FEMOSTON-CONTI

Main information

  • Trade name:
  • FEMOSTON-CONTI Film Coated Tablet 0.5/2.5 Milligram
  • Dosage:
  • 0.5/2.5 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FEMOSTON-CONTI Film Coated Tablet 0.5/2.5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0108/021/005
  • Authorization date:
  • 01-10-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Femoston-conti0.5mg/2.5mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains0.5mgestradiol(ashemihydrate)and2.5mgdydrogesterone.

Excipient(s):Lactose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Around,biconvexmarked379ononeside(7mm).

Yellow0.5/25.mgtablets

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonereplacementtherapy(HRT)foroestrogendeficiencysymptomsinpost-menopausalwomen.

Femoston-Conti0.5mg/2.5mgshouldbeusedonlyinwomenmorethan12monthspost-menopausal.

Theexperienceintreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

ThereisnorelevantuseofFemoston-Conti0.5mg/2.5mginchildrenandadolescents.

Femoston-Conti0.5mg/2.5mgisacontinuouscombinedHRTfororaluse.

Thedosageisonetabletperday.Femoston-Conti0.5mg/2.5mgshouldbetakencontinuouslywithoutabreakbetween

packs.

Femoston-Conti0.5mg/2.5mgcanbetakenwithorwithoutfood.

StartingFemoston-Conti0.5mg/2.5mg:

WomenexperiencinganaturalmenopauseshouldcommencetreatmentwithFemoston-Conti0.5mg/2.5mgnotearlier

thanatleast12monthsaftertheirlastnaturalmenstrualbleed.Forsurgicallyinducedmenopause,treatmentmaystart

immediately.

Inwomenwhoarenottakinghormonereplacementtherapyorwomen,whoswitchfromacontinuouscombined

hormonereplacementtherapy,treatmentmaybestartedonanyconvenientday.Inwomentransferringfromacyclicor

continuoussequentialHRTregimen,treatmentshouldbeginthedayfollowingcompletionofthepriorregimen.

Ifadosehasbeenforgotten,itshouldbetakenassoonaspossible.Whenmorethan12hourshaveelapsed,itis

recommendedtocontinuewiththenextdosewithouttakingtheforgottentablet.Thelikelihoodofbreakthrough

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/01/2012 CRN 2104281 page number: 1

Forinitiationandcontinuationoftreatmentofpost-menopausalsymptoms,thelowesteffectivedosefortheshortest

duration(seealsosection4.4)shouldbeused.

4.3Contraindications

Knownhypersensitivitytotheactivesubstancesortoanyoftheexcipients.

Known,pastorsuspectedbreastcancer

Knownorsuspectedoestrogen-dependentmalignanttumours(e.g.endometrialcancer)

Knownorsuspectedprogestogendependentneoplasms

Undiagnosedgenitalbleeding

Untreatedendometrialhyperplasia

Previousorcurrentvenousthromboembolism(deepvenousthrombosis,pulmonaryembolism)

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

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfarction)

Acuteliverdisease,orahistoryofliverdisease,aslongastheliverfunctiontestshavefailedtoreturntonormal

Porphyria

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpost-menopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk.

EvidenceregardingtherisksassociatedwithHRTinthetreatmentofprematuremenopauseislimited.Duetothelow

levelofabsoluteriskinyoungerwomen,however,thebalanceofbenefitsandrisksforthesewomenmaybemore

favourablethaninolderwomen:

Medicalexamination/follow-up

Beforeinitiatingorre-institutingHRT,acompletepersonalorfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythecontraindicationsandwarningsforuse.

Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.

Womenshouldbeadvisedwhatchangesintheirbreastsshouldbereportedtotheirdoctorornurse(see’Breastcancer’

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

withcurrentlyacceptedscreeningpractices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviously,and/orhavebeenaggravatedduringpregnancy

orprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccountthatthese

conditionsmayrecurorbeaggravatedduringtreatmentwithFemoston,inparticular:

Leiomyoma(uterinefibroids)orendometriosis

Riskfactorsforthromboembolicdisorders(seebelow)

Riskfactorsforoestrogendependenttumours,e.g.1stdegreeheredityforbreastcancer

Hypertension

Liverdisorders(e.g.liveradenoma)

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/01/2012 CRN 2104281 page number: 2

Cholelithiasis

Migraineor(severe)headache

Systemiclupuserythematosus.

