ALESSE

Main information

  • Trade name:
  • ALESSE Film Coated Tablet 100, 20 Microgram
  • Dosage:
  • 100, 20 Microgram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ALESSE Film Coated Tablet 100, 20 Microgram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0822/065/001
  • Authorization date:
  • 24-09-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Alessefilmcoatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains100microgramlevonorgestreland20microgramethinylestradiol.

Forexcipients,seesection6.1.

3PHARMACEUTICALFORM

Filmcoatedtablets.

Roundpinkbiconvexfilmcoatedtabletswith“W”embossedononesideand“912”embossedontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Oralcontraception.

4.2Posologyandmethodofadministration

HOWTOTAKEALESSE

Regulardailyintakeoftabletsfor21consecutivedaysisimportantforthepreservationofcontraceptiveefficacy.

Tabletsmustbetakenintheorderdirectedonthepackage,everyday,ataboutthesametime,withsomeliquidasneeded.

Onetabletistobetakendailyfor21consecutivedays.Eachsubsequentpackisstartedaftera7-daytablet-freeinterval,

duringwhichtimeawithdrawalbleedoccurs.Thisusuallystartsondays2-3afterthelasttabletandmaynothave

finishedbeforethenextpackisstarted.

HOWTOSTARTALESSE

Noprecedinghormonalcontraceptiveuse[inthepastmonth]

Tablet-takingshouldstartonday1ofthewoman’snaturalcycle(i.e.,thefirstdayofhermenstrualbleeding).Startingon

days2-7isallowed,butduringthefirstcycleaback-upmethodofbirthcontrol[suchascondomsandspermicide]is

recommendedinadditionforthefirst7daysoftablet-taking.

Changingfromanothercombinedoralcontraceptive(COC)

ThewomanshouldstartALESSEpreferablyonthedayafterthelastactivetabletofherpreviousCOC,butatthelatest

onthedayfollowingtheusualtablet-freeorinactivetabletintervalofherpreviousCOC.

Changingfromaprogestin-onlymethod(progestin-onlypill,injection,implant)

Thewomanmayswitchanydayfromtheprogestin-onlypillandshouldbeginALESSEthenextday.Sheshouldstart

ALESSEonthedayafteranimplantremovalor,ifusinganinjectable,thedayafterthenextinjectionwouldbedue.In

allofthesesituations,thewomanshouldbeadvisedtoadditionallyuseaback-upmethodforthefirst7daysoftablet-

taking.

Followingfirsttrimesterabortion

Thewomanmaystartimmediately.Whendoingso,sheneednottakeadditionalcontraceptivemeasures.

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Sincetheimmediatepost-partumperiodisassociatedwithanincreasedriskofthromboembolism,oralcontraceptives

shouldbestartednoearlierthanday28afterdeliveryorsecond-trimesterabortion.Thewomanshouldbeadvisedto

additionallyuseaback-upmethodforthefirst7daysoftablet-taking.However,ifintercoursehasalreadyoccurred,

pregnancyshouldbeexcludedbeforetheactualstartofCOCuse,orthewomanhastowaitforherfirstmenstrualperiod.

(SeeWARNINGS: 4.4 Thromboembolismand 4.6 .Pregnancyandlactation)

MANAGEMENTOFMISSEDTABLETS

Contraceptivereliabilitymaybereducediftabletsaremissed,andparticularlyifthemissedtabletsextendthetablet-free

interval.Iftabletsweremissedinthefirstweekofthecycleandintercoursetookplaceintheweekbeforethetablets

weremissed,thepossibilityofapregnancyshouldbeconsidered.

Providedthattheuserislessthan12hourslateintakinganytablet,sheshouldtakeitassoonassheremembers,and

furthertabletsshouldbetakenattheusualtime.

Ifsheismorethan12hourslateintakinganytablet,contraceptiveprotectionmaybereduced.

Theusershouldtakethelastmissedtabletassoonassheremembers,evenifthismeanstakingtwotabletsinone

day.Shethencontinuestotaketabletsatherusualtime.Inaddition,aback-upmethod,suchasthecondom,shouldbe

usedforthenext7days.

