CISPLATIN 1MG/ML CONCENTRATE FOR SOLUTION FOR INFU

Main information

  • Trade name:
  • CISPLATIN 1MG/ML CONCENTRATE FOR SOLUTION FOR INFU
  • Dosage:
  • 1
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CISPLATIN 1MG/ML CONCENTRATE FOR SOLUTION FOR INFU
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0437/004/007A
  • Authorization date:
  • 19-11-1986
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cisplatin1mg/mlConcentrateforSolutionforInfusion.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlofconcentrateforsolutionforinfusioncontains1mgofcisplatin.

1vialof10mlconcentrateforsolutionforinfusioncontains10mgofcisplatin.1vialof50mlconcentratefor

solutionforinfusioncontains50mgofcisplatin.1vialof100mlconcentrateforsolutionforinfusioncontains100mg

ofcisplatin.

Alsocontainssodium9mg/mL

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

ConcentrateforSolutionforInfusion.

Clear,colourlesstopaleyellowsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Cisplatinisindicatedinthemanagementofneoplasticdiseaseincludingmetastatic,non-seminomatousgermcell

carcinoma,advancedstageandrefractoryovariancarcinoma,advancedstageandrefractorybladdercarcinomaand

squamouscellcarcinomaofheadandneck.

Cisplatinisindicatedincombinationwithotherantineoplasticagentsforthetreatmentofmetastatictesticulartumours.

Thecombinationofcisplatin,vinblastine,andbleomycinisreportedtobehighlyeffective.

4.2Posologyandmethodofadministration

Interactionwithaluminium:

Cisplatinmayinteractwithmetalaluminiumtoformablackprecipitateofplatinum.

Allaluminium-containingIVsets,needles,cathetersandsyringesshouldbeavoided.

ADULTSANDCHILDREN

CisplatinshouldbeadministeredbyIVinfusionovera6-8hourperiod.Therecommendeddoseofcisplatininadults

andchildrenis50to100mg/m 2

asasingleIVdoseevery3to4weeks,or15to20mg/m 2

intravenouslydailyfor5

daysevery3to4weeks.Dosagemaybeadjustedifthedrugisusedincombinationwithothertumourtherapy.

PreparationofCisplatinInfusion:

Cisplatin1mg/mlSterileConcentratemaybeaddedto2litresof0.9%sodiumchlorideinjection.Donotrefrigerate

reconstitutedsolutions.

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PreTreatmentHydration:

Pre-treatmenthydrationisrequiredtoinducediuresisduring(andafter)cisplatinadministration.Thishydrationis

achievedbygiving2litresofeither0.9%sodiumchlorideordextrose4%inone-fifthnormalsaline(0.18%)overa2

hourperiod.

Duringthelast30minutesofthepre-treatmenthydrationorafterthehydration,administerbysidearmdrip37.5gof

mannitol(i.e.,375mlofmannitol10%injection).

Treatment:

Followingprehydration,administerthecisplatininfusionover1to2hours.Ithasbeenproposedthatalonger

infusiontimeof6to8hoursmaydecreasethegastrointestinalandrenaltoxicities.Thecontainershouldbecoveredto

excludelight.Discardremainingcontentsafteruse.

PostTreatmentHydration:

ContinueIVhydrationwiththeaimofadministeringanother2litresofsodiumchloride0..9%injection,ordextrose

4%insodiumchloride0.18%injection,overaminimumperiodof6to12hours.Adequatehydrationshouldbe

maintainedfor24hoursfollowinginfusion

4.3Contraindications

Cisplatinmaygiveallergicreactionsinsomepatients.Useiscontraindicatedinthosepatientswithahistoryof

allergicreactiontocisplatinorotherplatinumcontainingcompounds.

Cisplatininducesnephrotoxicitywhichiscumulative.Itisthereforecontraindicatedinpatientswithrenal

impairment.

Cisplatinhasbeenshowntobecumulativelyototoxicandshouldnotbegiventopatientswithhearingimpairment

Cisplatinisalsocontraindicatedinmyelosuppressedpatients.

Useofcisplatiniscontraindicatedinwomenwhoarebreastfeeding.

