CATHATE

Main information

  • Trade name:
  • CATHATE Tablets 0.625 Milligram
  • Dosage:
  • 0.625 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CATHATE Tablets 0.625 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0022/068/001
  • Authorization date:
  • 19-09-1995
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cathate*0.625mgCoatedTablet

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Cathatetabletcontains0.625mgConjugatedEstrogens.

Forexcipients,seesection6.1.

3PHARMACEUTICALFORM

CoatedTablet.

Awhite,oval,coatedtabletprinted“0.625”inblack.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Cathateisindicatedforhormonereplacementtherapy(HRT)forestrogendeficiencysymptomsinmenopausaland

postmenopausalwomen.

Preventionofosteoporosisinpostmenopausalwomenathighriskoffuturefractureswhoareintolerantof,or

contraindicatedfor,othermedicinalproductsapprovedforthepreventionofosteoporosis.

(Seealsosection4.4)

4.2Posologyandmethodofadministration

CathateTabletsareanestrogenonlyHRTfororaluse.

Posology:

Adults

Cathate0.625–1.25mgdailyistheusualstartingdoseforwomenwithoutauterus.Cyclicadministrationis

recommended(threeweeksonfollowedbyoneweekoff).

Fortreatmentofpostmenopausalsymptoms,thelowesteffectivedoseshouldbeadministered.Patientsshouldbere-

evaluatedperiodicallytodetermineiftreatmentforsymptomsisstillnecessary.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

duration(seealsoSection4.4)shouldbeused.

Vasomotorsymptoms:

0.625–1.25mgdailydependingontheresponseoftheindividual.

Atrophicvaginitis,kraurosisvulvae,atrophicurethritis:

0.625–1.25mgdailydependingontheresponseoftheindividual.

Prophylaxisofosteoporosis:

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Concomitantprogestogenuseforwomenwithauterus:

Unlessthereisapreviousdiagnosisofendometriosis,itisnotrecommendedtoaddaprogestogeninhysterectomised

women(see4.4–Specialwarningsandspecialprecautionsforuse).

Formostpostmenopausalwomen,therapymaybecommencedatanyconvenienttime.

Inwomenwhoarenottakinghormonereplacementtherapyorwomenwhoswitchfromacontinuouscombined

hormonereplacementtherapyproduct,treatmentmaybestartedonanyconvenientday.Inwomentransferringfroma

sequentialhormonereplacementtherapyregimen,treatmentshouldbeginthedayfollowingcompletionoftheprior

regimen.

Beforetherapycommencesitisrecommendedthatthepatientisfullyinformedofalltherelativerisksandbenefits,and

thequestionofcontinuedneedfortreatmentshouldbereviewedperiodically.Sheshouldhaveacompletephysicaland

gynaecologicalexaminationwithspecialemphasisonbloodpressure,breasts,abdomenandpelvicorgansandan

endometrialassessmentcarriedoutifappropriate.Follow-upexaminationsarerecommendedevery6-12months.

Forgottentablet:Ifatabletisforgotten,itshouldbetakenassoonasthepatientremembers;therapyshouldthenbe

continuedasbefore.Ifmorethanonetablethasbeenforgottenonlythemostrecenttabletshouldbetaken.

Missedpillsmaycausebreakthroughbleedinginwomenwithauterus.

Elderly:

Therearenospecialdosagerequirementsforelderlypatients,butaswithallmedicinethelowesteffectivedoseshould

beused.

Children:

Notrecommended.

4.3Contraindications

Known,pastorsuspectedbreastcancer.

Knownorsuspectedestrogen-dependentmalignanttumours(e.g.endometrialcancer).

Undiagnosedabnormalgenitalbleeding.

Untreatedendometrialhyperplasia.

Previousorcurrentvenousthromboembolism(deepvenousthrombosis,pulmonaryembolism).

Activeorrecentarterialthromboembolicdisease(e.g.angina,myocardialinfarction).

Acuteliverdiseaseorhistoryofliverdiseasewheretheliverfunctiontestshavefailedtoreturntonormal.

KnownhypersensitivitytotheactivesubstanceortoanyoftheexcipientsofCathatetablets.

Porphyria.

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffectthe

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk.

1.MedicalExamination/Follow-up

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythecontraindicationsandwarningsforuse.During

treatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwomen.Women

shouldbeadvisedwhatchangesintheirbreastsshouldbereportedtotheirdoctorornurse(see‘BreastCancer’

below).Investigations,includingmammography,shouldbecarriedoutinaccordancewithcurrentlyaccepted

screeningpractices,modifiedtotheclinicalneedsoftheindividual.

