FEMATAB

Main information

  • Trade name:
  • FEMATAB Film Coated Tablet 2 Milligram
  • Dosage:
  • 2 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FEMATAB Film Coated Tablet 2 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0108/018/001
  • Authorization date:
  • 12-12-1994
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Fematab2mgFilm-coatedtablet

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains:

Estradiolhemihydrateequivalentto2mgestradiolpertablet.

Excipients-ContainsLactoseMonohydrate118.2mg

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Round,biconvex,brick-redfilm-coatedtabletwithinscription'379'ononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapy(HRT)forestrogendeficiencysymptomsinmenopausalwomen.

Preventionofosteoporosisinpostmenopausalwomenathighriskoffuturefractureswhoareintolerantof,or

contraindicatedfor,othermedicinalproductsapprovedforthepreventionofosteoporosis.

(Seealsosection4.4).

Theexperienceoftreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

FematabisanestrogenonlycontinuousHRTforwomenwithorwithoutauterus.Inwomenwithauterus,a

progestagensuchasDydrogesterone10mgshouldbeaddedtoFematabfor12-14dayseachmonthtoreducetheriskto

theendometrium.Unlessthereisapreviousdiagnosisofendometriosis,itisnotrecommendedtoaddaprogestagenin

hysterectomisedwomen.

Ingeneral,treatmentshouldstartwithFematab1mg.Dependingontheclinicalresponse,thedosagecanafterwardsbe

adjustedtoindividualneed.Ifthecomplaintslinkedtoestrogendeficiencyarenotamelioratedthedosagecanbe

increasedbyusingFematab2mg.

Thedosageisonetabletperday.Fematabshouldbetakencontinuouslywithoutabreakbetweenpacks.

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StartingFematab

Inwomenwhoarenottakinghormonereplacementtherapy,haveestablishedamenorrhoea,arehysterectomised,or

womenwhoswitchfromacontinuouscombinedhormonereplacementtherapy,treatmentmaybestartedonany

convenientday.

InwomentransferringfromacyclicorcontinuoussequentialHRTregimen,treatmentshouldbeginthedayfollowing

completionofthepriorregimen.Ifthepatientismenstruating,treatmentisstartedwithinfivedaysofthestartof

bleeding.

Ifadosehasbeenforgotten,itshouldbetakenassoonaspossible.Whenmorethan12hourshaveelapsed,itis

recommendedtocontinuewiththenextdosewithouttakingtheforgottentablet.Thelikelihoodofbreakthrough

bleedingorspottingmaybeincreased.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

duration(seealsosection4.4)shouldbeused.

4.3Contraindications

Nonhysterectomizedwomenwithoutopposingprogestogen

Known,pastorsuspectedbreastcancer.

Knownorsuspectedestrogen-dependentmalignanttumours(e.g.endometrialcancer).

Undiagnosedgenitalbleeding.

Untreatedendometrialhyperplasia.

Previousidiopathicorcurrentvenousthromboembolism(deepveinthrombosis,pulmonaryembolism).

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfarction,cerebralvascularaccident);

Acuteliverdisease,orahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal.

Knownhypersensitivitytotheactivesubstanceortoanyoftheexcipients.

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/orhavebeenaggravatedduringpregnancyor

previoushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthattheseconditions

mayrecurorbeaggravatedduringtreatmentwithFematab,inparticular:

Leiomyoma(uterinefibroids)orendometriosis.

Ahistoryof,orriskfactorsfor,thromboembolicdisorders(seebelow).

Riskfactorsforestrogendependenttumours,e.g.1 st

degreeheredityforbreastcancer.

Hypertension.

Liverdisorders(e.g.liveradenoma).

Diabetesmellituswithorwithoutvascularinvolvement.

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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.

Fororaldosesofestradiol>2mgandpatches>50µg/daytheendometrialsafetyofaddedprogesteronehavenotbeen

studied.

Break-throughbleedingandspottingmayoccurduringthefirstfewmonthsoftreatment.Ifbreak-throughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshouldbe

investigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Unopposedestrogenstimulationmayleadtopremalignantormalignanttransformationintheresidualfociof

endometriosis.Therefore,theadditionofprogestagenstoestrogenreplacementtherapyshouldbeconsideredinwomen

whohaveundergonehysterectomybecauseofendometriosis,iftheyareknowntohaveresidualendometriosis.

