EPIESTROL-SEPTEM

Main information

  • Trade name:
  • EPIESTROL-SEPTEM Transdermal Patch 25 mg/24ho Milligram
  • Dosage:
  • 25 mg/24ho Milligram
  • Pharmaceutical form:
  • Transdermal Patch
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EPIESTROL-SEPTEM Transdermal Patch 25 mg/24ho Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0868/007/001
  • Authorization date:
  • 20-10-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0868/007/001

CaseNo:2051977

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

RottapharmLtd

DamastownIndustrialPark,Mulhuddart,Dublin15,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

EPIESTROL-Septem25micrograms/24hoursTransdermalPatch

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom01/12/2008.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 16/09/2009 CRN 2051977 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EPIESTROL-Septem25micrograms/24hoursTransdermalPatch

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onetransdermalpatchcontains:

2.58mgofestradiolhemihydrateequivalentto2.5mgestradiol/11.25cm 2

delivering25µgofestradiolin24hours.

Excipient(s):

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Transdermalpatch.Eachpatchistransparent,colourless,slightlyopaquewithanellipticalshapeandaprinted

identificationcode,andcoveredbyarectangular,transparentprotectiveliner.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapy(HRT)forestrogendeficiencysymptomsinpostmenopausalwomen.

Theexperiencetreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

Posology

EPIESTROL-Septemisanestrogen-onlypatchappliedtotheskinonceweeklyinordertoensureacontinuoussupply

ofestradioltothebody;thuseachusedsystemisremovedaftersevendaysandreplacedbyanewone.

ThreestrengthsofEPIESTROL-Septemareavailable,i.e.EPIESTROL-Septem25,50,75.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

duration(seealsoSection4.4)shouldbeused.

TreatmentisusuallyinitiatedwithEPIESTROL-Septem25.

Ifafteratreatmentof1-2monthswithEPIESTROL-Septem25appliedonceweeklythesymptomsofestrogen

deficiencyappearnottobeneutralised,ahigherdosagecanbegiven.

Incaseofundesirableeffectsorsymptomsofoverdose(e.g.breasttendernessand/orvaginalbleeding),thedoseshould

bereduced.

Inwomenwithanintactuterus,aprogestagenapprovedforadditiontoestrogentreatmentmustbeadditionally

administeredforatleast12-14dayseverymonth/28daycycletoopposethedevelopmentofanestrogen-stimulated

hyperplasiaoftheendometrium(seeSection4.4SpecialWarningsandSpecialPrecautionsforUse).

Unlessthereisapreviousdiagnosisofendometriosis,itisnotrecommendedtoaddaprogestageninhysterectomised

women.

Twotherapeuticregimenscanbeused:

a)Cyclic:EPIESTROL-Septemisdosedcyclicallywithatreatment-freeinterval,usually21daysonand7daysoff.

Theprogestagenisusuallyaddedfor12-14daysofthecycle.Withdrawalbleedingmayappearduringthisperiod.

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(ormore)ofevery28daycycle,inasequentialmanner.

Continuoussequentialtreatmentmayberecommendedincaseswhenmarkedsymptomsofestrogendeficiencyrecur

duringthetreatment-freeperiod.

Withdrawalbleedingmayoccurwhentheprogestageniswithdrawn.

ThetreatmentwithEPIESTROL-Septemmaybeinitiatedatanyconvenienttimeforwomenwhoarenotcurrentlyon

anyestrogentherapy.Womencurrentlyusingcyclicorsequentialestrogen/progestagentherapyshouldcompletetheon-

goingtreatmentcyclebeforebeginningtreatmentwithEPIESTROL-Septem;theappropriatetimetobegintreatment

withEPIESTROL-Septemwouldbethefirstdayofawithdrawalbleeding.

Womenwhoarealreadyusingcontinuouscombinedestrogen/progestagentherapymaybeswitchedtoEPIESTROL-

Septemdirectly.

