FLUCONAZOLE ACTAVIS

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1380/100/002
  • Authorization date:
  • 15-04-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FluconazoleActavis100mgcapsules,hard

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachhardcapsulecontains100mgfluconazole.

Excipient:

Eachhardcapsulecontains82mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,hard.

FluconazoleActavis100mgconsistsoflightbluecapandwhitebody,size“2”hardgelatinecapsules,filledwithwhite

powder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

FluconazoleActavisisindicatedfortreatmentoffollowinginfectionscausedbyfungiwhichareknowntobeorare

likelytobesusceptibletofluconazole:

-Acuteandrecurrentvaginalcandidiasiswhensystemictherapyisconsideredappropriate.

-Verifiedfungalinfectionsoftheskinsuchastineacorporis/tineacruris/tineapedis(causedbydermatophytes),tinea

versicolororcandidiasiswhentopicaltreatmenthasnotsucceededorisconsideredinadequate.Fluconazoleshould

onlybeusedtotreattineaversicolorwhentheinfectionisresistanttofirstlinetherapyorwhenthepatientis

immunocompromised.

-Mucosalcandidiasis,includingoropharyngeal,oesophagal,mucocutaneousandnon-invasivebronchopulmonary

candidiasis.

-Candiduriainimmunocompromisedpatients.

-Systemiccandidiasis(candidaemia,disseminateddeepcandidiasis,peritonitis)innon-neutropenicpatients.

-ProphylaxisofCandidainfectionsinpatientswithneutropenia(e.g.duetoAIDSorbonemarrowtransplantation).

-Treatmentandmaintenancetherapytopreventrelapseofcryptococcalmeningitisinimmunocompromisedpatients.

Paediatricuse

FluconazoleActavisshouldnotbeusedfortineacapitis.

Notallindicationsareapplicableforpaediatricpatients;seedetailsinsection4.2.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantifungalagents.

4.2Posologyandmethodofadministration

Thedailydoseoffluconazoledependsonthetypeandseverityofthefungalinfection.Thetreatmentofinfections

requiringmultipledosingmustbecontinueduntilclinicalparametersorlaboratoryresultsshowthattheactivefungal

infectionhasdeclined.Aninsufficienttreatmentperiodmayleadtorecurrenceoftheactiveinfection.

Dependingontheseverityofthediseaseandtheclinicalstateofthepatientsofthediseaseintravenousadministration

mayberequired.Itisnotnecessarytochangethedailydoseoffluconazolewhenchangingtherouteofadministration

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Adults:

Vaginalcandidiasis:150mgasasingledose.

Verifiedfungalinfectionsoftheskin:Tineacorporis,tineacruris,tineapedis,tineaversicolor:150mgonceweeklyfor

4–6weeks.

Mucousmembranecandidiasis:Oropharyngealcandidiasis:Normaldoseis50-100mgdailyfor7to14days.Duration

oftreatmentdependsonclinicalresponse.

Oesophagealmucocutaneousandnon-invasivebronchopulmonarycandidiasis:Normaldoseis50mgdailyfor14to

30days.Insevereandparticularrecurrentcasesthedosecanbeincreasedto100mg.

Candiuriainimmunocompromisedpatients:Normaldoseis50mgdailyfor14to30days.Inseverecasesthedaily

dosecanbeincreasedto100mgfluconazole.

Systemiccandidiasis:Thedoseincandidaemiaandotherinvasivecandidainfectionsis400to800mgonthefirstday

and200to400mgdailytherafter.Thedosedependsonthetypeandseverityoftheinfection.Inmostcasesaloading

doseof800mgonthefirstdayfollowedby400mgdailythereaftermaybepreferable.Thedurationoftreatment,often

uptoseveralweeks,isdeterminedbytheclinicalresponse.

Prophylaxisofcandidainfectionsinpatientswithneutropenia:400mgoncedaily.Thetreatmentshouldbeinitiateda

fewdaysbeforeneutropeniaoccursandshouldcontinueuntil7daysafterneutrophilcountshaveincreasedto>1x

Treatmentandmaintenancetreatmentofcryptococcalmeningitisinimmunocompromisedpatients:Initially400mgon

thefirstdayfollowedby200to400mgoncedaily.Durationoftreatmentforcryptococcalinfectionsdependsonthe

clinicalresponse,butisusuallyatleast6to8weeksforcryptococcal

meningitis.

Adailydoseof200mgisrecommendedinordertoavoidrecurrenceofcryptococcalmeningitis.Durationof

maintenancetreatmentinAIDSpatientsshouldbecarefullyjustifiedduetothehighriskofresistancetofluconazole.

Paediatricuse:

Thecapsulesareclearlyunsuitableforchildrenyoungerthan5-6years,whocannottakeoralmedication.Aswith

similarinfectionsinadult,thedurationoftreatmentisbasedontheclinicalandmycologicalresponse.Fluconazoleis

administeredasasingledailydose.

Forchildrenwithimpairedrenalfunction,seedosingin“Patients(adultsandpaediatric)withimpairedrenalfunction”.

Childrenoverfourweeksofage

Therecommendeddoseoffluconazoleformucosalcandidiasisis3mg/kgdaily.Aloadingdoseof6mg/kgmaybe

usedonthefirstdaytoachievesteadystatelevelsmorerapidly.

