AVODART

Main information

  • Trade name:
  • AVODART Capsules, Soft 0.5 Milligram
  • Dosage:
  • 0.5 Milligram
  • Pharmaceutical form:
  • Capsules, Soft
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AVODART Capsules, Soft 0.5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1500/048/001
  • Authorization date:
  • 19-02-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PPA1500/048/001

CaseNo:2083758

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ProfindWholesaleLtd.

Unit625,KilshaneAvenue,NorthwestBusinessPark,Dublin15,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Avodart0.5mgsoftcapsules

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom28/07/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 28/07/2010 CRN 2083758 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Avodart0.5mgsoftcapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains0.5mgdutasteride

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,soft

ProductimportedfromItaly:

Opaque,yellow,oblongsoftgelatincapsulesimprintedwithGXCE2ononesideinredink.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofmoderatetoseveresymptomsofbenignprostatichyperplasia(BPH).

Reductionintheriskofacuteurinaryretention(AUR)andsurgeryinpatientswithmoderatetoseveresymptomsof

BPH.

Forinformationoneffectsoftreatmentandpatientpopulationsstudiedinclinicaltrialspleaseseesection5.1.

4.2Posologyandmethodofadministration

Avodartcanbeadministeredaloneorincombinationwiththealpha-blockertamsulosin

(0.4mg)(seesections4.4,4.8and5.1).

Adults(includingelderly):

TherecommendeddoseofAvodartisonecapsule(0.5mg)takenorallyonceaday.Thecapsulesshouldbeswallowed

wholeandnotchewedoropenedascontactwiththecapsulecontentsmayresultinirritationoftheoropharyngeal

mucosa.Thecapsulesmaybetakenwithorwithoutfood.Althoughanimprovementmaybeobservedatanearly

stage,itcantakeupto6monthsbeforearesponsetothetreatmentcanbeachieved.Nodoseadjustmentisnecessaryin

theelderly.

Renalimpairment

Theeffectofrenalimpairmentondutasteridepharmacokineticshasnotbeenstudied.Noadjustmentindosageis

anticipatedforpatientswithrenalimpairment(seesection5.2).

Hepaticimpairment

Theeffectofhepaticimpairmentondutasteridepharmacokineticshasnotbeenstudiedsocautionshouldbeusedin

patientswithmildtomoderatehepaticimpairment(seesection4.4andsection5.2).Inpatientswithseverehepatic

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4.3Contraindications

Avodartiscontraindicatedin:

womenandchildrenandadolescents(seesection4.6).

patientswithhypersensitivitytodutasteride,other5-alphareductaseinhibitors,oranyoftheexcipients.

patientswithseverehepaticimpairment.

4.4Specialwarningsandprecautionsforuse

Combinationtherapyshouldbeprescribedaftercarefulbenefitriskassessmentduetothepotentialincreasedriskof

adverseeventsandafterconsiderationofalternativetreatmentoptionsincludingmonotherapies(seesection4.2).

Digitalrectalexamination,aswellasotherevaluationsforprostatecancer,mustbeperformedonpatientswithBPH

priortoinitiatingtherapywithAvodartandperiodicallythereafter.

Dutasterideisabsorbedthroughtheskin,therefore,women,childrenandadolescentsmustavoidcontactwithleaking

capsules(seesection4.6).Ifcontactismadewithleakingcapsules,thecontactareashouldbewashedimmediately

withsoapandwater.

Dutasteridewasnotstudiedinpatientswithliverdisease.Cautionshouldbeusedintheadministrationofdutasteride

topatientswithmildtomoderatehepaticimpairment(seesection4.2,section4.3andsection5.2).

Serumprostate-specificantigen(PSA)concentrationisanimportantcomponentinthedetectionofprostatecancer.

