FOLICID

Main information

  • Trade name:
  • FOLICID Solution for Injection 10
  • Dosage:
  • 10
  • Pharmaceutical form:
  • Solution for Injection
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FOLICID Solution for Injection 10
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1070/001/001
  • Authorization date:
  • 30-07-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Folicid,10mg/ml,solutionforinjection.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlFolicid10mg/mlSolutionforInjectioncontains10.8mgofcalciumfolinate,equivalentto10mgfolinicacid.

Onevialwith10mlcontains108mgofcalciumfolinateequivalentto100mgfolinicacid

Onevialwith20mlcontains216mgofcalciumfolinateequivalentto200mgfolinicacid

Onevialwith50mlcontains540mgofcalciumfolinateequivalentto500mgfolinicacid

Onevialwith100mlcontains1080mgofcalciumfolinateequivalentto1000mgfolinicacid

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinjection

Clear,slightlyyellowtoyellowsolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Calciumfolinateisusedtodiminishthetoxicityandcounteracttheactionoffolicacidantagonistssuchas

methotrexateincytotoxictherapy.Thisprocedureiscommonlyknownas“CalciumFolinateRescue”.

Treatmentofadvancedcolorectalcancerincombinationwith5-fluorouracil(5-FU).

4.2Posologyandmethodofadministration

Calciumfolinateisadministeredparenterallyasintramuscularinjectionorintravenousinjectionorinfusion.Donot

administercalciumfolinateintrathecally.Inthecaseofintravenousadministration,nomorethan160mgofcalcium

folinateshouldbeinjectedperminuteduetothecalciumcontentofthesolution.

Asarulecalciumfolinaterescuehastobeperformedbyparenteraladministrationinpatientswithmalabsorption

syndromesorothergastrointestinaldisorders(vomiting,diarrhoea,subileusetc.)whereenteralabsorptionisnot

assured.Dosagesabove50mgshouldbegivenparenterally.

Forintravenousinfusion,calciumfolinatemaybedilutedwith0.9%sodiumchloridesolutionor5%glucosesolution

beforeuse.Referalsoto6.3and6.6.

Calciumfolinaterescueinmethotrexatetherapy:

Sincethecalciumfolinaterescuedosageregimenheavilydependsontheposologyandmethodoftheintermediate-or

high-dosemethotrexateadministration,themethotrexateprotocolwilldictatethedosageregimenofcalciumfolinate

rescue.Therefore,itisbesttorefertotheappliedintermediateorhighdosemethotrexateprotocolforposologyand

methodofadministrationofcalciumfolinate.

Thefollowingguidelinesmayserveasanillustrationforacalciumfolinaterescuedosageregimen.

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Calciumfolinaterescueisnecessarywhenmethotrexateisgivenatdosesexceeding500mg/m 2

bodysurfaceandhas

tobeconsideredwithdosesof100mg-500mg/m 2

bodysurface.

Sincetolerancetofolicacidantagonistsdependsonvariousfactorstherearenostrictguidelinesforthecalcium

folinatedosageasafunctionofthemethotrexatedose.

Dosageanddurationofuseofcalciumfolinateprimarilydependonthetypeanddosageofmethotrexatetherapyand/or

ontheoccurrenceoftoxicitysymptoms.Asarule,thefirstdoseofcalciumfolinateis15mg(6-12mg/m²)tobegiven

12-24hours(24hoursatthelatest)afterthebeginningofmethotrexateinfusion.Thesamedoseisgivenevery6hours

throughoutaperiodof72hours.Afterseveralparenteraldosestreatmentcanbeswitchedovertotheoralform.

Fourty-eighthoursafterthestartofthemethotrexateinfusion,theresidualmethotrexate-levelshouldbemeasured.If

theresidualmethotrexate-levelis>0.5µmol/l,calciumfolinatedosagesshouldbeadaptedaccordingtothefollowing

table:

Laboratorytests:Patientsreceivingcalciumfolinateaftertherapywithmethotrexate,includingoverdosageorreduced

clearanceofmethotrexate,shouldbemonitoredandthelevelsofcreatinineandmethotrexateinserumshouldbe

measuredin24hrintervals.Thedosageofcalciumfolinateshouldbeadjustedaccordingtotheresultsofthelaboratory

tests.

Incombinationwith5-fluorouracilastreatmentforadvancedormetastaticcolorectalcancer:

Differentregimensanddifferentdosagesareused,withoutanydosagehavingbeenproventobetheoptimaldosage.

