FLUOROURACIL "EBEWE"

Main information

  • Trade name:
  • FLUOROURACIL "EBEWE"
  • Dosage:
  • 50 Mg/Ml
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FLUOROURACIL "EBEWE"
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0789/005/001
  • Authorization date:
  • 13-09-2002
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

5-Fluorouracil“Ebewe”50mg/ml,concentrateforsolutionforinfusion.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlcontains50mg5-Fluorouracil.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion.

Clear,colourlesstoslightlyyellow,aqueoussolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Palliativetreatment,insingleaswellasincombinationtherapy,ofcommoncarcinomas.

4.2Posologyandmethodofadministration

Adultsonly:

IntravenousInfusion:

15mg/kgor600mg/m 2

dilutedin300-500mlofglucoseinjectionBPin0.9%sodiumchloride,givenover2-4hours

daily,untilsideeffectsoccur.Totaldailydoseshouldnotexceed1gram.

Initialtreatmentwithweeklyapplication:

15mg/kgor600mg/m 2

onceaweekslowlyi.v.

24hourslongterminfusion:

5-7mg/kg/dayor200mg/m 2

/day

Anintervalof4-6weeksshouldbeallowedbetweencourses.

Maintenancetherapy:

Aninitialintensivecoursemaybefollowedbymaintenancetherapyprovidingtherearenosignificanttoxiceffects.In

allinstances,toxicsideeffectsmustdisappearbeforemaintenancetherapyisstarted.

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SpecialDosageRecommendations:

Children:

5-Fluorouracilisnotrecommendedforuseinchildren.

Maximumdailydose:of1gmaynotbeexceeded.

Durationoftreatment:willbedeterminedbyanexperiencedoncologistaccordingtonatureandclinicalcourseof

treatment.

4.3Contraindications

Hypersensitivitytooneofthecomponentsofthedrug.Useinseriouslydebilitatedpatientsorinthosewithsevere

changesinbloodcount,bonemarrowsuppression(especiallyafterradiotherapy),haemorrhage;malabsorption,severe

decreasedliverandkidneyfunction.

Useinthepresenceofsevereinfections,herpeszoster,varicella;stomatitis,ulcerationsinthemouthandthe

gastrointestinaltract,pseudomembraneousenteritis,severediarrhoea.

Seriousdebility.

Plasmabilirubingreaterthan85µmol/l.

Activevaccinationshouldbeavoidedduring5-FUtherapy.

Useinpregnantorbreast-feedingwomen.

Useinthetreatmentofnon-malignantdisease.

With: Dosereduction

poornutritionstatus

aftermajorsurgery

withmyelosuppression:leukocytes<4000/ µ l,thrombocytes<

100.000/ µ l 30-50%

gastrointestinalreactions(stomatitis,mucositis,severediarrhoea,

severevomiting,ulceration,bleeding)

leukocytes<3,000/ µ l,platelets<80,000/ µ l

neurologicalsideeffects(includingataxiaandtremor) Immediateinterruption

oftherapywith5-

Fluorouracil

severegastrointestinal

severecardiacor

severeneurologicaltoxicity-reactions Furthertherapyisnot

recommended.

reducedliverfunction(biotransformationcanbereduced)

reducedkidneyfunction(eliminationcanbereduced) Dependentonorgan

functionanindividual

dosereductioncanbe

necessary.

Incombinationwith

othercytotoxics,whichshowasimilarprofileofsideeffects

radiationtreatment Dosereduction

accordingtothe

expectedside-effects.

Inelderlypatientswithage-dependentreductionofkidneyfunction Individualdose

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4.4Specialwarningsandprecautionsforuse

ItisrecommendedthatFluorouracilbegivenonlyby,orunderthestrictsupervisionof,aqualifiedoncologistwhois

experiencedintheuseofpotentantimetabolitesandhasthefacilitiesforregularmonitoringofclinical,biochemical

andhaematologicaleffectsduringandafteradministration.

Allpatientsshouldbeadmittedtohospitalforinitialtreatment.

AdequatetreatmentwithFluorouracilisusuallyfollowedbyleucopoenia,thelowestwhitebloodcell(W.B.C.)count

commonlybeingobservedbetweenthe7thand14thdayofthefirstcourse,butoccasionallybeingdelayedforaslong

as20days.

Thecountusuallyreturnstonormalbythe30thday.DailymonitoringofplateletandW.B.C.countisrecommended

andtreatmentshouldbestoppedifplateletsfallbelow100,000permm 3

ortheW.B.C.countfallsbelow3,500per

.Ifthetotalcountislessthan2000permm 3

,andespeciallyifthereisgranulocytopenia,itisrecommendedthat

thepatientbetreatedwithappropriatemeasurestopreventsystemicinfection.

