ELOXATIN

Main information

  • Trade name:
  • ELOXATIN Pdr for Soln for Infusion 5 Mg/Ml
  • Dosage:
  • 5 Mg/Ml
  • Pharmaceutical form:
  • Pdr for Soln for Infusion
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ELOXATIN Pdr for Soln for Infusion 5 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0540/148/002
  • Authorization date:
  • 19-01-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA0540/148/002

CaseNo:2061120

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

Sanofi-aventisIrelandLimited

CitywestBusinessCampus,Dublin24,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Eloxatin5mg/ml,powderforsolutionforinfusion

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom31/07/2009.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 15/07/2010 CRN 2061120 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Eloxatin5mg/ml,powderforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

50mgvial:eachvialcontains50mgoxaliplatinforreconstitutionin10mlofsolvent.

100mgvial:eachvialcontains100mgoxaliplatinforreconstitutionin20mlofsolvent.

1mlofreconstitutedsolutionforinfusioncontains5mgoxaliplatin

Excipients-ContainsLactoseMonohydrate450mg/50mgvialand900mg/100mgvial

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Powderforsolutionforinfusion

Whitetooff-whitecakeorpowder

4CLINICALPARTICULARS

4.1TherapeuticIndications

Oxaliplatinincombinationwith5fluorouracil(5FU)andfolinicacid(FA)isindicatedfor:

AdjuvanttreatmentofstageIII(Duke'sC)coloncanceraftercompleteresectionofprimarytumor

Treatmentofmetastaticcolorectalcancer

4.2Posologyandmethodofadministration

Thepreparationofinjectablesolutionsofcytotoxicagentsmustbecarriedoutbytrainedspecialistpersonnelwith

knowledgeofthemedicinalproductsused,inconditionsthatguaranteetheintegrityofthemedicinalproduct,the

protectionoftheenvironmentandinparticulartheprotectionofthepersonnelhandlingthemedicinalproducts,in

accordancewiththehospitalpolicy.Itrequiresapreparationareareservedforthispurpose.Itisforbiddentosmoke,

eatordrinkinthisarea.

Posology:

FORADULTSONLY

Therecommendeddoseforoxaliplatininadjuvantsettingis85mg/m²intravenouslyrepeatedeverytwoweeksfor12

cycles(6months).

Therecommendeddoseforoxaliplatinintreatmentofmetastaticcolorectalcanceris85mg/m²intravenously

repeatedevery2weeks.

Dosagegivenshouldbeadjustedaccordingtotolerability(seesection4.4).

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Oxaliplatinisadministeredasa2-to6-hourintravenousinfusionin250to500mlofglucose5%(50mg/ml)

solutiontogiveaconcentrationbetween0.2mg/mland0.70mg/ml;0.70mg/mlisthehighestconcentrationin

clinicalpracticeforanoxaliplatindoseof85mg/m 2

Oxaliplatinhasmainlybeenusedincombinationwithcontinuousinfusion5fluorouracil(5FU)basedregimens.For

thetwo-weeklytreatmentschedule5fluorouracil(5FU)regimenscombiningbolusandcontinuousinfusionwere

used.

SpecialPopulations:

-Renalimpairment:

Oxaliplatinhasnotbeenstudiedinpatientswithsevererenalimpairment(seesection4.3).

Inpatientswithmoderaterenalimpairment,treatmentmaybeinitiatedatthenormallyrecommendeddose(see

section4.4).Thereisnoneedfordoseadjustmentinpatientswithmildrenaldysfunction.

-Hepaticinsufficiency:

InaphaseIstudyincludingpatientswithseverallevelsofhepaticimpairment,frequencyandseverityofhepato-

biliarydisordersappearedtoberelatedtoprogressivediseaseandimpairedliverfunctiontestsatbaseline.No

specificdoseadjustmentforpatientswithabnormalliverfunctiontestswasperformedduringclinicaldevelopment.

-Elderlypatients:

Noincreaseinseveretoxicitieswasobservedwhenoxaliplatinwasusedasasingleagentorincombinationwith

5fluorouracil(5FU)inpatientsovertheageof65.Inconsequencenospecificdoseadaptationisrequiredforelderly

patients.

-Pediatricpatients:

Thereisnorelevantindicationforuseofoxaliplatininchildren.Theeffectivenessofoxaliplatinsingleagentinthe

paediatricpopulationswithsolidtumorshasnotbeenestablished(seesection5.1).

Methodofadministration:

Oxaliplatinisadministeredbyintravenousinfusion.

Theadministrationofoxaliplatindoesnotrequirehyperhydration.

Oxaliplatindilutedin250to500mlofglucose5%(50mg/ml)solutiontogiveaconcentrationnotlessthan

0.2mg/mlmustbeinfusedviaacentralvenouslineoraperipheralveinover2to6hours.Oxaliplatininfusionmust

alwaysprecedetheadministrationof5fluorouracil(5FU).

Intheeventofextravasation,administrationmustbediscontinuedimmediately.

Instructionsforuse:

Oxaliplatinmustbereconstitutedandfurtherdilutedbeforeuse.Onlyglucose5%(50mg/ml)diluentsistobeused

toreconstituteandthendilutethefreeze-driedmedicinalproduct.(Seesection6.6).

4.3Contraindications

Oxaliplatiniscontraindicatedinpatientswho

-haveahypersensitivitytooxaliplatinortotheexcipient.

-arebreastfeeding.

-havemyelosuppressionpriortostartingfirstcourse,asevidencedbybaselineneutrophils<2x10 9

/land/orplatelet

countof<100x10 9

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-haveaperipheralsensoryneuropathywithfunctionalimpairmentpriortofirstcourse.

-haveaseverelyimpairedrenalfunction(creatinineclearancelessthan30ml/min).

