FLUCONAZOLE REDIBAG

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0167/127/001
  • Authorization date:
  • 07-09-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FluconazoleRedibag2mg/mlSolutionforInfusion

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1mlofSolutionforInfusioncontains2mgofFluconazole.

50mlSolutionforInfusioncontains100mgFluconazole

100mlSolutionforInfusioncontains200mgFluconazole

200mlSolutionforInfusioncontains400mgFluconazole

Excipients:

1mlcontains9mgofsodiumchloride.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinfusion.

Clear,colourlesssolutionandessentiallyfreefromparticles.

Thesolutionisiso-osmotic.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Adults

TreatmentofmycosescausedbyCandida,Cryptococciandothersusceptibleyeasts,inparticular:

Systemiccandidiasis(includingdisseminateddeepinfectionsandperitonitis)

Severemucosalcandidiasis(includingoropharyngealcandidiasis,oesophagealcandidiasisandnon-invasive

bronchopulmonarycandidiasis),whereoraltreatmentisnotpossible.

Cryptococcalmeningitisinadults

ProphylaxisagainstdeepCandidainfections(especiallyCandidaalbicans)inpatientswithneutropeniaduetobone

marrowtransplantation.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantifungalagents.Beforeinitiating

treatmentsamplesshouldbetakenformicrobiologicalanalysisandthesuitabilityofthetherapyshouldsubsequently

beconfirmed(seesections4.2Posologyandmethodofadministrationand5.1Pharmacodynamicproperties).

Insomepatientswithseverecryptococcalmeningitisthemycologicalresponseduringfluconazoletreatmentmaybe

slowercomparedtoothertreatments(seesection4.4).

Childrenandadolescents

TreatmentofmycosescausedbyCandidaandothersusceptibleyeasts,inparticular:

Systemiccandidiasis(includingdisseminateddeepinfectionsandperitonitis)

Severemucosalcandidiasis(includingoropharyngealcandidiasis,oesophagealcandidiasisandnon-invasive

bronchopulmonarycandidiasis),whereoraltreatmentisnotpossible.

Considerationshouldbegiventoofficialguidanceontheappropriateuseofantifungalagents.Beforeinitiating

treatmentsamplesshouldbetakenformicrobiologicalanalysisandthesuitabilityofthetherapyshouldsubsequently

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4.2Posologyandmethodofadministration

Treatmentwithfluconazoleshouldbeinitiatedbyaphysicianexperiencedinthemanagementofinvasivefungalinfections.The

doseisdependentonthetypeandseverityoftheinfection.Thetreatmentofinfectionsrequiringmultiple-dosingmustbe

continueduntilclinicalparametersorlaboratoryresultsshowthattheactiveinfectionhasdeclined.Aninsufficienttreatment

periodmayleadtorecurrenceoftheactiveinfection.

Fluconazoleisalsoavailablefororaltherapy.Thepatientshouldbeswitchedfromdosingbytheintravenousrouteto

dosingbytheoralrouteassoonaspossible.Itisnotnecessarytochangethedailydoseoffluconazolewhenchanging

therouteofadministrationfromintravenoustooral.

ADULTS

PleaserefertoTable1forspecificdosagerecommendations.

ELDERLY:

Thenormaladultdoseshouldbegivenifthereisnoevidenceofrenalimpairment.

PleaserefertoTable1.

Table1-GuidanceOnTheDoseToAdministerForAnAdultTreatedByTheIntravenousRoute

Treatmentwithfluconazoleshouldbeinitiatedbyaphysicianexperiencedinthemanagementofinvasivefungalinfections.

Indication Initialdailydose

(mg) Subsequentdailydose

(mg) Recommendedduration

oftreatment AdditionalGuidance

Systemic

candidiasis:

Candidaemia,

disseminated

candidiasisand

otherformsof

invasive

candidal

infection 400-800 200–400 Dependentupon

clinicalresponse Thedosechosenmust

takeintoaccount

localresistance

patternsto

fluconazole(see

section5.1

Pharmacodynamic

properties).Where

thesensitivityofthe

pathogenhasnotyet

beenestablished,the

higherdoseshould

initiallybe

considered.

Inmostcasesa

loadingdoseof

800mgonthefirst

dayfollowedby

400mgdaily

thereaftermaybe

preferable.

Candiduria 100 100 14-30days

Severe

Mucosal

candidiasis: Useonlywhenoral

dosingisnotpossible.

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PAEDIATRICUSE

FluconazoleRedibag2mg/mlSolutionforInfusionshouldnotbeusedinchildrenandadolescentsundertheageof

16yearsunlessthereisnotherapeuticalternative,becauseefficacyandsafetyhavenotbeensufficientlydemonstrated.

PleaserefertoTable2forspecificdosagerecommendations.

Aswithsimilarinfectionsinadults,thedurationoftreatmentisbasedupontheclinicalandmycologicalresponse.Note

candidiasis dosehigherthan

100mgmaybe

requiredand

treatmentcanbe

prolonged.

Othermucosal

candidal

infections

(exceptgenital

candidiasis) 100 100 14-30days Thedurationof

maintenance

treatmentofAIDS

patientsshouldbe

balancedagainstthe

increasedriskof

resistanceto

fluconazole.

