ESTRADIOL TTS

Main information

  • Trade name:
  • ESTRADIOL TTS
  • Dosage:
  • 1.5 Milligram
  • Pharmaceutical form:
  • Transdermal Patch
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0654/003/001
  • Authorization date:
  • 07-09-1999
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

EstradiolTTSTransdermalPatch.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onetransdermalpatch contains1.5 mg estradiolhemihydratedelivering 50 microgramsofestradiolin 24 hours.

Patch size15cmactivesurfacearea.

Forexcipients, see6.1

3PHARMACEUTICALFORM

Transdermalpatch.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapy foroestrogen deficiency symptomsin post-menopausalwomen.

Prevention ofosteoporosisin post-menopausalwomen athigh risk offuturefractureswho areintolerantof, or

contraindicated for, othermedicinalproductsapproved fortheprevention ofosteoporosis.

(Seealso section 4.4)

Theexperienceoftreating women olderthan 65 yearsislimited.

4.2Posologyandmethodofadminstration

EstradiolTTSisan oestrogen-only patch thatshould beapplied to theskin onceweekly on acontinuousbasis, i.e. each

patch isreplaced with anewoneafter7 days.

In women with an intactuterustheaddition ofaprogestogen foratleast12 to 14 dayspercycleisessentialto help

preventany endometrialhyperplasiainduced by theoestrogen.Formoredetailed information, pleasereferto section

4.4 (Specialwarningsand precautionsforuse–“Endometrialhyperplasia”).

Unlessthereisapreviousdiagnosisofendometriosis, theaddition ofaprogestogen in hysterectomised women isnot

recommended.

Forinitiation and continuation oftreatmentofpostmenopausalsymptoms, thelowesteffectivedosefortheshortest

duration (seealso section 4.4)should beused. Therefore, therapy should normally bestarted with oneEstradiolTTS

patch (delivering 50 microgramsofestradiolin 24 hours). Iftheprescribed dosedoesnoteliminatethemenopausal

symptomsthedoseshould beadjusted stepwiseafterthefirstfewmonthsbyusing atransdermalpatch delivering 75 or

100 microgramsestradiolperday. Amaximumof100 microgramsestradiolperday should notbeexceeded. Ifthere

arepersistentsignsofoverdose, such asbreasttenderness, thedoseshould bereduced accordingly.

Hysterectomised women nottaking HRTortransferring fromanotherHRTproductmay starttreatmentwith Estradiol

TTSon any convenientday. Thesameholdstruefornon-hysterectomised women nottaking HRTortransferring from

acontinuouscombined HRTproduct. In non-hysterectomised women switching fromsequentialHRTregimens,

treatmentwith EstradiolTTSshould startaftertheprevioustreatmentregimen hasended.

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wherelittlewrinkling oftheskinoccurse.g., buttocks, hip orabdomen. EstradiolTTSmustnotbeapplied on ornear

thebreasts. Thepatch should beapplied to clean, dry,healthy and intactskin. Thepatchshould beapplied to theskin

assoon asitisremoved fromitswrapping. Thepatch isapplied by removing both partsoftheprotectivelinerand then

holding itin contactwith theskin foratleast30 seconds(warmth isessentialto ensuremaximaladhesivestrength).

Should partorallofapatch detach prematurely (before7 days)itshould beremoved and anewpatch applied. To aid

complianceitisrecommended thepatientthen continuesto changethepatch on theusualday. Thisadvicealso applies

ifapatientforgetsto changethepatch on schedule. Forgetting apatch may increasethelikelihood ofbreak-through

bleeding orspotting.

4.3Contraindications

EstradiolTTSiscontraindicated in:

Known, pastorsuspected breastcancer;

Known orsuspected oestrogen-dependentmalignanttumours(e.g. endometrialcancer);

Undiagnosed genitalbleeding;

Untreated endometrialhyperplasia;

Previousidiopathicorcurrentvenousthromboembolism(deep venousthrombosis, pulmonary embolism);

Activeorrecentarterialthromboembolicdisease(e.g. angina, myocardialinfarction);

Acuteliverdisease, orahistory ofliverdiseaseaslong asliverfunction testshavefailed to return to normal;

Known hypersensitivity to theactivesubstancesorto any oftheexcipients;

Porphyria.

4.4Special warningsandspecialprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshould only beinitiated forsymptomsthatadversely affect

quality oflife. In allcases, acarefulappraisaloftherisksand benefitsshould beundertakenatleastannually and HRT

should only becontinued aslong asthebenefitoutweighstherisk.