4.4Specialwarningsandprecautionsforuse

Duetolimitedinformationonsafetyinpatientswithmoderatelyimpairedrenalfunction,administrationshouldonly

beconsideredaftersuitableappraisalofthebenefit/riskforthepatient.

Inthissituation,renalfunctionshouldbecloselymonitoredanddoseadjustedaccordingtotoxicity.

Patientswithahistoryofallergicreactiontoplatinumcompoundsshouldbemonitoredforallergicsymptoms.Incase

ofananaphylactic-likereactiontooxaliplatin,theinfusionshouldbeimmediatelydiscontinuedandappropriate

symptomatictreatmentinitiated.Oxaliplatinrechallengeiscontra-indicated.

Incaseofoxaliplatinextravasation,theinfusionmustbestoppedimmediatelyandusuallocalsymptomatictreatment

initiated.

Neurologicaltoxicityofoxaliplatinshouldbecarefullymonitored,especiallyifco-administeredwithothermedicinal

productswithspecificneurologicaltoxicity.Aneurologicalexaminationshouldbeperformedbeforeeach

administrationandperiodicallythereafter.

Forpatientswhodevelopacutelaryngopharyngealdysaesthesia(seesection4.8),duringorwithinthehoursfollowing

the2-hourinfusion,thenextoxaliplatininfusionshouldbeadministeredover6hours.

Ifneurologicalsymptoms(paraesthesia,dysaesthesia)occur,thefollowingrecommendedoxaliplatindosage

adjustmentshouldbebasedonthedurationandseverityofthesesymptoms:

-Ifsymptomslastlongerthansevendaysandaretroublesome,thesubsequentoxaliplatindoseshouldbereduced

from85to65mg/m 2

(metastaticsetting)or75mg/m 2

(adjuvantsetting).

-Ifparaesthesiawithoutfunctionalimpairmentpersistsuntilthenextcycle,thesubsequentoxaliplatindoseshouldbe

reducedfrom85to65mg/m 2

(metastaticsetting)or75mg/m 2

(adjuvantsetting).

-Ifparaesthesiawithfunctionalimpairmentpersistsuntilthenextcycle,oxaliplatinshouldbediscontinued.

-Ifthesesymptomsimprovefollowingdiscontinuationofoxaliplatintherapy,resumptionoftherapymaybe

considered.

Patientsshouldbeinformedofthepossibilityofpersistentsymptomsofperipheralsensoryneuropathyaftertheendof

thetreatment.Localizedmoderateparesthesiasorparesthesiasthatmayinterferewithfunctionalactivitiescanpersist

afterupto3yearsfollowingtreatmentcessationintheadjuvantsetting.

Gastrointestinaltoxicity,whichmanifestsasnauseaandvomiting,warrantsprophylacticand/ortherapeuticanti-

emetictherapy(seesection4.8).

Dehydration,paralyticileus,intestinalobstruction,hypokalemia,metabolicacidosisandrenalimpairmentmaybe

causedbyseverediarrhoea/emesisparticularlywhencombiningoxaliplatinwith5FU.

Ifhaematologicaltoxicityoccurs(neutrophils<1.5x10 9

/lorplatelets<50x10 9

/l),administrationofthenextcourse

oftherapyshouldbepostponeduntilhaemotologicalvaluesreturntoacceptablelevels.Afullbloodcountwithwhite

celldifferentialshouldbeperformedpriortostartoftherapyandbeforeeachsubsequentcourse.

Patientsmustbeadequatelyinformedoftheriskofdiarrhoea/emesis,mucositis/stomatitisandneutropeniaafter

oxaliplatin/5fluorouracil(5FU)administrationsothattheycanurgentlycontacttheirtreatingphysicianfor

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Ifmucositis/stomatitisoccurswithorwithoutneutropenia,thenexttreatmentshouldbedelayeduntilrecoveryfrom

mucositis/stomatitistograde1orlessand/oruntiltheneutrophilcountis 1.5x10 9

Foroxaliplatincombinedwith5fluorouracil(5FU)(withorwithoutfolinicacid(FA)),theusualdoseadjustments

for5fluorouracil(5FU)associatedtoxicitiesshouldapply.

Ifgrade4diarrhoea,grade3-4neutropenia(neutrophils<1.0x10 9

/l),grade3-4thrombocytopenia(platelets

<50x10 9

/l)occur,thedoseofoxaliplatinshouldbereducedfrom85to65mg/m²(metastaticsetting)or75mg/m 2

(adjuvantsetting),inadditiontoany5FUdosereductionsrequired.

Inthecaseofunexplainedrespiratorysymptomssuchasnon-productivecough,dyspnoea,cracklesorradiological

pulmonaryinfiltrates,oxaliplatinshouldbediscontinueduntilfurtherpulmonaryinvestigationsexcludeaninterstitial

lungdiseaseorpulmonaryfibrosis(seesection4.8).

Incaseofabnormalliverfunctiontestresultsorportalhypertensionwhichdoesnotobviouslyresultfromliver

metastases,veryrarecasesofdrug-inducedhepaticvasculardisordersshouldbeconsidered.

Foruseinpregnantwomen,seesection4.6.

Genotoxiceffectswereobservedwithoxaliplatininthepreclinicalstudies.Thereforemalepatientstreatedwith

oxaliplatinareadvisednottofatherachildduringandupto6monthsaftertreatmentandtoseekadviceon

conservationofspermpriortotreatmentbecauseoxaliplatinmayhaveananti-fertilityeffect,whichcouldbe

irreversible.

Womenshouldnotbecomepregnantduringtreatmentwithoxaliplatinandshoulduseaneffectivemethodof

contraception(seesection4.6).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Inpatientswhohavereceivedasingledoseof85mg/m 2

ofoxaliplatin,immediatelybeforeadministrationof

5fluorouracil(5FU),nochangeinthelevelofexposureto5fluorouracil(5FU)hasbeenobserved.

