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:
  • PPA1328/102/001
  • Authorization date:
  • 05-06-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cilest250/35microgramTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains250microgramsnorgestimateand35microgramsethinylestradiol

Excipient:containslactose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

ProductimportedfromtheUK

Adarkblue,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.

Disturbancesofmenstruation,suchasoligomenorrheaandamenorrheashouldbeinvestigatedpriortoprescription.

Disturbancesoftheclottingmechanismsshouldberuledoutifanymembersofthefamilyhavesufferedfromthrombo-

embolicdiseases(egdeepveinthrombosis,stroke,myocardialinfarction)atayoungage.

Pregnancymustbeexcludedideallybyapregnancytest.

Thewomanshouldbeinstructedtocarefullyreadtheuserleafletandtoadheretotheadvicegiven.

Asaprecaution,thoroughmedicalexaminationsshouldbeconductedatapproximatelysixmonthintervalsduringuse

ofthetablets.

Children:

SafetyandefficacyofCilestTabletshaveonlybeenestablishedinwomenofreproductiveage.

Elderly:

Notindicatedinpostmenopausalwomen.

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Tablet-takingfromthefirstpackofCilestisstartedonthe1stdayofthemenstrualcycle,iethefirstdayofmenstrual

bleeding.Ifmenstruationhasalreadybegun,Cilestmaybecommenceduptoday5ofthemenstrualperiod,provided

additionalcontraceptiveprecautionsaretakenforthefirst7daysoftablettaking.

Onetabletistobetakenataroundthesametimeofdayoneachof21consecutivedaysfollowedbyatablet-free

intervalof7days,duringwhichawithdrawalbleedingoccurs.

-Subsequentcycles

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)pack

shouldbediscarded.

ThepatientwillnothaveaperioduntiltheendofthefirstCilestpack,butthisisnotharmful,nordoesitmatterifshe

experiencessomebleedingontablet-takingdays.

-Changingfromaprogestogen-onlypill(POPorminipill)toCilest:

ThefirstCilesttabletshouldbetakenonthefirstdayoftheperiod,evenifthepatienthasalreadytakenaminipillon

thatday.Additionalcontraceptiveprecautionsarenotrequired.Alltheremainingprogestogen-onlypillsintheminipill

packshouldbediscarded.

Ifthepatientistakingaminipill,thenshemaynotalwayshaveaperiod,especiallywhensheisbreast-feeding.The

firstCilesttabletshouldbetakenonthedayafterstoppingtheminipill.Allremainingpillsintheminipillpacketmust

bediscarded.Additionalcontraceptiveprecautionsmustbetakenforthefirst7days.

Physiciansareadvisedtorefertoprescribinginformationforrecommendationsregardingswitchingfromanotherform

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

-Irregulartablet-taking

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

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Week2

Thepatientshouldtakethelastmissedtabletassoonassheremembers,evenifthismeanstakingtwotabletsatthe

sametime.Shethencontinuestotaketabletsatherusualtime.Providedthatthewomanhastakenhertabletscorrectly

inthe7daysprecedingthefirstmissedtablet,thereisnoneedtouseextracontraceptiveprecautions.

However,ifthisisnotthecase,orifshemissedmorethan1tablet,thewomanshouldbeadvisedtouseextra

precautionsfor7days.

Week3

Theriskofreducedreliabilityisimminentbecauseoftheforthcomingtablet-freeinterval.However,byadjustingthe

tablet-intakeschedule,reducedcontraceptiveprotectioncanstillbeprevented.Byadheringtoeitherofthefollowing

twooptions,thereisthereforenoneedtouseextracontraceptiveprecautions,providedthatinthe7daysprecedingthe

firstmissedtabletthewomanhastakenalltabletscorrectly.Ifthisisnotthecase,thewomanshouldbeadvisedto

followthefirstofthesetwooptionsandtouseextraprecautionsforthenext7daysaswell.

1.Thepatientshouldtakethelastmissedtabletassoonassheremembers,evenifthismeanstakingtwotabletsatthe

sametime.Shethencontinuestotaketabletsatherusualtime.Thenextpackmustbestartedassoonasthecurrent

packisfinished,i.e.nogapshouldbeleftbetweenpacks.Thepatientisunlikelytohaveawithdrawalbleeduntilthe

endofthesecondpack,butshemayexperiencespottingorbreakthroughbleedingontablet-takingdays.

