FLUCOMEL

Main information

  • Trade name:
  • FLUCOMEL Capsule 150 Milligram
  • Dosage:
  • 150 Milligram
  • Pharmaceutical form:
  • Capsule
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FLUCOMEL Capsule 150 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1044/005/002
  • Authorization date:
  • 21-10-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Flucomel150 mg Capsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each hard capsulecontains150mg fluconazole.

Forexcipients, see6.1.

3PHARMACEUTICALFORM

Hard capsule.

Size1 hard capsulewith awhitecap and awhitebody.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Therapy may beinstituted beforetheresultsoftheculturesand otherlaboratory studiesareknown;however, once

theseresultsbecomeavailableanti-infectivetherapy should beadjusted accordingly.

Flucomelisindicated for:

Genitalcandidiasis.Vaginalcandidiasis, acuteorrecurrent.Candidalbalanitis.

Mucosalcandidiasis.Theseincludeoropharyngeal, oesophageal, non-invasivebronchopulmonary infections,

candiduria, mucocutaneousand chronicoralatrophiccandidiasis(denturesoremouth).Normalhostsand patientswith

compromised immunefunction may betreated.

Systemiccandidiasisincluding candidaemia, disseminated candidiasisand otherformsofinvasivecandidal

infection.Theseincludeinfectionsoftheperitoneum, endocardiumand pulmonary and urinary tracts.Candidal

infectionsin patientswith malignancy, in intensivecareunitsofthosereceiving cytotoxicorimmunosuppressive

therapy, may betreated.

Cryptococcosis, including cryptococcalmeningitisand infectionsofothersites(e.g. pulmonary cutaneous).

Normalhostsand patientswith acquired immunedeficiency syndrome(AIDS), organ transplantsorothercausesof

immunosuppression maybetreated.Flucomelcan beused asmaintenancetherapy to preventrelapseofcryptococcal

diseasein patientswith AIDS.

Prevention offungalinfectionsin patientswith malignancy who arepredisposed to such infectionsasaresultof

cytotoxicchemotherapy orradiotherapy, including bonemarrowtransplantpatients.

Dermatomycosesincluding tineapedis, tineacorporis,tineacruris, tineaversicolorand candidainfections, only

wheretheseconditionsareresistantto firstlinetherapy orwhereoccurrenceisin immunocompromised patients.

4.2Posologyandmethodofadminstration

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Thedaily doseofFlucomelshould bebased on thenatureand severity ofthefungalinfection.Mostcasesofvaginal

candidiasisrespond tosingledosetherapy.Therapy forthosetypesofinfectionsrequiring multipledosetreatment

should becontinued untilclinicalparametersorlaboratory testsindicatethatactivefungalinfection hassubsided.

An inadequateperiod oftreatmentmay lead to recurrenceofactiveinfection.Patientswith AIDSand cryptococcal

meningitisusually requiremaintenancetherapy to preventrelapse.

Usein adults:

Candidalvaginitisorbalanitis.Theusualdosageis150mg asasingledose.

MucosalCandidiasis:

Oropharyngealcandidiasis:therecommended doseis50mg oncedaily for7 to 14 days.Treatmentmay continuefora

longerperiod ifthephysician so requires.

Atrophicoralcandidiasisassociated with dentures:therecommended doseis50mg oncedaily for14 daysadministered

concurrently with localantisepticmeasuresto thedenture.

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

bronchopulmonary infections, candiduria, mucocutaneouscandidiasisetc., therecommended doseis50mg daily, given

for14 to 30 days.

In unusually difficultcasesofmucosalcandidalinfectionsthedosemay beincreased to 100mg daily.

Forcandidaemia, disseminated candidiasisand otherinvasivecandidalinfections:therecommended doseis

400mg on thefirstday followed by 200mg oncedaily.Depending on theclinicalresponsethedosemay beincreased

to 400mg oncedaily.Duration oftreatmentisbasedupon theclinicalresponse.

