CILEST

Main information

  • Trade name:
  • CILEST Tablets 250/35 Microgram
  • Dosage:
  • 250/35 Microgram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CILEST Tablets 250/35 Microgram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1151/108/001
  • Authorization date:
  • 24-07-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cilest250/35microgramTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains250microgramsnorgestimateand35microgramsethinylestradiol.

Excipients:containsanhydrouslactose.

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Tablet

ProductimportedfromtheUK:

Alightblue,flat,bevel-edgedtabletengraved“C”over“250”onbothfaces.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonalcontraception.

4.2Posologyandmethodofadministration

Fororaladministration.

Adults:

Whenusedperfectly,withoutmissinganypills,thechanceofbecomingpregnantislessthan1%(i.e.<1pregnancyper

100womenintheirfirstyearofuse).Typicalfailureratesareactually5%inthefirstyear.Thechanceofbecoming

pregnantincreaseswitheachmissedpillduringamenstrualcycle.

BeforestartingCilest,athoroughgeneralmedicalandgynaecologicalexamination(includingthebreastsanda

cytologicalsmearofthecervix)ifappropriateshouldbecarriedoutandthefamilymedicalhistorycarefullynoted.

Disturbancesoftheclottingmechanismsshouldberuledoutifanymembersofthefamilyhavesufferedfromthrombo-

embolicdiseases(egdeepveinthrombosis,stroke,myocardialinfarction)atayoungage.

Pregnancymustbeexcludedideallybyapregnancytest.

Thewomanshouldbeinstructedtocarefullyreadtheuserleafletandtoadheretotheadvicegiven.

Asaprecaution,thoroughmedicalexaminationsshouldbeconductedatapproximatelysixmonthintervalsduringuse

ofthetablets.

Children:

SafetyandefficacyofCilestTabletshaveonlybeenestablishedinwomenofreproductiveage.

Elderly:

Notindicatedinpostmenopausalwomen.

-Firstcycle

Tablet-takingfromthefirstpackofCilestisstartedonthe1stdayofthemenstrualcycle,iethefirstdayofmenstrual

bleeding.Ifmenstruationhasalreadybegun,Cilestmaybecommenceduptoday5ofthemenstrualperiod,provided

additionalcontraceptiveprecautionsaretakenforthefirst7daysoftablettaking.

Onetabletistobetakenataroundthesametimeofdayoneachof21consecutivedaysfollowedbyatablet-free

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Subsequentstyles

Tablet-takingfromthenextpackofCilestiscontinuedafterthe7-dayinterval,beginningonthesamedayoftheweek

asthefirstpack.

-Changingfromanotheroralcontraceptive

-Changingfroma21daypilltoCilest:

Alltabletsintheoldpackshouldbefinished.ThefirstCilesttabletistakenthenextdayi.e.nogapisleftbetween

takingtabletsnordoesthepatientneedtowaitforherperiodtobegin.Additionalcontraceptiveprecautionsarenot

required.ThepatientwillnothaveaperioduntiltheendofthefirstCilestpack,butthisisnotharmful,nordoesit

matterifsheexperiencessomebleedingontablet-takingdays.

-Changingfromacombinedeverydaypill(28daytablets)toCilest:

Cilestshouldbestartedaftertakingthelastactivetabletfromthe'EverydayPill'pack(ieaftertaking21tablets).The

firstCilesttabletistakenthenextday,ienogapisleftbetweentakingtabletsnordoesthepatientneedtowaitforher

periodtobegin.Additionalcontraceptiveprecautionsarenotrequired.Remainingtabletsfromtheeveryday(ED)

packshouldbediscarded.

ThepatientwillnothaveaperioduntiltheendofthefirstCilestpack,butthisisnotharmful,nordoesitmatterifshe

experiencessomebleedingontablet-takingdays.

-Changingfromaprogestogen-onlypill(POPorminipill)toCilest:

ThefirstCilesttabletshouldbetakenonthefirstdayoftheperiod,evenifthepatienthasalreadytakenaminipillon

thatday.Additionalcontraceptiveprecautionsarenotrequired.Alltheremainingprogestogen-onlypillsinthemini

pillpackshouldbediscarded.

Ifthepatientistakingaminipill,thenshemaynotalwayshaveaperiod,especiallywhensheisbreast-feeding.The

firstCilesttabletshouldbetakenonthedayafterstoppingtheminipill.Allremainingpillsintheminipillpacket

mustbediscarded.Additionalcontraceptiveprecautionsmustbetakenforthefirst7days.

Physiciansareadvisedtorefertoprescribinginformationforrecommendationsregardingswitchingfromanotherform

ofhormonalcontraception(e.g.transdermalcontraceptivesystem,injectablesetc.).

-Irregulartablettaking

Ifthepatientislessthan12hourslateintakinganytablet,contraceptiveprotectionisnotreduced.Thewomanshould

takethetabletassoonassheremembersandshouldtakefurthertabletsattheusualtime.

Ifsheismorethan12hourslateintakinganytablet,contraceptiveprotectionmaybereduced.Themanagementof

missedtabletscanbeguidedbythefollowingtwobasicrules:

1.tablet-takingmustneverbediscontinuedforlongerthan7days.

2.7daysofuninterruptedtablet-takingarerequiredtoattainadequatesuppressionofthehypothalamic-pituitary-

ovarian-axis.