Forthetreatmentofsystemiccandidiasisandcryptococcalinfections,therecommendeddosageis6-12mg/kgdaily,

dependingontheseverityofthedisease.

Forthepreventionoffungalinfectionsinimmunocompromisedpatientsconsideredatriskasaconsequenceof

neutropeniafollowingcytotoxicchemotherapyorradiotherapy,thedoseshouldbe3-12mg/kgdaily,dependingonthe

extentanddurationofinducedneutropenia(seeadultdosing).

Amaximumdosageof400mgdailyshouldnotbeexceededinchildren.

Childrenfourweeksofageandyounger

Neonatesexcretefluconazoleslowly.Inthefirsttwoweeksoflife,thesamemg/kgdosingasinolderchildrenshould

beusedbutadministratedevery72hours.

Duringweeks3and4oflife,thesamedoseshouldbegivenevery48hours.TherearefewPKdatatosupportthis

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Amaximumdosageof12mg/kgevery72hoursshouldnotbeexceededinchildreninthefirsttwoweeksoflife.For

childrenbetween3and4weeksoflife,12mg/kgevery48hoursshouldnotbeexceeded.

Elderly:

Patientswithoutimpairedrenalfunctionusuallyreceivenormaldosing.Thedosagetopatientswithimpairedrenal

function(creatinineclearance<50ml/min)isgivenbelow.

Patients(adultsandpaediatric)withimpairedrenalfunction:

Fluconazoleismainlyexcretedunchangedintheurine.Changeofsingle-doseregimenisnotrequired.

Patientswithrenalimpairmentgivenmultipledosesof50-400mgshouldbegiventherecommendeddoseforthe

indicationthefirstday,afterwhichthedailydose(dependingontherapeuticindication)shouldbebasedonthe

followingtable:

Thepharmacokineticsoffluconazolehasnotbeenstudiedinchildrenwithrenalinsufficiency.

Methodofadministration

Thecapsulesmustbeswallowedwholewithasufficientamountoffluid(e.g.oneglassofwater)andcanbetaken

independentlyoffood.

4.3Contraindications

-Hypersensitivitytofluconazole,otherazolederivativesortoanyoftheexcipients.

-Co-administrationwithdrugsbothknowntoprolongtheQT-intervalandmetabolisedbyCYP3A4suchascisapride,

astemizole,terfenadine,pimozideandquinidine(seealsosection4.4and4.5).

4.4Specialwarningsandprecautionsforuse

Localguidelinesfortheuseofantifungalsshouldbefollowed(seesection4.1and5.1).

Inrarecasesseverehepatotoxicityincludingdeathhasbeenreported,primarilyinpatientssufferingfromserious

underlyingdiseases.Noobviouscausalrelationshipbetweenhepatotoxicityandthetotaldailydoseoffluconazole,

durationoftreatment,orthepatient’sgenderoragehasbeenobserved.

Patientswhodevelopabnormallivertestvaluesorsignificantincreasesoforiginallyabnormallevelsduringtreatment

withfluconazolemustbemonitoredclosely.Thebenefitsofthetreatmentshouldbeevaluatedagainsttherisksof

developingseriousliverdamageiftherapyiscontinuedinpatientswhoseliverenzymevaluesriseduringfluconazole

treatment.

Thetreatmentwithfluconazoleshouldbediscontinuedifthereisclinicalevidenceofdevelopmentofaliverdisease

causedbyfluconazole.Inmostcases,livertoxicityhasbeenreversibleatdiscontinuationofthetreatment.

Patientshaverarelydevelopedexfoliativecutaneousreactions,suchasStevens-Johnsonsyndromeandtoxicepidermal

necrolysis,duringtreatmentwithfluconazole.AIDSpatientsaremorepronetodevelopmentofseverecutaneous

reactionstomanymedicinalproducts.Ifarashdevelopsinapatienttreatedforasuperficialfungalinfectionthatis

consideredattributabletofluconazole,thetherapywithfluconazoleshouldbediscontinued.Ifpatientswith

invasive/systemicfungalinfectionsdeveloprashes,theyshouldbemonitoredcloselyandfluconazolediscontinuedif

bullouslesionsorerythemamultiformedevelop.

Aswithotherazoles,anaphylacticreactionshavebeenreportedinrarecases(seesection4.8).

Creatinineclearance(ml/min) Percentageofrecommendeddose

>50 100%

11-50(nodialysis) 50%

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prolongationandTorsadedepointeshavebeenobservedduringtreatmentwithfluconazole.Althoughtheassociation

offluconazoleandQT-prolongationhasnotbeenfullyestablished,fluconazoleshouldbeusedwithcautioninpatients

withpotentiallyproarrythmicconditionssuchas:

-CongenitalordocumentedacquiredQTprolongation

-Cardiomyopathy,inparticularwhenheartfailureispresent

-Sinusbradycardia

-Existingsymptomaticarrythmias

-Electrolytedisturbances,particularlyhypokalaemiaandhypomagnesaemia

-ConcurrenttreatmentwithmedicinesknowntoprolongtheQTintervalbutarenotmetabolisedbyCYP3A4(see

section4.5).

Electrolytedisturbancessuchashypokalaemia,hypomagnesaemiaandhypocalcaemiashouldbecorrectedpriorto

initiationoffluconazoletreatment.

