BYFLUC

Main information

  • Trade name:
  • BYFLUC Capsules Hard 200 Milligram
  • Dosage:
  • 200 Milligram
  • Pharmaceutical form:
  • Capsules Hard
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BYFLUC Capsules Hard 200 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0915/028/003
  • Authorization date:
  • 28-05-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ByFluc200mgCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontainsfluconazole200mg.

Eachcapsulealsocontainslactosemonohydrate188mgandazorubine(E122)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Hardcapsules.

Purpleopaquecapandwhiteopaquebody.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Therapymaybeinstitutedbeforetheresultsoftheculturesandotherlaboratorystudiesareknown;however,

oncetheseresultsbecomeavailable,anti-infectivetherapyshouldbeadjustedaccordingly.

ByFluc200mgCapsulesisindicatedfor:

Genitalcandidiasis.Vaginalcandidiasis,acuteorrecurrent.Candidalbalanitis.

Mucosalcandidiasis.Theseincludeoropharyngeal,oesophageal,non-invasivebronchopulmonary

infections,candiduria,mucocutaneousandchronicoralatrophiccandidiasis(denturesoremouth).Normalhosts

andpatientswithcompromisedimmunefunctionmaybetreated.

Systemiccandidiasisincludingcandidaemia,disseminatedcandidiasisandotherformsofinvasive

candidalinfection.Theseincludeinfectionsoftheperitoneum,endocardiumandpulmonaryandurinarytracts.

Candidalinfectionsinpatientswithmalignancy,inintensivecareunitsorthosereceivingcytotoxicor

immunosuppressivetherapy,maybetreated.

Cryptococcosis,includingcryptococcalmeningitisandinfectionsofothersites(e.g.pulmonary,

cutaneous).Normalhostsandpatientswithacquiredimmunedeficiencysyndrome(AIDS),organtransplantsor

othercausesofimmunosuppressionmaybetreated.ByFluc200mgCapsulescanbeusedasmaintenance

therapytopreventrelapseofcryptococcaldiseaseinpatientswithAIDS.

Preventionoffungalinfectionsinpatientswithmalignancywhoarepredisposedtosuchinfectionsasa

resultofcytotoxicchemotherapyorradiotherapy,includingbonemarrowtransplantpatients.

Dermatomycosesincludingtineapedis,tineacorporis,tineacruris,tineaversicolorandcandida

infections,onlywheretheseconditionsareresistanttofirstlinetherapyorwhereoccurrenceisin

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4.2Posologyandmethodofadministration

ByFluc200mgCapsulesshouldbeadministeredorally.

ThedailydoseofByFluc200mgCapsulesshouldbebasedonthenatureandseverityofthefungalinfection.

Mostcasesofvaginalcandidiasisrespondtosingledosetherapy.

Therapyforthosetypesofinfectionsrequiringmultipledosetreatmentshouldbecontinueduntilclinical

parametersorlaboratorytestsindicatethatactivefungalinfectionhassubsided.Aninadequateperiodof

treatmentmayleadtorecurrenceofactiveinfection.PatientswithAIDSandcryptococcalmeningitisusually

requiremaintenancetherapytopreventrelapse.

Adults:

Candidalvaginitisorbalanitis.Theusualdosageis150mgasasingledose.

MucosalCandidiasis

Oropharyngealcandidiasis:therecommendeddoseis50mgoncedailyfor7to14days.Treatmentmaycontinue

foralongerperiodifthephysiciansorequires.

Atropicoralcandidiasisassociatedwithdentures:therecommendeddoseis50mgoncedailyfor14days

administeredconcurrentlywithlocalantisepticmeasurestothedenture.

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

invasivebronchopulmonaryinfections,candiduria,mucocutaneouscandidiasisetc.,therecommendeddoseis

50mgdaily,givenfor14to30days.Inunusuallydifficultcasesofmucosalcandidalinfectionsthedosemaybe

increasedto100mgdaily.

Forcandidaemia,disseminatedcandidiasisandotherinvasivecandidalinfections:therecommended

doseis400mgonthefirstdayfollowedby200mgoncedaily.Dependingontheclinicalresponsethedosemay

beincreasedto400mgoncedaily.Durationoftreatmentisbasedupontheclinicalresponse.

Forcryptococcalmeningitisandcryptococcalinfectionsatothersites:therecommendeddoseis400mg

onthefirstdayfollowedby200mg-400mgoncedaily.Durationoftreatmentforcryptococcalinfectionswill

dependontheclinicalandmycologicalresponse,butisusuallyatleast6to8weeksforcryptococcalmeningitis.

