capecitabine

DrugMonograph

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

A-DrugName

capecitabine
SYNONYM(S):5'-Deoxy-5-fluoro-N-[(pentyloxy)carbonyl]-cytidine
COMMONTRADENAME(S):Xeloda(Hoffmann-LaRoche)

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B-MechanismofActionandPharmacokinetics
Capecitabineisanantimetabolite,belongingtothefluoropyrimidinecarbamateclassandcauses
cellinjuryviaRNA-andDNA-relatedmechanisms.Itisanorallyadministeredprecursorof5fluorouracil(5FU).Capecitabineisconvertedto5FUbycarboxyesterase,cytidinedeaminaseand
thymidinephosphorylase(presentintheliverandintumours).Docetaxelappearstoupregulate
thymidinephosphorylase.Thedailyoraladministrationofcapecitabinemimicsthecontinuous
intravenousinfusionof5-FU.

Absorption
70%rapidwithCmax1.5hours.
Pharmacokineticsarelargelydoseproportionalinsignificantfoodeffect.
Pharmacokineticsalteredwithadvancedageandrenalfunction,butnot
withgender,race,performancestatus,liverfunctionandalbumin

Distribution
Widelydistributed
Crossbloodbrainbarrier?

Notknown

PPB

<60%primarilyalbumin(35%)

Metabolism
Capecitabineisextensivelybioactivatedandmetabolizedintheliver

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capecitabine

Elimination

Activemetabolites

Yes(FdUMPandFuTP)

Inactivemetabolites

Yes

Urine

70%3%unchanged

Feces

2.6%

Half-life

terminal:45-60minutes

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C-IndicationsandStatus
HealthCanadaApprovals:
First-linetreatmentmetastaticcolorectalcancer
FortheadjuvanttreatmentofpatientswithstageIII(Dukes'stageC)coloncancer
Incombinationwithoxaliplatinforthetreatmentofmetastaticcolorectalcancerafterfailureof
irinotecan-containingcombinationchemotherapy
Advancedormetastaticbreastcancerafterfailureofstandardtherapy(includingataxane),
unlesstherapywithataxaneisclinicallycontraindicated
Incombinationwithdocetaxelforadvancedormetastaticbreastcancerafterfailureof
anthracycline-containingchemotherapy

OtherUses:
Neo-adjuvanttreatmentofrectalcancer
Metastaticadenocarcinomaofthestomachorgastro-esophagealjunction(ascombination
chemotherapy)
Cholangiocarcinoma(ascombinationchemotherapy)
Metastaticcarcinomaofthepancreas,headandneck,unknownprimarytumour,renalcell,
neuroendocrinetumour
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D-AdverseEffects
EmetogenicPotential:Low

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capecitabine
ExtravasationPotential:Notapplicable
Thefollowingtablecontainsadverseeffectsreportedmainlyinadjuvantcolorectalcanceror
advancedbreastcancerstudiesasmonotherapy.
ORGANSITE

SIDEEFFECT*(%)

Cardiovascular Arterialthromboembolism(rare)

Hypertension(<5%)

Hypotension(<5%)

Venousthromboembolism(1%)

Hepatobiliary

Hand-footsyndrome(60%)

Naildisorder(7%)

Rash(6%)(maybesevere)

Gastrointestinal Abdominalpain(10%)

Hematological

Cardiotoxicity(<5%)

Dermatological Alopecia(6%)

General

ONSET**

Anorexia,weightloss(9%)

Constipation(6%)

Diarrhea(46%)

Dyspepsia(5%)

GIhemorrhage(<5%)

GIobstruction(<5%)

GIperforation(rare)

Mucositis(22%)

Nausea,vomiting(33%)

Edema(9%)

Fatigue(15%)

Pain(6%)

Idiopathicthrombocytopenicpurpura(rare)

Myelosuppressioninfection,bleeding(2%)(grade3/4,maybe
severe,includingatypicalinfection)

LFTs(20%)(grade3/4,maybesevere)