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Ifanyofthefollowingconditionsarepresent,haveoccurredpreviously,and/orhavebeenaggravatedduring

pregnancyorprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccount

thattheseconditionsmayrecurorbeaggravatedduringtreatmentwithCathate,inparticular:

Leiomyoma(uterinefibroids)orendometriosis

Afamilyhistoryof,orriskfactorsforthromboembolicdisorders(seebelow)

Riskfactorsforestrogendependenttumours(e.g.firstdegreeheredityforbreastcancer)

Hypertension

Liverdisorders(e.g.liveradenoma)

Diabetesmellituswithorwithoutvascularinvolvement

Cholelithiasis

Migraineor(severe)headaches

Systemiclupuserythematosus(SLE)

Ahistoryofendometrialhyperplasia(seebelow)

Epilepsy

Asthma

Otosclerosis

3.Reasonsforimmediatewithdrawaloftherapy

Therapyshouldbediscontinuedifacontraindicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction

Significantincreaseinbloodpressure

Newonsetofmigraine-typeheadache

Pregnancy

4.Endometrialhyperplasia

Theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenestrogensareadministeredaloneforprolonged

periods(seesection4.8).Theadditionofaprogestogenforatleast12dayspercycleinnon-hysterectomisedwomen

greatlyreducesthisrisk.

Fororaldosesofestradiol>2mg,conjugatedequineestrogens>1.25mgandpatches>50 µ

g/daytheendometrialsafety

ofaddedprogestogenhavenotbeenstudied.

Breakthroughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreakthroughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshouldbe

investigated,whichmayincludeendometrialbiopsytoexcludeendometrialmalignancy.

Endometriosismaybeexacerbatedwithadministrationofestrogentherapy.Unopposedestrogenstimulationmaylead

topre-malignantormalignanttransformationintheresidualfociofendometriosis.Therefore,theadditionof

progestogenstoestrogenreplacementtherapyshouldbeconsideredinwomenwhohaveundergonehysterectomy

becauseofendometriosisiftheyareknowntohaveresidualendometriosis.

5.BreastCancer

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

includingtheMillionWomenStudy(MWS),havereportedanincreasedriskofbreastcancerinwomentaking

estrogen,estrogen-progestogencombinationsortiboloneforHRTforseveralyears(seeSection4.8).ForallHRT,an

excessriskbecomesapparentwithinafewyearsofuseandincreaseswithdurationofintakebutreturnstobaseline

withinafew(atmostfiveyears)afterstoppingtreatment.

IntheMWS,therelativeriskofbreastcancerwithconjugatedequineestrogens(CEE)orestradiol(E2)wasgreater

whenaprogestogenwasadded,eithersequentiallyorcontinuously,andregardlessoftypeofprogestogen.Therewas

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IntheWHIstudy,thecontinuouscombinedconjugatedequineestrogenandmedroxyprogesteroneacetate(CEE+

MPA)productusedwasassociatedwithbreastcancersthatwereslightlylargerinsizeandmorefrequentlyhadlocal

lymphnodemetastasescomparedtoplacebo.

HRT,especiallyestrogen-progestogencombinedtreatment,increasesthedensityofmammographicimageswhichmay

adverselyaffecttheradiologicaldetectionofbreastcancer.

6.Venousthromboembolism

Hormonereplacementtherapy(HRT)isassociatedwithahigherrelativeriskofdevelopingvenousthromboembolism

(VTE)i.e.deepveinthrombosisorpulmonaryembolism.Onerandomisedcontrolledtrialandepidemiologicalstudies

foundatwotothreefoldhigherriskforuserscomparedwithnon-users.Fornon-usersitisestimatedthatthenumber

ofcasesofVTEthatwilloccurovera5yearperiodisabout3per1000womenaged50-59yearsand8per1000

womenagedbetween60-69years.ItisestimatedthatinhealthywomenwhouseHRTfor5years,thenumberof

additionalcasesofVTEovera5yearperiodwillbebetween2and6(bestestimate4)per1000womenaged50-59

yearsandbetween5and15(bestestimate=9)per1000womenaged60-69years.Theoccurrenceofsuchaneventis

morelikelyinthefirstyearofHRTusethanlater.

GenerallyrecognisedriskfactorsforVTEincludeapersonalorfamilyhistoryandsevereobesity(BodyMassIndex

>30kg/m²)andsystemiclupuserythematosus(SLE).Thereisnoconsensusaboutthepossibleroleofvaricoseveinsin

VTE.

