FLUCONAZOLE PFIZER

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0822/043/001
  • Authorization date:
  • 28-01-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FluconazolePfizer150mgCapsules,Hard

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains150mgFluconazole

Excipients:Eachcapsulecontains149.12mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,hard

Hardcapsulewithabluecapandbody,overprintedwith‘Pfizer’andthecode‘FLU150’,containingawhitepowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Therapymaybeinstitutedbeforetheresultsoftheculturesandotherlaboratorystudiesareknown;however,once

theseresultsbecomeavailable,anti-infectivetherapyshouldbeadjustedaccordingly.

Diflucanisindicatedfor:

Genitalcandidiasis.Vaginalcandidiasis,acuteorrecurrent.Candidalbalanitis.

Useinchildren

Diflucanshouldnotbeusedfortineacapitis.

4.2Posologyandmethodofadministration

Diflucanmaybeadministeredeitherorallyorbyintravenousinfusionatarateofapproximately5-10ml/min,theroute

beingdependentontheclinicalstateofthepatient.Ontransferringfromtheintravenousroutetotheoralrouteorvice

versa,thereisnoneedtochangethedailydose.

ThedailydoseofDiflucanshouldbebasedonthenatureandseverityofthefungalinfection.Mostcasesofvaginal

candidiasisrespondtosingledosetherapy.Therapyforthosetypesofinfectionsrequiringmultipledosetreatment

shouldbecontinueduntilclinicalparametersorlaboratorytestsindicatethatactivefungalinfectionhassubsided.An

inadequateperiodoftreatmentmayleadtorecurrenceofactiveinfection.PatientswithAIDSandcryptococcal

meningitisusuallyrequiremaintenancetherapytopreventrelapse.

Useinadults

Candidalvaginitisorbalanitis.Theusualdosageis150mgasasingledose.

UseinchildrenAswithsimilarinfectionsinadults,thedurationoftreatmentisbasedontheclinicalandmycological

response.Diflucanisadministeredasasingledailydose.Amaximumdosageof400mgshouldnotbeexceededin

children.

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UseintheelderlyThenormaldoseshouldbeusedifthereisnoevidenceofrenalimpairment.Inpatientswithrenal

impairment(creatinineclearancelessthan50ml/min)thedosagescheduleshouldbeadjustedasdescribedbelow.

UseinpatientswithimpairedrenalfunctionFluconazoleisexcretedpredominantlyintheurineasunchangeddrug.

Noadjustmentsinsingledosetherapyarerequired.Inpatients(includingchildren)withimpairedrenalfunctionwho

willreceivemultipledosesofDiflucan,thenormalrecommendeddose(accordingtoindication)shouldbegivenon

day1,followedbyadailydosebasedonthefollowingtable:

Creatinineclearance(ml/min) Percentofrecommendeddose

4.3Contraindications

FluconazolePfizershouldnotbeusedinpatientswithknownhypersensitivitytofluconazoleortorelatedazole

compounds,oranyotheringredientintheformulation.

Co-administrationofterfenadineiscontra-indicatedinpatientsreceivingFluconazolePfizeratmultipledosesof

400mgperdayorhigherbaseduponresultsofamultipledoseinteractionstudy.

Co-administrationofcisaprideiscontra-indicatedinpatientsreceivingFluconazolePfizer.(See,Section4.5

“Interactionwithothermedicinalproductsandotherformsofinteraction”.)

4.4Specialwarningsandprecautionsforuse

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,abnormalitiesofhepatic,

renal,haematologicalandotherbiochemicalfunctiontestshavebeenobservedduringtreatmentwithFluconazole

Pfizerbuttheclinicalsignificanceandrelationshiptotreatmentisuncertain.

FluconazolePfizerhasbeenassociatedwithrarecasesofserioushepatictoxicityincludingfatalities,primarilyin

patientswithseriousunderlyingmedicalconditions.IncasesofFluconazolePfizer-associatedhepatotoxicity,no

obviousrelationshiptototaldailydose,durationoftherapy,sexorageofpatienthasbeenobserved.FluconazolePfizer

hepatotoxicityhasusuallybeenreversibleondiscontinuationoftherapy.Patientswhodevelopabnormalliverfunction

testsduringFluconazolePfizertherapyshouldbemonitoredforthedevelopmentofmoreserioushepaticinjury.

