irinotecan

DrugMonograph
DrugName|MechanismofActionandPharmacokinetics|IndicationsandStatus|AdverseEffects|Dosing|Administration Guidelines|SpecialPrecautions|Interactions|RecommendedClinicalMonitoring|SupplementaryPublicFunding| References|Disclaimer

ADrugName

irinotecan
SYNONYM(S): camptothecin11CPT11U101440E COMMONTRADENAME(S): Camptosar(Pfizer) backtotop BMechanismofActionandPharmacokinetics Irinotecanisasemisyntheticderivativeofcamptothecin,analkaloidextractfromcamptotheca acuminata.CamptothecinanditsanaloguebelongtotheclassoftopoisomeraseIinhibitors. Irinotecananditsactivemetabolite,SN38,bindtothetopoisomeraseDNAcomplex,preventing religationofthesinglestrandbreaksintheDNAmolecule.Thedruganditsactivemetaboliteare believedtoexerttheircytotoxiceffectsduringtheSphaseofcellcycle. Absorption Distribution Bioavailability Oral:Noinformationfound

Peakplasmaconcentrationsofirinotecanarereachedbytheendof intravenousinfusion,whereasthoseoftheSN38metaboliteoccurabout 0.5to2hoursaftertheinfusionperiod.Irinotecanexposureincreasedin adosedependentmannerovertheusualrange,whereSN38increases lessthanproportionallywithdose.Noimpactofgenderon pharmacokinetics. Crossbloodbrainbarrier? PPB Noinformationfound 3068%(irinotecan) 95%(SN38)(mainlyalbumin)

Metabolism

Irinotecanismetabolizedtoitsactiveform,SN38,inthepresenceof hepaticorgastrointestinalcarboxylesterase.BothirinotecanandSN38 undergopHdependent,reversiblehydrolysisfromtheactiveclosedring lactonetoanopeninactivecarboxylateform.Irinotecanisalso metabolizedinpartbyCYP3A4toinactivemetabolites.

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irinotecan
Activemetabolites Inactivemetabolites Elimination SN38 APC,NPC,SN38glucuronide

Thecompletedispositionofirinotecaninhumanhasnotbeenfully elucidated.SN38subsequentlyundergoesconjugation(byUDP glucuronyltransferaseUGT1A1)toformaglucuronidemetaboliteand isexcretedinbile.Approximately10%oftheNorthAmericanpopulation ishomozygousforthewildtypeUGT1A1*28allele,whichresultsin reductionsinUGT1A1enzymeactivityandhigherSN38systemic exposure. Urine Halflife Low(1120%unchanged,5%as metabolites) 5.811.7h(irinotecan)7.717h (SN38)

backtotop CIndicationsandStatus HealthCanadaApprovals:

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Singleagenttreatmentforrecurrentcolorectalcanceraftertreatmentwithfluorouracil basedchemotherapy Asacomponentofcombinationfirstlinechemotherapyforpatientswithmetastatic colorectalcancer

backtotop DAdverseEffects

Emetogenicpotential: Moderate ExtravasationPotential: None Theadverseeffectslistedbelowarereportedinsingleagenttreatment. ORGANSITE Cardiovascular SIDEEFFECT*(%) Arterialthromboembolism Bradycardia(duringinfusion) Flushing(11%) Hypotension(6%) Venousthromboembolism I I E E ONSET** E

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irinotecan
Dermatological Gastrointestinal Alopecia(61%) Rash(13%) Abdominalpain(57%) Anorexia,weightloss(55%) Constipation(30%) Diarrhea(51%)(earlylate88%) Dyspepsia(11%) Flatulence(12%) GIobstruction(rare) GIperforation(rare) Mucositis(12%) Nausea,vomiting(86%) General Edema(10%) Fatigue(76%) Other(28%)(cholinergicsymptoms) Pain(24%) Hematological Hepatobiliary Hypersensitivity Myelosuppressioninfection,bleeding(26%)(maybesevere) LFTs(88%)(<10%severe) Pancreatitis(rare) Hypersensitivity(rare) Tumorlysissyndrome(rare) NervousSystem Confusion(7%) Dizziness(15%) Dysarthria(orspeechdisorder) Headache(17%) Insomnia(19%) Somnolence(12%) Renal Respiratory Renalfailure(rare) Cough,dyspnea(22%) Pneumonitis(infrequent) Rhinitis(16%) I E I E I E I I E I E I E E I E I E I E I I I E E E E E I E I E E I E E E E E E I E E