Invitro,nosignificantdisplacementofoxaliplatinbindingtoplasmaproteinshasbeenobservedwiththefollowing

agents:erythromycin,salicylates,granisetron,paclitaxel,andsodiumvalproate.

4.6Pregnancyandlactation

Todatethereisnoavailableinformationonsafetyofuseinpregnantwomen.Inanimalstudies,reproductivetoxicity

wasobserved.Consequently,oxaliplatinisnotrecommendedduringpregnancyandinwomenofchildbearing

potentialnotusingcontraceptivemeasures.Theuseofoxaliplatinshouldonlybeconsideredaftersuitablyappraising

thepatientoftherisktothefoetusandwiththepatient’sconsent.

Appropriatecontraceptivemeasuresmustbetakenduringandaftercessationoftherapyduring4monthsforwomen

and6monthsformen.

Excretioninbreastmilkhasnotbeenstudied.Breast-feedingiscontra-indicatedduringoxaliplatintherapy.

Oxaliplatinmayhaveananti-fertilityeffect(seesection4.4).

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Howeveroxaliplatintreatment

resultinginanincreaseriskofdizziness,nauseaandvomiting,andotherneurologicsymptomsthataffectgaitand

balancemayleadtoaminorormoderateinfluenceontheabilitytodriveandusemachines.

Visionabnormalities,inparticulartransientvisionloss(reversiblefollowingtherapydiscontinuation),mayaffect

patients'abilitytodriveandusemachines.Therefore,patientsshouldbewarnedofthepotentialeffectoftheseevents

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4.8Undesirableeffects

Themostfrequentadverseeventsofoxaliplatinincombinationwith5fluorouracil(5FU)/folinicacid(FA),were

gastrointestinal(diarrhea,nausea,vomitingandmucositis),haematological(neutropenia,thrombocytopenia)and

neurological(acuteanddosecumulativeperipheralsensoryneurophathy).Overall,theseeventsweremorefrequent

andseverewithoxaliplatinand5fluorouracil(5FU)/folinicacid(FA)combinationthanwith5fluorouracil

(5FU)/folinicacid(FA)alone.

Thefrequenciesreportedinthetablebelowarederivedfromclinicaltrialsinthemetastaticandadjuvantsetting

(havingincluded416and1108patientsrespectivelyintheoxaliplatin+5fluorouracil(5FU)/folinicacid(FA)arm)

andfrompostmarketingexperience.

Frequenciesinthistablearedefinedusingthefollowingconvention:verycommon( ≥1/10)common(≥1/100,

<1/10),uncommon( ≥1/1000,<1/100),rare(≥1/10000,<1/1000),veryrare(<1/10000),notknown(cannotbe

estimatedfromtheavailabledata).

Furtherdetailsaregivenafterthetable.

MedDRA

Organsystem

classes Verycommon Common Uncommon Rare

Investigations -Hepatic

enzymeincrease

-Bloodalkaline

phosphatase

increase-Blood

bilirubin

increase

-Bloodlactate

dehydrogenase

increase

-Weight

increase

(adjuvant

-Bloodcreatinine

increase

-Weightdecrease

(metastatic

setting)

Bloodand

lymphatic

system

disorders* -Anaemia

-Neutropenia

-Thrombocyto-

penia

-Leukopenia

-Lymphopenia -Immunoallergic

thrombocytopenia

-Haemolytic

anaemia

Nervoussystem

disorders* -Peripheral

sensory

neuropathy

-Sensory

disturbance

-Dysgeusia-

Headache -Dizziness

-Motorneuritis

-Meningism -Dysarthria

Eyedisorders -Conjunctivitis

-Visual

disturbance -Visualacuity

reduced

transiently

-Visualfield

disturbances

-Opticneuritis

-Transientvision

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followingtherapy

discontinuation

Earand

labyrinth

disorders -

Ototoxicity -Deafness

Respiratory,

thoracicand

mediastinal

disorders -Dyspnoea

-Cough -Hiccups -Interstitiallung

disease,

sometimesfatal

-Pulmonary

fibrosis**

Gastrointestinal

disorders* -Nausea

-Diarrhoea

-Vomiting

Stomatitis/Mucositis

-Abdominal

pain

-Constipation -Dyspepsia

-Gastro-

esophagealreflux

-Gastrointestinal

hemorrhage

-Rectal

haemorrhage -Ileus

-Intestinal

obstruction -Colitis

including

clostridium

difficilediarrhea

Renaland

urinary

disorders -Haematuria

-Dysuria

-Micturition

frequency

abnormal

Skinand

subcutaneous

tissuedisorders -Skindisorder

-Alopecia -Skinexfoliation

(i.e.Hand&Foot

syndrome)

-Rash

erythematous

-Rash

-Hyperhidrosis

-Naildisorder

Musculoskeletal

andconnective

tissuedisorders -Backpain -Arthralgia

-Bonepain

Metabolism

andnutrition

disorders -Anorexia

-Glycemia

abnormalities

-Hypokalaemia

-Natraemia

abnormalities -Dehydration -Metabolic

acidosis

Infectionsand

infestations* -Infection -Rhinitis

-Upper

respiratorytract

infection

-Febrile

neutropenia/Neutropenic

sepsis

Vascular

disorders -Epistaxis -Haemorrhage

-Flushing

-Deepvein

thrombosis

-Pulmonary

embolism

-Hypertension

General

disordersand -Fatigue

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Seedetailedsectionbelow

Seesection4.4.

Commonallergicreactionssuchasskinrash(particularlyurticaria),conjunctivitis,rhinitis.

Commonanaphylacticreactions,includingbronchospasm,sensationofchestpain,angioeodema,hypotensionandanaphylacticshock.

Verycommonfever,rigors(tremors),eitherfrominfection(withorwithoutfebrileneutropenia)orpossiblyfromimmunological

mechanism.