FluconazolePfizershouldbediscontinuedifclinicalsignsorsymptomsconsistentwithliverdiseasedevelopthatmay

beattributabletoFluconazolePfizer.

Patientshaverarelydevelopedexfoliativecutaneousreactions,suchasStevens-Johnsonsyndromeandtoxic

epidermalnecrolysis,duringtreatmentwithfluconazole.AIDSpatientsaremorepronetothedevelopmentofsevere

cutaneousreactionstomanydrugs.Ifarashdevelopsinapatienttreatedforasuperficialfungalinfectionwhichis

consideredattributabletoFluconazolePfizer,furthertherapywiththisagentshouldbediscontinued.Ifpatientswith

invasive/systemicfungalinfectionsdeveloprashes,theyshouldbemonitoredcloselyandFluconazolePfizer

discontinuedifbullouslesionsorerythemamultiformedevelop.

Thereislittleinformationonsafetyinlong-termuse.

>50

50(nodialysis)

Regulardialysis 100%

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Someazoles,includingfluconazole,havebeenassociatedwithprolongationoftheQTintervalonthe

electrocardiogram.Duringpost-marketingsurveillance,therehavebeenveryrarecasesofQTprolongationandtorsade

depointesinpatientstakingfluconazole.AlthoughtheassociationoffluconazoleandQT-prolongationhasnotbeen

fullyestablished,fluconazoleshouldbeusedwithcautioninpatientswithpotentiallyproarrythmicconditionssuchas:

CongenitalordocumentedacquiredQTprolongation

Cardiomyopathy,inparticularwhenheartfailureispresent

Sinusbradycardia

Existingsymptomaticarrythmias

ConcomitantmedicationnotmetabolizedbyCY34AbutknowntoprolongQTinterval

Electrolytedisturbancessuchashypokalaemia,hypomagnesaemiaandhypocalaemia

(SeeSection4.5Interactionswithothermedicalproductsandotherformsofinteraction)

Patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactosemalabsorptionorsucrase-isomaltase

insufficiencyshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

RifampicinConcomitantadministrationoffluconazoleandrifampicinhasresultedina25%decreaseintheAUCand

20%shorterhalf-lifeoffluconazole.Inpatientsreceivingconcomitantrifampicin,anincreaseinthefluconazoledose

shouldbeconsidered.

HydrochlorothiazideInakineticinteractionstudy,co-administrationofmultiple-dosehydrochlorothiazidetohealthy

volunteersreceivingfluconazoleincreasedplasmaconcentrationsoffluconazoleby40%.Aneffectofthismagnitude

shouldnotnecessitateachangeinthefluconazoledoseregimeninsubjectsreceivingconcomitantdiuretics,although

theprescribershouldbearitinmind.

AnticoagulantsInaninteractionstudy,fluconazoleincreasedtheprothrombintime(12%)afterwarfarinadministration

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

gastrointestinalbleeding,hematuria,andmelaena)havebeenreported,inassociationwithincreasesinprothrombin

timeinpatientsreceivingfluconazoleconcurrentlywithwarfarin.Prothrombintimeinpatientsreceivingcoumarin-

typeanticoagulantsshouldbecarefullymonitored.

AzithromycinAnopen-label,randomized,three-waycrossoverstudyin18healthysubjectsassessedtheeffectofa

single1200mgoraldoseofazithromycinonthepharmacokineticsofasingle800mgoraldoseoffluconazoleaswell

astheeffectsoffluconazoleonthepharmacokineticsofazithromycin.Therewasnosignificantpharmacokinetic

interactionbetweenfluconazoleandazithromycin.