Metabolic/Endocrine Hyperglycemia

*"Incidence"mayrefertoanabsolutevalueorthehighervaluefromareportedrange. "Rare"mayrefertoeventswith<1%incidence,reportedinpostmarketing,phase1studies, isolateddataoranecdotalreports. Doselimitingsideeffectsareunderlined. **I=immediate(onsetinhourstodays)E=early(daystoweeks) D=delayed(weekstomonths)L=late(monthstoyears)

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irinotecan
Thedoselimitingtoxicitiesofirinotecanarediarrheaandneutropenia. Themostcommonandsevereadverseeffectofirinotecanisdiarrhea.Twodistincttypesof diarrheaassociatedwithirinotecanhavebeenidentifiedanearlyonsetcholinergicsyndrome andlateonsetdiarrhea.Theearlyonsetcholinergiceffects,usuallytransient,mayariseupto24 hoursaftertreatmentandincludesprofoundwarmth,rhinitis,lacrimation,increasedsalivation, diaphoresisorflushing,followedbyabdominalcrampingandsuddendiarrhea.Theyarethought toberelatedtotheanticholinesteraseactivityofirinotecanandaremorelikelytooccurathigher doselevels.AcuteeventsaremanagedsuccessfullybyadministeringIVorSCatropine0.25to1 mg.Becauseoftheshorthalflifeofatropine,usingittopreventcholinergicsymptomsis controversialhowever,prophylacticatropineshouldbeconsidered(unlesscontraindicated)in patientsexperiencingcholinergicsymptoms. Latediarrhea(occurringmorethan24hoursafteradministration)mayleadtodehydrationor electrolyteimbalances,andcanbelifethreatening.Themechanismoflateonsetdiarrheaisnot wellunderstood,butitappearstobelinkedtoasecretoryprocessthatmaybeasecondary consequenceofanirinotecancytotoxiceffectontheGImucosa.Itoccursin80%ofpatientsand themedianonsettimeis511days,dependingontheirinotecandosingschedule.Latediarrhea mustbetreatedpromptlywithloperamide,4mgatthefirstonsetoflatediarrheaandthen2mg every2hoursuntilthepatientisdiarrheafreeforatleast12hours.Duringthenightthepatient maytake4mgofloperamideevery4hours.Atthesedoses,loperamideisnotrecommendedto beusedformorethan48consecutivehoursduetotheriskofparalyticileus.Fluidintakeshould bemaintainedtoavoiddehydration.Premedicationwithloperamideisnotrecommendedand laxativesshouldbeavoided.Antibioticsshouldbeusedinpatientswithileus,feverorsevere neutropenia. Irinotecaninducedneutropeniaisdoserelated,generallybrief,andnoncumulative,witha typicalonsetbetweendays15and21andrecoverybetweendays28and35.Thefrequencyof grade3or4neutropeniaishigherinpatientswhohadpriorpelvicorabdominalirradiation,had elevatedserumbilirubinorwhoreceivedthedrugoverlessthan90minutes.Considertheuseof GCSFinpatientsexperiencingsevereneutropenia. Pneumonitishasbeenreportedinfrequently(predominantlyinstudiesfromJapan)following administrationofirinotecan.Thishasbeendescribedasdyspnea,anonproductivecough,ora diffusepulmonaryinfiltrateonchestxray.Theetiologyoftheseproblemsisunknown,anditisnot clearwhethertheytrulyarecausedbyirinotecanorareactuallyamanifestationofthedisease, primarylungcancer,orlungmetastases. Speechdisorders(e.g.dysarthria,stuttering,voicechanged)havebeenreportedinpost marketingofirinotecan,withmostcasesoccurringduringorshortlyaftertheirinotecaninfusion andresolvedspontaneouslywithinminutestohours.Thecauseofthesespeechdisorders appearedtobeunknownsomecasesoccurredwithotherneurologic,cholinergicor hypersensitivitysymptoms. backtotop

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irinotecan
EDosing Adequateantiemetictherapyandprophylacticloperamidemustbeprovided. Patientswithileus,feverorfebrileneutropeniashouldreceiveantibiotics. DonotuseinpatientswithECOGPSof3or4,norinpatientswithmoderateorsevereincreasesin bilirubinconsiderareductioninthestartingdosedescribedbelowforelderlypatients(70years), patientswithpriorabdominalorpelvicirradiation,patientswithapoorperformancestatus(ECOGof2) orpatientswithmildincreasesinbilirubin(includingGilbert'ssyndrome).

