ESTROFEM

Main information

  • Trade name:
  • ESTROFEM Tablets 1 mg Milligram
  • Dosage:
  • 1 mg Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ESTROFEM Tablets 1 mg Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0218/050/002
  • Authorization date:
  • 06-02-1998
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA0218/050/002

CaseNo:2067320

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

NovoNordiskA/S

NovoAlle,DK-2880,Bagsvaerd,Denmark

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Estrofem1mgfilm-coatedtablets

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom20/07/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/07/2010 CRN 2067320 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Estrofem1mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontainsestradiol1mgasestradiolhemihydrate.

Excipients:lactosemonohydrate37.3mg.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet(tablet).

Red,film-coated,biconvextablets,engravedwithNOVO282,diameter6mm.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapy(HRT)foroestrogendeficiencysymptoms.

Inwomenwithintactuterus,progestogentherapyshouldbeadded.

Theexperienceoftreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

Estrofemisanoestrogen-onlyproductforhormonalreplacement.Forinitiationandcontinuationoftreatmentof

menopausalsymptoms,thelowesteffectivedosefortheshortestduration(seealsosection4.4)shouldbeused.A

switchtoahigherdoseofEstrofemcouldbeindicatediftheresponseafterthreemonthsisinsufficientforsatisfactory

reliefofsymptoms.

Estrofemisadministeredorally,onetabletdailywithoutinterruption.Treatmentofhysterectomisedwomenand

postmenopausalwomenmaybestartedonanyconvenientday.Ifthewomanismenstruating,treatmentisstartedon

day5ofbleeding.Inwomenwithanintactuterusaprogestogenmustbeaddedfor12-14dayseverymonth/28-day

cycle.Theprogestogentype,dose,aswellasthedurationofprogestogenadministrationshouldprovideasufficient

inhibitionoftheoestrogen-inducedendometrialproliferation(seesection4.4)

Ifthepatienthasforgottentotakeonetablet,theforgottentabletistobediscarded.Forgettingadosefornon-

hysterectomisedwomenmayincreasethelikelihoodofbreakthroughbleedingandspotting.

Unlessthereisapreviousdiagnosisofendometriosisitisnotrecommendedtoaddaprogestogeninhysterectomised

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/07/2010 CRN 2067320 page number: 2

4.3Contraindications

Known,pastorsuspectedbreastcancer;

Knownorsuspectedoestrogen-dependantmalignanttumours(e.gendometrialcancer);

Undiagnosedgenitalbleeding;

Untreatedendometrialhyperplasia;

Previousidiopathicorcurrentvenousthromboembolism(deepvenousthrombosis,pulmonaryembolism);

Activeorrecentarterialthromboembolicdisease(angina,myocardialinfarction);

Acuteliverdisease,orahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal;

Knownhypersensitivitytotheactivesubstanceortoanyoftheexcipients;

Porphyria

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyeffectthe

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk.

Medicalexamination/follow-up

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshoulbeguidedbythisandbythecontra-indicationsandwarningsforuse.

Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.

Womenshouldbeadvisedthatchangesintheirbreastsshouldbereportedtotheirdoctorornurse(see‘Breastcancer’

below).Investigations,includingmammography,shouldbecarriedoutinaccordancewithcurrentlyaccepted

screeningpractices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviouslyand/orhaveaggravatedduringpregnancyor

previoushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthatthese

conditionsmayrecurorbeaggravatedduringtreatmentwithEstrofem,inparticular:

Leiomyoma(uterinefibroids),orendometriosis

Ahistoryof,orriskfactorsfor,thromboembolicdisorders(seebelow)

Riskfactorsforoestrogendependenttumours,e.g1 st

degreeheredityforbreastcancer;

Liverdisorders(e.g.liveradenoma);

Hypertension

Diabetesmellituswithorwithoutvascularinvolvement

Cholelithiasis

Migraineor(severe)headache

Systematiclupuserythematosus

Ahistoryofendometrialhyperplasia(seebelow)