Ahistoryofendometrialhyperplasia(seebelow)

Epilepsy

Asthma

Otosclerosis

Reasonsforimmediatewithdrawaloftherapy:

Therapyshouldbediscontinuedincaseacontra-indicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction

Significantincreaseinbloodpressure

Newonsetofmigraine-typeheadache

Pregnancy

Endometrialhyperplasiaandcarcinoma

Inwomenwithanintactuterustheriskofendometrialhyperplasiaandcarcinomaisincreasedwhenoestrogensare

administeredaloneforprolongedperiods.Thereportedincreaseinendometrialcancerriskamongoestrogen-onlyusers

variesfrom2-to12-foldgreatercomparedwithnon-users,dependingonthedurationoftreatmentandoestrogendose

(seesection4.8).Afterstoppingtreatmentriskmayremainelevatedforatleast10years.

Theadditionofaprogestogencyclicallyforatleast12dayspermonth/28daycycleorcontinuouscombinedoestrogen-

progestogentherapyinnon-hysterectomisedwomenpreventstheexcessriskassociatedwithoestrogen-onlyHRT.

Breakthroughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-throughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshouldbe

investigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Breastcancer

Theoverallevidencesuggestsanincreasedriskofbreastcancerinwomentakingcombinedoestrogen-progestogenand

possiblyalsooestrogen-onlyHRT,thatisdependentonthedurationoftakingHRT.

Combinedoestrogen-progestogentherapy

Therandomisedplacebo-controlledtrialthe(Women’sHealthInitiativestudy(WHI),andepidemiologicalstudiesare

consistentinfindinganincreasedriskofbreastcancerinwomentakingcombinedoestrogen-progestogenforHRTthat

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/01/2012 CRN 2104281 page number: 3

Oestrogen-onlytherapy

TheWHItrialfoundnoincreaseintheriskofbreastcancerinhysterectomisedwomenusingoestrogen-onlyHRT.

Observationalstudieshavemostlyreportedasmallincreaseinriskofhavingbreastcancerdiagnosedthatis

substantiallylowerthanthatfoundinusersofoestrogen-progestogencombinations(seeSection‘Undesirable

effects’4.8).

Theexcessriskbecomesapparentwithinafewyearsofusebutreturnstobaselinewithinafew(atmostfive)years

afterstoppingtreatment.

HRT,especiallyoestrogen-progestogencombinedtreatment,increasesthedensityofmammographicimageswhich

mayadverselyaffecttheradiologicaldetectionofbreastcancer.

Ovariancancer

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

hasbeenassociatedwithaslightlyincreasedriskofovariancancer(seeSection4.8).Somestudies,includingtheWHI

trialsuggestthatthelong-termuseofcombinedHRTmayconferasimilar,orslightlysmaller,risk(seeSection4.8).

Venousthromboembolism

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

pulmonaryembolism.TheoccurrenceofsuchaneventismorelikelyinthefirstyearofHRTthanlater(seeSection

4.8).

PatientswithknownthrombophilicstateshaveanincreasedriskofVTEandHRTmayaddtothisrisk.HRTis

thereforecontraindicatedinthesepatients(seeSection4.3).

GenerallyrecognisedriskfactorsforVTEinclude,useofoestrogens,olderage,majorsurgery,prolonged

immobilisation,obesity(BMI>30kg/m 2

),pregnancy/post-partumperiod,systemiclupuserythematosus(SLE),and

cancer.ThereisnoconsensusaboutthepossibleroleofvaricoseveinsinVTE.

Asinallpost-operativepatients,prophylacticmeasuresneedbeconsideredtopreventVTEfollowingsurgery.If

prolongedimmobilisationistofollowelectivesurgerytemporarilystoppingHRT4to6weeksearlierisrecommended.

Treatmentshouldnotberestarteduntilthewomaniscompletelymobilised.

InwomenwithnopersonalhistoryofVTEbutwithafirstdegreerelativewithahistoryofthrombosisatyoungage,

screeningmaybeofferedaftercarefulcounselingregardingitslimitations(onlyaproportionofthrombophilicdefects

areidentifiedbyscreening).

Ifathrombophilicdefectisidentifiedwhichsegregateswiththrombosisinfamilymembersorifthedefectis

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

Womenalreadyonchronicanticoagulanttreatmentrequirecarefulconsiderationofthebenefit-riskofuseofHRT.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorsimmediatelywhentheyareawareofapotentialthromboembolicsymptom(e.g.painfulswellingofaleg,

suddenpaininthechest,dyspnoea).

Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofprotectionagainstmyocardialinfarctioninwomenwithor

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/01/2012 CRN 2104281 page number: 4

Combinedoestrogen-progestogentherapy

TherelativeriskofCADduringuseofcombinedoestrogen+progestogenHRTisslightlyincreased.Asthebaseline

absoluteriskofCADisstronglydependentonage,thenumberofextracasesofCADduetooestrogen+progestogen

useisverylowinhealthywomenclosetomenopause,butwillrisewithmoreadvancedage.

Oestrogen-only

RandomisedcontrolleddatafoundnoincreasedriskofCADinhysterectomisedwomenusingoestrogen-onlytherapy.

IschaemicStroke

Combinedoestrogen-progestogenandoestrogen-onlytherapyareassociatedwithanupto1.5-foldincreaseinriskof

ischaemicstroke.Therelativeriskdoesnotchangewithageortimesincemenopause.However,asthebaselineriskof

strokeisstronglyage-dependent,theoverallriskofstrokeinwomenwhouseHRTwillincreasewithage(seeSection

4.8).

Otherconditions

Oestrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringoestrogenreplacementorhormone

replacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitishavebeen

reportedwithoestrogentherapyinthiscondition.

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

biologicalactivehormoneconcentrationsareunchanged.Otherplasmaproteinsmaybeincreased

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

HRTusedoesnotimprovecognitivefunction.Thereissomeevidenceofincreasedriskofprobabledementiain

womenwhostartusingcontinuouscombinedoroestrogen-onlyHRTaftertheageof65.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

Thisoestrogen-progestogencombinationtreatmentisnotcontraceptive.Patientsintheperi-menopausalphaseshould

beadvisedtotakenonhormonalcontraceptiveprecautions.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Nointeractionstudieshavebeenperformed.

Themetabolismofoestrogensandprogestogensmaybeincreasedbyconcomitantuseofsubstancesknowntoinduce

drug-metabolisingenzymes,specificallytheP450enzymes2B6,3A4,3A5,3A7,suchasanticonvulsants(e.g.

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

Ritonavirandnelfinavir,althoughknownasstronginhibitorsofCYP4503A4,A5,A7,bycontrastexhibitinducing

propertieswhenusedconcomitantlywithsteroidhormones

HerbalpreparationscontainingSt.John’sWort(Hypericumperforatum)mayinducethemetabolismofoestrogensand

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/01/2012 CRN 2104281 page number: 5

Clinically,anincreasedmetabolismofoestrogensandprogestogensmayleadtodecreasedeffectandchangesinthe

uterinebleedingprofile.

Femoston-Conti0.5mg/2.5mgcanbeadministeredirrespectiveoffoodintake.

4.6Fertility,pregnancyandlactation

Pregnancy

Femoston-Conti0.5mg/2.5mgisnotindicatedduringpregnancy.Ifpregnancyoccursduringmedicationwith

Femoston-Conti0.5mg/2.5mgtreatmentshouldbewithdrawnimmediately.

Theresultsofmostepidemiologicalstudiestodaterelevanttoinadvertentfetalexposuretocombinationsofoestrogens

+progestogensindicatenoteratogenicorfoetotoxiceffect.Therearenoadequatedatafromtheuseof

estradiol/dydrogesteroneinpregnantwomen.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Thepotentialriskforhumansisunknown.

Lactation

Femoston-Conti0.5mg/2.5mgisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

Femoston-Conti0.5mg/2.5mghasnoornegligibleinfluenceontheabilitytodriveandusemachines.

4.8Undesirableeffects

Undesirableeffectsreportedinclinicaltrialsandinpost-marketingexperienceofalldosageformsarethefollowing:

MedDRA

systemorgan

class Common

=1/100to<1/10 Uncommon

=1/1,000to<1/100 Rare

=1/10,000to

<1/1,000 Veryrare

<1/10,000incl.

notknown

(cannotbe

estimatedfrom

theavailable

data)

Infectionsand

infestations Cystitis-like

syndrome,

Vaginalcandidiasis

Neoplasms

benign,

malignantand

unspecified Increaseinsizeof

leiomyoma

Bloodandthe

lymphatic

systemdisorders Haemolytic

anaemia

Immunesystem

disorders Hypersensitivity

Psychiatric

disorders Depression,

influenceonlibido,

nervousness

Nervoussystem

disorders Migraine,

headache Dizziness Chorea

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/01/2012 CRN 2104281 page number: 6

ofcorneal

curvature,

contact

lenses

intolerance

Cardiac

disorders Myocardial

infarction

Vascular

disorders Peripheralvascular

disease,varicose

vein,venous

thromboembolism* Stroke

Gastrointestinal

disorders Nausea,

abdominalpain,

flatulence Dyspepsia Vomiting

Hepatobiliary

disorders Gallbladder

disease Hepatic

function

abnormal

sometimes

withjaundice

astheniaor

malaise,and

abdominal

pain.