ForthepreventionofrelapseofcryptococcalmeningitisinpatientswithAIDS,afterthepatientreceives

afullcourseofprimarytherapy,ByFluc200mgCapsulesmaybeadministeredindefinitelyatadailydoseof100

-200mg.

Therecommendeddosageforthepreventionofcandidiasisis50to400mgoncedaily,basedonthe

patient’sriskofdevelopingfungalinfection.Forpatientsathighriskofsystemicinfectione.g.patientswhoare

anticipatedtohaveprofoundorprolongedneutropeniasuchasduringbonemarrowtransplantation,the

recommendeddoseis400mgoncedaily.ByFluc200mgCapsulesadministrationshouldstartseveraldays

beforetheanticipatedonsetofneutropenia,andcontinuefor7daysaftertheneutrophilcountrisesabove1000

cellspermm.

Fordermalinfectionsincludingtineapedis,corporis,crurisandcandidainfectionstherecommended

dosageis150mgonceweeklyor50mgoncedaily.Durationoftreatmentisnormally2to4weeksbuttinea

pedismayrequiretreatmentforupto6weeks.Fortineaversicolortherecommendeddoseis50mgoncedaily

for2to4weeks.

Useinchildren:

Aswithsimilarinfectionsinadults,thedurationoftreatmentisbasedontheclinicalandmycologicalresponse.

Themaximumadultdosageshouldnotbeexceededinchildren.ByFluc200mgCapsulesisadministeredasa

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Forchildrenwithimpairedrenalfunctionthedailydoseshouldbereducedinaccordancewiththeguidelines

givenforadults,dependentonthedegreeofrenalimpairment.

Useintheelderly:

Thenormaldoseshouldbeusedifthereisnoevidenceofrenalimpairment.Inpatientswithrenalimpairment

(creatinineclearancelessthan50ml/min)thedosagescheduleshouldbeadjustedasdescribedbelow.

Useinrenalimpairment:

Fluconazoleisexcretedpredominantlyintheurineasunchangeddrug.Noadjustmentsinsingledosetherapy

arerequired.InpatientswithimpairedrenalfunctionwhowillreceivemultipledosesofByFluc200mg

Capsules,thenormalrecommendeddose(accordingtoindication)shouldbegivenonday1,followedbyadaily

dosebasedonthefollowingtable:

4.3Contraindications

ByFluc200mgCapsulesshouldnotbeusedinpatientswithknownhypersensitivitytofluconazoleortorelated

azolecompounds.

Co-administrationofterfenadineiscontra-indicatedinpatientsreceivingByFluc200mgCapsulesatmultiple

dosesof400mgperdayorhigherbaseduponresultsofamultipledoseinteractionstudy.

Co-administrationofcisaprideiscontra-indicatedinpatientsreceivingByFluc200mgCapsules.(see

“Interactionwithothermedicinalproductsandotherformsofinteraction”)

4.4Specialwarningsandprecautionsforuse

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,abnormalitiesofhepatic,

renal,haematologicalandotherbiochemicalfunctiontestshavebeenobservedduringtreatmentwithByFluc200mg

Capsulesbuttheclinicalsignificanceandrelationshiptotreatmentisuncertain.

ByFluc200mgCapsuleshasbeenassociatedwithrarecasesofserioushepatictoxicityincludingfatalities,primarilyin

patientswithseriousunderlyingmedicalconditions.IncasesofByFluc200mgCapsules-associatedhepatotoxicity,no

obviousrelationshiptototaldailydose,durationoftherapy,sexorageofpatienthasbeenobserved.ByFluc200mg

Capsuleshepatotoxicityhasusuallybeenreversibleondiscontinuationoftherapy.Patientswhodevelopabnormalliver

functiontestsduringByFluc200mgCapsulestherapyshouldbemonitoredforthedevelopmentofmoreserioushepatic

injury.ByFluc200mgCapsulesshouldbediscontinuedifclinicalsignsorsymptomsconsistentwithliverdisease

developthatmaybeattributabletoByFluc200mgCapsules.

Patientshaverarelydevelopedexfoliativecutaneousreactions,suchasStevens-JohnsonSyndromeandtoxicepidermal

necrolysis,duringtreatmentwithfluconazole.AIDSpatientsaremorepronetothedevelopmentofseverecutaneous

reactionstomanydrugs.Ifarashdevelopsinapatienttreatedforasuperficialfungalinfectionwhichisconsidered

attributabletoByFluc200mgCapsules,furthertherapywiththisagentshouldbediscontinued.Inpatientswith

invasive/systemicfungalinfectionswhodeveloprashes,theyshouldbemonitoredcloselyandByFluc200mgCapsules

discontinuedifbullouslesionsorerythemamultiformedevelop.

Thereislittleinformationonsafetyinlong-termuse.