Treatmentof

Cryptococcal

meningitis:

Initialtherapy

Preventionof

relapsein

AIDSpatients 400 200-400

Typical6-8weeks

Seeadditionalguidance Durationoftreatment

willdependupon

clinicaland

mycological

response.

Thedurationof

maintenance

treatmentofAIDS

patientsshouldbe

balancedagainstthe

increasedriskof

resistanceto

fluconazole.(see

section5.1

Pharmacodynamic

properties).InAIDS

patientsitmaybe

necessaryto

administerthedrug

forlife.

Prophylaxis

againstdeep

Candida

infections:

Inpatients

with

neutropenia

duetobone

marrow

SeeadditionalguidanceFluconazole

administrationshould

startseveraldays

beforetheanticipated

onsetofneutropenia,

andcontinuefor

sevendaysafterthe

neutrophilcountrises

above

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Therearefewpharmacokineticdatatosupportthisposologyinnewbornbabies(seeSection5.2Pharmacokinetic

Properties).

Table2-GuidanceOnTheDoseToAdministerInPaediatricsTreated

ByTheIntravenousRoute

Agerange Indication(s) Recommended

dosage AdditionalGuidance

Neonates Note: Therearefewpharmacokineticdatatosupportthe

posologiesinnewbornbabies(seesection5.2Pharmacokinetic

Properties).

2weeksor

less Allindicationslisted

below 6-12mg/kgevery

72hours Amaximumdoseof

12mg/kgevery72hours

shouldnotbeexceededin

childreninthefirsttwo

weeksoflife.

3-4weeks Allindicationslisted

below 6-12mg/kgevery

48hours. Forchildrenbetween3

and4weeksoflife,

12mg/kgevery48hours

shouldnotbeexceeded.

Childrenaged4

weeksand

above Note:Forchildrenagedfiveyearsorlessthemaximumdailydose

shouldnotexceed400mgperday.

Systemic

candidiasis 6-12mg/kg/day.

Mucosal

candidiasis 3mg/kg/day. Onthefirstdayaloading

doseof6mg/kgmaybe

giveninordertomore

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PATIENTS(ADULTANDPAEDIATRIC)WITHIMPAIREDRENALFUNCTION:

PleaserefertoTables1and3.

Fluconazoleismainlyexcretedunchangedintheurine.

Nochangeinthesingledosetreatmentisrequired(Table1)

Forpatientswithimpairedrenalfunctionthetreatmentwithaloadingdoseof100-400mgisgiveninitially,afterwhich

thedailydose(dependingonthetherapeuticindication)shouldbebasedupontheinformationinTable3.

Thepharmacokineticsoffluconazolehasnotbeenstudiedinchildrenwithrenalinsufficiency.

Table3–DoseModificationsRequiredFollowingtheInitialDose

ForPatientsWithImpairedRenalFunction

(Furtherdosageadjustmentsmaybeneededdependinguponclinicalcondition)

INTERACTIONSREQUIRINGDOSEADJUSTMENTS

ModificationstothedosingschedulesprovidedinTables1to3mayberequiredwhereconcomitantuseofeither

rifampicinorhydrochlorothiazideisproposed.

Furtherdetailsareprovidedinsection4.5Interactionwithothermedicinalproductsandotherformsofinteraction.

MethodofAdministration

Forintravenoususeasaninfusiononly

Fluconazoleisdissolvedinisotonicsalinesolution,withanelectrolytecontentofNa +

154mmolandCl -

154mmolper

1000ml,andmaybeadministereddirectlyasaninfusion.SeeSection4.4Specialwarningsandprecautionsforuse.

CreatinineClearance

(ml/minute) Percentofrecommendeddose

>50 Normaldoseregime(100%)

11-50 Halfnormaldailydose(50%)

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Forchildren,itisrecommendedthattheinfusionrateshouldnotexceed10mg(5ml)/minute.

Forprematureinfantstheinfusiontimeshouldbenotlessthan15minutes.

Inpatientsrequiringsodiumorfluidrestriction,therateofadministrationshouldbetakenintoconsiderationbecause

fluconazoleconsistsofasaltsolution.Insuchcasestheinfusionshouldbegivenoveralongerperiod.

4.3Contraindications

Knownhypersensitivitytofluconazole,otherrelatedazolederivatives,oranyoftheotherexcipients.

FluconazoleshouldnotbeusedconcomitantlywithanydrugswhichareknowntoprolongtheQTintervalandare

metabolisedbyCYP3A4,suchascisapride,astemizole,terfenadine,pimozideandquinidine

Seealsosections4.4and4.5SpecialwarningsandprecautionsforuseandInteractionwithothermedicinalproducts

andotherformsofinteraction.

4.4Specialwarningsandprecautionsforuse

Thereissomeevidencethatinsomepatientswithcryptococcalmeningitisthemycologicalresponseduringfluconazole

treatmentmaybeslowercomparedtotreatmentwithamphotericineBincombinationwithflucytosine.Thisshouldbe

takenintoaccountforthetreatmentchoiceinpatientswithseverecryptococcalmeningitis.

