CLIMARA

Main information

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

Documents

Localization

  • Available in:
  • CLIMARA Transdermal Patch 25 Microgram/day
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1410/015/003
  • Authorization date:
  • 19-10-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1410/015/003

CaseNo:2029216

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

BayerLimited

TheAtrium,BlackthornRoad,Dublin18,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Climara25micrograms/24hoursTransdermalPatch

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom15/04/2008.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Climara25micrograms/24hoursTransdermalPatch

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each6.5cm 2

patchcontains1.97mgestradiol(formedfrom2.04mgestradiolhemihydrate),releasinganominal25

microgramsofestradiolper24hours.

Forexcipients,seesection6.1.

3PHARMACEUTICALFORM

Transdermalpatch.

Ovaltransdermalpatchwithatranslucenthomogenousmatrixonatransparentcarrierfilm.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapy(HRT)foroestrogendeficiencysymptomsinpostmenopausalwomenmorethan1year

postmenopause.

Theexperiencetreatingwomenolderthan65yearsislimited.

Seealsosection4.4.

4.2Posologyandmethodofadministration

Posology

Climaraisanoestrogen-onlypatchappliedtotheskinonceweekly.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

duration(seealsoSection4.4)shouldbeused.Treatmenttocontrolmenopausalsymptomsshouldbeinitiatedwiththe

lowestClimarapatchdose.Ifconsiderednecessary,ahigherdosedpatchshouldbeused.Inwomenwithanintact

uterus,aprogestogenshouldbeaddedtoClimaraforatleast12–14dayseachmonth.Unlessthereisaprevious

diagnosisofendometriosis,itisnotrecommendedtoaddaprogestogeninhysterectomisedwomen.

Forcontinuoususe:Thepatchesshouldbeappliedonceweeklyonacontinuousbasis,eachusedpatchbeingremoved

after7daysandafreshpatchappliedtoadifferentsite.

Forcyclicaluse:Thepatchesmayalsobeprescribedonacyclicalbasis. Wherethisisthepreferredoption,the

patchesshouldbeappliedweeklyfor3consecutiveweeksfollowedbya7-dayinterval,withoutapatchbeingapplied,

beforethenextcourse.

HowtostartClimara

WomenwhodonottakeoestrogensorwomenwhochangefromacontinuouscombinedHRTproductmaystart

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PatientschangingfromacontinuoussequentialHRTregimen,shouldbeginthedayfollowingcompletionoftheprior

regimen.

PatientschangingfromacyclicHRTregimenshouldbeginthedayafterthetreatment-freeperiod.

Missedorlostpatch

Intheeventthatapatchfallsoffbefore7daysareup,itmaybereapplied.Ifnecessary,anewpatchshouldbeapplied

fortheremainderofthe7-daydosinginterval.

Ifthepatientforgetstoreplaceapatch,thisshouldbedoneassoonaspossibleaftersheremembersit.Thenextpatch

hastobeusedafterthenormal7-dayinterval.

Afterseveraldayswithoutreplacementofanewpatchthereisanincreasedlikelihoodofbreakthroughbleedingand

spotting.

Modeofapplication

FollowingremovaloftheprotectivelinertheadhesivesideofClimarapatchesshouldbeplacedonaclean,dryareaof

theskinofthetrunkorbuttocks.Climarapatchesshouldnotbeappliedtothebreasts.Thesitesofapplicationshould

berotated,withanintervalofatleastoneweekbetweenapplicationstoaparticularsite.Theareaselectedshouldnot

beoily,damaged,orirritated.Thewaistlineshouldbeavoidedsincetightclothingmayrubthepatchoff.

Thepatchshouldbeappliedimmediatelyafteropeningthepouchandremovingtheprotectiveliner.Thepatchshould

bepressedfirmlyinplacewiththepalmofthehandforabout10seconds,makingsurethereisgoodcontact,especially

aroundtheedges.

Ifthepatchisappliedcorrectly,thepatientcanbathorshowerasusual.Thepatchmight,however,becomedetached

fromtheskininveryhotbathwaterorinthesauna.