Inrarecases,aswithotherazoles,anaphylaxishasbeenreported.

Creatinineclearance(ml/min) Percentofrecommendeddose

>50 100%

11-50 50%

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malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Anticoagulants:Inaninteractionstudy,fluconazoleincreasedtheprothrombintimeafterwarfarin

administrationinhealthymales.Thoughthemagnitudeofchangewassmall(12%),carefulmonitoringof

prothrombintimeinpatientsreceivingcoumarin-typeanticoagulantsisrecommended.

Sulphonylureas:Fluconazolehasbeenshowntoprolongtheserumhalf-lifeofconcomitantlyadministeredoral

sulphonylureas(chlorpropamide,glibenclamide,glipizideandtolbutamide)inhealthyvolunteers.Fluconazole

andoralsulphonylureasmaybeco-administeredtodiabeticpatients,butthepossibilityofahypoglycaemic

episodeshouldbeborneinmind.

Hydrochlorothiazide:Inakineticinteractionstudy,co-administrationofmultiple-dosehydrochlorothiazideto

healthyvolunteersreceivingfluconazoleincreasedplasmaconcentrationsoffluconazoleby40%.Aneffectof

thismagnitudeshouldnotnecessitateachangeinthefluconazoledoseregimeninsubjectsreceivingconcomitant

diuretics,althoughtheprescribershouldbearitinmind.

Phenytoin:Concomitantadministrationoffluconazoleandphenytoinmayincreasethelevelsofphenytointoa

clinicallysignificantdegree.Ifitisnecessarytoadministerbothdrugsconcomitantly,phenytoinlevelsshould

bemonitoredandthephenytoindoseadjustedtomaintaintherapeuticlevels.

Rifampicin:Concomitantadministrationoffluconazoleandrifampicinhasresultedina25%decreaseinthe

AUCand20%shorterhalf-lifeoffluconazole.Inpatientsreceivingconcomitantrifampicin,anincreaseinthe

fluconazoledoseshouldbeconsidered.

Oralcontraceptives:Twokineticstudieswithcombinedoralcontraceptiveshavebeenperformedusingmultiple

dosesoffluconazole.Therewerenorelevanteffectsoneitherhormonelevelinthe50mgfluconazolestudy,

whileat200mgdailytheAUCsofethinylestradiolandlevonorgestrelwereincreased40%and24%

respectively.Thusmultipledoseuseoffluconazoleatthesedosesisunlikelytohaveaneffectontheefficacyof

thecombinedoralcontraceptive.

Endogenoussteroid:Fluconazole50mgdailydoesnotaffectendogenoussteroidlevelsinfemales.200-400mg

dailyhasnoclinicallysignificanteffectonendogenoussteroidlevelsoronACTHstimulatedresponseinhealthy

malevolunteers.

Cyclosporin:AkineticstudyinrenaltransplantpatientsfoundFluconazole200mgdailytoslowlyincrease

cyclosporinconcentrations.However,inanothermultipledosestudywith100mgdaily,fluconazoledidnot

affectcyclosporinlevelsinpatientswithbonemarrowtransplants.Cyclosporinplasmaconcentration

monitoringinpatientsreceivingfluconazoleisrecommended.

Theophylline:Inaplacebo-controlledinteractionstudy,theadministrationoffluconazole200mgfor14days

resultedinan18%decreaseinthemeanplasmaclearanceoftheophylline.Patientswhoarereceivinghighdoses

oftheophyllineorwhoareotherwiseatincreasedriskfortheophyllinetoxicityshouldbeobservedforsignsof

theophyllinetoxicitywhilereceivingfluconazole,andthetherapymodifiedappropriatelyifsignsoftoxicity

develop.

Terfenadine:BecauseoftheoccurrenceofseriouscardiacdysrhythmiassecondarytoprolongationoftheQTc

intervalinpatientsreceivingazoleantifungalsinconjunctionwithterfenadine,interactionstudieshavebeen

performed.

Onestudyata200mgdailydoseoffluconazolefailedtodemonstrateaprolongationinQTcinterval.Another

studyata400mgand800mgdailydoseoffluconazoledemonstratedthatfluconazoletakenindosesof400mg

perdayorgreatersignificantlyincreasesplasmalevelsofterfenadinewhentakenconcomitantly.Thecombined

useoffluconazoleatdosesof400mgorgreaterwithterfenadineiscontraindicated.(See“Contraindications”.)

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monitored.

Cisapride:Therehavebeenreportsofcardiaceventsincludingtorsadedepointesinpatientstowhom

fluconazoleandcisapridewereco-administered.Acontrolledstudyfoundthatconcomitantfluconazole200mg

oncedailyandcisapride20mgfourtimesadayyieldedasignificantincreaseincisaprideplasmalevelsand

prolongationofQTcinterval.Co-administrationofcisaprideiscontraindicatedinpatientsreceivingfluconazole.