Dosereductionoffluconazoleisrequiredifcreatinineclearanceisbelow50ml/min(seesection4.2).

Inwomenofchild-bearingpotential,appropriatecontraceptivemeasuresshouldbeconsideredincaselong-term

treatmentisindicated(seesection4.6).

Patientsreceivingtreatmentwithfluconazoledosesbelow400mgperdayandterfenadineshouldbemonitoredclosely

(seesection4.3andsection4.5).

FluconazoleisapotentcytochromeP450(CYP)isoenzyme2C9inhibitorandamoderateCYP3A4inhibitor.Patients

whoconcurrentlywithfluconazolearetreatedwithmedicinalproductswithanarrowtherapeutic

index,e.g.warfarinandphenytoin,thataremetabolisedviaCYP2C9andCYP3A4,mustbemonitored(seesection

4.5).

FluconazoleActaviscapsulescontainlactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Thefollowingcombinationswithfluconazolearecontraindicated:

Cisapride(CYP3A4substrate)

TherehavebeenreportsofcardiaceventsincludingTorsadesdepointesinpatientsreceivingfluconazole

concomitantlywithcisapride.Acontrolledstudyfoundthatconcomitantfluconazole200mgoncedailyandcisapride

20mgfourtimesadayyieldedasignificantincreaseincisaprideplasmalevelsandprolongationofQTcinterval.

Concurrenttreatmentwithfluconazoleandcisaprideiscontraindicated.

Terfenadine(CYP3A4substrate)withdosesof400mgfluconazoleorhigher

SeverecardiacdysrhythmiassecondarilytoprolongationoftheQTcintervalinpatientsontreatmentwithazole

productsconcomitantlywithterfenadinehavebeenobserved.

Onestudywith200mgfluconazoleoncedailyandconcurrenttreatmentwithterfenadinedidnotshowany

prolongationoftheQTcinterval.

Anotherstudywith400mgand800mgfluconazoleoncedailyshowedthatfluconazole400mgormoredaily

significantlyincreasestheplasmalevelofterfenadine.Concomitanttreatmentwithterfenadineandfluconazoleindaily

dosesof400mgormoreiscontraindicated.

Intreatmentwithfluconazoleindosesbelow400mgperdaythepatientshouldbemonitoredclosely.

Astemizole(CYP3A4substrate)

Concomitantadministrationoffluconazolewithastemizolemaydecreasetheclearanceofastemizole.Theresulting

increasedplasmaconcentrationsofastemizolecanleadtoprolongedQTintervalandsevereventriculararrhythmia,

Torsadesdepointesandcardiacarrest.Concomitanttreatmentwithfluconazoleandastemizoleiscontra-indicateddue

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Quinidine(CYP3Asubstrate)

Fluconazolemayinhibitthemetabolismofquinidine,leadingtoincreasedplasmaconcentrationsandthusriskto

prolongationoftheQTinterval.

Pimozide(CYP3A4-substrate)

Althoughnotstudiedinvitroorinvivo,concomitantadministrationoffluconazolewithpimozidemayresultin

inhibitionofpimozidemetabolism.IncreasedpimozideplasmaconcentrationscanleadtoQTprolongationandrare

occurrencesofTorsadedepointes.Co-administrationoffluconazoleandpimozideiscontraindicated.

Concurrentuseoffollowingothermedicinalproductsisnotrecommended:

Erythromycin

Thereisanincreasedriskofcardiotoxicity(prolongedQTinterval,Torsadedepointes)andthussuddencardiacdeath

whenusingfluconazoleanderythromycinconcomitantly.Thecombinationshouldbeavoided.

Concurrentuseoffollowingothermedicinalproductsrequiresmeasuresanddoseadjustments:

Medicinalproductsaffectingthemetabolismoffluconazole

Hydrochlorothiazide

Inapharmacokineticinteractionstudywithhealthyvolunteers,co-administrationoffluconazoleandmultiple-dosesof

hydrochlorothiazideincreasedtheplasmaconcentrationsoffluconazoleby40%.Thisdoesnotnecessitateachangein

thefluconazoledoseregimeninsubjectsreceivingconcomitantdiuretics,althoughtheprescribershouldbearitin

mind.

Rifampicin(CYP450inducer)

Concomitantintakeoffluconazoleandrifampicinresultedina25%reductionofAUCand20%shorterhalf-lifeof

fluconazoleduetohepaticenzymeinduction.Increaseofdosageshouldbeconsideredinpatientsconcomitantly

receivingrifampicin.

Didanosine

Althoughconcomitantintakeofdidanosineandfluconazoleappearshavelittleeffectondidanosinepharmacokinetics

orefficacy,theresponseoffluconazoleshouldbemonitored.Itmaybeadvantageoustoadministerfluconazolepriorto

didanosine.

Effectoffluconazoleonthemetabolismofothermedicinalproducts

FluconazoleisapotentinhibitorofcytochromeP450(CYP)isoenzyme2C9andamoderateinhibitorofCYP3A4.

Besidestheobserved/documentedinteractionslistedbelowthereisariskofincreasedplasmaconcentrationsofother

medicinalproductsmetabolisedbyCYP2C9orCYP3A4(e.g.ergotalkaloids,quinidine)whenco-administeredwith

fluconazole.Therefore,careshouldalwaysbetakenwhenusingthesecombinationsandthepatientsshouldbe

carefullymonitored.

