DIFLUCAN

Main information

  • Trade name:
  • DIFLUCAN Capsule 150 Milligram
  • Dosage:
  • 150 Milligram
  • Pharmaceutical form:
  • Capsule
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DIFLUCAN Capsule 150 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/093/001
  • Authorization date:
  • 19-09-2003
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Diflucan150mgCapsules.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains150mgfluconazole.

Excipents:containsLactoseMonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,hard.

ProductimportedfromGreece,theNetherlands,SpainandHungary:

Lightturquoisebluecapsule,coded‘FLU150’and‘PFIZER’.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Therapymaybeinstitutedbeforetheresultsoftheculturesandotherlaboratorystudiesareknown,oncetheseresults

becomeavailable,anti-infectivetherapyshouldbeadjustedaccordingly.

Diflucanisindicatedfor:

Genitalcandidiasis,Vaginalcandidiasis,acuteorrecurrent.Candidalbalanitis.

4.2Posologyandmethodofadministration

Diflucanmaybeadministeredeithearorallyorbyintravenousinfusionatarateofapproximatley5-10ml/min,theroute

beingdependentontheclinicalstateofthepatient.Ontransferringfromtheintravenousroutetotheoralrouteorvice

versa,thereisnoneedtochangethedailydose.

ThedailydoseofDiflucanshouldbebasedonthenatureandseverityofthefungalinfection.Mostcasesofvaginal

candidiasisrespondtosingledosetherapy.Therapyforthosetypesofinfectionsrequiringmultipledosetreatment

shouldbecontinueduntilclinicalparametersorlaboratorytestsindicatethatactivefungalinfectionhassubsided.An

inadequateperiodoftreatmentmayleadtorecurrenceofactiveinfection.PatientswithAIDSandcryptococcal

meningitisusuallyrequiremaintenancetherapytopreventrelapse.

Useinadults

Candidalvaginitisorbalanitis.Theusualdosageis150mgasasingledose.

Useinchildren

Aswithsimilarinfectionsinadults,thedurationoftreatmentisbasedontheclinicalandmycologicalresponse.The

maximumadultdosageshouldnotbeexceededinchildren.Diflucanisadministeredasasingledailydoseeachday.

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Useintheelderly

Thenormaldoseshouldbeusedifthereisnoevidenceofrenalimpairment.Inpatientswithrenalimpairment

(creatinineclearancelessthan50ml/min)thedosageshouldbeadjustedasdescribedbelow.

Useinpatientswithimpairedrenalfunction

Fluconazoleisexcretedpredominantlyintheurineasunchangeddrug.Noadjustmentsinsingledosetherapyare

required.Inpatients(includingchildren)withimpairedrenalfunctionwhowillreceivemultipledosesofDiflucan,the

normalrecommendeddose(accordingtoindication)shouldbegivenonday1,followedbyadailydosebasedonthe

followingtable:

4.3Contraindications

Diflucanshouldnotbeusedinpatientswithknownhypersensitivitytofluconazoleortorelatedazolecompoundsor

anyotheringredientintheformulation.

Co-administrationofterfenadineiscontraindicatedinpatientsreceivingDiflucanatmultipledosesof400mgperday

orhigherbaseduponresultsofamultipledoseinteractionstudy.

Co-administrationofcisaprideiscontraindicatedinpatientsreceivingDiflucan.(Seesection4.5,Interactionwith

othermedicinalproductsandotherformsofinteraction).

Diflucancapsulescontainsoyalecithin,whichisaderivativeofsoyaoil.Ifyouareallergictopeanutsorsoya,donot

usethismedicinalproduct.

4.4Specialwarningsandprecautionsforuse

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,abnormalitiesofhepatic,

renal,haematologicalandotherbiochemicalfunctiontestshavebeenobservedduringtreatmentwithDiflucanbutthe

clinicalsignificanceandrelationshiptotreatmentisuncertain.

Diflucanhasbeenassociatedwithrarecasesofserioushepatictoxicityincludingfatalities,primarilyinpatientswith

seriousunderlyingmedicalconditions.IncasesofDiflucan-associatedhepatotoxicity,noobviousrelationshiptototal

dailydose,durationoftherapy,sexorageofpatienthasbeenobserved.Diflucanhepatotoxicityhasusuallybeen

reversibleondiscontinuationoftherapy.PatientswhodevelopabnormalliverfunctiontestsduringDiflucantherapy

shouldbemonitoredforthedevelopmentofmoreserioushepaticinjury.