Medicalexamination/followup

Beforeinitiating orreinstituting HRT, acompletepersonaland family medicalhistory should betaken. Physical

(including pelvicand breast)examination should beguided by thisand by thecontraindicationsand warningsforuse.

During treatment, periodiccheck-upsarerecommended ofafrequency and natureadapted to theindividualwoman.

Women should beadvised whatchangesin theirbreastsshould bereported to theirdoctorornurse(see“Breast

cancer”below). Investigations,including mammography, should becarried outin accordancewith currently accepted

screening practices, modified to theclinicalneedsoftheindividual.

Conditionswhich need supervision

Ifanyofthefollowing conditionsarepresent, haveoccurred previously and/orhavebeen aggravated during pregnancy

orpervioushormonetreatment, thepatientshould beclosely supervised. Itshould betaken into accountthatthese

conditionsmay recurorbeaggravated during treatmentwith EstradiolTTS:

Leiomyoma(uterinefibroids)orendometriosis

Ahistory of, orrisk factorsfor, thromboembolicdisorders(seebelow)

Risk factorsforoestrogen dependenttumours, e.g. 1degreeheredity forbreastcancer

Hypertension

Liverdisorders(e.g.liveradenoma)

Diabetesmellituswith orwithoutvascularinvolvement

Cholelithiasis

Migraineorsevereheadache

Systemiclupuserythematosus

Ahistory ofendometrialhyperplasia(seebelow)

Epilepsy

Asthma

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Reasonsforimmediatewithdrawaloftherapy

Therapy should bediscontinued ifacontra-indication isdiscovered and in thefollowing situations:

Jaundiceordeterioration in liverfunction

Significantincreasein blood pressure

Newonsetofmigraine-typeheadache

Pregnancy

Endometrialhyperplasia

Therisk ofendometrialhyperplasiaand carcinomaisincreased when oestrogensareadministered alonefor

prolonged periods(seesection 4.8). Theaddition ofaprogestogen foratleast12 dayspercyclein non-

hysterectomised women greatly reducesthisrisk.

Break-through bleeding and spotting may occurduring thefirstmonthsoftreatment. Ifbreak-through bleeding or

spotting appearsaftersometimeon therapy, orcontinuesaftertreatmenthasbeen discontinued, thereason

should beinvestigated, which may includeendometrialbiopsy to excludeendometrialmalignancy.

Unopposed oestrogen stimulation may lead to premalignantormalignanttransformation in theresidualfociof

endometriosis. Therefore, theaddition ofprogestogensto oestrogen replacementtherapy should beconsidered in

women who haveundergonehysterectomy becauseofendometriosis, iftheyareknown to haveresidual

endometriosis.

Fortransdermaloestrogen patches>50µg/day, theendometrialsafetyofadded progestogenshasnotbeen

studied.

Breastcancer

Arandomized placebo-controlled trial, theWomen’sHealth Initiativestudy (WHI), and epidemiologicalstudies,

including theMillion Women Study (MWS), havereported an increased risk ofbreastcancerin women taking

oestrogens, oestrogen-progestogen combinationsortiboloneforHRTforseveralyears(seesection 4.8). ForallHRT,

an excessrisk becomesapparentwithin afewyearsofuseand increaseswith duration ofintakebutreturnsto baseline

within afew(atmostfive)yearsafterstopping treatment.

In theMWS, therelativerisk ofbreastcancerwith conjugated equineoestrogens(CEE)orestradiol(E2)wasgreater

when aprogestogenwasadded, eithersequentially orcontinuously, and regardlessoftypeofprogestogen. Therewas

no evidenceofadifferencein risk between thedifferentroutesofadministration.

In theWHIstudy, thecontinuouscombinedconjugated equineoestrogen and medroxyprogesteroneacetate(CEE+

MPA)productusedwasassociated with breastcancersthatwereslightly largerin sizeand morefrequently had local

lymph nodemetastasescompared to placebo.

HRT, especially oestrogen-progestogen combined treatment, increasesthedensity ofmammographicimageswhich

may adversely affecttheradiologicaldetection ofbreastcancer.

Venousthromboembolism

HRTisassociated with ahigherrelativerisk ofdeveloping venousthromboembolism(VTE), i.e. deep vein

thrombosisorpulmonary embolism. Onerandomized controlled trialand epidemiologicalstudiesfound atwo to

threefoldhigherrisk foruserscompared with non-users. Fornon-usersitisestimated thatthenumberofcasesof

VTEthatwilloccurovera5 yearperiod isabout3 per1000 women aged 50-59 yearsand 8 per1000 women

aged between 60-69 years.

