ALLURENE

Main information

  • Trade name:
  • ALLURENE Film Coated Tablet 1, 2 Milligram
  • Dosage:
  • 1, 2 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ALLURENE Film Coated Tablet 1, 2 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1410/014/001
  • Authorization date:
  • 27-07-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Allurene1mg/2mgfilm-coatedtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains:1mgestradiol(asestradiolhemihydrate)and2mgdrospirenone.

Excipient:46mglactose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Mediumred,roundtabletwithconvexfaces,onesideembossedwiththelettersDLinaregularhexagon.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapyforoestrogendeficiencysymptomsinpostmenopausalwomenmorethan1yearpost

menopause.

Preventionofosteoporosisinpostmenopausalwomenathighriskoffuturefractureswhoareintolerantof,or

contraindicatedfor,othermedicinalproductsapprovedforthepreventionofosteoporosis.

(SeealsoSection4.4)

Theexperiencetreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

Womenwhodonottakehormonereplacementtherapy(HRT)orwomenwhochangefromanothercontinuous

combinedproductmaystarttreatmentatanytime.Womenchangingfromacyclic,sequentialcombinedHRTregimen,

treatmentshouldbeginthedayfollowingcompletionofthepriorregimen.

Dosage

Onetabletistakendaily.Eachblisterisfor28daysoftreatment.

Administration

Thetabletsaretobeswallowedwholewithsomeliquidirrespectiveoffoodintake.Treatmentiscontinuous,which

meansthatthenextpackfollowsimmediatelywithoutabreak.Thetabletsshouldpreferablybetakenatthesametime

everyday.Ifatabletisforgottenitshouldbetakenassoonaspossible.Ifmorethan24hourshaveelapsednoextra

tabletneedstobetaken.Ifseveraltabletsareforgotten,vaginalbleedingmayoccur.

Fortreatmentofpostmenopausalsymptoms,thelowesteffectivedoseshouldbeused.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

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4.3Contraindications

Undiagnosedgenitalbleeding

Known,pastorsuspectedcancerofthebreast

Knownorsuspectedoestrogen-dependentmalignanttumours(e.g.endometrialcancer)

Untreatedendometrialhyperplasia

Previousidiopathicorcurrentvenousthromboembolism(deepvenousthrombosis,pulmonaryembolism)

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfarction)

Acuteliverdisease,orahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal

Porphyria

Severerenalinsufficiencyoracuterenalfailure

Knownhypersensitivitytotheactivesubstancesortoanyoftheexcipients

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk

Medicalexamination/follow-up

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythecontraindicationsandwarningsforuse.

Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.

Womenshouldbeadvisedwhatchangesintheirbreastsshouldbereportedtotheirdoctorornurse.Investigations,

includingmammography,shouldbecarriedoutinaccordancewithcurrentlyacceptedscreeningpractices,modifiedto

theclinicalneedsoftheindividual.

Conditionswhichneedsupervision

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviously,and/orhavebeenaggravatedduringpregnancy

orprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthatthese

conditionsmayrecurorbeaggravatedduringtreatmentwithAllurene,inparticular:

Leiomyoma(uterinefibroids)orendometriosis,

Ahistoryof,orriskfactorsfor,thromboembolicdisorders(seebelow

Riskfactorsforoestrogendependenttumours,e.g.1stdegreeheredityforbreastcancer

Hypertension

Liverdisorders(egliveradenoma)

Diabetesmellituswithorwithoutvascularinvolvement

Cholelithiasis

Migraineor(severe)headache

Systemiclupuserythematosus

Ahistoryofendometrialhyperplasia(seebelow)

Epilepsy

Asthma

Otosclerosis

Reasonsforimmediatewithdrawaloftherapy:

Therapyshouldbediscontinuedincaseacontra-indicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction

Significantincreaseinbloodpressure

Newonsetofmigraine-typeheadache

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Endometrialhyperplasia

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenoestrogensareadministeredaloneforprolonged

periods(seesection4.8).Theadditionofaprogestogenforatleast12dayspercycleinnon-hysterectomisedwomen

greatlyreducesthisrisk.

Breakthroughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreakthroughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshouldbe

investigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy

Breastcancer

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

includingtheMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentaking

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

anexcessriskbecomesapparentwithinafewyearsofuseandincreaseswithdurationofintakebutreturnstobaseline

withinafew(atmostfive)yearsafterstoppingtreatment.

