FEMOSTON 2/ 10

Main information

  • Trade name:
  • FEMOSTON 2/ 10
  • Dosage:
  • 2 mg, 10 m Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FEMOSTON 2/10
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0108/021/001
  • Authorization date:
  • 31-10-1997
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Femoston2/10mgfilm-coatedtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Thisproductcontainsestradiolhemihydrateequivalentto2mgestradiolpertabletforthefirst14daysofa28-day

cycle(brick-redtablets).Forthesecond14daysonetabletcontainsestradiolhemihydrateequivalentto2mgestradiol

and10mgdydrogesterone(yellowtablets).

Excipients:

Eachbrick-redtabletcontains118.2mgoflactosemonohydrate.

Eachyellowtabletcontains109.4mgoflactosemonohydrate.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Estradioltabletsonly:Round,biconvex,brick-red,film-coatedtabletwithinscription‘379’ononeside.

Estradiol/Dydrogesteronecombinationtablets:Round,biconvex,yellow,film-coatedtabletwithinscription‘379’on

oneside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapy(HRT)forestrogendeficiencysymptomsinmenopausalwomen.

Preventionofosteoporosisinpostmenopausalwomenathighriskoffuturefractureswhoareintolerantof,or

contraindicatedfor,othermedicinalproductsapprovedforthepreventionofosteoporosis.

(Seealsosection4.4)

Theexperienceintreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

Femoston1/10,andFemoston2/10,arecontinuoussequentialHRTs.

Ingeneral,treatmentshouldstartwithFemoston1/10.Dependingontheclinicalresponse,thedosagecanafterwards

beadjustedtoindividualneed.Ifthecomplaintslinkedtoestrogendeficiencyarenotamelioratedthedosagecanbe

increasedbyusingFemoston2/10.

Forthefirst14daysduringa28-cycle,onetabletcontainingestradiolistakendaily;duringthefollowing14daysone

tabletcontainingestradiolanddydrogesteroneistaken.

Afteracycleof28days,onthe29thday,anew28-daycyclebegins.Thismeansthatthetreatmentshouldbetaken

continuouslywithoutabreakbetweenpacks.Femostoncanbetakenwithorwithoutfood.

Thedaysoftheweekareprintedonthebackoftheblisterstrips.Firstlythetabletsfromthepartmarkedwitharrow1

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StartingFemoston

Inwomenwhoarenottakinghormonereplacementtherapy,haveestablishedamenorrhoeaorwomenwhoswitchfrom

acontinuouscombinedhormonereplacementtherapy,treatmentmaybestartedonanyconvenientday.Inwomen

transferringfromacyclicorcontinuoussequentialHRTregimen,treatmentshouldbeginthedayfollowingcompletion

ofthepriorregimen.Ifthepatientismenstruating,treatmentisstartedwithinfivedaysofthestartofbleeding.

Ifadosehasbeenforgotten,itshouldbetakenassoonaspossible.Whenmorethan12hourshaveelapsed,itis

recommendedtocontinuewiththenextdosewithouttakingtheforgottentablet.Thelikelihoodofbreakthrough

bleedingorspottingmaybeincreased.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

duration(seealsosection4.4)shouldbeused.

Femoston2/10isnotrecommendedfortheuseinchildrenbelowtheageof18duetoinsufficientdataonsafetyand

efficacy.

4.3Contraindications

Knownhypersensitivitytotheactivesubstancesortoanyoftheexcipients;

Known,pastorsuspectedbreastcancer;

Knownorsuspectedestrogen-dependentmalignanttumours(e.g.endometrialcancer);

Knownorsuspectedprogesteronedependantneoplasms;

Undiagnosedgenitalbleeding;

Untreatedendometrialhyperplasia;

Previousidiopathicorcurrentvenousthromboembolism(deepveinthrombosis,pulmonaryembolism);

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfarction);

Acuteliverdiseaseorahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal;

Porphyria;

Knownorsuspectedpregnancy.

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk.

Medicalexamination/followup

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical(including

pelvicandbreast)examinationshouldbeguidedbythisandbythecontraindicationsandwarningsforuse.During

treatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.Women

shouldbeadvisedthatchangesintheirbreastsshouldbereportedtotheirdoctorornurse(see‘breastcancer’below).