Injectionsitereactionsincludinglocalpain,redness,swellingandthrombosishavebeenreported.Extravasationmayalsoresultin

localpainandinflammationwhichmaybesevereandleadtocomplicationsincludingnecrosis,especiallywhenoxaliplatinisinfused

throughaperipheralvein(seesection4.4).

Bloodandlymphaticsystemdisorders

Incidencebypatient(%),bygrade

Postmarketingexperiencewithfrequencyunknown

Hemolyticuremicsyndrome

Immunesystemdisorders

Incidenceofallergicreactionsbypatient(%),bygrade

Nervoussystemdisorders

Thedoselimitingtoxicityofoxaliplatinisneurological.Itinvolvesasensoryperipheralneuropathycharacterisedby

dysaesthesiaand/orparaesthesiaoftheextremitieswithorwithoutcramps,oftentriggeredbythecold.These

symptomsoccurinupto95%ofpatientstreated.Thedurationofthesesymptoms,whichusuallyregressbetween

administration

siteconditions -Asthenia

-Pain

-Injectionsite

reaction+++

Immunesystem

disorders* -Allergy/

allergic

reaction+

Psychiatric

disorders -Depression

-Insomnia -

Nervousness

Oxaliplatin/

5FU/FA

85mg/m²

every2weeks Metastatic

setting Adjuvant

setting

grades gr3 gr4 All

grades gr3 gr4

Anaemia 82.2 3 <1 75.6 0.7 0.1

Neutropenia 71.4 28 14 78.9 28.8 12.3

Thrombocyto-

penia 71.6 4 <1 77.4 1.5 0.2

Febrile

neutropenia 5.0 3.6 1.4 0.7 0.7 0.0

Neutropenicsepsis 1.1 0.7 0.4 1.1 0.6 0.4

Oxaliplatin/

5FU/FA

85mg/m²

every2weeks Metastatic

setting Adjuvant

setting

grades gr3 gr4 All

grades gr3 gr4

Allergicreactions/

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Theonsetofpainand/orafunctionaldisorderareindications,dependingonthedurationofthesymptoms,fordose

adjustment,oreventreatmentdiscontinuation(seesection4.4).

Thisfunctionaldisorderincludesdifficultiesinexecutingdelicatemovementsandisapossibleconsequenceof

sensoryimpairment.Theriskofoccurrenceofpersistentsymptomsforacumulativedoseof850mg/m²(10cycles)is

approximately10%and20%foracumulativedoseof1020mg/m²(12cycles).

Inthemajorityofthecases,theneurologicalsignsandsymptomsimproveortotallyrecoverwhentreatmentis

discontinued.Intheadjuvantsettingofcoloncancer,6monthsaftertreatmentcessation,87%ofpatientshadnoor

mildsymptoms.Afterupto3yearsoffollowup,about3%ofpatientspresentedeitherwithpersistinglocalized

paresthesiasofmoderateintensity(2.3%)orwithparesthesiasthatmayinterferewithfunctionalactivities(0.5%).

Acuteneurosensorymanifestations(seesection5.3)havebeenreported.Theystartwithinhoursofadministration

andoftenoccuronexposuretocold.Theyusuallypresentastransientparesthesia,dysesthesiaandhypoesthesia.An

acutesyndromeofpharyngolaryngealdysesthesiaoccursin1%-2%ofpatientsandischaracterisedbysubjective

sensationsofdysphagiaordyspnoea/feelingofsuffocation,withoutanyobjectiveevidenceofrespiratorydistress(no

cyanosisorhypoxia)oroflaryngospasmorbronchospasm(nostridororwheezing);Althoughantihistaminesand

bronchodilatorshavebeenadministeredinsuchcases,thesymptomsarerapidlyreversibleevenintheabsenceof

treatment.Prolongationoftheinfusionhelpstoreducetheincidenceofthissyndrome(seesection4.4).Occasionally

othersymptomsthathavebeenobservedincludejawspasm/musclespasms/musclecontractions-involuntary/muscle

twitching/myoclonus,coordinationabnormal/gaitabnormal/ataxia/balancedisorders,throatorchesttightness/

pressure/discomfort/pain.Inaddition,cranialnervedysfunctionsmaybeassociated,oralsooccurasanisolated

eventsuchasptosis,diplopia,aphonia/dysphonia/hoarseness,sometimesdescribedasvocalcordparalysis,

abnormaltonguesensationordysarthria,sometimesdescribedasaphasia,trigeminalneuralgia/facialpain/eyepain,

decreaseinvisualacuity,visualfielddisorders.

Otherneurologicalsymptomssuchasdysarthria,lossofdeeptendonreflexandLhermitte'ssignwerereportedduring

treatmentwithoxaliplatin.Isolatedcasesofopticneuritishavebeenreported.

Postmarketingexperiencewithfrequencyunknown

Convulsion

Incidencebypatient(%),bygrade

Prophylaxisand/ortreatmentwithpotentantiemeticagentsisindicated.

Dehydration,paralyticileus,intestinalobstruction,hypokalemia,metabolicacidosisandrenalimpairmentmaybe

causedbyseverediarrhoea/emesisparticularlywhencombiningoxaliplatinwith5fluorouracil(5FU)(seesection

4.4).

Hepato-biliarydisorders

Oxaliplatin/

5FU/FA

85mg/m²

every2weeks Metastatic

setting Adjuvant

setting

grades gr3 gr4 All

grades gr3 gr4

Nausea 69.9 8 <1 73.7 4.8 0.3

Diarrhoea 60.8 9 2 56.3 8.3 2.5

Vomiting 49.0 6 1 47.2 5.3 0.5

Mucositis/

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Liversinusoidalobstructionsyndrome,alsoknownasveno-occlusivediseaseofliver,orpathologicalmanifestations

relatedtosuchliverdisorder,includingpeliosishepatis,nodularregenerativehyperplasia,perisinusoidalfibrosis.

Clinicalmanifestationsmaybeportalhypertensionand/orincreasedtransaminases.