IntheMWS,therelativeriskofbreastcancerwithconjugatedequineoestrogens(CEE)orestradiol(E2)wasgreater

whenaprogestogenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeofprogestogen.Therewas

noevidenceofadifferenceinriskbetweenthedifferentroutesofadministration.

IntheWHIstudy,thecontinuouscombinedconjugatedequineoestrogenandmedroxyprogesteroneacetate(CEE+

MPA)productusedwasassociatedwithbreastcancersthatwereslightlylargerinsizeandmorefrequentlyhadlocal

lymphnodemetastasescomparedtoplacebo.

HRT,especiallyoestrogen-progestogencombinedtreatment,increasesthedensityofmammographicimageswhich

mayadverselyaffecttheradiologicaldetectionofbreastcancer.

Venousthromboembolism

HRTisassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism(VTE),i.e.deepveinthrombosis

orpulmonaryembolism.Onerandomisedcontrolledtrialandepidemiologicalstudiesfoundatwo-tothreefoldhigher

riskforuserscomparedwithnon-users.Fornon-usersitisestimatedthatthenumberofcasesofVTEthatwilloccur

overa5yearperiodisabout3per1000womenaged50-59yearsand8per1000womenagedbetween60–69years.It

isestimatedthatinhealthywomenwhouseHRTfor5years,thenumberofadditionalcasesofVTEovera5year

periodwillbebetween2and6(bestestimate=4)per1000womenaged50-59yearsandbetween5and15(best

estimate=9)per1000womenaged60-69years.TheoccurrenceofsuchaneventismorelikelyinthefirstyearofHRT

thanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalhistoryorfamilyhistory,severeobesity(BMI>30kg/m

2)andsystemiclupuserythematosus(SLE).ThereisnoconsensusaboutthepossibleroleofvaricoseveinsinVTE.

PatientswithahistoryofVTEorknownthrombophilicstateshaveanincreasedriskofVTE.

HRTmayaddtothisrisk.Personalorstrongfamilyhistoryofthromboembolismorrecurrentspontaneousabortion

shouldbeinvestigatedinordertoexcludeathrombophilicpredisposition.Untilathoroughevaluationofthrombophilic

factorshasbeenmadeoranticoagulanttreatmentinitiated,useofHRTinsuchpatientsshouldbeviewedas

contraindicated.Thosewomenalreadyonanticoagulanttreatmentrequirecarefulconsiderationofthebenefit-riskof

useofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajorsurgery.Asinall

postoperativepatients,scrupulousattentionshouldbegiventoprophylacticmeasurestopreventVTEfollowing

surgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,particularlyabdominalororthopaedic

surgerytothelowerlimbs,considerationshouldbegiventotemporarilystoppingHRT4to6weeksearlier,ifpossible.

Treatmentshouldnotberestarteduntilthewomaniscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorsimmediatelywhentheyareawareofapotentialthromboembolicsymptom(eg,painfulswellingofaleg,

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Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombinedconjugated

oestrogensandmedroxyprogesteroneacetate(MPA).Twolargeclinicaltrials(WHIandHERSi.e.Heartand

Estrogen/progestinReplacementStudy)showedapossibleincreasedriskofcardiovascularmorbidityinthefirstyear

ofuseandnooverallbenefit.ForotherHRTproductsthereareonlylimiteddatafromrandomisedcontrolledtrials

examiningeffectsincardiovascularmorbidityormortality.Therefore,itisuncertainwhetherthesefindingsalsoextend

tootherHRTproducts.

Stroke

Onelargerandomisedclinicaltrial(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischaemicstrokein

healthywomenduringtreatmentwithcontinuouscombinedconjugatedoestrogensandMPA.Forwomenwhodonot

useHRT,itisestimatedthatthenumberofcasesofstrokethatwilloccurovera5yearperiodisabout3per1000

womenaged50-59yearsand11per1000womenaged60-69years.Itisestimatedthatforwomenwhouseconjugated

estrogensandMPAfor5years,thenumberofadditionalcaseswillbebetween0and3(bestestimate=1)per1000

usersaged50-59yearsandbetween1and9(bestestimate=4)per1000usersaged60-69years.Itisunknownwhether

theincreasedriskalsoextendstootherHRTproducts.

