BYFLUC

Main information

  • Trade name:
  • BYFLUC Capsules Hard 50 Milligram
  • Dosage:
  • 50 Milligram
  • Pharmaceutical form:
  • Capsules Hard
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BYFLUC Capsules Hard 50 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0915/028/001
  • Authorization date:
  • 28-05-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ByFluc50mgCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontainsfluconazole50mg.

Eachcapsulealsocontainslactosemonohydrate47mg

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Hardcapsules.

Lightblueopaquecapandwhiteopaquebody.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Therapymaybeinstitutedbeforetheresultsoftheculturesandotherlaboratorystudiesareknown;however,once

theseresultsbecomeavailable,anti-infectivetherapyshouldbeadjustedaccordingly.

ByFluc50mgCapsulesisindicatedfor:

Genitalcandidiasis.Vaginalcandidiasis,acuteorrecurrent.Candidalbalanitis.

Mucosalcandidiasis.Theseincludeoropharyngeal,oesophageal,non-invasivebronchopulmonaryinfections,

candiduria,mucocutaneousandchronicoralatrophiccandidiasis(denturesoremouth).Normalhostsandpatients

withcompromisedimmunefunctionmaybetreated.

Systemiccandidiasisincludingcandidaemia,disseminatedcandidiasisandotherformsofinvasivecandidal

infection.Theseincludeinfectionsoftheperitoneum,endocardiumandpulmonaryandurinarytracts.Candidal

infectionsinpatientswithmalignancy,inintensivecareunitsorthosereceivingcytotoxicorimmunosuppressive

therapy,maybetreated.

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

Normalhostsandpatientswithacquiredimmunedeficiencysyndrome(AIDS),organtransplantsorothercausesof

immunosuppressionmaybetreated.ByFluc50mgCapsulescanbeusedasmaintenancetherapytopreventrelapse

ofcryptococcaldiseaseinpatientswithAIDS.

Preventionoffungalinfectionsinpatientswithmalignancywhoarepredisposedtosuchinfectionsasaresult

ofcytotoxicchemotherapyorradiotherapy,includingbonemarrowtransplantpatients.

Dermatomycosesincludingtineapedis,tineacorporis,tineacruris,tineaversicolorandcandidainfections,

onlywheretheseconditionsareresistanttofirstlinetherapyorwhereoccurrenceisinimmunocompromised

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4.2Posologyandmethodofadministration

ByFluc50mgCapsulesshouldbeadministeredorally.

ThedailydoseofByFluc50mgCapsulesshouldbebasedonthenatureandseverityofthefungalinfection.Most

casesofvaginalcandidiasisrespondtosingledosetherapy.

Therapyforthosetypesofinfectionsrequiringmultipledosetreatmentshouldbecontinueduntilclinicalparameters

orlaboratorytestsindicatethatactivefungalinfectionhassubsided.Aninadequateperiodoftreatmentmayleadto

recurrenceofactiveinfection.PatientswithAIDSandcryptococcalmeningitisusuallyrequiremaintenancetherapy

topreventrelapse.

Adults:

Candidalvaginitisorbalanitis.Theusualdosageis150mgasasingledose.

MucosalCandidiasis

Oropharyngealcandidiasis:therecommendeddoseis50mgoncedailyfor7to14days.Treatmentmaycontinuefor

alongerperiodifthephysiciansorequires.

Atropicoralcandidiasisassociatedwithdentures:therecommendeddoseis50mgoncedailyfor14days

administeredconcurrentlywithlocalantisepticmeasurestothedenture.

Forothercandidalinfectionsofthemucosa,(exceptgenitalcandidiasisseeabove),e.g.oesophagitis,non-invasive

bronchopulmonaryinfections,candiduria,mucocutaneouscandidiasisetc.,therecommendeddoseis50mgdaily,

givenfor14to30days.Inunusuallydifficultcasesofmucosalcandidalinfectionsthedosemaybeincreasedto

100mgdaily.

