ETHINYLESTRADIOL / DROSPIRENONE LEON FARMA & PLACE

Main information

  • Trade name:
  • ETHINYLESTRADIOL / DROSPIRENONE LEON FARMA & PLACE
  • Dosage:
  • 0.03 / 3 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0711/210/002
  • Authorization date:
  • 30-03-2012
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Ethinylestradiol/DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Yellowtablets(activetablets):

Eachfilm-coatedtabletcontains0.03mgofethinylestradioland3mgofdrospirenone

Excipients:

Lactosemonohydrate62mg

Whitetablets(placebotablets)

Thetabletdoesnotcontainactivesubstances

Excipient:

Lactose,anhydrous89.5mg

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Activetablets:Yellow,roundfilm-coatedtablets.

Placebotablets:White,roundfilm-coatedtablets.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Oralcontraception

4.2Posologyandmethodofadministration

Routeofadministration:oraluse.

HowtotakeEthinylestradiol/DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-coatedTablets

Thetabletsmustbetakeneverydayataboutthesametime,ifnecessarywithalittleliquidintheordershownonblister

pack.

Tablettakingiscontinuous.Onetabletistobetakendailyfor28consecutivedays.Eachsubsequentpackisstartedthe

dayafterthelasttabletthepreviouspack.Withdrawalbleedingusuallystartsonday2-3afterstartingtheplacebo

tablets(lastrow)andmaynothavefinishedbeforethenextpackisstarted.

HowtostartEthinylestradiol/DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-coatedTablets

Noprecedinghormonalcontraceptiveuse(inthepastmonth)

Tablet-takinghastostartonday1ofthewoman’snaturalcycle(i.e.thefirstdayofhermenstrualbleeding).

Changingfromanothercombinedoralcontraceptive(COC)

ThewomanshouldstartEthinylestradiol/DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-coatedTabletson

thedayfollowingtheusualhormonefreeinterval(tablet-freeorplacebotabletinterval)ofherpreviouscombinedoral

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IncaseavaginalringortransdermalpatchhasbeenusedthewomanshouldstartusingEthinylestradiol/Drospirenone

LeonFarma&Placebo3mg/0.03mgFilm-coatedTabletspreferablyonthedayofremoval,butathelatestwhenthe

nextapplicationwouldhavebeendue.

-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

daysfollowingthelastforgottentablet.

Week3

Theriskofreducedreliabilityisimminentbecauseoftheforthcoming7-dayplacebophase.However,byadjustingthe

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Byadheringtoeitherofthefollowingtwooptions,thereisthereforenoneedtouseextracontraceptiveprecaution,

providedthatinthe7daysprecedingthefirstmissedtabletthewomanhastakenalltabletscorrectly.Ifthisisnotthe

case,sheshouldfollowthefirstofthesetwooptionsanduseextraprecautionsforthenext7daysaswell.

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

placebotabletphase,thepossibilityofapregnancyshouldbeconsidered.

Adviceincaseofgastro-intestinaldisturbances

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

additionalcontraceptivemeasuresshouldbetaken.Ifvomitingoccurswithin3-4hoursafteractivetablettaking,anew

tabletshouldbetakenassoonaspossible.Thenewtabletshouldbetakenwithin12hoursoftheusualtimeoftablet-

takingifpossible.

Ifmore12hourselapse,theadviceconcerningmissedtablets,asgiveinsection4.2“Managementofmissedtablets”is

applicable.Ifthewomandoesnotwanttochangehernormaltablet-takingschedule,shehastotaketheextratable(s)

fromanotherblisterpack.

Howtopostponeawithdrawalbleed

TodelayaperiodthewomanshouldcontinuewithanotherblisterpackofEthinylestradiol/DrospirenoneLeonFarma

&Placebo0.03mg/3mgFilm-coatedTabletswithouttakingtheplacebotabletsfromhercurrentpack.Theextension

canbecarriedonforaslongaswisheduntiltheendoftheactivetabletsinthesecondpack.Duringtheextensionthe

womanmayexperiencebreakthrough-bleedingorspotting.RegularintakeofEthinylestradiol/DrospirenoneLeon

Farma&Placebo0.03mg/3mgFilm-coatedTabletsisthenresumedaftertheplacebotabletphase.

