DIFLUCAN SOLUTION FOR INFUSION 2 MG/ML (50MG/25ML)

Main information

  • Trade name:
  • DIFLUCAN SOLUTION FOR INFUSION 2 MG/ML (50MG/25ML)
  • Dosage:
  • 2 Mg/Ml
  • Pharmaceutical form:
  • Solution for Infusion
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DIFLUCAN SOLUTION FOR INFUSION 2 MG/ML (50MG/25ML)
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0019/044/006
  • Authorization date:
  • 22-08-1989
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DiflucanSolutionforInfusion2mg/ml(50mg/25ml)

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each1mlcontains2mgfluconazole(50mg/25ml).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Solutionforinfusion

Aclear,sterile,colourlesssolution.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Therapymaybeinstitutedbeforetheresultsoftheculturesandotherlaboratorystudiesareknown;however,once

theseresultsbecomeavailable,anti-infectivetherapyshouldbeadjustedaccordingly.

Diflucanisindicatedfor:

Genitalcandidiasis.Vaginalcandidiasis,acuteorrecurrent.Candidalbalanitis.

Mucosalcandidiasis.Theseincludeoropharyngeal,oesophageal,non-invasivebronchopulmonary

infections,candiduria,mucocutaneousandchronicoralatrophiccandidiasis(denturesoremouth).

Normalhostsandpatientswithcompromisedimmunefunctionmaybetreated.

Systemiccandidiasisincludingcandidaemia,disseminatedcandidiasisandotherformsofinvasive

candidalinfection.Theseincludeinfectionsoftheperitoneum,endocardiumandpulmonaryand

urinarytracts.Candidalinfectionsinpatientswithmalignancy,inintensivecareunitsorthosereceiving

cytotoxicorimmunosuppressivetherapy,maybetreated.

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

Normalhostsandpatientswithacquiredimmunedeficiencysyndrome(AIDS),organtransplantsor

othercausesofimmunosuppressionmaybetreated.Diflucancanbeusedasmaintenancetherapyto

preventrelapseofcryptococcaldiseaseinpatientswithAIDS.

Preventionoffungalinfectionsinpatientswithmalignancywhoarepredisposedtosuchinfectionsasaresult

ofcytotoxicchemotherapyorradiotherapy,includingbonemarrowtransplantpatients.

Dermatomycosesincludingtineapedis,tineacorporis,tineacruris,tineaversicolorandcandidainfections,

onlywheretheseconditionsareresistanttofirstlinetherapyorwhereoccurrenceisinimmunocompromised

patients.

Useinchildren

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 1

4.2Posologyandmethodofadministration

Diflucanmaybeadministeredeitherorallyorbyintravenousinfusionatarateofapproximately5-10ml/min,theroute

beingdependentontheclinicalstateofthepatient.Ontransferringfromtheintravenousroutetotheoralrouteorvice

versa,thereisnoneedtochangethedailydose.DiflucanIntravenousInfusionisformulatedin0.9%sodiumchloride

solution,each200mg(100mlbottle)containing15mmoleachofNa +

andC1 -

ThedailydoseofDiflucanshouldbebasedonthenatureandseverityofthefungalinfection.Mostcasesofvaginal

candidiasisrespondtosingledosetherapy.Therapyforthosetypesofinfectionsrequiringmultipledosetreatment

shouldbecontinueduntilclinicalparametersorlaboratorytestsindicatethatactivefungalinfectionhassubsided.An

inadequateperiodoftreatmentmayleadtorecurrenceofactiveinfection.PatientswithAIDSandcryptococcal

meningitisusuallyrequiremaintenancetherapytopreventrelapse.

Useinadults

Candidalvaginitisorbalanitis.Theusualdosageis150mgasasingledose.

MucosalCandidiasis

Oropharyngealcandidiasis:therecommendeddoseis50mgoncedailyfor7to14days.Treatmentmaycontinuefora

longerperiodifthephysiciansorequires.

Atrophicoralcandidiasisassociatedwithdentures:therecommendeddoseis50mgoncedailyfor14days

administeredconcurrentlywithlocalantisepticmeasurestothedenture.

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

bronchopulmonaryinfections,candiduria,mucocutaneouscandidiasisetc.,therecommendeddoseis50mgdaily,given

for14to30days.

Inunusuallydifficultcasesofmucosalcandidalinfectionsthedosemaybeincreasedto100mgdaily.

Forcandidaemia,disseminatedcandidiasisandotherinvasivecandidalinfections:therecommendeddoseis

400mgonthefirstdayfollowedby200mgoncedaily.Dependingontheclinicalresponsethedosemaybe

increasedto400mgoncedaily.Durationoftreatmentisbasedupontheclinicalresponse.

Forcryptococcalmeningitisandcryptococcalinfectionsatothersites:therecommendeddoseis400mgonthe

firstdayfollowedby200mg-400mgoncedaily.Durationoftreatmentforcryptococcalinfectionswilldepend

ontheclinicalandmycologicalresponse,butisusuallyatleast6to8weeksforcryptococcalmeningitis.

ForthepreventionofrelapseofcryptococcalmeningitisinpatientswithAIDS,afterthepatientreceivesafull

courseofprimarytherapy,Diflucanmaybeadministeredindefinitelyatadailydoseof100-200mg.

Therecommendeddosageforthepreventionofcandidiasisis50to400mgoncedaily,basedonthepatient’s

riskofdevelopingfungalinfection.Forpatientsathighriskofsystemicinfectione.g.patientswhoare

anticipatedtohaveprofoundorprolongedneutropeniasuchasduringbonemarrowtransplantation,the

recommendeddoseis400mgoncedaily.Diflucanadministrationshouldstartseveraldaysbeforethe

anticipatedonsetofneutropenia,andcontinuefor7daysaftertheneutrophilcountrisesabove1000cellsper

Fordermalinfectionsincludingtineapedis,corporis,crurisandcandidainfectionstherecommendeddosageis

150mgonceweeklyor50mgoncedaily.Durationoftreatmentisnormally2to4weeksbuttineapedismay

requiretreatmentforupto6weeks.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 2

Useinchildren:

Aswithsimilarinfectionsinadults,thedurationoftreatmentisbasedontheclinicalandmycological

response.Diflucanisadministeredasasingledailydose.

