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(see