ESTRACOMBI TTS

Main information

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

Documents

Localization

  • Available in:
  • ESTRACOMBI TTS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0013/075/001
  • Authorization date:
  • 25-03-1993
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EstracombiTTSTransdermalPatches.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EstracombiTTSiscomprisedofanEstradermTTS50patchandanEstragestTTSpatch.

EstradermTTSsystemcontains4mgestradiol(ashemihydrate)withanabsorptionrateofapproximately50

microgramsofestradiolperdayfromadrugreleasingareaof10cm 2

EstragestTTSsystemcontains10mgestradiol(ashemihydrate)and30mgnorethisteroneacetate.The

absorptionratesfromthesystemareapproximately50microgramsofestradiolperdayand250microgramsof

norethisteroneacetateperdayfromadrugreleasingareaof20cm 2

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

TransdermalPatch.

EstradermTTS50:aself-adhesive,circular,transparent,transdermaltherapeuticsystem(patch)marked‘CGDWD’.

EstragestTTS:aself-adhesive,goggle-shaped,transparent,transdermaltherapeuticsystem(patch)marked‘CGFNF’.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Ashormonereplacementtherapyinpatientswithanintactuterusandwithdisordersduetonaturalorsurgically

inducedmenopause.

Preventionofosteoporosisinpostmenopausalwomenathighriskoffuturefractureswhoareintolerantof,or

contraindicatedfor,othermedicinalproductsapprovedforthepreventionofosteoporosis.

4.2Posologyandmethodofadministration

Dosage

Adultsandelderly:Forinitiationandcontinuationoftreatmentofpost-menopausalsymptoms,thelowesteffective

dosefortheshortestduration(seealsosection4.4,Specialwarningsandprecautionsforuse)shouldbeused.

EstracombiTTSprovidescontinuousoestrogenandsequentialprogestogentherapytowomenwithanintactuterus.

OnetreatmentcycleofEstracombiTTSconsistsof4patchesoftransdermalestradiol(EstradermTTS50)followedby

4patchesoftransdermalestradiolandnorethisteroneacetate(Estragest250/50).Therapyisstartedwithtransdermal

estradiol(EstradermTTS50)whichshouldbeappliedtwiceweeklyfor2weeks,i.e.thepatchshouldbechangedonce

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Forthefollowing2weeks,onetransdermalestradiolplusnorethisteroneacetatepatch(EstragestTTS)shouldbe

appliedtwiceweekly.ThenexttreatmentcycleshouldbestartedwithEstradermTTS50immediatelyafterrenewalof

thelastEstragestTTS(50/250)patch.

Eachfreshpatchshouldbeappliedtoaslightlydifferentsite.Recommendedapplicationsitesareclean,dryandintact

areasofskinonthetrunkbelowthewaistline.Thesiteselectedshouldbeoneatwhichlittlewrinklingoftheskin

occursduringmovementofthebody,e.g.buttock,hip,abdomen.

Ifawomenhasforgottentoapplyapatch,sheshouldapplyanewpatchassoonaspossible.Thesubsequentpatch

shouldbeappliedaccordingtotheoriginaltreatmentschedule.Theinterruptionoftreatmentmightincreasethe

likelihoodofrecurrenceofsymptomsandbreakthroughbleedingandspotting.

Experiencetodatehasshownthatlessirritationoftheskinoccursonthebuttocksthatatothersitesofapplicationand

thissiteispreferredbypatients.ItisthereforerecommendedtoapplyEstracombiTTStothebuttock.EstracombiTTS

shouldNOTbeappliedonornearthebreasts.Thepatchshouldnotbeaffixedtwiceinsuccessiontothesameskin

site.

EstracombiTTSincorporatesacombinedestrogenandprogestogenpatchtoinducewithdrawalbleeding,thereby

minimisingtheriskofendometrialhyperplasiaandcarcinoma,whichcanoccurwithunopposedestrogentherapy.