Benzodiazepines(shortacting)Followingoraladministrationofmidazolam,fluconazoleresultedinsubstantial

increasesinmidazolamconcentrationsandpsychomotoreffects.Thiseffectonmidazolamappearstobemore

pronouncedfollowingoraladministrationoffluconazolethanwithfluconazoleadministeredintravenously.If

concomitantbenzodiazepinetherapyisnecessaryinpatientsbeingtreatedwithfluconazole,considerationshouldbe

giventodecreasingthebenzodiazepinedosage,andthepatientsshouldbeappropriatelymonitored.

SulphonylureasFluconazolehasbeenshowntoprolongtheserumhalf-lifeofconcomitantlyadministeredoral

sulphonylureas(chlorpropamide,glibenclamide,glipizideandtolbutamide)inhealthyvolunteers.Fluconazoleandoral

sulphonylureasmaybeco-administeredtodiabeticpatients,butthepossibilityofahypoglycaemicepisodeshouldbe

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PhenytoinConcomitantadministrationoffluconazoleandphenytoinmayincreasethelevelsofphenytointoa

clinicallysignificantdegree.Ifitisnecessarytoadministerbothdrugsconcomitantly,phenytoinlevelsshouldbe

monitoredandthephenytoindoseadjustedtomaintaintherapeuticlevels.

OralcontraceptivesThreekineticstudieswithcombinedoralcontraceptiveshavebeenperformedusingmultipledoses

offluconazole.Therewerenorelevanteffectsoneitherhormonelevelinthe50mgfluconazolestudy,whileat200mg

dailytheAUCsofethinylestradiolandlevonorgestrelwereincreased40%and24%respectively.Ina300mgdaily

fluconazolestudy,theAUCsofethinylestradiolandnorethindronewereincreasedby24%and13%,respectively.

Thusmultipledoseuseoffluconazoleatthesedosesisunlikelytohaveaneffectontheefficacyofthecombinedoral

contraceptive.

EndogenoussteroidFluconazole50mgdailydoesnotaffectendogenoussteroidlevelsinfemales.200-400mgdaily

hasnoclinicallysignificanteffectonendogenoussteroidlevelsoronACTHstimulatedresponseinhealthymale

volunteers.

CiclosporinAkineticstudyinrenaltransplantpatientsfoundfluconazole200mgdailytoslowlyincreaseciclosporin

concentrations.However,inanothermultipledosestudywith100mgdaily,fluconazoledidnotaffectciclosporinlevels

inpatientswithbonemarrowtransplants.Ciclosporinplasmaconcentrationmonitoringinpatientsreceiving

fluconazoleisrecommended.

TheophyllineInaplacebo-controlledinteractionstudy,theadministrationoffluconazole200mgfor14daysresultedin

an18%decreaseinthemeanplasmaclearanceoftheophylline.Patientswhoarereceivinghighdosesoftheophylline

orwhoareotherwiseatincreasedriskfortheophyllinetoxicityshouldbeobservedforsignsoftheophyllinetoxicity

whilereceivingfluconazoleandthetherapymodifiedappropriatelyifsignsoftoxicitydevelop.

TacrolimusTherehavebeenreportsthataninteractionexistswhenfluconazoleisadministeredconcomitantlywith

tacrolimus,leadingtoincreasedserumlevelsoftacrolimus.Therehavebeenreportsofnephrotoxicityinpatientsto

whomfluconazoleandtacrolimuswereco-administered.Patientsreceivingtacrolimusandfluconazoleconcomitantly

shouldbecarefullymonitored.

RifabutinTherehavebeenreportsthataninteractionexistswhenfluconazoleisadministeredconcomitantlywith

rifabutin,leadingtoincreasedserumlevelsofrifabutin.Therehavebeenreportsofuveitisinpatientstowhom

fluconazoleandrifabutinwereco-administered.Patientsreceivingrifabutinandfluconazoleconcomitantlyshouldbe

carefullymonitored.