4.4Specialwarningsandprecautionsforuse

Thisagentshouldonlybeadministeredunderthedirectionofoncologistsinspecialistunitsunderconditions

permittingadequatemonitoringandsurveillance.Supportiveequipmentshouldbeavailabletocontrolanaphylactic

reactions.

Cisplatinreactswithmetallicaluminiumtoformablackprecipitateofplatinum.AllaluminiumcontainingI.V.sets,

needles,cathetersandsyringesshouldbeavoided.

Thesolutionforinfusionshouldnotbemixedwithotherdrugsoradditives.

Cisplatinproducescumulativenephrotoxicitywhichmaybepotentiatedbyaminoglycosideantibiotics.Cisplatin

shouldnotbegivenmorefrequentlythanonceevery3-4weeks(seesection4.8,UndesirableEffects).

Repeatcoursesofcisplatinshouldnotbegivenunlesslevelsofserumcreatininearebelow1.5mg/100ml(130

µmol/l)orbloodureabelow55mg/100ml(9mmol/l,andcirculatingbloodlevelsareatanacceptablelevel.Since

therenaltoxicityofcisplatiniscumulative,measurementofBUN,serumcreatinineorGFRshouldbeperformedprior

toinitiatingtherapyandpriortoeachsubsequentcourse.

Adequatepre-treatmentand‘duringtreatment’hydrationshouldbeensuredandsuchagentsasmannitolgivento

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monitored,particularlyduringthefirst24hoursfollowingadministration.

Theserumcreatinine,BUNandcreatinineclearanceshouldbemeasuredpriortoinitiaitingtherapyandmonitored

throughouttreatmentwithcisplatin.

Sinceototoxicityofcisplatiniscumulative,audiometrictestingshouldbeperformedpriortoinitiatingtherapyand

priortoeachsubsequentcourseofthedrug(seesection4.8,UndesirableEffects).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Cisplatincanbeusedincombinationwithothercytostaticswithcorrespondingmechanismsofaction.Additive

toxicitymightoccurinsuchcases.

Thenephrotoxicity,ototoxicityandmyelosuppressioninducedbycisplatinwillbeadditivetoexistentimpairmentor

tothesimilartoxicityofotheragentssuchascephaloridine,frusemide,aminoglycosides,etc.,administered

concurrently.

Otherknowninteractions:

Nephrotoxicitymightbeexacerbatedbyaminoglycosideantibiotics,administeredsimultaneouslyor1-2weeksafter

treatmentwithcisplatin.Theuseofotherpotentiallynephrotoxicdrugs(e.g.amphotericine)isnotrecommended

duringtreatmentwithcisplatin.

Treatmentwithototoxicdrugslikeaminoglycosideantibioticsorloop-diuretics,mightincreasetheototoxicpotential

ofcisplatin,especiallyinimpairedrenalfunction.

Theliteratureindicatesthatcisplatinmayreducerenalexcretionofbleomycinandmethotrexate(probablydueto

cisplatin-inducednephrotoxicity),andthusincreasetheirtoxicity.

Anti-epileptics:Inpatientsreceivingcisplatinandphenytoin,theserumlevelofphenytoinmightbereduced.Thisis

probablyduetoreducedabsorptionand/orincreasedmetabolism.Inthesepatients,oneshouldmonitorthelevelsof

phenytoininplasma,andadjustthedoseaccordingly.

Cisplatinmayinteractwithaluminium(seesection4.2,Posologyandmethodofadministration).

4.6Fertility,pregnancyandlactation

UseinPregnancy:

Thesafeuseofcisplatininhumanpregnancyhasnotbeenestablished.Cisplatinhasbeenshowntobemutagenicin

bacteria.Itproduceschromosomeaberrationsintissue-culturesofanimalcellsandisteratogenicandembryotoxicin

mice.Cisplatinshouldnotbeusedduringpregnancyunlesstheclinicianconsiderstherisktotheindividualpatientto

bejustified.

UseinLactation:

Cisplatinshouldnotbeadministeredtomotherswhoarebreastfeeding.