Mostpatientswillbleedtowardstheendofprogestogentherapy.Afewpatientswillexperienceamenorrhoea.The

firsttransdermalpatchofthenewcycleshouldbeappliedirrespectiveofthedurationofbleeding.Itisimportantthat

thepatchesbeusedinthecorrectsequencei.e.2weeksEstradermTTS50followedby2weeksEstragestTTSeach

cycle,toensureregularcyclicbleeding.

FormostpostmenopausalwomenEstracombiTTStherapymaybestartedatanyconvenienttime.However,ifthe

patientisstillmenstruatingcommencementwithin5daysoftheonsetofbleedingisrecommended.

Somebreakthroughbleedingorspottingmaybeseenuntiltherapyhasbecomeestablished.Someeffects,usuallyof

estrogenicorigin,e.g.breastdiscomfort,waterretentionorbloating,areoftenobservedatthestartoftreatment,

especiallyinpatientsreceivinghormonereplacementtherapyforthefirsttime.Howeverifsymptomspersistformore

than6weeks,treatmentshouldbereconsidered.

Thepatchshouldnotbeexposedtosunlight.

Theuseofcreams,oilsorlotionsshouldbeavoidedsincethesemayreducepatchadhesion.

4.3Contraindications

EstracombiTTSshouldnotbeusedbywomenwithanyofthefollowingconditions:

Known,pastorsuspectedbreastcancer,

Knownorsuspectedoestrogen-dependentmalignanttumours(e.g.endometrialcancer),

Undiagnosedabnormalvaginalbleeding,

Untreatedendometrialhyperplasia,

Previousidiopathicorcurrentvenousthromboembolism(VTE)

(deepvenousthrombosis,pulmonaryembolism),

Activeorrecentarterialthromboembolicdisease(e.g.anginaormyocardialinfarction)

Acuteliverdisease,orahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal,

Knownhypersensitivitytotheactivesubstance,oranyoftheexcipients,

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4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbetakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk.

Medicalexamination/follow-up:

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythecontraindicationsandwarningsforuse.

Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.

Womenshouldbeadvisedwhatchangesintheirbreastsshouldbereportedtotheirdoctorornurse(see‘BreastCancer’

below).Investigations,includingmammography,shouldbecarriedoutinaccordancewithcurrentlyaccepted

screeningpractices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision:

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviously,and/oraggravatedduringpregnancyor

previoushormonetreatment,thepatientshouldbecloselysupervised.

Leiomyoma(uterinefibroids)orendometriosis

Ahistoryof,orriskfactorsfor,thromboembolicdisorders(seebelow)

Riskfactorsforoestrogendependenttumours,e.g.1 st

degreeheredityforbreastcancer.

Hypertension

Liverdisorders(e.g.liveradenoma)

Diabetesmellituswithorwithoutvascularinvolvement

Cholelithiasis

Migraineor(severe)headache

Systemiclupuserythematosus

Ahistoryofendometrialhyperplasia(seebelow)

Epilepsy

Asthma

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Reasonsforimmediatewithdrawaloftherapy:

Therapyshouldbediscontinuedincaseacontraindicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction

Significantincreaseinbloodpressure

Newonsetofmigraine-typeheadache

Pregnancy

Osteoporosis

WheninitiatingHRTforthepreventionofosteoporosis,carefulconsiderationshouldbegiventothebenefitsversusthe

risksfortheindividual.Potentialalternativetherapiesshouldbeconsiderediftherisksoutweighthebenefits.Periodic

re-evaluationforcontinuingtreatmentisrecommended.

Contactsensitisation

Contactsensitisationisknowntooccurwithalltopicalapplications.Althoughitisextremelyrare,womenwho

developcontactsensitisationtoanyofthecomponentsofthepatchshouldbewarnedthataseverehypersensitivity

reactionmayoccurwithcontinuingexposuretothecausativeagent.