Children

Notrecommendedforchildren

4.3Contraindications

Known,pastorsuspectedbreastcancer

Knownorsuspectedoestrogendependentmalignanttumourse.g.endometrialcancer

Undiagnosedgenitalbleeding

Untreatedendometrialhyperplasia

Previousidiopathicorcurrentvenousthromboembolism(deepvenousthrombosis,pulmonaryembolism)

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfarction)

Acuteliverdisease,orahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal

Porphyria

Knownhypersensitivitytoestradiolortoanyoftheexcipients

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk.

Medicalexamination/follow-up

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythecontraindicationsandwarningsforuse.

Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.

Womenshouldbeadvisedwhatchangesintheirbreastsshouldbereportedtotheirdoctorornurse(see‘Breastcancer’

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Investigations,includingmammography,shouldbecarriedoutinaccordancewithcurrentlyacceptedscreening

practices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichrequiresupervision

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviouslyand/orhavebeenaggravatedduringpregnancy

orprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthatthese

conditionsmayrecurorbeaggravatedduringtreatmentwithClimara25,inparticular:

-Leiomyoma(uterinefibroids)orendometriosis

-Ahistoryof,orriskfactorsfor,thromboembolicdisorders(seebelow)

-Riskfactorsforoestrogendependenttumours,e.g.1stdegreeheredityforbreastcancer

-Hypertension

-Liverdisorders(e.g.liveradenoma)

-Diabetesmellituswithorwithoutvascularinvolvement

-Cholelithiasis

-Migraineor(severe)headache

-Systemiclupuserythematosus

-Ahistoryofendometrialhyperplasia(seebelow)

-Epilepsy

-Asthma

-Otosclerosis

-Hereditaryangioedema

Reasonsforimmediatewithdrawaloftherapy:

Therapyshouldbediscontinuedincaseacontra-indicationisdiscoveredandinthefollowingsituations:

-Jaundiceordeteriorationinliverfunction

-Significantincreaseinbloodpressure

-Newonsetofmigraine-typeheadache

-Pregnancy

Endometrialhyperplasia

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenoestrogensareadministeredalonefor

prolongedperiods(seesection4.8).Theadditionofaprogestogenforatleast12dayspercycleinnon-

hysterectomisedwomengreatlyreducesthisrisk.

Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-throughbleeding

orspottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereason

shouldbeinvestigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Unopposedoestrogenstimulationmayleadtopremalignantormalignanttransformationintheresidualfociof

endometriosis.Therefore,theadditionofprogestogenstooestrogenreplacementtherapyshouldbeconsidered

inwomenwhohaveundergonehysterectomybecauseofendometriosis,iftheyareknowntohaveresidual

endometriosis.

Breastcancer

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

includingtheMillionWomenStudy(MWS)havereportedanincreasedriskofbreastcancerinwomentaking

oestrogens,oestrogen-progestogencombinationsortiboloneforHRTforseveralyears(seeSection4.8).Forall

HRT,anexcessriskbecomesapparentwithinafewyearsofuseandincreaseswithdurationofintakebutreturns

tobaselinewithinafew(atmostfive)yearsafterstoppingtreatment.

IntheMWS,therelativeriskofbreastcancerwithconjugatedequineoestrogens(CEE)orestradiol(E2)was

greaterwhenaprogestogenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeof

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IntheWHIstudy,thecontinuouscombinedconjugatedequineoestrogenandmedroxyprogesteroneacetate(CEE

+MPA)productusedwasassociatedwithbreastcancersthatwereslightlylargerinsizeandmorefrequentlyhad

locallymphnodemetastasescomparedtoplacebo.

HRT,especiallyoestrogen-progestogencombinedtreatment,increasesthedensityofmammographicimages

whichmayadverselyaffecttheradiologicaldetectionofbreastcancer.

Venousthromboembolism

HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism(VTE),i.e.deepvein

thrombosisorpulmonaryembolism.Onerandomisedcontrolledtrialandepidemiologicalstudiesfoundatwo-to

threefoldhigherriskforuserscomparedwithnon-users.Fornon-users,itisestimatedthatthenumberofcases

ofVTEthatwilloccurovera5yearperiodisabout3per1000womenaged50-59yearsand8per1000women

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-

riskofuseofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajorsurgery.

