DERMESTRIL

Main information

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

Documents

Localization

  • Available in:
  • DERMESTRIL Transdermal Patch 50 Microgram/day
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0868/002/002
  • Authorization date:
  • 23-08-1999
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Dermestril50 TransdermalPatch

2QUALITATIVEANDQUANTITATIVECOMPOSITION

DERMESTRIL50 hasanominalin vivo releaserateof50microgramestradiolperday (activesurfacearea18 cm;

estradiolcontent4 mg as4.132 mgofEstradiolHemihydrate).

Forexcipients, see6.1

3PHARMACEUTICALFORM

Dermestrilisatransdermaldelivery system(transdermalpatch)consisting ofatransparentbacking foiland an

estradiol-containing self-adhesivematrix, covered by aprotectivelinerwhich isremoved priorto use.

An identification codenumberisprinted on theexternalpartofthebacking foilforeach Dermestril50 patch (ER50).

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapy (HRT)forestrogen deficiency symptomsin postmenopausalwomen.

Theexperiencetreating women olderthan 65 yearsislimited.

4.2Posologyandmethodofadminstration

Posology

Adultsand theelderly:

ThreestrengthsofDERMESTRIL ®

areavailable,DERMESTRIL25, 50 and 100, releasing respectively 25,50 and

100µg/day ofoestradiol. Forinitiation and continuation oftreatmentofpostmenopausalsymptoms, thelowesteffective

dosefortheshortestduration oftime(seealsosection 4.4)should beused.

Treatmentisusually initiated with oneDERMESTRIL ®

25 patch applied to theskin twiceweekly in orderto ensurea

continuoussupply ofoestradiolto thebody;thuseach used systemisremoved afterthreeorfourdaysand replacedby

anewone. Ifafteratreatmentof2-3 weekswith DERMESTRIL ®

25 thesymptomsofestrogen-deficiency appearnot

to beneutralized, ahigherdosagecan begiven. Amaximumdoseof100µg perday shouldnotbeexceeded.

In caseofundesirableeffectsorsymptomsofoverdose(e.g. breasttendernessand/orvaginalbleeding)thedoseshould

bereduced.

In women with an intactuterus, aprogestagen approved foraddition to estrogen treatmentmustbeadditionally

administered foratleast12-14 daysevery month/28 day cycleto opposethedevelopmentofan estrogen-stimulated

hyperplasiaoftheendometrium(seesection 4.4 SpecialWarningsand SpecialPrecautionsforUse). Unlessthereisa

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Two therapeuticregimenscan beused:

a)Cyclic:DERMESTRIL ®

isdosed cyclically with atreatment-freeinterval, usually 21 dayson and 7 daysoff. The

progestagen isusuallyadded for12-14 daysofthecycle. Withdrawalbleeding may appearduring thisperiod.

b)Continuoussequential:DERMESTRIL ®

isdosed continuously. Theprogestagen isusually added for12-14 days(or

more)ofevery 28 day cycle, in asequentialmanner. Continuoussequentialtreatmentmay berecommended in cases

when marked symptomsofestrogen deficiency recurduring thetreatment-freeperiod.

Withdrawalbleeding may occurwhen theprogestagen iswithdrawn.

Thetreatmentwith DERMESTRIL ®

may beinitiated atany convenienttimeforwomen who arenotcurrentlyon any

estrogen therapy. Women currently using cyclicorsequentialestrogen/progestagen therapy should completetheon-

going treatmentcyclebeforebeginning treatmentwith DERMESTRIL ®

;theappropriatetimeto begin treatmentwith

DERMESTRIL ®

would bethefirstday ofawithdrawalbleeding. Women who arealready using continuouscombined

estrogen/progestagen therapy may beswitched to DERMESTRIL ®

directly.

Children:

DERMESTRIL ®

isnotindicated in children.