2.Thewomanmayalsobeadvisedtodiscontinuetablet-takingfromthecurrentpack.Sheshouldthenhaveatablet-

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

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within3hoursoftakingthetablet,orifseverediarrhoealastsformorethan24hours,theeffectivenessofthe

contraceptionmaynotbeadequate,andanadditionalnon-hormonalmethodofcontraceptionshouldbeuseduntil7

tabletshavebeentakenfor7dayswithoutinterruption.Ifthese7daysoverruntheendofapack,thenextpackshould

bestartedwithoutabreak.Inthissituation,awithdrawalbleedshouldnotbeexpecteduntiltheendofthesecondpack.

Ifthepatientdoesnothaveawithdrawalbleedduringthetablet-freeintervalfollowingtheendofthesecondpack,the

possibilityofpregnancymustberuledoutbeforeresumingwiththenextpack.Othermethodsofcontraceptionshould

beconsideredifthegastro-intestinaldisorderislikelytobeprolonged(iegreaterthan12hours).

4.3Contraindications

1.Confirmedorsuspectedpregnancy

2.Patientsbreastfeedinginfants.

3.Acuteorchronicliverdiseasewithabnormalliverfunction,jaundiceorpersistentpruritusduringaprevious

pregnancy,Dubin-Johnsonsyndrome,Rotorsyndrome,porphyria.

4.Activeviralhepatitis

5.Severecirrhosisoftheliver

6.Existingorpreviousarterialorvenousthromboticorembolicprocessesorconditionswhichpredisposetothem,eg

disordersoftheclottingprocesses,coronaryarterydisease,cerebrovasculardisease,valvularheartdiseaseandatrial

fibrillation.Severeormultipleriskfactorsforvenousorarterialcardiovasculardisease(suchasolderage,smoking,

diabetesandhypertension).

7.Sickle-cellanaemia.

8.Currentorpreviousknownorsuspectedoestrogen-dependentneoplasia,egpreviousorexistinglivertumours,cancer

ofthebreastorendometrium.

9.Endometrialhyperplasia

10.Severediabetesmellituswithvascularchanges(includingretinopathy,nephropathyorneuropathy),or>20years'

duration.

11.Disordersoflipidmetabolism.(See4.4PrecautionsandWarnings).

12.Pemphigoidgestationis.

13.Manifestationordeteriorationofotosclerosisduringpregnancy.

14.Undiagnosedvaginalbleeding.

15.HypersensitivitytoanyofthecomponentsofCilest.

16.Cholelithiasis.

17.Cholestaticjaundiceofpregnancyorjaundicewithpriorpilluse

18.Systemiclupuserythematosusorahistoryofthiscondition.

19.Migrainewithfocalaura,orwithoutfocalaurainpatientsaged35yearsandover.

20.Persistentbloodpressurevaluesof160mmHgsystolicor100mmHgdiastolic.

21.Smokingmorethan15cigarettesperdayinpatientsaged35yearsormore.

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

Antithrombindeficiencies).

4.4Specialwarningsandprecautionsforuse

ReasonsforimmediatediscontinuationofmedicationwithCilest.

1.Suspectedorconfirmedsymptomsorsignsofthrombophlebitisorthrombo-embolicevents(egunusualpainsinor

swellingofthelegs).

2.Feelingofpainandtightnessinthechest(stabbingpainsonbreathingorcoughingfornoapparentreason).

3.Occurrenceforthefirsttime,orexacerbationofmigrainousheadachesordevelopmentofheadachewithanew

patternwhichisrecurrent,persistentorsevere.Evaluationofthecauseisrequired.

4.Suddendisturbancesofvisionorhearing.

5.Sixweeksbeforeelectivesurgeryandduringprolongedimmobilisationegafteraccidents,surgery.

6.Onsetofjaundice,hepatitis,itchingofthewholebody.

7.Recurrenceofcholestaticjaundicewhichoccurredfirstduringpregnancyorprevioususeofsexsteroids.

8.Onsetorworseningofepilepsy.

9.Significantriseinbloodpressure.

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11.Severeupperabdominalpainorliverenlargement.

12.Pregnancy.

