DIANETTE

Main information

  • Trade name:
  • DIANETTE Coated Tablets 2mg/35mcg
  • Dosage:
  • 2mg/35mcg
  • Pharmaceutical form:
  • Coated Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DIANETTE Coated Tablets 2mg/35mcg
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1473/032/001
  • Authorization date:
  • 29-10-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Dianette2mg/35microgramscoatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains2.0mgcyproteroneacetateand0.035mgethinylestradiol.

Excipients:

Lactosemonohydrate 31.115mg

Sucrose 19.371mg

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Coatedtablet(tablet).

ProductimportedfromtheUK:

Beige,sugar-coated,biconvextablets

4CLINICALPARTICULARS

4.1TherapeuticIndications

Foruseinthemanagementofsevereacnevulgaris,especiallythoseformswhichareaccompaniedbyseborrhoeaorby

inflammationorformationofnodes(acnepapulopustulosa,acnenodulocystica)inwomen.

Oralcontraceptionforthewomansufferingfromtheabove.

AlthoughDianettealsoactsasanoralcontraceptive,itshouldnotbeusedinwomensolelyforcontraception,but

shouldbereservedforthosewomenrequiringtreatmentfortheandrogen-dependentacnedescribed.

4.2Posologyandmethodofadministration

HowtotakeDianette

Dianetteistobetakenregularlyinordertoachievethetherapeuticefficacyandtherequiredcontraceptiveprotection.

Combinedoralcontraceptiveswhentakencorrectlyhaveafailurerateofapproximately1%peryear.

Tabletsmustbetakenintheorderdirectedonthepackageeverydayataboutthesametimewithsomeliquidas

needed.Onetabletistobetakendailyfor21consecutivedays.Eachsubsequentpackisstartedaftera7-daytablet-

freeinterval,duringwhichtimeawithdrawalbleedusuallyoccurs.

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HowtostartDianette

Noprecedinghormonalcontraceptiveuse(inthepastmonth)

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

Startingondays2-5isallowed,butduringthefirstcycleabarriermethodisrecommendedinadditionforthefirst

7daysoftablet-taking.

Switchingfromacombinedhormonalcontraceptive(combinedoralcontraceptive/COC,vaginalringor

transdermalpatch)

ThewomanshouldstartwithDianettepreferablyonthedayafterthelastactivetablet(thelasttabletcontainingthe

activesubstances)ofherCOC,butatthelatestonthedayfollowingtheusualtablet-freeorplacebotabletinterval

ofherCOC.Ifavaginalringortransdermalpatchhasbeenused,thewomanshould,preferably,startusing

Dianetteonthedayofremoval,butatthelatestwhenthenextapplicationwouldhavebeendue.

Switchingfromaprogestogen-only-method(minipill,injection,implant)orfromaprogestogen-releasing

intrauterinesystem(IUS)

Thewomanmayswitchanydayfromtheminipill(fromanimplantortheIUSonthedayofitsremoval,froman

injectablewhenthenextinjectionwouldbedue),butshouldinallofthesecasesbeadvisedtoadditionallyusea

barriermethodforthefirst7daysoftablet-taking.

Followingfirst-trimesterabortion

Thewomanmaystartimmediately.Whendoingso,sheneednottakeadditionalcontraceptivemeasures.

Followingdeliveryorsecond-trimesterabortion

Womenshouldbeadvisedtostartatday21to28afterdeliveryorsecond-trimesterabortion.Whenstartinglater,

thewomanshouldbeadvisedtoadditionallyuseabarriermethodforthefirst7daysoftablet-taking.However,if

intercoursehasalreadyoccurred,pregnancyshouldbeexcludedbeforetheactualstartofDianetteuseorthe

womanhastowaitforherfirstmenstrualperiod.

Forbreastfeedingwomenseesection4.6,Pregnancyandlactation.

Managementofmissedtablets

Iftheuserislessthan12hourslateintakinganytablet,contraceptiveprotectionisnotreduced.Thewomanshould

takethetabletassoonassheremembersandshouldtakefurthertabletsattheusualtime.

