FLUCONAZOLE TEVA

Main information

  • Trade name:
  • FLUCONAZOLE TEVA
  • Dosage:
  • 2 Mg/ Ml
  • Pharmaceutical form:
  • Solution for Infusion
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FLUCONAZOLE TEVA
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/041/001
  • Authorization date:
  • 19-06-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FluconazoleTeva2mg/mlsolutionforinfusion.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlsolutionforinfusioncontains2mgoffluconazole.

100mlofsolutionforinfusioncontains200mgoffluconazole.

200mlofsolutionforinfusioncontains400mgoffluconazole.

Excipient:

1mlsolutionforinfusioncontains9mgofsodiumchloride

(354mgsodiumin100mlofsolution,709mgsodiumin200mlofsolution).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinfusion

Clear,colourlesssolution.Thesolutionisiso-osmoticanditspHis6.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Adults

TreatmentofmycosescausedbyCandida,Cryptococcusandothersusceptibleyeasts,in

particular:

systemiccandidiasis(includingdisseminateddeepinfectionsandperitonitis)

severemucosalcandidiasis(includingoropharyngealcandidiasis,oesophagealcandidiasisandnon-invasive

bronchopulmonarycandidiasis),whereoraltreatmentisnotpossible

cryptococcalmeningitis

prophylaxisagainstdeepCandidainfections(especiallyCandidaalbicans)inpatientswithneutropeniadueto

bonemarrowtransplant.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantimycoticagents.Beforeinitiating

treatment,samplesshouldbetakenformicrobiologicalanalysis,andthesuitabilityofthetherapyshouldsubsequently

beconfirmed(seesection4.2andsection5.1).

Insomepatientswithseverecryptococcalmeningitisthemycologicalresponseduringfluconazoletreatmentmaybe

slowerthanduringothertreatments(seesection4.4).

Childrenandadolescents

TreatmentofmycosescausedbyCandidaandothersusceptibleyeasts,inparticular:

systemiccandidiasis(includingdisseminateddeepinfectionsandperitonitis)

severemucosalcandidiasis(includingoropharyngealcandidiasis,oesophagealcandidiasisandnon-invasive

bronchopulmonarycandidiasis),whereoraltreatmentisnotpossible.

Fluconazoleshouldnotbeusedfortineacapitis.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantimycoticagents.Beforeinitiating

treatment,samplesshouldbetakenformicrobiologicalanalysis,andthesuitabilityofthetherapyshouldsubsequently

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4.2Posologyandmethodofadministration

Onlyforintravenoususeasinfusion.

Treatmentwithfluconazoleshouldbeinitiatedbyaphysicianexperiencedinthemanagementofinvasivefungal

infections.Thedoseisdependentonthetypeandtheseverityoftheinfection.Thetreatmentofinfectionsrequiring

multipledosingmustbecontinueduntilclinicalparametersorlaboratoryresultsshowthattheactiveinfectionhas

declined.Aninsufficienttreatmentperiodmayleadtorecurrenceoftheactiveinfection.

Fluconazoleisalsoavailablefororaltreatment.Thepatientshouldbeswitchedfromintravenoustooraladministration

assoonaspossible.Itisnotnecessarytochangethedailydoseoffluconazolewhenchangingtherouteof

administrationfromintravenoustooral.

Adults:

PleaserefertoTable1forspecificdosagerecommendations.

ElderlyPatients:

Thenormaladultdoseshouldbegivenifthereisnoevidenceofrenalimpairment.PleaserefertoTable1.

Table1–Guidelinesforthedosetobeadministeredtoadultswhoaretreatedintravenously

Treatmentwithfluconazoleshouldbeinitiatedbyaphysicianexperiencedinthemanagementofinvasivefungal

infections.

Indication InitialDaily

dose(mg) Subsequent

dailydose(mg) Recommended

durationof

treatment Additional

recommendations

Systemic

candidiasis:

candidemia,

disseminated

candidiasisand

otherformsof

invasive

candidal

infection 400-800 200-400 dependentonthe

clinicalresponse Thedosechosen

musttakeinto

accountlocal

patternsof

resistanceto

fluconazole(see

section5.1).

Wherethe

sensitivityofthe

pathogenhasnot

yetbeen

established,the

higherdose

shouldinitially

beconsidered.

Inmostcasesa

loadingdoseof

800mgonthe

firstday,

followedby400

mgdaily

thereaftermaybe

preferable.

Severemucosal

candidiasis:

oropharyngeal

candidiasis 100 100 7to14days Useonlywhen

oral

administrationis

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Paediatricuse

Fluconazole2mg/mlisnotrecommendedforuseinchildrenandadolescentsundertheageof16yearsdueto

insufficientdataonsafetyandefficacy(seesection5.2).

Itmayonlybeusedifthereisnotherapeuticalternativeavailable.

Aswithsimilarinfectionsinadults,thedurationofthetreatmentisbasedontheclinicalandmycologicalresponse.

Fluconazole2mg/mlisadministeredasasingledailydose.

Forchildrenwithimpairedrenalfunction,seedosingin“Useinpatientswithimpairedrenalfunction.”

Childrenoverfourweeksofage

TherecommendeddoseofFluconazole2mg/mlformucosalcandidiasisis3mg/kgdaily.Aloadingdoseof6mg/kg

maybeusedonthefirstdaytoachievesteadystatelevelsmorerapidly.

Forthetreatmentofsystemiccandidiasisandcryptococcalinfections,therecommendeddosageis6-12mg/kgdaily,

othermucosal

Candida

infections

(exceptgenital

candidiasis) 100 100 14to30days Insomecasesa

dailydosehigher

than100mgmay

berequiredand

treatmentcanbe

prolonged.

Thedurationof

maintenance

treatmentof

AIDSpatients

shouldbe

weighedagainst

theincreasedrisk

ofresistanceto

fluconazole.

Treatmentof

cryptococcal

meningitis:

initial

treatment 400 200-400 Typically6to8

weeks Thedurationof

thetreatment

dependonthe

clinicaland

mycological

response.