Asinallpostoperativepatients,scrupulousattentionshouldbegiventoprophylacticmeasurestopreventVTE

followingsurgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,particularlyabdominalor

orthopaedicsurgerytothelowerlimbs,considerationshouldbegiventotemporarilystoppingHRT4to6weeks

earlier,ifpossible.Treatmentshouldnotberestarteduntilthewomaniscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorsimmediatelywhentheyareawareofapotentialthromboembolicsymptom(e.g.painfulswellingofaleg,

suddenpaininthechest,dyspnoea).

Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombined

conjugatedoestrogensandmedroxyprogesteroneacetate(MPA).Twolargeclinicaltrials(WHIandHERS,i.e.

HeartandEstrogen/progestinReplacementStudy)showedapossibleincreasedriskofcardiovascularmorbidity

inthefirstyearofuseandnooverallbenefit.ForotherHRTproductsthereareonlylimiteddatafrom

randomisedcontrolledtrialsexaminingeffectsincardiovascularmorbidityormortality.Therefore,itisuncertain

whetherthesefindingsalsoextendtootherHRTproducts.

Stroke

Onelargerandomisedclinicaltrial(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischaemic

strokeinhealthywomenduringtreatmentwithcontinuouscombinedconjugatedoestrogensandMPA.For

womenwhodonotuseHRT,itisestimatedthatthenumberofcasesofstrokethatwilloccurovera5year

periodisabout3per1000womenaged50-59yearsand11womenper1000womenaged60-69years.Itis

estimatedthatforwomenwhouseconjugatedoestrogensandMPAfor5years,thenumberofadditionalcases

willbebetween0and3(bestestimate=1)per1000usersaged50-59yearsandbetween1and9(bestestimate=

4)per1000usersaged60-69years.ItisunknownwhethertheincreasedriskalsoextendstootherHRT

products.

Ovariancancer

Long-term(atleast5-10years)useofoestrogenonlyHRTproductsinhysterectomisedwomenhasbeenassociated

withanincreasedriskofovariancancerinsomeepidemiologicalstudies.Itisuncertainwhetherlong-termuseof

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Otherconditions

Oestrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.Patientswithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitisexpectedthatthelevel

ofcirculatingactiveingredientsinClimara25isincreased.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringoestrogenreplacementor

hormonereplacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitis

havebeenreportedwithoestrogentherapyinthiscondition.

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.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Themetabolismofoestrogensmaybeincreasedbyconcomitantuseofsubstancesknowntoinducedrug-metabolising

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

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

Ritonavirandnelfinavir,althoughknownasstronginhibitors,bycontrastexhibitinducingpropertieswhenused

concomitantlywithsteroidhormones.HerbalpreparationscontainingSt.John'swort(Hypericumperforatum)may

inducethemetabolismofoestrogens.

Attransdermaladministration,thefirst-passeffectintheliverisavoidedand,thus,transdermallyappliedoestrogens

mightbelessaffectedthanoralhormonesbyenzymeinducers.

Clinically,anincreasedmetabolismofoestrogensmayleadtodecreasedeffectandchangesintheuterinebleeding

profile.

4.6Pregnancyandlactation

Pregnancy

Climaraisnotindicatedduringpregnancy.IfpregnancyoccursduringmedicationwithClimaratreatmentshouldbe

withdrawnimmediately.

Theresultsofmostepidemiologicalstudiestodaterelevanttoinadvertentfoetalexposuretooestrogensindicateno

teratogenicorfoetotoxiceffects.

Lactation

Climaraisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

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4.8Undesirableeffects

Duringthefirstfewmonthsoftreatment,breakthroughbleeding,spottingandbreasttendernessorenlargementcan

occur.Theseareusuallytemporaryandnormallydisappearaftercontinuedtreatment.Thetablebelowlistsadverse

drugreactionsrecordedinclinicalstudiesaswellasadversedrugreactionsreportedpost-marketing.Adversedrug

reactionswererecordedin3phaseIIIclinicalstudies(n=219women)andconsideredatleastpossiblyrelatedto

treatmentwith25µg/dayestradiolfollowingtransdermalapplication.

havebeenreportedinsinglecases.Giventhesmallstudypopulation(n=219)itcannotbedeterminedbasedontheseresultsiftheseeventsare

uncommonorrare.