Forcryptococcalmeningitisand cryptococcalinfectionsatothersites:therecommended doseis400mg on the

firstday followed by 200mg–400mg oncedaily.Duration oftreatmentforcryptococcalinfectionswilldependon the

clinicaland mycologicalresponse, butisusually atleast6 to 8 weeksforcryptococcalmeningitis.

Fortheprevention ofrelapsecryptococcalmeningitisin patientswith AIDS, afterthepatientreceivesafull

courseofprimary therapy.Flucomelmay beadministered indefinitely atadaily doseof100–200mg.

Therecommendeddosagefortheprevention ofcandidiasisis50to 400mg oncedaily, based on thepatient’srisk

ofdeveloping fungalinfection.Forpatientsathigh risk ofsystemicinfection e.g. patientswho areanticipated to have

profound orprolonged neutropeniasuch asduring bonemarrowtransplantation, therecommended doseis400mg once

daily.Flucomeladministration should startseveraldaysbeforetheanticipated onsetofneutropenia, and continuefor7

daysaftertheneutrophilcountrisesabove1000 cellspermm.

Fordermalinfectionsincluding tineapedis, corporis, crurisand candidainfectionstherecommended dosageis

150mg onceweekly or50mg oncedaily.Duration oftreatmentisnormally 2 to 4 weeksbuttineapedismay require

treatmentforup to 6 weeks.

Fortineaversicolortherecommendeddoseis50mgoncedaily for2 to 4 weeks.

Usein children:

Aswithsimilarinfectionsin adults, theduration oftreatmentisbased on theclinicaland mycologicalresponse.The

maximumadultdosageshould notbeexceeded in children.Flucomelisadministered asasingledaily doseeach day.

Forchildren with impairedrenalfunction, seedosing in“Usein patientswith impaired renalfunction”.

Children overfourweeksofage:

Mucosalcandidiasis:therecommended dosageofFlucomelis3 mg/kg daily.Aloading doseof6 mg/kg may beused

on thefirstday to achievesteady statelevelsmorerapidly.

Systemiccandidiasisand cryptococcalinfection:therecommended dosageoffluconazoleis6–12 mg/kg daily,

depending on theseverity ofthedisease.

Fortheprevention offungalinfectionsin immunocompromisedpatientsconsidered atrisk asaconsequenceof

neutropeniafollowing cytotoxicchemotherapy orradiotherapy, thedoseshould be3–12 mg/kg daily depending on

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Children fourweeksofageand younger:

Neonatesexcretefluconazoleslowly.In thefirsttwo weeksoflifethesamemg/kg dosing asin olderchildren should

beused butadministered every 72 hours.During weeks3 and 4 oflife, thesamedoseshould begiven every 48 hours.

Usein theelderly:

Thenormaldoseshouldbeused ifthereisno evidenceofrenalimpairment.In patientswith renalimpairment

(creatinineclearancelessthan 50 ml/min)thedosagescheduleshould beadjusted asdescribed below.

Usein patientswith impaired renalfunction:

Fluconazoleisexcreted predominatelyin theurineasan unchanged drug.No adjustmentsin singledosetherapy are

required.In patients(including children)with impairedrenalfunction who willreceivemultipledosesofFlucomel, the

normalrecommended dose(according to indication)should begiven on day 1, followed by adaily dosebased on the

followingtable:

Flucomelshould beswallowed whole.

4.3Contraindications

Flucomelshould notbeused in patientswith known hypersensitivity to fluconazoleortorelated azolecompounds, or

any otheringredientin theformulation.

Co-administration ofterfenadineiscontra-indicated in patientsreceiving Flucomelatmultipledosesof400mg perday

orhigherbased upon resultsofamultipledoseinteraction study.

Co-administration ofcisaprideiscontra-indicated in patientsreceiving Flucomel.(See“Interaction with other

medicinalproductsand otherformsofinteraction”.)

4.4Special warningsandprecautionsforuse

In somepatients, particularly thosewith seriousunderlying diseasessuch asAIDSand cancer, abnormalitiesofhepatic,

renal, haematologicaland otherbiochemicalfunction testshavebeen observed during treatmentwith fluconazolebut

theclinicalsignificanceand relationship to treatmentisuncertain.