Forcandidaemia,disseminatedcandidiasisandotherinvasivecandidalinfections:therecommendeddoseis

400mgonthefirstdayfollowedby200mgoncedaily.Dependingontheclinicalresponsethedosemaybe

increasedto400mgoncedaily.Durationoftreatmentisbasedupontheclinicalresponse.

Forcryptococcalmeningitisandcryptococcalinfectionsatothersites:therecommendeddoseis400mgon

thefirstdayfollowedby200mg-400mgoncedaily.Durationoftreatmentforcryptococcalinfectionswilldepend

ontheclinicalandmycologicalresponse,butisusuallyatleast6to8weeksforcryptococcalmeningitis.

ForthepreventionofrelapseofcryptococcalmeningitisinpatientswithAIDS,afterthepatientreceivesa

fullcourseofprimarytherapy,ByFluc50mgCapsulesmaybeadministeredindefinitelyatadailydoseof100-200

Therecommendeddosageforthepreventionofcandidiasisis50to400mgoncedaily,basedonthepatient’s

riskofdevelopingfungalinfection.Forpatientsathighriskofsystemicinfectione.g.patientswhoareanticipatedto

haveprofoundorprolongedneutropeniasuchasduringbonemarrowtransplantation,therecommendeddoseis

400mgoncedaily.ByFluc50mgCapsulesadministrationshouldstartseveraldaysbeforetheanticipatedonsetof

neutropenia,andcontinuefor7daysaftertheneutrophilcountrisesabove1000cellspermm.

Fordermalinfectionsincludingtineapedis,corporis,crurisandcandidainfectionstherecommendeddosage

is150mgonceweeklyor50mgoncedaily.Durationoftreatmentisnormally2to4weeksbuttineapedismay

requiretreatmentforupto6weeks.Fortineaversicolortherecommendeddoseis50mgoncedailyfor2to4weeks.

Useinchildren:

Aswithsimilarinfectionsinadults,thedurationoftreatmentisbasedontheclinicalandmycologicalresponse.The

maximumadultdosageshouldnotbeexceededinchildren.ByFluc50mgCapsulesisadministeredasasingledaily

doseeachday.

Forchildrenwithimpairedrenalfunctionthedailydoseshouldbereducedinaccordancewiththeguidelinesgiven

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Useintheelderly:

Thenormaldoseshouldbeusedifthereisnoevidenceofrenalimpairment.Inpatientswithrenalimpairment

(creatinineclearancelessthan50ml/min)thedosagescheduleshouldbeadjustedasdescribedbelow.

Useinrenalimpairment:

Fluconazoleisexcretedpredominantlyintheurineasunchangeddrug.Noadjustmentsinsingledosetherapyare

required.InpatientswithimpairedrenalfunctionwhowillreceivemultipledosesofByFluc50mgCapsules,the

normalrecommendeddose(accordingtoindication)shouldbegivenonday1,followedbyadailydosebasedonthe

followingtable:

4.3Contraindications

ByFluc50mgCapsulesshouldnotbeusedinpatientswithknownhypersensitivitytofluconazoleortorelatedazole

compounds.

Co-administrationofterfenadineiscontra-indicatedinpatientsreceivingByFluc50mgCapsulesatmultipledosesof

400mgperdayorhigherbaseduponresultsofamultipledoseinteractionstudy.

Co-administrationofcisaprideiscontra-indicatedinpatientsreceivingByFluc50mgCapsules.(see“Interactionwith

othermedicinalproductsandotherformsofinteraction”)

4.4Specialwarningsandprecautionsforuse

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,abnormalitiesofhepatic,

renal,haematologicalandotherbiochemicalfunctiontestshavebeenobservedduringtreatmentwithByFluc50mg

Capsulesbuttheclinicalsignificanceandrelationshiptotreatmentisuncertain.

ByFluc50mgCapsuleshasbeenassociatedwithrarecasesofserioushepatictoxicityincludingfatalities,primarilyin

patientswithseriousunderlyingmedicalconditions.IncasesofByFluc50mgCapsules-associatedhepatotoxicity,no

obviousrelationshiptototaldailydose,durationoftherapy,sexorageofpatienthasbeenobserved.ByFluc50mg

Capsuleshepatotoxicityhasusuallybeenreversibleondiscontinuationoftherapy.Patientswhodevelopabnormalliver

functiontestsduringByFluc50mgCapsulestherapyshouldbemonitoredforthedevelopmentofmoreserioushepatic

injury.

