CAMRATA

Main information

  • Trade name:
  • CAMRATA Concentrate for Soln for Inf 20 Mg/Ml
  • Dosage:
  • 20 Mg/Ml
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CAMRATA Concentrate for Soln for Inf 20 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1312/004/001
  • Authorization date:
  • 09-04-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Camrata20mg/mlconcentrateforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onemlofconcentratecontains20mgirinotecanhydrochloridetrihydrate(equivalentto17.33mg/mlirinotecan).

Each2mlvialcontains40mgofirinotecanhydrochloridetrihydrate.

Each5mlvialcontains100mgofirinotecanhydrochloridetrihydrate.

Excipients:

Alsocontainssorbitol(E420)45mg/mlandsodium(seeSection4.4)

Forafulllistofexcipients,seeSection6.1

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion.

Aclear,paleyellowsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Camrataisindicatedforthetreatmentofpatientswithadvancedcolorectalcancer:

Incombinationwith5-fluorouracil(5-FU)andfolinicacid(FA)inpatientswithoutpriorchemotherapyfor

advanceddisease,

Asasingleagentinpatientswhohavefailedanestablished5-FUcontainingtreatmentregimen.

Camrataincombinationwithcetuximabisindicatedforthetreatmentofpatientswithepidermalgrowthfactorreceptor

(EGFR)-expressing,KRASwild-typemetastaticcolorectalcancer,whohadnotreceivedpriortreatmentformetastatic

diseaseorafterfailureofirinotecan-includingcytotoxictherapy(seeSection5.1).

Camrataincombinationwith5-FU,FAandbevacizumabisindicatedforfirst-linetreatmentofpatientswithmetastatic

carcinomaofthecolonorrectum.

Camrataincombinationwithcapecitabinewithorwithoutbevacizumabisindicatedforfirst-linetreatmentofpatients

withmetastaticcolorectalcarcinoma.

4.2Posologyandmethodofadministration

Foruseinadultsonly.

Camratashouldbeinfusedintoaperipheralorcentralvein.

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Recommendeddosage:

Inmonotherapy(forpreviouslytreatedpatient):

TherecommendeddosageofCamratais350mg/m 2

administeredasanintravenousinfusionovera30to90minute

periodeverythreeweeks(seeSection4.4).

Incombinationtherapy(forpreviouslyuntreatedpatient):

Safetyandefficacyofirinotecanincombinationwith5-FUandFAhavebeenassessedwiththefollowingschedule

(seeSection5.1):

Irinotecanplus5-FU/FAinevery2weeksschedule

TherecommendeddoseofCamratais180mg/m 2

administeredonceevery2weeksasanintravenousinfusionovera

30to90minuteperiod,followedbyinfusionwithFAand5-FU.

Fortheposologyandmethodofadministrationofconcomitantcetuximab,refertothesummaryofproduct

characteristicsofthismedicinalproduct.Normally,thesamedoseofirinotecanisusedasadministeredinthelast

cyclesoftheprioririnotecan-containingregimen.Camratamustnotbeadministeredearlierthan1houraftertheendof

thecetuximabinfusion.

Fortheposologyandmethodofadministrationofbevacizumab,refertothebevacizumabsummaryofproduct

characteristics.

Fortheposologyandmethodofadministrationofcapecitabinecombination,seeSection5.1andrefertothe

appropriatesectionsinthecapecitabinesummaryofproductcharacteristics

Dosageadjustments:

Camratashouldbeadministeredafterappropriaterecoveryofalladverseeventstograde0or1NCI-CTCgrading

(NationalCancerInstituteCommonToxicityCriteria)andwhentreatment-relateddiarrhoeaisfullyresolved.Atthe

startofasubsequentinfusionoftherapy,thedoseofCamrata,and5-FUwhenapplicable,shouldbedecreased

accordingtotheworstgradeofadverseeventsobservedinthepriorinfusion.Treatmentshouldbedelayedby1to2

weekstoallowrecoveryfromtreatment-relatedadverseevents.

Withthefollowingadverseeventsadosereductionof15to20%shouldbeappliedforCamrataand/or5-FUwhen

applicable:

haematologicaltoxicity(neutropeniagrade4,febrileneutropenia(neutropeniagrade3-4andfever

grade2-4),thrombocytopeniaandleucopenia(grade4)),

non-haematologicaltoxicity(grade3-4).

RecommendationsfordosemodificationofcetuximabwhenadministeredincombinationwithCamratamustbe

followedaccordingtothesummaryofproductcharacteristicsforthismedicinalproduct.

Refertothebevacizumabsummaryofproductcharacteristicsfordosemodificationsofbevacizumabwhen

administeredincombinationwithCamrata/5-FU/FA.

Incombinationwithcapecitabineforpatients65yearsofageormore,areductionofthestartingdoseofcapecitabine

to800mg/m 2

twicedailyisrecommendedaccordingtothesummaryofproductcharacteristicsforcapecitabine.Refer

alsototherecommendationsfordosemodificationsincombinationregimengiveninthesummaryofproduct

characteristicsforcapecitabine.

Treatmentduration:

TreatmentwithCamratashouldbecontinueduntilthereisanobjectiveprogressionofthediseaseoranunacceptable

toxicity.

Specialpopulations:

Patientswithimpairedhepaticfunction:Inmonotherapy:Bloodbilirubinlevels(upto3timestheupperlimitofthe

normalrange(ULN))inpatientswithperformancestatus ≤2,shoulddeterminethestartingdoseofCamrata.Inthese

patientswithhyperbilirubinemiaandprothrombintimegreaterthan50%,theclearanceofirinotecanisdecreased(see

Section5.1)andthereforetheriskofhaematoxicityisincreased.Thus,weeklymonitoringofcompletebloodcounts

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Patientswithbilirubinupto1.5timestheULN,therecommendeddosageofCamratais350mg/m 2

Patientswithbilirubinrangingfrom1.5to3timestheULN,therecommendeddosageofCamratais

200mg/m 2

Patientswithbilirubinabove3timestheULNshouldnotbetreatedwithCamrata(seeSections4.3and

4.4).

Nodataisavailableinpatientswithhepaticimpairmenttreatedbyirinotecanincombination.

Patientswithimpairedrenalfunction:

Irinotecanisnotrecommendedforuseinpatientswithimpairedrenalfunction,asstudiesinthispopulationhavenot

beenconducted(seeSections4.4and5.1).