4.7Effectsonabilitytodriveandusemachines

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4.8Undesirableeffects

Nephrotoxicity:Renaltoxicityhasbeenshownin28-38%ofpatientstreatedwithasingledoseofcisplatin50

mg/m 2

.Renaltoxicitybecomesmoreprolongedandseverewithrepeatedcoursesofthedrug.

Gastrointestinaltoxicity:Nauseaandvomitingoccurinthemajorityofpatients,usuallystartingwithin1hourof

treatmentandlastingupto24hours.Anorexia,nauseaandoccasionalvomitingmaypersistforuptoaweek.

OcularToxicity:Therehavebeenreportsofopticneuritis,papilloedemaandcerebralblindnessfollowingtreatment

withcisplatin.Improvementand/ortotalrecoveryusuallyoccursfollowingimmediatediscontinuation.Blurred

visionandalteredcolourperceptionhavebeenreportedaftertheuseofregimenswithhigherdosesofcisplatinor

greaterdosefrequenciesthanthoserecommended.

Ototoxicity:Ototoxicityhasoccurredinupto31%ofpatientstreatedwithasingledoseofcisplatin50mg/m 2

Ototoxicitymaybemoresevereinchildrenandmorefrequentandseverewithrepeateddoses.Carefulmonitoring

shouldbeperformedpriortoinitiationoftherapyandpriortosubsequentdosesofcisplatin.

Unilateralorbilateraltinnitus,whichisusuallyreversible,and/orhearinglossinthehighfrequencyrangemayoccur.

Theoverallincidenceofaudiogramabnormalitiesis24%,butlargevariationsexist.Theseabnormalitiesusually

appearwithin4daysafterdrugadministrationandconsistofatleasta15decibellossinpuretonethreshold.The

damageseemstobecumulativeandisnotreversible.Theaudiogramabnormalitiesaremostcommoninthe4000-

8000Hzfrequencies.

Haemotoxicity:Myelosuppressionisobservedinabout30%ofpatientstreatedwithcisplatin.Leucopeniaand

thrombocytopeniaaremorepronouncedathigherdoses.

Thenadirsincirculatingplateletsandleucocytesgenerallyoccurbetweendays18-23(range7.3to45)withmost

patientsrecoveringbyday39(range13to62).Leucopeniaandthrombocytopeniaaremorepronouncedatdoses

greaterthan50mg/m 2

.Anaemia(decreasesofgreaterthan2g%haemoglobin)occursatapproximatelythesame

frequency,butgenerallywithalateronsetthanleucopeniaandthrombocytopenia.Subsequentcoursesofcisplatin

shouldnotbeinstituteduntilplateletsarepresentatlevelsgreaterthan100,000/mm 3

andwhitecellsgreaterthan

4,000/mm 3

.Ahighincidenceofsevereanaemiarequiringtransfusionofpackedredcellshasbeenobservedin

patientsreceivingcombinationchemotherapyincludingcisplatin.

Anaphylaxis:Reactionspossiblysecondarytocisplatintherapyhavebeenoccasionallyreportedinpatientswhowere

previouslyexposedtocisplatin.Patientswhoareparticularlyatriskarethosewithapriorhistoryorfamilyhistoryof

atopy.Facialoedema,wheezing,tachycardia,hypotensionandskinrashesofurticarialnon-specificmaculopapular

typecanoccurwithinafewminutesofadministration.SeriousreactionsseemtobecontrolledbyI.V.adrenaline,

corticosteroidsorantihistamines.

Neurotoxicity:Neurotoxicitymayoccur.Itiscumulativeandmaybeirreversible.Itisgenerallycharacterisedby

neuropathies,butseizuresandtastelosshaveoccurred.

Peripheralneuropathieswithparesthesiainbothupperandlowerextremities,tremorandlossoftastehavebeen

observedinsomepatients,generallythosetreatedwithrepeatedcourses.

HypomagnesaemiaandHypocalcaemia:Hypomagnesaemiaoccursquitefrequentlywithcisplatinadministration,

whilehypocalcaemiaoccurslessfrequently.Thelossofmagnesiumseemstobeassociatedwithrenaltubulardamage

whichpreventsresorptionofthiscation.Wherebothelectrolytesaredeficient,tetanymayresult.Itdoesnotappearto

bedoserelated.Monitoringofelectrolytesisnecessary.