Administration:

Thepatch should beapplied to theskin ofthehip, lumbarregion orabdomen and pressed firmly overthewholesurface

and along theedgesto ensuregood adhesion. Theskin oftheapplication siteshould beclean, dry, non-greasy and free

ofrednessorirritation. Areasofthebody which formfoldsoraresubjectto friction during movementshould be

avoided. Patchesshould notbeapplied twiceconsecutively to thesameskin site.DERMESTRIL ®

should NOTbe

applied on ornearthebreasts.

DERMESTRIL ®

isapplied twiceweekly, eitheron acyclic3-weektreatmentregimen orcontinuously ifappropriate

(seePosology). Itishelpfulforthepatientto establish aroutineofchanging thepatcheson thesametwo daysofeach

week(e.g. Mondaysand Thursdays). Ifthepatch iscorrectly applied, itwilladhereto theskin fortherequired threeor

fourdayswithoutproblems. In theeventthatapatch doescomeoff, itshould bereplaced with anewpatch. Thepatch

should then bechanged again attheregulartimeto re-establish thepatient'sroutineschedule.

Similarly, ifthepatch isnotchanged on thescheduled day, itshould bereplaced assoon aspossibleand should be

changed again on thenextscheduled day to re-establish thepatient'snormalroutine.

Forgetting to apply anewpatch atthescheduled timemay increasethelikelihood ofbreak-through bleeding and

spotting.

Ifthepatch iscorrectly applied,thepatientmay batheorshower. However, thepatch may becomedetached afteravery

hotbath orsaunaand should bereplaced with anewone, asdescribed above.

4.3Contraindications

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;

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4.4Special warningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshould only beinitiated forsymptomsthatadversely affect

quality oflife. In allcases, acarefulappraisaloftherisksand benefitsshould beundertakenatleastannually and HRT

should only becontinued aslong asthebenefitoutweighstherisk.

Medicalexamination/follow-up:

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‘BreastCancer’

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

orprevioushormonetreatment, thepatientshould beclosely supervised. Itshould betaken into accountthatthese

conditionsmay recurorbeaggravated during treatmentwith DERMESTRIL ®

,in particular:

Leiomyoma(uterinefibroids)orendometriosis

Ahistory of, orrisk factorsfor, thromboembolicdisorders(seebelow)

Risk factorsforoestrogen dependenttumours, e.g. 1degreeheredity forbreastcancer

Hypertension

Liverdisorders(e.g.liveradenoma)

Diabetesmellituswith orwithoutvascularinvolvement

Cholelithiasis

Migraineor(severe)headache

Systemiclupuserythematosus

Ahistory ofendometrialhyperplasia(seebelow)

Epilepsy

Asthma

Otosclerosis

Reasonsforimmediatewithdrawaloftherapy:

Therapy should bediscontinued in caseacontra-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 ofaprogestagen foratleast12 dayspercyclein non-

hysterectomised women greatly reducesthisrisk.

Forpatchesreleasing morethan 50µg/day theendometrialsafety ofadded progestagenshavenotbeen studied.

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 estrogen stimulation may lead to premalignantormalignanttransformation in theresidualfociof

endometriosis. Therefore, theaddition ofprogestagensto estrogen replacementtherapy should beconsidered in

women who haveundergonehysterectomy becauseofendometriosisiftheyareknown to haveresidual

endometriosis.

Breastcancer:

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

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oestrogens, oestrogen-progestagen combinationsortiboloneforHRTforseveralyears(seesection 4.8).

ForallHRT, an excessrisk becomesapparentwithin afewyearsofuseand increaseswith duration ofintakebut

returnsto baselinewithin afew(atmostfive)yearsafterstopping treatment.

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

when aprogestagen wasadded, eithersequentially orcontinuously, and regardlessoftypeofprogestagen. 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-progestagen combined treatment, increasesthedensity ofmammographicimageswhich

may adversely affecttheradiologicaldetection ofbreastcancer.

