CYTARABINE EBEWE

Main information

  • Trade name:
  • CYTARABINE EBEWE
  • Dosage:
  • 50 Mg/Ml
  • Pharmaceutical form:
  • Solution for Inj/Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CYTARABINE EBEWE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0754/009/002
  • Authorization date:
  • 10-11-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0754/009/002

CaseNo:2082584

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

Techno-PharmLimited

Pharmapark,Chapelizod,Dublin20,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

CytarabineEbewe50mg/mlsolutionforinjectionorinfusion

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom08/06/2010until09/11/2011.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 08/06/2010 CRN 2082584 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CytarabineEbewe50mg/mlsolutionforinjectionorinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each1mlsolutionforinjectionorinfusioncontains50mgCytarabine

Each10mlsolutionforinjectionorinfusioncontains500mgCytarabine

Each20mlsolutionforinjectionorinfusioncontains1000mgCytarabine

Each40mlsolutionforinjectionorinfusioncontains2000mgCytarabine

ForExcipientssee6.1

3PHARMACEUTICALFORM

Solutionforinjectionorinfusion

Clear,colourlesssterilesolution

4CLINICALPARTICULARS

4.1TherapeuticIndications

Cytarabinecanbeusedaloneorincombinationforinductionofremissionand/ormaintenancetherapyinpatientswith

acutemyeloidleukaemia,acutenon-lymphoplasticleukaemias,erythroleukaemia,blastcrisesofchronicmyeloid

leukaemia.

4.2Posologyandmethodofadministration

Maybeadministeredintravenously(IV)orsubcutaneously(SC)only.

Theproductishypertonicandmustnotbeadministeredbytheintrathecalroute.

Cytarabine“Ebewe”canbedilutedwithwaterforinjectionBP,GlucoseintravenousinfusionBPorsodiumchloride

intravenousinfusionBP.(seesection6.6).

Thefollowingdosesaregivenasaguide,buttheclinicianshouldconsultrelevantprotocolsfortheappropriatedosage

ofcytarabineandotherantineoplasticagentsgivenincombination.Mostdosesaregiveninmg/kgbutmaybe

convertedtodosesrelatedtosurfaceareabytheuseofstandardnomograms.

RemissionInduction(Adults):

ContinuousDosing:Theusualdoseinleukaemiais2mg/kgbyrapidintravenousinjectiondailyfortendays.Ifafter

tendaysneithertherapeuticresponsenortoxicityhasbeenobserved,thedosemaybeincreasedto4mg/kguntila

therapeuticresponseortoxicityisevident.Dailybloodcountsshouldbetaken.Almostallpatientscanbecarriedto

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 08/06/2010 CRN 2082584 page number: 2

Alternatively,0.5to1mg/kgmaybeinfuseddailyin1-24hoursfortendays,andthenatarateof2mg/kg/dayuntil

toxicityisobserved.Continuetotoxicityoruntilremissionoccurs.Resultsforonehourinfusionshavebeen

satisfactoryinthemajorityofpatients.

Intermittentdosing:CytarabinemaybegivenasintermittentIVdosesof3-5mg/kgdaily,forfiveconsecutivedays.

Thiscourseoftreatmentcanberepeatedafteranintervalof2to9days,andrepeateduntilthetherapeuticresponseor

toxicityisexhibited.

Evidenceofbonemarrowimprovementhasbeenreportedtooccur7-64daysafterthebeginningoftherapy.

Ingeneral,ifapatientshowsneitherremissionnortoxicityafteratrialperiod,thencautiouslyadministeredhigher

dosescanbeadministered.Generally,patientstoleratehigherdosesgivenbyrapidintravenousinjectionratherthan

slowinfusion.

Asasingleagentforinductionofremissioninpatientswithacuteleukaemia,cytarabinehavebeengivenindosesof

200mg/m2bycontinuousIVinfusionforfivedaysatapproximately2weekintervals.

MaintenanceTherapy:tomaintainremission,dosesof1-1.5mg/kgmaybegivenintravenouslyorsubcutaneously,

onceortwiceweekly.

Children:Childrenappeartotoleratehigherdosesofcytarabinethanadults,andwheretherangeofdosesisgiven,

childrenshouldreceivethehigherdose.

Elderly:Nodataisavailabletosuggestthatachangeindoseisnecessaryintheelderly.However,theelderlypatientis

moresusceptibletotoxicreactionsandthereforeparticularattentionshouldbepaidtothedruginducedleucopenia,

thrombocytopeniaandanaemia.

