FLUCONAZOLE

Main information

  • Trade name:
  • FLUCONAZOLE Capsules Hard 200 Milligram
  • Dosage:
  • 200 Milligram
  • Pharmaceutical form:
  • Capsules Hard
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FLUCONAZOLE Capsules Hard 200 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1666/003/003
  • Authorization date:
  • 30-03-2012
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Fluconazole200mghardcapsule

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachhardcapsulecontains200mgfluconazole

Excipients:Contains210mgofLactosemonohydrate

Forthefulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Hardcapsule

Capsuleshell:Size0,whitebodyandwhitecap.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Fluconazolecapsuleisindicatedinthefollowingfungalinfections(seesection5.1).

Fluconazolecapsuleisindicatedinadultsforthetreatmentof:

Cryptococcalmeningitis(seesection4.4).

Coccidioidomycosis(seesection4.4).

Invasivecandidiasis.

Mucosalcandidiasisincludingoropharyngeal,oesophagealcandidiasis,candiduriaandchronicmucocutaneous

candidiasis.

Chronicoralatrophiccandidiasis(denturesoremouth)ifdentalhygieneortopicaltreatmentareinsufficient.

Vaginalcandidiasis,acuteorrecurrent;whenlocaltherapyisnotappropriate.

Candidalbalanitiswhenlocaltherapyisnotappropriate.

Dermatomycosisincludingtineapedis,tineacorporis,tineacruris,tineaversicoloranddermalcandida

infectionswhensystemictherapyisindicated.

Tineaunguinium(onychomycosis)whenotheragentsarenotconsideredappropriate.

Fluconazolecapsuleisindicatedinadultsfortheprophylaxisof:

Relapseofcryptococcalmeningitisinpatientswithhighriskofrecurrence.

RelapseoforopharyngealoroesophagealcandidiasisinpatientsinfectedwithHIVwhoareathighriskof

experiencingrelapse.

Toreducetheincidenceofrecurrentvaginalcandidiasis(4ormoreepisodesayear).

Prophylaxisofcandidalinfectionsinpatientswithprolongedneutropenia(suchaspatientswithhaematological

malignanciesreceivingchemotherapyorpatientsreceivingHematopoieticStemCellTransplantation(see

section5.1)).

Fluconazoleisindicatedintermnewborninfants,infants,toddlers,children,andadolescentsagedfrom0to17years

old:

Fluconazoleisusedforthetreatmentofmucosalcandidiasis(oropharyngeal,oesophageal),invasivecandidiasis,

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beusedasmaintenancetherapytopreventrelapseofcryptococcalmeningitisinchildrenwithhighriskofreoccurrence

(seesection4.4).

Therapymaybeinstitutedbeforetheresultsoftheculturesandotherlaboratorystudiesareknown;however,once

theseresultsbecomeavailable,anti-infectivetherapyshouldbeadjustedaccordingly.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantifungals.

4.2Posologyandmethodofadministration

Posology

Thedoseshouldbebasedonthenatureandseverityofthefungalinfection.Treatmentofinfectionsrequiringmultiple

dosingshouldbecontinueduntilclinicalparametersorlaboratorytestsindicatethatactivefungalinfectionhas

subsided.Aninadequateperiodoftreatmentmayleadtorecurrenceofactiveinfection.

Indications Posology Durationoftreatment

Cryptococcosis -Treatmentof

cryptococcal

meningitis. Loadingdose:

400mgonDay1

Subsequentdose:

200mgto400mgdaily Usuallyatleast6to8

weeks.

Inlifethreatening

infectionsthedailydose

canbeincreasedto800

-Maintenance

therapytoprevent

relapseof

cryptococcal

meningitisin

patientswithhigh

riskofrecurrence. 200mgdaily Indefinitelyatadaily

doseof200mg

Coccidioidomycosis 200mgto400mg 11monthsupto

24monthsorlonger

dependingonthepatient.

800mgdailymaybe

consideredforsome

infectionsandespecially

formeningealdisease

Invasivecandidiasis Loadingdose:

800mgonDay1

Subsequentdose:

400mgdaily Ingeneral,the

recommendedduration

oftherapyfor

candidemiaisfor2

weeksafterfirstnegative

bloodcultureresultand

resolutionofsignsand

symptomsattributableto

candidemia.

Treatmentof -Oropharyngeal

candidiasis Loadingdose:200mg

to400mgonDay1

Subsequentdose:100

mgto200mgdaily 7to21days(until

oropharyngeal

candidiasisisin

remission).

Longerperiodsmaybe

usedin.patientswith

severelycompromised

immunefunction

Loadingdose: 14to30days(until

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mucosalcandidiasis

-Oesophageal

candidiasis 200mgto400mgon

Day1

Subsequentdose:100

mgto200mgdaily isinremission).

Longerperiodsmaybe

usedinpatientswith

severelycompromised

immunefunction

-Candiduria 200mgto400mgdaily 7to21days.Longer

periodsmaybeusedin

patientswithseverely

compromisedimmune

function.

-Chronicatrophic

candidiasis 50mgdaily 14days

-Chronic

mucocutaneous

candidiasis 50mgto100mgdaily Upto28days.Longer

periodsdependingon

boththeseverityof

infectionorunderlying

immunecompromisation

andinfection

Preventionof

relapseofmucosal

candidiasisin

patientsinfected

withHIVwhoare

athighriskof

experiencing

relapse -Oropharyngeal

candidiasis 100mgto200mgdaily

or200mg3timesper

week Anindefiniteperiodfor

patientswithchronic

immunesuppression

-Oesophageal

candidiasis 100mgto200mgdaily

or200mg3timesper

week Anindefiniteperiodfor

patientswithchronic

immunesuppression

Genitalcandidiasis -Acutevaginal

candidiasis

-Candidalbalanitis 150mg Singledose

-Treatmentand

prophylaxisof

recurrentvaginal

candidiasis(4or

moreepisodesa

year). 150mgeverythirdday

foratotalof3doses

(day1,4,and7)

followedby150mg

onceweekly

maintenancedose Maintenancedose:6

months.

-tineapedis,

-tineacorporis,

-tineacruris,

-candidainfections 150mgonceweeklyor

50mgoncedaily 2to4weeks,tineapedis

mayrequiretreatment

forupto6weeks

-tineaversicolor 300mgto400mgonce

weekly 1to3weeks

50mgoncedaily 2to4weeks

-tineaunguium

(onychomycosis) 150mgonceweekly Treatmentshouldbe

continueduntilinfected

nailisreplaced

(uninfectednailgrows

in).Regrowthof

fingernailsandtoenails

normallyrequires3to6

monthsand6to12

months,respectively.

