ESTALIS 50/ 250

Main information

  • Trade name:
  • ESTALIS 50/ 250
  • Dosage:
  • 50/ 250 Microgram/ day
  • Pharmaceutical form:
  • Transdermal Patch
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ESTALIS 50/250
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0013/095/001
  • Authorization date:
  • 16-10-1998
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0013/095/001

CaseNo:2041044

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

NovartisPharmaceuticalsLtd

FrimleyBusinessPark,Frimley,Camberley,Surrey,GU167SR,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Estalis50micrograms/250micrograms/24hours,transdermalpatch

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom06/03/2008.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 24/03/2009 CRN 2041044 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Estalis50micrograms/250micrograms/24hours,transdermalpatch

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachEstalis50micrograms/250micrograms/24hourstransdermalpatchcontainsestradiolhemihydrateequivalentto

0.51mgestradioland4.80mgnorethisteroneacetateinapatchof16cm 2

,releasingnominal50microgramsestradiol

and250microgramsnorethisteroneacetateper24hours.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Transdermalpatch.

Translucentroundpatcheswithapolymericbackingononesideandareleaselinerontheotherside,packed

individuallyinheat-sealedpouches.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Estalis50micrograms/250micrograms/24hoursisindicatedfor:

Hormonereplacementtherapy(HRT)foroestrogendeficiencysymptomsinpostmenopausalwomen.

Preventionofosteoporosisinpostmenopausalwomenathighriskoffuturefractureswhoareintolerantof,or

contraindicatedfor,othermedicinalproductsapprovedforthepreventionofosteoporosis.

Treatmentisintendedforwomenmorethanoneyearpostmenopause.

Theexperienceoftreatingwomenolderthan65yearsislimited

4.2Posologyandmethodofadministration

Estalis50micrograms/250micrograms/24hoursisacontinuouscombinedhormonereplacementtherapyfor

transdermaluse.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

duration(seesection4.4)shouldbeused.

Initiationoftherapy

Thetreatmentregimenmaybeinitiatedatanyconvenienttimeformenopausalwomenwhoarenotcurrentlyusingany

oestrogen/progestogentherapy.

Womenwhoarealreadyusingcontinuouscombinedoestrogen/progestogentherapymaybeswitchedtoEstalis50

micrograms/250micrograms/24hoursdirectly.

Womencurrentlyusingcyclicorsequentialoestrogen/progestogentherapyshouldcompletetheon-goingtreatment

cyclebeforetreatmentwithEstalis50micrograms/250micrograms/24hoursisinitiated.Theappropriatetimetobegin

treatmentwithEstalis50micrograms/250micrograms/24hourswouldbethefirstdayofawithdrawalbleedingor

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Estalisregimen

Estalis50micrograms/250micrograms/24hoursisusedasacontinuoustreatment(uninterruptedapplicationtwice

weekly).Onetransdermalpatchisappliedtotheskinoftheabdomenevery3to4days.

Estalis50micrograms/250micrograms/24hoursislesssuitabletowomenwhoareclosetomenopauseastheriskfor

irregularbleedingisthenincreased.

Womenshouldbeadvisedthatirregularbleedingmayoccurinthefirstfewmonthsoftreatment,usuallybefore

amenorrhoeaisestablished.

Methodofadministration

CareshouldbeexercisedwhenapplyingEstalis50micrograms/250micrograms/24hours.Itmustneverbeplacedon

ornearthebreasts.Itshouldbeplacedonaclean,dryareaoftheabdomenwhichisnotirritatedorabradedandnot

oily(i.e.shouldnotbeusedwithanymoisteningcream,lotionoroil).Thewaistlineshouldbeavoided,sincetight

clothingmayrubthepatchoff.

Thesitesofapplicationshouldbechangedwithanintervalofatleastoneweekallowedbetweenapplicationstoa

particularsite.

Afteropeningthepouch,removeonehalfoftheprotectiveliner,takingcarenottotouchtheadhesivepartofthe

transdermalpatchwiththefingers.Applythetransdermalpatchtotheskinimmediately.Removethesecondhalfofthe

protectiveliner.Pressthetransdermalpatchfirmlytotheskinwiththepalmofthehandforatleast10seconds,

carefullysmoothingdowntheedges.

