AERODIOL

Main information

  • Trade name:
  • AERODIOL Nasal Spray Solution 150 Micrograms/g
  • Dosage:
  • 150 Micrograms/g
  • Pharmaceutical form:
  • Nasal Spray Solution
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AERODIOL Nasal Spray Solution 150 Micrograms/g
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0568/014/001
  • Authorization date:
  • 23-03-2001
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AERODIOL150micrograms/dose,nasalspraysolution

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachspraydelivers0.07mlofsolutionwhichcontainsestradiolequivalentto150microgramsofestradiol

hemihydrate.

Forexcipients,see6.1.

3PHARMACEUTICALFORM

Nasalspray,solution

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapy(HRT)foroestrogendeficiencysymptomsinpostmenopausalwomen.

Theexperienceoftreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

NASALROUTE.

Therecommendeddoseforinitiationoftreatmentis150micrograms(1spray)inanostril.

After2or3cyclesthedosagemaybeadjustedinresponsetoclinicalsymptoms:

Theusualmaintenancedoseis300micrograms(2sprays)per24hours,i.e.1sprayineachnostriloncedaily.

Ifsymptomsofoestrogendeficiencypersist,thenumberofspraysmaybeincreasedupto3or4perday

(450microgramsor600micrograms),individeddoses,morningandevening.

Intheeventofsignsofhyperoestrogenismsuchasbreasttenderness,abdominalbloating,anxiety,nervousnessor

aggressiveness,thedosageshouldbereducedto1spray(150micrograms)daily.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

duration(seealsosection4.4"Specialwarningsandspecialprecautionsforuse")shouldbeused.

AERODIOLmaybeadministeredascyclicorcontinuoustreatment:

Cyclictreatment:AERODIOLisusedcyclicallyforadurationof21to28days,followedbya2-to7-day

treatment-freeperiod.

Continuoustreatment:AERODIOLisadministereddailywithoutabreakintreatment.Continuous(non-cyclic)

treatmentmaybeindicatedinhysterectomisedwomenandincaseswhereoestrogendeficiencysymptomsoccur

duringthetreatment-freeperiod.

Fornon-hysterectomisedwomen,AERODIOLisrecommendedtobecombinedwithprogestogentreatmentforatleast

12dayspercycletoavoidoestrogen-inducedendometrialhyperplasia.(seesection4.4"Specialwarningsandspecial

precautionsforuse").

Sequentialprogestogentreatmentshouldbeadministeredasfollows:

IfAERODIOLisadministeredcyclically,aprogestogenwillbeaddedtoestradiolforatleastthelast12daysof

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IfAERODIOLisadministeredcontinuously,itisrecommendedtotakeaprogestogenforatleast12dayseach

month.

Ineithercase,withdrawalbleedingwillusuallyoccurwhentheprogestogenisdiscontinued.

Unlessthereisapreviousdiagnosisofendometriosis,itisnotrecommendedtoaddaprogestogeninhysterectomised

women.

Patientschangingfromanothercyclicorcontinuoussequentialpreparationshouldcompletethecycleandmaythen

changetoAERODIOLwithoutabreakintherapy.Patientschangingfromacontinuouscombinedpreparationmay

starttherapyatanytime.

Priming:beforeitisfirstused,thebottlemustbeprimedbyfirmlyactivatingthepump3times.

Thebottleshouldbeheldverticallyduringadministration.Theheadisbentslightlyforwardandthenozzleintroduced

intoeachnostrilinturn.Pressureisthenexertedonthepump.Thepatientmustnotbreatheinduringsprayingnorblow

thenoseimmediatelyafterwards.

Intheeventofaseverelyblockednose,AERODIOLmaybeadministeredtemporarilyviatheoromucosalrouteby

administrationviatheuppergingivalsulcus.Insuchcircumstances,theusualdosageshouldbedoubled.

PatientswitharunnynoseshouldblowtheirnosebeforeadministrationofAERODIOL.

Dosingshouldpreferablytakeplaceatthesametimeeveryday.

Ifadoseisforgotten,itcanbegivenatanytimeuptothenextscheduleddosebutitshouldnotbedoubled.Forgetting

adosemayincreasethelikelihoodofbreakthroughbleedingandspotting.

