ETHINYLESTRADIOL/DROSPIRENONE LEON FARMA & PLACEBO

Main information

  • Trade name:
  • ETHINYLESTRADIOL/DROSPIRENONE LEON FARMA & PLACEBO
  • Dosage:
  • 0.02 / 3 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ETHINYLESTRADIOL/DROSPIRENONE LEON FARMA & PLACEBO
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1474/007/001
  • Authorization date:
  • 09-10-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1474/007/001

CaseNo:2046884

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

LaboratoriosLeonFarma,S.A.

C/RoadelaVega,15,1-24008Leon,Spain

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Ethinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom09/10/2009until08/10/2014.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 24/10/2009 CRN 2046884 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Ethinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Pinktablets:

Eachfilm-coatedtabletcontains0.02mgofethinylestradioland3mgofdrospirenone

Excipient:

Lactosemonohydrate44mg

Whitetablets(placebotablets):

Thetabletdoesnotcontainactivesubstances

Excipient:

Lactose,anhydrous89.5mg

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Activetablets:Pink,roundfilm-coatedtablets

Placebotablets:White,roundfilm-coatedtablets.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Oralcontraception

4.2Posologyandmethodofadministration

Routeofadministration:oraluse.

HowtotakeEthinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTablets

Thetabletsmustbetakeneverydayataboutthesametime,ifnecessarywithalittleliquidintheordershownon

blisterpack.

Tablettakingiscontinuous.Onetabletistobetakendailyfor28consecutivedays.Eachsubsequentpackisstartedthe

dayafterthelasttabletthepreviouspack.Withdrawalbleedingusuallystartsonday2-3afterstartingtheplacebo

tablets(lastrow)andmaynothavefinishedbeforethenextpackisstarted.

HowtostartEthinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTablets.

Noprecedinghormonalcontraceptiveuse(inthepastmonth)

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Changingfromanothercombinedoralcontraceptive(COC)

ThewomanshouldstartEthinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTabletson

thedayfollowingtheusualhormonefreeinterval(tablet-freeorplacebotabletinterval)ofherpreviouscombinedoral

contraceptivemethod.Incaseavaginalringortransdermalpatchhasbeenusedthewomanshouldstartusing

Ethinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTabletspreferablyonthedayof

removal,butatthelatestwhenthenextapplicationisdue.

-Changingfromaprogestogen-only-method(progestogen-onlypill,injection,implant)orfromaprogestogen-releasing

intrauterinesystem(IUS)

Thewomanmayswitchanydayfromtheprogestogen-onlypill(fromanimplantortheIUSonthedayofitsremoval,

fromaninjectablewhenthenextinjectionwouldbedue)butshouldinallofthesecasesbeadvisedtoadditionallyuse

abarriermethodforthefirst7daysoftablet-taking.

Followingfirsttrimesterabortion

Thewomanmaystartimmediately.Whendoingso,sheneednottakeadditionalcontraceptivemeasures.

Followingdeliveryorsecond-trimesterabortion

Womanshouldbeadvisedtostartatday21to28afterdeliveryorsecond-trimesterabortion.Whenstartinglater,the

womanshouldbeadvisedtoadditionallyuseabarriermethodforthefirst7days.However,ifintercoursehasalready

occurred,pregnancyshouldbeexcludedbeforetheactualstartofCOCuseorthewomanhastowaitforherfirst

menstrualperiod.

ForbreastfeedingwomenseeSection4.6.

Managementofmissedtablets

Missedpillsfromthelastrowoftheblisterareplacebotabletsandthuscanbedisregarded.However,theyshouldbe

discardedtoavoidunintentionallyprolongingtheplacebotabletphase.

Thefollowingadviceonlyreferstomissedactivetablets(rows1-3oftheblister):

Iftheuserislessthan12hourslateintakinganyactivetablet,contraceptiveprotectionisnotreduced.Thewoman

shouldtakethetabletassoonassheremembersandshouldtakefurthertabletsatusualtime.

Ifsheismorethan12hourslateintakinganyactivetablet,contraceptiveprotectionmaybereduced.The

managementofmissedtabletscanbeguidedbythefollowingtwobasicrules:

1.tablet-takingmustneverbediscontinuedforlongerthan7consecutivedays

2.7daysofuninterruptedtablet-takingarerequiredtoattainadequatesuppressionofthehypothalamic-pituitary-

ovarian-axis.

Accordinglythefollowingadvicecanbegivenindailypractice:

Week1

Theusershouldtakethelastmissedtabletassoonassheremembers,evenifthismeanstakingtwotabletsatthesame

time.Shethencontinuestotaketheremainingtabletsatherusualtime.Inaddition,abarriermethodsuchascondom

shouldbeusedforthenext7days.Ifintercoursetookplaceinthepreceding7days,thepossibilityofpregnancy

shouldbeconsidered.Themoretabletsaremissedandtheclosertheyaretotheplacebotabletphase,thehigherthe

riskofapregnancy.

Week2

Theusershouldtakethelastmissedtabletassoonassheremembers,evenifthismeanstakingtwotabletsatthesame

time.Shethencontinuestotaketabletstheremainingtabletsatherusualtime.Providedthatthewomanhastakenher

tabletscorrectlyinthe7daysprecedingthefirstmissedtablet,thereisnoneedtouseextracontraceptiveprecautions.