Careshouldbetakenduringbathingandotheractivitiestoensurethatthepatchdoesnotbecomedislodged.Ifthe

transdermalpatchfallsoff(afterstrenuousphysicalactivity,excessivesweatingorfrictionfromtightclothing),the

sametransdermalpatchmaybereappliedtoanotherarea.Theoriginaltreatmentshouldbethereafterfollowed,i.e.the

transdermalpatchshouldbeexchangedonthesamedaysasbefore.

Onceinplace,thepatchshouldnotbeexposedtothesunforprolongedperiodsoftime.

Shouldapatientforgettoapplyapatch,sheshouldapplyanewpatchassoonaspossible.Thesubsequentpatchshould

beappliedaccordingtotheoriginaltreatmentschedule.Theinterruptionoftreatmentmightincreasethelikelihoodof

recurrenceofsymptomsandirregularbleedingandspotting.

Shouldanyadhesiveremainafterremovalofthetransdermalpatch,theskinareashouldbegentlyrubbedwithanoil-

basedcreamorlotion.

4.3Contraindications

Estalis50micrograms/250micrograms/24hoursshouldnotbeusedbywomenwithanyofthefollowingconditions:

Known,pastorsuspectedbreastcancer

Knownorsuspectedoestrogen-dependentmalignanttumors(e.g.endometrialcancer)

Undiagnosedgenitalbleeding

Untreatedendometrialhyperplasia

Previousidiopathicorcurrentvenousthromboembolism(deepvenousthrombosis,pulmonaryembolism)

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfarction)

Hypersensitivitytotheactivesubstancesortoanyoftheexcipients(seesection6.1)

Acuteliverdisease,orahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal

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4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk.

Medicalexamination/follow-up

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythesections4.3and4.4.Duringtreatment,

periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.Womenshouldbe

advisedwhatchangesintheirbreastsshouldbereportedtotheirdoctorornurse(see“Breastcancer”below).

Investigations,includingmammography,shouldbecarriedoutinaccordancewithcurrentlyacceptedscreening

practices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviouslyand/orhavebeenaggravatedduringpregnancy

orprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthatthese

conditionsmayrecurorbeaggravatedduringtreatmentwithEstalis50micrograms/250micrograms/24hours,in

particular:

Leiomyoma(uterinefibroids)orendometriosis

Ahistoryof,orriskfactorsforthromboembolicdisorders(seebelow)

Risksfactorsforoestrogendependenttumours,e.g.1 st

degreeheredityforbreastcancer

Hypertension

Liverdisorders(e.g.liveradenoma)

Diabetesmellituswithorwithoutvascularinvolvement

Cholelithiasis

Migraineorsevereheadache

Systemiclupuserythematosus

Ahistoryofendometrialhyperplasia(seebelow)

Epilepsy

Asthma

Otosclerosis

Reasonsforimmediatewithdrawaloftherapy

Therapyshouldbediscontinuedincaseacontraindicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction

Significantincreaseinbloodpressure

Newonsetofmigraine-likeheadache

Pregnancy

Endometrialhyperplasia

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenoestrogensareadministratedaloneforprolonged

periods(seesection4.8).Theadditionofaprogestogenforatleast12dayspercycleinnon-hysterectomisedwomen

greatlyreducesthisrisk.

Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-throughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshouldbe

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Breastcancer

Arandomisedplacebo-controlledtrial,theWomen’sHealthInitiativestudy(WHI),andepidemiologicalstudies,

includingtheMillionWomenStudy(MWS)havereportedanincreasedriskofbreastcancerinwomentaking

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

anexcessriskbecomesapparentwithinafewyearsofuseandincreaseswithdurationofintakebutreturnstobaseline

withinafew(atmostfive)yearsafterstoppingtreatment.

IntheMWS,therelativeriskofbreastcancerwithconjugatedequineestrogens(CEE)orestradiol(E2)wasgreater

whenaprogestogenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeofprogestogen.Therewas

noevidenceofadifferenceinriskbetweenthedifferentroutesofadministration.

