CAMPTO

Main information

  • Trade name:
  • CAMPTO 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:
  • CAMPTO Concentrate for Soln for Inf 20 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0019/053/002
  • Authorization date:
  • 08-10-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CAMPTO20mg/mlconcentrateforsolutionforinfusion.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Theconcentratecontains20mg/mlirinotecanhydrochloride,trihydrate(equivalentto17.33mg/mlirinotecan).5ml

VialsofCAMPTOcontain100mgofirinotecanhydrochloride,trihydrate.Forexcipients,see‘listofexcipients’.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion.

4CLINICALPARTICULARS

4.1TherapeuticIndications

CAMPTOisindicatedforthetreatmentofpatientswithadvancedcolorectalcancer:

incombinationwith5-fluorouracilandfolinicacidinpatientswithoutpriorchemotherapyforadvanceddisease,

asasingleagentinpatientswhohavefailedanestablished5-fluorouracilcontainingtreatmentregimen.

CAMPTOincombinationwithcetuximabisindicatedforthetreatmentofpatientswithepidermalgrowthfactor

receptor(EGFR)-expressing,KRASwild-typemetastaticcolorectalcancer,whohadnotreceivedpriortreatmentfor

metastaticdiseaseorafterfailureofirinotecan-includingcytotoxictherapy(pleasesee5.1).

CAMPTOincombinationwith5-fluorouracil,folinicacidandbevacizumabisindicatedforfirst-linetreatmentof

patientswithmetastaticcarcinomaofthecolonorrectum.

Camptoincombinationwithcapecitabinewithorwithoutbevacizumabisindicatedforfirst-linetreatmentofpatients

withmetastaticcolorectalcarcinoma.

4.2Posologyandmethodofadministration

Foradultsonly.CAMPTOsolutionforinfusionshouldbeinfusedintoaperipheralorcentralvein.

Recommendeddosage:

Inmonotherapy(forpreviouslytreatedpatient):

TherecommendeddosageofCAMPTOis350mg/m²administeredasanintravenousinfusionovera30-to90-minute

periodeverythreeweeks(seesections4.4and6.6).

Incombinationtherapy(forpreviouslyuntreatedpatient):

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

withthefollowingschedule(seesection5.1):

CAMPTOplus5FU/FAinevery2weeksschedule

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30-to90-minuteperiod,followedbyinfusionwithfolinicacidand5-fluorouracil.

Fortheposologyandmethodofadministrationofconcomitantcetuximab,refertotheproductinformationforthis

medicinalproduct.

Normally,thesamedoseofirinotecanisusedasadministeredinthelastcyclesoftheprioririnotecan-containing

regimen.Irinotecanmustnotbeadministeredearlierthan1houraftertheendofthecetuximabinfusion

Fortheposologyandmethodofadministrationofbevacizumab,refertothebevacizumabsummaryproductof

characteristics.

Fortheposologyandmethodofadministrationofcapecitabinecombination,pleaseseesection5.1andrefertothe

appropriatesectionsinthecapecitabinesummaryofproductcharacteristics.

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.

Refertothebevacizumabsummaryproductofcharacteristicsfordosemodificationsofbevacizumabwhen

administeredincombinationwithCAMPTO/5FU/FA.

Incombinationwithcapecitabineforpatients65yearsofageormore,areductionofthestartingdoseofcapecitabine

to800mg/m 2

twicedailyisrecommendedaccordingtothesummaryofproductcharacteristicsforcapecitabine.Refer

alsototherecommendationsfordosemodificationsincombinationregimengiveninthesummaryofproduct

characteristicsforcapecitabine.

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,

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mg/m²,

Patientswithbilirubinbeyondto3timestheULNshouldnotbetreatedwithCAMPTO(seesections4.3and4.4).

NodataareavailableinpatientswithhepaticimpairmenttreatedbyCAMPTOincombination.