4.3Contraindications

Patientswhohavealreadyreceivedadrugwhichcaninducebonemarrowsuppressionshouldnotbetreatedwith

Cytarabine,unlessthecliniciandeemssuchatreatmenttobevitallyimportanttothepatient.

Hypersensitivitytocytarabineorofoneoftheotheringredients.

Themanagementofnon-malignantdiseaseexceptforimmunosuppression.

4.4Specialwarningsandprecautionsforuse

Cytarabinemustonlybeadministeredbyspecialistswithexperienceinchemotherapyofmalignantdisorders.

Cytarabineisacytotoxicproduct.PatientstreatedwithCytarabinemustthereforebekeptunderstrictsupervision.

Rapidintravenousdosesaregastro-intestinallybettertoleratedthanslowintravenousinfusions.

Inviewofthefactthattheproductistoalargeextentbrokendownintheliver,thedrugmustbeadministeredwith

extremecautionandinalowdosagetopatientswithliverfunctiondisorders.

Cytarabinemustnotbeadministeredtopatientswithacuteand/orseriousinfections.

Bothmaleandfemalepatientswhoaresexuallymaturemusttakecontraceptivemeasuresduringanduntilsixmonths

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 08/06/2010 CRN 2082584 page number: 3

Noeffectshavebeenobservedasaresultofexposureduringhandling.Slightirritationoftheeyeispossible.Repeated

orcontinuouscontactwiththeskincanleadtoirritation.Afteraccidentalcontact,washtheareaofskinwithcopious

amountsofwaterandsoap.

Eachtreatmentofapatientwithacuteleukaemiawillunavoidablyresultinamoreorlessserious-buttemporary-

bonemarrowdepression.Monitoringofthenumberofplateletsandgranulocytesinthebloodisnecessarytodetermine

whethersupporttreatmentisnecessary.Theeffectofthetreatmentisdeterminedbymeasuringthenumberof

leukaemicblastcellsinthebloodandbonemarrow.

Therapyshouldbesuspendedormodifiedwhendrug-inducedbonemarrowdepressionresultsinaplateletcountofless

than50,000orapolymorohonuclearcountofunder1000percubicmm.Countsmaycontinuetofallafterthetherapy

hasbeendiscontinuedandmayreachlowestvaluesafterfivetosevendays.Therapyshouldnotwaituntilthenirmal

bloodvaluesareobtainedtobere-initiated.

Itisimportantthatliverandkidneyfunctiontestsarecarriedoutregularly.

Cytarabinecanleadtoincreaseduricacidlevelsintheblood,asaresultofalysisoftheneoplasticcells.Regular

monitoringoftheuricacidlevelsinthebloodisthereforerecommended.Ifnecessary,supportingandpharmacological

measuresshouldbetakentogethyperuricaemiaundercontrol.Inthecaseofpatientswithahighnumberofblastcells

orlargetumourmasses(non-Hodgkin’slymphomas)prophylaxisofhyperuricaemiaisrequired.

Inadditiontothepredictablehaematologicaltoxicity,insomecasesseriousorlife-threateningsideeffectscanoccurto

theCNS,thegastrointestinaltractorthelungs.

Patientswithgastrointestinalulcers,orwhohaverecentlyhadanoperationmustbekeptundercloseobservationfor

indicationswhichpointtohaemorrhaging,andifnecessaryplateletsmustbeadministeredbytransfusion,asrequired.

High-dosecytarabinetoxicities:

Thetoxicityofhighdosecytarabinecanbemoreseverethanthetoxicityofnormaldoseofcytarabine,andmay

includecerebellarandcerebraltoxicity,conjunctivitis(makesurethepatientisonsteroideyedropsduringtherapy),

cornealkeratitis,exanthema,hyperbilirubinaemia,liverdamage,GIperforation,pancreatitis,pulmonaryoedema,

pericarditis,andtamponade.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

CombiningCytarabinewithotheroncolyticagents,myelosuppressivedrugsorradiationtreatmentcansometimes

reducetheimmunosuppressiveeffectofthesedrugs.Modificationofthedosagemaybenecessary.Cytarabineisoften

administeredincombinationwithotherdrugs.

Theabsorptionofdigoxinmaybereducedifdigoxiniscombinedwithchemotherapeutics(includingcytarabine).This

isprobablydependentontemporarydamagetothemucosa.Theplasmalevelsofdigoxinmustthereforebemonitored.