IntheWHIstudy,thecontinuouscombinedconjugatedequineoestrogenandmedroxyprogesteroneacetate(CEE+

MPA)productusedwasassociatedwithbreastcancersthatwereslightlylargerinsizeandmorefrequentlyhadlocal

lymphnodemetastasescomparedtoplacebo.

HRT,especiallyoestrogen-progestogencombinedtreatment,increasesthedensityofmammographicimageswhich

mayadverselyaffecttheradiologicaldetectionofbreastcancer.

Venousthromboembolism

HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism(VTE),i.e.deepvein

thrombosisorpulmonaryembolism.Onerandomisedcontrolledtrialandepidemiologicalstudiesfoundatwo-to

threefoldhigherriskforuserscomparedwithnon-users.Fornon-users,itisestimatedthatthenumberofcasesof

VTEthatwilloccurovera5-yearperiodisabout3per1000womenaged50-59yearsand8per1000womenaged

between60-69years.ItisestimatedthatinhealthywomenwhouseHRTfor5years,thenumberofadditional

casesofVTEovera5yearperiodwillbebetween2and6(bestestimate=4)per1000womenaged50-59years

andbetween5and15(bestestimate=9)per1000womenaged60-69years.Theoccurrenceofsuchaneventis

morelikelyinthefirstyearofHRTthanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalhistoryorfamilyhistory,severeobesity(BMI>30

kg/m 2

)andsystemiclupuserythematosus(SLE).Thereisnoconsensusaboutthepossibleroleofvaricoseveinsin

VTE.

PatientswithahistoryofVTEorknownthrombophilicstateshaveanincreasedriskofVTE.HRTmayaddtothis

risk.Personalorstrongfamilyhistoryofthromboembolismorrecurrentspontaneousabortionshouldbe

investigatedinordertoexcludeathrombophilicpredisposition.Untilathoroughevaluationofthrombophilic

factorshasbeenmadeoranticoagulanttreatmentinitiated,useofHRTinsuchpatientsshouldbeviewedas

contraindicated.Thosewomenalreadyonanticoagulanttreatmentrequirecarefulconsiderationofthebenefit-risk

ofuseofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajorsurgery.As

inallpostoperativepatients,scrupulousattentionshouldbegiventoprophylacticmeasurestopreventVTE

followingsurgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,particularlyabdominalor

orthopaedicsurgerytothelowerlimbs,considerationshouldbegiventotemporarilystoppingHRT4to6weeks

earlier,ifpossible.Treatmentshouldnotberestarteduntilthewomaniscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorimmediatelywhentheyareawareofapotentialthromboembolicsymptom(eg,painfulswellingofaleg,

suddenpaininthechest,dyspnoea).

Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombined

conjugatedoestrogensandmedroxyprogesteroneacetate(MPA).Twolargeclinicaltrials(WHIandHERSi.e.

HeartandEstrogen/progestinReplacementStudy)showedapossibleincreasedriskofcardiovascularmorbidityin

thefirstyearofuseandnooverallbenefit.ForotherHRTproductsthereareonlylimiteddatafromrandomised

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Therefore,itisuncertainwhetherthesefindingsalsoextendtootherHRTproducts.

Stroke

Onelargerandomisedclinicaltrial(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischemicstroke

inhealthywomenduringtreatmentwithcontinuouscombinedconjugatedoestrogensandMPA.Forwomenwho

donotuseHRT,itisestimatedthatthenumberofcasesofstrokethatwilloccurovera5-yearperiodisabout3per

1000womenaged50-59yearsand11per1000womenaged60-69years.Itisestimatedthatforwomenwhouse

conjugatedoestrogensandMPAfor5years,thenumberofadditionalcaseswillbebetween0and3(bestestimate

=1)per1000usersaged50-59yearsandbetween1and9(bestestimate=4)per1000usersaged60-69years.Itis

unknownwhethertheincreasedriskalsoextendstootherHRTproducts.