Ifthese7daysrunbeyondthelasttabletinthecurrentpack,thenextpackmustbestartedassoonasthecurrentpack

isfinished;nogapshouldbeleftbetweenpacks.Thispreventsanextendedbreakintablet-taking,whichmayincrease

theriskofescapeovulation.Theuserisunlikelytohaveawithdrawalbleeduntiltheendofthesecondpack,butshemay

experiencespottingorbreakthrough-bleedingontablet-takingdays.

Iftheuserdoesnothaveawithdrawalbleedattheendofthesecondpack,thepossibilityofpregnancymustberuled

outbeforeresumingtablet-takingfromthenextpack.

INCASEOFGASTROINTESTINALUPSET

Theonsetofintercurrentdigestivedisorderswithinfourhoursaftertakingthetablet,suchasvomitingorsevere

diarrhoea,maycausetransientinefficacyofthemethodbyreducingCOChormoneabsorption,andsucheventsshouldbe

dealtwithinthesamewayasinthecasewhereatablethasbeenforgottenforlessthan12hours.Theextratabletshould

betakenfromaback-uppack.Iftheseepisodesrecuroverseveraldays,anonhormonalback-upcontraceptivemethod

shouldthenbeused(condom,spermicide,etc.)untilthebeginningofthenextblisterpack.

HOWTODELAYAPERIOD

Todelayaperiod,thewomanshouldcontinuewithanotherpackofALESSEwithoutatablet-freeinterval.The

extensioncanbecarriedonforaslongaswisheduntiltheendofthesecondpack.Duringtheextension,thewomanmay

experiencebreakthrough-bleedingorspotting.

RegularintakeofALESSEisthenresumedaftertheusual7day,tablet-freeinterval.

4.3Contraindications

Oralcontraceptivesshouldnotbeusedinwomenwithanyofthefollowingconditions:

Thrombophlebitisorthromboembolic(arterialorvenous)disordersorotherdiseases,associatedwithanincreased

thromboembolicrisksuchasthrombogenicvalvulopathiesandthrombogenicrhythmdisorders(currentor

history)

Hereditaryoracquiredpredispositionforvenousorarterialthrombosis

Cerebrovascularorcoronaryarterydisease

Knownorsuspectedcarcinomaofthebreast

Carcinomaoftheendometriumorotherknownorsuspectedestrogen-dependentneoplasia

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Hepaticadenomasorcarcinomas,oracuteorchronicliverdisease,aslongasliverfunctionhasnotreturnedto

normal

Uncontrolledhypertension

Diabetesmellitusassociatedwithvascularabnormalities

Historyofmigrainewithfocalneurologicalsymptoms

Knownorsuspectedpregnancy

HypersensitivitytotheactivesubstancesortoanyoftheexcipientsofAlesse

4.4Specialwarningsandprecautionsforuse

Warnings

Cigarettesmokingincreasestheriskofseriouscardiovascularsideeffectsfromoral-contraceptiveuse.Thisrisk

increaseswithageandwiththeextentofsmokingandismarkedinwomenover35yearsofage.Allwomenwhouse

oralcontraceptivesshouldbestronglyadvisednottosmoke.Othermethodsofcontraceptionshouldbeconsideredfor

thosewomenover35yearsoldwhosmoke.

TheuseofCOCsisassociatedwithincreasedrisksofseveralseriousconditions,includingmyocardialinfarction,

thromboembolism,stroke,hepaticneoplasia,andhypertension.Theriskofmorbidityandmortalityincreases

significantlyinthepresenceofotherunderlyingriskfactors,suchashypertension,hyperlipidemias,obesity,and

particularly,diabeteswithvascularinvolvement.

Thromboembolicdisordersandothervascularproblems

Oralcontraceptionmustbeusedwithcautioninwomenwithriskfactorsforthromboticandthromboemboliceventsor

cardiovasculardisease.Anyofthefollowingriskfactorsforvenousorarterialdiseasemayconstituteanunacceptable

levelofrisk.

Myocardialinfarction

Anincreasedriskofmyocardialinfarctionhasbeenattributedtooral-contraceptiveuse.Thisriskisprimarilyin

smokersorwomenwithotherunderlyingriskfactorsforcoronary-arterydisease,suchashypertension,

hypercholesterolemia,morbidobesity,anddiabetes.

Smokingincombinationwithoral-contraceptiveusehasbeenshowntocontributesubstantiallytotheincidenceof

myocardialinfarctioninwomenintheirmid-thirtiesorolder,withsmokingaccountingforthemajorityofexcesscases.

