DUAGEN

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1077/105/001
  • Authorization date:
  • 17-12-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Duagen0.5mgsoftcapsules.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachcapsulecontains0.5mgdutasteride.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Capsule,soft.

Thecapsulesareopaque,yellow,oblongsoftgelatincapsulesimprintedwithGXCE2ononesideinredink.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofmoderatetoseveresymptomsofbenignprostatichyperplasia(BPH).

Reductionintheriskofacuteurinaryretention(AUR)andsurgeryinpatientswithmoderatetoseveresymptomsof

BPH.

Forinformationoneffectsoftreatmentandpatientpopulationsstudiedinclinicaltrialspleaseseesection5.1.

4.2Posologyandmethodofadministration

Adults(includingelderly):

TherecommendeddoseofDuagenisonecapsule(0.5mg)takenorallyonceaday.Thecapsulesshouldbeswallowed

wholeandmaybetakenwithorwithoutfood.Althoughanimprovementmaybeobservedatanearlystage,itcantake

upto6monthsbeforearesponsetothetreatmentcanbeachieved.Nodoseadjustmentisnecessaryintheelderly.

Renalimpairment

Theeffectofrenalimpairmentondutasteridepharmacokineticshasnotbeenstudied.Noadjustmentindosageis

anticipatedforpatientswithrenalimpairment(seesection5.2).

Hepaticimpairment

Theeffectofhepaticimpairmentondutasteridepharmacokineticshasnotbeenstudiedsocautionshouldbeusedin

patientswithmildtomoderatehepaticimpairment(seesection4.4andsection5.2).Inpatientswithseverehepatic

impairment,theuseofdutasterideiscontraindicated(Seesection4.3Contraindications).

4.3Contraindications

Duageniscontraindicatedin:

womenandchildrenandadolescents(seesection4.6).

patientswithhypersensitivitytodutasteride,other5-alphareductaseinhibitors,oranyoftheexcipients.

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4.4Specialwarningsandprecautionsforuse

Combinationtherapyshouldbeprescribedaftercarefulbenefitriskassessmentduetothepotentialincreasedriskof

adverseeventsandafterconsiderationofalternativetreatmentoptionsincludingmonotherapies(seesection4.2).

Digitalrectalexamination,aswellasotherevaluationsforprostatecancer,mustbeperformedonpatientswithBPH

priortoinitiatingtherapywithDuagenandperiodicallythereafter.

Dutasterideisabsorbedthroughtheskin,therefore,women,childrenandadolescentsmustavoidcontactwithleaking

capsules(seesection4.6).Ifcontactismadewithleakingcapsules,thecontactareashouldbewashedimmediately

withsoapandwater.

Dutasteridewasnotstudiedinpatientswithliverdisease.Cautionshouldbeusedintheadministrationofdutasteride

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

Serumprostate-specificantigen(PSA)concentrationisanimportantcomponentinthedetectionofprostatecancer.

Generally,atotalserumPSAconcentrationgreaterthan

4ng/mL(Hybritech)requiresfurtherevaluationandconsiderationofprostatebiopsy.Physiciansshouldbeawarethat

abaselinePSAlessthan4ng/mLinpatientstakingDuagendoesnotexcludeadiagnosisofprostatecancer.Duagen

causesadecreaseinserumPSAlevelsbyapproximately50%,after6months,inpatientswithBPH,eveninthe

presenceofprostatecancer.Althoughtheremaybeindividualvariation,thereductioninPSAbyapproximately50%

ispredictableasitwasobservedovertheentirerangeofbaselinePSAvalues(1.5to10ng/mL).Thereforetointerpret

anisolatedPSAvalueinamantreatedwithDuagenforsixmonthsormore,PSAvaluesshouldbedoubledfor

comparisonwithnormalrangesinuntreatedmen.ThisadjustmentpreservesthesensitivityandspecificityofthePSA

assayandmaintainsitsabilitytodetectprostatecancer.AnysustainedincreasesinPSAlevelswhileonDuagen

shouldbecarefullyevaluated,includingconsiderationofnoncompliancetotherapywithDuagen.

