FLUCONAZOLE NICHE

Main information

  • Trade name:
  • FLUCONAZOLE NICHE
  • Dosage:
  • 2 Mg/Ml
  • Pharmaceutical form:
  • Solution for Infusion
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1063/034/001
  • Authorization date:
  • 21-11-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1063/034/001

CaseNo:2072834

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

NicheGenericsLimited

1TheCamCentre,WilburyWay,Hitchin,HertfordshireSG4OTW,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

FluconazoleNiche2mg/mlsolutionforInfusion

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom03/12/2009until31/01/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FluconazoleNiche2mg/mlsolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachmlofSolutionforInfusioncontains2mgofFluconazole.

25mlSolutionforInfusioncontains50mgFluconazole

50mlSolutionforInfusioncontains100mgFluconazole

100mlSolutionforInfusioncontains200mgFluconazole

200mlSolutionforInfusioncontains400mgFluconazole

Excipients:

EachmlofSolutionforInfusioncontains0.15mmol(3.5mg)sodium(aschloride)

25mlSolutionforInfusioncontain3.9mmol(88mg)sodium(aschloride)

50mlSolutionforInfusioncontain7.7mmol(177mg)sodium(aschloride)

100mlSolutionforInfusioncontain15.4mmol(354mg)sodium(aschloride)

200mlSolutionforInfusioncontain30.8mmol(709mg)sodium(aschloride)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinfusion.

Aclearandcolourlesssolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Adults

TreatmentofmycosescausedbyCandida,Cryptococciandothersusceptibleyeasts,inparticular:

Systemiccandidiasis(includingdisseminateddeepinfectionsandperitonitis)

Severemucosalcandidiasis(includingoropharyngealcandidiasis,oesophagealcandidiasisandnon-invasive

bronchopulmonarycandidiasis),whereoraltreatmentisnotpossible.

Cryptococcalmeningitisinadults

ProphylaxisagainstdeepCandidainfections(especiallyCandidaalbicans)inpatientswithneutropeniadueto

bonemarrowtransplantation.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantifungalagents.Beforeinitiating

treatmentsamplesshouldbetakenformicrobiologicalanalysisandthesuitabilityofthetherapyshouldsubsequently

beconfirmed(seesections4.2and5.1).

Insomepatientswithseverecryptococcalmeningitisthemycologicalresponseduringfluconazoletreatmentmaybe

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Childrenandadolescents

TreatmentofmycosescausedbyCandidaandothersusceptibleyeasts,inparticular:

Systemiccandidiasis(includingdisseminateddeepinfectionsandperitonitis)

Severemucosalcandidiasis(includingoropharyngealcandidiasis,oesophagealcandidiasisandnon-invasive

bronchopulmonarycandidiasis),whereoraltreatmentisnotpossible.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantifungalagents.Beforeinitiating

treatmentsamplesshouldbetakenformicrobiologicalanalysisandthesuitabilityofthetherapyshouldsubsequently

beconfirmed(seesections4.2and5.1).

4.2Posologyandmethodofadministration

Treatmentwithfluconazoleshouldbeinitiatedbyaphysicianexperiencedinthemanagementofinvasivefungal

infections.Thedoseisdependentonthetypeandseverityoftheinfection.Thetreatmentofinfectionsrequiring

multiple-dosingmustbecontinueduntilclinicalparametersorlaboratoryresultsshowthattheactiveinfectionhas

declined.Aninsufficienttreatmentperiodmayleadtorecurrenceoftheactiveinfection.

Fluconazoleisalsoavailablefororaltherapy.Thepatientshouldbeswitchedfromdosingbytheintravenousrouteto

dosingbytheoralrouteassoonaspossible.Itisnotnecessarytochangethedailydoseoffluconazolewhenchanging

therouteofadministrationfromintravenoustooral.

Adults:

Pleaserefertotable1forspecificdosagerecommendations.

Elderly:

Thenormaladultdoseshouldbegivenifthereisnoevidenceofrenalimpairment.Pleaserefertotable1.

Table1–GuidanceonthedosetotheAdmistratorforanadulttreatedbytheIntravenousRoute

TreatmentwithFluconazoleshouldbeinitiatedbyaphysicianexperiencedinthemanagementofinvasivefungal

infections.

Indication Initialdaily

dose(mg) Subsequent

dailydose(mg) Recommended

durationof

treatment Additionalguidance

Systemiccandidiasis

Candidaemia,

disseminated

candidiasisandthe

otherformsofinvasive

candidainfection. 400-800 200-400 Dependantupon

clinicalresponse Thedosechosen

musttakeinto

accountlocal

resistancepatternsto

fluconazole9see

section5.1).Where

thesensitivityofthe

pathogenhasnotyet

beenestablished,the

higherdoseshould

initiallybe

considered.

Inmostcasesa

loadingdoseof

800mgonthefirst

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Paediatricuse

Fluconazole2mg/mlSolutionforInfusionshouldnotbeusedinchildrenandadolescentsundertheageof16years

unlessthereisnotherapeuticalternative,becauseefficacyandsafetyhavenotbeensufficientlydemonstrated.

400mgdaily

thereaftermaybe

preferable.

Severemucosal

candidiasis Useonlywhenoral

dosingisnot

possible.

Oropharyngeal

candidiasis 100 100 7-14days Insomecasesadaily

dosehigherthan

100mgmaybe

requiredand

treatmentcanbe

prolonged.