Mortalityratesassociatedwithcirculatorydiseasehavebeenshowntoincreasesubstantiallyinsmokersovertheageof

35andnon-smokersovertheageof40amongwomenwhouseoralcontraceptives.

Oralcontraceptivesmustbeusedwithcautioninwomenwithcardiovasculardiseaseriskfactors.

TheriskofarterialthromboemboliccomplicationsinCOCusersincreaseswith:

Increasingage

Smoking

Dyslipoproteinemia

Hypertension

Valvularheartdisease

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Obesity(bodymassindexover30kg/m 2

Venousthrombosisandthromboembolism

TheuseofanyCOCcarriesanincreasedriskofVTEcomparedwithnouse.Theexcessriskishighestduringthefirst

yearawomaneverusesacombinedoralcontraceptive.ThisincreasedriskislessthantheriskofVTEassociatedwith

pregnancy,whichisestimatedas60casesper100,000woman-years.VTEisfatalin1-2%ofcases.

Theoverallabsoluterisk(incidence)ofVTEforlevonorgestrelcontainingcombinedoralcontraceptiveswith30mg

ethinylestradiolisapproximately20casesper100,000woman-yearsofuse.

Atwo-tofour-foldincreaseinrelativeriskofpostoperativethromboemboliccomplicationshasbeenreportedwiththe

useoforalcontraceptives.Therelativeriskofvenousthrombosisinwomenwhohavepredisposingconditionsistwice

thatofwomenwithoutsuchmedicalconditions.

TheriskforvenousthromboemboliccomplicationsinCOCsusersincreaseswith:

·Increasingage

·Apositivefamilyhistory(venousthromboembolismeverinasiblingorparentatrelativelyearlyage)

·Prolongedimmobilisation,majorsurgery,anysurgerytothelegs,ormajortrauma.Inthesesituations,itisadvisable

todiscontinuethepill(inthecaseofelectivesurgery,atleastfourweeksinadvance)andnottoresumeuntiltwo

weeksaftercompleteremobilisation.Antithrombotictreatmentshouldbeconsideredifthepillshavenotbeen

discontinuedinadvance.

·Obesity(bodymassindexover30kg/m 2

Thepresenceofoneseriousormultipleriskfactors,dependingontypeandseverity,forvenousorarterialdisease,may

constituteanunacceptablelevelofrisk.

Thereisnoconsensusaboutthepossibleroleofvaricoseveinsandsuperficialthrombophlebitisintheonsetor

progressionofvenousthrombosis.

Cerebrovasculardisease

Oralcontraceptiveshavebeenshowntoincreaseboththerelativeandattributablerisksofcerebrovascularevents

(transientischaemicattacks,thromboticandhemorrhagicstrokes),although,ingeneral,theriskisgreatestamongolder

(>35years),hypertensivewomenwhoalsosmoke.Hypertensionhasbeenfoundtobeariskfactorforbothusersand

nonusers,forbothtypesofstrokes,whilesmokingappearstoincreasetheriskforhemorrhagicstroke.

COCuserswithmigraine(particularlymigrainewithaura)maybeatincreasedriskofstroke.

Carcinomaofthereproductiveorgans

Somestudiessuggestthatoral-contraceptiveusehasbeenassociatedwithanincreaseintheriskofcervical

intraepithelialneoplasiaorinvasivecervicalcancerinsomepopulationsofwomen.However,therecontinuestobe

controversyabouttheextenttowhichsuchfindingsmaybeduetodifferencesinsexualbehaviourandotherfactors.

Ameta-analysisfrom54epidemiologicalstudiesshowedthatthereisaslightlyincreasedrelativerisk(RR=1.24)of

havingbreastcancerdiagnosedinwomenwhoarecurrentlyusingCOCs.Theincreasedriskgraduallydisappears

duringthecourseofthe10yearsaftercessationofCOCuse.Becausebreastcancerisrareinwomenunder40yearsof

age,theexcessnumberofbreastcancerdiagnosesincurrentandrecentCOCusersissmallinrelationtothelifetime

riskofbreastcancer.Thesestudiesdonotprovideevidenceforcausation.Theobservedpatternofincreasedriskmay

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Breastcancersdiagnosedinever-userstendtobelessadvancedclinicallythanthecancersdiagnosedinnever-users.