Treatmentshouldalsobestoppedatthefirstsignoforalulcerationorifthereisevidenceofgastrointestinalsideeffects

suchasstomatitis,diarrhoea,bleedingfromtheG.I.tractorhaemorrhageatanysite.Theratiobetweeneffectiveand

toxicdoseissmallandtherapeuticresponseisunlikelywithoutsomedegreeoftoxicity.Caremustbetakentherefore,

intheselectionofpatientsandadjustmentofdosage.

Fluorouracilshouldbeusedwithcautioninpatientswithreducedrenalorliverfunctionorjaundice.Isolatedcasesof

angina,ECGabnormalitiesandrarely,myocardialinfarctionhavebeenreportedfollowingadministrationof

Fluorouracil.Careshouldthereforebeexercisedintreatingpatientswhoexperiencechestpainduringcoursesof

treatment,orpatientswithahistoryofheartdisease.

Fluorouracilhasbeenshowntobecarcinogenicinanimals.Thepossibilityofasimilareffectshouldbeborneinmind

whendesigningthelong-termmanagementofthepatient.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

TherapeutictreatmentincombinationwithCalciumfolinate(folinicacid)isdescribedintheliterature.Incombination

withCalciumfolinatetheside-effectsofFluorouracilmaybeincreasedandmaycauseseverediarrhoea.

Incombinationwithothercytotoxics(Interferons,Cyclophosphamide,Vincristine,Methotrexate,Cisplatin,

Doxorubicin)efficacyaswellastoxicityof5-Fluorouracilmaybeincreased.

Incombinationwithothermyelosuppressivesubstances,dosageadjustmentisnecessary;concomitantorprevious

radiationtherapymayrequiredosagereduction.Thecardiotoxicityofanthracyclesmaybeincreased.

Aminophenazone,phenylbutazoneandsulfonamidesshouldnotbeadministeredbeforeandduringtreatment.

VariousagentshavebeenreportedtobiochemicallymodulatetheantitumourefficacyortoxicityofFluorouracil.

CommondrugsincludeMethotrexate,Metronidazole,folinicacidandCimetidinewhichcanaffecttheavailabilityof

theactivedrug.

Chlordiazepoxide,Disulfiram,GriseofulvinandIsoniazidcanincreasetheefficacyof5-Fluorouracil.

Sulphonamideshouldnotbeadministeredbeforeorduringtreatment.

Vaccines:ThecommondefencemechanismisdecreasedbyFluorouracil;therebytheimmunologicresponseis

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Afterlong-termtreatmentwith5-FluorouracilincombinationwithMitomycintheappearanceofahaemolyticuraemic

syndromewasreported.

Cimetidinemayincreasetheplasmalevelof5-fluorouracil.

Metronidazolmayincreasetheplasmalevelandthetoxicityof5-fluorouracil.

Levamisolmayincreasethehepatotoxicityof5-fluorouracil.

Thiazidesmayincreasethebonemarrowtoxicityofanticancerdrugs.

Vinorelbinincombinationwith5-fluorouracil/folinicacidmayinduceseriousmucositis.

Allopurinolmayreducethetoxicityandefficacyof5-fluorouracil.

When5-FluorouracilandWarfarinareusedtogetherthereisthepossibilityofabnormallyelevatedinternational

normalisedration(INR)readingswhichwouldrequiremodificationofWarfarindosageandfrequencyofINRtesting.

4.6Fertility,pregnancyandlactation

Inanimalstudiesadversereactionsonthefoetuswereobservedand5-Fluorouracilisstrictlycontraindicatedduring

pregnancyandbreastfeeding.Itisrecommendedtouseanon-hormonalcontraception,duringtreatment.

4.7Effectsonabilitytodriveandusemachines

Theabilityofthepatientstodriveoroperatemachinerymaybeimpaired.

4.8Undesirableeffects

Duringtreatmentwith5-Fluorouracilthefollowingside-effectswereobserved:

Infectionsandinfestations:

Uncommon>0.1%-<1%

Fever

Bloodandlymphaticsystemdisorders:

Verycommon>10%

Leukopeniaandthrombocytopeniaarecommonandtheprecautionsdescribedaboveshouldbefollowed.

Common>1%-<10%

Agranulocytosis,anaemiaandbonemarrowdepression.