Adults: Singleagent: q1w:125mg/m2weeklyfor4weekswitha2weekrestperiod. Dosemaybeincreasedto150mg/m2intheabsenceoftoxicity. q3w:70years:300mg/m2 <70years:350mg/m2 Incombinationwith5fluorouracilandleucovorin: 2 l q2w:180mg/m (SeeFOLFIRIregimen) 2 l 6weekregimen:125mg/m D1,8,15,22(IFLregimen)

DosagewithToxicity: PatientsshouldnotberetreatedwithirinotecanuntilrecoveryfromGItoxicitytobaseline(without loperamideforatleast24hours)hasoccurred,platelets100x109/L,andANC1.5x109/L.All doseadjustmentsshouldbebasedontheworstprecedingtoxicity. (Continuedonnextpage)

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irinotecan
SingleAgent:
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Suggesteddoselevelsforweeklyx4scheduleare125,100,75and50mg/m2 Suggesteddoselevelsforq3wscheduleare350,300,250and200mg/m2 Suggesteddose Duringtreatmentcourse ofWeeklyschedule2 Nochange Atstartofsubsequentcourse1 Weeklyschedule2 Nochange Diarrheaaloneno change Hematologicaloneno change 3 Other :25mg/m2 25mg/m2 50mg/m2 3weeklyschedule2 Nochange Diarrheaaloneno change Hematologicaloneno change 3 Other :50mg/m2 50mg/m2 50mg/m2

Toxicity grade3 1

25mg/m2

3 4orfebrile neutropenia

Omit,then25mg/m2when grade2

Omit,then50mg/m2when grade2 Holdinvestigateandifconfirmed, Pneumonitis discontinue.

1Relativetothestartingdoseusedinthepreviouscycle. 2 PatientsshouldnotberetreateduntilGItoxicityresolvedtobaseline(withoutloperamideforatleast24h),platelets 100x109/L,andANC1.5x109/L.Ifnorecoveryaftera2weekdelay,considerdiscontinuingtreatment. 3Excludesalopecia,anorexia,andfatigue

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irinotecan
InCombinationTreatment: DoseLevels: Regimen FOLFIRI Drug Irinotecan Leucovorin infusion 5FUbolus 5FUinfusion* (startday1over 46h) Startingdose (mg/m2) 180 400or200# 400 2400 Doselevel1 (mg/m2) 150 Nochange 320 2000 DoseLevel2 (mg/m2) 120 Nochange 240 1600

Alternative 600 schedulefor5FU infusion(over22 hondays1and 2) IFL Irinotecan Leucovorinbolus 5FUbolus 125 20 500

480

360

100 20 400

75 20 300

*This5FUinfusiondosinghasnotbeenapprovedbyHealthCanada,buthasbeenusedinsomephaseIIItrials. #DosedependsondosingscheduleseeFOLFIRIregimen.

(Continuedonnextpage)

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irinotecan
DoseAdjustmentsforIrinotecaninCombinationwithFluorouracil: DuringaCycleofTherapy2 Toxicity Atthestartofsubsequentcycles1, 2(IFLorFOLFIRI) Grade (IFL) Hematologic Grade1 Nochange Nochange Grade2 Grade3 Grade4or febrile neutropenia Diarrhea Grade1: 23/day>pre treatment Grade2: 46/day>pre treatment Grade3: 79/day>pre treatment Grade4: 10/day> pretreatment Delayuntilrecoverytobaselinethen givesamedose Omituntilrecoverytobaselinethen reduceby1doselevel Omituntilrecoverytobaselinethen reduceby1doselevel Omituntilrecoverytobaselinethen reduceby2doselevels Nochange reduceby1doselevel Omituntilgrade2,thenreduceby1 doselevel Omituntilgrade2,thenreduceby2 doselevels Nochange reduceby1doselevel

reduceby2doselevels

Nochange

reduceby1doselevel

reduceby2doselevels

OtherNonhematologictoxicities(excludesalopecia,anorexiaandfatigue).For mucositis/stomatitis,decrease5FUonly,notirinotecan. Grade1 Grade2 Grade3 Grade4 Nochange Omituntilgrade1,thenreduceby1 doselevel Omituntilgrade2,thenreduceby1 doselevel Omituntilgrade2,thenreduceby2 doselevels Nochange Nochange reduceby1doselevel reduceby2doselevels

1 Relativetothestartingdoseusedinthepreviouscycle. 2 PatientsshouldnotberetreateduntilGItoxicityresolvedtobaseline(withoutloperamideforatleast24h),platelets 100x109/L,andANC1.5x109/L.Ifnorecoveryaftera2weekdelay,considerdiscontinuingtreatment.

