Capecitabine Orion

Document: Capecitabine Orion tablet ENG SmPC change

SUMMARYOFPRODUCTCHARACTERISTICS

1. NAMEOFTHEMEDICINALPRODUCT

Capecitabine Orion150 mgfilm-coatedtablets

Capecitabine Orion500 mgfilm-coatedtablets

2. QUALITATIVEANDQUANTITATIVECOMPOSITION

150 mg tablets: Eachfilm-coatedtabletcontains150 mgofcapecitabine.

500 mg tablets: Eachfilm-coatedtabletcontains500 mgofcapecitabine.

Excipientwithknowneffect:

^{150 mg tablets:} ^Each^fil^m^-c^o^ated^tablet^contains⁷^mg^an^h^y^d^r^ous^l^actose.

^{500 mg tablets:} ^Each^fil^m^-c^o^ated^tablet^contains²⁵^mg^an^h^y^d^r^ous^l^actose.

Forthefulllistofexcipients,seesection 6.1.

3. PHARMACEUTICALFORM

Film-coatedtablet (tablet)

Capecitabine Orion150 mg film-coated tablets are light peach-coloured, oblong-shaped, biconvex, film-coated tablets of 11.4 mm in length and 5.3 mm in width, debossed with ‘150’ on one side and plain on other side.

Capecitabine Orion500 mg film-coated tablets are peach-coloured, oblong-shaped, biconvex, film-coated tablets of 15.9 mm in length and 8.4 mm in width, debossed with ‘500’ on one side and plain on other side.

4. CLINICALPARTICULARS

4.1 Therapeuticindications

Capecitabine Orionisindicatedfortheadjuvanttreatmentofpatientsfollowingsurgeryofstage III(Dukes’stage C)coloncancer(seesection 5.1).

Capecitabine Orionisindicatedforthetreatmentofmetastaticcolorectalcancer(seesection 5.1).

Capecitabine Orionisindicatedforfirst-linetreatmentofadvancedgastriccancerincombinationwithaplatinum-basedregimen(seesection 5.1).

Capecitabine Orionincombinationwithdocetaxel(seesection 5.1)isindicatedforthetreatmentofpatientswith locallyadvancedormetastaticbreastcancerafterfailureofcytotoxicchemotherapy.Previoustherapy shouldhaveincludedananthracycline.Capecitabine Orionisalsoindicatedasmonotherapyforthetreatmentof patientswithlocallyadvancedormetastaticbreastcancerafterfailureoftaxanesandananthracycline-containingchemotherapyregimenorforwhomfurtheranthracyclinetherapyisnotindicated.

4.2 Posologyandmethodofadministration

Capecitabine Orionshouldonlybeprescribedbyaqualifiedphysicianexperiencedintheutilisationofanti-neoplasticmedicinalproducts.Carefulmonitoringduringthefirstcycleoftreatmentisrecommended forallpatients.

Treatmentshouldbediscontinuedifprogressivediseaseorintolerabletoxicityisobserved.Standard andreduceddosecalculationsaccordingtobodysurfaceareaforstartingdosesofCapecitabine Orionof 1,250 mg/m²and1,000 mg/m²areprovidedinTables 1and2,respectively.

_Posology

Recommendedposology(seesection 5.1):

Monotherapy

Colon,colorectalandbreastcancer

Givenasmonotherapy,therecommendedstartingdoseforcapecitabineintheadjuvanttreatmentof coloncancer,inthetreatmentofmetastaticcolorectalcanceroroflocallyadvancedormetastatic breastcanceris1,250 mg/m²administeredtwicedaily(morningandevening;equivalentto 2,500 mg/m² totaldailydose)for14 daysfollowedbya7‑dayrestperiod.Adjuvanttreatmentin patientswithstage IIIcoloncancerisrecommendedforatotalof6 months.

Combinationtherapy

Colon,colorectalandgastriccancer

Incombinationtreatment,therecommendedstartingdoseofcapecitabineshouldbereducedto800–1,000 mg/m²whenadministeredtwicedailyfor14 daysfollowedbya7‑dayrestperiod,orto 625 mg/m²twicedailywhenadministeredcontinuously(seesection 5.1).For combination with irinotecan, the recommended starting dose is 800 mg/m²when administered twice daily for 14 days followed by a 7-day rest period combined with irinotecan 200 mg/m²on day 1.Theinclusionofbevacizumabinacombinationregimenhasnoeffectonthestartingdoseofcapecitabine. Premedicationtomaintainadequatehydrationandanti-emesisaccordingtothecisplatinsummaryof productcharacteristicsshouldbestartedpriortocisplatinadministrationforpatientsreceivingthe capecitabinepluscisplatincombination.Premedicationwithantiemeticsaccordingtotheoxaliplatin summaryofproductcharacteristicsisrecommendedforpatientsreceivingthecapecitabineplus oxaliplatincombination.Adjuvanttreatmentinpatientswithstage IIIcoloncancerisrecommended forthedurationof6 months.

Breastcancer

Incombinationwithdocetaxel,therecommendedstartingdoseofcapecitabineinthetreatmentof metastaticbreastcanceris1,250 mg/m²twicedailyfor14 daysfollowedbya7‑dayrestperiod, combinedwithdocetaxelat75 mg/m²asa1‑hourintravenousinfusionevery3 weeks.Pre-medication withanoralcorticosteroidsuchasdexamethasoneaccordingtothedocetaxelsummaryofproduct characteristicsshouldbestartedpriortodocetaxeladministrationforpatientsreceivingthe capecitabineplusdocetaxelcombination.

Capecitabine Oriondosecalculations

Table 1: Standardandreduceddosecalculationsaccordingtobodysurfaceareaforastartingdoseof capecitabineof1,250 mg/m²

	Dose level 1,250 mg/m² (twice daily)
	Full dose 1,250 mg/m²	Number of 150 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening)		Reduced dose (75%) 950 mg/m²	Reduced dose (50%) 625 mg/m²
Body surface area (m²)	Dose per administration (mg)	150 mg	500 mg	Dose per administration (mg)	Dose per administration (mg)
≤ 1.26	1,500	-	3	1,150	800
1.271.38	1,650	1	3	1,300	800
1.391.52	1,800	2	3	1,450	950
1.531.66	2,000	-	4	1,500	1,000
1.671.78	2,150	1	4	1,650	1,000
1.791.92	2,300	2	4	1,800	1,150
1.932.06	2,500	-	5	1,950	1,300
2.072.18	2,650	1	5	2,000	1,300
≥ 2.19	2,800	2	5	2,150	1,450

Table 2: Standardandreduceddosecalculationsaccordingtobodysurfaceareaforastartingdoseof capecitabineof1,000 mg/m²

	^Dose ^level ^1,000^m^g^/m² ^(twice ^dail^y⁾
	Full dose 1,000 mg/m²	Number of 150 mg tablets and/or 500 mg tablets per administration (each administration to be given morning and evening)		Reduced dose (75%) 750 mg/m²	Reduced dose (50%) 500 mg/m²
_Body _surface area ⁽^m2)	Dose per administration (mg)	150 mg	500 mg	Dose per administration (mg)	Dose per administration (mg)
≤ 1.26	1,150	1	2	800	600
1.271.38	1,300	2	2	1,000	600
1.391.52	1,450	3	2	1,100	750
1.531.66	1,600	4	2	1,200	800
1.671.78	1,750	5	2	1,300	800
1.791.92	1,800	2	3	1,400	900
1.932.06	2,000	-	4	1,500	1,000
2.072.18	2,150	1	4	1,600	1,050
≥ 2.19	2,300	2	4	1,750	1,100

_Posology_a_d_j_u_stments_during_treatment

General

Toxicityduetocapecitabineadministrationmaybemanagedby symptomatictreatmentand/or modificationofthedose(treatmentinterruptionordosereduction).Oncethedosehasbeenreduced,it shouldnotbeincreasedat alatertime.Forthosetoxicitiesconsideredby thetreatingphysiciantobe unlikelytobecomeseriousorlife-threatening,e.g.alopecia,alteredtaste,nailchanges,treatmentcan becontinuedatthesamedosewithoutreductionorinterruption.Patientstakingcapecitabineshouldbe informedoftheneedtointerrupttreatmentimmediatelyifmoderateorseveretoxicityoccurs.Doses ofcapecitabineomittedfortoxicityarenotreplaced.Thefollowingaretherecommendeddose modificationsfortoxicity:

_Table_{3:
Capecitabine}_Dose_Reduction_Schedule_(3‑weekly_C_y_c_le_or_Continuous_Trea_t_m_e_n_t)

Toxicity grades*	Dose changes within a treatment cycle	Dose adjustment for next cycle/dose (% of starting dose)
• Grade 1	Maintain dose level	Maintain dose level
• Grade 2
-1st appearance	Interrupt until resolved to grade 01	100%
-2nd appearance		75%
-3rd appearance		50%
-4th appearance	Discontinue treatment permanently	Not applicable
• Grade 3
-1st appearance	Interrupt until resolved to grade 01	75%
-2nd appearance	Interrupt until resolved to grade 01	50%
-3rd appearance	Discontinue treatment permanently	Not applicable
• Grade 4
-1st appearance	Discontinue permanently or If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 01	50%
-2nd appearance	Discontinue permanently	Not applicable

*According to the National Cancer Instituteof Canada Clinical Trial Group (NCICCTG) CommonToxicity Criteria(version 1) ortheCommonTerminology CriteriaforAdverseEvents(CTCAE)of theCancerTherapy Evaluation Program,US National Cancer Institute, version 4.0.For handfootsyndromeand hyperbilirubinaemia, see section 4.4.

_Haematology

Patientswithbaselineneutrophilcountsof< 1.5 x 10⁹/Land/orthrombocytecountsof< 100 x 10⁹/L shouldnotbetreatedwithcapecitabine.Ifunscheduledlaboratoryassessmentsduringatreatment cycle showthattheneutrophilcountdropsbelow1.0 x 10⁹/Lorthattheplateletcountdropsbelow75 x 10⁹/L,treatmentwithcapecitabineshouldbeinterrupted.

Dosemodificationsfortoxicitywhencapecitabineisusedasa3weeklycycleincombinationwith othermedicinalproducts

Dosemodificationsfortoxicitywhencapecitabineisusedasa3‑weeklycycleincombinationwith othermedicinalproductsshouldbemadeaccordingtoTable 3aboveforcapecitabineandaccordingto theappropriatesummaryofproductcharacteristicsfortheothermedicinalproduct(s).