ByFluc50mgCapsulesshouldbediscontinuedifclinicalsignsorsymptomsconsistentwithliverdiseasedevelopthat

maybeattributabletoByFluc50mgCapsules.

Patientshaverarelydevelopedexfoliativecutaneousreactions,suchasStevens-JohnsonSyndromeandtoxicepidermal

necrolysis,duringtreatmentwithfluconazole.AIDSpatientsaremorepronetothedevelopmentofseverecutaneous

reactionstomanydrugs.Ifarashdevelopsinapatienttreatedforasuperficialfungalinfectionwhichisconsidered

attributabletoByFluc50mgCapsules,furthertherapywiththisagentshouldbediscontinued.Inpatientswith

invasive/systemicfungalinfectionswhodeveloprashes,theyshouldbemonitoredcloselyandByFluc50mgCapsules

discontinuedifbullouslesionsorerythemamultiformedevelop.

Thereislittleinformationonsafetyinlong-termuse.

Inrarecases,aswithotherazoles,anaphylaxishasbeenreported.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

Creatinineclearance(ml/min) Percentofrecommendeddose

>50 100%

11-50 50%

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Anticoagulants:Inaninteractionstudy,fluconazoleincreasedtheprothrombintimeafterwarfarinadministrationin

healthymales.Thoughthemagnitudeofchangewassmall(12%),carefulmonitoringofprothrombintimein

patientsreceivingcoumarin-typeanticoagulantsisrecommended.

Sulphonylureas:Fluconazolehasbeenshowntoprolongtheserumhalf-lifeofconcomitantlyadministeredoral

sulphonylureas(chlorpropamide,glibenclamide,glipizideandtolbutamide)inhealthyvolunteers.Fluconazole

Capsulesandoralsulphonylureasmaybeco-administeredtodiabeticpatients,butthepossibilityofahypoglycaemic

episodeshouldbeborneinmind.

Hydrochlorothiazide:Inakineticinteractionstudy,co-administrationofmultiple-dosehydrochlorothiazideto

healthyvolunteersreceivingfluconazoleincreasedplasmaconcentrationsoffluconazoleby40%.Aneffectofthis

magnitudeshouldnotnecessitateachangeinthefluconazoledoseregimeninsubjectsreceivingconcomitant

diuretics,althoughtheprescribershouldbearitinmind.

Phenytoin:Concomitantadministrationoffluconazoleandphenytoinmayincreasethelevelsofphenytointoa

clinicallysignificantdegree.Ifitisnecessarytoadministerbothdrugsconcomitantly,phenytoinlevelsshouldbe

monitoredandthephenytoindoseadjustedtomaintaintherapeuticlevels.

Rifampicin:Concomitantadministrationoffluconazoleandrifampicinhasresultedina25%decreaseintheAUC

and20%shorterhalf-lifeoffluconazole.Inpatientsreceivingconcomitantrifampicin,anincreaseinthefluconazole

doseshouldbeconsidered.

Oralcontraceptives:Twokineticstudieswithcombinedoralcontraceptiveshavebeenperformedusingmultiple

dosesoffluconazole.Therewerenorelevanteffectsoneitherhormonelevelinthe50mgfluconazolestudy,whileat

200mgdailytheAUCsofethinylestradiolandlevonorgestrelwereincreased40%and24%respectively.Thus

multipledoseuseoffluconazoleatthesedosesisunlikelytohaveaneffectontheefficacyofthecombinedoral

contraceptive.

Endogenoussteroid:Fluconazole50mgdailydoesnotaffectendogenoussteroidlevelsinfemales.200-400mg

dailyhasnoclinicallysignificanteffectonendogenoussteroidlevelsoronACTHstimulatedresponseinhealthy

malevolunteers.