Hypersensitivity Hypersensitivity(<5%)

Musculoskeletal Musculoskeletalpain(9%)

Nervous
System

Confusion(<5%)

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capecitabine
Dizziness(5%)(includingvertigo)

Dysgeusia(6%)

Headache(9%)

Leukoencephalopathy(%)(veryrare)

Neuropathy(9%)

Conjunctivitis(5%)

Eyedisorders(cataract,lacrimalductstenosis,keratitis-rare)

Renal

Nephrotoxicity(<5%)

Respiratory

Cough,dyspnea(7%)

Ophthalmic

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

Themostcommonsideeffectsforcapecitabineincludehand-footsyndrome,diarrhea,nausea,
vomiting,mucositis,lfts,fatigue,abdominalpain,anorexia,weightloss,edemaandheadache.
Themediantimetoonsetofdiarrhea,adose-limitingadverseeffectofcapecitabine,is34days.
Thediarrheamayrespondtostandardanti-diarrhealtherapy(e.g.loperamide).Patientswithsevere
diarrheashouldbecloselymonitoredandgivenfluidandelectrolytereplacementfordehydrationas
indicated.Dehydrationmayresultinacuterenalfailure,particularlywithotherriskfactors(preexistingrenaldysfunction,concomitantnephrotoxicagents).Capecitabineshouldbeheldandthe
dosereducedafterrecovery(SeeDosingsection).Olderpatients(65years)maybeathigherrisk.
Palmar-plantarerythrodysesthesia(commonlyreferredtoashand-footsyndrome)is
characterizedbynumbness,dysesthesiaorparesthesia,tingling,painlessorpainfulswelling,
erythema,desquamation,blistering,andseverepainofthehandsand/orfeetandismorecommon
inpatientsalsoreceivingdocetaxel.Themediantimetoonsetwas79days.Dosage
interruption/adjustmentisrequiredaccordingtoseverity.Inadditiontodoseinterruptionand
subsequentdosereduction,topicalemollients(e.g.handcreams,udderbalm)mayamelioratethe
manifestationsofhand-footsyndromeinpatientsreceivingcapecitabine.Currentevidence
indicatesthatoralpyridoxinemaynotbeeffectiveinamelioratinghand-footsyndromeinpatients
receivingcapecitabine.(Kang2010).
Severerasheshavebeenreported(Stevens-Johnsonsyndrome,ToxicEpidermalNecrolysis).
Capecitabinemustbepermanentlydiscontinuedandthepatienttreatedappropriately.
Hyperbilirubinemiaassociatedwithcapecitabinetherapyoccursmorefrequentlyinpatientswith
hepaticmetastases.
Patientswithdihydropyrimidinedehydrogenase(DPD)deficiency(rate-limitingenzymeof5fluorouracilcatabolism)areatriskofseveretoxicity(i.e.neutropenia,GIandneurotoxicity,including
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capecitabine
fatalities)secondarytoreduceddrugmetabolism.
CardiactoxicityissimilartothatreportedforotherfluorinatedpyrimidinesandincludesECG
changes,angina,infarction,EKGchanges,dysrhythmiasandcardiacfailure.Theriskmaybe
increasedinpatientswithpriorcoronaryarterydisease.
Veryrarecasesofleukoencephalopathyhavebeenreported.
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E-Dosing

Refertoprotocolbywhichpatientisbeingtreated.

Adults:
Dosesaregivenorallyapproximately12hoursapart,within30minutesaftertheendofa
meal.
Monotherapy:
Oral:1250mg/mBIDfor14days
(Totaldailydose2500mg/m2)
Incombinationwithoxaliplatin(q3w):
Oral:1000mg/mBIDfor14days
Incombinationwithdocetaxel(q3w):
Oral:1250mg/mBIDfor14days
DoseCalculationAccordingtoBodySurfaceArea
Doselevel1250mg/m2PERDOSE(2500mg/m2/day):
1250mg/m2 PERDOSE

SurfaceArea(m2)