Skinand

subcutaneous

tissuedisorders Allergicskin

reactions(e.g.rash,

urticaria,pruritus) Angioedema,

erythema

multiforme,

erythema

nodosum,

vascularpurpura,

chloasmaor

melasma,which

maypersist

whendrugis

discontinued.

Musculoskeletal

andconnective

tissuedisorders Legcramps Backpain

Reproductive

systemand

breastdisorders Breast

pain/tenderness,

metrorrhagia

andpost-

menopausal

spottingpelvic

pain Uterinecervical

erosion,cervical

discharge,

dysmenorrhoea,

menorrhagia, Breast

enlargement,

premenstrual

syndrome

Congenitaland

familial/genetic

disorders Porphyria

aggravated

General

disordersand

administration

sitereactions Asthenia Oedemaperipheral

Investigations Weight

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/01/2012 CRN 2104281 page number: 7

Breastcancerrisk

Anupto2-foldincreasedriskofhavingbreastcancerdiagnosedisreportedinwomentakingcombinedoestrogen-

progestogentherapyformorethan5years.

Anyincreasedriskinusersofoestrogen-onlytherapyissubstantiallylowerthanthatseeninusersofoestrogen-

progestogencombinations.

Thelevelofriskisdependentonthedurationofuse(seesection4.4).

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

arepresented:

MillionWomanStudy-Estimatedadditionalriskofbreastcancerafter5years'use

Takenfrombaselineincidenceratesindevelopedcountries

bWHIstudyinwomenwithnouterus,whichdidnotshowanincreaseinriskofbreastcancer

‡WhentheanalysiswasrestrictedtowomenwhohadnotusedHRTpriortothestudytherewasnoincreasedrisk

apparentduringthefirst5yearsoftreatment:after5yearstheriskwashigherthaninnon-users.

Endometrialcancerrisk

Post-menopausalwomenwithauterus

Theendometrialcancerriskisabout5inevery1000womenwithauterusnotusingHRT.

Inwomenwithauterus,useofoestrogen-onlyHRTisnotrecommendedbecauseitincreasestheriskofendometrial

cancer(seeSection4.4).

Dependingonthedurationofoestrogen-onlyuseandoestrogendose,theincreaseinriskofendometrialcancerin

epidemiologystudiesvariedfrombetween5and55extracasesdiagnosedinevery1000womenbetweentheagesof

50and65.

Addingaprogestogentooestrogen-onlytherapyforatleast12dayspercyclecanpreventthisincreasedrisk.Inthe

MillionWomenStudytheuseoffiveyearsofcombined(sequentialorcontinuous)HRTdidnotincreaseriskof

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

Ovariancancer

Long-termuseofoestrogen-onlyandcombinedoestrogen-progestogenHRThasbeenassociatedwithaslightly

range

(years) Additionalcases

per1000never-

usersofHRT

overa5year

period a Riskratio&

95%CI# Additionalcasesper1000HRTusersover5

years(95%CI)

OestrogenonlyHRT

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

Combinedoestrogen-progestogen

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

#Overallriskratio.Theriskratioisnotconstantbutwillincreasewithincreasingdurationof

Note:SincethebackgroundincidenceofbreastcancerdiffersbyEUcountry,thenumberof

additionalcasesofbreastcancerwillalsochangeproportionately.

USWHIstudies-additionalriskofbreastcancerafter5years’use

Agerange

(yrs) Incidenceper1000

womeninplaceboarm

over5years Riskratio&95%

Additionalcasesper1000

HRTusersover5years(95%

CEEoestrogen-only

50-79 21 0.8(0.7–1.0) -4(-6–0) b

CEE+MPAoestrogen&progestogen‡

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/01/2012 CRN 2104281 page number: 8

Riskofvenousthromboembolism

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

veinthrombosisorpulmonaryembolism.TheoccurrenceofsuchaneventismorelikelyinthefirstyearofusingHRT

(seeSection4.4).ResultsoftheWHIstudiesarepresented:

WHIStudies-AdditionalriskofVTEover5years’use

Studyinwomenwithnouterus

Riskofcoronaryarterydisease

Theriskofcoronaryarterydiseaseisslightlyincreasedinusersofcombinedoestrogen-progestogenHRTovertheage

of60(seeSection4.4).