Forchildrenwithimpairedrenalfunction,seedosingin‘Useinpatientswithimpairedrenalfunction’.

Childrenoverfourweeksofage:

TherecommendeddosageofDiflucanformucosalcandidiasisis3mg/kgdaily.Aloadingdoseof6mg/kgmaybeused

onthefirstdaytoachievesteadystatelevelsmorerapidly.

Forthetreatmentofsystemiccandidiasisandcryptococcalinfection,therecommendeddoseis6-12mg/kgdaily,

dependingontheseverityofdisease.

Forthepreventionoffungalinfectionsinimmunocompromisedpatientsconsideredatriskasaconsequenceof

neutropeniafollowingcytotoxicchemotherapyorradiotherapy,thedoseshouldbe3-12mg/kgdailydependingonthe

extentanddurationoftheinducedneutropenia.(Seeadultdosing).

Amaximumdosageof400dailyshouldnotbeexceededinchildren.

Childrenfourweeksofageandyounger:

Neonatesexcretefluconazoleslowly.Inthefirsttwoweeksoflifethesamemg/kgdosingasinolderchildrenshould

beusedbutadministeredevery72hours.Duringweeks3and4oflifethesamedoseshouldbegivenevery48hours.

TherearefewPKdatatosupportthisposologyintermnewbornbaby(Seesection5.2–Pharmacokineticproperties).

Amaximumdosageof12mg/kgevery72hoursshouldnotbeexceededinchildreninthefirsttwoweeksoflife.For

childrenbetween3and4weeksoflife,12mg/kgevery48hoursshouldnotbeexceeded.

Thepharmacokineticsoffluconazolehasnotbeenstudiedinchildrenwithrenalinsufficiency.

Useintheelderly:

Thenormaldoseshouldbeusedifthereisnoevidenceofrenalimpairment.Inpatientswithrenalimpairment

(creatinineclearancelessthan50ml/min)thedosagescheduleshouldbeadjustedasdescribedbelow.

Useinpatientswithimpairedrenalfunction:

Fluconazoleisexcretedpredominantlyintheurineasunchangeddrug.Noadjustmentsinsingledosetherapyare

required.Inpatients(includingchildren)withimpairedrenalfunctionwhowillreceivemultipledosesofDiflucan,the

normalrecommendeddose(accordingtoindication)shouldbegivenonday1,followedbyadailydosebasedonthe

followingtable:

CompatibilityofIntravenousInfusion

AlthoughfurtherdilutionisunnecessaryDiflucanIntravenousInfusioniscompatiblewiththefollowingadministration

fluids:

Dextrose20%

Ringer’ssolution

Hartmann’ssolution

Potassiumchlorideindextrose

Sodiumbicarbonate4.2%

Creatinineclearance(ml/min) Percentofrecommendeddose

>50 100%

<50(nodialysis) 50%

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 3

Peritonealdialysissolution

Normalsaline(0.9%)

Diflucanmaybeinfusedthroughanexistinglinewithoneoftheabovelistedfluids.Althoughnospecific

incompatibilitieshavebeennoted,mixingwithanyotherdrugpriortoinfusionisnotrecommended.

4.3Contraindications

Diflucanshouldnotbeusedinpatientswithknownhypersensitivitytofluconazoleortorelatedazolecompounds,or

anyotheringredientintheformulation.

Co-administrationofterfenadineiscontra-indicatedinpatientsreceivingDiflucanatmultipledosesof400mgperday

orhigherbaseduponresultsofamultipledoseinteractionstudy.

Co-administrationofotherdrugsknowntoprolongtheQTintervalandwhicharemetabolisedviatheenzyme

CYP3A4suchascisapride,astemizole,pimozideandquinidinearecontra-indicatedinpatientsreceivingDiflucan.

(See,Sections4.4Specialwarningsandspecialprecautionsforuseandsection4.5“Interactionwithothermedicinal

productsandotherformsofinteraction”).

4.4Specialwarningsandprecautionsforuse

Insomepatients,particularlythosewithseriousunderlyingdiseasessuchasAIDSandcancer,abnormalitiesofhepatic,

renal,haematologicalandotherbiochemicalfunctiontestshavebeenobservedduringtreatmentwithDiflucanbutthe

clinicalsignificanceandrelationshiptotreatmentisuncertain.

Diflucanhasbeenassociatedwithrarecasesofserioushepatictoxicityincludingfatalities,primarilyinpatientswith

seriousunderlyingmedicalconditions.IncasesofDiflucan-associatedhepatotoxicity,noobviousrelationshiptototal

dailydose,durationoftherapy,sexorageofpatienthasbeenobserved.Diflucanhepatotoxicityhasusuallybeen

reversibleondiscontinuationoftherapy.PatientswhodevelopabnormalliverfunctiontestsduringDiflucantherapy

shouldbemonitoredforthedevelopmentofmoreserioushepaticinjury.Diflucanshouldbediscontinuedifclinical

signsorsymptomsconsistentwithliverdiseasedevelopthatmaybeattributabletoDiflucan.

Patientshaverarelydevelopedexfoliativecutaneousreactions,suchasStevens-JohnsonSyndromeandtoxicepidermal

necrolysis,duringtreatmentwithfluconazole.AIDSpatientsaremorepronetothedevelopmentofseverecutaneous

reactionstomanydrugs.Ifarashdevelopsinapatienttreatedforasuperficialfungalinfectionwhichisconsidered

attributabletoDiflucan,furthertherapywiththisagentshouldbediscontinued.Ifpatientswithinvasive/systemic

fungalinfectionsdeveloprashes,theyshouldbemonitoredcloselyandDiflucandiscontinuedifbullouslesionsor

erythemamultiformedevelop.

Thereislittleinformationonsafetyinlong-termuse.

