CAMPTO

Main information

  • Trade name:
  • CAMPTO Concentrate for Soln for Inf 40 mg/2ml
  • Dosage:
  • 40 mg/2ml
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CAMPTO Concentrate for Soln for Inf 40 mg/2ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0019/053/001
  • Authorization date:
  • 08-10-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CAMPTO40mg/2ml,concentrateforsolutionforinfusion.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Theconcentratecontains20mg/mlirinotecanhydrochloride,trihydrate(equivalentto17.33mg/mlirinotecan).Vials

ofCAMPTOcontain40mgor100mgofirinotecanhydrochloride,trihydrate.

Forexcipients,see“6.1Listofexcipients”.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion.

4CLINICALPARTICULARS

4.1TherapeuticIndications

CAMPTOisindicatedforthetreatmentofpatientswithadvancedcolorectalcancer:

incombinationwith5-fluorouracilandfolinicacidinpatientswithoutpriorchemotherapyforadvanceddisease,

asasingleagentinpatientswhohavefailedanestablished5-fluorouracilcontainingtreatmentregimen.

CAMPTOincombinationwithcetuximabisindicatedforthetreatmentofpatientswithepidermalgrowthfactor

receptor(EGFR)-expressingmetastaticcolorectalcancerafterfailureofirinotecan-includingcytotoxictherapy.

CAMPTOincombinationwith5-fluorouracil,folinicacidandbevacizumabisindicatedforfirst-linetreatmentof

patientswithmetastaticcarcinomaofthecolonorrectum.

4.2Posologyandmethodofadministration

Foradultsonly.CAMPTOsolutionforinfusionshouldbeinfusedintoaperipheralorcentralvein.

Recommendeddosage:

Inmonotherapy(forpreviouslytreatedpatient):

TherecommendeddosageofCAMPTOis350mg/m²administeredasanintravenousinfusionovera30-to90-minute

periodeverythreeweeks(see«InstructionsforUse/Handling»and«SpecialWarningsandSpecialPrecautionsfor

Use»sections).

Incombinationtherapy(forpreviouslyuntreatedpatient):

SafetyandefficacyofCAMPTOincombinationwith5-fluorouracil(5FU)andfolinicacid(FA)havebeenassessed

withthefollowingschedule(see«Pharmacodynamicproperties»):

CAMPTOplus5FU/FAinevery2weeksschedule

TherecommendeddoseofCAMPTOis180mg/m²administeredonceevery2weeksasanintravenousinfusionovera

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Fortheposologyandmethodofadministrationofconcomitantcetuximab,refertotheproductinformationforthis

medicinalproduct.

Normally,thesamedoseofirinotecanisusedasadministeredinthelastcyclesoftheprioririnotecan-containing

regimen.Irinotecanmustnotbeadministeredearlierthan1houraftertheendofthecetuximabinfusion.

Fortheposologyandmethodofadministrationofbevacizumab,refertothebevacizumabsummaryproductof

characteristics.

Dosageadjustments:

CAMPTOshouldbeadministeredafterappropriaterecoveryofalladverseeventstograde0or1NCI-CTCgrading

(NationalCancerInstituteCommonToxicityCriteria)andwhentreatment-relateddiarrhoeaisfullyresolved.

Atthestartofasubsequentinfusionoftherapy,thedoseofCAMPTO,and5FUwhenapplicable,shouldbedecreased

accordingtotheworstgradeofadverseeventsobservedinthepriorinfusion.Treatmentshouldbedelayedby1to2

weekstoallowrecoveryfromtreatment-relatedadverseevents.

Withthefollowingadverseeventsadosereductionof15to20%shouldbeappliedforCAMPTOand/or5FUwhen

applicable:

haematologicaltoxicity(neutropeniagrade4,febrileneutropenia(neutropeniagrade3-4andfevergrade2-4),

thrombocytopeniaandleukopenia(grade4)),

nonhaematologicaltoxicity(grade3-4).

Recommendationsfordosemodificationsofcetuximabwhenadministeredincombinationwithirinotecanmustbe

followedaccordingtotheproductinformationforthismedicinalproduct.

Refertothebevacizumabsummaryofproductcharacteristicsfordosemodificationsofbevacizumabwhen

administeredincombinationwithCAMPTO/5FU/FA.

TreatmentDuration:

TreatmentwithCAMPTOshouldbecontinueduntilthereisanobjectiveprogressionofthediseaseoranunacceptable

toxicity.

Specialpopulations:

PatientswithImpairedHepaticFunction:Inmonotherapy:Bloodbilirubinlevels(upto3timestheupperlimitof

thenormalrange(UNL))inpatientswithperformancestatus 2,shoulddeterminethestartingdoseofCampto.In

thesepatientswithhyperbilirubinemiaandprothrombintimegreaterthan50%,theclearanceofirinotecanisdecreased

(see“Pharmacokineticproperties”section)andthereforetheriskofhematotoxicityisincreased.Thus,weekly

monitoringofcompletebloodcountsshouldbeconductedinthispatientpopulation.

Inpatientswithbilirubinupto1.5timestheupperlimitofthenormalrange(ULN),therecommendeddosageof

CAMPTOis350mg/m²,

Inpatientswithbilirubinrangingfrom1.5to3timestheULN,therecommendeddosageofCAMPTOis200

mg/m²,

Patientswithbilirubinbeyond3timestheULNshouldnotbetreatedwithCAMPTO(see«Contraindications»

and«SpecialWarningsandSpecialPrecautionsforUse»sections).