Hepaticneoplasia/liverdisease

Benignhepaticadenomasareassociatedwithoral-contraceptiveuse,althoughtheincidenceofthesebenigntumoursis

rare.Ruptureofrare,benign,hepaticadenomasmaycausedeaththroughintra-abdominalhaemorrhage.

Studieshaveshownanincreasedriskofdevelopinghepatocellularcarcinomainlong-termoralcontraceptiveusers;

however,thesecancersareextremelyrare.

WomenwithahistoryofCOC-relatedcholestasisorwomenwithcholestasisduringpregnancyaremorelikelytohave

thisconditionwithCOCuse.IfthesepatientsreceiveaCOC,theyshouldbecarefullymonitored;andifthecondition

recurs,theCOCshouldbediscontinued.

Ocularlesions

Therehavebeencasereportsofretinalthrombosiswiththeuseoforalcontraceptives.Oralcontraceptivesshouldbe

discontinuedifthereisunexplainedpartialorcompletelossofvision,onsetofproptosisordiplopia,papilledema,or

retinalvascularlesions.

Gallbladderdisease

Anincreasedrelativeriskofgallbladderdiseaseinusersoforalcontraceptivesandestrogenshasbeenreportedinsome

studies.

Carbohydrateandlipidmetaboliceffects

Glucoseintolerancehasbeenreportedinoral-contraceptiveusers.Someprogestinsareknowntoincreaseinsulin

secretionandcreateinsulinresistance,whileestrogens(>75mg)maycreateastateofhyperinsulinism.Womenwith

impairedglucosetoleranceordiabetesmellitusshouldbecarefullyobservedwhiletakingoralcontraceptives.

Duetoalterationsofglucosetolerance,therequireddoseofinsulinorotherantidiabeticagentsmightchange.

Asmallproportionofwomenwillhavepersistenthypertriglyceridemiawhileonthepill.Adeclineinserumhigh-

densitylipoproteins(HDL)hasbeenreportedwithmanyprogestationalagents.

Hypertension

Anincreaseinbloodpressurehasbeenreportedinwomentakingoralcontraceptives,andthisincreaseismorelikelyin

olderoral-contraceptiveusersandwithcontinueduse.DatafromtheRoyalCollegeofGeneralPractitionersand

subsequentrandomisedtrialshaveshownthattheincidenceofhypertensionincreaseswithincreasingquantitiesof

progestins.

Womenwithahistoryofhypertension,hypertension-relateddiseases,orrenaldiseasesshouldbeencouragedtouse

anothermethodofcontraception.Ifwomenwithhypertensionelecttouseoralcontraceptives,theyshouldbe

monitoredclosely;andifsignificantelevationofbloodpressureoccurs,oralcontraceptivesshouldbediscontinued.

Headache

Theonsetorexacerbationofmigraineordevelopmentofheadachewithanewpatternthatisrecurrent,persistentor

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Bleedingirregularities

Breakthrough-bleedingandspottingaresometimesencounteredinpatientsonoralcontraceptives,especiallyduringthe

firstthreemonthsofuse.Thetypeanddoseofprogestinmaybeimportant.Nonhormonalcausesshouldbeconsidered

andadequatediagnosticmeasurestakentoruleoutmalignancyorpregnancyintheeventofbreakthroughbleeding,as

inthecaseofanyabnormalvaginalbleeding.Ifpathologyhasbeenexcluded,continueduseoftheoralcontraceptive

orachangetoanotherformulationmaysolvetheproblem.Insomewomen,withdrawalbleedingmaynotoccurduring

theusualtablet-freeinterval.IftheCOChasbeentakenaccordingtodirections,itisunlikelythatthewomanis

pregnant.However,iftheCOChasnotbeentakenaccordingtodirectionspriortothefirstmissedwithdrawalbleedor

iftwoconsecutivewithdrawalbleedsaremissed,pregnancyshouldberuledout.