However,growthrates

mayvarywidelyin

individuals,andbyage.

Aftersuccessful

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Specialpopulations

Elderly

Dosageshouldbeadjustedbasedontherenalfunction(see"Renalimpairment").

Renalimpairment

Noadjustmentsinsingledosetherapyarenecessary.Inpatients(includingpaediatricpopulation)withimpairedrenal

functionwhowillreceivemultipledosesoffluconazole,aninitialdoseof50mgto400mgshouldbegiven,basedon

therecommendeddailydosefortheindication.Afterthisinitialloadingdose,thedailydose(accordingtoindication)

shouldbebasedonthefollowingtable:

Patientsonregulardialysisshouldreceive100%oftherecommendeddoseaftereachdialysis;onnon-dialysisdays,

patientsshouldreceiveareduceddoseaccordingtotheircreatinineclearance.

Hepaticimpairment

Limiteddataareavailableinpatientswithhepaticimpairment,thereforefluconazoleshouldbeadministeredwith

cautiontopatientswithliverdysfunction(seesections4.4and4.8).

Paediatricpopulation

Thephysicianshouldprescribethemostappropriatepharmaceuticalformandstrengthaccordingtoage,weightand

dose.Thecapsuleformulationisnotadaptedforuseininfantsandsmallchildren.Liquidformulationsoffluconazole

areavailablethataremoresuitableinthispopulation.

Amaximumdoseof400mgdailyshouldnotbeexceededinpaediatricpopulation.

Aswithsimilarinfectionsinadults,thedurationoftreatmentisbasedontheclinicalandmycologicalresponse.

Fluconazoleisadministeredasasingledailydose.

Forpaediatricpatientswithimpairedrenalfunction,seedosingin"Renalimpairment".Thepharmacokineticsof

fluconazolehasnotbeenstudiedinpaediatricpopulationwithrenalinsufficiency(for"Termnewborninfants"who

oftenexhibitprimarilyrenalimmaturitypleaseseebelow).

chronicinfections,nails

occasionallyremain

disfigured.

Prophylaxisof

candidalinfections

inpatientswith

prolonged

neutropenia 200mgto400mg Treatmentshouldstart

severaldaysbeforethe

anticipatedonsetof

neutropeniaandcontinue

for7daysafterrecovery

fromneutropeniaafter

theneutrophilcountrises

above1000cellsper

Creatinineclearance(ml/min) Percentofrecommendeddose

>50 100%

50(nodialysis) 50%

Regulardialysis 100%aftereachdialysis

Indication Posology Recommendations

-Mucosalcandidiasis Initialdose:6mg/kg

Subsequentdose:3mg/kg

daily Initialdosemaybeusedon

thefirstdaytoachievesteady

statelevelsmorerapidly

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Adolescents(from12to17yearsold):

Dependingontheweightandpubertaldevelopment,theprescriberwouldneedtoassesswhichposology(adultsor

children)isthemostappropriate.Clinicaldataindicatethatchildrenhaveahigherfluconazoleclearancethanobserved

foradults.Adoseof100,200and400mginadultscorrespondstoa3,6and12mg/kgdoseinchildrentoobtaina

comparablesystemicexposure.

Safetyandefficacyforgenitalcandidiasisindicationinpaediatricpopulationhasnotbeenestablished.Current

availablesafetydataforotherpaediatricindicationsaredescribedinsection4.8.Iftreatmentforgenitalcandidiasisis

imperativeinadolescents(from12to17yearsold),theposologyshouldbethesameasadultsposology.

Termnewborninfants(0to27days):

Neonatesexcretefluconazoleslowly.Therearefewpharmacokineticdatatosupportthisposologyintermnewborn

infants(seesection5.2).

Methodofadministration

Fluconazolemaybeadministeredeitherorallyorbyintravenousinfusion,theroutebeingdependentontheclinical

stateofthepatient.Ontransferringfromtheintravenoustotheoralroute,orviceversa,thereisnoneedtochangethe

dailydose.

Thecapsulesshouldbeswallowedwholeandindependentoffoodintake.

4.3Contraindications

Hypersensitivitytotheactivesubstance(s),tootherrelatedazolesubstances,ortoanyoftheexcipientslistedinsection

6.1.

Coadministrationofterfenadineiscontraindicatedinpatientsreceivingfluconazoleatmultipledosesof400mgperday

orhigherbaseduponresultsofamultipledoseinteractionstudy.Coadministrationofothermedicinalproductsknown

toprolongtheQTintervalandwhicharemetabolisedviathecytochromeP450(CYP)3A4,suchascisapride,

astemizole,pimozide,quinidineanderythromycinarecontraindicatedinpatientsreceivingfluconazole(seesections

-Cryptococcalmeningitis thedisease

-Maintenancetherapyto

preventrelapseof

cryptococcalmeningitisin

childrenwithhighriskof

recurrence Dose:6mg/kgdaily Dependingontheseverityof

thedisease

-ProphylaxisofCandidain

immunocompromisedpatients Dose:3to12mg/kgdaily Dependingontheextentand

durationoftheinduced

neutropenia(seeAdults

posology)

Agegroup Posology Recommendations

Termnewborninfants(0to14

days) Thesamemg/kgdoseasfor

infants,toddlersandchildren

shouldbegivenevery72

hours Amaximumdoseof12mg/kg

every72hoursshouldnotbe

exceeded

Termnewborninfants(from

15to27days) Thesamemg/kgdoseasfor

infants,toddlersandchildren

shouldbegivenevery48

hours Amaximumdoseof12mg/kg

every48hoursshouldnotbe

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4.4Specialwarningsandprecautionsforuse

Tineacapitis

Fluconazolehasbeenstudiedfortreatmentoftineacapitisinchildren.Itwasshownnottobesuperiortogriseofulvin

andtheoverallsuccessratewaslessthan20%.Therefore,Fluconazoleshouldnotbeusedfortineacapitis.

Cryptococcosis

Theevidenceforefficacyoffluconazoleinthetreatmentofcryptococcosisofothersites(e.g.pulmonaryandcutaneous

cryptococcosis)islimited,whichpreventsdosingrecommendations.

Deependemicmycoses

Theevidenceforefficacyoffluconazoleinthetreatmentofotherformsofendemicmycosessuchas

paracoccidioidomycosis,lymphocutaneoussporotrichosisandhistoplasmosisislimited,whichpreventsspecificdosing

recommendations.

