FEMOSTON-CONTI

Main information

  • Trade name:
  • FEMOSTON-CONTI Film Coated Tablet 1mg/5mg Milligram
  • Dosage:
  • 1mg/5mg Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FEMOSTON-CONTI Film Coated Tablet 1mg/5mg Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0108/021/004
  • Authorization date:
  • 08-12-2000
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Femoston-conti1mg/5mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains1mgestradiolasestradiolhemihydrateand5mgdydrogesterone.

Excipient(s):Lactose

Forafulllistofexcipients,see6.1

3PHARMACEUTICALFORM

Film-coated'tablet'

Round,biconvextabletsmarked379ononeside(7mm)

Salmoncoloured1/5mgtablets.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapy(HRT)forestrogendeficiencysymptomsinpostmenopausalwomen.Femoston-conti

shouldbeusedonlyinpostmenopausalwomenmorethan12monthsaftermenopause.

Preventionofosteoporosisinpostmenopausalwomenathighriskoffuturefractureswhoareintolerantof,or

contraindicatedfor,othermedicinalproductsapprovedforthepreventionofosteoporosis.(Seealsosection4.4)

Theexperienceintreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

Femoston-contiisacontinuouscombinedHRT.

Thedosageisonetabletperday.Femoston-contishouldbetakencontinuouslywithoutabreakbetweenpacks.

Femoston-conticanbetakenwithorwithoutfood.

StartingFemoston-conti:

WomenexperiencinganaturalmenopauseshouldcommencetreatmentwithFemoston-conti12monthsaftertheirlast

naturalmenstrualbleed.Forsurgicallyinducedmenopause,treatmentmaystartimmediately.

Inwomenwhoarenottakinghormonereplacementtherapyorwomen,whoswitchfromacontinuouscombinedhormone

replacementtherapy,treatmentmaybestartedonanyconvenientday.Inwomentransferringfromacyclicorcontinuous

sequentialHRTregimen,treatmentshouldbeginthedayfollowingcompletionofthepriorregimen.

Ifadosehasbeenforgotten,itshouldbetakenassoonaspossible.Whenmorethan12hourshaveelapsed,itis

recommendedtocontinuewiththenextdosewithouttakingtheforgottentablet.Thelikelihoodofbreakthroughbleeding

orspottingmaybeincreased.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

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4.3Contraindications

Hypersensitivitytotheactivesubstancesortoanyoftheexcipients.

Known,pastorsuspectedbreastcancer,

Knownorsuspectedestrogen-dependentmalignanttumours(e.g.endometrialcancer),

Undiagnosedgenitalbleeding,

Untreatedendometrialhyperplasia,

Previousidiopathicorcurrentvenousthromboembolism(deepveinthrombosis,pulmonaryembolism),

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfarction),

Acuteliverdiseaseorahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal,

Porphyria.

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthe

benefitoutweighstherisk.

Medicalexamination/followup

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythecontraindicationsandwarningsforuse.

Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.

Womenshouldbeadvisedthatchangesintheirbreastsshouldbereportedtotheirdoctorornurse.Investigations,

includingmammography,shouldbecarriedoutinaccordancewithcurrentlyacceptedscreeningpractices,modifiedto

theclinicalneedsoftheindividual.

Conditionswhichneedsupervision

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviously,and/orhavebeenaggravatedduringpregnancy

orprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthatthese

conditionsmayrecurorbeaggravatedduringtreatmentwithFemoston-contiinparticular:

-Leiomyoma(uterinefibroids)orendometriosis

-Ahistoryof,orriskfactorsfor,thromboembolicdisorders(seebelow)

-Riskfactorsforestrogendependenttumours,e.g.1

degreeheredityforbreastcancer

-Hypertension

-Liverdisorders(e.g.liveradenoma)

-Diabetesmellituswithorwithoutvascularinvolvement

-Cholelithiasis

-Migraineor(severe)headache

-Systemiclupuserythematosus

-Ahistoryofendometrialhyperplasia(seebelow)

-Epilepsy

-Asthma

-Otosclerosis

Reasonsforimmediatewithdrawaloftherapy:

Therapyshouldbediscontinuedincaseswhereacontra-indicationisdiscoveredandinthefollowingsituations:

-Jaundiceordeteriorationinliverfunction

-Significantincreaseinbloodpressure

-Newonsetofmigraine-typeheadache

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Endometrialhyperplasia

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenestrogensareadministeredaloneforprolonged

periods(seesection4.8).Theadditionofaprogestagenforatleast12dayspercycleinnon-hysterectomisedwomen

greatlyreducesthisrisk.

Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-throughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshouldbe

investigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Breastcancer

Arandomisedplacebo-controlledtrial,theWomensHealthInitiativestudy(WHI)andepidemiologicalstudies,

includingtheMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentaking

estrogens,estrogen-progestagencombinationsortiboloneforHRTforseveralyears(seeSection4.8).ForallHRT,an

excessriskbecomesapparentwithinafewyearsofuseandincreaseswithdurationofintakebutreturnstobaseline

withinafew(atmostfive)yearsafterstoppingtreatment.

IntheMWS,therelativeriskofbreastcancerwithconjugatedequineestrogens(CEE)orestradiol(E2)wasgreater

whenaprogestagenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeofprogestagen.Therewas

noevidenceofadifferenceinriskbetweenthedifferentroutesofadministration.IntheWHIstudy,thecontinuous

combinedconjugatedequineestrogenandmedroxyprogesteroneacetate(CEE+MPA)productusedwasassociated

withbreastcancersthatwereslightlylargerinsizeandmorefrequentlyhadlocallymphnodemetastasescomparedto

placebo.

HRT,especiallyestrogen-progestagencombinedtreatment,increasesthedensityofmammographicimageswhichmay

adverselyaffecttheradiologicaldetectionofbreastcancer.

Venousthromboembolism

HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism(VTE),i.e.deepveinthrombosis

orpulmonaryembolism.Onerandomisedcontrolledtrialandepidemiologicalstudiesfoundatwo-tothreefoldhigher

riskforuserscomparedwithnon-users.

Fornon-users,itisestimatedthatthenumberofcasesofVTEthatwilloccurovera5yearperiodisabout3per1000

womenaged50-59yearsand8per1000womenagedbetween60-69years.Itisestimatedthatinhealthywomenwho

useHRTfor5years,thenumberofadditionalcasesofVTEovera5yearperiodwillbebetween2and6(bestestimate

=4)per1000womenaged50-59yearsandbetween5and15(bestestimate=9)per1000womenaged60-69years.

TheoccurrenceofsuchaneventismorelikelyinthefirstyearofHRTthanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalorfamilyhistory;severeobesity(BMI >

30kg/m

andsystemiclupuserythematosus(SLE).Thereisnoconsensusaboutthepossibleroleofvaricoseveinsin

VTE.

PatientswithahistoryofVTEorknownthrombophilicstateshaveanincreasedriskofVTE.HRTmayaddto

thisrisk.Personalorstrongfamilyhistoryofthromboembolismorrecurrentspontaneousabortionshouldbe

investigatedinordertoexcludeathrombophilicpredisposition.Untilathoroughevaluationofthrombophilic

factorshasbeenmadeoranticoagulanttreatmentinitiated,useofHRTinsuchpatientsshouldbeviewedas

contraindicated.Thosewomenalreadyonanticoagulanttreatmentrequirecarefulconsiderationofthebenefit-

riskofuseofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajorsurgery.

Asinallpostoperativepatients,scrupulousattentionshouldbegiventoprophylacticmeasurestopreventVTE

followingsurgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,particularlyabdominal

ororthopaedicsurgerytothelowerlimbs,considerationshouldbegiventotemporarilystoppingHRT4to6

weeksearlier,ifpossible.Treatmentshouldnotberestarteduntilthewomaniscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontact

theirdoctorsimmediatelywhentheyareawareofapotentialthromboembolicsymptom(e.g.painfulswellingof

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Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombinedconjugated

estrogensandmedroxyprogesteroneacetate(MPA).Twolargeclinicaltrials(WHIandHERSi.e.Heartand

Estrogen/progestinReplacementStudy)showedapossibleincreasedriskofcardiovascularmorbidityinthefirstyear

ofuseandnooverallbenefit.ForotherHRTproductsthereareonlylimiteddatafromrandomisedcontrolledtrials

examiningeffectsincardiovascularmorbidityormortality.Therefore,itisuncertainwhetherthesefindingsalsoextend

tootherHRTproducts.