Ovariancancer

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

withanincreasedriskofovariancancerinsomeepidemiologicalstudies.Itisuncertainwhetherlong-termuseof

combinedHRTconfersadifferentriskthanoestrogen-onlyproducts

Otherconditions

Oestrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringoestrogenreplacementorhormone

replacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitishavebeen

reportedwithoestrogentherapyinthiscondition.

Estrogensincreasethyroidbindingglobulin(TBG),leadingtoincreasedcirculatingtotalthyroidhormone,asmeasured

byprotein-boundiodine(PBI),T4levels(bycolumnorbyradioimmunoassay)orT3levels(byradio-immunoassay).

T3resinuptakeisdecreased,reflectingtheelevatedTBG.FreeT4andfreeT3concentrationsareunaltered.Other

bindingproteinsmaybeelevatedinserum,i.e.corticoidbindingglobulin(CBG),sex-hormone-bindingglobulin

(SHBG)leadingtoincreasedcirculatingcorticosteroidsandsexsteroids,respectively.Freeorbiologicalactive

hormoneconcentrationsareunchanged.Otherplasmaproteinsmaybeincreased(angiotensinogen/reninsubstrate,

alpha-I-antitrypsin,ceruloplasmin).

Thereisnoconclusiveevidenceforimprovementofcognitivefunction.ThereissomeevidencefromtheWHItrialof

increasedriskofprobabledementiainwomenwhostartusingcontinuouscombinedCEEandMPAaftertheageof65.

Itisunknownwhetherthefindingsapplytoyoungerpost-menopausalwomenorotherHRTproducts.

TheprogestincomponentinAllureneisanaldosteroneantagonistexhibitingweakpotassiumsparingproperties.In

mostcases,noincreaseofserumpotassiumlevelsistobeexpected.Inaclinicalstudy,however,insomepatientswith

mildormoderaterenalimpairmentandconcomitantuseofpotassium-sparingmedicinalproducts(suchasACE

inhibitors,angiotensinIIreceptorantagonistsorNSAIDs)serumpotassiumlevelsslightly,butnotsignificantly

increasedduringdrospirenoneintake.Therefore,itisrecommendedtocheckserumpotassiumduringthefirstmonthof

treatmentinpatientspresentingwithrenalinsufficiencyandpretreatmentserumpotassiumintheupperreference

range,andparticularlyduringconcomitantuseofpotassiumsparingmedicinalproducts(seealsosection4.5).

WomenwithelevatedbloodpressuremayexperienceadecreaseinbloodpressureundertreatmentwithAllurenedue

tothealdosteroneantagonistactivityofdrospirenone(seesection5.1).Allureneshouldnotbeusedtotreat

hypertension.WomenwithhypertensionshouldbetreatedaccordingtoHypertensionGuidelines.

Chloasmamayoccasionallyoccur,especiallyinwomenwithahistoryofchloasmagravidarum.Womenwitha

tendencytochloasmashouldavoidexposuretothesunorultravioletradiationwhilsttakingHRT.

Eachtabletofthismedicinalproductcontains46mglactosepertablet.Patientswithrarehereditaryproblemsof

galactoseintolerance,theLapplactasedeficiencyorglucose-galactosemalabsorptionwhoareonalactose-freediet

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

EffectsofothermedicinalproductsonAllurene

Themetabolismofoestrogens[andprogestogens]maybeincreasedbyconcomitantuseofsubstancesknowntoinduce

drug-metabolisingenzymes,specificallycytochromeP450enzymes,suchasanticonvulsants(e.g.phenobarbital,

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

Ritonavirandnelfinavir,althoughknownasstronginhibitors,bycontrastexhibitinducingpropertieswhenused

concomitantlywithsteroidhormones.HerbalpreparationscontainingStJohn'sWort(HypericumPerforatum)may

inducethemetabolismofoestrogens[andprogestogens].

Clinically,anincreasedmetabolismofoestrogensandprogestogensmayleadtodecreasedeffectandchangesinthe

uterinebleedingprofile.

ThemainmetabolitesofdrospirenonearegeneratedwithoutinvolvementofthecytochromeP450system.Inhibitorsof

thisenzymesystemarethereforeunlikelytoinfluencethemetabolismofdrospirenone.