Prophylaxis

againstdeep

Candida

infections:

inpatientswith

neutropenia

duetobone

marrow

transplantation 400 400 Seeadditional

guidance Fluconazole

administration

shouldstart

severaldays

beforethe

expectedonsetof

neutropenia,and

continuefor

sevendaysafter

theneutrophil

countrisesabove

1000cellsper

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Forthepreventionoffungalinfectionsinimmunocompromisedpatientsconsideredatriskasaconsequenceof

neutropeniafollowingcytotoxicchemotherapyorradiotherapy,thedoseshouldbe3-12mg/kgdaily,dependingonthe

extentanddurationofinducedneutropenia(seeadultdosing).

Amaximumdosageof400mgdailyshouldnotbeexceededinchildren.

Childrenfourweeksofageandyounger

Neonatesexcretefluconazoleslowly.Inthefirsttwoweeksoflife,thesamemg/kgdosingasinolderchildrenshould

beusedbutadministeredevery72hours.Duringweeks3and4oflife,thesamedoseshouldbegivenevery48hours.

TherearefewPKdatatosupportthisposologyintermnewbornbabies(seesection5.2–Pharmacokineticproperties).

Amaximumdosageof12mg/kgevery72hoursshouldnotbeexceededinchildreninthefirsttwoweeksoflife.For

childrenbetween3and4weeksoflife,12mg/kgevery48hoursshouldnotbeexceeded.

Thepharmacokineticsoffluconazolehasnotbeenstudiedinchildrenwithrenalinsufficiency.

Patients(adultsandpaediatric)withimpairedrenalfunction

Fluconazoleisclearedprimarilybyrenalexcretionasunchangeddrug.

Inpatientswithimpairedrenalfunctionwhoreceivemultipledosetherapy,therecommendedinitialloadingdosecan

begiven(seeTable1).Aftertheloadingdose,thedailydose(accordingtoindication)isadjustedinrelationto

creatinineclearanceasfollows:

Table3– Requireddoseadjustmentsaftertheinitialdoseforpatientswithimpairedrenalfunction(depending

ontheclinicalcondition,extraadjustmentsofthedosemayberequired).

Thepharmacokineticsoffluconazolehavenotbeenstudiedinchildrenwithrenalinsufficiency.

Patientswithhepaticinsufficiency

Fluconazoleshouldonlybeadministeredwithspecialcareandundercarefulmonitoringinpatientswithliver

insufficiency(seesection4.4).

Interactionsrequiringdoseadjustments

ModificationstothedosingschedulesprovidedinTables1to3mayberequiredwhereconcomitantuseofeither

rifampicinorhydrochlorothiazideisproposed.

Furtherdetailsareprovidedinsection4.5.

Infusionratesandinstructionsforuse

Theinfusionrateshouldnotexceed10ml/min(20mg/min)foradults.

Inchildrentherateofintravenousinfusionshouldnotexceed5ml/min(10mg/min).

Creatinineclearance(ml/minute) Percentageoftherecommended

dose

>50 normaldosageregimen(100%)

11-50 halfthenormaldailydose(50%)

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Inpatientsrequiringsodiumorfluidrestriction,therateofadministrationshouldbetakenintoconsiderationas

Fluconazoleconsistsofasaltsolution.Insuchcasestheinfusionshouldbegivenoveralongerperiod.

Fluconazoleisformulatedin0.9%sodiumchloridesolution;each100mlofthesolutionforinfusioncontains15mmol

ofNa +

and15mmolC1 -

.Considerationshouldbegiventotherateoffluidadministrationinpatientsrequiringsodium

orfluidrestriction.

Fluconazolemaybeadministeredeitherorallyorbyintravenousinfusion.Thechoiceoftheappropriaterouteof

administrationwilldependontheclinicalconditionofthepatient.

Forinstructionsonthehandlingoftheproduct,seesection6.6.

4.3Contraindications

Hypersensitivitytofluconazoleorotherazolecompoundsortoanyoftheexcipients.Fluconazolemustnotbe

co-administeredwithdrugsbothknowntoprolongtheQTintervalandwhicharemetabolisedbyCYP3A4such

ascisapride,astemizole,terfenadine,pimozideandquinidine.Seesection4.4andsection4.5.

4.4Specialwarningsandprecautionsforuse

Thereissomeevidencethatinsomepatientswithcryptococcalmeningitisthemycologicalresponseduringfluconazole

treatmentmaybeslowercomparedtotreatmentwithamphotericineBincombinationwithflucytosine.Thisshouldbetaken

intoaccountforthetreatmentchoiceinpatientswithseverecryptococcalmeningitis.

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,abnormalitiesofhepatic,

renal,haematologicalandotherbiochemicalfunctiontestshavebeenobservedduringtreatmentwithFluconazole2

mg/mlsolutionforinfusionbuttheclinicalsignificanceandrelationshiptotreatmentisuncertain.

Becauseacausalrelationshipwithfluconazolecannotbeexcluded,patientswhodevelopabnormalliverfunctiontests

duringfluconazoletherapyshouldbemonitoredforsignsofthedevelopmentofmoreserioushepaticinjury.

Fluconazoleshouldbediscontinuedifclinicalsignsorsymptomsconsistentwithliverdiseasedevelopduring

treatment.

Severehepatictoxicity,includingdeath,hasbeenreportedinrarecases,mostofteninpatientswithsevereunderlying

diseases.Noobviousrelationshipbetweenhepatotoxicityandtotaldailydoseoffluconazole,durationoftherapy,

genderortheageofthepatienthasbeenobserved.

Thelivertoxicityhasmostoftenbeenreversiblefollowingwithdrawalofthetreatment.Thebenefitsofthetreatment

shouldbeevaluatedagainsttherisksofdevelopingseriousliverdamageiftherapyiscontinuedinpatientswhoseliver

enzymevaluesriseduringfluconazoletreatment.

Thedoseoffluconazolemustbereducedwhencreatinineclearanceisbelow50ml/min(seesection4.2).