Toshiftherperiodstoanotherdayoftheweekthanthewomanisusedtowithhercurrentscheme,shecanbeadvised

toshortenherforthcomingplacebotabletphasebyasmanydaysasshelikes.Theshortertheinterval,thehigherthe

riskthatshedoesnothaveawithdrawalbleedandwillexperiencebreakthrough-bleedingandspottingduring

subsequentpack(justaswhendelayingperiod).

4.3Contraindications

Combinedoralcontraceptives(COC)shouldnotbeusedinthepresenceofanytheconditionslistedbelow.Shouldany

oftheconditionsappearforthefirsttimeduringCOCuse,theproductshouldbestoppedimmediately.

Venousthrombosispresentorinhistory(deepvenousthrombosis,pulmonaryembolism)

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

andtransientischaemicattack).

Cerebro-vascularaccidentpresentorinhistory

Thepresenceofasevereormultipleriskfactor(s)forarterialthrombosis

Diabetesmellituswithavascularsymptoms

Severehypertension

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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&Placebo0.03mg/3mgFilm-coatedTablets.

4.4Specialwarningsandprecautionsforuse

Warnings

Ifanyoftheconditions/riskfactorsmentionedbelowarepresent,thebenefitsofCOCuseshouldbeweighedagainst

thepossiblerisksforeachindividualwomananddiscussedwiththewomanbeforeshedecidestostartusingit.Inthe

eventofaggravation,exacerbationorfirstappearanceofanyoftheseconditionsorriskfactors,thewomanshould

contactherphysician.ThephysicianshouldthendecideonwhetherCOCuseshouldbediscontinued.

CirculatoryDisorders

EpidemiologicalstudieshaveshownthattheincidenceofVTEinusersoforalcontraceptiveswithlowoestrogen

content(<50µgethinylestradiol)(includingEthinylestradiol/DrospirenoneLeonFarma&Placebo0.03mg/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&Placebo0.03mg/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.

Yellowtabletsofthismedicinalproductcontain62mglactosepertablet,thewhitetabletscontains65mg.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

Medicalexamination/consultation

PriortotheinitiationorreinstitutionofEthinylestradiol/DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-

coatedTabletsacompletemedicalhistory(includingfamilyhistory)shouldbetakenandpregnancymustberuledout.

Bloodpressureshouldbemeasuredandaphysicalexaminationshouldbeperformed,guidedbythecontra-indications

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

andtoadheretotheadvicegiven.Thefrequencyandnatureofexaminationsshouldbebasedonestablishedpractice

guidelinesandbeadaptedtotheindividualwoman.

WomenshouldbeadvisedthatoralcontraceptivesdonotprotectagainstHIVinfections(AIDS)andothersexually

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Reducedefficacy

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

disturbancesvomitingorseverediarrhea(seesection4.2)orconcomitantmedication(seesection4.5).

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.

Theyellowtabletsofthismedicinalproductcontain62mgoflactosepertablet,thewhitetabletscontain89.5mg.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionwhoareonalactose-freedietshouldtakethisamountintoconsideration.Shouldnottakethismedicine

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Note:Theprescribinginformationofconcomitantmedicationsshouldbeconsultedtoidentifypotentialinteractions.

InfluenceofothermedicinalproductsonEthinylestradiol/DrospirenoneLeonFarma&Placebo0.03mg/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

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ThemainmetabolitesofdrospirenoneinhumanplasmaaregeneratedwithoutinvolvementofthecytochromeP450

system.Inhibitorsofthisenzymesystemarethereforeunlikelytoinfluencethemetabolismofdrospirenone.

InfluenceofEthinylestradiol/DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-coatedTabletson

othermedicinalproducts

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&Placebo0.03mg/3mgFilm-coatedTablets

withaldosteroneantagonistsorpotassium-sparingdiureticshasnotbeenstudied.Inthiscase,serumpotassiumshould

betestedduringthefirsttreatmentcycle.Seealsosection4.4.