Coronaryarterydisease(CAD)

HRTshouldnotbeusedtopreventcardiovasculardisease.Thereisnoevidencefromrandomisedcontrolledtrialsof

cardiovascularbenefitwithcontinuouscombinedconjugatedoestrogensandMPA.Twolargeclinicaltrials(WHIi.e.

Women’sHealthInitiativeandHERSi.e.HeartandEstrogen/ProgestinReplacementStudy)showedapossible

increasedriskofcardiovascularmorbidityinthefirstyearofuseandnooverallbenefit.

Fortransdermaloestrogen-onlyandoestrogen-progestogencombinedHRTproducts,thereareonlylimiteddatafrom

randomisedcontrolledtrialstodateassessingtheHRT-associatedriskofcardiovascularmorbidityormortality.

Therefore,itisuncertainwhetherthesefindingsalsoextendtoEstracombi.

Stroke

Onelargerandomisedclinicaltrial(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischaemicstrokein

healthywomenduringtreatmentwithcontinuouscombinedconjugatedoestrogensandMPA.Forwomenwhodonot

useHRT,itisestimatedthatthenumberofcasesofstrokethatwilloccuroverafiveyearperiodisabout3per1000

womenaged50-59yearsand11per1000womenaged60-69years.Itisestimatedthatforwomenwhouseconjugated

oestrogensandMPAfor5years,thenumberofadditionalcaseswillbebetween0and3(bestestimate=1)per1000

usersaged50-59yearsandbetween1and9(bestestimate=4)per1000usersaged60-69years.

Fortransdermaloestrogen-onlyandoestrogen-progestogencombinedHRTproducts,therearenorandomised

controlledtrialstodateassessingtheHRT-associatedriskofcardiovascularmorbidityormortality.Therefore,there

arenodatatosupporttheconclusionthatthefrequencyofstrokeisdifferentwithEstracombi.

Venousthromboembolism(VTE)

HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism(VTE),i.e.deepveinthrombosis

orpulmonaryembolism.

Onerandomisedcontrolledtrialandepidemiologicalstudiesfoundatwotothreefoldhigherriskforuserscompared

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Fornon-users,itisestimatedthatthenumberofcasesofVTEthatwilloccurovera5yearperiodisabout3per1000

womenaged50-59yearsand8per1000womenagedbetween60-69years.Itisestimatedthatinhealthywomenwho

useHRTfor5years,thenumberofadditionalcasesofVTEovera5yearperiodwillbebetween2and6(bestestimate

=4)per1000womenaged50-59yearsandbetween5and15(bestestimate=9)per1000womenaged60-69years.

TheoccurrenceofsuchaneventismorelikelyinthefirstyearofHRTusethanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalhistoryorfamilyhistory,severeobesity(BMI>30

kg/m 2

)andsystemiclupuserythematosus(SLE).Thereisnoconsensusaboutthepossibleroleofvaricoseveinsin

VTE.

PatientswithahistoryofVTEorknownthrombophilicstateshaveanincreasedriskofVTE.HRTmayaddtothis

risk.Personalorstrongfamilyhistoryofthromboembolismorrecurrentspontaneousabortionshouldbeinvestigated

inordertoexcludeathrombophilicpredisposition.Untilathroughevaluationofthrombophilicfactorshasbeenmade

oranticoagulanttreatmentinitiated,useofHRTinsuchpatientsshouldbeviewedascontraindicated.Thosewomen

alreadyonanticoagulanttreatmentrequirecarefulconsiderationofthebenefit-riskofuseofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajorsurgery.Asin

allpostoperativepatients,scrupulousattentionshouldbegiventoprophylacticmeasurestopreventVTEfollowing

surgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,particularlyabdominalororthopaedic

surgerytothelowerlimbs,considerationshouldbegiventotemporarilystoppingHRT4to6weeksearlier,if

possible.Treatmentshouldnotberestarteduntilthewomaniscompletelymobile.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorsimmediatelywhentheyareawareofapotentialthromboembolicsymptom(e.g.painfulswellingofaleg,

suddenpaininthechest,dyspnoea).

