ESTREVA

Main information

  • Trade name:
  • ESTREVA Gel 0.1 %w/w
  • Dosage:
  • 0.1 %w/w
  • Pharmaceutical form:
  • Gel
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ESTREVA Gel 0.1 %w/w
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0908/001/001
  • Authorization date:
  • 22-01-1999
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ESTREVA0.1%w/wgel

2QUALITATIVEANDQUANTITATIVECOMPOSITION

1gofgelcontains1.0325mgofestradiolhemihydrate,correspondingto1.0000mgofanhydrousestradiol.

Eachdosedelivers0.5gofgel,ie0.5mgofestradiol(as0.516mgofestradiolhemihydrate).

Excipients:containsPropyleneglycol(6.0mg).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Translucentandodourlessgel

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapy(HRT)foroestrogendeficiencysymptomsinpostmenopausalwomen.

Theexperiencetreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

ESTREVA 0.1%w/wgelispresentedintube-bottleswithdosingpumps.

Itmaybenecessarytoprimethepumpwhenbeginninganewbottle.Thefirstdosemaynotbeaccurateandshouldbe

discarded.

Eachpushdelivers0.5gofgel,i.e.0.5mgofestradiol.

Theaveragedoseis1.5gofgelperday,i.e3consecutivedoses,for24to28days.

Thestartingdoseis0.5gofgelperdayfor24to28days.

Thisstartingdosecanbeadaptedtoindividualneeds.

Theindividualdosecanrangefrom0.5to3gofgelperday.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

duration(seealsosection4.4)shouldbeused.

Innon-hysterectomisedwomen,itishighlyrecommendedthataprogestogenbecombinedforatleast12to14daysof

useofestradiolgeltopreventanendometrialhyperplasiainducedbytheoestrogen.

Unlessthereisapreviousdiagnosisofendometriosis,itisnotrecommendedtoaddaprogestogeninhysterectomised

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Twotherapeuticregimenscanbeused:

1)Cyclicfor24to28days,followedbya2to7daystreatmentfreeperiod.Theprogestogenshouldbeadministered

atleastduringthelast12daysoftheestradioltreatmentinnon-hysterectomisedwomen.Withdrawalbleedingmay

occurduringthisperiod.

2)Continuous:withnotreatmentfreeperiod.Innon-hysterectomisedwomentheprogestogenshouldbeadministered

foratleast12dayspermonth.Withdrawalbleedingmayoccurwhentheprogestogeniswithdrawn.

Continuous,non-cyclic,treatmentmayberecommendedincaseswheremarkedsymptomsofoestrogendeficiency

recurduringthetreatment-freeperiod.

Theapplicationsurfaceshouldbe2timesthesizeofthehand.Thepatientappliesthegelontoclean,dryandintact

skin,preferablyafterwashinginthemorningorevening,ontheabdomen,thighs,arms,orshoulders.Thegelshould

notbeappliedonthebreastsortothemucosa.Eyecontactmustbeavoided.Itisnotnecessarytorubthegelin,

howeveritisrecommendedthatsubjectswaitfor2minutesbeforedressing.

Thegeldoesnotstainclothing.Handsshouldbewashedafterapplication.

Forgettingadosemayincreasethelikehoodofbreak-throughbleedingandspotting.

4.3Contraindications

Known,pastorsuspectedbreastcancer;

Knownorsuspectedoestrogen-dependentmalignanttumours(e.g.endometrialcancer);

Undiagnosedgenitalbleeding;

Untreatedendometrialhyperplasia;

Previousorcurrentvenousthromboembolism(deepvenousthombosis,pulmonaryembolism);

Knownthrombophilicdisorders(e.g.proteinC,proteinS,orantithrombindeficiency,seesection4.4);

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfarction);

Acuteliverdisease,orahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal;

Knownhypersensitivitytotheactivesubstancesortoanyoftheexcipients;

Porphyria.

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk.

