DUPHASTON

Main information

  • Trade name:
  • DUPHASTON Film Coated Tablet 10 Milligram
  • Dosage:
  • 10 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DUPHASTON Film Coated Tablet 10 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0108/010/001
  • Authorization date:
  • 28-01-1985
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Duphaston10mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mgDydrogesterone.

Excipients:eachtabletcontains111.1mgoflactosemonohydrate.

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Filmcoatedtablet

Around,biconvex,scored,whitefilm-coatedtablet,onesidewithinscription‘155’oneithersideofthe

score.

Thescorelineisonlytofacilitatebreakingforeaseofswallowingandnottodivideintoequaldoses.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Inthemanagementofconditionsassociatedwithprogesteroneinsufficiency:dysmenorrhoea,

endometriosis,infertility,irregularmenstrualcycles.

Thedrugmaybeusedwithanestrogeninthemanagementofdysfunctionalbleedingorsecondary

amenorrhoea,orinassociationwithestrogeninhormonereplacementtherapy.

4.2Posologyandmethodofadministration

Hormonereplacementtherapy:Thestandarddoseis10mgDuphastondailyforthelast14daysofeach28-day

estrogentreatmentcycle.Thedosemaybeincreasedto10mgtwicedailyifeitherearlywithdrawalbleeding

occurs,orifendometrialbiopsyrevealsinadequateprogestationalresponse.

Inwomenwhoarenottakinghormonereplacementtherapy,haveestablishedamenorrhoeaorwomenwho

switchfromacontinuouscombinedhormonereplacementtherapy,treatmentmaybestartedonanyconvenient

day.InwomentransferringfromacyclicorcontinuoussequentialHRTregimen,treatmentshouldbeginthe

dayfollowingcompletionofthepriorregimen.Ifthepatientismenstruating,treatmentisstartedwithinfive

daysofthestartofbleeding.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedoseforthe

shortestduration(seealsosection4.4)shouldbeused.

Dysfunctionalbleeding:

Toarrestbleeding-10mgb.d.(twiceaday)togetherwithanestrogenoncedailyforfivetosevendays.

Topreventbleeding-10mgb.d.togetherwithanestrogenoncedailyfromday11today25ofthecycle.

Dysmenorrhoea:

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Amenorrhoea:

Anestrogenoncedailyfromday1to25ofthecycle,andDuphaston10mgb.d.fromday11to25.

Endometriosis:

10mgtwotothreetimesdailyfromday5to25ofthecycle,orcontinuously.

Infertilityorirregularcycles:

10mgb.d.fromday11to25ofthecycle.Treatmentshouldbemaintainedforatleastsixconsecutivecycles.

Afterconception,itisadvisabletocontinuetreatment,10mgb.d.untilweek20ofpregnancy,thenthedosage

maybegraduallyreduced.

Pre-menstrualsyndrome:

10mgb.d.fromday12to26ofthecycle.Thedosagemaybeincreasedifnecessary.

Forgottendose:

Ifadosehasbeenforgotten,itshouldbetakenassoonaspossible.Whenmorethan12hourshaveelapsed,it

isrecommendedtocontinuewiththenextdosewithouttakingtheforgottentablet.Thelikelihoodof

breakthroughbleedingorspottingmaybeincreased.

Duphastonisnotrecommendedforuseinchildrenbelowage18duetoinsufficientdataonsafetyandefficacy.

4.3Contraindications

Knownhypersensitivitytotheactivesubstancesortoanyoftheexcipients.

Knownorsuspectedprogestogendependantneoplasms.

Useinpatientswithactivedeepveinthrombosis,thromboembolicdisorders,breastorgenitalcancer(knownor

suspectedtobehormone-dependent),orapasthistoryoftheseconditions.

Useinpatientswithundiagnosedirregularvaginalbleeding.

Whenusedinconjunctionwithanoestrogen,thecontraindicationsrelatingtotheparticularoestrogenusedshouldalso

beconsidered,forexample:

Known,pastorsuspectedbreastcancer.