Methodofadministration

ApplyEPIESTROL-Septemtotheskinofthehip,upperquadrantofthebuttock,lumbarregionorabdomenandpress

firmlyoverthewholesurfaceandalongtheedgestoensuregoodadhesion.

Theabsorptioncapacityoftheskinistherate-determiningfactorinthereleaseofestradiolfromEPIESTROL-Septem.

Theapplicationonanother(higher)skinregionthanonthementionedpreferredregionsisnotrecommended,asthis

mighthaveaninfluenceonthereleaseofestradiol.

Theskinoftheapplicationsiteshouldbeclean,dry,not-greasyandfreeofrednessorirritation.Areasofthebody

whichformfoldsoraresubjecttofrictionduringmovementshouldbeavoided.

EPIESTROL-Septemshouldnotbeappliedonornearthebreasts.

Patchesshouldnotbeappliedtwiceconsecutivelytothesameskinsite.

Ifthepatchiscorrectlyapplied,itwilladheretotheskinfortherequiredone-weekperiodwithoutproblems.Inthe

eventthatapatchdoescomeoff,itshouldbereplacedwithanewpatchfortherestoftheone-weekdosingperiod.The

patchshouldthenbechangedagainattheregulartimetore-establishthepatient’sroutineschedule.Similarly,ifthe

patchisnotchangedonthescheduledday,itshouldbereplacedassoonaspossibleandchangedagainonthenext

scheduledday.Forgettingtoapplyanewpatchatthescheduledtimemayincreasethelikelihoodofbreak-through

bleedingandspotting.

Ifthepatchiscorrectlyapplied,thepatientmaybatheorshower.However,thepatchmaybecomedetachedaftera

veryhotbathorsauna.Ifthisoccurs,thepatchshouldbereplacedwithanewone(asdescribedabove).Possiblythe

saunashouldbeplannedforadayscheduledforthechangeofthepatch.

4.3Contraindications

Known,pastorsuspectedbreastcancer;

Knownorsuspectedestrogen-dependentmalignanttumours(e.g.endometrialcancer);

Undiagnosedgenitalbleeding;

Untreatedendometrialhyperplasia;

Previousidiopathicorcurrentvenousthromboembolism(deepvenousthrombosis,pulmonaryembolism);

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfarction);

Acuteliverdisease,orahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal;

Knownhypersensitivitytotheactivesubstancesortoanyoftheexcipients;

Porphyria.

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk.

Medicalexamination/follow-up

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(includingpelvicandbreast)examinationshouldbeguidedbythisandbythecontraindicationsandwarningsforuse.

Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.

Womenshouldbeadvisedwhatchangesintheirbreastsshouldbereportedtotheirdoctorornurse(see‘Breastcancer’

below).Investigations,includingmammography,shouldbecarriedoutinaccordancewithcurrentlyacceptedscreening

practices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviouslyand/orhavebeenaggravatedduringpregnancy

orprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthatthese

conditionsmayrecurorbeaggravatedduringtreatmentwithEPIESTROL-Septem,inparticular:

Leiomyoma(uterinefibroids)orendometriosis

Ahistoryof,orriskfactorsfor,thromboembolicdisorders(seebelow)

Riskfactorsforestrogendependenttumours,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

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenoestrogensareadministeredalonefor

prolongedperiods(seesection4.8).Theadditionofaprogestagenforatleast12dayspercycleinnon-

hysterectomisedwomengreatlyreducesthisrisk.

Forpatchesreleasingmorethan50µg/day,theendometrialsafetyofaddedprogestagenshavenotbeenstudied.

Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-throughbleeding

orspottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereason

shouldbeinvestigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Unopposedestrogenstimulationmayleadtopremalignantormalignanttransformationintheresidualfociof

endometriosis.Therefore,theadditionofprogestagenstoestrogenreplacementtherapyshouldbeconsideredin

womenwhohaveundergonehysterectomybecauseofendometriosis,iftheyareknowntohaveresidual

endometriosis.