Inrarecases,aswithotherazoles,anaphylaxishasbeenreported.

Someazoles,includingfluconazole,havebeenassociatedwithprolongationoftheQTintervalonthe

electrocardiogram.Duringpost-marketingsurveillance,therehavebeenveryrarecasesofQTprolongationandtorsade

depointesinpatientstakingfluconazole.AlthoughtheassociationoffluconazoleandQT-prolongationhasnotbeen

fullyestablished,fluconazoleshouldbeusedwithcautioninpatientswithpotentiallyproarrythmicconditionssuchas:

CongenitalordocumentedacquiredQTprolongation

Cardiomyopathy,inparticularwhenheartfailureispresent

Sinusbradycardia

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 4

ConcomitantmedicationnotmetabolizedbyCY34AbutknowntoprolongQTinterval

Electrolytedisturbancessuchashypokalaemia,hypomagnesaemiaandhypocalaemia

(SeeSection4.5Interactionswithothermedicalproductsandotherformsofinteraction)

Patientswithrarehereditaryproblemsoffructoseintolerance,theLapplactosedeficiency,glucose-galactose

malabsorptionorsucrase-isomaltaseinsufficiencyshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantuseofthefollowingothermedicinalproductsiscontraindicated:

CisaprideTherehavebeenreportsofcardiaceventsincludingtorsadedepointesinpatientstowhomfluconazoleand

cisapridewereco-administered.Acontrolledstudyfoundthatconcomitantfluconazole200mgoncedailyand

cisapride20mgfourtimesadayyieldedasignificantincreaseincisaprideplasmalevelsandprolongationofQTc

interval.Co-administrationofcisaprideiscontra-indicatedinpatientsreceivingfluconazole(seesection4.3

Contraindiations).

TerfenadineBecauseoftheoccurrenceofseriouscardiacdysrhythmiassecondarytoprolongationoftheQTcinterval

inpatientsreceivingazoleantifungalsinconjunctionwithterfenadine,interactionstudieshavebeenperformed.One

studyata200mgdailydoseoffluconazolefailedtodemonstrateaprolongationinQTcinterval.Anotherstudyata

400mgand800mgdailydoseoffluconazoledemonstratedthatfluconazoletakenindosesof400mgperdayorgreater

significantlyincreasesplasmalevelsofterfenadinewhentakenconcomitantly.Thecombineduseoffluconazoleat

dosesof400mgorgreaterwithterfenadineiscontra-indicated.(See“Contraindications”.)Theco-administrationof

fluconazoleatdoseslowerthan400mgperdaywithterfenadineshouldbecarefullymonitored.

Astemizole:Concomitantadministrationoffluconazolewithastemizolemaydecreasetheclearanceofastemizole.

ResultingincreasedplasmaconcentrationsofastemizolecanleadtoQTprolongationandrareoccurrencesoftorsade

depointes.Coadministrationoffluconazoleandastemizoleiscontraindicated.

Pimozide:Althoughnotstudiedinvitroorinvivo,concomitantadministrationoffluconazolewithpimozidemay

resultininhibitionofpimozidemetabolism.IncreasedpimozideplasmaconcentrationscanleadtoQTprolongation

andrareoccurrencesoftorsadedepointes.Coadministrationoffluconazoleandpimozideiscontraindicated.

Concomitantuseofthefollowingothermedicinalproductscannotberecommended:

Erythromycin:Concomitantuseoffluconazoleanderythromycinhasthepotentialtoincreasetheriskofcardiotoxicity

(prolongedQTinterval,TorsadesdePointes)andconsequentlysuddenheartdeath.Thiscombinationshouldbe

avoided.

Concomitantuseofthefollowingothermedicinalproductsleadtoprecautionsanddoseadjustments:

RifampicinConcomitantadministrationoffluconazoleandrifampicinhasresultedina25%decreaseintheAUCand

20%shorterhalf-lifeoffluconazole.Inpatientsreceivingconcomitantrifampicin,anincreaseinthefluconazoledose

shouldbeconsidered.

HydrochlorothiazideInapharmacokineticinteractionstudy,co-administrationofmultiple-dosehydrochlorothiazide

tohealthyvolunteersreceivingfluconazoleincreasedplasmaconcentrationsoffluconazoleby40%.Aneffectofthis

magnitudeshouldnotnecessitateachangeintheDiflucandoseregimeninsubjectsreceivingconcomitantdiuretics,

althoughtheprescribershouldbearitinmind.

Theeffectoffluconazoleonothermedicinalproducts

FluconazoleisapotentinhibitorofcytochromeP450(CYP)isoenzyme2C9andamoderateinhibitorofCYP3A4.In

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 5

othercompoundsmetabolizedbyCYP2C9andCYP3A4co-administeredwithfluconazole.Thereforecautionshould

beexercisedwhenusingthesecombinationsandthepatientsshouldbecarefullymonitored.Theenzymeinhibiting

effectoffluconazolepersists4-5daysafterdiscontinuationoffluconazoletreatmentduetothelonghalf-lifeof

fluconazole(Seesection4.3Contraindications).

Alfentanil:AstudyobservedareductioninclearanceanddistributionvolumeaswellasprolongationofT½of

alfentanilfollowingconcomitanttreatmentwithfluconazole.Apossiblemechanismofactionisfluconazole’s

inhibitionofCYP3A4.Dosageadjustmentofalfentanilmaybenecessary.

Amitriptyline,nortriptyline:Fluconazoleincreasestheeffectofamitriptylineandnortriptyline.5-nortriptylineand/or

S-amitrptylinemaybemeasuredatinitiationofthecombinationtherapyandafteroneweek.Dosageof

amitriptyline/nortriptylineshouldbeadjusted,ifnecessary.

AmphotericineB:ConcurrentadministrationoffluconazoleandamphotericinBininfectednormaland

immunosuppressedmiceshowedthefollowingresults:asmalladditiveantifungaleffectinsystemicinfectionwithC.

albicans,nointeractioninintracranialinfectionwithCryptococcusneoformans,andantagonismofthetwodrugsin

systemicinfectionwithA.fumigatus.Theclinicalsignificanceofresultsobtainedinthesestudiesisunknown.