Ovariancancer

Long-term(atleast5to10years)useofoestrogen-onlyHRTproductsinhysterectomisedwomenhasbeen

associatedwithanincreasedriskofovariancancerinsomeepidemiologicalstudies.Itisuncertainwhetherlong-

termuseofcombinedHRTconfersadifferentriskthanoestrogen-onlyproducts.

Otherconditions

Oestrogensmaycausefluidretentionandthereforewomenwithcardiacorrenaldysfunctionshouldbecarefully

observed.Womenwithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitisexpectedthatthelevelof

circulatingactiveingredientsofEstalis50micrograms/250micrograms/24hoursisincreased.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringoestrogenreplacementorhormone

replacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitishavebeen

reportedwithoraloestrogentherapyinthiscondition.

Oestrogensincreasethyroidbindingglobulin(TBG),leadingtoincreasedcirculatingtotalthyroidhormone,as

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

immunoassay).T3resinuptakeisdecreased,reflectingtheelevatedTBG.FreeT4andfreeT3concentrationsare

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

bindingglobulin(SHBG)leadingtoincreasedcirculatingcorticosteroidsandsexsteroids,respectively.Freeor

biologicalactivehormoneconcentrationsareunchanged.Otherplasmaproteinsmaybeincreased

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

Thereisnoconclusiveevidenceforimprovementofcognitivefunction.ThereissomeevidencefromtheWHItrial

ofincreasedriskofprobabledementiainwomenwhostartusingcontinuouscombinedCEEandMPAaftertheage

of65.ItisunknownwhetherthefindingsapplytoyoungerpostmenopausalwomenorotherHRTproducts.

Contactsensitisationisknowntooccurwithalltopicalapplications.Althoughitisextremelyrare,womenwhodevelop

contactsensitisationtoanyofthecomponentsofthepatchshouldbewarnedthataseverehypersensitivityreaction

mayoccurwithcontinuingexposuretothecausativeagent.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Themetabolismofoestrogensandprogestogensmaybeincreasedbyconcomitantuseofsubstancesknowntoinduce

drug-metabolisingenzymes,specificallycytochromeP450enzymes,suchasanticonvulsants(e.g.phenobarbital,

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

nelfinavir,althoughknownasstronginhibitors,bycontrastexhibitinducingpropertieswhenusedconcomitantlywith

steroidhormones.

HerbalpreparationscontainingSt.John’swort(HypericumPerforatum)mayinducethemetabolismofoestrogensand

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Attransdermaladministration,thefirst-passeffectintheliverisavoidedand,thus,transdermallyappliedoestrogens

andprogestogensmightbelessaffectedthanoralhormonesbyenzymeinducers.

Clinically,anincreasedmetabolismofoestrogensandprogestogensmayleadtodecreasedeffectsandchangesinthe

uterinebleedingprofile.

4.6Pregnancyandlactation

Pregnancy

Estalis50micrograms/250micrograms/24hoursisnotindicatedduringpregnancy.Ifpregnancyoccursduring

medicationwithEstalis50micrograms/250micrograms/24hourstreatmentshouldbewithdrawnimmediately.

Dataonalimitednumberofexposedpregnanciesindicatenoadverseeffectsofnorethisteroneacetateonthefoetus.At

doseshigherthannormallyusedinoralcontraceptivesandHRTformulationsmasculinisationoffemalefoetuseswas

observed.

Theresultsofmostepidemiologicalstudiestodaterelevanttoinadvertentfoetalexposuretocombinationsof

oestrogensandprogestogensindicatenoteratogenicorfoetotoxiceffect.

Lactation

Estalis50micrograms/250micrograms/24hoursisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

Noknowneffectontheabilitytodriveandusemachines.

4.8Undesirableeffects

ApproximatelyonethirdofthewomentreatedwithEstalis50micrograms/250micrograms/24hourscanbeexpected

toexperienceadversereactions.Themostcommonlyreportedadverseexperiencesarebreasttensionandpain(31%),

applicationsitereactions(20%mostlymilderythema),dysmenorrhoea(19%),irregularbleeding(12,7%),and

headache(10%).