Stroke

Onelargerandomisedclinicaltrial(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischaemicstrokein

healthywomenduringtreatmentwithcontinuouscombinedconjugatedestrogensandMPA.Forwomenwhodonot

useHRT,itisestimatedthatthenumberofcasesofstrokethatwilloccurovera5yearperiodisabout3per1000

womenaged50-59and11per1000womenaged60-69years.Itisestimatedthatforwomenwhouseconjugated

estrogensandMPAfor5years,thenumberofadditionalcaseswillbebetween0and3(bestestimate=1)per1000

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

theincreasedriskalsoextendstootherHRTproducts.

Ovariancancer

Long-term(atleast5to10years)useofestrogen-onlyHRTproductsinhysterectomisedwomenhasbeenassociated

withanincreasedriskofovariancancerinsomeepidemiologicalstudies.Itisuncertainwhetherlongtermuseof

combinedHRTconfersadifferentriskthanestrogen-onlyproducts

Otherconditions

-Estrogensmaycausefluidretentionandthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.Patientswithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitisexpectedthatthelevelof

circulatingactiveingredientsinFemoston-contiisincreased.

-Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringestrogenreplacementorhormone

replacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitishavebeen

reportedwithestrogentherapyinthiscondition.

-Estrogensincreasethyroidbindingglobulin(TBG),leadingtoincreasedcirculatingtotalthyroidhormone,as

measuredbyprotein-boundiodine(PBI),T4levels(bycolumnorbyradio-immunoassay)orT3levels(byradio-

immunoassay).T3resinuptakeisdecreased,reflectingtheelevatedTBG.FreeT4andfreeT3concentrationsare

unaltered.Otherbindingproteinsmaybeelevatedinserum,i.e.corticoidbindingglobulin(CBG),sexhormone-

bindingglobulin(SHBG)leadingtoincreasedcirculatingcorticosteroidsandsexsteroids,respectively.Freeor

biologicaly active hormone concentrations are unchanged. Other plasma proteins may be increased

(angiotensinogen/reninsubstrate,alpha-1-antitrypsin,ceruloplasmin).

-Thereisnoconclusiveevidenceforimprovementofcognitivefunction.ThereissomeevidencefromtheWHItrialof

increasedriskofprobabledementiainwomenwhostartusingcontinuouscombinedCEEandMPAaftertheageof65.

Itisunknownwhetherthefindingsapplytoyoungerpost-menopausalwomenorotherHRTproducts.

Thismedicinalproductcontainslactosemonohydrateandthereforeshouldnotbeusedbypatientswithrarehereditary

problemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactosemalabsorption

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

-Themetabolismofestrogensandprogestagensmaybeincreasedbyconcomitantuseofsubstancesknowntoinduce

drug-metabolisingenzymes,specificallycytochromeP450enzymes,suchasanticonvulsants(eg.phenobarbital,

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

-Ritonavirandnelfinavir,althoughknownasstronginhibitors,bycontrastexhibitinducingpropertieswhenused

concomitantlywithsteroidhormones.

-HerbalpreparationscontainingStJohn’swort(Hypericumperforatum)mayinducethemetabolismofestrogensand

progestagens.

-Clinicallyanincreasedmetabolismofestrogensandprogestagensmayleadtodecreasedeffectandchangesinthe

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4.6Fertility,pregnancyandlactation

Pregnancy

Femostoncontiisnotindicatedduringpregnancy.IfpregnancyoccursduringmedicationwithFemostonconti,

treatmentshouldbewithdrawnimmediately.

Clinically,databasedonanassumedlargenumberofexposedpregnanciesindicatenoadverseeffectsof

dydrogesteroneonthefetus.

Theresultsofmostepidemiologicalstudiestodaterelevanttoinadvertentfetalexposuretocombinationsofestrogens

andprogestagensindicatenoteratogenicorfetotoxiceffect.

Lactation

Femostoncontiisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

Femoston-contidoesnotaffecttheabilitytodriveorusemachines.