Generally,atotalserumPSAconcentrationgreaterthan4ng/mL(Hybritech)requiresfurtherevaluationand

considerationofprostatebiopsy.PhysiciansshouldbeawarethatabaselinePSAlessthan4ng/mLinpatientstaking

Avodartdoesnotexcludeadiagnosisofprostatecancer.AvodartcausesadecreaseinserumPSAlevelsby

approximately50%,after6months,inpatientswithBPH,eveninthepresenceofprostatecancer.Althoughtheremay

beindividualvariation,thereductioninPSAbyapproximately50%ispredictableasitwasobservedovertheentire

rangeofbaselinePSAvalues(1.5to10ng/mL).ThereforetointerpretanisolatedPSAvalueinamantreatedwith

Avodartforsixmonthsormore,PSAvaluesshouldbedoubledforcomparisonwithnormalrangesinuntreatedmen.

ThisadjustmentpreservesthesensitivityandspecificityofthePSAassayandmaintainsitsabilitytodetectprostate

cancer.AnysustainedincreasesinPSAlevelswhileonAvodartshouldbecarefullyevaluated,includingconsideration

ofnoncompliancetotherapywithAvodart.

TotalserumPSAlevelsreturntobaselinewithin6monthsofdiscontinuingtreatment.TheratiooffreetototalPSA

remainsconstantevenundertheinfluenceofAvodart.IfclinicianselecttousepercentfreePSAasanaidinthe

detectionofprostatecancerinmenundergoingAvodarttherapy,noadjustmenttoitsvalueappearsnecessary.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ForinformationonthedecreaseofserumPSAlevelsduringtreatmentwithdutasterideandguidanceconcerning

prostatecancerdetection,pleaseseesection4.4.

Effectsofotherdrugsonthepharmacokineticsofdutasteride

UsetogetherwithCYP3A4and/orP-glycoprotein-inhibitors:

Dutasterideismainlyeliminatedviametabolism.Invitrostudiesindicatethatthismetabolismiscatalysedby

CYP3A4andCYP3A5.NoformalinteractionstudieshavebeenperformedwithpotentCYP3A4inhibitors.However,

inapopulationpharmacokineticstudy,dutasterideserumconcentrationswereonaverage1.6to1.8timesgreater,

respectively,inasmallnumberofpatientstreatedconcurrentlywithverapamilordiltiazem(moderateinhibitorsof

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Long-termcombinationofdutasteridewithdrugsthatarepotentinhibitorsoftheenzymeCYP3A4(e.g.ritonavir,

indinavir,nefazodon,itraconazole,ketoconazoleadministeredorally)mayincreaseserumconcentrationsof

dutasteride.Furtherinhibitionof5-alphareductaseatincreaseddutasterideexposure,isnotlikely.However,a

reductionofthedutasteridedosingfrequencycanbeconsideredifsideeffectsarenoted.Itshouldbenotedthatinthe

caseofenzymeinhibition,thelonghalf-lifemaybefurtherprolongedanditcantakemorethan6monthsofconcurrent

therapybeforeanewsteadystateisreached.

Administrationof12gcholestyramineonehourbeforea5mgsingledoseofdutasteridedidnotaffectthe

pharmacokineticsofdutasteride.

Effectsofdutasterideonthepharmacokineticsofotherdrugs

Dutasteridehasnoeffectonthepharmacokineticsofwarfarinordigoxin.Thisindicatesthatdutasteridedoesnot

inhibit/induceCYP2C9orthetransporterP-glycoprotein.Invitrointeractionstudiesindicatethatdutasteridedoesnot

inhibittheenzymesCYP1A2,CYP2D6,CYP2C9,CYP2C19orCYP3A4.

Inasmallstudy(N=24)oftwoweeksdurationinhealthymen,dutasteride(0.5mgdaily)hadnoeffectonthe

pharmacokineticsoftamsulosinorterazosin.Therewasalsonoindicationofapharmacodynamicinteractioninthis

study.

4.6Pregnancyandlactation

Avodartiscontraindicatedforusebywomen.

Fertility

Dutasteridehasbeenreportedtoaffectsemencharacteristics(reductioninspermcount,semenvolume,andsperm

motility)inhealthymen(seesection5.1).Thepossibilityofreducedmalefertilitycannotbeexcluded.

Pregnancy

Aswithother5alphareductaseinhibitors,dutasterideinhibitstheconversionoftestosteronetodihydrotestosteroneand

may,ifadministeredtoawomancarryingamalefoetus,inhibitthedevelopmentoftheexternalgenitaliaofthefoetus

(seesection4.4).SmallamountsofdutasteridehavebeenrecoveredfromthesemeninsubjectsreceivingAvodart

0.5mg/day.