PatientswithImpairedRenalFunction:CAMPTOisnotrecommendedforuseinpatientswithimpairedrenal

function,asstudiesinthispopulationhavenotbeenconducted.(Seesections4.4and5.2).

Elderly:Nospecificpharmacokineticstudieshavebeenperformedinelderly.However,thedoseshouldbechosen

carefullyinthispopulationduetotheirgreaterfrequencyofdecreasedbiologicalfunctions.Thispopulationshould

requiremoreintensesurveillance(seesection4.4).

4.3Contraindications

Chronicinflammatoryboweldiseaseand/orbowelobstruction(seesection4.4).

Historyofseverehypersensitivityreactionstoirinotecanhydrochloridetrihydrateortooneoftheexcipientsof

CAMPTO.

Pregnancyandlactation(seesections4.4and4.6).

Bilirubin>3timestheupperlimitofthenormalrange(seesection4.4).

Severebonemarrowfailure.

WHOperformancestatus>2.

ConcomitantusewithStJohn’sWort(seesection4.5).

Foradditionalcontraindicationsofcetuximaborbevacizumaborcapecitabine,refertotheproductinformationfor

thesemedicinalproducts.

4.4Specialwarningsandprecautionsforuse

Giventhenatureandincidenceofadverseevents,CAMPTOwillonlybeprescribedinthefollowingcasesafterthe

expectedbenefitshavebeenweightedagainstthepossibletherapeuticrisks:

inpatientspresentingariskfactor,particularlythosewithaWHOperformancestatus=2.

inthefewrareinstanceswherepatientsaredeemedunlikelytoobserverecommendationsregardingmanagement

ofadverseevents(needforimmediateandprolongedantidiarrhoealtreatmentcombinedwithhighfluidintakeat

onsetofdelayeddiarrhoea).Stricthospitalsupervisionisrecommendedforsuchpatients.

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

theweekly-dosageschedule(seesection5)maybeconsideredinpatientswhomayneedacloserfollow-uporwhoare

atparticularriskofsevereneutropenia.

Delayeddiarrhoea

Patientsshouldbemadeawareoftheriskofdelayeddiarrhoeaoccurringmorethan24hoursaftertheadministrationof

CAMPTOandatanytimebeforethenextcycle.Inmonotherapy,themediantimeofonsetofthefirstliquidstoolwas

onday5aftertheinfusionofCAMPTO.Patientsshouldquicklyinformtheirphysicianofitsoccurrenceandstart

appropriatetherapyimmediately.

Patientswithanincreasedriskofdiarrhoeaarethosewhohadapreviousabdominal/pelvicradiotherapy,thosewith

baselinehyperleucocytosis,thosewithperformancestatus 2andwomen.Ifnotproperlytreated,diarrhoeacanbe

TheuseofCAMPTOshouldbeconfinedtounitsspecialisedintheadministrationofcytotoxicchemotherapyandit

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Assoonasthefirstliquidstooloccurs,thepatientshouldstartdrinkinglargevolumesofbeveragescontaining

electrolytesandanappropriateantidiarrhoealtherapymustbeinitiatedimmediately.Thisantidiarrhoealtreatmentwill

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(seesection

4.2).

Haematology

WeeklymonitoringofcompletebloodcellcountsisrecommendedduringCAMPTOtreatment.Patientsshouldbe

awareoftheriskofneutropeniaandthesignificanceoffever.Febrileneutropenia(temperature>38°Candneutrophil

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

Inpatientswhoexperiencedseverehaematologicalevents,adosereductionisrecommendedforsubsequent

administration(seesection4.2).

Thereisanincreasedriskofinfectionsandhaematologicaltoxicityinpatientswithseverediarrhoea.Inpatientswith

severediarrhoea,completebloodcellcountsshouldbeperformed.

Liverimpairment

Liverfunctiontestsshouldbeperformedatbaselineandbeforeeachcycle.

