ESTALIS SEQUI

Main information

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

Documents

Localization

  • Available in:
  • ESTALIS SEQUI
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0013/096/001
  • 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)

PA0013/096/001

CaseNo:2041044

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

NovartisPharmaceuticalsLtd

FrimleyBusinessPark,Frimley,Camberley,Surrey,GU167SR,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

EstalisSequi50micrograms/250micrograms/24hours,TransdermalPatch

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom06/03/2008.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EstalisSequi50micrograms/250micrograms/24hours,TransdermalPatch

2QUALITATIVEANDQUANTITATIVECOMPOSITION

PhaseI

Eachpatchcontainsestradiolhemihydrateequivalentto4.33mgestradiolinapatchof14.5cm 2

releasingnominal

50microgramsestradiolper24hours.

PhaseII

Eachpatchcontainsestradiolhemihydrateequivalentto0.51mgestradioland4.80mgnorethisteroneacetateinapatch

of16cm 2

releasingnominal50microgramsestradiolandnominal250microgramsnorethisteroneacetateper24hours.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Transdermalpatch.

Translucentroundpatcheswithapolymericbackingononesideandareleaselinerontheotherside,packed

individuallyinheat-sealedpouches.

4CLINICALPARTICULARS

4.1TherapeuticIndications

EstalisSequi50/250isindicatedfor:

Hormonereplacementtherapy(HRT)foroestrogendeficiencysymptomsinpostmenopausalwomen.

Preventionofosteoporosisinpostmenopausalwomenathighriskoffuturefractureswhoareintolerantof,or

contraindicatedfor,othermedicinalproductsapprovedforthepreventionofosteoporosis.

Treatmentisintendedforwomenmorethanoneyearpostmenopause.

Theexperienceoftreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

EstalisSequi50µg/250µg/24hoursisacontinuoussequentialpreparationfortransdermaluse.Onetreatmentcycleof

EstalisSequi50µg/250µg/24hoursconsistsof4PhaseItransdermalpatchesfollowedby4PhaseIItransdermal

patches.TherapyisstartedwiththePhaseIpatch.Thenexttreatmentcycleshouldbestartedimmediatelyafterthe

removalofthelastPhaseIItransdermalpatch.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

duration(seesection4.4)shouldbeused.

Initiationoftherapy

Postmenopausalwomenwhoarenotalreadyreceivingoestrogen-progestogentherapymaystartusingEstalisSequiat

anyconvenienttime.

Womenwhoarealreadyusingcontinuouscombinedoestrogen/progestogentherapymaybeswitchedtoEstalisSequi

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Womencurrentlyusingcyclicorsequentialoestrogen/progestogentherapyshouldcompletetheon-goingtreatment

cyclebeforetreatmentwithEstalisSequi50µg/250µg/24hoursPhaseIisinitiated.

TheappropriatetimetobegintreatmentwithEstalisSequi50µg/250µg/24hoursPhaseIwouldbethefirstdayofa

withdrawalbleeding.

Generalinstructions

ThePhaseItransdermalpatchisappliedtotheskinoftheabdomenevery3to4daysforthefirst14daysofa28-day

cycle.Thereafter,thePhaseIItransdermalpatchisappliedtotheskinoftheabdomenevery3or4daysforthe

remaining14daysofthe28-daycycle.Womenshouldbeadvisedthatmonthlybleedingwillusuallyoccur.

MethodofAdministration

Careshouldbeexercisedwhenapplyingthepatch.Itmustneverbeplacedonornearthebreasts.Itshouldbeplaced

onaclean,dryareaoftheabdomenwhichisnotirritated,abradedoroily(i.e.shouldnotbeusedwithanymoisturizing

cream,lotionoroil).Thewaistlineshouldbeavoided,sincetightclothingmayrubthepatchoff.

Thesitesofapplicationshouldbechangedwithanintervalofatleastoneweekallowedbetweenapplicationstoa

particularsite.

Afteropeningthepouch,onehalfoftheprotectivelinermustberemovedwithouttouchingthestickysidewiththe

fingers.Thetransdermalpatchmustbeappliedtotheskinimmediately.Theotherhalfoftheprotectivelinermustbe

removedandthetransdermalpatchmustbepressedfirmlytotheskinwiththepalmofthehandforatleast10seconds,

carefullysmoothingdowntheedges.