Othermucosalcandida

infections(except

genitalcandidiasis) 100 100 14-30days Thedurationof

maintenance

treatmentofAIDS

patientsshouldbe

balancedagainstthe

riskofresistanceto

fluconazole.

Treatmentof

cryptococcal

meningitis

Initialtherapy 400 200-400 Typical6-8

weeks Durationof

treatmentwill

dependuponclinical

andmycological

response.

Prophylaxisagainst

deepcandida

infections

Inpatientswith

neutropeniadueto

bonemarrow

transplantation 400 400 Seeadditional

guidance Fluconazole

administration

shouldstartseveral

daysbeforethe

anticipatedonsetof

neutropeniaand

continueforseven

daysafterthe

neutropilcountrises

above1000cellsper

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Aswithsimilarinfectionsinadults,thedurationoftreatmentisbasedupontheclinicalandmycologicalresponse.Note

thatduetoaslowereliminationinnewborninfants,thedosingintervalsareincreased.

Therearefewpharmacokineticdatatosupportthisposologyinnewbornbabies(seeSection5.2).

Table2-GuidanceOnTheDoseToAdministerInPaediatricsTreatedByTheIntravenousRoute.

Patientswithimpairedrenalfunction

Fluconazoleisclearedprimarilybyrenalexcretionasunchangeddrug.Noadjustmentsinsingledosetherapyare

necessary.Inpatientswithimpairedrenalfunction(includingchildren)whoreceivemultipledosetherapy,the

recommendedinitialloadingdosecanbegiven.Aftertheloadingdose,thedailydose(accordingtoindication)based

onthetablebelow:

AgeRange Indication(s) Recommended

dosage AdditionalGuidance

Neonates Note:

Therearefewpharmacokineticdatatosupporttheposologiesin

newbornbabies.

(seesection5.2)

2weeksorless Allindicationslisted

below 6-12mg/kgevery72

hours Amaximumdoseof

12mg/kgevery72

hoursshouldnotbe

exceededinchildren

inthefirsttwoweeks

oflife.

3-4weeks Allindicationslisted

below 6-12mg/kgevery48

hours. Forchildrenbetween3

and4weeksoflife,12

mg/kgevery48hours

shouldnotbe

exceeded.

Childrenaged4

weeksandabove Note:

Forchildrenagedfiveyearsorlessthemaximumdailydoseshould

notexceed400mgperday.

Systemic

candidiasis

Mucosal

candidiasis 6-12mg/kg/day

3mg/kg/day Onthefirstdaya

loadingdoseof

5mg/kgmaybegiven

inordertomore

rapidlyreachsteady

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Table3–DoseModificationsRequiredFollowingtheInitialDoseForPatientsWithImpairedRenalFunction

(FurtherDosageadjustmentsmaybeneededdependinguponclinicalcondition)

Patientswithliverinsufficiency:

Fluconazoleshouldonlybeadministeredwithspecialcareandundercarefulmonitoringinpatientswithliver

insufficiency(seesection4.4).

Interactionsrequiringdoseadjustments:

ModificationstothedosingschedulesprovidedinTables1to3mayberequiredwhereconcomitantuseofeither

rifampicinorhydrochlorothiazideisproposed.

Furtherdetailsareprovidedinsection4.5.

Administration

Forintravenoususeasinfusion.Theproductcanbeinfusedatamaximumrateof10ml/min.Inchildrentherateof

intravenousinfusionshouldnotexceed5ml/min.Forprematureinfantstheinfusiontimeshouldbenolessthan15

minutes.Inpatientsrequiringsodium-orfluidrestriction,therateofadministrationshouldbetakenintoconsideration

asFluconazoleconsistsofasaltsolution.Insuchcasestheinfusionshouldbegivenoveralongerperiod.

Fluconazole2mg/mlsolutionforinfusionisformulatedin0.9%sodiumchloridesolution;each200mg(100mlbottle)

contains15mmolofNa+and15mmolCl-.Considerationshouldbegiventotherateoffluidadministrationin

patientsrequiringsodiumorfluidrestriction.

Fluconazolemaybeadministeredeitherorallyorbyintravenousinfusion.Therouteofadministrationselectionwill

dependontheclinicalconditionofthepatient.

Forinstructionsonthehandlingoftheproduct,seesection6.6.

4.3Contraindications

HypersensitivitytoFluconazoleorotherazolecompoundsortoanyoftheexcipients.Fluconazoleshouldnotbeco-

administeredwithdrugsbothknowntoprolongtheQT-intervalandmetabolisedbyCYP3A4suchascisapride,

astemizole,terfenadine,pimozideandquinidine.(seesection4.5).

4.4Specialwarningsandprecautionsforuse

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,abnormalitiesofhepatic,

renal,haematologicalandotherbiochemicalfunctiontestshavebeenobservedduringtreatmentwithFluconazole

2mg/mlsolutionforinfusionbuttheclinicalsignificanceandrelationshiptotreatmentisuncertain.

Severelivertoxicity,includingdeath,hasbeenreportedinrarecases,mostofteninpatientswithseriousunderlying

illnesses.Noobviousconnection,however,hasbeenfoundbetweendailydose,durationoftreatment,genderorage.

Patientsthatdevelopabnormalliverfunctiontestsorsignificantincreasesfromalreadyabnormallevelsduring

treatmentshouldbecarefullymonitored.

Treatmentshouldbediscontinuedifclinicalsignsofliverdisease,withpossibleconnectiontofluconazole,develop.