Renalsystem

Fluconazoleshouldbeadministeredwithcautiontopatientswithrenaldysfunction(seesection4.2).

Hepatobiliarysystem

Fluconazoleshouldbeadministeredwithcautiontopatientswithliverdysfunction.

Fluconazolehasbeenassociatedwithrarecasesofserioushepatictoxicityincludingfatalities,primarilyinpatients

withseriousunderlyingmedicalconditions.Incasesoffluconazoleassociatedhepatotoxicity,noobviousrelationship

tototaldailydose,durationoftherapy,sexorageofpatienthasbeenobserved.Fluconazolehepatotoxicityhasusually

beenreversibleondiscontinuationoftherapy.

Patientswhodevelopabnormalliverfunctiontestsduringfluconazoletherapymustbemonitoredcloselyforthe

developmentofmoreserioushepaticinjury.

Thepatientshouldbeinformedofsuggestivesymptomsofserioushepaticeffect(importantasthenia,anorexia,

persistentnausea,vomitingandjaundice).Treatmentoffluconazoleshouldbeimmediatelydiscontinuedandthe

patientshouldconsultaphysician.

Cardiovascularsystem

Someazoles,includingfluconazole,havebeenassociatedwithprolongationoftheQTintervalonthe

electrocardiogram.Duringpost-marketingsurveillance,therehavebeenveryrarecasesofQTprolongationand

torsadesdepointesinpatientstakingFluconazole.Thesereportsincludedseriouslyillpatientswithmultiple

confoundingriskfactors,suchasstructuralheartdisease,electrolyteabnormalitiesandconcomitanttreatmentthatmay

havebeencontributory.

Fluconazoleshouldbeadministeredwithcautiontopatientswiththesepotentiallyproarrhythmicconditions.

CoadministrationofothermedicinalproductsknowntoprolongtheQTintervalandwhicharemetabolisedviathe

cytochromeP450(CYP)3A4arecontraindicated(seesections4.3and4.5).

Halofantrine

HalofantrinehasbeenshowntoprolongQTcintervalattherecommendedtherapeuticdoseandisasubstrateof

CYP3A4.Theconcomitantuseoffluconazoleandhalofantrineisthereforenotrecommended(seesection4.5).

Dermatologicalreactions

Patientshaverarelydevelopedexfoliativecutaneousreactions,suchasStevens-Johnsonsyndromeandtoxicepidermal

necrolysis,duringtreatmentwithfluconazole.AIDSpatientsaremorepronetothedevelopmentofseverecutaneous

reactionstomanymedicinalproducts.Ifarash,whichisconsideredattributabletoFluconazole,developsinapatient

treatedforasuperficialfungalinfection,furthertherapywiththismedicinalproductshouldbediscontinued.Ifpatients

withinvasive/systemicfungalinfectionsdeveloprashes,theyshouldbemonitoredcloselyandfluconazole

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Hypersensitivity

Inrarecasesanaphylaxishasbeenreported(seesection4.3).

CytochromeP450

FluconazoleisapotentCYP2C9inhibitorandamoderateCYP3A4inhibitor.Fluconazoleisalsoaninhibitorof

CYP2C19.Fluconazoletreatedpatientswhoareconcomitantlytreatedwithmedicinalproductswithanarrow

therapeuticwindowmetabolisedthroughCYP2C9,CYP2C19andCYP3A4,shouldbemonitored(seesection4.5).

Terfenadine

Thecoadministrationoffluconazoleatdoseslowerthan400mgperdaywithterfenadineshouldbecarefully

monitored(seesections4.3and4.5).

Excipients

Capsulescontainlactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantuseofthefollowingothermedicinalproductsiscontraindicated:

Cisapride:Therehavebeenreportsofcardiaceventsincludingtorsadesdepointesinpatientstowhomfluconazoleand

cisapridewerecoadministered.Acontrolledstudyfoundthatconcomitantfluconazole200mgoncedailyandcisapride

20mgfourtimesadayyieldedasignificantincreaseincisaprideplasmalevelsandprolongationofQTcinterval.

Concomitanttreatmentwithfluconazoleandcisaprideiscontraindicated(seesection4.3).

Terfenadine:BecauseoftheoccurrenceofseriouscardiacdysrhythmiassecondarytoprolongationoftheQTcinterval

inpatientsreceivingazoleantifungalsinconjunctionwithterfenadine,interactionstudieshavebeenperformed.One

studyata200mgdailydoseoffluconazolefailedtodemonstrateaprolongationinQTcinterval.Anotherstudyata

400mgand800mgdailydoseoffluconazoledemonstratedthatfluconazoletakenindosesof400mgperdayor

greatersignificantlyincreasesplasmalevelsofterfenadinewhentakenconcomitantly.Thecombineduseof

fluconazoleatdosesof400mgorgreaterwithterfenadineiscontraindicated(seesection4.3).Thecoadministrationof

fluconazoleatdoseslowerthan400mgperdaywithterfenadineshouldbecarefullymonitored.

Astemizole:Concomitantadministrationoffluconazolewithastemizolemaydecreasetheclearanceofastemizole.

ResultingincreasedplasmaconcentrationsofastemizolecanleadtoQTprolongationandrareoccurrencesoftorsades

depointes.Coadministrationoffluconazoleandastemizoleiscontraindicated(seesection4.3).

Pimozide:Althoughnotstudiedinvitroorinvivo,concomitantadministrationoffluconazolewithpimozidemayresult

ininhibitionofpimozidemetabolism.IncreasedpimozideplasmaconcentrationscanleadtoQTprolongationandrare

occurrencesoftorsadesdepointes.Coadministrationoffluconazoleandpimozideiscontraindicated(seesection4.3).

Quinidine:Althoughnotstudiedinvitroorinvivo,concomitantadministrationoffluconazolewithquinidinemay

resultininhibitionofquinidinemetabolism.UseofquinidinehasbeenassociatedwithQTprolongationandrare

occurrencesoftorsadesdepointes.Coadministrationoffluconazoleandquinidineiscontraindicated(seesection4.3).

Erythromycin:Concomitantuseoffluconazoleanderythromycinhasthepotentialtoincreasetheriskofcardiotoxicity

(prolongedQTinterval,torsadesdepointes)andconsequentlysuddenheartdeath.Coadministrationoffluconazoleand

erythromyciniscontraindicated(seesection4.3).

Concomitantuseofthefollowingothermedicinalproductscannotberecommended:

Halofantrine:FluconazolecanincreasehalofantrineplasmaconcentrationduetoaninhibitoryeffectonCYP3A4.