Ifsheismorethan12hourslateintakinganytablet,contraceptiveprotectionmaybereduced.Themanagementof

missedtabletscanbeguidedbythefollowingtwobasicrules:

1.Tablet-takingmustneverbediscontinuedforlongerthan7days

2.7daysofuninterruptedtablet-takingarerequiredtoattainadequatesuppressionofthehypothalamic-pituitary-

ovarianaxis.

IfthewomanforgetstotakeanactiveDianettetabletthenitmustbetakenwithin12hoursoftheusualtimefortaking

it.Ifamissedtabletisnottakenwithin12hoursthenitshouldbetakenwhenrememberedandtheremainingtablets

takenasusualwithextranon-hormonalcontraceptivemeasures(exceptrhythmortemperaturemethod)usedforthe

next7days.Ifthesesevendaysextendbeyondtheendofthepackthenthenextpackoftabletsshouldbecommenced

atoncewithnotablet-freeinterval.Inthissituation,awithdrawalbleedshouldnotbeexpecteduntiltheendofthe

secondpack.Ifthepatientdoesnothaveawithdrawalbleedduringthetablet-freeintervalfollowingtheendofthe

secondpack,thepossibilityofpregnancymustbeexcludedbeforeresumingwiththenextpack.

Adviceincaseofgastro-intestinaldisturbances

Incaseofseveregastrointestinaldisturbances,absorptionmaynotbecompleteandadditionalcontraceptivemeasures

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Ifvomitingoccurswithin3-4hoursaftertablet-taking,theadviceconcerningmissedtablets,asgiveninsection4.2,

Posologyandmethodofadministrationisapplicable.

Tablet-takingfromthecurrentpackshouldbecontinued.Additionalnon-hormonalmethodsofcontraception(except

therhythmortemperaturemethods)shouldbeusedduringthegastro-intestinalupsetandfor7daysfollowingthe

upset.Ifthese7daysoverruntheendofapack,thenextpackshouldbestartedwithoutabreak.Inthissituation,a

withdrawalbleedshouldnotbeexpecteduntiltheendofthesecondpack.Ifthepatientdoesnothaveawithdrawal

bleedduringthetablet-freeintervalfollowingtheendofthesecondpack,thepossibilityofpregnancymustberuled

outbeforeresumingwiththenextpack.

Ifthewomandoesnotwanttochangehernormaltablet-takingschedule,shehastotaketheextratablet(s)neededfrom

anotherpack.Incasesofpersistingorrecurrentgastrointestinaldisturbancesadditionalcontraceptivemeasuresshould

betakenandthephysicianshouldbeinformed.

Lengthofuse

Thelengthofusedependsontheseverityoftheclinicalpicture.Completeremissionofacneisexpectedwithinafew

monthsofcommencingtreatment,butinparticularlyseverecasestreatmentforlongermaybenecessarybeforethefull

benefitisseen.Itisrecommendedthattreatmentbewithdrawn3to4cyclesaftertheacnehassatisfactorilyresolved

andthatDianetteisnotcontinuedsolelytoprovideoralcontraception.RepeatcoursesofDianettemaybegivenifthe

androgen-dependentacnerecurs.Inthiscase,anearlyrestartofDianetteshouldbeconsidered.

4.3Contraindications

Combinedoralcontraceptives(COCs)shouldnotbeusedinthepresenceofanyoftheconditionslistedbelow.Should

anyoftheconditionsappearforthefirsttimeduringCOCuse,Dianetteshouldbestoppedimmediately.

Presenceorhistoryofvenousthrombosis(deepvenousthrombosis,pulmonaryembolism).

Presenceorhistoryofarterialthrombosis(myocardialinfarction,cerebrovascularaccident)orprodromalconditions

(e.g.transientischaemicattack,anginapectoris).

Knownpredispositionforvenousorarterialthrombosis,suchasantithrombinIIIdeficiency,proteinCdeficiency,

proteinSdeficiency,ActivatedProteinC(APC)resistance(e.g.FactorVLeiden),hyperhomocysteinaemia,and

antiphospholipidantibodies.

Historyofmigrainewithfocalneurologicalsymptoms.

Diabetesmellituswithvascularinvolvement.