Basedonstudiesinanimals,itisunlikelythatamalefoetuswillbeadverselyaffectedifhismotherisexposedtothe

semenofapatientbeingtreatedwithAvodart(theriskofwhichisgreatestduringthefirst16weeksofpregnancy).

However,aswithall5alphareductaseinhibitors,whenthepatient'spartnerisormaypotentiallybepregnantitis

recommendedthatthepatientavoidsexposureofhispartnertosemenbyuseofacondom.

Lactation

Itisnotknownwhetherdutasterideisexcretedinhumanmilk.

4.7Effectsonabilitytodriveandusemachines

Basedonthepharmacodynamicpropertiesofdutasteride,treatmentwithdutasteridewouldnotbeexpectedtointerfere

withtheabilitytodriveoroperatemachinery.

4.8Undesirableeffects

AVODARTASMONOTHERAPY

Approximately19%ofthe2167patientswhoreceiveddutasterideinthe2yearPhaseIIIplacebo-controlledtrials

developedadversereactionsduringthefirstyearoftreatment.Themajorityofeventsweremildtomoderateand

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Nochangetotheadverseeventprofilewasapparentoverafurther2yearsinopen-labelextensionstudies.

Thefollowingtableshowsadversereactionsfromcontrolledclinicaltrialsandpost-marketingexperience.Thelisted

adverseeventsfromclinicaltrialsareinvestigator-judgeddrug-relatedevents(withincidencemorethanorequalto

1%)reportedwithahigherincidenceinpatientstreatedwithdutasteridecomparedwithplaceboduringthefirstyearof

treatment.Adverseeventsfrompost-marketingexperiencewereidentifiedfromspontaneouspost-marketingreports;

thereforethetrueincidenceisunknown:

AVODARTINCOMBINATIONWITHTHEALPHA-BLOCKERTAMSULOSIN

Year2datafromtheCombATStudy,comparingdutasteride0.5mg(n=1623)andtamsulosin0.4mg(n=1611)once

dailyaloneandincombination(n=1610)haveshownthattheincidenceofanyinvestigator-judgeddrug-relatedadverse

eventduringthefirstandsecondyearsoftreatmentrespectivelywas22%and5%fordutasteride/tamsulosin

combinationtherapy,14%and5%fordutasteridemonotherapyand13%and4%fortamsulosinmonotherapy.The

higherincidenceofadverseeventsinthecombinationtherapygroupinthefirstyearoftreatmentwasduetoahigher

incidenceofreproductivedisorders,specificallyejaculationdisorders,observedinthisgroup.

Thefollowinginvestigator-judgeddrug-relatedadverseeventshavebeenreportedwithanincidenceofgreaterthanor

equalto1%duringthefirstyearoftreatmentintheYear2analysisoftheCombATStudy;theincidenceofthese

Organsystem Adverse

reaction Incidencefromclinicaltrialdata

Incidenceduringyear1of

treatment(n=2167) Incidence

duringyear2

oftreatment

(n=1744)

Reproductive

systemand

breastdisorders Impotence 6.0% 1.7%

Altered(decreased)

libido 3.7% 0.6%

Ejaculationdisorders 1.8% 0.5%

Breastdisorders

(includesbreast

enlargementand/or

breasttenderness) 1.3% 1.3%

Immunesystem

disorders Allergicreactions

includingrash,

pruritus,urticaria,

localisedoedema,

andangioedema Incidenceestimatedfrompost-marketingdata

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4.9Overdose

InvolunteerstudiesofAvodart,singledailydosesofdutasterideupto40mg/day(80timesthetherapeuticdose)have

beenadministeredfor7dayswithoutsignificantsafetyconcerns.Inclinicalstudies,dosesof5mgdailyhavebeen

administeredtosubjectsfor6monthswithnoadditionaladverseeffectstothoseseenattherapeuticdosesof0.5mg.

ThereisnospecificantidoteforAvodart,therefore,insuspectedoverdosagesymptomaticandsupportivetreatment

shouldbegivenasappropriate.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:testosterone-5-alpha-reductaseinhibitors.

