FLUCONAZOLE

Main information

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

Documents

Localization

  • Available in:
  • FLUCONAZOLE Solution for Infusion 2 Mg/Ml
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0237/064/001
  • Authorization date:
  • 13-08-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA0237/064/001

CaseNo:2087402

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

TransferredfromPA0585/015/001.

TevaUKLimited

BramptonRoad,HampdenPark,Eastbourne,EastSussexBN229AG,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Fluconazole2mg/mlSolutionforInfusion

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom13/08/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Fluconazole2mg/mlSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Fluconazole2mgperml.

Each25mlvialcontains50mgfluconazole.

Each50mlvialcontains100mgfluconazole.

Each100mlvialcontains200mgfluconazole.

Alsocontains:sodium3.8mmolper25mlvial,7.6mmolper50mlvialand15.2mmolper100mlvial.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

SolutionforInfusion.

Fluconazole2mg/mlSolutionforInfusionisaclearcolourlesssolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Therapymaybestartedbeforetheresultsoftheculturesandotherlaboratorystudiesareknown;however,onceresults

becomeavailable,anti-infectivetherapyshouldbeadjustedaccordingly.

Fluconazoleisindicatedforthetreatmentofthefollowingconditions:

Genitalcandidiasis.Vaginalcandidiasis,acuteorrecurrent.Candidalbalanitis.Thetreatmentofpartnerswho

presentwithsymptomaticgenitalcandidiasisshouldbeconsidered.

Mucosalcandidiasis.Theseincludeoropharyngeal,oesophageal,non-invasivebronchopulmonaryinfections,

candiduria,mucocutaneousandchronicoralatrophiccandidiasis(denturesoremouth).Normalhostsandpatientswith

compromisedimmunefunctionmaybetreated.

Tineapedis,tineacorporis,tineacruris,tineaversicoloranddermalCandidainfections.Fluconazoleisnot

indicatedfornailinfections.

Systemiccandidiasisincludingcandidaemia,disseminatedcandidiasisandotherformsofinvasivecandidal

infection.Theseincludeinfectionsoftheperitoneum,endocardiumandpulmonaryandurinarytracts.Candidal

infectionsinpatientswithmalignancy,inintensivecareunitsorthosereceivingcytotoxicorimmunosuppressive

therapymaybetreated.

Cryptococcosis,includingcryptococcalmeningitisandinfectionsofothersites(e.g.pulmonary,cutaneous).

Normalhosts,andpatientswithAIDS,organtransplantsorothercausesofimmunosuppressionmaybetreated.

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Forthepreventionoffungalinfectionsinimmunocompromisedpatientsconsideredatriskasaconsequenceof

neutropeniafollowingcytotoxicchemotherapyorradiotherapy,includingbonemarrowtransplantpatients.

4.2Posologyandmethodofadministration

Fluconazolemaybeadministeredeitherorally(ascapsulesorsuspension),orbyintravenousinfusionatarateof

approximately5-10ml/min,theroutebeingdependentontheclinicalstateofthepatient.Ontransferringfromthe

intravenousroutetotheoralrouteorviceversa,thereisnoneedtochangethedailydose.

Thedailydoseoffluconazoleshouldbebasedonthenatureandseverityofthefungalinfection.Mostcasesofvaginal

candidiasisrespondtosingledosetherapy.Therapyforthosetypesofinfectionsrequiringmultipledosetreatment

shouldbecontinueduntilclinicalparametersorlaboratorytestsindicatethatactivefungalinfectionhassubsided.An

inadequateperiodoftreatmentmayleadtotherecurrenceofactiveinfection.PatientswithAIDSandcryptococcal

meningitisusuallyrequiremaintenancetherapytopreventrelapse.

Adults

Candidalvaginitisorbalanitis–150mgsingleoraldose.

Mucosalcandidiasis–theusualdoseis50mgoncedailyfor7–14days.Treatmentshouldnotnormally

exceed14daysexceptinseverelyimmunocompromisedpatients.

Atrophicoralcandidiasisassociatedwithdentures–theusualdoseis50mgoncedailyfor14daysadministered

concurrentlywithlocalantisepticmeasurestothedenture.

Forothercandidalinfectionsofmucosa(exceptgenitalcandidiasisseeabove),e.g.oesophagitis,non-invasive

bronchopulmonaryinfections,candiduria,mucocutaneouscandidiasisetc.,theusualeffectivedoseis50mgdaily,

givenfor14–30days.