BreastCancer

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

includingtheMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentaking

oestrogenoroestrogen-progestogencombinationsortiboloneforHRTforseveralyears(seesection4.8,Undesirable

effects).

ForallHRT,anexcessriskbecomesapparentwithinafewyearsofuseandincreaseswithdurationofintakebut

returnstobaselinewithinafew(atmostfive)yearsafterstoppingtreatment.

InMWS,therelativeriskofbreastcancerwithconjugatedequineoestrogens(CEE)orestradiol(E2)wasgreaterwhen

aprogestogenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeofprogestogen.Therewasno

evidenceofadifferenceinriskbetweenthedifferentroutesofadministration.

IntheWHIstudy,thecontinuouscombinedconjugatedequineoestrogenandmedroxyprogesteroneacetate

(CEE+MPA)productusedwasassociatedwithbreastcancersthatwereslightlylargerinsizeandmorefrequentlyhad

locallymphnodemetastasescomparedtoplacebo.

HRT,especiallyoestrogen-progestagencombinedtreatment,increasesthedensityofmammographicimageswhich

mayadverselyaffecttheradiologicaldetectionofbreastcancer.

EndometrialHyperplasia

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenoestrogensareadministeredaloneforprolonged

periods(seesection4.8,Undesirableeffects).Theadditionofaprogestogenforatleast12dayspercycleinnon-

hysterectomisedwomengreatlyreducesthisrisk.

Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-throughbleedingor

spottingappearsaftersometimeontherapy,orcontinuedaftertreatmenthasbeendiscontinued,thereasonshouldbe

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Unopposedoestrogenstimulationmayleadtopremalignantormalignanttransformationintheresidualfociof

endometriosis.Therefore,theadditionofprogestagenstooestrogensreplacementtherapyshouldbeconsideredin

womenwhohaveundergonehysterectomybecauseofendometriosis,iftheyareknowntohaveresidualendometriosis.

OvarianCancer

Long-term(atleast5–10years)useofoestrogen–onlyHRTproductsinhysterectomisedwomenhasbeenassociated

withanincreasedriskofovariancancerinsomeepidemiologicalstudies.Itisuncertainwhetherlong-termuseof

combinedHRTconfersadifferentriskthanoestrogen-onlyproducts.

Otherconditions

Oestrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.Patientswithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitisexpectedthatthelevelof

circulatingactiveingredientsinEstracombiisincreased.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringoestrogenreplacementtherapyor

hormonaltherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitishavebeenreported

withoraloestrogentherapyinthiscondition.

Estrogensincreasethyroidbindingglobulin(TBG),leadingtoincreasedcirculatingtotalthyroidhormone,asmeasured

byprotein-boundiodine(PBI),T4levels(bycolumnorbyradio-immunoassay)orT3levels(byradio-immunoassay).

T3resinuptakeisdecreased,reflectingtheelevatedTBG.FreeT4andfreeT3concentrationsareunaltered.Other

bindingproteinsmaybeelevatedinserum,i.e.corticoidbindingglobulin(CBG),sex-hormone-bindingglobulin

(SHBG)leadingtoincreasedcirculatingcorticosteroidsandsexsteroids,respectively.Freeorbiologicalactive

hormoneconcentrationsareunchanged.Otherplasmaproteinsmaybeincreased(angiotensinogen/reninsubstrate,

alpha-Iantitrypsin,ceruloplasmin).Withtransdermaladministration,stimulationoftheliverbythefirst-passeffectis

avoidedand,thus,transdermaloestrogensmightaffecthormonebindingproteinsandotherserumproteinsproducedby

theliverlessthanoralhormones.

Thereisnoconclusiveevidenceforimprovementofcognitivefunction.ThereissomeevidencefromtheWHItrialof

increasedriskofprobabledementiainwomenwhostartusingcontinuouscombinedCEEandMPAaftertheageof65.