TotalserumPSAlevelsreturntobaselinewithin6monthsofdiscontinuingtreatment.TheratiooffreetototalPSA

remainsconstantevenundertheinfluenceofDuagen.IfclinicianselecttousepercentfreePSAasanaidinthe

detectionofprostatecancerinmenundergoingDuagentherapy,noadjustmenttoitsvalueappearsnecessary.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ForinformationonthedecreaseofserumPSAlevelsduringtreatmentwithdutasterideandguidanceconcerning

prostatecancerdetection,pleaseseesection4.4.

Effectsofotherdrugsonthepharmacokineticsofdutasteride

UsetogetherwithCYP3A4and/orP-glycoprotein-inhibitors:

Dutasterideismainlyeliminatedviametabolism.Invitrostudiesindicatethatthismetabolismiscatalysedby

CYP3A4andCYP3A5.NoformalinteractionstudieshavebeenperformedwithpotentCYP3A4inhibitors.However,

inapopulationpharmacokineticstudy,dutasterideserumconcentrationswereonaverage1.6to1.8timesgreater,

respectively,inasmallnumberofpatientstreatedconcurrentlywithverapamilordiltiazem(moderateinhibitorsof

CYP3A4andinhibitorsofP-glycoprotein)thaninotherpatients.

Long-termcombinationofdutasteridewithdrugsthatarepotentinhibitorsoftheenzymeCYP3A4(e.g.ritonavir,

indinavir,nefazodon,itraconazole,ketoconazoleadministeredorally)mayincreaseserumconcentrationsof

dutasteride.Furtherinhibitionof5-alphareductaseatincreaseddutasterideexposure,isnotlikely.However,a

reductionofthedutasteridedosingfrequencycanbeconsideredifsideeffectsarenoted.Itshouldbenotedthatinthe

caseofenzymeinhibition,thelonghalf-lifemaybefurtherprolongedanditcantakemorethan6monthsofconcurrent

therapybeforeanewsteadystateisreached.

Administrationof12gcholestyramineonehourbeforea5mgsingledoseofdutasteridedidnotaffectthe

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Effectsofdutasterideonthepharmacokineticsofotherdrugs

Dutasteridehasnoeffectonthepharmacokineticsofwarfarinordigoxin.Thisindicatesthatdutasteridedoesnot

inhibit/induceCYP2C9orthetransporterP-glycoprotein.Invitrointeractionstudiesindicatethatdutasteridedoesnot

inhibittheenzymesCYP1A2,CYP2D6,CYP2C9,CYP2C19orCYP3A4.

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

pharmacokineticsoftamsulosinorterazosin.Therewasalsonoindicationofapharmacodynamicinteractioninthis

study.

4.6Pregnancyandlactation

Duageniscontraindicatedforusebywomen.

Fertility

Dutasteridehasbeenreportedtoaffectsemencharacteristics(reductioninspermcount,semenvolume,andsperm

motility)inhealthymen(seesection5.1).Thepossibilityofreducedmalefertilitycannotbeexcluded.

Pregnancy

Aswithother5alphareductaseinhibitors,dutasterideinhibitstheconversionoftestosteronetodihydrotestosteroneand

may,ifadministeredtoawomancarryingamalefoetus,inhibitthedevelopmentoftheexternalgenitaliaofthefoetus

(seesection4.4).

SmallamountsofdutasteridehavebeenrecoveredfromthesemeninsubjectsreceivingDuagen0.5mg/day.Basedon

studiesinanimals,itisunlikelythatamalefoetuswillbeadverselyaffectedifhismotherisexposedtothesemenofa

patientbeingtreatedwithDuagen(theriskofwhichisgreatestduringthefirst16weeksofpregnancy).

However,aswithall5alphareductaseinhibitors,whenthepatient'spartnerisormaypotentiallybepregnantitis

recommendedthatthepatientavoidsexposureofhispartnertosemenbyuseofacondom.