Precautionsforuse

Physicalexaminationandfollow-up

Acompletepersonalandfamilymedicalhistoryandphysicalexaminationshouldbetakenpriortotheinitiationof

COCuse,andshouldberepeatedperiodicallyduringtheuseofCOCs.Thephysicalexaminationshouldinclude

specialreferencetobloodpressure,breasts,abdomen,andpelvicorgans,includingcervicalcytology,andrelevant

laboratorytests.Incaseofundiagnosed,persistentorrecurrentabnormalvaginalbleeding,appropriatediagnostic

measuresshouldbeconductedtoruleoutmalignancy.Womenwithastrongfamilyhistoryofbreastcancerorwho

havebreastnodulesshouldbemonitoredwithparticularcare.

PatientsshouldbecounselledthatthisproductdoesnotprotectagainstHIVinfection(AIDS)andothersexually

transmitteddiseases.

Lipiddisorders

Womenwithhypertriglyceridemia,orafamilyhistorythereof,maybeatanincreasedriskofpancreatitiswhenusing

COCs.Somewomencanhaveadverselipidchangeswhiletakingoralcontraceptives(seeSection4.8).Nonhormonal

contraceptionmaybeconsideredinwomenwithuncontrolleddyslipidemias.

Liverfunction

AcuteorchronicliverdysfunctionmaynecessitatethediscontinuationofCOCuseuntilliverfunctionreturnsto

normal.Steroidhormonesmaybepoorlymetabolisedinpatientswithimpairedliverfunction.

Emotionaldisorders

Patientsbecomingsignificantlydepressedwhiletakingoralcontraceptivesshouldstopthemedicationandusean

alternatemethodofcontraceptioninanattempttodeterminewhetherthesymptomisdrug-related.Womenwitha

historyofdepressionshouldbecarefullyobserved,andthedrugdiscontinued,ifdepressionrecurstoaseriousdegree.

Folatelevels

Serumfolatelevelsmaybedepressedbyoral-contraceptivetherapy.Thismaybeofclinicalsignificanceifawoman

becomespregnantshortlyafterdiscontinuingoralcontraceptives.

St.John’swort

Ifcombinedoralcontraceptives(COCs)andSt.John’swortareusedconcomitantly,anon-hormonalback-upmethod

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Other

Diarrhoeaand/orvomitingmayreducehormoneabsorption,resultingindecreasedserumconcentration(seesection

4.5).

ThefollowingconditionshavebeenreportedtooccurordeterioratewithbothpregnancyandCOCuse,butthe

evidenceofanassociationwithCOCuseisinconclusive:jaundiceand/orpruritusrelatedtocholestasis,porphyria,

systemiclupuserythematosus,haemolyticuraemicsyndrome,Sydenham´schorea,herpesgestationis,otosclerosis-

relatedhearingloss.

Patientswithrarehereditaryproblemsofgalactoseintolerance,thelapplactasedeficiencyorglucose-glactose

malabsorptionshouldnottakeLoette.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionsbetweenethinylestradiol(EE)andothersubstancesmayleadtodecreasedorincreasedserumEE

concentrations.

DecreasedEEserumconcentrationsmaycauseanincreasedincidenceofbreakthroughbleedingandmenstrual

irregularitiesandmaypossiblyreduceefficacyoftheCOC.

DuringconcomitantuseofEE-containingproductsandsubstancesthatmayleadtodecreasedEEserumconcentrations,

itisrecommendedthatanonhormonalback-upmethodofbirthcontrol(suchascondomsandspermicide)beusedin

additiontotheregularintakeofAlesse.Inthecaseofprolongeduseofsuchsubstances,COCsshouldnotbe

consideredtheprimarycontraceptive.

ExamplesofsubstancesthatmaydecreaseserumEEconcentrations:

·Ritonavir

·Anysubstancethatreducesgastrointestinaltransittimeand,therefore,EEabsorption

·Substancesthatinducehepaticmicrosomalenzymes,suchas,carbamazepine,oxycarbamazepine,rifampicin,

rifabutin,barbiturates,primidone,phenylbutazone,phenytoin,griseofulvin,topiramateandmodafinil

·Certainantibiotics(e.g.,ampicillinandotherpenicillins,tetracyclines),byadecreaseofenterohepaticcirculationof

estrogens

·St.John’swort:BreakthroughbleedingandunintendedpregnancieshavebeenreportedinwomentakingCOCsand

St.John’swort(hypericumperforatum).St.John’swortmayinducemicrosomalenzymes,whichtheoreticallymay

resultinreducedclinicalefficacyofCOCs.Theinducingeffectmaypersistforatleast2weeksaftercessationof

treatmentwithSt.John’swort.IfCOCsandSt.John’swortareusedconcomitantly,anon-hormonalbackupmethodof

birthcontrolisrecommended.