Certainazoles,includingfluconazole,havebeenassociatedwithprolongationoftheQT-interval.Rarecasesoftorsade

depointeshavebeenreportedduringtreatmentwithfluconazole.Eventhoughaconnectionbetweenfluconazoleand

prolongedQT-intervalhasnotbeenformallyconfirmed,fluconazoleshouldbeadministeredwithcautioninpatients

withpotentiallypro-arrhythmicconditions,suchas:

CongenitalordocumentedacquiredQTprolongation

Cardiomyopathy,particularlyinthepresenceofheartfailure

Clinicallysignificant(includingsinus)bradycardia

Symptomaticarrhythmias

Electrolytedisturbances

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Electrolytedisturbancessuchashypokalaemia,hypomagnesaemiaandhypocalcaemiashouldbecorrectedpriorto

initiationoffluconazoletreatment.

InrarecasespatientshavedevelopedexfoliativeskinreactionsincludingStevens-Johnsonsyndromeandtoxic

epidermalnecrolysisduringtreatmentwithfluconazole.AIDS-patientshaveahighertendencyforthedevelopmentof

seriousskinreactionsfromvariousdrugs.

Wherepatientswithminorfungalinfectionsthatarebeingtreatedwithfluconazoledevelopaskinrash,consideredto

beconnectedtotreatmentwithfluconazole,thetreatmentshouldbestopped.

Ifpatientswhoarebeingtreatedforinvasivefungalinfectionsorsystemicinfectionsdevelopaskinrash,theyshould

becloselymonitoredandthetreatmentdiscontinuedifbullousskinreactionsorerythemamultiformedevelop.

FluconazoleisapotentinhibitorofcytochromeP450(CYP)isoenzyme2C9andamoderateinhibitorofCYP3A4.

Patientswhoreceiveconcomitanttreatmentwithfluconazoleanddrugswhichhaveanarrowtherapeuticinterval(e.g.

warfarinandphenytoin)andwhicharemetabolisedviaCYP2C9and/orCYP3A4shouldbecloselymonitored(see

sections4.3and4.5).

Fluconazolemayextendtheprothrombintimefollowingadministrationofwarfarin.Closemonitoringofthe

prothrombintimeisrecommended.

Rareinstancesofanaphylacticreactionshavebeenreported(seesection4.8).

Cautionmustbeexercisedinpatientswithrenalimpairment.Pleaserefertosection4.2.

Inwomenofchild-bearingpotential,appropriatecontraceptivemeasuresshouldbeconsideredincaselong-term

treatmentisindicated(seesection4.6).

Dataregardingefficacyandsafetyoffluconazoleinchildrenandadolescentslessthan16yearsofagearestilllimited.

Thereforethebenefitsofthetreatmentwithfluconazoleshouldbecarefullyevaluatedagainsttherisks.

Patientsconcurrentlyreceivingfluconazoleatdosesbelow400mg/dayandterfenadinerequireclosemonitoring(see

section4.5).

Thismedicinalproductcontains15.4mmol(354mg)sodiumper100mlofsolution.Thisshouldbetakenintoaccount

inpatientsonacontrolledsodiumdietandincaseswherefluidrestrictionisrequired.Refertosection2forsodium

contentsineachpacksize.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Inadditiontotheinteractionsgivenbelow,thereisariskofelevatedserumconcentrationsofotherdrugsmetabolised

viaCYP2C9andCYP3A4withconcomitantadministrationoffluconazole.Fluconazoleisapotentinhibitorof

cytochromeP450(CYP)isoenzyme2C9andamoderateinhibitorofCYP3A4.Thereforecautionshouldalwaysbe

observedduringcombinationtherapywithmedicationssuchastheseandthepatientcloselymonitored.Theeffects

maypersistfor4-5daysduetothelonghalf-lifeoffluconazole.

Afteradministrationoffluconazole,thefollowinginteractionshavebeenreported.

Thefollowingcombinationsarecontraindicated(seesection4.3):

Astemizole(CYP3A4substrate):

AstemizoleoverdoseshaveledtoprolongedQTinterval,severeventriculararrhythmia,torsadedepointesand

cardiacarrest.Concomitantadministrationofastemizoleandfluconazoleiscontraindicatedduetothepotential

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Cisapride(CYP3A4substrate):

Inpatientswhowereadministeredfluconazoleandcisapridesimultaneously,casesofheartdisordershavebeen

reported,includingtorsadedepointes.Cardiovasculareffects,includingtorsadedepointes,havebeenreported

inpatientshavingreceivedconcomitanttreatmentoffluconazoleandcisapride.Administrationof200mg

fluconazoleoncedailyconcomitantlywithcisapride20mgfourtimesdaily,ledtoasignificantincreasein

plasmalevelsofcisaprideandprolongationoftheQTc-interval.Concurrenttreatmentwithfluconazoleand

cisaprideiscontraindicated(seesection4.3).

Terfenadine(with400mgfluconazoleandhigher,CYP3A4substrate):

Seriouscardiacarrhythmias,secondarytoaprolongedQTcintervalhaveoccurredinpatientstreatedwithanti-

fungalmedicationssuchastriazolecompoundsandterfenadine.

Concomitanttreatmentwith200mgoffluconazoledailyshowednoprolongationoftheQTcinterval.Withdoses

of400mgand800mgfluconazoledailytheplasmaconcentrationsofterfenadineincreasedsignificantly.

Concomitanttreatmentwithfluconazole400mgperdayorhigherdosesiscontraindicated.Duringconcomitant

treatmentwithdosesbelow400mgperday,thetreatmentshouldbecloselymonitored.

Theeffectsofotherdrugsonfluconazole

Hydrochlorothiazide:

Inapharmacokineticinteractionstudywithhealthyvolunteerswhoconcomitantlyreceivedfluconazoleand

multipledosesofhydrochlorothiazidetheplasmaconcentrationsofthefluconazoleincreasedby40%.Even

thoughaneffectofthissizeshouldnotgiverisetoanyneedtochangethefluconazoledoseinpatientswhoare

concomitantlytreatedwithdiuretics,theprescribershouldbeawareofthis.