Concomitantuseoffluconazoleandhalofantrinehasthepotentialtoincreasetheriskofcardiotoxicity(prolongedQT

interval,torsadesdepointes)andconsequentlysuddenheartdeath.Thiscombinationshouldbeavoided(seesection

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Concomitantuseofthefollowingothermedicinalproductsleadtoprecautionsanddoseadjustments:

Theeffectofothermedicinalproductsonfluconazole

Rifampicin:Concomitantadministrationoffluconazoleandrifampicinresultedina25%decreaseintheAUCanda

20%shorterhalf-lifeoffluconazole.Inpatientsreceivingconcomitantrifampicin,anincreaseofthefluconazoledose

shouldbeconsidered.

Interactionstudieshaveshownthatwhenoralfluconazoleiscoadministeredwithfood,cimetidine,antacidsor

followingtotalbodyirradiationforbonemarrowtransplantation,noclinicallysignificantimpairmentoffluconazole

absorptionoccurs.

Theeffectoffluconazoleonothermedicinalproducts:

FluconazoleisapotentinhibitorofcytochromeP450(CYP)isoenzyme2C9andamoderateinhibitorofCYP3A4.

FluconazoleisalsoaninhibitoroftheisozymeCYP2C19.Inadditiontotheobserved/documentedinteractions

mentionedbelow,thereisariskofincreasedplasmaconcentrationofothercompoundsmetabolizedbyCYP2C9and

CYP3A4coadministeredwithfluconazole.Thereforecautionshouldbeexercisedwhenusingthesecombinationsand

thepatientsshouldbecarefullymonitored.Theenzymeinhibitingeffectoffluconazolepersists4-5daysafter

discontinuationoffluconazoletreatmentduetothelonghalf-lifeoffluconazole(seesection4.3).

Alfentanil:Duringconcomitanttreatmentwithfluconazole(400mg)andintravenousalfentanil(20 µ

g/kg)inhealthy

volunteersthealfentanilAUC

increased2-fold,probablythroughinhibitionofCYP3A4.Doseadjustmentof

alfentanilmaybenecessary.

Amitriptyline,nortriptyline:Fluconazoleincreasestheeffectofamitriptylineandnortriptyline.5-nortriptylineand/or

S-amitriptylinemaybemeasuredatinitiationofthecombinationtherapyandafteroneweek.Doseof

amitriptyline/nortriptylineshouldbeadjusted,ifnecessary.

AmphotericinB:ConcurrentadministrationoffluconazoleandamphotericinBininfectednormaland

immunosuppressedmiceshowedthefollowingresults:asmalladditiveantifungaleffectinsystemicinfectionwithC.

albicans,nointeractioninintracranialinfectionwithCryptococcusneoformans,andantagonismofthetwodrugsin

systemicinfectionwithA.fumigatus.Theclinicalsignificanceofresultsobtainedinthesestudiesisunknown.

Anticoagulants:Inpost-marketingexperiences,aswithotherazoleantifungals,bleedingevents(bruising,epistaxis,

gastrointestinalbleeding,hematuria,andmelena)havebeenreported,inassociationwithincreasesinprothrombintime

inpatientsreceivingfluconazoleconcurrentlywithwarfarin.Duringconcomitanttreatmentwithfluconazoleand

warfarintheprothrombintimewasprolongedupto2-fold,probablyduetoaninhibitionofthewarfarinmetabolism

throughCYP2C9.Inpatientsreceivingcoumarin-typeanticoagulantsconcurrentlywithfluconazoletheprothrombin

timeshouldbecarefullymonitored.Doseadjustmentofwarfarinmaybenecessary.

Benzodiazepines(shortacting),i.e.midazolam,triazolam:Followingoraladministrationofmidazolam,fluconazole

resultedinsubstantialincreasesinmidazolamconcentrationsandpsychomotoreffects.Concomitantintakeof

fluconazole200mgandmidazolam7.5mgorallyincreasedthemidazolamAUCandhalf-life3.7-foldand2.2-fold,

respectively.

Fluconazole200mgdailygivenconcurrentlywithtriazolam0.25mgorallyincreasedthetriazolamAUCandhalf-life

4.4-foldand2.3-fold,respectively.Potentiatedandprolongedeffectsoftriazolamhavebeenobservedatconcomitant

treatmentwithfluconazole.Ifconcomitantbenzodiazepinetherapyisnecessaryinpatientsbeingtreatedwith

fluconazole,considerationshouldbegiventodecreasingthebenzodiazepinedose,andthepatientsshouldbe

appropriatelymonitored.

Carbamazepine:Fluconazoleinhibitsthemetabolismofcarbamazepineandanincreaseinserumcarbamazepineof

30%hasbeenobserved.Thereisariskofdevelopingcarbamazepinetoxicity.Doseadjustmentofcarbamazepinemay

benecessarydependingonconcentrationmeasurements/effect.

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felodipine)aremetabolizedbyCYP3A4.Fluconazolehasthepotentialtoincreasethesystemicexposureofthecalcium

channelantagonists.Frequentmonitoringforadverseeventsisrecommended.

Celecoxib:Duringconcomitanttreatmentwithfluconazole(200mgdaily)andcelecoxib(200mg)thecelecoxibC

andAUCincreasedby68%and134%,respectively.Halfofthecelecoxibdosemaybenecessarywhencombinedwith

fluconazole.

Cyclophosphamide:Combinationtherapywithcyclophosphamideandfluconazoleresultsinanincreaseinserum

bilirubinandserumcreatinine.Thecombinationmaybeusedwhiletakingincreasedconsiderationtotheriskof

increasedserumbilirubinandserumcreatinine.

Fentanyl:Onefatalcaseoffentanylintoxicationduetopossiblefentanylfluconazoleinteractionwasreported.

Furthermore,itwasshowninhealthyvolunteersthatfluconazoledelayedtheeliminationoffentanylsignificantly.

Elevatedfentanylconcentrationmayleadtorespiratorydepression.Patientsshouldbemonitoredcloselyforthe

potentialriskofrespiratorydepression.Dosageadjustmentoffentanylmaybenecessary.

HMG-CoAreductaseinhibitors:Theriskofmyopathyandrhabdomyolysisincreaseswhenfluconazoleis

coadministeredwithHMG-CoAreductaseinhibitorsmetabolisedthroughCYP3A4,suchasatorvastatinand

simvastatin,orthroughCYP2C9,suchasfluvastatin.Ifconcomitanttherapyisnecessary,thepatientshouldbe

observedforsymptomsofmyopathyandrhabdomyolysisandcreatininekinaseshouldbemonitored.HMG-CoA

reductaseinhibitorsshouldbediscontinuedifamarkedincreaseincreatininekinaseisobservedor

myopathy/rhabdomyolysisisdiagnosedorsuspected.