Elderly:

Nospecificpharmacokineticstudieshavebeenperformedinelderly.However,thedoseshouldbechosencarefullyin

thispopulationduetotheirgreaterfrequencyofdecreasedbiologicalfunctions.Thispopulationshouldrequiremore

intensesurveillance(seeSection4.4).

4.3Contraindications

HistoryofseverehypersensitivitytoirinotecanorhypersensitivitytoanyoftheexcipientsofCamrata.

Chronicinflammatoryboweldiseaseand/orbowelobstruction(seeSection4.4).

Pregnancyandlactation(seeSection4.6).

Biliruibin>3timestheULN(seeSection4.4).

Severebonemarrowfailure.

WHOperformancestatus>2.

ConcomitantusewithSt.John’sWort(seeSection4.5)

Foradditionalcontraindicationsofcetuximaborbevacizumaborcapecitabine,refertothesummaryofproduct

characteristicsforthesemedicinalproducts.

4.4Specialwarningsandprecautionsforuse

TheuseofCamratashouldberestrictedtounitsspecialisedintheadministrationofcytotoxicchemotherapyandonly

underthesupervisionofaphysicianqualifiedintheuseofanticancerchemotherapy.Giventheadverseeventsprofile

ofirinotecanitshouldonlybeprescribedinthefollowingcasesafterconsiderationofthebenefitshavingbeenweighed

againstthepossibletherapeuticrisk:

Inpatientspresentingariskfactor,particularlywithaWHOperformancestatus=2.

Inthefewrareinstanceswherethepatientsaredeemedunlikelytoobserverecommendationsregarding

managementofadverseevents(needforimmediateandprolongedanti-diarrhoealtreatmentcombined

withhighfluidintakeattheonsetofdelayeddiarrhoea).Stricthospitalsupervisionisrecommendedin

suchpatients.

WhenCamrataisusedinmonotherapy,itisusuallyprescribedwiththeevery-3-week-dosageschedule.However,the

weekly-dosageschedule(seeSection5)maybeconsideredinpatientswhomayneedacloserfollow-uporwhoareat

particularriskofsevereneutropenia.

Delayeddiarrhoea:

Patientsmustbemadeawareoftheassociatedriskofdelayeddiarrhoeaoccurringmorethan24hoursafter

administrationofCamrataandatanytimebeforethenextcycle.Inmonotherapy,themediantimeforonsetofthefirst

liquidstoolwasonday5aftertheinfusion.Patientsshouldquicklyinformtheirphysicianandappropriatetherapybe

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Patientswhohavehadapreviousabdominal/pelvicradiotherapy,thosewithbaselinehyperleucocytosis,thosewith

performancestatus ≥2andwomenhaveanincreasedriskofdiarrhoea.Ifnotproperlytreated,diarrhoeacanbelife-

threatening,especiallyifthepatientisconcomitantlyneutropenic.

Assoonasthefirstliquidstoolsoccur,thepatientshouldstartdrinkinglargevolumesofbeveragescontaining

electrolytesandanappropriateanti-diarrhoealtreatmentinitiatedimmediately.Thisanti-diarrhoealtreatmentwillbe

prescribedbythedepartmentwheretheCamratahasbeenadministered.Afterdischargefromthehospitalthepatient

shouldbeprovidedwithanti-diarrhoealdrugssotheycaninitiatetreatmentimmediatelyitoccurs.Inaddition,the

patientmustinformtheirphysicianorthedepartmentadministeringtheCamratawhen/ifdiarrhoeaoccurs.

Ahighdoseofloperamide(4mgforthefirstintakeandthen2mgevery2hours)istherecommendedanti-diarrhoeal

treatment.Treatmentshouldcontinuefor12hoursafterpassingthelastliquidstoolandshouldnotbemodified.Inno

instanceshouldtheloperamidebeadministeredformorethan48consecutivehoursatthesedoses,becauseoftherisk

ofparalyticileus,norforlessthan12hours.

Inadditiontotheanti-diarrhoealtreatment,aprophylacticbroadspectrumantibioticshouldbegivenwhenthe

diarrhoeaisassociatedwithsevereneutropenia(neutrophilcount <

500cells/mm 3

Inadditiontotheantibiotictreatment,hospitalisationisrecommendedformanagementofthediarrhoea,inthe

followingcases:

Diarrhoeaassociatedwithfever

Severediarrhoea(requiringintravenoushydration)

Diarrhoeapersistingbeyond48hoursfollowingtheinitiationofhigh-doseloperamidetherapy.

Loperamideshouldnotbegivenprophylactically,evenforpatientswhohaveexperienceddelayeddiarrhoeaon

previouscycles.

Inpatientswhoexperiencedseverediarrhoeaareductionindoseisrecommendedforsubsequentcycles(seeSection

4.2).

Haematology:

WeeklymonitoringofcompletebloodcellcountsisrecommendedduringtreatmentwithCamrata.Patientsshouldbe

informedoftheriskofneutropeniaandthesignificanceoffever.Febrileneutropenia(temperature>38ºC,neutrophil

count ≤1,000cells/mm 3

)shouldbeurgentlytreatedinhospitalwithbroadspectrumintravenousantibiotics.In

patientswhoexperiencedseverehaematologicalevents,adosereductionisrecommendedforsubsequentcycles(see

Section4.2).Thereisanincreasedriskofinfectionsandhaematologicaltoxicityinpatientswithseverediarrhoea.In

patientswithseverediarrhoeacompletebloodcellcountsshouldbeperformed.

Liverimpairment:

Liverfunctiontestsshouldbeperformedatbaselineandbeforeeachcycle.Inpatientswithbilirubinrangingfrom1.5

to3timesULNweeklymonitoringofcompletebloodcountsshouldbeconductedduetodecreaseoftheclearanceof

irinotecan(seeSection5.2)andthusincreasingtheriskofhaematoxicityinthispopulation.Irinotecantreatmentis

contraindicatedforpatientswithbilirubin>3timesULN(seeSection4.3).

Nauseaandvomiting:

Asnauseaandvomitinghavebeenfrequentlyreportedprophylactictreatmentwithantiemeticsisrecommendedbefore

treatmentwithCamrata.Patientswithvomitingassociatedwithdelayeddiarrhoeashouldbehospitalisedassoonas

possiblefortreatment.

