaftertheintravenousinfusionof

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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.

Anaphylactic-likereactionstocisplatinhavebeenobserved.Thesereactionscanbecontrolledbyadministrationof

antihistamines,adrenalineand/orglucocorticoids.

Neurotoxicitysecondarytocisplatinadministrationhasbeenreportedandthereforeneurologicalexaminationsare

recommended.

Specialcautionmustbeexercisedforpatientswithperipheralneuropathynotcausedbycisplatin.

Specialcareisrequiredforpatientswithacutebacterialorviralinfections.

Incasesofextravasation:

immediatelyendtheinfusionofcisplatin;

donotmovetheneedle,aspiratetheextravasatefromthetissue,andrinsewithsodiumchloridesolution0.9%

(ifsolutionswithcisplatinconcentrationshigherthanrecommendedwereused;seesection6.6.).

Nausea,vomitinganddiarrhoeaoftenoccurafteradministrationofcisplatin(seesection4.8).Thesesymptoms

disappearinmostpatientsafter24hours.Lessseriousnauseaandanorexiamaycontinueuptosevendaysafterthe

treatment.

Prophylacticadministrationofananti-emeticmaybeeffectiveinalleviatingorpreventingnauseaandvomiting.

Theliquidlosscausedbyvomitinganddiarrhoeamustbecompensated.

Cisplatinhasbeenshowntobemutagenic.Itmayalsohaveananti-fertilityeffect.Otheranti-neoplasticsubstances

havebeenshowntobecarcinogenicandthispossibilityshouldbeborneinmindinlongtermuseofcisplatin.

Maleandfemalepatientsduringandforatleast6monthsafterthetreatmentwithcisplatin:seesection4.6.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Simultaneoususeofmyelosuppressivesorradiationwillboosttheeffectsofcisplatin’smyelosuppressiveactivity.

Theoccurrenceofnephrotoxicitycausedbycisplatinmaybeintensifiedbyconcomitanttreatmentwith

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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

,whoseurinesecretionislessthan1000mlper24

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

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4.6Fertility,pregnancyandlactation

Pregnancy

Thereisinsufficientdataabouttheuseofcisplatininpregnantwomen.However,basedonthepharmacological

properties,cisplatinissuspectedtocauseseriousbirthdefects.Animalstudieshaveshownreproductivetoxicityand

transplacentalcarcinogenity(seesection5.3).Cisplatinshouldnotbeusedduringpregnancyunlessclearlynecessary.

Womenofchildbearingpotentialandmalepatientshavetouseeffectivecontraceptionduringandupto6monthsafter

treatment.

Apreconceptualconsultisrecommendedwhenpatientswishtohavechildrenaftertreatmentwithcisplatin.Cisplatin

cancausetemporaryorpermanentinfertility.Spermcryopreservationcanbeconsidered(seealsosection4.4).

Lactation

Cisplatinisexcretedinbreastmilk.Breastfeedingiscontra-indicatedduringtreatmentwithcisplatin.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.

However,theprofilesofundesirableeffects(centralnervoussystemandspecialsenses)mayleadtominorormoderate

influenceontheabilitytodriveandusemachines.Patientswhosufferfromtheseeffects(e.g.sleepyorvomiting)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%

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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

agranulocytosisand/oraplasticanaemia)mayoccurafterhighdosesofcisplatin.

Veryrare:

Thromboticmicroangiopathycombinedwithhaemolyticuraemicsyndrome.

Immunesystemdisorders

Uncommon:

Hypersensitivitymaypresentasrash,urticaria,erythema,orpruritusallergic.

Rare:

Anaphylacticreactionshavebeenreported;hypotension,tachycardia,dyspnoea,bronchospasm,faceoedemaandfever

havebeenreported.

Treatmentwithantihistamines,epinephrine(adrenaline)andsteroidsmayberequired.

Immunosuppressionhasbeendocumented.

Endocrinedisorders

Veryrare:

Syndromeofinappropriateantiduretichormonesecretion.

Metabolismandnutritiondisorders

Rare:

Hypomagnaesaemia,hypocalcaemia,hyponatraemia,hypophosphataemiaandhypokalaemiawithmusclespasms

and/orelectrocardiogramchangesoccurasaresultofdamagetothekidneycausedbycisplatin,thusreducingthe

tubularresorptionofcations.

