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:
  • PA0969/004/003
  • Authorization date:
  • 07-03-2003
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Fluconazole200mgCapsules.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains200mgfluconazole

Thecapsulescontainlactose.

Forfulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Capsule,hard

Capsuleupperpart:darkblue,lowerpart:white.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Fluconazoleisindicatedforthetreatmentofthefollowinginfectionswhencausedbyfungithatareknownorarelikely

tobefluconazole-susceptible:

Acuteorrecurrentvaginalcandidiasis.

Mucousmembranecandidiasisincludingoropharyngeal,oesophageal,mucocutaneousandnon-invasive

bronchopulmonarycandidiasisandcandiduriainpatientswithimmunosuppression.

Systemiccandidiasis(candidaemia,disseminateddeepcandidiasis,peritonitis).

PreventionofCandidainfectionsinneutropenicpatients(eg.AIDS,bonemarrowtransplantation).

Treatmentandmaintenancetreatmentofcryptococcalmeningitisinimmunosuppressedpatients.

Verifiedfungalskininfectionscausedeitherbydermatophytesorotherspecies(tinea

corporis/cruris/pedis/versicolor)orCandidawhenlocaltreatmenthasfailedorisconsideredinappropriate.

FluconazoleshouldbeusedtotreatTineaversicoloronlywhentheinfectionisresistanttofirstlinetherapyor

whenthepatientisimmunosuppressed.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantifungalagents.

4.2Posologyandmethodofadministration

Thedailydosedependsonthetypeandseverityofthefungalinfection.

Thetreatmentofinfectionsrequiringmultipledosingmustbecontinueduntilclinicalparametersorlaboratoryresults

showthattheactivefungalinfectionhasresponded.Aninsufficienttreatmentperiodmayleadtorecurrenceofthe

activeinfection.

Adults:

Vaginalcandidiasis:

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Oropharyngealcandidiasis:

50mgfluconazoleoncedaily.Insevereandparticularlyrecurrentcasesthedailydosemaybeincreasedto100mg

fluconazole.

Durationoftreatment:1-2weeks.

Mucousmembranecandidiasisinpatientswithimmunosuppression:

Dailydose:50mgfor2-4weeks.Indifficultcasesthedosemaybeincreasedto100mgdaily.Inordertoprevent

relapse,treatmentmaybegivenforlongerperiods(6-8weeks).

Systemiccandidiasis:

Usually,asingle400mgloadingdoseshouldbeadministeredonDay1,followedby200mgdaily,thereafter.The

dosemaybeincreasedto400mgoncedaily.Thedurationoftreatmentdependsontheclinicalresponse.

Preventionofcandidainfectionsinneutropenicpatients:

50-400mgoncedailyaccordingtotheriskofinfection.Inpatientswithhighriskofsystemicinfection,suchas

patientswithorlikelytodevelopsevereorprolongedneutropenia,400mgoncedailyisrecommended.Treatment

shouldbeginafewdaysbeforetheappearanceofneutropeniaandshouldcontinueuntil7daysaftertheneutrophil

countshavereached>1000/mm 3

Treatmentandmaintenancetreatmentofcryptococcalmeningitisinimmunosuppressedpatients:

400mginitially,thereafter200-400mgdailyforatleast6-8weeks.A100-200mgdailydoseisrecommendedto

preventrecurrenceofcryptococcalmeningitis.

DurationofmaintenancetreatmentinAIDSpatientsshouldbecarefullyjustified,becauseoftheincreasedriskof

resistancetofluconazole.

Verifiedfungalskininfections:

-tineacorporis,tineacruris,tineaversicolor,tineapedis:

Oncedaily50mgfluconazole.Durationoftreatment:2-4weeks,exceptthatTineapedismayrequireupto6weeks.

Children:

Aswithsimilarinfectionsinadults,thedurationoftreatmentisbasedontheclinicalandmycologicalresponse.The

maximumdailydoseinchildrenis400mgasasingledailydoseandthisdoseshouldnotbeexceeded

Thecapsulesareunsuitableforchildrenwhocannottakeoralmedication.