PatientswithahistoryofVTEorknownthrombophilicstateshaveanincreasedriskofVTE.HRTmayaddtothis

risk.Strongfamilyhistoryofthromboembolismorpersonalhistoryofrecurrentspontaneousabortionshouldbe

investigatedinordertoexcludeathrombophilicpredisposition.Untilathoroughevaluationofthrombophilicfactors

hasbeenmade,useofHRTinsuchpatientsshouldbeviewedascontraindicated.Thosewomenalreadyon

anticoagulanttreatmentrequirecarefulconsiderationofthebenefit-riskofuseofHRT.

TheriskofVTEmaybetemporarilyincreasedwithprolongedimmobilisation,majortraumaormajorsurgery.Asin

allpost-operativepatients,scrupulousattentionshouldbegiventoprophylacticmeasurestopreventVTEfollowing

surgery.Whereprolongedimmobilisationisliabletofollowelectivesurgery,particularlyabdominalororthopaedic

surgerytothelowerlimbs,considerationshouldbegiventotemporarilystoppingHRT4-6weeksearlier,ifthisis

possible.Treatmentshouldnotberestarteduntilthewomaniscompletelymobilised.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorsimmediatelywhentheyareawareofpotentialthromboembolicsymptoms(e.g.painfulswellingofaleg,

suddenpaininthechest,dyspnoea).

7.CoronaryArteryDisease

Thereisnoevidencefromrandomisedcontrolledtrialsofcardiovascularbenefitwithcontinuouscombinedconjugated

estrogensandmedroxyprogesteroneacetate(MPA).Twolargeclinicaltrials(WHIandHERS,i.e.Heartand

Estrogen/progestinReplacementStudy)showedanincreasedriskofcardiovascularmorbidityparticularlyinthefirst

yearofuseandnooverallbenefit.ForotherHRTproducts,thereareonlylimiteddatafromrandomisedcontrolled

trialsexaminingeffectsincardiovascularmorbidityormortality.Therefore,itisuncertainwhetherthesefindingsalso

extendtootherHRTproducts.

8.Stroke

Onelargerandomisedclinicaltrial(WHI-trial)found,asasecondaryoutcome,anincreasedriskofischaemicstrokein

healthywomenduringtreatmentwithcontinuouscombinedconjugatedestrogensandMPA.Forwomenwhodonot

useHRT,itisestimatedthatthenumberofcasesofstrokethatwilloccurovera5yearperiodisabout3per1000

womenaged50-59yearsand11per1000womenaged60-69years.Itisestimatedthatforwomenwhouse

conjugatedestrogensandMPAfor5years,thenumberofadditionalcaseswillbebetween0and3(bestestimate=1)

per1000usersaged50-59yearsandbetween1and9(bestestimate=4)per1000usersaged60-69years.Itis

unknownwhethertheincreasedriskalsoextendstootherHRTproducts.

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Longterm(atleast5-10years)useofestrogen-onlyHRTproductsinhysterectomisedwomanhasbeenassociatedwith

anincreasedriskofovariancancerinsomeepidemiologicalstudies.Itisuncertainwhetherlong-termuseofcombined

HRTconfersdifferentriskthanestrogen-onlyproducts.

Otherconditions

10.Estrogensmaycausefluidretentionandthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.Patientswithterminalrenalinsufficiencyshouldbecloselyobserved,sinceitisexpectedthatthelevelof

circulatingactiveingredientsinCathateisincreased.

11.Theuseofestrogensmayinfluencethelaboratoryresultsofcertainendocrinetestsandliverenzymes.

Estrogensincreasethyroidbindingglobulin(TBG),leadingtoincreasedcirculatingtotalthyroidhormone,asmeasured

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

T3resinuptakeisdecreased,reflectingtheelevatedTBG.FreeT4andfreeT3concentrationsareusuallyunaltered.

Patientsdependentonthyroidhormonereplacementtherapymayrequireincreaseddosesinordertomaintaintheirfree

thyroidhormonelevelsinanacceptablerange.

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

(SHBG)leadingtoincreasedcirculatingcorticosteroidsandsexsteroids,respectively.Freeorbiologicalactive

hormoneconcentrationsareusuallyunchanged.Otherplasmaproteinsmaybeincreased(angiotensinogen/renin

substrate,alpha-I-antitripsin,ceruloplasmin).