Thepresenceofasevereormultipleriskfactor(s)forvenousorarterialthrombosismayalsoconstitutea

contraindication(seesection4.4,Specialwarningsandprecautionsforuse).

Pancreatitisorahistoryofthereofifassociatedwithseverehypertriglyceridemia.

Presenceorhistoryofseverehepaticdiseaseaslongasliverfunctionvalueshavenotreturnedtonormal.

Presenceorhistoryoflivertumours(benignormalignant).

Knownorsuspectedsex-steroidinfluencedmalignancies(e.g.ofthegenitalorgansorthebreasts).

Undiagnosedvaginalbleeding.

Knownorsuspectedpregnancy.

Lactation.

Hypersensitivitytotheactivesubstancesortoanyoftheexcipients.

Porphyria.

Uncontrolledhypertension.

4.4Specialwarningsandprecautionsforuse

Warnings

Ifanyoftheconditions/riskfactorsmentionedbelowispresent,thebenefitsoftheuseofDianetteshouldbeweighed

againstthepossibleriskforeachindividualwomananddiscussedwiththewomanbeforeshedecidestostartusingit.

Intheeventofaggravation,exacerbationorfirstappearanceofanyoftheseconditionsorriskfactors,thewoman

shouldcontactherphysician.

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Dianettecontainslactosemonohydrateandsucrose.Patientswithrarehereditaryproblemsoffructoseintoleranceor

glucose-galactosemalabsorptionshouldnottakethismedicine.

Conditionswhichneedsupervision

Ifanyofthefollowingconditionsarepresent,haveoccurredpreviouslyand/orhavebeenaggravatedduringpregnancy

orpreviousCOCuse,thewomanshouldbecloselysupervised.Itshouldbetakenintoaccountthattheseconditions

mayrecurorbeaggravatedduringtreatmentwithDianette,inparticular:

Riskfactorsforthrombo-embolicdisorders(seeabove)

Riskfactorsforoestrogendependenttumours,e.g.1 st

degreeheredityforbreastcancer

Hypertension

Liverdisorders(e.g.liveradenoma)

Cholelithiasis,jaundiceand/orpruritusrelatedtocholestasis

Herpesgestationis

Migraineor(severe)headache

Systemiclupuserythematosus

Endogenousdepression

Asthma

Otosclerosisrelatedhearingloss.

CirculatoryDisorders

TheuseofanyCOCcarriesanincreasedriskofvenousthromboembolism(VTE)comparedwithnouse.Theexcess

riskofVTEishighestduringthefirstyearawomaneverusesaCOC.ThisincreasedriskislessthantheriskofVTE

associatedwithpregnancywhichisestimatedas60casesper100,000pregnancies.VTEisfatalin1-2%ofcases

EpidemiologicalstudieshaveshownthattheincidenceofVTEinusersoforalcontraceptiveswithlowoestrogen

content(lessthan50µgofethinylestradiol)rangesfromabout20to40casesper100,000womenyears,butthisrisk

estimatevariesaccordingtotheprogestogen.Thiscompareswith5to10casesper100,000womenyearsfornon-users.

ThereissomeepidemiologicalevidencethattheincidenceofVTEishigherinusersofDianettewhencomparedto

usersofCOCswithlowoestrogencontent(<50µg).TheusergroupofDianetteasatreatmentforsevereacneislikely

toincludepatientsthatmayhaveaninherentlyincreasedcardiovascularrisksuchasthatassociatedwithpolycystic

ovariansyndrome.

Theriskofvenousembolismincreaseswith:

Increasingage;

Apositivefamilyhistory(i.e.venousthromboembolismeverinasiblingorparentatarelativelyearlyage).Ifa

hereditarypredispositionissuspectedthewomanshouldbereferredtoaspecialistforadvicebeforedecidingabout

anyhormonalcontraceptiveuse;

Obesity(bodymassindexover30kg/m 2

Prolongedimmobilization,majorsurgery,anysurgerytothelegs,ormajortrauma.Inthesesituationsitisadvisable

todiscontinueCOCuse(inthecaseofelectivesurgeryatleastfourweeksinadvance)andnottoresumeuntiltwo

weeksaftercompleteremobilization

Theincreasedriskofvenousthromboembolisminthepuerperiummustbeconsidered(seesection4.6,Pregnancy

andlactation);

Andpossiblyalsowithsuperficialthrombophlebitisandvaricoseveins.Thereisnoconsensusaboutthepossible

roleoftheseconditionsintheetiologyofvenousthromboembolism.