Also,therequireddoseinmg/kg(seebelow)oftencannotbeachievedwithcapsules.

Childrenover4weeks:

Mucousmembranecandidiasis:therecommendeddosageoffluconazoleis3mg/kgdaily.Aloadingdoseof6mg/kg

maybeusedonthefirstdaytoachievesteadystatelevelsmorerapidly.

Systemiccandidiasisandcryptococcalinfection:6-12mg/kgdaily,dependingontheseverityofdisease.

Preventionofcandidainfectionsinneutropenicchildren:3-12mg/kgdailydependingontheextentanddurationofthe

neutropenia(seeadultdosing).

Elderly:

Thenormaladultdoseshouldbegivenifthereisnoevidenceofrenalimpairment.

Patientswithimpairedrenalfunction:

Fluconazoleismainlyexcretedunchangedintheurine.Nochangeindoseisneededifthetreatmentconsistsofasingle

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Forpatientswithimpairedrenalfunctionwhorequiremultipledoses,thenormalrecommendeddosefortheindication

shouldbegivenonday1,followedbyadailydoseaccordingtothefollowingtable:

MethodofAdministration

Fluconazolecapsulesshouldbeswallowedwholeandmaybetakenwithoutregardtomeals.

Therouteofadministrationdependsontheclinicalconditionofthepatient.Itisnotnecessarytochangethedailydose

offluconazolewhenchangingtherouteofadministrationfromintravenoustooral.

4.3Contraindications

Fluconazolemustnotbeusedinpatientswithknownhypersensitivitytofluconazoleortorelatedtriazoleanti-fungal

agentsortoanyotheringredientintheformulation.

Fluconazolemustnotbeusedinpatientswhoaretakingcisapride,terfenadineorastemizole(seesection4.4,Special

warningsandprecautionsforuse.andsection4.5,Interactionwithothermedicinalproductsandotherformsof

interaction.).

FluconazolemustnotbeusedinpatientswithcongenitalordocumentedacquiredQTprolongation(seesection4.4,

Specialwarningsandprecautionsforuse).

FluconazolemustnotbeusedconcurrentlywithothermedicamentsthatprolongtheQTintervalsuchasanti-

arrhythmicsofclassesIAandIII.

Fluconazolemustnotbeusedinpatientswithelectrolytedisturbance,particularlyhypokalaemiaand

hypomagnesaemia.

Fluconazolemustnotbeusedinpatientswithclinicallyrelevantbradycardia,cardiacarrhythmiaorseverecardiac

insufficiency

4.4Specialwarningsandprecautionsforuse

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,abnormalitiesin

haematological,hepatic,renalandotherbiochemicalfunctiontestresultshavebeenobservedduringtreatmentwith

fluconazolebuttheclinicalsignificanceandrelationshiptotreatmentisuncertain.

Veryrarely,patientswhodiedwithsevereunderlyingdiseaseandwhohadreceivedmultipledosesoffluconazolehad

post-mortemfindingsthatincludedhepaticnecrosis.Thesepatientswerereceivingmultipleconcomitantmedications,

someknowntobepotentiallyhepatotoxic,and/orhadunderlyingdiseasesthatcouldhavecausedthehepaticnecrosis.

Incasesofhepatotoxicity,noobviousrelationshiptototaldailydoseoffluconazole,durationoftherapy,sexorageof

thepatienthasbeenobserved;theabnormalitieshaveusuallybeenreversibleondiscontinuationoffluconazoletherapy.

Asacasualrelationshipwithfluconazolecannotbeexcluded,patientswhodevelopabnormalliverfunctiontests

duringfluconazoletherapyshouldbemonitoredforthedevelopmentofmoreserioushepaticinjury.Fluconazole

shouldbediscontinuedifclinicalsignsorsymptomsconsistentwithliverdiseasedevelopduringtreatmentwith

fluconazole.