12.Atwo-tofourfoldincreaseintheriskofgallbladderdiseaserequiringsurgeryinwomenreceivingHRThasbeen

reported.

13.Aworseningofglucosetolerancemayoccurinpatientstakingestrogensandthereforediabeticpatientsshouldbe

carefullyobservedwhilereceivinghormonereplacementtherapy.

14.Estrogensshouldbeusedwithcautioninindividualswithseverehypocalcaemia.

15.Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringestrogenreplacementor

hormonereplacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitishave

beenreportedwithestrogentherapyinthiscondition.

16.Thereisnoconclusiveevidenceforimprovementofcognitivefunction.ThereissomeevidencefromtheWHI

trialofincreasedriskofprobabledementiainwomenwhostartusingcontinuouscombinedCEEandMPAafterthe

ageof65.ItisunknownwhetherthefindingsapplytoyoungerpostmenopausalwomenorotherHRTproducts.

17.Atpresentthereisnoestablishedscreeningprogrammefordeterminingwomenatriskofdevelopingosteoporotic

fractures.Epidemiologicalstudiessuggestanumberofindividualriskfactorswhichcontributetothedevelopmentof

postmenopausalosteoporosis.Theseinclude:earlymenopause;familyhistoryofosteoporosis;thin,smallframe;

cigaretteuse;recentprolongedsystemiccorticosteroiduse.

Ifseveraloftheseriskfactorsarepresentinapatientconsiderationshouldbegiventotreatment.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Datafromadrug-druginteractionstudyinvolvingconjugatedestrogensandmedroxyprogesteroneacetateindicated

thatthepharmacokineticdispositionofbothdrugswasnotalteredwhenthedrugswereco-administered.Other

clinicaldrug-druginteractionstudieshavenotbeenconductedwithconjugatedestrogens.

Themetabolismofestrogensmaybeincreasedbyconcomitantuseofsubstancesknowntoinducedrug-metabolising

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

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

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concomitantlywithsteroidhormones.

HotflushesandvaginalbleedinghavebeenreportedinpatientstakingHRTandSt.Johnswort(Hypericum

perforatum).St.John’swortmayinducehepaticmicrosomalenzymeswhichtheoreticallymayresultinreduced

efficacyofHRT.

CYP3A4inhibitorssuchascimetidine,erythromycinandketoconazolemayincreaseplasmaconcentrationsof17-

estradiolandmayresultinsideeffects.

Clinically,anincreasedmetabolismofestrogensandprogestogensmayleadtodecreasedeffectandchangesinthe

uterinebleedingprofile.

Theresponsetometyraponemaybereduced.

4.6Pregnancyandlactation

Pregnancy:

Cathateisnotindicatedforuseduringpregnancy.

Forwomenwithauterus:

IfpregnancyoccursduringmedicationwithCathate,treatmentshouldbewithdrawnimmediately.Theresultsofmost

epidemiologicalstudiestodaterelevanttoinadvertentfoetalexposuretoestrogensindicatenoteratogenicorfoetotoxic

effects.

Lactation:

Cathateisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

Notapplicable.

4.8Undesirableeffects

Seealso4.4.‘Specialwarningsandspecialprecautionsforuse’.

Adversedrugreactions(ADRs)

Theadversereactionslistedinthetablearebasedonpost-marketingspontaneousreportingrates,clinicaltrialsand

class-effects.

SystemOrgan

Class CommonADRs

(>1/100,<1/10) UncommonADRs

(>1/1000,<1/100) RareADRs

(>1/10000,

<1/1000) VeryRare

ADRs

(<1/10000),

isolated

reports

Infectionsand

infestations None Vaginitis,

includingvaginal

candidiasis None None

Neoplasms

benignand

malignant

(includingcysts

andpolyps) None None Breastcancer;

Fibrocystic

breastchanges

Ovariancancer Endometrial

cancer;

Enlargementof

hepatic

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Immunesystem

disorders None None Anaphylactic/

anaphylactoid

reactions,

including

urticariaand

angioedema None

Metabolismand

nutrition

disorders None None Glucose

intolerance Exacerbation

ofporphyria;

Hypocalcaemia

Psychiatric

disorders Depression Changesinlibido;

Mooddisturbances;

Dementia Irritability None

Nervoussystem

disorders None Dizziness;

Headache;

Migraine;Anxiety Stroke;