EvidenceregardingtherisksassociatedwithHRTinthetreatmentofprematuremenopauseislimited.Duetothelow

levelofabsoluteriskinyoungerwomen,however,thebalanceofbenefitsandrisksforthesewomenmaybemore

favourablethaninolderwomen.

Medicalexamination/follow-up

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythecontraindicationsandwarningsforuse.

Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.

Womenshouldbeadvisedwhatchangesintheirbreastsshouldbereportedtotheirdoctorornurse(see“Breatcancer”

below).Investigations,includingappropriateimagingtools,e.g.mammography,shouldbecarriedoutinaccordance

withcurrentlyacceptedscreeningpractices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision

Ifanyofthefollowingconditionsarepresent,haveoccuredpreviously,and/orhavebeenaggravatedduringpregnancy

orprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthatthese

conditionsmayrecurorbeaggravatedduringtreatmentwithESTREVA 0.1%w/wgel,inparticular:

Leiomyoma(uterinefibroids)orendometriosis

Riskfactorsforthromboembolicdisorders(seebelow)

Riskfactorsforoestrogendependenttumours,e.g.1 st

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Hypertension

Liverdisorders(e.g.liveradenoma)

Diabetesmellituswithorwithoutvascularinvolvement

Cholelithiasis

Migraineor(severe)headache

Systemiclupuserythematosus

Ahistoryofendometrialhyperplasia(seebelow)

Epilepsy

Asthma

Otosclerosis

Reasonsforimmediatewithdrawaloftherapy

Therapyshouldbediscontinuedincaseacontra-indicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction

Significantincreaseinbloodpressure

Newonsetofmigraine-typeheadache

Pregnancy

Endometrialhyperplasiaandcarcinoma

Inwomenwithanintactuterustheriskofendometrialhyperplasiaandcarcinomaisincreasedwhenoestrogensare

administeredaloneforprolongedperiods.Thereportedincreaseinendometrialcancerriskamongoestrogen-only

usersvariesfrom2-to12-foldgreatercomparedwithnon-users,dependingonthedurationoftreatmentand

oestrogendose(seesection4.8).Afterstoppingtreatmentriskmayremainelevatedforatleast10years.

Theadditionofaprogestagencyclicallyforatleast12dayspermonth/28daycycleorcontinuouscombined

oestrogen-progestagentherapyinnon-hysterectomisedwomenpreventstheexcessriskassociatedwithoestrogen-

onlyHRT.

Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-throughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshould

beinvestigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Unopposedoestrogenstimulationmayleadtopremalignantormalignanttransformationintheresidualfociof

endometriosis.Therefore,theadditionofprogestagenstooestrogenreplacementtherapyshouldbeconsideredin

womenwhohaveundergonehysterectomybecauseofendometriosis,iftheyareknowntohaveresidual

endometriosis.

Breastcancer

Theoverallevidencesuggestsanincreasedriskofbreastcancerinwomentakingcombinedoestrogen-progestagenand

possiblyalsooestrogen-onlyHRT,thatisdependentonthedurationoftakingHRT.

Therandomizedplacebo-controlledtrialtheWomen’sHealthInitiativestudy(WHI),andepidemiologicalstudiesare

consistentinfindinganincreasedriskofbreastcancerinwomentakingcombinedoestrogen-progestagenforHRTthat

becomesapparentafterabout3years(seeSection4.8).

TheWHItrialfoundnoincreaseintheriskofbreastcancerinhysterectomisedwomenusingoestrogen-onlyHRT.

Observationalstudieshavemostlyreportedasmallincreaseinriskofhavingbreastcancerdiagnosedthatis

substantiallylowerthanthatfoundinusersofoestrogen-progestagencombinations(seesection4.8).

Theexcessriskbecomesapparentwithinafewyearsofusebutreturnstobaselinewithinafew(atmostfive)years

afterstoppingtreatment.