Acutecholinergicsyndrome:

Ifacutecholinergicsyndromeappears(earlydiarrhoeaandvariousothersymptomssuchassweating,abdominal

cramping,lacrimation,myosisandsalivation),atropinesulphate(0.25mgsubcutaneously)shouldbeadministered

unlessclinicallycontraindicated(seeSection4.8).Cautionshouldbeexercisedinpatientswithasthma.Inpatients

whoexperiencedanacuteandseverecholinergicsyndrome,theuseofprophylacticatropinesulphateisrecommended

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Respiratorydisorders:

Interstitialpulmonarydiseasepresentingaspulmonaryinfiltratesisuncommonduringirinotecantherapy.Interstitial

pulmonarydiseasecanbefatal.Riskfactorspossiblyassociatedwiththedevelopmentofinterstitialpulmonarydisease

includetheuseofpneumotoxicdrugs,radiationtherapyandcolonystimulatingfactors.Patientswithriskfactors

shouldbecloselymonitoredforrespiratorysymptomsbeforeandduringirinotecantherapy.

Elderly:

DoseselectionwithCamratashouldbemadewithcautionintheelderlyduetodecreasedbiologicalfunction,in

particularhepaticfunction(seeSection4.2).

Patientswithbowelobstruction:

PatientsmustnotbetreatedwithCamratauntilresolutionofthebowelobstruction(seeSection4.3).

Patientswithimpairedrenalfunction:

Nostudieshavebeenconductedinthispopulation(seeSections4.2and5.2).

Others:

AsCamrataconcentrateforsolutionforinfusioncontainssorbitolpatientswithrarehereditaryproblemsoffructose

intoleranceshouldnotbegiventhismedicine.Thismedicinalproductcontainslessthan1mmolsodium(23mg)per

vial,i.e.essentially‘sodium-free’.Inpatientswhoexperiencedepisodesofdiarrhoeaand/orvomiting,orsepsis,

infrequentcasesofrenalinsufficiency,hypotensionorcirculatoryfailurehavebeenobserved.Contraceptivemeasures

mustbetakenwhilsttakingCamrataandforatleast3monthsafterendoftherapy.Concomitantadministrationof

stronginhibitorsorinducersofCYP3A4(e.g.ketoconazole,rifampicin,carbamazepine,phenobarbitol,phenytoin,St

John’sWort)mayalterthemetabolismofirinotecanandshouldbeavoided(seeSection4.5).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionbetweenirinotecanandneuromuscularblockingagentscannotberuledout.Irinotecanhas

anticholinesteraseactivitythereforedrugswithanticholinesteraseactivitymayprolongtheneuromuscularblocking

effectsofsuxamethoniumandtheneuromuscularblockadeofnon-depolarisingdrugsmaybeantagonised.

SeveralstudieshaveshownthatconcomitantadministrationofCYP3A-inducinganticonvulsantsdrugs(e.g.

carbamazepine,phenobarbitalorphenytoin)leadstoreducedexposureofirinotecan,SN-38andSN-38glucuronideand

reducedpharmacodynamiceffects.TheeffectofsuchanticonvulsantdrugswasreflectedbyadecreaseinAUCofSN-

38andSN-38Gby50%ormore.InadditiontoinductionofcytochromePA4503Aenzymes,enhanced

glucuronidationandenhancedbiliaryexcretionmayplayaroleinreducingexposuretoirinotecananditsmetabolites.

Astudyhasshownthattheco-administrationofketoconazoleresultedinadecreaseinAUCofAPCof87%andinan

increaseintheAUCofSN-38of109%incomparisontoirinotecangivenalone.

Cautionshouldbeexercisedinpatientsconcurrentlytakingdrugsknowntoinhibitorinducedrugmetabolismby

cytochromeP4503A4(e.g.ketoconazole,rifampicin,carbamazepine,phenobarbitol,phenytoin).Concurrent

administrationofCamratawithaninhibitor/inducerofthismetabolicpathwaymayalterthemetabolismofirinotecan

andshouldbeavoided(seeSection4.4).

Inasmallpharmacokineticstudy(n=5),inwhichirinotecan350mg/m 2

wasco-administeredwithSt.John’sWort

(Hypericumperforatum)900mg,a42%decreaseintheactivemetaboliteofirinotecan,SN-38,plasmaconcentration

wasobserved.

StJohn’sWortshouldnotbeadministeredwithCamrataasitdecreasesSN-38(anactivemetaboliteofirinotecan(see

Section4.3).

Co-administrationof5-FU/FAacidincombinationregimendoesnotchangethepharmacokineticsofirinotecan.

Inonestudy,irinotecanconcentrationsweresimilarinpatientsreceivingirinotecan/5-FU/FAaloneandincombination

withbevacizumab.ConcentrationsofSN-38,theactivemetaboliteofirinotecan,wereanalysedinasubsetofpatients

(approximately30pertreatmentarm).Concentrationsof38-SNwere33%higherinpatientsreceivingirinotecan/5-

FU/FAincombinationwithbevacizumabcomparewithirinotecan/5-FU/FAalone.ItisuncertainiftheincreaseinSN-

38levelswasduetobevacizumabduetohighinter-patientvariabilityandlimitedsampling.Therewasasmall

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Moredosereductionsofirinotecanwerereportedforpatientsreceivingthebevacizumabincombinationwith

irinotecan/5-FU/FA.Patientswhodevelopseverediarrhoea,leucopenia,orneutropeniawiththebevacizumaband

irinotecan/5-FU/FAcombinationshouldhaveamodificationoftheCamratadoseasspecifiedinSection4.2.

ThereisnoevidencethatthesafetyprofileofCamrataisinfluencedbycetuximaborviceversa.

4.6Fertility,pregnancyandlactation

Pregnancy:

Thereisnoinformationontheuseofirinotecaninpregnantwomen.Irinotecanhasbeenshowntobeembryotoxic,

foetotoxicandteratogenicinrabbitsandrats.Therefore,Camratamustnotbeusedduringpregnancy(seeSections4.3

and4.4).

Womenofchild-bearingpotential:

Womenofchild-bearingagereceivingCamratashouldbeadvisedtoavoidbecomingpregnant,andtoinformthe

treatingphysicianimmediatelyshouldthisoccur(seeSections4.3and4.4).

Lactation:

Inlactatingrats, 14

C-irinotecanwasdetectedinmilk.Itisnotknownifirinotecanisexcretedinhumanmilk.

Consequentlybecauseoftheriskofadversereactionsinnursinginfants,breast-feedingmustbediscontinuedforthe

durationoftheCamratatherapy(seeSection4.3).