Careshouldbetakenduringbathingorotheractivitiessothatthetransdermalpatchdoesnotbecomedislodged.Ifthe

transdermalpatchfallsoff(afterstrenuousphysicalactivity,excessivesweatingorfrictionfromtightclothing),the

sametransdermalpatchmaybereappliedtoanotherarea.Theoriginaltreatmentshouldbethereafterfollowed,i.e.the

transdermalpatchshouldbeexchangedonthesamedaysasbefore.

Onceinplace,thetransdermalpatchshouldnotbeexposedtothesunforprolongedperiodsoftime.

Shouldapatientforgettoapplyapatch,sheshouldapplyanewpatchassoonaspossible.Thesubsequentpatchshould

beappliedaccordingtotheoriginaltreatmentschedule.Theinterruptionoftreatmentmightincreasethelikelihoodof

recurrenceofpostmenopausalsymptoms,break-throughbleedingandspotting.

Shouldanyadhesiveremainafterremovalofthetransdermaldeliverysystem,theskinareashouldbegentlyrubbed

withanoil-basedcreamorlotion.

4.3Contraindications

EstalisSequi50µg/250µg/24hoursshouldnotbeusedbywomenwithanyofthefollowingconditions:

Known,pastorsuspectedbreastcancer

Knownorsuspectedoestrogen-dependentmalignanttumors(e.g.endometrialcancer)

Undiagnosedgenitalbleeding

Untreatedendometrialhyperplasia

Previousidiopathicorcurrentvenousthromboembolism(deepvenousthrombosis,pulmonaryembolism)

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfraction);

Hypersensitivitytotheactivesubstances,ortoanyoftheexcipients(seesection6.1)

Acuteliverdiseaseorahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal

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4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlycontinueaslongasthebenefitoutweighstherisk.

Medicalexamination/follow-up

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythesection4.3and4.4.Duringtreatment,

periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.Womenshouldbe

advisedwhatchangesinthebreastsshouldbereportedtotheirdoctorornurse(see“Breastcancer”below).

Investigations,includingmammography,shouldbecarriedoutinaccordancewithcurrentlyacceptedscreening

practices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviouslyand/orhavebeenaggravatedduringpregnancy

orprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthatthese

conditionsmayrecurorbeaggravatedduringtreatmentwithEstalisSequi50µg/250µg/24hours,inparticular:

Leiomyoma(uterinefibroids)orendometriosis

Ahistoryof,orriskfactorsforthromboembolicdisorders(seebelow)

Riskfactorsforoestrogendependenttumours,e.g.1 st

degreeheredityforbreastcancer

Hypertension

Liverdisorders(e.g.liveradenoma)

Diabetesmellituswithorwithoutvascularinvolvement

Cholelithiasis

Migraineorsevereheadache

Systemiclupuserythematosus(SLE)

Ahistoryofendometrialhyperplasia(seebelow)

Epilepsy

Asthma

Otosclerosis

Reasonsforimmediatewithdrawaloftherapy

Therapyshouldbediscontinuedincaseacontraindicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction

Significantincreaseinbloodpressure

Newonsetofmigraine-likeheadache

Pregnancy

Endometrialhyperplasia

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenoestrogensareadministratedalonefor

prolongedperiods(seesection4.8).Theadditionofaprogestogenforatleast12dayspercycleinnon-

hysterectomisedwomengreatlyreducesthisrisk.Break-throughbleedingandspottingmayoccurduringthefirst

monthsoftreatment.Ifbreak-throughbleedingorspottingappearsaftersometimeontherapy,orcontinuesafter

treatmenthasbeendiscontinued,thereasonshouldbeinvestigated,whichmayincludeendometrialbiopsyto

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Breastcancer

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

includingtheMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentaking

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

HRT,anexcessriskbecomesapparentwithinafewyearsofuseandincreaseswithdurationofintakebutreturns

tobaselinewithinafew(atmostfive)yearsafterstoppingtreatment.

IntheMWS,therelativeriskofbreastcancerwithconjugatedequineestrogens(CEE)orestradiol(E2)was

greaterwhenaprogestogenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeofprogestogen.

Therewasnoevidenceofadifferenceinriskbetweenthedifferentroutesofadministration.