Epilepsy

Asthma

Otosclerosis

Reasonsforimmediatewithdrawaloftherapy

Therapyshouldbediscontinuedincaseacontra-indicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction

Significantincreaseinbloodpressure

Newonsetofmigraine-typeheadache

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/07/2010 CRN 2067320 page number: 3

Endometrialhyperplasia

Womenwithanintactuteruswithabnormalbleedingofunknownaetiologyorwomenwithanintactuteruswhohave

previouslybeentreatedwithunopposedoestrogensshouldbeexamindedwithspecialcareinordertodisclosea

possiblehyperstimulation/malignancyoftheendometiumbeforeinitiationoftreatmentwithEstrofem.

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenoestrogensareadministeredaloneforprolonged

periods(seesection4.8).Theadditionofaprogestogenforatleast12dayspercycleinnon-hysterectomisedwomen

greatlyreducesthisrisk.

Fororaldosesofestradiol>2mgtheendometrialsafetyofaddedprogestogenshasnotbeenstudied.

Breakthroughbleedingandspottingmayoccurduringthefirstmonthsoftreatmentinwomenwithanintactuterus.If

breakthroughbleedingorspottingoccursaftersometimeontherapy,orcontinuesaftertreatmenthasbeen

discontinued,thereasonshouldbeinvestigated,whichmayincludeendometrialbiopsytoexcludeendometrial

malignancy.

Unopposedoestrogenstimulationmayleadtopremalignantormalignanttransformationintheresidualfociof

endometriosis.Therefore,theadditionofprogestogenstooestrogenreplacementtherapyisrecommendedinwomen

whohaveundergonehysterectomybecauseofendometriosis,especiallyiftheyareknowntohaveresidual

endometriosis.

Breastcancer

Arandomizedplacebo-controlledtrialtheWomen’sHealthInitiative(WHI),andepidemiologicalstudies,including

theMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentakingoestrogens,

oestrogen-progestogencombinationsortiboloneforHRTforseveralyears(seesection4.8).ForallHRT,anexcess

riskbecomesapparentwithinafewyearsofuseandincreaseswithdurationofintakebutreturnstobaselinewithina

few(atmostfive)yearsafterstoppingtreatment.

IntheMWS,therelativeriskofbreastcancerwithconjugatedequineoestrogens(CEE)orestradiol(E2)wasgreater

whenaprogestogenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeofprogestogen.Therewas

noevidenceofadifferenceintheriskbetweenthedifferentroutesofadministration.

IntheWHIstudy,thecontinuouscombinedconjugatedequineoestrogenandmedroxyprogesteroneacetate(CEE+

MPA)productusedwasassociatedwithbreastcancersthatwereslightlylargerinsizeandmorefrequentlyhadlocal

lymphnodemetastasescomparedtoplacebo.

HRT,especiallyoestrogen-progestogencombinedtreatment,increasesthedensityofmammographicimageswhich

mayadverselyaffecttheradiologicaldetectionofbreastcancer.

Venousthromboembolism

HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism(VTE),i.edeepveinthrombosis

orpulmonaryembolism.Onerandomizedcontrolledtrialandepidemiologicalstudiesfoundatwo-tothreefoldhigher

riskforuserscomparedwithnon-users.Fornon-users,itisestimatedthatthenumberofcasesofVTEthatwilloccur

overafiveyearperiodisabout3per1000womenaged50-59yearsand8per1000womenagedbetween60-69years.