Knownorsuspectedestrogen-dependentmalignanttumours(e.g.endometrialcancer);

Undiagnosedgenitalbleeding;

Untreatedendometrialhyperplasia;

Previousidiopathicorcurrentvenousthromboembolism(deepveinthrombosis,pulmonaryembolism);

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfarction);

Acuteliverdiseaseorahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal;

Porphyria.

4.4Specialwarningsandprecautionsforuse

Treatmentwithdydrogesteronehasinfrequentlybeenassociatedwithalterationsinliverfinction,sometimes

accompaniedbyclinicalsymptoms.Thus,dydrogesteroneshouldbeusedwithcautioninpatientswithacuteliver

diseaseorahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal.Incasesofsevere

hepaticimparimenttreatmentshouldbediscontinued.

Breakthroughbleedingmayoccurinafewpatients.Thiscan,however,bepreventedbyincreasingthedosage.

Adecreasedglucosetolerancemayoccurindiabeticpatientsonthistreatmentandtheircontrolmustbe

carefullysupervised.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

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Whenusedinconjunctionwithanestrogen,thespecialwarningsandprecautionsforuserelatingtothe

particularestrogenusedshouldalsobeconsidered,forexample:

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadversely

affectqualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleast

annuallyandHRTshouldonlybecontinuedaslongasthebenefitoutweighstherisk.

Medicalexamination/followup:BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamily

medicalhistoryshouldbetaken.Physical(includingpelvicandbreast)examinationshouldbeguidedby

thisandbythecontraindicationsandwarningsforuse.Duringtreatment,periodiccheck-upsare

recommendedofafrequencyandnatureadaptedtotheindividualwoman.Womenshouldbeadvisedwhat

changesintheirbreastsshouldbereportedtotheirdoctorornurse(see‘breastcancer’below).

Investigations,includingmammography,shouldbecarriedoutinaccordancewithcurrentlyaccepted

screeningpractices,modifiedtotheclinicalneedoftheindividual.

Conditionswhichneedsupervision:

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviously,and/orhavebeenaggravated

duringpregnancyorprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbe

takenintoaccountthattheseconditionsmayrecurorbeaggravatedduringtreatmentwithDuphaston,in

particular:

Leiomyoma(uterinefibroids)orendometriosis.

Ahistoryof,orriskfactorsfor,thromboembolicdisorders(seebelow).

Riskfactorsforestrogendependenttumours,e.g.1stdegreeheredityforbreastcancer.

Hypertension.

Liverdisorders(e.g.liveradenoma).

Diabetesmellituswithorwithoutvascularinvolvement.

Cholelithiasis.

Migraineor(severe)headache.

Systemiclupuserythematosus.

Ahistoryofendometrialhyperplasia(seebelow).

Epilepsy.

Asthma.

Otosclerosis.

Reasonsforimmediatewithdrawaloftherapy:

Therapyshouldbediscontinuedincaseswhereacontra-indicationisdiscoveredandinthefollowing

situations:

Jaundiceordeteriorationinliverfunction.

Significantincreaseinbloodpressure.

Newonsetofmigraine-typeheadache.

Pregnancy.

Endometrialhyperplasia:Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenestrogensare

administeredaloneforprolongedperiods(seesection4.8).Theadditionofaprogestagenforatleast12daysofthe

cycleinnon-hysterectomisedwomengreatlyreducesthisrisk.

Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-throughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshouldbe

investigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Breastcancer:Arandomisedplacebo-controlledtrial,theWomen’sHealthInitiativestudy(WHI)andepidemiological

studies,includingtheMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentaking

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ForallHRT,anexcessriskbecomesapparentwithinafewyearsofuseandincreaseswithdurationofintakebut

returnstobaselinewithinafew(atmostfive)yearsafterstoppingtreatment.

IntheMWS,therelativeriskofbreastcancerwithconjugatedequineestrogens(CEE)orestradiol(E2)was

greaterwhenaprogestagenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeof

progestagen.Therewasnoevidenceofadifferenceinriskbetweenthedifferentroutesofadministration.

IntheWHIstudy,thecontinuouscombinedconjugatedequineestrogenandmedroxyprogesteroneacetate

(CEEE+MPA)productusedwasassociatedwithbreastcancersthatwereslightlylargerinsizeandmore

frequentlyhadlocallymphnodemetastasescomparedtoplacebo.