4.7Effectsonabilitytodriveandusemachines

Patientsshouldbeadvisedofthepotentialfordizzinessorvisualdisturbanceswhichmayoccurwithin24hours

followingadministrationofCamrata,andadvisednottodriveoroperatemachineryifthesesymptomsoccur.

4.8Undesirableeffects

Theinformationprovidedinthissectionrefertoirinotecan.Thereisnoevidencethatthesafetyprofileofirinotecanis

influencedbycetuximaborviceversa.Incombinationwithcetuximab,additionalundesirableeffectswerethose

expectedwithcetuximab(e.g.acneformrash88%).Thereforealsorefertothecetuximabsummaryofproduct

characteristics.

Forinformationonadversereactionsincombinationwithbevacizumabrefertothebevacizumabsummaryofproduct

characteristics.

Adversedrugreactionsreportedinpatientstreatedwithcapecitabineincombinationwithirinotecaninadditiontothose

seenwithcapecitabinemonotherapyorseenatahigherfrequencygroupingcomparedtocapecitabinemonotherapy

include:Verycommon,allgradeadversedrugreactions:thrombosis/embolism;Common,allgradeadversedrug

reactions:hypersensitivityreaction,cardiacischemia/infarction;Common,grade3and4adversedrugreactions:

febrileneutropenia.Forcompleteinformationonadversereactionsofcapecitabine,refertothecapecitabinesummary

ofproductcharacteristics.

Grade3andGrade4adversedrugreactionsreportedinpatientstreatedwithcapecitabineincombinationwith

irinotecanandbevacizumabinadditiontothoseseenwithcapecitabinemonotherapyorseenatahigherfrequency

groupingcomparedtocapecitabinemonotherapyinclude:Common,grade3andgrade4adversedrugreactions:

neutropenia,thrombosis/embolism,hypertension,andcardiacischemia/infarction.Forcompleteinformationon

adversereactionsofcapecitabineandbevacizumab,refertotherespectivecapecitabineandbevacizumabsummaryof

productcharacteristics.

Thefollowingadversereactionsconsideredtobepossiblyorprobablyrelatedtotheadministrationofirinotecanhave

beenreportedfrom765patientsattherecommendeddoseof350mg/m 2

inmonotherapy,andfrom145patientsin

combinationtherapywith5-FU/FAinevery2weeksscheduleattherecommendeddoseof180mg/m 2

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Delayeddiarrhoea:

Diarrhoea(occurringmorethan24hoursafteradministration)isadose-limitingtoxicityofirinotecan.

Inmonotherapy:

Severediarrhoeawasobservedin20%ofpatientswhofollowrecommendationsforthemanagementofdiarrhoea.Of

theevaluablecycles,14%haveaseverediarrhoea.Themediantimeofonsetofthefirstliquidstoolwasonday5after

theinfusionofirinotecan.

Incombinationtherapy:

Severediarrhoeawasobservedin13.1%ofpatientswhofollowrecommendationsforthemanagementofdiarrhoea.

Oftheevaluablecycles,3.9%haveaseverediarrhoea.Uncommoncasesofpseudo-membranouscolitishavebeen

reported,oneofwhichhasbeendocumentedbacteriologically(Clostridiumdifficile).

Nauseaandvomiting:

Inmonotherapy:Nauseaandvomitingweresevereinapproximately10%ofpatientstreatedwithantiemetics.

Incombinationtherapy:lowerincidenceofseverenauseaandvomitingwasobserved(2.1%and2.8%ofpatients

respectively).

Dehydration:

Episodesofdehydrationcommonlyassociatedwithdiarrhoeaand/orvomitinghavebeenreported.Infrequentcasesof

renalinsufficiency,hypotensionorcardio-circulatoryfailurehavebeenobservedinpatientswhoexperiencedepisodes

ofdehydrationassociatedwithdiarrhoeaand/orvomiting.

Othergastrointestinaldisorders:

Constipationrelativetoirinotecanand/orloperamidehasbeenobserved,sharedbetween:

Inmonotherapy:inlessthan10%ofpatients.

Incombinationtherapy:3.4%ofpatients.

Infrequentcasesofintestinalobstruction,ileus,orgastrointestinalhaemorrhageandrarecasesofcolitis,including

typhlitis,ischemicandulcerativecolitis,werereported.Rarecasesofintestinalperforationwerereported.Othermild

effectsincludeanorexia,abdominalpainandmucositis.

Rarecasesofsymptomaticorasymptomaticpancreatitishavebeenassociatedwithirinotecantherapy.

Blooddisorders:

Neutropeniaisadose-limitingtoxiceffect.Neutropeniawasreversibleandnotcumulative;themediandaytonadir

was8dayswhatevertheuseinmonotherapyorcombinationtherapy.

Inmonotherapy:Neutropeniawasobservedin78.7%ofpatientsandsevere(neutrophilcount <

500cells/mm 3

)in

22.6%ofpatients.Oftheevaluablecycles,18%hadaneutrophilcountbetween1,000cells/mm 3

including7.6%with

aneutrophilcount <

500cells/mm 3

.Totalrecoverywasusuallyreachedbyday22.Feverwithsevereneutropeniawas

reportedin6.2%ofpatientsandin1.7%ofcycles.

Infectiousepisodesinabout10.3%ofpatients(2.5%ofcycles)andwereassociatedwithsevereneutropeniainabout

5.3%patients(1.1%ofcycles),andresultedindeathin2cases.

Anaemiawasreportedinabout58.7%ofpatients(8%withhaemoglobin <

8g/dland0.9%withhaemoglobin <

g/dl).

Thrombocytopenia( <

100,000cells/mm 3

)wasobservedin7.4%ofpatientsand1.8%ofcycleswith0.9%with

plateletscount ≤50,000cells/mm 3

and0.2%ofcycles.Nearlyallpatientsshowedarecoverybyday22.

Incombinationtherapy:Neutropeniawasobservedin82.5%ofpatientsandwassevere(neutrophilcount <

cells/mm 3

)in9.8%ofpatients.Oftheevaluablecycles,67.3%hadaneutrophilcountbelow1,000cells/mm 3

including2.7%withneutrophilcount <

500cells/mm 3

.Totalrecoverywasusuallyreachedwithin7-8days.Fever

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Infectiousepisodesoccurredinabout2%ofpatients(0.5%ofcycles)andwereassociatedwithsevereneutropeniain

about2.1%ofpatients(0.5%ofcycles),andresultedindeathin1case.