HRT,especiallyoestrogen-progestagencombinedtreatment,increasesthedensityofmammographicimageswhich

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Ovariancancer

Ovariancancerismuchrarerthanbreastcancer.Inlong-term(atleast5-10years)useofoestrogen-onlyHRTproducts

hasbeenassociatedwithaslightlyincreasedriskofovariancancer(seesection4.8).

SomestudiesincludingtheWHItrialsuggestthatthelong-termuseofcombinedHRTsmayconferasimilar,or

slightlysmaller,risk(seesection4.8).

Venousthromboembolism

HRTisassociatedwitha1.3-3foldriskofdevelopingvenousthromboembolism(VTE),i.e.deepveinthrombosis

orpulmonaryembolism.TheoccurrenceofsuchaneventismorelikelyinthefirstyearofHRTthanlater(see

section4.8).

PatientswithknownthrombophilicstateshaveanincreasedriskofVTEandHRTmayaddtothisrisk.HRTis

thereforecontraindicatedinthesepatients(seesection4.3).

GenerallyrecognizedriskfactorsforVTEinclude,useofoestrogens,olderage,majorsurgery,prolonged

immobilization,obesity(BMI>30kg/m 2

)),pregnancy/postpartumperiod,systemiclupuserythematosus(SLE),

andcancer.ThereisnoconsensusaboutthepossibleroleofvaricoseveinsinVTE.

AsinallpostoperativepatientsprophylacticmeasuresneedbeconsideredtopreventVTEfollowingsurgery.If

prolongedimmobilisationistofollowelectivesurgerytemporarilystoppingHRT4to6weeksearlieris

recommended.Treatmentshouldnotberestarteduntilthewomaniscompletelymobilised.

InwomenwithnopersonalhistoryofVTEbutwithafirstdegreerelativewithahistoryofthrombosisatyoung

age,screeningmaybeofferedaftercarefulcounsellingregardingitslimitations(onlyaproportionof

thrombophilicdefectsareidentifiedbyscreening).

Ifathrombophilicdefectisidentifiedwhichsegregateswiththrombosisinfamilymembersorifthedefectis

‘severe’(e.g.antithrombin,proteinS,orproteinCdeficienciesoracombinationofdefects)HRTis

contraindicated.

Womenalreadyonchronicanticoagulanttreatmentrequirecarefulconsiderationofthebenefit-riskofuseof

HRT.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorsimmediatelywhentheyareawareofapotentialthromboembolicsymptom(eg,painfulswellingofaleg,

suddenpaininthechest,dyspnea).

Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofprotectionagainstmyorcardialinfarctioninwomenwith

orwithoutCADwhoreceivedcombinedoestrogen-progestagenoroestrogens-onlyHRT.

TherelativeriskofCADduringuseofcombinedoestrogen+progestagenHRTisslightlyincreased.Asthe

baselineabsoluteriskofCADisstronglydependentonage,thenumberofextracasesofCADdueto

oestrogen+progestagenuseisverylowinhealthywomenclosetomenopause,butwillrisewithmoreadvanced

age.RandomisedcontrolleddatafoundnoincreasedriskofCADinhysterectomisedwomenusingoestrogen-only

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Ischaemicstroke

Combinedoestrogen-progestagenandoestrogen-onlytherapyareassociatedwithanupto1.5-foldincreaseinrisk

ofischaemicstroke.Therelativeriskdoesnotchangewithageortimesincemenopause.However,asthebaseline

riskofstrokeisstronglyage-dependent,theoverallriskofstrokeinwomenwhouseHRTwillincreasewithage

(seesection4.8).

Otherconditions

Oestrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.

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

biological activehormone concentrations areunchanged. Otherplasmaproteinsmay beincreased

(angiotensinogen/reninsubstrate,alpha-I-antitrypsin,ceruloplasmin).

HRTusedoesnotimprovecognitivefunction.Thereissomeevidenceofincreasedriskofprobabledementiain

womenwhostartusingcontinuouscombinedoroestrogen-onlyHRTaftertheageof65.

Potentialestradioltransfer

Ifnoprecautionistaken,estradiolgelcanbetransferredtootherpersonsbycloseskintoskincontact.