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,abnormalitiesin

haematological,hepatic,renalandotherbiochemicalfunctiontestresultshavebeenobservedduringtreatmentwith

fluconazole,buttheclinicalsignificanceandrelationshiptotreatmentisuncertain.

Becauseacausalrelationshipwithfluconazolecannotbeexcluded,patientswhodevelopabnormalliverfunctiontests

duringfluconazoletherapyshouldbemonitoredforsignsofthedevelopmentofmoreserioushepaticinjury.

Fluconazoleshouldbediscontinuedifclinicalsignsorsymptomsconsistentwithliverdiseasedevelopduring

treatment.

Severehepatictoxicity,includingdeath,hasbeenreportedinrarecases,primarilyinpatientssufferingfromserious

underlyingdiseases.Noobviousrelationshipbetweenhepatotoxicityandtotaldailydoseoffluconazole,durationof

therapy,genderorageofthepatienthasbeenobserved.Patientswhodevelopabnormallivertestvaluesorsignificant

increasesoforiginallyabnormallevelsduringtreatmentmustbemonitoredclosely.Thebenefitsoftreatmentshould

beevaluatedagainsttherisksofdevelopingseriousliverdamageiftherapyiscontinuedinpatientswhoseliverenzyme

valuesriseduringfluconazoletreatment.Inmostcases,livertoxicityhasbeenreversiblefollowingdiscontinuationof

thetreatment.Fluconazoleshouldbeadministeredwithcaretopatientswithliverinsufficiency.

Thedoseoffluconazolemustbereducedwhenpatient’screatinineclearanceisbelow50ml/min(seesection4.2

Posologyandmethodofadministration).

SomeazoleshavebeenassociatedwithQT-intervalprolongationleadingtoseriouscardiacarrhythmia.Rarecasesof

TorsadesdePointeshavebeenreportedduringfluconazoletreatment.

AlthoughtheassociationoffluconazoleandQT-prolongationhasnotbeenformallyestablished,fluconazoleshouldbe

usedwithcautioninpatientswithpotentiallyproarrhythmicconditionssuchas:

CongenitalordocumentedacquiredQTprolongation,

Cardiomyopathy,inparticularwhenheartfailureispresent,

Clinicallysignificant(includingsinus)bradycardia,

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ConcomitantmedicationwithClassIAorClassIIIantiarrythmicagentsknowntoprolongtheQTinterval.Thepatient

mustbecloselymonitored,includingECGmonitoring(seesections4.3and4.5ContraindicationsandInteractionwith

othermedicinalproductsandotherformsofinteraction),

ConcomitantmedicationnotmetabolisedbyCYP3A4butknowntoprolongtheQTinterval(seesection4.5Interaction

withothermedicalproductsandotherformsofinteraction).

HalofantrinehasbeenshowntoprolongQTcattherecommendedtherapeuticdoseandisasubstrateofCYP3A4(see

section4.5Interactionwithothermedicinalproductsandotherformsofinteraction.)

Electrolytedisturbancessuchashypokalaemia,hypomagnesaemiaandhypocalcaemiashouldbecorrectedpriorto

initiationoffluconazoletreatment.

Patientshaverarelydevelopedexfoliativecutaneousreactions,suchasStevens-Johnsonsyndromeandtoxicepidermal

necrolysisduringtreatmentwithfluconazole.AIDSpatientsaremorepronetothedevelopmentofseverecutaneous

reactionstomanymedicinalproducts.Ifpatientswithinvasivesystemicfungalinfectionsdeveloprashes,theyshould

bemonitoredcloselyandfluconazolediscontinuedifbullouslesionsorerythemamultiformedevelop.

Anaphylaxisandanaphylacticreactions,aswithotherazoleagents,haveinrarecasesbeenreported(Seesection4.8

Undesirableeffects).

Inwomenofchildbearingpotentialappropriatecontraceptivemeasureshouldbeconsideredincaseoflong-term

treatmentisindicated(seesection4.6PregnancyandLactation).

Thefollowingsodiumconcentrationsmustbetakenintoaccountwithpersonsonasodium-controlled(low-sodium)or

liquid-restricteddiet:

50mlcontains7.7mmol(177mg)sodium.

100mlcontains15.4mmol(354mg)sodium.

200mlcontains30.8mmol(709mg)sodium.

Seealsosection4.5Interactionswithothermedicinalproductsandotherformsofinteraction.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionshavebeenreportedfollowingtheadministrationoffluconazolewith:

Thefollowingconcomitantmedicationsarespecificallycontraindicated(Seealsosection4.3Contraindications):

Astemizole(CYP3A4substrate):AdministrationoffluconazolewithastemizolemayleadtoprolongationofQT

interval,severeventriculararrhythmia,torsadesdepointesandcardiacarrest(seesection4.3Contraindications).

Cisapride(CYP3A4substrate):TherehavebeenreportsofcardiaccasesincludingTorsadesdepointesinpatients

receivingfluconazoleconcomitantlywithcisapride.Concomitanttreatmentwithfluconazoleandcisaprideis

contraindicated.