Dose(mg)*

1.26
1.271.38
1.391.52
1.531.66
1.671.78
1.791.92
1.932.06

1500
1650
1800
2000
2150
2300
2500

Numberoftabletstobetakenateachdose
150mg
500mg
0
1
2
0
1
2
0

3
3
3
4
4
4
5

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capecitabine
2.072.18
>2.19

2650
2800

1
2

5
5

*giventwicedaily

Doselevel1000mg/m2PERDOSE(2000mg/m2/day):

Numberoftabletstobetakenateachdose
1000mg/m2 PERDOSE
2
Dose(mg)*
150mg
500mg
SurfaceArea(m )
1.26
1.271.38
1.391.52
1.531.66
1.671.78
1.791.92
1.932.06
2.072.18
>2.19
*giventwicedaily

1150
1300
1450
1600
1750
1800
2000
2150
2300

1
2
3
4
5
2
0
1
2

2
2
2
2
2
3
4
4
4

DosagewithToxicity:
DoseModificationGuidelinesformonotherapy:
Donotstarttreatmentwithcapecitabineunlessbaselineneutrophilcountsare1.5x109/L
and/orplateletcountsof100x109/L.Patientsshouldbeinformedoftheneedtointerrupt
treatmentimmediatelyifmoderateorseveretoxicityoccurs.Supportivecareshouldbe
provided,includingloperamidefordiarrhea.Dosesshouldnotbere-escalatedifreducedfor
toxicity.Missedoromitteddosesofcapecitabineshouldnotbereplaced.
Dosemodificationsaremandatoryforgastrointestinal,dermatologicaltoxicity,
neurotoxicityandhyperbilirubinemia.Practitionermayelectnottoreducedoseforother
toxicitiesunlikelytobecomeseriousorlife-threatening.

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capecitabine

Toxicity

ActionDuringaCourseofTherapy

DoseAdjustmentforNext
Cycle(%ofstartingdose)

Grade1

Maintaindoselevel

Grade2
1stappearance
2ndappearance
3rdappearance
4thappearance

Interruptuntilresolvedtograde0-1
Interruptuntilresolvedtograde0-1
Interruptuntilresolvedtograde0-1
Discontinuetreatmentpermanently

100%
75%
50%
--

Grade3
1stappearance
2ndappearance
3rdappearance,OR
anyevidenceof
Stevens-Johnson
syndromeorToxic
epidermalnecrolysis

Interruptuntilresolvedtograde0-1
Interruptuntilresolvedtograde0-1
Discontinuetreatmentpermanently

75%
50%
--

Grade4

1stappearance,
includingSJSorTEN,
ORcardiotoxicityOR
acuterenalfailure

2ndappearanceOR
anyoccurrenceof
confirmed
leukoencephalopathy

Discontinuepermanently
OR
Ifphysiciandeemsittobeinthepatients
bestinteresttocontinueandnoevidence
ofStevens-Johnsonsyndromeortoxic
epidermalnecrolysis,interruptuntil
resolvedtograde0-1.

Maintaindoselevel

Discontinue
OR

50%

--

Discontinuepermanently

Dosageinmyelosuppression:
Modifyaccordingtoprotocolbywhichpatientisbeingtreatedifnoguidelinesavailable,refer
toAppendix6"DosageModificationforHematologicandNon-HematologicToxicities."Hold

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capecitabine
capecitabineduringatreatmentcycleinthepresenceofgrade3or4hematologictoxicity.
Dosemodificationsfortoxicityforcombinationregimens:
Refertothedocetaxel,oxaliplatinmonographsandCAPEDOCE,XELOXregimen
monographsforrecommendeddosemodificationsincombinationuse.
Fortheindicatedcombinations,
Ifatreatmentdelayisindicatedforeitheragent,thenadministrationofboth
capecitabineandtheotherchemotherapydrugshouldbedelayeduntiltherequirement
forstartingbotharemet.
Duringatreatmentcycle,ifthetoxicitiesareconsideredbythephysicianasunrelatedto
capecitabine,maycontinuecapecitabineandadjustthedoseoftheotheragent
accordingtoitsproductmonograph.
Iftheotheragentneedstobediscontinuedpermanently,capecitabinetreatmentcanbe
resumedwhentherequirementsforrestartingcapecitabinearemet.