TerfenadinBecauseoftheoccurrenceofseriouscardiacdysrhythmiassecondarytoprolongationoftheQTcintervalin

patientsreceivingazoleantifungalsinconjunctionwithterfenadine,interactionstudieshavebeenperformed.Onestudy

ata200mgdailydoseoffluconazolefailedtodemonstrateaprolongationinQTcinterval.Anotherstudyata400mg

and800mgdailydoseoffluconazoledemonstratedthatfluconazoletakenindosesof400mgperdayorgreater

significantlyincreasesplasmalevelsofterfenadinewhentakenconcomitantly.Thecombineduseoffluconazoleat

dosesof400mgorgreaterwithterfenadineiscontra-indicated.(See“Contra-indications”.)Theco-administrationof

fluconazoleatdoseslowerthan400mgperdaywithterfenadineshouldbecarefullymonitored.

CisaprideTherehavebeenreportsofcardiaceventsincludingtorsadedepointesinpatientstowhomfluconazoleand

cisapridewereco-administered.Acontrolledstudyfoundthatconcomitantfluconazole200mgoncedailyand

cisapride20mgfourtimesadayyieldedasignificantincreaseincisaprideplasmalevelsandprolongationofQTc

interval.Co-administrationofcisaprideiscontra-indicatedinpatientsreceivingfluconazole.

TheuseoffluconazoleinpatientsconcurrentlytakingastemizoleorotherdrugsmetabolisedbythecytochromeP450

systemmaybeassociatedwithelevationsinserumlevelsofthesedrugs.Intheabsenceofdefinitiveinformation,

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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.

Interactionstudieshaveshownthatwhenoralfluconazoleisco-administeredwithfood,cimetidine,antacidsor

followingtotalbodyirradiationforbonemarrowtransplantation,noclinicallysignificantimpairmentoffluconazole

absorptionoccurs.

Physiciansshouldbeawarethatdrug-druginteractionstudieswithothermedicationshavenotbeenconducted,butthat

suchinteractionsmayoccur.

Fluvastatin

Astudyinhealthyvolunteersdemonstratedthatfluconazoleincreasedthemeanareaundertheplasmafluvastatin

concentrationtimecurveby84%,themeaneliminationhalflifeoffluvastatinby80%anditsmeanpeakplasma

concentrationby44%.Cautionshouldthereforebeexercisedwhenfluvastatinisadministeredconcomitantlywith

fluconazole.

4.6Fertility,pregnancyandlactation

Therearenoadequateandwellcontrolledstudiesinpregnantwomen.Therehavebeenreportsofmultiplecongential

abnormalitiesininfantswhosemotherswerebeingtreatedfor3ormoremonthswithhighdose(400–800mg/day)

fluconazoletherapyforcoccidioidomycosis.Therelationshipbetweenfluconazoleuseandtheseeventsisunclear.

Useinpregnancyshouldbeavoidedexceptinpatientswithsevereorpotentiallylife-threateningfungalinfectionsin

whomfluconazolemaybeusediftheanticipatedbenefitoutweighsthepossiblerisktothefetus.

UseduringlactationFluconazoleisfoundinhumanbreastmilkatconcentrationssimilartoplasma,henceitsusein

nursingmothersisnotrecommended.

4.7Effectsonabilitytodriveandusemachines

ExperiencewithFluconazolePfizerindicatesthattherapyisunlikelytoimpairapatient'sabilitytodriveoruse

machinery.

4.8Undesirableeffects

Fluconazoleisgenerallywelltolerated.Themostcommonundesirableeffectsobservedduringclinicaltrialsand

associatedwithfluconazoleare:

NervousSystemDisorders:Headache.

SkinandSubcutaneousTissueDisorders:Rash.

GastrointestinalDisorders:Abdominalpain,diarrhoea,flatulence,nausea.

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,changesinrenaland

haematologicalfunctiontestresultsandhepaticabnormalitieshavebeenobservedduringtreatmentwithfluconazole

andcomparativeagents,buttheclinicalsignificanceandrelationshiptotreatmentisuncertain(seeSection4.4“Special

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HepatobiliaryDisorders:Hepatictoxicityincludingrarecasesoffatalities,elevatedalkalinephosphatase,elevated

bilirubin,elevatedSGOT,elevatedSGPT.

Inaddition,thefollowingundesirableeffectshaveoccurredduringpost-marketing:

NervousSystemDisorders:Dizziness,seizures,tasteperversion.

