ESTRADERM TTS

Main information

  • Trade name:
  • ESTRADERM TTS
  • Dosage:
  • 25 Microgram/day
  • Pharmaceutical form:
  • Transdermal Patch
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0013/070/001
  • Authorization date:
  • 31-05-1993
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0013/070/001

CaseNo:2049910

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

NovartisPharmaceuticalsUKLtd

FrimleyBusinessPark,Frimley,Camberley,Surrey,GU167SR,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

EstradermTTS25mcg/24hoursTransdermalPatch

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom31/05/2008.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2049910 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EstradermTTS25mcg/24hoursTransdermalPatch

2QUALITATIVEANDQUANTITATIVECOMPOSITION

OneEstradermTTS25transdermalpatchcontains2mgestradiol(ashemihydrate).Thepatchhasanabsorptionrate

ofestradiolofapproximately25microgramsperdayfromanactivesurfaceareaof5cm 2

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

TransdermalPatch.

Athin,round,flattransparentpatchwithprotectivereleaseliner.Thebackingfilmisprintedwiththecode‘CG

DWD’.Theoutsidediameteris38mmandtheactivesurfaceareais5cm 2

4CLINICALPARTICULARS

4.1TherapeuticIndications

ormonereplacementtherapyforoestrogendeficiencysymptomsinpost-menopausalwomen.

Theexperiencetreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

Adultsandelderly:

Dosage

Forinitiationandcontinuationoftreatmentinpost-menopausalsymptomsthelowesteffectivedosefortheshortest

duration(seealsosection4.4)shouldbeused.

Inwomenwithanintactuterus,oestrogensshouldalwaysbesupplementedbyadministrationofaprogestogen.Unless

thereisapreviousdiagnosisofendometriosis,itisnotrecommendedtoaddaprogestogeninhysterectomisedwomen.

IfEstradermTTSisusedincombinationwithaprogestogen,theinterruptionoftreatmentmayincreasethelikelihood

ofrecurrenceofsymptomsincludingbreakthroughbleedingandspotting.

EstradermTTSshouldbeappliedtwiceweekly,e.g.thesystemshouldbechangedonceevery3to4days.Treatmentis

normallyinitiatedwithEstradermTTS50.Inthefurthercourseoftreatmentthedosageshouldbeindividually

adapted;breastdiscomfort,breakthroughbleeding,fluidretention(ifpersistingformorethansixweeks)aregenerally

signsthatthedoseistoohighandneedstobelowered.

If,however,thedoseselectedfailstoeliminatethesignsandsymptomsofoestrogendeficiencythehigherdoseshould

begiven.Fortreatmentofmenopausalsymptoms,thelowesteffectivedoseshouldalwaysbeused.Amaximumdose

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2049910 page number: 2

Forpreventionofboneloss,EstradermTTS50orEstradermTTS100isrecommended.EstradermTTS25isnot

recommendedforpreventionofboneloss.

Therapeuticregimen

EstradermTTSisadministeredascontinuoustreatment(uninterruptedapplicationtwiceweekly),inwomenwithan

intactuterus,oestrogentherapyshouldbesupplementedbysequentialadministrationofaprogestogen(e.g.

medroxyprogesteroneacetate10mg,norethisterone5mg,norethisteroneacetate1-5mg,ordydrogesterone20mgper

day)tobetakenonthelast12daysofeach4weektreatmentcycle.Withdrawalbleedingusuallyoccursfollowingthe

12daysormoreofprogestogenadministration.

Administration

Immediatelyafterremovaloftheprotectiveliner,thepatchshouldbeappliedtoanareaofclean,dryandintactskin.

Thesiteselectedshouldbeoneatwhichlittlewrinklingoftheskinoccursduringmovementofthebody,e.g.buttock,

hipor,abdomenandwhichisnotexposedtosunlight,e.g.thoseareasnormallycoveredbyclothing.

Experiencetodatehasshownthatlessirritationoftheskinoccursonthebuttockthanatothersitesofapplication.Itis

thereforerecommendedtoapplythepatchtothebuttock.Theareaofskinshouldbenon-greasyandfreeofirritation.

EstradermTTSmustNOTbeappliedtothebreasts.Thepatchshouldnotbeaffixedtwiceinsuccessiontothesame

skinsite.

Ifawomanhasforgottentoapplyapatch,sheshouldapplyanewpatchassoonaspossible.Thesubsequentpatch

shouldbeappliedaccordingtotheoriginaltreatmentschedule.Theinterruptionoftreatmentmightincreasethe

likelihoodofrecurrenceofsymptoms.