Rifampicin(CYP450inducer):

Concomitanttreatmentwithfluconazole(200mg)andrifampicin(600mgdaily)reducedAUCforfluconazole

by23%inhealthyvolunteers.Anincreaseinthedoseoffluconazoleshouldbeconsideredincombination

treatment.

Possibleeffectsoffluconazoleonthemetabolismofotherdrugs

Alfentanil(CYP3A4substrate):

Onsimultaneousintravenousadministrationof400mgfluconazoleand20microgram/kgalfentaniltohealthy

volunteers,theAUC

ofalfentanilincreasedtwofoldandclearancedecreasedby55%,probablythrough

inhibitionofCYP3A4.Thecombinationmayrequiredoseadjustment.

Amitriptyline:

Severalcasereportshavedescribedthedevelopmentofelevatedamitriptylineconcentrationsandsignsof

tricyclictoxicitywhenamitriptylineisusedincombinationwithfluconazole.Concomitantinfusionof

fluconazoleandnortriptyline,theactivemetaboliteofamitriptyline,hasbeenreportedtoleadtoincreased

nortriptylinelevels.Duetotheriskofamitriptylinetoxicity,monitoringofamitriptylinelevelsshouldbe

consideredwithdoseadjustmentwhereindicated.

Anticoagulants(CYP2C9substrate):

Inconcomitanttreatmentwithfluconazoleandwarfarin,theprothrombintimeincreaseduptotwofold.Thisis

probablyduetoaninhibitionofthemetabolismofwarfarinviaCYP2C9.Theprothrombintimeshouldbe

monitoredcloselyinpatientstreatedconcomitantlywithfluconazoleandcoumarin-typeanticoagulants.

Antiretroviraldrugs(CYP3A4substrate):

Therearereportsofincreasedserumlevelsfollowingconcurrentadministrationoffluconazolewithantiretroviral

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Benzodiazepines(CYP3A4substrate):

FluconazolemayinhibitthemetabolismofbenzodiazepinesmetabolisedviaCYP3A4,e.g.midazolamand

triazolam.Inconcomitantoralsingledosetreatmentwithfluconazole(400mg)andmidazolam(7.5mg)AUC

increased3.7timesandthehalflifeofmidazolam2.2times.Thecombinationshouldbeavoided.Where

concomitanttreatmentisconsiderednecessary,areductioninthedoseofmidazolamshouldbeconsideredand

thepatientmonitoredclosely.Inconcomitanttreatmentwithfluconazole(100mgdailyfor4days)andtriazolam

(0.25mg)theAUCandhalflifeoftriazolamincreasedrespectively2.5and1.8times.Prolongedandenhanced

effectsfromtriazolamhavebeenobserved.Thecombinationmayrequirereductioninthedoseoftriazolam.

Calciumantagonists(CYP3A4substrate):

Somedihydropyridinecalciumchannelantagonists,includingnifedipine,isradipine,nicardipine,amlodipineand

felodipine,aremetabolisedviaCYP3A4.Therearereportsofextensiveperipheraloedema,vertigo,hypotension,

headache,rednessofthefaceand/orelevatedserumcalciumantagonistconcentrationsarisingfollowingco-

administrationoftheazoleitraconazolewithfelodipine,isradipineornifedipine.Aninteractionmightoccuralso

withfluconazole.

Carbamazepine(CYP3A4substrate):

Therearereportsofincreasedserumcarbamazepinelevelsfollowingconcurrentadministrationoffluconazole

andcarbamazepine.

Celecoxib(CYP2C9substrate):

Inconcomitanttreatmentwithfluconazole(200mgdaily)andcelecoxib(200mg),C

andAUCforcelecoxib

increasedby68%and134%,respectively.Halvingofthedoseofcelecoxibisrecommendedincombination

therapywithfluconazole.

Ciclosporin(CYP3A4substrate):

Inconcomitanttreatmentwith200mgfluconazoledailyandciclosporin(2.7mg/kg/day),AUCforciclosporin

increasedapproximately1.8timesandclearancewasreducedbyapproximately55%.However,inanother

multipledosestudywith100mgdaily,fluconazoledidnotaffectciclosporinlevelsinpatientswithbonemarrow

transplants.Theplasmaconcentrationsofciclosporinshouldbemonitoredinconcomitanttreatmentwith

fluconazole.

Didanosine:

Co-administrationofdidanosineandfluconazoleappearstobesafeandhaslittleeffectondidanosine

pharmacokineticsorefficacy.However,itisimportanttomonitorthefluconazoleresponse.Itmaybe

advantageoustostaggerfluconazoledosingtoatimepriortodidanosineadministration.

Halofantrine(CYP3A4substrate):

DrugsthatinhibitCYP3A4leadtoinhibitionofhalofantrinemetabolismandcancauseaprolongationoftheQT

interval.Theconcomitantuseoffluconazoleandhalofantrineisnotrecommended.

HMG-CoAreductaseinhibitors(CYP2C9orCYP3A4substrate):

TheriskofmyopathyincreaseswhenfluconazoleisadministeredconcomitantlywithHMG-CoAreductase

inhibitorsthataremetabolisedviaCYP3A4,e.g.atorvastatinorsimvastatin,orbyCYP2C9suchasfluvastatin.

Forfluvastatinanindividualincreaseofupto200%intheareaunderthecurve(AUC)canoccurasaresultof

interactionbetweenfluvastatinandfluconazole.Anindividualpatientusingfluvastatin80mgdailymaybe

exposedtoconsiderablefluvastatinconcentrationsiftreatedwithhighdosesoffluconazole.Cautionshouldbe

observedwhereconcomitanttreatmentwithfluconazoleandHMG-CoAreductaseinhibitorsisconsidered

necessary.ThecombinationmayrequiredosereductionoftheHMG-CoAreductaseinhibitors.Patientsshouldbe

observedwithregardtosignsofmyopathyorrhabdomyolysisandcreatinekinaselevels(CK).TheHMG-CoA

treatmentshouldbediscontinuedifCKlevelsshowamarkedincreaseorifmyopathyorrhabdomyolysisis

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Losartan(CYP2C9substrate):

Fluconazoleinhibitstheconversionoflosartantoitsactivemetabolite(E-3174),whichisresponsibleformostof

theangiotensinIIreceptorantagonismthatoccurswithlosartantherapy.Simultaneoustreatmentwithfluconazole

mayleadtoincreasedlosartanconcentrationsanddecreasedconcentrationsoftheactivemetabolite.Itis

recommendedthatpatientsreceivingthecombinationbemonitoredforcontinuedcontroloftheirhypertension.

