FEMOSTON 2/20

Main information

  • Trade name:
  • FEMOSTON 2/20
  • Dosage:
  • 2 mg, 20 m %v/v
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FEMOSTON 2/20
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0108/021/002
  • Authorization date:
  • 31-10-1997
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Femoston2/20mgtablet

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Thisproductcontainsestradiolhemihydrateequivalentto2mgestradiolpertabletforthefirst14daysofa28-day

cycle(brick-redtablets).Forthesecond14dayseachtabletcontainsestradiolhemihydrateequivalentto2mgestradiol

and20mgdydrogesterone(bluetablets).

Forexcipients,see6.1

3PHARMACEUTICALFORM

Film-coatedtablet.

Round,biconvex,brick-red,film-coatedtabletwith379ononesideandSontheotherside.

Round,biconvex,blue,film-coatedtabletwith379ononesideandSontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapy(HRT)forestrogendeficiencysymptomsinmenopausalwomen.

Preventionofosteoporosisinpostmenopausalwomenathighriskoffuturefractureswhoareintolerantof,or

contraindicatedfor,othermedicinalproductsapprovedforthepreventionofosteoporosis.

(Seealsosection4.4,specialwarningsandprecautionsforuse)

Theexperienceintreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

Femoston2/20isacontinuoussequentialHRT.

Ingeneral,treatmentshouldstartwithFemoston1/10.Dependingontheclinicalresponse,thedosagecanafterwards

beadjustedtoindividualneed.Ifthecomplaintslinkedtoestrogendeficiencyarenotamelioratedthedosagecanbe

increasedbyusingFemoston2/10.Ifeitherearlywithdrawalbleedingoccursorifendometrialbiopsyreveals

inadequateprogestationalresponsethedosagecanbeincreasedbyusingFemoston2/20.

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,Specialwarningsandprecautionsforuse)shouldbeused.

4.3Contraindications

Known,pastorsuspectedbreastcancer;

Knownorsuspectedestrogen-dependentmalignanttumours(e.g.endometrialcancer);

Undiagnosedgenitalbleeding;

Untreatedendometrialhyperplasia;

Previousidiopathicorcurrentvenousthromboembolism(deepveinthrombosis,pulmonaryembolism);

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfarction);

Acuteliverdiseaseorahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal;

Knownhypersensitivitytotheactivesubstancesortoanyoftheexcipients;

Porphyria.

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk.

Medicalexamination/followup

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythecontraindicationsandwarningsforuse.

Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.

Womenshouldbeadvisedwhatchangesintheirbreastsshouldbereportedtotheirdoctorornurse(see‘breastcancer’

below).Investigations,includingmammography,shouldbecarriedoutinaccordancewithcurrentlyacceptedscreening

practices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviously,and/orhavebeenaggravatedduringpregnancy

orprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthatthese

conditionsmayrecurorbeaggravatedduringtreatmentwithFemoston,inparticular:

Leiomyoma(uterinefibroids)orendometriosis

Ahistoryof,orriskfactorsfor,thromboembolicdisorders(seebelow)

Riskfactorsforestrogendependenttumours,e.g.1 st

degreeheredityforbreastcancer

Hypertension

Liverdisorders(e.g.liveradenoma)

Diabetesmellituswithorwithoutvascularinvolvement

Cholelithiasis

Migraineor(severe)headache

Systemiclupuserythematosus

Ahistoryofendometrialhyperplasia(seebelow)

Epilepsy

Asthma

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Reasonsforimmediatewithdrawaloftherapy:

Therapyshouldbediscontinuedincaseswhereacontra-indicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction

Significantincreaseinbloodpressure

Newonsetofmigraine-typeheadache

Pregnancy

Endometrialhyperplasia

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenestrogensareadministeredaloneforprolonged

periods(seesection4.8,Undesirableeffects).Theadditionofaprogestagenforatleast12daysofthecycleinnon-

hysterectomisedwomengreatlyreducesthisrisk.

Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-throughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshouldbe

investigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Breastcancer

Arandomisedplacebo-controlledtrial,theWomensHealthInitiativestudy(WHI)andepidemiologicalstudies,

includingtheMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentaking

estrogens,estrogen-progestagencombinationsortiboloneforHRTforseveralyears(seeSection4.8,Undesirable

effects).

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.deepveinthrombosis

orpulmonaryembolism.Onerandomisedcontrolledtrialandepidemiologicalstudiesfoundatwo-tothreefoldhigher

riskforuserscomparedwithnon-users.Fornon-users,itisestimatedthatthenumberofcasesofVTEthatwilloccur

overa5yearperiodisabout3per1000womenaged50-59yearsand8per1000womenagedbetween60-69years.It

isestimatedthatinhealthywomenwhouseHRTfor5years,thenumberofadditionalcasesofVTEovera5year

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

estimate=9)per1000womenaged60-69years.Theoccurrenceofsuchaneventismorelikelyinthefirstyearof

HRTthanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalorfamilyhistoryandsevereobesity(BMI >

kg/m 2

)andsystemiclupuserythematosus(SLE).Thereisnoconsensusaboutthepossibleroleofvaricose

veinsinVTE.

PatientswithahistoryofVTEorknownthrombophilicstateshaveanincreasedriskofVTE.HRTmayadd

tothisrisk.Personalorstrongfamilyhistoryofthromboembolismorrecurrentspontaneousabortionshould

beinvestigatedinordertoexcludeathrombophilicpredisposition.Untilathoroughevaluationof

thrombophilicfactorshasbeenmadeoranticoagulanttreatmentinitiated,useofHRTinsuchpatientsshould

beviewedascontraindicated.Thosewomenalreadyonanticoagulanttreatmentrequirecarefulconsideration

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TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajor

surgery.Asinallpostoperativepatients,scrupulousattentionshouldbegiventoprophylacticmeasuresto

preventVTEfollowingsurgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,

particularlyabdominalororthopaedicsurgerytothelowerlimbs,considerationshouldbegivento

temporarilystoppingHRT4to6weeksearlier,ifpossible.Treatmentshouldnotberestarteduntilthewomen

iscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontact

theirdoctorsimmediatelywhentheyareawareofapotentialthromboembolicsymptom(e.g.painfulswelling

ofaleg,suddenpaininthechest,dyspnoea).

Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombinedconjugated

estrogensandmedroxyprogesteroneacetate(MPA).

Twolargeclinicaltrials(WHIandHERSi.e.HeartandEstrogen/progestinReplacementStudy)showedapossible

increasedriskofcardiovascularmorbidityinthefirstyearofuseandnooverallbenefit.ForotherHRTproductsthere

areonlylimiteddatafromrandomisedcontrolledtrialstodateexaminingeffectsincardiovascularmorbidityor

mortality.Therefore,itisuncertainwhetherthesefindingsalsoextendtootherHRTproducts.

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

Estrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbe

carefullyobserved.Patientswithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitisexpected

thatthelevelofcirculatingactiveingredientsinFemostonisincreased.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringestrogenreplacementor

hormonereplacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingto

pancreatitishavebeenreportedwithestrogentherapyinthiscondition.

Estrogensincreasethyroidbindingglobulin(TBG),leadingtoincreasedcirculatingtotalthyroidhormone,as

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

radio-immunoassay).T3resinuptakeisdecreased,reflectingtheelevatedTBG.FreeT4andfreeT3

concentrationsareunaltered.Otherbindingproteinsmaybeelevatedinserum,i.e.corticoidbindingglobulin

(CBG),sex-hormone-bindingglobulin(SHBG)leadingtoincreasedcirculatingcorticosteroidsandsex

steroids,respectively.Freeorbiologicalactivehormoneconcentrationsareunchanged.Otherplasmaproteins

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

Thereisnoconclusiveevidenceforimprovementofcognitivefunction.Thereissomeevidencefromthe

WHItrialofincreasedriskofprobabledementiainwomenwhostartusingcontinuouscombinedCEEand

MPAaftertheageof65.Itisunknownwhetherthefindingsapplytoyoungerpost-menopausalwomenor

otherHRTproducts.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Themetabolismofestrogensandprogestagensmaybeincreasedbyconcomitantuseofsubstancesknownto

inducedrug-metabolisingenzymes,specificallycytochromeP450enzymes,suchasanticonvulsants(e.g.