Diflucanshouldbediscontinuedifclinicalsignsorsymptomsconsistentwithliverdiseasedevelopthatmaybe

attributabletoDiflucan.

Patientshaverarelydevelopedexfoliativecutaneousreactions,suchasStevens-JohnsonSyndromeandtoxicepidermal

necrolysis,duringtreatmentwithfluconazole.AIDSpatientsaremorepronetothedevelopmentofseverecutaneous

reactionstomanydrugs.Ifarashdevelopsinapatienttreatedforasuperficialfungalinfectionwhichisconsidered

attributabletoDiflucan,furthertherapywiththisagentshouldbediscontinued.Ifpatientswithinvasive/systemic

fungalinfectionsdeveloprashes,theyshouldbemonitoredcloselyandDiflucandiscontinuedifbullouslesionsor

erythemamultiformedevelop.

Thereislittleinformationonsafetyinlong-termuse.

Creatinineclearance(ml/min) Percentofrecommendeddose

>50 100%

<50(nodialysis) 50%

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Someazoles,includingfluconazole,havebeenassociatedwithprolongationoftheQTintervalonthe

electrocardiogram.Duringpost-marketingsurveillance,therehavebeenveryrarecasesofQTprolongationandtorsade

depointesinpatientstakingfluconazole.AlthoughtheassociationoffluconazoleandQT-prolongationhasnotbeen

fullyestablished,fluconazoleshouldbeusedwithcautioninpatientswithpotentiallyproarrythmicconditionssuchas:

CongenitalordocumentedacquiredQT-prolongation

Cardiomyopathy,inparticularwhenheartfailureispresent

Sinusbradycardia

Existingsymptomaticarrythmias

ConcomitantmedicationnotmetabolizedbyCY34AbutknowntoprolongQTinterval

Electrolytedisturbancessuchashypokalaemia,hypomagnesaemiaandhypocalaemia

(Seesection4.5,Interactionswithothermedicalproductsandotherformsofinteraction)

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Rifampicin:Concomitantadministrationoffluconazoleandrifampicinhasresultedina25%decreaseintheAUCand

20%shorterhalf-lifeoffluconazole.Inpatientsreceivingconcomitantrifampicin,anincreaseinthefluconazoledose

shouldbeconsidered.

Hydrochlorothiazide:Inakineticinteractionstudy,co-administrationofmultiple-dosehydrochlorothiazidetohealthy

volunteersreceivingfluconazoleincreasedplasmaconcentrationsoffluconazoleby40%.Aneffectofthismagnitude

shouldnotnecessitateachangeinthefluconazoledoseregimeninsubjectsreceivingconcomitantdiuretics,although

theprescribershouldbearitinmind.

Anticoagulants:Inaninteractionstudy,fluconazoleincreasedtheprothrombintime(12%)

afterwarfarinadministrationinhealthymales.Inpost-marketingexperiences,aswithother

azoleantifungals,bleedingevents(bruising,epistaxis,gastrointestinalbleeding,hematuria,

andmelaena)havebeenreported,inassociationwithincreasesinprothrombintimein

patientsreceivingfluconazoleconcurrentlywithwarfarin.Prothrombintimeinpatients

receivingcoumarin-typeanticoagulantsshouldbecarefullymonitored.

Azithromycin:Anopen-label,randomized,three-waycrossoverstudyin18healthysubjectsassessedtheeffectofa

single1200mgoraldoseofazithromycinonthepharmacokineticsofasingle800mgoraldoseoffluconazoleaswell

astheeffectsoffluconazoleonthepharmacokineticsofazithromycin.Therewasnosignificantpharmacokinetic

interactionbetweenfluconazoleandazithromycin.

Benzodiazepines(shortacting):Followingoraladministrationofmidazolam,fluconazoleresultedinsubstantial

increasesinmidazolamconcentrationsandpsychomotoreffects.Thiseffectonmidazolamappearstobemore

pronouncedfollowingoraladministrationoffluconazolethanwithfluconazoleadministeredintravenously.If

concomitantbenzodiazepinetherapyisnecessaryinpatientsbeingtreatedwithfluconazole,considerationshouldbe

giventodecreasingthebenzodiazepinedosage,andthepatientsshouldbeappropriatelymonitored.