Immunesystemdisorders:

Uncommon>0.1%-<1%

Allergicreactions

Metabolismandnutritiondisorders:

Veryrare<0.01%

Patientswithlowlevelsofdihydropyrimidinedehydrogenasedeficiency(DPD)activityofanycase(incl.DPD-

inhibitorslikeeniluracilorantiviraldrugsoruvidine)areathighestrisktodevelopsevereandprolongedadverse

reactionsshortlyafterinitiationofa5-Fluorouraciltreatment.AninitialscreeningofDPDactivityisrecommended.

Nervoussystemdisorders:

Common>1%-<10%

Atransientreversiblecerebellarsyndrome,includingataxia,areversibleconfusionalstateandextrapyramidalmotor

andcorticaldisturbances,whichusuallyrespondtowithdrawalof5-Fluorouracil,mayoccur.

Uncommon>0.1%-<1%

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Veryrare<0.01%

Leukoencephalopathy,whichwasreversibleuponimmediatewithdrawal,hasbeenreported.Patientswith

dihydropyrimidinedehydrogenasedeficiencymaybeatincreasedrisk.DWI(Diffusion-WeightedImaging)maybe

helpfulforthediagnosisofleukoencephalopathy.Braininfarctionhasbeenreportedduringcombinedchemotherapy

(forexample:5-Fluorouracil+mitomycinCorcisplatin).

Eyedisorders:

Rare>0.01%-<1%

Myocardialinfarction

Veryrare<0.01%

Cardiogenicshock

Vasculardisorders:

Uncommon>0.1%-<1%

Epistaxis,hypotension,thrombophlebitis

Gastrointestinaldisorders:

Verycommon>10%

Theremayalsobemucositis–e.g.stomatitis,oesophagitis,pharyngitis,orproctitis.

Common>1%-<10%

Diarrhoea,nauseaandvomitingarecommonandcanbetreatedsymptomatically.Anorexia.

Uncommon>0.1%-<1%

Gastrointestinalulcerationandbleeding.

Veryrare<0.01%

Livercelldamage.Lethallivernecrosis.

Skinandsubcutaneoustissuedisorders:

Common>1%-10%

Alopeciamaybeseeninasubstantialnumberofcases,butitisreversible.

Uncommon>0.1%-<1%

Othersideeffectsincludedermatitis,skinalterations–e.g.dryskin,fissure,erosion,erythema,rash,pruritus-

photosensitivity,allergicskinreactions,pigmentation,streakyhyperpigmentationordepigmentationneartheveins,

changesinthenailsorlossofnails.Palmar-PlantarErythrodysesthesiaSyndromehasbeenreportedasanunusual

complicationofhighdosebolusinfusionorprotractedcontinuousinfusiontherapywith5-Fluorourcil.

Musculoskeletal,connectivetissueandbonedisorders:

Uncommon>0.1%-<1%

Nasalbonenecrosis

Renalandurinarydisorders:

Uncommon>0.1%-<1%

Renalfailure

Reproductivesystemandbreastdisorders:

Uncommon>0.1%-<1%

Tiredness

Investigations:

Veryrare:

Scatteredreportshavebeenrelatedprolongedprthrombontimetocoadministrationof5-Fluorourcilandwarfarin.

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4.9Overdose

Thesymptomsandsignsofoverdosagearequalitativelysimilartotheadversereactionsandshouldbemanagedas

indicatedundersection4.4,“Specialwarningsandprecautionsforuse”andsection4.8,“Undesirableeffects”.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Fluorouracilisananalogueofuracil,acomponentofribonucleicacid.Thedrugisbelievedtofunctionasan

antimetabolite.Afterintracellularconversiontotheactivedeoxynucleotide,itinterfereswiththesynthesisofDNAby

blockingtheconversionofdeoxyuridylicacidtothymidylicacidbythecellularenzymethymidylatesynthetase.

FluorouracilmayalsointerferewithRNAsynthesis.

5.2Pharmacokineticproperties

Afterintravenousadministration,Fluorouracilisdistributedthroughthebodywateranddisappearsfromtheblood

within3hours.Itispreferentiallytakenupbyactivelydividingtissuesandtumoursafterconversiontoitsnucleotide.

FluorouracilreadilyenterstheC.S.Fandbraintissue.

FollowingIVadministration,theplasmaeliminationhalf-lifeaveragesabout16minutesandisdose-dependent.

FollowingasingleIVdoseofFluorouracilapproximately15%ofthedoseisexcretedunchangedintheurinewithin6

hours;over90%ofthisisexcretedinthefirsthour.Theremainderismostlymetabolisedintheliverbytheusualbody

mechanismsforuracil.