ItisestimatedthatinhealthywomenwhouseHRTfor5years,thenumberofadditionalcasesofVTEovera5year

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

estimate=9)per1000womenaged60-69years.Theoccurrenceofsuchaneventismorelikelyinthefirstyearof

HRTthanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalhistoryorfamilyhistory,severeobesity(BodyMass

Index>30kg/m 2

)andsystemiclupuserythematosus(SLE).Thereisnoconsensusaboutthepossibleroleofvaricose

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/07/2010 CRN 2067320 page number: 4

PatientswithahistoryofVTEorknownthrombophilicstateshaveanincreasedriskofVTE.HRTmayaddtothis

risk.Personalorstrongfamilyhistoryofthromboembolismorrecurrentspontaneousabortionshouldbeinvestigated

inordertotoexcludeathrombophilicpredisposition.Untilathoroughevaluationofthrombophilicfactorshasbeen

madeoranticoagulanttreatmentinitiated,useofHRTinsuchpatientsshouldbeviewedascontraindicated.Those

womenalreadyonanticoagulanttreatmentrequirecarefulconsiderationofthebenefit-riskofuseofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajorsurgery.Asin

allpost-operativepatients,scrupulousattentionshouldbegiventoprophylacticmeasurestopreventVTEfollowing

surgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,particularlyabdominalororthopaedic

surgerytothelowerlimbs,considerationshouldbegiventotemporarilystoppingHRTfourtosixweeksearlier,if

possible.Treatmentshouldnotbestarteduntilthewomaniscompletelymobilized.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorsimmediately,iftheyareawareofapotentialthromboembolicsymptom(e.gpainfulswellingofaleg,sudden

paininthechest,dyspnoea).

Coronaryarertydisease(CAD)

Thereisnoevidencefromrandomizedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombinedconjugated

oestrogensandmedroxyprogesteroneacetate(MPA).Twolargeclinicaltrials(WHIandHERSi.eHeartand

Estrogen/progestinReplacementStudy)showedapossibleincreasedriskofcardiovascularmorbidityinthefirstyear

ofuseandnooverallbenefit.ForotherHRTproductsthereareonlylimiteddatafromrandomizedcontrolledtrials

examiningeffectsincardiovascularmorbidityormortality.Thereforeitisuncertainwhetherthesefindingsextendto

otherHRTproducts.

Stroke

Onelargerandomisedclinicaltrial(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischaemicstrokein

healthywomenduringtreatmentwithcontinuouscombinedconjugatedoestrogensandMPA.Forwomenwhodonot

useHRT,itisestimatedthatthenumberofcasesofstrokethatwilloccurovera5-yearperiodisabout3per1000

womenaged50-59yearsand11per1000aged60-69years.Itisestimatedforwomenwhouseconjugatedoestrogens

andMPAfor5years,thenumberofadditionalcaseswillbebetween0and3(bestestimate=1)per1000usersaged

50-59yearsandbetween1and9(bestestimate=4)per1000usersaged60-69years.Itisunknownwhetherthe

increasedriskalsoextendstootherHRTproducts.

Ovariancancer

Longterm(atleast5-10years)useofoestrogen-onlyHRTproductsinhysterectomisedwomenhasbeenassociated

withanincreasedriskofoveriancancerinsomeepidemiologicalstudies.Itisuncertainwhetherlong-termuseof

combinedHRTconfersadifferentriskthanoestrogen-onlyproducts.

Otherconditions

Oestrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.Patientswithterminalrenalinsufficiencyshouldbecloselyobservedsinceitisexpectedthatthelevel

ofcirculatingactiveingredientinEstrofemwillbeincreased.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringhormonereplacementtherapy,

sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitishavebeenreportedwith

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/07/2010 CRN 2067320 page number: 5

Oestrogensincreasethyroidbindingglobulin(TGB),leadingtoincreasedcirculatingtotalthyroidhormone,as

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

immunoassay).T3resinuptakeisdecreased,reflectingtheelevatedTGB.FreeT4andfreeT3concentrations

areunaltered.Otherbindingproteinsmaybeelevatedinserum,i.ecorticoidbindingglobulin(CBG),sex-

hormone-bindingglobulin(SHBG)leadingtoincreasecirculatingcorticosteroidsandsexsteroids,respectively.

Freeorbiologicallyactivehormoneconcentrationsareunchanged.Otherplasmaproteinsmaybeincreased

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

Estrofemhasnocontraceptiveeffect.HormonalcontraceptionshouldbestoppedwhentheuseofEstrofemis

startedandthepatentshouldbeadvisedtotakenon-hormonalcontraceptiveprecautionsifrequired.

