DIFLUCAN SOLUTION FOR INFUSION 2 MG/ ML (100MG/ 50ML

Main information

  • Trade name:
  • DIFLUCAN SOLUTION FOR INFUSION 2 MG/ ML (100MG/ 50ML
  • Dosage:
  • 2 mg/ ml Mg/ Ml
  • Pharmaceutical form:
  • Solution for Infusion
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DIFLUCAN SOLUTION FOR INFUSION 2 MG/ML (100MG/50ML
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0019/044/007
  • Authorization date:
  • 22-08-1989
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995

MEDICINALPRODUCTS(LICENSINGANDSALE)REGULATIONS,1998

(S.I.No.142of1998)

PA0019/044/007

CaseNo:2035051

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

PfizerLimited

RamsgateRoad,Sandwich,KentCT139NJ,England

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

DiflucanSolutionforInfusion2mg/ml(100mg/50ml)

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom10/05/2007until21/08/2009.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 16/05/2007 CRN 2035051 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DiflucanSolutionforInfusion2mg/ml(100mg/50ml)

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each1mlcontains2mgfluconazole(100mg/50ml).

Forexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinfusion

Aclear,sterile,colourlesssolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Therapymaybeinstitutedbeforetheresultsoftheculturesandotherlaboratorystudiesareknown;however,once

theseresultsbecomeavailable,anti-infectivetherapyshouldbeadjustedaccordingly.

Diflucanisindicatedfor:

Genitalcandidiasis.Vaginalcandidiasis,acuteorrecurrent.Candidalbalanitis.

Mucosalcandidiasis.Theseincludeoropharyngeal,oesophageal,non-invasivebronchopulmonaryinfections,

candiduria,mucocutaneousandchronicoralatrophiccandidiasis(denturesoremouth).Normalhostsand

patientswithcompromisedimmunefunctionmaybetreated.

Systemiccandidiasisincludingcandidaemia,disseminatedcandidiasisandotherformsofinvasivecandidal

infection.Theseincludeinfectionsoftheperitoneum,endocardiumandpulmonaryandurinarytracts.Candidal

infectionsinpatientswithmalignancy,inintensivecareunitsorthosereceivingcytotoxicor

immunosuppressivetherapy,maybetreated.

Cryptococcosis,includingcryptococcalmeningitisandinfectionsofothersites(e.g.pulmonary,cutaneous).

Normalhostsandpatientswithacquiredimmunedeficiencysyndrome(AIDS),organtransplantsorother

causesofimmunosuppressionmaybetreated.Diflucancanbeusedasmaintenancetherapytopreventrelapse

ofcryptococcaldiseaseinpatientswithAIDS.

Preventionoffungalinfectionsinpatientswithmalignancywhoarepredisposedtosuchinfectionsasaresultof

cytotoxicchemotherapyorradiotherapy,includingbonemarrowtransplantpatients.

Dermatomycosesincludingtineapedis,tineacorporis,tineacruris,tineaversicolorandcandidainfections,only

wheretheseconditionsareresistanttofirstlinetherapyorwhereoccurrenceisinimmunocompromised

patients.

4.2Posologyandmethodofadministration

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beingdependentontheclinicalstateofthepatient.Ontransferringfromtheintravenousroutetotheoralrouteorvice

versa,thereisnoneedtochangethedailydose.DiflucanIntravenousInfusionisformulatedin0.9%sodiumchloride

solution,each200mg(100mlbottle)containing15mmoleachofNa +

andC1 -

ThedailydoseofDiflucanshouldbebasedonthenatureandseverityofthefungalinfection.Mostcasesofvaginal

candidiasisrespondtosingledosetherapy.Therapyforthosetypesofinfectionsrequiringmultipledosetreatment

shouldbecontinueduntilclinicalparametersorlaboratorytestsindicatethatactivefungalinfectionhassubsided.An

inadequateperiodoftreatmentmayleadtorecurrenceofactiveinfection.PatientswithAIDSandcryptococcal

meningitisusuallyrequiremaintenancetherapytopreventrelapse.