Table1:

Verycommon( ≥1/10);Common(≥1/100to<1/10);Uncommon(≥1/1,000to<1/100);

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)Adversereactionsassociatedtoestrogenandprogestogenhavebeenfoundtoberelativelylessfrequentwiththe

Investigations

Uncommon Transaminasesincrease

Nervoussystemdisorders

Verycommon

Headache *

Common Dizziness *

,nervousness *

,insomnia *

,moodchanges

Uncommon Migraine,vertigo

Gastrointestinaldisorders

Common

Nausea,abdominaldistension *

,diarrhoea *

,dyspepsia *

,abdominal

pain

Uncommon Vomitting

Skinandsubcutaneoustissuedisorders

Verycommon Applicationsitereactions

Common

Acne *

,rash,pruritus *

,dryskin

Uncommon Skindiscoloration

Musculoskeletalandconnectivetissuedisorders

Common

Backpain *

,paininextremity *

Rare Myasthenia

Vasculardisorders

Uncommon Increaseinbloodpressure,varicoseveins

Rare Venousthromboembolism

Generaldisordersandadministrationsiteconditions

Common

Pain,asthenia,weightchanges *

,peripheraloedema *

Rare Allergicreactions,libidochanges,paraesthesia

Hepatobiliarydisorders

Rare Gallstones,gallbladderdisease

Veryrare Cholestaticjaundice

Reproductivesystemandbreastdisorders

Verycommon

Breastpain *

,breasttenderness,dysmenorrhoea *

,menstrual

disorder *

Common

Breastenlargement *

,menorrhagia *

,leucorrhoea *

,irregularvaginal

bleeding,uterinespasms,vaginitis,endometrialhyperplasia

Uncommon Breastcancer

Rare Uterineleiomyomata,paratubularcysts,endocervicalpolyps

Psychiatricdisorders

Common

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Breastcancer

Accordingtoevidencefromalargenumberofepidemiologicalstudiesandonerandomisedplacebo-controlledtrial,the

Women’sHealthInitiative(WHI),theoverallriskofbreastcancerincreaseswithincreasingdurationofHRTusein

currentorrecentHRTusers.

Foroestrogen-onlyHRT,estimatesofrelativerisk(RR)fromareanalysisoforiginaldatafrom51epidemiological

studies(inwhich>80%ofHRTusewasoestrogen-onlyHRT)andfromtheepidemiologicalMillionWomenStudy

(MWS)aresimilarat1.35(95%CI1.21–1.49)and1.30(95%CI1.21–1.40),respectively.

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%CI1.25-1.68).TheWHItrialreportedariskestimateof

1.24(95%CI1.01–1.54)after5.6yearsofuseofoestrogen-progestogencombinedHRT(CEE+MPA)inallusers

comparedwithplacebo.

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,an

additional8casesofinvasivebreastcancerwouldbeduetooestrogen-progestogencombinedHRT(CEE+MPA)

per10,000womenyears.

Accordingtocalculationsfromthetrialdata,itisestimatedthat:

For1000womenintheplacebogroup,about16casesofinvasivebreastcancerwouldbediagnosedin5years.

For1000womenwhousedoestrogen+progestogencombinedHRT(CEE+MPA),thenumberofadditional

caseswouldbebetween0and9(bestestimate=4)for5years’use.

ThenumberofadditionalcasesofbreastcancerinwomenwhouseHRTisbroadlysimilarforwomenwhostart

HRTirrespectiveofageatstartofuse(betweentheagesof45-65)(seesection4.4).

Endometrialcancer

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandendometrialcancerincreaseswith

increasingdurationofuseofunopposedoestrogens.Accordingtodatafromepidemiologicalstudies,thebest

estimateoftheriskisthatforwomennotusingHRT,about5inevery1000areexpectedtohaveendometrial

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Dependingonthedurationoftreatmentandoestrogendose,thereportedincreaseinendometrialcancerriskamong

unopposedoestrogenusersvariesfrom2-to12-foldgreatercomparedwithnon-users.Addingaprogestogento

oestrogen-onlytherapygreatlyreducesthisincreasedrisk.