4.8Undesirableeffects

Undesirableeffectsreportedinclinicaltrialsandinpostmarketingexperiencearethefollowing:

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

Bloodandthe

lymphaticsystem

disorders Haemolytic

anaemia

Psychiatric

disorders Depression,

changeinlibido,

nervousness

Nervoussystem

disorders Headache,

migraine Dizziness Chorea

Eyedisorders Intoleranceto

contactlenses,

steepeningof

cornealcurvature

Cardiacdisorders Myocardial

infarction

Vascular

disorders Hypertension,

Peripheral

vascular

disease,

Varicosevein,

Venous

thromboembolism Stroke

Gastrointestinal

disorders Nausea,

abdominalpain,

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Breastcancer

Accordingtoevidencefromalargenumberofepidemiologicalstudiesandonerandomisedplacebo-controlledtrial,the

Women’sHealthInitiative(WHI),theoverallriskofbreastcancerincreaseswithincreasingdurationofHRTusein

currentorrecentHRTusers.

Forestrogen-onlyHRT,estimatesofrelativerisk(RR)fromareanalysisoforiginaldatafrom51epidemiological

studies(inwhich>80%ofHRTusewasestrogen-onlyHRT)andfromtheepidemiologicalMillionWomenStudy

(MWS)aresimilarat1.35(95%CI1.21–1.49)and1.30(95%CI1.21–1.40),respectively.Forestrogenplus

progestagencombinedHRT,severalepidemiologicalstudieshavereportedanoverallhigherriskforbreastcancerthan

withestrogensalone.

TheMWSreportedthat,comparedtoneverusers,theuseofvarioustypesofestrogenprogestagencombinedHRTwas

associatedwithahigherriskofbreastcancer(RR=2.00,95%CI:1.88–2.12)thanuseofestrogensalone(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-progestagen

combinedHRT(CEE+MPA)inalluserscomparedwithplacebo.

Hepatobiliary

disorders Gallbladder

disease Alterationsin

liverfunction,

sometimeswith

astheniaor

malaise,jaundice

andabdominal

pain

Skinand

subcutaneous

tissuedisorders Allergicskin

reactions,rash,

urticaria,pruritus Chloasmaor

melasma,which

maypersistwhen

drugis

discontinued,

erythema

multiforme,

erythema

nodosum,

vascularpurpura,

angioedema

Musculoskeletal

andconnective

tissuedisorders Legcramps Backpain

Reproductive

systemandbreast

disorders Breast

pain/tenderness,

breakthrough

bleedingand

spotting

pelvicpain Changeincervical

erosion,changein

cervicalsecretion,

dysmenorrhoea,

menorrhagia,

metrorrhagia Breast

enlargement

Premenstrual-

like

symptoms

Congenitaland

familial/genetic

disorders Aggravationof

porphyria

Generaldisorders

administration

sitereactions Asthenia Peripheraloedema

Investigations Increase/decrease

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TheMWShasestimated,fromtheknownaverageincidenceofbreastcancerindevelopedcountries,that:

-ForwomennotusingHRT,about32inevery1000areexpectedtohavebreastcancerdiagnosedbetweentheagesof

50and64years.

-For1000currentorrecentusersofHRT,thenumberofadditionalcasesduringthecorrespondingperiodwillbe

-Forusersofestrogen-onlyreplacementtherapy

between0and3(bestestimate=1.5)for5years’use

between3and7(bestestimate=5)for10years’use.

-ForusersofestrogenplusprogestagencombinedHRT,

between5and7(bestestimate=6)for5years’use

between18and20(bestestimate=19)for10years’use.

TheWHItrialestimatedthatafter5.6yearsoffollow-upofwomenbetweentheagesof50and79years,anadditional

8casesofinvasivebreastcancerwouldbeduetoestrogenprogestagencombinedHRT(CEE+MPA)per10,000

womenyears.

Accordingtocalculationsfromthetrialdata,itisestimatedthat:

-For1000womenintheplacebogroup,about16casesofinvasivebreastcancerwouldbediagnosedin5years.

-For1000womenwhousedestrogen+progestagencombinedHRT(CEE+MPA),thenumberofadditionalcases

wouldbebetween0and9(bestestimate=4)for5years’use.