Investigations,includingmammography,shouldbecarriedoutinaccordancewithcurrentlyacceptedscreeningpractices,

modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviously,and/orhavebeenaggravatedduringpregnancyor

previoushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthattheseconditions

mayrecurorbeaggravatedduringtreatmentwithFemoston,inparticular:

Leiomyoma(uterinefibroids)orendometriosis

Progestagendependentneoplasms,e.g.meningioma

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Riskfactorsforestrogendependenttumours,e.g.1 st

degreeheredityforbreastcancer

Hypertension

Liverdisorders(e.g.liveradenoma)

Diabetesmellituswithorwithoutvascularinvolvement

Cholelithiasis

Migraineor(severe)headache

Systemiclupuserythematosus

Ahistoryofendometrialhyperplasia(seebelow)

Epilepsy

Asthma

Otosclerosis

Reasonsforimmediatewithdrawaloftherapy:

Therapyshouldbediscontinuedincaseswhereacontra-indicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction

Significantincreaseinbloodpressure

Newonsetofmigraine-typeheadache

Pregnancy

Endometrialhyperplasia

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenestrogensareadministeredaloneforprolonged

periods(seesection4.8).Theadditionofaprogestagenforatleast12daysofthecycleinnon-hysterectomisedwomen

greatlyreducesthisrisk.

Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-throughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshouldbe

investigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Breastcancer

Arandomisedplacebo-controlledtrial,theWomensHealthInitiativestudy(WHI)andepidemiologicalstudies,including

theMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentakingestrogens,estrogen-

progestagencombinationsortiboloneforHRTforseveralyears(seesection4.8).

ForallHRT,anexcessriskbecomesapparentwithinafewyearsofuseandincreaseswithdurationofintakebut

returnstobaselinewithinafew(atmostfive)yearsafterstoppingtreatment.

IntheMWS,therelativeriskofbreastcancerwithconjugatedequineestrogens(CEE)orestradiol(E2)wasgreater

whenaprogestagenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeofprogestagen.Therewas

noevidenceofadifferenceinriskbetweenthedifferentroutesofadministration.

IntheWHIstudy,thecontinuouscombinedconjugatedequineestrogenandmedroxyprogesteroneacetate(CEE+

MPA)productusedwasassociatedwithbreastcancersthatwereslightlylargerinsizeandmorefrequentlyhadlocal

lymphnodemetastasescomparedtoplacebo.

HRT,especiallyestrogen-progestagencombinedtreatment,increasesthedensityofmammographicimageswhichmay

adverselyaffecttheradiologicaldetectionofbreastcancer.

Venousthromboembolism

HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism(VTE),i.e.deepveinthrombosisor

pulmonaryembolism.Onerandomisedcontrolledtrialandepidemiologicalstudiesfoundatwo-tothreefoldhigherriskfor

userscomparedwithnon-users.Fornon-users,itisestimatedthatthenumberofcasesofVTEthatwilloccurovera5year

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ItisestimatedthatinhealthywomenwhouseHRTfor5years,thenumberofadditionalcasesofVTEovera5year

periodwillbebetween2and6(bestestimate=4)per1000womenaged50-59yearsandbetween5and15(best

estimate=9)per1000womenaged60-69years.Theoccurrenceofsuchaneventismorelikelyinthefirstyearof

HRTthanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalorfamilyhistoryandsevereobesity(BMI >

kg/m 2

)andsystemiclupuserythematosus(SLE).Thereisnoconsensusaboutthepossibleroleofvaricoseveins

inVTE.

PatientswithahistoryofVTEorknownthrombophilicstateshaveanincreasedriskofVTE.HRTmayaddto

thisrisk.Personalorstrongfamilyhistoryofthromboembolismorrecurrentspontaneousabortionshouldbe

investigatedinordertoexcludeathrombophilicpredisposition.Untilathoroughevaluationofthrombophilic

factorshasbeenmadeoranticoagulanttreatmentinitiated,useofHRTinsuchpatientsshouldbeviewedas

contraindicated.Thosewomenalreadyonanticoagulanttreatmentrequirecarefulconsiderationofthebenefit-risk

ofuseofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajorsurgery.