NodataareavailableinpatientswithhepaticimpairmenttreatedbyCAMPTOincombination.

PatientswithImpairedRenalFunction:CAMPTOisnotrecommendedforuseinpatientswithimpairedrenal

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Use»and«PharmacokineticProperties»).

Elderly:Nospecificpharmacokineticstudieshavebeenperformedinelderly.However,thedoseshouldbechosen

carefullyinthispopulationduetotheirgreaterfrequencyofdecreasedbiologicalfunctions.Thispopulationshould

requiremoreintensesurveillance(see«SpecialWarningsandSpecialPrecautionsforUse»).

4.3Contraindications

Chronicinflammatoryboweldiseaseand/orbowelobstruction(see«SpecialWarningsandSpecialPrecautions

forUse»).

Historyofseverehypersensitivityreactionstoirinotecanhydrochloridetrihydrateortooneoftheexcipientsof

CAMPTO.

Pregnancyandlactation(see«PregnancyandLactation»and«SpecialWarningsandSpecialPrecautionsfor

Use»sections).

Bilirubin>3timestheupperlimitofthenormalrange(see«SpecialwarningsandSpecialPrecautionsforUse»

section).

Severebonemarrowfailure.

WHOperformancestatus>2.

ConcomitantusewithStJohn’sWort(seesection4.5)

Foradditionalcontraindicationsofcetuximaborbevacizumab,refertotheproductinformationforthesemedicinal

products.

4.4Specialwarningsandprecautionsforuse

Giventhenatureandincidenceofadverseevents,CAMPTOwillonlybeprescribedinthefollowingcasesafterthe

expectedbenefitshavebeenweightedagainstthepossibletherapeuticrisks:

inpatientspresentingariskfactor,particularlythosewithaWHOperformancestatus=2.

inthefewrareinstanceswherepatientsaredeemedunlikelytoobserverecommendationsregardingmanagement

ofadverseevents(needforimmediateandprolongedantidiarrhoealtreatmentcombinedwithhighfluidintakeat

onsetofdelayeddiarrhoea).Stricthospitalsupervisionisrecommendedforsuchpatients.

WhenCAMPTOisusedinmonotherapy,itisusuallyprescribedwiththeevery-3-week-dosageschedule.However,

theweekly-dosageschedule(see«Pharmacologicalproperties»)maybeconsideredinpatientswhomayneedacloser

follow-uporwhoareatparticularriskofsevereneutropenia.

Delayeddiarrhoea

Patientsshouldbemadeawareoftheriskofdelayeddiarrhoeaoccurringmorethan24hoursaftertheadministrationof

CAMPTOandatanytimebeforethenextcycle.Inmonotherapy,themediantimeofonsetofthefirstliquidstoolwas

onday5aftertheinfusionofCAMPTO.Patientsshouldquicklyinformtheirphysicianofitsoccurrenceandstart

appropriatetherapyimmediately.

Patientswithanincreasedriskofdiarrhoeaarethosewhohadapreviousabdominal/pelvicradiotherapy,thosewith

baselinehyperleucocytosis,thosewithperformancestatus 2andwomen.Ifnotproperlytreated,diarrhoeacanbe

life-threatening,especiallyifthepatientisconcomitantlyneutropenic.

Assoonasthefirstliquidstooloccurs,thepatientshouldstartdrinkinglargevolumesofbeveragescontaining

TheuseofCAMPTOshouldbeconfinedtounitsspecialisedintheadministrationof

cytotoxicchemotherapyanditshouldonlybeadministeredunderthesupervisionofa

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beprescribedbythedepartmentwhereCAMPTOhasbeenadministered.Afterdischargefromthehospital,the

patientsshouldobtaintheprescribeddrugssothattheycantreatthediarrhoeaassoonasitoccurs.Inaddition,they

mustinformtheirphysicianorthedepartmentadministeringCAMPTOwhen/ifdiarrhoeaisoccurring.

Thecurrentlyrecommendedantidiarrhoealtreatmentconsistsofhighdosesofloperamide(4mgforthefirstintakeand

then2mgevery2hours).Thistherapyshouldcontinuefor12hoursafterthelastliquidstoolandshouldnotbe

modified.Innoinstanceshouldloperamidebeadministeredformorethan48consecutivehoursatthesedoses,

becauseoftheriskofparalyticileus,norforlessthan12hours.

Inadditiontotheanti-diarrhoealtreatment,aprophylacticbroadspectrumantibioticshouldbegiven,whendiarrhoeais

associatedwithsevereneutropenia(neutrophilcount<500cells/mm³).

Inadditiontotheantibiotictreatment,hospitalisationisrecommendedformanagementofthediarrhoea,inthe

followingcases:

Diarrhoeaassociatedwithfever,

Severediarrhoea(requiringintravenoushydration),

Diarrhoeapersistingbeyond48hoursfollowingtheinitiationofhigh-doseloperamidetherapy.

Loperamideshouldnotbegivenprophylactically,eveninpatientswhoexperienceddelayeddiarrhoeaatprevious

cycles.

Inpatientswhoexperiencedseverediarrhoea,areductionindoseisrecommendedforsubsequentcycles(see

«PosologyandMethodofAdministration»section).