Sulphonylureas:Fluconazolehasbeenshowntoprolongtheserumhalf-lifeofconcomitantlyadministeredoral

sulphonylureas(chlorpropamide,glibenclamide,glipizideandtolbutamide)inhealthyvolunteers.Fluconazoleandoral

sulphonylureasmaybeco-administeredtodiabeticpatients,butthepossibilityofahypoglycaemicepisodeshouldbe

borneinmind.

Phenytoin:Concomitantadministrationoffluconazoleandphenytoinmayincreasethelevelsofphenytointoa

clinicallysignificantdegree.Ifitisnecessarytoadministerbothdrugsconcomitantly,phenytoinlevelsshouldbe

monitoredandthephenytoindoseadjustedtomaintaintherapeuticlevels.

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dosesoffluconazole.Therewerenorelevanteffectsoneitherhormonelevelinthe50mgfluconazolestudy,whileat

200mgdailytheAUCsofethinylestradiolandlevonorgestrelwereincreased40%and24%respectively.Ina300mg

dailyfluconazolestudy,theAUCsofethinylestradiolandnorethindronewereincreasedby24%and13%,

respectively.Thusmultipledoseuseoffluconazoleatthesedosesisunlikelytohaveaneffectontheefficacyofthe

combinedoralcontraceptive.

Endogenoussteroid:Fluconazole50mgdailydoesnotaffectendogenoussteroidlevelsinfemales.200-400mgdaily

hasnoclinicallysignificanteffectonendogenoussteroidlevelsoronACTHstimulatedresponseinhealthymale

volunteers.

Cyclosporin:Akineticstudyinrenaltransplantpatientsfoundfluconazole200mgdailytoslowlyincreasecyclosporin

concentrations.However,inanothermultipledosestudywith100mgdaily,fluconazoledidnotaffectcyclosporin

levelsinpatientswithbonemarrowtransplants.Cyclosporinplasmaconcentrationmonitoringinpatientsreceiving

fluconazoleisrecommended.

Theophylline:Inaplacebo-controlledinteractionstudy,theadministrationoffluconazole200mgfor14daysresulted

inan18%decreaseinthemeanplasmaclearanceoftheophylline.

Patientswhoarereceivinghighdosesoftheophyllineorwhoareotherwiseatincreasedriskfortheophyllinetoxicity

shouldbeobservedforsignsoftheophyllinetoxicitywhilereceivingfluconazole,andthetherapymodified

appropriatelyifsignsoftoxicitydevelop.

Tacrolimus:Therehavebeenreportsthataninteractionexistswhenfluconazoleisadministeredconcomitantlywith

tacrolimus,leadingtoincreasedserumlevelsoftacrolimus.Therehavebeenreportsofnephrotoxicityinpatientsto

whomfluconazoleandtacrolimuswereco-administered.Patientsreceivingtacrolimusandfluconazoleconcomitantly

shouldbecarefullymonitored.

Rifabutin:Therehavebeenreportsthataninteractionexistswhenfluconazoleisadministeredconcomitantlywith

rifabutin,leadingtoincreasedserumlevelsofrifabutin.Therehavebeenreportsofuveitisinpatientstowhom

fluconazoleandrifabutinwereco-administered.Patientsreceivingrifabutinandfluconazoleconcomitantlyshouldbe

carefullymonitored.

Terfenadine:BecauseoftheoccurrenceofseriouscardiacdysrhythmiassecondarytoprolongationoftheQTcinterval

inpatientsreceivingazoleantifungalsinconjunctionwithterfenadine,interactionstudieshavebeenperformed.One

studyata200mgdailydoseoffluconazolefailedtodemonstrateaprolongationofQTcintervals.

Anotherstudyata400mgand800mgdailydoseoffluconazoledemonstratedthatfluconazoletakenindosesof400mg

perdayorgreatersignificantlyincreasesplasmalevelsofterfenadinewhentakenconcomitantly.Thecombineduseof

fluconazoleatdosesof400mgorgreaterwithterfenadineiscontra-indicated.(Seesection4.3,Contra-indications.)

Theco-administrationoffluconazoleatdoseslowerthan400mgperdaywithterfenadineshouldbecarefully

monitored.

Cisapride:Therehavebeenreportsofcardiaceventsincludingtorsadedepiontesinpatientstowhomfluconazoleand

cisapridewereco-administered.Acontrolstudyfoundthatconcomitantfluconazole200mgoncedailyandcisapride

20mgfourtimesadayyieldedasignificantincreaseincisaprideplasmalevelsandprolongationofQTcinterval.Co-

administrationofcisaprideiscontraindicatedinpatientsreceivingfluconazole.