Inunusuallydifficultcasesofmucosalcandidalinfectionsthedosemaybeincreasedto100mgdaily.

Fortineapedis,corporis,cruris,versicoloranddermalcandidalinfectionstherecommendeddosageis50mg

oncedaily.Durationoftreatmentisnormally2to4weeksbuttineapedismayrequiretreatmentforupto6weeks.

Durationoftreatmentshouldnotexceed6weeks.

Forcandidaemia,disseminatedcandidiasisandotherinvasivecandidalinfectionstheusualdoseis400mgon

thefirstdayfollowedby200mgdaily.Dependingontheclinicalresponsethedosemaybeincreasedto400mgdaily.

Durationoftreatmentisbasedupontheclinicalresponse.

Forcryptococcalmeningitisandcryptococcalinfectionsatothersites,theusualdoseis400mgonthefirstday

followedby200–400mgoncedaily.Durationoftreatmentforcryptococcalinfectionswilldependontheclinicaland

mycologicalresponse,butisusuallyatleast6–8weeksforcryptococcalmeningitis.

ForthepreventionofrelapseofcryptococcalmeningitisinpatientswithAIDS,afterthepatientreceivesafull

courseofprimarytherapy,fluconazolemaybeadministeredindefinitelyatadailydoseof100–200mg.

Forthepreventionoffungalinfectionsinimmunocompromisedpatientsconsideredatriskasaconsequenceof

neutropeniafollowingcytotoxicchemotherapyorradiotherapy,thedoseshouldbe50to400mgoncedaily,basedon

thepatient’sriskfordevelopingfungalinfection.Forpatientsathighriskofsystemicinfectione.g.patientswhoare

anticipatedtohaveprofoundorprolongedneutropeniasuchasduringbonemarrowtransplantation,therecommended

doseis400mgoncedaily.Fluconazoleadministrationshouldstartseveraldaysbeforetheanticipatedonsetof

neutropenia,andcontinuefor7daysaftertheneutrophilcountrisesabove1000cellspermm

Children

Aswithsimilarinfectionsinadults,thedurationoftreatmentisbasedontheclinicalandmycologicalresponse.

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ChildrenoverfourweeksofageTherecommendeddoseoffluconazoleformucosalcandidiasisis3mg/kgdaily.A

loadingdoseof6mg/kgmaybeusedonthefirstdaytoachievesteadystatelevelsmorerapidly.

Forthetreatmentofsystemiccandidiasisandcryptococcalinfection,therecommendeddosageis6–12mg/kgdaily,

dependingontheseverityofthedisease.

Forthepreventionoffungalinfectionsinimmunocompromisedpatientsconsideredatriskasaconsequenceof

neutropeniafollowingcytotoxicchemotherapyorradiotherapy,thedoseshouldbe3–12mg/kgdaily,dependingon

theextentanddurationoftheinducedneutropenia(seeadultdosing).

Amaximumdosageof400mgdailyshouldnotbeexceededinchildren.

Despiteextensivedatasupportingtheuseoffluconazoleinchildrentherearelimiteddataavailableontheuseof

fluconazoleforgenitalcandidiasisinchildrenbelow16years.Useatpresentisnotrecommendedunlessantifungal

treatmentisimperativeandnosuitablealternativeagentexists.

ChildrenfourweeksofageandyoungerNeonatesexcretefluconazoleslowly.Inthefirsttwoweeksoflifethesame

mg/kgdosingasinolderchildrenshouldbeusedbutadministeredevery72hours.Duringthethirdandfourthweeksof

lifethesamedoseshouldbegivenevery48hours.

Amaximumdosageof12mg/kgevery72hoursshouldnotbeexceededinchildrenbelowtwoweeksoflife.For

childrenbetween2–4weeksoflife12mg/kgevery48hoursshouldnotbeexceeded.

Forchildrenwithimpairedrenalfunctionthedailydoseshouldbereducedinaccordancewiththeguidelinesgivenfor

adults.

Tofacilitateaccuratemeasurementofdoseslessthan10mg,fluconazoleshouldonlybeadministeredtochildrenin

hospitalusingpreparationsavailableasoralsuspensionorintravenousinfusion,dependingontheclinicalconditionof

thechild.

Elderly

Thenormaldoseshouldbeusedifthereisnoevidenceofrenalimpairment.Inpatientswithrenalimpairment

(creatinineclearancelessthan50ml/min)thedosagescheduleshouldbeadjustedasdescribedbelow.