SkinandSubcutaneousTissueDisorders:Alopecia,exfoliativeskindisordersincludingStevens-Johnsonsyndrome

andtoxicepidermalnecrolysis.

GastrointestinalDisorders:Dyspepsia,vomiting.

BloodandLymphaticSystemDisorders:Leucopeniaincludingneutropeniaandagranulocytosis,thrombocytopenia.

ImmuneSystemDisorders:Anaphylaxis(includingangioedema,faceoedema,pruritus,urticaria).

HepatobiliaryDisorders:Hepaticfailure,hepatitis,hepatocellularnecrosis,jaundice.

MetabolismandNutritionDisorders:Hypercholesterolaemia,hypertriglyceridaemia,hypokalaemia.

CardiacDisorders:QTprolongation,torsadedepointes(seesection4.4SpecialWarningsandSpecialPrecautionsfor

Use).

Paediatricpopulation:Thepatternandincidenceofsideeffectsandlaboratoryabnormalitiesrecordedduring

paediatricclinicaltrialsarecomparabletothoseseeninadults.

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

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Fluconazolehasalsobeenshowntobeactiveinanimalmodelsofendemicmycoses,includinginfectionswith

Blastomycesdermatitides;withCoccidoidesimmitis,includingintracranialinfectionandwithHistoplasmacapsulatum

innormalandimmunosuppressedanimals.

TherehavebeenreportsofcasesofsuperinfectionwithCandidaspeciesotherthanC.albicans,whichareoften

inherentlynotsusceptibletofluconazole(e.g.Candidakrusei).Suchcasesmayrequirealternativeantifungaltherapy.

FluconazoleishighlyspecificforfungalcytochromeP-450dependentenzymes.Fluconazole50mgdailygivenupto

28dayshasbeenshownnottoaffecttestosteroneplasmaconcentrationsinmalesorsteroidconcentrationsinfemales

ofchild-bearingage.Fluconazole200-400mgdailyhasnoclinicallysignificanteffectonendogenoussteroidlevelsor

onACTHstimulatedresponseinhealthymalevolunteers.Interactionstudieswithantipyrineindicatethatsingleor

multipledosesoffluconazole50mgdonotaffectitsmetabolism.

Theefficacyoffluconazoleintineacapitishasbeenstudiedin2randomisedcontrolledtrialsinatotalof878patients

comparingfluconazolewithgriseofulvin.Fluconazoleat6mg/kg/dayfor6weekswasnotsuperiortogriseofulvin

administeredat11mg/kg/dayfor6weeks.Theoverallsuccessrateatweek6waslow(fluconazole6weeks:18.3%;

fluconazole3weeks:14.7%;griseofulvin:17.7%)acrossalltreatmentgroups.Thesefindingsarenotinconsistentwith

thenaturalhistoryoftineacapitiswithouttherapy.

5.2Pharmacokineticproperties

Thepharmacokineticpropertiesoffluconazolearesimilarfollowingadministrationbytheintravenousororalroute.

Afteroraladministrationfluconazoleiswellabsorbed,andplasmalevels(andsystemicbioavailability)areover90%

ofthelevelsachievedafterintravenousadministration.Oralabsorptionisnotaffectedbyconcomitantfoodintake.

Peakplasmaconcentrationsinthefastingstateoccurbetween0.5and1.5hourspostdosewithaplasmaelimination

half-lifeofapproximately30hours.Plasmaconcentrationsareproportionaltodose.Ninetypercentsteady-statelevels

arereachedbyday4-5withmultipleoncedailydosing.

Administrationofaloadingdose(onday1)oftwicetheusualdailydoseenablesplasmalevelstoapproximateto90%

steady-statelevelsbyday2.Theapparentvolumeofdistributionapproximatestototalbodywater.Plasmaprotein

bindingislow(11-12%).

Fluconazoleachievesgoodpenetrationintoallbodyfluidsstudied.Thelevelsoffluconazoleinsalivaandsputumare

similartoplasmalevels.Inpatientswithfungalmeningitis,fluconazolelevelsintheCSFareapproximately80%the

correspondingplasmalevels.