InteractionofAllurenewithothermedicinalproducts

Basedoninvitroinhibitionstudiesandoninvivointeractionstudiesinfemalevolunteersreceivingsteady-statedoses

of3mgdrospirenoneperdayandomeprazole,simvastatin,ormidazolamasmarkersubstrate,aclinicallyrelevant

interactionofdrospirenonewiththecytochromeP450enzymemediatedmetabolismofotherdrugsisunlikely.

ConcomitantuseofAllureneandeitherNSAIDsorACEinhibitors/angiotensinIIreceptorantagonistsisunlikelyto

increaseserumpotassium.However,concomitantuseofallthesethreetypesofmedicationstogethermaycauseasmall

increaseinserumpotassium,whichismorepronouncedindiabeticwomen.

HypertensivewomentreatedwithAllureneandantihypertensivemedicationsmayexperienceanadditionaldecreasein

bloodpressure(seesection4.4).

4.6Pregnancyandlactation

Pregnancy

Allureneisnotindicatedduringpregnancy.IfpregnancyoccursduringmedicationwithAllurene,treatmentshouldbe

discontinuedpromptly.NoclinicaldataonexposedpregnanciesareavailableforDrospirenone.Animalstudieshave

shownreproductivetoxicity(seeSection5.3).Thepotentialriskforhumansisunknown.Theresultsofmost

epidemiologicalstudiestodaterelevanttoinadvertentfoetalexposuretocombinationsofoestrogenswithother

progestogenshavenotindicatedateratogenicorfoetotoxiceffect.

Lactation

Allureneisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

Noeffectsontheabilitytodriveandusemachineshavebeenobserved.

4.8Undesirableeffects

ThetablebelowreportsadversereactionsbyMedDRAsystemorganclasses(MedDRASOCs).Thefrequenciesare

basedonclinicaltrialdata.Theadversereactionswererecordedin7phaseIIIclinicalstudies(n=2424women)and

consideredasatleastpossiblycausallyrelatedtoAllurene(E21mg/DRSPdoses0.5,1,2,or3mg).

Themostcommonlyreportedadversereactionswerebreastpain(>10%)andduringthefirstfewmonthsoftreatment,

bleedingandspotting(>10%).Bleedingirregularitiesusuallysubsideduringcontinuedtreatment(seesection5.1

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SystemOrganClass Common

(1/100to<1/10) Uncommon

(1/1000to<1/100) Rare

(<1/1000)

Bloodandlymphaticsystem

disorders Anemia

Metabolismandnutrition

disorders Weightincreaseor

Weightdecrease,

Anorexia,Increased

appetite,Hyperlipemia

Psychiatricdisorders Depression,Emotional

lability,Nervousness Sleepdisorder,Anxiety,

Libidodecreased

Nervoussystemdisorders Headache Paresthesia,

Concentrationability

impaired,Dizziness Vertigo

Eyedisorders Eyedisorder,Visual

disturbance

Earandlabyrinthdisorders Tinnitus

Cardiacdisorders Palpitation

Vasculardisorders Embolism,Venous

thrombosis,

Hypertension,

Migraine,

Thrombophlebitis,

Varicoseveins

Respiratory, thoracic and

mediastinaldisorders Dyspnea

Gastrointestinaldisorders Abdominalpain,

Nausea,Abdomen

enlarged Gastrointestinal

disorder,Diarrhea,

Constipation,Vomiting,

Drymouth,Flatulence,

Tastedisturbance

Hepatobiliarydisorders Liverfunctiontest

abnormal Cholelithiasis

Skinandsubcutaneous

tissuedisorders Skindisorder,Acne,

Alopecia,Pruritus,

Rash,Hirsutism,Hair

disorder

Musculoskeletaland

connectivetissuedisorders Paininextremity,Back

pain,Arthralgia,

Musclecramps Myalgia

Renalandurinarydisorders Urinarytractdisorder,

Urinarytractinfection

Reproductive system and

breastdisorders Benignbreast

neoplasm,Breast

enlargement,Uterine

fibroidsenlarged,

Benignneoplasmof

cervixuteri,Menstrual

disorder,Vaginal

discharge Breastcarcinoma,

Endometrial

hyperplasia,Benign

uterineneoplasm,

Fibrocysticbreast,

Uterinedisorder,

Ovariandisorder,

Cervixdisorder,Pelvic

pain,Vulvovaginal

disorder,Vaginal

candidiasis,Vaginitis,

Salpingitis,

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ThemostappropriateMedDRAtermisusedtodescribeacertainreactionanditssynonymsandrelatedconditions.