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

efavirenz).

Ritonavirandnelfinavir,althoughknownasstronginhibitors,bycontrastexhibitinducingpropertieswhen

usedconcomitantlywithsteroidhormones.

HerbalpreparationscontainingStJohn’swort(Hypericumperforatum)mayinducethemetabolismof

estrogensandprogestagens.

Clinicallyanincreasedmetabolismofestrogensandprogestagensmayleadtodecreasedeffectandchanges

intheuterinebleedingprofile.

4.6Pregnancyandlactation

Pregnancy:

Femostonisnotindicatedduringpregnancy.IfpregnancyoccursduringmedicationwithFemoston,treatmentshould

bewithdrawnimmediately.

Clinically,databasedonalargenumberofexposedpregnanciesindicatenoadverseeffectsofdydrogesteroneonthe

foetus.

Theresultsofmostepidemiologicalstudiestodaterelevanttoinadvertentfoetalexposuretocombinationsofestrogens

andprogestagensindicatenoteratogenicorfoetotoxiceffect.

Lactation:

Femostonisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

Femostondoesnotaffecttheabilitytodriveorusemachines.

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

Neoplasmsbenign,

malignantand

unspecified Increaseinsizeof

leiomyoma

Bloodandthe

lymphaticsystem

disorders Haemolytic

anaemia

Psychiatric

disorders Depression,

Changeinlibido,

Nervousness

Nervoussystem

disorders Headache,

Migraine Dizziness Chorea

Eyedisorders Intoleranceto

contactlenses,

Steepeningof

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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.

ForestrogenplusprogestagencombinedHRT,severalepidemiologicalstudieshavereportedanoverallhigherriskfor

Cardiacdisorders Myocardial

infarction

Vasculardisorders Hypertension,

Peripheralvascular

disease,Varicose

vein,

Venous

thromboembolism Stroke

Gastrointestinal

disorders Nausea,Abdominal

pain,Flatulence Dyspepsia Vomiting

Hepatobiliary

disorders Gallbladderdisease Alterationsinliver

function,sometimes

withAstheniaor

Malaise,Jaundice

andAbdominalpain

Skinand

subcutaneoustissue

disorders Allergicskin

reactions,Rash,

Urticaria,Pruritus Chloasmaor

melasma,which

maypersistwhen

drugis

discontinued,

Erythema

multiforme,

Erythemanodosum,

Vascularpurpura,

Angioedema

Musculoskeletal

andconnective

tissuedisorders Legcramps Backpain

Reproductive

systemandbreast

disorders Breast

pain/tenderness,

Breakthrough

bleedingand

spotting,

Pelvicpain Changeincervical

erosion,Changein

cervicalsecretion,

Dysmenorrhoea,

Menorrhagia,

Metrorrhagia Breastenlargement,

Premenstrual-like

symptoms

Congenitaland

familial/genetic

disorders Aggravationof

porphyria

Generaldisorders

andadministration

sitereactions Asthenia Peripheraloedema

Investigations Increase/decreasein

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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:

ForwomennotusingHRT,about32inevery1000areexpectedtohavebreastcancerdiagnosedbetweenthe

agesof50and64years.

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

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

womenyears.

Accordingtocalculationsfromthetrialdata,itisestimatedthat:

For1000womenintheplacebogroup,

about16casesofinvasivebreastcancerwouldbediagnosedin5years.

For1000womenwhousedestrogen+progestagencombinedHRT(CEE+MPA),thenumberofadditionalcases

wouldbe

between0and9(bestestimate=4)for5years’use.

ThenumberofadditionalcasesofbreastcancerinwomenwhouseHRTisbroadlysimilarforwomenwhostartHRT

irrespectiveofageatstartofuse(betweentheagesof45-65)(seesection4.4,Specialwarningsandprecautionsfor

use).’