Highskinconcentrationsoffluconazole,aboveserumconcentrations,areachievedinthestratumcorneum,epidermis-

dermisandeccrinesweat.Fluconazoleaccumulatesinthestratumcorneum.Atadoseof50mgoncedaily,the

concentrationoffluconazoleafter12dayswas73microgram/gand7daysaftercessationoftreatmentthe

concentrationwasstill5.8microgram/g.

Themajorrouteofexcretionisrenalwithapproximately80%oftheadministereddoseappearingintheurineas

unchangeddrug.Fluconazoleclearanceisproportionaltocreatinineclearance.Thereisnoevidenceofcirculating

metabolites.

Thelongplasmaeliminationhalf-lifeprovidesthebasisforsingledosetherapyforgenitalcandidiasisandonce-daily

dosinginthetreatmentofallotherindicatedfungalinfections.

Astudycomparedthesalivaandplasmaconcentrationsofasinglefluconazole100mgdoseadministrationinacapsule

orinanoralsuspensionbyrinsingandretaininginmouthfor2minutesandswallowing.Themaximumconcentration

offluconazoleinsalivaafterthesuspensionwasobserved5minutesafteringestion,andwas182timeshigherthanthe

maximumsalivaconcentrationafterthecapsulewhichoccurred4hoursafteringestion.Afterabout4hours,thesaliva

concentrationsoffluconazoleweresimilar.ThemeanAUC(0-96)insalivawassignificantlygreaterafterthe

suspensioncomparedtothecapsule.Therewasnosignificantdifferenceintheeliminationratefromsalivaorthe

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PharmacokineticsinChildren

Pharmacokineticdatawereassessedfor113paediatricpatientsfrom5studies;2singledosestudies,2multipledose

studiesandastudyinprematureneonates.Datafrom1studywerenotinterpretableduetochangesinformulation

partwaythroughthestudy.Additionaldatawereavailablefromacompassionateusestudy.

Afteradministrationof2-8mg/kgfluconazoletochildrenbetweentheagesof9monthsto15years,anAUCofabout

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

and18hoursandthedistributionvolumewasapproximately880ml/kgaftermultipledoses.

Ahigherfluconazoleplasmaeliminationhalf-lifeofapproximately24hourswasfoundafterasingledose.Thisis

comparablewiththefluconazoleplasmaeliminationhalf-lifeafterasingleadministrationof3mg/kgi.v.tochildrenof

11days-11monthsold.Thedistributionvolumeinthisagegroupwasabout950ml/kg.

Experiencewithfluconazoleinneonatesislimitedtopharmacokineticsstudiesinprematurenewborns.Themeanage

atfirstdosewas24hours(range9-36hours)andmeanbirthweightwas0.9Kg(range0.75-1.10Kg)for12preterm

neonatesofaveragegestationaround28weeks.Sevenpatientscompletedtheprotocol;amaximumoffive6mg/Kg

intravenousinfusionsoffluconazolewereadministeredevery72hours.

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

onday7and47(range27-68)onday13.

Theareaunderthecurve(microgram.h/ml)was271(range173-385)onday1whichincreasedwithameanof490

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

Thevolumeofdistribution(ml/kg)was1183(range1070-1470)onday1whichincreasedwithtimetoameanof1184

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

PharmacokineticsinElderly

Apharmacokineticstudywasconductedin22subjects,65yearsofageorolderreceivingasingle50mgoraldoseof

fluconazole.Tenofthesepatientswereconcomitantlyreceivingdiuretics.TheC

was1.54mcg/mlandoccurredat

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

pharmacokineticparametervaluesarehigherthananalogousvaluesreportedfornormalyoungmalevolunteers.