Patientswiththefollowingconditionsshouldonlyusetheoralcontraceptivepillafterdetaileddiscussionwith

theirGeneralPractitioner.Patientswiththeseconditionsrequirestrictmedicalsupervisionduringmedication:

1.Diabetesmellitus.

2.Varicoseveins.

3.Otosclerosis.

4.Multiplesclerosis.

5.Epilepsy.

6.Tetany.

7.Sydenham'schorea.

8.Renaldysfunction.

9.Familyhistoryofbreastcancerorpasthistoryofbreastnodules.

10.Fibrocysticdiseaseofthebreast.

11.Asthma.

12.Historyofclinicaldepression.

13.Systemiclupuserythematosus.

14.Uterinemyoma.

15.Migraine.

16.Endometriosis.

17.Conditionsimplicatedinanincreasedriskofdevelopingvenousthromboemboliccomplications,egseverevaricose

veinsorprolongedimmobilisationormajorsurgery.Disordersofcoagulation.Presenceofanyriskfactorforarterial

disease,suchassmoking,hyperlipidemia,hypertension(persistentbloodpressurevalues140mmHgsystolicor90

mmHgdiastolic)andobesity.Withregardstosmoking,theriskofcardiovascularcomplicationsincreaseswithage

andthenumberofcigarettessmoked.

18.Otherconditionsassociatedwithanincreasedriskofcirculatorydiseasesuchaslatentorovertcardiacfailure,renal

dysfunctionorahistoryoftheseconditions.

19.Ahistoryofcholelithiasis.

20.Concurrentadministrationofrifampicinoranyotherproductknowntoaffectliverenzymes(seesection4.5).

Deteriorationinanyoftheaboveconditionsmayindicatethatuseoftheoralcontraceptiveshouldbediscontinued.

OralcontraceptivesDONOTprotectagainstHIVinfections(AIDS)oranyothersexuallytransmitteddisease.

Incaseofundiagnosed,persistentorrecurrentabnormalvaginalbleeding,appropriatemeasuresshouldbeconductedto

ruleoutmalignancy.

Circulatorydisorders

Thephysicianshouldbealerttotheearliestmanifestationsofvenousandarterialthrombo-embolicdisease,i.e.

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

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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,thewomanshouldbereferredtoaspecialistforadvicebeforedeciding

aboutanyhormonalcontraceptiveuse;

obesity(bodymassindexover30kg/m2)

prolongedimmobilisation,majorsurgery,anysurgerytothelegs,ormajortrauma.Inthesesituationsitis

advisabletodiscontinueCOCuse(inthecaseofelectivesurgeryatleastfourweeksinadvance)andnotto

resumeuntiltwoweeksaftercompleteremobilisation.

andpossiblyalsowithsuperficialthrombophlebitisandvaricoseveins.However,thereisnoconsensusaboutthe

possibleroleoftheseconditionsintheetiologyofvenousthromboembolism.

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.

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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-

abdominalhaemorrhagehavebeenobservedaftertheuseofhormonalsubstancessuchasthosecontainedinCilest.If

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.Clinicallyrelevant

increasesarerare.ArelationshipbetweenCOCuseandclinicalhypertensionhasnotbeenestablished.Oral

contraceptivetherapyshouldbediscontinuedifsignificantpersistentelevationofbloodpressure(160mmHg

systolicor100mmHgdiastolic)occursandcannotbeadequatelycontrolled.Ingeneral,womenwhodevelop

hypertensionduringhormonalcontraceptivetherapyshouldbeswitchedtoanon-hormonalcontraceptive.If

othercontraceptivemethodsarenotsuitable,hormonalcontraceptivetherapymaycontinue,combinedwith

antihypertensivetherapy.RegularmonitoringofBPthroughouthormonalcontraceptivetherapyis

recommended.Elevatedbloodpressureusuallyreturnstonormalafterdiscontinuationoforalcontraceptives.

Atleastthreemonthsshouldelapseafterliverfunctiontestshavereturnedtonormalfollowinganyhepatitis

beforeadministrationoftheoralcontraceptivepill.