Atthebeginningofatreatmentcycle,ifatreatmentdelayisindicatedforeithercapecitabineorthe othermedicinalproduct(s),thenadministrationofalltherapyshouldbedelayeduntiltherequirements forrestartingall medicinalproductsaremet.

Duringatreatmentcycleforthosetoxicitiesconsideredby thetreatingphysiciannottoberelatedto capecitabine,capecitabineshouldbecontinuedandthedoseoftheothermedicinalproductshouldbe adjustedaccordingtotheappropriateprescribinginformation.

Iftheothermedicinalproduct(s)havetobediscontinuedpermanently,capecitabinetreatmentcanbe resumedwhentherequirementsforrestartingcapecitabinearemet.

Thisadviceisapplicabletoallindicationsandtoallspecialpopulations.

Dosemodificationsfortoxicitywhencapecitabineisusedcontinuouslyincombinationwithother medicinalproducts

Dosemodificationsfortoxicitywhencapecitabineisusedcontinuouslyincombinationwithother medicinalproductsshouldbemadeaccordingtoTable 3aboveforcapecitabineandaccordingtothe appropriatesummaryofproductcharacteristicsfortheothermedicinalproduct(s).

Posologyadjustmentsforspecialpopulations

Hepaticimpairment

Insufficientsafetyandefficacydataareavailableinpatientswithhepaticimpairmenttoprovideadose adjustmentrecommendation.Noinformationisavailableonhepaticimpairmentduetocirrhosisor hepatitis.

Renalimpairment

Capecitabineiscontraindicatedinpatientswithsevererenalimpairment(creatinineclearancebelow 30 ml/min[CockcroftandGault]atbaseline).Theincidenceofgrade 3or4adversereactionsin patientswithmoderaterenalimpairment(creatinineclearance3050 ml/minatbaseline)isincreased comparedtotheoverallpopulation.Inpatientswithmoderaterenalimpairmentatbaseline,adose reductionto75%forastartingdoseof1,250 mg/m²isrecommended.Inpatientswithmoderaterenal impairmentatbaseline,nodosereductionisrequiredforastartingdoseof1,000 mg/m².Inpatients withmildrenalimpairment(creatinineclearance5180 ml/minatbaseline)noadjustmentofthe startingdoseisrecommended.Carefulmonitoringandprompttreatmentinterruptionisrecommended ifthepatientdevelopsagrade 2,3or4adverseeventduringtreatmentandsubsequentdoseadjustment asoutlinedinTable 3above.Ifthecalculatedcreatinineclearancedecreasesduringtreatmenttoavalue below30 ml/min,Capecitabine Orionshouldbediscontinued.Thesedoseadjustmentrecommendationsforrenalimpairmentapplybothtomonotherapyandcombinationuse(seealsosection“Elderly”below).

Elderly

Duringcapecitabinemonotherapy,noadjustmentofthestartingdoseisneeded.However,grade 3or4 treatment-relatedadversereactionsweremorefrequentinpatients≥ 60 yearsofagecomparedto youngerpatients.

Whencapecitabinewasusedincombinationwithothermedicinalproducts,elderlypatients(≥ 65 years)experiencedmoregrade 3andgrade 4adversedrugreactions,includingthoseleadingto discontinuation,comparedtoyoungerpatients.Carefulmonitoringofpatients≥ 60 yearsofageis advisable.

In combination with docetaxel: an increased incidence of grade 3 or 4 treatment-related adverse reactions and treatment-related serious adverse reactions were observed in patients 60 years of age or more (see section 5.1). For patients 60 years of age or more, a starting dose reduction of capecitabine to 75% (950 mg/m² twice daily) is recommended. If no toxicity is observed in patients ≥ 60 years of age treated with a reduced capecitabine starting dose in combination with docetaxel, the dose of capecitabine may be cautiously escalated to 1,250 mg/m² twice daily.

Paediatricpopulation

Thereisnorelevantuseofcapecitabineinthepaediatricpopulationintheindicationscolon, colorectal,gastricandbreastcancer.

Methodofadministration

Capecitabine Oriontabletsshouldbeswallowedwithwaterwithin30 minutesaftera meal.

4.3 Contraindications

History of severe and unexpected reactions to fluoropyrimidine therapy
Hypersensitivity to capecitabine or to any of the excipients listed in section 6.1 or fluorouracil
In patients with known dihydropyrimidine dehydrogenase (DPD) deficiency (see section 4.4)
During pregnancy and lactation
In patients with severe leukopenia, neutropenia, or thrombocytopenia
In patients with severe hepatic impairment
In patients with severe renal impairment (creatinine clearance below 30 ml/min)
Treatment with sorivudine or its chemically related analogues, such as brivudine (see section 4.5)
If contraindications exist to any of the medicinal products in the combination regimen, that medicinal product should not be used.

4.4 Specialwarningsandprecautionsforuse

Doselimitingtoxicitiesincludediarrhoea,abdominalpain,nausea,stomatitisandhandfootsyndrome (handfootskinreaction,palmar-plantarerythrodysesthesia).Mostadversereactionsarereversibleand donotrequirepermanentdiscontinuationoftherapy,althoughdosesmayneedtobewithheldor reduced.

Diarrhoea:Patientswithseverediarrhoeashouldbecarefullymonitoredandgivenfluidand electrolytereplacementiftheybecomedehydrated. Standardantidiarrhoealtreatments(e.g. loperamide)maybeused.NCICCTCgrade 2diarrhoeaisdefinedasanincreaseof4to6 stools/day ornocturnalstools,grade 3diarrhoeaasanincreaseof7to9 stools/dayorincontinenceand malabsorption.Grade 4diarrhoeaisanincreaseof≥ 10 stools/dayorgrosslybloodydiarrhoeaorthe needforparenteralsupport.Dosereductionshouldbeappliedasnecessary(seesection 4.2).

Dehydration:Dehydrationshouldbepreventedorcorrectedattheonset.Patientswithanorexia, asthenia,nausea,vomitingordiarrhoeamayrapidlybecomedehydrated.Dehydration may cause acute renal failure, especially in patients with pre-existing compromised renal function or when capecitabine is given concomitantly with known nephrotoxic drugs. Acute renal failure secondary to dehydration might be potentially fatal. Ifgrade 2(orhigher) dehydrationoccurs,capecitabinetreatmentshouldbeimmediatelyinterruptedandthedehydration corrected.Treatmentshouldnotberestarteduntilthepatientisrehydratedandanyprecipitatingcauses havebeencorrectedorcontrolled.Dosemodificationsappliedshouldbeappliedfortheprecipitating adverseeventasnecessary(seesection 4.2).

Handfootsyndrome(alsoknownashandfootskinreactionorpalmar-plantarerythrodysesthesiaor chemotherapyinducedacralerythema):Grade 1handfootsyndromeisdefinedasnumbness, dysesthesia/paresthesia,tingling,painlessswellingorerythemaofthehandsand/orfeetand/or discomfortwhichdoesnotdisruptthepatient’snormalactivities.

Grade 2handfootsyndromeispainfulerythemaandswellingofthehandsand/orfeetand/or discomfortaffectingthepatient’sactivitiesofdailyliving.

Grade 3handfootsyndromeismoistdesquamation,ulceration,blisteringandseverepainofthe handsand/orfeetand/orseverediscomfortthatcausesthepatienttobeunabletoworkorperform activitiesofdailyliving.Ifgrade 2or3handfootsyndromeoccurs,administrationofcapecitabine shouldbeinterrupteduntiltheeventresolvesordecreasesinintensitytograde 1.Followinggrade 3 handfootsyndrome,subsequentdosesofcapecitabineshouldbedecreased.Whencapecitabineand cisplatinareusedincombination,theuseofvitaminB6(pyridoxine)isnotadvisedforsymptomatic orsecondaryprophylactictreatmentofhand–footsyndrome,becauseofpublishedreportsthatitmay decreasetheefficacyofcisplatin. There is some evidence that dexpanthenol is effective for hand-foot syndrome prophylaxis in patients treated with capecitabine.

Cardiotoxicity:Cardiotoxicityhasbeenassociatedwithfluoropyrimidinetherapy,including myocardialinfarction,angina,dysrhythmias,cardiogenicshock,suddendeathand electrocardiographic changes(includingveryrarecasesofQTprolongation).Theseadversereactions maybemorecommoninpatientswithapriorhistoryofcoronaryarterydisease.Cardiacarrhythmias (includingventricularfibrillation,torsadedepointes,andbradycardia),anginapectoris,myocardial infarction,heartfailureandcardiomyopathyhavebeenreportedinpatientsreceivingcapecitabine. Cautionmustbeexercisedinpatientswithhistoryofsignificantcardiacdisease,arrhythmiasand anginapectoris(seesection 4.8).

Hypo-orhypercalcaemia:Hypo-orhypercalcaemiahasbeenreportedduringcapecitabinetreatment. Cautionmustbeexercisedinpatientswithpre-existinghypo-orhypercalcaemia(seesection 4.8).

Centralorperipheralnervoussystemdisease:Cautionmustbeexercisedinpatientswithcentralor peripheralnervoussystemdisease,e.g.brainmetastasisorneuropathy(seesection 4.8).

Diabetesmellitusorelectrolytedisturbances:Cautionmustbeexercisedinpatientswithdiabetes mellitusorelectrolytedisturbances,asthesemaybeaggravatedduringcapecitabinetreatment.

Coumarin-derivativeanticoagulation:Inadruginteractionstudywithsingle-dosewarfarin administration,therewasa significantincreaseinthemeanAUC(+57%)ofS‑warfarin.Theseresults suggestaninteraction,probablyduetoaninhibitionofthecytochromeP450 2C9isoenzymesystem bycapecitabine.Patientsreceivingconcomitantcapecitabineandoralcoumarin-derivative anticoagulanttherapyshouldhavetheiranticoagulantresponse(INRorprothrombintime)monitored closelyandtheanticoagulantdoseadjustedaccordingly(seesection 4.5).

Hepaticimpairment:Intheabsenceofsafetyandefficacydatainpatientswithhepaticimpairment, Capecitabineuseshouldbecarefullymonitoredinpatientswithmildtomoderateliverdysfunction, regardlessofthepresenceorabsenceoflivermetastasis.Administrationofcapecitabineshouldbe interruptediftreatment-relatedelevationsinbilirubinof> 3.0 x ULNortreatment-relatedelevationsin hepaticaminotransferases(ALT,AST)of> 2.5 x ULNoccur.Treatmentwithcapecitabine monotherapymayberesumedwhenbilirubindecreasesto≤ 3.0 x ULNorhepaticaminotransferases decreaseto≤ 2.5 x ULN.