Patientshaverarelydevelopedexfoliativecutaneousreactions,suchasStevens-Johnsonsyndromeandtoxicepidermal

necrolysis,duringtreatmentwithfluconazole.AIDSpatientsaremorepronetothedevelopmentofseverecutaneous

reactionstomanymedicinalproducts.Ifarashdevelopsinapatienttreatedforasuperficialfungalinfectionthatis

consideredattributabletofluconazole,furthertherapywiththisagentshouldbediscontinued.Ifpatientswith

invasive/systemicfungalinfectionsdeveloprashes,theyshouldbemonitoredcloselyandfluconazolediscontinuedif

Creatinine

clearance(ml/min.) Percentageofrecommended

dose

>50 100%

<50(nodialysis) 50%

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Anaphylacticreactionshavebeenreportedrarely(seesection4.8,Undesirableeffects).

FluconazolemustnotbeusedinpatientswithcongenitalordocumentedacquiredQTprolongation(seesection4.3,

Contraindications).

Lactoseintolerance:the50mg,150mgand200mgcapsulescontain49.5,148.5,and198.0mglactose,respectively.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionorwithrarehereditaryproblemsoffructoseintoleranceshouldnottakethismedicinalproduct

Thedoseoffluconazolemustbereducedwhencreatinineclearanceisbelow50ml/min(seesection4.2,Posologyand

methodofadministration)

Thereislimitedexperiencewithlong-termadministrationofdoseshigherthan1-200mgdaily.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Thefollowingcombinationsarecontra-indicated:

Cisapride(CYP3A4substrate):

Therehavebeenreportsaboutcardiaceventsincludingtorsadesdepointesinpatientsreceivingfluconazole

concomitantlywithcisapride.Concomitantadministrationoffluconazoleandcisaprideiscontra-indicated.

Terfenadine(400mgorhigher,CYP3A4substrate):

DuetooccurrenceofseriouscardiacdysrhythmiassecondarytoprolongationoftheQTc-intervalinpatientsreceiving

azoleantifungalagentsinconjunctionwithterfenadine,interactionstudieshavebeenperformed.Onestudywith200

mgfluconazoledailydidnotshowanyprolongationoftheQTc-interval.Anotherstudywith400mgand800mg

fluconazoledailyshowedthatfluconazole400mgormoredailysignificantlyincreasestheplasmalevelofterfenadine

whentakenconcomitantly.Concomitantadministrationoffluconazoleandterfenadineiscontraindicated.

AstemizoleoverdoseshaveledtoprolongedQTintervalandsevereventriculararrhythmia,torsadesdepointesand

cardiacarrest.Concomitantadministrationofastemizoleandfluconazoleiscontra-indicatedduetothepotentialfor

serious,potentiallyfatal,cardiaceffects.

Medicinalproductsaffectingthemetabolismand/orexcretionoffluconazole:

Hydrochlorothiazide:

Inapharmacokineticinteractionstudywithhealthyvolunteerswhoconcomitantlyreceivedfluconazoleandmultiple

dosesofhydrochlorothiazide,theplasmaconcentrationsoffluconazoleincreasedby40%.Aneffectofthissizeshould

notnecessitateachangeinthefluconazoledoseregimeninpatientswhoareconcomitantlytreatedwithdiuretics,

althoughtheprescribershouldbearthisinmind.

Rifampicin(CYP450inducer):

Concomitantintakeoffluconazoleandrifampicinresultedina25%reductionintheAUCand20%reductioninthe

half-lifeoffluconazole.Anincreaseinthedoseoffluconazoleshouldbeconsideredinpatientsconcomitantly

receivingrifampicin.

Rifabutin(CYP450inducer):

Therehavebeenreportsthatconcomitantadministrationofrifabutinandfluconazoleresultsinincreasedserumlevels

ofrifabutin.Uveitishasbeenreportedinpatientstreatedconcomitantlywithfluconazoleandrifabutin.Patientswho

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Effectoffluconazoleonthemetabolismofothermedicinalproducts:

FluconazoleisapotentinhibitorofcytochromeP450(CYP)isoenzyme2C9andamoderateinhibitorofCYP3A4.