5.3Preclinicalsafetydata

Fluorouracilhasbeenshowntobecarcinogenicinanimals(seesection4.4,Specialwarningsandprecautionsforuse).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Waterforinjections

Sodiumhydroxide

6.2Incompatibilities

5-FluorouracilisincompatiblewithCarboplatin,Cisplatin,Cytarabine,Diazepam,Doxorubicin,otherAnthracyclines

andpossiblyMethotrexate.

Formulatedsolutionsarealkalineanditisrecommendedthatamixturewithacidicdrugsorpreparationsshouldbe

avoided.

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3Shelflife

Aspackagedforsale:2years.

PhysicalandchemicalstabilityofInfusionsolutionsof5-Fluorouracilin5%glucoseandin0.9%sodiumchloridewith

aconcentrationof0.35mg/mland15.0mg/ml,storedintherefrigerator,atroomtemperaturewithlightprotectionand

underinfluenceoflight,couldbedemonstratedfor28days.Microbiologicalstabilitywasnottested,thereforeitis

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AdministeredincombinationwithCalciumfolinat"EBEWE"

Amixtureof1000mgCalciumfolinat"Ebewe"(100mlCalciumfolinat"EBEWE"10mg/ml)with5000mg5-

Fluorouracil"Ebewe"(100mlat50mg/ml)and40mlphysiologicsalinesolutionininfusionpumps(e.g.type"Easy

pump")hasbeenstableatroomtemperaturefor48hours.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Donotrefrigerateorfreeze.

Storethevialintheoutercartontoprotectfromlight.

6.5Natureandcontentsofcontainer

Clearvialmadeofhydrolytic(typeI)glasswithagreybromobutylrubberstopper,packedsinglyinacarton:

ThevialmaybepackagedinaplasticscrewcapOnkosafecontainerwithatransparentcap,containedintheouter

cartonorthevialmaybepackageddirectlyintotheoutercarton.

5mlVial,containing5mlofsolution

10mlVial,containing10mlofsolution

20mlVial,containing20mlofsolution

100mlVial,containing100mlofsolution

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Fluorouracilisanirritant,contactwithskinandmucousmembranesshouldbeavoided.

Diluents

5-Fluorouracil“Ebewe”maybedilutedwithGlucoseorSodiumChlorideInjectionorWaterforInjections

immediatelybeforeparenteraluse.Theremainderofsolutionsshouldbediscardedafteruse:donotmakeupinto

multidosepreparations.

5-Fluorouracil“Ebewe”shouldonlybepreparedforadministrationbyprofessionalswhohavebeentrainedinthesafe

useofthepreparation.Preparationshouldonlybecarriedoutinadesignatedarea.

Preparation(Guidelines)

Pregnantpersonnelshouldnothandlecytotoxicagents.

Refertolocalcytotoxicguidelinesbeforecommencing.

Thepersonnelcarryingouttheseproceduresshouldbeadequatelyprotectedwithappropriatepersonal

protectionequipment,includinge.g.suitableprotectiveclothing,mask,glovesandeyeshields.

Appearanceoftheproductafterreconstitutionisacolourlessclearsolution.

Administration

Forinstructionsonadministration,seesection4.2,Posologyandmethodofadministration.

Contamination

Eyecontact:Irrigateimmediatelywithwaterandseekmedicaladvice.

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Inhalation,Ingestion:Seekmedicaladvice.

IntheEventofspillage,trainedpersonnelwearingappropriatepersonalprotectiveequipment,asoutlinedabove,

shouldmopthespilledmaterialwithaspillkitorspongekeptintheareaforthatpurpose.Rinsetheareawithcopious

amountsofwater.Putallsolutionsandspongesintoadesignatedimpervioussuitablehighriskwastedisposalbagand

thensealit.

Disposal

Syringes,containers,absorbentmaterials,solutionsandanyothercontaminatedmaterialshouldbeplacedina

designatedimperviouscontainerandincinerated,inaccordancewithlocalprocedures.

Ifaprecipitatehasformedasaresultofexposuretolowtemperatures,redissolvebyheatingto60°Caccompaniedby

vigorousshaking.Allowtocooltobodytemperaturepriortouse.

Forsingleuseonly.

7MARKETINGAUTHORISATIONHOLDER

EBEWEPharmaGes.m.b.H.Nfg.KG,

A-4866Unterach,

Austria.

8MARKETINGAUTHORISATIONNUMBER

PA789/5/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:13September2002

Dateoflastrenewal:12March2010

10DATEOFREVISIONOFTHETEXT

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