Thefollowingregimenshavebeenusedinadults:

Weeklyregimen:20or200mg/m²calciumfolinateasi.v.infusionoveraperiodof2hoursplus500mg/m²5-

fluorouracilasi.v.bolusinjectioninthemiddleorattheendofthecalciumfolinateinfusion.

Monthlyregimen:onceamonthduring5consecutivedays:20or200mg/m²calciumfolinatebolusimmediately

followedby425or370mg/m²5-fluorouracilasi.v.bolusinjection.

Forthecombinationtherapywith5-fluorouracil,modificationofthe5-fluorouracildosageandthetreatment-free

intervalmaybenecessarydependingonpatientcondition,clinicalresponseanddoselimitingtoxicityasstatedinthe

productinformationof5-fluorouracil.Areductionofcalciumfolinatedosageisnotrequired.

Thenumberofrepeatcyclesusedisatthediscretionoftheclinician.

4.3Contraindications

Hypersensitivitytocalciumfolinateortoanyoftheexcipients.

Calciumfolinateshouldnotbeusedforthetreatmentofperniciousanaemiaorothermegaloblasticanaemiascausedby

vitaminB

deficiency.Althoughhaematologicalremissionsmayoccur,theneurologicalmanifestationsremain

progressive.

4.4Specialwarningsandprecautionsforuse

Calciumfolinateshouldonlybeusedwithmethotrexateor5-fluorouracilunderthedirectsupervisionofaclinician

Residualmethotrexatebloodlevel48hours

after the start of the methotrexate

administration: Additionalcalciumfolinatetobeadministered

every6hoursfor48hoursuntillevelsof

methotrexatearelowerthan0.05µmol/l:

>0.5µmol/l 15mg/m²

>1.0µmol/l 100mg/m²

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Calciumfolinatehasnoeffectonnon-hematologicaltoxicitiesofmethotrexatesuchasthenephrotoxicityresulting

frommethotrexateand/ormetaboliteprecipitationinthekidney.

Excessivecalciumfolinatedosesmustbeavoidedsincethismightimpairtheantitumouractivityofmethotrexate,

especiallyinCNStumourswherecalciumfolinateaccumulatesafterrepeatedcourses.

Resistancetomethotrexateasaresultofdecreasedmembranetransportimpliesalsoresistancetofolinicacidrescue

asbothmedicinalproductssharethesametransportsystem.

ForspecificdetailsonreductionofmethotrexatetoxicityrefertotheSPCofmethotrexate.

Manycytotoxicmedicinalproducts–directorindirectDNAsynthesisinhibitors–leadtomacrocytosis

(hydroxycarbamide,cytarabine,mecaptopurine,thioguanine).Suchamacrocytosisisnotconsideredtobetreatedby

folinicacid.

Incombinationregimenwith5-fluorouracil,thetoxicityriskof5-fluorouracilisincreasedbycalciumfolinate,

particularlyinelderlyordebilitatedpatients.Themostcommonmanifestationsareleucopenia,mucositis,and/or

diarrhoeawhichmaybedoselimiting.Whencalciumfolinateand5-fluorouracilareusedinthetreatmentofcolorecal

cancer,the5-fluorouracildosagehastobereducedmoreincasesoftoxicitythanwhen5-fluorouracilisusedalone.

Thetoxicitiesobservedinpatientstreatedwiththecombinationtherapyarequalitativelysimilartothoseobservedin

patientstreatedwith5-fluorouracilmonotherapy.Gastrointestinaltoxicitiesareobservedmorecommonlyandmaybe

moresevereandevenlifethreatening.Inseverecasesthecombinationofcalciumfolinateand5-fluorouracilmustbe

withdrawn.

Whencalciumfolinatehasbeenadministeredintrathecallyfollowingintrathecaloverdoseofmethotrexate,adeathhas

beenreported.

Inepilepticpatientstreatedwithphenobarbital,phenytoine,primidone,thereisarisktoincreasethefrequencyof

seizuresduetodecreaseofplasmaconcentrationsofanti-epilepticdrugs.Clinicalmonitoring,possiblymonitoringof

theplasmaconcentrationsandifnecessary,doseadaptationoftheanti-epilepticdrugduringcalciumfolinate

administrationandafterdiscontinuationisrecommended(Seesection4.5,Interactionwithothermedicinalproducts

andotherformsofinteractions).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Whencalciumfolinateisgiveninconjunctionwithafolicacidantagonist(e.g.cotrimoxazole,pyrimethamine)the

efficacyofthefolicacidantagonistmayeitherbereducedorcompletelyneutralised.