Theuseoffluconazoleinpatientsconcurrentlytakingastemizoleorotherdrugsmetabolisedbythecytochrome

P450systemmaybeassociatedwithelevationsinserumlevelsofthesedrugs.Intheabsenceofdefinitive

information,cautionshouldbeusedwhenco-administeringfluconazole.Patientsshouldbecarefullymonitored.

Zidovudine:Twokineticstudiesresultedinincreasedlevelsofzidovudinemostlikelycausedbythedecreased

conversionofzidovudinetoitsmajormetabolite.OnestudydeterminedzidovudinelevelsinAIDSorARC

patientsbeforeandfollowingfluconazole200mgdailyfor15days.Therewasasignificantincreasein

zidovudineAUC(20%).Asecondrandomised,two-period,two-treatmentcross-overstudyexaminedzidovudine

levelsinHIVinfectedpatients.Ontwooccasions,21daysapart,patientsreceivedzidovudine200mgeveryeight

hourseitherwithorwithoutfluconazole400mgdailyforsevendays.TheAUCofzidovudinesignificantly

increased(74%)duringcoadministrationwithFluconazole.Patientsreceivingthiscombinationshouldbe

monitoredforthedevelopmentofzidovudine-relatedadversereactions.

Tacrolimus:Therehavebeenreportsthataninteractionexistswhenfluconazoleisadministeredconcomitantly

withtacrolimus,leadingtoincreasedserumlevelsoftacrolimus.Therehavebeenreportsofnephrotoxicityin

patientstowhomfluconazoleandtacrolimuswereco-administered.Patientsreceivingtacrolimusand

fluconazoleconcomitantlyshouldbecarefullymonitored.

Rifabutin:Therehavebeenreportsthataninteractionexistswhenfluconazoleisadministeredconcomitantly

withrifabutin,leadingtoincreasedserumlevelsofrifabutin.Therehavebeenreportsofuveitisinpatientsto

whomfluconazoleandrifabutinwereco-administered.Patientsreceivingrifabutinandfluconazole

concomitantlyshouldbecarefullymonitored.

Benzodiazepines(shortacting):Followingoraladministrationofmidazolam,fluconazoleresultedinsubstantial

increasesinmidazolamconcentrationsandpsychomotoreffects.Thiseffectonmidazolamappearstobemore

pronouncedfollowingoraladministrationoffluconazolethanwithfluconazoleadministeredintravenously.If

concomitantbenzodiazepinetherapyisnecessaryinpatientsbeingtreatedwithfluconazole,considerationshould

begiventodecreasingthebenzodiazepinedosage,andthepatientsshouldbeappropriatelymonitored.

Interactionstudieshaveshownthatwhenoralfluconazoleisco-administeredwithfood,cimetidine,antacidsor

followingtotalbodyirradiationforbonemarrowtransplantation,noclinicallysignificantimpairmentof

fluconazoleabsorptionoccurs.

Physiciansshouldbeawarethatdrug-druginteractionstudieswithothermedicationshavenotbeenconducted,

butthatsuchinteractionsmayoccur.

4.6Fertility,pregnancyandlactation

Useduringpregnancy

Therearenoadequateandwellcontrolledstudiesinpregnantwomen.Therehavebeenreportsofmultiple

congenitalabnormalitiesininfantswhosemotherswerebeingtreatedfor3ormoremonthswithhighdose(400-

800mg/day)fluconazoletherapyforcoccidioidomycosis.Therelationshipbetweenfluconazoleuseandtheseevents

isunclear.

Useinpregnancyshouldbeavoidedexceptinpatientswithsevereorpotentiallylife-threateningfungalinfectionsin

whomfluconazolemaybeusediftheanticipatedbenefitoutweighsthepossiblerisktothefoetus.

Useduringlactation

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notrecommended.

4.7Effectsonabilitytodriveandusemachines

ExperiencewithByFluc200mgCapsulesindicatesthattherapyisunlikelytoimpairapatient’sabilitytodriveor

usemachinery.

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),azorubine(E122)andbrilliantblueFCF(E133).

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Storebelow30°C.

6.5Natureandcontentsofcontainer

Byfluc200mgcapsulesaresuppliedinPVC/PVdC-aluminiumblisterswithincardboardcartons.

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

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

HelsinnBirexTherapeuticsLtd

Damastown

Mulhuddart

Dublin15

8MARKETINGAUTHORISATIONNUMBER

PA915/28/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:15 th

April2005

Dateoflastrenewal:15 th

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10DATEOFREVISIONOFTHETEXT

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