Laboratorytests

Theuseofcontraceptivesteroidsmayinfluencetheresultsofcertainlaboratorytests,includingbiochemicalparameters

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

lipid/lipoproteinfractions,parametersofcarbohydratemetabolismandparametersofcoagulationandfibrinolysis.

Changesgenerallyremainwithinthenormallaboratoryrange.Drospirenonecausesanincreaseinplasmareninactivity

andplasmaaldosteroneinducedbyitsmildantimineralocorticoidactivity.

4.6Fertility,pregnancyandlactation

Ethinylestradiol/DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-coatedTabletsisnotindicatedduring

pregnancy.

IfpregnancyoccursduringuseofEthinylestradiol/DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-coated

Tablets,thepreparationshouldbewithdrawnimmediately.Extensiveepidemiologicalstudieshaverevealedneitheran

increasedriskofbirthdefectsinchildrenborntowomenwhousedCOCspriortopregnancy,norateratogeniceffect

whenCOCsweretakeninadvertentlyduringpregnancy.NosuchstudiesareconductedwithEthinylestradiol/

DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-coatedTablets

Animalstudieshaveshownundesirableeffectsduringpregnancyandlactation(seesection5.3).Basedontheseanimal

data,undesirableeffectsduetohormonalactionoftheactivecompoundscannotbeexcluded.However,general

experiencewithCOCsduringpregnancydidnotprovideevidenceforanactualundesirableeffectinhumans.

TheavailabledataregardingtheuseofEthinylestradiol/DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-

coatedTabletsduringpregnancyaretoolimitedtopermitconclusionsconcerningnegativeeffectsofEthinylestradiol/

DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-coatedTabletsonpregnancy,healthofthefoetusorneonate.

Todate,norelevantepidemiologicaldataareavailable.

LactationmaybeinfluencedbyCOCsastheymayreducethequantityandchangethecompositionofbreastmilk.

Therefore,theuseofCOCsshouldgenerallynotberecommendeduntilthebreast-feedingmotherhascompletely

weanedherchild.Smallamountsofthecontraceptivesteroidsand/ortheirmetabolitesmaybeexcretedwiththemilk

duringCOCuse.Theseamountsmayaffectthechild.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Noeffectsonabilitytodrive

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4.8Undesirableeffects

ThefollowingadversedrugreactionshavebeenreportedduringuseofEthinylestradiol/DrospirenoneLeonFarma&

Placebo0.03mg/3mgFilm-coatedTablets:

ThetablebelowreportsadversereactionsbyMedDRAsystemorganclasses(MedDRASOCs).

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.

ThefrequencyofdiagnosisofbreastcancerisveryslightlyincreasedamongOCusers.Asbreastcancerisrarein

womenunder40yearsofagetheexcessnumberissmallinrelationtotheoverallriskofbreastcancer.Causationwith

SystemOrganClass Frequencyofadversereactions

Common Uncommon Rare

(1/100to<1/10) (1/1,000to<1/100) (1/10,000to<1/1,000)

Immunesystem

disorders Asthma

Endocrinedisorders Menstrualdisorders

Intermenstrualbleeding

Breastpain Breastsecretion

Nervoussystem

disorders Headache

Depressivemood Changesinlibido

Earandlabyrinth

disorders Hypacusis

Vasculardisease Migraine Hipertension

Hypotension Thromboembolism

Gastrointestinal

disorders Nausea Vomiting

Skinandsubcutaneous

tissuedisorders Acne

Eczema

Pruritus

Reproductivesystemand

breastdisorders Leucorrhoea

Vaginalmoniliasis Vaginitis

Generaldisorderand

administrationsite

conditions Fluidretention

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4.9Overdose

TherehasnotyetbeenanyexperienceofoverdosewithEthinylestradiol/DrospirenoneLeonFarma&Placebo0.03

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&Placebo0.03mg/3mgFilm-coatedTablets

isbasedontheinteractionofvariousfactors,themostimportantofwhichareseenastheinhibitionofovulationandthe

changesintheendometrium.