Thelivertoxicityhasmostoftenbeenreversiblefollowingwithdrawalofthetreatment.Thebenefitsofthetreatment

shouldbeevaluatedagainsttherisksofdevelopingseriousliverdamageiftherapyiscontinuedinpatientswhoseliver

CreatinineClearance(ml/min) PercentofRecommendedDose

>50 100%

11-50(nodialysis) 50%

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Thedoseoffluconazolemustbereducedwhencreatinineclearanceisbelow50ml/min(seesection4.2.).

Certainazoles,includingfluconazole,havebeenassociatedwithprolongationoftheQT-interval.Rarecasesoftorsade

depointeshavebeenreportedduringtreatmentwithfluconazole.Eventhoughaconnectionbetweenfluconazoleand

prolongedQT-intervalhasnotbeenformallyconfirmed,fluconazoleshouldbeadministeredwithcautioninpatients

withpotentiallypro-arrhythmicconditionssuchas:

CongenitalordocumentedacquiredQT-prolongation

Cardiomyopathy,particularlyinthepresenceofheartfailure

Sinusbradycardia

Symptomaticarrhythmias

Electrolytedisturbances

ConcomitantadministrationofpreparationsknowntoprolongtheQT-interval(seesection4.5).

Electrolytedisturbancessuchashypokalaemia,hypomagnesaemiaandhypocalcaemiashouldbecorrectedpriorto

initiationoffluconazoletreatment.

InrarecasespatientshavedevelopedexfoliativeskinreactionsincludingStevens-Johnsonsyndromeandtoxic

epidermalnecrolysisintreatmentwithfluconazole.AIDS-patientshaveahighertendencyforthedevelopmentof

seriousskinreactionsfromvariousdrugs.Wherepatientswithminorfungalinfectionsthatarebeingtreatedwith

fluconazoledevelopaskinrash,consideredtobeconnectedtotreatmentwithfluconazole,thetreatmentshouldbe

stopped.

Ifpatientswhoarebeingtreatedforinvasivefungalinfectionsorsystemicinfectionsdevelopaskinrash,theyshould

becloselymonitoredandthetreatmentdiscontinuedifbullousskinreactionsorerythemamultiformedevelop.

FluconazoleisapotentinhibitorofcytochromeP450(CYP)isoenzyme2C9andamoderateinhibitorofCYP3A4.

Patientswhoreceiveconcomitanttreatmentwithfluconazoleanddrugswhichhaveanarrowtherapeuticinterval(e.g.

warfarinandphenytoin)andwhicharemetabolisedviaCYP2C9and/orCYP3A4shouldbecloselymonitored(see

sections4.3and4.5).

Fluconazolemaylengthentheprothrombintimefollowingadministrationofwarfarin.Closemonitoringofthe

prothrombintimeisrecommended.

Rareinstancesofanaphylacticreactionshavebeenreported(seesection4.8).

Cautionmustbetakenwithpatientswithrenalimpairment,Pleaserefertosection4.2.

Inwomenofchildbearingpotentialappropriatecontraceptivemeasureshouldbeconsideredincaselong-term

treatmentisindicated(seesection4.6).

Dataregardingefficacyandsafetyoffluconazoleinchildrenandadolescentslessthan16yearsofagearestilllimited.

Thereforethebenefitsofthetreatmentwithfluconazoleshouldbecarefullyevaluatedagainsttherisks.

ThereareindicationsthatbyaportionofthepatientstreatedwithFluconazoleforcryptococcalmeningitis,the

mycologicresponsehasbeenslowerthanwiththetreatmentofamphotericinBincombinationwithflucytocin.This

shouldbekeptinmindwhenchoosingtreatmentforpatientswithseverecryptococcalmeningitis.

Patientsconcurrentlyreceivingfluconazoleatdosesbelow400mg/dayandterfenadinerequireclosemonitoring(see

section4.5).

Thismedicinalproductcontains15.4mmol(354mg)sodiumper100mlofsolution.Tobetakenintoaccountin

patientsonacontrolledsodiumdietandincaseswherefluidrestrictionisrequired.Refertosection2forsodium

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Inadditiontotheinteractionsgivenbelow,thereisariskofelevatedserumconcentrationsofotherdrugsmetabolised

viaCYP2C9andCYP3A4withconcomitantadministrationoffluconazole.Fluconazoleisapotentinhibitorof

cytochromeP450(CYP)isoenzyme2C9andamoderateinhibitorofCYP3A4.Thereforecautionshouldalwaysbe

observedduringcombinationtherapywithmedicationssuchastheseandthepatientcloselymonitored.Theeffects

maypersistfor4-5daysduetothelonghalflifeoffluconazole.

Thefollowingcombinationsarecontraindicated:

Astemizole(CYP3A4-substrate):

AstemizoleoverdoseshaveledtoprolongedQTintervalasevereventriculararrhythmia,torsadedepointesandcardiac

arrest.Concomitantadministrationofastemizoleandfluconazoleiscontraindicatedduetothepotentialforserious,

potentiallyfatal,cardiaceffects.

Cisapride(CYP3A4-substrate):

Cardiovasculareffects,includingtorsadedepointes,havebeenreportedinpatientshavingreceivedconcomitant

treatmentwithfluconazoleandcisapride.Inonecontrolledstudy,where200mgfluconazolewasadministeredonce

dailyconcomitantlywithcisapride20mgfourtimesdaily,asignificantincreaseinplasmalevelsofcisaprideand

prolongationoftheQTc-intervalwhereachieved.Concurrenttreatmentwithcisaprideandfluconazoleis

contraindicated(see4.3Contraindications).