Hypercholesterolemia.

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

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Eyedisorders

Rare:

Blindnessduringacombinationtreatmentwithcisplatin.Followinghigh-dosecisplatinapplicationimpairmentof

colourvisionandeyemovementhasbeenreported.

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.Severecoronaryartery

disease.

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,diarrhoea.

Hepatobiliarydisorders

Common:

Abnormalhepaticfunctionwithincreasedtransaminasesandbloodbilirubinarereversible.

Rare:

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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.

Uncommon:

Hiccups,asthenia,malaise

4.9Overdose

Symptomsofoverdoseinvolveabovementionedsideeffectsinanexcessivemanner.Efficienthydrationandosmotic

diuresiscanaidinreductionoftoxicity,providedthisisappliedimmediatelyafteroverdose.

Incaseofoverdose(200mg/m 2

),directeffectsontherespiratorycentrearepossible,whichmightresultinlife

threateningrespiratorydisordersandacid-baseequilibriumdisturbanceduetopassageofthebloodbrainbarrier.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Otherantineoplasticagents,Platinumcompounds,

ATCcode:L01XA01

Cisplatinisaninorganiccompoundwhichcontainsaheavymetal[cis-diamminedichloridoplatinum(II)].Itinhibits

DNA-synthesisbytheformationofDNAcross-links.ProteinandRNAsynthesisareinhibitedtoalesserextent.

AlthoughthemostimportantmechanismofactionseemstobeinhibitionofDNAsynthesis,othermechanismscanalso

contributetotheantineoplasticactivityofcisplatin,includingtheincreaseoftumourimmunogenicity.Theoncolytic

propertiesofcisplatinarecomparabletothealkylatingagents.Cisplatinalsohasimmunosuppressive,radiosensitising,

andantibacterialproperties.Cisplatinseemstobecell-cyclenon-specific.Thecytotoxicactionofcisplatiniscausedby

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5.2Pharmacokineticproperties

Afterintravenousadministrationcisplatinquicklydistributesacrossalltissues;cisplatinbadlypenetratesinthecentral

nervoussystem.Thehighestconcentrationsarereachedintheliver,kidneys,bladder,muscletissue,skin,testes,

prostate,pancreasandspleen.

Afterintravenousadministrationtheeliminationoffilterable,non-proteinboundcisplatinrunsbiphasic,withaninitial

andterminalhalflifeof10-20minutesand32-53minutes,respectively.Theeliminationofthetotalquantityof

platinumrunstriphasicwithhalflivesof14minutes,and274minuteand53daysrespectively.

Cisplatinisboundtoplasmaproteinsfor90%.

Theexcretionprimarilytakesplaceviatheurine:27-43%oftheadministereddoseisrecoveredintheurineinthefirst

fivedaysafterthetreatment.Platinumisalsoexcretedinthebile.

5.3Preclinicalsafetydata

Chronictoxicity

Inchronictoxicitymodelsindicationsforrenaldamage,bonemarrowdepression,gastro-intestinaldisordersand

ototoxicityhavebeenobserved.

Mutagenicityandcarcinogenity

Cisplatinismutagenicinnumerousinvitroandinvivotests(bacterialtestsystems,chromosomaldisordersinanimal

cellsandintissuecultures).Inlong-termstudiesithasbeenshownthatcisplatiniscarcinogenicinmiceandrats.

Reproductivetoxicity

Inmice,gonadalsuppression,resultinginamenorrhoeaorazoospermiahasbeenobserved,whichcanbeirreversible

andresultininfertility.Infemaleratscisplatininducedmorphologicalchangesintheovaries,causingpartialand

reversibleinfertility.

Studiesinratshaveshownthatexposureduringpregnancycancausetumoursinadultoffspring.

Cisplatinisembryotoxicinmiceandrats,andinbothspeciesdeformitieshavebeenreported.Cisplatinisexcretedin

thebreastmilk.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Waterforinjections

Sodiumchloride

Hydrochloricacid1NforpHadjustment

Sodiumhydroxide1NforpHadjustment

6.2Incompatibilities

Donotbringincontactwithaluminium.Cisplatinreactswithmetalaluminiumtoformablackprecipitateofplatinum.