Cyclosporin:Akineticstudyinrenaltransplantpatientsfoundfluconazole200mgdailytoslowlyincrease

cyclosporinconcentrations.However,inanothermultipledosestudywith100mgdaily,fluconazoledidnotaffect

cyclosporinlevelsinpatientswithbonemarrowtransplants.Cyclosporinplasmaconcentrationmonitoringin

patientsreceivingfluconazoleisrecommended.

Theophylline:Inaplacebo-controlledinteractionstudy,theadministrationoffluconazole200mgfor14days

resultedinan18%decreaseinthemeanplasmaclearanceoftheophylline.Patientswhoarereceivinghighdosesof

theophyllineorwhoareotherwiseatincreasedriskfortheophyllinetoxicityshouldbeobservedforsignsof

theophyllinetoxicitywhilereceivingfluconazole,andthetherapymodifiedappropriatelyifsignsoftoxicitydevelop.

Terfenadine:BecauseoftheoccurrenceofseriouscardiacdysrhythmiassecondarytoprolongationoftheQTc

intervalinpatientsreceivingazoleantifungalsinconjunctionwithterfenadine,interactionstudieshavebeen

performed.Onestudyata200mgdailydoseoffluconazolefailedtodemonstrateaprolongationinQTcinterval.

Anotherstudyata400mgand800mgdailydoseoffluconazoledemonstratedthatfluconazoletakenindosesof

400mgperdayorgreatersignificantlyincreasesplasmalevelsofterfenadinewhentakenconcomitantly.The

combineduseoffluconazoleatdosesof400mgorgreaterwithterfenadineiscontraindicated.

(See“Contraindications”.)Theco-administrationoffluconazoleatdoseslowerthan400mgperdaywithterfenadine

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Cisapride:Therehavebeenreportsofcardiaceventsincludingtorsadedepointesinpatientstowhomfluconazole

andcisapridewereco-administered.Acontrolledstudyfoundthatconcomitantfluconazole200mgoncedailyand

cisapride20mgfourtimesadayyieldedasignificantincreaseincisaprideplasmalevelsandprolongationofQTc

interval.Co-administrationofcisaprideiscontraindicatedinpatientsreceivingfluconazole.

TheuseoffluconazoleinpatientsconcurrentlytakingastemizoleorotherdrugsmetabolisedbythecytochromeP450

systemmaybeassociatedwithelevationsinserumlevelsofthesedrugs.Intheabsenceofdefinitiveinformation,

cautionshouldbeusedwhenco-administeringfluconazole.Patientsshouldbecarefullymonitored.

Zidovudine:Twokineticstudiesresultedinincreasedlevelsofzidovudinemostlikelycausedbythedecreased

conversionofzidovudinetoitsmajormetabolite.OnestudydeterminedzidovudinelevelsinAIDSorARCpatients

beforeandfollowingfluconazole200mgdailyfor15days.TherewasasignificantincreaseinzidovudineAUC

(20%).Asecondrandomised,two-period,two-treatmentcross-overstudyexaminedzidovudinelevelsinHIV

infectedpatients.Ontwooccasions,21daysapart,patientsreceivedzidovudine200mgeveryeighthourseitherwith

orwithoutfluconazole400mgdailyforsevendays.TheAUCofzidovudinesignificantlyincreased(74%)during

coadministrationwithfluconazole.Patientsreceivingthiscombinationshouldbemonitoredforthedevelopmentof

zidovudine-relatedadversereactions.

Tacrolimus:Therehavebeenreportsthataninteractionexistswhenfluconazoleisadministeredconcomitantlywith

tacrolimus,leadingtoincreasedserumlevelsoftacrolimus.Therehavebeenreportsofnephrotoxicityinpatientsto

whomfluconazoleandtacrolimuswereco-administered.Patientsreceivingtacrolimusandfluconazole

concomitantlyshouldbecarefullymonitored.