Additionalinformationonspecialpopulations:

Thefollowing,undesirableeffectsclassifiedasatleastpossiblyrelatedtoAllurenetreatmentbytheinvestigator,were

recordedin2clinicalstudiesinhypertensivewomen.

Metabolismandnutritiondisorders

Hyperkalemia

Cardiacdisorders

Cardiacfailure,Atrialflutter,QTintervalprolonged,Cardiomegaly

Investigations

Bloodaldosteroneincreased.

ThefollowingundesirableeffectshavebeenreportedinassociationwithHRTproducts:Erythemanodosum,eythema

multiforme,chloasmaandhemorrhagicdermatitis.

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,severalepidemiologicalstudieshavereportedanoverallhigherrisk

forbreastcancerthanwithoestrogensalone.

TheMWSreportedthat,comparedtoneverusers,theuseofvarioustypesofoestrogen-progestogencombinedHRT

wasassociatedwithahigherriskofbreastcancer(RR=2.00,95%CI:1.88–2.12)thanuseofoestrogensalone(RR=

1.30,95%CI:1.21–1.40)oruseoftibolone(RR=1.45;95%CI1.25-1.68).

TheWHItrialreportedariskestimateof1.24(95%CI1.01–1.54)after5.6yearsofuseofoestrogen-progestogen

combinedHRT(CEE+MPA)inalluserscomparedwithplacebo.

TheabsoluteriskscalculatedfromtheMWSandtheWHItrialarepresentedbelow:

TheMWShasestimated,fromtheknownaverageincidenceofbreastcancerindevelopedcountries,that:

ForwomennotusingHRT,about32inevery1000areexpectedtohavebreastcancerdiagnosedbetweenthe

agesof50and64years.

For1000currentorrecentusersofHRT,thenumberofadditionalcasesduringthecorrespondingperiodwillbe

Forusersofoestrogen-onlyreplacementtherapy

between0and3(bestestimate=1.5)for5years’use

between3and7(bestestimate=5)for10years’use.

ForusersofoestrogenplusprogestogencombinedHRT,

between5and7(bestestimate=6)for5years’use

between18and20(bestestimate=19)for10years’use.

TheWHItrialestimatedthatafter5.6yearsoffollow-upofwomenbetweentheagesof50and79years,anadditional

8casesofinvasivebreastcancerwouldbeduetooestrogen-progestogencombinedHRT(CEE+MPA)per10,000

Generaldisordersand

administrationsite

conditions Asthenia,Localized

edema Generalizededema,

Chestpain,Malaise,

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Accordingtocalculationsfromthetrialdata,itisestimatedthat:

For1000womenintheplacebogroup,

-about16casesofinvasivebreastcancerwouldbediagnosedin5years.

For1000womenwhousedoestrogen+progestogencombinedHRT(CEE+MPA),thenumberofadditionalcases

wouldbe

-between0and9(bestestimate=4)for5years’use.

ThenumberofadditionalcasesofbreastcancerinwomenwhouseHRTisbroadlysimilarforwomenwhostartHRT

irrespectiveofageatstartofuse(betweentheagesof45-65)(seesection4.4).’

Endometrialcancer

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandendometrialcancerincreaseswithincreasing

durationofuseofunopposedoestrogens.Accordingtodatafromepidemiologicalstudies,thebestestimateoftherisk

isthatforwomennotusingHRT,about5inevery1000areexpectedtohaveendometrialcancerdiagnosedbetween

theagesof50and65.Dependingonthedurationoftreatmentandoestrogendose,thereportedincreaseinendometrial

cancerriskamongunopposedoestrogenusersvariesfrom2-to12-foldgreatercomparedwithnon-users.Addinga

progestagentooestrogen-onlytherapygreatlyreducesthisincreasedrisk.

Otheradversereactionshavebeenreportedinassociationwithoestrogen/progestogentreatment:

Oestrogen-dependentneoplasmsbenignandmalignant,e.g.endometrialcancer.