Itisestimated thatin healthy women who useHRTfor5 yearsthenumberofadditionalcasesofVTEovera5

yearperiod willbebetween 2 and 6 (bestestimate=4)per1000 women aged 50-59 yearsand between 5 and 15

(bestestimate=9)per1000 women aged 60-69 years. Theoccurrenceofsuch an eventismorelikely in thefirst

yearofHRTthan later.

Generally recognized risk factorsforVTEincludeapersonalhistory orfamily history, severeobesity (Body

MassIndex >30 kg/m)and systemiclupuserythematosus(SLE). Thereisno consensusaboutthepossiblerole

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Patientswith ahistory ofVTEorknown thrombophilicstateshavean increased risk ofVTE. HRTmay add to

thisrisk. Personalorstrong family history ofthromboembolismorrecurrentspontaneousabortionsshould be

investigated in orderto excludeathrombophilicpredisposition. Untilathorough evaluation ofthrombophilic

factorshasbeen madeoranticoagulanttreatmentinitiated, useofHRTin such patientsshould beviewed as

contraindicated. Thosewomen already on anticoagulanttreatmentrequirecarefulconsideration ofthebenefit-

risk ofuseofHRT.

Therisk ofVTEmay betemporarily increased with prolonged immobilisation, majortraumaormajorsurgery.

Asin allpost-operativepatients, scrupulousattention should begiven to prophylacticmeasuresto preventVTE

followingsurgery. Whereprolonged immobilization isliableto followelectivesurgery, particularly abdominal

ororthopaedicsurgery to thelowerlimbs, consideration should begivento temporarily stopping HRTup tosix

weeksearlier, ifpossible. Treatmentshould notberestarted untilthewoman iscompletely mobilised.

IfVTEdevelopsafterinitiating therapy, thedrug should bediscontinued. Patientsshould betold to contacttheir

doctorsimmediately when they areawareofapotentialthromboembolicsymptom(e.g. painfulswelling ofaleg,

sudden pain in thechest, dyspnoea).

Coronaryarterydisease(CAD)

Thereisno evidencefromrandomized controlled trialsofcardiovascularbenefitwith continuouscombinedconjugated

oestrogensand medroxyprogesteroneacetate(MPA). Two clinicaltrials(WHIand HERSi.e. Heartand

Estrogen/Progestin ReplacementStudy)showed apossibleincreased risk ofcardiovascularmorbidity in thefirstyear

ofuseand no overallbenefit. ForotherHRTproductsthereareonly limited datafromrandomized controlled trials

examining effectsin cardiovascularmorbidity ormortality. Therefore, itisuncertain whetherthesefindingsalso

extend to otherHRTproducts.

Stroke

Onelargerandomized clinicaltrial(WHI-trial)found, asasecondary outcome, an increased risk ofischaemicstrokein

healthy women during treatmentwith continuouscombined conjugated oestrogensand MPA. Forwomen who do not

useHRT, itisestimatedthatthenumberofcasesofstrokethatwilloccurovera5 yearperiod isabout3 per1000

women aged 50-59 yearsand 11 per1000 women aged 60-69 years.

Itisestimated thatforwomen who useconjugated oestrogensand MPAfor5 years, thenumberofadditionalcaseswill

bebetween 0 and 3 (bestestimate=1)per1000 usersaged 50-59 yearsand between 1 and 9 (bestestimate=4)per

1000 usersaged 60-69 years. Itisunknown whethertheincreased risk also extendsto otherHRTproducts.

Ovarian cancer

Long-term(atleast5-10 years)useofoestrogen-only HRTproductsin hysterectomised women hasbeen associated

with an increased risk ofovarian cancerin someepidemiologicalstudies. Itisuncertain whetherlong-termuseof

combined HRTconfersadifferentrisk than oestrogen-only products.

Otherconditions

Oestrogensmay causefluid retention, and thereforepatientswith cardiacorrenaldysfunction should becarefully

observed. Patientswith terminalrenalinsufficiencyshould beclosely observed, sinceitisexpectedthatthelevel

ofcirculatingactiveingredientsin EstradiolTTSisincreased.