Accordinglythefollowingadvicecanbegivenindailypractice:

Week1

Thepatientshouldtakethelastmissedtabletassoonassheremembers,evenifthismeanstakingtwotabletsatthe

sametime.Shethencontinuestotaketabletsatherusualtime.Inaddition,abarriermethodsuchasacondomshould

beusedforthenext7days.Ifintercoursetookplaceinthepreceding7days,thepossibilityofapregnancyshouldbe

considered.Themoretabletsaremissedandtheclosertheyaretotheregulartablet-freeinterval,thehighertheriskof

apregnancy.

Week2

Thepatientshouldtakethelastmissedtabletassoonassheremembers,evenifthismeanstakingtwotabletsatthe

sametime.Shethencontinuestotaketabletsatherusualtime.Providedthatthewomanhastakenhertabletscorrectly

inthe7daysprecedingthefirstmissedtablet,thereisnoneedtouseextracontraceptiveprecautions.However,ifthis

isnotthecase,orifshemissedmorethan1tablet,thewomanshouldbeadvisedtouseextraprecautionsfor7days.

Week3

Theriskofreducedreliabilityisimminentbecauseoftheforthcomingtablet-freeinterval.However,byadjustingthe

tablet-intakeschedule,reducedcontraceptiveprotectioncanstillbeprevented.Byadheringtoeitherofthefollowing

twooptions,thereisthereforenoneedtouseextracontraceptiveprecautions,providedthatinthe7daysprecedingthe

firstmissedtabletthewomanhastakenalltabletscorrectly.Ifthisisnotthecase,thewomanshouldbeadvisedto

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Thepatientshouldtakethelastmissedtabletassoonassheremembers,evenifthismeanstakingtwotabletsat

thesametime.Shethencontinuestotaketabletsatherusualtime.Thenextpackmustbestartedassoonasthecurrent

packisfinished,i.e.nogapshouldbeleftbetweenpacks.Thepatientisunlikelytohaveawithdrawalbleeduntilthe

endofthesecondpack,butshemayexperiencespottingorbreakthroughbleedingontablet-takingdays.

Thewomanmayalsobeadvisedtodiscontinuetablet-takingfromthecurrentpack.Sheshouldthenhavea

tablet-freeintervalofupto7days,includingthedaysshemissedtablets,andsubsequentlycontinuewiththenextpack.

Ifthewomanmissedtabletsandsubsequentlyhasnowithdrawalbleedinthefirstnormaltablet-freeinterval,the

possibilityofapregnancyshouldbeconsidered.

-Postpartum

Womenwhochoosenottobreast-feedtheirnewborninfantmaystartanewCilesttreatmentonthefirstdayofthefirst

spontaneousmenstruationor3weeksafterdelivery,whichevercomesfirst.

-Postmiscarriage

Followingamiscarriageat,orbefore,20weeksgestation,oralcontraceptioncanbestartedimmediately(day2butno

laterthan5)forimmediatecover.Ovulationmayoccurwithin10daysofmiscarriage.

NB:Whenoralcontraceptivesareadministeredintheimmediatepostpartum/postmiscarriageperiod,theincreasedrisk

ofthrombo-embolicdiseasemustbeconsidered.

-Delayingofmenstruation

Whenallthetabletsofthestriphavebeentaken,anewstripcanbestartedandtabletstakenforthenumberofdays

needed.Subsequently,notabletsaretakenfor7days,followedbystartinganewstripof21tabletswithanewstart

day.

Absenceofwithdrawalbleeding

If,inexceptionalcases,withdrawalbleedingfailstooccur,pregnancymustberuledoutbeforetheuseofCilestis

continued.

-Procedureintheeventofirregularbleeding

Breakthroughbleedingandspottingaresometimesencountered,primarilyduringthefirstthreemonthsofuse,and

usuallyceasespontaneously.Thewoman,therefore,shouldcontinuetouseCilestevenifirregularbleedingoccurs.

Shouldbreak-throughbleedingpersistorrecur,appropriatediagnosticmeasurestoexcludeanorganiccauseare

indicated,andmayincludecurettage.

Thisalsoappliesinthecaseofspottingwhichoccursatirregularintervalsinseveralconsecutivecyclesorwhich

occursforthefirsttimeafterlonguseofCilest.

-Gastro-intestinalupset

Vomitingordiarrhoeamayreducetheefficacyoforalcontraceptivesbypreventingfullabsorption.Tablet-takingfrom

thecurrentpackshouldbecontinued.Additionalnon-hormonalmethodsofcontraception(excepttherhythmor

temperaturemethods)shouldbeusedduringthegastro-intestinalupsetandfor7daysfollowingtheupset.Ifthese7

daysoverruntheendofapack,thenextpackshouldbestartedwithoutabreak.Inthissituation,awithdrawalbleed

shouldnotbeexpecteduntiltheendofthesecondpack.Ifthepatientdoesnothaveawithdrawalbleedduringthe

tablet-freeintervalfollowingtheendofthesecondpack,thepossibilityofpregnancymustberuledoutbefore

resumingwiththenextpack.Othermethodsofcontraceptionshouldbeconsideredifthegastro-intestinaldisorderis

likelytobeprolonged(iegreaterthan12hours).

4.3Contraindications

Confirmedorsuspectedpregnancy

Patientsbreastfeedinginfants.

Acuteorchronicliverdiseasewithabnormalliverfunction,jaundiceorpersistentpruritusduringaprevious

pregnancy,Dubin-Johnsonsyndrome,Rotorsyndrome,porphyria.