AfterdiscontinuationofsubstancesthatmayleadtodecreasedEEserumconcentrations,useofanonhormonalback-up

methodisrecommendedforatleast7days.Longeruseofaback-upmethodisadvisableafterdiscontinuationof

substancesthathaveleadtoinductionofhepaticmicrosomalenzymes,resultingindecreasedEEserumconcentrations.

Itmaysometimestakeseveralweeksuntilenzymeinductionhascompletelysubsided,dependingondosage,duration

ofuseandrateofeliminationoftheinducingsubstance.

ExamplesofsubstancesthatmayincreaseserumEEconcentrations:

·Competitiveinhibitorsforsulfationinthegastrointestinalwall,suchasascorbicacid(vitaminC)andparacetamol

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EEmayinterferewiththemetabolismofotherdrugsbyinhibitinghepaticmicrosomalenzymes,orbyinducinghepatic

drugconjugation,particularlyglucuronidation.Accordingly,plasmaandtissueconcentrationsmayeitherbeincreased

(e.g.,cyclosporine,theophylline)ordecreased(e.g.lamotrigine).

Inpatientstreatedwithflunarizine,useoforalcontraceptiveshasbeenreportedtoincreasetheriskofgalactorrhoea.

Theprescribinginformationofconcomitantmedicationsshouldbeconsultedtoidentifypotentialinteractions.

Laboratorytests

Theuseofcontraceptivesteroidsmayinfluencetheresultsofcertainlaboratorytests,includingbiochemicalparameters

ofliver,thyroid,adrenalandrenalfunction,plasmalevelsof(carrier)proteins(e.g.,corticosteroidbindingglobulinand

lipid/lipoproteinfractions),parametersofcarbohydratemetabolismandparametersofcoagulationandfibrinolysis.

Changesgenerallyremainwithinthenormallaboratoryrange.

4.6Fertility,pregnancyandlactation

ALESSEisnotindicatedduringpregnancy.

BeforecommencingatreatmentwithALESSE,pregnancyhastobeexcluded.Ifpregnancyoccursduringusewith

ALESSE,treatmentshouldbewithdrawnimmediately.

Extensiveepidemiologicalstudieshaverevealednoincreasedriskofbirthdefectsinchildrenborntowomenwhoused

COCspriortopregnancy.Mostepidemiologicalstudiesalsodonotsuggestateratogeniceffect;particularlyinsofaras

cardiacanomaliesandlimb-reductiondefectsareconcerned,whencombinationsofestrogensandprogestagensindose

levelsrelevantforALESSEorotherCOCsweretakeninadvertentlyduringearlypregnancy.Studiesinanimalshave

shownreproductivetoxicity,includingadverseeffectonthedevelopmentofthefemaleurogenitalsystem(section5.3

PreclinicalSafetyData.

Lactation

LactationmaybeinfluencedbyCOCs,astheymayreducethequantityandchangethecompositionofbreastmilk,

therefore,theuseofCOCsshouldgenerallynotberecommendeduntilthenursingmotherhascompletelyweanedher

child.Smallamountsofcontraceptivesteroidsand/ormetaboliteshavebeenidentifiedinthemilkofnursingmothers,

andafewadverseeffectsonthechildhavebeenreported,includingjaundiceandbreastenlargement.

4.7Effectsonabilitytodriveandusemachines

Notapplicable.

4.8Undesirableeffects

ForseriousadverseeffectswhentakingCOCs,seesection4.4.“Specialwarningsandprecautionforuse”.For

thromboemebolicevents,lipiddisorders,gallbladderdiseases,breastcancer,seealsoscetion4.4“Specialwarningsand

precautionforuse”.