Renalandurinarydisorders

Veryrare(<1/10,000):

Acutetubularnecrosis,acuteinterstitialnephritisandacuterenalfailure.

4.9Overdose

Thereisknownantidotetooxaliplatin.Incasesofoverdose,exacerbationofadverseeventscanbeexpected.

Monitoringofhaematologicalparametersshouldbeinitiatedandsymptomatictreatmentgiven.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Otherantineoplasticagents,platinumcompounds

ATCcode:L01XA03

Oxaliplatinisanantineoplasticactivesubstancebelongingtoanewclassofplatinum-basedcompoundsinwhichthe

platinumatomiscomplexedwith1,2-diaminocyclohexane(“DACH”)andanoxalategroup.

Oxaliplatinisasingleenantiomer,(SP-4-2)-[(1R,2R)-Cyclohexane-1,2-diamine-kN,kN'][ethanedioato(2-)-kO 1 ,kO 2 ]

platinum.

Oxaliplatinexhibitsawidespectrumofbothinvitrocytotoxicityandinvivoantitumouractivityinavarietyof

tumourmodelsystemsincludinghumancolorectalcancermodels.Oxaliplatinalsodemonstratesinvitroandinvivo

activityinvariouscisplatinresistantmodels.

Asynergisticcytotoxicactionhasbeenobservedincombinationwith5fluorouracil(5FU)bothinvitroandinvivo.

Studiesonthemechanismofactionofoxaliplatin,althoughnotcompletelyelucidated,showthattheaqua-derivatives

resultingfromthebiotransformationofoxaliplatin,interactwithDNAtoformbothinterandintra-strandcross-links,

resultinginthedisruptionofDNAsynthesisleadingtocytotoxicandantitumoureffects.

Inpatientswithmetastaticcolorectalcancer,theefficacyofoxaliplatin(85mg/m 2

repeatedeverytwoweeks)

combinedwith5fluorouracil(5FU)/folinicacid(FA)isreportedinthreeclinicalstudies:

Infront-linetreatment,the2-armcomparativephaseIIIEFC2962studyrandomized420patientseitherto

5fluorouracil(5FU)/folinicacid(FA)alone(LV5FU2,N=210)orthecombinationofoxaliplatinwith5fluorouracil

(5FU)/folinicacid(FA)(FOLFOX4,N=210)

Inpretreatedpatientsthecomparative3-armphaseIIIEFC4584studyrandomized821patientsrefractorytoan

irinotecan(CPT-11)+5fluorouracil(5FU)/folinicacid(FA)combinationeitherto5fluorouracil(5FU)/folinicacid

(FA)alone(LV5FU2,N=275),oxaliplatinsingleagent(N=275),orcombinationofoxaliplatinwith5fluorouracil

(5FU)/folinicacid(FA)(FOLFOX4,N=271)Finally,thenoncontrolledphaseIIEFC2964studyincludedpatients

refractoryto5fluorouracil(5FU)/folinicacid(FA)alone,thatweretreatedwiththeoxaliplatinand5fluorouracil

(5FU)/folinicacid(FA)combination(FOLFOX4,N=57)

Thetworandomizedclinicaltrials,EFC2962infront-linetherapyandEFC4584inpretreatedpatients,demonstrateda

significantlyhigherresponserateandaprolongedprogressionfreesurvival(PFS)/timetoprogression(TTP)as

comparedtotreatmentwith5FU/FAalone.

InstudyEFC4584performedinpretreatedrefractorypatients,thedifferenceinthemedianoverallsurvival(OS)

betweenthecombinationofoxaliplatinand5fluorouracil(5FU)/folinicacid(FA)didnotreachstatistical

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ResponserateunderFOLFOX4versusLV5FU2

NA:NotApplicable

MedianProgressionFreeSurvival(PFS)/MedianTimetoProgression(TTP)

FOLFOX4versusLV5FU2

Responserate,%

(95%CI)

independentradiological

reviewITTanalysis LV5FU2 FOLFOX4 Oxaliplatin

Singleagent

Front-linetreatment

EFC2962

Responseassessmentevery

8weeks 22

(16-27) 49

(42-46) NA

Pvalue=0.0001

Pretreatedpatients

EFC4584

(refractoryto

CPT-11+5FU/FA)

Responseassessmentevery

6weeks 0.7

(0.0-2.7) 11.1

(7.6-15.5) 1.1

(0.2-3.2)

Pvalue<0.0001

Pretreatedpatients

EFC2964

(refractoryto5FU/FA)

Responseassessmentevery

12weeks NA 23

(13-36) NA

MedianPFS/TTP,months

(95%CI)

independentradiological

reviewITTanalysis LV5FU2 FOLFOX4 Oxaliplatin

Singleagent

Front-linetreatment

EFC2962(PFS) 6.0

(5.5-6.5) 8.2

(7.2-8.8) NA

Log-rankPvalue=0.0003

Pretreatedpatients

EFC4584(TTP)

(refractoryto

CPT-11+5FU/FA) 2.6

(1.8-2.9) 5.3

(4.7-6.1) 2.1

(1.6-2.7)

Log-rankPvalue<0.0001

Pretreatedpatients

EFC2964

(refractoryto5FU/FA) NA 5.1

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MedianOverallSurvival(OS)underFOLFOX4versusLV5FU2

NA:NotApplicable

Inpretreatedpatients(EFC4584),whoweresymptomaticatbaseline,ahigherproportionofthosetreatedwith

oxaliplatin/5fluorouracil(5FU)/folinicacid(FA)experiencedasignificantimprovementoftheirdisease-related

symptomscomparedtothosetreatedwith5fluorouracil(5FU)/folinicacid(FA)alone(27.7%vs14.6%,p<0.0033).