Terfenadine(400mgfluconazoleandhigher;CYP3A4-substrate):

Seriouscardiacarrhythmias,secondarytoprolongedQTc-interval,haveoccurredinpatientstreatedwithanti-fungal

medicationssuchastriazoliccompoundsandterfenadine.Concomitanttreatmentwith200mgfluconazoledaily

showednoprolongationoftheQTc-interval.Withdosesof400mgand800mgfluconazoledaily,theplasma

concentrationofterfenadineincreasedsignificantly.Concomitanttreatmentwithfluconazole400mgperdayorhigher

doseiscontraindicated.Withconcomitanttreatmentwithdosesbelow400mgperday,thetreatmentshouldbeclosely

monitored.

Theeffectsofotherdrugsonfluconazole:

Hydrochlorothiazide:

Theplasmaconcentrationoffluconazoleincreasedby40%withconcomitantadministrationofhydrochlorthiazidein

healthyvolunteers.Anincreaseofthisdimensiondoesnotnecessitateadjustmentinthedoseoffluconazolecapsulesin

patientsundergoingtreatmentwithdiuretics,buttheprescribingdoctorshouldbeawareofthefact.

Rifampicin(CYP450-inducers):

Concomitanttreatmentwithfluconazole(200mg)andrifampicin(600mgdaily)reducedAUCforfluconazoleby

23%inhealthyvolunteers.

Anincreaseinthedoseoffluconazoleshouldbeconsideredincombinationtreatment.

Theeffectsoffluconazoleonotherdrugs:

Alfentanil(CYP3A4-substrate):

Inconcomitanttreatmentwithfluconazole(400mg)andintravenousalfentanil(20µg/kg)inhealthyvolunteers,

AUC10–increasedtwofoldandclearancedecreasedby55%foralfentanil,probablythroughinhibitionofCYP3A4.

Thecombinationmayrequiredoseadjustment.

AmphotericinB:

In-vitroandin-vivoanimalstudieshavefoundantagonismbetweenamphotericinBandazolederivatives.The

mechanismofactionofimidazolesistoinhibitergosterolsynthesisinfungalcellmembranes.AmphotericinBactsby

bindingtosterolsinthecellmembraneandchangingmembranepermeability.Clinicaleffectsofthisantagonismareto

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Amitriptyline(CYP2D6-substrate):

Severalcasehistorieshavedescribedthedevelopmentofelevatedamitriptyllineconcentrationsandsignsoftricyclic

toxicitywhenamitriptyllineisusedincombinationwithfluconazole.Concomitantinfusionoffluconazoleand

nortriptylline,theactivemetaboliteofamitriptylline,hasbeenreportedtoleadtoincreasednortriptyllinelevels.Dueto

theriskofamitriptyllinetoxicity,monitoringofamitriptyllinelevelsshouldbeconsideredwithdoseadjustmentwhere

indicated.

Anticoagulants(CYP2C9-substrate):

Inconcomitanttreatmentwithfluconazoleandwarfarin,theprothrombintimeincreaseduptotwofold.Thisisprobably

duetoaninhibitionofthemetabolismofwarfarinviaCYP2C9.Theprothrombintimeshouldbemonitoredcloselyin

patientstreatedconcomitantlywithfluconazoleandcoumarin-typeanticoagulants.

Benzodiazepines(CYP3A4-substrate):

FluconazolemayinhibitthemetabolismofbenzodiazepinesmetabolisedviaCYP3A4,e.g.midazolamandtriazolam.

Inconcomitantoralsingledosetreatmentwithfluconazole(400mg)andmidazolam(7.5mg)AUCincreased3.7times

andthehalflifeofmidazolam2.2times.Thecombinationshouldbeavoided.Whereconcomitanttreatmentis

considerednecessary,areductioninthedoseofmidazolamshouldbeconsideredandthepatientmonitoredcloselyIn

concomitanttreatmentwithfluconazole(100mgdailyfor4days)andtriazolam(0.25mg)theAUCandhalf-lifeof

triazolamincreasedrespectively2.5and1.8times.Prolongedandenhancedeffectsfromtriazolamhavebeenobserved.

Thecombinationmayrequirereductioninthedoseoftriazolam.

Calciumchannelantagonists(CYP3A4-substrates):

Somedihydropyridinecalciumchannelantagonists,includingnifedipine,isradipine,nicardipine,amlodipine,and

felodipine,aremetabolisedviaCYP3A4.Literaturereportshavedocumentedsubstantialperipheraloedemaand/or

elevatedcalciumantagonistserumconcentrationsduringconcurrentuseofitraconazoleandfelodipine,isradipine,or

nifedipine.Aninteractionmightoccuralsowithfluconazole.

Carbamazepine(CYP3A4-substrate):

CarbamazepineismetabolizedbyisozymeCYP3A4.Fluconazoleisthuslikelytocausecarbamazepinetoxicity,

probablyduetoinhibitionofisozymeCYP3A4.

Celecoxib(CYP2C9-substrate):

Inconcomitanttreatmentwithfluconazole(200mgdaily)andcelecoxib(200mg),CmaxandAUCforcelecoxib

increasedby68%and134%respectively.

Halvingthedoseofcelecoxibisrecommendedincombinationtherapywithfluconazole.