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irinotecan

DosagewithHepaticImpairment: EliminationisdecreasedinhepaticimpairmentwithincreasedexposuretoSN38.Patientswith bilirubin11.5xULNorGilbertssyndromeareatanincreasedriskofmyelosuppression. Bilirubin1 2235moL/L(11.5x ULN)orwithGilberts syndrome >35moL/L or Transaminases Irinotecandose Monitorcloselymayconsiderdose reduction

>3xULN(withoutliver Usagenotrecommended. metastases)or>5x ULN(withliver metastases) 1Considerinvestigatingforreversiblecausessuchasbiliaryobstructionandreevaluate afterstent

DosagewithRenalImpairment: Nospecificstudies,butasthekidneyisnotamajorrouteofexcretion,noadjustmentanticipatedtobe required. Dosageintheelderly: Monitorpatients65yearscloselyforincreasedriskofdiarrhea.Patients70yearsofageusingthe q3wscheduleshouldreceive300mg/m2or100mg/m2(ifusingweeklyx4dosing). Children: Safetyandefficacynotestablished.

backtotop FAdministrationGuidelines Mixin500mLbag(D5WpreferredorNS)inaconcentrationrangebetween0.12to3 mg/mLinfuseIVover90minutes DonotrefrigerateadmixturesinNS(mayresultinprecipitation) Avoidfreezingirinotecananditsadmixturessincethismayresultindrugprecipitation. Donotadmixwithotherdrugs Protectfromlight Priortotheinitialirinotecantreatment,patientsshouldbegivenasufficientsupplyof loperamideandinstructedonitsappropriateuse. Avoidgrapefruit,starfruit,Sevilleoranges,theirjuicesorproductsduringirinotecantreatment

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irinotecan

backtotop GSpecialPrecautions Other: Irinotecaniscontraindicatedinpatientswithaknownhypersensitivitytotheproductoranyofits ingredients,inpatientswithECOGperformancestatusof3or4andinpatientswithmoderate severehepaticdysfunction.Itshouldnotbecoadministeredwithazoleantifungals(ketoconazole etc),norbegiventopatientswithhereditaryfructoseintolerancesincetheproductcontains sorbitol.Avoidtheuseofliveorliveattenuatedvaccines. Elderlypatients,patientswithpoorperformancestatus(=2),limitedmarrowreserve,3rdspace accumulation,orGilbertssyndromemaybemoresusceptibletothetoxiceffectsofthedrugthey shouldbecarefullymonitoredanddosereductionconsidered.Theconcurrentadministrationof irinotecanwithirradiationisnotrecommended.Patientswithpriorpelvicorabdominalirradiation areatanincreasedriskofseveremyelosuppressionfollowingirinotecantherapy. Thelongtermcarcinogenicpotentialofirinotecanhasnotbeenstudied.Irinotecanisembryotoxic andteratogenicandshouldnotbeusedinpregnancy.Althoughirinotecanisnotmutagenic,it hasbeenshowntohaveclastogeniceffects.Adequatecontraceptionshouldbeusedbyboth sexesduringirinotecantreatment,andforatleast6monthsaftertreatmentcessation.Nursing shouldbediscontinuedwhilereceivingthedrugbecauseirinotecanisexpressedinanimalmilk.

backtotop HInteractions AGENT Dexamethasone Dexamethasone EFFECT Lymphocytopenia Hyperglycemia (especiallyinpatients withglucose intolerance) MECHANISM Additive Lowersglucose tolerance MANAGEMENT Monitorbloodcount Monitorbloodglucose

Prochlorperazine

akathisiaobserved Unknown whengivenonsame dayasirinotecan weekly dehydration Additive