Theenzymeinhibitingeffectoffluconazolemaypersistfor4-5daysfollowingdiscontinuationoffluconazole

treatmentduetothelongfluconazolehalf-life.

Alfentanil(CYP3A4substrate)

Astudyobservedareductioninclearanceanddistributionvolumeaswellasprolongationoft½ofalfentanilfollowing

concomitanttreatmentwithfluconazole.Apossiblemechanismofactionisfluconazole’sinhibitionofCYP3A4.

Dosageadjustmentofalfentanilmaybenecessary.

Amitriptyline,nortriptyline

Fluconazoleincreasestheeffectofamitriptylineandnortriptyline.S-nortriptylineand/orA-amitriptylinemaybe

measuredatinitiationofcombinationtreatmentandafteroneweek.Thedoseofamitriptylin/nortriptylinshouldbe

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Anticoagulants(CYP2C9substrate)

Inaninteractionstudy,fluconazoleincreasedtheprothrombintime(12%)afterwarfarinadministrationinhealthy

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

gastrointestinalbleeding,hematuria,andmelena)havebeenreported,inassociationwithincreasesinprothrombintime

inpatientsreceivingfluconazoleconcurrentlywithwarfarin.Prothrombintimeinpatientsreceivingcoumarin-type

anticoagulantsshouldbecarefullymonitored.Doseadjustmentofwarfarinmaybenecessary.

Benzodiazepines(shortacting)(CYP3A4substrate)

Followingoraladministrationofmidazolam,fluconazoleresultedinsubstantialincreasesinmidazolamconcentrations

andpsychomotoreffects.Thiseffectonmidazolamappearstobemorepronouncedfollowingoraladministrationof

fluconazolethanwithfluconazoleadministeredintravenously.Ifconcomitantbenzodiazepinetherapyisnecessaryin

patientsbeingtreatedwithfluconazole,considerationshouldbegiventodecreasingthebenzodiazepinedosage,andthe

patientsshouldbeappropriatelymonitored.

FluconazoleincreasestheAUCoftriazolam(singledose)byapproximately50%,Cmaxwith20-32%andincreasest½

by25-50%duetotheinhibitionofmetabolismoftriazolam.Dosageadjustmentsoftriazolammaybenecessary.

Calciumchannelantagonists(CYP3A4substrates)

Certaindihydropyridinecalciumchannelantagonists(nifedipine,isradipine,nicardipine,amlodipineandfelodipine)

aremetabolisedbyCYP3A4.Substantialperipheraloedemaand/orincreasedcalciumantagonistserumlevelshasbeen

describedinliteraturewhenitraconazoleandfelodipine,isradipineornifedipineareco-administered.Suchinteraction

couldalsooccurwithfluconazole.

Carbamazepine

Fluconazoleinhibitsthebiotransformationofcarbamazepineandanincreaseofabout30%inserumcarbamzepineis

seen.Thereisariskofdevelopmentofcarbamazepinetoxicity.Doseadjustmentofcarbamazepinemaybenecessary

dependingonconcentrationmeasurements/effect.

Celecoxib(CYP2C9substrate)

Inaclinicalstudy,concomitanttreatmentwithfluconazole200mgdailyandcelecoxib200mgresultedinan68%and

134%increaseincelecoxibCmaxandAUC,respectively.Theinteractionisbelievedtobeduetoinhibitionof

cytochromeP4502C9metabolismofcelecoxib.Halvingthecelecoxibdoseisrecommendedtopatientsconcurrently

treatedwithfluconazole.

Ciclosporin(CYP3A4substrate)

Clinicallysignificantinteractionswithciclosporinhavebeenshownatfluconazoledosesof200mgandhigher.Ina

pharmacokineticstudywithrenaltransplantpatientsreceivingfluconazole200mgdailyandciclosporin2.7

mg/kg/day,therewasa1.8-foldincreaseinciclosporinAUCanda55%decreaseinclearance.Itisrecommendedto

followtheciclosporinplasmaconcentrationsinpatientsontreatmentwithfluconazole.

Cyclophosphamide

Combinationtreatmentwithcyclophosphamideandfluconazoleresultsinincreaseinserumbilirubinandserum

creatinine.Thecombinationcanbeusedwhenincreasedattentionisgiventotheriskofincreaseinserumbilirubinand

serumcreatinine.

Fentanyl

Fluconazolemayincreasetheconcentrationoffentanylandthustheriskofopioidintoxication.Themodeofactionis

thoughttobeinhibitionCYP3A4byfluconazole.Onefatalcaseofpossiblefentanylfluconazoleinteractionhasbeen

reported.Theauthorjudgedthatthepatientdiedfromfentanylintoxication.

Furthermore,inarandomizedcrossoverstudywithtwelvehealthyvolunteersitwasshownthatfluconazoledelayedthe

eliminationoffentanylsignificantly.Elevatedfentanylconcentrationmayleadtorespiratorydepression.Dose

adjustmentoffentanylmaybenecessary.