Ciclosporin(CYP3A4-substrate):

Clinicallysignificantinteractionsbetweenciclosporinandfluconazolehavebeenobservedatdosesoffluconazoleof

200mgandhigher.Inconcomitanttreatmentwith200mgfluconazoledailyandciclosporin(2.7mg/kg/day),AUCfor

ciclosporinincreasedapproximately1.8timesandclearancewasreducedbyapproximately55%.Theplasma

concentrationofciclosporinshouldbemonitoredinconcomitanttreatmentwithfluconazole.

However,inanothermultipledosestudywith100mgdaily,fluconazoledidnotaffectciclosporinlevelsinpatients

withbonemarrowtransplants.Ciclosporinplasmaconcentrationmonitoringinpatientsreceivingfluconazoleis

recommended.

Didanosine:

Coadministrationofdidanosineandfluconazoleappearstobesafeandhaslittleeffectondidanosinepharmacokinetics

orefficacy.However,itisimportanttomonitorfluconazoleresponse.Itmaybeadvantageoustostaggerfluconazole

dosingtoatimepriortodidanosineadministration.

Halofantrin(CYP3A4-substrate):

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HMG-CoA-reductase-inhibitors(CYP2C9-orCYP3A4-substrate):

TheriskofmyopathyincreaseswhenfluconazoleisadministeredconcomitantlywithHMG-CoA-reductaseinhibitors

thataremetabolisedviaCYP3A4,e.g.atorvastatinandsimvastatin,orviaCYP2C9,suchasfluvastatin.Forfluvastatin

anindividualincreaseofupto200%intheareaunderthecurve(AUC)canoccurasaresultofinteractionbetween

fluvastatinandfluconazole.Anindividualpatientusingfluvastatin80mgdailymaybeexposedtoconsiderable

fluvastatinconcentrationsiftreatedwithhighdosesoffluconazole.Cautionshouldbeobservedwhereconcomitant

treatmentwithfluconazoleandHMG-CoA-reductase-inhibitorsisconsiderednecessary.

ThecombinationmayrequiredosereductionoftheHMG-CoAreductaseinhibitors.Thepatientshouldbeobserved

withregardtosignsofmyopathyorrhabdomyolysisandcreatinekinaseconcentrations(CK).TheHMG-CoA

treatmentshouldbestoppedifCKconcentrationsshowamarkedincreaseorifmyopathyorrhabdomyolysisis

diagnosedorsuspected.

Losartan(CYP2C9-substrate):

Fluconazoleinhibitstheconversionoflosartantoitsactivemetabolite(E-3174),whichisresponsibleforthemostof

theangiotensinIIreceptorantagonismthatoccurswithlosartantherapy.Concomitanttreatmentwithfluconazolemight

leadtoincreasedconcentrationsoflosartananddecreasedconcentrationsoftheactivemetabolite.Itisrecommended

thatpatientsreceivingthecombinationbemonitoredforcontinuedcontroloftheirhypertension.

Methadone:

Therearereportsofareinforcedimpactofmethadoneafterconcomitantadministrationoffluconazoleandmethadone.

ApharmacokineticsstudyshowedincreasedAUCofmethadone(35%onaverage).

Oralcontraceptiveagents(CYP3A4-substrate):

Inakineticstudywithcombinedoralcontraceptivesand50mgfluconazoledaily,hormonallevelswerenotaffected.

With200mgfluconazoledaily,AUCforethynylestradiolincreasedby40%andlevonorgestrelby24%.

Ina300mgdailyfluconazolestudy,theAUCsofethinylestradiolandnorethindronewereincreasedby24%and13%

respectively.

Thusmultipledoseuseoffluconazoleatthesedosesisunlikelytohaveaneffectontheefficacyofthecombinedoral

contraceptive.

Phenytoin(CYP2C9-substrate):

Concomitant,repeatedtreatmentwith200mgfluconazoleand250mgphenytoinintravenouslyincreasedAUC24for

phenytoinby75%andCminby128%.Incombinationtreatment,plasmaphenytoinconcentrationsshouldbe

monitoredandthedoseadjusted.

Prednisone(CYP3A4-substrate):

AlivertransplantrecipientreceivingprednisoneexperiencedanAddisoniancrisiswhenathree-monthcourseof

fluconazolewasdiscontinued.ThewithdrawaloffluconazolelikelycausedanincreaseinCYP3A4activity,leadingto

anincreaseinthedegradationofprednisone.Patientsreceivinglong-termtherapywithfluconazoleandprednisone

shouldbecloselymonitoredforsignsofadrenalinsufficiencywhenfluconazoleiswithdrawn.

Rifabutin(CYP3A4-substrate):

Inconcomitanttreatmentwithfluconazoleandrifabutin,theserumconcentrationsofrifabutinincreased.Uveitishas

beenreported.Patientsundergoingconcomitanttreatmentshouldbemonitoredclosely.

Sirolimusandtacrolimus(3A4-substrate):

Inconcomitantoraltreatmentwithfluconazoleandtacrolimus(0.15mg/kgtwicedaily)theplasmaconcentration

troughleveloftacrolimusincreased1.4and3.1timeswithadailyfluconazoledoseof100mgand200mg

respectively.Nephrotoxicityhasbeenreported.Eventhoughnointeractionstudieshavebeenperformedwith

fluconazoleandsirolimus,asimilarinteractioncanbeanticipated.Inconcomitanttreatmentwithfluconazoleand

tacrolimusorsirolimus,patientsshouldbecloselymonitoredandanadjustmentindoseconsidered.

