FEMSEVEN CONTI

Main information

  • Trade name:
  • FEMSEVEN CONTI
  • Dosage:
  • 50/ 7 Microgram/ day
  • Pharmaceutical form:
  • Transdermal Patch
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FEMSEVEN CONTI
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0654/015/001
  • Authorization date:
  • 25-03-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FemSevenConti,50micrograms/7micrograms/24hours,transdermalpatch.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachpatchcontains1.5mgofestradiolhemihydrateand0.525mglevonorgestrelinapatchsizeof15cm 2

,releasing

50microgramsofestradioland7microgramsoflevonorgestrelper24hours.

Forthefulllistofexcipients,see6.1.

3PHARMACEUTICALFORM

Transdermalpatch

Octagonal,transparent,flexible,rounded-edgetransdermalmatrixpatchlocatedonanoversizedremovableprotective

liner.

4CLINICALPARTICULARS

4.1TherapeuticIndications

HormoneReplacementTherapy(HRT)foroestrogendeficiencysymptomsinpostmenopausalwomenmorethanone

yearaftermenopause.

Experienceoftreatingwomenolderthan65yearsislimited.

4.2Posologyandmethodofadministration

Fortransdermaluse.

Fem7Plushastobeappliedonceaweek,i.e.eachpatchisreplacedevery7days.Fem7Plusisacontinuouscombined

hormonereplacementtherapy(HRT)treatmentwithoutatreatment-offphase:asonepatchisremoved,thenextis

appliedimmediately.Forgettingtochangeapatchonschedulemayincreasethelikelihoodofbreak-throughbleeding

orspotting.

InwomenwithamenorrhoeaandnottakingHRTorwomentransferringfromanothercontinuouscombinedHRT

product,treatmentwithFem7Plusmaybestartedonanyconvenientday.

InwomentransferringfromsequentialHRTregimens,treatmentshouldstartrightaftertheirwithdrawalbleedinghas

ended.

Forinitiationandcontinuationoftreatmentofpostmenopausalsymptoms,thelowesteffectivedosefortheshortest

duration(seealsosection4.4)shouldbeused.

Methodofadministration

Fem7Plusshouldbeappliedtoclean,dry,healthyskin(whichisneitherirritatednorgrazed),freefromanycream,

lotionorotheroilyproduct.

Fem7Plusshouldbeappliedtoanareaofskinwithoutmajorskinfolds,i.e.thebuttocksorhips,andnotsubjectto

chafingbyclothing(avoidthewaistandalsoavoidwearingtightclothingthatcouldloosenthetransdermalpatch).

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sitetwicerunning.Atleastoneweekshouldbeallowedtoelapsebetweenapplicationstothesamesite.

Afteropeningthesachet,one-halfoftheprotectivefoilispeeledoff,beingcarefulnottotouchtheadhesivepartofthe

transdermalpatchwiththefingers.Thenthepatchmustbeapplieddirectlytotheskin.Afterthattheotherhalfofthe

protectivefoilispeeledoff,andthepatchmustbefirmlypressedwiththepalmofthehandforatleast30seconds,

concentratingontheedges.Pressureandthewarmthofthehandareessentialtoensuremaximaladhesive

strengthofthepatch.

Itispossibletotakeashowerorhaveabathwithoutremovingthetransdermalpatch.Intheeventthatthetransdermal

patchshouldbecomedetachedprematurely,i.e.beforetheseventhday(duetovigorousphysicalactivity,excessive

sweating,abnormalchafingofclothing),anewpatchshouldbeapplied(toaidcomplianceitisrecommendedthatthe

patientthencontinuestochangethepatchontheoriginalscheduledday).

Onceapplied,thetransdermalpatchhastobecoveredbyclothestoavoiddirectexposuretosunlight.

Removalofthetransdermalpatchshouldbecarriedoutslowlytoavoidirritatingtheskin.Intheeventofsomeofthe

adhesiveremainingontheskin,thiscanusuallyberemovedbygentlyrubbingwithacreamoranoilylotion.

Afteruse,Fem7Plusistobefoldedintwo(withtheadhesivesurfacetotheinside)anddisposedofwithnormal

householdsolidwaste.