Lactation

Itisnotknownwhetherdutasterideisexcretedinhumanmilk.

4.7Effectsonabilitytodriveandusemachines

Basedonthepharmacodynamicpropertiesofdutasteride,treatmentwithdutasteridewouldnotbeexpectedtointerfere

withtheabilitytodriveoroperatemachinery.

4.8Undesirableeffects

Approximately19%ofthe2167patientswhoreceiveddutasterideinthe2yearPhaseIIIplacebo-controlledtrials

developedadversereactions.Themajorityofeventsweremildtomoderateandoccurredinthereproductivesystem.

Nochangetotheadverseeventprofilewasapparentoverafurther2yearsinopen-labelextensionstudies.

Thefollowingtableshowsadversereactionsfromcontrolledclinicaltrialsandpost-marketingexperience.Thelisted

adverseeventsfromclinicaltrialshavebeenreportedwithahigherincidenceinpatientstreatedwithdutasteride

comparedwithplaceboduringthefirstyearoftreatment.Adverseeventsfrompost-marketingexperiencewere

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*Incidencefromclinicaltrialdata

**Adverseeventsfrompost-marketingdata

4.9Overdose

InvolunteerstudiesofDuagen,singledailydosesofdutasterideupto40mg/day(80timesthetherapeuticdose)have

beenadministeredfor7dayswithoutsignificantsafetyconcerns.Inclinicalstudies,dosesof5mgdailyhavebeen

administeredtosubjectsfor6monthswithnoadditionaladverseeffectstothoseseenattherapeuticdosesof0.5mg.

ThereisnospecificantidoteforDuagen,therefore,insuspectedoverdosagesymptomaticandsupportivetreatment

shouldbegivenasappropriate.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:testosterone-5-alpha-reductaseinhibitors.

ATCcode:G04CB02.

Dutasteridereducescirculatinglevelsofdihydrotestosterone(DHT)byinhibitingbothtype1andtype2,5-reductase

isoenzymeswhichareresponsiblefortheconversionoftestosteroneto5-DHT.

DUAGENASMONOTHERAPY

EffectsonDHT/Testosterone:

EffectofdailydosesofDuagenonthereductiononDHTisdosedependantandisobservedwithin1-2weeks(85%

and90%reduction,respectively).

InpatientswithBPHtreatedwithdutasteride0.5mg/day,themediandecreaseinserumDHTwas94%at1yearand

93%at2yearsandthemedianincreaseinserumtestosteronewas19%atboth1and2years.

EffectonProstateVolume:

Significantreductionsinprostatevolumehavebeendetectedasearlyasonemonthafterinitiationoftreatmentand

reductionscontinuedthroughMonth24(p<0.001).Duagenledtoameanreductionoftotalprostatevolumeof23.6%

(from54.9mlatbaselineto42.1ml)atMonth12comparedwithameanreductionof0.5%(from54.0mlto53.7ml)in

theplacebogroup.Significant(p<0.001)reductionsalsooccurredinprostatetransitionalzonevolumeasearlyasone

monthcontinuingthroughMonth24,withameanreductioninprostatetransitionalzonevolumeof17.8%(from

26.8mlatbaselineto21.4ml)intheDuagengroupcomparedtoameanincreaseof7.9%(from26.8mlto27.5ml)inthe

placebogroupatMonth12.Thereductionoftheprostatevolumeseenduringthefirst2yearsofdouble-blindtreatment

wasmaintainedduringanadditional2yearsofopen-labelextensionstudies.Reductionofthesizeofprostateleadsto

Organsystem Adversereaction Incidence

*Reproductivesystemand

breastdisorders Impotence 6.0%

Altered(decreased)libido 3.7%

Ejaculationdisorders 1.8%

Gynecomastia(includesbreast

enlargementand/orbreast

tenderness) 1.3%

**Immunesystemdisorders Allergicreactionsincluding

rash,pruritus,urticaria,

localisedoedema,and

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CLINICALSTUDIES:

Duagen0.5mg/dayorplacebowasevaluatedin4325malesubjectswithmoderatetoseveresymptomsofBPHwho

hadprostates30mlandaPSAvaluewithintherange1.5-10ng/mLinthreeprimaryefficacy2-yearmulticenter,

multinational,placebo-controlled,double-blindstudies.