HRT,especiallyestrogen-progestagencombinedtreatment,increasesthedensityofmammographicimages

whichmayadverselyaffecttheradiologicaldetectionofbreastcancer.

Venousthromboembolism:HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism

(VTE),i.e.deepveinthrombosisorpulmonaryembolism.Onerandomisedcontrolledtrialandepidemiologicalstudies

foundatwo-tothreefoldhigherriskforuserscomparedwithnon-users.Fornon-users,itisestimatedthatthenumber

ofcasesofVTEthatwilloccurovera5yearperiodisabout3per1000womenaged50-59yearsand8per1000

womenagedbetween60-69years.ItisestimatedthatinhealthywomenwhouseHRTfor5years,thenumberof

additionalcasesofVTEovera5yearperiodwillbebetween2and6(bestestimate=4)per1000womenaged50-59

yearsandbetween5and15(bestestimate=9)per1000womenaged60-69years.Theoccurrenceofsuchaneventis

morelikelyinthefirstyearofHRTthanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalorfamilyhistoryandsevereobesity

(BMI>30kg/m2)andsystemiclupuserythematosus(SLE).Thereisnoconsensusaboutthepossible

roleofvaricoseveinsinVTE.

PatientswithahistoryofVTEorknownthrombophilicstateshaveanincreasedriskofVTE.HRT

mayaddtothisrisk.Personalorstrongfamilyhistoryofthromboembolismorrecurrentspontaneous

abortionshouldbeinvestigatedinordertoexcludeathrombophilicpredisposition.Untilathorough

evaluationofthrombophilicfactorshasbeenmadeoranticoagulanttreatmentinitiated,useofHRTin

suchpatientsshouldbeviewedascontraindicated.Thosewomenalreadyonanticoagulanttreatment

requirecarefulconsiderationofthebenefit-riskofuseofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajor

surgery.Asinallpostoperativepatients,scrupulousattentionshouldbegiventoprophylactic

measurestopreventVTEfollowingsurgery.Whereprolongedimmobilisationisliabletofollow

electivesurgery,particularlyabdominalororthopaedicsurgerytothelowerlimbs,consideration

shouldbegiventotemporarilystoppingHRT4to6weeksearlier,ifpossible.Treatmentshouldnotbe

restarteduntilthewomeniscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldto

contacttheirdoctorsimmediatelywhentheyareawareofapotentialthromboembolicsymptom(e.g.

painfulswellingofaleg,suddenpaininthechest,dyspnea).

Coronaryarterydisease(CAD):Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascular

benefitwithcontinuouscombinedconjugatedestrogensandmedroxyprogesteroneacetate(MPA).Two

largeclinicaltrials(WHIandHERSi.e.HeartandEstrogen/progestinReplacementStudy)showeda

possibleincreasedriskofcardiovascularmorbidityormortality.Therefore,itisuncertainwhetherthese

findingsalsoextendtootherHRTproducts.

Stroke:Onelargerandomisedclinicaltrial(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischaemic

strokeinhealthywomenduringtreatmentwithcontinuouscombinedconjugatedestrogensandMPA.Forwomenwho

donotuseHRT,itisestimatedthatthenumberofcasesofstrokethatwilloccurovera5yearperiodisabout3per

1000womenaged50-59and11per1000womenaged60-69years.Itisestimatedthatforwomenwhouseconjugated

estrogensandMPAfor5years,thenumberofadditionalcaseswillbebetween0and3(bestestimate=1)per1000

usersaged50-59yearsandbetween1and9(bestestimate=4)per1000usersaged60-69years.Itisunknownwhether

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Ovariancancer:Long-term(atleast5to10years)useofestrogen-onlyHRTproductsinhysterectomised

womenhasbeenassociatedwithanincreasedriskofovariancancerinsomeepidemiologicalstudies.Itis

uncertainwhetherlongtermuseofcombinedHRTconfersadifferentriskthanestrogen-onlyproducts.