4.3Contraindications

Known,pastorsuspectedbreastcancer;

Knownorsuspectedoestrogen-dependentmalignanttumours(e.g.endometrialcancer);

Undiagnosedgenitalbleeding;

Untreatedendometrialhyperplasia;

Previousidiopathicorcurrentvenousthromboembolism(deepvenousthrombosis,pulmonaryembolism);

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

Activeorrecentarterialthromboembolicdisease,(e.g.angina,myocardialinfarction);

Acuteliverdisease,orahistoryofliverdiseaseaslongasliverfunctiontestshavefailedtoreturntonormal;

Knownhypersensitivitytotheactivesubstancesortoanyoftheexcipients;

Porphyria.

4.4Specialwarningsandprecautionsforuse

Forthetreatmentofpostmenopausalsymptoms,HRTshouldonlybeinitiatedforsymptomsthatadverselyaffect

qualityoflife.Inallcases,acarefulappraisaloftherisksandbenefitsshouldbeundertakenatleastannuallyandHRT

shouldonlybecontinuedaslongasthebenefitoutweighstherisk.

EvidenceregardingtherisksassociatedwithHRTinthetreatmentofprematuremenopauseislimited.Duetothelow

levelofabsoluteriskinyoungerwomen,however,thebalanceofbenefitsandrisksforthesewomenmaybemore

favourablethaninolderwomen.

Medicalexamination/follow-up

BeforeinitiatingorreinstitutingHRT,acompletepersonalandfamilymedicalhistoryshouldbetaken.Physical

(includingpelvicandbreast)examinationshouldbeguidedbythisandbythecontraindicationsandwarningsforuse.

Duringtreatment,periodiccheck-upsarerecommendedofafrequencyandnatureadaptedtotheindividualwoman.

Womenshouldbeadvisedwhatchangesintheirbreastsshouldbereportedtotheirdoctorornurse(see"Breast

cancer"below).Investigations,includingappropriateimagingtools,e.gmammography,shouldbecarriedoutin

accordancewithcurrentlyacceptedscreeningpractices,modifiedtotheclinicalneedsoftheindividual.

Conditionswhichneedsupervision

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pregnancyorprevioushormonetreatment,thepatientshouldbecloselysupervised.Itshouldbetakenintoaccount

thattheseconditionsmayrecurorbeaggravatedduringtreatmentwithFem7Plus,inparticular:

Leiomyoma(uterinefibroids)orendometriosis

Riskfactorsfor,thromboembolicdisorders(seebelow)

-Riskfactorsforoestrogen-dependenttumours,e.g.1 st

degreeheredityforbreastcancer

Hypertension

Liverdisorders(e.g.liveradenoma)

Diabetesmellituswithorwithoutvascularinvolvement

Cholelithiasis

Migraineor(severe)headache

Systemiclupuserythematosus

Ahistoryofendometrialhyperplasia(seebelow)

Epilepsy

Asthma

Otosclerosis

Reasonsforimmediatewithdrawaloftherapy:

Therapyshouldbediscontinuedincaseacontra-indicationisdiscoveredandinthefollowingsituations:

Jaundiceordeteriorationinliverfunction

Significantincreaseinbloodpressure

Newonsetofmigraine-typeheadache

Pregnancy

Endometrialhyperplasiaandcarcinoma

Inwomenwithanintactuterus,theriskofendometrialhyperplasiaandcarcinomaisincreasedwhenoestrogens

areadministratedaloneforprolongedperiods.thereportedincreaseinendometrialcancerriskamongoestrogen-

onlyusersvariesfrom2-to12-foldgreatercomparedwithnon-users,dependingonthedurationoftreatmentand

oestrogendose(seesection4.8).Afterstoppingtreatmentriskmayremainelevatedforatleast10years.

Theadditionofaprogestagencyclicallyforatleast12dayspermonths/28daycycleorcontinuouscombined

oestrogen-progestagentherapyinnon-hysterectomisedwomenpreventstheexcessriskassociatedwithoestrogen-

onlyHRT.

Break-throughbleedingandspottingmayoccurduringthefirstmonthsoftreatment.Ifbreak-throughbleedingor

spottingappearsaftersometimeontherapy,orcontinuesaftertreatmenthasbeendiscontinued,thereasonshould

beinvestigated,whichmayincludeanendometrialbiopsytoexcludeendometrialmalignancy.

Breastcancer

Theoverallevidencesuggestsanincreasedriskofbreastcancerinhysterectomisedwomenusingoestrogen-

progestagenandpossiblyalsooestrogen-onlyHRT,thatisdependantonthedurationoftakingHRT.