Immunosuppresors(i.e.ciclosporin,everolimus.sirolimusandtacrolimus):

Ciclosporin:FluconazolesignificantlyincreasestheconcentrationandAUCofciclosporin.Duringconcomitant

treatmentwithfluconazole200mgdailyandciclosporin(2.7mg/kg/day)therewasa1.8-foldincreaseinciclosporin

AUC.Thiscombinationmaybeusedbyreducingthedoseofciclosporindependingonciclosporinconcentration.

Everolimus:Althoughnotstudiedinvivoorinvitro,fluconazolemayincreaseserumconcentrationsofeverolimus

throughinhibitionofCYP3A4.

Sirolimus:Fluconazoleincreasesplasmaconcentrationsofsirolimuspresumablybyinhibitingthemetabolismof

sirolimusviaCYP3A4andp-glycoprotein.Thiscombinationmaybeusedwithadoseadjustmentofsirolimus

dependingontheeffect/concentrationmeasurements.

Tacrolimus:Fluconazolemayincreasetheserumconcentrationsoforallyadministeredtacrolimusupto5timesdueto

inhibitionoftacrolimusmetabolismthroughCYP3A4intheintestines.Nosignificantpharmacokineticchangeshave

beenobservedwhentacrolimusisgivenintravenously.Increasedtacrolimuslevelshavebeenassociatedwith

nephrotoxicity.Doseoforallyadministeredtacrolimusshouldbedecreaseddependingontacrolimusconcentration.

Losartan:Fluconazoleinhibitsthemetabolismoflosartantoitsactivemetabolite(E-3174),whichisresponsiblefor

mostoftheangiotensinII-receptorantagonismwhichoccursduringtreatmentwithlosartan.Patientsshouldhavetheir

bloodpressuremonitoredcontinuously.

Methadone:Fluconazolemayenhancetheserumconcentrationofmethadone.Doseadjustmentofmethadonemaybe

necessary.

Non-steroidalanti-inflammatorydrugs:TheC

andAUCofflurbiprofenwasincreasedby23%and81%,

respectively,whencoadministeredwithfluconazolecomparedtoadministrationofflurbiprofenalone.Similarly,the

andAUCofthepharmacologicallyactiveisomer[S-(+)-ibuprofen]wasincreasedby15%and82%,respectively,

whenfluconazolewascoadministeredwithracemicibuprofen(400mg)comparedtoadministrationofracemic

ibuprofenalone.

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aremetabolizedbyCYP2C9(e.g.naproxen,lornoxicam,meloxicam,diclofenac).Frequentmonitoringforadverse

eventsandtoxicityrelatedtoNSAIDsisrecommended.AdjustmentofdoseofNSAIDsmaybeneeded.

Phenytoin:Fluconazoleinhibitsthehepaticmetabolismofphenytoin.Concomitantrepeatedadministrationof200mg

fluconazoleand250mgphenytoinintravenously,causedanincreaseofthephenytoinAUC24by75%andC

128%.Withcoadministration,serumphenytoinconcentrationlevelsshouldbemonitoredinordertoavoidphenytoin

toxicity.

Prednisone:Therewasacasereportthataliver-transplantedpatienttreatedwithprednisonedevelopedacuteadrenal

cortexinsufficiencywhenathreemonththerapywithfluconazolewasdiscontinued.Thediscontinuationoffluconazole

presumablycausedanenhancedCYP3A4activitywhichledtoincreasedmetabolismofprednisone.Patientsonlong-

termtreatmentwithfluconazoleandprednisoneshouldbecarefullymonitoredforadrenalcortexinsufficiencywhen

fluconazoleisdiscontinued.

Rifabutin:Fluconazoleincreasesserumconcentrationsofrifabutin,leadingtoincreaseintheAUCofrifabutinupto

80%.Therehavebeenreportsofuveitisinpatientstowhomfluconazoleandrifabutinwerecoadministered.In

combinationtherapy,symptomsofrifabutintoxicityshouldbetakenintoconsideration.

Saquinavir:FluconazoleincreasestheAUCandC

ofsaquinavirwithapproximately50%,and55%respectively,

duetoinhibitionofsaquinavir’shepaticmetabolismbyCYP3A4andinhibitionofP-glycoprotein.Interactionwith

saquinavir/ritonavirhasnotbeenstudiedandmightbemoremarked.Doseadjustmentofsaquinavirmaybenecessary.

Sulfonylureas:Fluconazolehasbeenshowntoprolongtheserumhalf-lifeofconcomitantlyadministeredoral

sulfonylureas(e.g.,chlorpropamide,glibenclamide,glipizide,tolbutamide)inhealthyvolunteers.Frequentmonitoring

ofbloodglucoseandappropriatereductionofsulfonylureadoseisrecommendedduringcoadministration.

Theophylline:Inaplacebocontrolledinteractionstudy,theadministrationoffluconazole200mgfor14daysresulted

inan18%decreaseinthemeanplasmaclearancerateoftheophylline.Patientswhoarereceivinghighdose

theophyllineorwhoareotherwiseatincreasedriskfortheophyllinetoxicityshouldbeobservedforsignsof

theophyllinetoxicitywhilereceivingfluconazole.Therapyshouldbemodifiedifsignsoftoxicitydevelop.

Vincaalkaloids:Althoughnotstudied,fluconazolemayincreasetheplasmalevelsofthevincaalkaloids(e.g.

vincristineandvinblastine)andleadtoneurotoxicity,whichispossiblyduetoaninhibitoryeffectonCYP3A4.

VitaminA:Basedonacase-reportinonepatientreceivingcombinationtherapywithall-trans-retinoidacid(anacid

formofvitaminA)andfluconazole,CNSrelatedundesirableeffectshavedevelopedintheformofpseudotumour

cerebri,whichdisappearedafterdiscontinuationoffluconazoletreatment.Thiscombinationmaybeusedbutthe

incidenceofCNSrelatedundesirableeffectsshouldbeborneinmind.