Haematology

WeeklymonitoringofcompletebloodcellcountsisrecommendedduringCAMPTOtreatment.Patientsshouldbe

awareoftheriskofneutropeniaandthesignificanceoffever.Febrileneutropenia(temperature>38°Candneutrophil

count 1,000cells/mm³)shouldbeurgentlytreatedinthehospitalwithbroad-spectrumintravenousantibiotics.

Inpatientswhoexperiencedseverehaematologicalevents,adosereductionisrecommendedforsubsequent

administration(see«PosologyandMethodofAdministration»section).

Thereisanincreasedriskofinfectionsandhaematologicaltoxicityinpatientswithseverediarrhoea.Inpatientswith

severediarrhoea,completebloodcellcountsshouldbeperformed.

Liverimpairment

Liverfunctiontestsshouldbeperformedatbaselineandbeforeeachcycle.

Weeklymonitoringofcompletebloodcountsshouldbeconductedinpatientswithbilirubinrangingfrom1.5to3times

ULN,duetodecreaseoftheclearanceofirinotecan(see“Pharmacokineticproperties“section)andthusincreasingthe

riskofhematotoxicityinthispopulation.Forpatientswithabilirubin>3timesULN(see«Contraindications»

section).

Nauseaandvomiting

AprophylactictreatmentwithantiemeticsisrecommendedbeforeeachtreatmentwithCAMPTO.Nauseaand

vomitinghavebeenfrequentlyreported.Patientswithvomitingassociatedwithdelayeddiarrhoeashouldbe

hospitalisedassoonaspossiblefortreatment.

Acutecholinergicsyndrome

Ifacutecholinergicsyndromeappears(definedasearlydiarrhoeaandvariousothersymptomssuchassweating,

abdominalcramping,lacrimation,myosisandsalivation),atropinesulphate(0.25mgsubcutaneously)shouldbe

administeredunlessclinicallycontraindicated(see«UndesirableEffects»section).Cautionshouldbeexercisedin

patientswithasthma.Inpatientswhoexperiencedanacuteandseverecholinergicsyndrome,theuseofprophylactic

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Respiratorydisorders

Interstitialpulmonarydiseasepresentingaspulmonaryinfiltratesisuncommonduringirinotecantherapy.Interstitial

pulmonarydiseasecanbefatal.Riskfactorspossiblyassociatedwiththedevelopmentofinterstitialpulmonarydisease

includetheuseofpneumotoxicdrugs,radiationtherapyandcolonystimulatingfactors.Patientswithriskfactors

shouldbecloselymonitoredforrespiratorysymptomsbeforeandduringirinotecantherapy.

Elderly

Duetothegreaterfrequencyofdecreasedbiologicalfunctions,inparticularhepaticfunction,inelderlypatients,dose

selectionwithCAMPTOshouldbecautiousinthispopulation(see«PosologyandMethodofAdministration»

section).

Patientswithbowelobstruction

PatientsmustnotbetreatedwithCAMPTOuntilresolutionofthebowelobstruction(see«Contraindications»).

PatientswithImpairedRenalFunction

Studiesinthispopulationhavenotbeenconducted.(see«PosologyandMethodofAdministration»and

«PharmacokineticProperties»).

Others

Sincethismedicinalcontainssorbitol,itisunsuitableinhereditaryfructoseintolerance.Infrequentcasesofrenal

insufficiency,hypotensionorcirculatoryfailurehavebeenobservedinpatientswhoexperiencedepisodesof

dehydrationassociatedwithdiarrhoeaand/orvomiting,orsepsis.Contraceptivemeasuresmustbetakenduringandfor

atleastthreemonthsaftercessationoftherapy.

Concomitantadministrationofirinotecanwithastronginhibitor(e.g.ketoconazole)orinducer(e.g.rifampicin,

carbamazepine,phenobarbital,phenytoin,StJohn’sWort)ofCYP3A4mayalterthemetabolismofirinotecanand

shouldbeavoided(seesection4.5).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionbetweenirinotecanandneuromuscularblockingagentscannotberuledout.SinceCAMPTOhas

anticholinesteraseactivity,drugswithanticholinesteraseactivitymayprolongtheneuromuscularblockingeffectsof

suxamethoniumandtheneuromuscularblockadeofnon-depolarisingdrugsmaybeantagonised.

SeveralstudieshaveshownthatconcomitantadministrationofCYP3A-inducinganticonvulsantdrugs(e.g.,

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

reducedpharmacodynamiceffects.TheeffectsofsuchanticonvulsantdrugswasreflectedbyadecreaseinAUCofSN-

38andSN-38Gby50%ormore.InadditiontoinductionofcytochromeP4503Aenzymes,enhancedglucuronidation

andenhancedbiliaryexcretionmayplayaroleinreducingexposuretoirinotecananditsmetabolites.

Astudyhasshownthattheco-administrationofketoconazoleresultedinadecreaseintheAUCofAPCof87%andin

anincreaseintheAUCofSN-38of109%incomparisontoirinotecangivenalone.

Cautionshouldbeexercisedinpatientsconcurrentlytakingdrugsknowntoinhibit(e.g.,ketoconazole)orinduce(e.g.,

rifampicin,carbamazepine,phenobarbitalorphenytoin)drugmetabolismbycytochromeP4503A4.Concurrent

administrationofirinotecanwithaninhibitor/inducerofthismetabolicpathwaymayalterthemetabolismofirinotecan

andshouldbeavoided(seesection4.4).