Ethinylestradiol/DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-coatedTabletsisacombinedoral

contraceptivewithethinylestradiolandtheprogestogendrospirenone.Inatherapeuticdosage,drospirenonealso

possessesantiandrogenicandmildantimineralocorticoidproperties.Ithasnoestrogenic,glucocorticoidand

antiglucocorticoidactivity.Thisgivesdrospirenoneapharmacologicalprofilecloselyresemblingthenaturalhormone

progesterone.

ThereareindicationsfromclinicalstudiesthatthemildantimineralocorticoidpropertiesofEthinylestradiol/

DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-coatedTabletsresultinamildantimineralocorticoideffect.

Withtheuseofthehigher-dosedCOCs(50µgethinylestradiol)theriskofendometrialandovariancancerisreduced.

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.

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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(twofactorsthatcan

predisposeapatienttohyperkalemia)anincreaseinserumpotassiumconcentrationsabovetheupperlimitofthe

normalrangewasnotobserved.Itcanbeconcludedthatdrospirenoneiswelltoleratedinpatientswithmildor

moderatehepaticimpairment(Child-PughB).

Ethnicgroups

NoclinicallyrelevantdifferencesinthepharmacokineticsofdrospirenoneorethinylestradiolbetweenJapaneseand

Caucasianwomenhavebeenobserved.

Ethinylestradiol

Absorption

Orallyadministeredethinylestradiolisabsorbedrapidlyandcompletely.

Afteradministrationof30µg,peakplasmaconcentrationsof100pg/mLarereached1-2hoursafteringestion.

Ethinylestradiolundergoesanextensivefirst-passeffect,whichdisplaysgreatinter-individualvariation.Theabsolute

bioavailabilityisapprox.45%.

Distribution

Ethinylestradiolhasanapparentvolumeofdistributionof5L/kgandbindingtoplasmaproteinsisapprox.98%.

EthinylestradiolinducesthehepaticsynthesisofSHBG.Duringtreatmentwith30µgethinylestradioltheplasma

concentrationofSHBGincreasesfrom70toabout350nmol/L.

Ethinylestradiolpassesinsmallamountsintobreastmilk(0.02%ofthedose).

Metabolism

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Elimination

Ethinylestradiolisnotexcretedinunchangedformtoanysignificantextent.Themetabolitesofethinylestradiolare

excretedataurinarytobiliaryratioof4:6.Thehalf-lifeofmetaboliteexcretionisabout1day.

Steady-stateconditions

Steady-stateconditionsarereachedduringthesecondhalfofatreatmentcycleandserumlevelsofethinylestradiol

accumulatebyafactorofabout1.4to2.1.

5.3Preclinicalsafetydata

Inlaboratoryanimals,theeffectsofdrospirenoneandethinylestradiolwereconfinedtothoseassociatedwiththe

recognisedpharmacologicalaction.Inparticular,reproductiontoxicitystudiesrevealedembryotoxicandfetotoxic

effectsinanimalswhichareconsideredasspeciesspecific.Atexposurestodrospirenoneexceedingthoseinusersof

Ethinylestradiol/DrospirenoneLeonFarma&Placebo0.03mg/3mgFilm-coatedTablets,effectsonsexual

differentiationwereobservedinratfetusesbutnotinmonkeys.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Activetablets(yellowtablets):

Tabletcore:

Lactosemonohydrate

Maizestarch

Pregelatinizedstarch(maize)

Crospovidone

Povidone

Polysorbate80

Magnesiumstearate

Coating:

Polyvinylalcoholpartialhydrolyzed

Titaniumdioxide(E171)

Macrogol3350

Talc

Yellowironoxide(E172)

Placebotablets(whitetablets):

Tabletcore:

Lactoseanhydrous

Povidone

Magnesiumstearate

Coating:

Polyvinylalcoholpartialhydrolyzed

Titaniumdioxide(E171)

Macrogol3350

Talc

6.2Incompatibilities

Notapplicable.

6.3Shelflife

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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

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

RowexLimited

Bantry

Co.Cork

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA711/210/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:9thOctober2009

10DATEOFREVISIONOFTHETEXT

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