Therisk/benefitratioshouldbere-evaluatedregularlytoadjustthetreatmentifneeded:

ForthedurationoftreatmentwithAERODIOL.

WhenchangingfromanotherhormonaltreatmenttoAERODIOL.

4.3Contraindications

Known,pastorsuspectedbreastcancer.

Knownorsuspectedoestrogen-dependentmalignanttumours(e.g.endometrialcancer).

Undiagnosedgenitalbleeding.

Untreatedendometrialhyperplasia.

Previousidiopathicorcurrentvenousthromboembolism(deepvenousthrombosis,pulmonaryembolism).

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfarction).

Acuteliverdisease,orahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal.

Knownhypersensitivitytoestradiolhemihydrateortoanyoftheexcipients.

Porphyria.

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk

Medicalexamination/followup

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythecontraindicationsandwarningsfor

use.Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividual

woman.Womenshouldbeadvisedwhatchangesintheirbreastsshouldbereportedtotheirdoctorornurse.

Investigations,includingmammography,shouldbecarriedoutinaccordancewithcurrentlyacceptedscreening

practices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision

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pregnancyorprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccount

thattheseconditionsmayrecurorbeaggravatedduringtreatmentwithAerodiol,inparticular:

Leiomyoma(uterinefibroids)orendometriosis.

Ahistoryof,orriskfactorsfor,thromboembolicdisorders(seebelow).

Riskfactorsforoestrogen-dependenttumours,e.g.firstdegreeheredityforbreastcancer.

Hypertension.

Liverdisorders(e.g.liveradenoma).

Diabetesmellituswithorwithoutvascularinvolvement.

Cholelithiasis.

Migraineor(severe)headache.

Systemiclupuserythematosus.

Ahistoryofendometrialhyperplasia(seebelow).

Epilepsy.

Asthma.

Otosclerosis.

Recurrentepistaxis.

Reasonsforimmediatewithdrawaloftherapy:

Therapyshouldbediscontinuedifacontraindicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction.

Significantincreaseinbloodpressure.

Newonsetofmigraine-typeheadache.

Pregnancy.

Endometrialhyperplasia

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenoestrogensareadministeredalonefor

prolongedperiods(seesection4.8).Theadditionofaprogestogenforatleast12dayspercycleinnon-

hysterectomisedwomengreatlyreducesthisrisk.Fordosesof450micrograms/dand600micrograms/d,the

endometrialsafetyofaddedgestagenshasnotbeenstudied.

Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-throughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshould

beinvestigated.Suchinvestigationsmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Unopposedoestrogenstimulationmayleadtopremalignantormalignanttransformationintheresidualfociof

endometriosis.Therefore,theadditionofprogestogenstooestrogenreplacementtherapyshouldbeconsideredin

womenwhohaveundergonehysterectomybecauseofendometriosis,especiallyiftheyareknowntohaveresidual

endometriosis.

Breastcancer

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

includingtheMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentaking

oestrogensoroestrogen-progestogencombinationsortiboloneforHRTforseveralyears(seesection4.8

“Undesirableeffects”).ForallHRT,anexcessriskbecomesapparentwithinafewyearsofuseandincreaseswith

durationofintakebutreturnstobaselinewithinafew(atmostfive)yearsafterstoppingtreatment.

IntheMWS,therelativeriskofbreastcancerwithconjugatedequineoestrogens(CEE)orestradiol(E2)wasgreater

whenaprogestogenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeofprogestogen.Therewas

noevidenceofadifferenceinriskbetweenthedifferentroutesofadministration.

IntheWHIstudy,thecontinuouscombinedconjugatedequineoestrogenandmedroxyprogesteroneacetate(CEE+

MPA)productusedwasassociatedwithbreastcancersthatwereslightlylargerinsizeandmorefrequentlyhadlocal

lymphnodemetastasescomparedtoplacebo.