Innonpretreatedpatients(EFC2962),nostatisticaldifferencebetweenthetwotreatmentgroupswasfoundforanyof

thequalityoflifedimensions.However,thequalityoflifescoresweregenerallybetterinthecontrolarmfor

measurementofglobalhealthstatusandpainandworseintheoxaliplatinarmfornauseaandvomiting.

Intheadjuvantsetting,thecomparativeMOSAICphaseIIIstudy(EFC3313)randomised2246patients(899stageII/

Duke'sB2and1347stageIII/Duke'sC)furthertocompleteresectionoftheprimarytumorofcoloncancereitherto

5FU/FAalone(LV5FU2N=1123,B2/C=448/675)ortocombinationofoxaliplatinand5FU/FA(FOLFOX4N

=1123,B2/C=451/672).

EFC33133-yeardiseasefreesurvival(ITTanalysis)*fortheoverallpopulation.

*medianfollowup44.2months(allpatientsfollowedforatleast3years)

Thestudydemonstratedanoverallsignificantadvantagein3-yeardiseasefreesurvivalfortheoxaliplatinand5FU/FA

MedianOS,months

(95%CI)

ITTanalysis LV5FU2 FOLFOX4 Oxaliplatin

Singleagent

Front-linetreatment

EFC2962 14.7

(13.0-18.2) 16.2

(14.7-18.2) NA

Log-rankPvalue=0.12

Pretreatedpatients

EFC4584*

(refractoryto

CPT-11+5FU/FA) 8.8

(7.3–9.3) 9.9

(9.1-10.5) 8.1

(7.2-8.7)

Log-rankPvalue=0.09

Pretreatedpatients

EFC2964

(refractoryto5FU/FA) NA 10.8

(9.3-12.8) NA

Treatmentarm LV5FU2 FOLFOX4

Percent3-yeardiseasefree

survival(95%CI) 73.3

(70.6-75.9) 78.7

(76.2-81.1)

Hazardratio(95%CI) 0.76

(0.64-0.89)

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EFC33133-yeardiseasefreesurvival(ITTanalysis)*accordingtodiseasestage

*medianfollowup44.2months(allpatientsfollowedforatleast3years)

OverallSurvival(ITTanalysis)

Attimeoftheanalysisofthe3-yeardiseasefreesurvival,whichwastheprimaryendpointoftheMOSAICtrial,

85.1%ofthepatientswerestillaliveintheFOLFOX4armversus83.8%intheLV5FU2arm.Thistranslatedintoan

overallreductioninmortalityriskof10%infavorofFOLFOX4notreachingstatisticalsignificance(hazardratio

=0.90).

Thefigureswere92.2%versus92.4%intheStageII(Duke'sB2)sub-population(hazardratio=1.01)and80.4%

versus78.1%intheStageIII(Duke'sC)sub-population(hazardratio=0.87),forFOLFOX4andLV5FU2,

respectively.

Oxaliplatinsingleagenthasbeenevaluatedinpediatricpopulationin2PhaseI(69patients)and2PhaseII(90

patients)studies.Atotalof159pediatricpatients(7months-22yearsofage)withsolidtumorshavebeentreated.The

effectivenessofoxaliplatinsingleagentinthepediatricpopulationstreatedhasnotbeenestablished.Accrualinboth

PhaseIIstudieswasstoppedforlackoftumorresponse.

5.2Pharmacokineticproperties

Thepharmacokineticsofindividualactivecompoundshavenotbeendetermined.Thepharmacokineticsof

ultrafiltrableplatinum,representingamixtureofallunbound,activeandinactiveplatinumspecies,followingatwo-

hourinfusionofoxaliplatinat130mg/m²everythreeweeksfor1to5cyclesandoxaliplatinat85mg/m²everytwo

weeksfor1to3cyclesareasfollows:

SummaryofPlatinumPharmacokineticParameterEstimatesinUltrafiltrateFollowingMultipleDosesof

Oxaliplatinat85mg/m 2

EveryTwoWeeksorat130mg/m 2

EveryThreeWeeks

MeanAUC

0-48 ,andC

valuesweredeterminedonCycle3(85mg/m 2 )orcycle5(130mg/m 2 ).

MeanAUC,V

,CL,andCL

Patientstage StageII

(Duke'sB2) StageIII

(Duke'sC)

Treatment

arm LV5FU2 FOLFOX4 LV5FU2 FOLFOX4

Percent3-year

diseasefree

survival

(95%CI) 84.3

(80.9-

87.7) 87.4

(84.3-90.5) 65.8

(62.2-

69.5) 72.8

(69.4-76.2)

Hazardratio

(95%CI) 0.79

(0.57-1.09) 0.75

(0.62-0.90)

Log-ranktest P=0.151 P=0.002

Dose C

max

µg/mL AUC

0-48

µg.h/mL AUC

µg.h/mL t

1/2

h t

1/2

h t

1/2

h V

ss

L CL

L/h

85mg/m2

Mean

0.814

0.193 4.19

0.647 4.68

1.40 0.43

0.35 16.8

5.74 391

17.4

6.35

130mg/m2

Mean

1.21

0.10 8.20

2.40 11.9

4.60 0.28

0.06 16.3

2.90 273

19.0 582

10.1

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,C

,AUC,AUC

0-48 ,V

andCLvaluesweredeterminedbynon-compartmentalanalysis.

,t

,andt

weredeterminedbycompartmentalanalysis(Cycles1-3combined).

Attheendofa2-hourinfusion,15%oftheadministeredplatinumispresentinthesystemiccirculation,the

remaining85%beingrapidlydistributedintotissuesoreliminatedintheurine.Irreversiblebindingtoredbloodcells

andplasma,resultsinhalf-livesinthesematricesthatareclosetothenaturalturnoverofredbloodcellsandserum

albumin.Noaccumulationwasobservedinplasmaultrafiltratefollowing85mg/m 2

everytwoweeksor130mg/m 2

everythreeweeksandsteadystatewasattainedbycycleoneinthismatrix.Inter-andintra-subjectvariabilityis

generallylow.