Otherconditions

Estrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbe

carefullyobserved.Patientswithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitis

expectedthatthelevelofcirculatingactiveingredientsinDuphastonisincreased.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringestrogen

replacementorhormonereplacementtherapy,sincerarecasesoflargeincreasesofplasma

triglyceridesleadingtopancreatitishavebeenreportedwithestrogentherapyinthiscondition.

Estrogensincreasethyroidbindingglobulin(TBG),leadingtoincreasedcirculatingtotalthyroid

hormone,asmeasuredbyprotein-boundiodine(PBI),T4levels(bycolumnorbyradio-immunoassay)

orT3levels(byradio-immunoassay).T3resinuptakeisdecreased,reflectingtheelevatedTBG.Free

T4andfreeT3concentrationsareunaltered.Otherbindingproteinsmaybeelevatedinserum,i.e.

corticoidbindingglobulin(CBG),sex-hormone-bindingglobulin(SHBG)leadingtoincreased

circulatingcorticosteroidsandsexsteroids,respectively.Freeorbiologicalactivehormone

concentrationsareunchanged.Otherplasmaproteinsmaybeincreased(angiotensinogen/rennin

substrate,alpha-1-antitrypsin,ceruloplasmin).

Thereisnoconclusiveevidenceforimprovementofcognitivefunction.Thereissomeevidencefrom

theWHItrialofincreasedriskofprobabledementiainwomenwhostartusingcontinuouscombined

CEEandMPAaftertheageof65.Itisunknownwhetherthefindingsapplytoyoungerpot-

menopausalwomenorotherHRTproducts.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-

galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Nointeractionstudieshavebeenperformed.

Themetabolismofprogestagensmaybeincreasedbyconcomitantuseofsubstancesknowntoinduce

drug-metabolisingenzymes,specificallycytochromeP450enzymes,suchasanticonvulsants(eg.

Phenobarbital,phenytoin,carbamezapine)andanti-infectives(e.g.rifampicin,rifabutin,nevirapine,

efavirenz).

Ritonavirandnelfinavir,althoughknownasstronginhibitors,bycontrastexhibitinducingproperties

whenusedconcomitantlywithsteroidhormones.

HerbalpreparationscontainingStJohn’sWort(Hypericumperforatum)mayinducethemetabolismof

progestagens.

Clinicallyanincreasedmetabolismofprogestagensmayleadtodecreasedeffectandchangesinthe

uterinebleedingprofile.

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4.6Fertility,pregnancyandlactation

Pregnancy:

Duphastonisnotindicatedduringpregnancy.IfpregnancyoccursduringmedicationwithDuphaston,

treatmentshouldbewithdrawnimmediately.

Itisestimatedthataltogether35millionwomenhavebeentreatedwithdydrogesterone.Althoughthenumberof

pregnanciesisdifficulttoestimate,asanapproximateitcanbeassumedthatinuterofoetuseswereexposedto

dydrogesteroneinaround9millionpregnancies.Fromspontaneoussurveillancesystemuntilnow,thereisnoevidencethat

dydrogesteronecannotbeusedduringpregnancy.Nootherrelevantepidemiologicaldataondydrogesteroneareavailable.

However,arecentUScase-controlstudyinvestigating502caseswithhypospadiasand1286healthycontrolssuggested

atleasta2-foldincreasedriskofsecond/thirddegreehypospadiasamongboysborntomotherswhotookprogestogens

(predominatelyprogesterone)shortlypriororduringpregnancy(OR2.2,95%CI1.0-5.0).Thecasualityisunclearas

theunderlyingdiseaseitselfforprogesteroneuseinpregnancymaybepotentiallyassociatedwithariskof

hypospadias.Fordydrogesterone,theriskofhypospadiasisunknown.

Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespecttopregnancy,embryonal/foetal,or

postnatal,development.Animalsafetydataarelimitedwithrespecttoeffectsonparturition(see5.3).

Thereisnoevidencethatdydrogesteronedecreasesfertility.

Lactation

Dydrogesteroneisexcretedinthemilkofnursingmothers.Arisktothesucklingchildcannotbeexcluded.

Dydrogesteroneshouldnotbeusedduringbreast-feeding.

4.7Effectsonabilitytodriveandusemachines

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4.8Undesirableeffects

Sideeffectsincludeheadaches,gastrointestinalupset,candidiasis,weightchanges,fluidretentionand

occasionalhypertension.