Fluconazolehasbeen associated with rarecasesofserioushepatictoxicity including fatalities, primarily in patients

with seriousunderlying medicalconditions.In casesoffluconazole-associated hepatotoxicity no obviousrelationship

to totaldaily dose, duration oftherapy, sex orageofpatienthasbeen observed.

Fluconazolehepatotoxicity hasusually been reversibleon discontinuation oftherapy.Patientswhodevelop abnormal

liverfunction testsduring fluconazoletherapy shouldbemonitored forthedeveloped ofmoreserioushepaticinjury.

Flucomelshould bediscontinued ifclinicalsignsofsymptomsconsistentwith liverdiseasedevelop thatmay be

attributableto Flucomel.

Patientshaverarely developed exfoliativecutaneousreactions, such asStevens-Johnson Syndromeand toxicepidermal

necrolysis, during treatmentwith fluconazole.AIDSpatientsaremoreproneto thedevelopmentofseverecutaneous

reactionsto many drugs.Ifarash developsin apatienttreated forasuperficialfungalinfection which isconsidered

attributableto Flucomel, furthertherapy with thisagentshould bediscontinued.Ifpatientswith invasive/systemic

fungalinfection develop rashes, they should bemonitored closely and Flucomeldiscontinued ifbullouslesionsor

erythemamultiformedevelop.

Creatinineclearance(ml/min) Percentofrecommended dose

>50

50 (no dialysis)

Regulardialysis 100%

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In rarecases, aswith otherazoles, anaphylaxishasbeen reported.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Rifampicin:Concomitantadministration offluconazoleand rifampicin hasresulted in a25%decreasein theAUCand

20%shorterhalf-lifeoffluconazole.In patientsreceiving concomitantrifampicin, anincreasein thefluconazoledose

should beconsidered.

Hydrochlorothiazide:In akineticinteraction study, co-administration ofmultiple-dosehydrochlorothiazideto healthy

volunteersreceiving fluconazoleincreased plasmaconcentrationsoffluconazoleby 40%.An effectofthismagnitude

should notnecessitateachangein thefluconazoledoseregimen insubjectsreceiving concomitantdiuretics, although

theprescribershould bearitin mind.

Anticoagulants:In an interaction study, fluconazoleincreased theprothrombin time(12%)afterwarfarin

administration in healthy males.In post-marketing experiences, aswith otherazoleantifungals, bleeding events

(bruising, epistaxis, gastrointestinalbleeding, hematuriaand melaena)havebeen reported, in association with increases

in prothrombin timein patientsreceiving fluconazoleconcurrently with warfarin.Prothrombin timein patients

receiving coumarin-typeanticoagulantsshould becarefully monitored.

Benzodiazepines(shortacting):Following oraladministration ofmidazolam, fluconazoleresulted in substantial

increased in midazolamconcentrationsand psychomotoreffects.Thiseffecton midazolamappearsto bemore

pronounced following oraladministration offluconazolethan with fluconazoleadministered intravenously.If

concomitantbenzodiazepinetherapy isnecessary in patientsbeing treated with fluconazole, consideration should be

given to decreasing thebenzodiazepinedosage, and thepatientsshould beappropriately monitored.

Sulphonylureas:Fluconazolehasbeen shown to prolong theserumhalf-lifeofconcomitantly administered oral

sulphonylureas(chlorpropamide, glibenclamide, glipzideand tolbutamide)in healthy volunteers.Fluconazoleand oral

sulphonylureasmay beco-administered to diabeticpatients, butthepossibility ofhypoglycaemicepisodeshould be

bornein mind.

Phenytoin:Concomitantadministration offluconazoleand phenytoin may increasethelevelsofphenytoin to a

clinically significantdegree.Ifitisnecessary to administerboth drugsconcomitantly, phenytoin levelsshould be

monitored and phenytoin doseadjusted to maintain therapeuticlevels.

Oralcontraceptives:Two kineticstudieswith combined oralcontraceptiveshavebeen performed using multipledoses

offluconazole.