CoadministrationofdiureticsdidnotsignificantlyalterAUCorC

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

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

ml/min/kg)fortheelderlyweregenerallylowerthanthoseofyoungervolunteers.Thus,thealterationoffluconazole

dispositionintheelderlyappearstoberelatedtoreducedrenalfunctioncharacteristicofthisgroup.Aplotofeach

subject’sterminaleliminationhalf-lifeversuscreatinineclearancecomparedwiththepredictedhalf-life-creatinine

clearancecurvederivedfromnormalsubjectsandsubjectswithvaryingdegreesofrenalinsufficiencyindicatedthat21

of22subjectsfellwithinthe95%confidencelimitofthepredictedhalf-life-creatinineclearancecurves.Theseresults

areconsistentwiththehypothesisthathighervaluesforthepharmacokineticparametersobservedintheelderly

subjectscomparedwithnormalyoungmalevolunteersareduetothedecreasedkidneyfunctionthatisexpectedinthe

elderly.

5.3Preclinicalsafetydata

ReproductivetoxicityTherewerenofetaleffectsat5or10mg/kg;increasesinfetalanatomicalvariants

(supernumeraryribs,renalpelvisdilation)anddelaysinossificationwereobservedat25and50mg/kgandhigher

doses.Atdosesrangingfrom80mg/kg(approximately20-60xtherecommendedhumandose)to320mg/kg

embryolethalityinratswasincreasedandfetalabnormalitiesincludedwavyribs,cleftpalateandabnormalcranio-

facialossification.Theseeffectsareconsistentwiththeinhibitionofoestrogensynthesisinratsandmaybearesultof

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CarcinogenesisFluconazoleshowednoevidenceofcarcinogenicpotentialinmiceandratstreatedorallyfor24

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

hepatocellularadenomas.

MutagenesisFluconazole,withorwithoutmetabolicactivation,wasnegativeintestsformutagenicityin4strainsof

S.typhimuriumandinthemouselymphomaL5178Ysystem.Cytogeneticstudiesinvivo(murinebonemarrowcells,

followingoraladministrationoffluconazole)andinvitro(humanlymphocytesexposedtofluconazoleat1000µg/ml)

showednoevidenceofchromosomalmutations.

ImpairmentofFertilityFluconazoledidnotaffectthefertilityofmaleorfemaleratstreatedorallywithdailydosesof

5,10or20mg/kgorwithparenteraldosesof5,25or75mg/kg,althoughtheonsetofparturitionwasslightlydelayedat

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

wereobservedinafewdamsat20mg/kgand40mg/kg,butnotat5mg/kg.

Thedisturbancesinparturitionwerereflectedbyaslightincreaseinthenumberofstill-bornpupsanddecreaseof

neonatalsurvivalatthesedoselevels.Theeffectsonparturitioninratsareconsistentwiththespeciesspecific

oestrogen-loweringpropertyproducedbyhighdosesoffluconazole.Suchahormonechangehasnotbeenobservedin

womentreatedwithfluconazole.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontents

lactosemonohydrate

maizestarch

colloidalanhydroussilica

magnesiumstearate

sodiumlaurilsulfate

Capsuleshell

patentblueV(E131)

titaniumdioxide(E171)

gelatin

Printingink

OpacodeS-I-27794HVblack1028:

shellac

blackironoxide(E172)

propyleneglycol

TekPrintSW-9008blackink1014:

shellac

blackironoxide(E172)

propyleneglycol

potassiumhydroxide

6.2Incompatibilities

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 30/03/2011 CRN 2096898 page number: 9

6.3ShelfLife

5years.

6.4Specialprecautionsforstorage

Donotstoreabove30ºC.

6.5Natureandcontentsofcontainer

FluconazolePfizerCapsuleswillbesuppliedasapackcontainingonecapsuleinclear

oropaquePVCoraluminiumfoilbacking,oraluminiumblisterpackswithaluminiumfoilbacking.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

FluconazolePfizerCapsulesshouldbeswallowedwhole.

7MARKETINGAUTHORISATIONHOLDER

PfizerHealthcareIreland

9Riverwalk

NationalDigitalPark

CitywestBusinessCampus

Dublin24

8MARKETINGAUTHORISATIONNUMBER

PA822/43/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28 th

January2011

Irish Medicines Board

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Date Printed 30/03/2011 CRN 2096898 page number: 10