BreastCancer

Arandomisedplacebo-controlledtrial,theWomen’sHealthInitiativestudy(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

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Venousthromboembolism

HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism(VTE),i.e.deepveinthrombosisor

pulmonaryembolism.Onerandomisedcontrolledtrialandepidemiologicalstudiesfoundatwo-tothreefoldhigherriskfor

userscomparedwithnon-users.Fornon-users,itisestimatedthatthenumberofcasesofVTEthatwilloccurovera5year

periodisabout3per1000womenaged50-59yearsand8per1000womenagedbetween60-69years.Itisestimatedthat

inhealthywomenwhouseHRTfor5years,thenumberofadditionalcasesofVTEovera5yearperiodwillbebetween2

and6(bestestimate=4)per1000womenaged50-59yearsandbetween5and15(bestestimate=9)per1000womenaged

60-69years.TheoccurrenceofsuchaneventismorelikelyinthefirstyearofHRTthanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalorfamilyhistoryandsevereobesity(BMI

>

30kg/m 2

)andsystemiclupuserythematosus(SLE).Thereisnoconsensusaboutthepossibleroleof

varicoseveinsinVTE.

PatientswithahistoryofVTEorknownthrombophilicstateshaveanincreasedriskofVTE.HRTmay

addtothisrisk.Personalorstrongfamilyhistoryofthromboembolismorrecurrentspontaneousabortion

shouldbeinvestigatedinordertoexcludeathrombophilicpredisposition.Untilathoroughevaluationof

thrombophilicfactorshasbeenmadeoranticoagulanttreatmentinitiated,useofHRTinsuchpatients

shouldbeviewedascontraindicated.Thosewomenalreadyonanticoagulanttreatmentrequirecareful

considerationofthebenefit-riskofuseofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajor

surgery.Asinallpostoperativepatients,scrupulousattentionshouldbegiventoprophylacticmeasures

topreventVTEfollowingsurgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,

particularlyabdominalororthopaedicsurgerytothelowerlimbs,considerationshouldbegivento

temporarilystoppingHRT4to6weeksearlier,ifpossible.Treatmentshouldnotberestarteduntilthe

womeniscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldto

contacttheirdoctorsimmediatelywhentheyareawareofapotentialthromboembolicsymptom(e.g.

painfulswellingofaleg,suddenpaininthechest,dyspnea).

Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombinedconjugated

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

Estrogen/progestinReplacementStudy)showedapossibleincreasedriskofcardiovascularmorbidityinthefirstyearof

useandnooverallbenefit.ForotherHRTproductsthereareonlylimiteddatafromrandomisedcontrolledtrialsexamining

effectsincardiovascularmorbidityormortality.Therefore,itisuncertainwhetherthesefindingsalsoextendtootherHRT

products.

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

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Otherconditions

Estrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.Patientswithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitisexpectedthatthe

levelofcirculatingactiveingredientsinFematabisincreased.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringestrogenreplacementor

hormonereplacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitis

havebeenreportedwithestrogentherapyinthiscondition.

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)leadingtoincreasedcirculatingcorticosteroidsandsexsteroids,

respectively.Freeorbiologicalactivehormoneconcentrationsareunchanged.Otherplasmaproteinsmaybe

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

Thereisnoconclusiveevidenceforimprovementofcognitivefunction.ThereissomeevidencefromtheWHI

trialofincreasedriskofprobabledementiainwomenwhostartusingcontinuouscombinedCEEandMPAafter

theageof65.Itisunknownwhetherthefindingsapplytoyoungerpost-menopausalwomenorotherHRT

products.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Themetabolismofestrogensmaybeincreasedbyconcomitantuseofsubstancesknowntoinducedrug-

metabolisingenzymes,specificallycytochromeP450enzymes,suchasanticonvulsants(eg.phenobarbital,

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

Ritonavirandnelfinavir,althoughknownasstronginhibitors,bycontrastexhibitinducingpropertieswhenused

concomitantlywithsteroidhormones.