DosagewithHepaticImpairment:
Inpatientswithmildtomoderatehepaticimpairment,exposureisincreasedbutnodose
adjustmentisnecessary,althoughcautionshouldbeexercised.Usedosemodificationtable
aboveforincreasesinbilirubin.Theuseofcapecitabineinpatientswithseverehepatic
impairmenthasnotbeenstudied.

DosagewithRenalImpairment:
Moderaterenalimpairmentresultsinanincreaseinseveretoxicity.
CreatinineClearance
(mL/min)
51-80
30-50
<30

%ofstartingdose
100%withclose
monitoring
75%(usewithcaution)
CONTRAINDICATED

Dosageintheelderly:

Nodoseadjustmentforthestartingdoseisrequired,butpatientsshouldbecloselymonitored
anddosemodificationshouldbeperformedasdescribedabove.Olderpatientsaremore
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capecitabine
susceptibletotheeffectsoffluoropyrimidine-basedtherapieswithincreasedgrade3/4
adverseeffects,especiallywhenusedincombination.

Children:
Safetyandefficacynotestablished.

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F-AdministrationGuidelines
Oralself-administrationdrugavailablebyoutpatientprescription.
Clinicalstudiesperformedwithcapecitabineadministered30minutesafterfood.
Administeringcapecitabineonanemptystomachmayresultinslightlyhigherexposureand
thustoxicity.
Ifacapecitabinedoseismissed,skipthisandgivethenextdoseattheusualtime.Missedor
omitteddosesshouldnotbereplaced.
Storetabletsat15Cto30Cintheoriginalpackage.
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G-SpecialPrecautions
Contraindications:
Patientswhohaveaknownhypersensitivitytocapecitabine,itsexcipients,or5-fluorouracil
Patientswithsevererenalimpairment(CrCl<30mL/min)
PatientswithknownDPD(dihydropyrimidinedehydrogenase)deficiency
Concomitantusewithsorivudineorrelatedanalogues(i.e.brivudine),givenpotentialfataldrug
interaction
Containslactoseandshouldnotbeusedinpatientswithhereditarygalactose/glucose/lactase
disorders.
OtherWarnings/Precautions:
Patientswithriskfactorsfordehydration,pre-existingrenaldysfunctionoronnephrotoxic
agents
Patientswithahistoryofcardiovasculardisease
Patientstakinganticoagulantssuchaswarfarin(seeDrugInteractionssection)

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capecitabine
OtherDrugProperties:
Carcinogenicity:Probable
Thelong-termcarcinogenicpotentialofcapecitabinehasnotbeenstudied,although5fluorouracilhaspotentialcarcinogenicandmutageniceffects.
PregnancyandLactation:
Teratogenicity:Yes
Embryotoxicity:Yes
Capecitabineisnotrecommendedforuseinpregnancy.Adequatecontraceptionshouldbe
usedbybothsexesduringtreatment,andforatleast6monthsafterthelastdose.
Excretionintobreastmilk:Probable
Breastfeedingisnotrecommended.
Fertilityeffects:Probable
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H-Interactions
Capecitabineisconvertedtoactive5-FUbytheenzymeDPD.ThedruglikelyinhibitsCYP2C9,
resultinginpossibledruginteractionswithCYP2C9substrates.
AGENT