However,ifshehasmissedmorethan1tablet,thewomanshouldbeadvisedtouseextraprecautionsforthenext7

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Week3

Theriskofreducedreliabilityisimminentbecauseoftheforthcoming7-dayplacebotabletphase.

However,byadjustingthetablet-intakeschedule,reducedcontraceptiveprotectioncanstillbeprevented.Byadhering

toeitherofthefollowingtwooptions,thereisthereforenoneedtouseextracontraceptiveprecaution,providedthatin

the7daysprecedingthefirstmissedtabletthewomanhastakenalltabletscorrectly.Ifthisisnotthecase,sheshould

followthefirstofthesetwooptionsanduseextraprecautionsforthenext7daysaswell.

Theusershouldtakethelastmissedtabletassoonassheremembers,evenifthismeanstakingtwotabletsat

sametime.

Shethencontinuestotakeremainingtabletsatherusualtime.Thenextblisterpackmustbestartedassoonasthe

currentblisterpackisfinishedi.e.nogapshouldbeleftbetweenpacks.

Shethencontinuestotaketabletsatherusualtimeuntiltheactivetabletsareusedup.The7tabletsfromthelastrow

(placebotablets)shouldbediscarded.Thenextblisterpackmustbestartedrightaway.

Theuserisunliketohaveawithdrawalbleeduntiltheendoftheactivetabletssectionofthesecondpack,butshemay

experiencespottingorbreakthroughbleedingontablet-takingdays.

Thewomanmayalsobeadvisedtodiscontinueactivetablet-takingfromthecurrentblisterpack.Sheshould

thenhaveatablet-freeintervalofup7daystaketabletsfromthelastrow(placebotablets)forupto7days,including

thedaysshemissedtablets,andsubsequentlycontinuewiththenextblisterpack.

Ifthewomanmissedtabletsandsubsequentlyhasnowithdrawalbleedinthefirstnormaltablet–freeintervalinthe

placebophase,thepossibilityofapregnancyshouldbeconsidered.

Adviceincaseofgastro-intestinaldisturbances

Incaseofseveregastro-intestinaldisturbances(e.g.,vomitingorseverediarrhoea),absorptionmaynotbecomplete

andadditionalcontraceptivemeasuresshouldbetaken.Ifvomitingoccurswithin3-4hoursafteractivetablettaking,a

newtabletshouldbetakenassoonaspossible.Thenewtabletshouldbetakenwithin12hoursoftheusualtimeof

tablet-takingifpossible.

Ifmore12hourselapse,theadviceconcerningmissedtablets,asgiveinsection4.2“Managementofmissedtablets”is

applicable.Ifthewomandoesnotwanttochangehernormaltablet-takingschedule,shehastotaketheextratable(s)

fromanotherblisterpack.

Howtopostponeawithdrawalbleed

TodelayaperiodthewomanshouldcontinuewithanotherblisterpackofEthinylestradiol/DrospirenoneLeonFarma

&Placebo0.02mg/3mgFilm-coatedTabletswithouttakingtheplacebotabletsfromhercurrentpack.Theextension

canbecarriedonforaslongaswisheduntiltheendoftheactivetabletsinthesecondpack.Duringtheextensionthe

womanmayexperiencebreakthrough-bleedingorspotting.RegularintakeofEthinylestradiol/DrospirenoneLeon

Farma&Placebo0.02mg/3mgFilm-coatedTabletsisthenresumedaftertheplacebotabletphase.

Toshiftherperiodstoanotherdayoftheweekthanthewomanisusedtowithhercurrentscheme,shecanbeadvised

toshortenherforthcomingplacebotabletphasebyasmanydaysasshelikes.Theshortertheinterval,thehigherthe

riskthatshedoesnothaveawithdrawalbleedandwillexperiencebreakthrough-bleedingandspottingduring

subsequentpack(justaswhendelayingperiod).

4.3Contraindications

Combinedoralcontraceptives(COC)shouldnotbeusedinthepresenceofanytheconditionslistedbelow.Should

anyoftheconditionsappearforthefirsttimeduringCOCuse,theproductshouldbestoppedimmediately.

Venousthrombosispresentorinhistory(deepvenousthrombosis,pulmonaryembolism)

Arterialthrombosispresentorinhistory(e.g.myocardialinfarction)orprodomalconditions(e.g.anginapectoris

andtransientischaemicattack).

Cerebro-vascularaccidentpresentorinhistory

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Diabetesmellituswithavascularsymptoms

Severehypertension

Severedyslipoproteinemia

Hereditaryoracquiredpredispositionforvenousorarterialthrombosis,suchasAPC-resistance,antithrombin-

III-deficiency,proteinCdeficiency,proteinSdeficiency,hyperhomocysteinemiaandantiphospholipid-

antibodies(anticardiolipin-antibodies,lupusanticoagulant).

Pancreatitisorahistorythereofifassociatedwithseverehypertriglyceridemia

Presenceorhistoryofseverehepaticdiseaseaslongasliverfunctionvalueshavenotreturnedtonormal

Severerenalinsufficiencyoracuterenalfailure.

Presenceorhistoryoflivertumours(benignormalignant).