Inasmallpharmacokineticstudy(n=5),inwhichirinotecan350mg/m2wasco-administeredwithSt.John'sWort

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

wasobserved.

St.John’sWortdecreasesSN-38plasmalevels.Asaresult,St.John'sWortshouldnotbeadministeredwithirinotecan

(seesection4.3).

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irinotecan.

Thereisnoevidencethatthesafetyprofileofirinotecanisinfluencedbycetuximaborviceversa.

Inonestudy,irinotecanconcentrationsweresimilarinpatientsreceivingCAMPTO/5FU/FAaloneandincombination

withbevacizumab.ConcentrationsofSN-38,theactivemetaboliteofirinotecan,wereanalyzedinasubsetofpatients

(approximately30pertreatmentarm).ConcentrationsofSN-38wereonaverage33%higherinpatientsreceiving

CAMPTO/5FU/FAincombinationwithbevacizumabcomparedwithCAMPTO/5FU/FAalone.Duetohighinter-

patientvariabilityandlimitedsampling,itisuncertainiftheincreaseinSN-38levelsobservedwasdueto

bevacizumab.Therewasasmallincreaseindiarrhoeaandleukopeniaadverseevents.Moredosereductionsof

irinotecanwerereportedforpatientsreceivingCAMPTO/5FU/FAincombinationwithbevacizumab.

Patientswhodevelopseverediarrhoea,leukopenia,orneutropeniawiththebevacizumabandirinotecancombination

shouldhaveirinotecandosemodificationsasspecifiedinsection4.2Posologyandmethodofadministration.

4.6Pregnancyandlactation

Pregnancy:

ThereisnoinformationontheuseofCAMPTOinpregnantwomen.

CAMPTOhasbeenshowntobeembryotoxic,foetotoxicandteratogenicinrabbitsandrats.Therefore,CAMPTO

mustnotbeusedduringpregnancy(see«Contraindications»and«SpecialWarningsandSpecialPrecautionsfor

Use»).

Womenofchild-bearingpotential:

Womenofchild-bearingagereceivingCAMPTOshouldbeadvisedtoavoidbecomingpregnant,andtoinformthe

treatingphysicianimmediatelyshouldthisoccur(see«Contraindications»and«SpecialWarningsandSpecial

PrecautionsforUse»).

Lactation:

Inlactatingrats, 14

C-irinotecanwasdetectedinmilk.Itisnotknownwhetheririnotecanisexcretedinhumanmilk.

Consequently,becauseofthepotentialforadversereactionsinnursinginfants,breast-feedingmustbediscontinuedfor

thedurationofCAMPTOtherapy(see«Contraindications»).

4.7Effectsonabilitytodriveandusemachines

Patientsshouldbewarnedaboutthepotentialfordizzinessorvisualdisturbanceswhichmayoccurwithin24hours

followingtheadministrationofCAMPTO,andadvisednottodriveoroperatemachineryifthesesymptomsoccur.

4.8Undesirableeffects

Undesirableeffectsdetailedinthissectionrefertoirinotecan.Thereisnoevidencethatthesafetyprofileofirinotecan

isinfluencedbycetuximaborviceversa.Incombinationwithcetuximab,additionalreportedundesirableeffectswere

thoseexpectedwithcetuximab(suchasacneformrash88%).Thereforealsorefertotheproductinformationof

cetuximab.

Forinformationonadversereactionsincombinationwithbevacizumab,refertothebevacizumabsummaryproductof

characteristics.

ThefollowingadversereactionsconsideredtobepossiblyorprobablyrelatedtotheadministrationofCAMPTOhave

beenreportedfrom765patientsattherecommendeddoseof350mg/m²inmonotherapy,andfrom145patientstreated

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Gastrointestinaldisorders

Delayeddiarrhoea

Diarrhoea(occurringmorethan24hoursafteradministration)isadose-limitingtoxicityofCAMPTO.

Inmonotherapy:

Severediarrhoeawasobservedin20%ofpatientswhofollowrecommendationsforthemanagementofdiarrhoea.Of

theevaluablecycles,14%haveaseverediarrhoea.Themediantimeofonsetofthefirstliquidstoolwasonday5after

theinfusionofCAMPTO.

Incombinationtherapy:

Severediarrhoeawasobservedin13.1%ofpatientswhofollowrecommendationsforthemanagementofdiarrhoea.

Oftheevaluablecycles,3.9%haveaseverediarrhoea.

Uncommoncasesofpseudo-membranouscolitishavebeenreported,oneofwhichhasbeendocumented

bacteriologically(Clostridiumdifficile).

Nauseaandvomiting

Inmonotherapy:

Nauseaandvomitingweresevereinapproximately10%ofpatientstreatedwithantiemetics.

Incombinationtherapy:

Alowerincidenceofseverenauseaandvomitingwasobserved(2.1%and2.8%ofpatientsrespectively).

Dehydration

Episodesofdehydrationcommonlyassociatedwithdiarrhoeaand/orvomitinghavebeenreported.

Infrequentcasesofrenalinsufficiency,hypotensionorcardio-circulatoryfailurehavebeenobservedinpatientswho

experiencedepisodesofdehydrationassociatedwithdiarrhoeaand/orvomiting.

Othergastrointestinaldisorders

ConstipationrelativetoCAMPTOand/orloperamidehasbeenobserved,sharedbetween:

inmonotherapy:inlessthan10%ofpatients

incombinationtherapy:3.4%ofpatients.