Rifabutin:Therehavebeenreportsthataninteractionexistswhenfluconazoleisadministeredconcomitantlywith

rifabutin,leadingtoincreasedserumlevelsofrifabutin.Therehavebeenreportsofuveitisinpatientstowhom

fluconazoleandrifabutinwereco-administered.Patientsreceivingrifabutinandfluconazoleconcomitantlyshouldbe

carefullymonitored.

Benzodiazepines(shortacting):Followingoraladministrationofmidazolam,fluconazoleresultedinsubstantial

increasesinmidazolamconcentrationsandpsychomotoreffects.Thiseffectonmidazolamappearstobemore

pronouncedfollowingoraladministrationoffluconazolethanwithfluconazoleadministeredintravenously.If

concomitantbenzodiazepinetherapyisnecessaryinpatientsbeingtreatedwithfluconazole,considerationshouldbe

giventodecreasingthebenzodiazepinedosage,andthepatientsshouldbeappropriatelymonitored.

Interactionstudieshaveshownthatwhenoralfluconazoleisco-administeredwithfood,cimetidine,antacidsor

followingtotalbodyirradiationforbonemarrowtransplantation,noclinicallysignificantimpairmentoffluconazole

absorptionoccurs.

Physiciansshouldbeawarethatdrug-druginteractionstudieswithothermedicationshavenotbeenconducted,but

thatsuchinteractionsmayoccur.

4.6Fertility,pregnancyandlactation

Useduringpregnancy

Therearenoadequateandwellcontrolledstudiesinpregnantwomen.Therehavebeenreportsofmultiple

congenitalabnormalitiesininfantswhosemotherswerebeingtreatedfor3ormoremonthswithhighdose(400-

800mg/day)fluconazoletherapyforcoccidioidomycosis.Therelationshipbetweenfluconazoleuseandtheseevents

isunclear.

Useinpregnancyshouldbeavoidedexceptinpatientswithsevereorpotentiallylife-threateningfungalinfectionsin

whomfluconazolemaybeusediftheanticipatedbenefitoutweighsthepossiblerisktothefoetus.

Useduringlactation

Fluconazoleisfoundinhumanbreastmilkatconcentrationssimilartoplasma,henceitsuseinnursingmothersis

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4.7Effectsonabilitytodriveandusemachines

ExperiencewithByFluc50mgCapsulesindicatesthattherapyisunlikelytoimpairapatient’sabilitytodriveoruse

machinery.

4.8Undesirableeffects

Fluconazoleisgenerallywelltolerated.Themostcommonundesirableeffectsobservedduringclinicaltrialsand

associatedwithfluconazoleare:

CentralandPeripheralNervousSystemHeadache.

Skin/AppendagesRash.

GastrointestinalAbdominalpain,diarrhoea,flatulence,nausea.

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,changesinrenaland

haematologicalfunctiontestresultsandhepaticabnormalitieshavebeenobservedduringtreatmentwithfluconazole

andcomparativeagents,buttheclinicalsignificanceandrelationshiptotreatmentisuncertain(seeSection4.4

“Specialwarningsandprecautionsforuse”).

Liver/BiliaryHepatictoxicityincludingrarecasesoffatalities,elevatedalkalinephosphatase,elevatedbilirubin,

elevatedSGOT,elevatedSGPT.

Inaddition,thefollowingundesirableeffectshaveoccurredduringpost-marketing:

CentralandPeripheralNervousSystemDizziness,seizures.

Skin/AppendagesAlopecia,exfoliativeskindisordersincludingStevens-Johnsonsyndromeandtoxicepidermal

necrolysis.

GastrointestinalDyspepsia,vomiting.

HaematopoieticandLymphaticLeucopeniaincludingneutropeniaandagranulocytosis,thrombocytopenia.

BodyAsAWholeAnaphylaxis(includingangioedema,faceoedema,pruritis,urticaria).

Liver/BiliaryHepaticfailure,hepatitis,hepatocellularnecrosis,jaundice.

Metabolic/NutritionalHypercholesterolaemia,hypertriglyceridaemia,hypokalaemia.

OthersensesTasteperversion.