Venousthromboembolism,i.e.deeplegorpelvicvenousthrombosisandpulmonaryembolism,ismorefrequent

amonghormonereplacementtherapyusersthanamongnon-users.Forfurtherinformation,seesection4.3

Contraindicationsand4.4Specialwarningsandprecautionsforuse.

Myocardialinfarctionandstroke

Gallbladderdisease.

Skinandsubcutaneousdisorders:chloasma,erythemamultiforme,erythemanodosum,vascularpurpura.

Probabledementia(seesection4.4)

4.9Overdose

Inclinicalstudiesinmalevolunteersdosesupto100mgofdrospirenonewerewelltolerated.Basedongeneral

experiencewithcombinedoralcontraceptives,symptomsthatmaypossiblyoccurarenauseaandvomitingand–in

younggirlsandsomewomen–vaginalbleeding.Therearenospecificantidotes,and,therefore,treatmentshouldbe

symptomatic.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:

Progestogensandestrogens,combinations;ATCcodeG03FA

Estradiol

Allurenecontainssynthetic17ß-estradiol,whichischemicallyandbiologicallyidenticaltoendogenoushuman

estradiol.Itsubstitutesforthelossofoestrogenproductioninmenopausalwomen,andalleviatesmenopausal

symptoms.Oestrogenspreventbonelossfollowingmenopauseorovariectomy.

Drospirenone:

Drospirenoneisasyntheticprogestogen.

Asoestrogenspromotethegrowthoftheendometrium,unopposedoestrogensincreasetheriskofendometrial

hyperplasiaandcancer.Theadditionofaprogestogenreduces,butdoesnoteliminatetheoestrogen-inducedriskof

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Drospirenonedisplaysaldosteroneantagonistactivity.Therefore,increasesinsodiumandwaterexcretionand

decreasesinpotassiumexcretionmaybeobserved.

Inanimalstudies,drospirenonehasnoestrogenic,glucocorticoidorantiglucocorticoidactivity.

Clinicaltrialinformation

Reliefofoestrogen-deficiencysymptomsandbleedingpatterns

Reliefofmenopausalsymptomswasachievedduringthefirstfewweeksoftreatment.

Amenorrheawasseenin73%ofthewomenduringmonths10-12oftreatment.Breakthroughbleedingand/or

spottingappearedin59%ofthewomenduringthefirstthreemonthsoftreatmentandin27%duringmonths

10-12oftreatment.

Preventionofosteoporosis

Oestrogendeficiencyatmenopauseisassociatedwithanincreasingboneturnoveranddeclineinbonemass.

Theeffectofoestrogenonthebonemineraldensityisdose-dependent.Protectionappearstobeeffectiveas

longastreatmentiscontinued.AfterdiscontinuationofHRT,bonemassislostataratesimilartothatin

untreatedwomen.

EvidencefromWHItrialandmeta-analysedtrialsshowsthatcurrentuseofHRT,aloneorincombinationwith

aprogestogen–giventopredominantlyhealthywomen–reducestheriskofhip,vertebral,andother

osteoporoticfractures.HRTmayalsopreventfracturesinwomenwithlowbonedensityand/orestablished

osteoporosis,buttheevidenceforthatislimited.

After2yearsoftreatmentwithAllurene,theincreaseinhipbonemineraldensity(BMD)was3.96+/-3.15%

(mean+/-SD)inosteopenicpatientsand2.78+/-1.89%(mean+/-SD)innon-osteopenicpatients.The

percentageofwomenwhomaintainedorgainedBMDinhipzoneduringtreatmentwas94.4%inosteopenic

patientsand96.4%innon-osteopenicpatients.

AllurenealsohadaneffectonlumbarspineBMD.Theincreaseafter2yearswas5.61+/-3.34%(mean+/-

SD)inosteopenicwomenand4.92+/-3.02%(mean+/-SD)innon-osteopenicwomen.Thepercentageof

osteopenicwomenwhomaintainedorgainedBMDinlumbarzoneduringtreatmentwas100%,whereasthis

percentagewas96.4%innon-osteopenicwomen.

Antimineralocorticoidactivity

DRSPhasaldosteroneantagonisticpropertiesthatcanresultinadecreaseinbloodpressureinhypertensive

women.Inadouble-blindplacebo-controlledtrialhypertensivepostmenopausalwomentreatedwithAllurene

(n=123)for8weeksexperiencedasignificantdecreaseinsystolic/diastolicbloodpressurevalues(officecuff

versusbaseline-12/-9mmHg,correctedforplaceboeffect-3/-4mmHg;24hambulatorybloodpressure

measurementversusbaseline-5/-3mmHg,correctedforplaceboeffect-3/-2mmHg).