Calciumfolinatemaydiminishtheeffectofanti-epilepticsubstances:phenobarbital,primidone,phenytoineand

succinimides,andmayincreasethefrequencyofseizures(adecreaseofplasmalevelsofenzymaticinductor

anticonvulsivantdrugsmaybeobservedbecausethehepaticmetabolismisincreasedasfolatesareoneofthe

cofactors).

Concomitantadministrationofcalciumfolinatewith5-fluorouracilhasbeenshowntoenhancetheefficacyandtoxicity

of5-fluorouracil(seesection4.2,Posologyandmethodofadministration,section4.4,Specialwarningsand

precautionsforuseandsection4.8,Undesirableeffects).

4.6Fertility,pregnancyandlactation

Methotrexatetherapyiscontraindicatedduringpregnancyandlactation.Should,aftercorrespondingexactdiagnosis,

treatmentwithmethotrexatetakeplacedespitepregnancyorlactationtherearenolimitationsastotheuseofcalcium

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Thereisnoexperienceintreatmentofpregnantornursingwomenwiththecombinationofcalciumfolinate/5-

fluorouraciland/orotherantineoplasticagents,however,suchatreatmentisgenerallycontraindicatedduring

pregnancyandlactation,evenunderinclusionofcalciumfolinate.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Calciumfolinateishowever

notexpectedtoaffecttheability.

Ifcalciumfolinateisusedconcomitantlywith5-fluorouracil,theriskofexperiencingadverseeventscausedby5-

fluorouracil(eg,dizziness,drowsiness,visiondisorders,andnausea)maybeenhanced.Therefore,patientsreceiving

thiscombinationshouldnotdriveorusemachines.

4.8Undesirableeffects

Boththerapeuticindications:

Nervoussystemdisorders

Rare(1/10,000to<1/1,000):increaseinthefrequencyofattacksinepileptics.

Gastrointestinaldisorders

Rare(1/10,000to<1/1,000):gastrointestinaldisordersafterhighdoses.

Generaldisordersandadministrationsiteconditions

Uncommon(1/1,000to<1/100):feverhasbeenobservedafteradministrationofcalciumfolinateassolutionfor

injection.

Immunesystemdisorders

Veryrare(<1/10,000):allergicreactions,includinganaphylactoidreactionsandurticaria.

Psychiatricdisorders

Rare(1/10,000to<1/1,000):insomnia,agitationanddepressionafterhighdoses.

Combinationtherapywith5-fluorouracil:

Generally,thesafetyprofiledependsontheappliedregimenof5-fluorouracilduetoenhancementofthe5-fluorouracil

inducedtoxicities:

Monthlyregimen:

Gastrointestinaldisorders

Verycommon(1/10):vomitingandnausea

Generaldisordersandadministrationsiteconditions

Verycommon(1/10):(severe)mucosaltoxicity.

Noenhancementofother5-fluorouracilinducedtoxicities(e.g.neurotoxicity).

Weeklyregimen:

Gastrointestinaldisorders

Verycommon(1/10):diarrhoeawithhighergradesoftoxicity,anddehydration,resultinginhospitaladmissionfor

treatmentandevendeath.Everyoccurrenceofdiarrhoeaormucositis(evengrade1)requiresimmediatecessationof

thechemotherapyuntilsymptomshavefullydisappeared.

Especiallytheelderlyandpatientswithalowphysicalperformanceduetotheirillnessarepronetothesetoxicities.

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4.9Overdose

Theacutetoxicityislow.Overdosingdoesnotgenerallygiveanysymptomsandsymptomatictreatmentofoverdosing

isprobablynotneeded.

Shouldoverdosageofthecombinationof5-fluorouracilwithcalciumfolinateoccur,followtheoverdosageinstructions

for5-fluorouracil.

Whenusingmethotrexate,anoverdosageofcalciumfolinatemayresultinadecreaseofefficacyofmethotrexate

(„over-rescue“)(seesection4.4,Specialwarningsandprecautionsforuse).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcode:V03AF03

Pharmacotherapeuticgroup:Detoxifyingagentsforantineoplastictreatment.

Folinicacidisaformylderivateoffolicacid,anutritionalfactoressentialforthehumanorganism.Itisinvolvedin

variousmetabolicprocesses,e.g.purinesynthesis,pyrimidinenucleotidesynthesisandaminoacidmetabolism.

Folinicacidismainlyusedtocanceltheeffectsoffolicacidantagonistssuchasmethotrexate.Thesubstanceonthe

otherhandstrengthenstheeffectoffluoropyrimidinessuchas5-fluorouracil.