Whenusedinconjunctionwithanestrogen,theUndesirableeffectsrelatingtotheparticularestrogenused

shouldalsobeconsidered,forexample:

Theundesirableeffectsreportedinclinicaltrialsandinpostmarketingexperiencefollowing

estrogen/progestagentherapyare:

MedDRAsystem

organclass Common

1/100,<1/10 Uncommon

1/1,000,<1/100 Rare

1/10,000,<1/1,000 Veryrare

<1/10,000incl.

isolatedreports

Infectionsand

infestations Cystitis-like

syndrome,Vaginal

candidiasis

Neoplasms

benign,

malignantand

unspecified Increaseinsizeof

leiomyoma

Bloodand

lymphaticsystem

disorders Haemolytic

anaemia

Immunesystem

disorders Hypersensitivity

reactions

Psychiatric

disorders Depression,Change

inlibido,

Nervousness

Nervoussystem

disorders Headache,

Migraine Dizziness Chorea

Eyedisorders Intolerancetocontact

lenses,Steepeningof

cornealcurvature

Cardiacdisorders Myocardial

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Otheradversereactionsobtainedfromthemarketwithunknownfrequencyinassociationwithdydrogesterone

treatment:

-Increaseinsizeofprogestogendependantneoplasms(e.g.meningioma)(seesection4.3).

BreastCancer

Accordingtoevidencefromalargenumberofepidemiologicalstudiesandonerandomisedplacebo-controlledtrial,the

Women’sHealthInitiative(WHI),theoverallriskofbreastcancerincreaseswithincreasingdurationofHRTusein

currentorrecentHRTusers.

Forestrogen-onlyHRT,estimatesofrelativerisk(RR)fromareanalysisoforiginaldatafrom51epidemiological

studies(inwhich>80%ofHRTusewasestrogen-onlyHRT)andfromtheepidemiologicalMillionWomenStudy

Vascular

disorders Hypertension,

Peripheralvascular

disease,Varicose

vein,Venous

thromboembolism Stroke

Gastrointestinal

disorders Nausea,

Abdominalpain,

Flatulence Dyspepsia Vomiting

Hepatobiliary

disorders Gallbladderdisease

Alterationsinliver

function,sometimes

withAstheniaor

Malaise,Jaundice

andAbdominalpain

Skinand

subcutaneous

tissuedisorders Allergicskin

reactions,Rash,

Urticaria,Pruritus Chloasmaor

melasma,which

maypersistwhen

drugis

discontinued,

Erythema

nodosum,

Vascularpurpura,

Angioedema

Musculoskeletal

andconnective

tissuedisorders Legcramps Backpain

Reproductive

systemand

breastdisorders Breakthrough

bleedingand

spotting,Pelvic

pain Changeincervical

erosion,Changein

cervicalsecretion,

Dysmenorrhoea,

Menorrhagia,

Metrorrhagia

Breast

pain/tenderness Breastenlargement,

Premenstrual-like

symptoms

Congenitaland

familial/genetic

disorders Aggravationof

porphyria

Generaldisorders

administration

sitereactions Asthenia Peripheral

oedema

Investigations Increase/decrease

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ForestrogenplusprogestagencombinedHRT,severalepidemiologicalstudieshavereportedanoverallhigher

riskforbreastcancerthanwithestrogensalone.

TheMWSreportedthat,comparedtoneverusers,theuseofvarioustypesofestrogen-progestagencombined

HRTwasassociatedwithahigherriskofbreastcancer(RR=2.00,95%CI:1.88–2.12)thanuseofestrogens

alone(RR=1.30,95%CI:1.21–1.40)oruseoftibolone(RR=1.45,95%CI1.25–1.68).

TheWHItrialreportedariskestimateof1.24(95%CI1.01–1.54)after5.6yearsofuseofestrogen-

progestagencombinedHRT(CEE+MPA)inalluserscomparedwithplacebo.