Infrequentcasesofintestinalobstruction,ileus,orgastrointestinalhaemorrhageandrarecasesofcolitis,including

typhlitis,ischemicandulcerativecolitis,werereported.Rarecasesofintestinalperforationwerereported.Othermild

effectsincludeanorexia,abdominalpainandmucositis.Rarecasesofsymptomaticorasymptomaticpancreatitishave

beenassociatedwithirinotecantherapy.

Blooddisorders

Neutropeniaisadose-limitingtoxiceffect.Neutropeniawasreversibleandnotcumulative;themediandaytonadir

was8dayswhatevertheuseinmonotherapyorincombinationtherapy.

Inmonotherapy:

Neutropeniawasobservedin78.7%ofpatientsandwassevere(neutrophilcount<500cells/mm3)in22.6%of

patients.Oftheevaluablecycles,18%hadaneutrophilcountbelow1,000cells/mm³including7.6%witha

neutrophilcount<500cells/mm³.

Totalrecoverywasusuallyreachedbyday22.

Feverwithsevereneutropeniawasreportedin6.2%ofpatientsandin1.7%ofcycles.

Infectiousepisodesoccurredinabout10.3%ofpatients(2.5%ofcycles)andwereassociatedwithsevereneutropenia

inabout5.3%ofpatients(1.1%ofcycles),andresultedindeathin2cases.

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<6.5g/dl).

Thrombocytopenia(<100,000cells/mm³)wasobservedin7.4%ofpatientsand1.8%ofcycleswith0.9%with

plateletscount 50,000cells/mm3and0.2%ofcycles.

Nearlyallthepatientsshowedarecoverybyday22.

Incombinationtherapy:

Neutropeniawasobservedin82.5%ofpatientsandwassevere(neutrophilcount<500cells/mm3)in9.8%of

patients.

Oftheevaluablecycles,67.3%hadaneutrophilcountbelow1,000cells/mm³including2.7%withaneutrophilcount

<500cells/mm³.

Totalrecoverywasusuallyreachedwithin7-8days.

Feverwithsevereneutropeniawasreportedin3.4%ofpatientsandin0.9%ofcycles.

Infectiousepisodesoccurredinabout2%ofpatients(0.5%ofcycles)andwereassociatedwithsevereneutropeniain

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

Anaemiawasreportedin97.2%ofpatients(2.1%withhaemoglobin<8g/dl).

Thrombocytopenia(<100,000cells/mm³)wasobservedin32.6%ofpatientsand21.8%ofcycles.Nosevere

thrombocytopenia(<50,000cells/mm³)hasbeenobserved.

Onecaseofperipheralthrombocytopeniawithantiplateletantibodieshasbeenreportedinthepost-marketing

experience.

InfectionandInfestation

Infrequentcasesofrenalinsufficiency,hypotensionorcardio-circulatoryfailurehavebeenobservedinpatientswho

experiencedsepsis.

Generaldisordersandinfusionsitereactions

Acutecholinergicsyndrome

Severetransientacutecholinergicsyndromewasobservedin9%ofpatientstreatedinmonotherapyandin1.4%of

patientstreatedincombinationtherapy.Themainsymptomsweredefinedasearlydiarrhoeaandvariousother

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

dizziness,visualdisturbances,myosis,lachrimationandincreasedsalivationoccurringduringorwithinthefirst

24hoursaftertheinfusionofCAMPTO.Thesesymptomsdisappearafteratropineadministration(see«Special

WarningandSpecialPrecautionsforUse»).

Astheniawassevereinlessthan10%ofpatientstreatedinmonotherapyandin6.2%ofpatientstreatedin

combinationtherapy.ThecausalrelationshiptoCAMPTOhasnotbeenclearlyestablished.Feverintheabsenceof

infectionandwithoutconcomitantsevereneutropenia,occurredin12%ofpatientstreatedinmonotherapyandin

6.2%ofpatientstreatedincombinationtherapy.

Mildinfusionsitereactionshavebeenreportedalthoughuncommonly.

Cardiacdisorder

Rarecasesofhypertensionduringorfollowingtheinfusionhavebeenreported.

Respiratorydisorders

Interstitialpulmonarydiseasepresentingaspulmonaryinfiltratesisuncommonduringirinotecantherapy.Earlyeffects

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Skinandsubcutaneoustissuedisorders

Alopeciawasverycommonandreversible.Mildcutaneousreactionshavebeenreportedalthoughuncommonly.

Immunesystemdisorders

Uncommonmildallergyreactionsandrarecasesofanaphylactic/anaphylactoidreactionshavebeenreported.

Musculoskeletaldisorders

Earlyeffectssuchasmuscularcontractionorcrampsandparesthesiahavebeenreported.

Laboratorytests

Inmonotherapy,transientandmildtomoderateincreasesinserumlevelsofeithertransaminases,alkalinephosphatase

orbilirubinwereobservedin9.2%,8.1%and1.8%ofthepatients,respectively,intheabsenceofprogressiveliver

metastasis.

Transientandmildtomoderateincreasesofserumlevelsofcreatininehavebeenobservedin7.3%ofthepatients.

Incombinationtherapytransientserumlevels(grades1and2)ofeitherSGPT,SGOT,alkalinephosphataseor

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

metastasis.Transientgrade3wereobservedin0%,0%,0%and1%ofthepatients,respectively.Nograde4was

observed.