Knownorsuspectedsex-steroidinfluencedmalignancies(e.g.ofthegenitalorgansorthebreasts).

Undiagnosedvaginalbleeding.

Historyofmigrainewithfocalneurologicalsymptoms

HypersensitivitytotheactivesubstancesortoanyoftheexcipientsofEthinylestradiol/DrospirenoneLeon

Farma&Placebo0.02mg/3mgFilm-coatedTablets.

4.4Specialwarningsandprecautionsforuse

Warnings

Ifanyoftheconditions/riskfactorsmentionedbelowarepresent,thebenefitsofCOCuseshouldbeweighedagainst

thepossiblerisksforeachindividualwomananddiscussedwiththewomanbeforeshedecidestostartusingit.Inthe

eventofaggravation,exacerbationorfirstappearanceofanyoftheseconditionsorriskfactors,thewomanshould

contactherphysician.ThephysicianshouldthendecideonwhetherCOCuseshouldbediscontinued.

CirculatoryDisorders

EpidemiologicalstudieshaveshownthattheincidenceofVTEinusersoforalcontraceptiveswithlowoestrogen

content(<50µgethinylestradiol)(includingEthinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mg

Film-coatedTablets)rangesfromabout20to40casesper100,000woman-years,butthisriskestimatevaries

accordingtotheprogestogen.Thiscompareswith5to10casesper100,000woman-yearsfornon-users.

Theuseofanycombinedoralcontraceptivecarriesanincreasedriskofvenousthromboembolism(VTE)compared

withnouse.TheexcessriskofVTEishighestduringthefirstyearawomaneverusesacombinedoralcontraceptive.

TheincidenceofVTEassociatedwithpregnancyisestimatedas60casesper100,000pregnancies.VTEisfatalin1-

2%ofcases.

EpidemiologicalstudieshavealsoassociatedtheuseofcombinedCOCswithanincreasedriskforarterial(myocardial

infarction,transientischaemicattack)thromboembolism.

Extremelyrarely,thrombosishasbeenreportedtooccurinotherbloodvessels,e.g.hepatic,mesenteric,renal,cerebral

orretinalveinsandarteries,incontraceptivepillusers.Thereisnoconsensusastowhethertheoccurrenceofthese

eventsisassociatedwiththeuseofhormonalcontraceptives.

Symptomsofvenousorarterialthrombotic/thromboemboliceventsorofacerebrovascularaccidentcaninclude:

unusualunilaterallegpainand/orswelling

suddenseverepaininthechest,whetherornotitradiatestotheleftarm

suddenbreathlessness

suddenonsetofcoughingwithoutaclearcause

anyunusual,severe,prolongedheadache

suddenpartialorcompletelossofvision

diplopia

slurredspeechoraphasia

vertigo

collapsewithorwithoutfocalseizure

weaknessorverymarkednumbnesssuddenlyaffectingonesideoronepartofthebody

motordisturbances

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TheriskforvenousthromboemboliccomplicationsinCOCusersincreaseswith:

increasingage.

apositivefamilyhistory(venousthromboembolismeverinasiblingorparentatrelativelyearlyage).Ifa

hereditarypredispositionissuspected,thewomanshouldbereferredtoaspecialistforadvicebeforedeciding

aboutanyCOCuse.

prolongedimmobilisation,majorsurgery,anysurgerytothelegs,ormajortrauma.Inthesesituationsitis

advisabletodiscontinuethepill(inthecaseofelectivesurgeryatleastfourweeksinadvance)andnotresume

untiltwoweeksaftercompleteremobilisation.Antithrombotictreatmentshouldbeconsideredifthepillshave

notbeendiscontinuedinadvance.

obesity(bodymassindexover30kg/m²).

thereisnoconsensusaboutthepossibleroleofvaricoseveinsandsuperficialthrombophlebitisintheonsetor

progressionofvenousthrombosis.

Theriskofarterialthrombo-emboliccomplicationsorofacerebrovascularaccidentinCOCusersincreaseswith:

increasingage.

smoking(womenover35yearsshouldbestronglyadvisednottosmokeiftheywishtouseanCOC).

dyslipoproteinemia.

hypertension.

migraine.

obesity(bodymassindexover30kg/m²).

valvularheartdisease.

atrialfibrillation.

Thepresenceofoneseriousriskfactorormultipleriskfactorsforvenousorarterialdisease,respectively,canalso

constituteacontraindication.Thepossibilityofanticoagulanttherapyshouldalsobetakenintoaccount.COCusers

shouldbespecificallypointedouttocontacttheirphysicianincaseofpossiblesymptomsofthrombosis.Incaseof

suspectedorconfirmedthrombosis,COCuseshouldbediscontinued.Adequatealternativecontraceptionshouldbe

initiatedbecauseoftheteratogenicityofanticoagulanttherapy(coumarins).

Theincreasedriskofthromboembolisminthepuerperiummustbeconsidered(forinformationon"Pregnancyand

Lactation"seesection4.6).

Othermedicalconditionswhichhavebeenassociatedwithadversevasculareventsincludediabetesmellitus,systemic

lupuserythematosus,haemolyticuremicsyndromeandchronicinflammatoryboweldisease(Crohn'sdiseaseor

ulcerativecolitis)andsicklecelldisease.