Therandomisedplacebo-controlledtrialtheWomen'sHealthInitiativeStudy(WHI)andepidemiologicalstudiesare

consistentinfindinganincreasedriskofbreastcancerinwomentakingcombinedoestrogen-progestagenforHRTthat

becomesapparentafterabout3years(seesection4.8).

Theexcessriskbecomesapparentwithinafewyearsofusebutreturnstobaselinewithinafew(atmostfive)years

afterstoppingtreatment.

HRT,especiallyoestrogen/progestagencombinedtreatment,increasesthedensityofmammographicimageswhich

mayadverselyaffecttheradiologicaldetectionofbreastcancer.

Ovariancancer

Ovariancancerismuchrarerthanbreastcancer.Longterm(atleast5-10years)useofoestrogen-onlyHRTproducts

hasbeenassociatedwithaslightlyincreasedriskofovariancancer(seesection4.8).SomestudiesincludingtheWHI

trialsuggestthatthelong-termuseofcombinedHRTsmayconferasimilarorslightlysmallerrisk(seesection4.8).

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

orpulmonaryembolism.TheoccurrenceofsuchaneventismorelikelyinthefirstyearofHRTthanlater(see

section4.8)

PatientswithknownthrombophilicstateshaveanincreasedriskofVTEandHRTmayaddtothisrisk.HRTis

thereforecontraindicatedinthesepatients(seesection4.3).

GenerallyrecognisedriskfactorsforVTEinclude,useofoestrogens,olderage,majorsurgery,prolonged

immobilisation,obesity(BMI>30kg/m2),pregnancy/postpartumperiod,systemiclupuserythematosus(SLE)and

cancer.ThereisnoconsensusaboutthepossibleroleofvaricoseveinsinVTE.

Asinallpostoperativepatients,prophylacticmeasuresneedbeconsideredtopreventVTEfollowingsurgery,if

prolongedimmobilisationistofollowelectivesurgerytemporarilystoppingHRTfor4to6weeksearlieris

recommended.Treatmentshouldnotberestarteduntilthewomaniscompletelymobilised.

InwomenwithnopersonalhistoryofVTEbutwithafirst-degreerelativewithahistoryofthrombosisatyoung

age,screeningmaybeofferedaftercarefulcounsellingregardingitslimitations(onlyaproportionofthrombophilic

defectsareidentifiedbyscreening).

Ifathrombophilicdefectisidentifiedwhichsegregateswiththrombosisinfamilymembersorifthedefectis

‘severe’(e.g.antithrombin,proteinSorproteinCdeficienciesoracombinationofdefects)HRTiscontraindicated.

Womenalreadyonchronicanticoagulanttreatmentrequirecarefulconsiderationofthebenefit-riskofuseofHRT.

IfVTEdevelopsafterinitiatingtherapy,thedrugshouldbediscontinued.Patientsshouldbetoldtocontacttheir

doctorsimmediatelywhentheyareawareofapotentialthromboembolicsymptom(e.g.painfulswellingofaleg,

suddenpaininthechest,dyspnoea).

Coronaryarterydisease(CAD)

Thereisnoevidencefromrandomisedcontrolledtrialsofprotectionagainstmyocardialinfarctioninwomenwithor

withoutexistingCADwhoreceivedcombinedoestrogen-progestagenoroestrogen-onlyHRT.

TherelativeriskofCADduringuseofcombinedoestrogen+progestagenHRTisslightlyincreased.Asthebaseline

absoluteriskofCADisstronglydependentonage,thenumberofextracasesofCADduetooestrogen

+progestagenuseisverylowinhealthywomenclosetomenopause,butwillrisewithmoreadvancedage.

Ischaemicstroke

Combinedoestrogen-progestagenandoestrogen-onlytherapyareassociatedwithanupto1.5-foldincreaseinrisk

inischaemicstroke.Therelativeriskdoesnotchangewithageortimesincemenopause.However,asthebaseline

riskofstrokeisstronglyage-dependant,theoverallriskofstrokeinwomenwhouseHRTwillincreasewithage

(seesection4.8).

Otherconditions

Oestrogensmaycausefluidretention,andthereforepatientswithcardiacorrenaldysfunctionshouldbecarefully

observed.