Thereisnoconclusiveevidenceforimprovementofcognitivefunction.ThereissomeevidencefromtheWHI

trialofincreasedriskofprobabledementiainwomenwhostartusingcontinuouscombinedCEEandMPAafter

theageof65.Itisunknownwhetherthefindingsapplytoyoungerpost-menopausalwomenorotherHRT

products.

Estrofemtabletscontainlactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Themetabolismofoestrogens(andprogestogens)maybeincreasedbyconcomitantuseofsubstancesknowntoinduce

drug-metabolisingenzymes,specificallycytochromeP450enzymes,suchasanticonvulsants(e.gphenobarbital,

phenytoin,carbamezapin)andanti-infectives(e.grifampicin,rifabutin,nevirapine,efavirenz).

Ritonavirandnelfinavir,althoughknownasstronginhibitors,bycontrastexhibitinducingpropertieswhenused

concomitantlywithsteroidhormones.HerbalpreparationsincludingSt.John’sWort(Hypericumperforatum)may

inducethemetabolismofoestrogens(andprogestogens).

Clinically,anincreasedmetabolismofoestrogens(andprogestogens)mayleadtodecreasedeffectandchangesinthe

uterinebleedingprofile.

4.6Pregnancyandlactation

Estrofemisnotindicatedduringpregnancy.IfpregnancyoccursduringmedicationwithEstrofemtreatmentshouldbe

withdrawnimmediately.Theresultsofepidemiologicalstudiesto-daterelevanttoinadvertentfoetalexposureto

combinationsofoestrogensandprogestogensindicatenoteratogenicorfoetotoxiceffect.

Estrofemisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/07/2010 CRN 2067320 page number: 6

4.8Undesirableeffects

Clinicalexperience

Inclinicaltrialslessthan10%ofthepatientsexperiencedadversedrugreactions.Themostfrequentlyreported

adversereactionsarebreasttenderness/breastpain,abdominalpain,oedemaandheadache.

TheadversereactionslistedbelowmayoccurduringEstrofemtreatment:

Breastcancer

Accordingtoevidencefromalargenumberofepidemiologicalstudiesandonerandomisedplacebo-controlledtrial,the

Women’sHealthInitiative(WHI),theoverallriskorbreastcancerincreaseswithincreasingdurationofHRTusein

currentorrecentHRTusers.

Foroestrogen-onlyHRT,estimatesofrelativerisk(RR)fromareanalysisoforiginaldatafrom51epidemiological

studies(inwhich>80%ofHRTusewasoestrogen-onlyHRT)andfromtheepidemiologicalMillionWomenstudy

System Organ

Class Very

common

>1/10 Common

>1/100,<1/10 Uncommon

>1/1000,<1/100 Rare

(>1/10,000,

<1/1000)

Psychiatric

disorders Depression

Nervoussystem

disorder Headache

Eyedisorder Visionabnormal

Vascular

disorders Venous

embolismNOS

Gastrointestinal

disorders Abdominalpain

ornausea Dyspepsia,

vomiting,

flatulence or

bloating

Hepatobiliary

disorders Cholelithiasis

Skin and

subcutaneous

tissuedisorders Rashorurticaria

Musculosketal

andconnective

tissuedisorders Legcramps

Reproductive

system and

breast

disorders Breast

tenderness,

breast

enlargementor

breastpain

General

disorders and

administration

siteconditions Oedema

Investigations Weight

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/07/2010 CRN 2067320 page number: 7

ForoestrogenplusprogestogencombinedHRT,severalepidemiologicalstudieshavereportedanoverallhigherrisk

forbreastcancerthanwithoestrogensalone.

TheMWSreportedthat,comparedtoneverusers,theuseofvarioustypesofoestrogen-progestogencombinedHRT

wasassociatedwithahigherriskofbreastcancer(RR=2.00,95%CI:1.88-2.12)thanuseofoestrogensalone(RR=

1.30,95%CI:1.21-1.40)oruseoftibolone(RR=1.45,95%CI:1.25-1.68).