Otheradversereactionshavebeenreportedinassociationwithoestrogen-progestogentreatment:

Oestrogen-dependentneoplasmsbenignandmalignant,e.g.endometrialcancer.

Venousthromboembolism,i.e.deeplegorpelvicvenousthrombosisandpulmonaryembolism,ismorefrequent

amonghormonereplacementtherapyusersthanamongnon-users(seesection4.3andsection4.4).

Myocardialinfarctionandstroke.

Gallbladderdisease.

Skinandsubcutaneousdisorders:chloasma,erythemamultiform,erythemanodosum,vascularpurpura.

Probabledementia(seesection4.4).

4.9Overdose

Duetothemodeofadministration,overdoseofestradiolornorethisteroneisunlikelytooccur.Ifsignsofoverdose

appeartheEstalis50micrograms/250micrograms/24hourstransdermalpatchshouldberemoved.Theeffectsof

overdosagewithoraloestrogensarebreasttenderness,nausea,vomitingand/ormetrorrhagia.Overdosageof

progestogensmayleadtoadepressivemood,fatigue,acneandhirsutism.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Genitourinarysystemandsexhormones

ATCcode:G03FA01.

Theactiveingredient,estradiolhemihydrate,asynthetic17-estradiol,ischemicallyandbiologicallyidenticalto

endogenoushumanestradiol.Itsubstitutesforthelossofoestrogenproductioninmenopausalwomen,andalleviates

menopausalsymptoms.

Oestrogenspreventbonelossfollowingmenopauseorovariectomy.

Asoestrogenspromotethegrowthoftheendometrium,unopposedoestrogensincreasetheriskofendometrial

hyperplasiaandcancer.Theadditionofnorethisteroneacetate,aprogestogen,reducestheoestrogen-inducedriskof

endometrialhyperplasiainnon-hysterectomisedwomen.

Informationfromclinicaltrials

Reliefofoestrogen-deficiencysymptomsandbleedingpatterns

Reliefofmenopausalsymptomswasachievedduringthefirstfewweeksoftreatment.

Amenorrhoeawasseenin38%ofthewomenduringmonths10-12treatment.Bleedingand/orspottingappearedin77

%ofthewomenduringthefirstthreemonthsoftreatmentandin62%duringmonths10-12oftreatment.

Preventionofosteoporosis

Oestrogendeficiencyatmenopauseisassociatedwithanincreasingboneturnoveranddeclineinbonemass.Theeffect

ofoestrogensonthebonemineraldensityisdose-dependent.Protectionappearstobeeffectiveforaslongastreatment

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EvidencefromtheWHItrialandmeta-analysedtrialsshowsthatcurrentuseofHRT,aloneorincombinationwitha

progestogen–giventopredominantlyhealthywomen–reducestheriskofhip,vertebral,andotherosteoporotic

fractures.HRTmayalsopreventfracturesinwomenwithlowbonedensityand/orestablishedosteoporosis,butthe

evidenceforthatislimited.

AftertwoyearsoftreatmentwithEstalis50microgram/250microgram/24hours,theincreaseinlumbarspinebone

mineraldensity(BMD)was5.53%±0.63%(mean±SD).ThepercentageofwomenwhomaintainedorgainedBMD

inlumbarzoneduringtreatmentwas95.0%.

Estalis50micrograms/250micrograms/24hoursalsohadaneffectonhipBMD.Theincreaseaftertwoyearswas

3.07%±0.64%(mean±SD)atfemoralneckand3.12%±0.46%(mean±SD)attotalhip.

5.2Pharmacokineticproperties

Absorption

Transdermallydeliveredestradiolbypassesthefirstpasseffectseenwithorallyadministeredoestrogenproducts.

Estradiol:Estalis50microgram/250microgram/24hourstransdermalpatchachievesestradiolserumlevelsand

oestrone/oestradiolratiosintherangeofthoseobservedinpremenopausalwomenattheearly(oestradiol>40pg/ml)to

mid-follicularphase.Thesefeaturesaremaintainedforanentire84to96hourwearperiod.Multipleapplicationsofthe

transdermalpatchresultedinsteadystatemaximumestradiolserumconcentration(C

)of71pg/mlandaverage

estradiolserumconcentration(C

)of52pg/ml.Attheendoftheapplicationperiods,themeanestradiolserum

concentrations(troughconcentration)was46pg/ml.

