FOLINIC ACID

Main information

  • Trade name:
  • FOLINIC ACID
  • Dosage:
  • 10 Mg/ Ml
  • Pharmaceutical form:
  • Solution for Inj/Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FOLINIC ACID
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0789/011/001
  • Authorization date:
  • 27-07-2001
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA0789/011/001

CaseNo:2057845

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

EbewePharmaGes.m.b.HNfg.KG

Mondseestrasse11,A-4866Unterach,Austria

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Folinicacid(ascalciumfolinate)10mg/mlsolutionforinjectionorinfusion,ampoules

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom03/10/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 11/10/2010 CRN 2057845 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Folinicacid(ascalciumfolinate)10mg/mlsolutionforinjectionorinfusion,ampoules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

12.71mgofcalciumfolinate5H

Oequivalentto10mgoffolinicacidperml

Each3mlampoulecontains30mgoffolinicacidprovidedascalciumfolinate.

Each5mlampoulecontains50mgoffolinicacidprovidedascalciumfolinate.

Each10mlampoulecontains100mgoffolinicacidprovidedascalciumfolinate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinjectionorinfusion

Folinicacid(ascalciumfolinate)10mg/mlisaclear,colourlesstopaleyellowsolutionforinjectionorinfusion.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Calciumfolinateisindicated

todiminishthetoxicityandcounteracttheactionoffolicacidantagonistssuchasmethotrexateincytotoxic

therapyandoverdoseinadultsandchildren.Incytotoxictherapy,thisprocedureiscommonlyknownas"Calcium

FolinateRescue".

incombinationwith5-fluorouracilincytotoxictherapy.

4.2Posologyandmethodofadministration

Calciumfolinateshouldonlybegivenbyintramuscularorintravenousinjectionandmustnotbeadministered

intrathecally.

Deathhasbeenreportedwhenfolinicacidhasbeenadministeredintrathecally,followingintrathecaloverdoseof

methotrexate.

Inthecaseofintravenousadministration,nomorethan160mgofcalciumfolinateshouldbeinjectedperminutedueto

thecalciumcontentofthesolution.

Forintravenousinfusion,calciumfolinatemaybedilutedwith0.9%sodiumchloridesolutionor5%glucosesolution

beforeuse.Referalsotosections6.3and6.6.

CalciumFolinateRescueinmethotrexatetherapy:

Refertotheappliedintermediate-orhigh-dosemethotrexateprotocolforposologyandmethodofadministrationof

calciumfolinate.ThemethotrexateprotocolwilldictatethedosageregimenofCalciumFolinateRescuebecauseit

dependsheavilyontheposologyandmethodoftheintermediate-orhigh-dosemethotrexateadministration.

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CalciumFolinateRescueisnecessarywhenmethotrexateisgivenatdosesexceeding500mg/m 2

bodysurfaceandhas

tobeconsideredwithdosesof100mg–500mg/m 2

bodysurface.CalciumFolinateRescueshouldbeperformedby

parenteraladministrationinpatientswithmalabsorptionsyndromesorothergastrointestinaldisorderswhereenteral

absorptionisnotassured.Dosagesabove25-50mgshouldbegivenparenterallyduetosaturableenteralabsorptionof

calciumfolinate.

DosageanddurationofuseofCalciumfolinateprimarilydependonthetypeanddosageofmethotrexatetherapy,the

occurrenceoftoxicitysymptoms,andtheindividualexcretioncapacityformethotrexate.Asarule,thefirstdoseof

Calciumfolinateis15mg(6-12mg/m²)tobegiven12-24hours(24hoursatthelatest)afterthebeginningofthe

methotrexateinfusion.Thesamedoseisgivenevery6hoursthroughoutaperiodof72hours.Afterseveralparenteral

dosestreatmentcanbeswitchedovertotheoralform.

Inadditiontocalciumfolinateadministration,measurestoensuretherapidexcretionofmethotrexate(maintenanceof

highurineoutputandalkalinisationofurine)areintegralpartsoftheCalciumFolinateRescuetreatment.Renal

functionshouldbemonitoredbymeasuringserumcreatininelevelsdaily.