Anaemiawasreportedin97.2%ofpatients(2.1%withhaemoglobin <

8g/dl).

Thrombocytopenia( <

100,000cells/mm 3

)wasobservedin32.6%ofpatientsand21.8%ofcycles.Nosevere

thrombocytopenia( <

50,000cells/mm 3

)hasbeenobserved.Onecaseofperipheralthrombocytopeniawithantiplatelet

antibodieshasbeenreported.

Infectionandinfestation:

Infrequentcasesofrenalinsufficiency,hypotensionorcardio-circulatoryfailurehavebeenobservedinpatientswho

experiencedsepsis.

Generaldisordersandinfusionsitereactions:

Acutecholinergicsyndrome:

Severetransientacutecholinergicsyndromewasobservedin9%ofpatientstreatedinmonotherapyandin1.4%of

patientstreatedincombinationtherapy.Themainsymptomsweredefinedasearlydiarrhoeaandvariousother

symptomssuchasabdominalpain,conjunctivitis,rhinitis,hypotension,vasodilatation,sweating,chills,malaise,

dizziness,visualdisturbances,myosis,lacrimationandincreasedsalivationoccurringduringorwithinthefirst24hours

aftertheinfusionofirinotecan.Thesesymptomsdisappearafteratropineadministration(seeSection4.4).

Astheniawassevereinlessthan10%ofpatientstreatedinmonotherapyandin6.2%ofpatientstreatedincombination

therapy.Thecausalrelationshiptoirinotecanhasnotbeenclearlyestablished.Feverintheabsenceofinfectionand

withoutconcomitantsevereneutropenia,occurredin12%ofpatientsinmonotherapyandin6.2%ofpatientstreatedin

combinationtherapy.

Mildinfusionsitereactionshavebeenreporteduncommonly.

Cardiacdisorder:

Rarecasesofhypotensionduringorfollowingtheinfusionhavebeenreported.

Respiratorydisorders:

Interstitialpulmonarydiseasepresentingaspulmonaryinfiltratesisuncommonduringirinotecantherapy.Earlyeffects

suchasdyspnoeahavebeenreported(seeSection4.4)

Skinandsubcutaneousdisorders:

Alopeciawasverycommonandreversible.Mildcutaneousreactionshavebeenreportedalthoughuncommonly.

Immunesystemdisorders:

Uncommonmildallergicreactionsandrarecasesofanaphylactic/anaphylactoidreactionshavebeenreported.

Musculoskeletaldisorders:

Earlyeffectssuchasmuscularcontractionorcrampsandparasthesiahavebeenreported.

Laboratorytests:

Inmonotherapy:Transientandmildtomoderateincreasesinserumlevelsofeithertransaminases,alkaline

phosphataseorbilirubinwereobservedin9.2%,8.1%and1.8%ofthepatients,respectively,intheabsenceof

progressivelivermetastasis.Transientandmildtomoderateincreasesofserumlevelsofcreatininehavebeen

observedin7.3%ofthepatients.

Incombinationtherapy:Transientserumlevels(grades1and2)ofeitherSGPT,SGOT,alkalinephosphataseor

bilirubinwereobservedin15%,11%,11%and10%ofthepatients,respectively,intheabsenceofprogressiveliver

metastasis.Transientgrade3wasobservedin0%,0%,0%and1%ofthepatients,respectively.Nograde4was

observed.Increasesofamylaseand/orlipasehavebeenveryrarelyreported.

Rarecasesofhypokalemiaandhyponatremiamostlyrelatedwithdiarrhoeaandvomitinghavebeenreported.

Nervoussystemdisorders:

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4.9Overdose

Therehavebeenreportsofoverdosageatuptoapproximatelytwicetherecommendedtherapeuticdose,whichmaybe

fatal.Mostsignificantadversereactionsreportedweresevereneutropeniaandseverediarrhoea.Thereisnoantidote

toCamrata,maximumsupportivecareshouldbeinstitutedtopreventdehydrationduetodiarrhoeaandtotreatany

infectiouscomplications.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:cytostatictopoisomeraseIinhibitor

ATCCode:L01XX19

Experimentaldata

Irinotecanisasemi-syntheticderivativeofcamptothecin.Itisanantineoplasticagentwhichactsasaspecificinhibitor

ofDNAtopoisomeraseI.ItismetabolisedbycarboxylesteraseinmosttissuestoSN-38,whichwasfoundtobemore

activethanirinotecaninpurifiedtopoisomeraseIandmorecytotoxicthanirinotecanagainstseveralmurineandhuman

tumourcelllines.TheinhibitionofDNAtopoisomeraseIbyirinotecanorSN-38inducessingle-strandedDNAlesions

whichblockstheDNAreplicationforkandareresponsibleforthecytotoxicity.Thiscytotoxicityactivitywasfound

time-dependentandwasspecifictotheSphase.Invitro,irinotecanandSN-38werenotfoundtobesignificantly

recognisedbytheP-glycoproteinMDR,anddisplayscytotoxicactivitiesagainstdoxorubicinandvinblastineresistant

celllines.Furthermore,irinotecanhasabroadantitumouractivityinvivoagainstmurinetumourmodels(P03

pancreaticductaladenocarcinoma,MA16/Cmammaryadenocarcinoma,C38andC51colonadenocarcinomas)and

againsthumanxenografts(Co-4colonadenocarcinoma,Mx-1mammaryadenocarcinoma,ST-15andSC-16gastric

adenocarcinomas).IrinotecanisalsoactiveagainsttumoursexpressingtheP-glycoproteinMDR(vincristine-and

doxorubicin-resistantP388leukaemia’s).Besidestheanti-tumouractivityofirinotecan,themostrelevant

pharmacologicaleffectistheinhibitionofacetylcholinesterase.

Clinicaldata

Incombinationtherapyforthefirst-linetreatmentofmetastaticcolorectalcarcinoma

IncombinationtherapywithFAand5-FU

AphaseIIIstudywasperformedin385previouslyuntreatedmetastaticcolorectalcancerpatientstreatedwitheither

every2weeksschedule(seeSection4.2)orweeklyscheduleregimens.Intheevery2weeksschedule,onday1,the

administrationofirinotecanat180mg/m 2

onceevery2weeksisfollowedbyinfusionwithFA(200mg/m 2

overa2-

hourintravenous)and5-FU(400mg/m 2

asanintravenousbolus,followedby600mg/m 2

overa22-hourintravenous

infusion).Onday2,FAand5-FUareadministeredatthesamedosesandschedules.Intheweeklyschedule,the

administrationofirinotecanat80mg/m 2

isfollowedbyinfusionwithFA(500mg/m 2

overa2-hourintravenous

infusion)andthenby5-FU(2300mg/m 2

overa24-hourintravenousinfusion)over6weeks.