Women with pre-existing hypertriglyceridemiashould befollowed closely during oestrogen replacementor

hormonereplacementtherapy, sincerarecasesoflargeincreasesofplasmatriglyceridesleading to pancreatitis

havebeen reported with oestrogen therapy in thiscondition.

Oestrogensincreasethyroid binding globulin (TBG), leading to increased circulating totalthyroid hormone, as

measured by protein-bound iodine(PBI), T4 levels(by column orby radio-immunoassay)orT3 levels(by radio-

immunoassay). T3 resin uptakeisdecreased, reflecting theelevated TBG. FreeT4and freeT3 concentrationsare

unaltered. Otherbinding proteinsmay beelevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-

binding globulin (SHBG)leading to increased circulating corticosteroidsand sex steroids, respectively. Freeor

biologicalactivehormoneconcentrationsareunchanged. Otherplasmaproteinsmay beincreased

(angiotensinogen/renin substrate, alpha-lantitrypsin, ceruloplasmin).

Thereisno conclusiveevidenceforimprovementofcognitivefunction. ThereissomeevidencefromtheWHI

trialofincreasedrisk ofprobabledementiain women who startusing continuouscombinedCEEand MPAafter

theageof65. Itisunknown whetherthefindingsapply to youngerpost-menopausalwomen orotherHRT

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Themetabolismofoestrogensmay beincreased by concomitantuseofsubstancesknown to inducedrug-metabolising

enzymes, specifically cytochromeP450 enzymes, such asanticonvulsants(e.g. phenobarbital, phenytoin,

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

Ritonavirand nelfinavir, although known asstronginhibitors, by contrastexhibitinducing propertieswhen used

concomitantly with steroid hormones. Herbalpreparationscontaining St. John’swort(HypericumPerforatum)may

inducethemetabolismofoestrogens.

With transdermaladministration,thefirst-passeffectin theliverisavoided and, thus, transdermally applied oestrogens

mightbelessaffected than oralhormonesby enzymeinducers.

Clinically, an increased metabolismofoestrogensmay lead to decreased effectand changesin theuterinebleeding

profile.

4.6Pregnancyandlactation

Pregnancy:

EstradiolTTSisnotindicated during pregnancy. Ifpregnancy occursduring medication with EstradiolTTS, treatment

should bewithdrawn immediately.Theresultsofmostepidemiologicalstudiesto daterelevantto inadvertentfoetal

exposureto oestrogensindicateno teratogenicorfoetotoxiceffects.

Lactation:

EstradiolTTSisnotindicated during lactation.

4.7Effectsonabilitytodriveandusemachines

Thereisno evidencefromtheclinicaldataavailableonoestrogen therapy to suggestthatEstradiolTTSshould have

any effecton patient’sability to driveoroperatemachinery.

4.8Undesirableeffects

Themostfrequently reported undesirableeffects(>10%)in clinicaltrialsduring treatmentwith EstradiolTTSwere

application sitereactions, e.g. pruritus, erythema, eczema, urticaria, oedemaand changesin skin pigmentation. They

weremostly mild skin reactionsand usually disappeared 2-3 daysafterpatch removal. Theseeffectsareusually

observed with transdermaloestrogen replacementtherapy.

Alladverseeventsconsidered to bedrug-related, which wereobserved during thephaseIII(>500 patients)and Phase

IV(>10,000 patients)clinicaltrialsorfromthespontaneousreporting systemand literature, aresummarisedin the

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Breastcancer

According toevidencefromalargenumberofepidemiologicalstudiesand onerandomised placebo-controlled trial,

theWomen’sHealth Initiative(WHI), theoverallrisk ofbreastcancerincreaseswith increasing duration ofHRTuse

in currentorrecentHRTusers.

Foroestrogen-onlyHRT, estimatesofrelativerisk (RR)fromareanalysisoforiginaldatafrom51 epidemiological

studies(inwhich >80%ofHRTusewasoestrogen-only HRT)and fromtheepidemiologicalMillion Women Study

(MWS)aresimilarat1.35 (95%CI:1.21–1.49)and 1.30 (95%CI:1.21–1.40), respectively.

Foroestrogen plusprogestogen combinedHRT, severalepidemiologicalstudieshavereported an overallhigherrisk

forbreastcancerthan with oestrogensalone.

TheMWSreported that, comparedto neverusers, theuseofvarioustypesofoestrogen-progestogen combined HRT

wasassociated with ahigherrisk ofbreastcancer(RR=2.00, 95%CI:1.88–2.12)than useofoestrogensalone(RR=

1.30, 95%CI:1.21–1.40)oruseoftibolone(RR=1.45, 95%CI:1.25–1.68).