Theresidualmethotrexate-level,intheblood,shouldbemeasured,forty-eighthoursafterthestartofthemethotrexate-

infusion.Iftheresidualmethotrexate-levelis>0.5µmol/l,thenthedosageofcalciumfolinatedosagesshouldbe

adaptedaccordingtothefollowingtable:

Incombinationwith5-fluorouracilincytotoxictherapy:

Differentregimensanddifferentdosagesareused,however,nooptimaldosageorregimenhavebeendetermined.

Thefollowingregimenshavebeenusedinadultsandtheelderlyinthetreatmentofadvancedormetastaticcolorectal

cancerandaregivenasexamples.Therearenodataontheuseofcalciumfolinateincombinationwith5-fluorouracil

inchildren:

Bimonthlyregimen:Calciumfolinate200mg/m²byintravenousinfusionovertwohours,followedbyanintravenous

bolusof400mg/m²of5-Fluorouracilanda22-hourintravenousinfusionof5-Fluorouracil(600mg/m²)for2

consecutivedays,every2weeksondays1and2.

Weeklyregimen:Calciumfolinate20mg/m²byintravenousbolus.injectionor200to500mg/m²intravenous.infusion

overaperiodof2hours,plus500mg/m²5-fluorouracilasanintravenousbolusinjectioninthemiddle,orattheend,of

thecalciumfolinateinfusion.

Monthlyregimen:Calciumfolinate20mg/m²bybolusi.v.injectionor200to500mg/m²asi.v.infusionoveraperiod

of2hoursimmediatelyfollowedby425or370mg/m²5-fluorouracilasanintravenousbolusinjectionoverfive

consecutivedays.

Fortheuseofcalciumfolinateincombinationwith5-fluorouracil,modificationofthe5-fluorouacildosageandthe

treatment-freeintervalmaybenecessarydependingonpatientcondition,clinicalresponseanddoselimitingtoxicityas

statedintheproductinformationof5-fluorouracil.Areductionofcalciumfolinatedosageisnotrequired.

Thenumberofrepeatcyclesusedisatthediscretionoftheclinician.

Antidotetothefolicacidantagoniststrimetrexate,trimethoprime,andpyrimethamine:

Residualmethotrexatelevelinthe

blood48hoursafterthestartofthe

methotrexateadministration: AdditionalCalciumfolinatetobe

administeredevery6hoursfor

48hoursoruntillevelsof

methotrexatearelowerthan

0.05µmol/l:

>0.5µmol/l 15mg/m²

>1.0µmol/l 100mg/m²

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Prevention:Calciumfolinateshouldbeadministeredeverydayduringtreatmentwithtrimetrexateandfor72

hoursafterthelastdoseoftrimetrexate.Calciumfolinatecanbeadministeredeitherintravenouslyatadoseof

20mg/m²for5to10minutesevery6hours(totaldailydoseof80mg/m²),ororallywithfourdosesof20mg/m²

administeredatequaltimeintervals.Dailydosesofcalciumorcalciumfolinateshouldbeadjusteddependingon

thehaematologicaltoxicityoftrimetrexate.

Overdosage(possiblyoccurringwithtrimetrexatedosesabove90mg/m²withoutconcomitantadministrationof

calciumfolinate):Calciumfolinateshouldbeadministeredintravenouslyatadoseof40mg/m²every6hoursfor

3days,followingcessationoftreatmentwithtrimetrexate.

Trimethoprimetoxicity:

Followingcessationoftreatmentwithtrimethoprime,calciumfolinateshouldbeadministeredintravenouslyata

doseof3-10mg/daycalciumfolinateuntilrecoveryofanormalbloodcount.

Pyrimethaminetoxicity:

Incasesofhighdosepyrimethamineorprolongedtreatmentwithlowdoses,calciumfolinate5to50mg/day

shouldbesimultaneouslyadministered,basedontheresultsoftheperipheralbloodcounts.