Methadone(CYP3A4substrate):

Therehavebeenreportsofanintensifiedeffectofmethadoneaftersimultaneousadministrationoffluconazole

andmethadone.OnepharmacokineticstudyshowedanaverageincreaseoftheAUCofmethadoneby35%.

Oralcontraceptives:

Twopharmacokineticstudieshavebeencarriedoutwithcombinedoralcontraceptivesandrepeateddosesof

fluconazole.Therewerenorelevanteffectsoneitherhormonelevelwhen50mgfluconazolewasadministered.

Fluconazolegiven200mgdailyraisedtheAUCofethinylestradiolandlevonorgestrelby40%and24%

respectively.Multipledoseuseoffluconazoleisthereforeunlikelytoinfluencetheeffectofthecombinedoral

contraceptive.

Phenytoin(CYP2C9substrate):

Withintravenousadministrationof200mgfluconazoletogetherwith250mgofphenytoin,theAUC

andthe

ofphenytoinincreasedby75%and128%,respectively.Incombinationtreatment,plasmaphenytoin

concentrationsshouldbemonitoredandthedoseadjusted.

Prednisone(CYP3A4substratethatismetabolisedtoprednisolone):

AlivertransplantrecipientreceivingprednisoneexperiencedanAddisoniancrisiswhenathreemonthcourseof

fluconazolewasdiscontinued.WithdrawaloffluconazoleprobablycausedanincreaseinCYP3A4activity,so

thatdegradationofprednisoneincreased.Patientsundergoinglong-termtreatmentwithfluconazoleand

prednisone(orotheradrenocorticoidtherapy)shouldbecloselymonitoredforsignsofadrenalinsufficiencywhen

fluconazoleisdiscontinued.

Rifabutin(CYP3A4substrate):

Inconcomitanttreatmentwithfluconazoleandrifabutin,theserumconcentrationsofrifabutinincreased.Uveitis

hasbeenreported.Patientsundergoingconcomitanttreatmentshouldbemonitoredclosely.

Sulphonylureas(CYP2C9substrate):

Fluconazolehasdisplayedprolongedhalf-lifeinserumforconcomitantlyadministeredsulphonylureas

(glibenclamide,glipizide,chlorpropamideandtolbutamide)inhealthyvolunteers.Fluconazolemaybe

administeredtodiabeticstogetherwithsulphonylureas,buttheriskofhypoglycaemiashouldbeconsidered.

Bloodglucoselevelsshouldbecloselymonitored.

Tacrolimusandsirolimus(CYP3A4substrate):

Inconcomitantoraltreatmentwithfluconazoleandtacrolimus(0.15mg/kgtwicedaily)theplasmaconcentration

troughleveloftacrolimusincreased1.4and3.1timeswithadailyfluconazoledoseof100mgand200mg

respectively.Nephrotoxicityhasbeenreported.Eventhoughnointeractionstudieshavebeenperformedwith

fluconazoleandsirolimus,asimilarinteractioncanbeanticipated.Inconcomitanttreatmentwithfluconazole

andtacrolimusorsirolimus,patientsshouldbecloselymonitoredandanadjustmentindoseconsidered.

Theophylline:

Administrationof200mgfluconazolefor14daysledtoan18%decreaseinthemeanplasmaclearanceof

theophylline.Patientswhoarereceivinghighdosesoftheophyllineorwhoareotherwiseatincreasedriskfor

theophyllinetoxicityshouldbeobservedforsignsoftheophyllinetoxicitywhilereceivingfluconazole,andthe

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Trimetrexate:

Fluconazolemayinhibitthemetabolismoftrimetrexate,leadingtoincreasedtrimetrexateplasmaconcentrations.

Ifthecombinationcannotbeavoided,trimetrexateserumlevelsandtoxicity(bonemarrowsuppression,renaland

hepaticdysfunction,andgastro-intestinalulceration)mustbecloselymonitored.

Xanthinebases,otheranti-epilepticdrugsandisoniazide:

Follow-uptestsmustbecarriedoutwhenfluconazoleisadministeredconcomitantlywithxanthinebases,other

anti-epilepticdrugsandisoniazide.

Zidovudine:

Interactionstudieshaveshownthatwhenzidovudineistakentogetherwithfluconazole200mgor400mgdaily

thezidovudineAUCvaluesmayberaisedbybetween20%and70%,probablyasaresultoftheinhibitionof

conversiontotheglucuronide.Patientsreceivingthiscombinationshouldbemonitoredforzidovudine-related

adversereactions.

Otherinteractionswithmedicinalproducts

AmphotericinB:

InvitroandinvivoanimalstudieshaveshownantagonismbetweenamphotericinBandazolederivatives.The

mechanismofactionofimidazolesistoinhibitergosterolsynthesisinfungalcellmembranes.AmphotericinB

actsbybindingtosterolsinthecellmembraneandchangingitsmembranepermeability.Theclinicaleffectof

thisantagonismisstillunknown,andasimilareffectmayoccurwiththeamphotericinBcholesterolsulfate

complex.

DrugsthatcauseQTprolongation:

CasereportsindicatethatfluconazolemighthavethepotentialtoinduceQTprolongationleadingtoserious

cardiacarrhythmia.PatientstreatedconcomitantlywithfluconazoleandotherdrugsthatprolongtheQTinterval

shouldbecarefullymonitoredsinceanadditiveeffectcannotbeexcluded.

Interactionstudiesshowthatconcomitantadministrationoffluconazolewithfoodintake,cimetidine,antacid,or

followingtotalbodyirradiationinbonemarrowtransplantation,doesnotsignificantlyaffectfluconazoleabsorption.