Renalimpairment:Theincidenceofgrade 3or4adversereactionsinpatientswithmoderaterenal impairment(creatinineclearance3050 ml/min)isincreasedcomparedtotheoverallpopulation(see sections 4.2and4.3).

DPDdeficiency:Rarely,unexpected,severetoxicity(e.g.stomatitis,diarrhoea,neutropeniaand neurotoxicity)associatedwith5‑FUhasbeenattributedtoadeficiencyofDPDactivity.Alink betweendecreasedlevelsofDPDandincreased,potentiallyfataltoxiceffectsof5‑FUtherefore cannotbeexcluded.

PatientswithknownDPDdeficiencyshouldnotbetreatedwithcapecitabine(seesection 4.3).In patientswithunrecognisedDPDdeficiencytreatedwithcapecitabine,life-threateningtoxicities manifestingasacuteoverdosemayoccur(seesection 4.9).Intheeventofgrade 24acutetoxicity, treatmentmustbediscontinuedimmediatelyuntilobservedtoxicityresolves.Permanent discontinuationshouldbeconsideredbasedonclinicalassessmentoftheonset,durationandseverity oftheobservedtoxicities.

Ophthalmologic complications:Patients should be carefully monitored for ophthalmological complications such as keratitis and corneal disorders, especially if they have a prior history of eye disorders. Treatment of eye disorders should be initiated as clinically appropriate.

Severe skin reactions:Capecitabine can induce severe skin reactions such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis. Capecitabine Orion should be permanently discontinued in patients who experience a severe skin reaction during treatment.

Asthismedicinalproductcontainsanhydrouslactoseasanexcipient,patientswithrarehereditary problemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactosemalabsorption shouldnottakethismedicine.

4.5 Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionstudieshaveonlybeenperformedinadults.

Interactionwithothermedicinalproducts

Cytochrome P450 2C9 substrates:Otherthanwarfarin,noformaldrug-druginteractionstudies betweencapecitabineandotherCYP2C9substrateshavebeenconducted.Careshouldbeexercised whencapecitabineisco-administeredwith2C9substrates(e.g.,phenytoin).Seealsointeractionwith coumarin-derivativeanticoagulantsbelow,andsection 4.4.

Coumarin-derivativeanticoagulants:Alteredcoagulationparametersand/orbleedinghavebeen reportedinpatientstakingcapecitabineconcomitantlywithcoumarin-derivativeanticoagulantssuch aswarfarinandphenprocoumon.Thesereactionsoccurredwithinseveraldaysanduptoseveral monthsafterinitiatingcapecitabinetherapyand,inafewcases,withinonemonthafterstopping capecitabine.Inaclinicalpharmacokineticinteractionstudy,afterasingle20 mgdoseofwarfarin, capecitabinetreatmentincreasedtheAUCofS‑warfarinby57%witha91%increaseinINRvalue. SincemetabolismofR‑warfarinwasnotaffected,theseresultsindicatethatcapecitabinedown- regulatesisozyme2C9,buthasnoeffectonisozymes1A2and3A4.Patientstakingcoumarin- derivativeanticoagulantsconcomitantlywithcapecitabineshouldbemonitoredregularlyfor alterationsintheircoagulationparameters(PTorINR)andtheanti-coagulantdoseadjusted accordingly.

Phenytoin:Increasedphenytoinplasmaconcentrationsresultinginsymptomsofphenytoin intoxicationinsinglecaseshavebeenreportedduringconcomitantuseofcapecitabinewithphenytoin. Patientstakingphenytoinconcomitantlywithcapecitabineshouldberegularlymonitoredforincreased phenytoinplasmaconcentrations.

Folinicacid/folicacid:Acombinationstudywithcapecitabineandfolinicacidindicatedthatfolinicacidhasno majoreffectonthepharmacokineticsofcapecitabineanditsmetabolites.However,folinicacidhasan effectonthepharmacodynamicsofcapecitabineanditstoxicitymaybeenhancedby folinicacid:the maximumtolerateddose(MTD)ofcapecitabinealoneusingtheintermittentregimenis 3,000 mg/m²per daywhereasitisonly2,000 mg/m²perdaywhencapecitabinewascombinedwithfolinicacid (30 mgorallybid). The enhanced toxicity may be relevant when switching from 5-FU/LV to a capecitabine regimen. This may also be relevant with folic acid supplementation for folate deficiency due to the similarity between folinic acid and folic acid.

Sorivudineandanalogues:Aclinicallysignificantdrug-druginteractionbetweensorivudineand5‑FU, resultingfromtheinhibitionofdihydropyrimidinedehydrogenaseby sorivudine,hasbeendescribed. Thisinteraction,whichleadstoincreasedfluoropyrimidinetoxicity,ispotentiallyfatal.Therefore, capecitabinemustnotbeadministeredconcomitantlywithsorivudineoritschemicallyrelated analogues,suchasbrivudine(seesection 4.3).Theremustbeatleasta4‑weekwaitingperiodbetween endoftreatmentwithsorivudineoritschemicallyrelatedanaloguessuchasbrivudineandstartof capecitabinetherapy.

Antacid:Theeffectofanaluminumhydroxideandmagnesiumhydroxide-containingantacidonthe pharmacokineticsofcapecitabinewasinvestigated.Therewasasmallincreaseinplasma concentrationsofcapecitabineandonemetabolite(5’-DFCR);therewasnoeffectonthe3major metabolites(5’‑DFUR,5‑FUandFBAL).

Allopurinol:Interactionswithallopurinolhavebeenobservedfor5‑FU;withpossibledecreased efficacyof5‑FU.Concomitantuseofallopurinolwithcapecitabineshouldbeavoided.

Interferonalpha:TheMTDofcapecitabinewas2,000 mg/m²perdaywhencombinedwithinterferon alpha‑2a(3 MIU/m²perday)comparedto3,000 mg/m²perdaywhencapecitabinewasusedalone.

Radiotherapy:TheMTDofcapecitabinealoneusingtheintermittentregimenis3,000 mg/m²perday, whereas,whencombinedwithradiotherapyforrectalcancer,theMTDofcapecitabineis2,000 mg/m²perdayusingeitheracontinuousscheduleorgivendailyMondaythroughFridayduringa 6‑week courseofradiotherapy.

Oxaliplatin:Noclinicallysignificantdifferencesinexposuretocapecitabineoritsmetabolites,free platinumortotalplatinumoccurredwhencapecitabinewasadministeredincombinationwith oxaliplatinorincombinationwithoxaliplatinandbevacizumab.

Bevacizumab:therewasnoclinicallysignificanteffectofbevacizumabonthepharmacokinetic parametersofcapecitabineoritsmetabolitesinthepresenceofoxaliplatin.

Foodinteraction

Inallclinicaltrials,patientswereinstructedtoadministercapecitabinewithin30 minutesaftera meal. Sincecurrentsafetyandefficacydataarebaseduponadministrationwithfood,itisrecommendedthat capecitabinebeadministeredwithfood.Administrationwithfooddecreasestherateofcapecitabine absorption(seesection 5.2).

4.6 Fertility,pregnancyandlactation

Womenofchildbearingpotential/Contraceptioninmalesandfemales

Womenofchildbearingpotentialshouldbeadvisedtoavoidbecomingpregnantwhilereceiving treatmentwithcapecitabine.Ifthepatientbecomespregnantwhilereceivingcapecitabine,thepotentialhazardtothefoetusmustbeexplained.Aneffectivemethodofcontraceptionshouldbeusedduring treatment.

Pregnancy

Therearenostudiesinpregnantwomenusingcapecitabine;however,itshouldbeassumedthat capecitabinemaycausefoetalharmifadministeredtopregnantwomen.Inreproductivetoxicity studiesinanimals,capecitabineadministrationcausedembryolethalityandteratogenicity.These findingsareexpectedeffectsoffluoropyrimidinederivatives.Capecitabineiscontraindicatedduring pregnancy.

Breast-feeding

Itisnotknownwhethercapecitabineisexcretedinhumanbreastmilk.Inlactatingmice,considerable amountsofcapecitabineanditsmetaboliteswerefoundinmilk.Breast-feedingshouldbediscontinued whilereceivingtreatmentwithcapecitabine.

Fertility

Thereisnodataoncapecitabine andimpactonfertility.Thecapecitabine pivotalstudiesincludedfemalesof childbearingpotentialandmalesonlyiftheyagreedtouseanacceptablemethodofbirthcontrolto avoidpregnancyforthedurationofthestudyandforareasonableperiodthereafter.

Inanimalstudies effectsonfertilitywereobserved(seesection 5.3).

4.7 Effectsonabilitytodriveandusemachines

Capecitabinehasminorormoderateinfluenceontheabilitytodriveandusemachines.Capecitabine maycausedizziness,fatigueandnausea.

4.8 Undesirableeffects

Summaryofthesafetyprofile

Theoverallsafetyprofileofcapecitabineisbasedondatafromover3,000 patientstreatedwith capecitabineasmonotherapyorcapecitabineincombinationwithdifferentchemotherapyregimensin multipleindications.Thesafetyprofilesofcapecitabinemonotherapyforthemetastaticbreastcancer, metastaticcolorectalcancerandadjuvantcoloncancerpopulationsarecomparable.Seesection 5.1for detailsof majorstudies,includingstudydesignsandmajorefficacyresults.

Themostcommonlyreportedand/orclinicallyrelevanttreatment-relatedadversedrugreactions (ADRs)weregastrointestinaldisorders(especiallydiarrhoea,nausea,vomiting,abdominalpain, stomatitis),handfootsyndrome(palmar-plantarerythrodysesthesia),fatigue,asthenia,anorexia, cardiotoxicity,increasedrenaldysfunctiononthosewithpreexistingcompromisedrenalfunction,and thrombosis/embolism.

_Tabulated_summ_a_ry_of_adverse_re_a_ctions

ADRsconsideredbytheinvestigatortobepossibly,probably,orremotelyrelatedtothe administrationofcapecitabinearelistedinTable 4forcapecitabinegivenasmonotherapyandinTable 5forcapecitabinegivenincombinationwithdifferentchemotherapyregimensin multipleindications. ThefollowingheadingsareusedtoranktheADRsbyfrequency:verycommon(≥ 1/10),common (≥ 1/100 to< 1/10),uncommon(≥ 1/1,000 to< 1/100),rare(≥ 1/10,000to< 1/1,000),veryrare (< 1/10,000).Withineachfrequencygrouping,ADRsarepresentedinorderofdecreasingseriousness.