Themostfrequently(greaterthan10%)reportedadverseeventsduringphaseIIIstudiesandpostmarketingsurveillance

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OtheradverseeventshavebeenreportedinwomentakingALESSE:

Thefollowingadverseeventshavebeenclassifiedasveryrareadverseevents(<0.01%):

Exacerbationofsystemiclupuserythematosus

Exacerbationofporphyria

Systemorgan

class Frequencyofadverseevents

Common

1%and <

Uncommon

0.1%and <

Rare

0.01%and <

0.1%

Infectionsand

infestations Vaginitis,including

candidiasis

Immunesystem

disorders Anaphylactic/anaphylactoid

reactions,includingveryrare

casesofurticaria,

angioedemaandsevere

reactionswithrespiratory

andcirculatorysymptoms

Metabolismand

nutrition

disorders Changesinappetite

(increaseordecrease) Glucoseintolerance

Psychiatric

disorders Moodchanges,

includingdepression;

changesinlibido

Nervoussystem

disorders Nervousness;

dizziness

Eyedisorder Intolerancetocontactlenses

Gastrointestinal

disorders Nausea,vomiting,

abdominalpain Abdominalcramps,

bloating

Hepatobiliary

disorder Cholestaticjaundice

Skinand

subcutaneous

tissuedisorders Acne Rash,chloasma

(melasma)whichmay

persist,hirsutism,

alopecia Erythemanodosum

Reproductive

systembreast

disorders Breastpain,

tenderness,

enlargement,

secretion,

dysmenorrhoea,

changeinmenstrual

flow,changein

cervicalectropionand

secretion,

amenorrhoea

General

disorders Fluid

retention/oedema

Investigations Changeinweight

(increaseordecrease) Increaseinblood

pressure,changesin

serumlipidlevels,

including

hypertriglyceridemia Decreaseinserumfolate

levels(Serumfolatelevels

maybedepressedbyCOC

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Opticneuritis(opticneuritismayleadtopartialorcompletelossofvision)

Aggravationofvaricoseveins

Retinalvascularthrombosis

Pancreatitis

Hepaticadenomas

Hepatocellularcarcinomas

Gallbladderdisease,includinggallstones(COCsmayworsenexistinggallbladderdiseaseandmayaccelerate

thedevelopmentofthisdiseaseinpreviouslyasymptomaticwomen.)

Erythemamultiforme

Haemolyticuraemicsyndrome

4.9Overdose

Symptomsoforalcontraceptiveoverdosagehavebeenreportedinadultsandchildrenunder12.Symptomsof

overdosagedonotappeartobedosedependantandmayincludenausea,vomiting,drowsiness/fatigue,andvaginal

bleedinginyounggirls.Thereisnoantidoteandthetreatmentissymptomatic.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Progestin/estrogencombinedoralcontraceptive

ATCcode:G03A07

PearlIndex(excludingpregnanciesaftermissing3ormorepills)is0.93andPearlIndexformethodfailureis0.64

(26,554cycles).

ALESSEisacombinationoralcontraceptive(COC)containingethinylestradiol(EE)andlevonorgestrel.COCshave

beenshowntoexerttheireffectbydecreasinggonadotropinsecretiontosuppressovarianactivity,tosuppress

proliferationoftheendometriumandtocausethickeningofcervicalmucus.

5.2Pharmacokineticproperties

PHARMACOKINETICS

Absorption

NospecificinvestigationoftheabsolutebioavailabilityofALESSEinhumanshasbeenconducted.However,

literatureindicatesthatlevonorgestrelisrapidlyandcompletelyabsorbedafteroraladministration(bioavailability

about100%)andisnotsubjecttofirst-passmetabolism.Ethinylestradiolisrapidlyandalmostcompletelyabsorbed

fromthegastrointestinaltract,butduetofirst-passmetabolismingutmucosaandliver,thebioavailabilityof

ethinylestradiolisbetween38%and48%.

AfterasingledoseofALESSEto22womenunderfastingconditions,maximumserumconcentrationsof

levonorgestrelare2.8±0.9ng/mL(mean±SD)at1.6±0.9hours.Atsteadystate,attainedfromday19onwards,

maximumlevonorgestrelconcentrationsof6.0±2.7ng/mLarereachedat1.5±0.5hoursafterthedailydose.The

minimumserumlevelsoflevonorgestrelatsteadystateare1.9±1.0ng/mL.Observedlevonorgestrelconcentrations

increasedfromday1(singledose)todays6and21(multipledoses)by34%and96%,respectively.Unbound

levonorgestrelconcentrationsincreasedfromday1todays6and21by25%and83%,respectively.Thekineticsof

totallevonorgestrelarenon-linearduetoanincreaseinbindingoflevonorgestreltosexhormonebindingglobulin

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Followingasingledose,maximumserumconcentrationsofethinylestradiolof62±21pg/mLarereachedat1.5±0.5

hours.Atsteadystate,attainedfromatleastday6onwards,maximumconcentrationsofethinylestradiolwere77±30

pg/mLandwerereachedat1.3±0.7hoursafterthedailydose.Theminimumserumlevelsofethinylestradiolat

steadystateare10.5±5.1pg/mL.Ethinylestradiolconcentrationsdidnotincreasefromdays1to6,butdidincreaseby

19%fromdays1to21.