Itisunknownwhetherthefindingsapplytoyoungerpost-menopausalwomenorotherHRTproducts.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Themetabolismofoestrogensandprogestogensmaybeincreasedbyconcomitantuseofsubstancesknowntoinduce

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

phenytoin,carbamezpine),meprobamate,phenylbutazone,andanti-infectives(e.g.rifampicin,rifabutin,nevirapine,

efavirenz).

Cautionshouldbeusedifthewomanisreceivingproteaseinhibitors(e.g.ritonavirandnelfinavir),whichareknownas

stronginhibitorsofcytochromeP450enzymes,andbycontrastexhibitinducingpropertieswhenusedconcomitantly

withsteroidhormones.

HerbalpreparationscontainingSt.John’sWort(Hypericumperforatum)mayinducethemetabolismofoestrogensand

progestogens.

Clinically,increasedmetabolismofoestrogensandprogestogensmayleadtodecreasedeffectsandchangesinuterine

bleedingprofile.

WithtransdermalHRTadministraion,thefirst-passeffectintheliverisavoidedandthustransdermallyapplied

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4.6Pregnancyandlactation

Pregnancy

EstracombiTTSisnotindicatedduringpregnancy.IfpregnancyoccursduringmedicationwithEstracombitreatment

shouldbewithdrawnimmediately.Theresultsofmostepidemiologicalstudiestodaterelevanttoinadvertentfoetal

exposuretocombinationsofoestrogensandprogestagensindicatenoteratogenicorfoetotoxiceffect.

Lactation

EstracombiTTSmustnotbeusedwhilebreast-feeding.Oestrogensorprogestogensareexcretedinbreastmilkand

mayreducetheproductionofbreastmilk.

4.7Effectsonabilitytodriveandusemachines

Noneknown.

4.8Undesirableeffects

ApproximatelyonethirdofwomentreatedwithEstracombicanbeexpectedtoexperienceadversereactions.Mostof

theseeffectsaremildandtransient.

Themostfrequentlyreportedadversereactions( ≥10%)areheadache,applicationsitereactions,breastpain,breast

tenderness,dysmenorrheaandmenstrualdisorders.

Frequencyestimate:common ≥1%to<10%,uncommon≥0.1%to<1%,rare≥0.01%to<0.1%,veryrare<0.01%.

Nervoussystemdisorders

Common Headache

Rare Dizziness

CardiovascularDisorders

Veryrare Thromboembolicdisorders,

exacerbationofvaricoseveins,

increasesinbloodpressure.

GastrointestinalDisorders

Common Nausea,abdominalcramps,bloating

Veryrare Asymptomaticimpairedliver

function

Skinandsubcutaneoustissuedisorders

Verycommon Transienterythemaandirritationat

thesiteofapplicationwithor

withoutpruritus.

Veryrare Allergiccontactdermatitis,

reversiblepost-inflammatory

pigmentation,generalisedpruritus

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BreastCancer:

Accordingtoevidencefromalargenumberofepidemiologicalstudiesandonerandomisedplacebo-controlledtrial,

theWomen’sHealthInitiative(WHI),theoverallriskofbreastcancerincreaseswithincreasingdurationofHRTuse

incurrentorrecentHRTusers.

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.

ForoestrogenplusprogestagencombinedHRT,severalepidemiologicalstudieshavereportedanoverallhigherrisk

forbreastcancerthanwithoestrogensalone.

TheMWSreportedthat,comparedtoneverusers,theuseofvarioustypesofoestrogen-progestagencombinedHRT

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).

TheWHItrialreportedariskestimateof1.24(95%CI1.01–1.54)after5.6yearsofuseofoestrogen-progestagen

combinedHRT(CEE+MPA)inalluserscomparedwithplacebo.

Theabsoluterisks,calculatedfromtheMWSandtheWHItrial,arepresentedbelow:

TheMWShasestimated,fromtheknownaverageincidenceofbreastcancerindevelopedcountries,that:

ForwomennotusingHRT,about32inevery1000areexpectedtohavebreastcancerdiagnosedbetween

theagesof50and64years.