Weeklymonitoringofcompletebloodcountsshouldbeconductedinpatientswithbilirubinrangingfrom1.5to3times

ULN,duetodecreaseoftheclearanceofirinotecan(seesection5.2)andthusincreasingtheriskofhematotoxicityin

thispopulation.Forpatientswithabilirubin>3timesULN(seesection4.3).

Nauseaandvomiting

AprophylactictreatmentwithantiemeticsisrecommendedbeforeeachtreatmentwithCAMPTO.Nauseaand

vomitinghavebeenfrequentlyreported.Patientswithvomitingassociatedwithdelayeddiarrhoeashouldbe

hospitalisedassoonaspossiblefortreatment.

Acutecholinergicsyndrome

Ifacutecholinergicsyndromeappears(definedasearlydiarrhoeaandvariousothersymptomssuchassweating,

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

administeredunlessclinicallycontraindicated(seesection4.8).Cautionshouldbeexercisedinpatientswithasthma.

Inpatientswhoexperiencedanacuteandseverecholinergicsyndrome,theuseofprophylacticatropinesulphateis

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Respiratorydisorders

Interstitialpulmonarydiseasepresentingaspulmonaryinfiltratesisuncommonduringirinotecantherapy.Interstitial

pulmonarydiseasecanbefatal.Riskfactorspossiblyassociatedwiththedevelopmentofinterstitialpulmonarydisease

includetheuseofpneumotoxicdrugs,radiationtherapyandcolonystimulatingfactors.Patientswithriskfactors

shouldbecloselymonitoredforrespiratorysymptomsbeforeandduringirinotecantherapy.

Elderly

Duetothegreaterfrequencyofdecreasedbiologicalfunctions,inparticularhepaticfunction,inelderlypatients,dose

selectionwithCAMPTOshouldbecautiousinthispopulation(seesection4.2).

Patientswithbowelobstruction

PatientsmustnotbetreatedwithCAMPTOuntilresolutionofthebowelobstruction(seesection4.3).

PatientswithImpairedRenalFunction

Studiesinthispopulationhavenotbeenconducted.(seesections4.2and5.3).

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).

Coadministrationof5-fluorouracil/folinicacidinthecombinationregimendoesnotchangethepharmacokineticsof

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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(seesections4.3and4.4).

Womenofchild-bearingpotential:

Womenofchild-bearingagereceivingCAMPTOshouldbeadvisedtoavoidbecomingpregnant,andtoinformthe

treatingphysicianimmediatelyshouldthisoccur(seesections4.3and4.4).

Lactation:

Inlactatingrats, 14

C-irinotecanwasdetectedinmilk.Itisnotknownwhetheririnotecanisexcretedinhumanmilk.

Consequently,becauseofthepotentialforadversereactionsinnursinginfants,breast-feedingmustbediscontinuedfor

thedurationofCAMPTOtherapy(seesection4.3).

4.7Effectsonabilitytodriveandusemachines

Patientsshouldbewarnedaboutthepotentialfordizzinessorvisualdisturbanceswhichmayoccurwithin24hours

followingtheadministrationofCAMPTO,andadvisednottodriveoroperatemachineryifthesesymptomsoccur.

4.8Undesirableeffects

Undesirableeffectsdetailedinthissectionrefertoirinotecan.Thereisnoevidencethatthesafetyprofileofirinotecan

isinfluencedbycetuximaborviceversa.Incombinationwithcetuximab,additionalreportedundesirableeffectswere

thoseexpectedwithcetuximab(suchasacneformrash88%).Forinformationonadversereactionsonirinotecanin

combinationwithcetuximab,alsorefertotheirrespectivesummariesofproductcharacteristics.

Forinformationonadversereactionsincombinationwithbevacizumab,refertothebevacizumabsummaryofproduct

characteristics.