TheuseofCOCsingeneralhasbeenassociatedwithanincreasedriskofarterialthrombotic/thromboembolicevents

suchasacutemyocardialinfarction(AMI)orcerebrovascularaccidenti.e.stroke,ariskthatisstronglyinfluencedby

thepresenceofotherriskfactors(e.g.smoking,highbloodpressure,andage)(seealsobelow).Theseeventsoccur

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Theriskofarterialthrombotic/thromboembolicevents(cerebrovascularaccident,myocardialinfarction,peripheral

arterydisease)increaseswith:

Increasingage;

Smoking(withheaviersmokingandincreasingagetheriskfurtherincreases,especiallyinwomenover35yearsof

age).Therefore,theCOCusershouldberecommendedtostopsmoking.Inwomenover35yearsofage,an

alternativecontraceptivemethodshouldbediscussed;

Apositivefamilyhistory(i.e.venousorarterialthromboembolismeverinasiblingorparentatarelativelyearly

age).Ifahereditarypredispositionissuspected,thewomanshouldbereferredtoaspecialistforadvicebefore

decidingaboutanyCOCuse;

-Obesity(bodymassindexover30kg/m 2

-Dyslipoproteinaemia;

-Hypertension;

-Migraine;

-Valvularheartdisease;

-Atrialfibrillation.

Tumors

ThemostimportantriskfactorforcervicalcancerispersistentHPVinfection.Someepidemiologicalstudieshave

indicatedthatlong-termuseofCOCsmayfurthercontributetothisincreasedriskbuttherecontinuestobecontroversy

abouttheextenttowhichthisfindingisattributabletoconfoundingeffects,e.g.,cervicalscreeningandsexualbehavior

includinguseofbarriercontraceptives.

Ameta-analysisfrom54epidemiologicalstudiesreportedthatthereisaslightlyincreasedrelativerisk(RR=1.24)of

havingbreastcancerdiagnosedinwomenwhoarecurrentlyusingCOCs.Theexcessriskgraduallydisappearsduring

thecourseofthe10yearsafterthecessationofCOCuse.

Becausebreastcancerisrareinwomenunder40yearsofage,theexcessnumberofbreastcancerdiagnosesincurrent

andrecentCOCusersissmallinrelationtotheoverallriskofbreastcancer.Thesestudiesdonotprovideevidencefor

causation.TheobservedpatternofincreasedriskmaybeduetoanearlierdiagnosisofbreastcancerinCOCusers,the

biologicaleffectsofCOCsoracombinationofboth.Thebreastcancersdiagnosedinever-userstendtobeless

advancedclinicallythanthecancersdiagnosedinnever-users.

Inrarecases,benignlivertumors,andevenmorerarely,malignantlivertumorshavebeenreportedinusersofCOCs.

Inisolatedcases,thesetumorshaveledtolife-threateningintra-abdominalhemorrhages.

Ahepatictumorshouldbeconsideredinthedifferentialdiagnosiswhensevereupperabdominalpain,liver

enlargementorsignsofintra-abdominalhemorrhageoccurinwomentakingCOCs.

Otherconditions

Womenwithhypertriglyceridemia,orafamilyhistorythereof,maybeatanincreasedriskofpancreatitiswhenusing

COCs.

AlthoughsmallincreasesinbloodpressurehavebeenreportedinmanywomentakingCOCs,clinicallyrelevant

increasesarerare.However,ifasustainedclinicallysignificanthypertensiondevelopsduringtheuseofaCOCthenit

isprudentforthephysiciantowithdrawtheCOCandtreatthehypertension.Whereconsideredappropriate,COCuse

mayberesumedifnormotensivevaluescanbeachievedwithantihypertensivetherapy.