TheWHItrialreported arisk estimateof1.24 (95%CI:1.01–1.54)after5.6 yearsofuseofoestrogen-progestogen

combined HRT(CEE+MPA)in alluserscompared with placebo.

Organsystemclass CommonADRs

>1/100;<1/10 UncommonADRs

>1/1000;<1/100 RareADRs

>1/10000;

<1/1000

Skin and subcutaneoustissue Hairchanges, sweating

increased

Muscularand skeletal Arthralgia,leg cramps

Central&peri. nervoussystem Headache Dizziness, paresthesia,

migraine

Psychiatricdisorders Anxiety, appetite

increase, depression,

insomnia, nervousness

Gastrointestinalsystemdis. Nausea, dyspepsia,

abdominalpain,

vomiting

Cardiovasc. Blood pressure

changes

Myo-, endo-, pericards Chestpain

Vascular(extracardial) Vein disorders

Reproductivediseasefemale Breastdiscomfort

(e.g. Mastalgia/

mastopathies, breast

tenderness, breast

enlargement) Vaginaldischarge,

breakthrough bleeding Worsening of

uterinefibroids

Body asawhole/generaldis. Edema, fatigue, weight

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TheMWShasestimated, fromtheknown averageincidenceforbreastcancerin developed countries, that:

Forwomen notusing HRT, about32 in every 1000 areexpected to havebreastcancerdiagnosed between the

agesof50 and 64 years.

For1000 currentorrecentusersofHRT, thenumberofadditionalcasesduring thecorresponding period willbe

Forusersofoestrogen-onlyreplacementtherapy

-between 0 and 3 (bestestimate=1.5)for5 years’use

-between 3 and 7 (bestestimate=5)for10 years’use

Forusersofoestrogen plusprogestogencombined HRT,

-between 5 and 7 (bestestimate=6)for5 years’use

-between 18 and 20 (bestestimate=19)for10 years’use.

TheWHItrialestimated thatafter5.6yearsoffollow-up ofwomen between theagesof50 and 79 years, anadditional

8 casesofinvasivebreastcancerwould beduetooestrogen-progestogen combinedHRT(CEE+MPA)per10,000

women years.

According tocalculationsformthetrialdata, itisestimated that:

For1000 women n theplacebo group,

about16 casesofinvasivebreastcancerwould bediagnosed in 5 years.

For1000 women who used oestrogen +progestogen combined HRT(CEE+MPA), thenumberofadditional

caseswould be

between 0 and 9 (bestestimate=4)for5 years’use.

Thenumberofadditionalcasesofbreastcancerin women whouseHRTisbroadly similarforwomen who startHRT

irrespectiveofageatstartofuse(between theagesof45-65)(seesection 4.4).

Endometrialcancer

In women with an intactuterus, therisk ofendometrialhyperplasiaand endometrialcancerincreaseswith increasing

duration ofuseofunopposed oestrogens. According to datafromepidemiologicalstudies, thebestestimateoftherisk

isthatforwomen notusing HRT, about5 in every 1000 areexpected to haveendometrialcancerdiagnosed between

theagesof50 and 65. Depending on theduration ofuseofunopposed oestrogen usersvariesfrom2-to 12-fold greater

compared with non-users. Adding aprogestogen to oestrogen-only therapy greatly reducesthisincreased risk.

Otheradversereactionshavebeen reported in association with oestrogen/progestogen treatment(class-effect):

Oestrogen-dependentneoplasmsbenign and malignant, e.g. endometrialcancer.

Venousthromboembolism, i.e. deep leg orpelvicvenousthrombosisand pulmonaryembolism, ismorefrequent

among hormonereplacementtherapy usersthan among non-users. Forfurtherinformation, seesection 4.3

Contraindicationsand 4.4 Specialwarningsand precautionsforuse.

Myocardialinfarction and stroke

Gallbladderdisease

Skin and subcutaneousdisorders:chloasma, erythemamultiforme, erythemanodosum, vascularpurpura

Deterioration ofliverfunction

Probabledementia(seesection 4.4).

4.9Overdose

Themodeofadministration makessignificantoverdoseunlikely;removalofthepatchesisallthatisrequired should it

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcode:GO3 AO3

Oestrogens

Theactiveingredient, synthetic17-estradiol, ischemically and biologically identicalto endogenoushuman estradiol.