Sulphonylureas(CYP2C9-substrate):

Fluconazolehasdisplayedprolongedhalf-lifeinserumforconcomitantlyadministeredsulphonylureas(glibencamide,

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Fluconazolemaybeadministeredtodiabeticstogetherwithsulphonylureas,buttheriskofhypoglycemiashouldbe

considered.Bloodglucoselevelsshouldbecloselymonitored.

Theophylline:

Inaplacebo-controlledinteractionstudy,theadministrationoffluconazole200mgfor14daysresultedinan18%

decreaseinthemeanplasmaclearanceoftheophylline.Patientswhoarereceivinghighdosesoftheophyllineorwho

areotherwiseatincreasedriskfortheophyllinetoxicityshouldbeobservedforsignsoftheophyllinetoxicitywhile

receivingfluconazole,andthetherapymodifiedappropriatelyifsignsoftoxicitydevelop.

Trimetrexate:

Fluconazolemayinhibitthemetabolismoftrimetrexate,leadingtoincreasedtrimetrexateplasmaconcentrations.Ifthe

combinationcannotbeavoided,trimetrexateserumlevelsandtoxicity(bonemarrowsuppression,renalandhepatic

dysfunction,andgastro-intestinalulceration)mustbecloselymonitored.

Xanthinebases,otherantiepilepticdrugsandisoniazid:

Follow-uptestsmustbecarriedoutwhenfluconazolisadministeredconcomitantlywithxanthinebases,other

antiepilepticdrugsandisoniazide.

Zidovudine:

Twokineticstudiesresultedinincreasedlevelsofzidovudinemostlikelycausedbythedecreasedconversionof

zidovudinetoitsmajormetabolite.OnestudydeterminedzidovudinelevelsinAIDSorARCpatientsbeforeand

followingfluconazole200mgdailyfor15days.TherewasasignificantincreaseinzidovudineAUC(20%).

Asecondrandomised,two-period,two-treatmentcrossoverstudyexaminedzidovudinelevelsinHIVinfectedpatients.

Ontwooccasions,21daysapart,patientsreceivedzidovudine200mgeveryeighthourseitherwithorwithout

fluconazole400mgdailyforsevendays.TheAUCofzidovudinesignificantlyincreased(74%)during

coadministrationwithfluconazole.Patientsreceivingthiscombinationshouldbemonitoredforthedevelopmentof

zidovudine-relatedadversereactions.

InteractionstudiesshowthatconcomitantadministrationofFluconazolewithfoodintake,cimetidine,antacid,or

followingtotalbodyirradiationinbonemarrowtransplantation,doesnotsignificantlyaffectFluconazoleabsorption.

Physiciansshouldbeawarethatdrug-druginteractionstudieswithothermedicationshavenotbeenconducted,butthat

suchinteractionsmayoccur.

4.6Pregnancyandlactation

Pregnancy

Datafromseveralhundredpregnantwomentreatedwithstandarddosesoffluconazole(lessthan200mg/day)asa

singleorrepeateddoseduringthefirsttrimesterofpregnancy,doesnotindicateundesirableeffectsonthefoetus.

Therearereportsonmultiplecongenitalabnormalities(includingbrachycephalia,earsdysplasia,giantanterior

fontanelle,femoralbowingandradio-humeralsynostosis)inchildrenwhosemothersweretreatedforcoccidiomycosis

withhighdosefluconazole(400-800mg/day),for3monthsorlonger.Therelationbetweentheuseoffluconazoleand

theseeffectsisunclear.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3),butthepotentialriskinhumansisunknown.

Fluconazoleinstandarddosesandshort-termtreatmentshouldnotbeusedduringpregnancyunlessclearlynecessary.

Fluconazoleinhighdosesorinprolongedregimensshouldnotbeusedduringpregnancyexceptforlifethreatening

infections.

Lactation

Fluconazolepassesintobreastmilkinconcentrationslowerthanthoseinplasma.

Breast-feedingmaybemaintainedafterasingledoseoffluconazoleof200mgorless.Breast-feedingisnot

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4.7Effectsonabilitytodriveandusemachines

Fluconazole2mg/mlSolutionforInfusionhasnegligibleinfluenceontheabilitytodriveandusemachines.However,

itshouldbeborneinmindthatdizzinessandseizuresmayoccur.

4.8Undesirableeffects

Side-effectsassociatedwithfluconazoleobservedinclinicaltrialsandpost-marketingstudiesarelistedbelow.

FrequenciesaredefinedasVerycommon(1/10);Common(1/100to<1/10);Uncommon(1/1,000to<1/100);Rare

(1/10,000to<1/1,000);Veryrare(<1/10,000),notknown(cannotbeestimatedfromtheavailabledata).Withineach

frequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

System

Organ

Classes Very

Common

>1/10 Common

>1/100,

<1/10 Un-common

>1/1,000,

<1/100 Rare>1/10,000,

<1/1,000 VeryRare

<1/10,000 Not

Known

(cannotbe

estimated

fromthe

available

data)

Bloodand

lymphatic

system

disorders Anaemia Agranulocytosis,

Luukopenia,

neutropenia,

thrombocyto-

penia

Immune

System

Disorders Anaphylactic

reactions,itching Angio-

edema

face

oedema Urticaria

Psychiatric

disorders Insomnia,

Somnol-

ence

Nervous

System

disorders Headache Convulsions,

Seizures,

Dizziness,

paresthesia,

taste

perversion,

tremor,

vertigo

Metabolism

nutrition

disorders Hypercholesterolemia,

hypertriglycer-

idemia,

hypokalaemia

Cardiac

Disorders Ventricular

arrhythmia(QT

prolongation,

Torsadede

Pointes)

Gastrointestinal

Disorders Nausea,

Vomiting,

abdominal

painand

diarrhoea Dyspepsia,

flatulence,

anorexia,

constipa-

tion,dry

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AdverseclinicaleventswerereportedmorefrequentlyinHIVinfectedpatients(21%)thaninnon-HIVinfected

patients(13%).However,thepatternsofadverseeventsinHIVinfectedandnon-HIVinfectedpatientsweresimilar.