ThefollowingconditionshavebeenreportedtooccurordeterioratewithbothpregnancyandCOCuse,butthe

evidenceofanassociationwithCOCuseisinconclusive:hemolyticuremicsyndrome;Sydenham’schorea;herpes

gestationis.

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AcuteorchronicdisturbancesofliverfunctionmaynecessitatethediscontinuationofCOCuseuntilmarkersofliver

functionreturntonormal.Recurrenceofcholestaticjaundicewhichoccurredfirstduringpregnancyorprevioususeof

sexsteroidsnecessitatesthediscontinuationofCOCs.

TheuseofCOCsmayhaveaneffectonperipheralinsulinresistanceandglucosetolerance.Therefore,diabeticwomen

shouldbecarefullymonitoredduringthefirstmonthsofCOCuse.

Crohn’sdiseaseandulcerativecolitishavebeenassociatedwithCOCuse.

Chloasmamayoccasionallyoccur,especiallyinwomenwithahistoryofchloasmagravidarum.Womenwitha

tendencytochloasmashouldavoidexposuretothesunorultravioletradiationwhilsttakingCOCs.

HerbalpreparationscontainingSt.John’sWort(Hypericumperforatum)shouldnotbeusedwhiletakingDianettedue

totheriskofdecreasedplasmaconcentrationsandreducedclinicaleffectsofDianette(seesection4.5,Interactionwith

othermedicinalproductsandotherformsofinteraction).

Medicalexamination/consultation

AcompletemedicalhistoryandphysicalexaminationshouldbetakenpriortotheinitiationorreinstitutionofDianette,

guidedbythecontraindicationsandwarnings(seesection4.3,Containdicationsandsection4.4,Specialwarningsand

precautionsforuse),andshouldberepeatedperiodically.Periodicmedicalassessmentisalsoofimportancebecause

contraindications(e.g.atransientischaemicattack,etc.)orriskfactors(e.g.afamilyhistoryofvenousorarterial

thrombosis)mayappearforthefirsttimeduringtheuseofDianette.Thefrequencyandnatureoftheseassessments

shouldbebasedonestablishedlocalguidelinesandbeadaptedtotheindividualwomanbutshouldgenerallyinclude

specialreferencetobloodpressure,breasts,abdomenandpelvicorgans,includingcervicalcytology.

WomenshouldbeadvisedthatpreparationslikeDianettedonotprotectagainstHIVinfections(AIDS)andother

sexuallytransmitteddiseases.

Reducedefficacy

ThecontraceptiveeffectofDianettemaybereducedintheeventofe.g.missedtablets(seesection4.2,Posologyand

methodofadministration),gastro-intestinaldisturbances(seesection4.2,Posologyandmethodofadministration),or

concomitantmedication(seesection4.5,Interactionwithothermedicinalproductsandotherformsofinteraction).

Reducedcyclecontrol

WithallCOCs,irregularbleeding(spottingorbreakthroughbleeding)mayoccur,especiallyduringthefirstmonthsof

use.

Ifbleedingirregularitiespersistoroccurafterpreviouslyregularcycles,thennon-hormonalcausesshouldbe

consideredandadequatediagnosticmeasuresareindicatedtoexcludemalignancyandpregnancy.Thesemayinclude

curettage.

Insomewomenwithdrawalbleedingmaynotoccurduringthetablet-freeinterval.IftheCOChasbeentaken

accordingtothedirectionsdescribedinsection4.2,Posologyandmethodofadministrationitisunlikelythatthe

womanispregnant.However,iftheCOChasnotbeentakenaccordingtothesedirectionspriortothefirstmissed

withdrawalbleedoriftwowithdrawalbleedsaremissed,pregnancymustberuledoutbeforeCOCuseiscontinued.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactions

Interactionsbetweenestrogen-progestogencombinationslikeDianetteandotherdrugsmayleadtobreakthrough

bleedingand/orcontraceptivefailure.Thefollowinginteractionshavebeenreportedintheliterature.