Besidesthefollowingobservedinteractionsthereisariskofincreasedplasmaconcentrationsofothermedicinal

productsmetabolisedbyCYP2C9orCYP3A4(i.e.ergot-alcaloids,HMG-CoAreductaseinhibitors,quinidine)when

coadministeredwithfluconazole.Therefore,careshouldalwaysbetakenwhenusingthesecombinationsandthe

patientsshouldbecarefullymonitored.Theeffectmaypersistfor4-5daysafterendoffluconazoletreatmentduetothe

longfluconazolehalf-life.

Anticoagulants(CYP2C9substrate):

Concomitantintakeoffluconazoleduringwarfarintreatmentmayprolongtheprothrombintimeupto2-fold.Asfor

otherazolestherehavebeenreportsofbleeding(bruises,nosebleeding,gastrointestinalbleeding,bloodintheurine

andfaeces)inconnectionwithanincreaseofprothrombintimeinpatientsconcomitantlytreatedwithwarfarin.The

prothrombintimemustbecloselymonitoredinpatientsontreatmentwithfluconazoleandcoumarinderivatives.

Phenytoin(CYP2C9substrateandpotentCYP450inducer):

Intakeoffluconazole200mgconcomitantlywithphenytoin250mgintravenouslyincreasedthephenytoinAUCby

75%andC

by128%.Ifitisnecessarytoadministerbothsubstancesconcomitantly,thephenytoinconcentration

mustbecontrolledbydoseadjustmentinordertomaintaintherapeuticbutnon-toxicplasmaconcentrations.

Benzodiazepines(CYP3A4substrate):

Concomitantintakeoffluconazole400mgandmidazolam7.5mgorallyincreasedthemidazolamAUCandhalf-life

3.7-foldand2.2-fold,respectively,andalsothepsychomotoreffects.Fluconazole100mgdailyandtriazolam0.25mg

increasedthetriazolamAUCandhalf-life2.5-foldand1.8-foldwithpotentiatedandprolongedeffects.Ifitis

necessarytotreatpatientswithabenzodiazepineconcomitantlywithfluconazole,considerationshouldbegivento

decreasingthedoseofthebenzodiazepine.Patientsshouldbecloselyfollowed.

Fluvastatin:

Upto200%increasesintheareaunderthecurve(AUC)offluvastatinmayoccurasaresultoftheinteractionbetween

fluvastatinandfluconazole.Anindividualpatientusingfluvastatin80mgdailymaybeexposedtoconsiderable

fluvastatinconcentrationsiftreatedwithhighdosesoffluconazole.Cautionshouldbeexercisedwhenfluconazoleor

otherpotentcytochromeP4502C9(CYP2C9)inhibitorsareprescribedtopatientswhoarealsotakingfluvastatin.The

clinicalsignificanceofincreasedplasmaconcentrationsandprolongedeliminationoffluvastatinremainsunclear.

Calciumchannelantagonists:

CYP3A4isinvolvedinthemetabolismofsomedihydropyridinecalciumchannelantagonists,includingnifedipine,

isradipine,nicardipine,amlodipine,andfelodipine.Therehavebeenpublishedreportsofmarkedperipheraloedema

and/orelevatedcalciumantagonistserumconcentrationsduringconcurrentuseofitraconazoleandfelodipine,

isradipine,ornifedipine.Thisinteractionwouldbeexpectedtooccurwithothertriazoleantifungalagents.

Considerationshouldbegiventoreducingthedoseofthecalciumantagonist.

Sulphonylureadrugs(CYP2C9substrates):

Ithasbeendemonstratedthatfluconazoleprolongstheplasmahalf-lifeofconcomitantlyadministeredsulphonylurea

drugs(chlorpropamide,glibenclamide,glipizideandtolbutamide)inhealthyvolunteers.Fluconazoleandoral

sulphonylureaderivativesmaybeusedconcomitantlytodiabetics,butpatientsshouldbewarnedaboutthepossibility

ofhypoglycaemia.