Riskofischaemicstroke

Theuseofoestrogen-onlyandoestrogen+progestogentherapyisassociatedwithanupto1.5foldincreasedrelative

riskofischaemicstroke.TheriskofhaemorrhagicstrokeisnotincreasedduringuseofHRT.

Thisrelativeriskisnotdependentonageorondurationofuse,butasthebaselineriskisstronglyage-dependent,the

overallriskofstrokeinwomenwhouseHRTwillincreasewithage(seeSection4.4).

WHIstudiescombined-Additionalriskofischaemicstroke d

over5years’use

nodifferentiationwasmadebetweenischaemicandhaemorrhagicstroke.

Otheradversereactionshavebeenreportedinassociationwithoestrogen/progestogentreatment:

Neoplasmsbenign,malignantandunspecified:

Oestrogendependentneoplasmsbothbenignandmalignant,e.g.endometrialcancer,ovariancancer

Increaseinsizeofprogestogendependentneoplasms(e.g.meningioma),(seesection4.3).

Immunesystemdisorders:

Systemiclupuserythematosus

Nervoussystemdisorders:

Probabledementia-exacerbationofepilepsy

Vasculardisorders:

Arterialthromboembolism

4.9Overdose

NocaseofoverdosehasbeenreportedforFemoston-Conti0.5mg/2.5mg.

Bothestradiolanddydrogesteronearesubstanceswithlowtoxicity.Theoretically,symptomssuchasnausea,vomiting,

Agerange

(years) Incidenceper1000

womeninplaceboarm

over5years Riskratioand

95%CI Additionalcasesper

1000HRTusers

Oraloestrogen-only c

50-59 7 1.2(0.6-2.4) 1(-3–10)

Oralcombinedoestrogen-progestogen

50-59 4 2.3(1.2–4.3) 5(1-13)

Agerange(years) Incidence

per1000womenin

placeboarmover5

years Riskratioand

95%CI Additionalcasesper

1000

HRTusersover5years

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/01/2012 CRN 2104281 page number: 9

Itisunlikelythatanyspecificsymptomatictreatmentwillbenecessary.Aforementionedinformationisapplicablefor

overdosingbychildrenalso.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Genitourinarysystemandsexhormones,progestogensandoestrogens,fixed

combinations,ATCcode:G03FA14.

Estradiol

Theactiveingredient,synthetic17-estradiol,ischemicallyandbiologicallyidenticaltoendogenoushumanestradiol.

Itsubstitutesforthelossofoestrogenproductioninmenopausalwomen,andalleviatesmenopausalsymptoms.

Dydrogesterone

Asoestrogenspromotethegrowthoftheendometrium,unopposedoestrogensincreasetheriskofendometrial

hyperplasiaandcancer.Theadditionofaprogestogengreatlyreducestheoestrogen-inducedriskofendometrial

hyperplasiainnon-hysterectomisedwomen.

Clinicaltrialinformation

WithFemoston0.5mg/2.5mgthereductionofmoderatetoseverehotflusheswasstatisticallysignificantversus

placebofromweek4onward.Thenumberofmoderatetoseverehotflushesdecreasedfurtheruntilendoftreatment

periodinweek13.

Intwostudiesamenorrhoea(nobleedingorspotting)wasseenin91%andin88%ofthewomenrespectivelyduring

months10-12oftreatment.Irregularbleedingandorspottingappearedin10%and21%ofthewomenduringthefirst

3monthsoftreatmentandin9%andin12%duringmonths10-12oftreatment.

5.2Pharmacokineticproperties

Estradiol

Followingoraladministration,micronizedestradiolisreadilyabsorbed,butextensivelymetabolised.Themajor

unconjugatedandconjugatedmetabolitesareestroneandestronesulphate.Thesemetabolitescancontributetothe

oestrogenactivity,eitherdirectlyorafterconversiontoestradiol.