IntheWHIstudy,thecontinuouscombinedconjugatedequineestrogensandmedroxyprogesteroneacetate(CEE

+MPA)productusedwasassociatedwithbreastcancersthatwereslightlylargerinsizeandmorefrequentlyhad

locallymphnodemetastasescomparedtoplacebo.

HRT,especiallyoestrogen-progestogencombinedtreatment,increasesthedensityofmammographicimages

whichmayadverselyaffecttheradiologicaldetectionofbreastcancer.

Venousthromboembolism

HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism(VTE),i.e.deepvein

thrombosisorpulmonaryembolism.Onerandomisedcontrolledtrialandepidemiologicalstudiesfoundatwo-to

threefoldhigherriskforuserscomparedwithnon-users.Fornon-users,itisestimatedthatthenumberofcasesof

VTEthatwilloccurovera5-yearperiodisabout3per1000womenaged50-59yearsand8per1000women

agedbetween60-69years.

ItisestimatedthatinhealthywomenwhouseHRTfor5years,thenumberofadditionalcasesofVTEovera5

yearperiodwillbebetween2and6(bestestimate=4)per1000womenaged50-59yearsandbetween5and15

(bestestimate=9)per1000womenaged60-69years.Theoccurrenceofsuchaneventismorelikelyinthefirst

yearofHRTthanlater.

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,particularlyabdominalor

orthopaedicsurgerytothelowerlimbs,considerationshouldbegiventotemporarilystoppingHRT4to6weeks

earlier,ifpossible.Treatmentshouldnotberestarteduntilthewomaniscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorimmediatelywhentheyareawareofapotentialthromboembolicsymptom(e.g.painfulswellingofaleg,

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Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombined

conjugatedoestrogensandmedroxyprogesteroneacetate(MPA).Twolargeclinicaltrials(WHIandHERSi.e.

HeartandEstrogen/progestinReplacementStudy)showedapossibleincreasedriskofcardiovascularmorbidity

inthefirstyearofuseandnooverallbenefit.ForotherHRTproductsthereareonlylimiteddatafrom

randomisedcontrolledtrialsexaminingeffectsincardiovascularmorbidityormortality.Therefore,itisuncertain

whetherthesefindingsalsoextendtootherHRTproducts.

Stroke

Onelargerandomisedclinicaltrial(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischemic

strokeinhealthywomenduringtreatmentwithcontinuouscombinedconjugatedoestrogensandMPA.For

womenwhodonotuseHRT,itisestimatedthatthenumberofcasesofstrokethatwilloccurovera5-year

periodisabout3per1000womenaged50to59yearsand11per1000womenaged60to69years.

ItisestimatedthatforwomenwhouseconjugatedoestrogensandMPAfor5years,thenumberofadditional

caseswillbebetween0and3(bestestimate=1)per1000usersaged50to59yearsandbetween1and9(best

estimate=4)per1000usersaged60to69years.Itisunknownwhethertheincreasedriskalsoextendstoother

HRTproducts.

Ovariancancer

Long-term(atleast5to10years)useofoestrogen-onlyHRTproductsinhysterectomisedwomenhasbeen

associatedwithanincreasedriskofovariancancerinsomeepidemiologicalstudies.Itisuncertainwhetherlong-

termuseofcombinedHRTconfersadifferentriskthanoestrogen-onlyproducts.

Otherconditions

Oestrogensmaycausefluidretentionandthereforewomenwithcardiacorrenaldysfunctionshouldbecarefully

observed.Womenwithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitisexpectedthatthelevel

ofcirculatingactiveingredientsofEstalisSequi50µg/250µg/24hoursisincreased.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringoestrogenreplacementor

hormonereplacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitis

havebeenreportedwithoraloestrogentherapyinthiscondition.

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.ThereissomeevidencefromtheWHI

trialofincreasedriskofprobabledementiainwomenwhostartusingcontinuouscombinedCEEandMPAafter

theageof65.ItisunknownwhetherthefindingsapplytoyoungerpostmenopausalwomenorotherHRT

products.

Contactsensitisationisknowntooccurwithalltopicalapplications.Althoughitisextremelyrare,womenwhodevelop

contactsensitisationtoanyofthecomponentsofthepatchshouldbewarnedthataseverehypersensitivityreaction

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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

progestogens.