AnticoagulantsInaninteractionstudy,fluconazoleincreasedtheprothrombintime(12%)afterwarfarinadministration

inhealthymales.Inpost-marketingexperiences,aswithotherazoleantifungals,bleedingevents(bruising,epistaxis,

gastrointestinalbleeding,hematuria,andmelaena)havebeenreported,inassociationwithincreasesinprothrombin

timeinpatientsreceivingfluconazoleconcurrentlywithwarfarin.Prothrombintimeinpatientsreceivingcoumarin-

typeanticoagulantsshouldbecarefullymonitored.

AzithromycinAnopen-label,randomized,three-waycrossoverstudyin18healthysubjectsassessedtheeffectofa

single1200mgoraldoseofazithromycinonthepharmacokineticsofasingle800mgoraldoseoffluconazoleaswell

astheeffectsoffluconazoleonthepharmacokineticsofazithromycin.Therewasnosignificantpharmacokinetic

interactionbetweenfluconazoleandazithromycin.

Benzodiazepines(shortacting)Followingoraladministrationofmidazolam,fluconazoleresultedinsubstantial

increasesinmidazolamconcentrationsandpsychomotoreffects.Thiseffectonmidazolamappearstobemore

pronouncedfollowingoraladministrationoffluconazolethanwithfluconazoleadministeredintravenously.If

concomitantbenzodiazepinetherapyisnecessaryinpatientsbeingtreatedwithfluconazole,considerationshouldbe

giventodecreasingthebenzodiazepinedosage,andthepatientsshouldbeappropriatelymonitored.

FluconazoleincreasestheAUCoftriazolam(singledose)byapproximately50%,Cmaxwith20-32%andincreasest½

by25-50%duetotheinhibitionofmetabolismoftriazolam.Dosageadjustmentsoftriazolammaybenecessary.

Carbamazepine:Fluconazoleinhibitsthemetabolismofcarbamazepineandanincreaseinserumcarbamazepineof

30%hasbeenobserved.Thereisariskofdevelopingcarbamazepinetoxicity.Dosageadjustmentofcarbamazepine

maybenecessarydependingonconcentrationmeasurements/effect.

CalciumChannelBlockers:Certaindihydropyridinecalciumchannelantagonists(nifedipine,isradipine,amlodipine

andfelodipine)aremetabolizedbyCYP3A4.Fluconazolehasthepotentialtoincreasethesystemicexposureofthe

calciumchannelantagonists.Frequentmonitoringforadverseeventsisrecommended.

Celecoxib:Duringconcomitanttreatmentwithfluconazole(200mgdaily)andcelecoxib(200mg)thecelecoxibCmax

andAUCincreasedby68%and134%,respectively.Halfofthecelecoxibdosemaybenecessarywhencombinedwith

fluconazole.

CiclosporinAkineticstudyinrenaltransplantpatientsfoundfluconazole200mgdailytoslowlyincreaseciclosporin

concentrations.However,inanothermultipledosestudywith100mgdaily,fluconazoledidnotaffectciclosporinlevels

inpatientswithbonemarrowtransplants.Ciclosporinplasmaconcentrationmonitoringinpatientsreceiving

fluconazoleisrecommended.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 6

bilirubinandserumcreatinine.Thecombinationmaybeusedwhiletakingincreasedconsiderationtotheriskof

increasedserumbilirubinandserumcreatinine.

Fentanyl:Onefatalcaseofpossiblefentanylfluconazoleinteractionwasreported.Theauthorjudgedthatthepatient

diedfromfentanylintoxication.Furthermore,inarandomizedcrossoverstudywithtwelvehealthyvolunteersitwas

shownthatfluconazoledelayedtheeliminationoffentanylsignificantly.Elevatedfentanylconcentrationmayleadto

respiratorydepression.

Halofantrine:FluconazolecanincreasehalofantrineplasmaconcentrationduetoaninhibitoryeffectonCYP3A4.

HMG-CoAreductaseinhibitors:Theriskofmyopathyandrhabdomyolysisincreaseswhenfluconazoleis

coadministeredwithHMG-CoAreductaseinhibitorsmetabolisedthroughCYP3A4,suchasatorvastatinand

simvastatin,orthroughCYP2C9,suchasfluvastatin.Ifconcomitanttherapyisnecessary,thepatientshouldbe

observedforsymptomsofmyopathyandrhabdomyolysisandcreatininekinaseshouldbemonitored.HMG-CoA

reductaseinhibitorsshouldbediscontinuedifamarkedincreaseincreatininekinaseisobservedor

myopathy/rhabdomyolysisisdiagnosedorsuspected.

Losartan:Fluconazoleinhibitsthemetabolismoflosartantoitsactivemetabolite(E-3174)whichisresponsiblefor

mostoftheangiotensinIl-receptorantagonismwhichoccursduringtreatmentwithlosartan.Patientsshouldhavetheir

bloodpressuremonitoredcontinuously.

Methadone:Fluconazolemayenhancetheserumconcentrationofmethadone.Dosageadjustmentofmethadonemay

benecessary.

Non-steroidalanti-inflammatorydrugs:TheCmaxandAUCofflurbiprofenwasincreasedby23%and81%,

respectively,whencoadministeredwithfluconazolecomparedtoadministrationofflurbiprofenalone.Similarly,the

CmaxandAUCofthepharmacologicallyactiveisomer[S-(+)-ibuprofen]wasincreasedby15%and82%,

respectively,whenfluconazolewascoadministeredwithracemicibuprofen(400mg)comparedtoadministrationof

racemicibuprofenalone.

Althoughnotspecificallystudied,fluconazolehasthepotentialtoincreasethesystemicexposureofotherNSAIDsthat

aremetabolizedbyCYP2C9(e.g.naproxen,lornoxicam,meloxicam,diclofenac).Frequentmonitoringforadverse

eventsandtoxicityrelatedtoNSAIDsisrecommended.AdjustmentofdosageofNSAIDsmaybeneeded.