Asinallpostoperativepatients,scrupulousattentionshouldbegiventoprophylacticmeasurestopreventVTE

followingsurgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,particularlyabdominal

ororthopaedicsurgerytothelowerlimbs,considerationshouldbegiventotemporarilystoppingHRT4to6

weeksearlier,ifpossible.Treatmentshouldnotberestarteduntilthewomeniscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorsimmediatelywhentheyareawareofapotentialthromboembolicsymptom(e.g.painfulswellingofaleg,

suddenpaininthechest,dyspnea).

Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombinedconjugated

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

Estrogen/progestinReplacementStudy)showedapossibleincreasedriskofcardiovascularmorbidityinthefirstyearof

useandnooverallbenefit.ForotherHRTproductsthereareonlylimiteddatafromrandomisedcontrolledtrialstodate

examiningeffectsincardiovascularmorbidityormortality.Therefore,itisuncertainwhetherthesefindingsalsoextendto

otherHRTproducts.

Stroke

Onelargerandomisedclinicaltrial(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischaemicstrokein

healthywomenduringtreatmentwithcontinuouscombinedconjugatedestrogensandMPA.Forwomenwhodonotuse

HRT,itisestimatedthatthenumberofcasesofstrokethatwilloccurovera5yearperiodisabout3per1000womenaged

50-59and11per1000womenaged60-69years.ItisestimatedthatforwomenwhouseconjugatedestrogensandMPA

for5years,thenumberofadditionalcaseswillbebetween0and3(bestestimate=1)per1000usersaged50-59yearsand

between1and9(bestestimate=4)per1000usersaged60-69years.Itisunknownwhethertheincreasedriskalsoextends

tootherHRTproducts.

Ovariancancer

Long-term(atleast5to10years)useofestrogen-onlyHRTproductsinhysterectomisedwomenhasbeenassociatedwith

anincreasedriskofovariancancerinsomeepidemiologicalstudies.Itisuncertainwhetherlongtermuseofcombined

HRTconfersadifferentriskthanestrogen-onlyproducts.

Otherconditions

Estrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.Patientswithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitisexpectedthatthelevel

ofcirculatingactiveingredientsinFemostonisincreased.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringestrogenreplacementor

hormonereplacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitis

havebeenreportedwithestrogentherapyinthiscondition.

Estrogensincreasethyroidbindingglobulin(TBG),leadingtoincreasedcirculatingtotalthyroidhormone,as

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

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unaltered.Otherbindingproteinsmaybeelevatedinserum,i.e.corticoidbindingglobulin(CBG),sex-hormone-

bindingglobulin(SHBG)leadingtoincreasedcirculatingcorticosteroidsandsexsteroids,respectively.

Freeorbiologicalactivehormoneconcentrationsareunchanged.Otherplasmaproteinsmaybeincreased

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

Thereisnoconclusiveevidenceforimprovementofcognitivefunction.ThereissomeevidencefromtheWHI

trialofincreasedriskofprobabledementiainwomenwhostartusingcontinuouscombinedCEEandMPAafter

theageof65.Itisunknownwhetherthefindingsapplytoyoungerpost-menopausalwomenorotherHRT

products.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Nointeractionstudieshavebeenperformed.

Themetabolismofestrogensandprogestagensmaybeincreasedbyconcomitantuseofsubstancesknownto

inducedrug-metabolisingenzymes,specificallycytochromeP450enzymes,suchasanticonvulsants(eg.

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

Ritonavirandnelfinavir,althoughknownasstronginhibitors,bycontrastexhibitinducingpropertieswhenused

concomitantlywithsteroidhormones.

HerbalpreparationscontainingStJohn’sWort(Hypericumperforatum)mayinducethemetabolismofestrogens

andprogestagens.

Clinicallyanincreasedmetabolismofestrogensandprogestagensmayleadtodecreasedeffectandchangesinthe

uterinebleedingprofile.

Femoston2/10canbeadministeredirrespectiveoffoodintake.