Attransdermaladministration,thefirst-passeffectintheliverisavoidedand,thus,transdermallyappliedoestrogens

andprogestogensmightbelessaffectedthanoralhormonesbyenzymeinducers.

Clinically,anincreasedmetabolismofoestrogensandprogestogensmayleadtodecreasedeffectsandchangesinthe

uterinebleedingprofile.

4.6Pregnancyandlactation

Pregnancy

EstalisSequi50µg/250µg/24hoursisnotindicatedduringpregnancy.Ifpregnancyoccursduringmedicationwith

EstalisSequi50µg/250µg/24hourstreatmentshouldbewithdrawnimmediately.

Dataonalimitednumberofexposedpregnanciesindicatenoadverseeffectsofnorethisteroneacetateonthefoetus.At

doseshigherthannormallyusedinoralcontraceptivesandHRTformulationsmasculinisationoffemalefoetuseswas

observed.

Theresultsofmostepidemiologicalstudiestodaterelevanttoinadvertentfoetalexposuretocombinationsof

oestrogensandprogestogensindicatenoteratogenicorfoetotoxiceffect.

Lactation

EstalisSequi50µg/250µg/24hoursisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

EstalisSequi50µg/250µg/24hourshasnoknowneffectsontheabilitytodriveandusemachines.

4.8Undesirableeffects

ApproximatelyonethirdofthewomentreatedwithEstalisSequi50µg/250µg/24hourscanbeexpectedtoexperience

adversereactions.Themostcommonlyreportedadverseexperiencesarebreasttensionandpain(31%),applicationsite

reactions(20%mostlymilderythema),dysmenorrhoea(19%),irregularbleeding(16%)andheadache(10%).

Table1:

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

1/1,000);Veryrare(<1/10,000)

Investigations

Uncommon Transaminasesincrease

Nervoussystemdisorders

Verycommon Headache

Common Dizziness,nervousness,insomnia,moodchanges

Uncommon Migraine,vertigo

Gastrointestinaldisorders

Common Nausea,flatulence,diarrhoea,dyspepsia,abdominalpain

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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).

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

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,irregular

vaginalbleeding,uterinespasms,vaginitis,endometrial

hyperplasia

Uncommon Breastcancer

Rare Uterineleiomyomata,paratubularcysts,endocervicalpolyps

Psychiatricdisorders

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TheabsoluteriskscalculatedfromtheMWSandtheWHItrialarepresentedbelow:

TheMWShasestimated,fromtheknownaverageincidenceofbreastcancerindevelopedcountries,that:

ForwomennotusingHRT,about32inevery1000areexpectedtohavebreastcancerdiagnosedbetweenthe

agesof50and64years.

For1000currentorrecentusersofHRT,thenumberofadditionalcasesduringthecorrespondingperiodwillbe:

Forusersofoestrogen-onlyreplacementtherapy

between0and3(bestestimate=1.5)for5years’use,

between3and7(bestestimate=5)for10years’use.

ForusersofoestrogenplusprogestogencombinedHRT

between5and7(bestestimate=6)for5years’use,

between18and20(bestestimate=19)for10years’use.

TheWHItrialestimatedthatafter5.6yearsoffollow-upofwomenbetweentheagesof50and79years,anadditional

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

womenyears.

Accordingtocalculationsfromthetrialdata,itisestimatedthat:

For1000womenintheplacebogroup,about16casesofinvasivebreastcancerwouldbediagnosedin5years.

For1000womenwhousedoestrogen+progestogencombinedHRT(CEE+MPA),thenumberofadditional

caseswouldbebetween0and9(bestestimate=4)for5years’use.

ThenumberofadditionalcasesofbreastcancerinwomenwhouseHRTisbroadlysimilarforwomenwhostartHRT

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

Endometrialcancer

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandendometrialcancerincreaseswithincreasing

durationofuseofunopposedoestrogens.Accordingtodatafromepidemiologicalstudies,thebestestimateoftherisk

isthatforwomennotusingHRT,about5inevery1000areexpectedtohaveendometrialcancerdiagnosedbetween

theagesof50and65.Dependingonthedurationoftreatmentandoestrogendose,thereportedincreaseinendometrial

cancerriskamongunopposedoestrogenusersvariesfrom2-to12-foldgreatercomparedwithnon-users.Addinga

progestogentooestrogen-onlytherapygreatlyreducesthisincreasedrisk.