ThenumberofadditionalcasesofbreastcancerinwomenwhouseHRTisbroadlysimilarforwomenwhostartHRT

irrespectiveofageatstartofuse(betweentheagesof45-65)(seesection4.4)

Endometrialcancer

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandendometrialcancerincreaseswithincreasing

durationofuseofunopposedestrogens.Accordingtodatafromepidemiologicalstudies,thebestestimateoftheriskis

thatforwomennotusingHRT,about5inevery1000areexpectedtohaveendometrialcancerdiagnosedbetweenthe

agesof50and65.Dependingonthedurationoftreatmentandestrogendose,thereportedincreaseinendometrial

cancerriskamongunopposedestrogenusersvariesfrom2-to12-foldgreatercomparedwithnon-users.Addinga

progestagentoestrogen-onlytherapygreatlyreducesthisincreasedrisk.

Otheradversereactionshavebeenreportedinassociationwithestrogen/progestagentreatment:

-Estrogen-dependentneoplasmsbenignandmalignant,e.g.endometrialcancer.

-Venousthromboembolism,i.e.deeplegorpelvicvenousthrombosisandpulmonaryembolism,ismorefrequent

amonghormonereplacementtherapyusersthanamongnon-users.Forfurtherinformation,seesection4.3

Contraindicationsand4.4Specialwarningsandprecautionsforuse.

-Probabledementia(seesection4.4)

4.9Overdose

Bothestradiolanddydrogesteronearesubstanceswithlowtoxicity.Theoretically,symptomssuchasnausea,vomiting,

sleepinessanddizzinesscouldoccurincasesofoverdosing.Itisunlikelythatanyspecificorsymptomatictreatment

willbenecessary.

Aforementionedinformationisapplicableforoverdosingbychildrenalso.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Genitourinarysystemandsexhormones,progestogensandestrogens,fixedcombinations.

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Estradiol

Theactiveingredient,synthetic17-estradiol,ischemicallyandbiologicallyidenticaltoendogenoushumanestradiol.

Itsubstitutesforthelossofestrogenproductioninmenopausalwomen,andalleviatesmenopausalsymptoms.

Estrogenspreventbonelossfollowingmenopauseorovariectomy.

Dydrogesterone

Asestrogenspromotethegrowthoftheendometrium,unopposedestrogensincreasetheriskofendometrialhyperplasia

andcancer.Theadditionofaprogestagengreatlyreducestheestrogeninducedriskofendometrialhyperplasiainnon-

hysterectomisedwomen.

ClinicaltrialInformation

Reliefofestrogen-deficiencysymptomsandbleedingpatterns.

Reliefofmenopausalsymptomswasachievedduringthefirstfewweeksoftreatment.

Amenorrhoeawasseenin76%ofwomenduringmonths10-12oftreatment.

Breakthroughbleedingand/orspottingappearedin29%ofthewomenduringthefirstthreemonthsoftreatmentandin

24%duringmonths10-12oftreatment.

Preventionofosteoporosis

Estrogendeficiencyatmenopauseisassociatedwithanincreasingboneturnoveranddeclineinbonemass.Theeffect

ofestrogensonthebonemineraldensityisdose-dependent.Protectionappearstobeeffectiveforaslongastreatment

iscontinued.AfterdiscontinuationofHRT,bonemassislostat

aratesimilartothatinuntreatedwomen.

EvidencefromtheWHItrialandmeta-analysedtrialsshowsthatcurrentuseofHRT,aloneorincombinationwitha

progestagen–giventopredominantlyhealthywomen–reducestheriskofhip,vertebral,andotherosteoporotic

fractures.HRTmayalsopreventfracturesinwomenwithlowbonedensityand/orestablishedosteoporosis,butthe

evidenceforthatislimited.

AftertwoyearsoftreatmentwithFemoston-conti,theincreaseinlumbarspinebonemineraldensity(BMD)was

5.20%±3.76%(mean±SD).ThepercentageofwomenwhomaintainedorgainedBMDinlumbarzoneduring

treatmentwas95%.