4.6Fertility,pregnancyandlactation

Pregnancy:

Femostonisnotindicatedduringpregnancy.IfpregnancyoccursduringmedicationwithFemoston,treatmentshouldbe

withdrawnimmediately.

Clinically,databasedonalargenumberofexposedpregnanciesindicatenoadverseeffectsofdydrogesteroneonthe

foetus.

Theresultsofmostepidemiologicalstudiestodaterelevanttoinadvertentfoetalexposuretocombinationsofestrogens

andprogestagensindicatenoteratogenicorfoetotoxiceffect.

Lactation:

Femostonisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

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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

Immunesystem

disorders Hypersensitivity

reactions

Psychiatric

disorders Depression,

Changeinlibido,

Nervousness

Nervoussystem

disorders Headache,

Migraine Dizziness Chorea

Eyedisorders Intoleranceto

contactlenses,

Steepeningof

corneal

curvature

Cardiacdisorders Myocardial

infarction

Vascular

disorders Hypertension,

Peripheralvascular

disease,

Varicosevein,

Venous

thromboembolism* Stroke

Gastrointestinal

disorders Nausea,

Abdominalpain,

Flatulence Dyspepsia Vomiting

Hepatobiliary

disorders Gallbladder

disease Alterationsin

liverfunction,

sometimeswith

Astheniaor

Malaise,

Jaundiceand

Abdominal

pain

Skinand

subcutaneous

tissuedisorders Allergicskin

reactions(e.g.

Rash,Urticaria, Chloasmaor

melasma,which

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*seebelowforfurtherinformation

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.

ForestrogenplusprogestagencombinedHRT,severalepidemiologicalstudieshavereportedanoverallhigherriskfor

breastcancerthanwithestrogensalone.

TheMWSreportedthat,comparedtoneverusers,theuseofvarioustypesofestrogen-progestagencombinedHRTwas

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.

TheabsoluteriskscalculatedfromtheMWSandtheWHItrialsarepresentedbelow:

TheMWShasestimated,fromtheknownaverageincidenceofbreastcancerindevelopedcountries,that:

Pruritus) drugis

discontinued,

Erythema

multiforme,

Erythema

nodosum,

Vascular

purpura,

Angioedema

Musculoskeletal

andconnective

tissuedisorders Legcramps Backpain

Reproductive

systemand

breastdisorders Breast

pain/tenderness,

Breakthrough

bleedingand

spotting,

Pelvicpain Changeincervical

erosion,Changein

cervicalsecretion,

Dysmenorrhoea,

Menorrhagia,

Metrorrhagia Breast

enlargement,

Premenstrual-

likesymptoms

Congenitaland

familial/genetic

disorders Aggravationof

porphyria

General

disordersand

administration

sitereactions Asthenia Peripheraloedema

Investigations Increase/decrease

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theagesof50and64years.

For1000currentorrecentusersofHRT,thenumberofadditionalcasesduringthecorrespondingperiod

willbe

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

8casesofinvasivebreastcancerwouldbeduetoestrogen-progestagencombinedHRT(CEE+MPA)per10,000

womenyears.

Accordingtocalculationsfromthetrialdata,itisestimatedthat:

For1000womenintheplacebogroup,

about16casesofinvasivebreastcancerwouldbediagnosedin5years.

For1000womenwhousedestrogen+progestagencombinedHRT(CEE+MPA),thenumberofadditional

caseswouldbe

between0and9(bestestimate=4)for5years’use.

ThenumberofadditionalcasesofbreastcancerinwomenwhouseHRTisbroadlysimilarforwomenwhostartHRT

irrespectiveofageatstartofuse(betweentheagesof45-65)(seesection4.4).’

Otheradversereactionshavebeenreportedinassociationwithestrogen/progestagentreatment:

Estrogen-dependentneoplasmsbenignandmalignant,e.g.**endometrialcancer,ovariancancer

Arterialthromboembolism.Forfurtherinformationseesections4.3and4.4

Venousthromboembolism,i.e.deeplegorpelvicvenousthrombosisandpulmonaryembolism,ismore

frequentamonghormonereplacementtherapyusersthanamongnon-users.Forfurtherinformation,see

section4.3Contraindicationsand4.4Specialwarningsandprecautionsforuse.