Allureneshouldnotbeusedtotreathypertension.Womenwithhypertensionshouldbetreatedaccordingto

HypertensionGuidelines.

5.2Pharmacokineticproperties

Drospirenone

Absorption

Afteroraladministrationdrospirenoneisrapidlyandcompletelyabsorbed.Withasingleadministration,peakserum

levelsofapprox.21.9ng/mlarereachedabout1hourafteringestion.Afterrepeatedadministration,amaximum

steady-stateconcentrationof35.9ng/mlisreachedafterabout10days.Theabsolutebioavailabilityisbetween76and

85%.Concomitantingestionoffoodhadnoinfluenceonthebioavailability.

Distribution

Afteroraladministration,serumdrospirenonelevelsdecreaseintwophaseswhicharecharacterisedbyameanterminal

half-lifeofabout35–39h.Drospirenoneisboundtoserumalbuminanddoesnotbindtosexhormonebinding

globulin(SHBG)orcorticoidbindingglobulin(CBG).Only3-5%ofthetotalserumdrugconcentrationsarepresent

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Metabolism

Drospirenoneisextensivelymetabolizedafteroraladministration.Themajormetabolitesintheplasmaaretheacid

formofdrospirenone,generatedbyopeningofthelactonering,andthe4,5-dihydro-drospirenone-3-sulfate,bothof

whichareformedwithoutinvolvementoftheP450system.Bothmajormetabolitesarepharmacologicallyinactive.

DrospirenoneismetabolizedtoaminorextentbycytochromeP4503A4basedoninvitrodata.Invitroandclinical

studiesdonotindicateaninhibitoryeffectofDRSPonCYPenzymesafteradministrationofAllurene.

Elimination

Themetabolicclearancerateofdrospirenoneinserumis1.2-1.5ml/min/kgshowinganintersubjectvariabilityof

about25%.Drospirenoneisexcretedonlyintraceamountsinunchangedform.Themetabolitesofdrospirenoneare

excretedwiththefecesandurineatanexcretionratioofabout1.2to1.4.Thehalf-lifeofmetaboliteexcretionwiththe

urineandfecesisabout40h.

Steady-stateconditionsandlinearity

FollowingdailyoraladministrationofAllurene,drospirenoneconcentrationsreachedasteady-stateafterabout10days.

Serumdrospirenonelevelsaccumulatedbyafactorofabout2to3asaconsequenceoftheratioofterminalhalf-life

anddosinginterval.Atsteady-state,meanserumlevelsofdrospirenonefluctuateintherangeof14–36ng/mlafter

administrationofAllurene.Pharmacokineticsofdrospirenonearedose-proportionalwithinthedoserangeof1to4mg.

Estradiol

Absorption

Followingoraladministration,estradiolisrapidlyandcompletelyabsorbed.Duringtheabsorptionandthefirstliver

passage,estradiolundergoesextensivemetabolism,thusreducingtheabsolutebioavailabilityofestrogenafteroral

administrationtoabout5%ofthedose.Maximumconcentrationsofabout22pg/mlwerereached6-8haftersingle

oraladministrationofAllurene.Theintakeoffoodhadnoinfluenceonthebioavailabilityofestradiolascomparedto

drugintakeonanemptystomach.

Distribution

FollowingoraladministrationofAllureneonlygraduallychangingserumlevelsofestradiolareobservedwithinan

administrationintervalof24hours.Becauseofthelargecirculatingpoolofestrogensulfatesandglucuronidesonthe

onehandandtheenterohepaticrecirculationontheotherhand,theterminalhalf-lifeofestradiolrepresentsacomposite

parameterthatisdependentonalloftheseprocessesandisintherangeofabout13-20hafteroraladministration.

Estradiolisboundnon-specificallytoserumalbuminandspecificallytoSHBG.Onlyabout1-2%ofthecirculating

estradiolispresentasfreesteroid,40-45%isboundtoSHBG.Theapparentvolumeofdistributionofestradiolafter

singleintravenousadministrationisabout1l/kg.