Activeviralhepatitis

Severecirrhosisoftheliver

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egdisordersoftheclottingprocesses,coronaryarterydisease,cerebrovasculardisease,valvularheartdiseaseandatrial

fibrillation.Multipleriskfactorsforarterialcardiovasculardisease(suchasolderage,smoking,diabetesand

hypertension).

Sickle-cellanaemia.

Currentorpreviousknownorsuspectedoestrogen-dependentneoplasia,egpreviousorexistinglivertumours,

cancerofthebreastorendometrium.

Endometrialhyperplasia.

Severediabetesmellituswithvascularchanges(includingretinopathy,nephropathyorneuropathy),or>20

years’duration.

Disordersoflipidmetabolism.(seesection4.4,Specialwarningsandprecautionsforuse).

Pemphigoidgestationis.

Manifestationordeteriorationofotosclerosisduringpregnancy.

Undiagnosedvaginalbleeding.

HypersensitivitytoanyofthecomponentsofCilest.

Cholelithiasis.

Cholestaticjaundiceofpregnancyorjaundicewithpriorpilluse.

Systemiclupuserythematosusorahistoryofthiscondition.

Migrainewithfocalaura,orwithoutfocalaurainpatientsaged35yearsandover.

Persistentbloodpressurevalues ≥160mmHgsystolicor≥100mmHgdiastolic.

Smokingmorethan15cigarettesperdayinpatientsaged35yearsormore.

Knownthrombogenicmutations(e.g.FactorVLeiden;Prothrombinmutation;ProteinS,ProteinC,and

Antithrombindeficiencies).

4.4Specialwarningsandprecautionsforuse

ReasonsforimmediatediscontinuationofmedicationwithCilest.

Suspectedorconfirmedsymptomsorsignsofthrombophlebitisorthrombo-embolicevents(egunusualpainsin

orswellingofthelegs).

Feelingofpainandtightnessinthechest(stabbingpainsonbreathingorcoughingfornoapparentreason).

Occurrenceforthefirsttime,orexacerbationofmigrainousheadachesordevelopmentofheadachewithanew

patternwhichisrecurrent,persistentorsevere.Evaluationofthecauseisrequired.

Suddendisturbancesofvisionorhearing.

Sixweeksbeforeelectivesurgeryandduringprolongedimmobilisationegafteraccidents,surgery.

Onsetofjaundice,hepatitis,itchingofthewholebody.

Recurrenceofcholestaticjaundicewhichoccurredfirstduringpregnancyorprevioususeofsexsteroids.

Onsetorworseningofepilepsy.

Significantriseinbloodpressure.

Onsetofseveredepression.

Severeupperabdominalpainorliverenlargement.

Pregnancy.

Patientswiththefollowingconditionsshouldonlyusetheoralcontraceptivepillafterdetaileddiscussionwith

theirGeneralPractitioner.Patientswiththeseconditionsrequirestrictmedicalsupervisionduringmedication:

Diabetesmellitus.

Varicoseveins.

Otosclerosis.

Multiplesclerosis.

Epilepsy.

Tetany.

Sydenham’schorea.

Renaldysfunction.

Familyhistoryofbreastcancerorpasthistoryofbreastnodules.

Fibrocysticdiseaseofthebreast.

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Historyofclinicaldepression.

Systemiclupuserythematosus.

Uterinemyoma.

Migraine.

Endometriosis.

Conditionsimplicatedinanincreasedriskofdevelopingvenousthrombo-emboliccomplications,egsevere

varicoseveinsorprolongedimmobilisationormajorsurgery.Disordersofcoagulation.Presenceofanyrisk

factorforarterialdisease,suchassmoking,hyperlipidemia,hypertension(persistentbloodpressurevalues ≥140

mmHgsystolicor ≥90mmHgdiastolic)orobesity.Withregardstosmoking,theriskofcardiovascular

complicationsincreaseswithageandthenumberofcigarettessmoked.

Otherconditionsassociatedwithanincreasedriskofcirculatorydiseasesuchaslatentorovertcardiacfailure,

renaldysfunctionorahistoryoftheseconditions.

Ahistoryofcholelithiasis.

Concurrentadministrationofrifampicinoranyotherproductknowntoaffectliverenzymes(Seesection4.5)

Deteriorationinanyoftheaboveconditionsmayindicatethatuseoftheoralcontraceptiveshouldbe

discontinued.

OralcontraceptivesDONOTprotectagainstHIVinfections(AIDS)oranyothersexuallytransmitteddisease.

Incaseofundiagnosed,persistentorrecurrentabnormalvaginalbleeding,appropriatemeasuresshouldbeconductedto

ruleoutmalignancy.

Circulatorydisorders

Thephysicianshouldbealerttotheearliestmanifestationsofvenousandarterialthrombo-embolicdisease,ie

myocardialinfarction,pulmonaryembolism,thrombophlebitis,strokeorretinalthrombosis.

Symptomsofvenousorarterialthrombosiscaninclude:unilaterallegpainand/orswelling;suddenseverepaininthe

chest,whetherornotitradiatestotheleftarm;suddenbreathlessness;suddenonsetofcoughing;anyunusual,severe,

prolongedheadache;suddenpartialorcompletelossofvision;diplopia;slurredspeechoraphasia;vertigo;collapse

withorwithoutfocalseizure;weaknessorverymarkednumbnesssuddenlyaffectingonesideoronepartofthebody;

motordisturbances;'acute'abdomen.