Breastcancer

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

includingtheMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentaking

oestrogens,oestrogen-progestagencombinationsortiboloneforHRTforseveralyears(seeSection4.8).

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returnstobaselinewithinafew(atmostfive)yearsafterstoppingtreatment.

IntheMWS,therelativeriskofbreastcancerwithconjugatedequineoestrogens(CEE)orestradiol(E2)wasgreater

whenaprogestagenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeofprogestagen.Therewas

noevidenceofadifferenceinriskbetweenthedifferentroutesofadministration.

IntheWHIstudy,thecontinuouscombinedconjugatedequineoestrogenandmedroxyprogesteroneacetate(CEE+

MPA)productusedwasassociatedwithbreastcancersthatwereslightlylargerinsizeandmorefrequentlyhadlocal

lymphnodemetastasescomparedtoplacebo.

HRT,especiallyoestrogen-progestagencombinedtreatment,increasesthedensityofmammographicimageswhich

mayadverselyaffecttheradiologicaldetectionofbreastcancer.

Venousthromboembolism

HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism(VTE),i.e.deepvein

thrombosisorpulmonaryembolism.Onerandomisedcontrolledtrialandepidemiologicalstudiesfoundatwo-to

threefoldhigherriskforuserscomparedwithnon-users.Fornon-users,itisestimatedthatthenumberofcasesof

VTEthatwilloccurovera5yearperiodisabout3per1000womenaged50-59yearsand8per1000women

agedbetween60-69years.ItisestimatedthatinhealthywomenwhouseHRTfor5years,thenumberof

additionalcasesofVTEovera5yearperiodwillbebetween2and6(bestestimate=4)per1000womenaged

50-59yearsandbetween5and15(bestestimate=9)per1000womenaged60-69years.Theoccurrenceofsuch

aneventismorelikelyinthefirstyearofHRTthanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalhistoryorfamilyhistory,severeobesity(BMI>30

kg/m 2

)andsystemiclupuserythematosus(SLE).Thereisnoconsensusaboutthepossibleroleofvaricoseveins

inVTE.

PatientswithahistoryofVTEorknownthrombophilicstateshaveanincreasedriskofVTE.HRTmayaddto

thisrisk.Personalorstrongfamilyhistoryofthromboembolismorrecurrentspontaneousabortionshouldbe

investigatedinordertoexcludeathrombophilicpredisposition.Untilathoroughevaluationofthrombophilic

factorshasbeenmadeoranticoagulanttreatmentinitiated,useofHRTinsuchpatientsshouldbeviewedas

contraindicated.Thosewomenalreadyonanticoagulanttreatmentrequirecarefulconsiderationofthebenefit-risk

ofuseofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajorsurgery.

Asinallpostoperativepatients,scrupulousattentionshouldbegiventoprophylacticmeasurestopreventVTE

followingsurgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,particularlyabdominal

ororthopaedicsurgerytothelowerlimbs,considerationshouldbegiventotemporarilystoppingHRT4to6

weeksearlier,ifpossible.Treatmentshouldnotberestarteduntilthewomaniscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorsimmediatelywhentheyareawareofapotentialthromboembolicsymptom(e.g.painfulswellingofaleg,

suddenpaininthechest,dyspnea).

Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombinedconjugated

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

Estrogen/progestinReplacementStudy)showedapossibleincreasedriskofcardiovascularmorbidityinthefirstyear

ofuseandnooverallbenefit.ForotherHRTproductsthereareonlylimiteddatafromrandomisedcontrolledtrials

examiningeffectsincardiovascularmorbidityormortality.Therefore,itisuncertainwhetherthesefindingsalsoextend

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Stroke

Onelargerandomisedclinicaltrial(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischaemicstrokein

healthywomenduringtreatmentwithcontinuouscombinedconjugatedestrogensandMPA.Forwomenwhodonot

useHRT,itisestimatedthatthenumberofcasesofstrokethatwilloccurovera5yearperiodisabout3per1000

womenaged50-59yearsand11per1000womenaged60-69years.