Voriconazole:(CYP2C9andCYP3A4inhibitor):Coadministrationoforalvoriconazole(400mgQ12hfor1day,then

200mgQ12hfor2.5days)andoralfluconazole(400mgonday1,then200mgQ24hfor4days)to8healthymale

subjectsresultedinanincreaseinC

andAUC

ofvoriconazolebyanaverageof57%(90%CI:20%,107%)and

79%(90%CI:40%,128%),respectively.Thereduceddoseand/orfrequencyofvoriconazoleandfluconazolethat

wouldeliminatethiseffecthavenotbeenestablished.Monitoringforvoriconazoleassociatedadverseeventsis

recommendedifvoriconazoleisusedsequentiallyafterfluconazole.

Zidovudine:FluconazoleincreasesC

andAUCofzidovudineby84%and74%,respectively,duetoanapprox.

45%decreaseinoralzidovudineclearance.Thehalf-lifeofzidovudinewaslikewiseprolongedbyapproximately128%

followingcombinationtherapywithfluconazole.Patientsreceivingthiscombinationshouldbemonitoredforthe

developmentofzidovudine-relatedadversereactions.Dosereductionofzidovudinemaybeconsidered.

Azithromycin:Anopen-label,randomized,three-waycrossoverstudyin18healthysubjectsassessedtheeffectofa

single1200mgoraldoseofazithromycinonthepharmacokineticsofasingle800mgoraldoseoffluconazoleaswell

astheeffectsoffluconazoleonthepharmacokineticsofazithromycin.Therewasnosignificantpharmacokinetic

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Oralcontraceptives:Twopharmacokineticstudieswithacombinedoralcontraceptivehavebeenperformedusing

multipledosesoffluconazole.Therewerenorelevanteffectsonhormonelevelinthe50mgfluconazolestudy,while

at200mgdaily,theAUCsofethinylestradiolandlevonorgestrelwereincreased40%and24%,respectively.Thus,

multipledoseuseoffluconazoleatthesedosesisunlikelytohaveaneffectontheefficacyofthecombinedoral

contraceptive.

4.6Fertility,pregnancyandlactation

Pregnancy

Datafromseveralhundredpregnantwomentreatedwithstandarddoses(<200mg/day)offluconazole,administeredas

asingleorrepeateddoseinthefirsttrimester,shownoundesirableeffectsinthefoetus.

Therehavebeenreportsofmultiplecongenitalabnormalities(includingbrachycephalia,earsdysplasia,giantanterior

fontanelle,femoralbowingandradio-humeralsynostosis)ininfantswhosemothersweretreatedforatleastthreeor

moremonthswithhighdoses(400-800mgdaily)offluconazoleforcoccidioidomycosis.Therelationshipbetween

fluconazoleuseandtheseeventsisunclear.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).

Fluconazoleinstandarddosesandshort-termtreatmentsshouldnotbeusedinpregnancyunlessclearlynecessary.

Fluconazoleinhighdoseand/orinprolongedregimensshouldnotbeusedduringpregnancyexceptforpotentiallylife-

threateninginfections.

Breast-feeding

Fluconazolepassesintobreastmilktoreachconcentrationslowerthanthoseinplasma.Breast-feedingmaybe

maintainedafterasingleuseofastandarddose200mgfluconazoleorless.Breast-feedingisnotrecommendedafter

repeateduseorafterhighdosefluconazole.

Fertility

Fluconazoledidnotaffectthefertilityofmaleorfemalerats(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

NostudieshavebeenperformedontheeffectsofFluconazoleontheabilitytodriveorusemachines.Patientsshould

bewarnedaboutthepotentialfordizzinessorseizures(seesection4.8)whiletakingFluconazoleandshouldbeadvised

nottodriveoroperatemachinesifanyofthesesymptomsoccur.

4.8Undesirableeffects

Themostfrequently(>1/10)reportedadversereactionsareheadache,abdominalpain,diarrhoea,nausea,vomiting,

alanineaminotransferaseincreased,aspartateaminotransferaseincreased,bloodalkalinephosphataseincreasedand

rash.

ThefollowingadversereactionshavebeenobservedandreportedduringtreatmentwithFluconazolewiththefollowing

frequencies:Verycommon(1/10);common(1/100to<1/10);uncommon(1/1,000to<1/100);rare(1/10,000to

<1/1,000)andveryrare(<1/10,000),notknown(cannotbeestimatedformtheavailabledata).

SystemOrganClass Common Uncommon Rare

Bloodandthe

lymphaticsystem

disorders Anaemia Agranulocytosis,

leukopenia,

thrombocytopenia,

neutropenia

Immunesystem

disorders Anaphylaxis

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PaediatricPopulation:

Thepatternandincidenceofadversereactionsandlaboratoryabnormalitiesrecordedduringpaediatricclinicaltrials,

excludingthegenitalcandidiasisindication,arecomparabletothoseseeninadults.

4.9Overdose

Therehavebeenreportsofoverdosewithfluconazoleandhallucinationandparanoidbehaviourhavebeen

nutritiondisorders hypertriglyceridaemia,

hypokalemia

Psychiatricdisorders Somnolence,

insomnia

Nervoussystem

disorders Headache Seizures,

paraesthesia,

dizziness,

tasteperversion Tremor

Earandlabyrinth

disorders Vertigo

Cardiacdisorders Torsadedepointes(see

section4.4),QT

prolongation(seesection

4.4)

Gastrointestinal

disorders Abdominalpain,

vomiting,

diarrhoea,nausea Constipation

dyspepsia,

flatulence,

drymouth

Hepatobiliarydisorders Alanine

aminotransferase

increased(see

section4.4),

aspartate

aminotransferase

increased(see

section4.4),blood

alkaline

phosphatase

increased(see

Cholestasis(see

section4.4),

jaundice(seesection

4.4),bilirubin

increased(see

section4.4) Hepaticfailure(see

section4.4),

hepatocellularnecrosis

(seesection4.4),hepatitis

(seesection4.4),

hepatocellulardamage

(seesection4.4)

Skinandsubcutaneous

tissuedisorders Rash(seesection

4.4) Drugeruption(see

section4.4),

urticaria(seesection

4.4),

pruritus,

increasedsweating Toxicepidermal

necrolysis(seesection

4.4),Stevens-Johnson

syndrome(seesection

4.4),acutegeneralised

exanthematous-pustulosis

(seesection4.4),

dermatitisexfoliative,

angioedema,face

oedema,alopecia

Musculoskeletaland

connectivetissue

disorders Myalgia

Generaldisordersand

administrationsite

conditions Fatigue,malaise,

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Intheeventofoverdose,symptomatictreatment(withsupportivemeasuresandgastriclavageifnecessary)maybe

adequate.