AninvitrostudyhasshownthatcytarabinecancounteracttheeffectofgentamicinagainstKlebsiellapneumoniae.

Theconcomitantadministrationofcytarabinewithothercytotoxicdrugscanpotentiatetoxicity,especiallybone

marrowtoxicity.

Combinationoffluorocytosinewithcytarabinecanleadtoareducedeffectivenessoffluorocytosine.Strictmonitoring

ofbloodflucytosinelevelsisrequirediftwomedicinesaregivenconcurrently.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 08/06/2010 CRN 2082584 page number: 4

4.6Pregnancyandlactation

Pregnancy

Duringpregnancy,cytarabinemayonlybeadministeredonstrictindication,inwhichcontextthebenefitsofthedrug

forthemothermustbeweighedagainstthepossibledangerstothefoetus.Animalstudieshaveshownthatcytarabine

hasembryotoxicandteratogeniceffects(seesection5.3).

Menandwomenmustuseeffectivecontraceptivesduringtreatmentandforsixmonthsthereafter.

Lactation

Itisnotknownwhethercytarabineissecretedinmother’smilk.Asmanydrugsaresecretedinmother’smilkandas

cytarabinecanberesponsibleforserioussideeffectsintheneonate,breastfeedingshouldbestoppedduringtreatment

withCytarabine.

4.7Effectsonabilitytodriveandusemachines

Cytarabinehasnoeffectonpsychomotorperformance.Nevertheless,patientsreceivingchemotherapyhaveareduced

abilitytodriveoroperatemachinery,andshouldbewarnedoftheriskandadvisedtoavoidthistypeofactivityifthis

occurs.

Patientswhoaresubjecttoincidentaloccurrencesofvomiting,dizzinessandeyecomplaintsareadvisednottodrive

vehiclesoroperatemachinery.

4.8Undesirableeffects

Sideeffectsofcytarabinearedosedependent.Themostcommonaregastrointestinalsideeffects,andcytarabineis

toxictothebonemarrow(myelosuppression)andcauseshaematologicalsideeffects.

Bloodandlymphaticsystemdisorders

Common(1%-<10%):

Anaemia,megaloblastosis,leukopenia,granulocytopenia,thrombocytopenia,bleeding,

Verycommon(10%):

sepsis,immunosuppression.

Immunesystemedisorders

Verycommon(10%):

Cytarabine(Ara-C)syndrome:fever,myalgia,bonepain,incidentalchestpain,exanthema,conjunctivitisandnausea

mayoccur6-12hoursafterthestartofthetherapy.Corticosteroidscanbeusedasprophylaxisandtherapy.Iftheseare

effective,thetherapywithcytarabinecanbecontinued.Myelosuppressioncanbesevereandprolonged.

Uncommon( ≥0.1%-<1%):

Allergicoedema,anaphylaxis.Onecaseofanaphylaxishasbeenreported,whichresultedincardiopulmonaryarrestfor

whichresuscitationhadtobeapplied.Thisoccurredimmediatelyafterintravenousadministrationofcytarabine.

Nervoussystemdisorders

ThechanceofCNStoxicityincreasesifcytarabineisadministeredintrathecally,theintrathecalcytarabinetreatmentis

combinedwithothertreatmentswhicharetoxictotheCNS,suchasradiation,highdosetherapy,orintrathecal

methotrexate,orifthecytarabinetreatmentisintrathecallyadministeredwithshortintervalsorindosesabove30

mg/m².

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 08/06/2010 CRN 2082584 page number: 5

Intheeventofhighdosages,cerebellarorcerebraltoxicitywithdecreasedconsciousnesslevel,dysarthria,nystagmus,

seizure(whengivenintrathecally),headache,dizziness,neuritis.

Uncommon(0.1%-<1%):

Paraplegiainthecaseofintrathecaladministration.

Veryrare:

Necrotisingleukoencephalopathy,paraplegiaorquadriplegiahavebeenreportedafterintrathecaltreatment.

Eyedisorders

Common(1%-<10%):

Reversiblehaemorrhagicconjunctivitis(photophobia,stinging,visualdisorders,increasedlacrymation),keratitis.

Locallyadministeredglucocorticoidsarerecommendedasprophylaxisagainsthaemorrhagicconjunctivitis.

Veryrare:

Blindnesshasbeenreportedafterintrathecaltreatment.