TheWHItrialreportedariskestimateof1.24(95%CI:1.01-1.54)after5.6yearsofuseofoestrogen-progestogen

combinedHRT(CEE+MPA)inalluserscomparedwithplacebo.

TheabsoluteriskscalculatedfromtheMWSandtheWHItrialarepresentedbelow:

TheMWShasestimated,fromtheknownaverageincidenceofbreastcancerindevelopedcountries,that:

ForwomennotusingHRT,about32inevery1000areexpectedtohavebreastcancerdiagnosedbetweentheages

of50and64years.

For1000currentorrecentusersofHRT,thenumberofadditionalcasesduringthecorrespondingperiodwillbe

Forusersofoestrogen-onlyreplacementtherapy,

between0and3(bestestimate=1.5)for5years’use

between3and7(bestestimate=5)for10years’use

ForusersofoestrogenplusprogestogencombinedHRT

between5and7(bestestimate=6)for5years’use

between18and20(bestestimate=19)for10years’use

TheWHItrialestimatedthatafter5.6yearsoffollow-upofwomenbetweentheagesof50and79years,anadditional

8casesofinvasivebreastcancerwouldbeduetooestrogen-progestogencombinedHRT(CEE+MPA)per10,000

womenyears.Accordingtocalculationsfromthetrialdata,itisestimatedthat:

For1000womenintheplacebogroup,

About16casesofinvasivebreastcancerwouldbediagnosedin5years

For1000womenwhousedoestrogen+progestogencombinedHRT(CEE+MPA),thenumberofadditionalcases

wouldbe:

Between0and9(bestestimate=4)for5years’use

ThenumberofadditionalcasesofbreastcancerinwomenwhouseHRTisbroadlysimilarforwomenwhostartHRT

irrespectiveofageatstartofuse(betweentheagesof45-65)(seesection4.4)

Endometrialcancer

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandendometrialcancerincreaseswithincreasing

durationofuseofunopposedoestrogens.Accordingtodatafromepidemiologicalstudies.Thebestestimateoftherisk

isthatforwomennotusingHRT,about5inevery1000areexpetedtohaveendometrialcancerdiagnosedbetweenthe

agesof50and65.Dependingonthedurationoftreatmentandoestrogendose,thereportedincreaseinendometrial

cancerriskamongunopposedoestrogenusersvariesfrom2-to12-foldgreatercomparedwithnon-users.Addinga

progestogentooestrogen-onlytherapygreatlyreducesthisincreasedrisk.

Post-marketingexperience:

Inadditiontotheabove-mentionedadversedrugreactions,thosepresentedbelowhavebeenspontaneouslyreported,

andarebyanoveralljudgementconsideredpossiblyrelatedtoEstrofemtreatment.Thereportingrateofthese

spontaneousadversedrugreactionsisveryrare(<1/10,000patientyears).Post-marketingexperienceissubjectto

under-reportingespeciallywithregardtotrivialandreactionswell-knownadversedrug.Thepresentedfrequencies

shouldbeinterpretedinthatlight:

Reproductivesystemandbreastdisorders:Irregularvaginalbleeding*

Nervoussystemdisorders:Deteriorationofmigraine,stroke,dizziness,depression

Gastrointestinaldisorder:Diarrhoea

Skinandsubcutaneoustissuedisorders:Alopecia

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/07/2010 CRN 2067320 page number: 8

Thefollowingadversereactionshavebeenreportedinassociationwithotheroestrogentreatment:

Myocardialinfarction,congestiveheartdisease

Gallbladderdisease

Skinandsubcutaneousdisorders:chloasma,erythemamultiforme,erythemanodosum,vascularpurpura,pruritis

Vaginalcandidiasis

Riskofdevelopingendometrialcancer(seesection4.4),endometrialhyperplasiaorincreaseinsizeofuterine

fibroids*

Insomnia

Epilepsy

LibidodisorderNOS(nototherwisespecified)

Deteriorationofasthma

Probabledementia(seesection4.4)

*Innon-hysterectomisedwomen

4.9Overdose

Overdosagemaybemanifestedbynauseaandvomiting.Thereisnospecificantidoteandtreatmentshouldbe

symptomatic.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcode:G03CA03

Oestrogen–onlyproductforcontinuoushormonereplacementtherapy(HRT).