Adversedrugreactionsreportedinpatientstreatedwithcapecitabineincombinationwithirinotecaninadditiontothose

seenwithcapecitabinemonotherapyorseenatahigherfrequencygroupingcomparedtocapecitabinemonotherapy

include:

Verycommon,allgradeadversedrugreactions:thrombosis/embolism;

Common,allgradeadversedrugreactions:hypersensitivityreaction,cardiacischemia/infarction;

Common,grade3andgrade4adversedrugreactions:febrileneutropenia.

Forcompleteinformationonadversereactionsofcapecitabine,refertothecapecitabinesummaryproductof

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Grade3andGrade4adversedrugreactionsreportedinpatientstreatedwithcapecitabineincombinationwith

irinotecanandbevacizumabinadditiontothoseseenwithcapecitabinemonotherapyorseenatahigherfrequency

groupingcomparedtocapecitabinemonotherapyinclude:Common,grade3andgrade4adversedrugreactions:

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

reactionsofcapecitabineandbevacizumab,refertotherespectivecapecitabineandbevacizumabsummaryofproduct

characteristics.

ThefollowingadversereactionsconsideredtobepossiblyorprobablyrelatedtotheadministrationofCAMPTOhave

beenreportedfrom765patientsattherecommendeddoseof350mg/m²inmonotherapy,andfrom145patientstreated

byCAMPTOincombinationtherapywith5FU/FAinevery2weeksscheduleattherecommendeddoseof180mg/m².

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

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Inmonotherapy:

Neutropeniawasobservedin78.7%ofpatientsandwassevere(neutrophilcount<500cells/mm 3

)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.

Anaemiawasreportedinabout58.7%ofpatients(8%withhaemoglobin<8g/dland0.9%withhaemoglobin

<6.5g/dl).

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

plateletscount 50,000cells/mm 3

and0.2%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(seesection4.4).

Astheniawassevereinlessthan10%ofpatientstreatedinmonotherapyandin6.2%ofpatientstreatedin

combinationtherapy.ThecausalrelationshiptoCAMPTOhasnotbeenclearlyestablished.Feverintheabsenceof

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6.2%ofpatientstreatedincombinationtherapy.

Mildinfusionsitereactionshavebeenreportedalthoughuncommonly.

Cardiacdisorder

Rarecasesofhypertensionduringorfollowingtheinfusionhavebeenreported.

Respiratorydisorders

Interstitialpulmonarydiseasepresentingaspulmonaryinfiltratesisuncommonduringirinotecantherapy.Earlyeffects

suchasdyspnoeahavebeenreported(seesection4.4).

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.

Rarecasesofhypokalemiaandhyponatremiamostlyrelatedwithdiarrheaandvomitinghavebeenreported.

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

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tumourcelllines.TheinhibitionofDNAtopoisomeraseIbyirinotecanorSN-38inducessingle-strandDNAlesions

whichblockstheDNAreplicationforkandareresponsibleforthecytotoxicity.Thiscytotoxicactivitywasfoundtime-

dependentandwasspecifictotheSphase.

Invitro,irinotecanandSN-38werenotfoundtobesignificantlyrecognisedbytheP-glycoproteinMDR,anddisplays

cytotoxicactivitiesagainstdoxorubicinandvinblastineresistantcelllines.

Furthermore,irinotecanhasabroadantitumoractivityinvivoagainstmurinetumourmodels(P03pancreaticductal

adenocarcinoma,MA16/Cmammaryadenocarcinoma,C38andC51colonadenocarcinomas)andagainsthuman

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

adenocarcinomas).IrinotecanisalsoactiveagainsttumorsexpressingtheP-glycoproteinMDR(vincristine-and

doxorubicin-resistantP388leukaemia’s).

BesidetheantitumoractivityofCAMPTO,themostrelevantpharmacologicaleffectofirinotecanistheinhibitionof

acetylcholinesterase.