Terfenadine(with400mgFluconazoledoseorhigherCYP3A4substrate):Duetotheoccurrenceofseriouscardiac

dysrhythmiassecondarilytoprolongationoftheQTc-intervalinpatientsontreatmentwithazoleproducts

concomitantlywithterfenadine,interactionstudieshavebeenperformed.Onestudywith200mgfluconazoledailydid

notshowanyprolongationoftheQTC-interval.

Anotherstudywith400mgand800mgfluconazoledailyshowedthatfluconazole400mgormoredailysignificantly

increasestheplasmalevelterfenadine,ifthetwomedicinalproductsaretakenconcomitantly.Concomitanttreatment

withterfenadineandfluconazoledosesof400mgormoreiscontra-indicated.Atfluconazoledosesbelow400mg,the

patientshouldbecloselymonitored.

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Hydrochlorothiazide:Inapharmacokineticinteractionstudywithhealthyvolunteerswhoconcomitantlyreceived

fluconazoleandmultipledosesofhydrochlorothiazidetheplasmaconcentrationsofthefluconazoleincreasedby40%.

Eventhoughaneffectofthissizeshouldnotgiverisetoanyneedtochangethefluconazoledoseinpatientswhoare

concomitantlytreatedwithdiuretics,theprescribershouldbeawareofthis.

Rifampicin(CYP450inducer):Concomitantintakeoffluconazoleandrifampicinresultedina25%reductionofAUC

and20%shorterhalf-lifeoffluconazole.Whereconcomitantuseofrifampicinisintended,anappropriatemodification

(increase)inthefluconazoledoseshouldbeconsidered.

Effectsthatfluconazolemayhaveonthemetabolismofothermedicinalproducts

FluconazoleisapotentinhibitorofcytochromeP450(CYP)2C9isoenzymeandamoderateinhibitorofCYP3A4.In

additiontotheobserved/documentedinteractionsmentionedbelow,thereisariskofelevatedplasmaconcentrationsof

otherdrugsmetabolisedbyCYP2C9orCYP3A4(e.g.secalealkaloidsandquinidine)iftheyareco-administeredwith

Fluconazole.Thesecombinationsshouldthereforealwaysbegivenwithcaution,andthepatientmustbemonitored

closely.TheinhibitoryeffectofFluconazoleonenzymesmaypersist4-5daysaftertheendofFluconazoletreatment,

owingtothelonghalf-lifeofFluconazole.

Alfentanil(CYP3A4substrate):Intravenousco-administrationoffluconazole400mgandalfentanil

20microgrammes/kginhealthyvolunteersraisedthealfentanilAUC

approximatelytwo-foldandreducedthe

clearanceby55%,probablythroughinhibitionofCYP3A4.Thesecombinationsmayrequireadjustmentofthedose.

Amitriptyline:Severalcasereportshavedescribedthedevelopmentofincreasedamitriptylineconcentrationsandsigns

oftricyclictoxicitywhenamitriptylinewasusedincombinationwithfluconazole.Coadministrationwithnortriptyline,

theactivemetaboliteofamitriptyline,hasbeenreportedtoresultinincreasednortriptylinelevels.Duetotheriskof

amitriptylinetoxicity,considerationshouldbegiventomonitoringamitryptylinelevelsandmakingdoseadjustments

asmaybenecessary.

Anticoagulants(CYP2C9substrate):Concomitantintakeoffluconazoleduringwarfarintreatmenthasbeenfoundto

prolongtheprothrombintimetoasmuchastwicetheoriginalvalue.Thisisprobablyduetoinhibitionofthewarfarin

metabolismviaCYP2C9.Prothrombintimemustbemonitoredcloselyinpatientsreceivingtreatmentwithcoumarin

derivatives.

Antiretroviraldrugs(CYP3A4substrate):Therearereportsofincreasedserumlevelsfollowingconcurrent

administrationoffluconazolewithantiretroviralagentssuchanevirapine.

Benzodiazepines(CYP3A4substrate):Concomitantintakeoffluconazole400mgandmidazolam7.5mgorally

increasedthemidazolamAUCandhalf-life3.7-foldand2.2-foldrespectively.Fluconazole100mggivenconcurrently

withtriazolam0.25mgorallyincreasesthetriazolamAUCandhalf-life2.5-foldand1.8-foldrespectively.Potentiated

andprolongedeffectsoftriazolamhavebeenobservedwithconcomitanttreatmentwithfluconazole.Ifitisnecessary

totreatpatientswithabenzodiazepineconcomitantlywithfluconazole,areductionofthebenzodiazepinedoseshould

beconsidered,andthepatientshouldbecloselymonitored.

Calciumchannelantagonists(CYP3A4substrate):Somedihydropyridinecalciumantagonistssuchasnifedipine,

isradipine,nicardipine,amlodipineandfelodipinearemetabolisedviaCYP3A4.Therearereportsofextensive

peripheraloedema,vertigo,hypotension,headache,rednessofthefaceand/orelevatedserumcalciumantagonist

concentrationsarisingfollowingonco-administrationoftheazoleitraconazolewithfelodipine,isradipineornifedipine.

Asimilarinteractionwithfluconazoleisthereforepossible.