AnincreaseinfrequencyorseverityofmigraineduringCOCuse(whichmaybeprodromalofacerebrovascularevent)

maybeareasonforimmediatediscontinuationoftheCOC.

Tumours

Anincreasedriskofcervicalcancerinlong-termusersofCOCshasbeenreportedinsomeepidemiologicalstudies,

buttherecontinuestobecontroversyabouttheextenttowhichthisfindingisattributabletotheconfoundingeffectsof

sexualbehaviourandotherfactorssuchashumanpapillomavirus(HPV).

Ameta-analysisfrom54epidemiologicalstudiesreportedthatthereisaslightlyincreasedrelativerisk(RR=1.24)of

havingbreastcancerdiagnosedinwomenwhoarecurrentlyusingCOCs.Theexcessriskgraduallydisappearsduring

thecourseofthe10yearsaftercessationofCOCuse.Becausebreastcancerisrareinwomenunder40yearsofage,

theexcessnumberofbreastcancerdiagnosesincurrentandrecentCOCusersissmallinrelationtotheoverallriskof

breastcancer.Thesestudiesdonotprovideevidenceforcausation.Theobservedpatternofincreasedriskmaybedue

toanearlierdiagnosisofbreastcancerinCOCusers,thebiologicaleffectsofCOCsoracombinationofboth.The

breastcancersdiagnosedinever-userstendtobelessadvancedclinicallythanthecancersdiagnosedinnever-users.

Inrarecases,benignlivertumours,andevenmorerarely,malignantlivertumourshavebeenreportedinusersof

COCs.Inisolatedcases,thesetumourshaveledtolife-threateningintra-abdominalhaemorrhages.Ahepatictumour

shouldbeconsideredinthedifferentialdiagnosiswhensevereupperabdominalpain,liverenlargementorsignsof

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Otherconditions

TheprogestincomponentinEthinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTablets

isanaldosteroneantagonistwithpotassiumsparingproperties.Inmostcases,noincreaseofpotassiumlevelsistobe

expected.Inaclinicalstudy,howeverinsomepatientswithmildormoderaterenalimpairmentandconcomitantuseof

potassium-sparingmedicinalproductsserumpotassiumlevelsslightly,butnotsignificantly,increasedduring

drospirenoneintake.Therefore,itisrecommendedtocheckserumpotassiumduringthefirsttreatmentcycleinpatients

presentingwithrenalinsufficiencyandapretreatmentserumpotassiumintheupperreferencerange,andparticularly

duringconcomitantuseofpotassiumsparingmedicinalproducts.Seealsosection4.5.

Womenwithhypertriglyceridemia,orafamilyhistorythereof,maybeatanincreasedriskofpancreatitiswhenusing

COCs.

AlthoughsmallincreasesinbloodpressurehavebeenreportedinmanywomentakingCOCs,clinicallyrelevant

increasesarerare.OnlyintheserarecasesanimmediatediscontinuationofCOCuseisjustified.If,duringtheuseofa

COCinpre-existinghypertension,constantlyelevatedbloodpressurevaluesorasignificantincreaseinbloodpressure

donotrespondadequatelytoantihypertensivetreatment,theCOCmustbewithdrawn.Whereconsideredappropriate,

COCusemayberesumedifnormotensivevaluescanbeachievedwithantihypertensivetherapy.

ThefollowingconditionshavebeenreportedtooccurordeterioratewithbothpregnancyandCOCuse,butthe

evidenceofanassociationwithCOCuseisinconclusive:jaundiceand/orpruritusrelatedtocholestasis;gallstones;

porphyria;systemiclupuserythematosus;haemolyticuremicsyndrome;Sydenham'schorea;herpesgestationis;

otosclerosis-relatedhearingloss.

Inwomenwithhereditaryangioedemaexogenousestrogensmayinduceorexacerbatesymptomsofangioedema.

AcuteorchronicdisturbancesofliverfunctionmaynecessitatethediscontinuationofCOCuseuntilmarkersofliver

functionreturntonormal.Recurrenceofcholestaticjaundiceand/orcholestasis-relatedprurituswhichpreviously

occurredduringpregnancyorduringprevioususeofsexsteroidsnecessitatesthediscontinuationofCOCs.

AlthoughCOCsmayhaveaneffectonperipheralinsulinresistanceandglucosetolerance,thereisnoevidencefora

needtoalterthetherapeuticregimenindiabeticsusinglow-doseCOCs(containing<0.05mgethinylestradiol).

However,diabeticwomenshouldbecarefullyobserved,particularlyintheearlystageofCOCuse.

Worseningofendogenousdepression,ofepilepsy,ofCrohn'sdiseaseandofulcerativecolitishasbeenreportedduring

COCuse.

Chloasmamayoccasionallyoccur,especiallyinwomenwithahistoryofchloasmagravidarum.Womenwitha

tendencytochloasmashouldavoidexposuretothesunorultravioletradiationwhilsttakingCOCs.

Pinktabletsofthismedicinalproduct44mglactosepertablet,thewhitetabletscontains47mg

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

Medicalexamination/consultation

PriortotheinitiationorreinstitutionofEthinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-

coatedTabletsacompletemedicalhistory(includingfamilyhistory)shouldbetakenandpregnancymustberuledout.