Halofantrine(CYP3A4substrate)

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HMG-CoAreductaseinhibitors(CYP2C9orCYP3A4substrates)

TheriskofmyopathyisincreasedwhenfluconazoleisadministeredconcurrentlywithHMG-CoAreductaseinhibitors

thataremetabolisedviaCYP3A4,suchasatorvastatinandsimvastatin,orviaCYP2C9,suchasfluvastatin.Upto

200%individualincreasesintheareaunderthecurve(AUC)offluvastatinmayoccurasaresultoftheinteraction

betweenfluvastatinandfluconazole.CautioniswarrantedifconcurrentadministrationoffluconazoleandHMG-CoA

reductaseinhibitorsisdeemednecessary.ThecombinationmayrequireadosereductionoftheHMG-CoAreductase

inhibitors.Patientsshouldbemonitoredforsignsandsymptomsofmyopathyorrhabdomyolysisandcreatinekinase

(CK)levels.HMG-CoAtherapyshouldbediscontinuedifCKlevelsshowamarkedincrease,orifmyopathyor

rhabdomyolysisisdiagnosedorsuspected.

Losartan(CYP2C9substrate)

Fluconazoleinhibitsthebiotransformationoflosartanintoitsactivemetabolite(E-3174)whichisresponsibleforthe

majorpartoftheangiotensin-IIreceptorantagonismthatoccursduringlosartantreatment.Concomitanttreatmentwith

fluconazolemightleadtoincreasedconcentrationsoflosartananddecreasedconcentrationsoftheactivemetabolite.It

isrecommendedthatpatientsreceivingthecombinationbemonitoredforcontinuedcontroloftheirhypertension.

Methadone

Fluconazolemayincreasetheserumconcentrationofmethadone.Doseadjustmentofmethadonemaybenecessary.

Non-steroidalanti-inflammatorydrugs

TheCmaxandAUCofflurbiprofenwasincreasedby23%and81%,respectively,whenco-administeredwith

fluconazolecomparedtoadministrationofflurbiprofenalone.Similarly,theCmaxandAUCofthepharmacologically

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

withracemicibuprofen(400mg)comparedtoadministrationofracemicibuprofenalone.

Althoughnotspecificallystudied,fluconazolehasthepotentialtoincreasethesystemicexposureofotherNSAIDsthat

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

eventsandtoxicityrelatedtoNSAIDsisrecommended.AdjustmentofdosageofNSAIDsmaybeneeded.

Oralcontraceptives

Twopharmacokineticstudieswithcombinedoralcontraceptiveshavebeenperformedusingmultipledosesof

fluconazole.Therewerenorelevanteffectsoneitherhormonelevelinthe50mgfluconazolestudy,whileat200mg

dailytheAUCsofethinyloestradiolandlevonorgestrelwereincreased40%and24%,respectively.Thusmultipledose

useoffluconazoleatthesedosesisunlikelytohaveaneffectontheefficacyofthecombinedoralcontraceptive.

Phenytoin(CYP2C9substrate)

Fluconazoleinhibitsthehepaticbiotransformationofphenytoin.Intakeoffluconazole200mgconcomitantlywith

phenytoin250mgintravenouslyincreasedthephenytoinAUCby75%andCminby128%.Ifitisnecessaryto

administerbothsubstancesconcomitantly,thephenytoinconcentrationmustbecontrolled,andthephenytoindose

adjusted,inordertoavoidtoxicconcentrations.

Prednisone(CYP3A4substrate)

Alivertransplantrecipientreceivingprednisonedevelopedacuteadrenalinsufficiencywhenathree-monthcourseof

fluconazolewasdiscontinued.ThewithdrawaloffluconazolecausedprobablyanincreaseinCYP3A4activity,leading

toanincreaseinthedegradationofprednisone.Patientsreceivinglong-termtherapywithfluconazoleandprednisone

shouldbecloselymonitoredforsignsofadrenalinsufficiencywhenfluconazoleiswithdrawn.

Rifabutin(CYP3A4substrate)

FluconazoleincreasesAUCofrifabutinbyupto80%resultinginincreasedserumconcentrationsofrifabutin.There

havebeenreportsofuveitisinpatientstowhomfluconazoleandrifabutinwerecoadministered.

Atcombinationtherapyincreasedattentionregardingsymptomsofintoxicationwithrifabutinisrecommended.

Saquinavir

FluconazoleincreasesAUCofsaquinavirbyapproximately50%,Cmaxbyapproximately55%andreducesclearance

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glycoproteininthegut.

Doseadjustmentofsaquinavirmaybenecessarybasedoneffect/concentrationmeasurement.

Sulphonylurea(CYP2C9substrates)

Fluconazoleincreasestheplasmaconcentrationsofglibenclamide,gliclazide,glimpepiride,glipizide,chlorpropamide

andtolbitamidewhenusedconcomitantly.Fluconazoleandoralsulphonylureaderivativesmaybeusedconcomitantly

todiabetics,butthepossibilityofdevelopmentofhypoglycaemiamustbekeptinmindandbloodglucoselevels

closelymonitored.

Tacrolimusandsirolimus(CYP3A4substrates)

Concomitantintakeoffluconazoleandtacrolimus0.15mg/kgtwicedailyincreasedtacrolimusCmin1.4and3.1-fold

withfluconazoledosesof100mgand200mg,respectively.Renaltoxicityhasbeenreportedinpatientsconcomitantly

receivingfluconazoleandtacrolimus.Fluconazolemayincreasetheserumconcentrationsoforallyadministered

tacrolimusbyupto5-foldduetoinhibitionofthetransformationoftacrolimusviaCYP3A4inthegut.Nosignificant

pharmacokineticchangesareseeniftacrolimusisgivenintravenously.Theoraldoseoftacrolimusshouldbereduced

dependingonconcentrationmeasurements.