Physiciansshouldbeawarethatdrug-druginteractionstudieswithothermedicationshavenotbeenconducted,butthat

suchinteractionsmayoccur.

4.6Fertility,pregnancyandlactation

Pregnancy:

Datafromseveralhundredpregnantwomentreatedwithstandarddosesoffluconazole(lessthan200mg/day)

administeredasasingleorrepeateddoseduringthefirsttrimesterofpregnancy,doesnotindicateundesirableeffects

onthefoetus.

Therearereportsonmultiplecongenitalabnormalities(includingbrachycephalia,earsdysplasia,giantanterior

fontanelle,femoralbowingandradiohumeralsynostosis)inchildrenwhosemothersweretreatedforcoccidiomycosis

withhighdosefluconazole(400-800mg/day),for3monthsorlonger.Therelationbetweentheuseoffluconazoleand

theseeffectsisunclear.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3),butthepotentialriskinhumansisunknown.

Fluconazoleinstandarddosesandshort-termtreatmentshouldnotbeusedduringpregnancyunlessclearlynecessary.

Fluconazoleathighdosesorinprolongedregimensshouldnotbeusedduringpregnancyexceptforlifethreatening

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Duetopotentialteratogeniceffectswomenofchildbearingpotentialmustuseeffectivecontraceptionduringtreatment.

Lactation:

Fluconazoleissecretedintobreastmilkatconcentrationslowerthanthoseinplasma.Breast-feedingmaybecontinued

afterasingledoseof200mgfluconazoleorless.Breast-feedingisnotrecommendedafterrepeateduseorafterhigh-

dosefluconazole.

4.7Effectsonabilitytodriveandusemachines

Fluconazole2mg/mlsolutionforinfusionhasnegligibleinfluenceontheabilitytodriveandusemachines.However,

itshouldbeborneinmindthatdizziness,seizuresandothersideeffectsmayoccur(seesection4.8).

4.8Undesirableeffects

Adversereactionsassociatedwithfluconazoleobservedinclinicaltrialsandpost-marketingstudiesarelistedbelow.

Frequenciesaredefinedas:

Verycommon(1/10)

Common(1/100to<1/10)

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

Rare(1/10,000to<1/1,000)

Veryrare(<1/10,000)

Notknown(cannotbeestimatedfromtheavailabledata).

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

Adversereactionswithverycommon(1/10)frequencyuntilnowhavenotbeenrecognized.

Systemorgan

classes Common

(1/100to

<1/10) Uncommon

(1/1,000to

<1/100) Rare

(1/10,000to

<1/1,000) Veryrare

(1/10,000) Notknown

(cannotbe

estimatedfrom

theavailabledata)

Infectionand

infestation infectiondueto

resistantmicro-

organisms

Bloodand

lymphatic

system

disorders anaemia agranulocytosis.

leukopenia,

neutropenia,

throm-

bocytopenia

Immune

system

disorders anaphylactic

reactions angioedema,

faceoedema

Metabolism

andnutrition

disorders hypercholes-

terolemia,

hyper-

triglyceridemia,

hypokalaemia

Psychiatric

disorders insomnia,

somnolence

Nervous

system

disorders headache convulsions,

dizziness,

paraesthesiae,

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AdversereactionswerereportedmorefrequentlyinHIVinfectedpatients(21%)thaninnon-HIVinfectedpatients

(13%).However,thepatternsofadversereactionsinHIVinfectedandnon-HIVinfectedpatientsweresimilar.

Paediatricpopulation:

Thepatternandincidenceofsideeffectsandlaboratoryabnormalitiesrecordedduringpaediatricusearecomparableto

taste

sensations,

tremor,

vertigo

Cardiac

disorders ventricular

arrhythmia(QT

prolongation,

Torsadede

Pointes)(see

section4.4)

Gastrointestinal

disorders vomiting,

nausea,

abdominal

pain,

diarrhoea dyspepsia,

flatulence,

anorexia,

constipation,

drymouth

Hepato-biliary

disorders increaseinthe

serum

activitiesof

liver-derived

enzymessuch

asALP,ALT

andAST cholestasis,a

clinically

relevantrise

intotal

bilirubin,

jaundice,

hepatotoxicity hepatitis,liver

cellnecrosis,

liverfailure

withisolated

fatalities.The

appropriate

laboratory

valuesshould

beveryclosely

monitored(see

section4.4)

Skinand

subcutaneous

tissue

disorders maculopapular

erythema,rash urticaria,

pruritus,

increased

sweating exfoliativeskin

disorders

(Stevens-

Johnson

syndrome),

alopecia exfoliative

skindisorders

(toxic

epidermal

necrolysisor

Lyell

syndrome) acutegeneralised

exanthematous

pustulosis(fixed)

drugeruption

Musculoskeletal

connective

tissueand

bone

disorders myalgia

Renaland

urinary

disorders changesin

renal

function

tests

General

disordersand

administration

siteconditions fatigue,

malaise,

asthenia,

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4.9Overdose

Inmostpatientsoverdoseresultsingastrointestinalcomplaintsandskinreactions(itch,rash,etc.).Therehasbeena

reportofanoverdosewithfluconazolewherea42yearoldHIVinfectedpatientdevelopedhallucinationsandexhibited

paranoidbehaviourafterreportedlyingesting8,200mgofFluconazolewithoutmedicalsupervision.Thepatientwas

admittedtohospitalandhissymptomsresolvedwithin48hours.

Treatment:

Intheeventofoverdose,supportivemeasuresandsymptomatictreatment,andgastriclavageifnecessary,maybe

adequate.

Fluconazoleismainlyexcretedintheurine.A3-hourhaemodialysissessionreducesplasmalevelsbyapproximately

50%.Nodataareavailableontheeffectofforceddiuresis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticcategory:

Antimycoticsforsystemicuse,triazolederivates.

ATCcode:J02AC01.

Mechanismofaction

Fluconazolebelongstothetriazoleclassofantimycotics,withamainlyfungistaticaction.Itisapotentandselective

inhibitorofergosterolsynthesisinfungi,whichleadstodefectsinthecellmembrane.Fluconazoleisveryspecificfor

fungalcytochromeP450enzymes.