Bloodpressureshouldbemeasuredandaphysicalexaminationshouldbeperformed,guidedbythecontra-indications

(seesection4.3)andwarnings(seesection4.4).Thewomanshouldalsobeinstructedtocarefullyreadtheuserleaflet

andtoadheretotheadvicegiven.Thefrequencyandnatureofexaminationsshouldbebasedonestablishedpractice

guidelinesandbeadaptedtotheindividualwoman.

WomenshouldbeadvisedthatoralcontraceptivesdonotprotectagainstHIVinfections(AIDS)andothersexually

transmitteddiseases.

Reducedefficacy

TheefficacyofCOCsmaybereducedintheeventofe.g.missedactivetablets(seesection4.2),gastro-intestinal

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Reducedcyclecontrol

DuringtheuseofanyCOCs,irregularbleeding(spottingorbreakthroughbleeding)mayoccur,especiallyduringthe

firstmonthsofuse.Therefore,theevaluationofanyirregularbleedingisonlymeaningfulafteranadaptationinterval

ofaboutthreecycles.

Ifbleedingirregularitiespersistoroccurafterpreviouslyregularcycles,thennon-hormonalcausesshouldbe

consideredandadequatediagnosticmeasuresareindicatedtoexcludemalignancyorpregnancy.Thesemayinclude

curettage.

Insomewomenwithdrawalbleedingmaynotoccurduringtheplacebotabletphase.IftheCOChasbeentaken

accordingtothedirectionsdescribedinsection4.2,itisunlikelythatthewomanispregnant.However,iftheCOChas

notbeentakenaccordingtothesedirectionspriortothefirstmissedwithdrawalbleedoriftwowithdrawalsbleedsare

missed,pregnancymustberuledoutbeforeCOCuseiscontinued.

Thepinktabletsofthismedicinalproductcontain44mgoflactosepertablet,thewhitetabletscontain89.5mg

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionwhoareonalactose-freedietshouldtakethisamountintoconsideration.shouldnottakethismedicine

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Note:Theprescribinginformationofconcomitantmedicationsshouldbeconsultedtoidentifypotentialinteractions.

InfluenceofothermedicinalproductsonEthinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mg

Film-coatedTablets

Interactionsbetweenoralcontraceptivesandothermedicinalproductsmayleadtobreakthroughbleedingand/or

contraceptivefailure.Thefollowinginteractionshavebeenreportedintheliterature.

Thishasbeenestablishedwithhydantoins,barbiturates,primidone,carbamazepineandrifampicin;oxcarbazepine,

topiramate,felbamate,ritonavir,griseofulvinandtheherbalremedySt.John'sWort(hypericumperforatum)arealso

suspected.Themechanismofthisinteractionappearstobebasedonthehepaticenzyme-inducingpropertiesofthese

activesubstances.Maximalenzymeinductionisgenerallynotseenfor2-3weeksbutmaythenbesustainedforatleast

4weeksafterthecessationofdrugtherapy.

Contraceptivefailureshavealsobeenreportedwithantibiotics,suchasampicillinandtetracyclines.Themechanismof

thiseffecthasnotbeenelucidated.

Womenonshort-termtreatment(uptooneweek)withanyoftheabove-mentionedclassesofmedicinalproductsor

individualactivesubstancesshouldtemporarilyuseabarriermethodinadditiontotheCOC,i.e.duringthetimeof

concomitantmedicinalproductadministrationandfor7daysaftertheirdiscontinuation.

ForwomenonrifampicinabarriermethodshouldbeusedinadditiontotheCOCduringthetimeofrifampicin

administrationandfor28daysafteritsdiscontinuation.

IfconcomitantmedicinalproductadministrationrunsbeyondtheendoftheactivetabletsintheCOCblisterpack,the

placebotabletsmustbediscardedandthenextCOCpackshouldbestartedrightaway.

Inwomenonlong-termtreatmentwithhepaticenzyme-inducingdrugs,expertshaverecommendedtoincreasethe

contraceptivesteroiddoses.

Ifahighcontraceptivedosageisnotdesirableorappearstobeunsatisfactoryorunreliable,e.g.inthecaseof

breakthroughbleeding,anothernon-hormonalcontraceptionmethodshouldbeadvised.

ThemainmetabolitesofdrospirenoneinhumanplasmaaregeneratedwithoutinvolvementofthecytochromeP450

system.Inhibitorsofthisenzymesystemarethereforeunlikelytoinfluencethemetabolismofdrospirenone.

InfluenceofEthinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTabletson

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Oralcontraceptivesmayaffectthemetabolismofcertainotheractivesubstances.Accordingly,plasmaandtissue

concentrationsmayeitherincrease(e.g.cyclosporin)ordecrease(e.g.lamotrigine).

Basedoninvitroinhibitionstudiesandinvivointeractionstudiesinfemalevolunteersusingomeprazole,simvastatin

andmidazolamasmarkersubstrate,aninteractionofdrospirenoneatdosesof3mgwiththemetabolismofotheractive

substancesisunlikely.