Shouldanyoftheseoccurorbesuspected,Cilestshouldbediscontinuedimmediately.Thepresenceofoneseriousrisk

factorormultipleriskfactorsforvenousorarterialdisease,respectively,mayalsocontributetoacontraindication.

Biochemicalfactorsthatmaybeindicativeofhereditaryoracquiredpredispositionforvenousorarterialthrombosis

includeActivatedProteinC(APC)resistance,hyperhomocysteinemia,antithrombin-IIIdeficiency,proteinC

deficiency,proteinSdeficiency,antiphospholipidantibodies(anticardiolipinantibodies,lupusanticoagulant).

Thephysicianshouldbearinmindthepossibilityofvascularaccidentsoccurringandthattheremaynotbefull

recoveryfromsuchdisordersandtheymaybefatal.

VenousThrombo-Embolism(VTE)

Theuseofcombinedoralcontraceptivescarriesanincreasedriskofvenousthrombo-embolism(VTE)comparedwith

nouse.TheexcessriskofVTEishighestduringthefirstyearawomaneverusesacombinedoralcontraceptive.The

approximateoccurrenceofVTEinusersoforalcontraceptiveswithlowoestrogencontent(<50µgethinylestradiol)is

about20casesper100,000women-yearscomparedto5to10casesper100,000women-yearsfornon-users.This

increasedriskislessthantheriskofVTEassociatedwithpregnancy,whichisestimatedas60casesper100,000

pregnancies.VTEisfatalin1to2%ofthesecases.

ItisnotknownhowCilestinfluencestheriskofVTEcomparedwithotheroralcontraceptives.

Theriskofvenousthromboembolismincreaseswith:

increasingage;

apositivefamilyhistory(i.e.venousthromboembolismeverinasiblingorparentatarelativelyearlyage).Ifa

hereditarypredispositionissuspected,thewomanshouldbereferredtoaspecialistforadvicebeforedecidingabout

anyhormonalcontraceptiveuse;

obesity(bodymassindexover30kg/m 2

prolongedimmobilisation,majorsurgery,anysurgerytothelegs,ormajortrauma.Inthesesituationsitisadvisable

todiscontinueCOCuse(inthecaseofelectivesurgeryatleastfourweeksinadvance)andnottoresumeuntiltwo

weeksaftercompleteremobilisation.

andpossiblyalsowithsuperficialthrombophlebitisandvaricoseveins.However,thereisnoconsensusaboutthe

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Arterialthrombo-embolism

Therelativeriskofarterialthromboses(egstroke,myocardialinfarction)isincreasedbythepresenceofother

predisposingfactorssuchas:

a)cigarettesmoking(withheaviersmokingandincreasingage,theriskisfurtherincreased,especiallyinwomenover

35yearsofage)

b)dyslipoproteinaemia

c)hypertension

d)valvularheartdisease

e)atrialfibrillation

f)obesity

g)diabetes

h)historyofpre-eclamptictoxaemia

i)increasingage

j)positivefamilyhistory(i.e.arterialthrombosiseverinasiblingorparentatarelativelyearlyage).Ifahereditary

predispositionissuspected,thewomanshouldbereferredtoaspecialistforadvicebeforedecidingaboutanyhormonal

contraceptiveuse.

Aftertheageof35years,thephysicianandpatientsshouldcarefullyreassesstherisk/benefitratioofusingcombined

oralcontraceptivesasopposedtoalternativemethodsofcontraception.

Tumours

Studiesinanimalshaveindicatedthatadministrationofveryhighdosesofoestrogensand/orprogestogenswillinduce

neoplastictumoursinsomeanimalspecies.

Numerousepidemiologicalstudieshavebeenreportedontheriskofovarian,endometrial,cervicalandbreastcancerin

womenusingcombinedoralcontraceptives.Theevidenceisclearthatcombinedoralcontraceptivesoffersubstantial

protectionagainstbothovarianandendometrialcancer.

Breastcancer

Whilethereareconflictingreports,moststudiessuggestthatuseoforalcontraceptivesisnotassociatedwithanoverall

increaseintheriskofdevelopingbreastcancer.Somestudieshavereportedanincreasedrelativeriskofdeveloping

breastcancer,particularlyatayoungerage.Thisincreasedrelativeriskhasbeenreportedtoberelatedtodurationof

use.

Ameta-analysisof54epidemiologicalstudiesreportsthatwomenwhoarecurrentlyusingcombinedoral

contraceptivesorhaveusedtheminthepast10yearsareataslightlyincreasedriskofhavingbreastcancerdiagnosed,

althoughtheadditionalcancerstendtobelocalizedtothebreast.Theexcessriskgraduallydisappearsduringthe

courseofthe10yearsaftercessationofCOCuse.Becausebreastcancerisrareinwomenunder40yearsofage,the

excessnumberofbreastcancerdiagnosesincurrentandrecentCOCusersissmallinrelationtotheoverallriskof

breastcancer.

Itisnotpossibletoinferfromthedatawhetherthepatternsofriskobservedareduetoanearlierdiagnosisofbreast

cancerinever-users,thebiologicaleffectsofhormonalcontraceptives,oracombinationofbothfactors.Thismeta-

analysisalsosuggeststhattheageatwhichwomendiscontinuetheuseofcombinedoralcontraceptivesisanimportant

riskfactorforbreastcancer;theoldertheageatstopping,themorebreastcancersarediagnosed.Durationofusewas

consideredlessimportant.