Losartan:

DuetoinhibitionofCYP2C9byfluconazole,thereisdecreasedconversionoflosartantoitsactivemetabolite(E-3174),

whichisresponsibleformostoftheangiotensinIIreceptorantagonismthatoccurswithlosartantherapy.Thepatient

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Chemotherapeuticagents

Didanosine:

Althoughco-administrationofdidanosineandfluconazoleappearstohavelittleeffectonthepharmacokineticsor

efficacyofdidanosine,theresponsetofluconazoleshouldbemonitored.Itmaybeadvantageoustoadminister

fluconazoleatsometimepriortodidanosine.

Trimetrexate:

MedicamentssuchasfluconazolethatinhibittheP450enzymesystemmaycauseinteractionsthatincreasetrimetrexate

plasmaconcentrations.Ifitisnotpossibletoavoidconcomitantadministrationoftrimetrexateandfluconazole,

trimetrexateserumlevelsandtrimetrexatetoxicity(bonemarrowsuppression,renalandhepaticdysfunction,and

gastrointestinalulceration)mustbemonitoredcarefully.

Zidovudine:

InteractionstudiesshowedincreasedzidovudineAUCbyapproximately20%and70%whentakenconcomitantlywith

fluconazole200mgor400mgdaily,respectively,probablyduetoinhibitionofglucuronidation.Patientsreceivingthis

combinationmustbemonitoredforzidovudine-relatedside-effects.

Immunosuppressants

Cyclosporin(CYP3A4substrate):

Inapharmacokineticstudywithrenaltransplantpatients,200mgdailyoffluconazoleslowlyincreasedplasma

concentrationsofcyclosporin.However,inanotherstudy,multipledosingwithfluconazole100mgdailydidnot

influencecyclosporinconcentrationsinpatientsafterbonemarrowtransplants.Cyclosporinplasmaconcentrations

shouldbemonitoredduringconcomitanttreatmentwithfluconazole.

Prednisone:

AlivertransplantrecipientreceivingprednisoneexperiencedanAddisoniancrisiswhenathree-monthcourseof

fluconazolewasdiscontinued.ThewithdrawaloffluconazolecausedanincreaseinCYP3A4activity,leadingtoan

increaseinthedegradationofprednisoneandtheprecipitationofanAddisoniancrisis.Patientsreceivinglong-term

therapywithfluconazoleandprednisoneshouldbecloselymonitoredforsignsofadrenalinsufficiencywhen

fluconazoleiswithdrawn.

Tacrolimusandsirolimus(CYP3A4substrates):

Concomitantintakeoffluconazoleandtacrolimus0.15mg/kgb.i.d.increasedtacrolimusC

1.4and3.1-foldwith

fluconazoledosesof100mgand200mg,respectively.Renaltoxicityhasbeenreportedinpatientsconcomitantly

receivingfluconazoleandtacrolimus.Althoughnointeractionstudieshavebeenconductedwithfluconazoleand

sirolimus,itisrecommendedthatsirolimuslevelsshouldbemonitoredbecauseanadjustmentofthedosemaybe

required.Patientswhoreceivetacrolimusorsirolimusandfluconazoleconcomitantlymustbecloselymonitoredfor

increasedtoxicity(anaemia,leukopenia,thrombocytopenia,hypokalaemia,diarrhoea).

Otherdrugs

Oralcontraceptives:

Twopharmacokineticstudieshavebeenperformedwithacombinedoralcontraceptiveandmultipledosingof

fluconazole.50mgfluconazoledidnotinfluenceanyofthehormoneconcentrations,but200mgdailyincreasedAUC

ofethinyloestradiolandlevonorgestrelwith40and24%,respectively.Thus,fluconazoleatthesedosesisunlikelyto

impairtheefficacyofcombinedoralcontraceptivepills.