Itsubstitutesforthelossofoestrogen production in menopausalwomen, and alleviatesmenopausalsymptoms.

Oestrogenspreventbonelossfollowing menopauseorovariectomy.

ClinicalTrialInformation:

Reliefofmenopausalsymptomswasachieved during thefirstfewweeksofthetreatment. In non-

hysterectomised women thebleeding profiledependson thetypeand dosefortheprogestogen and duration used

in combination with EstradiolTTS.

Prevention ofosteoporosis

Oestrogen deficiency atmenopauseisassociated with an increasing boneturnoverand declinein bonemass. The

effectofoestrogenson thebonemineraldensity isdose-dependent. Protection appearsto beeffectiveforaslong

astreatmentiscontinued. Afterdiscontinuation ofHRT, bonemassislostataratesimilarto thatin untreated

women.

EvidenceoftheWHItrialand meta-analysed trialsshowsthatcurrentuseofHRT, aloneorin combination with a

progestogen–given to predominantly healthy women–reducestherisk ofhip, vertebral, and otherosteoporotic

fractures. HRTmayalso preventfracturesin women withlowbonedensity and/orestablished osteoporosis, but

theevidenceforthatislimited.

5.2Pharmacokineticproperties

Afterapplication ofthetransdermalsystemcontaining estradiol, therapeuticconcentrationsofestradiolareachieved

within 3 hoursand maintained throughouttheentireapplication period ofthetransdermalpatch (7 days). Estradiol

peak plasmaconcentrations(C )rangefrom59 to 155 pg/ml(baselinecorrected geometricmean 92 pg/ml)and

valueswerebetween 2478 and 10694 h*pg/ml(baselinecorrected geometricmean 5188 h*pg/ml). The

mean averageplasmaconcentration (C)is42 pg/ml(range:20 to 145 pg/ml)and mean C (trough concentration

beforenextpatch application)is29 pg/ml. Afterremovalofthetransdermalpatch, estradiolconcentrationsreturn to

pre-treatmentvalues(below10pg/ml)within 12 hours.

By transdermaladministration ofEstradiolTTS, thereisno hepaticfirst-passeffectand theestradiolreachesthe

bloodstreamdirectly in unchanged formand in physiologicalamounts. With theuseofEstradiolTTStheestradiol

concentrationsareraised to valuessimilarto thoseoftheearly to middlefollicularphase.

Theliveristhemajorsiteforestradiolmetabolism. Theprimary metabolitesareestroneand estrioland their

conjugates(glucuronideand sulfate). Estradiolisexcreted into theurinemostly asglucuronideand sulfate. Theurinary

excretion approachespretreatmentlevelswithin 24 hoursafterpatch removal.

5.3Preclinical safetydata

No adverseeffectscan bepredicted fromanimaltoxicologystudiesotherthan thosedocumented fromhuman useof

0-168h

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Backing layer: Transparentpolyethyleneterephthalate(PET)foil.

Adhesivematrix: Styrene-isoprene-styreneblock copolymer, glycerineestersofcompletely hydrogenated resins.

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2 years.

6.4Special precautionsforstorage

Do notstoreabove30°C.

6.5Natureandcontentsofcontainer

Thecontainer(primary packaging)consistsofasealed laminated sachet.Thiscompriseslayersoffood grade

paper/polyethylene/aluminium/ethylenecopolymer.

Packagesizes:Cartonsof1,4, 8, 9 and 12 patches.

Notallpack sizesmay bemarketed.

6.6Instructionsforuseandhandling

Afterremovalfromthelaminated sachet, peeloffthetwo partprotectiveliner.Try to avoid touching theadhesive.

Stick theadhesivesidedown to theupperleftorrightbuttock on aclean and dry areaofskin.Hold theapplied patch

to theskin with thepalmofthehand foratleast30 seconds, in orderto ensureoptimaladhesion to theskin.

Recommended application sitesareclean, dry and intactareasofskin on thetrunk belowthewaistline.EstradiolTTS

Patch should notbeapplied on ornearthebreasts.Afterremovaltheused patch should befolded and disposed ofwith

thenormalhousehold solid waste.

7MARKETINGAUTHORISATIONHOLDER

MerckLtd

t/aMerck Pharmaceuticals(ADivision ofMerck Ltd)

HarrierHouse

High Street

WestDrayton, UB7 7QG

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 7 th

September1999

Dateoflastrenewal: 7 th

September2004

10DATEOFREVISIONOFTHETEXT

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