Otheradversereactionshavebeenreportedinassociationwithoestrogen-progestogentreatments:

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

appeartheEstalisSequi50µg/250µg/24hourstransdermalpatchshouldberemoved.Theeffectsofoverdosagewith

oraloestrogensarebreasttenderness,nausea,vomitingand/ormetrorrhagia.Overdosageofprogestogensmayleadtoa

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Genitourinarysystemandsexhormones

ATCcode:G03FB05.

Theactiveingredient,estradiolhemihydrate,asynthetic17-estradiol,ischemicallyandbiologicallyidenticalto

endogenoushumanestradiol.Itsubstitutesforthelossofoestrogenproductioninmenopausalwomen,andalleviates

menopausalsymptoms.

Oestrogenspreventbonelossfollowingmenopauseorovariectomy.

Asoestrogenspromotethegrowthoftheendometrium,unopposedoestrogensincreasetheriskofendometrial

hyperplasiaandcancer.Theadditionofnorethisteroneacetate,aprogestogen,reducestheoestrogen-inducedriskof

endometrialhyperplasiainnon-hysterectomisedwomen.

Informationfromclinicaltrials

Reliefofoestrogen-deficiencysymptomsandbleedingpatterns:

Reliefofmenopausalsymptomswasachievedduringthefirstfewweeksoftreatment.

Regularwithdrawalbleedingoccurredin64%ofwomenafter11treatmentcycleswithEstalisSequi50µg/250µg/24

hours.Irregularbleedingand/orspottingwerereportedin28%,andamenorrheain8%.

Preventionofosteoporosis

Oestrogendeficiencyatmenopauseisassociatedwithanincreasingboneturnoveranddeclineinbonemass.Theeffect

ofoestrogensonthebonemineraldensityisdose-dependent.Protectionappearstobeeffectiveforaslongastreatment

iscontinued.AfterdiscontinuationofHRT,bonemassislostataratesimilartothatinuntreatedwomen.

EvidencefromtheWHItrialandmeta-analysedtrialsshowsthatcurrentuseofHRT,aloneorincombinationwitha

progestogen–giventopredominantlyhealthywomen–reducestheriskofhip,vertebral,andotherosteoporotic

fractures.HRTmayalsopreventfracturesinwomenwithlowbonedensityand/orestablishedosteoporosis,butthe

evidenceforthatislimited.

AftertwoyearsoftreatmentwithEstalisSequi50µg/250µg/24hours,theincreaseinlumbarspinebonemineral

density(BMD)was5.53%±0.63%(mean±SD).ThepercentageofwomenwhomaintainedorgainedBMDinlumbar

zoneduringtreatmentwas95.0%.

EstalisSequi50µg/250µg/24hoursalsohadaneffectonhipBMD.Theincreaseaftertwoyearswas3.07%±0.64%

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

5.2Pharmacokineticproperties

Absorption

Transdermallydeliveredestradiolbypassesthefirstpasseffectseenwithorallyadministeredoestrogenproducts.

Estradiol:EstalisSequi50µg/250µg/24hourstransdermalpatchachievesestradiolserumlevelsandestrone/estradiol

ratiosintherangeofthoseobservedinpremenopausalwomenattheearly(estradiol>40pg/ml)tomid-follicular

phase.Thesecharacteristicsaremaintainedforanentire84to96hourwearperiod.RepeatedapplicationoftheEstalis

SequiPhaseIpatchresultedinsteady-statemaximumestradiolserumconcentration(C

)of71pg/mlandaverage

estradiolserumconcentration(C

)of51pg/ml.Attheendoftheapplicationperiods,themeanserumestradiol

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RepeatedapplicationoftheEstalisSequiPhaseIIpatchresultedinsteady-statemaximumestradiolserum

concentration(C

)of71pg/mlandaverageestradiolserumconcentration(C

)of51pg/ml.Attheendofthe

applicationperiods,themeanserumestradiolconcentration(troughconcentration)was46pg/ml.