Althoughnointeractionstudieshavebeenconductedwithfluconazoleandsirolimus,asimilarinteractionaswith

tacrolimusmightbeexpected.Patientswhoreceivetacrolimusorsirolimusandfluconazoleconcomitantlymustbe

closelymonitoredfortacrolimus/sirolimusplasmalevelsandtoxicity.

Theophyllin

Inaplacebocontrolledinteractionstudy,theintakeoffluconazole200mgfor14daysresultedin18%decreaseinthe

meanplasmaclearanceoftheophylline.Patientsontreatmentwithhighdosesoftheophyllineorwithotherreasontobe

atincreasedriskoftheophyllinetoxicityshouldbecarefullyobservedfortheophyllintoxicityduringfluconazole

therapy.Thetreatmentshouldbeadjustedifsignsoftoxicitydevelop.

Vincaalkaloids

Althoughnotstudied,fluconazolemayincreasetheplasmalevelsofthevincaalkaloids(e.g.vincristineand

vinblastine)andleadtoneurotoxicity,whichispossiblyduetoaninhibitoryeffectonCYP3A4.

Trimetrexate

Fluconazolemayinhibitthemetabolismoftrimetrexate,leadingtoincreasedtrimetrexateplasmaconcentrations.Ifthe

combinationcannotbeavoided,trimetrexateserumlevelsandtoxicityshouldbecloselymonitored.

VitaminA

Basedonacase-reportinonepatientreceivingcombinationtherapywithall-trans-retinoidacid(anacidformof

vitaminA)andfluconazole,CNSrelatedundesirableeffectshavedevelopedintheformofpseudotumourcerebri,

whichdisappearedafterdiscontinuationoffluconazoletreatment.Thiscombinationmaybeusedbuttheincidenceof

CNSrelatedundesirableeffectsshouldbeborneinmind.

Zidovudine

FluconazoleincreasesCmaxandAUCofzidovudineby85%and75%,respectively,duetoadecreaseintheoral

clearanceofzidovudioneofabout45%.Thehalf-lifeofzidovudinewasalsoprolongedbyapproximately128%atco-

administrationwithfluconazole.Patientsreceivingthiscombinationshouldbemonitoredforthedevelopmentof

zidovudine-relatedadversereactions.Doseadjustmentofzidovudinemaybeconsidered.

Pharmacodynamicinteractions

MedicinalproductsthatprolongQTinterval

CasereportsindicatethatfluconazolemighthavethepotentialtoinduceQTprolongationleadingtoseriouscardiac

arrhythmia.PatientstreatedconcomitantlywithfluconazoleandotherdrugsthatprolongQTintervalshouldbe

carefullymonitored,sinceanadditiveeffectcannotbeexcluded.

AmphotericinB

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mechanismofactionofimidazolesistoinhibitergosterolsynthesisinfungalcellmembranes.AmphotericinBactsby

bindingtosterolsinthecellmembraneandchangingmembranepermeability.Clinicaleffectsofthisantagonismareto

dateunknown,andasimilareffectmayoccurwithamphotericinBcholesterylsulfatecomplex.

Interactionstudieshaveshownthatthereisnoclinicalsignificantchangeintheabsorptionoffluconazoleatoraluse

withfood,cimetidine,antacidsorfollowingradiationtherapyoftheentirebodyinassociationwithbonemarrow

transplantation.

4.6Fertility,pregnancyandlactation

Pregnancy

Standarddosesoffluconazole(<200mg/day)andshort-termtreatmentshouldnotbegivenduringpregnancyunless

thebenefitsoutweighthefoetalrisk.

Highdosesoffluconazoleand/orlong-termtreatmentshouldonlybegivenduringpregnancyatlifethreatening

infections.

Datafromseveralhundredpregnantwomentreatedwithstandarddoses(<200mg/day)offluconazoleadministeredas

singleormultipledosesduringfirsttrimester,donotindicateundesirableeffectsonthefoetus.

Multiplecongenitalabnormalities(includingbrachycephalia,earsdysplasia,giantanteriorfontanelle,femoralbowing

andradio-humeralsynostosis)havebeenreportedininfantsofmotherswhowerereceivingtreatmentforatleast3or

severalmonthswithhighdoses(400-800mg/day)offluconazoleforcoccidioidomycosis.Thecausalrelationship

betweenfluconazoleandtheseeventshasnotbeenestablished.

Animalstudieshaveshownteratogeniceffects(seesection5.3).

Lactation

Fluconazoleisexcretedinhumanbreastmilkatconcentrationslowerthaninplasma.Lactationcanbecontinued

followingasingledoseof200mgfluconazoleorless.Lactationshouldbediscontinuedattreatmentwithfluconazole

withmultipleand/orhigherdoses.

Fertility

Datadoesnotindicateundesirableeffectsonfertilityinmalesorfemales.Ithasbeendemonstratedthatintakeof50

mgfluconazoledailyforupto28daysdidnotaffecttheplasmaconcentrationsoftestosteroneinmenorsteroid

hormoneconcentrationinwomenofchild-bearingpotential.200to400mgfluconazoleperdayhasnoclinicaleffect

onendogeneoussteroidlevelsoronACTHstimulatedresponseinhealthy,malevolunteers.