HerbalpreparationscontainingStJohn’sWort(Hypericumperforatum)mayinducethemetabolismof

estrogensandprogestagens.

Clinicallyanincreasedmetabolismofestrogensandprogestagensmayleadtodecreasedeffectandchangesin

theuterinebleedingprofile.

4.6Fertility,pregnancyandlactation

Pregnancy

Fematabisnotindicatedduringpregnancy.IfpregnancyoccursduringmedicationwithFematab,treatmentshouldbe

withdrawnimmediately.

Theresultsofmostepidemiologicalstudiestodaterelevanttoinadvertentfoetalexposuretoestrogensindicateno

teratogenicorfoetotoxiceffects.

Lactation:

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4.7Effectsonabilitytodriveandusemachines

Fematabdoesnotaffecttheabilitytodriveorusemachines.

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

Immunesystem

disorders Hypersensitivity

reactions

Neoplasms

benign,malignant

andunspecified Increaseinsize

ofleiomyoma

Bloodandthe

lymphaticsystem

disorders Haemolytic

anaemia

Immunesystem

disorder

Psychiatric

disorders Depression,

Changeinlibido,

Nervousness

Nervoussystem

disorders Headache,

Migraine Dizziness Chorea

Eyedisorders Intoleranceto

contact

lenses,

Steepeningof

corneal

curvature

Cardiacdisorders Myocardial

infarction

Vascular

disorders Hypertension,

Peripheral

vasculardisease,

Varicosevein,

Venous

thromboembolism Stroke

Gastrointestinal

disorders Nausea,

Abdominal

pain,

Flatulence Dyspepsia Vomiting

Hepatobiliary

disorders Gallbladder

disease Alterationsin

liverfunction,

sometimes

withAsthenia

orMalaise,

Jaundiceand

Abdominal

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Changesincarbohydratemetabolismhavebeenreported.

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.

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 Changein

cervicalerosion,

Changein

cervical

secretion,

Dysmenorrhoea,

Menorrhagia,

Metrorrhagia Breast

enlargement,

Premenstrual-

like

symptoms

Congenitaland

familial/genetic

disorders Aggravationof

porphyria

Generaldisorders

administration

sitereactions Asthenia Peripheral

oedema

Investigations Increase/decrease

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TheMWShasestimated,fromtheknownaverageincidenceofbreastcancerindevelopedcountries,that:

ForwomennotusingHRT,about32inevery1000areexpectedtohave breastcancerdiagnosedbetween

theagesof50and64years.

For1000currentorrecentusersofHRT,thenumberofadditionalcasesduringthecorrespondingperiodwill

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).’

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.

Probabledementia(seesection4.4).

4.9Overdose

Bothestradiolanddydrogesteronearesubstanceswithlowtoxicity.Theoretically,symptomssuchasnausea,vomiting,

sleepinessanddizzinesscouldoccurincasesofoverdosing.Itisunlikelythatanyspecificorsymptomatictreatment

willbenecessary.Aforementionedinformationisapplicableforoverdosingbychildrenalso.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Naturalandsemisyntheticestrogens,plain.ATCcode:G03CA03

Estradiol

Theactiveingredient,synthetic17-beta-estradiolischemicallyandbiologicallyidenticaltotheendogenoushuman

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Estrogenspreventbonelossfollowingmenopauseorovariectomy.

Combinedtherapywithprogestagensisalsorecommendedinhysterectomisedwomenwithahistoryofendometriosis

ascancerdevelopmentinextra-uterineendometrioticimplantsinwomenonestrogen-onlytherapyhasbeenreported

(seesection4.4Specialwarningsandprecautions).

Clinicaltrialinformation

Reliefofestrogen-deficiencysymptomsandbleedingpatterns

Reliefofmenopausalsymptomswasachievedduringthefirstfewweeksoftreatment.

RegularwithdrawalbleedinginwomentreatedwithFematab1mgdailyfor28daysandDydrogesterone10mg

dailyforthelast12-14daysofa28daycycle,occurredinapproximately75-80%ofwomenwithamean

durationof5days.Withdrawalbleedingusuallystartedonthedayofthelastpilloftheprogestagenphase.