Inthecombinationtherapytrialwiththe2regimensdescribedabove,theefficacyofirinotecanwasevaluatedin198

treatedpatients:

Combinedregimens

n=198 Weeklyschedule

n=50 Every2weeksschedule

n=148

Irinotecan+

5-FU/FA 5-FU/FA Irinotecan+

5-FU/FA 5-FU/FA Irinotecan+

5-FU/FA 5-FU/FA

Response

rate(%) 40.8* 23.1* 51.2* 28.6* 37.5* 21.6*

pvalue p <

0.001 p=0.045 p=0.005

Mediantime

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5-FU:5-fluorouracil,FA:folinicacid,NS:nonsignificant,*:asperprotocolpopulationanalysis

Intheweeklyschedule,theincidenceofseverediarrhoeawas44.4%inpatientstreatedbyirinotecanincombination

with5-FU/FAand25.6%inpatientswith

5-FU/FAalone.Theincidenceofsevereneutropenia(neutrophilcount <

500cells/mm 3

)was5.8%inpatientstreated

byirinotecanincombinationwith5-FU/FAand2.4%inpatientstreatedby5-FU/FAalone.Additionally,mediantime

todefinitiveperformancestatusdeteriorationwassignificantlylongerinirinotecancombinationthanin5-FU/FAalone

group(p=0.046).

QualityoflifewasassessedinthisphaseIIIstudyusingtheEORTCQLC-C30questionnaire.Timetodefinitive

deteriorationconstantlyoccurredlaterintheirinotecangroups.TheevolutionoftheGlobalHealthStatus/Qualityof

lifewasslightlybetterinirinotecancombinationgroupalthoughnotsignificant,showingthattheefficacyofirinotecan

incombinationcouldbereachedwithoutaffectingthequalityoflife.

Incombinationwithbevacizumab:

AphaseIIrandomised,double-blind,active-controlledclinicaltrialevaluatedbevacizumabincombinationwith

irinotecan/5-FU/FAasthefirst-linetreatmentformetastaticcarcinomaofthecolonorrectum(studyAVF2107g).The

additionofbevacizumabtothecombinationresultedinastatisticallyincreaseinoverallsurvival.Theclinicalbenefit,

measuredbyoverallsurvival,wasseeninallpre-specifiedpatientsubgroups,includingthosedefinedbyage,sex,

performancestatus,locationofprimarytumour,numberoforgansinvolved,anddurationofmetastaticdisease.Refer

progression

(months)

pvalue p <

0.001 NS p=0.001

Median

durationof

response

(months) 9.3 8.8 8.9 6.7 9.3 9.5

Pvalue NS P=0.043 NS

Median

durationof

responseand

stabilisation

(months) 8.6 6.2 8.3 6.7 8.5 5.6

pvalue p <

0.001 NS p=0.003

Mediantime

totreatment

failure

(months) 5.3 3.8 5.4 5.0 5.1 3.0

Pvalue p=0.0014 NS p <

0.001

Median

survival

(months) 16.8 14.0 119.2 14.1 15.6 13.0

pvalue p=0.028 NS p=0.041

AVF2107g

Arm1

Irinotecan/5-Fu/FA+

placebo Arm2

Irinotecan/5-FU/FA+

bevacizumab a

Numberofpatients 411 402

Overallsurvival

Mediantime(months) 15.6 20.3

95%CI 14.29–16.99 18.46–24.18

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5mg/kgevery2weeks, b

relativetocontrolarm,CIconfidenceinterval

Incombinationwithcetuximab:

EMR62202-013:Thisrandomisedstudyinpatientswithmetastaticcolorectalcancerwhohadnotreceivedprior

treatmentformetastaticdiseasecomparedthecombinationofcetuximabandirinotecanplusinfusional5-FU/FA(599

patients)tothesamechemotherapyalone(599patients).TheproportionofpatientswithKRASwild-typetumours

fromthepatientpopulationevaluableforKRASstatuscomprised64%.Theefficacydatageneratedinthisstudyare

summarisedinthetablebelow:

CIconfidenceinterval,FOLFRIirinotecan+infusional5-FU/FA,ORRobjectiveresponserate(patientswith

completeresponseorpartialresponse),PFSprogression-freesurvivaltime

Incombinationtherapywithcapecitabine

Datafromrandomised,controlledphaseIIIstudy(CARIO)supporttheuseofcapecitabineatastartingdoseof1000

mg/m 2

for2weeksevery3weeksincombinationwithirinotecanforthefirst-linetreatmentofpatientswithmetastatic

colorectalcancer.820patientswererandomisedtoreceiveeithersequentialtreatment(n=410)orcombination

treatment(n=410).Sequentialtreatmentconsistedoffirst-linetreatmentwithcapecitabine(1250mg/m 2

twicedailyfor

14days),second-lineirinotecan(350mg/m 2

onday1),andthird-linecombinationofcapecitabine(1000mg/m 2

twice

dailyfor14days)withoxaliplatin(130mg/m 2

onday1).Combinationtreatmentconsistedoffirst-linetreatmentof

capecitabine(1000mg/m 2

twicedailyfor14days)combinedwithirinotecan~(250mg/m 2

onday1)(XELRI)and

second-linecapecitabine(1000mg/m 2

twicedailyfor14days)plusoxaliplatin(130mg/m 2

onday1).Alltreatment

cycleswereadministeredatintervalsof3weeks.Infirst-linetreatmentthemedianprogression-freesurvivalinthe

intent-to-treatpopulationwas5.8months(95%CI,5.1–6.2months)forcapecitabinemonotherapyand7.8months

p-value 0.00004

Progression-freesurvival

Mediantime(months) 6.2 10.6

Hazardratio 0.54

p-value <0.0001

Overallresponserate

Rate(%) 34.8 44.8

95%CI 30.2–39.6 39.9–49.8

p-value 0.0036

Durationofresponse

Mediantime(months) 7.1 10.4

25–75percentile(months) 4.7–11.8 6.7–15.0

Overallpopulation KRASwild-typepopulation

Variable/statistic Cetuximab

+FOLFRI

(n=599) FOLFRI

(n=599)( Cetuximab

+FOLFRI

(n=172) FOLFRI

(n=176)