TheabsoluteriskscalculatedfromtheMWSandtheWHItrialsarepresentedbelow:

TheMWShasestimated,fromtheknownaverageincidenceofbreastcancerindevelopedcountries,that:

ForwomennotusingHRT,about32inevery1000areexpectedtohavebreastcancerdiagnosed

betweentheagesof50and64years.

For1000currentorrecentusersofHRT,thenumberofadditionalcasesduringthecorresponding

periodwillbe:

Forusersofestrogen-onlyreplacementtherapy,between0and3(bestestimate=1.5)for5years’use,

between3and7(bestestimate=5)for10yearsuse.

ForusersofestrogenplusprogestagencombinedHRT,between5and7(bestestimate=6)for5years’

use,between18and20(bestestimate=19)for10yearsuse.

TheWHItrialestimatedthatafter5.6yearsoffollow-upofwomenbetweentheagesof50and79yearsan

additional8casesofinvasivebreastcancerwouldbeduetoestrogen-progestagencombinedHRT(CEE+

MPA)per10,000womenyears.

Accordingtocalculationsfromthetrialdata,itisestimatedthat:

For1000womenintheplacebogroup,about16casesofinvasivebreastcancerwouldbediagnosedin

5years.

For1000womenwhousedestrogen+progestagencombinedHRT(CEE+MPA),thenumberof

additionalcaseswouldbebetween0and9(bestestimate=4)for5years’use.

ThenumberofadditionalcasesofbreastcancerinwomenwhouseHRTisbroadlysimilarforwomenwho

startHRTirrespectiveofageatstartofuse(betweentheagesof45-65)(seesection4.4).

Endometrialcancer

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandendometrialcancerincreaseswith

increasingdurationofuseofunopposedestrogens.Accordingtodatafromepidemiologicalstudies,thebest

estimateoftheriskisthatforwomennotusingHRT,about5inevery1000areexpectedtohaveendometrial

cancerdiagnosedbetweentheagesof50and65.Dependingonthedurationoftreatmentandestrogenusers

variesfrom2-to12-foldgreatercomparedwithnon-users.Addingaprogestagentoestrogen-onlytherapy

greatlyreducesthisincreasedrisk.

Otheradversereactionshavebeenreportedinassociationwithestrogen/progestagentreatment:

Estrogen-dependentneoplasmabenignandmalignant,e.g.endometrialcancer.

Venousthromboembolism,i.e.deeplegorpelvicvenousthrombosisandpulmonaryembolism,ismore

frequentamonghormonereplacementtherapyusersthanamongnon-users.Forfurtherinformation,see

section4.3Contraindicationsand4.4Specialwarningsandprecautionsforuse.

Probabledementia(seesection4.4).

4.9Overdose

Limiteddataareavailablewithregardtooverdoseinhumans.Dydrogesteronewaswelltoleratedafteroraldosing

(maximumdailydosetakentodateinhumans360mg).Noreportsofilleffectsfromoverdosehavebeenrecorded.Ifa

largeoverdoseisdiscoveredwithintwoorthreehoursandtreatmentseemsdesirable,gastriclavageisrecommended.

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:GenitoUrinarysystemandsexhormones,ATCcode:G03DB01

Dydrogesterone

Dydrogesteroneisanorally-activeprogestogen,whichproducesacompletesecretoryendometriuminanestrogen-

primeduterus,therebyprovidingprotectionforestrogen-inducedincreasedriskofendometrialhyperplasiaand/or

carcinogenesis.Itisindicatedinallcasesofendogeneousprogesteronedeficiency.Duphastonisnon-androgenic,non-

estrogenic,non-thermogenic,non-corticoidandnon-anabolic.

Whenusedinconjunctionwithanestrogen,thepharmacodynamicpropertiesrelatingtotheparticularestrogenused

shouldalsobeconsidered,forexample:

Clinicaltrialinformation:

Reliefofestrogen-deficiencysymptomsandbleedingpatterns.

Reliefofmenopausalsymptomswasachievedduringthefirstfewweeksoftreatment.

RegularwithdrawalbleedingwithDuphastonandEstradiol1mgoccurredinapproximately75-80%ofwomen

withameandurationof5days.Withdrawalbleedingusuallystartedonthedayofthelastpillofthe

progestagenphase.Break-throughbleedingand/orspottingoccurredinapproximately10%ofthewomen;

amenorrhoea(nobleedingorspotting)occurredin10-25%ofthewomenpercycleduringthefirstyearof

treatment.