Carbamazepine(CYP3A4substrate):Therearereportsofincreasedserumcarbamazepinelevelsfollowingconcurrent

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Celecoxib(CYP2C9substrate):Inaclinicalstudyfluconazole200mgdailyadministeredwithcelecoxib200mgraised

thecelecoxibC

andAUCby68%and134%respectively.Thisinteractionisprobablyduetoinhibitionofthe

cytochromeP4502C9metabolismofcelecoxib.A50%reductionofthecelecoxibdoseisrecommendedinpatients

receivingconcomitantfluconazole.

Ciclosporin(CYP3A4substrate):Clinicallysignificantinteractionswithciclosporinhavebeenshownatfluconazole

dosesof200mgandabove.Inapharmacokineticstudywithrenaltransplantpatientsreceivingfluconazole200mg

dailyandciclosporin2.7mg/kg/day,therewasa1.8-foldincreaseinciclosporinAUCanda55%decreasein

clearance.Ciclosporinplasmamonitoringisrecommendedinpatientsreceivingfluconazoleisrecommended.

Didanosine:Co-administrationofdidanosineandfluconazoledoesnotappeartoaffectthepharmacokineticsandaction

ofdidanosine.ItmaybehelpfultoretimetheadministrationofFluconazolesothatitprecedesadministrationof

didanosine.

Halofantrin(CYP3A4substrate):DrugsthatinhibitCYP3A4leadtoaninhibitionofhalofantrinmetabolismandcan

causeaprolongationoftheQTinterval.Theconcomitantuseoffluconazoleandhalofantrineisnotrecommended.

HMG-CoAreductaseinhibitors(CYP2C9orCYP3A4substrate):Theriskofmyopathyisincreasediffluconazoleis

givenconcomitantlywithHMG-CoAreductaseinhibitorsthataremetabolisedviaCYP3A4,suchasatorvastatinor

simvastatin,orviaCYP2C9,suchasfluvastatin.Forfluvastatinanindividualincreaseofupto200%intheareaunder

thecurve(AUC)canoccurasaresultofinteractionbetweenfluvastatinandfluconazole.Cautionisnecessaryifco-

administrationoffluconazoleandHMG-CoAreductaseinhibitorsisconsiderednecessary.Thecombinationmay

necessitateareductioninHMG-CoAreductaseinhibitordose.Patientsshouldbemonitoredforsignsandsymptomsof

myopathyorrhabdomyolysisandcreatinekinaseconcentrations(CK).TheHMG-CoAtreatmentshouldbestoppedif

CKconcentrationsshowamarkedincreaseorifmyopathyorrhabdomyolysisisdiagnosedorsuspected.

Losartan(CYP2C9substrate):Fluconazoleinhibitstheconversionoflosartantoitsactivemetabolite(E-3174),which

isresponsibleforalargepartoftheangiotensinIIreceptorantagonismthatoccursonlosartantreatment.Concomitant

fluconazoletreatmentmayleadtoincreasedlosartanconcentrationsandreducedconcentrationsoftheactive

metabolite.Ongoingmonitoringforhypertensionisadvisableinpatientsreceivingthecombination.

Methadone(CYP3A4substrate):Therehavebeenreportsofanenhancedeffectofmethadonefollowingconcurrent

administrationoffluconazoleandmethadone.Onepharmacokineticstudyshowedameanincreaseof35%intheAUC

ofmethadone.

Oralcontraceptives:Twopharmacokineticstudieshavebeencarriedoutwithcombinedoralcontraceptivesand

repeateddosesoffluconazole.Therewerenorelevanteffectsoneitherhormonelevelwhen50mgfluconazolewas

administered.Fluconazolegiven200mgdailyraisedtheAUCofethinylestradiolandlevonorgestrelby40%and24%

respectively.Multipledoseuseoffluconazoleisthereforeunlikelytoinfluencetheeffectofthecombinedoral

contraceptive.

Phenytoin(CYP2C9substrate):Concomitantadministrationoffluconazoleandphenytoinmayincreasethelevelsof

phenytointoaclinicallysignificantdegree.Intakeof200mgfluconazoleconcomitantlywithphenytoin250mgIV

increasedthephenytoinAUCby75%andC

by128%.Ifitisnecessarytoadministerbothdrugsconcomitantly,the

phenytoinconcentrationmustbemonitoredandthedoseadjustedtomaintaintherapeuticlevelsandavoidtoxic

concentration

Prednisone(CYP3A4substrate):AlivertransplantrecipientreceivingprednisoneexperiencedanAddisoniancrisis

whenathree-monthcourseoffluconazolewasdiscontinued.Thewithdrawaloffluconazolelikelycausedanincrease

inCYP3A4activity,leadingtoanincreaseinthedegradationofprednisone.Patientsreceivinglong-termtherapywith

fluconazoleandprednisoneshouldbecloselymonitoredforsignsofadrenalinsufficiencywhenfluconazoleis

withdrawn.

Rifabutin(CYP3A4substrate):Therehavebeenreportsthataninteractionexistsbetweenfluconazoleandrifabutin,

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PatientsreceivingrifabutinandFluconazolesimultaneouslyshouldbemonitoredclosely.