Thereno relevanteffectson eitherhormonelevelin the50mg fluconazolestudy, whileat200mg daily theAUCs’of

ethinylestradioland levonorgestrelwereincreased 40%and 24%respectively.Thusmultipledoseuseoffluconazole

atthesedosesisunlikely to havean effecton theefficacy ofthecombined oralcontraceptive.

Endogenoussteroid:Fluconazole50mg daily doesnotaffectendogenoussteroid levelsin females.200–400mg daily

hasno clinically significanteffecton endogenoussteroid levelsoron ACTHstimulated responsein healthy male

volunteers.

Cyclosporin:Akineticstudy in renaltransplantpatientsfound fluconazole200mg daily to slowly increasecyclosporin

concentrations.

However, in anothermultipledosestudy with 100mg daily fluconazoledid notaffectcyclosporin levelsin patients

with bonemarrowtransplants.Cyclosporin plasmaconcentrationsmonitoring patientsreceiving fluconazoleis

recommended.

Theophylline:In aplacebo-controlled interaction study, theadministration offluconazole200mg for14 daysresulted

in an 18%decreasein themean plasmaclearanceoftheophylline.Patientswhoarereceiving high dosesof

theophyllineorwho areotherwiseatincreased risk fortheophyllinetoxicity should beobserved forsignsof

theophyllinetoxicity whilereceiving fluconazoleand thetherapy modified appropriately ifsignsoftoxicity develop.

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tacrolimus, leading to increased serumlevelsoftacrolimus.

Therehavebeen reportsofnephrotoxicity in patientsto whomfluconazoleand tacrolimuswereco-administered.

Patientsreceiving tacrolimusand fluconazoleconcomitantly should becarefully monitored.

Rifabutin:Therehavebeen reportsthataninteraction existswhen fluconazoleisadministered concomitantly with

rifabutin, leading to increased serumlevelsofrifabutin.Therehavebeen reportsofuveitisin patientsto whom

fluconazoleand rifabutin wereco-administered.Patientsreceiving rifabutin and fluconazoleconcomitantly should be

carefully monitored.

Terfenadine:Becauseoftheoccurrenceofserouscardiacdysrhythmiassecondary to prolongation oftheQTcinterval

in patientsreceiving azoleantifungalsin conjunction with terfenadine, interaction studieshavebeen performed.One

study ata200mg daily doseoffluconazolefailed to demonstrateaprolongation in QTcinterval.Anotherstudy ata

400mg and 800mg daily doseoffluconazoledemonstrated thatfluconazoletaken in dosesof400mg perdayorgreater

significantly increasesplasmalevelsofterfenadinewhentaken concomitantly.Thecombined useoffluconazoleat

dosesof400mg orgreaterwith terfenadineiscontra-indicated.(See“Contra-indications”.)Theco-administration of

fluconazoleatdoseslowerthan 400mg perdaywith terfenadineshould becarefully monitored.

Cisapride:Therehavebeen reportsofcardiaceventsincluding torsadedepointesin patientsto whomfluconazoleand

cisapridewereco-administered.Co-administration ofcisaprideiscontra-indicated in patientsreceiving fluconazole.

Theuseoffluconazolein patientsconcurrently taking astemizoleorotherdrugsmetabolised by thecytochromeP450

systemmay beassociated with elevationsin serumlevelsofthesedrugs.In theabsenceofdefinitiveinformation,

caution should beused when co-administering fluconazole.Patientsshould becarefully monitored.

Zidovudine:Two kineticstudiesresulted in increased levelsofzidovudinemostlikely caused by thedecreased

conversion ofzidovudineto itsmajormetabolite.Onestudy determined zidovudinelevelsinAIDSorARCpatients

beforeand following fluconazole200mg daily for15 days.Therewasasignificantincreasein zidovudineAUC

(20%).Asecondrandomised, two period, two-treatmentcrossoverstudy examined zidovudinelevelsin HIVinfected

patients.