HRT,especiallyoestrogen-progestogencombinedtreatment,increasesthedensityofmammographicimageswhich

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Venousthromboembolism

HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism(VTE)i.e.deepvein

thrombosisorpulmonaryembolism.Onerandomisedcontrolledtrialandepidemiologicalstudiesfoundatwoto

threefoldhigherriskforuserscomparedwithnon-users.Fornon-usersitisestimatedthatthenumberofcasesof

VTEthatwilloccurovera5-yearperiodisabout3per1,000womenaged50-59yearsand8per1,000women

agedbetween60-69years.ItisestimatedthatinhealthywomenwhouseHRTfor5years,thenumberof

additionalcasesofVTEovera5-yearperiodwillbebetween2and6(bestestimate=4)per1000womenaged50-

59yearsandbetween5and15(bestestimate=9)per1000womenaged60-69years.Theoccurrenceofsuchan

eventismorelikelyinthefirstyearofHRTthanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalhistoryorfamilyhistory,severeobesity(BodyMass

Index>30kg/m²)andsystemiclupuserythematosus(SLE).Thereisnoconsensusabouttheroleofvaricoseveins

inVTE.

PatientswithahistoryofVTEorknownthrombophilicstateshaveanincreasedriskofVTE.HRTmayaddtothis

risk.Personalorstrongfamilyhistoryofthromboembolismorrecurrentspontaneousabortionshouldbe

investigatedinordertoexcludeathrombophilicpredisposition.Untilathoroughevaluationofthrombophilic

factorshasbeenmadeoranticoagulanttreatmentinitiated,useofHRTinsuchpatientsshouldbeviewedas

contraindicated.Thosewomenalreadyonanticoagulanttreatmentrequirecarefulconsiderationofthebenefit-risk

ofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajorsurgery.As

inallpost-operativepatients,scrupulousattentionshouldbegiventoprophylacticmeasurestopreventVTE

followingsurgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,particularlyabdominalor

orthopaedicsurgerytothelowerlimbs,considerationshouldbegiventotemporarilystoppingHRTfourtosix

weeksearlier,ifpossible.Treatmentshouldnotberestarteduntilthewomaniscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorsimmediatelyiftheyareawareofapotentialthromboembolicsymptom(e.g.painfulswellingofaleg,

suddenpaininthechest,dyspnoea).

Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombined

conjugatedoestrogensandmedroxyprogesteroneacetate(MPA).Twolargeclinicaltrials(WHIandHERSi.e.

HeartandEstrogen/progestinReplacementStudy)showedapossibleincreasedriskofcardiovascularmorbidityin

thefirstyearofuseandnooverallbenefit.ForotherHRTproductsthereareonlylimiteddatafromrandomised

controlledtrialsexaminingeffectsincardiovascularmorbidityormortality.Therefore,itisuncertainwhether

thesefindingsalsoextendtootherHRTproducts.

Stroke

Onelargerandomisedclinicaltrial(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischaemic

strokeinhealthywomenduringtreatmentwithcontinuouscombinedconjugatedoestrogensandMPA.For

womenwhodonotuseHRT,itisestimatedthatthenumberofcasesofstrokethatwilloccurovera5yearperiod

isabout3per1000womenaged50-59yearsand11per1000womenaged60-69years.Itisestimatedthatfor

womenwhouseconjugatedoestrogensandMPAfor5years,thenumberofadditionalcaseswillbebetween0

and3(bestestimate=1)per1000usersaged50-59yearsandbetween1and9(bestestimate=4)per1000users

aged60-69years.ItisunknownwhethertheincreasedriskalsoextendstootherHRTproducts.

Ovariancancer

Long-term(atleast5-10years)useofoestrogen-onlyHRTproductsinhysterectomisedwomenhasbeen

associatedwithanincreasedriskofovariancancerinsomeepidemiologicalstudies.Itisuncertainwhetherlong-

termuseofcombinedHRTconfersadifferentriskthanoestrogen-onlyproducts.

Otherconditions

Oestrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.Patientswithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitisexpectedthatthelevels

ofcirculatingoestrogensfromAERODIOLisincreased.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringoestrogenreplacementor

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havebeenreportedwithoestrogentherapyinthiscondition.