Increasesofamylaseand/orlipasehavebeenveryrarelyreported.

Rarecasesofhypokalemiaandhyponatremiamostlyrelatedwithdiarrhoeaandvomitinghavebeenreported.

Nervoussystemdisorders

TherehavebeenveryrarepostmarketingreportsoftransientspeechdisordersassociatedwithCAMPTOinfusions.

4.9Overdose

Therehavebeenreportsofoverdosageatdosesuptoapproximatelytwicetherecommendedtherapeuticdose,which

maybefatal.Themostsignificantadversereactionsreportedweresevereneutropeniaandseverediarrhoea.Thereis

noknownantidoteforCAMPTO.Maximumsupportivecareshouldbeinstitutedtopreventdehydrationdueto

diarrhoeaandtotreatanyinfectiouscomplications.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:CytostatictopoisomeraseIinhibitor.

ATCCode:L01XX19

Experimentaldata

Irinotecanisasemi-syntheticderivativeofcamptothecin.Itisanantineoplasticagentwhichactsasaspecificinhibitor

ofDNAtopoisomeraseI.ItismetabolisedbycarboxylesteraseinmosttissuestoSN-38,whichwasfoundtobemore

activethanirinotecaninpurifiedtopoisomeraseIandmorecytotoxicthanirinotecanagainstseveralmurineandhuman

tumourcelllines.TheinhibitionofDNAtopoisomeraseIbyirinotecanorSN-38inducessingle-strandDNAlesions

whichblockstheDNAreplicationforkandareresponsibleforthecytotoxicity.Thiscytotoxicactivitywasfoundtime-

dependentandwasspecifictotheSphase.

Invitro,irinotecanandSN-38werenotfoundtobesignificantlyrecognisedbytheP-glycoproteinMDR,anddisplays

cytotoxicactivitiesagainstdoxorubicinandvinblastineresistantcelllines.

Furthermore,irinotecanhasabroadantitumoractivityinvivoagainstmurinetumourmodels(P03pancreaticductal

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

adenocarcinomas).IrinotecanisalsoactiveagainsttumorsexpressingtheP-glycoproteinMDR(vincristine-and

doxorubicin-resistantP388leukaemia’s).

BesidetheantitumoractivityofCAMPTO,themostrelevantpharmacologicaleffectofirinotecanistheinhibitionof

acetylcholinesterase.

Clinicaldata

Inmonotherapy:

ClinicalphaseII/IIIstudieswereperformedinmorethan980patientsintheevery3weekdosageschedulewith

metastaticcolorectalcancerwhofailedaprevious5-FUregimen.TheefficacyofCAMPTOwasevaluatedin

765patientswithdocumentedprogressionon5-FUatstudyentry.

NA:NonApplicable

*:Statisticallysignificantdifference

InphaseIIstudies,performedon455patientsintheevery3-weekdosageschedule,theprogressionfreesurvivalat

6monthswas30%andthemediansurvivalwas9months.Themediantimetoprogressionwas18weeks.

Additionally,non-comparativephaseIIstudieswereperformedin304patientstreatedwithaweeklyschedule

regimen,atadoseof125mg/m²administeredasanintravenousinfusionover90minutesfor4consecutiveweeks

followedby2weeksrest.Inthesestudies,themediantimetoprogressionwas17weeksandmediansurvivalwas10

months.Asimilarsafetyprofilehasbeenobservedintheweekly-dosageschedulein193patientsatthestartingdose

of125mg/m²,comparedtotheevery3-week-dosageschedule.Themediantimeofonsetofthefirstliquidstoolwas

onday11.

Incombinationtherapy:

AphaseIIIstudywasperformedin385previouslyuntreatedmetastaticcolorectalcancerpatientstreatedwitheither

every2weeksschedule(see«Posologyandmethodofadministration»)orweeklyscheduleregimens.Intheevery

PhasesIII

CAMPTOversussupportivecare CAMPTOversus5FU

CAMPTO

n=183 Supportive

care

n=90 pvalues CAMPTO

n=127 5FU

n=129 pvalues

Progression

Free

Survival

at6months

(%) NA NA 33.5* 26.7 p=0.03

Survival

at12months

(%) 36.2* 13.8 p=0.0001 44.8* 32.4 p=0.0351

Median

survival

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withfolinicacid(200mg/m²overa2-hourintravenousinfusion)and5-fluorouracil(400mg/m²asanintravenous

bolus,followedby600mg/m²overa22-hourintravenousinfusion).Onday2,folinicacidand5-fluorouracilare

administeredatthesamedosesandschedules.Intheweeklyschedule,theadministrationofCAMPTOat80mg/m²is

followedbyinfusionwithfolinicacid(500mg/m²overa2-hourintravenousinfusion)andthenby5-fluorouracil

(2300mg/m²overa24-hourintravenousinfusion)over6weeks.