On two occasions, 21 daysapart, patientsreceived zidovudine200mg every eighthourseitherwith orwithout

fluconazole400mg daily forseven days.TheAUCofzidovudinesignificantly increased (74%)during co-

administration with fluconazole.Patientsreceiving thiscombination should bemonitored forthedevelopmentof

zidovudinerelated adversereactions.

Interaction studieshaveshown thatwhen oralfluconazoleisco-administered with food, cimetidine, antacidsor

followingtotalbody irradiation forbonemarrowtransplantation, no clinically significantimpairmentoffluconazole

absorption occurs.

Physiciansshould beawarethatdrug-drug interaction studieswith othermedicationshavenotbeen conducted, butthat

such interactionsmay occur.

4.6Pregnancyandlactation

Thereareno adequateand well-controlled studiesin pregnantwomen.Therehavebeen reportsofmultiplecongenital

abnormalitiesin infantswhosemotherswerebeing treated for3 ormoremonthswith high dose(400–800 mg/day)

fluconazoletherapy forcoccidioidomycosis.Therelationship betweenfluconazoleuseand theseeventsisunclear.

Usein pregnancy should beavoided expectin patientswith severeorlife-threatening fungalinfectionsin whom

fluconazolemay beused iftheanticipated benefitoutweighsthepossiblerisk to thefoetus.

Useduring lactation:Fluconazoleisfoundin human breastmilk atconcentrationssimilarto plasma, henceitsusein

nursing mothersisnotrecommended.

4.7Effectsonabilitytodriveandusemachines

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4.8Undesirableeffects

Fluconazoleisgenerally welltolerated.Themostcommon sideeffectsobserved during clinicaltrialsand associated

with fluconazoleare:

Centraland PeripheralNervousSystem:Headache.

Dermatological:Rash.

Gastrointestinal:Abdominalpain, diarrhoea, flatulence, nausea.

In somepatients, particularly thosewith seriousunderlying diseasessuch asAIDSand cancer, changesin renaland

haematologicalfunction testresultsand hepaticabnormalitieshavebeen observed during treatmentwith fluconazole

and comparativeagents, buttheclinicalsignificanceand relationship to treatmentisuncertain(see“Specialwarnings

and specialprecautionsforuse”).

Liver/Biliary:Hepatictoxicity including rarecasesoffatalities, elevated alkalinephosphatase, elevated bilirubin,

elevated SGOT, elevated SGPT.

In addition, thefollowing adverseeventshaveoccurred during post-marketing:

Centraland PeripheralNervousSystem:Dizziness, seizures.

Dermatological:Alopecia, exfoliativeskin disordersincluding Stevens-Johnson syndromeand toxicepidermal

necrolysis.

Gastrointestinal:Dyspepsia, vomiting.

Haematopoieticand Lymphatic:Leucopeniaincluding neutropeniaand agranulocytosis, thrombocytopenia.

ImmunologicalAnaphylaxis:(including angioedema, faceoedema, pruritus).

Liver/Biliary:Hepaticfailure, hepatitis, hepatocellularnecrosis, jaundice.

Metabolic/Nutritional:Hypercholesterolaemia, hyper-triglyceridaemia, hypokalaemia.

Othersenses:Tasteperversion.

4.9Overdose

Therehavebeen reportsofoverdosagewith fluconazoleand in onecase, a42 yearoldpatientinfected with human

immunodeficiency virusdeveloped hallucinationsand exhibitedparanoid behaviourafterreportedly ingesting 8200mg

offluconazole.Thepatientwasadmitted to hospitaland hiscondition resolved within 48 hours.

In theeventofoverdosage,supportivemeasuresand symptomatictreatmentwith gastriclavageifnecessary, may be

adequate.Asfluconazoleislargely excreted in urine, forced volumediuresiswould probably increasetheelimination

rate.Athreehourhaemodialysissession decreasesplasmalevelsby approximately 50%.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Fluconazole, amemberofthetriazoleclassofantifungalagents, isapotentand selectiveinhibitoroffungalenzymes

necessary forthesynthesisofergosterol.