For1000currentorrecentusersofHRT,thenumberofadditionalcasesduringthecorrespondingperiod

willbe;

Forusersofoestrogen-onlyreplacementtherapy:-

between0and3(bestestimate=1.5)for5years’use

between3and7(bestestimate=5)for10years’use

ForusersofoestrogenplusprogestagencombinedHRT:-

between5and7(bestestimate=6)for5years’use

Reproductivesystemandbreastdisorders

Verycommon Breastdiscomfort(1),breakthrough

bleeding,spotting.

Common Changeinmenstrualflow,

dysmenorrhoea,premenstruallike

syndrome,endometrialhyperplasia

(1.5%)

Uncommon Breastcancer

Generaldisordersandadministration

sitecondition

Rare Oedema,weightchanges,legpain

(2).

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TheWHItrialestimatedthatafter5.6yearsoffollow-upofwomenbetweentheagesof50and79years,anadditional

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

womenyears.

Accordingtocalculationsfromthetrialdata,itisestimatedthat:

For1000womenintheplacebogroup:-about16casesofinvasivebreastcancerwouldbediagnosedin5

years.

For1000womenwhousedoestrogen+progestagencombinedHRT(CEE+MPA),thenumberof

additionalcaseswouldbe:-between0and9(bestestimate=4)for5years’use.

ThenumberofadditionalcasesofbreastcancerinwomenwhouseHRTisbroadlysimilarforwomenwhostartHRT

isirrespectiveofageatstartofHRTuse(betweentheagesof45and65).(Seesection4.4,Specialwarningsand

precautionsforuse).

Endometrialcancer:

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandendometrialcancerincreaseswithincreasing

durationofuseofunopposedoestrogens.Accordingtodatafromepidemiologicalstudies,thebestestimateoftherisk

isthatforwomennotusingHRT;about5inevery1000areexpectedtohaveendometrialcancerdiagnosedbetween

theagesof50and65.Dependingonthedurationoftreatmentandoestrogendose,thereportedincreaseinendometrial

cancerriskamongunopposedoestrogenusersvariesfrom2-to12-foldgreatercomparedwithnon-users.Addinga

progestagentooestrogen-onlytherapygreatlyreducesthisincreasedrisk.

Otheradversereactionshavebeenreportedinassociationwithsomeoestrogen-progestogentreatments:

Oestrogens-dependentneoplasms,benignandmalignant,e.g.endometrialcancer,

Venousthromboembolism,i.e.deeplegorpelvicvenousthrombosisandpulmonaryembolism,exacerbation

ofvaricoseveins,hypertension.

Stroke,

Myocardialinfarction,

Skinandsubcutaneousdisorders:chloasma,erythemamultiforme,erythemanodosum,vascularpurpura.

Probabledementia(seesection4.4,Specialwarningsandprecautionsforuse).

4.9Overdose

Duetomodeofadministrationoverdosageisunlikely.

Signsandsymptoms:Signsofacuteoestrogenoverdosagemaybeeitheroneof,oracombinationofbreastdiscomfort,

fluidretentionandbloating,ornausea.

Signsofprogestogenoverdosagemaybenausea,vomiting,breastenlargementandvaginalbleeding.

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Progestogensandoestrogens,sequentialcombinations(ATCcodeG03FBO5).

Estradiol

Theactiveingredient,synthetic17-estradiol,ischemicallyandbiologicallyidenticaltoendogenoushumanestradiol.

Itsubstitutesforthelossofoestrogenproductioninmenopausalwomen,andalleviatesmenopausalsymptoms.

Oestrogenspreventbonelossfollowingmenopauseorovariectomy.

Thepatchformulation(transdermaltherapeuticsystem,TTS)delivershormoneintothebloodstreamviaintactskin.

EstradermTTSandEstragestTTSarebothdesignedtodeliver17ß-oestradiolatalowrateoverseveraldays.