Useinpatientswithimpairedrenalfunction

Fluconazoleisexcretedpredominantlyintheurineasunchangeddrug.Noadjustmentsinsingledosetherapyare

required.Inpatientswithimpairedrenalfunctionwhowillreceivemultipledosesoffluconazole,thenormal

recommendeddose(accordingtoindication)shouldbegivenonday1,followedbyadailydosebasedonthefollowing

table:

4.3Contraindications

Fluconazoleshouldnotbeusedinpatientswithknownhypersensitivitytofluconazoleortorelatedazolecompoundsor

toanyotheringredientwithintheformulation(seesection6.1.).

Co-administrationwithterfenadineorcisaprideiscontra-indicatedinpatientsreceivingfluconazole.See‘Interactions

Creatinineclearance(ml/min) Percentofrecommendeddose

>50 100%

≤50(nodialysis) 50%

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4.4Specialwarningsandprecautionsforuse

Insomepatients,especiallythosewithseriousunderlyingdiseasessuchasAIDSandcancer,abnormalitiesin

haematological,hepatic,renalandotherbiochemicalfunctiontestresultshavebeenobservedduringtreatmentwith

fluconazolebuttheclinicalsignificanceandrelationshiptotreatmentisuncertain.

Veryrarely,patientswhodiedwithsevereunderlyingdiseaseandwhohadreceivedmultipledosesoffluconazolehad

post-mortemfindingwhichincludedhepaticnecrosis.

Thesepatientswerereceivingmultipleconcomitantmedications,someknowntobepotentiallyhepatotoxic,and/or

hadunderlyingdiseaseswhichcouldhavecausedthehepaticnecrosis.

Incasesofhepatotoxicity,noobviousrelationshiptototaldailydoseoffluconazole,durationoftherapy,sexorageof

thepatienthasbeenobserved;theabnormalitieshaveusuallybeenreversibleondiscontinuationoffluconazoletherapy.

Sinceacausalrelationshipwithfluconazolecannotbeexcluded,patientswhodevelopabnormalliverfunctiontests

duringfluconazoletherapyshouldbemonitoredforthedevelopmentofmoreserioushepaticdamage.Fluconazole

shouldbediscontinuedifclinicalsignsorsymptomsconsistentwithliverdiseasedevelopduringtreatmentwith

fluconazole.

Patientshaveoccasionallydevelopedexfoliativecutaneousreactions,suchasStevens-JohnsonSyndromeandtoxic

epidermalnecrolysis,duringtreatmentwithfluconazole.AIDSpatientsaremorepronetothedevelopmentofmore

severecutaneousreactionstomanydrugs.

Ifarashdevelopsinapatienttreatedforasuperficialfungalinfectionwhichmaybeattributedtofluconazole,further

therapywiththisagentshouldbediscontinued.Ifpatientswithinvasive/systemicfungalinfectionsdeveloprashes,

theyshouldbemonitoredcloselyandfluconazolediscontinuedifbullouslesionsorerythemamultiformedevelop.

Inrarecases,aswithotherazoles,anaphylaxishasbeenreported.

Thismedicinalproductcontains3.8mmolofsodiumper25mlvial,7.6mmolper50mlvialand15.2mmolper100ml

vial.Thisshouldbetakenintoconsiderationbypatientsonasodiumcontrolleddiet.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Thefollowingdruginteractionsrelatetotheuseofmultiple-dosefluconazole,andtherelevancetosingle-dose

fluconazolehasnotyetbeenestablished:

AnticoagulantsInaninteractionstudy,fluconazoleincreasedtheprothrombintime(12%)afterwarfarinadministration

inhealthymales.Inpost-marketingexperience,aswithotherazoleantifungals,bleedingevents(bruising,epistaxis,

gastrointestinalbleeding,haematuriaandmelaena)havebeenreportedinassociationwithincreasesinprothrombin

timeinpatientsreceivingfluconazoleconcurrentlywithwarfarin.Prothrombintimeinpatientsreceivingcoumarin-

typeanticoagulantsshouldbecarefullymonitored.