Useinadults:

Candidalvaginitisorbalanitis.Theusualdosageis150mgasasingledose.

MucosalCandidiasis.

Oropharyngealcandidiasis:therecommendeddoseis50mgoncedailyfor7to14days.Treatment

maycontinueforalongerperiodifthephysiciansorequires.

Atrophicoralcandidiasisassociatedwithdentures:therecommendeddoseis50mgoncedailyfor14days

administeredconcurrentlywithlocalantisepticmeasurestothedenture.

Forothercandidalinfectionsofthemucosa,(exceptgenitalcandidiasisseeabove),e.g.oesophagitis,

non-invasivebronchopulmonaryinfections,candiduria,mucocutaneouscandidiasisetc.,therecommended

doseis50mgdaily,givenfor14to30days.

Inunusuallydifficultcasesofmucosalcandidalinfectionsthedosemaybeincreasedto100mgdaily.

Forcandidaemia,disseminatedcandidiasisandotherinvasivecandidalinfections:therecommendeddoseis

400mgonthefirstdayfollowedby200mgoncedaily.Dependingontheclinicalresponsethedosemaybe

increasedto400mgoncedaily.Durationoftreatmentisbasedupontheclinicalresponse.

Forcryptococcalmeningitisandcryptococcalinfectionsatothersites:therecommendeddoseis400mgonthe

firstdayfollowedby200mg-400mgoncedaily.Durationoftreatmentforcryptococcalinfectionswilldepend

ontheclinicalandmycologicalresponse,butisusuallyatleast6to8weeksforcryptococcalmeningitis.

ForthepreventionofrelapseofcryptococcalmeningitisinpatientswithAIDS,afterthepatientreceivesafull

courseofprimarytherapy,Diflucanmaybeadministeredindefinitelyatadailydoseof100-200mg.

Therecommendeddosageforthepreventionofcandidiasisis50to400mgoncedaily,basedonthepatient’s

riskofdevelopingfungalinfection.Forpatientsathighriskofsystemicinfectione.g.patientswhoare

anticipatedtohaveprofoundorprolongedneutropeniasuchasduringbonemarrowtransplantation,the

recommendeddoseis400mgoncedaily.Diflucanadministrationshouldstartseveraldaysbeforethe

anticipatedonsetofneutropenia,andcontinuefor7daysaftertheneutrophilcountrisesabove1000cellsper

Fordermalinfectionsincludingtineapedis,corporis,crurisandcandidainfectionstherecommendeddosageis

150mgonceweeklyor50mgoncedaily.Durationoftreatmentisnormally2to4weeksbuttineapedismay

requiretreatmentforupto6weeks.

Fortineaversicolortherecommendeddoseis50mgoncedailyfor2to4weeks.

Useinchildren: Aswithsimilarinfectionsinadults,thedurationoftreatmentisbasedontheclinicaland

mycologicalresponse.Themaximumadultdosageshouldnotbeexceededinchildren.Diflucanisadministeredasa

singledailydoseeachday.

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Childrenoverfourweeksofage: Mucosalcandidiasis:therecommendeddosageofDiflucanis3mg/kgdaily.A

loadingdoseof6mg/kgmaybeusedonthefirstdaytoachievesteadystatelevelsmorerapidly.

Systemiccandidiasisandcryptococcalinfection:therecommendeddosageoffluconazoleis6-12mg/kgdaily,

dependingontheseverityofdisease.

Forthepreventionoffungalinfectionsinimmunocompromisedpatientsconsideredatriskasaconsequenceof

neutropeniafollowingcytotoxicchemotherapyorradiotherapy,thedoseshouldbe3-12mg/kgdailydependingonthe

extentanddurationoftheinducedneutropenia.(Seeadultdosing).