Capecitabinemonotherapy

Table 4listsADRsassociatedwiththeuseofcapecitabinemonotherapybasedonapooledanalysisof safetydatafromthreemajorstudiesincludingover1,900 patients(studiesM66001,SO14695,and SO14796).ADRsareaddedtotheappropriatefrequencygroupingaccordingtotheoverallincidence fromthepooledanalysis.

Table 4: SummaryofrelatedADRsreportedinpatientstreatedwithcapecitabinemonotherapy

Body system	Very common All grades	Common All grades	Uncommon Severe and/or life-threatening (grade 34) or considered medically relevant
Infections and infestations	-	Herpes viral infection, nasopharyngitis, lower respiratory tract infection	Sepsis, urinary tract infection, cellulitis, tonsillitis, pharyngitis, oral candidiasis, influenza, gastroenteritis, fungal infection, infection, tooth abscess
Neoplasm benign, malignant and unspecified	-	-	Lipoma
Blood and lymphatic system disorders	-	Neutropenia, anaemia	Febrile neutropenia, pancytopenia, granulocytopenia, thrombocytopenia, leukopenia, haemolytic anaemia, international normalised ratio (INR) increased/prothrombin time prolonged
Immune system disorders	-	-	Hypersensitivity
Metabolism and nutrition disorders	Anorexia	Dehydration, weight decreased	Diabetes, hypokalaemia, appetite disorder, malnutrition, hypertriglyceridaemia
Psychiatric disorders	-	Insomnia, depression	Confusional state, panic attack, depressed mood, libido decreased
Nervous system disorders	-	Headache, lethargy, dizziness, paraesthesia, dysgeusia	Aphasia, memory impairment, ataxia, syncope, balance disorder, sensory disorder, neuropathy peripheral
Eye disorders	-	Lacrimation increased, conjunctivitis, eye irritation	Visual acuity reduced, diplopia
Ear and labyrinth disorders	-	-	Vertigo, ear pain
Cardiac disorders	-	-	Angina unstable, angina pectoris, myocardial ischaemia, atrial fibrillation, arrhythmia, tachycardia, sinus tachycardia, palpitations
Vascular disorders	-	Thrombophlebitis	Deep vein thrombosis, hypertension, petechiae, hypotension, hot flush, peripheral coldness
Respiratory, thoracic and mediastinal disorders	-	Dyspnoea, epistaxis, cough, rhinorrhoea	Pulmonary embolism, pneumothorax, haemoptysis, asthma, dyspnoea exertional
Gastrointestinal disorders	Diarrhoea, vomiting, nausea, stomatitis, abdominal pain	Gastrointestinal haemorrhage, constipation, upper abdominal pain, dyspepsia, flatulence, dry mouth	Intestinal obstruction, ascites, enteritis, gastritis, dysphagia, abdominal pain lower, oesophagitis, abdominal discomfort, gastroesophageal reflux disease, colitis, blood in stool
Hepatobiliary disorders	-	Hyperbilirubinaemia, liver function test abnormalities	Jaundice
Skin and subcutaneous tissue disorders	Palmar-plantar erythrodysaesthesia syndrome	Rash, alopecia, erythema, dry skin, pruritus, skin hyperpigmentation, rash macular, skin desquamation, dermatitis, pigmentation disorder, nail disorder	Blister, skin ulcer, rash, urticaria, photosensitivity reaction, palmar erythema, swelling face, purpura, radiation recall syndrome
Musculoskeletal and connective tissue disorders	-	Pain in extremity, back pain, arthralgia	Joint swelling, bone pain, facial pain, musculoskeletal stiffness, muscular weakness
Renal and urinary disorders	-	-	Hydronephrosis, urinary incontinence, haematuria, nocturia, blood creatinine increased
Reproductive system and breast disorders	-	-	Vaginal haemorrhage
General disorders and administration site conditions	Fatigue, asthenia	Pyrexia, oedema peripheral, malaise, chest pain	Oedema, chills, influenza-like illness, rigors, body temperature increased

Capecitabineincombinationtherapy

Table 5listsADRsassociatedwiththeuseofcapecitabineincombinationwithdifferentchemotherapyregimensin multipleindicationsbasedonsafetydatafromover3,000 patients.ADRsareaddedtothe appropriatefrequencygrouping(verycommonorcommon)accordingtothehighest incidenceseeninanyofthemajorclinicaltrialsandareonlyaddedwhentheywereseeninaddition tothoseseenwithcapecitabinemonotherapyorseenatahigherfrequencygroupingcomparedto capecitabinemonotherapy(seeTable 4).UncommonADRsreportedforcapecitabineincombination therapyareconsistentwiththeADRsreportedforcapecitabinemonotherapyorreportedfor monotherapywiththecombinationmedicinalproduct(inliteratureand/orrespectivesummaryof productcharacteristics).

SomeoftheADRsarereactionscommonlyseenwiththecombinationmedicinalproduct(e.g. peripheralsensoryneuropathywithdocetaxeloroxaliplatin,hypertensionseenwithbevacizumab); howeveranexacerbationbycapecitabinetherapycannotbeexcluded.

Table 5: SummaryofrelatedADRsreportedinpatientstreatedwithcapecitabineincombination treatmentinadditiontothoseseenwithcapecitabinemonotherapyorseenatahigher frequencygroupingcomparedtocapecitabinemonotherapy

Body system	Very common All grades	Common All grades
Infections and infestations	-	Herpes zoster, urinary tract infection, oral candidiasis, upper respiratory tract infection, rhinitis, influenza, ⁺infection, oral herpes
Blood and lymphatic system disorders	⁺Neutropenia, ⁺leukopenia, ⁺anaemia, ⁺neutropenic fever, thrombocytopenia	Bone marrow depression, ⁺febrile neutropenia
Immune system disorders	-	Hypersensitivity
Metabolism and nutrition disorders	Appetite decreased	Hypokalaemia, hyponatraemia, hypomagnesaemia, hypocalcaemia, hyperglycaemia
Psychiatric disorders	-	Sleep disorder, anxiety
Nervous system disorders	Paraesthesia, dysaesthesia, peripheral neuropathy, peripheral sensory neuropathy, dysgeusia, headache	Neurotoxicity, tremor, neuralgia, hypersensitivity reaction, hypoaesthesia
Eye disorders	Lacrimation increased	Visual disorders, dry eye, eye pain, visual impairment, vision blurred
Ear and labyrinth disorders	-	Tinnitus, hypoacusis
Cardiac disorders	-	Atrial fibrillation, cardiac ischaemia/infarction
Vascular disorders	Lower limb oedema, hypertension, ⁺embolism and thrombosis	Flushing, hypotension, hypertensive crisis, hot flush, phlebitis
Respiratory, thoracic and mediastinal system disorders	Sore throat, dysaesthesia pharynx	Hiccups, pharyngolaryngeal pain, dysphonia
Gastrointestinal disorders	Constipation, dyspepsia	Upper gastrointestinal haemorrhage, mouth ulceration, gastritis, abdominal distension, gastroesophageal reflux disease, oral pain, dysphagia, rectal haemorrhage, abdominal pain lower, oral dysaesthesia, paraesthesia oral, hypoaesthesia oral, abdominal discomfort
Hepatobiliary disorders	-	Hepatic function abnormal
Skin and subcutaneous tissue disorders	Alopecia, nail disorder	Hyperhidrosis, rash erythematous, urticaria, night sweats
Musculoskeletal and connective tissue disorders	Myalgia, arthralgia, pain in extremity	Pain in jaw, muscle spasms, trismus, muscular weakness
Renal and urinary disorders	-	Haematuria, proteinuria, creatinine renal clearance decreased, dysuria
General disorders and administration site conditions	Pyrexia, weakness, ⁺lethargy, temperature intolerance	Mucosal inflammation, pain in limb, pain, chills, chest pain, influenza-like illness, ⁺fever, infusion-related reaction, injection site reaction, infusion site pain, injection site pain
Injury, poisoning and procedural complications	-	Contusion

⁺Foreachterm,thefrequencycountwasbasedonADRsofallgrades.Fortermsmarkedwitha“+”, thefrequencycountwasbasedongrade 34ADRs.ADRsareaddedaccordingtothehighest incidenceseeninanyofthemajorcombinationtrials.

Post-marketingexperience

Thefollowingadditionalseriousadversereactionshavebeenidentifiedduringpost-marketing exposure:

_{Table 6: Summary}_of_events_reported_with_capecitabine_in_the_{post-marketing}_setting

Body system	Rare	Very rare
Eye disorders	Lacrimal duct stenosis, corneal disorders, keratitis, punctate keratitis
Cardiac disorders	Ventricular fibrillation, QT prolongation, torsade de pointes, bradycardia, vasospasm
Hepatobiliary disorders	Hepatic failure, cholestatic hepatitis
Skin and subcutaneous disorders	Cutaneous lupus erythematosus	Severe skin reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (see section 4.4)
Renal and urinary disorders	Acute renal failure secondary to dehydration

_Des_c_ription_of_selec_t_ed_adverse_r_e_actions

_Hand_foot_syndrome_(see_section_4.4)

Forthecapecitabinedoseof1,250 mg/m²twicedailyondays 1to14every3 weeks,afrequencyof 53%to60%ofall-gradesHFSwasobservedincapecitabinemonotherapytrials(comprisingstudiesin adjuvanttherapyincoloncancer,treatmentofmetastaticcolorectalcancer,andtreatmentofbreast cancer)anda frequencyof63%wasobservedinthecapecitabine/docetaxelarmforthetreatmentof metastaticbreastcancer.Forthecapecitabinedoseof1,000 mg/m²twicedailyondays 1to14every3 weeks,afrequencyof22%to30%ofall-gradeHFSwasobservedincapecitabinecombination therapy.