OralcontraceptivesTwopharmacokineticstudieswithcombinedoralcontraceptiveshavebeenperformedusing

multipledosesoffluconazole.Therewerenorelevanteffectsoneitherhormonelevelinthe50mgfluconazolestudy,

whileat200mgdailytheAUCsofethinylestradiolandlevonorgestrelwereincreased40%and24%respectively.Ina

300mgdailyfluconazolestudy,theAUCsofethinylestradiolandnorethindronewereincreasedby24%and13%,

respectively.Thusmultipledoseuseoffluconazoleatthesedosesisunlikelytohaveaneffectontheefficacyofthe

combinedoralcontraceptive.

PhenytoinConcomitantadministrationoffluconazoleandphenytoinmayincreasethelevelsofphenytointoa

clinicallysignificantdegree.Ifitisnecessarytoadministerbothdrugsconcomitantly,phenytoinlevelsshouldbe

monitoredandthephenytoindoseadjustedtomaintaintherapeuticlevels.

Pimozide:Althoughnotstudiedinvitroorinvivo,concomitantadministrationoffluconazolewithpimozidemay

resultininhibitionofpimozidemetabolism.IncreasedpimozideplasmaconcentrationscanleadtoQTprolongation

andrareoccurrencesoftorsadedepointes.Coadministrationoffluconazoleandpimozideiscontraindicated.

Prednisone:Therewasacasereportthataliver-transplantedpatienttreatedwithprednisonedevelopedacuteadrenal

cortexinsufficiencywhenathreemonththerapywithfluconazolewasdiscontinued.Thediscontinuationoffluconazole

presumablycausedanenhancedCYP3A4activitywhichledtoincreasedmetabolismofprednisone.Patientsonlong-

termtreatmentwithfluconazoleandprednisoneshouldbecarefullymonitoredforadrenalcortexinsufficiencywhen

fluconazoleisdiscontinued.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 7

rifabutin,leadingtoincreasedserumlevelsofrifabutin.Therehavebeenreportsofuveitisinpatientstowhom

fluconazoleandrifabutinwereco-administered.Patientsreceivingrifabutinandfluconazoleconcomitantlyshouldbe

carefullymonitored.

Saquinavir:FluconazoleincreasestheAUCofsaquinavirwithapproximately50%,Cmaxwithapproximately55%

anddecreasesclearanceofsaquinavirwithapproximately50%duetoinhibitionofsaquinavir’shepaticmetabolismby

CYP3A4andinhibitionofP-glycoprotein.Dosageadjustmentofsaquinavirmaybenecessary.

Sirolimus:Fluconazoleincreasesplasmaconcentrationsofsirolimuspresumablybyinhibitingthemetabolismof

sirolimusviaCYP3A4andP-glycoprotein.Thiscombinationmaybeusedwithadosageadjustmentofsirolimus

dependingontheeffect/concentrationmeasurements.

EndogenoussteroidFluconazole50mgdailydoesnotaffectendogenoussteroidlevelsinfemales.200-400mgdaily

hasnoclinicallysignificanteffectonendogenoussteroidlevelsoronACTHstimulatedresponseinhealthymale

volunteers.

SulphonylureasFluconazolehasbeenshowntoprolongtheserumhalf-lifeofconcomitantlyadministeredoral

sulphonylureas(chlorpropamide,glibenclamide,glipizideandtolbutamide)inhealthyvolunteers.Fluconazoleandoral

sulphonylureasmaybeco-administeredtodiabeticpatients,butthepossibilityofahypoglycaemicepisodeshouldbe

borneinmind.

TacrolimusTherehavebeenreportsthataninteractionexistswhenfluconazoleisadministeredconcomitantlywith

tacrolimus,leadingtoincreasedserumlevelsoftacrolimus.Therehavebeenreportsofnephrotoxicityinpatientsto

whomfluconazoleandtacrolimuswereco-administered.Patientsreceivingtacrolimusandfluconazoleconcomitantly

shouldbecarefullymonitored.

TheophyllineInaplacebo-controlledinteractionstudy,theadministrationoffluconazole200mgfor14daysresultedin

an18%decreaseinthemeanplasmaclearanceoftheophylline.Patientswhoarereceivinghighdosesoftheophylline

orwhoareotherwiseatincreasedriskfortheophyllinetoxicityshouldbeobservedforsignsoftheophyllinetoxicity

whilereceivingfluconazoleandthetherapymodifiedappropriatelyifsignsoftoxicitydevelop.

VincaAlkaloids:Althoughnotstudied,fluconazolemayincreasetheplasmalevelsofthevincaalkaloids(e.g.

vincristineandvinblastine)andleadtoneurotoxicity,whichispossiblyduetoaninhibitoryeffectonCYP3A4.

VitaminA:Basedonacase-reportinonepatientreceivingcombinationtherapywithall-trans-retinoidacid(anacid

formofvitaminA)andfluconazole,CNSrelatedundesirableeffectshavedevelopedintheformofpseudotumour

cerebri,whichdisappearedafterdiscontinuationoffluconazoletreatment.Thiscombinationmaybeusedbutthe

incidenceofCNSrelatedundesirableeffectsshouldbeborneinmind.

ZidovudineTwokineticstudiesresultedinincreasedlevelsofzidovudinemostlikelycausedbythedecreased

conversionofzidovudinetoitsmajormetabolite.OnestudydeterminedzidovudinelevelsinAIDSorARCpatients

beforeandfollowingfluconazole200mgdailyfor15days.TherewasasignificantincreaseinzidovudineAUC(20%).

Asecondrandomised,two-period,two-treatmentcross-overstudyexaminedzidovudinelevelsinHIVinfected

patients.Ontwooccasions,21daysapart,patientsreceivedzidovudine200mgeveryeighthourseitherwithorwithout

fluconazole400mgdailyforsevendays.TheAUCofzidovudinesignificantlyincreased(74%)duringco-

administrationwithfluconazole.Patientsreceivingthiscombinationshouldbemonitoredforthedevelopmentof

zidovudine-relatedadversereactions.