TableIprovidesasummaryoflevonorgestrelandethinylestradiolpharmacokineticparameters.

Distribution

LevonorgestrelinserumisprimarilyboundtoSHBG.Ethinylestradiolisabout97%boundtoplasmaalbumin.

EthinylestradioldoesnotbindtoSHBG,butinducesSHBGsynthesis.

Metabolism

Levonorgestrel:Themostimportantmetabolicpathwayoccursinthereductionofthe 4 -3-oxogroupand

hydroxylationatpositions2,1,and16,followedbyconjugation.Mostofthemetabolitesthatcirculateinthe

bloodaresulfatesof3,5-tetrahydro-levonorgestrel,whileexcretionoccurspredominantlyintheformof

glucuronides.Someoftheparentlevonorgestrelalsocirculatesas17-sulfate.Metabolicclearanceratesmaydiffer

amongindividualsbyseveral-fold,andthismayaccountinpartforthewidevariationobservedinlevonorgestrel

concentrationsamongusers.

Ethinylestradiol:CytochromeP450enzymes(CYP3A4)intheliverareresponsibleforthe2-hydroxylationthatisthe

majoroxidativereaction.The2-hydroxymetaboliteisfurthertransformedbymethylationandglucuronidationpriorto

urinaryandfaecalexcretion.LevelsofCytochromeP450(CYP3A)varywidelyamongindividualsandcanexplainthe

variationinratesofethinylestradiol2-hydroxylation.Ethinylestradiolisexcretedintheurineandfaecesas

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Excretion

Theeliminationhalf-lifeforlevonorgestrelisapproximately36±13hoursatsteadystate.Levonorgestrelandits

metabolitesareprimarilyexcretedintheurine(40%to68%)andabout16%to48%areexcretedinfaeces.The

eliminationhalf-lifeofethinylestradiolis18±4.7hoursatsteadystate.

5.3Preclinicalsafetydata

Thetoxicityprofilesofethinylestradiolandlevonorgestrelaloneandincombinationarewellknown.Becauseof

markedspeciesdifferences,preclinicalresultspossessalimitedpredictivevaluefortheapplicationofestrogensin

humans.

Inexperimentalanimals,ethinylestradioldisplayedanembryotoxiceffect;malformationoftheurogenitaltractand

feminisationofmalefetuseswereobserved.

Levonorgestreldisplayedanembryotoxiceffectinanimalexperimentsavirilisingeffectonfemalefetuses.

Reproductiontoxicologystudiesinrats,miceandrabbitsprovidednootherevidenceofteratogenicity.

Preclinicaldatabasedonconventionalstudiesofrepeateddosetoxicity,genotoxicityandcarcinogenicpotential

revealednoparticularhumanriskbeyondthosediscussedinothersectionsoftheSmPC.However,itmustbebornein

mindthatsexsteroidscanpromotethegrowthofcertainhormone-dependenttissuesandtumours.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Microcrystallinecellulose

Polacrilinpotassium

Magnesiumstearate

Filmcoatingmaterial:

Macrogol1450

Hypromellose

TitaniumdioxideE171

SyntheticredironoxideE172

Montanglycolwax.

6.2Incompatibilities

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6.3Shelflife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove25 o

6.5Natureandcontentsofcontainer

Primarycontainer

PVC/aluminiumfoilblisterpack

Secondarycontainer

Cardboardcartonorvinylwalletincardboardcarton

Presentation

Packcontaining1x21,3x21,6x21and13x21tablets.Notallpacksmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

PfizerHealthcareIreland

9Riverwalk

NationalDigitalPark

CitywestBusinessCampus

Dublin24

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA822/65/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:24January2003

Dateoflastrenewal:07December2008

10DATEOFREVISIONOFTHETEXT

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