Benzodiazepines(Shortacting)Followingoraladministrationofmidazolam,fluconazoleresultedinsubstantial

increasesinmidazolamconcentrationsandpsychomotoreffects.Thiseffectonmidazolamappearstobemore

pronouncedfollowingoraladministrationoffluconazolethanwithfluconazoleadministeredintravenously.If

concomitantbenzodiazepinetherapyisnecessaryinpatientsbeingtreatedwithfluconazole,considerationshouldbe

giventodecreasingthebenzodiazepinedosageandthepatientsshouldbeappropriatelymonitored.

SulphonylureasFluconazolehasbeenshowntoprolongtheserumhalf-lifeofconcomitantlyadministeredoral

sulphonylureas(chlorpropamide,glibenclamide,glipizideandtolbutamide)inhealthyvolunteers.Fluconazoleandoral

sulphonylureasmaybeco-administeredtodiabeticpatients,butthepossibilityofahypoglycaemicepisodeshouldbe

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HydrochlorothiazideInakineticinteractionstudy,co-administrationofmultiple-dosehydrochlorothiazidetohealthy

volunteersreceivingfluconazoleincreasedplasmaconcentrationsoffluconazoleby40%.Aneffectofthismagnitude

shouldnotnecessitateachangeinthefluconazoledoseregimeninsubjectsreceivingconcomitantdiuretics,although

theprescribershouldbearitinmind.

PhenytoinConcomitantadministrationoffluconazoleandphenytoinmayincreasethelevelsofphenytointoa

clinicallysignificantdegree.Ifitisnecessarytoadministerbothdrugsconcomitantly,phenytoinlevelsshouldbe

monitoredandthephenytoindoseadjustedtomaintaintherapeuticlevels.

OralcontraceptivesTwokineticstudieswithcombinedoralcontraceptiveshavebeenperformedusingmultipledoses

offluconazole.Therewerenorelevanteffectsoneitherhormonelevelinthe50mgfluconazolestudy,whileat200mg

dailytheAUCsofethinylestradiolandlevonorgestrelwereincreased40%and24%respectively.Thusmultipledose

useoffluconazoleattheselevelsisunlikelytohaveaneffectontheefficacyofthecombinedoralcontraceptive.

RifampicinConcomitantadministrationoffluconazoleandrifampicinresultedina25%decreaseintheAUCand20%

shorterhalf-lifeoffluconazole.Inpatientsreceivingconcomitantrifampicin,anincreaseinthefluconazoledoseshould

beconsidered.

EndogenoussteroidFluconazole50mgdailydoesnotaffectendogenoussteroidlevelsinfemales:200–400mgdaily

hasnoclinicallysignificanteffectonendogenoussteroidlevelsoronACTHstimulatedresponseinhealthymale

volunteers.

CiclosporinAkineticstudyinrenaltransplantpatientsfoundfluconazole200mgdailytoslowlyincreaseciclosporin

concentrations.However,inanothermultipledosestudywith100mgdaily,fluconazoledidnotaffectciclosporin

levelsinpatientswithbonemarrowtransplants.Ciclosporinplasmaconcentrationmonitoringinpatientsreceiving

fluconazoleisrecommended.

TheophyllineInaplacebocontrolledinteractionstudy,theadministrationoffluconazole200mgfor14daysresulted

inan18%decreaseinthemeanplasmaclearanceoftheophylline.Patientswhoarereceivinghighdosesof

theophyllineorwhoareotherwiseatincreasedriskfortheophyllinetoxicityshouldbeobservedforsignsof

theophyllinetoxicitywhilereceivingfluconazole,andthetherapymodifiedifsignsoftoxicitydevelop.

TerfenadineBecauseoftheoccurrenceofseriousdysrhythmiassecondarytoprolongationoftheQTcintervalin

patientsreceivingotherazoleantifungalsinconjunctionwithterfenadine,interactionstudieshavebeenperformed.One

studyatadailydoseof200mgoffluconazolefailedtodemonstrateaprolongedQTcinterval.Anotherstudyata400

mgand800mgdailydoseoffluconazoledemonstratedthatfluconazoletakeninmultipledosesof400mgperdayor

greaterdidsignificantlyincreaseplasmalevelsofterfenadinewhentakenconcomitantly.

Therehavebeenspontaneouslyreportedcasesofpalpitations,tachycardia,dizziness,andchestpaininpatientstaking

concomitantfluconazoleandterfenadinewheretherelationshipofthereportedadverseeventstodrugtherapyor

underlyingmedicalconditionswasunclear.Becauseofthepotentialseriousnessofsuchaninteraction,itis

recommendedthatterfenadineshouldnotbetakenincombinationwithfluconazole.See‘Contraindications’.