Paediatricpatients:

Adverseeventshavebeenreportedwithagreaterfrequencyinchildrenascomparedtoallpatients.Moreover,

irritabilityandanaemiahavebeenreportedasspecificforchildren.

4.9Overdose

Inmostpatientsoverdosingresultsingastrointestinalcomplaintsandskinreactions(itch,rash,etc.).Therehasbeena

reportofanoverdosewithFluconazolewherea42yearoldHIVinfectedpatientdevelopedhallucinationsand

exhibitedparanoidbehaviorafterreportedlyingesting8,200mgofFluconazolewithoutmedicalsupervision.The

patientwasadmittedtothehospital,andhissymptomsresolvedwithin48hours.

Intheeventofoverdosage,supportivemeasuresandsymptomatictreatment,andgastriclavageifnecessary,maybe

Renaland

Urinary

disorders Changesin

renal

function

tests

Hepatobi-

liary

disorders Elevated

alkaline

phosphate-

aseASAT

andALAT Cholestasis,

Hepato-

cellular

damage,

Jaundice,

clinically

significant

increaseof

total

Hepatictoxicity,

hepaticnecrosis,

hepaticfailure,

hepatitis,

heptocellular

necrosis

Skinand

Subcutaneous

tissue

disorders (maculopapular

-erythema)

rash Urticaria,

pruritis,

sweating Alopecia,

exfoliativeskin

disorders

(Stevens-Johnson

syndrome) Exfoliative

skin

disorders

(toxic

epidermal

necroly-sis

orLyell

syndrome Urticaria,

acute

generalized

exanthematous

pustulosis,

(fixeddrug

eruption

Musculo-

skeleta1

connective

tissue

disorders Myalgia

General

disorders

administration

site

conditions Fatigue,

malaise,

asthenia,

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AsFluconazoleislargelyexcretedintheurine,forceddiuresiswouldprobablyincreasetheeliminationrate.Athree

hourhaemodialysissessiondecreasesplasmalevelsbyapproximately50%.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Messeretal,2006:SENTRYAntimicrobialSurveillanceProgram(2003)

RexJH,2000:IDSAPracticeGuidelinesfortheTreatmentofCandidiasis]

TheantifungalspectrumoffluconazoleincludesanumberofpathogensincludingCandidaalbicans,andnon-Candida

albicansspecies,Cryptococcusspeciesandotherdermatophytes.

Theprevalenceofacquiredresistancemayvaryforsomespeciesgeographicallyandwithtime.Thereforeitisdesirable

toobtaininformationonlocalresistancepatterns,particularlyinthelightoftheadequatetreatmentofsevereinfections.

InterpretivebreakpointsforCandidaspecies:

TherearereportsofresistantisolatesofCandidaalbicansarisinginAIDSpatientswhohavereceivedlong-term

treatmentwithfluconazole.

Cryptococcusneoformansispredominantlysensitivetofluconazole.StrainswithanMICvalueofgreaterthan32

microgrammespermlareconsideredresistant.

InfectionsresultingfromAspergillusspecies,ZygomycetesincludingMucorandRhizopus,Microsporumand

Trichophytonspeciesshouldnotbetreatedwithfluconazolesincefluconazolehaslittleornoactivityagainstthese

Classification MIC

(microgrammes/ml) Species Datasource

Sensitive(S) NMT8 C.albicans,

C.parapsilosis,

C.lusitaniae

C.kefyr,

C.dubliniensis

C.pelliculosa PfallerMAetal,2006

MesserSAetal,2006

RexJH,2000

Susceptibility

dependsonthe

dose(S-DD) 16-32 C.glabrata(approx17%R)

C.guillermondii(approx

10%R)

C.famata(approx12%R)

C.tropicalis(approx4%R) PfallerMAetal,2006

MesserSAetal,2006

RexJH,2000

Resistant(R) Greaterthan32 C.krusei,

C.rugosa,

C.inconspicua,

C.norvegensis,

C.lipolytica,

C.zeylanoides. PfallerMAetal,2006

MesserSAetal,2006

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5.2Pharmacokineticproperties

Absorption:

Thepharmacokineticpropertiesoffluconazolearesimilarfollowingadministrationbytheintravenousororalroute.

Fluconazoleiswellabsorbedafteroralintake.Theabsolutebioavailabilityisabove90%.Oralabsorptionisnot

affectedbyconcomitantfoodintake.Themaximumfastingplasmaconcentrationisreached0.5-1.5hoursafterdose

intake.90%ofthesteady-statelevelisreached4-5daysafterdosingoncedaily.