Somewomenmayexperienceamenorrhoeaoroligomenorrhoeaafterdiscontinuationoforalcontraceptives,

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Oralcontraceptivesmaycauseadecreaseinglucosetolerance.Thiseffecthasbeenshowntobedirectlyrelated

tooestrogendose.Additionally,progestogensmayincreaseinsulinsecretionandcreateinsulinresistance,this

effectvarieswithdifferentprogestationalagents.However,inthenon-diabeticwoman,oralcontraceptives

appeartohavenoeffectonfastingbloodglucose.Becauseofthesedemonstratedeffects,pre-diabeticand

diabeticwomeninparticularshouldbecarefullymonitoredwhiletakingoralcontraceptives.

Asmallproportionofwomenwillhavepersistenthypertriglyceridemiawhileonthepill.Changesinserum

triglycerides,cholesterolandlipoproteinlevelshavebeenreportedinusersoforalcontraceptives.Womenwith

hypertriglyceridaemia,orafamilyhistorythereof,maybeatanincreasedriskofpancreatitiswhenusingCOCs.

Crohn'sdiseaseandulcerativecolitishavebeenassociatedwithCOCuse.

ThefollowingconditionshavebeenreportedtooccurordeterioratewithbothpregnancyandCOCuse,butthe

evidenceofanassociationwithCOCuseisinconclusive:jaundiceand/orpruritusrelatedtocholestasis;

gallstoneformation;porphyria;systemiclupuserythematosus;haemolyticuraemicsyndrome;Sydenham's

chorea;herpesgestationis;otosclerosis-relatedhear-loss.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ChangesinContraceptiveEffectivenessAssociatedWithCo-AdministrationofOtherDrugs:

Drugsorherbalproductsthatinduceenzymes,includingCYP3A4,thatmetabolisecontraceptivehormones,may

decreasetheplasmaconcentrationsofcontraceptivehormones,andmaydecreasetheeffectivenessofhormonal

contraceptivesorincreasebreakthroughbleeding.Somedrugsorherbalproductsthatmaydecreasetheeffectivenessof

hormonalcontraceptivesinclude:

barbiturates

bosentan

carbamazepine

felbamate

griseofulvin

modafinil

oxcarbazepine

phenytoin

rifampicin

St.John'sWort

topiramate

HIVproteaseinhibitorsandnon-nucleosidereversetranscriptaseinhibitors:Significantchanges(increaseordecrease)

intheplasmalevelsoftheestrogenandprogestinhavebeennotedinsomecasesofco-administrationofHIVprotease

inhibitorsandnon-nucleosidereversetranscriptaseinhibitors.

Antibiotics:

Therehavebeenreportsofpregnancywhiletakinghormonalcontraceptivesandantibiotics,butclinical

pharmacokineticstudieshavenotshownconsistenteffectsofantibioticsonplasmaconcentrationsofsyntheticsteroids.

Womenreceivingshortcoursesofenzymeinducersorbroadspectrumantibioticsshouldtakeadditional,non-hormonal

(exceptrhythmortemperaturemethod)contraceptiveprecautionsduringthetimeofconcurrentmedicationandfor7

daysafterwards.Ifthese7daysoverruntheendofthepack,thenextpackshouldbestartedwithoutabreak.Inthis

situation,awithdrawalbleedshouldnotbeexpecteduntiltheendofthesecondpack.Ifthepatientdoesnothavea

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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.

Therequirementfororalantidiabeticsorinsulincanchangeasaresultoftheeffectonglucosetolerance.

Theuseoforalcontraceptivesmayinfluencetheresultsofcertainlaboratorytestsincludingbiochemicalparametersof

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

carbohydratemetabolismandparametersofcoagulationandfibrinolysis.Laboratorystaffshouldthereforebeinformed

aboutoralcontraceptiveusewhenlaboratorytestsarerequested.

Serumfolatelevelsmaybedepressedbyoralcontraceptivetherapy.Thismaybeofclinicalsignificanceifawoman

becomespregnantshortlyafterdiscontinuingoralcontraceptives.

4.6Fertility,pregnancyandlactation

Pregnancy

Cilestiscontraindicatedduringpregnancy.

IfpregnancyoccursduringmedicationwithCilest,thepreparationshouldbewithdrawnimmediately.

Epidemiologicalstudiesindicatenoincreasedriskofcongenitalanomaliesinchildrenborntowomenwhousedoral

contraceptivespriortopregnancy.Themajorityofrecentepidemiologicalstudiesalsodonotindicateateratogenic

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Lactation

TheuseofCilestduringlactationmayleadtoareductioninthevolumeofmilkproducedandtoachangeinits

composition.Minuteamountsoftheactivesubstancesareexcretedwiththemilk.