InteractionstudieshaveshownthatwhenoralDiflucanisco-administeredwithfood,cimetidine,antacidsorfollowing

totalbodyirradiationforbonemarrowtransplantation,noclinicallysignificantimpairmentoffluconazoleabsorption

occurs.

Physiciansshouldbeawarethatdrug-druginteractionstudieswithothermedicationshavenotbeenconducted,butthat

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 8

Fluvastatin

Astudyinhealthyvolunteersdemonstratedthatfluconazoleincreasedthemeanareaundertheplasmafluvastatin

concentrationtimecurveby84%,themeaneliminationhalflifeoffluvastatinby80%anditsmeanpeakplasma

concentrationby44%.Cautionshouldthereforebeexercisedwhenfluvastatinisadministeredconcomitantlywith

fluconazole.

4.6Fertility,pregnancyandlactation

Datafromseveralhundredpregnantwomentreatedwithstandarddoses(<200mg/day)offluconazole,administeredas

asingleorrepeateddosageinthefirsttrimester,shownoundesiredeffectsinthefoetus.

Therehavebeenreportsofmultiplecongentialabnormalitiesininfantswhosemotherswerebeingtreatedfor3ormore

monthswithhighdose(400–800mg/day)fluconazoletherapyforcoccidioidomycosis.Therelationshipbetween

fluconazoleuseandtheseeventsisunclear.

Animalstudiesshowteratogeniceffects(seesection5.3).

Useinpregnancyshouldbeavoidedexceptinpatientswithsevereorpotentiallylife-threateningfungalinfectionsin

whomfluconazolemaybeusediftheanticipatedbenefitoutweighsthepossiblerisktothefetus.

UseduringlactationFluconazoleisfoundinhumanbreastmilkatconcentrationssimilartoplasma,henceitsusein

nursingmothersisnotrecommended.

4.7Effectsonabilitytodriveandusemachines

Whendrivingvehiclesoroperatingmachinesitshouldbetakenintoaccountthatoccasionallydizzinessorseizures

mayoccur.

4.8Undesirableeffects

Fluconazoleisgenerallywelltolerated.Insomepatients,particularlythosewithseriousunderlyingdiseasessuchas

AIDSandcancer,changesinrenalandhaematologicalfunctiontestresultsandhepaticabnormalitieshavebeen

observedduringtreatmentwithfluconazoleandcomparativeagents,buttheclinicalsignificanceandrelationshipto

treatmentisuncertain(seeSection4.4“Specialwarningsandspecialprecautionsforuse”).

Thefollowingundesirableeffectshavebeenobservedandreportedduringtreatmentwithfluconazolewiththe

followingfrequencies:Verycommon( ≥1/10);common(≥1/100to<1/10);uncommon(≥1/1,000to≤1/100);rare(≥

1/10,000to ≤1/1,000);veryrare(≤1/10,000),notknown(cannotbeestimatedformtheavailabledata).

SystemOrganClass Frequency Undesirableeffects

Bloodandthelymphatic

systemdisorders Rare Agranulocytosis,leukopenia,

neutropenia,thrombocytopenia

Immunesystemdisorders Rare Anaphylaxis

Metabolismandnutrition

disorders Uncommon Hypokalaemia

Rare Hypertriglyceredaemia,

hypercholesterolaemia

Psychiatricdisorders Uncommon Insomnia,somnolence

Nervoussystemdisorders Common Headache

Uncommon Seizures,dizziness,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 9

PaediatricPopulation

Thepatternandincidenceofsideeffectsandlaboratoryabnormalitiesrecordedduringpaediatricclinicaltrialsare

Rare Tremor

Earandlabyrinthdisorders Uncommon Vertigo

Cardiacdisorders Rare Torsadedepointes,QT

prolongation

Gastrointestinaldisorders Common Abdominalpain,diarrhoea,

nausea,vomiting

Uncommon Dyspepsia,flatulence,dry

mouth

Hepato-biliarydisorders Common Alanineaminotransferase

increased,aspartate

aminotransferaseincreased,

bloodalkalinephosphatase

increased

Uncommon Cholestasis,jaundice,bilirubin

increased

Rare Hepaticfailure,hepatocellular

necrosis,hepatitis,

hepatocellulardamage

Skinandsubcutaneoustissue

disorders Common Rash

Uncommon Pruritus,urticaria,increased

sweating,drugeruption

Rare Toxicepidermalnecrolysis,

Stevens-Johnsonsyndrome,

acutegeneralised

exanthematous-pustulosis,

dermatitisexfoliative,

angioedema,faceoedema,

alopecia

Musculoskeletal,connective

tissueandbonedisorders Uncommon Myalgia

Generaldisordersand

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 10

4.9Overdose

Therehavebeenreportsofoverdosagewithfluconazoleandinonecase,a42year-oldpatientinfectedwithhuman

immunodeficiencyvirusdevelopedhallucinationsandexhibitedparanoidbehaviourafterreportedlyingesting8200mg

offluconazole.Thepatientwasadmittedtothehospitalandhisconditionresolvedwithin48hours.

Intheeventofoverdosage,supportivemeasuresandsymptomatictreatment,withgastriclavageifnecessary,maybe

adequate.

Asfluconazoleislargelyexcretedintheurine,forcedvolumediuresiswouldprobablyincreasetheeliminationrate.A

three-hourharmodialysissessiondecreaseplasmalevelsbyapproximately50%.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Triazolederivarives,ATCcodeJ02AC.

Fluconazole,amemberofthetriazoleclassofantifungalagents,isapotentandselectiveinhibitoroffungalenzymes

necessaryforthesynthesisofergosterol.

Fluconazoleshowslittlepharmacologicalactivityinawiderangeofanimalstudies.Someprolongationof

pentobarbitalsleepingtimesinmice(p.o.),increasedmeanarterialandleftventricularbloodpressureandincreased

heartrateinanaesthetisedcats(i.v.)occurred.Inhibitionofratovarianaromatasewasobservedathighconcentrations.