Exacerbationof

epilepsy; Exacerbation

ofchorea

Eyedisorders None Intoleranceto

contactlenses None Retinal

vascular

thrombosis

Cardiac

disorders None None Myocardial

infarction None

Vascular

disorders None Venousthrombosis Pulmonary

embolism;

Superficial

thrombophlebitis None

Respiratory,

thoracicand

mediastinal

disorders None None Exacerbationof

asthma None

Gastrointestinal

disorders None Nausea;Bloating;

Abdominalpain Vomiting;

Pancreatitis None

Hepatobiliary

disorders None Gallbladderdisease None Cholestatic

jaundice

Skinand

subcutaneous

tissuedisorders Alopecia Chloasma/melasma;

Hirsutism;Pruritus;

Rash None Erythema

multiforme;

erythema

nodosum

Musculoskeletal,

connective

tissueandbone

disorders Arthralgias;Leg

cramps None None None

Reproductive

system&breast

disorders Breakthrough

bleeding/spotting;

breastpain,

tenderness,

enlargement,

discharge Changein

menstrualflow;

Changeincervical

ectropionand

secretion Dysmenorrhoea;

Galactorrhoea;

Increasedsizeof

uterine

leiomyomata Endometrial

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Breastcancer

Accordingtoevidencefromalargenumberofepidemiologicalstudiesandonerandomisedplacebo-controlledtrial,the

Women’sHealthInitiative(WHI),theoverallriskofbreastcancerincreaseswithincreasingdurationofHRTusein

currentorrecentHRTusers.

Forestrogen-onlyHRT,estimatesofrelativerisk(RR)fromare-analysisoforiginaldatafrom51epidemiological

studies(inwhich>80%ofHRTusewasestrogen-onlyHRT)andfromtheepidemiologicalMillionWomenStudy

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

ForestrogenplusprogestogencombinedHRT,severalepidemiologicalstudieshavereportedanoverallhigherriskfor

breastcancerthanwithestrogensalone.

TheMWSreportedthat,comparedtoneverusers,theuseofvarioustypesofestrogen-progestogencombinedHRTwas

associatedwithahigherriskofbreastcancer(RR=2.00,95%CI:1.88–2.12)thanuseofestrogensalone(RR=1.30,

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

TheWHItrialreportedariskestimateof1.24(95%CI:1.01–1.54)after5.6yearsofuseofestrogen-progestogen

combinedHRT(CEE+MPA)inalluserscomparedwithplacebo.

TheabsoluteriskscalculatedfromtheMWSandtheWHItrialarepresentedbelow:

TheMWShasestimated,fromtheknownaverageincidenceofbreastcancerindevelopedcountries,that:

ForwomennotusingHRT,about32inevery1000areexpectedtohavebreastcancerdiagnosedbetweentheages

of50and64years.

For1000currentorrecentusersofHRT,thenumberofadditionalcasesduringthecorrespondingperiodwillbe

Forusersofestrogen-onlyreplacementtherapy

between0and3(bestestimate=1.5)for5years’use

between3and7(bestestimate=5)for10years’use.

ForusersofestrogenplusprogestogencombinedHRT

between5and7(bestestimate=6)for5years’use

between18and20(bestestimate=19)for10years’use.

TheWHItrialestimatedthatafter5.6yearsoffollow-upofwomenbetweentheagesof50and79years,anadditional

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

womenyears.

Accordingtocalculationsfromthetrialdata,itisestimatedthat:

For1000womenintheplacebogroup.

about16casesofinvasivebreastcancerwouldbediagnosedin5years.

General

disordersand

administration

siteconditions None Oedema None None

Investigations Changesin

weight(increase

ordecrease);

Increased

triglycerides None None Increasein

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caseswouldbe

between0and9(bestestimate=4)for5years’use.

ThenumberofadditionalcasesofbreastcancerinwomenwhouseHRTisbroadlysimilarforwomenwhostartHRT

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

Endometrialcancer

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandendometrialcancerincreaseswithincreasing

durationofuseofunopposedestrogens.Accordingtodatafromepidemiologicalstudies,thebestestimateofriskis

thatforwomennotusingHRT,about5inevery1000areexpectedtohaveendometrialcancerdiagnosedbetweenthe

agesof50and65.Dependingonthedurationoftreatmentandestrogendose,thereportedincreaseinendometrial

cancerriskamongunopposedestrogenusersvariesfrom2-to12-foldgreatercomparedwithnon-users.Addinga

progestogentoestrogen-onlytherapygreatlyreducesthisincreasedrisk.