Sulfonylureaderivatives(CYP2C9substrate):Fluconazolehasbeenshowntoprolongtheserumhalf-lifeof

concomitantlyadministeredoralsulfonylureas(chlorpropamide,glibenclamide,glipizideandtolbutamide)inhealthy

volunteers.Fluconazoleandoralsulfonylureaderivativesmaybeadministeredtodiabeticpatients,butthepossibility

ofahypoglycaemicepisodemustbeborneinmind.Bloodglucoselevelsshouldbecloselymonitored.

Tacrolimusandsirolimus(CYP3A4substrate):ConcomitantintakeofFluconazole(100mgand200mg)and

tacrolimus0.15mg/kgb.i.d.increasedtacrolimusC

1.4and3.1-foldrespectively.Renaltoxicityhasbeenreportedin

patientsconcomitantlyreceivingfluconazoleandtacrolimus.Althoughnointeractionstudieshavebeenconductedwith

fluconazoleandsirolimus,asimilarinteractiontothatwithtacrolimuscanbeexpected.Patientswhoreceivetacrolimus

orsirolimusandfluconazoleconcomitantlymustbecloselymonitoredfortacrolimus/sirulimusplasmalevelsand

toxicity.

Theophylline:Intakeoffluconazole200mgfor14daysresultedinan18%decreaseinthemeanplasmaclearanceof

theophylline.Patientswhoarereceivinghighdosesoftheophylline,orwhoareotherwiseatincreasedriskof

theophyllinetoxicityshouldbecarefullymonitoredandthetheophyllinedoseshouldbeadjustedasnecessary.

Trimetrexate:Fluconazolemayinhibitthemetabolismoftrimetrexate,leadingtoincreasedplasmatrimetrexate

concentrations.Ifthecombinationisunavoidabletheserumconcentrationsandtoxicityoftrimetrexatemustbe

monitoredclosely.

Xanthinebases,otherantiepilepticdrugsandisoniazid:Follow-uptestsshouldbeperformedifthereisconcurrent

administrationofxanthinebases,otherantiepilepticdrugsandisoniazid.

Zidovudine:Interactionstudieshaveshownthatwhenzidovudineistakentogetherwithfluconazole200mgor400mg

dailythezidovudineAUCvaluesmayberaisedbybetween20%and70%,probablyasaresultoftheinhibitionof

conversiontotheglucuronide.Patientsreceivingthiscombinationshouldbemonitoredforzidovudine-relatedadverse

reactions.

Otherinteractionswithmedicinalproducts

AmphotericinB:InvitroandinvivoanimalstudieshaveshownantagonismbetweenamphotericinBandazole

derivatives.Themechanismofactionofimidazolesistoinhibitergosterolsynthesisinfungalcellmembranes.

AmphotericinBactsbybindingtosterolsinthecellmembraneandchangingitsmembranepermeability.Theclinical

effectofthisantagonismisstillunknown,andasimilareffectmayoccurwiththeamphotericinBcholesterolsulfate

complex.

DrugsthatcauseQTprolongation:CasereportsindicatethatfluconazolemighthavethepotentialtoinduceQT

prolongationleadingtoseriouscardiacarrhythmia.Patientstreatedconcomitantlywithfluconazoleandotherdrugsthat

prolongtheQTintervalshouldbecarefullymonitoredsinceanadditiveeffectcannotbeexcluded.

Interactionstudieshaveshownthatnoclinicallysignificantchangeinabsorptionoffluconazoleoccursafterradiation

therapyofthewholebodyinconnectionwithbonemarrowtransplantation.

4.6Fertility,pregnancyandlactation

Pregnancy

Datafromseveralhundredpregnantwomentreatedwithstandarddoses(below200mg/day)offluconazole,

administeredassingleorrepeateddosesduringthefirsttrimesterdonotindicateundesirableeffectsonfoetus.

Therearereportsofmultiplecongenitalabnormalitieswererecorded(includingbrachycephalia,earsdysplasia,giant

anteriorfrontanelle,femoralbowingandradio-humeralsynostosis)inchildrenwhosemothersweretreatedfor3

monthsorlongerwithhighdoses(400to800mg/day)ofFluconazoleforcoccidioidomycosis.Therelationship

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Studiesinanimalshaveshownteratogeniceffects(seesection5.3Preclinicalsafetydata).

Fluconazoleinstandarddosesandshort-termtreatmentshouldnotbeusedinpregnancyunlessclearlynecessary.

Fluconazoleinhighdosesand/orinprolongedregimensshouldnotbeusedduringpregnancyunlessclearlynecessary

(inthecaseofalife-threateninginfection).Duetopotentialteratogeniceffectswomenofchildbearingpotentialmust

useeffectivecontraceptionduringtreatment.

Lactation

Fluconazolepassesintobreastmilkinconcentrationslowerthanthoseinplasma.

Breastfeedingmaybemaintainedaftersingleuseofastandarddoseof200mgfluconazoleorless.Breastfeedingis

notrecommendedafterrepeateduseorafterhigh-dosefluconazole.

4.7Effectsonabilitytodriveandusemachines

Experiencewithuseoffluconazoleindicatesthatitisunlikelytoimpairabilitytodriveorusemachinery.However,

whendrivingvehiclesoroperatingmachinessideeffectsmayoccur(e.gdizzinessorseizures),(seesection4.8,

Undesirableeffects).