Estrogensincreasethyroidbindingglobulin(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.Itisunknownwhetherthefindingsapplytoyoungerpost-menopausalwomenorotherHRT

products.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Combinationsrequiringprecautionsforuse:

Enzymeinducers:

Themetabolismofoestrogensmaybeincreasedbyconcomitantuseofsubstancesknowntoinducedrug-metabolising

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

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

Afternasaladministration,thefirst-passeffectintheliverisavoidedand,therefore,nasallyadministeredoestrogens

suchasAERODIOLmightbelessaffectedbyenzymeinducersthanorallyadministeredhormones.

Antiretroviralagents:

Ritonavirandnelfinavir,althoughknownasstrongenzymeinhibitors,bycontrastexhibitenzymeinducingproperties

whenusedconcomitantlywithsteroidhormones.

HerbalpreparationscontainingStJohn’sWort(Hypericumperforatum)mayinducethemetabolismofoestrogens.

Clinically,anincreasedmetabolismofoestrogensandprogestogensmayleadtoadecreasedeffectandchangesinthe

uterinebleedingprofile.

Nasalcorticosteroidsandnasallyadministeredvasoconstrictingagents:

Theeffectofconcomitantadministrationofnasalcorticosteroidsornasalvasoconstrictingagentshasnotbeenstudied.

AERODIOLshouldnotbeadministeredimmediatelyafternasalcorticosteroidsornasalvasoconstrictingagents.

4.6Pregnancyandlactation

Pregnancy:

AERODIOLisnotindicatedduringpregnancy.IfpregnancyoccursduringmedicationwithAERODIOLtreatment

shouldbewithdrawnimmediately.

Theresultstodateofmostepidemiologicalstudiesrelevanttoinadvertentfoetalexposuretooestrogensindicateno

teratogenicorfoetotoxiceffects.

Lactation:

AERODIOLisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

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4.8Undesirableeffects

Themostfrequentlyreportedundesirableeffects(>10%)duringtreatmentwithAERODIOLaresymptomsatthe

applicationsite:prickling-tinglingsensation,sneezingandrhinorrhoea.

OtherundesirableeffectsreportedinusersofAERODIOLorothernon-oralestradiolpreparationsarelistedinthe

table.

Breastcancer

Accordingtoevidencefromalargenumberofepidemiologicalstudiesandonerandomisedplacebo-controlledtrial,the

Women’sHealthInitiative(WHI),theoverallriskofbreastcancerincreaseswithincreasingdurationofHRTusein

currentorrecentHRTusers.

Foroestrogen-onlyHRT,estimatesofrelativerisk(RR)fromareanalysisoforiginaldatafrom51epidemiological

studies(inwhich>80%ofHRTusewasoestrogen-onlyHRT)andfromtheepidemiologicalMillionWomenStudy

(MWS)aresimilarat1.35(95%CI1.21–1.49)and1.30(95%CI1.21–1.40),respectively.

ForoestrogenplusprogestogencombinedHRT,severalepidemiologicalstudieshavereportedanoverallhigherriskfor

breastcancerthanwithoestrogensalone.

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,thenumberofadditionalcasesduringthecorrespondingperiodwillbe

Forusersofoestrogen-onlyreplacementtherapy

between0and3(bestestimate=1.5)for5years’use.

Organsystem CommonADRs

>1/100,<1/10 UncommonADRs

>1/1000,<1/100 RareADRs

>1/10.000,<1/1000

Bodyasawhole Headache, Fluidretention/oedema,

weightincrease/loss,

dizziness,fatigue,

legcramps,migraine

Gastrointestinal Nausea Bloating,

abdominalcramps Cholelithiasis,

cholestaticjaundice

Reproductive Breakthrough

bleeding,spotting,

mastodynia Dysmenorrhoea,

endometrial

hyperplasia,benign

breasttumours, Increaseinsizeof

uterinefibroids

Respiratorytract Epistaxis

Skinandappendages Acne,pruritus Urticaria

Cardiovascular Hypertension

Psychiatric Increase/decreasein

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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"Specialwarningsandspecialprecautions

foruse").