Plasmaconcentrationisproportionaltothedose.Afteradministrationof200mgoffluconazole,C

isaround4.6

mg/landplasmaconcentrationsatsteady-stateafter15daysarearound10mg/l.Afteradministrationof400mgof

fluconazole,C

isaround9mg/landplasmaconcentrationsatsteady-stateafter15daysarearound18mg/l.Intake

ofadoubledoseonDay1resultsinplasmaconcentrationsofapproximately90%ofsteady-stateonDay2.

Distribution:

Theapparentvolumeofdistributionoffluconazolecorrespondstototalbodywater.Plasmaproteinbindingislow(11-

12%).

Fluconazoleachievesgoodpenetrationinallbodyfluidsstudied.Thelevelsoffluconazoleinsalivaandsputumare

similartoplasmalevels.InpatientswithfungalmeningitisthefluconazolelevelsintheCSFareabout80%ofthe

correspondingplasmalevels.

Inthestratumcorneum,epidermis-dermisandexocrinesweathigherconcentrationsoffluconazolearereached

comparedwiththoseinserum.Fluconazoleaccumulatesinthestratumcorneum.Forexample,atadoseof150mg

onceweekly,theconcentrationoffluconazoleinstratumcorneumaftertwodoseswas23.3microgrammes/gandseven

daysaftertheendoftreatmentitwasstill7.1microgrammes/g.

Biotransformation:

Breakdownoffluconazoleismodest.Only11%ofaradioactivedoseisexcretedintheurineasmetabolites.

Elimination:

Themajorrouteofexcretionisrenal.Approximately80%ofthedoseexcretedintheurineinthenon-metabolised

form.Fluconazoleclearanceisproportionaltocreatinineclearance.Thereisnoevidenceofcirculatingmetabolites.

Theaverageplasmahalf-lifeisabout30hours.Thelongplasmahalf-lifeprovidesthebasisfortreatmentwithsingle

dailydosesinallindications.

Pharmacokineticsinchildren:

Childreneliminatefluconazolemorerapidlythanadultsdo.

Inchildren(aftertheneonatalphase)andadolescentsof5-15yearsofagetheplasmahalf-lifeisbetween15.2-17.6.

Prematurebabieshaveashorterplasmahalf-life(about70hours)andalargervolumeofdistribution(1.2-2.3litres/kg)

thanbabiesbornatfullterm.Duringthefirstweekafterbirthandinthecourseoftheneonatalperiod,plasma

Fluconazoleclearancerises(andtheplasmahalf-lifefalls).

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5.3Preclinicalsafetydata

Preclinicaldatafromconventionalstudiesonrepeat-dose/generaltoxicity,genotoxicityorcarcinogenicityindicateno

specialhazardforhumansnotalreadyconsideredinothersectionsoftheSPC.

Inreproductiontoxicitystudiesinratanincreasedincidenceofhydronephrosisandextensionofrenalpelviswas

reportedandembryonallethalitywasincreased.Anincreaseinanatomicalvariationsanddelayedossificationwas

notedaswellasprolongeddeliveryanddystocia.Inreproductiontoxicitystudiesinrabbitsabortionswererecorded.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Waterforinjections,

Sodiumchloride,

Hydrochloricacid(forpHadjustment),

Sodiumhydroxide(forpHadjustment).

6.2Incompatibilities

Thismedicinalproductmustnotbemixedwithothermedicinalproductsexceptthosementionedinsection6.6.

6.3ShelfLife

5years(25ml,50ml,100mland200ml)

Afterfirstopening:

Fromthemicrobiologicalpointofview,unlessthemethodofopeningprecludestheriskofmicrobialcontamination,

theproductshouldbeusedimmediately.

Ifnotusedimmediately,in-usestoragetimesandconditionsaretheresponsibilityoftheuser.

6.4Specialprecautionsforstorage

Donotrefrigerateorfreeze.

6.5Natureandcontentsofcontainer

Cleartype1glassbottle,closedwithabromobutylrubberstopperandaluminumcap.

Packsize:

1x25ml,1x50ml,1x100mland1x200ml.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Forsingleuseonly.Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocal

requirements.

Theproductshouldbeinspectedvisuallyforparticlesanddiscolorationpriortoadministration.Onlyclearand

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Fluconazole2mg/mlsolutionforinfusioniscompatiblewiththefollowinginfusionfluids:

a.glucose20%whenavailable

b.Ringer’ssolutionwhenavailable

c.Hartmann’ssolutionwhenavailable

d.Potassiumchlorideinglucosewhenavailable

e.sodiumcarbonate4.2%whenavailable

f.0.9%sodiumchloride(isotonicsaline)whenavailable

Compatibilityhasonlybeenshownforshortduration(10minutes).

DilutionofFluconazole2mg/mlsolutionforinfusionisnotrequiredpriortoadministration.Ifnecessary,Fluconazole

andthesolutionsmentionedaboveshouldbeadministeredthroughseparateinfusioncontainers.Thetworeservoirs

shouldbeconnectedusinga"Y"connection.Thetwosolutionsarethenmixedinasinglelineandtheadministrationis

performed.Theabovemethodisrecommendedinordertoavoideffectssuchasthe“layeringeffect”ifthetwo

solutionsweremixedinoneinfusioncontainerforthetotalperiodoftheadministration.

7MARKETINGAUTHORISATIONHOLDER

NicheGenericsLimited

1TheCamCentre

WilburyWay

Hitchin

Herts

SG40TW

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1063/34/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

1stFebruary2008

10DATEOFREVISIONOFTHETEXT

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