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pentobarbitonesleeping timesin mice(p.o.), increased mean arterialand leftventricularblood pressureand increased

heartratein anaesthetised cats(i.v.)occurred.Inhibition ofratovarian aromatasewasobserved athigh concentrations.

Both orally and intravenously administered fluconazolewasactivein avariety ofanimalfungalinfected models.

Activity hasbeendemonstrated againstopportunisticmycoses, suchasinfectionswithCandidaspp.including systemic

candidiasisin immunocompromised animals;withCryptococcusneoformans, including intracranialinfections;with

Microsporumspp.and withTrichophytonspp.Fluconazolehasalso been shown to beactivein animalmodelsof

endemicmycoses, including infectionswithBlastomycesdermatitides;withCoccidioidesimmitis,including

intracranialinfection withHistoplasma capsulatumin normaland immunosuppressed animals.

Therehavebeen reportsofcasesofsuperinfection withCandidaspeciesotherthanC. albicans,which areoften

inherently notsusceptibleto fluconazole(e.g.Candida krusei).Such casesmay requirealternativeantifungaltherapy.

Fluconazoleishighly specificforfungalcytochromeP-450 dependentenzymes.Fluconazole50mg daily given up to

28 dayshasbeen shown notto affecttestosteroneplasmaconcentrationsin malesorsteroid concentrationsin females

ofchild-bearing age.Fluconazole200–400mg daily hasnotclinically significanteffecton endogenoussteroid levels

oron ACTHstimulated responsein healthy malevolunteers.

Interaction studieswith antipyrineindicatethatsingleormultipledosesoffluconazole50mg do notaffectit

metabolism.

5.2Pharmacokineticproperties

Thepharmacokineticpropertiesoffluconazolearesimilarfollowing administration by theintravenousororalroute.

Afteroraladministration, fluconazoleiswellabsorbed, and plasmalevels(and systemicbioavailability)areover90%

ofthelevelsachieved afterintravenousadministration.Oralabsorptionisnotaffected by concomitantfood intake.

Peak plasmaconcentrationsin thefasting stateoccurbetween 0.5 and 1.5 hourspostdosewith aplasmaelimination

half-lifeofapproximately 30 hours.Plasmaconcentrationsareproportionalto dose.Ninety percentsteady-statelevels

arereached byday 4–5 with multipleoncedaily dosing.

Administration ofloading dose(on day 1)oftwicetheusualdaily doseenablesplasmalevelsto approximateto 90%

steady-statelevelsby day 2.Theapparentvolumeofdistribution approximatesto totalbody water.

Plasmaprotein binding islow(11-12%).Fluconazoleachievesgood penetration into allbody fluidsstudied.The

levelsoffluconazoleinsalivaand sputumaresimilarto plasmalevels.In patientswith fungalmeningitis, fluconazole

levelsin theCSFareapproximately 80%thecorrespondingplasmalevels.High skin concentrationsoffluconazole,

aboveserumconcentrations, areachieved in thestratumcorneum, epidermis-dermisand eccrinesweat.Fluconazole

accumulatesin thestratumcorneum.Atadoseof50mg oncedaily, theconcentrationsoffluconazoleafter12 dayswas

73 microgram/g and 7 daysaftercessation oftreatmenttheconcentration wasstill5.8 microgram/g.

Themajorrouteofexcretion isrenalwith approximately 80%oftheadministered doseappearing in theurineas

unchanged drug.Fluconazoleclearanceisproportionalto creatinineclearance.Thereisno evidenceofcirculating

metabolites.

Thelong plasmaelimination half-lifeprovidesthebasisforsingledosetherapy forgenitalcandidiasisand once-daily

dosing in thetreatmentofallotherindicatedfungalinfections.

Pharmacokineticsin Children:In children, thefollowing pharmacokineticdatahavebeen reported:

AgeStudied Dose

(mg/kg) Half-life

(hours) AUC

(microgram/ml)

11 days–11 months Single-IV

3 mg/kg 23 110.1

9 months–13 years Single-Oral

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* Denotesfinalday

In prematurenew-borns(gestationalagearound 28 weeks), intravenousadministration offluconazoleof6 mg/kg was

given every third day foramaximumoffivedayswhiletheprematurenew-bornsremained in theintensivecareunit.