Theresultsofrecentstudiesinhumanbeingssuggestthatthereisasmallbutstatisticallyincreasedincidenceofbreast

cancerinwomenwhohavebeentreatedwithoestrogens.Thepossibleincreaseinriskofbreastcancershouldbe

discussedwithwomenandweighedagainstthebenefitsofcombinedoralcontraceptives.

Allwomen,inparticularthoseover35years,shouldhaveregularbreastexaminationswhileonthepill.

Cervicalcancer

Anincreasedriskofcervicalcancerinlongtermusersofcombinedoralcontraceptiveshasbeenreportedinsome

studies,buttherecontinuestobecontroversyabouttheextenttowhichthisisattributabletotheconfoundingeffectsof

sexualbehaviourandotherfactors.

Hepaticadenomas

Inrarecasesbenignand,inevenrarercases,malignantlivertumoursleadinginisolatedcasestolife-threateningintra-

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severeupperabdominalcomplaints,liverenlargementorsignsofintra-abdominalhaemorrhageoccur,thepossibilityof

alivertumourshouldbeincludedinthedifferentialdiagnosis.

Chloasma

Chloasmamayoccasionallyoccur,especiallyinwomenwithahistoryofchloasmagravidarum.Womenwitha

tendencytochloasmashouldavoidexposuretothesunorultravioletradiationwhiletakingthispreparation.Chloasma

isoftennotfullyreversible.

Reducedefficacy

TheefficacyofCOCsmaybereducedintheeventofmissedtablets(section4.2),vomiting(section4.2)or

concomitantmedication(section4.5).

HerbalpreparationscontainingStJohn'sWort(Hypericumperforatum)shouldnotbeusedwhiletakingCilestdueto

theriskofdecreasedplasmaconcentrationsandreducedclinicaleffectsofCilest(seeSection4.5Interactions).

Otherwarnings

Anincreaseinbloodpressurehasbeenreportedinwomentakingoralcontraceptives.Clinicallyrelevantincreasesare

rare.ArelationshipbetweenCOCuseandclinicalhypertensionhasnotbeenestablished.Oralcontraceptivetherapy

shouldbediscontinuedifsignificantpersistentelevationofbloodpressure( ≥160mmHgsystolicor≥100mmHg

diastolic)occursandcannotbeadequatelycontrolled.Ingeneral,womenwhodevelophypertensionduringhormonal

contraceptivetherapyshouldbeswitchedtoanon-hormonalcontraceptive.Ifothercontraceptivemethodsarenot

suitable,hormonalcontraceptivetherapymaycontinue,combinedwithantihypertensivetherapy.Regularmonitoring

ofBPthroughouthormonalcontraceptivetherapyisrecommended.Elevatedbloodpressureusuallyreturnstonormal

afterdiscontinuationoforalcontraceptives.

Atleastthreemonthsshouldelapseafterliverfunctiontestshavereturnedtonormalfollowinganyhepatitisbefore

administrationoftheoralcontraceptivepill.

Somewomenmayexperienceamenorrhoeaoroligomenorrhoeaafterdiscontinuationoforalcontraceptives,

especiallywhentheseconditionsexistedpriortouse.Womenshouldbeinformedofthispossibility.

Oralcontraceptivesmaycauseadecreaseinglucosetolerance.Thiseffecthasbeenshowntobedirectlyrelatedto

oestrogendose.Additionally,progestogensmayincreaseinsulinsecretionandcreateinsulinresistance,thiseffect

varieswithdifferentprogestationalagents.However,inthenon-diabeticwoman,oralcontraceptivesappeartohaveno

effectonfastingbloodglucose.Becauseofthesedemonstratedeffects,pre-diabeticanddiabeticwomeninparticular

shouldbecarefullymonitoredwhiletakingoralcontraceptives.

Asmallproportionofwomenwillhavepersistenthypertriglyceridemiawhileonthepill.Changesinserum

triglycerides,cholesterolandlipoproteinlevelshavebeenreportedinusersoforalcontraceptives.Womenwith

hypertriglyceridaemia,orafamilyhistorythereof,maybeatanincreasedriskofpancreatitiswhenusingCOCs.

Crohn'sdiseaseandulcerativecolitishavebeenassociatedwithCOCuse.

ThefollowingconditionshavebeenreportedtooccurordeterioratewithbothpregnancyandCOCuse,butthe

evidenceofanassociationwithCOCuseisinconclusive:jaundiceand/orpruritusrelatedtocholestasis;gallstone

formation;porphyria;systemiclupuserythematosus;haemolyticuraemicsyndrome;Sydenham'schorea;herpes

gestationis;otosclerosis-relatedhear-loss.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Drugsorherbalproductsthatinduceenzymes,includingCYP3A4,thatmetabolisecontraceptivehormones,may

decreasetheplasmaconcentrationsofcontraceptivehormones,andmaydecreasetheeffectivenessofhormonal

contraceptivesorincreasebreakthroughbleeding.Somedrugsorherbalproductsthatmaydecreasetheeffectivenessof

hormonalcontraceptivesinclude:

barbiturates

bosentan

carbamazepine

felbamate

griseofulvin

modafinil

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phenytoin

rifampicin

St.John'sWort

topiramate

HIVproteaseinhibitorsandnon-nucleosidereversetranscriptaseinhibitors:

Significantchanges(increaseordecrease)intheplasmalevelsoftheestrogenandprogestinhavebeennotedinsome

casesofco-administrationofHIVproteaseinhibitorsandnon-nucleosidereversetranscriptaseinhibitors.