Hepaticmetabolism:Interactionscanoccurwithdrugsthatinducemicrosomalenzymeswhichcanresultinincreased

clearanceofsexhormones(e.g.phenytoin,barbiturates,primidone,carbamazepine,rifampicin,andpossiblyalso

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AlsoHIVprotease(e.g.ritonavir)andnon-nucleosidereversetranscriptaseinhibitors(e.g.nevirapine),and

combinationsofthem,havebeenreportedtopotentiallyaffecthepaticmetabolism.

InterferencewithEnterohepaticCirculation:Someclinicalreportssuggestthatenterohepaticcirculationofestrogens

maydecreasewhencertainantibioticagentsaregiven,whichmayreduceethinylestradiolconcentrations(e.g.

penicillins,tetracyclines).

WomenontreatmentwithanyofthesedrugsshouldtemporarilyuseabarriermethodinadditiontoDianetteorchoose

anothermethodofcontraception.Withmicrosomalenzyme-inducingdrugs,thebarriermethodshouldbeusedduring

thetimeofconcomitantdrugadministrationandfor28daysaftertheirdiscontinuation.Womenontreatmentwith

antibiotics(exceptrifampicinandgriseofulvin)shouldusethebarriermethoduntil7daysafterdiscontinuation.Ifthe

periodduringwhichthebarriermethodisusedrunsbeyondtheendofthetabletsintheDianettepack,thenextpack

shouldbestartedwithouttheusualtablet-freeinterval.

Estrogen/progestogencombinationslikeDianettemayaffectthemetabolismofcertainotherdrugs.Accordingly,

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

Note:Theprescribinginformationofconcomitantmedicationsshouldbeconsultedtoidentifypotentialinteractions.

Laboratorytests

TheuseofpreparationslikeDianettemayinfluencetheresultsofcertainlaboratorytests,includingbiochemical

parametersofliver,thyroid,adrenalandrenalfunctions,plasmalevelsof(carrier)proteins,e.g.corticosteroidbinding

globulinandlipid/lipoproteinfractions,parametersofcarbohydratemetabolismandparametersofcoagulationand

fibrinolysis.Changesgenerallyremainwithinthenormallaboratoryrange.

4.6Fertility,pregnancyandlactation

TheadministrationofDianetteiscontraindicatedduringpregnancy.Ifpregnancyoccursduringmedicationwith

Dianette,thepreparationistobewithdrawnimmediately(seesection5.3,Preclinicalsafetydata).

Althoughlowdoseexposuretocyproteroneacetateduringpregnancyhasnotbeenassociatedwithteratogeniceffects

ormalformations,clinicaldataonfetaloutcomesfollowingexposuretocyproteroneacetateislimited.

Animalstudieshaverevealedthatfeminizationofmalefetusesmayoccurifcyproteroneacetateisadministeredduring

thephaseofembryogenesisatwhichdifferentiationoftheexternalgenitaliaoccurs.Althoughtheresultsofthesetests

arenotnecessarilyrelevanttoman,thepossibilitymustbeconsideredthatadministrationofDianettetowomenafter

the45 th

dayofpregnancycouldcausefeminizationofmalefetuses.

Itfollowsfromthisthatpregnancyisanabsolutecontra-indicationfortreatmentwithDianette,andmustbeexcluded

beforesuchtreatmentisbegun(seesection5.3,Preclinicalsafetydata).

TheadministrationofDianetteisalsocontraindicatedduringlactation.Cyproteroneacetateistransferredintothemilk

oflactatingwomen.About0.2%ofthematernaldosewillreachthenewbornviamilkcorrespondingtoadoseof

about1mcg/kg.0.02%ofthedailymaternaldoseofethinylestradiolcouldbetransferredtothenewbornviamilk

duringestablishedlactation.

4.7Effectsonabilitytodriveandusemachines

Notapplicable

4.8Undesirableeffects

ThemostseriousundesirableeffectsassociatedwiththeuseofCOCsarelistedinsection4.4,Specialwarningsand

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OthersideeffectsthathavebeenreportedinusersofDianettebutforwhichtheassociationhasbeenneitherconfirmed

norrefutedare:

*ThemostappropriateMedDRAterm(version7.0)todescribeacertainadversereactionislisted.Synonymsor

relatedconditionsarenotlisted,butshouldbetakenintoaccountaswell.