CisaprideTherehavebeenreportsofcardiaceventsincludingtorsadedepointesinpatientstowhomfluconazoleand

cisapridewereco-administered.Inmostofthesecases,thepatientsappeartohavebeenpredisposedtoarrhythmiasor

hadseriousunderlyingillnesses,andtherelationshipofthereportedeventstoapossiblefluconazole-cisapridedrug

interactionisunclear.Becauseofthepotentialseriousnessofsuchaninteraction,co-administrationofcisaprideis

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ZidovudineTwokineticstudiesresultedinincreasedlevelsofzidovudinemostlikelycausedbythedecreased

conversionofzidovudinetoitsmajormetabolite.OnestudydeterminedzidovudinelevelsinAIDSorARCpatients

beforeandfollowingfluconazole200mgdailyfor15days.TherewasasignificantincreaseinzidovudineAUC(20

%).Asecondrandomised,two-period,two-treatmentcross-overstudyexaminedzidovudinelevelsinHIVinfected

patients.Ontwooccasions,21daysapart,patientsreceivedzidovudine200mgeveryeighthourseitherwithorwithout

fluconazole400mgdailyforsevendays.TheAUCofzidovudinesignificantlyincreased(74%)duringco-

administrationwithfluconazole.Patientsreceivingthiscombinationshouldbemonitoredforthedevelopmentof

zidovudine-relatedadversereactions.

RifabutinTherehavebeenreportsthataninteractionexistswhenfluconazoleisadministeredwithrifabutin,leadingto

increasedserumlevelsofrifabutin.Therehavebeenreportsofuveitisinpatientstowhomfluconazoleandrifabutin

wereco-administered.Patientsreceivingthetwoconcomitantlyshouldbecarefullymonitored.

TacrolimusTherehavebeenreportsofaninteractionwhenfluconazoleisgivenconcomitantlywithtacrolimus,

leadingtoincreasedserumlevelsoftacrolimus.Therehavebeenreportsofnephrotoxicityinpatientstowhom

fluconazoleandtacrolimuswereco-administered.Patientsreceivingthetwoconcomitantlyshouldbecarefully

monitored.

Theuseoffluconazoleinpatientsconcurrentlytakingastemizole,rifabutin,tacrolimus,orotherdrugsmetabolisedby

thecytochromeP450systemmaybeassociatedwithelevationsinserumlevelsofthesedrugs.Intheabsenceof

definitiveinformation,cautionshouldbeusedwhenco-administeringfluconazole.Patientsshouldbecarefully

monitored.

Interactionstudieshaveshownthatwhenoralfluconazoleisco-administeredwithfood,cimetidine,antacidsor

followingtotalbodyirradiationforbonemarrowtransplantation,noclinicallysignificantimpairmentoffluconazole

absorptionoccurs.

Physiciansshouldbeawarethatdrug-druginteractionstudieswithothermedicationshavenotbeenconducted,butthat

suchinteractionsmayoccur.

4.6Pregnancyandlactation

Useduringpregnancy:

Therearenoadequateandwellcontrolledstudiesinpregnantwomen.Therehavebeenreportsofmultiplecongenital

abnormalitiesininfantswhosemotherswerebeingtreatedfor3ormoremonthswithhighdose(400–800mg/day)

fluconazoletherapyforcoccidioidomycosis.Therelationshipbetweenfluconazoleandtheseeventsisunclear.

Accordingly,fluconazolecapsulesshouldnotbeusedinpregnancyorinwomenofchildbearingpotential,unless

adequatecontraceptionisemployed.

Useduringlactation:

Fluconazoleisfoundinhumanbreastmilkatconcentrationssimilartoplasma,henceitsuseinnursingmothersisnot

recommended.

4.7Effectsonabilitytodriveandusemachines

Experiencewithfluconazoleindicatesthattherapyisunlikelytoimpairapatient’sabilitytodriveorusemachinery.

4.8Undesirableeffects

Fluconazoleisgenerallywelltolerated.Themostcommonsideeffectsobservedduringclinicaltrialsandassociated

withfluconazoleare:

NervousSystemDisorders:Headache.

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GastrointestinalDisorders:Abdominalpain,diarrhoea,flatulence,nausea.