Otheradversereactionsreportedinassociationwithestrogen/progestogentreatmentincludingPremarin:

Estrogen-dependentneoplasmsbenignandmalignant,e.g.endometrialhyperplasia,endometrialcancer

Venousthromboembolism,i.e.deeplegorpelvicvenousthrombosisandpulmonaryembolism,ismorefrequent

amonghormonereplacementtherapyusersthanamongnon-users.Forfurtherinformation,seesection4.3

Contraindicationsand4.4Specialwarningsandspecialprecautionsforuse.

Retinalvascularthrombosis

Myocardialinfarctionandstroke

Increasesinbloodpressure

Cholestaticjaundice

Enlargementofhepatichaemangiomas

Skinandsubcutaneousdisorders:erythemamultiforme,erythemanodosum,vascularpurpura

Probabledementia(seeSection4.4)

Exacerbationofchorea

Exacerbationofporphyria

Exacerbationofhypocalcaemia

4.9Overdose

Numerousreportsofingestionoflargedosesofestrogencontainingoralcontraceptivesbyyoungchildrenindicatethat

acuteseriousilleffectsdonotoccur.Overdosageofestrogensmaycausenauseaandvomiting,andwithdrawal

bleedingmayoccurinfemales.Thereisnospecificantidoteandfurthertreatmentshouldbesymptomatic.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Cathateisamixtureofequineconjugatedestrogens.

Estrogensareimportantinthedevelopmentandmaintenanceofthefemaleurogenitalsystemandsecondarysex

characteristics.Duringthefemalereproductivestageoflife,theovaryisthechiefsourceofestrogensalthoughthe

amountsofcirculatingandexcretedhormonevarygreatlyduringthemenstrualcycle.Estrogensalsoaffecttherelease

ofpituitarygonadotrophins.

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(FSH)levelsrise.Estradiollevelsdiminish,andthepredominantpost-menopausalestrogenisestronewhichis

producedperipherally.Neartheendoftheperi-menopausalperiodluteinisinghormone(LH)beginstoincrease.

Finallytheendometriumfailstoproliferate,primarilybecauseofthelowaveragelevelofestrogensandpermanent

amenorrhoeaoccurs.

Initialchangesthatoccurasaresultofthesediminishedlevelsofcirculatinghormonearelargelyvasomotorand

includehotflushesandnightsweats(withinsomnia).

Intermediatechangesarerepresentedbyatrophyofthegenitourinarysystemsleadingtopruritusvulvae,vaginal

drynessandurinarysymptomsofbladderinstability.Along-termeffectofestrogendeficiencyisosteoporosis(lossof

bonemass).

Thepharmacologicaleffectsofconjugatedestrogensaresimilartothoseofendogenousestrogens.Inresponsive

tissuesestrogensenterthecellandspecificRNAandproteinsynthesisoccurs.

5.2Pharmacokineticproperties

Conjugatedestrogensaresolubleinwaterandarewellabsorbedfromthegastrointestinaltract.Metabolismand

inactivationoccurprimarilyintheliver.Someestrogensareexcretedinthebile:however,theyarereabsorbedfrom

theintestineandreturnedtotheliverthroughtheportalvenoussystem.Water-solubleestrogenconjugatesarestrongly

acidicandareionisedinbodyfluids,whichfavoursexcretionthroughthekidneyssincetubularre-absorptionis

minimal.

5.3Preclinicalsafetydata

Long-termcontinuousadministrationofnaturalandsyntheticestrogensincertainanimalspeciesincreasesthe

frequencyofcarcinomasofthebreast,cervix,vaginaandliver.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

TabletCore:

Lactosemonohydrate

Methylcellulose

Magnesiumstearate

Coating:

Sucrose

GlycerolMono-oleate(60%Acylglycerol)

Macrogol20000

Carnaubawax

Calciumsulphate

Shellacsolution

Microcrystallinecellulose

Stearicacid

Titaniumdioxide(E171)

Edibleprintingink(containingironoxideblack(E172),shellac,ethanol,n-butylalcohol,propyleneglycolandethyl

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6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Threeyears.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

Polyvinylchloride(PVC)/AluminiumfoilblistersandpolypropyleneSecuritainers.

Blisterstripsof21or28tabletsandSecuritainersof100tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

JohnWyethandBrotherLimited

Tradingas:WyethLaboratories

HuntercombeLaneSouth

TaplowMaidenhead

BerkshireSL60PH

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0022/068/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19September1995

Dateoflastrenewal:19September2005

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 20/10/2010 CRN 2088921 page number: 11