Ameta-analysisof14 clinicaltrialswithdatafromover4,700 patientstreatedwithcapecitabine monotherapyorcapecitabineincombinationwithdifferentchemotherapyregimensinmultiple indications(colon,colorectal,gastricandbreastcancer)showedthatHFS(allgrades)occurredin 2,066(43%)patientsaftera mediantimeof239[95%CI201,288]daysafterstartingtreatmentwith capecitabine.Inallstudiescombined,thefollowingcovariateswerestatisticallysignificantly associated withanincreasedriskofdevelopingHFS:increasingcapecitabinestartingdose(gram), decreasingcumulativecapecitabinedose(0.1*kg),increasingrelativedoseintensityinthefirstsix weeks,increasingdurationofstudytreatment(weeks),increasingage(by10‑yearincrements),female gender,andgoodECOGperformancestatusatbaseline(0versus≥ 1).

Diarrhoea(seesection 4.4)

Capecitabinecaninducetheoccurrenceofdiarrhoea,whichhasbeenobservedinupto50%of patients.

Theresultsofa meta-analysisof14 clinicaltrialswithdatafromover4,700 patientstreatedwith capecitabineshowedthatinallstudiescombined,thefollowingcovariateswerestatistically significantlyassociatedwithanincreasedriskofdevelopingdiarrhoea:increasingcapecitabinestarting dose(gram),increasingdurationofstudytreatment(weeks),increasingage(by10‑yearincrements), andfemalegender.Thefollowingcovariateswerestatisticallysignificantlyassociatedwitha decreasedriskofdevelopingdiarrhoea:increasingcumulativecapecitabinedose(0.1*kg)and increasingrelativedoseintensityinthefirstsixweeks.

Cardiotoxicity(seesection 4.4)

InadditiontotheADRsdescribedinTables 4and5,thefollowingADRswithanincidenceoflessthan 0.1%wereassociatedwiththeuseofcapecitabinemonotherapybasedonapooledanalysisfrom clinicalsafetydatafrom7 clinicaltrialsincluding949 patients(2 phase IIIand5 phase IIclinicaltrials inmetastaticcolorectalcancerandmetastaticbreastcancer):cardiomyopathy,cardiacfailure,sudden death,andventricularextrasystoles.

Encephalopathy

InadditiontotheADRsdescribedinTables4 and5,andbasedontheabovepooledanalysisfrom clinicalsafetydatafrom7 clinicaltrials,encephalopathywasalsoassociatedwiththeuseof capecitabinemonotherapywithanincidenceoflessthan0.1%.

Specialpopulations

Elderlypatients(seesection 4.2)

Ananalysisofsafetydatainpatients≥ 60 yearsofagetreatedwithcapecitabinemonotherapy andan analysisofpatientstreatedwithcapecitabineplusdocetaxelcombinationtherapyshowedanincrease intheincidenceoftreatment-relatedgrade 3and4adversereactionsandtreatment-relatedserious adversereactions compared topatients< 60 yearsofage.Patients≥ 60 yearsofagetreatedwith capecitabine plusdocetaxelalsohadmoreearlywithdrawals fromtreatmentduetoadversereactions comparedtopatients< 60 yearsofage.

Theresultsofameta-analysisof14 clinicaltrialswithdatafromover4,700 patientstreatedwith capecitabineshowedthatinallstudiescombined,increasingage(by10‑yearincrements) was statisticallysignificantly associated withanincreasedriskofdevelopingHFSanddiarrhoeaandwitha decreasedriskofdevelopingneutropenia.

Gender

Theresultsofameta-analysisof14 clinicaltrialswithdatafromover4,700 patientstreatedwith capecitabine showedthatinallstudiescombined, femalegenderwasstatisticallysignificantly associatedwithanincreasedriskofdeveloping HFSanddiarrhoeaandwithadecreasedriskof developingneutropenia.

Patientswithrenalimpairment(seesections 4.2,4.4,and5.2)

Ananalysisofsafetydatainpatientstreatedwithcapecitabinemonotherapy(colorectalcancer)with baselinerenalimpairmentshowedanincreaseintheincidenceoftreatment-relatedgrade 3and4 adversereactionscomparedtopatientswithnormalrenalfunction(36%inpatientswithoutrenal impairmentn = 268,vs.41%in mildn = 257and54%in moderaten = 59,respectively)(seesection 5.2). Patientswithmoderatelyimpairedrenalfunctionshowanincreasedrateofdosereduction(44%)vs. 33%and32%inpatientswithnoormildrenalimpairmentandanincreaseinearlywithdrawalsfrom treatment(21%withdrawalsduringthefirsttwocycles)vs.5%and8%inpatientswithnoormild renalimpairment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

Themanifestationsofacuteoverdoseincludenausea,vomiting,diarrhoea,mucositis,gastrointestinal irritationandbleeding,andbonemarrowdepression.Medicalmanagementofoverdoseshouldinclude customarytherapeuticandsupportivemedicalinterventionsaimedatcorrectingthepresentingclinical manifestationsandpreventingtheirpossiblecomplications.

5. PHARMACOLOGICALPROPERTIES

5.1 Pharmacodynamicproperties

Pharmacotherapeuticgroup:cytostatic(antimetabolite),ATCcode:L01BC06

Capecitabineisanon-cytotoxicfluoropyrimidinecarbamate,whichfunctionsasanorally administeredprecursorofthecytotoxicmoiety5‑fluorouracil(5‑FU).Capecitabineisactivatedvia severalenzymaticsteps(seesection 5.2).Theenzymeinvolvedinthefinalconversionto5‑FU, thymidinephosphorylase(ThyPase),isfoundintumourtissues,butalsoinnormaltissues,albeit usuallyatlowerlevels.In humancancerxenograftmodelscapecitabinedemonstratedasynergistic effectincombinationwithdocetaxel,whichmayberelatedtotheup-regulationofthymidine phosphorylasebydocetaxel.

Thereisevidencethatthemetabolismof5‑FUintheanabolicpathwayblocksthemethylation reaction ofdeoxyuridylicacidtothymidylicacid,therebyinterferingwiththesynthesisof deoxyribonucleicacid(DNA).Theincorporationof5‑FUalsoleadstoinhibitionofRNAandprotein synthesis.SinceDNAandRNAareessentialforcelldivisionandgrowth,theeffectof5‑FUmaybe to createathymidinedeficiencythatprovokesunbalancedgrowthanddeathofacell.Theeffectsof DNAandRNAdeprivationaremostmarkedonthosecellswhichproliferatemorerapidlyandwhich metabolise5‑FUata morerapidrate.

Colonandcolorectalcancer

Monotherapywithcapecitabineinadjuvantcoloncancer

Datafromonemulticentre,randomised,controlledphase IIIclinicaltrialinpatientswithstage III (Dukes’ C)coloncancersupportstheuseofcapecitabinefortheadjuvanttreatmentofpatientswith coloncancer(XACTStudy;M66001).Inthistrial,1,987 patientswererandomisedtotreatmentwith capecitabine(1,250 mg/m²twicedailyfor2 weeksfollowedby a1‑weekrestperiodandgivenas3‑weekcyclesfor24 weeks)or5‑FUandleucovorin(MayoClinicregimen:20 mg/m²leucovorinIV followedby425 mg/m²IVbolus5‑FU,ondays 1to5,every28 daysfor24 weeks).Capecitabinewas atleastequivalenttoIV5‑FU/LVindisease-freesurvivalinperprotocolpopulation(hazardratio 0.92;95%CI0.801.06).Intheall-randomisedpopulation,testsfordifferenceofcapecitabinevs.5‑FU/LVindisease-freeandoverallsurvivalshowedhazardratiosof0.88(95%CI0.77–1.01;p = 0.068)and0.86(95%CI 0.74–1.01;p = 0.060),respectively.Themedianfollow-upatthetimeofthe analysiswas6.9 years.InapreplannedmultivariateCoxanalysis,superiorityofcapecitabine comparedwithbolus5‑FU/LVwasdemonstrated.Thefollowingfactorswerepre-specifiedinthe statisticalanalysisplanforinclusioninthemodel:age,timefromsurgerytorandomization,gender, CEAlevelsatbaseline,lymphnodesatbaseline,andcountry.Intheall-randomisedpopulation, capecitabinewasshowntobesuperiorto5‑FU/LVfordisease-freesurvival(hazardratio0.849;95% CI0.7390.976;p = 0.0212),aswellasforoverallsurvival(hazardratio0.828;95%CI0.7050.971;p = 0.0203).

Combinationtherapyinadjuvantcoloncancer

Datafromonemulticentre,randomised,controlledphase IIIclinicaltrialinpatientswithstage III (Dukes’ C)coloncancersupportstheuseofcapecitabineincombinationwithoxaliplatin(XELOX) fortheadjuvanttreatmentofpatientswithcoloncancer(NO16968study).Inthistrial,944 patients wererandomisedto3‑weekcyclesfor24 weekswithcapecitabine(1,000 mg/m²twicedailyfor2 weeksfollowedby a1‑weekrestperiod)incombinationwithoxaliplatin(130 mg/m²intravenous infusionover2 hoursonday 1every3 weeks);942 patientswererandomizedtobolus5‑FUand leucovorin.IntheprimaryanalysisforDFSintheITTpopulation,XELOXwasshowntobe significantlysuperiorto5‑FU/LV(HR = 0.80,95%CI = [0.69;0.93];p = 0.0045).The3‑yearDFSrate was 71%forXELOXversus67%for5‑FU/LV.TheanalysisforthesecondaryendpointofRFS supportstheseresultswithaHRof0.78(95%CI = [0.67;0.92];p = 0.0024)forXELOXvs.5‑FU/LV. XELOXshowedatrendtowardssuperiorOSwitha HRof0.87(95%CI = [0.72;1.05];p = 0.1486) whichtranslatesintoa13%reductioninriskofdeath.The5‑yearOSratewas78%forXELOXversus 74%for5‑FU/LV.Theefficacydataisbasedonamedianobservationtimeof59 monthsforOSand 57 monthsforDFS.TherateofwithdrawalduetoadverseeventswashigherintheXELOX combinationtherapyarm(21%)ascomparedwiththatofthe5‑FU/LVmonotherapyarm(9%)inthe ITTpopulation.

Monotherapywithcapecitabineinmetastaticcolorectalcancer

Datafromtwoidentically-designed,multicentre,randomised,controlledphase IIIclinicaltrials (SO14695;SO14796)supporttheuseofcapecitabineforfirst-linetreatmentofmetastaticcolorectal cancer.Inthesetrials,603 patientswererandomisedtotreatmentwithcapecitabine(1,250 mg/m²twice dailyfor2 weeksfollowedby a1‑weekrestperiodandgivenas3‑weekcycles).604 patientswere randomisedtotreatmentwith5‑FUandleucovorin(Mayoregimen:20 mg/m²leucovorinIVfollowed by 425 mg/m²IVbolus5‑FU,ondays 1to5,every28 days).Theoverallobjectiveresponseratesin theall-randomisedpopulation(investigatorassessment)were25.7%(capecitabine)vs.16.7%(Mayo regimen);p < 0.0002.Themediantimetoprogressionwas140 days(capecitabine)vs.144 days(Mayo regimen).Mediansurvivalwas392 days(capecitabine)vs.391 days(Mayoregimen).Currently,no comparativedataareavailableoncapecitabinemonotherapyincolorectalcancerincomparisonwith first-linecombinationregimens.