Forpatcheswithdoseofestradiolabove50micrograms/daytheendometrialsafetyofaddedprogestogenshavenot

beenstudied.

Children:

EstradermTTSshouldnotbeusedinchildren.

4.3Contraindications

EstradermTTSshouldnotbeusedbywomenwithanyofthefollowingconditions:

Known,pastorsuspectedbreastcancer,

Knownorsuspectedoestrogen-dependentmalignanttumours(e.g.endometrialcancer),

Undiagnosedvaginalbleeding,

Untreatedendometrialhyperplasia,

Previousidiopathicorcurrentvenousthromboembolism(VTE)(deepvenousthrombosis,pulmonaryembolism),

Activeorrecentarterialthromboembolicdisease(e.g.anginaormyocardialinfarction)

Knownhypersensitivitytotheactivesubstance,oranyoftheexcipients,

Acuteliverdisease,orahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal,

Porphyria

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbetakenatleastannuallyandHRT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2049910 page number: 3

Medicalexamination/follow-up:

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythecontraindicationsandwarningsforuse.

Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.

Womenshouldbeadvisedwhatchangesintheirbreastshouldbereportedtotheirdoctorornurse(see‘BreastCancer’

below).Investigations,includingmammography,shouldbecarriedoutinaccordancewithcurrentlyacceptedscreening

practices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision:

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviously,and/orhavebeenaggravatedduringpregnancy

orprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthatthese

conditionsmayrecurorbeaggravatedduringtreatmentwithEstradermTTS,inparticular:

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

Otosclerosis

Reasonsforimmediatewithdrawaloftherapy:

Therapyshouldbediscontinuedincaseacontra-indicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction

Significantincreaseinbloodpressure

Newonsetofmigraine-typeheadache

Pregnancy

Endometrialhyperplasia

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenoestrogensareadministeredaloneforprolonged

periods(seesection4.8).Theadditionofaprogestagenforatleast12dayspercycleinnon-hysterectomisedwomen

greatlyreducesthisrisk.

Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreakthroughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshouldbe

investigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Unopposedoestrogenstimulationmayleadtopremalignantormalignanttransformationintheresidualfociof

endometriosis.Therefore,theadditionofprogestagenstooestrogenreplacementtherapyshouldbeconsideredin

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2049910 page number: 4

Breastcancer

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

includingtheMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentaking

oestrogensoroestrogen-progestagencombinationsortiboloneforHRTforseveralyears(seeSection4.8).Forall

HRT,anexcessriskbecomesapparentwithinafewyearsofuseandincreaseswithdurationofintakebutreturnsto

baselinewithinafew(atmostfive)yearsafterstoppingtreatment.

IntheMWS,therelativeriskofbreastcancerwithconjugatedequineoestrogens(CEE)orestradiol(E2)wasgreater

whenaprogestogenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeofprogestogen.Therewas

noevidenceofadifferenceinriskbetweenthedifferentroutesofadministration.

IntheWHIstudy,thecontinuouscombinedconjugatedequineoestrogenandmedroxyprogesteroneacetate(CEE+

MPA)productusedwasassociatedwithbreastcancersthatwereslightlylargerinsizeandmorefrequentlyhadlocal

lymphnodemetastasescomparedtoplacebo.

HRT,especiallyoestrogen-progestagencombinedtreatment,increasesthedensityofmammographicimageswhich

mayadverselyaffecttheradiologicaldetectionofbreastcancer.

Venousthromboembolism(VTE)

HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism(VTE),i.e.deepveinthrombosis

orpulmonaryembolism.

Onerandomisedcontrolledtrialandepidemiologicalstudiesfoundatwo-tothreefoldhigherriskforuserscompared

withnon-users.

Fornon-usersitisestimatedthatthenumberofcasesofVTEthatwilloccurovera5yearperiodisabout3per1000

womenaged50-59yearsand8per1000womenagedbetween60-69years.Itisestimatedthatinhealthywomenwho

useHRTfor5years,thenumberofadditionalcasesofVTEovera5yearperiodwillbebetween2and6(bestestimate

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

TheoccurrenceofsuchaneventismorelikelyinthefirstyearofHRTthanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalhistoryorfamilyhistory,severeobesity(BMI>30

kg/m2)andsystemiclupuserythematosus(SLE).Thereisnoconsensusaboutthepossibleroleofvaricoseveinsin

VTE.

PatientswithahistoryofVTEorknownthrombophilicstateshaveanincreasedriskofVTE.HRTmayaddtothisrisk.