Antibiotics:

Therehavebeenreportsofpregnancywhiletakinghormonalcontraceptivesandantibiotics,butclinical

pharmacokineticstudieshavenotshownconsistenteffectsofantibioticsonplasmaconcentrationsofsyntheticsteroids.

Womenreceivingshortcoursesofenzymeinducersorbroadspectrumantibioticsshouldtakeadditional,non-hormonal

(exceptrhythmortemperaturemethod)contraceptiveprecautionsduringthetimeofconcurrentmedicationandfor7

daysafterwards.Ifthese7daysoverruntheendofthepack,thenextpackshouldbestartedwithoutabreak.Inthis

situation,awithdrawalbleedshouldnotbeexpecteduntiltheendofthesecondpack.Ifthepatientdoesnothavea

withdrawalbleedduringthetablet-freeintervalfollowingtheendofthesecondpack,thepossibilityofpregnancymust

beruledoutbeforeresumingwiththenextpack.Withrifampicin,additionalcontraceptiveprecautionsshouldbe

continuedfor4weeksaftertreatmentstops,evenifonlyashortcoursewasadministered.

IncreaseinPlasmaHormoneLevelsAssociatedWithCo-AdministeredDrugs:

Somedrugsandgrapefruitjuicemayincreasetheplasmalevelsofethinylestradiolifco-administered.Examples

include:

paracetamol

ascorbicacid

CYP3A4inhibitors(includingitraconazole,ketoconazole,voriconazoleandfluconazole)

grapefruitjuice

HMG-CoAreductaseinhibitors(includingatorvastatinandrosuvastatin)

ChangesinPlasmaLevelsofCo-AdministeredDrugs:

Combinationhormonalcontraceptivesmayalsoaffectthepharmacokineticsofsomeotherdrugsifusedconcomitantly.

Examplesofdrugswhoseplasmalevelsmaybeincreased(duetoCYPinhibition)include:

ciclosporin

omeprazole

prednisolone

theophylline

voriconazole

Drugswhoseplasmalevelsmaybedecreased(duetoinductionofglucuronidation):

Examplesinclude:

paracetamol

clofibricacid

lamotrigine(seebelow)

morphine

salicylicacid

temazepam

Combinedhormonalcontraceptiveshavebeenshowntosignificantlydecreaseplasmaconcentrationsoflamotrigine

whenco-administeredduetoinductionoflamotrigineglucuronidation.Thismayreduceseizurecontrol;therefore,

dosageadjustmentsoflamotriginemaybenecessary.

Physiciansareadvisedtoconsultthelabellingofconcurrently-useddrugstoobtainfurtherinformationabout

interactionswithhormonalcontraceptivesorthepotentialforenzymealterations.

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Theuseoforalcontraceptivesmayinfluencetheresultsofcertainlaboratorytestsincludingbiochemicalparametersof

liver,thyroid,adrenal,andrenalfunction,plasmalevelsofcarrierproteinsandlipid/lipoproteinfractions,parametersof

carbohydratemetabolismandparametersofcoagulationandfibrinolysis.Laboratorystaffshouldthereforebeinformed

aboutoralcontraceptiveusewhenlaboratorytestsarerequested.

Serumfolatelevelsmaybedepressedbyoralcontraceptivetherapy.Thismaybeofclinicalsignificanceifawoman

becomespregnantshortlyafterdiscontinuingoralcontraceptives.

4.6Pregnancyandlactation

Pregnancy

Cilestiscontraindicatedduringpregnancy.

IfpregnancyoccursduringmedicationwithCilest,thepreparationshouldbewithdrawnimmediately.

Epidemiologicalstudiesindicatenoincreasedriskofcongenitalanomaliesinchildrenborntowomenwhousedoral

contraceptivespriortopregnancy.Themajorityofrecentepidemiologicalstudiesalsodonotindicateateratogenic

effect,whentakeninadvertentlyduringearlypregnancy.

Lactation

TheuseofCilestduringlactationmayleadtoareductioninthevolumeofmilkproducedandtoachangeinits

composition.Minuteamountsoftheactivesubstancesareexcretedwiththemilk.

Cilestiscontraindicatedduringbreast-feeding.Adecisionmustbemadewhethertodiscontinuebreast-feedingorto

discontinue/abstainfromCilest.

4.7Effectsonabilitytodriveandusemachines

Noeffectsonabilitytodriveandusemachineshavebeenobserved.

4.8Undesirableeffects

Thefollowingadversereactionshavebeenassociatedwiththeuseofnorgestimate/ethinylestradiol(seesection4.4.

SpecialWarningsandPrecautionsforUse):

Cilest

TheevaluationoftheclinicalsafetyofCilestwasbasedonthreePhase3studiesconducted:acontrolled2-cellsafety

andefficacycomparisonstudy(A-3437),acontrolled2-cellcomparisonstudyofcoagulationeffects(D83-001)andan

openefficacyandsafetystudy(C82-083).All3studiesweretwoyear(24cycles)studiesandcumulativelyevaluateda

totalof1647womenand22,237cycles.Informationonundesirableadversereactionsfromthesecombinedstudiesis

presentedbelow.

Headachewasthemostfrequentlyreportedandonlyverycommonlyreportedadversereaction(30%).

Otheradversereactionsreportedintheclinicaltrialswithafrequencybelow10%arelistedinthetable.