Thefollowingprecautionsarethereforerecommended:

·forthepatient:

owashhandswithsoapafterapplyingthegel,

ocovertheapplicationareawithclothingoncethegelhasdried,

oshowerbeforeanysituationinwhichthistypeofcontactisforeseen.

·forpeoplenotbeingtreatedwithESTREVA0.1%w/wgel:

ointheeventofcontactwithanapplicationareawhichhasnotbeenwashedorisnotcoveredwith

clothing,washtheareaofskinontowhichestradiolmayhavebeentransferred,usingsoapandwater.

Excipientsknowntohavearecognizedactionoreffect

Thepresenceofpropyleneglycol,maycauseskinirritation.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Themetabolismofoestrogensmaybeincreasedbyconcomitantuseofsubstancesknowntoinducedrug-metabolising

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

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

Ritonavirandnelfinavir,althoughknownasstronginhibitors,bycontrastexhibitinducingpropertieswhenused

concomitantlywithsteroidhormones.

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Attransdermaladministration,thefirst-passeffectintheliverisavoidedand,thus,transdermallyappliedoestrogens

mightbelessaffectedthanoralhormonesbyenzymeinducers.

Clinically,anincreasedmetabolismofoestrogensandprogestagensmayleadtodecreasedeffectandchangesinthe

uterinebleedingprofile.

4.6Fertility,pregnancyandlactation

Pregnancy:

ESTREVA 0.1%w/wgelisnotindicatedduringpregnancy.Ifpregnancyoccursduringmedicationwith

ESTREVA 0.1%w/wgeltreatmentshouldbewithdrawnimmediately.

Theresultsofmostepidemiologicalstudiestodaterelevanttoinadvertentfœtalexposuretooestrogensindicateno

teratogenicorfoetotoxiceffects.

Lactation:

ESTREVA 0.1%w/wgelisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

Noeffectsonabilitytodriveandusemachineshavebeenobserved.

4.8Undesirableeffects

DuringphaseIIIclinicaltrials,thefollowingadversedrugreactionshavebeenreported,withafrequencyunder10%

forallofthem.Theseadversedrugreactionsarethosewhicharereportedduringoestrogenreplacementtherapy.

Organsystemclass

(e.g.MedDRASOC

level) CommonADRs

>1/100;<1/10 UncommonADRs

>1/1,000;<1/100

Reproductivesystem

andbreastdisorders Metrorrhagia

Uterinehaemorrhage

Breastpain Benignbreastneoplasm

Vaginaldischarge

Gastrointestinal

disorders Nausea

Abdominaldistension Vomiting

Nervoussystem

disorders Headache -

Musculoskeletaland

connectivetissue

disorders Sensationofheaviness Musculoskeletalpain

Psychiatricdisorders - -

Vasculardisorders - Thrombophlebitis

Respiratory,thoracic

andmediastinal

disorders - Pulmonaryembolism

Investigations - Weightincrease

Generaldisordersand

administrationsite

conditions - Oedemaperipheral

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Basedonthepost-marketingdata,casesofallergicreactions,contactdermatitisattheapplicationsitehavebeen

reported(unknowneffect).

Breastcancerrisk

Anupto2-foldincreasedriskofhavingbreastcancerdiagnosedisreportedinwomentakingcombined

oestrogen-progestagentherapyformorethan5years.

Anyincreasedriskinusersofoestrogen-onlytherapyissubstantiallylowerthanthatseeninusersofoestrogen-

progestagencombinations.

Thelevelofriskisdependentontheduration(seesection4.4).

Resultsofthelargestrandomizedplacebo-controlledtrial(WHI-study)andlargestepidemiologicalstudy(MWS)

arepresented.

MillionWomenstudy–Estimatedadditionalriskofbreastcancerafter5years’use

USWHIstudies-additionalriskofbreastcancerafter5years’use

‡WhentheanalysiswasrestrictedtowomenwhohadnotusedHRTpriortothestudytherewasnoincreasedrisk

apparentduringthefirst5yearsoftreatment:after5yearstheriskwashigherthaninnon-users.