Personalorstrongfamilyhistoryofthromboembolismorrecurrentspontaneousabortionshouldbeinvestigatedin

ordertoexcludeathrombophilicpredisposition.Untilathoroughevaluationofthrombophilicfactorshasbeenmadeor

anticoagulanttreatmentinitiated,useofHRTinsuchpatientsshouldbeviewedascontraindicated.Thosewomen

alreadyonanticoagulanttreatmentrequirecarefulconsiderationofthebenefit-riskofuseofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajorsurgery.Asinall

postoperativepatients,scrupulousattentionshouldbegiventoprophylacticmeasurestopreventVTEfollowing

surgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,particularlyabdominalororthopaedic

surgerytothelowerlimbs,considerationshouldbegiventotemporarilystoppingHRT4to6weeksearlier,ifpossible.

Treatmentshouldnotberestarteduntilthewomaniscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorsimmediatelywhentheyareawareofapotentialthromboembolicsymptom(e.g.,painfulswellingofaleg,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2049910 page number: 5

Coronaryarterydisease(CAD)

HRTshouldnotbeusedtopreventcardiovasculardisease.

Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombinedconjugated

oestrogensandMPA.Twolargeclinicaltrials(WHIandHERSi.e.HeartandEstrogen/progestinReplacementStudy)

showedapossibleincreasedriskofcardiovascularmorbidityinthefirstyearofuseandnooverallbenefit.

Fortransdermaloestrogen-onlyandoestrogen-progestogencombinedHRTproducts,thereareonlylimiteddatafrom

randomisedcontrolledtrialstodateassessingtheHRT-associatedriskofcardiovascularmorbidityormortality.

Therefore,itisuncertainwhetherthesefindingsalsoextendtoEstradermTTS.

Stroke

Onelargerandomisedclinical(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischaemicstrokein

healthywomenduringtreatmentwithcontinuouscombinedconjugatedoestrogensandMPA.Forwomenwhodonot

useHRT,itisestimatedthatthenumberofcasesofstrokethatwilloccurovera5yearperiodisabout3per1000

womenaged50-59yearsand11per1000womenaged60-69years.Itisestimatedthatforwomenwhouseconjugated

estrogensandMPAfor5years,thenumberofadditionalcaseswillbebetween0and3(bestestimate=1)per1000

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

Fortransdermaloestrogen-onlyandoestrogen-progestogencombinedHRTproducts,therearenorandomised

controlledtrialstodateassessingtheHRT-associatedriskofstrokemorbidityormortality.Therefore,therearenodata

tosupporttheconclusionthatthefrequencyofstrokeisdifferentwithEstradermTTS.

Ovariancancer

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

withanincreasedriskofovariancancerinsomeepidemiologicalstudies.Itisuncertainwhetherlong-termuseof

combinedHRTconfersadifferentriskthanoestrogen-onlyproducts.

Contactsensitisation

Contactsensitisationisknowntooccurwithalltopicalapplications.Althoughitisextremelyrare,womenwhodevelop

contactsensitisationtoanyofthecomponentsofthepatchshouldbewarnedthataseverehypersensitivityreaction

mayoccurwithcontinuingexposuretothecausativeagent.

Otherconditions

Oestrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.Patientswithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitisexpectedthatthelevelof

circulatingactiveingredientsinEstradermTTSisincreased.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringoestrogenreplacementorhormone

replacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitishavebeen

reportedwithoraloestrogentherapyinthiscondition.

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/renninsubstrate,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2049910 page number: 6

Withtransdermaladministration,stimulationoftheliverbythefirst-passeffectisavoidedand,thus,transdermal

oestrogensmightaffecthormonebindingproteinsandotherserumproteinsproducedbytheliverlessthanoral

hormones.

Thereisnoconclusiveevidenceforimprovementofcognitivefunction.ThereissomeevidencefromtheWHItrialof

increasedriskofprobabledementiainwomenwhostartusingcontinuouscombinedCEEandMPAaftertheageof65.

Itisunknownwhetherthefindingsapplytoyoungerpost-menopausalwomenorotherHRTproducts.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Themetabolismofoestrogensandprogestogensmaybeincreasedbyconcomitantuseofsubstancesknowntoinduce

drug–metabolisingenzymes,specificallycytochromeP450enzymes,suchas,anticonvulsants(e.g.Phenobarbital,

phenytoin,carbamazepine),meprobamate,phenylbutazone,andanti-infectives(egrifampicin,rifabutinnevirapine,

efavirenz).