Cilestiscontraindicatedduringbreast-feeding.Adecisionmustbemadewhethertodiscontinuebreast-feedingorto

discontinue/abstainfromCilest.

4.7Effectsonabilitytodriveandusemachines

Noeffectsonabilitytodriveandusemachineshavebeenobserved.

4.8Undesirableeffects

ThesafetyofCilestwasevaluatedin1,891healthywomenofchildbearingpotentialwhoparticipatedin5clinical

trials(2randomizedactive-controlledtrialsand3uncontrolledopen-labeltrials)andreceivedatleast1doseofCilest

forcontraception.In3trials,subjectswerefollowedforupto24cyclesandintheother2trials,subjectswerefollowed

forupto12cycles.InthesestudiesthefollowingADRsweresolicitedordeterminedfrombleedingpatternorcycle

characteristicsdataandtheincidencecouldonlybedeterminedbytreatmentcycle(bycycle)andnotoverall:nausea,

gastrointestinaldisorder(reportedasnauseaorvomiting),vomiting,dysmenorrhoea,metrorrhagia,abnormal

withdrawalbleeding,amenorrhoea,anddiarrhoea(diarrhoeawasidentifiedasanADRduringpost-marketingreview).

Anadditionaluncontrolledstudy(N=8,331)reportedADRsbycycleonlyandwasonlyincludedintheincidence

calculationfortheby-cycleADRs.ForthesebycycleADRs,thepooledincidencesforcycles1,3,6,12and24were

calculatedandthehighestcycleincidence(cycle1forallexceptvomitinganddiarrhoea)presentedandusedtoassign

theADRtoafrequencycategory.

Basedonpooledsafetydatafromtheseclinicaltrials,themostcommonlyreported(i.e.,5%incidence)ADRs(with%

incidence)wereheadache(27.9%),vaginalinfection(7.5%),gentialdischarge(6.0%)andbreastpain(5.7%).Allby-

cycleADRs,exceptamenorrhoea,wereverycommon(10%)incycle1(dysmenorrhoea:40.4%;nausea:29.1%;

metrorrhagia:26.3%;gastrointestinaldisorder[reportedasnauseaorvomiting]:24.6%;abnormalwithdrawalbleeding:

16.9%andvomiting:7.0%).Withtheexceptionofvomitinganddysmenorrhoea,theincidenceoftheseADRswas

highestincycle1anddecreasedovertimewithfurthertreatmentcycles(basedonincidencedatafromcycles1,3,6,

12and24).Vomitingincreasedinsomelatercycles,whereasdysmenorrhoearemainedrelativelystable,withaslight

decreaseovertime.Themostcommonlyreported(5%incidence)ADRsidentifiedduringpostmarketingexperience

withnorgestimateandethinylestradioltablets(incidencefrompooledclinicaltrialdata)werediarrhoea(11.8%)and

backpain*(5.4%)

*Thiscalculatedincidencevaluemaybeslightlyhigherthantheactualincidence,asmorethan1eventtermreportedin

thesametrialcodedtotheMedDRApreferredtermof'Backpain'.Itispossiblethatthesamesubject(s)mayhave

reportedmorethan1oftheeventtermsandmaythereforebecountedmorethanonceforthePreferredTermof'Back

pain'.

Theclinicaltrialincidenceofdiarrhoeawasreportedbycycle,thereforeassignmentoffrequencycategorywasbased

onthehighestcycleincidence(cycle12).Includingtheabove-mentionedADRs,TableAdisplaysallADRsthathave

beenreportedwiththeuseofCilestinclinicaltrialsorfrompostmarketingexperienceswithnorgestimateandethinyl

estradioltablets.

Thedisplayedfrequencycategoriesusethefollowingconvention:Verycommon(>1/10);common(>1/100to<1/10);

uncommon(>1/1,000to<1/100);rare(>1/10,000to<1/1,000);veryrare(<1/10,000);andnotknown(cannotbe

estimatedfromtheavailabledata).