Metabolism

Estradiolisrapidlymetabolized,andbesidesestroneandestronesulfate,alargenumberofothermetabolitesand

conjugatesareformed.Estroneandestriolareknownaspharmacologicallyactivemetabolitesofestradiol;onlyestrone

occursinrelevantconcentrationsinplasma.Estronereachesabout6-foldhigherserumlevelsthanestradiol.Theserum

levelsoftheestroneconjugatesareabout26timeshigherthanthecorrespondingconcentrationsoffreeestrone.

Elimination

Themetabolicclearancehasbeenfoundtobeabout30ml/min/kg.Themetabolitesofestradiolareexcretedviaurine

andbilewithahalf-lifeofabout1day.

Steady-stateconditions

FollowingdailyoraladministrationofAllurene,estradiolconcentrationsreachedasteady-stateafteraboutfivedays.

Serumestradiollevelsaccumulateapprox.2-fold.OrallyadministeredestradiolinducestheformationofSHBGwhich

influencesthedistributionwithrespecttotheserumproteins,causinganincreaseoftheSHBG-boundfractionanda

decreaseinthealbumin-boundandunboundfractionindicatingnon-linearityofthepharmacokineticsofestradiolafter

ingestionofAllurene.Withadosingintervalof24hours,meansteady-stateserumlevelsofestradiolfluctuateinthe

rangeof20-43pg/mlfollowingadministrationofAllurene.PharmacokineticsofEstradiolaredose-proportionalat

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SpecialPopulations

HepaticImpairment

Thepharmacokineticsofasingleoraldoseof3mgDRSPincombinationwith1mgestradiol(E2)wasevaluatedin10

femalepatientswithmoderatehepaticimpairment(ChildPughB)and10healthyfemalesubjectsmatchedforage,

weight,andsmokinghistory.MeanserumDRSPconcentration-timeprofileswerecomparableinbothgroupsof

womenduringtheabsorption/distributionphaseswithsimilarCmaxandtmaxvalues,suggestingthattherateof

absorptionwasnotaffectedbythehepaticimpairment.Themeanterminalhalf-lifewasabout1.8timesgreaterandan

about50%decreaseinapparentoralclearance(CL/f)wasseeninvolunteerswithmoderatehepaticimpairmentas

comparedtothosewithnormalliverfunction.

RenalImpairment

TheeffectofrenalinsufficiencyonthepharmacokineticsofDRSP(3mgdailyfor14days)wereinvestigatedinfemale

subjectswithnormalrenalfunctionandmildandmoderaterenalimpairment.Atsteady-stateofDRSPtreatment,serum

DRSPlevelsinthegroupwithmildrenalimpairment(creatinineclearanceCLcr,50-80mL/min)werecomparableto

thoseinthegroupwithnormalrenalfunction(CLcr,>80mL/min).TheserumDRSPlevelswereonaverage37%

higherinthegroupwithmoderaterenalimpairment(CLcr,30-50mL/min)comparedtothoseinthegroupwith

normalrenalfunction.LinearregressionanalysisoftheDRSPAUC(0-24h)valuesinrelationtothecreatinine

clearancerevealeda3.5%increasewitha10ml/minreductionofcreatinineclearance.Thisslightincreaseisnot

expectedtobeofclinicalrelevance.

5.3Preclinicalsafetydata

Animalstudieswithestradiolanddrospirenonehaveshownexpectedestrogenicandgestageniceffects.Thereareno

preclinicaldataofrelevancetotheprescriberthatareadditionaltothosealreadyincludedinothersectionsoftheSPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

TabletCore:

Lactosemonohydrate

Maizestarch

Pregelatinisedmaizestarch

Povidone

Magnesiumstearate

Film-coatingmaterial:

Hypromellose

Macrogol6000

Talc

Titaniumdioxide(E171)

Ferricoxide,red(E172)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

5years.

6.4Specialprecautionsforstorage

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6.5Natureandcontentsofcontainer

Transparentpolyvinylfilm(250µm)/aluminumfoil(20µm)blistersof28tabletswithimprintedweekdays

Thepacksizesare1x28tabletsand3x28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

BayerLimited

TheAtrium

BlackthornRoad

Dublin18

8MARKETINGAUTHORISATIONNUMBER

PA1410/014/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:05March2004

Dateoflastrenewal:11December2007

10DATEOFREVISIONOFTHETEXT

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