Cardiacdisorders

Uncommon(0.1%-<1%):

Pericarditis,chestpain.

Veryrare:

Arrhythmia.Cardiomyopathyhasbeenreportedaftercytarabinetherapy.

Respiratory,thoracicandmediastinaldisorders

Uncommon(0.1%-<1%):

Pneumonia,dyspnea,sorethroat,interstitialpneumonitis,syndromeofsuddenrespiratorydistressprogressingto

pulmonaryoedema.

Gastrointestinaldisorders

Common(1%-<10%):

Mucositis,stomatitis,anorexia,dysphagia,abdominalpain,nausea,vomiting,diarrhoea,oral/analinflammationor

ulceration.

Uncommon(0.1%-<1%):

Oesophagitis,oesophagealulceration,pneumatosis,cystoidesintestinalis,necrotisingcolitis,GIperforation,nausea,

vomitingafterintrathecaladministration.

Veryrare(0.1%)

Pancreatitis

Hepato-biliarydisorders

Common(1%-<10%):

Reversibleeffectsontheliverwithincreasedenzymevalues,jaundice.

Skinandsubcutaneoustissuedisorders

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 08/06/2010 CRN 2082584 page number: 6

Reversiblesideeffectstotheskin,suchaserythema,bullosis,urticaria,vasculitis,alopecia,painfulrednessand

blisteringonthepalmsofthehandsandsolesofthefeet(highdosetherapy),lentigo,cellulitisattheinjectionsite,skin

ulceration,pruritis,burningpainonthepalmsofthehandsandsolesofthefeet.

Veryrare:

Neutrophiliceccrinehidradenitis.

Musculoskeletal,connectivetissueandbonedisorders

Uncommon(0.1%-<1%):

Myalgia,arthralgia.

Veryrare:

Rhabdomyolysishasbeenreportedaftercytarabinetherapy.

Renalandurinarypassagedisorders

Common(1%-<10%):

Kidneyfunctiondisorders,urinaryretention.

Generaldisordersandadministrationsitedisorders

Common(1%-<10%):

Fever,thrombophlebitisattheinjectionsite,hyperuricaemia.

4.9Overdose

Intheeventofanoverdose,therapymustbestopped,followedbytreatmentofthesubsequentbonemarrow

depression,includingtotalbloodorplatelettransfusionandantibiotics,asrequired.

Cytarabinecanberemovedbymeansofhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticcategory:Antimetabolite(pyrimidineanalogue)

ATCCode:L01BC01

Cytarabinecontainstheactiveingredientcytarabine,anantimetabolitefromtheseriesofpyrimidineantagonists.

Cytarabineisacell-cycle-phase-specificantineoplasticagent,whichcanonlyaffectcellsduringtheS-phaseofcell

division.Itisconvertedintracellularlyintocytarabine-5’triphosphate(ara-CTP),whichistheactivemetabolite.The

mechanismofactionisnotcompletelyunderstood,butitappearsthatara-CTPactsprimarilythroughinhibitionof

DNApolymerase.IncorporationintoDNAandRNAmayalsocontributetocytarabinecytotoxicity.Cytarabineis

cytotoxictoawidevarietyofproliferatingmammaliancellsinculture.

Cytarabinehasnoeffectonnon-proliferatingcellsnoronproliferatingcellsunlessintheSphase.Itisacellcycle

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 08/06/2010 CRN 2082584 page number: 7

5.2Pharmacokineticproperties

Absorption

Cytarabineisrapidlymetabolisedandisorallyineffective.Lessthan20%ofadoseadministeredorallyisabsorbedin

thegastrointestinaltract.

Intheeventofcontinuousintravenousadministration,virtuallyconstantplasmalevelsareachieved.

Aftersubcutaneousorintramuscularadministrationofcytarabine,peakplasmalevelsareachievedapproximately20to

60minutesafterinjectionwhicharesignificantlylowerthanafterintravenousadministration.

Cytarabineserumlevelscanvaryconsiderablyfrompatienttopatientforanidenticaldose.Somestudieshaveshown

thatthesevariationscouldbelinkedtotheclinicalresponse:highserumlevelsguaranteethebestchanceof

haematologicalremissions.

Distribution

Cytarabinehasadistributionvolumeof0.7l/kg.