Fertilewomenshoulduseadequatecontraceptionduringlong-termtreatmentwithfluconazole.

4.7Effectsonabilitytodriveandusemachines

Fluconazolehasnoornegligibleinfluenceontheabilitytodriveandusemachines.Howeverwhendrivingvehiclesor

operatingmachinesitshouldbetakenintoaccountthatoccasionallydizzinessorseizuresmayoccur.

4.8Undesirableeffects

Undesirableeffectsarelistedbelowbybodysystemorganclassandbyfrequency.

Thefollowingfrequencycategoriesareusedforclassificationofadverseeffects:

Verycommon( ≥1/10)

Common( ≥1/100to<1/10)

Uncommon( ≥1/1,000to<1/100)

Rare( ≥1/10,000to<1/1,000)

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Notknown(cannotbeestimatedfromtheavailabledata).

Systemorganclass/Frequency Undesirableeffects

Bloodandlymphaticdisorders

Uncommon( ≥1/1,000to<1/100)

Rare( ≥1/10,000to<1/1,000) Anaemia.

Agranulocytosis,leukopenia,neutropenia,

thrombocytopenia.

Immunesystemdisorders

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

Metabolismandnutritiondisorders

Uncommon( ≥1/1,000to<1/100)

Rare( ≥1/10,000to<1/1,000) Anorexia,hypokalaemia.

Hypercholesterolaemia,hypertriglyceridaemia.

Psychiatricdisorders

Uncommon( ≥1/1,000to<1/100) Insomnia.

Nervoussystemdisorders

Common( ≥1/100to<1/10)

Uncommon( ≥1/1,000to<1/100) Headache.

Dizziness,convulsions,paraesthesia,tremor,

vertigo,somnolence,tastedisturbances.

Cardiacdisorders

Rare( ≥1/10,000to<1/1,000) ProlongationoftheQTinterval,Torsadesde

pointes(seesection.4.4).

Gastrointestinaldisorders

Common( ≥1/100to<1/10)

Uncommon( ≥1/1,000to<1/100) Abdominalpain,diarrhoea,nausea,vomiting.

Flatulence,dyspepsia,drymouth,constipation.

Hepatobiliarydisorders

Common( ≥1/100to<1/10)

Uncommon( ≥1/1,000to<1/100)

Rare( ≥1/10,000to<1/1,000) Increasedalkalinephosphatase,AST,andALT.

Jaundice,cholestasis,hepatocellulardamage,

increasedbilirubin.

Hepatotoxicity(rarelyfatal),hepaticfailure,

hepatitis,hepatocellularnecrosis.

Skinandsubcutaneoustissuedisorders

Common( ≥1/100to<1/10)

Uncommon( ≥1/1,000to<1/100)

Rare( ≥1/10,000to<1/1,000) Rash.

Pruritus,urticaria,increasedsweating.

Angioedema,alopecia,faceoedema,exfoliative

cutaneousreactionsincludingerythema

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Paediatricpopulation

Thepatternandincidenceofsideeffectsandlaboratoryabnormalitiesrecordedduringpaediatricusearecomparableto

thoseseeninadults.

4.9Overdose

Therehavebeenreportsofoverdosewithfluconazole.

Symptoms:

Inoneisolatedcasea42yearoldAIDSpatientsdevelopedhallucinationsandexertedparanoidbehaviourfollowing

intakeof8200mgfluconazole.Thepatientwashospitalisedandrecoveredwithin48hours.

Treatment:

Symptomaticandsupportivetreatmentand-ifnecessary-gastriclavage.Fluconazoleisprimarilyexcretedwiththe

urine.Forcedvolumediuresiswillprobablyincreasetheeliminationrate.Threehoursofhaemodialysiswilllowerthe

plasmalevelsbyapprox.50%.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Antimycoticsforsystemicuse,triazolederivatives.ATCcode:J02AC01

Fluconazoleisatriazolederivativewithfungistaticeffect,whichspecificallyinhibitsthesynthesisofthefungi’s

ergosterol,whichisbelievedtoleadtodefectsinthecellmembrane.Fluconazoleishighlyspecificforfungal

cytochromeP-450enzymes.Dosesoffluconazole50mgdailyfor28dayshavenotbeenshowntoinfluenceserum

levelsoftestosteroneinmenorthesteroidconcentrationinfertilewomen.

ThespectrumofapplicationincludesanumberofpathogensincludingCandidaalbicansandnon-Candidaalbicans

species,Cryptococcusspeciesanddermatophytes.Candidakruseiisresistanttofluconazole.FortypercentofCandida

glabrataareprimarilyresistanttofluconazole.InfectionscausedbyAspergillus-speciesshouldnotbetreatedwith

fluconazole.

Theefficacyoffluconazoleintineacapitishasbeenstudiedin2randomisedcontrolledtrialsinatotalof878patients

comparingfluconazolewithgriseofulvin.Fluconazoleat6mg/kg/dayfor6weekswasnotsuperiortogriseofulvin

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

fluconazole3weeks:14.7%;griseofulvin:17.8%)acrossalltreatmentgroups.Thesefindingsarenotinconsistentwith

thenaturalhistoryoftineacapitiswithouttherapy.