Amitriptyline:

Severalcasereportshavedescribedthedevelopmentofincreasedamitriptylineconcentrationsandsignsoftricyclic

toxicitywhenamitriptylinewasusedincombinationwithfluconazole.Co-administrationoffluconazolewith

nortriptyline,theactivemetaboliteofamitriptyline,hasbeenreportedtoresultinincreasednortriptylinelevels.Dueto

theriskofamitriptylinetoxicity,considerationshouldbegiventomonitoringamitriptylinelevelsandmakingdose

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Celecoxib:

Aclinicalstudywithcelecoxibhasdemonstratedatwo-foldincreaseincelecoxibplasmaconcentrationswhengiven

concurrentlywithfluconazole200mg.ThisinteractionisbelievedtobeduetoinhibitionofcytochromeP4502C9-

mediatedmetabolismofcelecoxib.Celecoxibtherapyshouldbecommencedatthelowestrecommendeddosein

patientswhoarealsoreceivingfluconazole.

Theophylline:

Inaplacebocontrolledinteractionstudy,intakeoffluconazole200mgfor14daysresultedin18%decreaseinthe

meanplasmaclearanceoftheophylline.Patientsontreatmentwithhighdosesoftheophyllineorwithanyotherreason

tobeatincreasedriskoftheophyllinetoxicityshouldbeobservedcarefullyduringconcomitanttreatmentwith

fluconazoleandthedoseoftheophyllinemustbeadjustedasnecessary.

Othertypesofinteraction

AmphotericinB:

In-vitroandin-vivoanimalstudieshavefoundantagonismbetweenamphotericinBandazolederivatives.The

mechanismofactionofimidazolesistoinhibitergosterolsynthesisinfungalcellmembranes.AmphotericinBactsby

bindingtosterolsinthecellmembraneandchangingmembranepermeability.Clinicaleffectsofthisantagonismareto

dateunknown,AsimilareffectmayoccurwithamphotericinBcholesterylsulphatecomplex.

HMG-CoA:

TheriskofmyopathyorrhabdomyolysisisincreasedwhenazoleantifungalsareadministeredconcurrentlywithHMG-

CoAreductaseinhibitorssuchasatorvastatin.Ifconcurrenttherapyisrequired,patientsshouldbemonitoredforsigns

andsymptomsofmyopathyorrhabdomyolysis(musclepain,tenderness,orweakness),andcreatinekinase(CK)

levels.HMG-CoAtherapyshouldbediscontinuedifCKlevelsshowamarkedincrease,orifmyopathyor

rhabdomyolysisisdiagnosedorsuspected.

Interactionstudieshaveshownthatnoclinicallysignificantchangeinabsorptionoffluconazoleoccurswithoraluse

togetherwithfood,cimetidine,antacidsorafterradiationtherapyofthewholebodyinconnectionwithbonemarrow

transplantation.

4.6Pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseoffluconazoleinpregnantwomen.Studiesinanimalshaveshown

reproductivetoxicity(seesection5.3,Preclinicalsafteydata).Thepotentialriskforhumansisunknown.Datafroma

fewhundredpregnantwomentreatedwithsinglelowdosesoffluconazoleduringearlypregnancydonotindicateany

undesirableeffectsonthefoetus.Therearereportsonmultiplecongenitalabnormalitiesinchildrenwhosemothers

weretreatedfor3monthsorlongerwithhighdosesoffluconazole(400-800mg/day)forcoccidioidalmycosis.

Therelationbetweentheseeffectsandtreatmentwithfluconazoleisnotclear.Fluconazoleshouldonlybeusedduring

pregnancyinpatientswithseriousorpotentiallife-threateninginfectionsandwhentheexpectedbenefittothemother

hasbeenweighedagainstthepotentialriskforthefoetus.

Lactation

Fluconazolepassesintobreastmilkinquantitiescomparabletothoseinplasma.Fluconazoleisthereforenot

recommendedtobreastfeedingwomenoralternatively,breast-feedingshouldbediscontinuedduringtherapywith

fluconazole.