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,ismore

frequentamonghormonereplacementtherapyusersthanamongnon-users.Forfurtherinformation,seesection

4.3Contraindicationsand4.4Specialwarningsandprecautionsforuse.

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4.9Overdose

Bothestradiolanddydrogesteronearesubstanceswithlowtoxicity.Theoretically,symptomssuchasnausea,vomiting,

sleepinessanddizzinesscouldoccurincasesofoverdosing.Itisunlikelythatanyspecificorsymptomatictreatment

willbenecessary.

Aforementionedinformationisapplicableforoverdosingbychildrenalso.

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.

WithFemoston2/20,approximately95%ofwomenhadregularwithdrawalbleeding.Thestartdayandduration

ofbleedingwasthesameaswithFemoston1/10and2/10.Break-throughbleedingand/orspottingoccurredin

approximately12%ofthewomen;amenorrhoeaoccurredin1-7%ofthewomenpercycleduringthefirstyear

oftreatment.

Preventionofosteoporosis.

Estrogendeficiencyatmenopauseisassociatedwithanincreasingboneturnoveranddeclineinbonemass.The

effectofestrogensonthebonemineraldensityisdose-dependent.Protectionappearstobeeffectiveforaslongas

treatmentiscontinued.AfterdiscontinuationofHRT,bonemassislostataratesimilartothatinuntreated

women.

EvidencefromtheWHItrialandmeta-analysedtrialsshowsthatcurrentuseofHRT,aloneorincombination

withaprogestagen–giventopredominantlyhealthywomen–reducestheriskofhip,vertebral,andother

osteoporoticfractures.HRTmayalsopreventfracturesinwomenwithlowbonedensityand/orestablished

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AftertwoyearsoftreatmentwithFemoston1/10,theincreaseinlumbarspinebonemineraldensity(BMD)was

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

treatmentwas95%.ForFemoston2/10andFemoston2/20theincreaseinlumbarspineBMDwas6.6%±3.8%

(mean±SD),andthepercentageofwomenwithnochangeoranincreaseinlumbarspineBMDwas95%.

FemostonalsohadaneffectonhipBMD.Theincreaseaftertwoyearsoftreatmentwith1mgestradiolwas2.7%

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

Wardstriangle,aftertwoyearsoftreatmentwith2mgestradiolthesefigureswhererespectively,2.6%±5.0%;

4.6%±5.0%and4.1%±7.4%.ThepercentageofwomenwhomaintainedorgainedBMDinthe3hipareasafter

treatmentwith1mgestradiolwas67-78%and71-88%aftertreatmentwith2mgestradiol.

5.2Pharmacokineticproperties

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

Supraphysiologicallyhighdoses(prolongedoverdoses)ofestradiolhavebeenassociatedwiththeinductionoftumours

inestrogen-dependenttargetorgansforallrodentspeciestestedcharacteristicforprogesterone-likecompounds.In-

vitroandin-vivodatagavenoindicationsofmutageniceffectsofdydrogesterone.Inlong-termstudies,doses

administeredtoratsandmiceweresufficienttoproducehormone-mediatedchanges,butdidnotprovidetumorogenic

Irish Medicines Board

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactose

Hypromellose

Maizestarch

Colloidalanhydroussilica

Magnesiumstearate

FilmCoating

Methylcullulose

Macrogol400

Quinolineyellow,E104(bluetabletsonly)

PatentblueV,E131(bluetabletsonly)

Ponceau4R,E124(bluetabletsonly)

Titaniumdioxide,E171

Ironoxidesred,blackandyellow,E172(brickredtabletsonly)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Thetabletsarepackedinblisterstripsof28.TheblisterstripsaremadeofPVCfilmwithacoveringaluminiumfoil.

Eachcartoncontains28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

SolvayHealthcareLimited,

MansbridgeRoad

WestEnd,

SouthamptonSO183JD,

England.

8MARKETINGAUTHORISATIONNUMBER

Irish Medicines Board

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:31October1997

Dateoflastrenewal:31October2003

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 21/03/2008 CRN 2048559 page number: 11