4.9Overdose

TherehasbeenareportedcaseofoverdosagewithFluconazole.A42year-oldpatientinfectedwithhuman

immunodeficiencyvirusdevelopedhallucinationsandexhibitedparanoidbehaviourafterreportedlyingesting

8200mgofFluconazole.Thepatientwasadmittedtothehospitalandhisconditionwasresolvedwithin48hours.

Intheeventofoverdosage,supportivemeasuresandsymptomatictreatment,withgastriclavageifnecessary,maybe

adequate.

Asfluconazoleislargelyexcretedintheurine,forcedvolumediuresiswouldprobablyincreasetheeliminationrate.

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Fluconazole,amemberofthetriazoleclassofantifungalagents,isapotentandselectiveinhibitoroffungalenzymes

necessaryforthesynthesisofergosterol.

Fluconazoleshowslittlepharmacologicalactivityinawiderangeofanimalstudies.Someprolongationof

pentobarbitonesleepingtimesinmice(p.o.),increasedmeanarterialandleftventricularbloodpressureand

increasedheartrateinanaesthetisedcats(i.v.)occurred.Inhibitionofratovarianaromatasewasobservedathigh

concentrations.

Bothorallyandintravenouslyadministeredfluconazolewasactiveinavarietyofanimalfungalinfectionmodels.

Activityhasbeendemonstratedagainstopportunisticmycoses,suchasinfectionswithCandidaspp.including

systemiccandidiasisinimmunocompromisedanimals;withCryptococcusneoformans,includingintracranial

infections;withMicrosporumspp.andwithTrichophytonspp.Fluconazolehasalsobeenshowntobeactivein

animalmodelsofendemicmycoses,includinginfectionswithBlastomycesdermatitides;withCoccidioidesimmitis,

includingintracranialinfectionandwithHistoplasmacapsulatuminnormalandimmunosuppressedanimals.

Therehavebeenreportsofcasesofsuper-infectionwithCandidaspeciesotherthanC.albicans,whichareoften

inherentlynotsusceptibletofluconazole(e.g.Candidakrusei).Suchcasesmayrequirealternativeantifungal

therapy.

5.2Pharmacokineticproperties

FluconazoleishighlyspecificforfungalcytochromeP-450dependentenzymes.Fluconazole50mgdailygivenup

to28dayshasbeenshownnottoaffecttestosteroneplasmaconcentrationsinmalesorsteroidconcentrationsin

femalesofchild-bearingage.Fluconazole200-400mgdailyhasnoclinicallysignificanteffectonendogenous

steroidlevelsoronACTHstimulatedresponseinhealthymalevolunteers.

Interactionstudieswithantipyrineindicatethatsingleormultipledosesoffluconazole50mgdonotaffectits

metabolism.

Inchildren,thefollowingpharmacokineticdatahavebeenreported:

*Denotesfinalday

Inprematurenew-borns(gestationalagearound28weeks),intravenousadministrationoffluconazoleof6mg/kgwas

giveneverythirddayforamaximumoffivedoseswhiletheprematurenew-bornsremainedintheintensivecare

Agestudied Dose(mg/kg) Half-life

(hours) AUC

(microgram/h/ml)

11days-11months Single-IV

3mg/kg 23 110.1

9months-13years Single-Oral

2mg/kg 25.0 94.7

9months-13years Single-Oral

8mg/kg 19.5 362.5

5years-15years Multiple-IV

2mg/kg 17.4* 67.4

5years-15years Multiple-IV

4mg/kg 15.2* 139.1

5years-15years Multiple-IV

8mg/kg 17.6* 196.7

MeanAge7Years Multiple-Oral

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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/mlandoccurred

at1.3hourspostdose.ThemeanAUCwas76.4±20.3mcg/h/ml,andthemeanterminalhalf-lifewas46.2hours.