Bothorallyandintravenouslyadministeredfluconazolewasactiveinavarietyofanimalfungalinfectionmodels.

Activityhasbeendemonstratedagainstopportunisticmycoses,suchasinfectionswithCandidaspp.includingsystemic

candidiasisinimmunocompromisedanimals;withCryptococcusneoformans,includingintracranialinfections;with

Microsporumspp.andwithTrichophytonspp.Fluconazolehasalsobeenshowntobeactiveinanimalmodelsof

endemicmycoses,includinginfectionswithBlastomycesdermatitides;withCoccidoidesimmitis,includingintracranial

infectionandwithHistoplasmacapsulatuminnormalandimmunosuppressedanimals.

TherehavebeenreportsofcasesofsuperinfectionwithCandidaspeciesotherthanC.albicans,whichareoften

inherentlynotsusceptibletofluconazole(e.g.Candidakrusei).Suchcasesmayrequirealternativeantifungaltherapy.

FluconazoleishighlyspecificforfungalcytochromeP-450dependentenzymes.Fluconazole50mgdailygivenupto

28dayshasbeenshownnottoaffecttestosteroneplasmaconcentrationsinmalesorsteroidconcentrationsinfemales

ofchild-bearingage.Fluconazole200-400mgdailyhasnoclinicallysignificanteffectonendogenoussteroidlevelsor

onACTHstimulatedresponseinhealthymalevolunteers.Interactionstudieswithantipyrineindicatethatsingleor

multipledosesoffluconazole50mgdonotaffectitsmetabolism.

Theefficacyoffluconazoleintineacapitishasbeenstudiedin2randomisedcontrolledtrialsinatotalof878patients

comparingfluconazolewithgriseofulvin.Fluconazoleat6mg/kg/dayfor6weekswasnotsuperiortogriseofulvin

administeredat11mg/kg/dayfor6weeks.Theoverallsuccessrateatweek6waslow(fluconazole6weeks:18.3%;

fluconazole3weeks:14.7%;griseofulvin:17.7%)acrossalltreatmentgroups.Thesefindingsarenotinconsistentwith

thenaturalhistoryoftineacapitiswithouttherapy.

5.2Pharmacokineticproperties

Thepharmacokineticpropertiesoffluconazolearesimilarfollowingadministrationbytheintravenousororalroute.

Afteroraladministrationfluconazoleiswellabsorbed,andplasmalevels(andsystemicbioavailability)areover90%

ofthelevelsachievedafterintravenousadminstration.Oralabsorptionisnotaffectedbyconcomitantfoodintake.Peak

plasmaconcentrationsinthefastingstateoccurbetween0.5and1.5hourspostdosewithaplasmaeliminationhalf-life

ofapproximately30hours.Plasmaconcentrationsareproportionaltodose.Ninetypercentsteady-statelevelsare

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 11

Administrationofaloadingdose(onday1)oftwicetheusualdailydoseenablesplasmalevelstoapproximateto90%

steady-statelevelbyday2.Theapparentvolumeofdistributionapproximatestototalbodywater.Plasmaprotein

bindingislow(11-12%).

Fluconazoleachievesgoodpenetrationintoallbodyfluidsstudied.Thelevelsoffluconazoleinsalivaandsputumare

similartoplasmalevels.InpatientswithfungalmeningitisfluconazolelevelsintheCSFareapproximately80%the

correspondingplasmalevels.

Highskinconcentrationsoffluconazole,aboveserumconcentrations,areachievedinthestratumcorneum,epidermis-

dermisandeccrinesweat.Fluconazoleaccumulatesinthestratumcorneum.Atadoseof50mgoncedaily,the

concentrationoffluconazoleafter12dayswas73microgram/gand7daysaftercessationoftreatmentthe

concentrationwasstill5.8microgram/g.

Themajorrouteofexcretionisrenalwithapproximately80%oftheadministereddoseappearingintheurineas

unchangeddrug.Fluconazoleclearanceisproportionaltocreatinineclearance.Thereisnoevidenceofcirculating

metabolites.

Thelongplasmaeliminationhalf-lifeprovidesthebasisforsingledosetherapyforgenitalcandidiasisandonce-daily

dosinginthetreatmentofallotherindicatedfungalinfections.

Astudycomparedthesalivaandtheplasmaconcentrationsofasinglefluconazole100mgdoseadministrationina

capsuleorinanoralsuspensionbyrinsingandretaininginmouthfor2minutesandswallowing.Themaximum

concentrationoffluconazoleinsalivaafterthesuspensionwasobserved5minutesafteringestion,andwas182times

higherthanthemaximumsalivaconcentrationafterthecapsule,whichoccurred4hoursafteringestion.Afterabout4

hours,thesalivaconcentrationsoffluconazoleweresimilar.ThemeanAUC(0-96)insalivawassignificantlygreater

afterthesuspensioncomparedtothecapsule.Therewasnosignificantdifferenceintheeliminationratefromsalivaor

theplasmapharmacokineticparametersforthetwoformulations.

PharmacokineticsinChildren

Pharmacokineticdatawereassessedfor113paediatricpatientsfrom5studies;2singledosestudies,2multipledose

studiesandastudyinprematureneonates.Datafrom1studywerenotinterpretableduetochangesinformulation

partwaythroughthestudy.Additionaldatawereavailablefromacompassionateusestudy.

Afteradministrationof2–8mg/kgfluconazoletochildrenbetweentheagesof9monthsto15years,anAUCofabout

38µg.h/mlwasfoundper1mg/kgdoseunits.Theaveragefluconazoleplasmaeliminationhalf-lifevariedbetween15

and18hoursandthedistributionvolumewasapproximately880ml/kgaftermultipledoses.Ahigherfluconazole

plasmaeliminationhalf-lifeofapproximately24hourswasfoundafterasingledose.Thisiscomparablewiththe

fluconazoleplasmaeliminationhalf-lifeafterasingleadministrationof3mg/kgi.v.tochildrenof11days–11months

old.Thedistributionvolumeinthisagegroupwasabout950ml/kg.