Themean half-life(hours)was74 (range44–185)on day 1 which decreased with timetoameanof53 (range30–

131)on day 7 and 47 (range27–68)on day 13.

Theareaunderthecurve(microgram.h/ml)was271 (range173–385)on day 1 which increased with amean of490

(range292–734)on day 7 and decreased with amean of360 (range167–566)on day 13.

Thevolumeofdistribution (ml/kg)was1183 (range1070–1470)on day 1 which increasedwith timeto amean of

1184 (range510–2130)on day 7 and 1328 (range1040–1680)on day 13.

5.3Preclinical safetydata

Reproductivetoxicity:Therewereno fetaleffectson 5 or10 mg/kg;increasesin fetalanatomicalvariants

(supernumerary ribs, renalpelvis, dilation)and delaysin ossification wereobserved at25 and 50 mg/kg and higher

doses.Atdosesranging from80 mg/kg(approximately 20-60x therecommended human dose)to 320 mg/kg

embryolethality in ratswasincreased and fetalabnormalitiesincluded wavy ribs, cleftpalateand abnormalcranio-

facialossification.Theseeffectsareconsistentwith theinhibition ofoestrogen synthesisin ratsand may bearesultof

known effectsoflowered oestrogen on pregnancy, organogenesisand parturition.

Carcinogenesis:Fluconazoleshowed no evidenceofcarcinogenicpotentialin miceand ratstreated orally for24

monthsatdosesof2.5, 5 or10 mg/kg/day.Maleratstreated with 5 and 10 mg/kg/day had an increased incidenceof

hepatocellularadenomas.

Mutagenesis:Fluconazole, with orwithoutmetabolicactivation, wasnegativein testsformutagenicity in 4 strainsatS.

typhimuriumand in themouselymphomaL5178Ysystem.Cytogeneticstudiesinvivo(murinebonemarrowcells,

followingoraladministration offluconazole)andin vitro(human lymphocytesexposed to fluconazoleat1000µg/ml)

showed no evidenceofchromosomalmutations.

Impairmentoffertility:Fluconazoledid notaffectthefertility ofmaleorfemaleratstreated orally withdaily dosesof

5, 10, 20 mg/kg orwithparenteraldosesof5, 25 or75 mg/kg, although theonsetofparturition wasslightly delayed at

20 mg/kg p.o.In an intravenousperinatalstudy in ratsat5, 20 and 40 mg/kg, dystociaand prolongation ofparturition

wereobserved in afewdamsat20 mg/kg and40 mg/kg, butnotat5 mg/kg.Thedisturbancesin parturition were

reflected by aslightincreasein thenumberofstill-born pupsand decreaseofneonatalsurvivalatthesedoselevels.

Theeffectsonparturition in ratsareconsistentwith thespeciesspecificoestrogen-lowering property produced by high

9 months–13 years Single-Oral

8 mg/kg 19.5 362.5

5 years–15 years Multiple-Oral

2 mg/kg 17.4* 67.4

5 years–15 years Multiple-Oral

4 mg/kg 15.2* 139.1

5 years–15 years Multiple-Oral

8 mg/kg 17.6* 196.1

5 years–15 years Multiple-Oral

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Pregelatinised starch

Colloidalanhydroussilica

Magnesiumstearate

Gelatin

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3 years.

6.4Special precautionsforstorage

No specialprecautionsforstorage.

6.5Natureandcontentsofcontainer

PVC/PVdCaluminiumblistersin packsof1, 2, 4, 6, 7, 10, 14, 20, 21, 28, 30, 50,60, 90 and 100 capsules.

Notallpack sizesmay bemarketed.

6.6Instructionsforuseandhandling

No specialrequirements.

7MARKETINGAUTHORISATIONHOLDER

KellpharmLtd.

127 Chapelgate

Dublin 9

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA1044/5/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 21 st

October2005

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