5.2Pharmacokineticproperties

Thepharmacokineticpropertiesoffluconazoleareidenticalafteri.v.andoraladministration.

Absorption:

epidermalnecrolysis.

Musculoskeletalandconnectivetissue

disorders

Uncommon( ≥1/1,000to<1/100) Myalgia.

Generaldisordersandadministrationsite

conditions

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isnotaffectedbyconcomitantfoodintake.Themaximumfastingplasmaconcentrationisachieved0.5–1.5hours

afterdoseintake.90%ofthesteady-statelevelisachieved4-5daysafterdosingoncedaily.

Theplasmaconcentrationisproportionaltothedose:

Followingadministrationof200mgoffluconazole,Cmaxisaround4.6mg/Landplasmaconcentrationsatsteady-

stateafter15daysarearound10mg/L.

Afteradministrationof400mgoffluconazole,Cmaxisaround9mg/Landplasmaconcentrationsatsteady-stateafter

15daysarearound18mg/L.

Administrationofadoubledoseonday1resultsinplasmaconcentrationsofapprox.90%ofsteady-stateonday2.

Distribution:

Distributionvolumecorrespondstothetotalbodywater.Theplasmaproteinbindingislow(11-12%).

Fluconazoleisdistributedoverthetotalbodywater.Theconcentrationinsputumcorrespondstotheplasma

concentration.Inpatientswithfungalmeningitistheconcentrationoffluconazoleinthecerebrospinalfluidisapprox.

80%ofthecorrespondingplasmaconcentration.

Higherlevelsoffluconazolearereachedinstratumcorneum,epidermis-dermisandinexocrinesweatthaninserum.

Fluconazoleaccumulatesinstratumcorneum.After150mgonceaweektheconcentrationoffluconazoleinstratum

corneumfollowing2doseswas23.4µg/gonday7,and7daysaftertheseconddosestill7.1µg/g.

Elimination:

Fluconazoleisprimarilyeliminatedviathekidneys.Approximately80%oftheadministereddosewillbeexcretedvia

theurineinanon-metabolisedform.Fluconazoleclearanceisproportionalwiththecreatinineclearance.Nocirculating

metabolitesweredetected.

Theplasmahalf-lifeisapprox.30hours,whichhascreatedthebasisfortreatmentwithonesingledoseinvaginal

candidiasisandasingledoseoncedailyandonceperweekinconnectionwithotherindications.

Ithasbeendemonstratedthatintakeof50mgfluconazoledailyforupto28daysdidnotaffecttheplasma

concentrationsoftestosteroneinmenorsteroidhormoneconcentrationinwomenofchild-bearingpotential.200to400

mgfluconazoleperdayhasnoclinicaleffectonendogeneoussteroidlevelsoronACTHstimulatedresponsein

healthy,malevolunteers.

Pharmacokineticsinchildren:

Pharmacokineticdatawereassessedfor113paediatricpatientsfrom5studies;2singledosestudies,2multipledose

studiesandastudyinprematureneonates.Datafrom1studywerenotinterpretableduetochangesinformulation

partwaythroughthestudy.Additionaldatawereavailablefromacompassionateusestudy.

Afteradministrationof2–8mg/kgfluconazoletochildrenbetweenagesof9monthsto15years,aAUCofabout38

µg.h/mlwasfoundper1mg/kgdoseunits.Theaveragefluconazoleplasmaeliminationhalf-lifevariedbetween15and

18hoursandthedistributionvolumewasapproximately880ml/kgaftermultipledoses.Ahigherfluconazoleplasma

eliminationhalf-lifeofapproximately24hourswasfoundafterasingledose.Thisiscomparablewiththefluconazole

plasmaeliminationhalf-lifeafterasingleadministrationof3mg/kgi.v.tochildrenof11days–11monthsold.The

distributionvolumeinthisagegroupwasabout950ml/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)onday1whichdecreased,withtime,toameanof53(range30-131)onday7and47(range27-68)onday13.

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

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

1183(range1070-1470)onday1andincreased,withtime,toameanof1184(range510-2130)onday7and1328

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5.3Preclinicalsafetydata

Preclinicaldatafromconventionalstudiesonrepeat-dose/generaltoxicity,genotoxicityorcarcinogenicityindicateno

specialhazardforhumansnotalreadyconsideredinothersectionsoftheSmPC.

Inreproductiontoxicitystudiesinratanincreasedincidenceofhydronephrosisandextensionofrenalpelviswas

reportedandembryonallethalitywasincreased.Anincreaseinanatomicalvariationsanddelayedossificationwas

notedaswellasprolongeddeliveryanddystocia.Inreproductiontoxicitystudiesinrabbitsabortionswererecorded.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontent:

Lactosemonohydrate

Maizestarch,pregelatinised

Silica,colloidalanhydrous

Magnesiumstearate

Capsuleshell:

Gelatin

Titaniumdioxide(E171)

Indigocarmine(E132)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

PVC/PVDC/aluminiumblister.

Packsizes:1,2,4,6,7,10,12,14,20,21,28,30,50,60,90,100capsules

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

ActavisGroupPTCehf,

Reykjavikurvegi76-78,

220Hafnarfjordur,

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8MARKETINGAUTHORISATIONNUMBER

PA1380/100/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:15thApril2011

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