Womenwithpre-existinghypertriglyceridemiashouldbefollowedcloselyduringoestrogenreplacementor

hormonereplacementtherapy,sincerarecasesoflargeincreasesofplasmatriglyceridesleadingtopancreatitis

havebeenreportedwithoestrogentherapyinthiscondition.

Oestrogensincreasethyroidbindingglobulin(TBG),leadingtoincreasedcirculatingtotalthyroidhormone,as

measuredbyprotein-boundiodine(PBI),T4levels(bycolumnorbyradio-immunoassay)orT3levels(byradio-

immunoassay).T3resinuptakeisdecreased,reflectingtheelevatedTBG.FreeT4andfreeT3concentrationsare

unaltered.Otherbindingproteinsmaybeelevatedinserum,i.e.corticoidbindingglobulin(CBG),sexhormone-

bindingglobulin(SHBG)leadingtoincreasedcirculatingcorticosteroidsandsexsteroids,respectively.Freeor

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

HRTusedoesnotimprovecognitivefunction.Thereissomeevidenceofincreasedriskofprobabledementiain

womenwhostartusingcontinuouscombinedoroestrogen-onlyHRTaftertheageof65.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Themetabolismofoestrogensandprogestagensmaybeincreasedbyconcomitantuseofsubstancesknowntoinduce

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

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

Ritonavirandnelfinavir,althoughknownasstronginhibitors,bycontrastexhibitinducingpropertieswhenused

concomitantlywithsteroidhormones.

HerbalpreparationscontainingStJohn’swort(HypericumPerforatum)mayinducethemetabolismofoestrogensand

progestagens.

Attransdermaladministration,thefirst-passeffectintheliverisavoidedand,thus,transdermallyappliedoestrogens

andprogestagensHRTmightbelessaffectedthanoralhormonesbyenzymeinducers.

Clinically,anincreasedmetabolismofoestrogensandprogestagensmayleadtodecreasedeffectandchangesinthe

uterinebleedingprofile.

4.6Fertility,pregnancyandlactation

Pregnancy

Fem7Plusisnotindicatedduringpregnancy.IfpregnancyoccursduringtreatmentwithFem7Plus,treatmentshould

bewithdrawnimmediately.

Clinically,dataonalargenumberofexposedpregnanciesindicatenoadverseeffectsoflevonorgestrelonthefoetus.

Theresultsofmostepidemiologicalstudiestodatethatarerelevanttoinadvertentfoetalexposuretocombinationof

oestrogens+progestagensindicatenoteratogenicorfoetotoxiceffect.

Lactation

Fem7Plusisnotindicatedduringlactation.

4.7Effectsonabilitytodriveandusemachines

Noeffectsonabilitytodriveandusemachineshavebeenobserved.

4.8Undesirableeffects

Themostfrequentlyreportedundesirableeffects(>10%)inclinicaltrialsduringtreatmentwithFem7Pluswere

applicationsitereactions,breasttendernessandbleedingorspotting.Theapplicationsitereactionsweremostlymild

skinreactionsandusuallydisappeared2–3daysafterpatchremoval.Inthemajorityofcasesbreasttendernesswas

reportedasmildormoderateandtendstodecreaseduringtreatmenttime.

Otherpotentialsystemicundesirableeffectsarethosecommonlyobservedwithoestrogenandprogestintreatments.

Organsystem

class(e.g.

MedDRASOC

level) CommonADRs

>1/100,<1/10 UncommonADRs

>1/1000,<1/100 RareADRs

>1/10.000,<1/1000

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Breastcancerrisk

Anupto2-foldincreasedriskofhavingbreastcancerdiagnosedisreportedinwomentakingcombined

oestrogen-progestagentherapyformorethan5years.

Anyincreasedriskinusersofoestrogen-onlytherapyissubstantiallylowerthanthatseeninusersofoestrogen-

progestagencombinations.

Thelevelofriskisdependentonthedurationofuse(seesection4.4).

Resultsofthelargestrandomisedplacebo-controlledtrial(WHI-study)andlargestepidemiologicalstudy

(MWS)arepresented.

MillionWomenstudy–Estimatedadditionalriskofbreastcancerafter5years’use

USWHIstudies-additionalriskofbreastcancerafter5years’use

‡WhentheanalysiswasrestrictedtowomenwhohadnotusedHRTpriortothestudytherewasnoincreasedrisk

apparentduringthefirst5yearsoftreatment:after5yearstheriskwashigherthaninnon-users.