ADVERSEREACTIONSREPORTEDINCLINICALTRIALSOFCILEST

OrganSystem Commonadverse

events(>1/100,

<1/10) Uncommon

adverseevents

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

events(>1/10000,

<1/1000)

Cardiovascular Edema Slightriseofblood

pressure,

hypertension Myocardial

infarction,deep

venousthrombosis,

pulmonary

embolismand

otherembolisms

Neoplasms Cervicalcancer,

breastcancer

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Listedbelowareadversereactionsthathavebeenassociatedwiththeuseofhormonalcontraceptives:

CardiovascularSystem:cerebrovascularaccidents,arterialthromboembolism,myocardialinfarction,hypertension

Neoplasms:benignlivertumors,malignanthepatictumors

Hepatobiliary:intrahepaticcholestasis,cholelithiasis,cholestaticjaundice,Budd-Chiarisyndrome

GenitalTract:absenceofwithdrawalbleeding,changeinmenstrualflow,increaseinsizeofuterinefibromyoma,

increaseincervicalerosionandsecretion,temporaryinfertilityafterdiscontinuationoftreatment,pre-menstrual

syndrome

Breast:diminutioninlactationwhengivenimmediatelypost-partum

Skinandsubcutaneoustissue:seborrhea,hypertrichosis,pemphigoid(herpesgestationis),melasmawhichmaypersist,

hemorrhagiceruption,uriticaria,angiodema.

Eyes:changeincornealcurvature(steepening),intolerancetocontactlenses,cataracts,neuro-ocularlesions

CNS:chorea,severeheadache

Metabolic:reducedglucose-tolerance

Urinary:impairedrenalfunction,hemolyticuremicsyndrome

4.9Overdose

Overdosagemaycausenausea,vomitingandwithdrawalbleedinginfemales.Seriousilleffectshavenotbeenreported

followinglargedosesoforalcontraceptivesinchildren.Therearenoantidotesandtreatmentshouldbesymptomatic.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCCode:G03AA11

Althoughthepharmacologicalactionsofestrogensandprogestogenswhicharepresentinallcombinedoral

contraceptivesarelargelyunderstood,theexactmechanismoftheiractionsotherthansuppressionofovulationremains

controversial.

Cilestactsthroughthemechanismofgonadotropinsuppressionbytheestrogenicandprogestationalactionsofethinyl

estradiolandnorelgestromin.Theprimarymechanismofactionisinhibitionofovulation,butalterationstothecervical

mucus,thefallopiantubemotilityandtotheendometriummayalsocontributetotheefficacyoftheproduct.

Receptorandsexhormonebindingglobulin(SHBG)bindingstudies,aswellasstudiesinanimalsandhumans,have

shownthatbothnorgestimate(NGM)andnorelgestromin,themajorserummetaboliteofnorgestimatefollowingoral

administration,exhibitshighprogestationalactivitywithminimalintrinsicandrogenicity,whichillustratestheselective

actionofCilest.Norgestimate,incombinationwithethinylestradiol,doesnotcounteracttheestrogen-induced

increasesinSHBG,resultinginlowerlevelsoffreetestosteroneinserumcomparedtobaseline.

bleeding,spotting,

amenorrhea,

vaginalcandidiasis

Breast Tenderness Galactorrhea,pain,

enlargement

Gastro-intestinal

tract Abdominalcramps,

bloating Nausea,vomiting

colitis

Skin Acne,rash Alopecia,

hirsuitism,

chloasma Erythema

(nodosum,

multiforme)

Migraine,mood

changes,depression Irritability,changes

inlibido

Metabolic Fluidretention,

changesinbody

weight(increaseor

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Absorption:Norgestimateandethinylestradiolarerapidlyabsorbedfollowingoraladministration.Followingsingle

ormultiple(threecycles)administrationofCilest,serumconcentrationsofnorgestimateremainbelowthequantitation

limitoftheassay(0.1ng/mL)duetorapidmetabolism(seeMetabolismbelow).Itsmetabolites,norelgestrominand

norgestrel,arefoundinmeasurableconcentrationsincirculation,reachingmaximalserumlevelsapproximately1.5

hourspost-dose.Exposuretonorelgestrominisproportionaltodosefollowingnorgestimatedosesof0.180to0.250

mg.Ethinylestradiolserumconcentrationsaremeasurablewithin0.5hoursofdosing,reachingpeaklevels

approximately1.2hourspost-dose.

Distribution:Norelgestrominandnorgestrelarehighlybound(>97%)toserumproteins.norelgestrominisboundto

albuminbutnottoSHBG,whilenorgestrelisboundprimarilytoSHBGandtoamuchlesserextenttoalbumin.Ethinyl

estradiolisextensivelyboundtoserumalbumin.

StudieshaveshownthatthelackofbindingofnorelgestromintoSHBGisuniquewhencomparedtoother

progestogensinoralcontraceptivesandplaysakeyroleinenhancingitsbiologicalactivity.Incontrast,norgestrel

formedfromnorgestimateislargelyboundtoSHBG,whichlimitsitsbiologicactivity.Thesefindingstogetherwith

theselectivityofnorelgestrominfortheprogesteronereceptorindicatethatthismetabolitemayexplaintheunique

clinicalprofileofnorgestimate.

Metabolism:Norgestimateisrapidlymetabolizedbyfirst-pass(intestinaland/orhepatic)mechanismsto

norelgestromin(peakserumconcentrationsobservedwithin2hours)andnorgestrel,bothofwhichare

pharmacologicallyactiveprogestogens.Ethinylestradiolismetabolizedtovarioushydroxylatedmetabolitesandtheir

glucuronideandsulfateconjugates.