WithDuphastonandEstradiol2mg,approximately90%ofwomenhadregularwithdrawalbleeding.Thestart

dayanddurationofbleeding,andthenumberofwomenwithintermittentbleedingwasthesameaswith

DuphastonandEstradiol1mg,amenorrhoeaoccurredin5–15%ofthewomenpercycleduringthefirstyearof

treatment.

5.2Pharmacokineticproperties

Afteroraladministrationoflabelleddydrogesterone,onaverage63%ofthedoseisexcretedintotheurine.

Within72hours,excretioniscomplete.

Inman,dydrogesteroneiscompletelymetabolised.Themainmetaboliteofdydrogesteroneis20-

dihydrodydrogesterone(DHD)andispresentintheurinepredominantlyastheglucoronicacidconjugate.A

commonfeatureofallmetabolitescharacterisedistheretentionofthe4,6diene-3-oneconfigurationofthe

parentcompoundandtheabsenceof17-hydroxylation.Thisexplainstheabsenceofestrogenicand

androgenicactivity.

Afteroraladministrationofdydrogesterone,plasmaconcentrationsofDHDaresubstantiallyhigheras

comparedtotheparentdrug.TheAUCandCmaxratiosofDHDtodydrogesteroneareintheorderof40and

25,respectively.Dydrogesteroneisrapidlyabsorbed.TheTmaxvaluesofdydrogesteroneandDHDvary

between0.5and2.5hours.

Meanterminalhalf-livesofdydrogesteroneandDHDvarybetween5to7and14to17hours,respectively.

ThedihydrodydrogesteroneC

average is13ng/ml,theCminis4.1ng/mlandtheCmaxis63ng/ml.The

dydrogesteroneC

average is0.38ng/mltheCminis<0.1ng/mlandtheCmaxis2.5ng/ml.

Dydrogesteroneisnotexcretedinurineaspregnanediol,likeprogesterone.Analysisofendogenous

progesteroneproductionbasedonpregnanediolexcretionthereforeremainspossible.

Dydrogesteroneisnotexcretedinurineaspregnanediol,likeprogesterone.Analysisofendogenous

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5.3Preclinicalsafetydata

Receptorbindingstudiesandfunctionalactivitystudiesrevealedantiandrogenicpotencyofprogesterone,

dydrogesteroneanditsmetaboliteDHDisprobablynoticeablyweakerthanthatofaprogesterone.Withregardto

antiandrogeniceffectsmediatedbyinhibitionof5-reductasetypeII,animportantenzymefordifferentiationofthe

maleexternalgenitalia,progesteroneisaspotentasthesyntheticenzymeinhibitorfinasteride,whereasdydrogesterone

andDHDareinactive.Theoverallpotentialtoactasantiandrogenicendocrinedisruptorsmayberatedashighestfor

progesterone,lowerfordydrogesteroneandlowestforDHD.

Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespecttopregnancy,embryonal/foetalor

postnataldevelopment.

Limitedanimalsafetydatasuggestthatdydrogesteronehasdelayingeffectsonparturition,whichisconsistentwithits

progestogenicactivity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

LactoseMonohydrate

MaizeStarch

Hypromellose

ColloidalAnhydrousSilica

MagnesiumStearate

Macrogol400

TitaniumDioxide(E171)

PurifiedWater

6.2Incompatibilities

Notapplicable.

6.3Shelflife

5years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Keeptheblisterintheoutercarton,inordertoprotectfrommoistureandlight.

6.5Natureandcontentsofcontainer

Cartonsof42or60blisterpackedtabletsinAl/PVCblisterstrips.

Notallpackssizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7MARKETINGAUTHORISATIONHOLDER

AbbottHealthcareProductsLimited

MansbridgeRoad

WestEnd

SouthamptonSO183JD

England

8MARKETINGAUTHORISATIONNUMBER

PA108/10/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28January1985

Dateoflastrenewal:28January2010

10DATEOFREVISIONOFTHETEXT

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