FOMEPIZOLE EUSA PHARMA 5 MG/ML, CONCENTRATE FOR SOLUTION FOR INFUSION

Main information

  • Trade name:
  • FOMEPIZOLE EUSA PHARMA 5 MG/ML, CONCENTRATE FOR SOLUTION FOR INFUSION
  • Dosage:
  • 5 Mg/Ml
  • Pharmaceutical form:
  • Concentrate for Soln for Inf
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FOMEPIZOLE EUSA PHARMA 5 MG/ML, CONCENTRATE FOR SOLUTION FOR INFUSION
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1020/001/001
  • Authorization date:
  • 11-10-2002
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FomepizoleEUSAPharma5mg/mL,concentrateforsolutionforinfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachmlcontains8mgfomepizolesulphate,equivalentto5mgfomepizole.

Anampouleof20mlcontains160mgfomepizolesulphate,equivalentto100mgfomepizole.

Excipients:Anampouleof20mlcontains2.4mmolsodium.

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Concentrateforsolutionforinfusion

FomepizoleEUSAPharmaisaclearandcolourlesssolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

FomepizoleEUSAPharmaisanantidoteusedinthetreatmentofacuteethyleneglycolpoisoning.

4.2Posologyandmethodofadministration

Thetreatmentshouldbeginwheneverethyleneglycolpoisoningissuspected,asearlyaspossibleafteritsingestion,

evenintheabsenceofsignsoftoxicity.

Intheabsenceofethyleneglycolassay,ethyleneglycolpoisoningshouldbesuspectedonthefollowingcriteria:

-patient’shistory;

-osmolargap>20mOsm/kgH

0;

-metabolicacidosiswithaniongap>16mmol/l(presenceofhighlevelsofglycolates);

-calciumoxalatecrystalsintheurine.

Anassayforplasmaethyleneglycolshouldbeperformedatadmission,butthisdeterminationshouldnotdelaystartof

treatmentwithfomepizole.Plasmaethyleneglycollevelsshouldbemonitoredevery12to24hours.

FomepizoleEUSAPharma5mg/mL,concentrateforsolutionforinfusion,istobedilutedbeforeuse(seesection6.6).

Thedilutedsolutionshouldbeadministeredbyslowintravenousinfusion.

Dosagedependsonplasmaethyleneglycolconcentrationandrenalfunction:

-patientswithnormalrenalormildtomoderateimpairedrenalfunctionasassessedbyserumcreatinine(100to265

µmol/l)inwhomhemodialysisisnotrequired:

Administrationshouldbeperformedbyslowintravenousinfusion,over30to45minutes,givenasfollows:infusionof

aloadingdoseof15mg/kgfollowedbydosesevery12hoursuntilethyleneglycollevelshasbeenreducedbelow0.2

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Thenumberofmaintenancedosesandthedoseafter48hourswilldependoninitialconcentrationandthetimecourse

oftheethyleneglycollevels.

Generally4to5maintenancedosesarerecommendedforinitialethyleneglycollevelsbetween3to6g/l(48to96

mmol/l)and1to3maintenancedosesarerecommendedforinitialethyleneglycollevelsbetween0.35to1.5g/l(5.6to

24mmol/l).

-patientswithsevereimpairedrenalfunctionasassessedbyserumcreatinine (>265µmol/l)

Hemodialysisisindicatedincombinationwithfomepizole.

Aloadingdoseof15mg/kgisinfusedover30to45minutes,followedby1mg/kg/hourcontinuousinfusionforthe

entiredurationofthehemodialysis.

Thedosageoffomepizoleduringcontinuousvenovenoushemodiafiltration,anothermodeofextracorporalelimination,

isnotknown.

Hemodialysisandfomepizolesulphateadministrationshouldbediscontinuedwhenthemetabolicacidosisiscorrected

andplasmaethyleneglycollevelshavebeenreducedbelow0.2g/l(3.2mmol/l).

-Hemodialysisshouldalsobeinitiatedunderatleastoneofthefollowingfeaturesincombinationwithfomepizole:

-arterialpH<7.10;

-dropinarterialpH>0.05resultinginapHoutsidethenormalrangedespitebicarbonateinfusion;

-inabilitytomaintainarterialpH>7.30despitebicarbonatetherapy;

-decreaseinserumbicarbonateconcentrationofmorethan5mmol/ldespitebicarbonatetherapy;

-riseinserumcreatinineby>90µmol/l(1mg/dl).

-elderlypatients:

Clinicalexperienceinelderlypatientsislimited.Theregimenhastobeadjustedtotherenalfunction(seeabove).

-children:

Thereisnoavailabledataregardingthepharmacokineticsoffomepizoleinchildren.Clinicalexperienceislimitedand

basedonsimilarweight-adjusteddoses.

-patientswithimpairedliverfunction:

Noclinicaldataareavailable.

4.3Contraindications

Thismedicinalproductshouldnotbeadministeredincaseofknownhypersensitivitytofomepizoleortoother

pyrazoles.