Thesepharmacokineticparametervaluesarehigherthananalogousvaluesreportedfornormalyoungmale

volunteers.Co-administrationofdiureticsdidnotsignificantlyalterAUCorC .Inaddition,creatinineclearance

(74ml/min),thepercentofdrugrecoveredunchangedinurine(0-24hr,22%)andthefluconazolerenalclearance

estimates(0.124ml/min/kg)fortheelderlyweregenerallylowerthanthoseofyoungervolunteers.Thus,the

alterationoffluconazoledispositionintheelderlyappearstoberelatedtoreducedrenalfunctioncharacteristicof

thisgroup.Aplotofeachsubject’sterminaleliminationhalf-lifeversuscreatinineclearancecomparedwiththe

predictedhalf-life–creatinineclearancecurvederivedfromnormalsubjectsandsubjectswithvaryingdegreesof

renalinsufficiencyindicatedthat21of22subjectsfellwithinthe95%confidencelimitofthepredictedhalf-life–

creatinineclearancecurves.Theseresultsareconsistentwiththehypothesisthathighervaluesforthe

pharmacokineticobservedintheelderlysubjectscomparedwithnormalyoungmalevolunteersareduetothe

decreasedkidneyfunctionthatisexpectedintheelderly.

5.3Preclinicalsafetydata

ReproductiveToxicity:Therewerenofetaleffectsat5or10mg/kg;increasesinfetalanatomicalvariants

(supernumeraryribs,renalpelvisdilation)anddelaysinossificationwereobservedat25and50mg/kgandhigher

doses.Atdosesrangingfrom80mg/kg(approximately20-60xtherecommendedhumandose)to320mg/kg

embryolethalityinratswasincreasedandfetalabnormalitiesincludedwavyribs,cleftpalateandabnormalcranio-

facialossification.Theseseffectsareconsistentwiththeinhibitionofoestrogensynthesisinratsandmaybearesult

ofknowneffectsofloweredoestrogenonpregnancy,organogenesisandparturition.

Carcinogenesis:Fluconazoleshowednoevidenceofcarcinogenicpotentialinmiceandratstreatedorallyfor24

monthsatdosesof2.5,5or10mg/kg/day.Maleratstreatedwith5and10mg/kg/dayhadanincreasedincidenceof

hepatocellularadenomas.

Mutagenesis:Fluconazole,withorwithoutmetabolicactivation,wasnegativeintestsformutagenicityin4strains

ofS.typhimuriumandinthemouselymphomaL5178Ysystem.Cytogeneticstudiesinvivo(murinebonemarrow

cells,followingoraladministrationoffluconazole)andinvitro(humanlymphocytesexposedtofluconazoleat1000

µg/ml)showednoevidenceofchromosomalmutations.

Impairmentoffertility:Fluconazoledidnotaffectthefertilityofmaleorfemaleratstreatedorallywithdailydoses

of5,10or20mg/kgorwithparenteraldosesof5,25or75mg/kg,althoughtheonsetofparturitionwasslightly

delayedat20mg/kgp.o.Inanintravenousperinatalstudyinratsat5,20and40mg/kg,dystociaandprolongation

ofparturitionwereobservedinafewdamsat20mg/kgand40mg/kg,butnotat5mg/kg.Thedisturbancesin

parturitionwerereflectedbyaslightincreaseinthenumberofstill-bornpupsanddecreaseofneonatalsurvivalat

thesedoselevels.Theeffectsonparturitioninratsareconsistentwiththespeciesspecificoestrogen-lowering

propertyproducedbyhighdosesoffluconazole.Suchahormonechangehasnotbeenobservedinwomentreated

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

Colloidalanhydroussilica

Magnesiumstearate

Sodiumlaurilsulfate

Thecapsuleshellscontaingelatin,titaniumdioxide(E171)andbrilliantblueFCF(E133).

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Storebelow30°C.

6.5Natureandcontentsofcontainer

Byfluc50mgcapsulesaresuppliedinPVC/PVdC-aluminiumblisterswithincardboardcartons.

Thepackscontain1,7,10,20,30,50,or100capsules.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

HelsinnBirexTherapeuticsLtd

Damastown

Mulhuddart

Dublin15

8MARKETINGAUTHORISATIONNUMBER

PA915/28/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:15 th

April2005

Dateoflastrenewal:15 th

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10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 26/11/2010 CRN 2085924 page number: 10