2*Takenfrombaselineincidenceratesindevelopedcountries

oedema/weight

increase/loss,fatigue,

legcramps

Nervoussystem

disorders Headache Dizziness,migraine

Gastrointestinal

disorders Dyspepsia Bloating,abdominal

cramps,nausea Cholelithiasis,

cholestaticjaundice

Cardiovascular

disorders Hypertension

Reproductive

systemandbreast

disorders Mastodynia Endometrial

hyperplasia,benign

breasttissuechanges, Increaseinsizeof

uterinefibrosis

Psychiatric

disorders Depression

range

(years) Additionalcases

per1000never-users

ofHRT

overa5year-period*2 Riskratio&

95%CI# Additionalcasesper1000HRTusersover5years

(95%CI)

OestrogenonlyHRT

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

Combinedoestrogen-progestagen

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

#Overallriskratio.Theriskratioisnotconstantbutwillincreasewithincreasingdurationonuse

Note:SincethebackgroundincidenceofbreastcancerdiffersbyEUcountry,thenumberofadditional

casesofbreastcancerwillalsochangeproportionately.

Agerange

(yrs) Incidenceper1000women

inplaceboarmover5years Riskratio&95%CI Additionalcasesper1000HRT

usersover5years(95%CI)

CEEoestrogen-only

50-79 21 0.8(0.7–1.0) -4(-6–0)*3

CEE+MPAoestrogen&progestagen‡

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Endometrialcancerrisk

Postmenopausalwomenwithauterus

Theendometrialcancerriskisabout5inevery1000womenwithauterusnotusingHRT.

Inwomenwithauterus,useofoestrogen-onlyHRTisnotrecommendedbecauseitincreasestheriskofendometrial

cancer(seesection4.4).

Dependingonthedurationofoestrogen-onlyuseandoestrogendose,theincreaseinriskofendometrialcancerin

epidemiologystudiesvariedfrombetween5and55extracasesdiagnosedinevery1000womenbetweentheagesof

50and65.

Addingaprogestagentooestrogen-onlytherapyforatleast12dayspercyclecanpreventthisincreasedrisk.Inthe

MillionWomenStudytheuseoffiveyearsofcombined(sequentialorcontinuous)HRTdidnotincreaseriskof

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

Ovariancancer

Long-termuseofoestrogen-onlyandcombinedoestrogen-progestagenHRThasbeenassociatedwithaslightly

increasedriskofovariancancer.IntheMillionWomenStudy5yearsofHRTresultedin1extracaseper2500users.

Riskofvenousthromboembolism

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

veinthrombosisorpulmonaryembolism.TheoccurrenceofsuchaneventismorelikelyinthefirstyearofusingHT

(seesection4.4).ResultsoftheWHIstudiesarepresented:

WHIStudies-AdditionalriskofVTEover5years’use

Riskofcoronaryarterydisease

Theriskofcoronaryarterydiseaseisslightlyincreasedinusersofcombinedoestrogen-progestagenHRTovertheage

of60(seesection4.4).

Riskofischaemicstroke

Theuseofoestrogen-onlyandoestrogen+progestagentherapyisassociatedwithanupto1.5foldincreased

relativeriskofischaemicstroke.TheriskofhaemorrhagicstrokeisnotincreasedduringuseofHRT.

Thisrelativeriskisnotdependentonageorondurationofuse,butasthebaselineriskisstronglyage-

dependent,theoverallriskofstrokeinwomenwhouseHRTwillincreasewithage,seesection4.4.

WHIstudiescombined-Additionalriskofischaemicstroke*5over5years’use

4*Studyinwomenwithnouterus

Agerange(years) Incidence per 1000

womeninplacebo

armover5years Riskratioand95%CI Additionalcasesper1000

HRTusers

Oraloestrogen-only*4

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

Oralcombinedoestrogen-progestagen

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

Agerange(years) Incidence

per1000womenin

placeboarmover5years Riskratioand

95%CI Additionalcasesper1000

HRTusersover5years

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Otheradversereactionshavebeenreportedinassociationwithoestrogen/progestagentreatment:

Gallbladderdisease.

Skinandsubcutaneousdisorders:chloasma,erythemamultiforme,erythemanodosum,vascularpurpura.

Probabledementiaovertheageof65(seesection4.4).