Electrolytedisturbances:Hyponatraemia,hypokalaemiaandhypophosphataemiacanoccur.

Hyperuricaemia:Hyperuricaemiaoccurringwithcisplatinismorepronouncedwithdosesgreaterthan50mg/m 2

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CardiacandVascularDisorders:Cardiacreactionsincludingtachycardiaandarrhythmiahavebeenreported.

Vasculartoxicitiescoincidentwiththeuseofcisplatinincombinationwithotherantineoplasticagentshavebeen

reportedrarely. Theseeventsmayincludemyocardialinfarction,cerebrovascularaccident,thrombotic

microangiopathy(Haemolyticuraemicsyndrome)orcerebralarteritis.

OtherToxicities:TherearealsoreportsofRaynaud’sphenomenonoccurringinpatientstreatedwiththecombination

ofbleomycin,vinblastineandwithorwithoutcisplatin.Ithasbeensuggestedthathypomagnesaemiadevelopingwith

theuseofcisplatinmaybeanadded,althoughnotessentialfactor,associatedwiththisevent.Howeverthecauseof

thisRaynaud’sphenomenoniscurrentlyunknown.

4.9Overdose

Overdosagecanbeexpectedtocausethetoxiceffectsdescribedabove,buttoanexaggerateddegree.Adequate

hydrationandosmoticdiuresismayhelpreducethetoxicityofcisplatinifadministeredpromptlyfollowing

overdosage.Convulsionsmaybetreatedwithappropriateanticonvulsants.

Renalfunction,cardiovascularfunctionandbloodcountsshouldbemonitoreddailyinordertoassessthepotential

toxicitytothesesystems.Serummagnesiumandcalciumlevelsshouldbecarefullymonitoredasshouldsymptoms

andsignsofvoluntarymuscleirritability.Ifsymptomatictetanydevelops,electrolytesupplementsshouldbe

administered.Serumliverenzymesanduricacidshouldalsobemonitoreddailyafteranacuteoverdose.

Iffeverdevelopsduringprolongedmyelosuppression,appropriatepresumptiveantibioticcoverageshouldbeinstilled

aftercultureshavebeenobtained.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:OtherAntineoplasticAgents

ATCcode:L01XA01

Cisplatinhasbiochemicalpropertiessimilartothoseofbifunctionalalkylatingagents.ThedruginhibitsDNA

synthesisbyproducingintrastrandandinterstrandcrosslinksinDNA.ProteinandRNAsynthesisarealsoinhibited

toalesserextent.

AlthoughtheprincipalmechanismofactionofcisplatinappearstobeinhibitionofDNAsynthesis,othermechanisms,

includingenhancementoftumourimmunogenicity,maybeinvolvedinitsantineoplasticactivity.Cisplatinalsohas

immunosuppressive,radiosensitising,andantimicrobialproperties.

Cisplatindoesnotappeartobecellcyclespecific.

5.2Pharmacokineticproperties

Thereisgooduptakeofcisplatinbythekidneys,liverandintestine.Morethan90%ofplatinumcontainingspecies

remaininginthebloodarebound(possiblyirreversibly)toplasmaproteins.PenetrationintotheCSFispooralthough

significantamountsofcisplatincanbedetectedinintracerebraltumours.

Theclearanceoftotalplatinumfromplasmaisrapidduringthefirstfourhoursafterintravenousadministration,but

thenproceedsmoreslowlybecauseofcovalentbindingtoserumproteins.Levelsofunboundplatinumfallwitha

half-lifeof20minutesto1hourdependingontherateofdruginfusion.