Venousthromboembolism:

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

thrombosisorpulmonary embolism. Onerandomised controlled trialand epidemiologicalstudiesfound atwo-to

threefoldhigherrisk foruserscompared with non-users. Fornon-usersitisestimated thatthenumberofcasesof

VTEthatwilloccurovera5 yearsperiod isabout3 per1000 women aged50-59 yearsand 8 per1000 women

aged between 60-69 years. Itisestimated thatin healthy women who useHRTfor5 years, thenumberof

additionalcasesofVTEovera5 yearperiod willbebetween 2 and 6 (bestestimate=4)per1000 women aged

50-69 yearsand between 5 and 15 (bestestimate=9)per1000 women aged 60-69 years. Theoccurrenceofsuch

an eventismorelikely in thefirstyearofHRTthan later.

Generally recognised risk factorsforVTEincludeapersonalhistory orfamily history, severeobesity (BMI>30

kg/m)and systemiclupuserythematosus(SLE). Thereisno consensusaboutthepossibleroleofvaricoseveins

in VTE.

Patientswith ahistory ofVTEorknown thrombophilicstateshavean increased risk ofVTE. HRTmay add to

thisrisk. Personalorstrong family history ofthromboembolismorrecurrentspontaneousabortion should be

investigated in orderto excludeathrombophilicpredisposition.

Untilathorough evaluation ofthrombophilicfactorshasbeen madeoranticoagulanttreatmentinitiated, useof

HRTin such patientsshould beviewed ascontraindicated. Thosewomen already on anticoagulanttreatment

requirecarefulconsideration ofthebenefit-risk ofuseofHRT.

Therisk ofVTEmay betemporarily increased with prolonged immobilisation, majortraumaormajorsurgery.

Asin allpostoperativepatients, scrupulousattention should begiven to prophylacticmeasuresto preventVTE

followingsurgery. Whereprolonged immobilisation isliableto followelectivesurgery, particularly abdominalor

orthopaedicsurgery to thelowerlimbs, consideration should begiven to temporarily stopping HRT4 to 6 weeks

earlier, 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).

Coronary artery disease(CAD):

Thereisno evidencefromrandomised controlledtrialsofcardiovascularbenefitwithcontinuouscombined conjugated

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

Estrogen/Progestin ReplacementStudy)showed apossibleincreased risk ofcardiovascularmorbidity in thefirstyear

ofuseand no overallbenefit. ForotherHRTproductsthereareonly limited datafromrandomised controlled trials

examining effectsin cardiovascularmorbidity ormortality. Therefore, itisuncertain whetherthesefindingsalso extend

to otherHRTproducts.

Stroke:

Onelargerandomised 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

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estrogensand MPAfor5 years, thenumberofadditionalcaseswillbebetween 0 and 3 (bestestimate=1)per1000

usersaged 50-59 yearsand between 1 and 9 (bestestimate=4)per1000 usersaged 60-69 years. Itisunknown whether

theincreased risk alsoextendsto 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 HRTconfersto adifferentrisk than oestrogen-only products.

Otherconditions:

Estrogensmay causefluid retention, and thereforepatientswith cardiacorrenaldysfunction should becarefully

observed. Patientswith terminalrenalinsufficiencyshould beclosely observed, sinceitisexpectedthatthelevelof

circulating activeingredientsinDERMESTRIL ®

isincreased.

Women with pre-existing hypertriglyceridemiashould befollowed closely during oestrogen replacementorhormone

replacementtherapy, sincerarecasesoflargeincreasesofplasmatriglyceridesleading to pancreatitishavebeen

reported with estrogen therapy in thiscondition.

Estrogensincreasethyroid binding globulin (TBG), leading to increased circulating totalthyroid hormone, asmeasured

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

T3 resin uptakeisdecreased, reflecting theelevated TBG. FreeT4 and freeT3 concentrationsareunaltered.Other

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

(SHBG)leading to increased circulating corticosteroidsand sex steroids, respectively. Freeorbiologicalactive

hormoneconcentrationsareunchanged. Otherplasmaproteinsmay beincreased (angiotensinogen/renin substrate,

alpha-I-antitrypsin, ceruloplasmin).