Childrenfourweeksofageandyounger: Neonatesexcretefluconazoleslowly.Inthefirsttwoweeksoflifethe

samemg/kgdosingasinolderchildrenshouldbeusedbutadministeredevery72hours.Duringweeks3and4oflife

thesamedoseshouldbegivenevery48hours.

Useintheelderly:Thenormaldoseshouldbeusedifthereisnoevidenceofrenalimpairment.Inpatientswithrenal

impairment(creatinineclearancelessthan50ml/min)thedosagescheduleshouldbeadjustedasdescribedbelow.

Useinpatientswithimpairedrenalfunction:Fluconazoleisexcretedpredominantlyintheurineasunchangeddrug.

Noadjustmentsinsingledosetherapyarerequired.Inpatients(includingchildren)withimpairedrenalfunctionwho

willreceivemultipledosesofDiflucan,thenormalrecommendeddose(accordingtoindication)shouldbegivenon

day1,followedbyadailydosebasedonthefollowingtable:

CompatibilityofIntravenousInfusion

AlthoughfurtherdilutionisunnecessaryDiflucanIntravenousInfusioniscompatiblewiththefollowingadministration

fluids:

a)Dextrose20%

b)Ringer’ssolution

c)Hartmann’ssolution

d)Potassiumchlorideindextrose

e)Sodiumbicarbonate4.2%

Aminofusin

g)Peritonealdialysissolution

h)Normalsaline(0.9%)

Diflucanmaybeinfusedthroughanexistinglinewithoneoftheabovelistedfluids.Althoughnospecific

incompatibilitieshavebeennoted,mixingwithanyotherdrugpriortoinfusionisnotrecommended.

4.3Contraindications

Diflucanshouldnotbeusedinpatientswithknownhypersensitivitytofluconazoleortorelatedazolecompounds,or

anyotheringredientintheformulation.

Co-administrationofterfenadineiscontra-indicatedinpatientsreceivingDiflucanatmultipledosesof400mgperday

orhigherbaseduponresultsofamultipledoseinteractionstudy.

Co-administrationofcisaprideiscontraindicatedinpatientsreceivingDiflucan.(See‘Interactionwithothermedicinal

Creatinineclearance(ml/min) Percentofrecommendeddose

>50 100%

<50(nodialysis) 50%

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4.4Specialwarningsandprecautionsforuse

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,abnormalitiesofhepatic,

renal,haematologicalandotherbiochemicalfunctiontestshavebeenobservedduringtreatmentwithDiflucanbutthe

clinicalsignificanceandrelationshiptotreatmentisuncertain.

Diflucanhasbeenassociatedwithrarecasesofserioushepatictoxicityincludingfatalities,primarilyinpatientswith

seriousunderlyingmedicalconditions.IncasesofDiflucan-associatedhepatotoxicity,noobviousrelationshiptototal

dailydose,durationoftherapy,sexorageofpatienthasbeenobserved.Diflucanhepatotoxicityhasusuallybeen

reversibleondiscontinuationoftherapy.PatientswhodevelopabnormalliverfunctiontestsduringDiflucantherapy

shouldbemonitoredforthedevelopmentofmoreserioushepaticinjury.Diflucanshouldbediscontinuedifclinical

signsorsymptomsconsistentwithliverdiseasedevelopthatmaybeattributabletoDiflucan.

Patientshaverarelydevelopedexfoliativecutaneousreactions,suchasStevens-JohnsonSyndromeandtoxicepidermal

necrolysis,duringtreatmentwithfluconazole.AIDSpatientsaremorepronetothedevelopmentofseverecutaneous

reactionstomanydrugs.Ifarashdevelopsinapatienttreatedforasuperficialfungalinfection,whichisconsidered

attributabletoDiflucan,furthertherapywiththisagentshouldbediscontinued.Ifpatientswithinvasive/systemic

fungalinfectionsdeveloprashes,theyshouldbemonitoredcloselyandDiflucandiscontinuedifbullouslesionsor

erythemamultiformedevelop.