Fluconazoleislargelyexcretedintheurine;forcedvolumediuresiswouldprobablyincreasetheeliminationrate.A

three-hourofhaemodialysissessiondecreasesplasmalevelsbyapproximately50%.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antimycoticsforsystemicuse,triazolederivatives,ATCcode:J02AC01.

Modeofaction

Fluconazoleisatriazoleantifungalagent.ItsprimarymodeofactionistheinhibitionoffungalcytochromeP-450-

mediated14alpha-lanosteroldemethylation,anessentialstepinfungalergosterolbiosynthesis.Theaccumulationof14

alpha-methylsterolscorrelateswiththesubsequentlossofergosterolinthefungalcellmembraneandmaybe

responsiblefortheantifungalactivityoffluconazole.Fluconazolehasbeenshowntobemoreselectiveforfungal

cytochromeP-450enzymesthanforvariousmammaliancytochromeP-450enzymesystems.

Fluconazole50mgdailygivenupto28dayshasbeenshownnottoeffecttestosteroneplasmaconcentrationsinmales

orsteroidconcentrationinfemalesofchild-bearingage.Fluconazole200mgto400mgdailyhasnoclinically

significanteffectonendogenoussteroidlevelsoronACTHstimulatedresponseinhealthymalevolunteers.Interaction

studieswithantipyrineindicatethatsingleormultipledosesoffluconazole50mgdonotaffectitsmetabolism.

Susceptibilityinvitro

Invitro,fluconazoledisplaysantifungalactivityagainstmostclinicallycommonCandidaspecies(includingC.

albicans,C.parapsilosis,C.tropicalis).C.glabratashowsawiderangeofsusceptibilitywhileC.kruseiisresistantto

fluconazole.

FluconazolealsoexhibitsactivityinvitroagainstCryptococcusneoformansandCryptococcusgattiiaswellasthe

endemicmouldsBlastomycesdermatiditis,Coccidioidesimmitis,HistoplasmacapsulatumandParacoccidioides

brasiliensis.

PK/PDrelationship

Inanimalstudies,thereisacorrelationbetweenMICvaluesandefficacyagainstexperimentalmycosesduetoCandida

spp.Inclinicalstudies,thereisanalmost1:1linearrelationshipbetweentheAUCandthedoseoffluconazole.Thereis

alsoadirectthoughimperfectrelationshipbetweentheAUCordoseandasuccessfulclinicalresponseoforal

candidosisandtoalesserextentcandidaemiatotreatment.Similarlycureislesslikelyforinfectionscausedbystrains

withahigherfluconazoleMIC.

Mechanism(s)ofresistance

Candidaspp.havedevelopedanumberofresistancemechanismstoazoleantifungalagents.Fungalstrainswhichhave

developedoneormoreoftheseresistancemechanismsareknowntoexhibithighminimuminhibitoryconcentrations

(MICs)tofluconazolewhichimpactsadverselyefficacyinvivoandclinically.

TherehavebeenreportsofsuperinfectionwithCandidaspeciesotherthanC.albicans,whichareofteninherentlynot

susceptibletofluconazole(e.g.Candidakrusei).Suchcasesmayrequirealternativeantifungaltherapy.

Breakpoints(accordingtoEUCAST)

Basedonanalysesofpharmacokinetic/pharmacodynamic(PK/PD)data,susceptibilityinvitroandclinicalresponse

EUCAST-AFST(EuropeanCommitteeonAntimicrobialsusceptibilityTesting-subcommitteeonAntifungal

SusceptibilityTesting)hasdeterminedbreakpointsforfluconazoleforCandidaspecies(EUCASTFluconazolerational

document(2007)-version2).Thesehavebeendividedintonon-speciesrelatedbreakpoints;whichhavebeen

determinedmainlyonthebasisofPK/PDdataandareindependentofMICdistributionsofspecificspecies,and

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giveninthetablebelow:

S=Susceptible,R=Resistant

A=Non-speciesrelatedbreakpointshavebeendeterminedmainlyonthebasisofPK/PDdataandareindependentof

MICdistributionsofspecificspecies.Theyareforuseonlyfororganismsthatdonothavespecificbreakpoints.

--=Susceptibilitytestingnotrecommendedasthespeciesisapoortargetfortherapywiththemedicinalproduct.

IE=Thereisinsufficientevidencethatthespeciesinquestionisagoodtargetfortherapywiththemedicinalproduct.

5.2Pharmacokineticproperties

Thepharmacokineticspropertiesoffluconazolearesimilarfollowingadministrationbytheintravenousororalroute.

Absorption

Afteroraladministrationfluconazoleiswellabsorbed,andplasmalevels(andsystemicbioavailability)areover90%

ofthelevelsachievedafterintravenousadministration.Oralabsorptionisnotaffectedbyconcomitantfoodintake.

Peakplasmaconcentrationsinthefastingstateoccurbetween0.5and1.5hourspost-dose.Plasmaconcentrationsare

proportionaltodose.Ninetypercentsteadystatelevelsarereachedbyday4-5withmultipleoncedailydosing.

Administrationofaloadingdose(onday1)oftwicetheusualdailydoseenablesplasmalevelstoapproximateto90%

steady-statelevelsbyday2.

Distribution:

Theapparentvolumeofdistributionapproximatestototalbodywater.Plasmaproteinbindingislow(11-12%).

Fluconazoleachievesgoodpenetrationinallbodyfluidsstudied.Thelevelsoffluconazoleinsalivaandsputumare

similartoplasmalevels.Inpatientswithfungalmeningitis,fluconazolelevelsintheCSFareapproximately80%the

correspondingplasmalevels.

Highskinconcentrationoffluconazole,aboveserumconcentrationsareachievedinthestratumcorneum,epidermis-

dermisandeccrinesweat.Fluconazoleaccumulatesinthestratumcorneum.Atadoseof50mgoncedaily,the

concentrationoffluconazoleafter12dayswas73µg/gand7daysaftercessationoftreatmenttheconcentrationwas

still5.8µg/g.Atthe150mgonce-a-weekdose,theconcentrationoffluconazoleinstratumcorneumonday7was23.4

µg/gand7daysaftertheseconddosewasstill7.1µg/g.

Concentrationoffluconazoleinnailsafter4monthsof150mgonce-a-weekdosingwas4.05µg/ginhealthyand1.8

µg/gindiseasednails;and,fluconazolewasstillmeasurableinnailsamples6monthsaftertheendoftherapy.