Thereisno conclusiveevidenceforimprovementofcognitivefunction. ThereissomeevidenceformtheWHItrialof

increased risk ofprobabledementiain women who startusing continuouscombined CEEand MPAaftertheageof65.

Itisunknown whetherthefindingsapply to youngerpost-menopausalwomen orotherHRTproducts.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Themetabolismofestrogensmay 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

inducethemetabolismofestrogens.

Attransdermaladministration, thefirst-passeffectin theliverisavoided and, thus, transdermally applied estrogens

mightbelessaffected than oralhormonesby enzymeinducers.

Clinically, an increased metabolismofestrogensand progestagensmay lead to decreased effectand changesin the

uterinebleeding profile.

4.6Pregnancyandlactation

DERMESTRIL ®

isnotindicated during pregnancy.Ifpregnancy occursduring medication withDERMESTRIL ®

treatmentshould bewithdrawn immediately. Theresultsofmostepidemiologicalstudiesto daterelevantto inadvertent

fetalexposureto estrogensindicateno teratogenicorfoetotoxiceffects.

Lactation:

DERMESTRIL ®

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4.7Effectsonabilitytodriveandusemachines

Notapplicable.

4.8Undesirableeffects

Approximately 10 to 15%ofthepatientstreated withDERMESTRIL ®

in clinicaltrialsexperienced systemicadverse

reactions, which weremild and transient. Breasttendernesswasreported in 20-35%ofpatients. Localreactionsatthe

application site, mostly mild erythemawith orwithoutpruritus, occurred in 10-25%ofpatients.

Thetablebelowliststheadversereactionsobserved withDERMESTRIL ®

and HRTproductscontaining 17-estradiol.

Skin reactionsarelessfrequentifDERMESTRIL ®

isapplied on theouterupperquadrantofthebuttock, changing

thesiteateach application.

BreastCancer:

According toevidencefromalargenumberofepidemiologicalstudiesand onerandomised placebo-controlled trial, the

Women’sHealth Initiative(WHI), theoverallrisk ofbreastcancerincreaseswith increasing duration ofHRTusein

Organ systemclass Common ADRs,

>1/100, <1/10 Uncommon ADRs,

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

>1/10,000, <1/1000

PSYCHIATRIC

DISORDERS -Depression

CENTRAL

NERVOUSSYSTEM -Irritability

-Headache -Migraine

-Dizziness -Changesin libido

-Worsening ofepilepsy

VASCULAR

DISORDERS -Increasein blood

pressure -Venousthromboembolism

GASTRO-

INTESTINAL

DISORDERS -Nausea

-Abdominal

cramps

-Meteorism -Vomiting

HEPATOBILIARY

DISORDERS -Disturbed or

abnormalliver

function tests

SKINAND

SUBCUTANEOUS

TISSUEDISORDERS -Allergic-contactdermatitis

-Reversiblepost-inflammatory

pigmentation

-Generalised pruritusand

exanthema

REPRODUCTIVE

SYSTEMAND

BREAST

DISORDERS -Breasttenderness

and breastpain

-Break-through

bleeding

-Changesin

vaginalsecretions

-Endometrial

hyperplasia -Uterinetumours

GENERAL

DISORDERS -Fluid retention

with edema

-Feeling of

heavinessin the

legs

-Weightincrease

ordecrease -Alterationsin

glucosetolerance

and blood

coagulation -Ocularirritation during contact

lensesuse

-Anaphylacticreactions

(sometimesin patientswith

allergicreactionsin the

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Foroestrogen-onlyHRT, estimatesofrelativerisk (RR)fromareanalysisoforiginaldatafrom51 epidemiological

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

(MWS)aresimilarat1.35 (95%CI1.21–1.49)and 1.30 (95%CI1.21–1.40), respectively.