Theeliminationofintactdrugandvariousplatinum-containingbiotransformationproductsisviatheurine.About15-

25%ofadministeredplatinumisrapidlyexcretedinthefirst2-4hoursafteradministrationofcisplatin.Thisearly

excretionismostlyofintactcisplatin.Inthefirst24hoursafteradministration,20-80%isexcreted;theremainder

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5.3Preclinicalsafetydata

Cisplatinhasbeenshowntobemutagenic.Itmayalsohaveananti-fertilityeffect.Otheranti-neoplasticsubstances

havebeenshowntobecarcinogenicandthispossibilityshouldbeborneinmindinlongtermuseofcisplatin.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Mannitol(E421)

Sodiumchloride

Dilutehydrochloricacid(forpHadjustment)

Waterforinjections

6.2Incompatibilities

Thereisatotallossofcisplatinin30minutesatroomtemperaturewhenmixedwithmetoclopramideandsodium

metabisulphiteinconcentrationsequivalenttothosethatwouldbefoundonmixingwithacommercialformulationof

metoclopramide.

Cisplatinandsodiumbisulphitehavebeenknowntoreactchemically.Suchantioxidantsmightinactivatecisplatin

beforeadministrationiftheyarepresentinintravenousfluids.

Interactionwithaluminium:

Cisplatinmayinteractwithmetalaluminiumtoformablackprecipitateofplatinum.Allaluminium-containingIV

sets,needles,cathetersandsyringesshouldbeavoided.

6.3Shelflife

Priortofirstuse:24months.

Inuse:Seesection6.4,Specialprecautionsforstorage

6.4Specialprecautionsforstorage

Priortofirstuse:Donotstoreabove25°C.Donotrefrigerateorfreeze.Keepvialintheoutercartoninorderto

protectfromlight.

Inuse:Followingdilutionin0.9%SodiumChlorideInjection,chemicalandphysicalin-usestabilityhasbeen

demonstratedforupto14daysat4°Cwhenprotectedfromlight.Fromamicrobiologicalpointofview,however,the

productshouldbeusedimmediately.Ifnotusedimmediately,in-usestoragetimesandconditionspriortousearethe

responsibilityoftheuserandwouldnotnormallybelongerthan24hoursat2-8°C,unlessdilutionhastakenplacein

controlledandvalidatedasepticconditions.

6.5Natureandcontentsofcontainer

10mg/10ml,50mg/50mland100mg/100mlpresentationsinTypeIamberglassvialsandOnco-Tainvials.Packs

containasinglevial.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Singleuseonly.Discardanyunusedcontents.

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Dilution:

Cisplatin1mg/mlSterileConcentrateshouldbeaddedto2litresof0.9%sodiumchlorideinjection.

Administration:

Shouldbeadministeredonlybyorunderthedirectsupervisionofaqualifiedphysicianwhoisexperiencedintheuse

ofcancerchemotherapeuticagents.

Preparation(Guidelines):

Chemotherapeuticagentsshouldbepreparedforadministrationonlybyprofessionalswhohavebeen

trainedinthesafeuseofthepreparation

Operationssuchasreconstitution,dilutionandtransfertosyringesshouldbecarriedoutonlyinthe

designatedarea.

Thepersonnelcarryingouttheseproceduresshouldbeadequatelyprotectedwithclothing,glovesandeye

shield.

Pregnantpersonnelareadvisednottohandlechemotherapeuticagents.

Contamination:

Intheeventofcontactwiththeskinoreyes,theaffectedareashouldbewashedwithcopious

amountsofwaterornormalsaline.Ablandcreammaybeusedtotreatthetransientstingingthe

skin.Medicaladviceshouldbesoughtiftheeyesareaffected.

Intheeventofspillage,operatorsshouldputonglovesandmopupthespilledmaterialwitha

spongekeptintheareaforthatpurpose.Rinsetheareatwicewithwater.Putallsolutionsand

spongesintoaplasticbagandsealit.

Disposal:

Syringes,container,absorbentmaterials,solutionandanyothercontaminatedmaterialshouldbeplacedinathick

plasticbagorotherimperviouscontainerandincinerated.

7MARKETINGAUTHORISATIONHOLDER

HospiraUKLImited

Queensway

RoyalLeamingtonSpa

Warwickshire,CV313RW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0437/004/007

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19November1986

Dateoflastrenewal:18December2006

10DATEOFREVISIONOFTHETEXT

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