Thereislittleinformationonsafetyinlong-termuse.

Inrarecases,aswithotherazoles,anaphylaxishasbeenreported.

Someazoles,includingfluconazole,havebeenassociatedwithprolongationoftheQTintervalonthe

electrocardiogram.Duringpost-marketingsurveillance,therehavebeenveryrarecasesofQTprolongationandtorsade

depointesinpatientstakingfluconazole.Thesereportsincludedseriouslyillpatientswithmultipleconfoundingrisk

factors,suchasstructuralheartdisease,electrolyteabnormalitiesandconcomitantmedicationsthatmayhavebeen

contributory.

Fluconazoleshouldbeadministeredwithcautiontopatientswiththesepotentiallyproarryhthmicconditions.

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%)afterwarfarin

administrationinhealthymales.Inpost-marketingexperiences,aswithotherazoleantifungals,bleedingevents

(bruising,epistaxis,gastrointestinalbleeding,hematuria,andmelaena)havebeenreported,inassociationwith

increasesinprothrombintimeinpatientsreceivingfluconazoleconcurrentlywithwarfarin.Prothrombintimein

patientsreceivingcoumarin-typeanticoagulantsshouldbecarefullymonitiored.

Azithromycin:Anopen-label,randomised,three-waycrossoverstudyin18healthysubjectsassessedtheeffectofa

single1200mgoraldoseofazithromycinonthepharmacokineticsofasingle800mgoraldoseoffluconazoleaswell

astheeffectsoffluconazoleonthepharmacokineticsofazithromycin.Therewasnosignificantpharmacokinetic

interactionbetweenfluconazoleandazithromycin.

Benzodiazepines(shortacting):Followingoraladministrationofmidazolam,fluconazoleresultedinsubstantial

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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.

Oralcontraceptives:Threekineticstudieswithcombinedoralcontraceptiveshavebeenperformedusingmultiple

dosesoffluconazole.Therewerenorelevanteffectsoneitherhormonelevelinthe50mgfluconazolestudy,whileat

200mgdailytheAUCsofethinylestradiolandlevonorgestrelwereincreased40%and24%respectively.Ina300mg

dailyfluconazolestudy,theAUCsofethinylestradiolandnorethindronewereincreasedby24%and13%

respectively.Thusmultipledoseuseoffluconazoleatthesedosesisunlikelytohaveaneffectontheefficacyofthe

combinedoralcontraceptive.

Endogenoussteroid:Fluconazole50mgdailydoesnotaffectendogenoussteroidlevelsinfemales.200-400mgdaily

hasnoclinicallysignificanteffectonendogenoussteroidlevelsoronACTHstimulatedresponseinhealthymale

volunteers.

Ciclosporin:Akineticstudyinrenaltransplantpatientsfoundfluconazole200mgdailytoslowlyincreaseciclosporin

concentrations.However,inanothermultipledosestudywith100mgdaily,fluconazoledidnotaffectciclosporin

levelsinpatientswithbonemarrowtransplants.Ciclosporinplasmaconcentrationmonitoringinpatientsreceiving

fluconazoleisrecommended.

Theophylline:Inaplacebo-controlledinteractionstudy,theadministrationoffluconazole200mgfor14daysresulted

inan18%decreaseinthemeanplasmaclearanceoftheophylline.Patientswhoarereceivinghighdosesof

theophyllineorwhoareotherwiseatincreasedriskfortheophyllinetoxicityshouldbeobservedforsignsof

theophyllinetoxicitywhilereceivingfluconazole,andthetherapymodifiedappropriatelyifsignsoftoxicitydevelop.