Endometrialcancer

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandendometrialcancerincreaseswithincreasing

durationofuseofunopposedoestrogens.Accordingtodatafromepidemiologicalstudies,thebestestimateoftherisk

isthatforwomennotusingHRT,about5inevery1000areexpectedtohaveendometrialcancerdiagnosedbetween

theagesof50and65.Dependingonthedurationoftreatmentandoestrogendose,thereportedincreaseinendometrial

cancerriskamongunopposedoestrogenusersvariesfrom2-to12-foldgreatercomparedwithnon-users.Addinga

progestogentooestrogen-onlytherapygreatlyreducesthisincreasedrisk.

Otheradversereactionshavebeenreportedinassociationwithoestrogentreatment:

4.9Overdose

Therouteofadministrationmakessignificantacuteoverdoseunlikely.Theeffectsofoverdosearegenerallybreast

tenderness,abdominal/pelvicbloating,nauseaandaggressiveness.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCClassification:G03CA03.

OESTROGENS(Genitourinarysystemandsexhormones).

Theactiveingredient,synthetic17beta-estradiol,ischemicallyandbiologicallyidenticaltoendogenoushuman

estradiol.Itsubstitutesforthelossofoestrogenproductioninmenopausalwomen,andalleviatesmenopausal

symptoms.AERODIOLconstitutespulsedoestrogentherapythatprovidesahormoneexposuresimilartothatfound

duringtheearlytomidfollicularphasesofthemenstrualcycle.

Duringtreatment,duetothemechanismofaction,theminimumFSHvaluesareobserved6to8hourspost-dosingand

adecreaseisstillpresentimmediatelybeforethenextdose.

-Oestrogen-dependentneoplasmsbenignandmalignant,e.g.endometrialcancer.

-Venousthromboembolism,i.e.deeplegorpelvicvenousthrombosisandpulmonaryembolism,ismorefrequent

amongHRTusersthanamongnon-users.Forfurtherinformation,seesections4.3"Contraindications"and4.4

"Specialwarningsandspecialprecautionsforuse".

-Myocardialinfarctionandstroke.

-Gallbladderdisease.

-Skinandsubcutaneousdisorders:chloasma,erythemamultiforme,erythemanodosum,vascularpurpura.

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5.2Pharmacokineticproperties

Whenadministeredatadoseof300microgramsAERODIOLachievespeakserumestradiollevelsaround1000

pg/mL,10to30minutespost-dosing.17beta-estradiol(E

)israpidlydistributed.Returntovaluesclosetobaseline

occurswithin12hoursofdosing.

Theabsolutebioavailabilityofestradiolwhenadministeredbythenasalrouteisaround25%andishigherthanthat

followingoraladministrationbecauseAERODIOLavoidsintestinalandliverfirstpasseffectsincontrasttoorally

administeredoestrogens.

Hormoneexposure,asexpressedbytheareaunderthecurveofplasmaestradiolconcentrationagainsttime(AUC

isproportionaltothedose.Followingnasaladministrationof300micrograms,theAUC

issimilartothatobtained

usingotheradministrationroutes(patchdelivering50micrograms/d,2-mgtablet)butwithadifferentkineticprofile

(pulse).

Inclinicaltrials,nocaseofnon-absorptionwasobserved.

(Estrone)/E

ratiosarearound1.A20%decreaseinbioavailabilityofestradiolhasbeenobservedinheavysmokers

(1pack/day).

CigarettesmokingimmediatelybeforeAERODIOLadministrationdoesnotmodifythenasalabsorptionofestradiol.

5.3Preclinicalsafetydata

Localtolerabilitystudiesinanimalshaveshownthatnasaladministrationofestradioldoesnotdamagethenasal

mucosa.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Methylbeta-cyclodextrin(RAMEB)

Sodiumchloride

Sodiumhydroxideorhydrochloricacid

Purifiedwater

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Nospecialprecautionsforstorage.

6.5Natureandcontentsofcontainer

4.2ml(60sprays)inabottle(Type-1glass)withameteringpump(polypropylene)andanasalapplicator

(polypropylene);packsof1and3bottles.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7MARKETINGAUTHORISATIONHOLDER

LesLaboratoiresServier

22rueGarnier

92000NeuillySurSeine

France

8MARKETINGAUTHORISATIONNUMBER

PA568/14/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:23March2001

Dateoflastrenewal:19May2005

10DATEOFREVISIONOFTHETEXT

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