4.9Overdose

Themethodofadministrationmakessignificantoverdoseunlikely.Signsofanoverdosearegenerallybreast

tenderness,swellingoftheabdomen/pelvis,anxiety,irritability,nauseaandvomiting.Removalofthetransdermal

patchesisallthatisrequiredshoulditoccur.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:

Progestagensandoestrogens,combinations,levonorgestrelandoestrogen

ATCcode:G03FA11

Fem7Pluscontainsacontinuouscombinedcombinationofoestrogenandprogestagenforcontinuoususe,combining

estradiolhemihydrateandlevonorgestrel.

Estradiol:Theactiveingredient,synthetic17-estradiol,ischemicallyandbiologicallyidenticaltoendogenous

humanestradiol.Itsubstitutesforthelossofoestrogenproductioninmenopausalwomen,andalleviatesmenopausal

symptoms.

Levonorgestrel:Asoestrogenspromotethegrowthoftheendometrium,unopposedoestrogensincreasetherisk

ofendometrialhyperplasiaandcancer.Theadditionoflevonorgestrelgreatlyreducestheoestrogen-inducedriskof

endometrialhyperplasiainnon-hysterectomisedwomen.

Clinicaltrialinformation

Reliefofoestrogen-deficiencysymptomsandbleedingpatterns:

UndertreatmentwithFem7Plus,reliefofmenopausalsymptomswasachievedduringthefirstweeksof

treatment.

Fem7Plusisacontinuous-combinedHRTgivenwiththeintentofavoidingtheregularwithdrawalbleeding

associatedwithcyclicorsequentialHRT.

Amenorrhoeawasseenin59-68%ofthewomenduringmonths10-12oftreatment.Irregular_bleedingand/orspotting

appearedin28-39%ofthewomenduringthefirstthreemonthsoftreatmentandin37%duringmonths10-12of

treatment.

5.2Pharmacokineticproperties

Bytransdermaladministrationthereisnohepaticfirst-passeffectasobservedwithoraladministration;estradiol

reachesthebloodstreaminunchangedformandinphysiologicalamounts.Therapeuticestradiolconcentrationsare

comparabletothoseobservedinthefollicularphase.

AftercontinuousapplicationofFemSevenConti,maximumplasmaconcentrationofestradiol(Cmax)reaches82pg/ml

andaverageplasmaconcentration(Cav)isabout34pg/ml.Troughplasmaconcentration(Ctrough)attheendofa7-

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valueswithin12to24hours.

ThemaximumplasmaconcentrationoflevonorgestrelisreachedafterthreetofourdaysandCmaxisapproximately

113pg/mlatsteadystate.Theaverageplasmaconcentrationoflevonorgestrelduringa7-dayperiodisapproximately

88pg/mlandtroughplasmaconcentration(Ctrough)reaches72pg/ml.

Afterpercutaneousabsorption,levonorgestrelisboundtoplasmaproteins,i.e.albumin(50%),andsexhormone-

bindingglobulin(SHBG)(47.5%).AffinitytoSHBGishigherthanforothercommonlyusedprogestagens.

5.3Preclinicalsafetydata

Inexperimentalanimalsestradioldisplayedanembryolethaleffectalreadyatrelativelylowdoses;malformationsofthe

urogenitaltractandfeminisationofmalefoetuseswereobserved.Levonorgestraldisplayedanembryolethaleffectin

animalexperimentsand,inhighdoses,avirilisingeffectonfemalefetuses.Becauseofmarkeddifferencesbetween

animalspeciesandbetweenanimalsandhumans,preclinicalresultsareoflimitedpredictivevalueforthetreatmentof

humanswithoestrogens.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Backinglayer: Polyethyleneterephthalate(PET)foil.

Adhesivematrix: Styrene-isoprene-styreneblockcopolymer,glycerineestersofcompletelyhydrogenatedresins.

Protectiveliner: Siliconizedpolyethyleneterephthalate(PET)foil.

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Sachet(Paper/PE/aluminium/ethylenecopolymer).Cartonof4or12sachets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Seesection4.2,Posologyandmethodofadministration.Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

MerckSeronoLtd

BedfontCross

StanwellRoad

Feltham

Middlesex,TW148NX

UnitedKingdom

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PA0654/015/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:19March2004

Dateoflastrenewal:5November2007

10DATEOFREVISIONOFTHETEXT

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