Breastcancer

Accordingtoevidencefromalargenumberofepidemiologicalstudiesandonerandomisedplacebo-controlledtrial,the

Women’sHealthInitiative(WHI),theoverallriskofbreastcancerincreaseswithincreasingdurationofHRTusein

Organsystem Adversedrugreactionsreportedin

clinicaltrials Adversedrug

reactions

reportedpost

marketing Common

(1/100,<1/10) Uncommon

(1/1000,<1/100)

BODYASAWHOLE Laboratorytest

abnormal. Paininbackor

extremity,asthenia 1

CARDIOVASCULAR

SYSTEM Migraine 1

hypertension 1

tachycardia 1

DIGESTIVE Nausea,diarrhoea,

flatulence 1

,abnormal

liverfunctiontest 1

IMMUNESYSTEM

DISORDERS Exacerbationof

hereditary

angioedema

METABOLICAND

NUTRITIONAL Localizedor

generalised

oedema. Weightgain.

MUSCULOSKELETAL

SYSTEM Arthralgia 1

Musclecramps

NERVOUSSYSTEM Headache. Hotflushes,

dizziness 1

Paraesthesia,

Insomnia,

Nightsweats

SKINand

APPENDAGES Applicationsite

reaction,skin

disorder,breast

pain Rashskindisorder,

alopecia 1

,dryskin 1

skindiscoloration 1

erythemanodosum 1

benignbreast

neoplasm 1

SPECIALSENSES

Tastedisturbance 1

UROGENITAL Leucorrhoea,

urinarydisorder,

vaginalbleeding. cervicalsmear

changes,candidiasis,

dyspareunia 1

,uterine

disorder 1

,vaginal

dryness 1

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Foroestrogen-onlyHRT,estimatesofrelativerisk(RR)fromareanalysisoforiginaldatafrom51epidemiological

studies(inwhich>80%ofHRTusewasoestrogen-onlyHRT)andfromtheepidemiologicalMillionWomenStudy

(MWS)aresimilarat1.35(95%CI1.21-1.49)and1.30(95%CI1.211.40),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

combinedHRT(CEE+MPA)inalluserscomparedwithplacebo.

TheabsoluteriskscalculatedfromtheMWSandtheWHItrialarepresentedbelow:

TheMWShasestimated,fromtheknownaverageincidenceofbreastcancerindevelopedcountries,that:

ForwomennotusingHRT,about32inevery1000areexpectedtohavebreastcancerdiagnosedbetweenthe

agesof50and64years.

For1000currentorrecentusersofHRT,thenumberofadditionalcasesduringthecorrespondingperiodwill

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

caseswouldbe

between0and9(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/progestogentreatment:

-Oestrogen-dependentneoplasmsbenignandmalignant,e.g.endometrialcancer.

-Venousthromboembolism,i.e.deeplegorpelvicvenousthrombosisandpulmonaryembolism,ismorefrequent

amonghormonereplacementtherapyusersthanamongnon-users.Forfurtherinformation,seesection4.3

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-Myocardialinfarctionandstroke(seealsosection4.4).

-Gallbladderdisease.

-Skinandsubcutaneousdisorders:chloasma,erythemamultiforme,erythemanodosum,vascularpurpura.

-Probabledementia(seesection4.4).

4.9Overdose

Overdosageisunlikelywiththistypeofapplication.Nausea,vomitingandwithdrawalbleedingmayoccurinsome

women.Thereisnospecificantidoteandtreatmentshouldbesymptomatic.Thepatch(es)shouldberemoved.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Naturalandsemisyntheticoestrogens,plain

ATCcode:G03CA03

TheactiveingredientofClimara,synthetic17ß-estradiol,ischemicallyandbiologicallyidenticaltoendogenoushuman

estradiol.Itsubstitutesforthelossofoestrogenproductioninmenopausalwomen,andalleviatesmenopausal

symptoms.

Reliefofmenopausalsymptomswasachievedduringthefirstfewweeksoftreatment.