TableA:AdverseDrugReactions

InfectionsandInfestations

Common Urinarytractinfection,Vaginalinfection

Neoplasmsbenign,malignantandunspecified(includingcystsandpolyps)

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Rare Breastcyst

Frequencynotknown Breastcancer,Hepaticadenoma,Benignbreast

neoplasm,Focalnodularhyperplasia,

Fibroadenomaofbreast,Hepatictumours

ImmuneSystemDisorders

Common Hypersensitivity

Metabolismandnutritiondisorders

Common Fluidretention,Weightincreased

Uncommon Weightfluctuation,Weightdecreased,

Decreasedappetite,Increasedappetite

Rare Appetitedisorder

Frequencynotknown Dyslipidaemia

Psychiatricdisorders

Common Depression,Nervousness,Moodaltered,

Insomnia

Uncommon Anxiety,Libidodisorder

Rare Lossoflibido

Nervoussystemdisorders

Verycommon Headache

Common Migraine,Dizziness

Uncommon Syncope,Paraesthesia

Frequencynotknown Cerebrovascularaccident,convulsion,Arterial

thromboembolism

Eyedisorders

Uncommon Visualimpairment,Dryeye

Frequencynotknown Retinalvascularthrombosis,Contactlens

intolerance

EarandLabyrinthDisorders

Rare Vertigo

Cardiacdisorders

Uncommon Palpitations

Rare Tachycardia

Frequencynotknown Myocardialinfarction

Vasculardisorders

Uncommon Thrombosis,Hypertension,Hotflush

Frequencynotknown Deepveinthrombosis

Respiratory,ThoracicandMediastinalDisorders

Uncommon Dyspnoea

Frequencynotknown Pulmonaryembolism

Gastrointestinaldisorders

VeryCommon GastrointestinaldisorderVomitingDiarrhoea,

Nausea

Common Gastrointestinalpain,Abdominalpain,

Abdominaldistension,Constipation,Flatulence

Rare Pancreatitis

Hepato-biliarydisorders

Rare Hepatitis

Frequencynotknown Cholestaticjaundice

Skinandsubcutaneoustissuedisorders

Common Acne,Rash

Uncommon Alopecia,Hirsutism,Urticaria,Pruritus,

Erythema,Skindiscoloration

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4.9Overdose

Overdosagemaycausenausea,vomitingand,inyounggirls,withdrawalbleeding.Seriousilleffectshavenotbeen

reportedfollowinglargedosesoforalcontraceptivesinchildren.Therearenoantidotesandtreatmentshouldbe

symptomatic.

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.

5.2Pharmacokineticproperties

Absorption:Norgestimateandethinylestradiolarerapidlyabsorbedfollowingoraladministration.Followingsingleor

multiple(threecycles)administrationofCilest,serumconcentrationsofnorgestimateremainbelowthequantitation

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

norgestrel,arefoundinmeasurableconcentrationsincirculation,reachingmaximalserumlevelsapproximately1.5

hourspost-dose.Exposuretonorelgestrominisproportionaltodosefollowingnorgestimatedosesof0.180to0.250

mg.Ethinylestradiolserumconcentrationsaremeasurablewithin0.5hoursofdosing,reachingpeaklevels

Frequencynotknown Angioedema,Erythemanodosum,Nightsweats

MusculoskeletalandConnectiveTissueDisorders

Common Musclespasms,Paininextremity,Backpain

Uncommon Myalgia

Reproductivesystemandbreastdisorders

VeryCommon Dysmenorrhoea,Metrorrhagia,Abnormal

withdrawalbleeding

Common Amenorrhoea,Genitaldischarge,Breastpain

Uncommon Breastdischarge,Galactorrhea,Breast

enlargement,Ovariancyst,Vulvovaginal

dryness

Rare Vaginaldischarge

Frequencynotknown Suppressedlactation

Generaldisordersandadministrationsiteconditions

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Distribution:Norelgestrominandnorgestrelarehighlybound(>97%)toserumproteins.norelgestrominisboundto

albuminbutnottoSHBG,whilenorgestrelisboundprimarilytoSHBGandtoamuchlesserextenttoalbumin.Ethinyl

estradiolisextensivelyboundtoserumalbumin.

StudieshaveshownthatthelackofbindingofnorelgestromintoSHBGisuniquewhencomparedtoother

progestogensinoralcontraceptivesandplaysakeyroleinenhancingitsbiologicalactivity.Incontrast,norgestrel

formedfromnorgestimateislargelyboundtoSHBG,whichlimitsitsbiologicactivity.