Cautionshouldbeusedifthepatientisreceivingproteaseinhibitors(e.g.ritonavirandnelfinavir),whichareknownas

stronginhibitorsofcytochromeP450enzymes,andbycontrastexhibitinducingpropertieswhenusedconcomitantly

withsteroidhormones.

HerbalpreparationscontainingSt.John’swort(HypericumPerforatum)mayinducethemetabolismofoestrogensand

progestogens.

Clinically,increasedmetabolismofoestrogensandprogestogensmayleadtodecreasedeffectsandchangesinthe

uterinebleedingprofile.

WithtransdermalHRTadministration,thefirst-passeffectintheliverisavoidedandthustransdermallyapplied

oestrogensandprogestogensmaybelessaffectedbyenzymeinducersthanoralhormones.

4.6Pregnancyandlactation

EstradermTTSisnotindicatedduringpregnancy.IfpregnancyoccursduringmedicationwithEstradermTTS

treatmentshouldbewithdrawnimmediately.

Theresultsofmostepidemiologicalstudiestodaterelevanttoinadvertentfoetalexposuretooestrogensindicateno

teratogenicorfoetotoxiceffects.

4.7Effectsonabilitytodriveandusemachines

Noneknown.

4.8Undesirableeffects

Transienterythemaandirritationatthesiteofapplication,withorwithoutpruritus.Thisusuallydisappears3-4days

afterpatchremovalandissimilartotheeffectobservedafterocclusionoftheskinwithhouseholdmedicaladhesive

plasters.Additionally,breastdiscomfort(signofoestrogeneffect,signofoverdose)andbreakthroughbleedingwere

themostfrequentlyreportedundesirableeffects(thelatterisusuallyasignofestrogenoverdose);iftheoestrogenis

adequatelycombinedwithaprogestogen,regularwithdrawalbleedingoccurs,asobservedinthenormalmenstrual

cycle.Likeanyoestrogentherapy,transdermaloestrogentreatmentcaninduceendometrialhyperplasiaunless

oestrogenintakeissupplementedbyadequatedosesofaprogestogen.

Frequencyestimate:Verycommon>10%;common>1%to10%;uncommon>0.1%to<1%;rare>0.01%to<0.1%.

Skindisorders:

Uncommon:Localswelling,papules/vesiclesandscalinghavebeenreported,whichalsoresolvedspontaneouslyand

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2049910 page number: 7

Nervoussystemdisorders:

Common:headache,migraine.

Rare:dizziness.

Gastrointestinaldisorders:

Common:nausea,abdominalcramps,bloating.

Reproductivesystemandbreastdisorders:

Uncommon:breastcancer(seesection4.4).

Generaldisorders:

Uncommon:legcramps(notrelatedtothromboembolicdiseaseandusuallytransientlasting3-6weeks,ifsymptoms

persist,theoestrogendoseshouldbereduced).

Rare:Oedema,weightincreaseordecrease,legpain(notrelatedtothromboembolicdiseaseandusuallytransient,

lasting3-6weeks.Ifsymptomspersist,theoestrogendoseshouldbereduced).

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.

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)inalluserscomparedtoplacebo.

TheabsoluteriskscalculatedfromtheMWSandtheWHItrialarepresentedbelow:

TheMWShasestimated,fromtheknownaverageincidenceofbreastcancerindevelopedcountries,that:

ForwomennotusingHRT,about32inevery1000areexpectedtohavebreastcancerdiagnosedbetweentheages

of50and64years.

For1000currentorrecentusersofHRT,thenumberofadditionalcasesduringthecorrespondingperiodwillbe;

Forusersofoestrogen-onlyreplacementtherapy:-

between0and3(bestestimate=1.5)for5years’use

between3and7(bestestimate=5)for10years’use

ForusersofoestrogenplusprogestagencombinedHRT:-

between5and7(bestestimate=6)for5years’use

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2049910 page number: 8

TheWHItrialestimatedthatafter5.6yearsoffollow-upofwomenbetweentheagesof50and79years,anadditional

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

womenyears.

Accordingtocalculationsfromthetrialdata,itisestimatedthat:

For1000womenintheplacebogroup:-

about16casesofinvasivebreastcancerwouldbediagnosedin5years.

For1000womenwhousedoestrogen+progestagencombinedHRT(CEE+MPA),thenumberofadditional

caseswouldbe:-

between0and9(bestestimate=4)for5years’use.

