FEMUREST-CONTI

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0108/024/001
  • Authorization date:
  • 08-12-2000
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Femurest-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.Femurest-conti

shouldbeusedonlyinpostmenopausalwomenmorethan12monthsaftermenopause.Preventionofosteoporosisin

postmenopausalwomenathighriskoffuturefractureswhoareintolerantof,orcontraindicatedfor,othermedicinal

productsapprovedforthepreventionofosteoporosis.(Seealsosection4.4)

Theexperienceintreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

Femurest-contiisacontinuouscombinedHRT.

Thedosageisonetabletperday.Femurest-contishouldbetakencontinuouslywithoutabreakbetweenpacks.

Femurest-conticanbetakenwithorwithoutfood.

StartingFemurest-conti:

WomenexperiencinganaturalmenopauseshouldcommencetreatmentwithFemurest-conti12monthsaftertheirlast

naturalmenstrualbleed.Forsurgicallyinducedmenopause,treatmentmaystartimmediately.

Inwomenwhoarenottakinghormonereplacementtherapyorwomen,whoswitchfromacontinuouscombined

hormonereplacementtherapy,treatmentmaybestartedonanyconvenientday.Inwomentransferringfromacyclicor

continuoussequentialHRTregimen,treatmentshouldbeginthedayfollowingcompletionofthepriorregimen.

Ifadosehasbeenforgotten,itshouldbetakenassoonaspossible.Whenmorethan12hourshaveelapsed,itis

recommendedtocontinuewiththenextdosewithouttakingtheforgottentablet.Thelikelihoodofbreakthrough

bleedingorspottingmaybeincreased.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/01/2012 CRN 2104280 page number: 1

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

shouldonlybecontinuedaslongasthebenefitoutweighstherisk.

Medicalexamination/followup

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythecontraindicationsandwarningsforuse.

Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.

Womenshouldbeadvisedthatchangesintheirbreastsshouldbereportedtotheirdoctorornurse.

Investigations,includingmammography,shouldbecarriedoutinaccordancewithcurrentlyacceptedscreening

practices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviously,and/orhavebeenaggravatedduringpregnancy

orprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthatthese

conditionsmayrecurorbeaggravatedduringtreatmentwithFemurest-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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/01/2012 CRN 2104280 page number: 2

Endometrialhyperplasia

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenestrogensareadministeredaloneforprolonged

periods(seesection4.8).Theadditionofaprogestagenforatleast12dayspercycleinnonhysterectomisedwomen

greatlyreducesthisrisk.Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-

throughbleedingorspottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,the

reasonshouldbeinvestigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Breastcancer

Arandomisedplacebo-controlledtrial,theWomensHealthInitiativestudy(WHI)andepidemiologicalstudies,

includingtheMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentaking

estrogens,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.deepveinthrombosis

orpulmonaryembolism.

Onerandomisedcontrolledtrialandepidemiologicalstudiesfoundatwo-tothreefoldhigherriskforuserscompared

withnon-users.Fornon-users,itisestimatedthatthenumberofcasesofVTEthatwilloccurovera5yearperiodis

about3per1000womenaged50-59yearsand8per1000womenagedbetween60-69years.Itisestimatedthatin

healthywomenwhouseHRTfor5years,thenumberofadditionalcasesofVTEovera5yearperiodwillbebetween

2and6(bestestimate=4)per1000womenaged50-59yearsandbetween5and15(bestestimate=9)per1000

womenaged60-69years.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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/01/2012 CRN 2104280 page number: 3

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

circulatingactiveingredientsinFemurest-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

biological 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-galactosemalabsortion.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/01/2012 CRN 2104280 page number: 4

4.6Fertility,pregnancyandlactation

Pregnancy

Femurest-contiisnotindicatedduringpregnancy.IfpregnancyoccursduringmedicationwithFemurest-conti,

treatmentshouldbewithdrawnimmediately.

Clinically,databasedonanassumedlargenumberofexposedpregnanciesindicatenoadverseeffectsof

dydrogesteroneonthefetus.

Theresultsofmostepidemiologicalstudiestodaterelevanttoinadvertentfetalexposuretocombinationsofestrogens

andprogestagensindicatenoteratogenicorfetotoxiceffect.

Lactaction

Femurest-contiisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

Femurest-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

corneal

curvature

Cardiacdisorders Myocardial

infarction

Vascular

disorders Hypertension,

peripheralvascular

disease,

varicosevein,

venous

thromboembolism Stroke

Gastrointestinal

disorders Nausea,

abdominalpain,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/01/2012 CRN 2104280 page number: 5

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

Hepatobiliary

disorders Gallbladder

disease Alterationsin

liverfunction,

sometimeswith

astheniaor

malaise,jaundice

andabdominal

pain

Skinand

subcutaneous

tissuedisorders Allergicskin

reactions,rash,

urticaria,pruritus Chloasmaor

melasma,

which

maypersist

when

drugis

discontinued,

erythema

multiforme,

erythema

nodosum,

vascular

purpura,

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/01/2012 CRN 2104280 page number: 6

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,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

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).

Endometrialcancer

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandendometrialcancerincreaseswithincreasing

durationofuseofunopposedestrogens.Accordingtodatafromepidemiologicalstudies,thebestestimateoftheriskis

thatforwomennotusingHRT,about5inevery1000areexpectedtohaveendometrialcancerdiagnosedbetweenthe

agesof50and65.