4.4Specialwarningsandprecautionsforuse

Previoustreatmentofethyleneglycolpoisoningwithethanoldoesnotprecludetheuseoffomepizole.Nevertheless,the

combinationofethanolandfomepizoleisusuallynotrecommended.(Seesection4.5.Interactionwithmedicinal

Fomepizoledose(mg/kgbodyweight)

loadingdose 2 nd

dose

(12hours) 3 rd

dose

(24hours) 4 th

dose

(36hours) 5 th

dose

(48hours) 6 th

dose

(60hours)

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Minorhypersensitivityreactionshavebeenreportedinafewpatients(rash,hypereosinophilia).Thesesymptoms

shouldbemonitored.

Managementshouldbemodifiedincaseofamajorhypersensitivityreaction(angioedema,bronchospasms,

anaphylacticshock).Inthesecases,thefomepizolesulphateinfusionshouldbeimmediatelydiscontinuedinthe

absenceofanotherestablishedcause;symptomatictreatmentshouldstartandfomepizolesulphateshouldnotbere-

administeredtothepatient.Treatmentbyethanolshouldbestartedandhemodialysisconsidered.

Ethyleneglycolpoisoninginitssevereformsisexpressedbymetabolicacidosis(aniongap>16mmol/l),convulsive

comaandrenalfailure.

Treatmentofethyleneglycolintoxicationinvolvespreventionofthemetabolismofethyleneglycoltoitstoxic

metabolites,correctionofmetabolicacidosis,sufficienthydration(oralorvenousifapplicable)topreventtherisksof

dehydrationandhypernatremiaandtoincreaseurineclearanceofethyleneglycol,andifnecessary,removaloftoxic

metaboliteswithhemodialysis.Monitoringrequiresfrequentmeasurementsofplasmaethyleneglycol,bloodgas,pH,

electrolytes,serumcreatinine,urineanalysisandpresenceofurinaryoxalatecrystals.

Evaluationofhepatictransaminasesandbloodcellcountsbeforeandonemonthaftertreatmentisrecommended.

Pre-existingimpairedliverfunctionrequirescarefulmonitoringofhepatictransaminases.

FomepizoleEUSAPharma5mg/mL,concentrateforsolutionforinfusion,shouldnotbegivenundiluted.Thediluted

concentrateshouldnotbegivenbybolusinjection.

Thismedicinalproductcontains2.4mmolsodiumperampoule.Tobetakenintoconsiderationbypatientsona

controlledsodiumdiet.Moreover,fomepizoleisrecommendedtobedilutedinaglucosesolutionforthesepatients(see

paragraph6.6).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Combinationwithethanol:

Concurrentuseofalcoholandfomepizolereducestheeliminationrateforbothsubstances.Althoughtheclinical

efficacyoffomepizoleseemsnotimpaired,forsafetyreason,theconcomitantuseoffomepizolewithalcoholisnot-

recommended(Seesection4.4Specialwarningsandprecautionforuse).

4.6Fertility,pregnancyandlactation

Noclinicaldataonexposedpregnanciesareavailable.Animalstudieshaveshownreproductivetoxicity(seesection

5.3).Thepotentialriskforhumansisunknown.

Fomepizoleshouldnotbeusedduringpregnancyunlessclearlynecessary.

Therearenodataontheextenttowhichfomepizoleisexcretedinmilk.Itisadvisedtostopbreastfeedingtemporarily

duringtreatmentwithfomepizole.

4.7Effectsonabilitytodriveandusemachines

Thepossiblerisksofdizzinessandvertigorelatedtothetreatmentshouldbepointedout.

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4.8Undesirableeffects

4.9Overdose

Dizziness,drunkenness,nausea,vertigo,headaches,nystagmusandspeechdisturbanceshavebeenobservedfordoses

of50to100mg/kginhealthyvolunteers.

Incaseofasubstantialoverdose,asfomepizolesulphateisdialysable,hemodialysiscouldbeconsidered.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antidote

ATCcode:VO3AB34

Fomepizoleisacompetitiveinhibitorofalcoholdehydrogenase(ADH).ADHcatalysesthefirststageofthe

metabolismofethyleneglycolintheliver.Fomepizoletreatmentblockstheformationofthetoxicmetabolitesof

ethyleneglycolandprolongsitsplasmahalf-life.Ethyleneglycolisthuseliminatedunchangedinurineandinduces

osmoticpolyuria.