Allaluminium-containingIVsets,needles,cathetersandsyringesshouldbeavoided.Cisplatindecomposeswith

solutioninmediawithlowchloridecontent;thechlorideconcentrationshouldatleastbeequivalentto0.45%of

sodiumchloride.

Intheabsenceofcompatibilitystudies,thismedicinalproductmustnotbemixedwithothermedicinalproducts.

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

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6.3ShelfLife

Beforeopening

20ml:2years

50ml:2years

100ml:3years

Afterdilution

Afterdilutionininfusionfluidsdescribedinsection6.6,theproductcanbestoredforatmost14daysatroom

temperature(15–25°C)underprotectionfromlight.

Exposuretoambientlightmustbelimitedtoatmost6hours.Ifexceeding6hours,thebagsmustbethoroughly

wrappedinaluminiumfoilinordertoprotectthecontentsfromambientlight.

Fromamicrobiologicalpointofview,thedilutedsolutionshouldbeusedimmediately.Ifnotusedimmediately,in-use

storagetimesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24

hoursat2to8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions

6.4Specialprecautionsforstorage

Undilutedsolution:Storebelow25°C.Donotrefrigerateorfreeze.Keepcontainerintheoutercartoninorderto

protectfromlight.

Forthestorageconditionsofthedilutedmedicinalproduct:seesection6.3.

Donotstoredilutedsolutionsintherefrigeratororfreezer.

6.5Natureandcontentsofcontainer

Brown,typeIglassvialsof20,50and100mlwithbutylrubberstop,aluminiumclosingandplasticsnap-cap.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Preparationandhandlingoftheproduct

Likewithallanti-neoplasticproductscautionisneededwiththeprocessingofcisplatin.Dilutionshouldtakeplace

underasepticconditionsbytrainedpersonnelinanareaspecificallyintendedforthis.Protectiveglovesshouldbeworn

forthis.Precautionsshouldbetakentoavoidcontactwiththeskinandmucousmembranes.Ifskincontactdidoccur

anyway,theskinshouldbewashedwithsoapandwaterimmediately.Withskincontacttingling,burnsandredness

havebeenobserved.Incaseofcontactwiththemucousmembranestheyshouldbecopiouslyrinsedwithwater.After

inhalationdyspnoea,paininthechest,throatirritationandnauseahavebeenreported.

Pregnantwomenmustavoidcontactwithcytostaticdrugs.

Bodilywastematterandvomitshouldbedisposedwithcare.

Ifthesolutioniscloudyoradepositthatdoesnotdissolveisnoticed,thebottleshouldbediscarded.

Adamagedbottlemustberegardedandtreatedwiththesameprecautionsascontaminatedwaste.Contaminatedwaste

mustbestoredinwastecontainersspecificallymarkedforthis.Seesection“Waste”.

Preparationoftheintravenousadministration

Takethequantityofthesolutionthatisneededfromthebottleanddilutewithatleast1litreofthefollowingsolutions:

sodiumchloride0.9%

mixtureofsodiumchloride0.9%/glucose5%(1:1),(resultingfinalconcentrations:sodiumchloride

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sodiumchloride0.9%and1.875%mannitol,forinjection

sodiumchloride0.45%,glucose2.5%and1.875%mannitolforinjection

Alwayslookattheinjectionbeforeuse.Onlyaclearsolution,freefromparticlesshouldbeadministered.

DONOTbringincontactwithinjectionmaterialthatcontainsaluminium

DONOTadministerundiluted

Withrespecttomicrobiological,chemicalandphysicalstabilitywithuseoftheundilutedsolutions,seesection6.3.

Disposal

Allmaterialsthathavebeenusedforthepreparationandadministration,orwhichhavebeenincontactwithcisplatinin

anyway,mustbedisposedofaccordingtolocalcytotoxicguidelines.Remnantsofthemedicinalproductsaswellasall

materialsthathavebeenusedfordilutionandadministrationmustbedestroyedaccordingtohospitalstandard

proceduresapplicabletocytotoxicagentsandinaccordancewithlocalrequirementsrelatedtothedisposalof

hazardouswaste.

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V.

Computerweg10

3542DRUtrecht

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA0749/119/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:30thJanuary2009

Dateoflastrenewal:31 st

August2010

10DATEOFREVISIONOFTHETEXT

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