Clinicaldata

Incombinationtherapyforthefirst-linetreatmentofmetastaticcolorectalcarcinoma

IncombinationtherapywithFolinicAcidand5-Fluorouracil

AphaseIIIstudywasperformedin385previouslyuntreatedmetastaticcolorectalcancerpatientstreatedwitheither

every2weeksschedule(seesection4.2)orweeklyscheduleregimens.Intheevery2weeksschedule,onday1,the

administrationofCAMPTOat180mg/m²onceevery2weeksisfollowedbyinfusionwithfolinicacid(200mg/m²

overa2-hourintravenousinfusion)and5-fluorouracil(400mg/m²asanintravenousbolus,followedby600mg/m²

overa22-hourintravenousinfusion).Onday2,folinicacidand5-fluorouracilareadministeredatthesamedosesand

schedules.Intheweeklyschedule,theadministrationofCAMPTOat80mg/m²isfollowedbyinfusionwithfolinic

acid(500mg/m²overa2-hourintravenousinfusion)andthenby5-fluorouracil(2300mg/m²overa24-hour

intravenousinfusion)over6weeks.

Inthecombinationtherapytrialwiththe2regimensdescribedabove,theefficacyofCAMPTOwasevaluatedin

198treatedpatients:

Combinedregimens

(n=198) Weeklyschedule

(n=50) Every2weeksschedule

(n=148)

CAMPTO

+5FU/FA 5FU/FA CAMPTO

+5FU/FA 5FU/FA CAMPTO

+5FU/FA 5FU/FA

Responserate

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

pvalue p<0.001 p=0.045 p=0.005

Mediantime

toprogression

(months) 6.7 4.4 7.2 6.5 6.5 3.7

pvalue p<0.001 NS p=0.001

Median

durationof

response

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5FU:5-fluorouracil

FA:folinicacid

NS:NonSignificant

*:Asperprotocolpopulationanalysis

Intheweeklyschedule,theincidenceofseverediarrhoeawas44.4%inpatientstreatedbyCAMPTOincombination

with5FU/FAand25.6%inpatientstreatedby5FU/FAalone.

Theincidenceofsevereneutropenia(neutrophilcount<500cells/mm 3

)was5.8%inpatientstreatedbyCAMPTOin

combinationwith5FU/FAandin2.4%inpatientstreatedby5FU/FAalone.

Additionally,mediantimetodefinitiveperformancestatusdeteriorationwassignificantlylongerinCAMPTO

combinationgroupthanin5FU/FAalonegroup(p=0.046).

QualityoflifewasassessedinthisphaseIIIstudyusingtheEORTCQLQ-C30questionnaire.Timetodefinitive

deteriorationconstantlyoccurredlaterintheCAMPTOgroups.TheevolutionoftheGlobalHealthStatus/Qualityof

lifewasslightlybetterinCAMPTOcombinationgroupalthoughnotsignificant,showingthatefficacyofCAMPTOin

combinationcouldbereachedwithoutaffectingthequalityoflife.

Incombinationtherapywithbevazicumab

AphaseIIIrandomised,double-blind,active-controlledclinicaltrialevaluatedbevacizumabincombinationwith

CAMPTO/5FU/FAasfirst-linetreatmentformetastaticcarcinomaofthecolonorrectum(StudyAVF2107g).The

additionofbevacizumabtothecombinationofCAMPTO/5FU/FAresultedinastatisticallysignificantincreasein

overallsurvival.Theclinicalbenefit,asmeasuredbyoverallsurvival,wasseeninallpre-specifiedpatientsubgroups,

includingthosedefinedbyage,sex,performancestatus,locationofprimarytumour,numberoforgansinvolved,and

durationofmetastaticdisease.Referalsotothebevacizumabsummaryofproductcharacteristics.Theefficacyresults

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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5mg/kgevery2weeks.

Relativetocontrolarm.