Thestudiesthencontinuedwithanopen-labelextensionto4yearswithallpatientsremaininginthestudyreceiving

dutasterideatthesame0.5mgdose.37%ofinitiallyplacebo-randomizedpatientsand40%ofdutasteride-randomized

patientsremainedinthestudyat4years.Themajority(71%)ofthe2,340subjectsintheopen-labelextensions

completedthe2additionalyearsofopen-labeltreatment.

ThemostimportantclinicalefficacyparameterswereAmericanUrologicalAssociationSymptomIndex(AUA-SI),

maximumurinaryflow(Qmax)andtheincidenceofacuteurinaryretentionandBPH-relatedsurgery.

AUA-SIisaseven-itemquestionnaireaboutBPH-relatedsymptomswithamaximumscoreof35.Atbaselinethe

averagescorewasapprox.17.

Aftersixmonths,oneandtwoyearstreatmenttheplacebogrouphadanaverageimprovementof2.5,2.5and2.3points

respectivelywhiletheDuagengroupimproved3.2,3.8and4.5pointsrespectively.Thedifferencesbetweenthe

groupswerestatisticallysignificant.TheimprovementinAUA-SIseenduringthefirst2yearsofdouble-blind

treatmentwasmaintainedduringanadditional2yearsofopen-labelextensionstudies.

Qmax(maximumurineflow):

MeanbaselineQmaxforthestudieswasapprox10ml/sec(normalQmax15ml/sec).Afteroneandtwoyears

treatmenttheflowintheplacebogrouphadimprovedby0.8and0.9ml/secrespectivelyand1.7and2.0ml/sec

respectivelyintheDuagengroup.ThedifferencebetweenthegroupswasstatisticallysignificantfromMonth1to

Month24.Theincreaseinmaximumurineflowrateseenduringthefirst2yearsofdoubleblindtreatmentwas

maintainedduringanadditional2yearsofopen-labelextensionstudies.

AcuteUrinaryRetentionandSurgicalIntervention

Aftertwoyearsoftreatment,theincidenceofAURwas4.2%intheplacebogroupagainst1.8%intheDuagengroup

(57%riskreduction).Thisdifferenceisstatisticallysignificantandmeansthat42patients(95%CI30-73)needtobe

treatedfortwoyearstoavoidonecaseofAUR.

TheincidenceofBPH-relatedsurgeryaftertwoyearswas4.1%intheplacebogroupand2.2%intheDuagengroup

(48%riskreduction).Thisdifferenceisstatisticallysignificantandmeansthat51patients(95%CI33-109)needtobe

treatedfortwoyearstoavoidonesurgicalintervention.

Hairdistribution

TheeffectofdutasterideonhairdistributionwasnotformallystudiedduringthephaseIIIprogramme,however,5

alpha-reductaseinhibitorscouldreducehairlossandmayinducehairgrowthinsubjectswithmalepatternhairloss

(maleandrogeneticalopecia).

Thyroidfunction:

Thyroidfunctionwasevaluatedinaoneyearstudyinhealthymen.Freethyroxinelevelswerestableondutasteride

treatmentbutTSHlevelsweremildlyincreased(by0.4MCIU/mL)comparedtoplaceboattheendofoneyear's

treatment.

However,asTSHlevelswerevariable,medianTSHranges(1.4-1.9MCIU/mL)remainedwithinnormallimits(0.5-

5/6MCIU/mL),freethyroxinelevelswerestablewithinthenormalrangeandsimilarforbothplaceboanddutasteride

treatment,thechangesinTSHwerenotconsideredclinicallysignificant.Inalltheclinicalstudies,therehasbeenno

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Breastneoplasia:

Inthe2yearclinicaltrials,providing3374patientyearsofexposuretodutasteride,andatthetimeofregistrationinthe

2yearopenlabelextension,therewere2casesofbreastcancerreportedindutasteride-treatedpatientsand1caseina

patientwhoreceivedplacebo.