TheuseoffluconazoleinpatientsconcurrentlytakingastemizoleorotherdrugsmetabolisedbythecytochromeP450

systemmaybeassociatedwithelevationsinserumlevelsofthesedrugs.Intheabsenceofdefinitiveinformation,

cautionshouldbeusedwhenco-administeringfluconazole.Patientsshouldbecarefullymonitored.

Zidovudine:Twokineticstudiesresultedinincreasedlevelsofzidovudinemostlikelycausedbythedecreased

conversionofzidovudinetoitsmajormetabolite.OnestudydeterminedzidovudinelevelsinAIDSorARCpatients

beforeandfollowingfluconazole200mgdailyfor15days.TherewasasignificantincreaseinzidovudineAUC(20%).

Asecondrandomised,two-period,two-treatmentcross-overstudyexaminedzidovudinelevelsinHIVinfected

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fluconazole400mgdailyforsevendays.TheAUCofzidovudinesignificantlyincreased(74%)during

coadministrationwithfluconazole.Patientsreceivingthiscombinationshouldbemonitoredforthedevelopmentof

zidovudine-relatedadversereactions.

Interactionstudieshaveshownthatwhenoralfluconazoleisco-administeredwithfood,cimetidine,antacidsor

followingtotalbodyirradiationforbonemarrowtransplantation,noclinicallysignificantimpairmentoffluconazole

absorptionoccurs.

Physiciansshouldbeawarethatdrug-druginteractionstudieswithothermedicationshavenotbeenconducted,butthat

suchinteractionsmayoccur.

Fluvastatin:Astudyinhealthyvolunteersdemonstratedthatfluconazoleincreasedthemeanareaundertheplasma

fluvastatinconcentrationtimecurveby84%,themeaneliminationhalflifeoffluvastatinby80%anditsmeanpeak

plasmaconcentrationby44%.Cautionshouldthereforebeexercisedwhenfluvastationisadministeredconcomitantly

withfluconazole.

4.6Fertility,pregnancyandlactation

Useduringpregnancy:

Therearenoadequateandwellcontrolledstudiesinpregnantwomen.Therehavebeenreportsofmultiplecongenital

abnormalitiesininfantswhosemotherswerebeingtreatedfor3ormoremonthswithhighdose(400-800mg/day)

fluconazoletherapyforcoccidioidomycosis.Therelationshipbetweenfluconazoleandtheseeventsisunclear.

Useinpregnancyshouldbeavoidedexceptinpatientswithsevereorpotentiallylife-threateningfungalinfectionsin

whomfluconazolemaybeusediftheanticipatedbenefitoutweighthepossiblerisktothefoetus.

Useduringlactation:

Fluconazoleisfoundinhumanbreastmilkatconcentrationssimilartoplasma,henceitsuseinnursingmothersisnot

recommended.

4.7Effectsonabilitytodriveandusemachines

ExperiencewithDiflucanindicatesthattherapyisunlikelytoimpairapatient'sabilitytodriveorusemachinery.

4.8Undesirableeffects

Fluconazoleisgenerallywelltolerated.Themostcommonsideeffectsobservedduringclinicaltrialsandassociated

withfluconazoleare:

NervousSystemdisorders:

Headache.

Skinand/subcutaneousTissueDisorders:

Rash.

GastrointestinalDisorders:

Abdominalpain,diarrhoea,flatulence,nausea.

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,changesinrenaland

haematologicalfunctiontestresultsandhepaticabnormalitieshavebeenobservedduringtreatmentwithfluconazole

andcomparativeagents,buttheclinicalsignificanceandrelationshiptotreatmentisuncertain(seesection4.4Special

warningsandspecialprecautionsforuse).

HepatobiliaryDisorders:

Hepatictoxicityincludingrarecasesoffatalities,elevatedalkalinephosphatase,elevatedbilirubin,elevatedSGOT,

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Inaddition,thefollowingadverseeventshaveoccurredduringpost-marketing:

NervousSystemdisorders:

Dizziness,seizures,tasteperversion.

SkinandSubcutaneousTissueDisorders:

Alopecia,exfoliativeskindisordersincludingStevens-JohnsonSyndromeandtoxicepidermalnecrosis.

GastrointestinalDisorders:

Dyspepsia,vomiting.