4.8Undesirableeffects

Inclinicaltrialsupto10%haveexperiencedadversereactions.Approximately1%discontinuedthetreatmentdueto

adversereactions.

Thefollowingtreatment-relatedundesirableeffectswerereportedin4,048patientsreceivingfluconazoleforsevenor

moredaysinclinicaltrials

Organsystems Verycommon

1/10 Common

1/100,<1/10 Uncommon

1/1,000,<1/100 Rare

1/10,000,

<1/1,000 Veryrare

<1/10,000,

notknown

(cannotbe

estimatedfrom

availabledata)

Bloodand

lymphaticsystem Anaemia

Immunesystem Anaphylaxis

Psychiatric Insomnia

Somnolence

Centraland

peripheral

nervoussystem Headache Convulsion

Dizziness

Paresthesia

Tremor

Vertigo

Autonomic

nervoussystem Drymouth

Increasedsweating

Specialsenses Tasteperversion

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AdverseclinicaleventswerereportedmorefrequentlyinHIVinfectedpatients(21%)thaninnon-HIVinfected

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

Inaddition,thefollowingadditionaladverseeventshaveoccurredunderconditionswhereacausalrelationshipis

uncertain(e.g.opentrials,duringpost-marketingexperience):

4.9Overdose

Intheeventofoverdosage,supportivemeasuresandsymptomatictreatmentshouldbeprovided.

Fluconazoleislargelyexcretedintheurinehenceforceddiuresiscanincreasetheeliminationrate.

Vomiting

Abdominalpain

Diarrhea Constipation

Dyspepsia

Flatulence

Hepato-biliary Clinically

significant

increaseofAST,

ALTand

alkaline

phosphatase Cholestasis

Hepatocellular

damage

Jaundice

Clinically

significantincrease

Hepatic

necrosis

Skinand

appendages Skinrash Pruritus Exfoliativeskin

disorder

(Stevens-

Johnson

syndrome)

Musculoskeletal

General Myalgia

Fatigue

Malaise

Asthenia

Fever

SystemOrganClass Adverseevent

InfectionandInfestation Infectiontodueresistantmicroorganisms

Bloodandlymphaticsystemdisorders Leucopenia,includingneutropeniaandagranulocytosis,

thrombocytopenia,eosinophilia.

Immunesystemdisorders Angiooedema,faceoedema,itching,urticaria

Metabolismandnutritiondisorders Hypercholesterolemia,hypertriglyceridaemia,hypokalemia

Nervoussystemdisorders Seizures

Cardiacdisorders Prolonged-QT,torsadesdepointes(SeeSection4.4Special

warningsandprecautionsforuse)

Hepatobiliarydisorders Hepaticfailure,hepatitis

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup

Antimycoticforsystemicuse,triazolederivatives.

ATCCode:J02AC01

Mechanismofaction

Fluconazoleisamemberofthetriazoleclassofantifungalagentswithprimarilyfungistaticeffects.Itisapotentand

selectiveinhibitorofthesynthesisoffungalergosterolwhichleadstodefectsinthecellmembrane.Fluconazoleis

highlyspecificforfungalcytochromeP-450enzymes.

Resistancemechanism

Dependingontheyeastspeciesinvolved,theprincipalmechanismsofresistancetofluconazole,incommonwithother

azoleantifungalagents,involveimpairingtheaccumulationofthedruginthecellby(i)alteringtheaminoacid

compositionoflanosterol14

-demethylase,(ii)increasingdrugefflux,and(iii)alteringtheergosterolbiosyntheticpathways.InCandidaalbicans,

blockageoftheergosterolsyntheticpathwaysisthoughttoprimarilyarisefromblockageofsterolC5,6-desaturase

whichisencodedbyERG3,Inthemoreresistantspecies,Candidaglabrata,thepredominantpathwayhasnotbeen

fullyelucidatedbutisthoughttoarisefromupregulationofCDRgenes(CDR1,CDR2andMMDR1)responsiblefor

effluxofthedrugsubstancefromthecells.ResistancetoFluconazolethereforeusuallyconfersresistancetootherazole

antifungalagents.InCryptococcusneoformansthestudieshavedemonstratedthatthesameprinciplemechanismsof

resistanceexistinthisspecies,andthatthesemaybeaffectedbypriorexposuretoazoleantifungalagents.

Similarcarefulconsiderationofthebenefitsoftheproposeddoseversustheriskofdevelopmentofresistancemust

thereforebeappliedwithfluconazoleasforanyotherantimicrobialchemotherapy.

Antifungalsusceptibility

[Source:Pfalleretal,2006:ARTEMISDISKGlobalAntifungalSurveillanceStudy.

Messeretal,2006:SENTRYAntimicrobialSurveillanceProgram(2003)

RexJH,2000:IDSAPracticeGuidelinesfortheTreatmentofCandidiasis]

TheantifungalspectrumoffluconazoleincludesanumberofpathogensincludingCandidaalbicans,andnon-Candida

albicansspecies,Cryptococcusspeciesandotherdermatophytes.

Theprevalenceofacquiredresistancemayvaryforsomespeciesgeographicallyandwithtime.Thereforeitisdesirable

toobtaininformationonlocalresistancepatterns,particularlyinthelightoftheadequatetreatmentofsevereinfections.