Thesefindingstogetherwiththeselectivityofnorelgestrominfortheprogesteronereceptorindicatethatthismetabolite

mayexplaintheuniqueclinicalprofileofnorgestimate.

Metabolism:Norgestimateisrapidlymetabolizedbyfirst-pass(intestinaland/orhepatic)mechanismsto

norelgestromin(peakserumconcentrationsobservedwithin2hours)andnorgestrel,bothofwhichare

pharmacologicallyactiveprogestogens.Ethinylestradiolismetabolizedtovarioushydroxylatedmetabolitesandtheir

glucuronideandsulfateconjugates.

Elimination:Bothnorelgestrominandnorgestrel,andethinylestradiolaresubsequentlymetabolizedandtheir

metabolitesareeliminatedbyrenalandfecalpathways.Eliminationhalf-lifevaluesatsteady-statewere10to15hours

forethinylestradiol,24.9hoursfornorelgestrominand45hoursfornorgestrel.Followingadministrationof14C-

norgestimate,47%oftheadministeredradioactivitywaseliminatedintheurineand37%inthefeces.

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

(meanAUC0-24h)atsteady-state,basedonnon-SHBGboundserumlevels,was18.1hng/mLfornorelgestrominand

3.64hng/mLfornorgestrel.Followingoraladministrationof0.150mglevonorgestrel/0.030mgethinylestradiol,

meandailyexposureatsteady-state,basedonnon-SHBGboundserumlevels,was18.9hng/mLfornorgestrel.The

exposuretonorgestrelfollowingadministrationof0.250mg/0.035mgethinylestradiol,correspondstotheexposure

afteralevonorgestreldoseofapproximately30microgramsincombinationwithethinylestradiol.

5.3Preclinicalsafetydata

Acomprehensivesetoftoxicitystudieshavebeenconductedoneachofthecomponentsindividuallyandin

combination.Thesestudiesincludesingledosestudiesinmultiplespecies,repeateddosestudiesuptotwoyearsinthe

rat,sevenyearsinthedogandtenyearsinthemonkey,reproductiveanddevelopmentaltoxicity,andgenetictoxicity.

ResultsshowthattheacuteoralLD50ofnorgestimate(NGM)plusethinylestradiol(EE)inratsisgreaterthan5g/kg,

indicatingaveryloworderofacutetoxicityandawidemarginofsafety.Repeateddosestudiesingenerallaboratory

animals(rats,dogs,monkeys),atNGM+EEratiosofupto10:1insubchronic(3-monthstudies,atdosesof~1000

timestheclinicaldose)andratiosofupto5:1inchronic(2-yearstudies,atdosesof~100timestheclinicaldose)

studies,showedsomewhatsimilarresults,suchasreductionofestruscyclesormenstruation,decreaseduterineand

ovarianweights,increasedliverandpituitaryweights,decreasedserumcholesterollevelsanderythrocyticparameters,

withmostoftheprimarytreatmentrelatedeffectsjudgedtobeduetoanexaggeratedpharmacologyactionofNGM+

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,itgenerallyhasalongerlatencyperiod.

Neoplasm'sobservedinthe10-yearmonkeystudy(atdosesupto50timestheclinicaldose),aresingleoccurrences

andgenerallyindifferentorgans,withsimilarspontaneousoccurrencesbeingreportedinthescientificliterature.

Inreproductionstudies,noted,doserelatedeffectsonfertility,maternalandfetalparameters,andlactationareexpected

responsestothepharmacologicalactionsofthisclassofanti-fertilitycompoundsandwereobservedatdoselevels

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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

Lactose(anhydrous)

MagnesiumStearate

Pregelatinisedstarch

FD&CBlueNo2Lake(132)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25°C.Storeblisterintheoutercartontoprotectfromlight.

6.5Natureandcontentsofcontainer

Over-labelledcardboardcartoncontaining3blisterstrips(21tabletsperstrip).

Packsizeof3x21tablets

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

B&SHealthcare

Unit4,BradfieldRoad

Ruislip

Middlesex

HA40NU

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8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1328/102/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:5 th

June2009

10DATEOFREVISIONOFTHETEXT

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