Break-throughbleedingand/orspottingoccurredinapproximately10%ofthewomen;amenorrhoeaoccurredin

10-25%ofthewomenpercycleduringthefirstyearoftreatment.

InwomentreatedwithFematab2mgdailyfor28daysandDydrogesterone10mgdailyforthelast12-14days

ofa28daycycle,approximately90%ofwomenhadregularwithdrawalbleeding.Thestartdayanddurationof

bleeding,andthenumberofwomenwithintermittentbleedingwasthesameaswithFematab1mg,

amenorrhoea(nobleedingorspotting)occurredin5-15%ofthewomenpercycleduringthefirstyearof

treatment.

Preventionofosteoporosis

Estrogendeficiencyatmenopauseisassociatedwithanincreasingboneturnoveranddeclineinbonemass.The

effectofestrogensonthebonemineraldensityisdose-dependent.Protectionappearstobeeffectiveforaslong

astreatmentiscontinued.

AfterdiscontinuationofHRT,bonemassislostataratesimilartothatinuntreatedwomen.

EvidencefromtheWHItrialandmeta-analysedtrialsshowsthatcurrentuseofHRT,aloneorincombination

withaprogestagen–giventopredominantlyhealthywomen–reducestheriskofhip,vertebral,andother

osteoporoticfractures.HRTmayalsopreventfracturesinwomenwithlowbonedensityand/orestablished

osteoporosis,buttheevidenceforthatislimited.

AftertwoyearsoftreatmentwithFematab1mg,theincreaseinlumbarspinebonemineraldensity(BMD)was

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

treatmentwas95%.ForFematab2mgtheincreaseinlumbarspineBMDwas6.6%±3.8%(mean±SD),and

thepercentageofwomenwithnochangeoranincreaseinlumbarspineBMDwas95%.

FematabalsohadaneffectonhipBMD.Theincreaseaftertwoyearsoftreatmentwith1mgestradiolwas2.7%

±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

areasaftertreatmentwith1mgestradiolwas67-78%and71-88%aftertreatmentwith2mgestradiol.

5.2Pharmacokineticproperties

Orallyadministeredestradiol,comprisingparticleswhosesizehasbeenreducedtolessthan5micrometer,isquickly

andefficientlyabsorbedfromthegastrointestinaltract.Theprimaryunconjugatedandconjugatedmetabolitesareestrone

andestronesulphate.Thesemetabolitescancontributetotheestrogeneffect,bothdirectlyandafterconversiontoestradiol.

Estrogensareexcretedinthebileandreabsorbedfromtheintestine.Duringthisenterohepaticcycletheestrogensare

brokendown.Estrogensareexcretedintheurineasbiologicallyinactiveglucuronideandsulphatecompounds(90to

95%),orinthefaeces(5to10%),mostlyunconjugated.Estrogensaresecretedinthemilkofnursingmothers.

TheC

average is58pg/ml,theC

is44pg/mlandtheC

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

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5.3Preclinicalsafetydata

Supra-physiologicallyhighdoses(prolongedoverdoses)ofestradiolhavebeenassociatedwiththeinductionof

tumoursinestrogen-dependenttargetorgansforallrodentspeciestested.Thechangesobservedwithdydrogesteronein

animaltoxicitystudiesarecharacteristicforprogesterone-likecompounds.In-vitroandin-vivodatagavenoindicationsof

mutageniceffectsofdydrogesterone.Inlong-termstudies,dosesadministeredtoratsandmiceweresufficienttoproduce

hormone-mediatedchanges,butdidnotprovidetumorogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

LactoseMonohydrate

Hypromellose

Maizestarch

Colloidalanhydroussilica,

Magnesiumstearate

OpadryOY6957Pinkcoatingcontaining:

Macrogol400,

Titaniumdioxide(E171)

Hypromellose

Black,redandYellowIronOxides(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Blisterstripsof28tablets.TheblisterstripismadeofPVCfilmwithcoveringaluminiumfoil.Eachcartoncontains28

tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

AbbottHealthcareProductsLtd

MansbridgeRoad

WestEnd

Southampton

SO183JD

Irish Medicines Board

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

8MARKETINGAUTHORISATIONNUMBER

PA108/18/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:12December1994

Dateoflastrenewal:12December2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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