However,therelationshipbetweenbreastcanceranddutasterideisnotclear.

Effectsonmalefertility

Theeffectsofdutasteride0.5mg/dayonsemencharacteristicswereevaluatedinhealthyvolunteersaged18to52(n=27

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

themeanpercentreductionfrombaselineintotalspermcount,semenvolumeandspermmotilitywere23%,26%and

18%,respectively,inthedutasteridegroupwhenadjustedforchangesfrombaselineintheplacebogroup.Sperm

concentrationandspermmorphologywereunaffected.After24weeksoffollow-up,themeanpercentchangeintotal

spermcountinthedutasteridegroupremained23%lowerthanbaseline.Whilemeanvaluesforallparametersatall

timepointsremainedwithinthenormalrangesanddidnotmeetthepredefinedcriteriaforaclinicallysignificant

change(30%),twosubjectsinthedutasteridegrouphaddecreasesinspermcountofgreaterthan90%frombaselineat

52weeks,withpartialrecoveryatthe24weekfollow-up.Thepossibilityofreducedmalefertilitycannotbeexcluded.

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

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Elderly

Dutasteridepharmacokineticswereevaluatedin36healthymalesubjectsbetweentheagesof24and87years

followingadministrationofasingle5mgdoseofdutasteride.Nosignificantinfluenceofagewasseenontheexposure

ofdutasteridebutthehalf-lifewasshorterinmenunder50yearsofage.Half-lifewasnotstatisticallydifferentwhen

comparingthe50-69yearoldgrouptothegreaterthan70yearsold.

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

Currentstudiesofgeneraltoxicity,genotoxicityandcarcinogenicitydidnotshowanyparticularrisktohumans.

Reproductiontoxicitystudiesinmaleratshaveshownadecreasedweightoftheprostateandseminalvesicles,

decreasedsecretionfromaccessorygenitalglandsandareductioninfertilityindices(causedbythepharmacological

effectofdutasteride).Theclinicalrelevanceofthesefindingsisunknown.

Aswithother5alphareductaseinhibitors,feminisationofmalefoetusesinratsandrabbitshasbeennotedwhen

dutasteridewasadministeredduringgestation.Dutasteridehasbeenfoundinbloodfromfemaleratsaftermatingwith

dutasteridetreatedmales.Whendutasteridewasadministeredduringgestationtoprimates,nofeminisationofmale

foetuseswasseenatbloodexposuressufficientlyinexcessofthoselikelytooccurviahumansemen.Itisunlikely

thatamalefoetuswillbeadverselyaffectedfollowingseminaltransferofdutasteride.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontents:

mono-anddiglyceridesofcaprylic/capricacid

butylhydroxytoluene(E321).

Capsuleshell:

gelatin

glycerol

titaniumdioxide(E171)

ironoxideyellow(E172)

triglycerides,mediumchain

lecithin.

Redprintinginkcontainingironoxidered(E172)asthecolourant,polyvinylacetatephthalate,propyleneglycoland

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6.2Incompatibilities

Notapplicable.

6.3ShelfLife

4years.

6.4Specialprecautionsforstorage

Donotstoreabove30 °

6.5Natureandcontentsofcontainer

BlistersofopaquePVC/PVDCfilmcontaining10softgelatincapsulespackedintocontainersof10,30,50,60and90

capsules.Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Dutasterideisabsorbedthroughtheskin,thereforecontactwithleakingcapsulesmustbeavoided.Ifcontactismade

withleakingcapsules,thecontactareashouldbewashedimmediatelywithsoapandwater(seesection4.4).

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

GlaxoSmithKline(Ireland)Limited

StonemasonsWay

Rathfarnham

Dublin16

8MARKETINGAUTHORISATIONNUMBER

PA1077/105/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:17December2004

Dateoflastrenewal:19July2007

10DATEOFREVISIONOFTHETEXT

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