%(95%CI) 46.9(42.9,

51.0) 38.7(34.8,

42.8) 59.3(51.6,66.7) 43.2(35.8,

50.9)

p-value 0.0038 0.0025

Hazardratio

(95%CI) 0.85(0.726,0.998) 0.68(0.501,0.934)

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Datafromaninterimanalysisofamulticentre,randomised,controlledphaseIIstudy(AIOKRK0604)supporttheuse

ofcapecitabineatastartingdoseof800mg/m 2

for2weeksevery3weeksincombinationwithirinotecanand

bevacizumabforthefirst-linetreatmentofpatientswithmetastaticcolorectalcancer.115patientswererandomisedto

treatmentwithcapecitabinecombinedwithirinotecan(XELIRI)andbevacizumab:capecitabine(800mg/m 2

twice

dailyfor2weeksfollowedbya7-dayrestperiod),irinotecan(200mg/m 2

asa30minuteinfusiononday1every3

weeks),andbevacizumab(7.5mg/kgasa30to90minuteinfusiononday1every3weeks);atotalof118patients

wererandomisedtotreatmentwithcapecitabinecombinedwithoxaliplatinplusbevacizumab:capecitabine(1000

mg/m 2

twicedailyfor2weeksfollowedbya7-dayrestperiod),oxaliplatin(130mg/m 2

asa2hourinfusiononday1

every3weeks),andbevacizumab(7.5mg/kgAsa30to90minuteinfusiononday1every3weeks).Progression-free

survivalat6monthsintheintent-to-treatpopulationwas80%(XELRIplusbevacizumab)versus74%(XELOXplus

bevacizumab).Overallresponserate(completeresponsepluspartialresponse)was45%(XELOXplusbevacizumab)

versus47%(XELIRIplusbevacizumab).

Inmonotherapyforthesecond-linetreatmentofmetastaticcolorectalcarcinoma:

ClinicalphaseII/IIIstudieswereperformedinmorethan980patientsintheevery3weekdosageschedulewith

metastaticcolorectalcancerwhofailedaprevious5-FUregimen.Theefficacyofirinotecanwasevaluatedin765

patientswithdocumentedprogressionon5-FUatstudyentry.

n/anonapplicable,*statisticallysignificantdifference

InphaseIIstudies,performedon455patientsintheevery3-weekdosageschedule,theprogressionfreesurvivalat6

monthswas30%andthemediansurvivalwas9months.Themediantimetoprogressionwas18weeks.

Additionally,non-comparativephaseIIstudieswereperformedin304patientstreatedwithaweeklyscheduleregimen,

atadoseof125mg/m 2

administeredasanintravenousinfusionover90minutesfor4consecutiveweeksfollowedby2

weeksrest.Inthesestudies,themediantimetoprogressionwas17weeksandmediansurvivalwas10months.A

similarsafetyprofilehasbeenobservedintheweekly-dosageschedulein193patientsatthestartingdoseof125

mg/m 2

,comparedtotheevery3-week-dosageschedule.Themediantimeofonsetofthefirstliquidstoolwasonday

Incombinationwithcetuximabafterfailureofirinotecan-includingcytotoxictherapy

Theefficacyofthecombinationofcetuximabwithirinotecanwasinvestigatedintwoclinicalstudies.Atotalof356

patientswithEGFR-expressingmetastaticcolorectalcancerwhohadrecentlyfailedirinotecan-includingcytotoxic

therapyandwhohadaminimumKarnofskyperformancestatusof60,butthemajorityofwhomhadaKarnofsky

performancestatusof>80receivedthecombinationtreatment.

EMR62202-007:Thisrandomisedstudycomparedthecombinationofcetuximabandirinotecan(218patients)with

cetuximabmonotherapy(111patients).

PhaseIII

Irinotecanversussupportivecare Irinotecanversus5-FU

Irinotecan

n=183 Supportive

care

n=90 p-values Irinotecan

n=127 5-FU

n=129 p-values

Progression

freesurvival

at6months

33.5* 26.7 p=0.03

Survivalat

12months

36.2* 13.8 p=0.0001 44.8* 32.4 p=0.0351

Median

survival

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Theefficacydatafromthesestudiesaresummarisedinthetablebelow:

CIconfidenceinterval,DCRdiseasecontrolrate(patientswithcompleteresponse,partialresponse,orstabledisease

foratleast6weeks),ORRobjectiveresponserate(patientswithcompleteresponseorpartialresponse),OSoverall

survivaltime,PFSprogression-freesurvival

Theefficacyofthecombinationofthecetuximabmonotherapy,intermsofobjectiveresponserate(ORR),disease

controlrate(DCR)andprogression-freesurvival(PFS).Intherandomisedtrial,noeffectsonoverallsurvivalwere

demonstrated(hazardratio0.91,p=0.48).

Pharmacokinetic/Pharmacodynamicdata:

Theintensityofthemajortoxicitiesencounteredwithirinotecan(e.g.leuconeutropeniaanddiarrhoea)isrelatedto

exposure(AUC)toparentdrugandmetaboliteSN-38.Significantcorrelationswereobservedbetweenhaematological

toxicity(decreasesinwhitebloodcellsandneutrophilsatnadir)ordiarrhoeaintensityandbothirinotecanand

metaboliteSN-38AUCvaluesinmonotherapy.

5.2Pharmacokineticproperties

InaphaseIstudyin60patientswithadosageregimenofa30minuteintravenousinfusionof100to750mg/m 2

every

threeweeks,irinotecanshowedabiphasicortriphasiceliminationprofile.Themeanplasmaclearancewas15L/h/m 2

andthevolumeofdistributionatsteadystate(Vss):157L/m 2

.Themeanplasmahalf-lifeofthefirstphaseofthe

triphasicmodelwas12minutes,ofthesecondphase2.5hours,andtheterminalphasehalf-lifewas14.2hours.SN-38

showedabiphasiceliminationprofilewithameanterminaleliminationhalf-lifeof13.8hours.Attheendofthe

infusion,attherecommendeddoseof350mg/m 2

,themeanpeakplasmaconcentrationsofirinotecanandSN-38were

7.7µg/mland56ng/ml,respectively,andthemeanareaunderthecurve(AUC)valueswere34µg.h/mland451

ng.h/ml,respectively.AlargeinterindividualvariabilityinpharmacokineticparametersisgenerallyobservedforSN-

Apopulationpharmacokineticanalysishasbeenperformedin148patientswithmetastaticcolorectalcancer,treated

withvariousschedulesandatdifferentdosesinphaseIItrials.Pharmacokineticparametersestimatedwithathree

compartmentmodelweresimilartothoseobservedinphaseIstudies.AllstudieshaveshownthatirinotecanandSN-

38exposureincreaseproportionallywithirinotecanadministereddose;theirpharmacokineticsareindependentofthe

numberofpreviouscyclesandoftheadministrationschedule.