BloodandLymphaticsystemdisorders:

Leukopeniaincludingneutropeniaandagranulocytosis,thrombocytopenia.

Immunesystemdisorders:

Anaphylaxis(includingangioedema,faceoedema,pruritus,urticaria).

HepatobiliaryDisorders:

Hepaticfailure,hepatitis,hepatocellularnecrosis,jaundice.

MetabolismandNutritionaldisorders:

Hypercholesterolaemia,hypertriglyceridaemia,hypokalaemia.

CardiacDisorders:QTprolongation,torsadedepointes(seeSection4.4,SpecialWarningandSpecialPrecautionsfor

Use).

4.9Overdose

Therehavebeenreportsofoverdosagewithfluconazoleandinonecase,a42year-oldpatientinfectedwithhuman

immunodeficiencyvirusdevelopedhallucinationsandexhibitedparanoidbehaviourafterreportedlyingesting8200mg

offluconazole.Thepatientwasadmittedtothehospitalandhisconditionresolvedwithin48hours.

Intheeventofoverdosage,supportivemeasuresandsymptomatictreatment,withgastriclavageifnecessary,maybe

adequate.

Asfluconazoleislargelyexcretedintheurine,forcedvolumediuresiswouldprobablyincreasetheeliminationrate.A

threehourhaemodialysissessiondecreasesplasmalevelsbyapproximately50%.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Triazolederivatives,ATCcodeJ02AC.

Fluconazole,amemberofthetriazoleclassofantifungalagents,isapotentandselectiveinhibitoroffungalenzymes

necessaryforthesynthesisofergosterol.

Fluconazoleshowslittlepharmacologicalactivityinawiderangeofanimalstudies.Someprolongationof

pentobarbitalsleepingtimesinmice(p.o.),increasedmeanarterialandleftventricularbloodpressureandincreased

heartrateinanaesthetisedcats(i.v.)occurred.Inhibitionofratovarianaromatasewasobservedathighconcentrations.

Bothorallyandintravenouslyadministeredfluconazolewasactiveinavarietyofanimalfungalinfectionmodels.

Activityhasbeendemonstratedagainstopportunisticmycoses,suchasinfectionswithCandidaspp.includingsystemic

candidiasisinimmunocompromisedanimals;withCryptococcusneoformans,includingintracranialinfections;with

Microsporumspp.andwithTrichophytonspp.Fluconazolehasalsobeenshowntobeactiveinanimalmodelsof

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infectionandwithHistoplasmacapsulatuminnormalandimmunosuppressedanimals.

TherehavebeenreportsofcasesofsuperinfectionwithCandidaspeciesotherthanC.albicans,whichareoften

inherentlynotsusceptibletofluconazole(e.g.Candidakrusei).Suchcasesmayrequirealternativeantifungaltherapy.

FluconazoleishighlyspecificforfungalcytochromeP-450dependentenzymes.Fluconazole50mgdailygivenupto

28dayshasbeenshownnottoaffecttestosteroneplasmaconcentrationsinmalesorsteroidconcentrationsinfemales

ofchild-bearingage.Fluconazole200-400mgdailyhasnoclinicallysignificanteffectonendogenoussteroidlevelsor

onACTHstimulatedresponseinhealthymalevolunteers.Interactionstudieswithantipyrineindicatethatsingleor

multipledosesoffluconazole50mgdonotaffectitsmetabolism.

5.2Pharmacokineticproperties

Thepharmacokineticpropertiesoffluconazolearesimilarfollowingadministrationbytheintravenousororalroute.

Afteroraladministrationfluconazoleiswellabsorbedandplasmalevels(andsystemicbioavailability)areover90%of

thelevelsachievedafterintravenousadministration.Oralabsorptionisnotaffectedbyconcomitantfoodintake.Peak

plasmaconcentrationsinthefastingstateoccurbetween0.5and1.5hourspost-dosewithaplasmaeliminationhalf-life

ofapproximately30hours.Plasmaconcentrationsareproportionaltodose.Ninetypercentsteady-statelevelsare

reachedbyday4-5withmultipleoncedailydosing.

Administrationofloadingdose(onday1)oftwicetheusualdailydoseenablesplasmalevelstoapproximateto90%

steady-statelevelsbyday2.Theapparentvolumeofdistributionapproximatestototalbodywater.Plasmaprotein

bindingislow(11-12%).