Tacrolimus:Therehavebeenreportsthataninteractionexistswhenfluconazoleisadministeredconcomitantlywith

tacrolimus,leadingtoincreasedserumlevelsoftacrolimus.Therehavebeenreportsofnephrotoxicityinpatientsto

whomfluconazoleandtacrolimuswereco-administered.Patientsreceivingtacrolimusandfluconazoleconcomitantly

shouldbecarefullymonitored.

Rifabutin:Therehavebeenreportsthataninteractionexistswhenfluconazoleisadministeredconcomitantlywith

rifabutin,leadingtoincreasedserumlevelsofrifabutin.Therehavebeenreportsofuveitisinpatientstowhom

fluconazoleandrifabutinwereco-administered.Patientsreceivingrifabutinandfluconazoleconcomitantlyshouldbe

carefullymonitored.

Terfenadine:BecauseoftheoccurrenceofseriouscardiacdysrhythmiassecondarytoprolongationoftheQTcinterval

inpatientsreceivingazoleantifungalsinconjunctionwithterfenadine,interactionstudieshavebeenperformed.One

studyata200mgdailydoseoffluconazolefailedtodemonstrateaprolongationinQTcinterval.Anotherstudyata

400mgand800mgdailydoseoffluconazoledemonstratedthatfluconazoletakenindosesof400mgperdayorgreater

significantlyincreasesplasmalevelsofnterfenadinewhentakenconcomitantly.Thecombineduseoffluconazoleat

dosesof400mgorgreaterwithterfenadineiscontra-indicated.(See‘Contra-indications’.)Theco-administrationof

fluconazoleatdoseslowerthan400mgperdaywithterfenadineshouldbecarefullymonitored.

Cisapride:Therehavebeenreportsofcardiaceventsincludingtorsadedepointesinpatientstowhomfluconazoleand

cisapridewereco-administered.Acontrolledstudyfoundthatconcomitantfluconazole200mgoncedailyand

cisapride20mgfourtimesadayyieldedasignificantincreaseincisaprideplasmalevelsandprolongationofQTc

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TheuseoffluconazoleinpatientsconcurrentlytakingastemizoleorotherdrugsmetabolisedbythecytochromeP450

systemmaybeassociatedwithelevationsinserumlevelsofthesedrugs.Intheabsenceofdefinitiveinformation,

cautionshouldbeusedwhenco-administeringfluconazole.Patientsshouldbecarefullymonitored.

Zidovudine:Twokineticstudiesresultedinincreasedlevelsofzidovudinemostlikelycausedbythedecreased

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.

4.6Pregnancyandlactation

Therearenoadequateandwell-controlledstudiesinpregnantwomen.Therehavebeenreportsofmultiplecongential

abnormalitiesininfantswhosemotherswerebeingtreatedfor3ormoremonthswithhighdose(400-800mg/day)

fluconazoletherapyforcoccidioidomycosis.Therelationshipbetweenfluconazoleuseandtheseeventsisunclear.

Useinpregnancyshouldbeavoidedexceptinpatientswithsevereorpotentiallylife-threateningfungalinfectionsin

whomFluconazolemaybeusediftheanticipatedbenefitoutweighsthepossiblerisktothefetus.

Useduringlactation: Fluconazoleisfoundinhumanbreastmilkatconcentrationssimilartoplasma,henceits

useinnursingmothersisnotrecommended.

4.7Effectsonabilitytodriveandusemachines

ExperiencewithDiflucanindicatesthattherapyisunlikelytoimpairapatient'sabilitytodriveorusemachinery.

4.8Undesirableeffects

Fluconazoleisgenerallywelltolerated.Themostcommonundesirableeffectsobservedduringclinicaltrialsand

associatedwithfluconazoleare:

NervousSystemDisorders:Headache.

SkinandSubcutaneousTissueDisorders:Rash.

GastrointestinalDisorders:Abdominalpain,diarrhoea,flatulence,nausea.