Dependingonthedurationoftreatmentandestrogendose,thereportedincreaseinendometrialcancerriskamong

unopposedestrogenusersvariesfrom2-to12-foldgreatercomparedwithnon-users.Addingaprogestagento

estrogen-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.Itis

unlikelythatanyspecificorsymptomatictreatmentwillbenecessary.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/01/2012 CRN 2104280 page number: 7

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Genitourinarysystemandsexhormones,progestogensandestrogens,fixedcombinations.

TheATCcodeisG03FA14.

Estradiol

Theactiveingredient,synthetic17-estradiol,ischemicallyandbiologicallyidenticaltoendogenoushumanestradiol.

Itsubstitutesforthelossofestrogenproductioninmenopausalwomen,andalleviatesmenopausalsymptoms.

Estrogenspreventbonelossfollowingmenopauseorovariectomy.

Dydrogesterone

Asestrogenspromotethegrowthoftheendometrium,unopposedestrogensincreasetheriskofendometrialhyperplasia

andcancer.Theadditionofaprogestagengreatlyreducestheestrogen-inducedriskofendometrialhyperplasiainnon-

hysterectomisedwomen.

ClinicaltrialInformation

Reliefofestrogen-deficiencysymptomsandbleedingpatterns.

Reliefofmenopausalsymptomswasachievedduringthefirstfewweeksoftreatment.

Amenorrhoeawasseenin76%ofwomenduringmonths10-12oftreatment.

Breakthroughbleedingand/orspottingappearedin29%ofthewomenduringthefirstthreemonthsoftreatmentandin

24%duringmonths10-12oftreatment.

Preventionofosteoporosis

Estrogendeficiencyatmenopauseisassociatedwithanincreasingboneturnoveranddeclineinbonemass.Theeffect

ofestrogensonthebonemineraldensityisdosedependent.Protectionappearstobeeffectiveforaslongastreatment

iscontinued.AfterdiscontinuationofHRT,bonemassislostataratesimilartothatinuntreatedwomen.

EvidencefromtheWHItrialandmeta-analysedtrialsshowsthatcurrentuseofHRT,aloneorincombinationwitha

progestagen–giventopredominantlyhealthywomenreducestheriskofhip,vertebral,andotherosteoporotic

fractures.HRTmayalsopreventfracturesinwomenwithlowbonedensityand/orestablishedosteoporosis,butthe

evidenceforthatislimited.

AftertwoyearsoftreatmentwithFemurest,theincreaseinlumbarspinebonemineraldensity(BMD)was5.20%±

3.76%(mean±SD).ThepercentageofwomenwhomaintainedorgainedBMDinlumbarzoneduringtreatmentwas

95%.

FemurestalsohadaneffectonhipBMD.Theincreaseaftertwoyearswas2.7%±4.2%(mean±SD)atfemoralneck,

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

whomaintainedorgainedBMDinthe3hipareasduringtreatmentwas67-78%.

5.2Pharmacokineticproperties

Estradiol

Orallyadministeredestradiol,comprisingparticleswhosesizehasbeenreducedtolessthan5µm,isquicklyand

efficientlyabsorbedfromthegastrointestinaltract.Theprimaryunconjugatedandconjugatedmetabolitesareestrone

andestronesulphate.Thesemetabolitescancontributetotheestrogeneffect,bothdirectlyandafterconversionto

estradiol.Estrogensareexcretedinthebileandreabsorbedfromtheintestine.Duringthisenterohepaticcyclethe

estrogensarebrokendown.Estrogensareexcretedintheurineasbiologicallyinactiveglucuronideandsulphate

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/01/2012 CRN 2104280 page number: 8

TheC

average is28pg/ml,theC

is20pg/mlandtheC

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

Dydrogesterone

Afteroraladministrationoflabelleddydrogesterone,onaverage63%ofthedoseisexcretedintotheurine.Within72

hours,excretioniscomplete.

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

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.Analysisofendogenousprogesterone

productionbasedonpregnanediolexcretionthereforeremainspossible.

5.3Preclinicalsafetydata

Supraphysiologicallyhighdoses(prolongedapplication)ofestradiolhavebeenassociatedwiththeinductionoftumoursin

estrogen-dependenttargetorgansforallrodentspeciestested.Furthermore,inherenttoitshormonalactivity,estradiol

displaysuntowardembryotoxiceffectsandfeminisationofmalefetuseswasoccasioallyobserved.Thechangesobserved

withdydrogesteroneinanimaltoxicitystudiesareassociatedwiththeeffectsofprogesterone-likecompounds.Doses

administeredtoratsandmicesufficienttoproducehormonemediatedchangesgavenoevidenceofcarcinogenesis

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Hypromellose

Maizestarch

Colloidalanhydroussilica

Magnesiumstearate

Filmcoat:

Hypromellose

Macrogol400

Titaniumdioxide(E171)

Ironoxides,yellowandred(E172 )

6.2Incompatibilities

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 11/01/2012 CRN 2104280 page number: 9

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Keepblisterintheoutercartoninordertoprotectfromlightandmoisture.

6.5Natureandcontentsofcontainer

Calendarpacksof14,28,84(3x28)or280(10x28)tabletsinPVCAluminiumblisterstrips.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

AbbottHealthcareProductsLtd.

MansbridgeRoad,WestEnd

SouthamptonSO183JD

UnitedKingdom.

8MARKETINGAUTHORISATIONNUMBER

PA108/24/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:08December2000

Dateoflastrenewal: 21November2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

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