NorethisteroneAcetate

Asoestrogenspromotethegrowthoftheendometrium,unopposedoestrogensincreasetheriskofendometrial

hyperplasiaandcancer.Theadditionofaprogestogenreducesbutdoesnoteliminatetheoestrogen-inducedriskof

endometrialhyperplasiainnon-hysterectomisedwomen.WithEstragestTTSprogestogenisaddedforthelast14days

ineachcycleinordertopreventendometrialhyperstimulation.Aregularcyclicbleedcanbeexpectedtostartonday

24-26oftreatment.

5.2Pharmacokineticproperties

WithinfourhoursofapplicationofthefirstEstradermTTS50patch,plasmaestradiollevelsreachthetherapeutic

range,andthesearemaintainedthroughoutthedoseinterval(foruptofourdays).

Afterremovalofthelastpatch,plasmaestrogenlevelsreturntobaselinevaluesinlessthan24hours,andurinary

estrogenconjugateswithin2-3days.

Meanplasmaconcentrationsofestradiolaresimilarduringbothphasesofthetreatment(i.e.transdermalestradiolalone

withEstradermTTS50,ortransdermaloestradiolplusnorethisteroneacetatewithEstragestTTS).

Norethisteroneacetateismetabolisedtotheactiveprogestogen,norethisterone,whichreachesplasmalevelsof0.5-1.0

ng/mlwithin2daysafterEstragestTTSapplication.Theselevelsaremaintainedthroughoutthedoseintervalandare

sufficienttopreventendometrialhyperstimulation.Afterremovalofthesystem,levelsofnorethisteronereturnto

baselinewithin2days.

Absorptionratesmayvarybetweenindividualpatients.

5.3Preclinicalsafetydata

Atlowphysiologicaldosesofestradiol(similartothosedeliveredbyEstracombiTTS),thepotentialofneoplasiais

negligibleinexperimentalanimals.Mostofthedocumentedeffectsofexogenouslyadministeredestradiolinanimal

studieshavebeenconsequencesoftheadministrationofhigherdosesandareconsistentwithanexaggerated

pharmacologicalresponse(mostnotablythepromotionoftumoursinoestrogen-responsivetissues).However,long

termunopposedtreatmentwithphysiologicaldosesofestradiolmaypotentiallyleadtohyperplasticchangesin

oestrogen-dependentreproductiveorgansliketheuterus.

AsimilarspectrumoftumourformationisknowntooccurinlongtermlaboratoryanimalstudieswithNETandNETA

aloneorincombinationwithoestrgogenwithsomespeciesdifferences.However,resultsfromclinicalstudiesand

epidemiologicalevidenceonthecarcinogenicrisktohumansareaddressedunderSection4.4‘Specialwarningsand

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Ethanol

Hyprolose

Polyethyleneterephthalate

Ethylenevinylacetatecopolymer

Liquidparaffin

Polyisobutylene

Silicone

Lightpetroleumether

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove25 o

6.5Natureandcontentsofcontainer

Estradermsystemsareindividuallypackagedinaheat-sealedsachetmadeofaluminium/Surlynfoil.Estragestsystems

areindividuallypackagedinaheat-sealedsachetmadeofpaper/polyethylene/aluminium/Surlynfoil.Onepackageof

EstracombiTTScomprises4EstradermTTS50patchesand4EstragestTTSpatches.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Ultravioletlight(i.e.sunlight)

ExposureoftheestradermTTSandEstragestTTSpatchestoultravioletlightresultsindegradationofestradioland

norethisteroneacetate.Patchesshouldnotbeexposedtosunlight.Theyshouldbeappliedimmediatelyafterremoval

fromthesachettoskinsitescoveredbyclothes.

7MARKETINGAUTHORISATIONHOLDER

NovartisPharmaceuticalsUKLimited

FrimleyBusinessPark

Frimley

Camberley

SurreyGU167SR

England

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 25March1993

Dateoflastrenewal: 25March2008

10DATEOFREVISIONOFTHETEXT

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