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,changesinrenaland

haematologicalfunctiontestresultsandhepaticabnormalitieshavebeenobservedduringtreatmentwithfluconazole

andcomparativeagents,buttheclinicalsignificanceandrelationshiptotreatmentisuncertain(seeSection4.4‘Special

warningsandprecautionsforUse’).

HepatobiliaryDisorders:Hepatictoxicityincludingrarecasesoffatalities,elevatedalkalinephosphatase,elevated

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Inaddition,thefollowingundesirableeffectshaveoccurredduringpost-marketing:

NervousSystemDisorders:Dizziness,seizures,tasteperversion.

SkinandSubcutaneousTissueDisorders:Alopecia,exfoliativeskindisordersincludingStevens-Johnsonsyndrome

andtoxicepidermalnecrolysis.

GastrointestinalDisorders:Dyspepsia,vomiting.

BloodandLymphaticSystemDisorders:Leucopoeniaincludingneutropeniaandagranulocytosis,thrombocytopenia.

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

HepatobiliaryDisorders:Hepaticfailure,hepatitis,hepatocellularnecrosis,jaundice.

MetabolismandNutritionDisorders:Hypercholesterolaemia,hypertriglyceridaemia,hypokalaemia.

CardiacDisorders:QTprolongation,torsadedepointes(seesection4.4SpecialwarningsandprecautionsforUse).

4.9Overdose

Therehavebeenreportsofoverdosagewithfluconazoleandinonecasea42year-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

endemicmycoses,includinginfectionswithBlastomycesdermatitides;withCoccidoidesimmitis,includingintracranial

infectionandwithHistoplasmacapsulatuminnormalandimmunosuppressedanimals.

TherehavebeenreportsofcasesofsuperinfectionwithCandidaspeciesotherthanC.albicans,whichareoften

inherentlynotsusceptibletofluconazole(e.g.Candidakrusei).Suchcasesmayrequirealternativeantifungaltherapy.

FluconazoleishighlyspecificforfungalcytochromeP-450dependentenzymes.Fluconazole50mgdailygivenupto

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ofchild-bearingage.Fluconazole200-400mgdailyhasnoclinicallysignificanteffectonendogenoussteroidlevelsor

onACTHstimulatedresponseinhealthymalevolunteers.Interactionstudieswithantipyrineindicatethatsingleor

multipledosesoffluconazole50mgdonotaffectitsmetabolism.

5.2Pharmacokineticproperties

Thepharmacokineticpropertiesoffluconazolearesimilarfollowingadministrationbytheintravenousororalroutes.

Afteroraladministrationfluconazoleiswellabsorbed,andplasmalevels(andsystemicbioavailability)areover90%

ofthelevelsachievedafterintravenousadminstration.Oralabsorptionisnotaffectedbyconcomitantfoodintake.

Peakplasmaconcentrationsinthefastingstateoccurbetween0.5and1.5hourspostdosewithaplasmaelimination

half-lifeofapproximately30hours.Plasmaconcentrationsareproportionaltodose.Ninetypercentsteadylevelsare

reachedbyday4-5withmultipleoncedailydosing.

Administrationofaloadingdose(onday1)oftwicetheusualdailydoseenablesplasmalevelstoapproximateto90%

steadystatelevelbyday2.Theapparentvolumeofdistributionapproximatestototalbodywater.Plasmaprotein

bindingislow(11-12%).

Fluconazoleachievesgoodpenetrationintoallbodyfluidsstudied.Thelevelsoffluconazoleinsalivaandsputumare

similartoplasmalevels.InpatientswithfungalmeningitisfluconazolelevelsintheCSFareapproximately80%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.