ItisestimatedthatforwomenwhouseconjugatedestrogensandMPAfor5years,thenumberofadditionalcaseswill

bebetween0and3(bestestimate=1)per1000usersaged50-59yearsandbetween1and9(bestestimate=4)per

1000usersaged60-69years.ItisunknownwhethertheincreasedriskalsoextendstootherHRTproducts.

Ovariancancer

Long-term(atleast5-10years)useofestrogen-onlyHRTproductsinhysterectomisedwomenhasbeenassociatedwith

anincreasedriskofovariancancerinsomeepidemiologicalstudies.Itisuncertainwhetherlong-termuseofcombined

HRTconfersadifferentriskthanestrogen-onlyproducts.

Otherconditions

Estrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.Patientswithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitisexpectedthatthelevel

ofcirculatingactiveingredientsinEPIESTROL-Septemisincreased.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringestrogenreplacementor

hormonereplacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitis

havebeenreportedwithestrogentherapyinthiscondition.

Estrogensincreasethyroidbindingglobulin(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.ThereissomeevidencefromtheWHI

trialofincreasedriskofprobabledementiainwomenwhostartusingcontinuouscombinedCEEandMPAafter

theageof65.Itisunknownwhetherthefindingsapplytoyoungerpost-menopausalwomenorotherHRT

products.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Themetabolismofestrogensmaybeincreasedbyconcomitantuseofsubstancesknowntoinducedrug-metabolising

enzymes,specificallycytochromeP450enzymes,suchasanticonvulsants(e.g.phenobarbital,phenytoin,

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

Ritonavirandnelfinavir,althoughknownasstronginhibitors,bycontrastexhibitinducingpropertieswhenused

concomitantlywithsteroidhormones.HerbalpreparationscontainingStJohn’swort(HypericumPerforatum)may

inducethemetabolismofestrogens.

Attransdermaladministration,thefirst-passeffectintheliverisavoidedand,thus,transdermallyappliedestrogens

mightbelessaffectedthanoralhormonesbyenzymeinducers.

Clinically,anincreasedmetabolismofestrogensandprogestagensmayleadtodecreasedeffectandchangesinthe

uterinebleedingprofile.

4.6Pregnancyandlactation

EPIESTROL-Septemisnotindicatedduringpregnancy.IfpregnancyoccursduringmedicationwithEPIESTROL-

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Theresultsofmostepidemiologicalstudiestodaterelevanttoinadvertentfetalexposuretoestrogensindicateno

teratogenicorfoetotoxiceffects.

Lactation

EPIESTROL-Septemisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

EPIESTROL-Septemhasnoknowneffectsontheabilitytodriveorusemachines.

4.8Undesirableeffects

Approximately10to17%ofthepatientstreatedwithEPIESTROL-Septeminclinicaltrialsexperiencedsystemic

adversereactions,whichweremildandtransient.Breasttendernesswasreportedin20-35%ofpatients.Localreactions

attheapplicationsite,mostlymilderythemawithorwithoutpruritus,occurredin10-25%ofpatients.

ThetablebelowliststheadversereactionsobservedwithEPIESTROL-SeptemandHRTproductscontaining17-

estradiol.