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,changesinrenaland

haematologicalfunctiontestresultsandhepaticabnormalitieshavebeenobservedduringtreatmentwithfluconazole

andcomparativeagents,buttheclinicalsignificanceandrelationshiptotreatmentisuncertain(see4.4Special

warningsandspecialprecautionsforuse).

HepatobiliaryDisorders:Hepatictoxicityincludingrarecasesoffatalities,elevatedalkalinephosphatase,elevated

bilirubin,elevatedSGOT,elevatedSGPT.

Inaddition,thefollowingundesirableeffectshaveoccurredduringpost-marketing:

NervousSystemDisorders:Dizziness,seizures,tasteperversion.

SkinandSubcutaneousTissueDisorders:Alopecia,exfoliativeskindisordersincludingStevens-Johnsonsyndrome

andtoxicepidermalnecrolysis.

GastrointestinalDisorders:Dyspepsia,vomiting.

BloodandLymphaticDisorders:Leukopeniaincludingneutropeniaandagranulocytosis,thrombocytopenia.

ImmuneSystemDisorders:Allergicreaction:anaphylaxis(includingangio-oedema,faceoedema,pruritus),urticaria.

HepatobiliaryDisorders:Hepaticfailure,hepatitis,hepatocellularnecrosis,jaundice.

MetabolismandNutritionDisorders:Hypercholesterolaemia,hypertriglyceridaemia,hypokalaemia.

4.9Overdose

Therehasbeenareportedcaseofoverdosagewithfluconazole.A42yearoldpatientinfectedwithHIVdeveloped

hallucinationsandexhibitedparanoidbehaviourafterreportedlyingesting8200mgoffluconazole,unverifiedbyhis

physician.Thepatientwashospitalisedandhisconditionresolvedwithin48hours.

Intheeventofoverdosage,supportivemeasuresandsymptomatictreatment,withgastriclavageifnecessary,maybe

adequate.

Asfluconazoleislargelyexcretedintheurine,forcedvolumediuresiswouldprobablyincreasetheeliminationrate.A

threehourhaemodialysissessiondecreasesplasmalevelsbyapproximately50%.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

PharmacotherapeuticGroup:Triazolederivatives,ATCcode:J02AC01

Fluconazole,amemberofthetriazoleclassofantifungalagents,isapotentandselectiveinhibitoroffungalenzymes

necessaryforthesynthesisofergosterol.

Fluconazoleshowslittlepharmacologicalactivityinawiderangeofanimalstudies.Someprolongationof

pentobarbitalsleepingtimesinmice(p.o.),increasedmeanarterialandleftventricularbloodpressureandincreased

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FluconazoleishighlyspecificforfungalcytochromeP-450dependentenzymes.Fluconazole50mgdailygivenforup

to28dayshasbeenshownnottoaffecttestosteroneplasmaconcentrationsinmalesorsteroidconcentrationsin

femalesofchild-bearingage.Fluconazole200-400mgdailyhasnoclinicallysignificanteffectonendogenoussteroid

levelsoronACTHstimulatedresponseinhealthymalevolunteers.Interactionstudieswithantipyrineindicatethat

singleormultipledosesoffluconazole50mgdonotaffectitsmetabolism.

TherehavebeenreportsofcasesofsuperinfectionwithCandidaspeciesotherthanC.albicans,whichareoften

inherentlynotsusceptibletofluconazole(e.g.Candidakrusei).Suchcasesmayrequirealternativeantifungaltherapy.

5.2Pharmacokineticproperties

Thepharmacokineticpropertiesoffluconazolearesimilarfollowingadministrationbytheintravenousororalroute.

Afteroraladministrationfluconazoleiswellabsorbedandplasmalevels(andsystemicbioavailability)areover90%of

thelevelsachievedafterintravenousadministration.Oraladministrationisnotaffectedbyconcomitantfoodintake.

Peakplasmaconcentrationsinthefastingstateoccurbetween0.5–1.5hourspost-dosewithaplasmaeliminationhalf-

lifeofapproximately30hours.Plasmaconcentrationsareproportionaltodose.Ninetypercentsteady-statelevelsare

reachedbyday4–5withmultipleoncedailydosing.

Theadministrationofahigherdoseonthefirstday,doublethatofthenormaldailydose,raisesplasmalevelsto

approximateto90%steady-statelevelsbythesecondday.