4.3Contraindications

Knownhypersensitivitytocalciumfolinate,ortoanyoftheexcipients.

PerniciousanaemiaorotheranaemiasduetovitaminB

deficiency

Fortheuseofcalciumfolinatewithmethotrexateor5-fluorouracilduringpregnancyandlactation,seesection4.6,

"PregnancyandLactation"andthesummariesofproductcharacteristicsformethotrexate-and5-fluorouracil-

containingmedicinalproducts.

4.4Specialwarningsandprecautionsforuse

Calciumfolinateshouldonlybegivenbyintramuscularorintravenousinjectionandmustnotbeadministered

intrathecally.

Deathhasbeenreportedwhenfolinicacidhasbeenadministeredintrathecally,followingintrathecaloverdoseof

methotrexate.

General:

Calciumfolinateshouldbeusedwithmethotrexateor5-fluorouracilonlyunderthedirectsupervisionofaclinician

experiencedintheuseofcancerchemotherapeuticagents.

CalciumfolinatetreatmentmaymaskperniciousanaemiaandotheranaemiasresultingfromvitaminB

deficiency.

Manycytotoxicmedicinalproducts(directorindirectDNAsynthesisinhibitorssuchashydroxycarbamide,cytarabine,

mecaptopurine,thioguanine)leadtomacrocytosis.Suchmacrocytosisshouldnotbetreatedwithfolinicacid.

Inepilepticpatientstreatedwithphenobarbital,phenytoine,primidone,andsuccinimidesthereisariskofincreased

frequencyofseizuresduetoadecreaseofplasmaconcentrationsofanti-epilepticdrugs.Clinicalmonitoring,possible

monitoringoftheplasmaconcentrationsand,ifnecessary,doseadaptationoftheanti-epilepticdrugduringandafter

calciumfolinateadministrationisrecommended(seealsosection4.5.Interactions).

Calciumfolinate/5-fluorouracil

Calciumfolinatemayenhancethetoxicityof5-fluorouracil,particularlyinelderlyordebilitatedpatients.Themost

commonmanifestationsareleucopenia,mucositis,stomatitisand/ordiarrhoeawhichmaybedoselimiting.Incasesof

toxicitywhencalciumfolinateand5-fluorouracilareusedincombination,the5-fluorouracildosageshouldbereduced

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Combined5-fluorouracil/calciumfolinatetreatmentshouldneitherbeinitiatednormaintainedinpatientswith

symptomsofgastrointestinaltoxicity,regardlessoftheseverity,untilallofthesesymptomshavecompletely

disappeared.

Becausediarrhoeamaybeasignofgastrointestinaltoxicity,patientspresentingwithdiarrhoeamustbecarefully

monitoreduntilthesymptomshavedisappearedcompletely,sincearapidclinicaldeteriorationleadingtodeathcan

occur.Ifdiarrhoeaand/orstomatititsoccur,itisadvisabletoreducethedoseof5-FUuntilsymptomshavefully

disappeared.Theelderlyandpatientswithalowphysicalperformanceduetotheirillnessareespeciallypronetothese

toxicities.Therefore,particularcareshouldbetakenwhentreatingthesepatients.

Inelderlypatientsandpatientswhohaveundergonepreliminaryradiotherapy,itisrecommendedtobeginwitha

reduceddosageof5-fluorouracil.

Calciumfolinatemustnotbemixedwith5-fluorouracilinthesameintravenousinjectionorinfusion.

Calciumlevelsshouldbemonitoredinpatientsreceivingcombined5-fluorouracil/calciumfolinatetreatmentand

calciumsupplementationshouldbeprovidedifcalciumlevelsarelow.

Calciumfolinate/methotrexate

ForspecificdetailsonreductionofmethotrexatetoxicityrefertotheSummaryofProductCharacteristicsfor

methotrexate.