Organsystemclass CommonADRs,

>1/100,<1/10 UncommonADRs,

>1/1,000,<1/100 RareADRs

>1/10,000,<1/1000

Psychiatricdisorders -Depression

Centralnervoussystem -Irritability

-Headache -Migraine

-Dizziness -Changesinlibido

-Worseningofepilepsy

Vasculardisorders -Increaseinblood

pressure -Venous

thromboembolism

Gastro-intestinaldisorders-Nausea

-Abdominalcramps

-Meteorism -Vomiting

Hepatobilarydisorders -Disturbedor

abnormalliver

functiontests

Skinandsubcutaneous

tissuedisorders

-Allergic-contact

dermatitis

-Reversible

post-inflammatory

pigmentation

-Generalisedpruritus

andexanthema

Reproductivesystemand

breastdisorders -Breast

tenderness and

breastpain

-Break-through

bleeding

-Changesinvaginal

secretions

-Endometrial

hyperplasia -Uterinetumours

Generaldisorders -Fluidretention

withedema

-Feelingof

heavinessinthe

legs -Alterationsin

glucosetolerance

andblood

coagulation -Ocularirritationduring

contactlensesuse

-Anaphylacticreactions

(sometimesinpatients

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(1)SkinreactionsarelessfrequentifEPIESTROL-Septemisappliedontheouterupperquadrantofthebuttock,

changingthesiteateachapplication

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,severalepidemiologicalstudieshavereportedanoverallhigherriskfor

breastcancerthanwithoestrogensalone.

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.

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

between18and20(bestestimate=19)for10years’use.

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

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

Endometrialcancer

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandendometrialcancerincreaseswithincreasing

durationofuseofunopposedoestrogens.Accordingtodatafromepidemiologicalstudies,thebestestimateoftherisk

isthatforwomennotusingHRT,about5inevery1000areexpectedtohaveendometrialcancerdiagnosedbetween

-Weightincreaseor

decrease intheanamnesis) Irish Medicines Board

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cancerriskamongunopposedoestrogenusersvariesfrom2-to12-foldgreatercomparedwithnon-users.Addinga

progestagentooestrogen-onlytherapygreatlyreducesthisincreasedrisk.

Otheradversereactionshavebeenreportedinassociationwithestrogen/progestagentreatment:

Estrogen-dependentneoplasmsbenignandmalignant,e.g.endometrialcancer(seeSection4.4SpecialWarnings

andSpecialPrecautionsforUse).

Venousthromboembolism,i.e.deeplegorpelvicvenousthrombosisandpulmonaryembolism,ismorefrequent

amonghormonereplacementtherapyusersthanamongnon-users.Forfurtherinformation,seesection4.3

Contraindicationsand4.4SpecialWarningsandSpecialPrecautionsforUse.

Myocardialinfarctionandstroke(seeSection4.4SpecialWarningsandSpecialPrecautionsforUse).

Gallbladderdisease.

Skinandsubcutaneousdisorders:chloasma,erythemamultiforme,erythemanodosum,vascularpurpura.

Probabledementia(seeSection4.4SpecialWarningsandSpecialPrecautionsforUse).

4.9Overdose

Overdosesymptomsgenerallyleadtobreasttenderness,abdominalorpelvisswelling,anxiety,irritabilityorfluid

retention.Flatulencemayalsooccurasasymptomofoverdosage.

Break-throughbleedingmayoccurasaresultofrelativeestradioloverdosageduringprogestagenadministration(i.e.

underdosageoftheprogestagen).

Thesesymptomsdisappearwhenthetransdermalpatchisremovedorwhenthedoseisreduced.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcode:G03CA03

Urogenitalsystemandsexhormones

Theactiveingredient,synthetic17-estradiol,ischemicallyandbiologicallyidenticaltoendogenoushumanestradiol.

Itsubstitutesforthelossofestrogenproductioninmenopausalwomen,andalleviatesmenopausalsymptoms.

ClinicaltrialInformation

Reliefofmenopausalsymptomswasachievedduringthefirstfewweeksoftreatment.