4.7Effectsonabilitytodriveandusemachines

Fluconazolehasnoornegligibleinfluenceontheabilitytodriveandusemachines.

Howeverwhendrivingvehiclesoroperatingmachinesitshouldbetakenintoaccountthatoccasionallydizzinessor

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4.8Undesirableeffects

ThemostCommonundesirableeffectsseeninclinicalstudiesinconnectionwithfluconazoleareasfollows:

Frequency

SystemOrganClass Common

≥1/100, <

1/10 Uncommon

≥1/1,000, <

1/100 Rare

≥1/10,000,

<

1/1,000

Bloodand

lymphaticsystem

disorders Anaemia

Immunesystem

disorders Anaphylactic

reaction

Metabolismand

nutritiondisorders Anorexia

Psychiatric

disorders Insomnia

Nervoussystem

disorders Headache Convulsion

Dizziness

Dysgeusia

Paraesthesia

Somnolence

Tremor

Earandlabyrinth

disorders Vertigo

Gastrointestinal

disorders Nausea

Vomiting

Abdominalpain

Diarrhoea Constipation

Drymouth

Dyspepsia

Flatulence

Hepatobiliary

disorders Cholestasis

Hepaticnecrosis

Hepatocellular

damage

Jaundice

Skinand

subcutaneoustissue

disorders Rash Hyperhidrosis

Pruritus Dermatitis

exfoliative

Stevens-

Johnson

syndrome

Musculoskeletal

andconnective

tissuedisorders Myalgia

Generaldisorders

andadministration

siteconditions Asthenia

Fatigue

Malaise

Pyrexia

Investigations Aspartate

aminotransferase

increased

Alanine

aminotransferase

increased

Bloodalkaline

phosphataseincreased Bloodbilirubin

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Inadditionthefollowingundesirableeffectshaveoccurredaftermarketing:

4.9Overdose

Inonesinglecasea42yearoldAIDSpatientdevelopedhallucinationsandshowedparanoidbehaviourafterintakeof

8200mgfluconazole.Thepatientwashospitalisedandwithin48hoursthepatient’sconditionwasnormal.

Incaseofanoverdose,treatmentissymptomaticwithsupportingmeasuresandgastriclavage,ifnecessary.

Fluconazoleismainlyexcretedintheurine.Forcedvolumediuresiswillprobablyincreasetheeliminationrate.

Haemodialysisfor3hoursdecreasestheplasmalevelsbyapproximately50%.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

PharmacotherapeuticGroup:AntymycoticsforSystemicUse

ATCcode:J02AC01

Frequency

SystemOrgan

Class Very

common

≥1/10 Common

≥1/100,

<

1/10 Uncommon

≥1/1,000,

<

1/100 Rare

≥1/10,000, <

1/1,000 Veryrare

<

1/10,000

Bloodand

lymphatic

system

disorders Leukopenia,including

Neutropeniaand

Agranulocytosis,

Thrombocytopenia

Immunesystem

disorders Anaphylactic

reaction

Metabolismand

nutrition

disorders Hypercholesterolemia,

Hypertriglyceridemia,

Hypokalemia

Nervoussystem

disorders Convulsion

Cardiac

disorders Torsadedepointes

Hepatobiliary

disorders Hepaticfailure

Hepatitis

Hepaticnecrosis

Skinand

subcutaneous

tissuedisorders Angioneurotic

oedema

Pruritus

Stevens-

Johnson

syndrome

Toxic

epidermal

necrolysis

General

disordersand

administration

siteconditions Face

oedema

Investigations ElectrocardiogramQT

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5.2Pharmacokineticproperties

Thepharmacokineticpropertiesoffluconazoleareidenticalafterintravenousandoraladministration.

Absorption:Fluconazoleiswellabsorbedafteroralintake.Theabsolutebioavailabilityisabove90%.Oralabsorption

isnotaffectedbyconcomitantfoodintake.Themaximumfastingplasmaconcentrationisreached0.5–1.5hoursafter

doseintake.90%ofthesteady-statelevelisreached4-5daysafterdosingoncedaily.