Calciumfolinatehasnoeffectonthenon–haematologicaltoxicitiesofmethotrexate,suchasthenephrotoxicity

resultingfrommethotrexateand/ormetaboliteprecipitationinthekidney.Patientswhoexperiencedelayedearly

methotrexateeliminationarelikelytodevelopreversiblerenalfailureandothertoxicitiesassociatedwithmethotrexate

(pleaserefertotheSummaryofProductCharacteristicsformethotrexate).Thepresenceofpre-existingor

methotrexate-inducedrenalinsufficiencyispotentiallyassociatedwithdelayedexcretionofmethotrexateandmay

increasetheneedforhigherdoses,ormoreprolongeduse,ofcalciumfolinate.

Excessivecalciumfolinatedosesmustbeavoidedsincethismightimpairtheantitumouractivityofmethotrexate,

especiallyinCNStumourswherecalciumfolinateaccumulatesafterrepeatedcourses.

Resistancetomethotrexateasaresultofdecreasedmembranetransportalsoimpliesresistancetofolinicacidrescueas

bothmedicinalproductssharethesametransportsystem.

Anaccidentaloverdosewithafolinateantagonist,suchasmethotrexate,shouldbetreatedasamedicinalemergency.

AsthetimeintervalbetweenmethotrexateadministrationandCalciumFolinateRescueincreases,theeffectivenessof

calciumfolinatetocounteractthetoxicitydecreases.

Thepossibilitythatthepatientistakingothermedicationsthatinteractwithmethotrexate(eg.medicationwhichmay

interferewithmethotrexateeliminationorbindingtoserumalbumin)shouldalwaysbeconsideredwhenlaboratory

abnormalitiesorclinicaltoxicitiesareobserved.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Whencalciumfolinateisgiveninconjunctionwithafolicacidantagonist(e.g.co-trimoxazole,pyrimethamine)the

efficacyofthefolicacidantagonistmayeitherbereducedorcompletelyneutralised.

Calciumfolinatemaydiminishtheeffectoftheanti-epilepticsubstances:phenobarbital,primidoneandphenytoine,

succinimides,andmayincreasethefrequencyofseizures(adecreaseofplasmalevelsofenzymaticinductor

anticonvulsantdrugsmaybeobservedbecausethehepaticmetabolismisincreasedasfolatesareoneofthecofactors)

(seealsosection4.4and4.8).

Concomitantadministrationofcalciumfolinatewith5-fluorouracilhasbeenshowntoenhanceboththeefficacyand

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4.6Pregnancyandlactation

Pregnancy

Therearenoadequateandwell-controlledclinicalstudiesconductedinpregnantorbreast-feedingwomen.Noformal

animalreproductivetoxicitystudieswithcalciumfolinatehavebeenconducted.Thereisnoindicationthatfolinicacid

inducesharmfuleffectsifadministeredduringpregnancy.Duringpregnancy,methotrexateshouldonlybeadministered

onstrictindications,wherethebenefitsofthedrugtothemothershouldbeweighedagainstpossiblehazardstothe

foetus.Shouldtreatmentwithmethotrexateorotherfolinateantagoniststakeplacedespitepregnancyorlactation,there

arenolimitationsastotheuseofcalciumfolinatetodiminishtoxicityorcounteracttheeffects.

5-fluorouraciluseisgenerallycontraindicatedduringpregnancyandcontraindicatedduringbreast-feeding;thisapplies

alsotothecombineduseofcalciumfolinatewith5-fluorouracil.

PleasereferalsototheSummariesofProductCharacteristicsformethotrexate-,otherfolateantagonistsand5-

fluorouracilcontainingmedicinalproducts.

Lactation

Itisnotknowwhethercalciumfolinateisexcretedintohumanbreastmilk.Calciumfolinatecanbeusedduringbreast

feedingwhenconsiderednecessaryaccordingtothetherapeuticindications.

4.7Effectsonabilitytodriveandusemachines

Thereisnoevidencethatcalciumfolinatehasaneffectontheabilitytodriveorusemachines.

4.8Undesirableeffects

Boththerapeuticindications:

Immunesystemdisorders

Veryrare(<0.01%):allergicreactions,includinganaphylactoidreactionsandurticaria.