Mechanismofresistance

Dependingontheyeastspeciesinvolved,theprincipalmechanismsofresistancetofluconazole,incommonwithother

azoleantifungalagents,involveimpairingtheaccumulationofthedruginthecellby

alteringtheaminoacidcompositionoflanosterol14-demethylase,

(ii) increasingdrugefflux,and

(iii) alteringtheergosterolbiosyntheticpathways.

InCandidaalbicans,blockageoftheergosterolsyntheticpathwaysisthoughttoprimarilyarisefromblockageof

sterolC5,6-desaturasewhichisencodedbyERG3,Inthemoreresistantspecies,Candidaglabrata,the

predominantpathwayhasnotbeenfullyelucidatedbutisthoughttoarisefromupregulationofCDRgenes(CDR1,

CDR2andMMDR1)responsibleforeffluxofthedrugsubstancefromthecells.Resistancetofluconazoletherefore

usuallyconfersresistancetootherazoleantifungalagents.InCryptococcusneoformansthestudieshave

demonstratedthatthesameprinciplemechanismsofresistanceexistinthisspecies,andthatthesemaybeaffected

bypriorexposuretoazoleantifungalagents.Similarcarefulconsiderationofthebenefitsoftheproposeddose

versustheriskofdevelopmentofresistancemustthereforebeappliedwithfluconazoleasforanyother

antimicrobialchemotherapy.

Breakpoints

AccordingtoEUCAST,thefollowingclinicalbreakpointsapplyforfluconazole:

Organism EUCASTBreakpoints

(µg/ml)

S R>

Candidaalbicans,Candida

parapsilosis,Candidatropicalis 2 4

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TheantimycoticspectrumoffluconazoleincludesanumberofpathogensincludingthespeciesCandidaalbicans,non-

Candidaalbicans,Cryptococcusanddermatophytes.

Theprevalenceofacquiredresistancemayvarygeographicallyandwithtimeforselectedspeciesandlocalinformation

onresistanceisdesirable,particularlywhentreatingsevereinfections.Asnecessary,expertadviceshouldbesought

whenthelocalprevalenceofresistanceissuchthattheutilityoftheagentinatleastsometypesofinfectionsis

questionable.

ResistantisolatesofCandidaalbicanshavebeenfoundinAIDSpatientswhohaveundergonelong-termtreatmentwith

fluconazole.

InfectionsresultingfromAspergillusspecies,ZygomycetesincludingMucorandRhizopus,Microsporumand

Trychophytonspeciesshouldnotbetreatedwithfluconazolesincefluconazolehaslittleornoactivityagainstthese

fungi.

Theefficacyoffluconazoleintineacapitishasbeenstudiedin2randomisedcontrolledtrialsinatotalof878patients,

comparingfluconazolewithgriseofulvin.Fluconazoleat6mg/kg/dayfor6weekswasnotsuperiortogriseofulvin

administeredat11mg/kg/dayfor6weeks.Theoverallsuccessrateat6weekswaslow(fluconazole6weeks:18.3%;

fluconazole3weeks:14.7%;griseofulvin:17.7%)acrossallthetreatmentgroups.Thesefindingsarenotinconsistent

withthenaturalhistoryoftineacapitiswithouttherapy.

5.2Pharmacokineticproperties

Absorption

Thepharmacokineticpropertiesoffluconazolearesimilarfollowingadministrationbytheintravenousororalroute.

Fluconazoleiswellabsorbedafteroralintake.Theabsolutebioavailabilityisgreaterthan90%.Oralabsorptionisnot

affectedbysimultaneousfoodintake.Themaximumfastingplasmaconcentrationisreached0.5-1.5hafter

administrationofthedose.90%ofthesteady-statelevelisreached4-5daysafterdosingoncedaily.

Theplasmaconcentrationisproportionaltothedose.Afteradministrationof200mgfluconazole,C

isapprox.4.6

mg/landtheplasmasteady-stateconcentrationsafter15daysareabout10mg/l.Afteradministrationof400mg

fluconazole,C

isapprox.9mg/landtheplasmasteady-stateconcentrationsafter15daysareabout18mg/l.Taking

adoubledoseonday1leadstoplasmaconcentrationsofapprox.90%oftheplasmasteady-stateconcentrationsonday

Commonlysusceptiblespecies

C.albicans

C.kefyr

C.lusitaniae

C.parapsilosis

Speciesforwhichacquiredresistancemaybe

aproblem

C.dubliniensis

C.famata

C.guillermondii

C.pelliculosa

C.tropicalis

Inherentlyresistantorganisms

C.glabrata

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Distribution

Theapparentvolumeofdistributionoffluconazolecorrespondstototalbodywater.Bindingtoplasmaproteinsislow

(11%-12%).

Fluconazoleachievesgoodpenetrationintoallbodyfluidsstudied.Thefluconazoleconcentrationsinsalivaand

sputumarecomparabletotheplasmaconcentrations.Inpatientswithfungalmeningitisthefluconazoleconcentrations

incerebrospinalfluid(CSF)areapprox.80%ofthecorrespondingplasmaconcentrations.

Inthestratumcorneum,theepidermis-dermisandexocrinesweat,higherfluconazoleconcentrationsarereachedthan

inserum.Fluconazoleaccumulatesinthestratumcorneum.Withaonceweeklydoseof150mg,forexample,the

fluconazoleconcentrationinthestratumcorneumaftertwodoseswas23.3micrograms/g.Sevendaysaftertheendof

thetreatmentthefluconazoleconcentrationwasstill7.1micrograms/g.

Biotransformation

Fluconazoleisbrokendowntoamodestextent.Only11%ofaradioactivedoseisexcretedintheformofmetabolites

intheurine.

Elimination

Fluconazoleismainlyexcretedviathekidneys.Approximately80%ofthedoseisexcretedinnon-metabolizedformin

theurine.Fluconazoleclearanceisproportionaltothecreatinineclearance.Thereisnoevidenceofcirculating

metabolites.

Themeanhalf-lifeintheplasmaisapprox.30h.Thelongplasmahalf-lifeprovidesthebasisfortreatmentwithsingle

dailydosesinallindications.