Otherinteractions

Inpatientswithoutrenalinsufficiency,theconcomitantuseofdrospirenoneandACE-inhibitorsorNSAIDsdidnot

showasignificanteffectonserumpotassium.Nevertheless,concomitantuseofEthinylestradiol/DrospirenoneLeon

Farma&Placebo0.02mg/3mgFilm-coatedTabletswithaldosteroneantagonistsorpotassium-sparingdiureticshas

notbeenstudied.Inthiscase,serumpotassiumshouldbetestedduringthefirsttreatmentcycle.Seealsosection4.4.

Laboratorytests

Theuseofcontraceptivesteroidsmayinfluencetheresultsofcertainlaboratorytests,includingbiochemicalparameters

ofliver,thyroid,adrenalandrenalfunction,plasmalevelsof(carrier)proteins,e.g.corticosteroid-bindingglobulinand

lipid/lipoproteinfractions,parametersofcarbohydratemetabolismandparametersofcoagulationandfibrinolysis.

Changesgenerallyremainwithinthenormallaboratoryrange.Drospirenonecausesanincreaseinplasmareninactivity

andplasmaaldosteroneinducedbyitsmildantimineralocorticoidactivity.

4.6Pregnancyandlactation

Ethinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTabletsisnotindicatedduring

pregnancy.

IfpregnancyoccursduringuseofEthinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coated

Tablets,thepreparationshouldbewithdrawnimmediately.Extensiveepidemiologicalstudieshaverevealedneitheran

increasedriskofbirthdefectsinchildrenborntowomenwhousedCOCspriortopregnancy,norateratogeniceffect

whenCOCsweretakeninadvertentlyduringpregnancy.NosuchstudiesareconductedwithEthinylestradiol/

DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTablets

Animalstudieshaveshownundesirableeffectsduringpregnancyandlactation(seesection5.3).Basedontheseanimal

data,undesirableeffectsduetohormonalactionoftheactivecompoundscannotbeexcluded.However,general

experiencewithCOCsduringpregnancydidnotprovideevidenceforanactualundesirableeffectinhumans.

TheavailabledataregardingtheuseofEthinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-

coatedTabletsduringpregnancyaretoolimitedtopermitconclusionsconcerningnegativeeffectsofEthinylestradiol/

DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTabletsonpregnancy,healthofthefoetusorneonate.

Todate,norelevantepidemiologicaldataareavailable.

LactationmaybeinfluencedbyCOCsastheymayreducethequantityandchangethecompositionofbreastmilk.

Therefore,theuseofCOCsshouldgenerallynotberecommendeduntilthebreast-feedingmotherhascompletely

weanedherchild.Smallamountsofthecontraceptivesteroidsand/ortheirmetabolitesmaybeexcretedwiththemilk

duringCOCuse.Theseamountsmayaffectthechild.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Noeffectsonabilitytodrive

andusemachineshavebeenobservedinusersofCOCs.

4.8Undesirableeffects

ThefollowingadversedrugreactionshavebeenreportedduringuseofEthinylestradiol/DrospirenoneLeonFarma&

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ThetablebelowreportsadversereactionsbyMedDRAsystemorganclasses(MedDRASOCs).

SystemOrganClass Frequencyofadversereactions

Common

≥1/100to<1/10)> Uncommon

≥1/1,000to<1/100)>

Infectionsandinfestations Candidiasis

Herpessimplex

Immunesystemdisorders Allergicreaction

Metabolismandnutrition

disorders Increasedappetite

Psychiatricdisorders Emotionallability Depression

Nervousness

Sleepdisorder

Libidodecreased

Nervoussystemdisorders Headache Paresthesia

Dizziness

Eyedisorders Visualdisturbance

Cardiacdisorders Extrasystoles

Tachycardia

Vasculardisorders Pulmonaryembolism

Hypertension

Migraine

Varicosevein

Respiratory,thoracicand

mediastinaldisorders Pharyngitis

Gastrointestinaldisorders Abdominalpain Nausea

Vomiting

Gastroenteritis

Diarrhoea

Constipation

Gastrointestinaldisorder

Skinandsubcutaneoustissue

disorders Acne Angioedema

Alopecia

Pruritus

Rash

Dryskin

Seborrhoea

Skindisorder

Musculoskeletaland

connectivetissuedisorders Neckpain

Paininextremity

Musclecramps

Renalandurinarydisorders Cystitis

Reproductivesystemand

breastdisorders Breastpain

Breastenlargement

Dysmenorrhoea

Metrorrhagia Breastneoplasm

Fibrocysticbreast

Galactorrhea

Ovariancyst

Hotflushes

Menstrualdisorder

Amenorrhea

Menorrhagia

Vaginalcandidiasis

Vaginitis

Genitaldischarge

Vulvovaginaldisorder

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ThefollowingseriousadverseeventshavebeenreportedinwomenusingCOCs,whicharediscussedinsection4.4

Specialwarningsandprecautionsforuse:

Venousthromboembolicdisorders;

Arterialthromboembolicdisorders;

Hypertension;

Livertumours;

OccurrenceordeteriorationofconditionsforwhichassociationwithCOCuseisnotconclusive:Crohn'sdisease,

ulcerativecolitis,epilepsy,migraine,endometriosis,uterinemyoma,porphyria,systemiclupuserythematosus,herpes

gestationis,Sydenham'schorea,haemolyticuremicsyndrome,cholestaticjaundice;

Chloasma;

AcuteorchronicdisturbancesofliverfunctionmaynecessitatethediscontinuationofCOCuseuntilmarkersofliver

functionreturntonormal.

Ethinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTablets,inwomenwithhereditary

angioedemaexogenousestrogensmayinduceorexacerbatesymptomsofangioedema.

ThefrequencyofdiagnosisofbreastcancerisveryslightlyincreasedamongOCusers.Asbreastcancerisrarein

womenunder40yearsofagetheexcessnumberissmallinrelationtotheoverallriskofbreastcancer.Causationwith

COCuseisunknown.Forfurtherinformation,seesections4.3and4.4.

4.9Overdose

TherehasnotyetbeenanyexperienceofoverdosewithEthinylestradiol/DrospirenoneLeonFarma&Placebo0.02

mg/3mgFilm-coatedTablets.Onthebasisofgeneralexperiencewithcombinedoralcontraceptives,symptomsthat

maypossiblyoccurinthiscaseare:nausea,vomitingand,inyounggirls,slightvaginalbleeding.Thereareno

antidotesandfurthertreatmentshouldbesymptomatic.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup(ATC):Progestogensandestrogens,fixedcombinationsATCCode:G03AA12

PearlIndex:0.31(upperlimit97.5%confidenceinterval:0.91)

ThecontraceptiveeffectofEthinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTablets

isbasedontheinteractionofvariousfactors,themostimportantofwhichareseenastheinhibitionofovulationand

thechangesintheendometrium.

Ethinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTabletsisacombinedoral

contraceptivewithethinylestradiolandtheprogestogendrospirenone.Inatherapeuticdosage,drospirenonealso

possessesantiandrogenicandmildantimineralocorticoidproperties.Ithasnoestrogenic,glucocorticoidand

antiglucocorticoidactivity.Thisgivesdrospirenoneapharmacologicalprofilecloselyresemblingthenaturalhormone

progesterone.

ThereareindicationsfromclinicalstudiesthatthemildantimineralocorticoidpropertiesofEthinylestradiol/

DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTabletsresultinamildantimineralocorticoideffect.

Pelvicpain

Papanicolaousmearsuspicious

Generaldisordersand

administrationsiteconditions Edema

Asthenia

Pain

Excessivethirst

Sweatingincreased

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Whetherthisalsoappliestolower-dosedCOCsremainstobeconfirmed.

5.2Pharmacokineticproperties

Drospirenone

Absorption

Orallyadministereddrospirenoneisrapidlyandalmostcompletelyabsorbed.Maximumconcentrationsoftheactive

substanceinserumofabout38ng/mlarereachedatabout1-2haftersingleingestion.Bioavailabilityisbetween76

and85%.

Concomitantingestionoffoodhasnoinfluenceonthebioavailabilityofdrospirenone.

Distribution

Afteroraladministration,serumdrospirenonelevelsdecreasewithaterminalhalf-lifeof31h.

Drospirenoneisboundtoserumalbuminanddoesnotbindtosexhormonebindingglobulin(SHBG)orcorticoid

bindingglobulin(CBG).Only3-5%ofthetotalserumconcentrationsoftheactivesubstancearepresentasfree

steroid.Theethinylestradiol-inducedincreaseinSHBGdoesnotinfluencetheserumproteinbindingofdrospirenone.

Themeanapparentvolumeofdistributionofdrospirenoneis3.7±1.2l/kg.

Metabolism

Drospirenoneisextensivelymetabolizedafteroraladministration.Themajormetabolitesintheplasmaaretheacid

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

whichareformedwithoutinvolvementoftheP450system.Drospirenoneismetabolizedtoaminorextentby

cytochromeP4503A4andhasdemonstratedacapacitytoinhibitthisenzymeandcytochromeP4501A1,cytochrome

P4502C9andcytochromeP4502C19invitro.

Elimination

Themetabolicclearancerateofdrospirenoneinserumis1.5±0.2ml/min/kg.Drospirenoneisexcretedonlyintrace

amountsinunchangedform.Themetabolitesofdrospirenoneareexcretedwiththefecesandurineatanexcretionratio

ofabout1.2to1.4.Thehalf-lifeofmetaboliteexcretionwiththeurineandfecesisabout40h.

Steady-StateConditions

Duringatreatmentcycle,maximumsteady-stateconcentrationsofdrospirenoneinserumofabout70ng/mlare

reachedafterabout8daysoftreatment.Serumdrospirenonelevelsaccumulatedbyafactorofabout3asa

consequenceoftheratioofterminalhalf-lifeanddosinginterval.

SpecialpatientPopulations

Effectofrenalimpairment

Steady-stateserumdrospirenonelevelsinwomenwithmildrenalimpairment(creatinineclearanceCLcr,50-80

mL/min)werecomparabletothoseofwomenwithnormalrenalfunction.Theserumdrospirenonelevelswereon

average37%higherinwomenwithmoderaterenalimpairment(CLcr,30-50mL/min)comparedtothoseinwomen

withnormalrenalfunction.Drospirenonetreatmentwasalsowelltoleratedbywomenwithmildandmoderaterenal

impairment.Drospirenonetreatmentdidnotshowanyclinicallysignificanteffectonserumpotassiumconcentration.