ATCcode:G04CB02.

Dutasteridereducescirculatinglevelsofdihydrotestosterone(DHT)byinhibitingbothtype1andtype2,5-reductase

isoenzymeswhichareresponsiblefortheconversionoftestosteroneto5-DHT.

AVODARTASMONOTHERAPY

EffectsonDHT/Testosterone:

EffectofdailydosesofAvodartonthereductiononDHTisdosedependantandisobservedwithin1-2weeks(85%and90%

reduction,respectively).

InpatientswithBPHtreatedwithdutasteride0.5mg/day,themediandecreaseinserumDHTwas94%at1yearand93%at2

System

OrganClass Adverse

reaction Incidenceduringyear1of

treatment Incidenceduringyear2of

treatment

Dutasteride

Tamsulosin

(n=1610) Dutasteride

(n=1623) Tamsulosin

(n=1611) Dutasteride

Tamsulosin

(n=1424) Dutasteride

(n=1457) Tamsulosin

(n=1468)

Reproductive

systemand

breast

disorders,

Psychiatric

disordersand

Investigations Impotence 6.5% 4.9% 3.3% 1.1% 1.3% 0.7%

Altered

(decreased)

libido 5.2% 3.8% 2.5% 0.4% 0.9% 0.6%

Ejaculation

disorders 8.9% 1.6% 2.7% 0.5% 0.3% 0.5%

Breast

disorders

(includes

breast

enlargement

and/or

breast

tenderness) 2.0% 1.8% 0.8% 0.9% 1.2% 0.3%

Nervous

system

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EffectonProstateVolume:

Significantreductionsinprostatevolumehavebeendetectedasearlyasonemonthafterinitiationoftreatmentandreductions

continuedthroughMonth24(p<0.001).Avodartledtoameanreductionoftotalprostatevolumeof23.6%(from54.9mlat

baselineto42.1ml)atMonth12comparedwithameanreductionof0.5%(from54.0mlto53.7ml)intheplacebogroup.

Significant(p<0.001)reductionsalsooccurredinprostatetransitionalzonevolumeasearlyasonemonthcontinuingthrough

Month24,withameanreductioninprostatetransitionalzonevolumeof17.8%(from26.8mlatbaselineto21.4ml)intheAvodart

groupcomparedtoameanincreaseof7.9%(from26.8mlto27.5ml)intheplacebogroupatMonth12.Thereductionofthe

prostatevolumeseenduringthefirst2yearsofdouble-blindtreatmentwasmaintainedduringanadditional2yearsofopen-label

extensionstudies.ReductionofthesizeofprostateleadstoimprovementofsymptomsandadecreasedriskforAURandBPH-

relatedsurgery.

CLINICALSTUDIES:

Avodart0.5mg/dayorplacebowasevaluatedin4325malesubjectswithmoderatetoseveresymptomsofBPHwhohadprostates

30mlandaPSAvaluewithintherange1.5-10ng/mLinthreeprimaryefficacy2-yearmulticenter,multinational,

placebo-controlled,double-blindstudies.Thestudiesthencontinuedwithanopen-labelextensionto4yearswithallpatients

remaininginthestudyreceivingdutasterideatthesame0.5mgdose.37%ofinitiallyplacebo-randomizedpatientsand40%of

dutasteride-randomizedpatientsremainedinthestudyat4years.Themajority(71%)ofthe2,340subjectsintheopen-label

extensionscompletedthe2additionalyearsofopen-labeltreatment.

ThemostimportantclinicalefficacyparameterswereAmericanUrologicalAssociationSymptomIndex(AUA-SI),maximum

urinaryflow(Qmax)andtheincidenceofacuteurinaryretentionandBPH-relatedsurgery.

AUA-SIisaseven-itemquestionnaireaboutBPH-relatedsymptomswithamaximumscoreof35.Atbaselinetheaveragescore

wasapprox.17.Aftersixmonths,oneandtwoyearstreatmenttheplacebogrouphadanaverageimprovementof2.5,2.5and2.3

pointsrespectivelywhiletheAvodartgroupimproved3.2,3.8and4.5pointsrespectively.Thedifferencesbetweenthegroups

werestatisticallysignificant.TheimprovementinAUA-SIseenduringthefirst2yearsofdouble-blindtreatmentwasmaintained

duringanadditional2yearsofopen-labelextensionstudies.