Cautionavoidon samedayofirinotecan treatment MonitororAvoid

Diuretics

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irinotecan
Azoleantifungals irinotecantoxicity exposureofSN38 (110%) CONTRAINDICATED. (Discontinue1week beforefirstdoseof irinotecan)

Otherinhibitorsof CYP3A4(ciprofloxacin, clarithromycin, verapamil,grapefruit juice,etc) CYP3A4inducers(i.e. phenytoin,rifampin, dexamethasone, carbamazepine, phenobarbital,St. JohnsWort,etc) Curcumin(tumeric) Atazanavir Bevacizumab

irinotecantoxicity

Avoidconcomitantuse exposure increasedformationof oradjustirinotecan dose SN38

irinotecaneffects

exposurebecause oflowerSN38levels

Avoidconcomitantuse switchtonon enzymeinducing anticonvulsants discontinueSt.John's Wort1weekpriorto irinotecan. Avoidconcomitantuse Avoidconcomitantuse Caution

mayreduceeffectof irinotecan effectofirinotecan Unclear.Potential increasedtoxicityof irinotecan

inhibitsIrinotecan inducedapoptosis inhibitsUGT1A1and CYP3A4 Some pharmacokinetic studieshave suggestedSN38 levelswith coadministrationof bevacizumab Additive anticholinesterase activity InhibitionofUGT1A1 (upto120% exposureinSN38 andirinotecan) Additive

Neuromuscularblocking Prolonged agents(ie. neuromuscular suxamethonium, blockingeffects succinylcholine) Sorafenib effectofirinotecan

Caution

Caution.Monitorfor signsandsymptoms ofirinotecantoxicity. Avoid

laxatives

Worsensdiarrhea

backtotop IRecommendedClinicalMonitoring (Continuedonnextpage)

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irinotecan
RecommendedClinicalMonitoring
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CBCbaselineandregular Liverfunctiontestsbaselineandregular ToxicityratingofdiarrheaandotherGIeffects,cholinergicsymptoms,pneumonitis, neurological,bleeding,infection,dehydration,fatigue,pancreatitis,thromboembolismroutine GradetoxicityusingthecurrentNCICTCAE(CommonTerminologyCriteriaforAdverse Events)version

SuggestedClinicalMonitoring
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Renalfunctiontestsperiodic Bloodglucose,especiallyinpatientswithdiabetesbaselineandregular

backtotop JSupplementaryPublicFunding NewDrugFundingProgram(NDFPWebsite)

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IrinotecanFirstLineMetastaticColorectalCancer IrinotecanSecondLineMetastaticColorectalCancer Irinotecan(withCetuximab)ThirdLineMetastaticColorectalCancer Irinotecan(withOxaliplatin)MetastaticPancreaticAdenocarcinoma

backtotop KReferences BergD.IrinotecanHydrochloride:drugprofileandnursingimplicationsofatopoisomeraseI inhibitorinpatientswithadvancedcolorectalcancer.ONF199825(3):53543. DrenglerRL,KuhnJG,SchaafLJetal.PhaseIandpharmacokinetictrialoforalirinotecan administereddailyfor5daysevery3weeksinpatientswithsolidtumor.JClinOncol1999:17 (2):68596. McEvoyGK,editor.AHFSDrugInformation2013.Bethesda:AmericanSocietyofHealthSystem Pharmacists,p.108993. ProductMonograph:Avastin(bevacizumab).HoffmannLaRocheLtd.,February23,2012. ProductMonograph:Camptosar(irinotecan).PfizerCanadaInc.,September19,2012.
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irinotecan
ProductMonograph:Nexavar(sorafenib).BayerInc.,May1,2013. SomasundaramS,EdmundNA,MooreDT,SmallGW,ShiYY,OrlowskiRZ.Dietarycurcumin inhibitschemotherapyinducedapoptosisinmodelsofhumanbreastcancer.CancerRes2002Jul 162(13):386875. TournigandC,AndrT,AchileE,etal.FOLFIRIfollowedbyFOLFOX6orthereversesequencein advancedcolorectalcancer:arandomizedGERCORstudy.JClinOncol200422(2):22937. WisemanLR,MarkhamA.Irinotecan:areviewofitspharmacologicalpropertiesandclinical efficacyinthemanagementofadvancedcolorectalcancer.Drugs199652(4):60623.

September2013:Fulldocumentrevision,especiallyadverseeffects,dosemodifications, interactionsandmonitoring backtotop LDisclaimer

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irinotecan
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