Combinationtherapyinfirst-linetreatmentofmetastaticcolorectalcancer

Datafromamulticentre,randomised,controlledphase IIIclinicalstudy(NO16966)supporttheuseof capecitabineincombinationwithoxaliplatinorincombinationwithoxaliplatinandbevacizumabfor thefirst-linetreatmentofmetastaticcolorectalcancer.Thestudycontainedtwoparts:aninitial2‑arm partinwhich634 patientswererandomisedtotwodifferenttreatmentgroups,includingXELOXor FOLFOX-4,andasubsequent2 x 2factorialpartinwhich1,401 patientswererandomisedtofour differenttreatmentgroups,includingXELOXplusplacebo,FOLFOX-4plusplacebo,XELOXplus bevacizumab,andFOLFOX-4plusbevacizumab.SeeTable 7fortreatmentregimens.

Table 7: Treatment regimens in Study NO16966 (mCRC)

	Treatment	Starting dose	Schedule
FOLFOX‑4 or FOLFOX‑4 + bevacizumab	Oxaliplatin	85 mg/m² IV 2 h	Oxaliplatin on day 1, every 2 weeks Leucovorin on days 1 and 2, every 2 weeks 5‑fluorouracil IV bolus/infusion, each on days 1 and 2, every 2 weeks
	Leucovorin	200 mg/m² IV 2 h
	5‑fluorouracil	400 mg/m² IV bolus, followed by 600 mg/m² IV 22 h
	Placebo or bevacizumab	5 mg/kg IV 3090 min	Day 1, prior to FOLFOX‑4, every 2 weeks
XELOX or XELOX+ bevacizumab	Oxaliplatin	130 mg/m² IV 2 h	Oxaliplatin on day 1, every 3 weeks capecitabine oral twice daily for 2 weeks (followed by 1 week off- treatment)
	Capecitabine	1,000 mg/m² oral twice daily
	Placebo or bevacizumab	7.5 mg/kg IV 3090 min	Day 1, prior to XELOX, every 3 weeks
5‑fluorouracil: IV bolus injection immediately after leucovorin

Non-inferiorityoftheXELOX-containingarmscomparedwiththeFOLFOX-4-containingarmsinthe overallcomparisonwasdemonstratedintermsofprogression-freesurvivalintheeligiblepatient populationandtheintent-to-treatpopulation(seeTable 8).TheresultsindicatethatXELOXis equivalenttoFOLFOX-4intermsofoverallsurvival(seeTable 8).AcomparisonofXELOXplus bevacizumabversusFOLFOX-4plusbevacizumabwasapre-specifiedexploratoryanalysis.Inthis treatmentsubgroupcomparison,XELOXplusbevacizumabwassimilarcomparedtoFOLFOX-4plus bevacizumabintermsofprogression-freesurvival(hazardratio1.01;97.5%CI0.841.22).The medianfollow-upatthetimeoftheprimaryanalysesintheintent-to-treatpopulationwas1.5 years; datafromanalysesfollowinganadditional1 yearoffollow-uparealsoincludedinTable 8.However, theon-treatmentPFSanalysisdidnotconfirmtheresultsofthegeneralPFSandOSanalysis:the hazardratioofXELOXversusFOLFOX-4was1.24with97.5%CI1.071.44.Althoughsensitivity analysesshowthatdifferencesinregimenschedulesandtimingoftumourassessmentsimpacttheon- treatmentPFSanalysis,afullexplanationforthisresulthasnotbeenfound.

Table 8: Key efficacy results for the non-inferiority analysis of Study NO16966

PRIMARY ANALYSIS

XELOX/ XELOX+P/

XELOX+BV

(EPP*: N = 967; ITT**: N = 1,017)

FOLFOX-4/ FOLFOX-4+P

/FOLFOX-4+BV

(EPP*: N = 937; ITT**: N = 1,017)

Population

Median time to event (days)

HR (97.5% CI)

Parameter: Progression-free survival

EPP

ITT

241

244

259

1.05 (0.94; 1.18)

1.04 (0.93; 1.16)

Parameter: Overall survival

EPP

ITT

577

581

549

553

0.97 (0.84; 1.14)

0.96 (0.83; 1.12)

ADDITIONAL 1 YEAR OF FOLLOW-UP

Population

Median time to event (days)

HR (97.5% CI)

Parameter: Progression-free survival

EPP

ITT

242

244

259

1.02 (0.92; 1.14)

1.01 (0.91; 1.12)

Parameter: Overall survival

EPP

ITT

600

602

594

596

1.00 (0.88; 1.13)

0.99 (0.88; 1.12)

*EPP = eligible patient population; **ITT = intent-to-treat population.

Inarandomised,controlledphase III study(CAIRO),theeffectofusing capecitabineata startingdoseof1000 mg/m²for2 weeksevery3 weeksincombinationwithirinotecanforthefirst-linetreatmentofpatientswithmetastaticcolorectalcancer was studied.820 patientswererandomizedtoreceive eithersequentialtreatment(n = 410)orcombinationtreatment(n = 410).Sequentialtreatmentconsisted offirst-linetreatmentwithcapecitabine(1,250 mg/m²twicedailyfor14 days),second-lineirinotecan (350 mg/m²onday 1),andthird-linecombinationofcapecitabine(1,000 mg/m²twicedailyfor14 days)withoxaliplatin(130 mg/m²onday 1).Combinationtreatmentconsistedoffirst-linetreatment ofcapecitabine(1,000 mg/m²twicedailyfor14 days)combinedwithirinotecan(250 mg/m²onday 1)(XELIRI)andsecond-linecapecitabine(1,000 mg/m²twicedailyfor14 days)plusoxaliplatin (130 mg/m²onday 1).Alltreatmentcycleswereadministeredat intervalsof3 weeks.Infirst-line treatmentthemedianprogression-freesurvivalintheintent-to-treatpopulationwas5.8 months (95%CI5.16.2 months)forcapecitabinemonotherapyand7.8 months(95%CI7.08.3 months; p = 0.0002)forXELIRI. However this was associated with an increased incidence of gastrointestinal toxicity and neutropenia during first-line treatment with XELIRI (26% and 11% for XELIRI and first line capecitabine respectively).

The XELIRI has been compared with 5-FU + irinotecan (FOLFIRI) in three randomised studies in patients with metastatic colorectal cancer. The XELIRI regimens included capecitabine 1000 mg/m²twice daily on days 1 to 14 of a three-week cycle combined with irinotecan 250 mg/m²on day1. In the largest study (BICC-C), patients were randomised to receive either open label FOLFIRI (n=144), bolus 5-FU (mIFL) (n=145) or XELIRI (n=141) and were additionally randomised to receive either double-blind treatment with celecoxib or placebo. Median PFS was 7.6 months for FOLFIRI, 5.9 months for mIFL (p=0.004) for the comparison with FOLFIRI), and 5.8 months for XELIRI (p=0.015). Median OS was 23.1 months for FOLFIRI, 17.6 months for mIFL (p=0.09), and 18.9 months for XELIRI (p=0.27). Patients treated with XELIRI experienced excessive gastrointestinal toxicity compared with FOLFIRI (diarrhoea 48% and 14% for XELIRI and FOLFIRI respectively).

In the EORTC study patients were randomised to receive either open label FOLFIRI (n=41) or XELIRI (n=44) with additional randomisation to either double-blind treatment with celecoxib or placebo. Median PFS and overall survival (OS) times were shorter for XELIRI versus FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months), in addition to which excessive rates of diarrhoea were reported in patients receiving the XELIRI regimen (41% XELIRI, 5.1% FOLFIRI).

In the study published by Skof et al, patients were randomised to receive either FOLFIRI or XELIRI. Overall response rate was 49% in the XELIRI and 48% in the FOLFIRI arm (p=0.76). At the end of treatment, 37% of patients in the XELIRI and 26% of patients in the FOLFIRI arm were without evidence of the disease (p=0.56). Toxcity was similar between treatments with the exception of neutropenia reported more commonly in patients treated with FOLFIRI.

Montagnani et al used the results from the above three studies to provide an overallanalysis of randomised studies comparing FOLFIRI and XELIRI treatment regimens in the treatment of mCRC. A significant reduction in the risk of progression was associated with FOLFIRI (HR, 0.76; 95%CI, 0.62-0.95; P <0.01), a result partly due to poor tolerance to the XELIRI regimens used.

Data from a randomised clinical study (Souglakos et al, 2012) comparing FOLFIRI + bevacizumab with XELIRI + bevacizumab showed no significant differences in PFS or OS between treatments. Patients were randomised to receive either FOLFIRI plus bevacizumab (Arm-A, n=167) or XELIRI plus bevacizumab (Arm-B, n-166). For Arm B, the XELIRI regimen used capecitabine 1000 mg/m² twice daily for 14 days +irinotecan 250 mg/m² on day 1. Median progression-free survival (PFS) was 10.0 and 8.9 months; p=0.64, overall survival 25.7 and 27.5 months; p=0.55 and response rates 45.5 and 39.8%; p=0.32 for FOLFIRI-Bev and XELIRI-Bev, respectively. Patients treated with XELIRI + bevacizumab reported a significantly higher incidence of diarrhoea, febrile neutropenia and hand-foot skin reactions than patients treated with FOLFIRI + bevacizumab with significantly increased treatment delays, dose reductions and treatment discontinuations.