Plasmaconcentrationisproportionaltothedose:

afteradministrationof200mgoffluconazole,C

isaround4.6mg/landplasmaconcentrationsobtainedat

steady-stateafter15daysarearound10mg/l,

afteradministrationof400mgoffluconazole,C

isaround9mg/landplasmaconcentrationsobtainedat

steady-stateafter15daysarearound18mg/l.

Intakeofadoubledoseonday1resultsinplasmaconcentrationsthatareapproximately90%ofsteadystateonday2.

Distribution:

Thevolumeofdistributioncorrespondstothetotalbodywater.Theproteinbindinginplasmaislow(11-12%).

Fluconazoleisdistributedoverthetotalbodywater.Theconcentrationinsalivacorrespondstotheplasma

concentration.Inpatientswithfungalmeningitistheconcentrationoffluconazoleinthecerebrospinalfluidis

approximately80%ofthecorrespondingplasmaconcentration.

Instratumcorneum,epidermis-dermisandinexocrinesweathigherconcentrationsoffluconazolearereached

comparedtothoseinserum.Fluconazoleisaccumulatedinstratumcorneum.Atadoseof150mgonceweeklythe

concentrationoffluconazoleinstratumcorneumwasafter2doses23.4µg/gand7daysaftertheseconddosingitwas

still7.1µg/g.

Elimination:

Fluconazoleismainlyrenallyexcreted.Approximately80%oftheadministereddoseisexcretedintheurineinnon-

metabolisedform.Fluconazoleclearanceisproportionaltothecreatinineclearance.Circulatingmetaboliteshavenot

beendemonstrated.

Thehalf-lifeinplasmaisapproximately30hours,whichallowsforsingledosetreatmentinvaginalcandidiasisand

oncedailydosingandonceweeklydosinginconnectionwithotherindications.

Childrenmetabolisefluconazolemorerapidly.Accordinglythehalf-lifeinchildrenof5-15yearsisbetween15.2-17.6

hours,aboutthehalfofthatofadults.

Ithasbeendemonstratedthatfluconazole50mgdailygivenforupto28daysdoesnotinfluenceplasmaconcentrations

oftestosteroneinmenorsteroidalhormoneconcentrationsinwomenofchildbearingage.Fluconazole200-400mg

dailyhasnoclinicallysignificanteffectonendogenoussteroidlevelsoronACTHstimulatedresponsesinhealthy,

malevolunteers.

5.3Preclinicalsafetydata

Preclinicaldatafromconventionalstudiesonrepeat-dose/generaltoxicity,genotoxicityorcarcinogenicityindicateno

specialhazardforhumansnotalreadyconsideredinothersectionsoftheSPC.

Inreproductiontoxicitystudiesinratanincreasedincidenceofhydronephrosisandextensionofrenalpelviswas

reportedandembryonallethalitywasincreased.Anincreaseinanatomicalvariationsanddelayedossificationwas

notedaswellasprolongeddeliveryanddystocia,effectsconsistentwithinhibitionofoestrogensynthesisinrat.In

Irish Medicines Board

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Date Printed 12/08/2008 CRN 2054076 page number: 10

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulescontent:

Silica,colloidalanhydrous

Magnesiumstearate

Talc

Maizestarch

Povidone

Lactose,anhydrous

Capsuleshell:

Gelatin

Titaniumdioxide(E171)

Indigocarmine(E132).

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

5years.

6.4Specialprecautionsforstorage

Donotstoreabove30 °

6.5Natureandcontentsofcontainer

Blister(PVC/Al).

Packsizes:7,10,14,20,28,30,50,100

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

8MARKETINGAUTHORISATIONNUMBER

PA0969/004/003

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorization: 07March2003

Renewalofauthorization 04July2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 12/08/2008 CRN 2054076 page number: 11