Increaseinsizeofprogestogendependentneoplasms(e.g.meningioma),(seesection4.3)

Probabledementia(seesection4.4)

**Endometrialcancer

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandendometrialcancerincreaseswithincreasing

durationofuseofunopposedestrogens.Accordingtodatafromepidemiologicalstudies,thebestestimateoftheriskis

thatforwomennotusingHRT,about5inevery1000areexpectedtohaveendometrialcancerdiagnosedbetweenthe

agesof50and65.Dependingonthedurationoftreatmentandestrogendose,thereportedincreaseinendometrial

cancerriskamongunopposedestrogenusersvariesfrom2-to12-foldgreatercomparedwithnon-users.Addinga

progestagentoestrogen-onlytherapygreatlyreducesthisincreasedrisk.

4.9Overdose

NocasesofoverdosehavebeenreportedforFemoston2/10.

Bothestradiolanddydrogesteronearesubstanceswithlowtoxicity.Theoretically,symptomssuchasnausea,vomiting,

sleepinessanddizzinesscouldoccurincasesofoverdosing.Itisunlikelythatanyspecificorsymptomatictreatmentwill

benecessary.

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

TheATCcodeisG03FB08.(Estrogens:urogenitalsystemandsexhormones).

Sequentialhormonereplacementtherapy(combinedestradiolanddydrogesterone).

Estradiol

Theactiveingredient,synthetic17-estradiol,ischemicallyandbiologicallyidenticaltoendogenoushumanestradiol.

Itsubstitutesforthelossofestrogenproductioninmenopausalwomen,andalleviatesmenopausalsymptoms.

Estrogenspreventbonelossfollowingmenopauseorovariectomy.

Dydrogesterone

Asestrogenspromotethegrowthoftheendometrium,unopposedestrogensincreasetheriskofendometrialhyperplasia

andcancer.Theadditionofaprogestagengreatlyreducestheestrogen-inducedriskofendometrialhyperplasiainnon-

hysterectomisedwomen.

Clinicaltrialinformation

Reliefofestrogen-deficiencysymptomsandbleedingpatterns.

Reliefofmenopausalsymptomswasachievedduringthefirstfewweeksoftreatment.

RegularwithdrawalbleedingwithFemoston1/10occurredinapproximately75-80%ofwomenwithamean

durationof5days.Withdrawalbleedingusuallystartedonthedayofthelastpilloftheprogestagenphase.

Break-throughbleedingand/orspottingoccurredinapproximately10%ofthewomen;amenorrhoea(nobleeding

orspotting)occurredin10-25%ofthewomenpercycleduringthefirstyearoftreatment.

WithFemoston2/10,approximately90%ofwomenhadregularwithdrawalbleeding.Thestartdayandduration

ofbleeding,andthenumberofwomenwithintermittentbleedingwasthesameaswithFemoston1/10,

amenorrhoeaoccurredin5-15%ofthewomenpercycleduringthefirstyearoftreatment.

Preventionofosteoporosis

Estrogendeficiencyatmenopauseisassociatedwithanincreasingboneturnoveranddeclineinbonemass.The

effectofestrogensonthebonemineraldensityisdose-dependent.Protectionappearstobeeffectiveforaslong

astreatmentiscontinued.AfterdiscontinuationofHRT,bonemassislostataratesimilartothatinuntreated

women.

EvidencefromtheWHItrialandmeta-analysedtrialsshowsthatcurrentuseofHRT,aloneorincombination

withaprogestagen–giventopredominantlyhealthywomen–reducestheriskofhip,vertebral,andother

osteoporoticfractures.HRTmayalsopreventfracturesinwomenwithlowbonedensityand/orestablished

osteoporosis,buttheevidenceforthatislimited.

AftertwoyearsoftreatmentwithFemoston1/10,theincreaseinlumbarspinebonemineraldensity(BMD)was

5.2%±3.7%(mean±SD).ThepercentageofwomenwhomaintainedorgainedBMDinlumbarzoneduring

treatmentwas95%.ForFemoston2/10theincreaseinlumbarspineBMDwas6.6%±3.8%(mean±SD),and

thepercentageofwomenwithnochangeoranincreaseinlumbarspineBMDwas95%.