Inthecombinationtherapytrialwiththe2regimensdescribedabove,theefficacyofCAMPTOwasevaluatedin

198treatedpatients:

5FU:5-fluorouracil

Combinedregimens

(n=198) Weeklyschedule

(n=50) Every2weeksschedule

(n=148)

CAMPTO

+5FU/FA 5FU/FA CAMPTO

+5FU/FA 5FU/FA CAMPTO

+5FU/FA 5FU/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

to

progression

(months) 6.7 4.4 7.2 6.5 6.5 3.7

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 19.2 14.1 15.6 13.0

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NS:NonSignificant

*:Asperprotocolpopulationanalysis

Intheweeklyschedule,theincidenceofseverediarrhoeawas44.4%inpatientstreatedbyCAMPTOincombination

with5FU/FAand25.6%inpatientstreatedby5FU/FAalone.Theincidenceofsevereneutropenia(neutrophilcount

<500cells/mm 3

)was5.8%inpatientstreatedbyCAMPTOincombinationwith5FU/FAandin2.4%inpatients

treatedby5FU/FAalone.

Additionally,mediantimetodefinitiveperformancestatusdeteriorationwassignificantlylongerinCAMPTO

combinationgroupthanin5FU/FAalonegroup(p=0.046).

QualityoflifewasassessedinthisphaseIIIstudyusingtheEORTCQLQ-C30questionnaire.Timetodefinitive

deteriorationconstantlyoccurredlaterintheCAMPTOgroups.TheevolutionoftheGlobalHealthStatus/Qualityof

lifewasslightlybetterinCAMPTOcombinationgroupalthoughnotsignificant,showingthatefficacyofCAMPTOin

combinationcouldbereachedwithoutaffectingthequalityoflife.

Incombinationwithcetuximab:

Theefficacyofthecombinationofcetuximabwithirinotecanwasinvestigatedintwoclinicalstudies.Atotalof356

patientswithEGFR-expressingmetastaticcolorectalcancerwhohadrecentlyfailedirinotecan-includingcytotoxic

therapyandwhohadaminimumKarnofskyperformancestatusof60,butthemajorityofwhomhadaKarnofsky

performancestatusof ≥80receivedthecombinationtreatment.

EMR62202-007:Thisrandomisedstudycomparedthecombinationofcetuximabandirinotecan(218patients)with

cetuximabmonotherapy(111patients).

IMCLCP02-9923:Thissinglearmopen-labelstudyinvestigatedthecombinationtherapyin138patients.

Theefficacydatafromthesestudiesaresummarisedinthetablebelow:

CI=confidenceinterval,DCR=diseasecontrolrate(patientswithcompleteresponse,partialresponse,orstabledisease

foratleast6weeks),ORR=objectiveresponserate(patientswithcompleteresponseorpartialresponse),OS=overall

survivaltime,PFS=progression-freesurvival

Theefficacyofthecombinationofcetuximabwithirinotecanwassuperiortothatofcetuximabmonotherapy,interms

ofobjectiveresponserate(ORR),diseasecontrolrate(DCR)andprogression-freesurvival(PFS).Intherandomised

trial,noeffectsonoverallsurvivalweredemonstrated(hazardration0.91,p=0.48).

Incombinationwithbevazicumab:

AphaseIIIrandomised,double-blind,active-controlledclinicaltrialevaluatedbevacizumabincombinationwith

Study N ORR DCR PFS(months) OS(months)

n(%) 95%CI n(%) 95%CI Median95%CIMedian 95%CI

Cetuximab+irinotecan

EMR62202-

007 218 50

(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 138 21

(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

EMR62202-

007 111 12

(10.8) 5.7,18.1 36

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additionofbevacizumabtothecombinationofCAMPTO/5FU/FAresultedinastatisticallysignificantincreasein

overallsurvival.Theclinicalbenefit,asmeasuredbyoverallsurvival,wasseeninallpre-specifiedpatientsubgroups,

includingthosedefinedbyage,sex,performancestatus,locationofprimarytumour,numberoforgansinvolved,and

durationofmetastaticdisease.Referalsotothebevacizumabsummaryofproductcharacteristics.Theefficacyresults

ofStudyAVF2107garesummarizedinthetablebelow.

5mg/kgevery2weeks.

Relativetocontrolarm.

Pharmacokinetic/Pharmacodynamicdata

TheintensityofthemajortoxicitiesencounteredwithCAMPTO(e.g.,leukoneutropeniaanddiarrhoea)arerelatedto

theexposure(AUC)toparentdrugandmetaboliteSN-38.Significantcorrelationswereobservedbetween

haematologicaltoxicity(decreaseinwhitebloodcellsandneutrophilsatnadir)ordiarrhoeaintensityandboth

irinotecanandmetaboliteSN-38AUCvaluesinmonotherapy.

5.2Pharmacokineticproperties

InaphaseIstudyin60patientswithadosageregimenofa30-minuteintravenousinfusionof100to750mg/m²every

threeweeks,irinotecanshowedabiphasicorthriphasiceliminationprofile.Themeanplasmaclearancewas15L/h/m²

andthevolumeofdistributionatsteadystate(Vss):157L/m².Themeanplasmahalf-lifeofthefirstphaseofthe

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

showedabiphasiceliminationprofilewithameanterminaleliminationhalf-lifeof13.8hours.Attheendofthe

infusion,attherecommendeddoseof350mg/m²,themeanpeakplasmaconcentrationsofirinotecanandSN-38were

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

ng.h/ml,respectively.AlargeinterindividualvariabilityinpharmacokineticparametersisgenerallyobservedforSN-

Apopulationpharmacokineticanalysisofirinotecanhasbeenperformedin148patientswithmetastaticcolorectal

cancer,treatedwithvariousschedulesandatdifferentdosesinphaseIItrials.Pharmacokineticparametersestimated

withathreecompartmentmodelweresimilartothoseobservedinphaseIstudies.Allstudieshaveshownthat

irinotecan(CPT-11)andSN-38exposureincreaseproportionallywithCPT-11administereddose;their

AVF2107g

Arm1

CAMPTO/5FU/FA

Placebo Arm2

CAMPTO/5FU/FA

Avastin a

NumberofPatients 411 402

Overallsurvival

Mediantime(months) 15.6 20.3

95%Confidence

Interval 14.29–16.99 18.46–24.18

Hazardratio b 0.660

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

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Invitro,plasmaproteinbindingforirinotecanandSN-38wasapproximately65%and95%respectively.