Pharmacokineticsinchildren

Pharmacokineticdatawereassessedfor113paediatricpatientsfrom5studies;2singledosestudies,2multipledose

studiesandastudyinprematureneonates.Datafrom1studywerenotinterpretableduetochangesinformulation

partwaythroughthestudy.Additionaldatawereavailablefromacompassionateusestudy.

Afteradministrationof2-8mg/kgfluconazoletochildrenbetweenagesof9monthsto15years,aAUCofabout38

µg.h/mlwasfoundper1mg/kgdoseunits.Theaveragefluconazoleplasmaeliminationhalf-lifevariedbetween15

and18hoursandthedistributionvolumewasapproximately880ml/kgaftermultipledoses.Ahigherfluconazole

plasmaeliminationhalf-lifeofapproximately24hourswasfoundafterasingledose.Thisiscomparablewiththe

fluconazoleplasmaeliminationhalf-lifeaftersingleadministrationof3mg/kgi.v.tochildrenof11days–11months

old.Thedistributionvolumeinthisagegroupwasabout950ml/kg.

Experiencewithfluconazoleinneonatesislimitedtopharmacokineticstudiesinprematurenew-borns.Themeanage

atfirstdosewas24hours(range9-36hours)andmeanbirthweightwas0.9Kg(range0.75-1.10Kg)for12pre-term

neonatesofaveragegestationaround28weeks.Sevenpatientscompletedtheprotocol;amaximumoffive6mg/Kg

intravenousinfusionsoffluconazolewereadministeredevery72hours.Themeanhalf-life(hours)was74(range44-

185)onday1whichdecreased,withtime,toameanof53(range30-131)onday7and47(range27-68)onday13.

Theareaunderthecurve(microgram.h/ml)was271(range173-385)onday1andincreasedwithameanof490(range

292-734)onday7anddecreasewithameanof360(range167-566)onday13.Thevolumeofdistribution(ml/Kg)

was1183(range1070-1470)onday1andincreased,withtime,toameanof1184(range510-2130)onday7and1328

(range1040-1680)onday13.

Thepharmacokineticpropertiesoffluconazolehavenotbeeninvestigatedinchildrenwithrenalinsufficiency.

5.3Preclinicalsafetydata

Preclinicaldatafromconventionalstudiesonrepeat-dose/generaltoxicity,genotoxicityorcarcinogenicityindicateno

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Inreproductiontoxicitystudiesinratanincreasedincidenceofhydronephrosisandextensionofrenalpelviswas

reportedandembryonallethalitywasincreased.Anincreaseinanatomicalvariationsanddelayedossificationwas

notedaswellasprolongeddeliveryanddystocia.Inreproductiontoxicitystudiesinrabbits,abortionswererecorded.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumchloride

Waterforinjections

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3Shelflife

2years.

Fromthemicrobiologicalpointofview,onceopenedtheproductshouldbeusedimmediately.Ifnotusedimmediately,

in-usestoragetimesandconditionspriortousearetheresponsibilityoftheuser.

6.4Specialprecautionsforstorage

Donotstoreabove30ºC.Donotfreeze.

6.5Natureandcontentsofcontainer

Polyolefin/Styrene-ethylene-buthyleneblockcopolymerinfusionbagsfittedwithapolypropyleneSFC(Single

FunctionConnection)port.Theportissealedwithasyntheticisoprenerubberstopperandapolypropylenesnap-cap.

Theinfusionbagsarecontainedinaclearpolypropyleneoverpouch.

Packsizes

100mlbags(200mgfluconazole)inpacksof1or10bags

200mlbags(400mgfluconazole)inpacksof1or10bags

Notallpackagesizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Theinfusionisforsingleuseonly.Discardanyremainingsolution.

Anyunusedsolutionorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

Thesolutionshouldbeinspectedvisuallyforparticulatematteranddiscolourationpriortoadministration.Onlyclear

solutions,withoutparticles,shouldbeused.Checkforthepresenceofsmallleaksbyfirmlysqueezingtheinner-bag.In

caseofleaksthesolutionmustbedestroyedassterilitymaybeaffected.

Althoughfurtherdilutionisunnecessary,theinfusioniscompatiblewiththefollowinginfusionsolutions:

Glucose50mg/ml(5%)solution

Ringer’ssolution

Hartmann’ssolution

Potassiumchloride3mg/ml(0.3%)in50mg/ml(5%)glucosesolution

Sodiumbicarbonate13.02mg/ml(4.2%)solution

Sodiumchloride9mg/ml(0.9%)solution

Thedilutedsolutionsshouldbeinspectedvisuallyforparticulatematteranddiscolorationpriortoadministration.Only

clearandcolourlesssolutionsshouldbeused.

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Nospecificincompatibilitieshavebeennoted,althoughmixingwithanyotherdrugpriortoinfusionisnot

recommended.

Handling:

Donotremovethebagfromoverpouchuntilreadyforuse.

Toopen,carefullycutoverpouchatoneendandremovesolutionbag.Afterremovingoverwrap,checkforminute

leaksbysqueezinginnerbagfirmly.Ifleaksarefound,discardsolutionassterilitymaybeimpaired.

Preparingtheadministration:

Usesterilematerialsforpreparationandadministration.Hangthebagontheinfusionstandthroughthehole.The

solutionmustbeadministeredwithsterileequipmentandanaseptictechnique.Theequipmentmustbeprimedwiththe

solutioninordertopreventthesystemfromairpenetration.Connectanadministrationset.Consulttheinstructionsof

thesetinordertoconnectthesetandtoprime,andadministerthesolution.

CAUTION:Donotuseplasticbagsinseriesconnections.Suchusecouldresultinairembolismduetoresidualair

beingdrawnfromtheprimarycontainerbeforeadministrationofthefluidfromthesecondarycontaineriscompleted.

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V.

Computerweg10

3542DRUtrecht

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA749/41/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19 th

June2009.

Dateoflastrenewal:30 th

November2011

10DATEOFREVISIONOFTHETEXT

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