Biotransformationinvitroisconsideredtobetheresultofnon-enzymaticdegradationandthereisnoevidenceof

cytochromeP450-mediatedmetabolismofthediaminocyclohexane(DACH)ring.

Oxaliplatinundergoesextensivebiotransformationinpatients,andnointactactivesubstancewasdetectableinplasma

ultrafiltrateattheendofa2h-infusion.Severalcytotoxicbiotransformationproductsincludingthemonochloro-,

dichloro-anddiaquo-DACHplatinumspecieshavebeenidentifiedinthesystemiccirculationtogetherwithanumber

ofinactiveconjugatesatlatertimepoints.

Platinumispredominantlyexcretedinurine,withclearancemainlyinthe48hoursfollowingadministration.

Byday5,approximately54%ofthetotaldosewasrecoveredintheurineand<3%inthefaeces.

Asignificantdecreaseinclearancefrom17.6 ±

2.18l/hto9.95 ±

1.91l/hinrenalimpairmentwasobservedtogether

withastatisticallysignificantdecreaseindistributionvolumefrom330 ±

40.9to241 ±

36.1l.Theeffectofsevere

renalimpairmentonplatinumclearancehasnotbeenevaluated.

5.3Preclinicalsafetydata

Thetargetorgansidentifiedinpreclinicalspecies(mice,rats,dogs,and/ormonkeys)insingle-andmultiple-dose

studiesincludedthebonemarrow,thegastrointestinalsystem,thekidney,thetestes,thenervoussystem,andthe

heart.Thetargetorgantoxicitiesobservedinanimalsareconsistentwiththoseproducedbyotherplatinum-

containingmedicinalproductsandDNA-damaging,cytotoxicmedicinalproductsusedinthetreatmentofhuman

cancerswiththeexceptionoftheeffectsproducedontheheart.Effectsontheheartwereobservedonlyinthedog

andincludedelectrophysiologicaldisturbanceswithlethalventricularfibrillation.Cardiotoxicityisconsidered

specifictothedognotonlybecauseitwasobservedinthedogalonebutalsobecausedosessimilartothose

producinglethalcardiotoxicityindogs(150mg/m 2

)werewell-toleratedbyhumans.Preclinicalstudiesusingrat

sensoryneuronssuggestthattheacuteneurosensorysymptomsrelatedtoOxaliplatinmayinvolveaninteractionwith

voltage-gatedNa +

channels.

Oxaliplatinwasmutagenicandclastogenicinmammaliantestsystemsandproducedembryo-fetaltoxicityinrats.

Oxaliplatinisconsideredaprobablecarcinogen,althoughcarcinogenicstudieshavenotbeenconducted.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

6.2Incompatibilities

Thedilutedmedicinalproductshouldnotbemixedwithothermedicinalproductsinthesameinfusionbagorinfusion

line.Underinstructionsforusedescribedinsection6.6,oxaliplatincanbeco-administeredwithfolinicacid(FA)via

aY-line.

-DONOTmixwithalkalinemedicinalproductsorsolutions,inparticular5fluorouracil(5FU),folinicacid(FA)

preparationscontainingtrometamolasanexcipientandtrometamolsaltsofothersactivesubstances.Alkaline

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-DONOTreconstituteordiluteoxaliplatinwithsalineorothersolutionscontainingchlorideions(includingcalcium,

potassiumorsodiumchlorides).

-DONOTmixwithothermedicinalproductsinthesameinfusionbagorinfusionline(seesection6.6forinstructions

concerningsimultaneousadministrationwithfolinicacid(FA)).

-DONOTuseinjectionequipmentcontainingaluminium.

6.3ShelfLife

3years

Reconstitutedsolutionintheoriginalvial:

Thereconstitutedsolutionshouldbedilutedimmediately.

Solutionforinfusion:

Afterdilutionofthereconstitutedsolutioninglucose5%(50mg/ml)solution,chemicalandphysicalin-usestability

hasbeendemonstratedfor24hoursat2°Cto8°C.

Fromamicrobiologicalpointofview,thesolutionforinfusionshouldbeusedimmediately.

Ifnotusedimmediately,in-usestoragetimesandconditionspriortousearetheresponsibilityoftheuserandwould

normallynotbelongerthan24hoursat2°Cto8°Cunlessdilutionhastakenplaceincontrolledandvalidated

asepticconditions.

6.4Specialprecautionsforstorage

Medicinalproductaspackagedforsale:

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

36mlvial(TypeIclearglass)ofoxaliplatinpowder(50mg)withchlorobutylelastomerstopper

50mlvial(TypeIclearglass)ofoxaliplatinpowder(100mg)withchlorobutylelastomerstopper

Packsize:1vialperbox.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Aswithotherpotentiallytoxiccompounds,cautionshouldbeexercisedwhenhandlingandpreparingoxaliplatin

solutions.

InstructionsforHandling

Thehandlingofthiscytotoxicagentbyhealthcarepersonnelrequireseveryprecautiontoguaranteetheprotectionof

thehandlerandhissurroundings.

Thepreparationofinjectablesolutionsofcytotoxicagentsmustbecarriedoutbytrained

specialistpersonnelwithknowledgeofthemedicinalproductsused,inconditionsthat

guaranteetheintegrityofthemedicinalproduct,theprotectionoftheenvironmentandin

particulartheprotectionofthepersonnelhandlingthemedicinalproducts,inaccordance

withthehospitalpolicy.Itrequiresapreparationareareservedforthispurpose.Itis

forbiddentosmoke,eatordrinkinthisarea.

Personnelmustbeprovidedwithappropriatehandlingmaterials,notablylongsleeved

gowns,protectionmasks,caps,protectivegoggles,sterilesingle-usegloves,protective

coversfortheworkarea,containersandcollectionbagsforwaste.