Qmax(maximumurineflow):

MeanbaselineQmaxforthestudieswasapprox10ml/sec(normalQmax15ml/sec).Afteroneandtwoyearstreatmenttheflow

intheplacebogrouphadimprovedby0.8and0.9ml/secrespectivelyand1.7and2.0ml/secrespectivelyintheAvodartgroup.

ThedifferencebetweenthegroupswasstatisticallysignificantfromMonth1toMonth24.Theincreaseinmaximumurineflow

rateseenduringthefirst2yearsofdoubleblindtreatmentwasmaintainedduringanadditional2yearsofopen-labelextension

studies.

AcuteUrinaryRetentionandSurgicalIntervention

Aftertwoyearsoftreatment,theincidenceofAURwas4.2%intheplacebogroupagainst1.8%intheAvodartgroup(57%risk

reduction).Thisdifferenceisstatisticallysignificantandmeansthat42patients(95%CI30-73)needtobetreatedfortwoyears

toavoidonecaseofAUR.

TheincidenceofBPH-relatedsurgeryaftertwoyearswas4.1%intheplacebogroupand2.2%intheAvodartgroup(48%risk

reduction).Thisdifferenceisstatisticallysignificantandmeansthat51patients(95%CI33-109)needtobetreatedfortwoyears

toavoidonesurgicalintervention.

Hairdistribution

TheeffectofdutasterideonhairdistributionwasnotformallystudiedduringthephaseIIIprogramme,however,5alpha-reductase

inhibitorscouldreducehairlossandmayinducehairgrowthinsubjectswithmalepatternhairloss(maleandrogeneticalopecia).

Thyroidfunction:

Thyroidfunctionwasevaluatedinaoneyearstudyinhealthymen.Freethyroxinelevelswerestableondutasteridetreatmentbut

TSHlevelsweremildlyincreased(by0.4MCIU/mL)comparedtoplaceboattheendofoneyear'streatment.However,asTSH

levelswerevariable,medianTSHranges(1.4-1.9MCIU/mL)remainedwithinnormallimits(0.5-5/6MCIU/mL),free

thyroxinelevelswerestablewithinthenormalrangeandsimilarforbothplaceboanddutasteridetreatment,thechangesinTSH

werenotconsideredclinicallysignificant.Inalltheclinicalstudies,therehasbeennoevidencethatdutasterideadverselyaffects

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Breastneoplasia:

Inthe2yearclinicaltrials,providing3374patientyearsofexposuretodutasteride,andatthetimeofregistrationinthe2year

openlabelextension,therewere2casesofbreastcancerreportedindutasteride-treatedpatientsand1caseinapatientwho

receivedplacebo.

However,therelationshipbetweenbreastcanceranddutasterideisnotclear.

Effectsonmalefertility

Theeffectsofdutasteride0.5mg/dayonsemencharacteristicswereevaluatedinhealthyvolunteersaged18to52(n=27

dutasteride,n=23placebo)throughout52weeksoftreatmentand24weeksofpost-treatmentfollow-up.At52weeks,themean

percentreductionfrombaselineintotalspermcount,semenvolumeandspermmotilitywere23%,26%and18%,respectively,in

thedutasteridegroupwhenadjustedforchangesfrombaselineintheplacebogroup.Spermconcentrationandspermmorphology

wereunaffected.After24weeksoffollow-up,themeanpercentchangeintotalspermcountinthedutasteridegroupremained

23%lowerthanbaseline.Whilemeanvaluesforallparametersatalltimepointsremainedwithinthenormalrangesanddidnot

meetthepredefinedcriteriaforaclinicallysignificantchange(30%),twosubjectsinthedutasteridegrouphaddecreasesinsperm

countofgreaterthan90%frombaselineat52weeks,withpartialrecoveryatthe24weekfollow-up.Thepossibilityofreduced

malefertilitycannotbeexcluded.