InterpretivebreakpointsforCandidaspecies:

Classification MIC

(microgrammes/ml) Species Datasource

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TherearereportsofresistantisolatesofCandidaalbicansarisinginAIDSpatientswhohavereceivedlong-term

treatmentwithfluconazole.

Cryptococcusneoformans

ispredominantlysensitivetofluconazole.StrainswithanMICvalueofgreaterthan32microgrammespermlare

consideredresistant.

FluconazolehaslittleornoactivityagainstAspergillus,Zygomycetes,MicrosporumandTrychophytonspecies.

5.2Pharmacokineticproperties

Absorption:

Thepharmacokineticpropertiesoffluconazolearesimilarfollowingadministrationbytheintravenousororalroute.

Fluconazoleiswellabsorbedafteroralintake.Theabsolutebioavailabilityisabove90%.Oralabsorptionisnot

affectedbyconcomitantfoodintake.Themaximumfastingplasmaconcentrationisreached0.5-1.5hoursafterdose

C.parapsilosis,

C.lusitaniae,

C.kefyr,

C.dubliniensis,

MesserSAetal,2006

RexJH,2000

Susceptibility

depends on the

dose(S-DD) 16-32 C.glabrata

(approx17%R),

C.guillermondii

(approx10%R),

C.famata

(approx12%R),

C.tropicalis

PfallerMAetal,2006

MesserSAetal,2006

RexJH2000

Resistant(R) Greaterthan32 C.krusei,

C.rugosa,

C.inconspicua,

C.norvegensis,

C.lipolytica,

PfallerMAetal,2006

MesserSAetal,2006

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Plasmaconcentrationisproportionaltothedose.Afteradministrationof200mgoffluconazole,C

isaround

4.6mg/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/gand

sevendaysaftertheendoftreatmentitwasstill7.1microgrammes/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).

Thepharmacokineticsoffluconazolehasnotbeenstudiedinchildrenwithrenalinsufficiency.

5.3Preclinicalsafetydata

Preclinicaldatafromconventionalstudiesonrepeat-dose/generaltoxicity,genotoxicityorcarcinogenicityindicateno

specialhazardforhumansnotalreadyconsideredinothersectionsoftheSPC.

Inreproductiontoxicitystudiesinratanincreasedincidenceofhydronephrosisandextensionofrenalpelviswas

reportedandembryonallethalitywasincreased.Anincreaseinanatomicalvariationsanddelayedossificationwas

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Listofexcipients

Sodiumchloride

WaterforInjections

6.2Incompatibilities

Althoughnospecificincompatibilitiesareknown,FluconazoleRedibag2mg/mlSolutionforInfusionshouldnotbe

mixedwithotherdrugsforintravenousinfusion.

SeealsoSection6.6Specialprecautionsfordisposalandotherhandling.

6.3ShelfLife

2years

6.4Specialprecautionsforstorage

Storeintheoriginalpackageinordertoprotectfromlightormoisture.

Donotfreeze.

6.5Natureandcontentsofcontainer

FluconazoleRedibag2mg/mlSolutionforInfusionissuppliedinaflexibleplasticinfusionbagcomposedof

polyolefinicresins.Threebagsizesareavailable50ml,100mland200ml.Eachbagisoverwrappedwitha

protectivealuminiumoverpouch.

Packsizes:10x50ml,20x50ml,10x100ml20x100ml,10x200mlor20x200ml.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Eachbagisintendedforsingleuseonly.

Onlyuseabagifthesolutionisclear,withoutvisibleparticlesandifthecontainerisundamaged.

Donotremovethebagfromtheoverpouchuntilreadyforuse.

Donotconnectbagstoeachother.Suchusecouldresultinairembolismduetoresidualairbeingdrawnfromthe

primarycontainerbeforetheadministrationofthefluidfromthesecondarycontaineriscompleted.

Thesolutionshouldbeadministeredwithsterileequipmentusinganaseptictechnique.Theequipmentshouldbe

primedwiththesolutioninordertopreventairenteringthesystem.

Additivesarenotallowed.

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Discardanyunusedportion.

Donotreconnectpartiallyusedbags.

Opening

Removethebagfromtheoverpouchjustbeforeuse.

Checkforminuteleaksbysqueezinginnerbagfirmly.Ifleaksarefound,discardsolution,assterilitymaybe

impaired.

Someopacityoftheplasticbagduetomoistureabsorptionduringthesterilisationprocessmaybeobserved.Thisis

normalanddoesnotaffectthesolutionqualityorsafety.Theopacitywilldiminishgradually.

Checkthesolutionforclarityandabsenceofforeignmatters.Ifsolutionisnotclearorcontainsforeignmatters,discard

thesolution.

Preparationforadministration

Usesterilematerialforpreparationandadministration.

Suspendcontainerfromeyeletsupport.

Attachanadministrationset.Refertocompletedirectionsaccompanyingsetforconnection,primingofthesetand

administrationofthesolution.

7MARKETINGAUTHORISATIONHOLDER

BaxterHealthcareLtd

CaxtonWay

Thetford

NorfolkIP243SE

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA167/127/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

7thSeptember2007

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