Data from a multicentre, randomised, controlled phaseII study (AIO KRK 0604)supportstheuseofcapecitabineatastartingdoseof800 mg/m²for2 weeksevery3 weeksin combinationwithirinotecanandbevacizumabforthefirst-linetreatmentofpatientswithmetastatic colorectalcancer.120 Patientswererandomisedtoa modified XELIRI regimenwithcapecitabine800 mg/m²twicedailyfortwoweeksfollowed by a7-dayrestperiod),irinotecan(200 mg/m²asa30 minuteinfusiononday 1every3 weeks),and bevacizumab(7.5 mg/kgasa30to90 minuteinfusiononday 1every3 weeks) ; 127 patients wererandomisedtotreatmentwithcapecitabine(1000 mg/m²twicedailyfortwoweeksfollowedby a7-dayrestperiod),oxaliplatin (130 mg/m²asa2 hourinfusiononday 1every3 weeks),andbevacizumab(7.5 mg/kgasa30to90 minuteinfusiononday 1every3 weeks).Following a mean duration of follow-up forthestudy populationof 26.2 months, treatment responses were as shown below:

Table 9 Key efficacy results for AIO KRK study

XELOX + bevacizumab

_(ITT:
N=127)

Modified XELIRI+

bevacizumab

_{(ITT:
N= 120)}

Hazard ratio

95% CI

_P
value

_{Progression-free Survival after 6 months}

ITT

_95%
CI

76%

_{69 -
84%}

84%

_{77 -
90%}

_{Median
progression free survival}

ITT

_95%
CI

10.4 months

_{9.0 -
12.0}

12.1 months

_{10.8 -
13.2}

0.93

0.82 - 1.07

_P=0.30

Median overall survival

ITT

95% CI

24.4 months

19.3 - 30.7

25.5 months

21.0 - 31.0

0.90

0.68 - 1.19

P=0.45

Combinationtherapyinsecond-linetreatmentofmetastaticcolorectalcancer

Datafromamulticentre,randomised,controlledphase IIIclinicalstudy(NO16967)supporttheuseof capecitabineincombinationwithoxaliplatinforthesecond-linetreatmentofmetastaticcolorectal cancer.Inthistrial,627 patientswithmetastaticcolorectalcarcinomawhohavereceivedprior treatmentwithirinotecanincombinationwithafluoropyrimidineregimenasfirst-linetherapywere randomisedtotreatmentwithXELOXorFOLFOX-4.ForthedosingscheduleofXELOXand FOLFOX-4(withoutadditionofplaceboorbevacizumab),referto Table 7.XELOXwasdemonstrated tobenon-inferiortoFOLFOX-4intermsofprogression-freesurvivalintheper-protocolpopulation andintent-to-treatpopulation(seeTable 10).TheresultsindicatethatXELOXisequivalentto FOLFOX-4intermsofoverallsurvival(seeTable 10).Themedianfollow-upatthetimeoftheprimary analysesintheintent-to-treatpopulationwas2.1 years;datafromanalysesfollowinganadditional6 monthsoffollow-uparealsoincludedinTable 10.

Table 10: Key efficacy results for the non-inferiority analysis of Study NO16967

PRIMARY ANALYSIS

XELOX

(PPP*: N = 251; ITT**: N = 313)

FOLFOX-4

(PPP*: N = 252; ITT**: N = 314)

Population

Median time to event (days)

HR (95% CI)

Parameter: Progression-free survival

PPP

ITT

154

144

168

146

1.03 (0.87; 1.24)

0.97 (0.83; 1.14)

Parameter: Overall survival

PPP

ITT

388

363

401

382

1.07 (0.88; 1.31)

1.03 (0.87; 1.23)

ADDITIONAL 6 MONTHS OF FOLLOW-UP

Population

Median time to event (days)

HR (95% CI)

Parameter: Progression-free survival

PPP

ITT

154

143

166

146

1.04 (0.87; 1.24)

0.97 (0.83; 1.14)

Parameter: Overall survival

PPP

ITT

393

363

402

382

1.05 (0.88; 1.27)

1.02 (0.86; 1.21)

*PPP = per-protocolpopulation; **ITT = intent-to-treatpopulation

_Advanced_gastric_can_c_er

Datafromamulticentre,randomised,controlledphase IIIclinicaltrialinpatientswithadvancedgastric cancersupportstheuseofcapecitabineforthefirst-linetreatmentofadvancedgastriccancer (ML17032).Inthistrial,160 patientswererandomisedtotreatmentwithcapecitabine(1,000 mg/m²twicedailyfor2 weeksfollowedby a7‑dayrestperiod)andcisplatin(80 mg/m²asa2‑hourinfusion every3 weeks).Atotalof156 patientswererandomisedtotreatmentwith5‑FU(800 mg/m²perday, continuousinfusionondays 1 to5every3 weeks)andcisplatin(80 mg/m²asa 2‑hourinfusiononday 1,every3 weeks).Capecitabineincombinationwithcisplatinwasnon-inferiorto5‑FUincombinationwithcisplatinintermsofprogression-freesurvivalintheperprotocolanalysis(hazardratio0.81;95% CI0.631.04).Themedianprogression-freesurvivalwas5.6 months(capecitabine+cisplatin)versus 5.0 months(5‑FU+cisplatin).Thehazardratiofordurationofsurvival(overallsurvival)wassimilarto thehazardratioforprogression-freesurvival(hazardratio0.85;95%CI0.641.13).Themediandurationofsurvivalwas10.5 months(capecitabine+cisplatin)versus9.3 months (5‑FU+cisplatin).

Datafromarandomisedmulticentre,phase IIIstudycomparingcapecitabineto5‑FUandoxaliplatin tocisplatininpatientswithadvancedgastriccancersupportstheuseofcapecitabineforthefirst-line treatmentofadvancedgastriccancer(REAL-2).Inthistrial,1,002 patientswererandomisedina2 x 2 factorialdesigntooneofthefollowing4 arms:

ECF: epirubicin (50 mg/m² as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m² as a 2‑hour infusion on day 1 every 3 weeks) and 5‑FU (200 mg/m² daily given by continuous infusion via a central line).
ECX: epirubicin (50 mg/m² as a bolus on day 1 every 3 weeks), cisplatin (60 mg/m² as a 2‑hour infusion on day 1 every 3 weeks), and capecitabine (625 mg/m² twice daily continuously).
EOF: epirubicin (50 mg/m² as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m² given as a 2‑hour infusion on day 1 every three weeks), and 5‑FU (200 mg/m² daily given by continuous infusion via a central line).
EOX: epirubicin (50 mg/m² as a bolus on day 1 every 3 weeks), oxaliplatin (130 mg/m² given as a 2‑hour infusion on day 1 every three weeks), and capecitabine (625 mg/m² twice daily continuously).

Theprimaryefficacyanalysesintheperprotocolpopulationdemonstratednon-inferiorityinoverall survivalforcapecitabine-vs.5‑FU-basedregimens(hazardratio0.86;95%CI0.80.99)andfor oxaliplatin-vs.cisplatin-basedregimens(hazardratio0.92;95%CI0.801.1).Themedianoverall survivalwas10.9 monthsincapecitabine-basedregimensand9.6 monthsin5‑FUbasedregimens. Themedianoverallsurvivalwas10.0 monthsincisplatin-basedregimensand10.4 monthsin oxaliplatin-basedregimens.

Capecitabinehasalsobeenusedincombinationwithoxaliplatinforthetreatmentofadvancedgastric cancer.Studieswithcapecitabinemonotherapyindicatethatcapecitabinehasactivityinadvanced gastriccancer.

Colon,colorectalandadvancedgastriccancer:meta-analysis

Ameta-analysisofsixclinicaltrials(studiesSO14695,SO14796,M66001,NO16966,NO16967, M17032)supportscapecitabinereplacing5‑FUinmono-andcombinationtreatmentingastrointestinal cancer.Thepooledanalysisincludes3,097 patientstreatedwithcapecitabine-containingregimensand 3,074 patientstreatedwith5‑FU-containingregimens.Medianoverallsurvivaltimewas703 days (95%CI:671;745)inpatientstreatedwithcapecitabine-containingregimensand683 days(95%CI: 646;715)inpatientstreatedwith5‑FU-containingregimens.Thehazardratioforoverallsurvivalwas 0.94(95%CI:0.89;1.00,p = 0.0489)indicatingthatcapecitabine-containingregimensarenon-inferiorto 5‑FU-containingregimens.

_Breast_cance_r

Combinationtherapywithcapecitabineanddocetaxelinlocallyadvancedormetastaticbreastcancer Datafromonemulticentre,randomised,controlledphase IIIclinicaltrialsupporttheuseof capecitabineincombinationwithdocetaxelfortreatmentofpatientswithlocallyadvancedor metastatic breastcancerafterfailureofcytotoxicchemotherapy,includingananthracycline.Inthis trial,255 patientswererandomisedtotreatmentwithcapecitabine(1,250 mg/m²twicedailyfor2 weeks followedby 1‑weekrestperiodanddocetaxel75 mg/m²as a1‑hourintravenousinfusionevery 3 weeks).256 patientswererandomisedtotreatmentwithdocetaxelalone(100 mg/m²asa1‑hour intravenousinfusionevery3 weeks).Survivalwassuperiorinthecapecitabine+docetaxel combinationarm(p = 0.0126).Mediansurvivalwas442 days(capecitabine+docetaxel)vs.352 days (docetaxelalone).Theoverallobjectiveresponseratesintheall-randomisedpopulation(investigator assessment)were41.6%(capecitabine+docetaxel)vs.29.7%(docetaxelalone);p = 0.0058.Timeto progressivediseasewassuperiorinthecapecitabine+docetaxelcombinationarm(p < 0.0001).The mediantimetoprogressionwas186 days(capecitabine+docetaxel)vs.128 days(docetaxelalone).

Monotherapywithcapecitabineafterfailureoftaxanes,anthracyclinecontainingchemotherapy,and forwhomanthracyclinetherapyisnotindicated

Datafromtwomulticentrephase IIclinicaltrialssupporttheuseofcapecitabinemonotherapyfor treatmentofpatientsafterfailureoftaxanesandananthracycline-containingchemotherapyregimenor forwhomfurtheranthracyclinetherapyisnotindicated.Inthesetrials,atotalof236 patientswere treatedwithcapecitabine(1,250 mg/m²twicedailyfor2 weeksfollowedby 1‑weekrestperiod).The overallobjectiveresponserates(investigatorassessment)were20%(firsttrial)and25%(secondtrial). Themediantimetoprogressionwas93and98 days.Mediansurvivalwas384and373 days.

Allindications

Paediatricpopulation

TheEuropeanMedicinesAgencyhaswaivedtheobligationtoconductstudieswiththe reference medicinal product containing capecitabineinall subsetsofthepaediatricpopulationinadenocarcinomaofthecolonandrectum,gastric adenocarcinomaandbreastcarcinoma(seesection 4.2forinformationonpaediatricuse).