ThemultipledosepharmacokineticsofE2andE1werelinear.ForE1SAUC

atsteadystatewasestimatedtobe

79%oftheAUCaftersingledose.SteadystateconcentrationswerereachedforE2andthemetabolitesE1andE1S

within11daysofdosing.ThefollowingtabledepictstherespectiveCmax,Cminandsteadystatevaluesofestradiol

anditsmetabolites:

*:calculatedasAUC(0-tau)/24

TheAUCandCmaxratiosofestronetoestradiolarearound6atsteadystate.ThemetaboliteratiosE1/E2andE1S/E2

showednomarkeddifferencesbetweensingleandmultipledosing.

TheT

valuesofE2,E1andE1Swere2,4and3.5hoursrespectively.Themeanterminalhalflivesofbaseline

correctedestradiol,estroneandestronesulphateare16,15and15hours,respectively.

Estronesulphatemayundergoenterohepaticcirculation.Inurine,themajorcompoundsaretheglucuronidesofestrone

andestradiol.

pg/ml pg/ml ng/ml

28.3 160 6.35

12.4 70.6 1.52

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/01/2012 CRN 2104281 page number: 10

Dydrogesterone

Afteroraladministrationoflabelleddydrogesterone,onaverage63%ofthedoseisexcretedintotheurine.Within72

hoursexcretioniscomplete.Inman,dydrogesteroneiscompletelymetabolised.

Themainmetaboliteofdydrogesteroneis20-dihydrodydrogesterone(DHD)andispresentintheurine

predominantlyastheglucuronicacidconjugate.

Acommonfeatureofallmetabolitescharacterisedistheretentionofthe4,6diene-3-oneconfigurationoftheparent

compoundandtheabsenceof17-hydroxylation.Thisexplainsthelackofoestrogenicandandrogeniceffectsof

dydrogesterone.

Afteroraladministrationofdydrogesterone,plasmaconcentrationsofDHDaresubstantiallyhigherascomparedtothe

parentdrug.TheAUCandC

ratiosofDHDtodydrogesteroneareintheorderof40and25,respectively.The

followingtabledepictstherespectiveCmax,CminandsteadystatevaluesofdydrogesteroneanditsmetaboliteDHD:

*:calculatedasAUC(0-tau)/24

Dydrogesteroneisrapidlyabsorbed.TheT

valuesofdydrogesteroneandDHDvarybetween0.5and2.5hours.

MeanterminalhalflivesofdydrogesteroneandDHDvarybetween5to7and14to17hours,respectively.

Dydrogesteroneisnotexcretedinurineaspregnanediol,likeprogesterone.Analysisofendogenousprogesterone

productionbasedonpregnanediolexcretionthereforeremainspossible.

5.3Preclinicalsafetydata

Supraphysiologicallyhighdoses(andprolongedapplication)ofestradiolhavebeenassociatedwiththeinductionof

tumoursinoestrogen-dependenttargetorgansinallrodentspeciestested.Furthermore,inherenttoitshormonal

activity,estradioldisplaysuntowardembryotoxiceffectsandfeminisationofmalefetuseswasoccasionallyobserved.

Thechangesobservedwithdydrogesteroneinanimaltoxicitystudiesareassociatedwiththeeffectsofprogesterone-

likecompounds.Genotoxicitystudieswithdydrogesteroneshowednegativeresultsinvitroandinvivo.

Dosesofdydrogesteroneadministeredtoratsandmicesufficienttoproducehormonemediatedchangesgaveno

evidenceofcarcinogenesis.

Embryo-foetaldevelopmentaltoxicitystudiesinrabbitsshowedadverseeffects(reducedfoetalweightandslightly

increasedincidenceofminorskeletalabnormalities)atthehighestdosetested.Suchfindingswereattributedto

maternaltoxicityandnotconsideredanindicationofateratogeniceffect.Apre-andpostnataldevelopmentalstudyin

ratswithdydrogesteroneshowedanelongatedgestationalperiodandpotentialofincreasingtheincidenceof

hypospadiasassociatedwithinfertilityinmalepupsathighdosage.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Lactosemonohydrate

Hypromellose

Maizestarch

Colloidalanhydroussilica

ng/ml ng/ml

0.695 17.6

0.0251 1.10

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/01/2012 CRN 2104281 page number: 11

Film-coating:

Macrogol3350

Polyvinylalcohol

Talc

Titaniumdioxide(E171)

Ironoxideyellow(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

48months.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC/Aluminiumblisterstripsinaprintedcarton.

Packsof28,84,280and14film-coatedtablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

AbbotHealthcareProductsLtd

MansbridgeRoad

WestEnd

Southampton

SO183JD

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA108/21/5

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:1stOctober2010

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 12/01/2012 CRN 2104281 page number: 12