Astudycomparedthesalivaandtheplasmaconcentrationsofasinglefluconazole100mgdoseadministrationina

capsuleorinanoralsuspensionbyrinsingandretaininginmouthfor2minutesandswallowing.Themaximum

concentrationoffluconazoleinsalivaafterthesuspensionwasobserved5minutesafteringestion,andwas182times

higherthanthemaximumsalivaconcentrationafterthecapsule,whichoccurred4hoursafteringestion.Afterabout4

hours,thesalivaconcentrationsoffluconazoleweresimilar.ThemeanAUC(0-96)insalivawassignificantlygreater

afterthesuspensioncomparedtothecapsule.Therewasnosignificantdifferenceintheeliminationratefromsalivaor

theplasmapharmacokineticparametersforthetwoformulations.

PharmacokineticsinChildren

Inchildren,thefollowingpharmacokineticdatahavebeenreported:

Agestudied Dose(mg/kg) Half-life

(hours) AUC

(microgram.h/ml)

11days-11months Single-IV3mg/kg 23 110.1

9months-13years Single-Oral2mg/kg 25.0 94.7

9months-13years Single-Oral8mg/kg 19.5 362.5

5years-15years Multiple-IV2mg/kg 17.4* 67.4

5years-15years Multiple-IV4mg/kg 15.2* 139.1

5years-15years Multiple-IV8mg/kg 17.6* 196.7

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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)onday1whichincreasedwithameanof490

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

Thevolumeofdistribution(ml/kg)was1183(range1070-1470)onday1andincreasedwithtimetoameanof1184

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

PharmacokineticsinElderly

Apharmacokineticstudywasconductedin22subjects,65yearsofageorolderreceivingasingle50mgoraldoseof

fluconazole.Tenofthesepatientswereconcomitantlyreceivingdiuretics.TheC

was1.54mcg/mlandoccurredat

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

pharmacokineticparametervaluesarehigherthananalogousvaluesreportedfornormalyoungmalevolunteers.Co-

administrationofdiureticsdidnotsignificantlyalterAUCorC

.Inaddition,creatinineclearance(74ml/min),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

areconsistentwiththehypothesisthathighervaluesforthepharmacokineticobservedintheelderlysubjectscompared

withnormalyoungmalevolunteersareduetothedecreasedkidneyfunctionthatisexpectedintheelderly.

5.3Preclinicalsafetydata

ReproductiveToxicityTherewerenofetaleffectsat5or10mg/kg:increasesinfetalanatomicalvariants

(supernumeraryribs,renalpelvisdilation)anddelaysinossificationwereobservedat25and50mg/kgandhigher

doses.Atdosesrangingfrom80mg/kg(approximately20to60xtherecommendedhumandose)to320mg/kg

embryolethalityinratswasincreasedandfetalabnormalitiesincludedwavyribs,cleftplateandabnormalcranio-facial

ossification,theseeffectsareconsistentwiththeinhibitionofoestrogensynthesisinratsanmaybearesultofknown

effectsofloweredoestrogenonpregnancy,organogenesisandparturition.

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.Thedisturbancesinparturitionwere

reflectedbyaslightincreaseinthenumberofstillbornpupsanddecreaseofneonatalsurvivalatthesedoselevels.The

effectsonparturitioninratsareconsistentwiththespeciesspecificoestrogen-loweringpropertyproducedbyhigh

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumchloride

Waterforinjections

6.2Incompatibilities

Althoughnospecificincompatibilitieshavebeennoted,mixingwithanyotherdrugpriortoinfusionisnot

recommended.

6.3ShelfLife

5years.

6.4Specialprecautionsforstorage

Donotstoreabove30 o

Donotfreeze.

6.5Natureandcontentsofcontainer

50mlTypeIglassinfusionvialsealedwitharubberstopperandanaluminiumovercap.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Donotfreeze.Theinfusiondoesnotcontainanypreservative.Itisforsingleuseonly.Discardanyremainingsolution.

7MARKETINGAUTHORISATIONHOLDER

PfizerLimited

RamsgateRoad

Sandwich

KentCT139NJ

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA19/44/7

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:22August1989

Dateoflastrenewal:22August2004

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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