Theactiveingredient,synthetic17ß-estradiol,ischemicallyandbiologicallyidenticaltoendogenoushuman

oestradiol.Itsubstitutesforthelossofoestrogenproductioninmenopausalwomen,andalleviatesmenopausal

symptoms.Reliefofmenopausalsymptomsisachievedduringthefirstfewweeksoftreatment.

Endogenous17ß-estradiolinducesandmaintainstheprimaryandsecondarysexualcharacteristics.Thebiological

effectof17ß-estradioliscarriedoutthroughanumberofspecificestrogenreceptors.Thesteroidreceptorcomplexis

boundtothecell’sDNAandinducessynthesisofspecificproteins

17-oestradiolincreasesSHBG-BC(sex-hormone-binding-globulinbindingcapacity)andCBG-BC(corticosteroid-

binding-globulinbindingcapacity).ThegonadotrophinsFSH(folliclestimulatinghormone)andLH(luteinizing

hormone)aresuppressed.`

5.2Pharmacokineticproperties

NovoNordisk’sorallyadministeredmicronised17-oestradiolascontainedinEstrofemisrapidlyandefficiently

absorbedfromthegastrointestinaltract,reachingapeakplasmaconcentrationofapproximately44pg/ml(range30-53

pg/ml)within6hoursafterintakeof2mg.17-oestradiolhasahalflifeofapproximately18hours.Morethan90%of

17-oestradiolisboundtoplasmaproteins.

17-oestradiolisoxidisedtooestrone,whichinturnisconvertedtooestronesulphate.Bothtransformationstakeplace

mainlyintheliver.Oestrogensareexcretedintothebileandthenundergoreabsorptionfromtheintestine.

Duringthisenterohepaticcirculation,degradationoccurs.17-oestradiolanditsmetabolitesareexcretedintheurine

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/07/2010 CRN 2067320 page number: 9

5.3Preclinicalsafetydata

Acutetoxicityofoestrogensislow.Becauseofmarkeddifferencesbetweenanimalspeciesandhumanspreclinical

resultspossessalimitedpredictivevaluefortheapplicationofoestrogenstohumans.

Inexperimentalanimalsestradiolorestradiolvaleratedisplayedanembryolethaleffectatrelativelylowdoses;

malformationoftheurogenitaltractandfeminisationofmalefoetuseswereobserved.

Preclinicaldatabasedonconventionalstudiesofrepeateddosetoxicity,genotoxicityandcarcinogenicpotential

revealednoparticularhumanriskbeyondthosediscussedinothersectionsoftheSPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

Hydroxypropylcellulose

Talc

Magnesiumstearate

Hypromellose

Redironoxide(E172)

Titaniumdioxide(E171)

Propyleneglycol

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

4years.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Storeintheoriginalpackageinordertoprotectfromlight.Donotrefrigerateorfreeze.

6.5Natureandcontentsofcontainer

Calendarpackwith28tabletsconsistsofthefollowingthreeparts:

Thebasemadeofcoloured,non-transparentpolypropylene.

Thering-shapedlidmadeoftransparentpolystyrene.

Thecentre-dialmadeofwhitenon-transparentpolystyrene.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/07/2010 CRN 2067320 page number: 10

7MARKETINGAUTHORISATIONHOLDER

NovoNordiskA/S

NovoAlle

DK-2880Bagsvaerd

Denmark

8MARKETINGAUTHORISATIONNUMBER

PA0218/050/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 06February1998

Dateoflastrenewal: 06February2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 20/07/2010 CRN 2067320 page number: 11