Massbalanceandmetabolismstudieswith14C-labelleddrughaveshownthatmorethan50%ofanintravenously

administereddoseofirinotecanisexcretedasunchangeddrug,with33%inthefaecesmainlyviathebileand22%in

urine.

Twometabolicpathwaysaccounteachforatleast12%ofthedose:

HydrolysisbycarboxylesteraseintoactivemetaboliteSN-38,SN-38ismainlyeliminatedbyglucuronidation,and

furtherbybiliaryandrenalexcretion(lessthan0.5%oftheirinotecandose)TheSN-38glucuroniteissubsequently

probablyhydrolysedintheintestine.

CytochromeP4503Aenzymes-dependentoxidationsresultinginopeningoftheouterpiperidineringwith

formationofAPC(aminopentanoicacidderivate)andNPC(primaryaminederivate)(seesection4.5).

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

significantcytotoxicactivity.

Irinotecanclearanceisdecreasedbyabout40%inpatientswithbilirubinemiabetween1.5and3timestheupper

normallimit.Inthesepatientsa200mg/m²irinotecandoseleadstoplasmadrugexposurecomparabletothatobserved

at350mg/m²incancerpatientswithnormalliverparameters.

5.3Preclinicalsafetydata

IrinotecanandSN-38havebeenshowntobemutagenicinvitrointhechromosomalaberrationtestonCHO-cellsas

wellasintheinvivomicronucleustestinmice.

However,theyhavebeenshowntobedevoidofanymutagenicpotentialintheAmestest.

Inratstreatedonceaweekduring13weeksatthemaximumdoseof150mg/m²(whichislessthanhalfthehuman

recommendeddose),notreatmentrelatedtumourswerereported91weeksaftertheendoftreatment.

Single-andrepeated-dosetoxicitystudieswithCAMPTOhavebeencarriedoutinmice,ratsanddogs.Themaintoxic

effectswereseeninthehaematopoieticandlymphaticsystems.Indogs,delayeddiarrhoeaassociatedwithatrophyand

focalnecrosisoftheintestinalmucosawasreported.Alopeciawasalsoobservedinthedog.

Theseverityoftheseeffectswasdose-relatedandreversible.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sorbitol,

Lacticacid,

Sodiumhydroxide(toadjusttopH3.5),

andwaterforinjections.

6.2Incompatibilities

Noneknown.

Donotadmixwithothermedications.

6.3ShelfLife

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TheCAMPTOsolutionshouldbeusedimmediatelyafterreconstitutionasitcontainsnoantibacterialpreservative.If

reconstitutionanddilutionareperformedunderstrictasepticconditions(e.g.onLaminarAirFlowbench)CAMPTO

solutionshouldbeused(infusioncompleted)within12hoursatroomtemperatureor24hoursifstored2°-8°Cafterthe

firstbreakage.

6.4Specialprecautionsforstorage

VialsofCAMPTOconcentrateforsolutionforinfusionshouldbeprotectedfromlight.

6.5Natureandcontentsofcontainer

CAMPTO40mg:

One2-mlbrownglassvial,withahalobutylrubberclosurecoatedwithteflonontheinnerside.

CAMPTO100mg:

One5-mlbrownglassvial,withahalobutylrubberclosurecoatedwithteflonontheinnerside.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Aswithotherantineoplasticagents,CAMPTOmustbepreparedandhandledwithcaution.Theuseofglasses,mask

andglovesisrequired.

IfCAMPTOsolutionorinfusionsolutionshouldcomeintocontactwiththeskin,washimmediatelyandthoroughly

withsoapandwater.IfCAMPTOsolutionorinfusionsolutionshouldcomeintocontactwiththemucousmembranes,

washimmediatelywithwater.

Preparationfortheintravenousinfusionadministration:

Aswithanyotherinjectabledrugs,theCAMPTOsolutionmustbeprepared ASEPTICALLY (see«Shelf-life»).

Ifanyprecipitateisobservedinthevialsorafterreconstitution,theproductshouldbediscardedaccordingtostandard

proceduresforcytotoxicagents.

AsepticallywithdrawtherequiredamountofCAMPTOsolutionfromthevialwithacalibratedsyringeandinjectinto

a250mlinfusionbagorbottlecontainingeither0.9%sodiumchloridesolutionor5%dextrosesolution.Theinfusion

shouldthenbethoroughlymixedbymanualrotation.

Disposal:

Allmaterialsusedfordilutionandadministrationshouldbedisposedofaccordingtohospitalstandardprocedures

applicabletocytotoxicagents.

7MARKETINGAUTHORISATIONHOLDER

PfizerLimited

RamsgateRoad

Sandwich

Kent

CT139NJ

UnitedKingdom.

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 27July1998

Dateoflastauthorisation: 05May2005

10DATEOFREVISIONOFTHETEXT

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