AVODARTINCOMBINATIONWITHTHEALPHA-BLOCKERTAMSULOSIN

Avodart0.5mg/day(n=1,623),tamsulosin0.4mg/day(n=1,611)orthecombinationofAvodart0.5mgplustamsulosin0.4mg

(n=1,610)wereevaluatedinmalesubjectswithmoderatetoseveresymptomsofBPHwhohadprostates ≥30mlandaPSAvalue

withintherange1.5-10ng/mLinamulticentre,multinational,randomizeddouble-blind,parallelgroupstudy.Approximately

52%ofsubjectshadpreviousexposureto5-alphareductaseinhibitororalpha-blockertreatment.Efficacyendpointsduringthe

first2yearsoftreatmentwerechangeinInternationalProstateSymptomScore(IPSS),maximumurineflowrate(Qmax)and

prostatevolume.IPSSisan8-iteminstrumentbasedonAUA-SIwithanadditionalquestiononqualityoflife.

Resultsfollowing2yearsoftreatmentarepresentedbelow:

a.Combinationachievedsignificance(p<0.001)vs.AvodartfromMonth3

b.Combinationachievedsignificance(p<0.001)vs.tamsulosinfromMonth9

c.Combinationachievedsignificance(p<=0.006)vs.AvodartfromMonth6

d.Combinationachievedsignificance(p<0.001)vs.tamsulosinfromMonth6

Parameter Time-point Combination Avodart Tamsulosin

IPSS(units) [Baseline]

Month24(Changefrom

Baseline) [16.6]

-6.2 [16.4]

-4.9a [16.4]

-4.3b

Qmax(mL/sec) [Baseline]

Month24(Changefrom

Baseline) [10.9]

[10.6]

1.9c* [10.7]

0.9d*

ProstateVolume [Baseline](ml)

Month24(%Changefrom

Baseline) [54.7]

-26.9 [54.6]

-28.0 [55.8]

0.0*

ProstateTransition

ZoneVolume [Baseline](ml)

Month24(%Changefrom

Baseline) [27.7]

-23.4 [30.3]

-22.8 [30.5]

8.8*

BPHImpactIndex

(BII)(units) [Baseline]

Month24(Changefrom

Baseline) [5.3]

-2.1 [5.3]

-1.7* [5.3]

-1.5*

IPSSQuestion8

(BPH-related

HealthStatus) [Baseline]

Month24(Changesfrom

Baseline) [3.6]

-1.4 [3.6]

-1.1* [3.6]

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5.2Pharmacokineticproperties

Absorption

Followingoraladministrationofasingle0.5mgdutasteridedose,thetimetopeakserumconcentrationsofdutasteride

is1to3hours.Theabsolutebioavailabilityisapproximately60%.Thebioavailabilityofdutasterideisnotaffectedby

food.

Distribution

Dutasteridehasalargevolumeofdistribution(300to500L)andishighlyboundtoplasmaproteins(>99.5%).

Followingdailydosing,dutasterideserumconcentrationsachieve65%ofsteadystateconcentrationafter1monthand

approximately90%after3months.

Steadystateserumconcentrations(C

)ofapproximately40ng/mLareachievedafter6monthsofdosing0.5mgonce

aday.Dutasteridepartitioningfromserumintosemenaveraged11.5%.

Elimination

Dutasterideisextensivelymetabolizedinvivo.Invitro,dutasterideismetabolizedbythecytochromeP4503A4and

3A5tothreemonohydroxylatedmetabolitesandonedihydroxylatedmetabolite.

Followingoraldosingofdutasteride0.5mg/daytosteadystate,1.0%to15.4%(meanof5.4%)oftheadministered

doseisexcretedasunchangeddutasterideinthefaeces.Theremainderisexcretedinthefaecesas4majormetabolites

comprising39%,21%,7%,and7%eachofdrug-relatedmaterialand6minormetabolites(lessthan5%each).Only

traceamountsofunchangeddutasteride(lessthan0.1%ofthedose)aredetectedinhumanurine.

Theeliminationofdutasterideisdosedependentandtheprocessappearstobedescribedbytwoeliminationpathways

inparallel,onethatissaturableatclinicallyrelevantconcentrationsandonethatisnonsaturable.