Effectofhepaticimpairment

Inasingledosestudy,oralclearance(CL/F)wasdecreasedapproximately50%involunteerswithmoderatehepatic

impairmentascomparedtothosewithnormalliverfunction.Theobserveddeclineindrospirenoneclearancein

volunteerswithmoderatehepaticimpairmentdidnottranslateintoanyapparentdifferenceintermsofserumpotassium

concentrations.

Eveninthepresenceofdiabetesandconcomitanttreatmentwithspironolactone(twofactorsthatcanpredisposea

patienttohyperkalemia)anincreaseinserumpotassiumconcentrationsabovetheupperlimitofthenormalrangewas

notobserved.Itcanbeconcludedthatdrospirenoneiswelltoleratedinpatientswithmildormoderatehepatic

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Ethnicgroups

NoclinicallyrelevantdifferencesinthepharmacokineticsofdrospirenoneorethinylestradiolbetweenJapaneseand

Caucasianwomenhavebeenobserved.

Ethinylestradiol

Absorption

Orallyadministeredethinylestradiolisabsorbedrapidlyandcompletely.

Afteradministrationof30µg,peakplasmaconcentrationsof100pg/mLarereached1-2hoursafteringestion.

Ethinylestradiolundergoesanextensivefirst-passeffect,whichdisplaysgreatinter-individualvariation.Theabsolute

bioavailabilityisapprox.45%.

Aftersingledoseadministration,peakplasmaconcentrationsof33pg/mLarereached1-2hoursafteringestion.

Ethinylestradiolundergoesanextensivefirst-passeffect,whichdisplaysgreatinter-individualvariation.Theabsolute

bioavailabilityisapprox.60%.Concomitantintakeoffoodreducedthebioavailabilityofethinylestradiolinabout25%

oftheinvestigatedsubjectswhilenochangewasobservedintheothers.

Distribution

Ethinylestradiolhasanapparentvolumeofdistributionof5L/kgandbindingtoplasmaproteinsisapprox.98%.

EthinylestradiolinducesthehepaticsynthesisofSHBG.Duringtreatmentwith30µgethinylestradioltheplasma

concentrationofSHBGincreasesfrom70toabout350nmol/L.

Ethinylestradiolpassesinsmallamountsintobreastmilk(0.02%ofthedose).

Serumethinylestradiollevelsdecreaseintwophases,theterminaldispositionphaseischaracterizedbyahalf-lifeof

approximately24hours.Ethinylestradiolishighlybutnon-specificallyboundtoserumalbumin(approximately98.5

%),andinducesanincreaseintheserumconcentrationsofSHBGandcorticoidbindingglobulin(CBG).Anapparent

volumeofdistributionofabout5l/kgwasdetermined

Metabolism

Ethinylestradiolismetabolizedcompletely(metabolicplasmaclearance5ml/min/kg).

Elimination

Ethinylestradiolisnotexcretedinunchangedformtoanysignificantextent.Themetabolitesofethinylestradiolare

excretedataurinarytobiliaryratioof4:6.Thehalf-lifeofmetaboliteexcretionisabout1day.

Steady-stateconditions

Steady-stateconditionsarereachedduringthesecondhalfofatreatmentcycleandserumlevelsofethinylestradiol

accumulatebyafactorofabout2.0to2.3

5.3Preclinicalsafetydata

Inlaboratoryanimals,theeffectsofdrospirenoneandethinylestradiolwereconfinedtothoseassociatedwiththe

recognisedpharmacologicalaction.Inparticular,reproductiontoxicitystudiesrevealedembryotoxicandfetotoxic

effectsinanimalswhichareconsideredasspeciesspecific.Atexposurestodrospirenoneexceedingthoseinusersof

Ethinylestradiol/DrospirenoneLeonFarma&Placebo0.02mg/3mgFilm-coatedTablets,effectsonsexual

differentiationwereobservedinratfetusesbutnotinmonkeys.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Activetablets(pinktablets):

Tabletcore:

Lactosemonohydrate

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Povidone

Sodiumcroscarmellose

Polysorbate80

Magnesiumstearate

Coating:

Polyvinylalcoholpartialhydrolyzed

Titaniumdioxide(E171)

Macrogol3350

Talc

Yellowironoxide(E172)

Redironoxide(E172)

Blackironoxide(E172)

Placebotablets(whitetablets):

Tabletcore:

Lactoseanhydrous

Povidone

Magnesiumstearate

Coating:

Polyvinylalcoholpartialhydrolyzed

Titaniumdioxide(E171)

Macrogol3350

Talc

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Blistersofaluminiumpush-throughfoilandPVC/PVDCfilm.

Packsizes:

1x28film-coatedtablets(21activetabletsplus7placebotablets)

2x28film-coatedtablets(21activetabletsplus7placebotablets)

3x28film-coatedtablets(21activetabletsplus7placebotablets)

6x28film-coatedtablets(21activetabletsplus7placebotablets)

13x28film-coatedtablets(21activetabletsplus7placebotablets)

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

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7MARKETINGAUTHORISATIONHOLDER

LaboratoriosLeonFarmaS.A.

C/RoadelaVega15

1-24008Leon

Spain

8MARKETINGAUTHORISATIONNUMBER

PA1474/7/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:9thOctober2009

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