Biotransformation

Fluconazoleismetabolisedonlytoaminorextent.Ofaradioactivedoseisonly11%isexcretedinachangedformin

theurine.FluconazoleisaselectiveinhibitoroftheisozymesCYP2C9andCYP3A4(seesection4.5).Fluconazoleis

alsoaninhibitoroftheisozymeCYP2C19.

Excretion

Plasmaeliminationhalf-lifeforfluconazoleisapproximately30hours.Themajorrouteofexcretionisrenal,with

approximately80%oftheadministereddoseappearingintheurineasunchangedmedicinalproduct.Fluconazole

clearanceisproportionaltocreatinineclearance.Thereisnoevidenceofcirculatingmetabolites.

Thelongplasmaeliminationhalf-lifeprovidesthebasisforthesingledosetherapyforvaginalcandidiasis,oncedaily

Antifungal Species-relatedbreakpoints(S/R>) Non-species

related

breakpoints A

S/R>

Candida

albicans Candida

glabrata Candida

krusei Candida

parapsilosis Candida

tropicalis

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Pharmacokineticsinrenalimpairment

Inpatientswithsevererenalinsufficiency,(GFR<20ml/min)halflifeincreasedfrom30to98hours.Consequently,

reductionofthedoseisneeded.Fluconazoleisremovedbyhaemodialysisandtoalesserextentbyperitonealdialysis.

Afterthreehoursofhaemodialysissession,around50%offluconazoleiseliminatedfromblood.

Pharmacokineticsinchildren

Pharmacokineticdatawereassessedin113paediatricpatientsfrom5studies,2single-dosestudies,twomultiple-dose

studiesandastudyinprematureneonates.Datafromonestudywerenotinterpretableduetochangesinformulation

pathwaythroughthestudy.Additionaldatawereavailablefromacompassionateusestudy.

Afteradministrationof2-8mg/kgfluconazoletochildrenbetweentheagesof9monthsto15years,anAUCofabout

38µg.h/mlwasfoundper1mg/kgdoseunit.Theaveragefluconazoleplasmaeliminationhalf-lifevariedbetween15

and18hoursandthedistributionvolumewasapproximately880ml/kgaftermultipledoses.Ahigherfluconazole

plasmaeliminationhalf-lifeofapproximately24hourswasfoundafterasingledose.Thisiscomparablewiththe

fluconazoleplasmaeliminationhalf-lifeafterasingleadministrationof3mg/kgi.v.tochildrenof11days-11months

old.Thedistributionvolumeinthisagegroupwasabout950ml/kg.

Experiencewithfluconazoleinneonatesislimitedtopharmacokineticstudiesinprematurenewborns.Themeanageat

firstdosewas24hours(range9-36hours)andmeanbirthweightwas0.9kg(range0.75-1.10kg)for12pre-term

neonatesofaveragegestationaround28weeks.Sevenpatientscompletedtheprotocol;amaximumoffive6mg/kg

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

185)onday1,whichdecreased,withtimetoameanof53(range30-131)onday7and47(range27-68)onday13.

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

(range292-734)onday7anddecreasedwithameanof360(range167-566)onday13.Thevolumeofdistribution

(ml/kg)was1183(range1070-1470)onday1andincreasedwithtimetoameanof1184(range510-2130)onday7

and1328(range1040-1680)onday13.

Pharmacokineticsinelderly

Apharmacokineticstudywasconductedin22subjects,65yearsofageorolderreceivingasingle50mgoraldoseof

fluconazole.Tenofthesepatientswereconcomitantlyreceivingdiuretics.TheC

was1.54µg/mlandoccurredat

1.3hourspostdose.ThemeanAUCwas76.4±20.3µg.h/ml,andthemeanterminalhalf-lifewas46.2hours.These

pharmacokineticparametervaluesarehigherthananalogousvaluesreportedfornormalyoungmalevolunteers.

CoadministrationofdiureticsdidnotsignificantlyalterAUCorC

.Inaddition,creatinineclearance(74ml/min),the

percentofmedicinalproductrecoveredunchangedinurine(0-24hr,22%)andthefluconazolerenalclearance

estimates(0.124ml/min/kg)fortheelderlyweregenerallylowerthanthoseofyoungervolunteers.Thus,thealteration

offluconazoledispositionintheelderlyappearstoberelatedtoreducedrenalfunctioncharacteristicofthisgroup.

5.3Preclinicalsafetydata

Effectsinnon-clinicalstudieswereobservedonlyatexposuresconsideredsufficientlyinexcessofthehumanexposure

indicatinglittlerelevancetoclinicaluse.

Carcinogenesis

Fluconazoleshowednoevidenceofcarcinogenicpotentialinmiceandratstreatedorallyfor24monthsatdosesof2.5,

5,or10mg/kg/day(approximately27timestherecommendedhumandose).Maleratstreatedwith5and10mg/kg/day

hadanincreasedincidenceofhepatocellularadenomas.

Reproductivetoxicity

Fluconazoledidnotaffectthefertilityofmaleorfemaleratstreatedorallywithdailydosesof5,10,or20mg/kgor

withparenteraldosesof5,25,or75mg/kg.

Therewerenofoetaleffectsat5or10mg/kg;increasesinfoetalanatomicalvariants(supernumeraryribs,renalpelvis

dilation)anddelaysinossificationwereobservedat25and50mg/kgandhigherdoses.Atdosesrangingfrom80

mg/kgto320mg/kgembryolethalityinratswasincreasedandfoetalabnormalitiesincludedwavyribs,cleftpalate,and

abnormalcranio-facialossification.Theonsetofparturitionwasslightlydelayedat20mg/kgorallyanddystociaand

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parturitionwerereflectedbyaslightincreaseinthenumberofstill-bornpupsanddecreaseofneonatalsurvivalatthese

doselevels.Theseeffectsonparturitionareconsistentwiththespeciesspecificoestrogen-loweringpropertyproduced

byhighdosesoffluconazole.Suchahormonechangehasnotbeenobservedinwomentreatedwithfluconazole(see

section5.1).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontent:

Lactosemonohydrate

Maizestarch

Sodiumlaurilsulfate

Magnesiumstearate(E470b)

Silica,colloidalanhydrous

Capsuleshell:

Gelatin

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Storebelow30 °

C.Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

FluconazolearepackedinPVC-Aluminiumblister.

Packsizeof7and14hardcapsules

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Anyunusedmedicinalproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

IntasPharmaceuticalsLimited

SageHouse,

319PinnerRoad,

NorthHarrow,

MiddlesexHA14HF,

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8MARKETINGAUTHORISATIONNUMBER

PA1666/003/003

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:30thMarch2012

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