Incombinationtherapywithcetuximab

EMR62202-013:Thisrandomisedstudyinpatientswithmetastaticcolorectalcancerwhohadnotreceivedprior

treatmentformetastaticdiseasecomparedthecombinationofcetuximabandirinotecanplusinfusional5-

fluorouracil/folinicacid(5-FU/FA)(599patients)tothesamechemotherapyalone(599patients).Theproportionof

AVF2107g

Arm1

CAMPTO/5FU/FA

+Placebo Arm2

CAMPTO/5FU/FA

+Avastin a

NumberofPatients 411 402

Overallsurvival

Mediantime(months) 15.6 20.3

95%ConfidenceInterval 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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Theefficacydatageneratedinthisstudyaresummarisedinthetablebelow:

CI=confidenceinterval,FOLFIRI=irinotecanplusinfusional5-FU/FA,ORR=objectiveresponserate(patients

withcompleteresponseorpartialresponse),PFS=progression-freesurvivaltime

Incombinationtherapywithcapecitabine

Datafromarandomised,controlledphaseIIIstudy(CAIRO)supporttheuseofcapecitabineatastartingdoseof1000

mg/m 2

for2weeksevery3weeksincombinationwithirinotecanforthefirst-linetreatmentofpatientswithmetastatic

colorectalcancer.820Patientswererandomizedtoreceiveeithersequentialtreatment(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)(XELIRI)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

(95%CI,7.0-8.3months)forXELIRI(p=0.0002).

Datafromaninterimanalysisofamulticentre,randomised,controlledphaseIIstudy(AIOKRK0604)supporttheuse

ofcapecitabineatastartingdoseof800mg/m 2

for2weeksevery3weeksincombinationwithirinotecanand

bevacizumabforthefirst-linetreatmentofpatientswithmetastaticcolorectalcancer.115patientswererandomisedto

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

twice

dailyfortwoweeksfollowedbya7-dayrestperiod),irinotecan(200mg/m 2

asa30minuteinfusiononday1every3

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

wererandomisedtotreatmentwithcapecitabinecombinedwithoxaliplatinplusbevacizumab:capecitabine(1000

mg/m 2

twicedailyfortwoweeksfollowedbya7-dayrestperiod),oxaliplatin(130mg/m 2

asa2hourinfusiononday

1every3weeks),andbevacizumab(7.5mg/kgasa30to90minuteinfusiononday1every3weeks).Progression-free

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

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

versus47%(XELIRIplusbevacizumab).

Inmonotherapyforthesecond-linetreatmentofmetastaticcolorectalcarcinoma:

ClinicalphaseII/IIIstudieswereperformedinmorethan980patientsintheevery3weekdosageschedulewith

metastaticcolorectalcancerwhofailedaprevious5-FUregimen.TheefficacyofCAMPTOwasevaluatedin

Overallpopulation KRASwild-typepopulation

Variable/statistic Cetuximab

plusFOLFIRI

(N=599) FOLFIRI

(N=599) Cetuximab

plusFOLFIRI

(N=172) FOLFIRI

(N=176)

ORR

%(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

PFS

HazardRatio(95%

0.85(0.726,0.998) 0.68(0.501,0.934)

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NA:NonApplicable

*:Statisticallysignificantdifference

InphaseIIstudies,performedon455patientsintheevery3-weekdosageschedule,theprogressionfreesurvivalat

6monthswas30%andthemediansurvivalwas9months.Themediantimetoprogressionwas18weeks.

Additionally,non-comparativephaseIIstudieswereperformedin304patientstreatedwithaweeklyscheduleregimen,

atadoseof125mg/m²administeredasanintravenousinfusionover90minutesfor4consecutiveweeksfollowedby2

weeksrest.Inthesestudies,themediantimetoprogressionwas17weeksandmediansurvivalwas10months.A

similarsafetyprofilehasbeenobservedintheweekly-dosageschedulein193patientsatthestartingdoseof125

mg/m²,comparedtotheevery3-week-dosageschedule.Themediantimeofonsetofthefirstliquidstoolwasonday

Incombinationwithcetuximabafterfailureofirinotecan-includingcytotoxictherapy

Theefficacyofthecombinationofcetuximabwithirinotecanwasinvestigatedintwoclinicalstudies.Atotalof356

patientswithEGFR-expressingmetastaticcolorectalcancerwhohadrecentlyfailedirinotecan-includingcytotoxic

therapyandwhohadaminimumKarnofskyperformancestatusof60,butthemajorityofwhomhadaKarnofsky

performancestatusof ≥80receivedthecombinationtreatment.