5.2 Pharmacokineticproperties

Thepharmacokineticsofcapecitabinehavebeenevaluatedoveradoserangeof5023,514 mg/m²/day. Theparametersofcapecitabine,5'‑deoxy-5-fluorocytidine(5'‑DFCR)and5'‑deoxy‑5‑fluorouridine (5'‑DFUR)measuredondays 1and14weresimilar.TheAUCof5‑FUwas3035%higheronday 14.Capecitabinedosereductiondecreasessystemicexposureto5‑FUmorethandose-proportionally, duetonon-linearpharmacokineticsfortheactivemetabolite.

Absorption

Afteroraladministration,capecitabineisrapidlyandextensivelyabsorbed,followedbyextensive conversiontothemetabolites,5'‑DFCRand5'‑DFUR.Administrationwithfooddecreasestherateof capecitabineabsorption,butonlyresultsinaminoreffectontheAUCof5'‑DFUR,andontheAUCof thesubsequentmetabolite5‑FU.Atthedoseof1,250 mg/m²onday 14withadministrationafterfood intake,thepeakplasmaconcentrations(C_maxinµg/ml)forcapecitabine,5'‑DFCR,5'‑DFUR,5‑FUand FBALwere4.67,3.05,12.1,0.95and5.46respectively.Thetimetopeakplasmaconcentrations(t_maxinhours)were1.50,2.00,2.00,2.00and3.34.TheAUC₀_-∞valuesinµg•h/ml were7.75,7.24,24.6, 2.03and36.3.

Distribution

Invitrohumanplasmastudieshavedeterminedthatcapecitabine,5'‑DFCR,5'‑DFURand5‑FUare 54%,10%,62%and10%proteinbound,mainlytoalbumin.

Biotransformation

Capecitabineisfirstmetabolisedby hepaticcarboxylesteraseto5'-DFCR,whichisthenconvertedto 5'-DFURbycytidinedeaminase,principallylocatedintheliverandtumourtissues.Furthercatalytic activationof5'-DFURthenoccursby thymidinephosphorylase(ThyPase).Theenzymesinvolvedin thecatalyticactivationarefoundintumourtissuesbutalsoinnormaltissues,albeitusuallyatlower levels.Thesequentialenzymaticbiotransformationofcapecitabineto5‑FUleadstohigher concentrationswithintumourtissues.Inthecaseofcolorectaltumours,5‑FUgenerationappearstobe inlargepartlocalisedintumourstromalcells.Followingoraladministrationofcapecitabineto patientswithcolorectalcancer,theratioof5‑FUconcentrationincolorectaltumourstoadjacent tissueswas3.2(rangedfrom0.9to8.0).Theratioof5‑FUconcentrationintumourtoplasmawas21.4 (rangedfrom3.9to59.9,n = 8)whereastheratioinhealthytissuestoplasmawas8.9(rangedfrom3.0 to 25.8,n = 8).Thymidinephosphorylaseactivitywasmeasuredandfoundtobe4 timesgreaterin primarycolorectaltumourthaninadjacentnormaltissue.Accordingtoimmunohistochemicalstudies, thymidinephosphorylaseappearstobeinlargepartlocalisedintumourstromalcells.

5‑FUisfurthercatabolisedby theenzymedihydropyrimidinedehydrogenase(DPD)tothemuchless toxicdihydro-5‑fluorouracil(FUH₂).Dihydropyrimidinasecleavesthepyrimidineringtoyield 5‑fluoro‑ureidopropionicacid(FUPA).Finally,β‑ureido-propionasecleavesFUPAtoα‑fluoro‑β‑alanine(FBAL)whichisclearedintheurine.Dihydropyrimidinedehydrogenase(DPD)activityisthe ratelimitingstep.DeficiencyofDPDmayleadtoincreasedtoxicityofcapecitabine(seesections 4.3 and4.4).

Elimination

Theeliminationhalf-life(t_1/2inhours)ofcapecitabine,5'‑DFCR,5'‑DFUR,5‑FUandFBALwere 0.85,1.11,0.66,0.76and3.23respectively.Capecitabineanditsmetabolitesarepredominantly excretedinurine;95.5%ofadministeredcapecitabinedoseisrecoveredinurine.Faecalexcretionis minimal(2.6%).ThemajormetaboliteexcretedinurineisFBAL,whichrepresents57%ofthe administereddose.About3%oftheadministereddoseisexcretedinurineasunchangeddrug.

Combinationtherapy

Phase Istudiesevaluatingtheeffectofcapecitabineonthepharmacokineticsofeitherdocetaxelor paclitaxelandviceversashowednoeffectby capecitabineonthepharmacokineticsofdocetaxelor paclitaxel(C_maxandAUC)andnoeffectby docetaxelorpaclitaxelonthepharmacokineticsof5’‑DFUR.

Pharmacokineticsinspecialpopulations

Apopulationpharmacokineticanalysiswascarriedoutaftercapecitabinetreatmentof505 patients withcolorectalcancerdosedat1,250 mg/m²twicedaily.Gender,presenceorabsenceofliver metastasisatbaseline,KarnofskyPerformanceStatus,totalbilirubin,serumalbumin,ASATand ALAThadnostatisticallysignificanteffectonthepharmacokineticsof5'‑DFUR,5‑FUandFBAL.

Patientswithhepaticimpairmentduetolivermetastases:Accordingtoapharmacokineticstudyin cancerpatientswithmildtomoderateliverimpairmentduetolivermetastases,thebioavailabilityof capecitabineandexposureto5‑FUmayincreasecomparedtopatientswithnoliverimpairment.There arenopharmacokineticdataonpatientswithseverehepaticimpairment.

Patientswithrenalimpairment:Basedonapharmacokineticstudyincancerpatientswithmildto severerenalimpairment,thereisnoevidenceforaneffectofcreatinineclearanceonthe pharmacokineticsofintactdrugand5‑FU.Creatinineclearancewasfoundtoinfluencethesystemic exposureto5’‑DFUR(35%increaseinAUCwhencreatinineclearancedecreasesby50%)andto FBAL(114%increaseinAUCwhencreatinineclearancedecreasesby 50%).FBALisa metabolite withoutantiproliferativeactivity.

Elderly:Basedonthepopulationpharmacokineticanalysis,whichincludedpatientswithawiderange ofages(27to86 years)andincluded234(46%)patientsgreaterorequalto65,agehasnoinfluence onthepharmacokineticsof5'‑DFURand5‑FU.TheAUCofFBALincreasedwithage(20%increase inageresultsina15%increaseintheAUCofFBAL).Thisincreaseislikelyduetoachangeinrenal function.

Ethnicfactors:Followingoraladministrationof825 mg/m²capecitabinetwicedailyfor14 days, Japanesepatients(n = 18)hadabout36%lowerC_maxand24%lowerAUCforcapecitabinethan Caucasianpatients(n = 22).Japanesepatientshadalsoabout25%lowerC_maxand34%lowerAUCfor FBALthanCaucasianpatients.Theclinicalrelevanceofthesedifferencesisunknown.Nosignificant differencesoccurredintheexposuretoothermetabolites(5'‑DFCR,5'‑DFUR,and5‑FU).

5.3 Preclinicalsafetydata

Inrepeat-dosetoxicitystudies,dailyoraladministrationofcapecitabinetocynomolgusmonkeysand miceproducedtoxiceffectsonthegastrointestinal,lymphoidandhaemopoieticsystems,typicalfor fluoropyrimidines.Thesetoxicitieswerereversible.Skintoxicity,characterisedby degenerative/regressivechanges,wasobservedwithcapecitabine.Capecitabinewasdevoidofhepatic andCNStoxicities.Cardiovasculartoxicity(e.g.PR‑andQT intervalprolongation)wasdetectablein cynomolgusmonkeysafterintravenousadministration(100 mg/kg)butnotafterrepeatedoraldosing (1,379 mg/m²/day).

Atwo-yearmousecarcinogenicitystudyproducednoevidenceofcarcinogenicityby capecitabine.

Duringstandardfertilitystudies,impairmentoffertilitywasobservedinfemalemicereceiving ^{capecitabine;}^however,^this^effect^w^as^r^e^versible^after^a^drug-free^period.^In^addⁱ^tion,^d^u^riⁿ^g^a13‑weekstudy,atrophicanddegenerativechangesoccurredinreproductiveorgansofmalemice; howevertheseeffectswerereversibleafteradrug-freeperiod(seesection 4.6).

Inembryotoxicityandteratogenicitystudiesinmice,dose-relatedincreasesinfoetalresorptionand teratogenicitywereobserved.Inmonkeys,abortionandembryolethalitywereobservedathighdoses, buttherewasnoevidenceofteratogenicity.

Capecitabinewasnotmutagenicinvitrotobacteria(Amestest)ormammaliancells(Chinesehamster V79/HPRTgenemutationassay).However,similartoothernucleosideanalogues(i.e.,5‑FU), capecitabinewasclastogenicinhumanlymphocytes(invitro)andapositivetrendoccurredinmouse bonemarrowmicronucleustests(invivo).

6. PHARMACEUTICALPARTICULARS

6.1 Listofexcipients

Tabletcore

Anhydrous lactose

Microcrystallinecellulose (E460)

Croscarmellose sodium

Hypromellose

Magnesiumstearate

Tabletcoating

Hypromellose

Talc

Titaniumdioxide(E171)

Ironoxidered(E172)

Ironoxideyellow(E172)

6.2 Incompatibilities

Notapplicable.

6.3 Shelflife

Aluminium/aluminium blisters: 3 years.

PVC/PVdC/aluminium blisters: 3 years.

6.4 Specialprecautionsforstorage

Aluminium/aluminium blisters: This medicinal product does not require any special storage conditions.

PVC/PVdC/aluminium blisters: Do not store above 30°C.

6.5 Natureandcontentsofcontainer

Aluminium/aluminium or PVC/PVdC/aluminium blister containing 10 film‑coated tablets per blister, in pack sizes of 30, 60 or 120 film‑coated tablets.

Not all pack sizes may be marketed.

6.6 Specialprecautionsfordisposal

Nospecialrequirements.

7. MARKETINGAUTHORISATIONHOLDER

<[To be completed nationally]>

8. MARKETINGAUTHORISATIONNUMBER(S)

<[To be completed nationally]>

9. DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Date of first authorisation: 9 January 2014

<[To be completed nationally]>

10. DATEOFREVISIONOFTHETEXT

17 July 2014

<[To be completed nationally]>