2*Takenfrombaselineincidenceratesindevelopedcountries

3*WHIstudyinwomenwithnouterus,whichdidnotshowanincreaseinriskofbreastcancer

Endometrialcancerrisk

Postmenopausalwomenwithauterus

Theendometrialcancerriskisabout5inevery1000womenwithanuterusnotusingHRT.

Inwomenwithauterus,useofoestrogen-onlyHRTisnotrecommendedbecauseitincreasestheriskofendometrial

Skinandsubcutaneous

tissuedisorders - Pruritus

range

(years) Additionalcases

per1000neverusers

ofHRT

overa5year

period*2 Riskratio Additionalcasesper1000HRTusersover5years

(95%CI)

OestrogenonlyHRT

50-65 9-12 1.2 1-2(0-3)

Combinedoestrogen-progestagen

50-65 9-12 1.7 6(5-7)

#Overallriskratio.Theriskratioisnotconstantbutwillincreasewithincreasingdurationonuse

Note:SincethebackgroundincidenceofbreastcancerdiffersbyEUcountry,thenumberofadditional

casesofbreastcancerwillalsochangeproportionately.

Agerange

(yrs) Incidenceper1000women

inplaceboarmover5years Riskratio&95%CI Additionalcasesper1000HRT

usersover5years(95%CI)

CEEoestrogen-only

50-79 21 0.8(0.7–1.0) -4(-6–0)*3

CEE+MPAoestrogen&progestagen‡

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Dependingonthedurationofoestrogen-onlyuseandoestrogendose,theincreaseinriskofendometrialcancerin

epidemiologystudiesvariedfrombetween5and55extracasesdiagnosedinevery1000womenbetweentheagesof

50and65.

Addingaprogestagentooestrogen-onlytherapyforatleast12dayspercyclecanpreventthisincreasedrisk.Inthe

MillionWomenStudytheuseoffiveyearsofcombined(sequentialorcontinuous)HRTdidnotincreaseriskof

endometrialcancer(RRof1.0(0.8-1.2)).

Ovariancancer

Long-termuseofoestrogen-onlyandcombinedoestrogen-progestagenHRThasbeenassociatedwithaslightly

increasedriskofovariancancer.IntheMillionWomenStudy5yearsofHRTresultedin1extracaseper2500users.

Riskofvenousthromboembolism

HRTisassociatedwitha1.3-3-foldincreasedrelativeriskofdevelopingvenousthromboembolism(VTE),i.e.deep

veinthrombosisorpulmonaryembolism.TheoccurrenceofsuchaneventismorelikelyinthefirstyearofusingHT

(seesection4.4).ResultsoftheWHIstudiesarepresented:

WHIStudies-AdditionalriskofVTEover5years’use

Riskofcoronaryarterysidease

TheriskofcoronaryarterydiseaseisslightlyincreasedinusersofcombinedoestrogenprogestagenHRTovertheage

of60(seesection4.4).

Riskofischaemicstroke

Theuseofoestrogen-onlyandoestrogen+progestagentherapyisassociatedwithanupto1.5foldincreasedrelative

riskofischaemicstroke.TheriskofhaemorrhagicstrokeisnotincreasedduringuseofHRT.

Thisrelativeriskisnotdependentonageorondurationofuse,butasthebaselineriskisstronglyage-dependent,the

overallriskofstrokeinwomenwhouseHRTwillincreasewithage,seesection4.4.

WHIstudiescombined-Additionalriskofischaemicstroke*5over5years’use

4*Studyinwomenwithnouterus

5*nodifferentiationwasmadebetweenischaemicandhaemorrhagicstroke.

Otheradversereactionshavebeenreportedinassociationwithoestrogen/progestagentreatment:

Gallbladderdisease.

Skinandsubcutaneousdisorders:chloasma,erythemamultiforme,erythemanodosum,vascularpurpura.