Bloodandlymphaticsystemdisorders:

Common: Eosinophilia,anaemia

Psychiatricdisorders:

Common: Anxiety,agitation

Nervoussystemdisorders:

Verycommon: Dizziness,headache

Common: Vertigo,convulsion,nystagmus,speechdisorder

Eyedisorders:

Common: Visualimpairment

Cardiacdisorders:

Common: Bradycardia,tachycardia

Vasculardisorders:

Common: Increasedbloodpressure

Gastrointestinaldisorders:

Common: Nausea,vomiting,diarrhoea,dyspepsia,hiccups

Hepatobiliarydisorders:

Common: Increasedtransaminases

Skinandsubcutaneoustissuedisorders:

Common: Pruritus,rash

Musculoskeletalandconnectivetissuedisorders:

Common: Increasedbloodcreatinephosphokinase

Generaldisordersandadministrationsiteconditions:

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Theefficacyoffomepizoleinthetreatmentofethyleneglycolpoisoninghasbeenshownindogsandmonkeys,with

loadingdosesof20and50mg/kg,respectively.

Inhealthyvolunteers,pharmacologicaleffectsoffomepizolehavebeenshownindirectly,bythedemonstrationofa

metabolicinteractionwithethanol,whichisalsometabolisedbyADH.Dosesoffomepizolerangingfrom7to20

mg/kgareefficientbothorallyorintravenously.

5.2Pharmacokineticproperties

Fomepizolehasavolumeofdistributionofapproximately0.7l/kg.Theeliminationoffomepizoleisnon-linearandis

saturablefordosesrangingfrom7to20mg/kg.Uponrepeatedadministration,fomepizoleinducesitsownmetabolism.

Fomepizoleisalmostentirelyeliminatedbymetabolism.Theprincipalmetabolite,4-carboxypyrazoledoesnothave

anyinhibitoryeffectonhumanADHinvitro.

Theenzymesinvolvedinthemetabolismoffomepizolehavenotbeenidentified.Inpreclinicalstudies,fomepizolehas

beenshowntobebothaninhibitorandaninducerofCYP450isoenzymes.Correspondingstudieshavenotbeen

performedinhumanandthepotentialtoaffectthepharmacokineticsofdrugsmetabolisedbyCYP450cannotbe

predicted.

Fomepizoleanditsmetabolitesareexcretedinurine.Only2to3%offomepizoleadministeredisexcretedunchanged

intheurine.

Fomepizoleisdialysable.Theextractionratioisabout0.75,andthehourlyextractionrangesbetween0.41and1.15

mg/kg/h.

5.3Preclinicalsafetydata

Toxicitystudiesinanimalshavenotdemonstratedfomepizoletohaveanyparticulartoxicity.

Fomepizolesulphatehasshownnosignofmutagenicityorclastogenicity.

Itscarcinogenicpotentialanditsreproductivetoxicityhavenotbeenstudied.

Withrespecttoreproductivetoxicologynoconventionalstudieswereperformed.Itisknownfromliteraturethat

fomepizoleadministeredintraperitoneallytomiceonceatday11ofpregnancyatadose(mg/kg/day)of6.5timesthe

loadingtherapeuticdoseinducedembryotoxic(increasedrateoffetalresorption)andteratogenic(increasednumberof

anteriorlimbmalformations)effects.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumchloride

Waterforinjections

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptforthosementionedin6.6.

6.3Shelflife

3years.

Afterdilution(seesection6.4):24hours.

6.4Specialprecautionsforstorage

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Afterdilution(seesection6.6):chemicalandphysicalin-usestabilityhasbeendemonstratedfor24hoursat25°C.

Fromamicrobiologicalpointofview,theproductshouldbeusedimmediately.Ifnotusedimmediately,in–usestorage

timesandconditionspriortousearetheresponsibilityoftheuserandwouldnormallynotbelongerthan24hoursat2

to8°C,unlessdilutionhastakenplaceincontrolledandvalidatedasepticcondition.

6.5Natureandcontentsofcontainer

20mlinOne-PointCut(OPC)ampoule(typeIcolourlessglass);boxof5.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Onlyclearandcolourlesssolutionwithoutvisibleparticlesshouldbeused.

Forsingleuseonly.Anyunusedproductmustbediscarded.

FOMEPIZOLEEUSAPharma5mg/mL,concentrateforsolutionforinfusion,istobedilutedbeforeuse.Preparation

ofsolutionforinfusionmusttakeplaceinasepticconditions.

Theconcentrateshouldbedilutedwith0.9%sodiumchloridesolutionor5%glucosesolutionforintravenoususe.

Inpatientwithnormalrenalfunction:

Eachsingledosewillbedilutedwith100to250mloftheabovesolutionsandinfusedover30to45minutesas

outlinedinsection4.2.

Inpatientwithimpairedrenalfunction:

Forcontinuousinfusioninpatientundergoinghaemodialysis,theconcentratemayexceptionallybedilutedinareduced

volumeoftheabovesolutions,inordertoavoidfluidoverload.

7MARKETINGAUTHORISATIONHOLDER

EUSAPharmaSAS

LesJardinsd'Eole

3AlléedesSéquoias

69760Limonest

France

8MARKETINGAUTHORISATIONNUMBER

PA1020/1/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:11October2002

Dateoflastrenewal:21September2010

10DATEOFREVISIONOFTHETEXT

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