Fluconazoleachievesgoodpenetrationinallbodyfluidsstudied.Thelevelsoffluconazoleinsalivaandsputumare

similartoplasmalevels.Inpatientswithfungalmeningitis,fluconazolelevelsintheCSFareapproximately80%ofthe

correspondingplasmalevels.

Highskinconcentrationsoffluconazole,aboveserumconcentrations,areachievedinthestratumcorneum,

epidemis-dermisandeccrinesweat.Fluconazoleaccumulatesinthestratumcorneum.Atadoseof50mgoncedaily,

theconcentrationoffluconazoleafter12dayswas73microgram/gand7daysaftercessationoftreatmentthe

concentrationwasstill5.8microgram/g.

Themajorrouteofexcretionisrenal,withapproximately80%oftheadministereddoseappearingintheurineas

unchangeddrug.Fluconazoleclearanceisproportionaltocreatinineclearance.Thereisnoevidenceofcirculating

metabolites.

Thelongplasmaeliminationhalf-lifeprovidesthebasisforsingledosetherapyforgenitalcandidiasisandonce-daily

dosinginthetreatmentofallotherindicatedfungalinfections.

Astudycomparedthesalivaandplasmaconcentrationsofasinglefluconazole100mgdoseadministrationinacapsule

orinanoralsuspensionbyrinsingandretaininginmouthfor2minutesandswallowing.Themaximumconcentration

offluconazoleinsalivaafterthesuspensionwasobserved5minutesafteringestion,andwas182timeshigherthanthe

maximumsalivaconcentrationafterthecapsulewhichoccurred4hoursafteringestion.Afterabout4hours,thesaliva

concentrationsoffluconazoleweresimilar.

ThemeanAUC(0-96)insalivawassignificantlygreaterafterthesuspensioncomparedtothecapsule.Therewasno

significantdifferenceintheeliminationratefromsalivaortheplasmapharmacokineticparametersforthetwo

formulations.

PharmacokineticsinChildren

Inchildren,thefollowingpharmacokineticsdatahavebeenreported:

AgeStudied Dose

(mg/kg) Half-life

(hours) AUC

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*Denotesfinalday

Inprematurenew-borns(gestationalagearound28weeks),intravenousadministrationoffluconazoleof6mg/kgwas

giveneverythirddayforamaximumoffivedoseswhiletheprematurenew-bornsremainedintheintensivecareunit.

Themeanhalf-life(hours)was74(range44-185)onday1whichdecreasedwithtimetoameanof53(range30-131)

onday7and47(range27-68)onday13.

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

292-734)onday7anddecreasedwithameanof360(range167-566)onday13.

Thevolumeofdistribution(ml/kg)was1183(range1070-1470)onday1andwhichincreasedwithtimetoameanof

1184(range510-2130)onday7and1328(range1040-1680)onday13.

PharmacokineticsinElderly

Apharmacokineticstudywasconductedin22subjects,65yearsofageorolderreceivingasingle50mgoralof

fluconazole.Tenofthesepatientswereconcomitantlyreceivingdiuretics.TheC max was1.54mcg/mlabdoccurredat

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

pharmacokineticparametervaluesarehigherthananalogousvaluesreportedfornormalyoungmalevolunteers.

CoadministrationofdiureticsdidnotsignificantlyalterAUCorC max. Inaddition,creatinineclearance(74ml/mm),the

percentofdrugrecoveredunchangedinurine(0-24hr,22%)andthefluconazolerenalclearanceestimates(0.124

ml/min/kg)fortheelderlyweregenerallylowerthanthoseofyoungervolunteers.Thus,thealterationsoffluconazole

dispositionintheelderlyappearstoberelatedtoreducerenalfunctioncharacteristicofthisgroup.Aplotofeach

subject’sterminaleliminationhalf-lifeversuscreatinineclearancecomparedwiththepredictedhalf-life-creatinine

clearancecurvederivedfromnormalsubjectsandsubjectswithvaryingdegreesofrenalinsufficiencyindicatedthat21

to22subjectsfellwithinthe95%confidencelimitofthepredictedhalf-life-creatinineclearancecurves.Theseresults

areconsistentwiththehypothesisthathighervaluesforthepharmacokineticparametersobservedintheelderly

subjectscomparedwithnormalyoungmalevolunteersareduetothedecreasedkidneyfunctionthatisexpectedinthe

elderly.