Metabolism

Cytarabineisconvertedrapidlybydeoxycitidinekinaseandothernucleotidasesintoitsactiveform(cytarabine-5’

triphosphate)byphosphorylationinleukaemicblastcellsandinhealthybonemarrow.Metabolismintotheinactive

compounduracilarabinoside(1-beta-D-arabinofuranosyluracil)bymeansofcytidinedeaminaseactivitytakesplace

primarilyintheliver,andtoalesserextentintheothertissuesandblood.

Itisassumedthatthebalancebetweenkinaseanddeaminaselevelscanformanimportantfactorinthedetermination

ofwhetherthecellissensitiveorresistanttocytarabine.

Proteinbinding

Bindingtoplasmaproteinislow(13.3%)withconcentrationsof0.005-1mg/l.

Thepercentageofbounddrugwasindependentoftheconcentrationwithinthelimitsindicated.

Excretion

Afterarapidintravenousinfusionofcytarabine,biphasiceliminationfromthebloodtakesplace.Thereisaninitial

distributionphasewithahalflifeofapprox.10minutes,followedbyasecondaryeliminationphasewithahalflifeof

1-3hours.

After24hours,approx.80%oftheadministeredcytarabineisfoundintheurine,90%ofwhichisexcretedas

inactivatedmetaboliteand10%asunchangedcytarabine.

Duetothelowcytarabinedeaminaseactivityinthecerebrospinalfluid,cytarabinehasaneliminationhalflifeinthe

CNSof3-3.5hours.

5.3Preclinicalsafetydata

Studieshavereportedthatcytarabineisgenotoxic(invivoandinvitro)aswellasembryotoxicandteratogenic,if

exposedtopregnantmammalsduringtheorganogenesisinclinicallyrelevantdosageregimen.

Itisalsoreportedthatcytarabinecausesdamagetothedevelopingbrainifadministeredtonewbornmammals(period

equivalenttothirdtrimesterinhumans)andincreasesthefrequencyofabnormalspermatozoainvivoinmice.

Ithasbeenshownthatcytarabineiscarcinogenicinanimals.Thepossibilityofacomparableeffectmustbetakeninto

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 08/06/2010 CRN 2082584 page number: 8

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumlactate

Lacticacid

Waterforinjections

6.2Incompatibilities

Cytarabineisphysicallyincompatiblewithheparin,insulin,methotrexate,5-fluorouracil,nafcillin,oxacillin,

benzylpenicillinandmethylprednisolonesodiumsuccinate.

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6

6.3ShelfLife

Unopened:2years

Theproductshouldbeusedimmediatelyafteropening

Storagelifeafterreconstitution

Chemicalandphysicalstabilityafterdilutionwith0.9%(m/f)sodiumchloridesolutionand5%(m/f)glucosesolution

hasbeendemonstratedfor4daysat2-8 o

Candfor24hourswhenstoredatatemperaturebelow25 o

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2

–8 o

Cunlessreconstitution/dilutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Donotstoreabove25 o

C.Storeinoriginalpackaging.

Donotrefrigerateorfreeze

6.5Natureandcontentsofcontainer

Clearglassvialstype1withbutylrubberclosure

Vialsizes:10ml,20ml,40ml

1vialpercarton

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Thedilutedsolutionforinfusionisaclear,colourlessorpaleyellowsolution.

Cytarabinemustbedilutedforinfusionwith0.9%sodiumchloridesolutionor5%glucosesolution.

Compatibilitywith0.9%sodiumchloridesolutionand5%glucosesolutionhasbeenstudiedinconcentrationsof0.2–

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 08/06/2010 CRN 2082584 page number: 9

Ifcytarabinecomesintocontactwiththeskin,theexposedareamustberinsedwithcopiousamountsofwater,andthen

washedthoroughlywithwaterandsoap.Ifthesolutioncomesincontactwiththeeyes,rinsetheeyesextremely

carefullywithcopiousamountsofwater,thecontactaneyespecialistimmediately.

Pregnantemployeesshouldbeexcludedfromworkingwiththisdrug.

Afteruse,bottlesandinjectionmaterials,includinggloves,mustbedestroyedinaccordancewiththerulesforcytotoxic

drugs.

Spilledorleakedproductcanbeinactivatedwith5%sodiumhypochloritesolution.Allcleaningmaterialsmustbe

clearedawayasindicatedabove

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

TechnoPharmLimited

Pharmapark

Chapelizod

Dublin20

Ireland

8MARKETINGAUTHORISATIONNUMBER

754/9/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:10 th

November2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 08/06/2010 CRN 2082584 page number: 10