ThenumberofadditionalcasesofbreastcancerinwomenwhouseHRTisbroadlysimilarforwomenwhostartHRT

isirrespectiveofageatstartofHRTuse(betweentheagesof45and65).(seesection4.4).

Endometrialcancer:

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandendometrialcancerincreaseswithincreasing

durationofuseofunopposedoestrogens.Accordingtodatafromepidemiologicalstudies,thebestestimateoftherisk

isthatforwomennotusingHRT,about5inevery1000areexpectedtohaveendometrialcancerdiagnosedbetween

theagesof50and65.Dependingonthedurationoftreatmentandoestrogendose,thereportedincreaseinendometrial

canceramongunopposedoestrogenusersvariesfrom2-to12-foldgreatercomparedwithnon-users.Addinga

progestagentooestrogen-onlytherapygreatlyreducesthisincreasedrisk.

Otheradversereactionshavebeenreportedinassociationwithoestrogenaloneandoestrogen-progestogentreatments.

Oestrogen-dependentneoplasma,benignandmalignant,e.g.endometrialcancer,

Venousthromboembolism,i.e.deeplegorpelvicvenousthrombosisandpulmonaryembolism,thrombophlebitis,

exacerbationofvaricoseveins,hypertension,

Stroke,

Myocardialinfarction,

Skinandsubcutaneousdisorders:chloasma,erythemamultiforme,erythemanodosum,vascularpurpura,allergic

contactdermatitis,reversiblepost-inflammatorypigmentation;generalisedpruritusandexanthema,

Gallbladderdisease,

Cholestaticjaundice,

Asymptomaticimpairedliverfunction,

Anaphylactoidreactions(historyofpreviousallergyorallergicdisordersinsomecases).

Probabledementia(seesection4.4)

4.9Overdose

Thisisnotlikelyduetothemodeofadministration.

Signsandsymptoms:Signsofacuteoestrogenoverdosagemaybeeitheroneof,oracombinationofbreastdiscomfort,

fluidretentionandbloating,ornausea.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2049910 page number: 9

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:HormoneReplacementTherapy(ATCCodeG03FA01).

Estradiol:Theactiveingredient,synthetic17-estradiol,ischemicallyandbiologicallyidenticaltoendogenoushuman

estradiol.Itsubstitutesforthelossofoestrogenproductioninmenopausalwomen,andalleviatesmenopausal

symptoms.

Thepatchformulation(transdermaltherapeuticsystem,TTS)delivershormoneintothebloodstreamviaintactskin.

EstradermTTSisdesignedtodeliver17-estradiolatalowrateoverseveraldays.

5.2Pharmacokineticproperties

Withinfourhoursafterapplicationofthefirstsystem,plasmaestradiollevelsreachthetherapeuticrangeandtheseare

maintainedthroughoutthedoseinterval(foruptofourdays).

Afterremovalofthelastsystemplasmaoestrogenlevelsreturntobaselinevaluesinlessthan24hoursandurinary

oestrogenconjugateswithin2-3days.

Absorptionratemayvarybetweenindividualpatients.However,theplasmaestradiollevelsachievedwithdifferent

sizedsystemshavebeenshowntobeproportionaltothedrug-releasingareaofthedosageform.

5.3Preclinicalsafetydata

Preclinicaleffectswereobservedonlyatexposuresconsideredsufficientlyinexcessofthemaximumhumanexposure

indicatinglittlerelevancetoclinicaluse.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Ethanol

Hydroxypropylcellulose

Polyethyleneterephthalate

Ethylenevinylacetatecopolymer

Paraffinliquid,light

Polyisobutylene

Lightpetroleum

Silicone

Printingink:CFA4215Weiss

6.2Incompatibilities

Ultravioletlight(i.e.sunlight)

ExposureofEstradermTTS25TransdermalPatchestoultravioletlightresultsindegradationofestradiol.Patches

shouldnotbeexposedtosunlight.Theyshouldbeappliedimmediatelyafterremovalfromthesachettoskinsites

coveredbyclothes.

6.3ShelfLife

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2049910 page number: 10

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Storeintheoriginalpackageinordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Cartonscontain8EstradermTTS25transdermalpatches,eachindividuallysealedinaprotectivepouch(i.e.Surlyn

coatedaluminiumfoilliner).

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

NovartisPharmaceuticalsUKLtd

FrimleyBusinessPark

Frimley

Camberley

Surrey,GU167SR

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA13/70/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffistauthorisation:31 st

May1988

Dateoflastrenewal:31 st

May2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 21/03/2010 CRN 2049910 page number: 11