Theapparentvolumeofdistributionapproximatestototalbodywater.Fluconazoleachievesgoodpenetrationinall

bodyfluidsstudied.Thelevelsoffluconazoleinsalivaandsputumaresimilartoplasmalevels.Inpatientswithfungal

meningitis,fluconazolelevelsintheCSFareapproximately80%ofthecorrespondingplasmalevels.Highskin

concentrationsoffluconazole,aboveserumconcentrations,areachievedinthestratumcorneum,epidermis-dermisand

eccrinesweat.Fluconazoleaccumulatesinthestratumcorneum.Plasmaproteinbindingislow(11-12%).

Themajorrouteofexcretionisrenal,withapproximately80%oftheadministereddoseappearingintheurineas

unchangeddrug.Fluconazoleclearanceisproportionaltocreatinineclearance.Thereisnoevidenceofcirculating

metabolites.

Itslongclearanceplasmaeliminationhalf-lifemakesitpossibletoadministerasingledoseinthetreatmentofgenital

candidiasisandadailydoseinthetreatmentofotherindications.

5.3Preclinicalsafetydata

ReproductivetoxicityIncreasesinfoetalanatomicalvariants(supernumeraryribs,renalpelvisdilation)anddelaysin

ossificationwereobservedat25and50mg/kgandhigherdoses.Atdosesfrom80mg/kgto320mg/kg

embryolethalityinratswasincreasedandfoetalabnormalitiesincludedwavyribs,cleftpalateandabnormalcranio-

facialossification.

CarcinogenesisFluconazoleshowednoevidenceofcarcinogenicpotentialinmiceandratstreatedorallyfor24

monthsatdosesof2.5,5or10mg/kg/day.Maleratstreatedwith5and10mg/kg/dayhadanincreasedincidenceof

hepatocellularadenomas.

MutagenesisFluconazole,withorwithoutmetabolicactivation,wasnegativeintestsformutagenicityin4strainsofS.

typhimuriumandinthemouselymphomaL5178Ysystem.Cytogeneticstudiesinvivo(murinebonemarrowcells,

followingoraladministrationoffluconazole)andinvitro(humanlymphocytesexposedtofluconazoleat1000µg/ml)

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ImpairmentoffertilityFluconazoledidnotaffectthefertilityofmaleorfemaleratstreatedorallywithdailydosesof5,

10or20mg/kgorwithparenteraldosesof5,25or75mg/kg,althoughtheonsetofparturitionwasslightlydelayedat

20mg/kgp.o.Inanintravenousperinatalstudyinratsat5,20and40mg/kg,dystociaandprolongationofparturition

wereobservedinafewdamsat20mg/kgand40mg/kg,butnotat5mg/kg.Thedisturbancesinparturitionwere

reflectedbyaslightincreaseinthenumberofstill-bornpupsanddecreaseofneonatalsurvivalatthesedoses.The

effectsonparturitioninratsareconsistentwiththespeciesspecificoestrogen-loweringpropertyproducedbyhigh

dosesoffluconazole.Suchahormonechangehasnotbeenobservedinwomentreatedwithfluconazole.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Waterforinjections

Sodiumchloride

Hydrochloricacid(forpHadjustment)

Sodiumhydroxide(forpHadjustment)

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

TypeIglassvials:25ml,50mland100ml.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Forsingleuseonly.Discardanyremainingsolution.

Althoughfurtherdilutionisunnecessary,fluconazoleintravenousinfusioniscompatiblewiththefollowing

administrationfluids:

Dextrose20%

Ringer’ssolution

Hartmann’ssolution

Potassiumchlorideindextrose

Sodiumbicarbonate4.2%

Normalsaline(0.9%)

Recommendedmethodofadministration:

Fluconazoleintravenousinfusiondoesnotrequiredilutionpriortoadministration.Ifnecessary,thesolutionmaybe

infusedthroughanexistingadministrationsetcontainingoneofthecompatiblefluidslistedaboveusingasuitable‘Y’

Irish Medicines Board

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Date Printed 16/08/2010 CRN 2087402 page number: 10

Fluconazoleintravenousinfusionmaybeinfusedthroughanexistinglinewithoneoftheabovelistedfluids.No

specificincompatibilitieshavebeennoted,althoughmixingwithanyotherdrugpriortoinfusionisnotrecommended.

7MARKETINGAUTHORISATIONHOLDER

TevaUKLimited

BramptonRoad

HampdenPark

Eastbourne

EastSussexBN229AG

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0237/064/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 8October2004

Dateoflastrenewal: 13March2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 16/08/2010 CRN 2087402 page number: 11