Foroestrogen plusprogestagencombined HRT, severalepidemiologicalstudieshavereported an overallhigherrisk

forbreastcancerthan with oestrogensalone.

TheMWSreported that, comparedto neverusers, theuseofvarioustypesofoestrogen-progestagen 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%CI1.25–1.68).

TheWHItrialreported arisk estimateof1.24 (95%CI1.01–1.54)after5.6 yearsofuseofoestrogen-progestagen

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

Theabsoluteriskscalculated fromtheMWSand theWHItrialarepresented below:

TheMWShasestimated, fromtheknown averageincidenceofbreastcancerindeveloped countries, that:

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

of50 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 plusprogestagencombined 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-progestagen combinedHRT(CEE+MPA)per10,000

women years.

According tocalculationsfromthetrialdata, itisestimated that:

For1000 women in theplacebo group,

about16 casesofinvasivebreastcancerwould bediagnosed in 5 years.

For1000 women who used oestrogen +progestagen combined HRT(CEE+MPA), thenumberofadditionalcases

would 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 oftreatmentand oestrogen dose, thereported increasein endometrial

cancerrisk among unopposed oestrogen usersvariesfrom2-to 12-fold greatercomparedwith non-users. Adding a

progestagen to oestrogen-only therapy greatly reducesthisincreased risk.

Otheradversereactionshavebeen reported in association with oestrogen/progestagen treatment:

-Estrogen-dependentneoplasmsbenign and malignant, e.g. endometrialcancer(seeSection 4.4 SpecialWarningsand

SpecialPrecautionsforUse).

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

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Contraindicationsand 4.4 SpecialWarningsand SpecialPrecautionsforUse. Myocardialinfarction and stroke(see

Section 4.4 SpecialWarningsand SpecialPrecautionsforUse).

-Gallbladderdisease.

-Skin and subcutaneousdisorders:chloasma, erythemamultiforme, erythemanodosum, vascularpurpura.

-Probabledementia(seesection 4.4 SpecialWarningsand SpecialPrecautionsforUse).

4.9Overdose

Overdosageisunlikely with thistypeofapplication. Nausea, vomiting and withdrawalbleeding may occurin some

women. Thereisno specificantidoteand treatmentshould besymptomatic. Thepatch(es)should beremoved.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

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

Itsubstitutesforthelossofestrogen production in menopausalwomen, and alleviatesmenopausalsymptoms.

ClinicaltrialInformation:

Reliefofmenopausalsymptomswasachieved during thefirstfewweeksoftreatment.

5.2Pharmacokineticproperties

Theaveragehalf-lifeofestradiolin plasmaisofaboutonehour. Oestradiolismetabolized mainly in theliver. The

mostimportantmetabolitesareoestriol, oestroneandtheirconjugates(glucuronides, sulphates), which aremuch less

activethanoestradiol. Themetabolitesofoestradiolareeliminated mainly bythekidney asglucuronidesandsulphates.

Themajority oforally-administered oestradiolismetabolised to estroneand itsconjugatesby theintestineand theliver

beforereaching thecirculation, giving riseto high, unphysiologicallevelsofoestronein theblood. Theconsequences

ofchronicaccumulation ofoestronein thebody arenotyetclear. However, ithasbeen confirmed thatprolonged oral

administration ofoestrogensleadsto increased protein synthesisby theliver, in particularofrenin substrate, resulting

in hypertension.

Following cutaneousapplication ofDERMESTRIL ®

,oestradiolisreleased fromthedrug-containing adhesivematrix

through theskin and reachesthesystemiccirculation directly, avoiding first-passmetabolismby theliver, andhence

avoiding hepaticprotein synthesisstimulation and oestroneaccumulation.

Consequently, theoestradiol:oestroneratio in plasma, which fallsto valuesbelow1 afterthemenopauseand during

oraloestrogen replacementtherapy, returnsto premenopausallevels(approximately 1)with transdermaloestradiol.