Psychiatricdisorders

Rare(0.01–0.1%):insomnia,agitationanddepressionafterfollowinghighdoses.

Gastrointestinaldisorders:

Rare(0.01–0.1%):gastrointestinaldisordersafterfollowinghighdoses.

Neurologicaldisorders:

Rare(0.01–0.1%):increaseinthefrequencyofattacksinepileptics(seealsosection4.5Interactions).

Generaldisordersandadministrationsiteconditions

Uncommon(0.1-1%):fever.

Combinationtherapywith5-fluorouracil:

Generally,thesafetyprofiledependsontheappliedregimenof

5-fluorouracil,duetoenhancementofthe5-fluorouracilinducedtoxicities:

Monthlyregimen:

Gastrointestinaldisorder

Verycommon(>10%):vomitingandnausea

Generaldisordersandadministrationsiteconditions

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Noenhancementofother5-fluorouracilinducedtoxicities(e.g.neurotoxicity).

Weeklyregimen:

Gastrointestinaldisorders

Verycommon(>10%):diarrhoeawithhighergradesoftoxicity,anddehydration,resultinginhospitaladmissionfor

treatmentandevendeath.

4.9Overdose

Therehavebeennoreportedsequelaeinpatientswhohavereceivedsignificantlymorecalciumfolinatethanthe

recommendeddosage.However,excessiveamountsofcalciumfolinatemaynullifythechemotherapeuticeffectof

folicacidantagonists.

Shouldover-dosageofthecombinationof5-fluorouracilandcalciumfolinateoccur,theover-dosageinstructionsfor5-

FUshouldbefollowed,refertotheSummaryofProductCharacteristicsfor5-fluorouracilcontainingproducts.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Detoxifyingagentsforantineoplastictreatment,ATC-Code:V03AF03

Calciumfolinateisthecalciumsaltof5-formyltetrahydrofolicacid.Itisanactivemetaboliteoffolinicacidand

essentialcoenzymefornucleicacidsynthesisincytotoxictherapy.

Calciumfolinateisfrequentlyusedtodiminishthetoxicityandcounteracttheactionoffolateantagonists,suchas

methotrexate.Calciumfolinateandfolateantagonistssharethesamemembranetransportcarrierandcompetefor

transportintocells,stimulatingfolateantagonistefflux.Calciumfolinatealsoprotectscellsfromtheeffectsoffolate

antagonistsbyrepletionofthereducedfolatepool.Calciumfolinateservesasapre-reducedsourceofH4folate;itcan

thereforebypassfolateantagonistblockageandprovideasourceforthevariouscoenzymeformasoffolicacid.

Calciumfolinateisalsofrequentlyusedinthebiochemicalmodulationoffluoropyridine(5-fluorouracil)toenhanceits

cytotoxicactivity.5-fluorouracilinhibitsthymidylatesynthase(TS),akeyenzymeinvolvedinpyrimidine

biosyntheses,andcalciumfolinateenhancesTSinhibitionbyincreasingtheintracellularfolatepool,thusstabilisingthe

5-fluorouracil-TScomplexandincreasingactivity.

Finallyintravenouscalciumfolinatecanbeadministeredforthepreventionandtreatmentoffolatedeficiencywhenit

cannotbepreventedorcorrectedbytheoraladministrationoffolicacid.Thismaybethecaseduringtotalparenteral

nutritionandseveremalabsorptiondisorders.Itisalsoindicatedforthetreatmentofmegaloblasticanaemiaduetofolic

aciddeficiency,whenoraladministrationisnotfeasible.

5.2Pharmacokineticproperties

Absorption

Followingintramuscularadministrationoftheaqueoussolution,systemicavailabilityiscomparabletoanintravenous

administration.However,lowerpeakserumlevels(C

)areachieved.

Metabolism

CalciumfolinateisaracematewheretheL-form(L-formyl-tetrahydrofolate,L-5-formyl-THF),istheactive

enantiomer.