5.2Pharmacokineticproperties

Theaveragehalf-lifeofestradiolinplasmaisaboutonehour.Plasmaclearanceis650-900litre/day/m.Estradiolis

metabolisedmainlyintheliver,themostimportantmetabolitesareestriol,estroneandtheirconjugates(glucuronides,

sulphates),whicharemuchlessactivethanestradiol.Themetabolitesofestradiolareeliminatedmainlybythekidney

asglucuronidesandsulphates.Themetabolitesofestradiolarealsofoundinfaeces,duetoanentero-hepaticcirculation

FollowingcutaneousapplicationofEPIESTROL-Septem,estradiolisreleasedfromthedrug-containingadhesivematrix

throughtheskinandreachesthesystemiccirculationdirectly,avoidingfirst-passmetabolismbytheliver.

Consequently,theestradiol:estroneratioinplasma,whichfallstovaluesbelow1afterthemenopauseandduringoral

estrogenreplacementtherapy,returntopre-menopausallevels(approximately1)withtransdermalestradiol.

ThenominaldailyinvivoreleaserateofEPIESTROL-Septem25is25µgofestradiol;thesystemisactiveforone

week.Thisreleaserateresultsinphysiologicalestradiolserumconcentrations,i.e.intherangeofthoseobservedduring

thepremenopausalearlyfollicularphase,whichareconstantlymaintainedthroughoutthepatchapplicationperiod.

Physiologicalconcentrationsofestradiolwereachieved6hoursafterapplicationofEPIESTROL-Septem25in

postmenopausalwomen,withaverageconcentrationsover147pmol/lafter12hours.

FollowingrepeatedapplicationsofEPIESTROL-Septem25patchesatoneweekintervals,meanmaximumserum

estradiolconcentrationsof169pmol/lwereobtainedatsteady-state.Theserumconcentrationofestradiolremained

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baselinewithin12-24hoursafterremovalofthepatch.

Theaverageconcentrationofestradiolinsteady-stateconditionswas95pmol/l.TheC

ofestradiol,showntobeat

thesteadystate,was48pmol/l.

5.3Preclinicalsafetydata

AnimalstudieswithestradiolhaveshownexpectedestrogeniceffectsTherearenopreclinicaldataofrelevancetothe

prescriberthatareadditionaltothosealreadyincludedinothersectionsoftheSPC.

Localtolerancestudiesperformedintherabbithavedemonstratedthegoodskintolerabilityofthetransdermalpatch

aftersingleandrepeatedapplications.Thepatchdidnotshowanysensitisationpotentialintheguineapig.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Estradiol-containing

adhesivematrix:acryliccopolymers(Durotak387-2353;Durotak387-2287)

Backingfoil:polyethyleneterephthalate.

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Twoyears.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

EPIESTROL-Septemshouldbestoredinanintactsachet.

6.5Natureandcontentsofcontainer

EPIESTROL-Septem25ispackedinacardboardboxcontaining4or12transdermaldeliverysystemssealed

individuallyinprotectivesachetsconsistingof4layers:Surlyn,heat-sealablematerial(innerlayer),aluminiumfoil,

polyethyleneandpaper(outerlayer).

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Tearopenthesachetattheindentation(donotusescissorstoavoiddamagingthepatch)andremovethepatch.Holdthe

patchbetweenthethumbandindexfingeratthecornerofthepull-off-tag.Detachtheprotectivelinerwiththeother

handanddiscardit.

Donottouchtheadhesivesideofthepatch.Applythepatchtotheskinholdingbetweenthethumbandindexfingerthe

partstillcoveredbytheprotectiveliner.Detachtheremainingpartoftheprotectivelinerandpressfirmlyforabout10

secondsonthewholesurfaceofthepatch.

Passafingeralongtheedgestoassuregoodadhesion.

Irish Medicines Board

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Date Printed 16/09/2009 CRN 2051977 page number: 10

7MARKETINGAUTHORISATIONHOLDER

RottapharmLtd.,

DamastownIndustrialPark,

Mulhuddart,

Dublin15

8MARKETINGAUTHORISATIONNUMBER

PA868/7/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:23August1999

Dateoflastrenewal:1December2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 16/09/2009 CRN 2051977 page number: 11