EMR62202-007:Thisrandomisedstudycomparedthecombinationofcetuximabandirinotecan(218patients)with

cetuximabmonotherapy(111patients).

IMCLCP02-9923:Thissinglearmopen-labelstudyinvestigatedthecombinationtherapyin138patients.

PhasesIII

CAMPTOversussupportive

care CAMPTOversus5FU

CAMPTO

n=183 Supportive

care

n=90 pvalues CAMPTO

n=127 5FU

n=129 pvalues

ProgressionFree

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

Mediansurvival

(months) 9.2* 6.5 p=0.0001 10.8* 8.5 p=0.0351

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

n(%) 95%

CI n(%) 95%

CI Median 95%

CI Median 95%

CI

Cetuximab+irinotecan

EMR

62202-007 218 50

(22.9) 17.5,

29.1 121

(55.5) 48.6,

62.2 4.1 2.8,

7.6,

IMCLCP02-

9923 138 21

(15.2) 9.7,

22.3 84

(60.9) 52.2,

69.1 2.9 2.6,

7.2,

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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(hazardratio0.91,p=0.48).

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

pharmacokineticsareindependentofthenumberofpreviouscyclesandoftheadministrationschedule.

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

Cetuximab

EMR

62202-007 111 12

(10.8) 5.7,

18.1 36

(32.4) 23.9,

42.0 1.5 1.4,

5.6,

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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

Theshelf-lifeofunopenedvialsis36months.

TheCAMPTOsolutionshouldbeusedimmediatelyafterreconstitutionasitcontainsnoantibacterialpreservative.If

reconstitutionanddilutionareperformedunderstrictasepticconditions(e.g.onLaminarAirFlowbench)CAMPTO

solutionshouldbeused(infusioncompleted)within12hoursatroomtemperatureor24hoursifstored2°-8°Cafterthe

firstbreakage.

6.4Specialprecautionsforstorage

VialsofCAMPTOconcentrateforsolutionforinfusionshouldbestoredbelow25°Candprotectedfromlight.

6.5Natureandcontentsofcontainer

CAMPTO100mg:

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Aswithotherantineoplasticagents,CAMPTOmustbepreparedandhandledwithcaution.Theuseofglasses,mask

andglovesisrequired.

IfCAMPTOsolutionorinfusionsolutionshouldcomeintocontactwiththeskin,washimmediatelyandthoroughly

withsoapandwater.IfCAMPTOsolutionorinfusionsolutionshouldcomeintocontactwiththemucousmembranes,

washimmediatelywithwater.

Preparationfortheintravenousinfusionadministration:

Aswithanyotherinjectabledrugs,theCAMPTOsolutionmustbepreparedaseptically(seesection6.3).

Ifanyprecipitateisobservedinthevialsorafterreconstitution,theproductshouldbediscardedaccordingtostandard

proceduresforcytotoxicagents.

AsepticallywithdrawtherequiredamountofCAMPTOsolutionfromthevialwithacalibratedsyringeandinjectinto

a250mlinfusionbagorbottlecontainingeither0.9%sodiumchloridesolutionor5%dextrosesolution.Theinfusion

shouldthenbethoroughlymixedbymanualrotation.

Disposal:

Allmaterialsusedfordilutionandadministrationshouldbedisposedofaccordingtohospitalstandardprocedures

applicabletocytotoxicagents.

7MARKETINGAUTHORISATIONHOLDER

PfizerLimited

RamsgateRoad

Sandwich

KentCT139NJ

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0019/053/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 27July1998

Dateoflastrenewal: 05May2005

10DATEOFREVISIONOFTHETEXT

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