EFFECT

MECHANISM

MANAGEMENT

Phenytoin/Fosphenytoin phenytoinlevels
andCYP2C9
substrates

Capecitabinemay
inhibitCYP2C9

Monitorphenytoin
levelsavoid
concomitant
administration

Leucovorin

capecitabinetoxicity

Potentiates
cytotoxicitywithout
increaseinefficacy

Avoid

Coumadin

AbnormalINR/PT
bleedingmayoccurat
anytime

Capecitabinemay
inhibitCYP2C9swarfarinexposureby
57%

CautionmonitorPT
andINRandadjust
anticoagulantdose
accordingly

Antacidscontaining
aluminumor
magnesiumhydroxide

smallinplasma
concentrationof
capecitabine

rateandextentof
absorption

Avoidconcomitant
administration

Docetaxel

incidenceofgrade3/4
treatment-relatedadverse
eventsinpatients60
yearsold

SynergisticPossibly Caution
duetoupregulationof
thymidine
phosphorylase

sorivudineand

capecitabinetoxicity

InhibitionofDPDby

Avoidconcomitant

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capecitabine
analogues

potentiallyfatal

sorivudine

administrationwait4
weeksafter
sorivudinetreatment
beforestarting
capecitabine

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I-RecommendedClinicalMonitoring
RecommendedClinicalMonitoring
MonitorType

MonitorFrequency

CBC

Baselineandregular

Renalfunctiontests

Baselineandregular

INRand/orPT

Baselineandregularifon
anticoagulants

Clinicaltoxicityassessmentfordiarrhea,
dehydration,infection,stomatitis,rashorhand-foot
syndrome,cardiac,hepaticandneurotoxicity

regular

GradetoxicityusingthecurrentNCI-CTCAE(CommonTerminologyCriteriaforAdverseEvents)
version

SuggestedClinicalMonitoring
MonitorType

MonitorFrequency

Liverfunctiontests

Baselineandregular(ifsevere
organfailuresuspected)

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J-SupplementaryPublicFunding
ODBLimitedUse(ODBFormulary)
PartoftheCAPOXregimenforthefirst-lineandsecond-linetreatmentofmetastaticcolorectal
cancer
Adjuvanttreatmentofstage3orhighriskstage2coloncancerinpatientswhohave
completedsurgery(withinthreemonths),whowouldnormallybecandidatesforadjuvant
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capecitabine
chemotherapywith5FU/LV
First-linetreatmentofpatientswithmetastaticcolorectalcancerinwhomcombination
chemotherapyisnotrecommended
Treatmentofmetastaticbreastcancerwherepatientshaveprogressedafterprior
chemotherapy
IncombinationwithtrastuzumabandcisplatinforthetreatmentofpatientswithHER2-positive
metastaticadenocarcinomaofthestomachorgastro-esophagealjunctionwhohavenot
receivedprioranti-cancertreatmentfortheirmetastaticdisease
Neo-adjuvanttreatmentofrectalcancer
Incombinationwithaplatinum-containingproductandepirubicinforthetreatmentofadvanced
(non-resectableeitherlocallyadvancedormetastatic)gastricorgastroesophagealjunction
cancer
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K-References
DooleyM,GoaKL:Capecitabine.Drugs1999Jul:58(1):69-76.
HoffmanLaRoche.DearDoctorLetter:Importantdrugwarning(Xeloda).December18th,2000.
KangY,LeeSS,YoonDH,etal.Pyridoxineisnoteffectivetopreventhand-footsyndrome
associatedwithcapecitabinetherapy:resultsofarandomized,double-blind,placebo-controlled
study.JClinOncol201028(24):3824-3829.
McEvoyGK,editor.AHFSDrugInformation2009.Bethesda:AmericanSocietyofHealth-System
Pharmacists,p.963-71.
Personalcommunications.HoffmannLaRoche:RevisedHFStreatmentguidelines.October2000.
Productmonograph:Xeloda(Capecitabine).Hoffmann-LaRoche,December11,2014.
TheMedicalLetter:40(1039)November6,1998:106-7.

May2015updatedsupplementarypublicfundingsection
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L-Disclaimer

RefertotheNewDrugFundingProgramorOntarioPublicDrugProgramswebsitesforthemostup-to-datepublic
fundinginformation.
Theinformationsetoutinthedrugmonographs,regimenmonographs,appendicesandsymptommanagement

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capecitabine
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