Themajormetabolicproductoffolinicacidis5-methyl-tetrahydrofolicacid(5-methyl-THF)whichispredominantly

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Distribution

Thedistributionvolumeoffolinicacidisnotknown.

Peakserumlevelsoftheparentsubstance(D/L-formyl-tetrahydrofolicacid,folinicacid)arereached10minutesafter

intravenousadministration.

TheAUCforL-5-formyl-THFand5-methyl-THFwere28.4 ±

3.5mg.min/land129 ±

11mg.min/l,respectively,aftera

doseof25mg.TheinactiveD-isomerispresentinhigherconcentrationthanL-5-formyl-tetrahydrofolate.

Elimination

Theeliminationhalf-lifeis32–35minutesfortheactiveL-formand352–485minutesfortheinactiveD-form,

respectively.

Thetotalhalf-lifeoftheactivemetabolitesisabout6hours(afterbothintravenousandintramuscularadministration).

Excretion

80-90%isexcretedintheurineastheinactivemetabolites,5-and10-formyl-tetrahydrofolate,5-8%isexcretedinthe

faeces.

5.3Preclinicalsafetydata

Therearenopreclinicaldataconsideredrelevanttoclinicalsafetybeyonddataincludedinothersectionsofthis

SummaryofProductCharacteristics.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

SodiumChloride

WaterforInjections

6.2Incompatibilities

Incompatibilitieshavebeenreportedbetweeninjectableformsofcalciumfolinateandinjectableformsofdroperidol,

fluorouracil,foscarnetandmethotrexate.

Droperidol

Droperidol1.25mg/0.5mlwithcalciumfolinate5mg/0.5ml;immediateprecipitationwasobservedafterdirect

admixtureinasyringefor5minutesat25 o

Cfollowedby8minutesofcentrifugation.

Droperidol2.5mg/0.5mlwithcalciumfolinate10mg/0.5ml;immediateprecipitationwasobservedwhenthe

drugswereinjectedsequentiallyintoaY-connectorwithoutflushingtheY-sidearmbetweeninjections.

Fluorouracil

Calciumfolinatemustnotbemixedinthesameinfusionas5-fluorouracilbecauseaprecipitatemayform.Fluorouracil

50mg/mlwithcalciumfolinate20mg/ml,withorwithoutdextrose5%inwater,hasbeenshowntobeincompatible

whenmixedindifferentamountsandstoredat4 o

C,23 o

C,or32 o

Cinpolyvinylchloridecontainers.

Foscarnet

TheformationofacloudyyellowsolutionhasbeenreportedwhenFoscarnet24mg/mlismixedwithwithcalcium

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6.3ShelfLife

Unopened-24months.

Thechemicalandphysicalin-usestabilityofthesolutiondilutedwithSodiumChloride0.9%orGlucose5%for

intravenousinfusionhasbeendemonstratedfor24hoursatatemperaturenotexceeding25°C.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2

to8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Storeat2-8°C(inarefrigerator).

Storeinoriginalcontainertoprotectfromlight

6.5Natureandcontentsofcontainer

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Priortoadministration,calciumfolinateshouldbeinspectedvisually.Thesolutionforinjectionorinfusionshouldbea

clearyellowishsolution.Ifcloudyinappearanceorparticlesareobserved,thesolutionshouldbediscarded.Calcium

folinatesolutionforinjectionorinfusionisintendedforsingleuseonly.Anyunusedportionofthesolutionshouldbe

disposedofinaccordancewiththelocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

EBEWEPharmaGes.m.b.H.Nfg.KG

Mondseestrasse11

A-4866Unterach

Austria

8MARKETINGAUTHORISATIONNUMBER

PA789/11/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 27July2001

Dateoflastrenewal: 03October2010

10DATEOFREVISIONOFTHETEXT

AmberampoulesofhydrolytictypeIglass,packedinacarton.

5ampoulescontaining30mg/3mlofCalciumfolinate,each.

5ampoulescontaining50mg/5mlofCalciumfolinate,each.

5ampoulescontaining100mg/10mlofCalciumfolinate,each.

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