Norethisteroneacetate:RepeatedapplicationofEstalisSequiPhaseIIpatchesresultedinsteady-statemaximumserum

norethisteroneconcentration(C

)of1060pg/mlandaverageserumnorethisteroneconcentration(C

)of832

pg/ml.Attheendoftheapplicationperiods,themeanserumconcentrationofnorethisteronewas681pg/ml.

Metabolismandelimination

Estradiol:Estradiolhasashorteliminationhalf-lifeofapproximately2to3hours,whichmeansthatserumlevels

quicklydropwhenthetransdermalpatchisremoved.Afterthetransdermalpatchhasbeenremoved,serumestradiol

concentrationsreturntountreatedpostmenopausallevels(<20pg/ml)within4to8hours.

Norethisterone:Theeliminationhalf-lifeofnorethisteroneisreportedtobe6to8hours.AfterremovaloftheEstalis

SequiPhaseIIpatch,serumnorethisteroneconcentrationsdiminishrapidlyandarelessthan50pg/mlwithin48hours.

Minimalfluctuationsinserumestradiolandnorethisteroneconcentrationsdemonstrateconsistentdeliveriesoverthe

applicationinterval.

Thereisnoaccumulationofestradiolornorethisteroneinthecirculationfollowingmultipleapplications.

5.3Preclinicalsafetydata

Theacutetoxicityofestrogensislow.Becauseofmarkeddifferencesbetweenanimalspeciesandbetweenanimalsand

humanspreclinicalresultspossessalimitedpredictivevaluefortheapplicationofestrogensinhumans.

Inexperimentalanimalsestradiolorestradiolvaleratedisplayedanembryolethaleffectalreadyatrelativelylowdoses;

malformationsoftheurogenitaltractandfeminisationofmalefoetuseswereobserved.

Norethisterone,likeotherprogestogens,causedvirilisationoffemalefoetusesinratsandmonkeys.Afterhighdosesof

norethisteroneembryolethaleffectswereobserved.

Non-clinicaldatabasedonconventionalstudiesofrepeateddosetoxicity,genotoxicityandcarcinogenicpotential

revealednoparticularhumanrisksbeyondthosediscussedinothersectionsoftheSPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

EstalisSequiPhaseI

Acrylicadhesive

Rubber-basedsyntheticadhesive

Polyisobutylene

Oleicacid

Bentonite

Ethylenevinylacetateresin

1,3-Butanediol

Mineraloil

Dipropyleneglycol

Lecithin/propyleneglycolmixture.

Thebackinglayerconsistsofapolyurethane/ethylenevinylalcoholcopolymerfilm.Theprotective(release)linerisa

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EstalisSequiPhaseII

Siliconeadhesives

Acrylicadhesives

Povidone

Oleicacid

Dipropyleneglycol

Thebackinglayerconsistsofapolyesterfilmlaminate.Theprotective(release)linerisafluoropolymercoated

polyesterfilm.

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

24months:18monthsstoredinarefrigerator(2°Cto8°C)plus6monthsstoredbelow25°C.

6.4Specialprecautionsforstorage

Storeandtransportrefrigerated(2°C-8°C).Donotfreeze.Oncedispensedtothepatient,EstalisSequi50

micrograms/250micrograms/24hoursmaybestoredbelow25°Cforamaximumperiodof6months.Storeinthe

original(sealed)pouch.Eachpatchshouldbeusedimmediatelyafteropeningthepouch.

6.5Natureandcontentsofcontainer

EstalisSequi50micrograms/250micrograms/24hourstransdermalpatchesarepackedindividuallyinheat-sealed

paper/polyethylenesachets.

EstalisSequi50micrograms/250micrograms/24hourspackconsistsof4or12PhaseIroundtransdermalpatcheseach

containingestradiolhemihydrateequivalentto4.33mgestradioland4or12PhaseIIroundtransdermalpatches,each

containingestradiolhemidhydrateequivalentto0.51mgestradioland4.80mgnorethisteroneacetate.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Usedpatchesshouldbefoldedinhalfwithadhesivesurfacespressedtogetheranddiscardedsafelyandawayfromthe

reachandsightofchildren.

7MARKETINGAUTHORISATIONHOLDER

NovartisPharmaceuticalsLimited

FrimleyBusinessPark

Frimley

Camberley

SurreyGU167SR

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:16October1998

Dateoflastrenewal: 06March2008

10DATEOFREVISIONOFTHETEXT

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