5.3Preclinicalsafetydata

11days-11 Single-IV 23 110.1

months

3mg/kg

9months-13

years Single-Oral 25.0 94.7

2mg/kg

9months-13

years Single-Oral 19.5 362.5

8mg/kg

5years-15years Multiple-IV 17.4* 67.4

2m/kg

5years-15years Multiple-IV 15.2* 139.1

4mg/kg

5years-15years Multiple-IV 17.6* 196.7

8mg/kg

Meanage7

years Multiple-Oral 15.5 41.6

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Therewerenofetaleffectsat5or10mg/kgincreasesinfetalanatomicalvariants(supernumeraryribs,renalpelvis

dilation)anddelaysinossificationwereobservedat25and50mg/kgandhigherdoses.Atdosesrangingfrom80mg/kg

(approximately20-60xtherecommendedhumandose)to320mg/kgembryolethalityinratswasincreasedandfoetal

abnormalitiesincludedwavyribs,cleftpalateandabnormalcranio-facialossification.Theseeffectsareconsistentwith

theinhibitionofoestrogensynthesisinratsandmaybearesultofknowneffectsofloweredoestrogenonpregnancy,

organogenesisandparturition.

Carcinogenesis:

Fluconazoleshowednoevidenceofcarcinogenicpotentialinmiceandratstreatedorallyfor24monthsatdosesof2.5,

5or10mg/kg/day.Maleratstreatedwith5and10mg/kg/dayhadanincreasedincidenceofhepatocellularadenomas.

Mutagenesis:

Fluconazole,withorwithoutmetabolicactivation,wasnegativeintestsformutagenicityin4strainsofS.typhimurium

andinthemouselymphomaL5178Ysystem.

Cytogeneticstudiesinvivo(murinebonemarrowcells,followingoraladministrationoffluconazole)andinvitro

(humanlymphocytesexposedtofluconazoleat1000µg/ml)showednoevidenceofchromosomalmutations.

Impairmentoffertility:

Fluconazoledidnotaffectthefertilityofmaleorfemaleratstreatedorallywithdailydosesof5,10or20mg/kgorwith

parenteraldosesof5,25or75mg/kgalthoughtheonsetofparturitionwasslightlydelayedat20mg/kgp.o.

Inanintravenousperinatalstudyinratsat5,20and40mg/kg,dystociaandprolongationofparturitionwereobserved

inafewdamsat20mg/kgand40mg/kg,butnotat5mg/kg.Thedisturbancesinparturitionwerereflectedbyaslight

increaseinthenumberofstill-bornpupsanddecreaseofneonatalsurvivalatthesedoselevels.

Theeffectsonparturitioninratsareconsistentwiththespeciesspecificoestrogen-loweringpropertyproducedbyhigh

dosesoffluconazole.Suchahormonechangehasnotbeenobservedinwomentreatedwithfluconazole.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

ProductsourcedfromSpain:

LactoseMonohydrate

Maizestarch

Colloidalanhydroussilica

Magnesiumstearate

Sodiumlaurilsulfate

PatentBlueV(E131)

Titaniumdioxide(E171)

Gelatin

Printinginkcontains:

blackiron

oxide(E172)

shellac

soyalecithin

Antifoam

N-butyl-alcohol

ProductsourcedfromGreece

Lactosemonohydrate

Maizestarch

Colloidalanhydroussilica

Magnesiumstearate

Irish Medicines Board

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Date Printed 27/06/2011 CRN 2101974 page number: 9

Gelatin

Sulfurdioxide

Titaniumdioxide(E171)

Patentblue(E131)

ProductsourcedfromtheNetherlands

Lactosemonohydrate

Maizestarch

Colloidalanhydroussilica

Magnesiumstearate

Sodiumlaurilsulfate

Patentblue(E131)

TitaniumDioxide(E171)

Gelatin

Shellac

IronOxide(E172)

PropyleneGlycol

ProductsourcedfromHungary

Lactose

MaizeStarch

ColloidalAnhydrousSilica

MagnesiumStearate

SodiumLaurilsulfate

Gelatin

PatentBlueV(E131)

TitaniumDioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateforthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Blisterpackscontaining1capsuleinanoverlabelledoutercarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Irish Medicines Board

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Date Printed 27/06/2011 CRN 2101974 page number: 10

Ashbourne

Co.Meath

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA0465/093/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19thSeptember2003

Dateoflastrenewal:19thSeptember2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 27/06/2011 CRN 2101974 page number: 11