Excretaandvomitmustbehandledwithcare.

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Specialprecautionsforadministration

-DONOTuseinjectionequipmentcontainingaluminium.

-DONOTadministerundiluted.

-Onlyglucose5%(50mg/ml)infusionsolutionistobeusedasadiluent.DONOTreconstituteordiluteforinfusion

withsodiumchlorideorchloridecontainingsolutions.

-DONOTmixwithanyothermedicinalproductsinthesameinfusionbagoradministersimultaneouslybythesame

infusionline.

-DONOTmixwithalkalinemedicinalproductsorsolutions,inparticular5fluorouracil(5FU),folinicacid(FA)

preparationscontainingtrometamolasanexcipientandtrometamolsaltsofothersactivesubstances.Alkaline

medicinalproductsorsolutionswilladverselyaffectthestabilityofoxaliplatin

Instructionforusewithfolinicacid(FA)(ascalciumfolinateordisodiumfolinate)

Oxaliplatin85mg/m²intravenousinfusionin250to500mlofglucose5%(50mg/ml)solutionisgivenatthesame

timeasfolinicacid(FA)intravenousinfusioninglucose5%(50mg/ml)solution,over2to6hours,usingaY-line

placedimmediatelybeforethesiteofinfusion.Thesetwomedicinalproductsshouldnotbecombinedinthesame

infusionbag.Folinicacid(FA)mustnotcontaintrometamolasanexcipientandmustonlybedilutedusingisotonic

glucose5%(50mg/ml)solution,neverinalkalinesolutionsorsodiumchlorideorchloridecontainingsolutions.

Instructionforusewith5fluorouracil(5FU)

Oxaliplatinshouldalwaysbeadministeredbeforefluoropyrimidines–i.e.5fluorouracil(5FU).

Afteroxaliplatinadministration,flushthelineandthenadminister5fluorouracil(5FU).

Foradditionalinformationonmedicinalproductscombinedwithoxaliplatin,seethecorrespondingmanufacturer’s

summaryofproductcharacteristics.

-Anyreconstitutedsolutionthatshowsevidenceofprecipitationshouldnotbeusedandshouldbedestroyedwithdue

regardtolegalrequirementsfordisposalofhazardouswaste(seebelow).

Reconstitutionofthesolution

-Waterforinjectionsorglucose5%(50mg/ml)solutionshouldbeusedtoreconstitutethesolution.

-Foravialof50mg:add10mlofsolventtoobtainaconcentrationof5mgoxaliplatin/ml.

-Foravialof100mg:add20mlofsolventtoobtainaconcentrationof5mgoxaliplatin/ml.

Inspectvisuallypriortouse.Onlyclearsolutionswithoutparticlesshouldbeused.

Themedicinalproductisforsingleuseonly.Anyunusedsolutionshouldbediscarded(seedisposalbelow).

Dilutionforintravenousinfusion

Withdrawtherequiredamountofreconstitutedsolutionfromthevial(s)andthendilutewith250mlto500mlofa

glucose5%(50mg/ml)solutiontogiveanoxaliplatinconcentrationbetweennotlessthan0.2mg/mland0.7mg/ml.

Theconcentrationrangeoverwhichthephysico-chemicalstabilityofoxaliplatinhasbeendemonstratedis0.2mg/ml

Anybrokencontainermustbetreatedwiththesameprecautionsandconsideredas

contaminatedwaste.Contaminatedwasteshouldbeincineratedinsuitablylabelledrigid

containers.Seebelowchapter“Disposal”.

Ifoxaliplatinpowder,reconstitutedsolutionorsolutionforinfusion,shouldcomeinto

contactwithskin,washimmediatelyandthoroughlywithwater.

Ifoxaliplatinpowder,reconstitutedsolutionorsolutionforinfusion,shouldcomeinto

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Administerbyintravenousinfusion.

Afterdilutioninglucose5%(50mg/ml)solution,chemicalandphysicalin-usestabilityhasbeendemonstratedfor

24hoursat+2°Cto+8°C.

Fromamicrobiologicalpointofview,thisinfusionpreparationshouldbeusedimmediately.

Ifnotusedimmediately,in-usestoragetimesandconditionspriortousearetheresponsibilityoftheuserandwould

normallynotbelongerthan24hoursat2°Cto8°Cunlessdilutionhastakenplaceincontrolledandvalidated

asepticconditions

Inspectvisuallypriortouse.Onlyclearsolutionswithoutparticlesshouldbeused.

Themedicinalproductisforsingleuseonly.Anyunusedsolutionshouldbediscarded(seechapter“disposal”below).

NEVERusesodiumchlorideorchloridecontainingsolutionsforeitherreconstitutionordilution.

ThecompatibilityofOxaliplatinsolutionforinfusionhasbeentestedwithrepresentative,PVC-based,administration

sets.

Infusion

Theadministrationofoxaliplatindoesnotrequireprehydration.

Oxaliplatindilutedin250to500mlofaglucose5%(50mg/ml)solutiontogiveaconcentrationnotlessthan

0.2mg/mlmustbeinfusedviaacentralvenouslineoraperipheralveinover2to6hours.Whenoxaliplatinis

administeredwith5fluorouracil(5FU),theoxaliplatininfusionmustprecedetheadministrationof5fluorouracil

(5FU).

Disposal

Remnantsofthemedicinalproductaswellasallmaterialsthathavebeenusedforreconstitution,fordilutionand

administrationmustbedestroyedaccordingtohospitalstandardproceduresapplicabletocytotoxicagentsin

accordancewithlocalrequirementsrelatedtothedisposalofhazardouswaste.

7MARKETINGAUTHORISATIONHOLDER

Sanofi-aventisIrelandLimited,

CitywestBusinessCampus

Dublin24

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA540/148/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorization:05May2006

Dateoflastrenewal:31July2009

10DATEOFREVISIONOFTHETEXT

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