Femoston-contialsohadaneffectonhipBMD.Theincreaseaftertwoyearswas2.7%±4.2%(mean±SD)atfemoral

neck,3.5%+/-5.0%(mean±SD)attrochanterand2.7%±6.7%(mean±SD)atWardstriangle.Thepercentageof

womenwhomaintainedorgainedBMDinthe3hipareasduringtreatmentwas67-78%.

5.2Pharmacokineticproperties

Estradiol

Orallyadministeredestradiol,comprisingparticleswhosesizehasbeenreducedtolessthan5µm,isquicklyand

efficientlyabsorbedfromthegastrointestinaltract.Theprimaryunconjugatedandconjugatedmetabolitesareestrone

andestronesulphate.Thesemetabolitescancontributetotheestrogeneffect,bothdirectlyandafterconversionto

estradiol.Estrogensareexcretedinthebileandreabsorbedfromtheintestine.Duringthisenterohepaticcyclethe

estrogensarebrokendown.Estrogensareexcretedintheurineasbiologicallyinactiveglucuronideandsulphate

compounds(90to95%),orinthefaeces(5to10%),mostlyunconjugated.Estrogensaresecretedinthemilkofnursing

mothers.

TheC

average is28pg/ml,theC

is20pg/mlandtheC

is54pg/ml.TheE1/E2(Estrone/Estradiol)ratiois7.0.

Dydrogesterone

Afteroraladministrationoflabelleddydrogesterone,onaverage63%ofthedoseisexcretedintotheurine.Within72

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man, dydrogesterone is completely metabolised. The main metabolite of dydrogesterone is 20-

dihydrodydrogesterone(DHD)andispresentintheurinepredominantlyastheglucoronicacidconjugate.Acommon

featureofallmetabolitescharacterisedistheretentionofthe4,6diene-3-oneconfigurationoftheparentcompoundand

theabsenceof17-hydroxylation.Thisexplainstheabsenceofestrogenicandandrogenicactivity.

Afteroraladministrationofdydrogesterone,plasmaconcentrationsofDHDarehigherascomparedtotheparentdrug.

TheAUCandC

ratiosofDHDtodydrogesteroneareintheorderof40and25,respectively.Dydrogesteroneis

rapidlyabsorbed.TheT max valuesofdydrogesteroneandDHDvarybetween0.5and2.5hours.

MeanterminalhalflivesofdydrogesteroneandDHDvarybetween5to7and14to17hours,respectively.

ThedihydrodydrogesteroneC

average is13ng/ml,theC

is4.1ng/mlandtheC

is63ng/ml.

ThedydrogesteroneC average is0.38ng/mltheC min is<0.1ng/mlandtheC max is2.5ng/ml.

Dydrogesteroneisnotexcretedinurineaspregnanediol,likeprogesterone.Analysisofendogenousprogesterone

productionbasedonpregnanediolexcretionthereforeremainspossible.

5.3Preclinicalsafetydata

Supraphysiologicallyhighdoses(prolongedapplication)ofestradiolhavebeenassociatedwiththeinductionoftumoursin

estrogen-dependenttargetorgansforallrodentspeciestested.Furthermore,inherenttoitshormonalactivity,estradiol

displaysuntowardembryotoxiceffectsandfeminisationofmalefetuseswasoccasionallyobserved.Thechangesobserved

withdydrogesteroneinanimaltoxicitystudiesareassociatedwiththeeffectsofprogesterone-likecompounds.

Dosesadministeredtoratsandmicesufficienttoproducehormonemediatedchangesgavenoevidenceofcarcinogenesis

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Hypromellose

Maizestarch

Colloidalanhydroussilica

Magnesiumstearate

Filmcoat:

Hypromellose

Macrogol400

Titaniumdioxide(E171)

Ironoxides,yellowandred(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

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6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Keepblisterintheoutercartoninordertoprotectfromlightandmoisture.

6.5Natureandcontentsofcontainer

Calendarpacksof14,28,84(3x28)or280(10x28)tabletsinPVC-Aluminiumblisterstrips.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

AbbottHealthcareProductsLtd.

MansbridgeRoad,WestEnd

SouthamptonSO183JD

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA108/21/4

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:08December2000

Dateoflastrenewal:21November2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 11/01/2012 CRN 2104280 page number: 10