Norethisteroneacetate:Multipleapplicationsofthetransdermalpatchresultedinsteadystatemaximumnorethisterone

concentration(C

)of1060pg/mlandaverageserumnorethisteroneconcentration(C

)of832pg/ml.Attheendof

theapplicationperiod,themeannorethisteroneserumconcentrations(troughconcentration)was681pg/ml.

Metabolismandelimination

Estradiol:Estradiolhasashorteliminationhalf-lifeofapproximately2to3hours,therefore,arapiddeclineinserum

levelsisobservedafterthetransdermalpatchisremoved.Afterremovalofthetransdermalpatch,serumconcentrations

ofestradiolreturntountreatedpostmenopausallevels(<20pg/ml)within4to8hours.

Norethisterone:Theeliminationhalf-lifeofnorethisteroneisreportedtobe6to8hours.Afterremovalofthe

transdermalpatch,norethisteroneserumconcentrationsdiminishrapidlyandarelessthan<50pg/mlwithin48hours.

Minimalfluctuationsinserumestradiolandnorethisteroneconcentrationsdemonstrateconsistentdeliveriesoverthe

applicationinterval.

Thereisnoaccumulationofestradiolornorethisteroneinthecirculationfollowingmultipleapplications.

5.3Preclinicalsafetydata

Acutetoxicityofestrogensislow.Becauseofmarkeddifferencesbetweenanimalspeciesandbetweenanimalsand

humanspreclinicalresultspossessalimitedpredictivevaluefortheapplicationofestrogensinhumans.

Inexperimentalanimalsestradiolorestradiolvaleratedisplayedanembryolethaleffectalreadyatrelativelylowdoses;

malformationsoftheurogenitaltractandfeminisationofmalefoetuseswereobserved.

Norethisterone,likeotherprogestogens,causedvirilisationoffemalefoetusesinratsandmonkeys.Afterhighdosesof

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Non-clinicaldatabasedonconventionalstudiesofrepeateddosetoxicity,genotoxicityandcarcinogenicpotential

revealednoparticularhumanrisksbeyondthosediscussedinothersectionsoftheSPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Siliconeadhesives

Acrylicadhesives

Povidone

Oleicacid

Dipropyleneglycol.

Thebackinglayerconsistsofapolyesterfilmlaminate.Theprotective(release)linerisafluoropolymercoated

polyesterfilm.

6.2Incompatibilities

Notapplicable

6.3ShelfLife

30months;

24monthsstoredinarefrigerator(2°Cto8°C)plus6monthsstoredbelow25°C.

6.4Specialprecautionsforstorage

Storeandtransportrefrigerated(2°C-8°C).Donotfreeze.Oncedispensedtothepatient,Estalis50micrograms/250

micrograms/24hoursmaybestoredbelow25°Cforamaximumperiodof6months.Storeintheoriginal(sealed)

pouch.Eachpatchshouldbeusedimmediatelyafteropeningthepouch.

6.5Natureandcontentsofcontainer

Estalis50micrograms/250micrograms/24hourstransdermalpatchesarepackedindividuallyinheat-sealed

paper/polyethylenesachets.

Estalis50micrograms/250micrograms/24hourspackconsistsof2,8or24roundtransdermalpatches.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Usedpatchesshouldbefoldedinhalfwithadhesivesurfacespressedtogetheranddiscardedsafelyandawayfromthe

reachandsightofchildren.

7MARKETINGAUTHORISATIONHOLDER

NovartisPharmaceuticalsLimited

FrimleyBusinessPark

Frimley

Camberley

SurreyGU167SR

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8MARKETINGAUTHORISATIONNUMBER

PA13/95/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:16 th

October1998

Dateoflastrenewal:6 th

March2008

10DATEOFREVISIONOFTHETEXT

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