Methotrexatecompetitivelyinhibitsthedihydrofolatereductaseandtherebypreventstheformationofreducedfolates

inthecell.Asaconsequence,itinhibitsDNA,RNAandproteinsynthesis.

Thefolinicacidreleasedfromcalciumfolinateisrapidlyconvertedintotheactive5-methyl-tetrahydrofolicacid

(calciumfolinaterescue).Unlikefolicacid,folinicaciddoesnotrequireareductionbydihydrofolatereductase.

Therefore,dihydrofolatereductaseblockershavenoeffectonfolinicacid.

Theeffectofmethotrexateprimarilydependsontherateofcelldivisionandthereforeitexertsitscytostaticeffecton

allrapidlygrowingtissues,i.e.inadditiontotumourtissuealsoonotherrapidlyproliferatingtissues(skinandmucosa,

hematopoieticbonemarrow,gonads).Thesevitaltissuesandorganscanbeprotectedfromthecellulartoxicityof

methotrexatebycalciumfolinate(5-formyl-THF=folinicacid=citrovorumfactor).

Thecytotoxiceffectof5-fluorouracilconsistsofthebindingofFdUMPtothymidylatesynthase,therebyinhibitingthe

activityofthymidylatesynthase.Administrationofcalciumfolinateresultsinhigheramountsoffolatecofactors,which

enhancethebindingbetweenFdUMPandthymidylatesynthase.

5.2Pharmacokineticproperties

Absorption

Followingintramuscularapplicationoftheaqueoussolution,systemicavailabilityiscomparabletoanintravenous

application.However,lowerpeakserumlevels(C

)areachieved.

Metabolism

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

enantiomer.

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

producedintheliverandintestinalmucosa.

Distribution

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Peakserumlevelsoftheparentsubstance(D/L-5-formyl-tetrahydrofolicacid,folinicacid)arereached10minutesafter

i.v.administration.

AUCforL-5-formyl-THFand5-methyl-THFwere28.4±3.5mg.min/Land129±112mg.min/Lafteradoseof25mg.

TheinactiveD-isomerispresentinhigherconcentrationthanL-5-formyl-tetrahydrofolate.

Elimination

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

respectively.

Thetotalterminalhalf-lifeoftheactivemetabolitesisabout6hours(afterintravenousandintramuscular

administration).

Excretion

80-90%withtheurine(5-and10-formyl-tetrahydrofolatesinactivemetabolites),5-8%withthefaeces.

5.3Preclinicalsafetydata

Preclinicaltestresultsshowednorisksnotpreviouslyknownfromclinicalexperience(seeothersectionsoftheSPC).

Nomutageniceffectsareexpectedatphysiologicaldosages.Long-termstudiesonthetumorigenicpotentialoffolinic

acidaswellasanimalstudiesforclarificationofreproductivetoxicologicalpropertiesarenotavailable.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Trometamol

Hydrochloricacid,conc.

Waterforinjections

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.,

Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfromsuchamedicinalproduct

andotherhandlingoftheproduct.

6.3Shelflife

2years.

Shelf-lifeafterdilution

Chemicalandphysicalin-usestabilityafterdilutionin5%glucosesolutionor0.9%sodiumchloridesolutionhasbeen

demonstratedfor72hoursat+2°Cto+8°Candat+25°C,whenprotectedfromlight.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in-usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat

+2°Cto+8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticconditions.

6.4Specialprecautionsforstorage

Store(inarefrigerator(2°C–8°C).

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6.5Natureandcontentsofcontainer

Brownvials(typeIglass)withchlorobutyl/butylrubberstopperandaluminiumoverseal.

Clearvials(typeIglass)withchlorobutyl/butylrubberstopperandaluminiumoverseal.

Packagesizes:

1x10mland5x10mlSolutionforInjection.

1x20mland5x20mlSolutionforInjection.

1x50mland5x50mlSolutionforInjection.

1x100mland5x100mlSolutionforInjection.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

IfnecessaryFolicidmaybedilutedwiththefollowingsolutionsforinfusion:5%glucosesolutionor0.9%sodium

chloridesolution.

Themedicinalproductisforsingleuseonly.Anyunusedsolutionshouldbediscarded.

Thesolutionforinjectionshouldbeinspectedvisuallypriortouse.Onlyclearsolutionswithoutparticlesshouldbe

used.

7MARKETINGAUTHORISATIONHOLDER

CellPharmGmbH

MedicalPark

Feodor-Lynen-Strae23

30625Hannover

Germany

8MARKETINGAUTHORISATIONNUMBER

PA1070/001/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:30July2004

Dateoflastrenewal:03May2007

10DATEOFREVISIONOFTHETEXT

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