Elimination:Bothnorelgestrominandnorgestrel,andethinylestradiolaresubsequentlymetabolizedandtheir

metabolitesareeliminatedbyrenalandfecalpathways.Eliminationhalf-lifevaluesatsteady-statewere10to15hours

forethinylestradiol,24.9hoursfornorelgestrominand45hoursfornorgestrel.Followingadministrationof 14

norgestimate,47%oftheadministeredradioactivitywaseliminatedintheurineand37%inthefaeces.

Steady-StatePharmacokinetics:Followingadministrationof0.250mg/0.035mgethinylestradiol,thedaily

exposure(meanAUC

0-24h )atsteady

state,basedonnon-SHBGboundserumlevels,was18.1hng/mLfornorelgestrominand3.64hng/mLfornorgestrel.

Followingoraladministrationof0.150mglevonorgestrel/0.030mgethinylestradiol,meandailyexposureatsteady-

state,basedonnon-SHBGboundserumlevels,was18.9hng/mLfornorgestrel.Theexposuretonorgestrelfollowing

administrationof0.250mg/0.035mgethinylestradiol,correspondstotheexposureafteralevonorgestreldoseof

approximately30microgramsincombinationwithethinylestradiol.

5.3Preclinicalsafetydata

Acomprehensivesetoftoxicitystudieshavebeenconductedoneachofthecomponentsindividuallyandin

combination.Thesestudiesincludesingledosestudiesinmultiplespecies,repeateddosestudiesuptotwoyearsinthe

rat,sevenyearsinthedogandtenyearsinthemonkey,reproductiveanddevelopmentaltoxicity,andgenetictoxicity.

ResultsshowthattheacuteoralLD

ofnorgestimate(NGM)plusethinylestradiol(EE)inratsisgreaterthan5g/kg,

indicatingaveryloworderof

acutetoxicityandawidemarginofsafety.Repeateddosestudiesingenerallaboratoryanimals(rats,dogs,monkeys),

atNGM+EEratiosofupto10:1insubchronic(3-monthstudies,atdosesof~1000timestheclinicaldose)andratios

ofupto5:1inchronic(2-yearstudies,atdosesof~100timestheclinicaldose)studies,showedsomewhatsimilar

results,suchasreductionofestruscyclesormenstruation,decreaseduterineandovarianweights,increasedliverand

pituitaryweights,decreasedserumcholesterollevelsanderythrocyticparameters,withmostoftheprimarytreatment

relatedeffectsjudgedtobeduetoanexaggeratedpharmacologyactionofNGM+EE,orgeneralageingphenomenon.

Inlong-termstudies,increasedincidenceofmammaryneoplasm'sandlenticularopacitiesinrats(2-yearstudyatdoses

upto600timestheclinicaldose)wasconsideredahighdoseeffectandprobablynotrelevantatoptimally

pharmacologicaldoselevels.Inthe7-yeardogstudy,atdosesupto25timestheclinicaldose,leiomyomas(fibroids)

wereobservedataslightlygreaterincidenceinthehigh-dosegroup.Thesetumoursarethemostfrequentoccurring

spontaneousneoplasm'softhereproductivetractinfemaledogsandareapparentlyduetoestrogenoverloadingandare

unlikelytooccuratoptimallypharmacologicaldoses.Anon-doserelatedlenticularopacitieswerealsoobservedinthe

7-yeardogstudy.Althoughlenticularopacitiesisanormalobservationindogs,itgenerallyhasalongerlatency

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occurrencesandgenerallyindifferentorgans,withsimilarspontaneousoccurrencesbeingreportedinthescientific

literature.

Inreproductionstudies,noted,doserelatedeffectsonfertility,maternalandfetalparameters,andlactationareexpected

responsestothepharmacologicalactionsofthisclassofanti-fertilitycompoundsandwereobservedatdoselevels

withinthepharmacodynamicrange.

Embryolethalityandskeletalvariationsinratswasobservedwithnoincreaseinextragenitalanomalies.NGM+EEis

notconsideredateratogen.NGM+EE,NGMandit'sprimarymetabolitenorelgestromin(NGMN),haveshownno

indicationofanymutagenicpotential.

Inconclusion,thecombinationofnorgestimate(NGM)andethinylestradiol(EE)inlaboratoryanimalshasshown

somepreclinicaleffects,whichwereobservedatexposuresconsideredsufficientlyinexcessofthemaximumhuman

exposure,orweretheresultofnormalageingprocessorfromanexaggerationofpharmacologicaleffectsathigherthan

therapeuticdosesindicatinglittlerelevancetoclinicaluse.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Anhydrouslactose

Magnesiumstearate

Pregelatinisedstarch

FD&CBlueNo2(E132)

6.2Incompatibilities

Notapplicable

6.3ShelfLife

Theshelflifeexpirydateofthisproductisthedateshownontheblisterstripsandoutercartonoftheproductas

marketedinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Storeblisterinoutercartontoprotectfromlight.

6.5Natureandcontentsofcontainer

Cardboardoutercontainingblisterstrips.

Packsize:21tablets

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ImbatLtd

UnitL2

NorthRingBusinessPark

Santry

Dublin9

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PPANo:1151/108/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:24thJuly2009

10DATEOFREVISIONOFTHETEXT

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