5.2Pharmacokineticproperties

Absorption

AfterdermalapplicationofClimara,estradioliscontinuouslyreleasedandtransportedacrossintactskinleadingto

sustainedcirculatinglevelsofestradiolduringa7-daytreatmentperiod.Thesystemicavailabilityofestradiolafter

transdermaladministrationisabout20timeshigherthanthatafteroraladministration.Thisdifferenceisduetothe

absenceoffirstpassmetabolismwhenestradiolisgivenbythetransdermalroute.Themajorpharmacokinetic

parametersofestradiolaresummarisedinthefollowingtable:

Distribution

Thedistributionofexogenousoestrogensissimilartothatofendogenousoestrogens.Theapparentvolumeof

distributionofestradiolaftersingleintravenousadministrationisabout1l/kg.Oestrogenscirculateinthebloodlargely

boundtoserumproteins.About61%ofestradiolisboundnon-specificallytoserumalbuminandabout37%

specificallytosexhormonebindingglobulin(SHBG).

Metabolism

Thebiotransformationofthetransdermallyadministeredestradiolisthesameasthatoftheendogenoushormone:

Estradiolismainlymetabolisedintheliverbutalsoextrahepaticallye.g.ingut,kidney,skeletalmusclesandtarget

organs.Theseprocessesinvolvetheformationofestrone,estriol,catecholoestrogensandsulphateandglucuronide

Transdermal

Delivery

System Daily

Delivery

Rate,

mg/day Application

Site AUC(0-Tlast)

ngxh/mL/

nmolxh/L Cmax

pg/mL/

pmol/L Cavg

pg/mL/

pmol/L tmax

Cmin

pg/mL/

pmol/L

Climara25 0.025 Abdomen 3.57/

31/

21/

17/

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Excretion

Thetotalserumclearanceofestradiolfollowingsingleintravenousadministration,showshighvariabilityintherange

of10-30ml/min/kg.Estradiolanditsmetabolitesareexcretedinthebileandundergoaso-calledenterohepatic

circulation.Ultimatelyestradiolanditsmetabolitesaremainlyexcretedassulfatesandglucuronideswiththeurine.

Steady-stateconditions

Accumulationofestradiolandestronewasnotobservedfollowingmultiple1weekpatchapplicationsofhigher

strengthsofClimara.Accordingly,steady-stateserumlevelsofestradiolandestronecorrespondtothoseobservedafter

asingleapplication.

5.3Preclinicalsafetydata

Thetoxicityprofileofestradioliswellknown.Therearenopreclinicaldataofrelevancetotheprescriberwhichare

additionaltothatalreadyincludedinothersectionsoftheSPC.

Inprimarydermalirritationstudiesinrabbits,applicationoftheClimarapatchresultedinmildirritationrelatedto

mechanicaltraumaatremoval.InsensitisationstudiestheClimarapatchhadnodermalsensitisingpotential.

Studiesonthecomponents(adhesivematrix,backingandreleaseliner)didnotindicateanyriskrelatedtotheuseof

theClimarapatch.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Adhesivematrix:Isooctylacrylate/acrylamide/vinylacetatecopolymer,ethyloleate,isopropylmyristate,glycerol

monolaurate

Adhesivebackingfilm:polyethylene

Protectivereleaseliner(removable):polyethyleneterphthalate

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Storebelow30°C.

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Eachpatchissealedinamultilaminatepouchcontainingadesiccant.Thepouchconsistsof

polyester/aluminium/acrylonitril,methylacrylatecopolymer(BAREX210).Thedesiccantconsistsofsodiumalumino

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Afterusethepatchstillcontainssubstantialquantitiesofestradiol,whichmayhaveharmfuleffectsifreachingthe

aquaticenvironment.Therefore,theusedpatchshouldbediscardedcarefully.Anyusedorunusedpatchesshouldbe

foldedinhalf,adhesivesidestogether,anddisposedofinthesolidwastedisposalsystem.Usedpatchesshouldnotbe

flusheddownthetoiletnorplacedinliquidwastedisposalsystems.

7MARKETINGAUTHORISATIONHOLDER

BayerLimited

TheAtrium

BlackthornRoad

Dublin18

8MARKETINGAUTHORISATIONNUMBER

PA1410/15/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:5 th

May2006

Dateoflastrenewal:15 th

April2007

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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