Thenominaldailyin vivoreleaserateofDERMESTRIL ®

50 is50µg ofoestradiol;thesystemisactiveforfourdays.

Thesereleaseratesresultin physiologicaloestradiolserumconcentrations, i.e. thoseofthepremenopausalearly

follicularphase, which areconstantly maintained throughoutthepatch application period.

Afterasingleapplication ofDERMESTRIL ®

with adaily oestradiolreleaseof100µg in postmenopausalwomen,

physiologicalserumlevelsofoestradiolwerereached approximately fourhoursafterapplicationand mean maximum

serumoestradiollevelsof70 pg/mlwereobtained. Theserumconcentration ofoestradiolremained within the

physiologicallevelsofpremenopausalwomen throughoutthe3-4 daysoftheapplication period and returned to

baselinewithin 12 hoursafterremovalofDERMESTRIL ®

.

Following repeatedapplicationsofDERMESTRIL ®

50 patchesat84-96 hourintervals, steady-statewasreached

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In adoseproportionality studyonDERMESTRIL ®

25, 50 and 100, themaximumplasmaconcentrationsofestradiol

measured during theapplication ofthesecond patchwere37.2, 60.9 and 116.9 pg/mlforDERMESTRIL ®

25, 50 and

100, respectively. Theaverageconcentrationsofestradiolwere22.8, 40.1 and 79.3 pg/mlforDERMESTRIL ®

25, 50

and 100, respectively. TheC were12.51, 20.53 and 44.39 pg/mlforDERMESTRIL ®

25, 50 and 100, respectively.

5.3Preclinical safetydata

In primary dermalirritation studies, application ofDermestrilresulted in mild irritation related to mechanicaltraumaat

removal. Insensitisation studies, Dermestrilhad no dermalsensitising potential.

Thecomponentsoftheadhesivematrix ofDermestril(acryliccopolymers)havebeen studied extensively and, atmany

multiplesoftheprojectedhuman exposure, presentalowrisk.

Othercomponentsexcipientsused in theadhesivematrix areeithergenerallyregarded assafeforusein eitherfood

componentsorconsideredacceptableasan inactiveingredientforprescription and topicaltransdermalproducts.

Theadhesivebacking and releaselinerofDermestrilweretested in biologicaltestmethodsand wereconsidered to be

compatiblewith biologicsystems.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Estradiol-containing adhesivematrix: Acryliccopolymers

Backing foil: Polyethyleneterephthalate

Each transdermaldelivery systemiscovered by aprotectiveliner(siliconised polyethyleneterephthalate)which is

removed priorto use.

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2 years.

6.4Special precautionsforstorage

Do notstoreabove25°C.

6.5Natureandcontentsofcontainer

Cardboard box containing 8 transdermaldelivery systemssealed individually in protectivesachetsconsisting of4

layers:Surlin, hotsealablematerial(innerlayer), aluminiumfoil, polyethyleneand paper(outerlayer).

6.6Instructionsforuseandhandling

Tearopen thesachetattheindentation (do notusescissorsto avoid damaging thepatch)and removethepatch. Hold

thepatch between thethumb and index fingeratthecornerwith thepull-offtag. Detach theprotectivelinerwith the

otherhandand discard it.

Do nottouch theadhesivesideofthepatch. Apply thepatch to theskin holding between thumb and index fingerthe

Irish Medicines Board

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Date Printed 16/12/2005 CRN 2017894 page number: 9

secondson thewholesurfaceofthepatch. Passafingeralong theedgesto assuregood adhesion.

7MARKETINGAUTHORISATIONHOLDER

RottapharmLtd.

Damastown IndustrialPark

Mulhuddart

Dublin 15

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA868/2/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 23 rd

August1999

Dateoflastrenewal: 23 rd

August2004

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 16/12/2005 CRN 2017894 page number: 10