Experiencewithfluconazoleinneonatesislimitedtopharmacokineticstudiesinprematurenew-borns.Themeanage

atfirstdosewas24hours(range9-36hours)andmeanbirthweightwas0.9Kg(range0.75-1.10Kg)for12pre-term

neonatesofaveragegestationaround28weeks.Sevenpatientscompletedtheprotocol;amaximumoffive6mg/Kg

intravenousinfusionsoffluconazolewereadministeredevery72hours.Themeanhalf-life(hours)was74(range44-

185)onday1whichdecreasedwithtimetoameanof53(range30-131)onday7and47(range27-68)onday13.The

areaunderthecurve(microgram.h/ml)was271(range173-385)onday1andincreasedwithameanof490(range

292-734)onday7anddecreasedwithameanof360(range167-566)onday13.Thevolumeofdistribution(ml/kg)

was1183(range1070-1470)onday1andincreasedwithtimetoameanof1184(range510-2130)onday7and1328

(range1040-1680)onday13.

PharmacokineticsinElderly

Apharmacokineticstudywasconductedin22subjects,65yearsofageorolderreceivingasingle50mgoraldoseof

fluconazole.Tenofthesepatientswereconcomitantlyreceivingdiuretics.TheC

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 12

1.3hourspostdose.ThemeanAUCwas76.4±20.3mcg·h/ml,andthemeanterminalhalf-lifewas46.2hours.These

pharmacokineticparametervaluesarehigherthananalogousvaluesreportedfornormalyoungmalevolunteers.Co-

administrationofdiureticsdidnotsignificantlyalterAUCorC

.Inaddition,creatinineclearance(74ml/min),the

percentofdrugrecoveredunchangedinurine(0-24hr,22%)andthefluconazolerenalclearanceestimates(0.124

ml/min/kg)fortheelderlyweregenerallylowerthanthoseofyoungervolunteers.Thus,thealterationoffluconazole

dispositionintheelderlyappearstoberelatedtoreducedrenalfunctioncharacteristicofthisgroup.Aplotofeach

subject’sterminaleliminationhalf-lifeversuscreatinineclearancecomparedwiththepredictedhalf-life–creatinine

clearancecurvederivedfromnormalsubjectsandsubjectswithvaryingdegreesofrenalinsufficiencyindicatedthat21

of22subjectsfellwithinthe95%confidencelimitofthepredictedhalf-life–creatinineclearancecurves.Theseresults

areconsistentwiththehypothesisthathighervaluesforthepharmacokineticobservedintheelderlysubjectscompared

withnormalyoungmalevolunteersareduetothedecreasedkidneyfunctionthatisexpectedintheelderly.

5.3Preclinicalsafetydata

Reproductivetoxicity:

Therewerenofetaleffectsat5or10mg/kg;increasesinfetalanatomicalvariants(supernumeraryribs,renalpelvis

dilation)anddelaysinossificationwereobservedat25and50mg/kgandhigherdoses.Atdosesrangingfrom80

mg/kg(approximately20-60xtherecommendedhumandose)to320mg/kgembryolethalityinratswasincreasedand

fetalabnormalitiesincludedwavyribs,cleftpalateandabnormalcranio-facialossification.Theseeffectsareconsistent

withtheinhibitionofoestrogensysnthesisinratsandmaybearesultofknowneffectsofloweredoestrogenon

pregnancy,organogenesisandparturition.

Carcinogenesis:

Fluconazoleshowednoevidenceofcarcinogenicpotentialinmiceandratstreatedorallyfor24monthsatdosesof2.5,

5or10mg/kg/day.Maleratstreatedwith5and10mg/kg/dayhadanincreasedincidenceofhepatocellularadenomas.

Mutagenesis:

Fluconazole,withorwithoutmetabolicactivation,wasnegativeintestsformutagenicityin4strainsofS.typhimurium

andinthemouselymphomaL5178Ysystem.Cytogeneticstudiesinvivo(murinebonemarrowcells,followingoral

administrationoffluconazole)andinvitro(humanlymphocytesexposedtofluconazoleat1000µg/ml)showedno

evidenceofchromosomalmutations.

Impairmentoffertility:

Fluconazoledidnotaffectthefertilityofmaleorfemaleratstreatedorallywithdailydosesof5,10or20mg/kgorwith

parenteraldosesof5,25or75mg/kg,althoughtheonsetofparturitionwasslightlydelayedat20mg/kgp.o.Inan

intravenousperinatalstudyinratsat5,20and40mg/kg,dystociaandprolongationofparturitionwereobservedina

fewdamsat20mg/kgand40mg/kg,butnotat5mg/kg.Thedisturbancesinparturitionwerereflectedbyaslight

increaseinthenumberofstill-bornpupsanddecreaseofneonatalsurvivalatthesedoselevels.Theeffectson

parturitioninratsareconsistentwiththespeciesspecificoestrogen-loweringpropertyproducedbyhighdosesof

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 13

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Sodiumchloride

Waterforinjections

6.2Incompatibilities

Intheabsenceofcompatibilitystudies,thismedicinalproductmustnotbemixedwithothermedicinalproducts.

6.3ShelfLife

5years.

Forsingleuseonly.Discardanyremainingsolution.

6.4Specialprecautionsforstorage

Donotstoreabove30 o

Donotfreeze.

6.5Natureandcontentsofcontainer

30ml,TypeIglassinfusionvialsealedwitharubberstopperandanaluminiumovercap.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Donotfreeze.Theinfusiondoesnotcontainanypreservative.Itisforsingleuseonly.Discardanyremainingsolution.

7MARKETINGAUTHORISATIONHOLDER

PfizerLimited

RamsgateRoad

Sandwich

KentCT139NJ

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA19/44/6

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:22August1989

Dateoflastrenewal:22August2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 24/01/2011 CRN 2067187 page number: 14