Invitro,plasmaproteinbindingforirinotecanandSN-38wasapproximately65%and95%respectively.Massbalance

andmetabolismstudieswith 14

Clabelleddrughaveshownthatmorethan50%ofanintravenouslyadministereddose

Study n ORR DCR PFS

(months) OS(months)

n(%) 95%CI n(%) 95%

Median 95%

Median 95%

Cetuximab+irinotecan

EMR62

202-007

(22.9) 17.5,

29.1 121

(55.5) 48.6,

62.2 4.1 2.8,4.3 8.6 7.6,9.6

IMCLCP02

-9923

(15.2) 9.7,

22.3 84

(60.9) 52.2,

69.1 2.9 2.6,4.1 8.4 7.2,

10.3

Cetuximab

EMR62

202-007

(10.8) 5.7,

18.1 36

(32.4) 23.9,

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Twometabolicpathwaysaccounteachforatleast12%ofthedose:

HydrolysisbycarboxylesteraseintoactivemetaboliteSN-38,SN-38ismainlyeliminatedby

glucuronidation,andfurtherbybiliaryandrenalexcretion(lessthan0.5%oftheirinotecandose).TheSN-38

glucuroniteissubsequentlyprobablyhydrolysedintheintestine.

CytochromeP4503Aenzymes-dependentoxidationsresultinginopeningoftheouterpiperidineringwith

formationofAPC(aminopentanoicacidderivative)andNPC(primaryaminederivative)(seeSection4.5).

Unchangedirinotecanisthemajorentityinplasma,followedbyAPC,SN-38glucuronideandSN-38.OnlySN-38has

significantcytotoxicactivity.Irinotecanclearanceisdecreasedbyabout40%inpatientswithbilirubinemiabetween

1.5and3timestheULN.Inthesepatientsa200mg/m 2

irinotecandoseleadstoplasmadrugexposurecomparableto

thatobservedat350mg/m 2

incancerpatientswithnormalliverparameters.

5.3Preclinicalsafetydata

IrinotecanandSN-38havebeenshowntobemutagenicinvitrointhechromosomalaberrationtestonCHO-cellsas

wellasintheinvivomicronucleustestinmice.However,theyhavebeenshowntobedevoidofanymutagenic

potentialintheAmestest.

Inratstreatedonceaweekduring13weeksatthemaximumdoseof150mg/m 2

(whichislessthanhalfthehuman

recommendeddose),notreatmentrelatedtumourswerereported91weeksaftertheendoftreatment.Singleand

repeateddosetoxicitystudieswithirinotecanhavebeencarriedoutinmice,ratsanddogs.Themaintoxiceffectswere

seeninthehaematopoieticandlymphaticsystems.Indogs,delayeddiarrhoeaassociatedwithatrophyandfocal

necrosisoftheintestinalmucosawerereported.Alopeciawasalsoobservedindogs.Theseverityoftheseeffectswas

doserelatedandreversible.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sorbitol(E420)

Lacticacid

Sodiumhydroxideand/orhydrochloricacid(forpHadjustment)

Waterforinjections.

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproducts,exceptthosementionedinSection6.6.

6.3ShelfLife

Theshelflifeoftheunopenedvialis24months.

Afteropening:Thecontentofthevialshouldbeusedimmediatelyafterthefirstbreakageofvial.

Chemicalandphysicalin-usestabilityhasbeendemonstratedin5%(w/v)glucoseand0.9%(w/v)sodiumchloridefor

48hoursat2-8ºCand24hoursatroomtemperature.Fromamicrobiologicalpointofview,theproductshouldbe

usedimmediately.Ifnotusedimmediately,in-usestoragetimesandconditionspriortousearetheresponsibilityofthe

userandwouldnotnormallybelongerthan24hoursat2–8ºC,unlessdilutionhastakenplaceincontrolledand

validatedasepticconditions.

6.4Specialprecautionsforstorage

Storebelow25ºC.Storeintheoriginalpackageinordertoprotectfromlight.Forstorageconditionsofthediluted

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6.5Natureandcontentsofcontainer

Camrataconcentrateforsolutionforinfusionissuppliedaseither40mg/2mlor100mg/5ml.intypeIamberglass

vial(2mlor5ml),withachlorobutylrubberstoppercoatedwithteflonontheinnersurfacewithanaluminiumshell

andablueplasticflip-offbutton.

Packsof1vialcontainingeither40mgor100mgCamrata.

6.6Specialprecautionsfordisposal

Mustbedilutedbeforeuse.Forsingleuseonly.Anyremainingsolutionshouldbediscarded.

Aswithotherantineoplasticagents,Camratamustbepreparedandhandledwithcaution.Theuseofglasses,maskand

glovesisrequired.IfCamrataconcentratesolutionorinfusionsolutioncomeintocontactwiththeskin,wash

immediatelyandthoroughlywithsoapandwater.IfCamrataconcentratesolutionorinfusionsolutionshouldcome

intocontactwithmucousmembranes,washimmediatelywithwater.

Preparationoftheintravenousinfusionadministration:

Aswithotherinjectabledrugs,Camratasolutionmustbepreparedaseptically(seeSection6.3).Ifanyprecipitateis

observedinthevialsorafterreconstitution,theproductshouldbediscardedaccordingtothestandardproceduresfor

cytotoxicagents.AsepticallywithdrawtherequiredamountofCamratasolutionfromthevialwithacalibratedsyringe

andinjectintoa250mlinfusionbagorbottlecontainingeither0.9%sodiumchlorideor5%glucosesolution.The

infusionshouldthenbethoroughlymixedbymanualrotation.

Disposal:

Allmaterialsusedfordilutionandadministrationshouldbedisposedofaccordingtohospitalstandardprocedures

applicabletocytotoxicagents.

7MARKETINGAUTHORISATIONHOLDER

BeaconPharmaceuticalsLtd.

85HighStreet

TunbridgeWells

KentTN11YG

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1312/4/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:9thApril2010

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