Atlowserumconcentrations(lessthan3ng/mL),dutasterideisclearedrapidlybyboththeconcentrationdependent

andconcentrationindependenteliminationpathways.Singledosesof5mgorlessshowedevidenceofrapidclearance

andashorthalf-lifeof3to9days.

Attherapeuticconcentrations,followingrepeatdosingof0.5mg/day,theslower,lineareliminationpathwayis

dominatingandthehalf-lifeisapprox.3-5weeks.

Elderly

Dutasteridepharmacokineticswereevaluatedin36healthymalesubjectsbetweentheagesof24and87years

followingadministrationofasingle5mgdoseofdutasteride.

Nosignificantinfluenceofagewasseenontheexposureofdutasteridebutthehalf-lifewasshorterinmenunder50

yearsofage.Half-lifewasnotstatisticallydifferentwhencomparingthe50-69yearoldgrouptothegreaterthan70

yearsold.

Renalimpairment

Theeffectofrenalimpairmentondutasteridepharmacokineticshasnotbeenstudied.However,lessthan0.1%ofa

steady-state0.5mgdoseofdutasterideisrecoveredinhumanurine,sonoclinicallysignificantincreaseofthe

dutasterideplasmaconcentrationsisanticipatedforpatientswithrenalimpairment(seesection4.2).

Hepaticimpairment

Theeffectonthepharmacokineticsofdutasterideinhepaticimpairmenthasnotbeenstudied(seesection4.3).

Becausedutasterideiseliminatedmainlythroughmetabolismtheplasmalevelsofdutasterideareexpectedtobe

elevatedinthesepatientsandthehalf-lifeofdutasteridebeprolonged(seesection4.2andsection4.4).

5.3Preclinicalsafetydata

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Reproductiontoxicitystudiesinmaleratshaveshownadecreasedweightoftheprostateandseminalvesicles,

decreasedsecretionfromaccessorygenitalglandsandareductioninfertilityindices(causedbythepharmacological

effectofdutasteride).Theclinicalrelevanceofthesefindingsisunknown.

Aswithother5alphareductaseinhibitors,feminisationofmalefoetusesinratsandrabbitshasbeennotedwhen

dutasteridewasadministeredduringgestation.Dutasteridehasbeenfoundinbloodfromfemaleratsaftermatingwith

dutasteridetreatedmales.Whendutasteridewasadministeredduringgestationtoprimates,nofeminisationofmale

foetuseswasseenatbloodexposuressufficientlyinexcessofthoselikelytooccurviahumansemen.Itisunlikely

thatamalefoetuswillbeadverselyaffectedfollowingseminaltransferofdutasteride.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontents:

Mono-anddiglyceridesofcaprylic/capricacid

Butylhydroxytolune(E321)

Capsuleshell:

Gelatin

Glycerol

Titaniumdioxide(E171)

Ironoxideyellow(E172)

Triglycerides,mediumchain

Lecithin

Redprintinginkcontainingironoxidered(E172)asthecolourant,polyvinylacetatephthalate,propyleneglycoland

macrogol

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelflifeexpirydateofthisproductshallbethedateshownontheblisterstripsandoutercartonoftheproductas

marketedinthecountryoforigin.

6.4Specialprecautionsforstorage

Irish Medicines Board

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Date Printed 28/07/2010 CRN 2083758 page number: 10

6.5Natureandcontentsofcontainer

Over-labelledcardboardcartoncontaining3blisterstrips(10capsulesperstrip).

Packsize:30softcapsules

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Dutasterideisabsorbedthroughtheskin;thereforecontactwithleakingcapsulesmustbeavoided.Ifcontactismade

withleakingcapsules,thecontactareashouldbewashedimmediatelywithsoapandwater(seesection4.4)

Anyunusedproductorwastermaterialshouldbedisposedofinaccordancewithlocalrequirements

7PARALLELPRODUCTAUTHORISATIONHOLDER

ProfindWholesaleLtd

Unit625,KilshaneAvenue

NorthwestBusinessPark

Dublin15

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1500/48/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19thFebruary2010

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 28/07/2010 CRN 2083758 page number: 11