FemostonalsohadaneffectonhipBMD.Theincreaseaftertwoyearsoftreatmentwith1mgestradiolwas

2.7%±4.2%(mean±SD)atfemoralneck,3.5%+/-5.0%(mean±SD)attrochanterand2.7%±6.7%(mean±

SD)atWardstriangle,aftertwoyearsoftreatmentwith2mgestradiolthesefigureswhererespectively,2.6%±

5.0%;4.6%±5.0%and4.1%±7.4%.ThepercentageofwomenwhomaintainedorgainedBMDinthe3hip

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5.2Pharmacokineticproperties

Estradiol

Orallyadministeredestradiol,comprisingparticleswhosesizehasbeenreducedtolessthan5µm,isquicklyand

efficientlyabsorbedfromthegastrointestinaltract.Theprimaryunconjugatedandconjugatedmetabolitesareestrone

andestronesulphate.Thesemetabolitescancontributetotheestrogeneffect,bothdirectlyandafterconversionto

estradiol.Estrogensareexcretedinthebileandreabsorbedfromtheintestine.Duringthisenterohepaticcyclethe

estrogensarebrokendown.Estrogensareexcretedintheurineasbiologicallyinactiveglucuronideandsulphate

compounds(90to95%),orinthefaeces(5to10%),mostlyunconjugated.Estrogensareexcretedinmothers'milk.

TheC

average is58pg/ml,theC

is44pg/mlandtheC

is93pg/ml.TheE1/E2(Estrone/Estradiol)ratiois5.8.

Dydrogesterone

Afteroraladministrationoflabelleddydrogesterone,onaverage63%ofthedoseisexcretedintotheurine.Within72

hoursexcretioniscomplete.

Inman,dydrogesteroneiscompletelymetabolized.Themainmetaboliteofdydrogesteroneis20-

dihydrodydrogesterone(DHD)andispresentintheurinepredominantlyastheglucuronicacidconjugate.Acommon

featureofallmetabolitescharacterizedistheretentionofthe4,6diene-3-oneconfigurationoftheparentcompoundand

theabsenceof17-hydroxylation.Thisexplainstheabsenceofestrogenicandandrogenicactivity.

Afteroraladministrationofdydrogesterone,plasmaconcentrationsofDHDaresubstantiallyhigherascomparedtothe

parentdrug.TheAUCandC

ratiosofDHDtodydrogesteroneareintheorderof40and25,respectively.

Dydrogesteroneisrapidlyabsorbed.TheT

valuesofdydrogesteroneandDHDvarybetween0.5and2.5hours.

MeanterminalhalflivesofdydrogesteroneandDHDvarybetween5to7and14to17hours,respectively.

ThedihydrodydrogesteroneC

average is13ng/ml,theC

is4.1ng/mlandtheC

is63ng/ml.Thedydrogesterone

average is0.38ng/mltheC

is<0.1ng/mlandtheC

is2.5ng/ml.

Dydrogesteroneisnotexcretedinurineaspregnanediol,likeprogesterone.

Analysisofendogenousprogesteroneproductionbasedonpregnanediolexcretionthereforeremainspossible.

5.3Preclinicalsafetydata

Therearenopreclinicalsafetydatawhichcouldberelevanttotheprescriberandwhicharenotalreadyincludedin

otherrelevantsectionsoftheSPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

Lactosemonohydrate

Hypromellose

Maizestarch

Colloidalanhydroussilica

Magnesiumstearate

Filmcoats

Hypromellose

Macrogol400

Titaniumdioxide(E171)

Irish Medicines Board

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Date Printed 01/09/2011 CRN 2104954 page number: 10

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Storeinoriginalpackage.

6.5Natureandcontentsofcontainer

PVCfilmwithacoveringaluminiumfoil.

Blisterpacks:28film-coatedtablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

AbbottHealthcareProductsLimited,

MansbridgeRoad,

WestEnd

Southampton,

SO183JD,

U.K.

8MARKETINGAUTHORISATIONNUMBER

PA108/21/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation : 31October1997

Dateoflastrenewal : 31October2007

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 01/09/2011 CRN 2104954 page number: 11