Probabledementiaovertheageof65(seesection4.4).

4.9Overdose

Signsofanoverdosearegenerallybreasttenderness,swellingoftheabdomen/pelvis,anxietyandirritability(see

Agerange(years) Incidenceper1000womenin

placebo

armover5years Riskratioand95%CI Additionalcasesper1000

HRTusers

Oraloestrogen-only*4

50-59 7 1.2(0.6-2.4) 1(-3-10)

Oralcombinedoestrogen-progestagen

50-59 4 2.3(1.2-4.3) 5(1-13)

Agerange(years) Incidence

per1000womenin

placeboarmover5years Riskratioand

95%CI Additionalcasesper1000

HRTusersover5years

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcode:G03CA03

OESTROGENS(Genitourinarysystemandsexhormones)

Naturaloestrogenbytransdermalroute.

Theactiveingredient,synthetic17-estradiol,ischemicallyandbiologicallyidenticaltoendogenoushumanestradiol.

Itsubstitutesforthelossofoestrogenproductioninmenopausalwomen,andalleviatesmenopausalsymptoms

ClinicalTrialInformation:

Reliefofmenopausalsymptomswasachievedduringthefirstfewweeksoftreatment.

5.2Pharmacokineticproperties

Inapharmacokineticstudy,applicationasingledoseof1.5gofESTREVA 0.1%w/wgel(i.e.1.5mg)overasurface

areaof400cm2ofabdominalskinisfollowedbyaprogressiveincreaseinestradiolaemiawhichreachesameanpeak

of40pg/mlafterasingleadministration.Withrepeatedadministrationofthesamedoseoverthesamearea,steady

stateisreachedin4days.Averagelevels24hoursafterthelastapplicationareintheorderof40pg/mlandthemean

peakatthe22nddayis70pg/ml.

Repeatedadministrationof3gofESTREVA 0.1%w/wgelleadstoadoublingoftheareaunderthecurveobserved

with1.5gofgel.

Thebioavailabilityofpercutaneousestradiolisdependentontheareaofapplicationandvariesfromonesubjectto

anothermakingitnecessarytoadaptthedosagetoeachindividualcaseasafunctionoftheclinicalsymptomatology.

5.3Preclinicalsafetydata

Acutetoxicityofestrogensislow.Becauseofmarkeddifferencesbetweenanimalspeciesandbetweenanimalsand

humanspreclinicalresultspossessalimitedpredictivevaluefortheapplicationofestrogensinhumans.

Inexperimentalanimalsestradioldisplayedanembryolethaleffectalreadyatrelativelylowdoses;malformationsof

theurogenitaltractandfeminizationofmalefetuseswereobserved.

Preclinicaldatabasedonconventionalstudiesofrepeateddosetoxicity,genotoxicityandcarcinogeneticpotential

revealedestrogeniceffectsinrelationshipwiththepharmacologicalactivityofthemolecule.

Thefinishedproductisamildirritantfortheskin,anirritantfortheeyes,showsgoodtolerancewithrepeatedtopical

administrationandisnon-sensitizing.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Ethanol96percent,Purifiedwater,Propyleneglycol,Diethyleneglycolmonoethylether(Transcutol),Carbomer

(Carbopol1382),Trolamine,Disodiumedetate.

6.2Incompatibilities

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6.3Shelflife

3years

6.4Specialprecautionsforstorage

Nospecialprecautionsforstorage.

6.5Natureandcontentsofcontainer

High-densitywhitepolyethylenetube-bottlecontaining50gofgel,withadosingpump.

Boxofoneorthreebottlesof50g.

Thepumpdeliverspushesof0.5gofgelcorrespondingto0.5mgofestradiol.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

BELPHARMAS.A.

WinstonChurchillAv.,67

1180Brussels

Belgium

8MARKETINGAUTHORISATIONNUMBER

PA0908/001/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:22January1999

Dateoflastrenewal:15July2010

10DATEOFREVISIONOFTHETEXT

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