Inwomenwithhereditaryangioedema,exogenousestrogensmayinduceorexacerbatesymptomsofangiodema.

4.9Overdose

Therehavebeennoreportsofseriousdeleteriouseffectfromoverdose.Symptomsthatmayoccurinthiscaseare:

nausea,vomitingand,inyounggirls,slightvaginalbleeding.Therearenoantidotesandfurthertreatmentshouldbe

SystemOrgan

Class Common

(>1/100) Uncommon

(>1/1000

and<1/100) Rare

(<1/1000)

Eyedisorders

contactlens

intolerance

Gastrointestinal

disorders nausea,

abdominal

pain vomiting,

diarrhea

Immunesystem

disorders hypersensitivity

Investigations

weight

increased weight

decreased

Metabolismand

nutrition

disorders fluid

retention

Nervoussystem

disorders headache migraine

Psychiatric

disorders depressed

mood,

mood

altered libido

decreased libidoincreased

Reproductive

systemand

breastdisorders breast

pain,

breast

tenderness breast

hypertrophy vaginal

discharge,

breastdischarge

Skinand

subcutaneous

tissuedisorders rash,

urticaria erythema

nodosum,

erythema

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Thepilosebaceousunit–consistingofthesebaceousglandandthehairfollicle–isanandrogen-sensitiveskin

component.Acneandseborrheaareclinicalconditionsresultingfromaberrationsofthistargetorganwhichmaybe

causedbyincreasedsensitivityorhigherplasmalevelsofandrogen.BothsubstancescontainedinDianetteinfluence

beneficiallythehyperandrogenicstate:Cyproteroneacetateisacompetitiveantagonistontheandrogenreceptor,has

inhibitoryeffectsontheandrogen-synthesisintargetcellsandproducesadecreaseoftheandrogenbloodconcentration

throughanantigonadotropiceffect.Thisantigonadotropiceffectisamplifiedbyethinylestradiolwhichup-regulatesas

wellthesynthesisofSexual-Hormone-Binding-Globulin(SHBG)inplasma.Ittherebyreducesfree,biologically

availableandrogeninthecirculation.TreatmentwithDianetteleads–usuallyafter3to4monthsoftherapy–tothe

healingofexistingacneefflorescences.Theexcessivegreasinessofthehairandskingenerallydisappearsearlier.The

lossofhairwhichfrequentlyaccompaniesseborrhealikewisediminishes.

ThecontraceptiveeffectofDianetteisbasedontheinteractionofvariousfactors,themostimportantofwhichareseen

astheinhibitionofovulationandthechangesinthecervicalsecretion.

5.2Pharmacokineticproperties

CyproteroneAcetate

Absorption

Orallyadministeredcyproteroneacetateisrapidlyandcompletelyabsorbed.Peakserumconcentrationsof15ng/ml

arereachedatabout1.6hoursaftersingleingestion.

Bioavailabilityisabout88%.

Distribution

Cyproteroneacetateisalmostexclusivelyboundtoserumalbumin.Only3.5–4.0%ofthetotalserumdrug

concentrationsarepresentasfreesteroid.Theethinylestradiol-inducedincreaseinSHBGdoesnotinfluencetheserum

proteinbindingofcyproteroneacetate.Theapparentvolumeofdistributionofcyproteroneacetateisabout986+437l.

Metabolism

Cyproteroneacetateisalmostcompletelymetabolized.Themainmetaboliteinplasmawasidentifiedas15-OH-CPA

whichisformedviathecytochromeP450enzymeCYP3A4.Theclearanceratefromserumisabout3.6ml/min/kg.

Elimination

Cyproteroneacetateserumlevelsdecreaseintwophaseswhicharecharacterizedbyhalf-livesofabout0.8handabout

2.3–3.3days.Cyproteroneacetateispartlyexcretedinunchangedform.Itsmetabolitesareexcretedataurinaryto

biliaryratioofabout1:2.Thehalf-lifeofmetaboliteexcretionisabout1.8days.

Steady-stateconditions

CyproteroneacetatepharmacokineticsarenotinfluencedbySHBGlevels.Followingdailyingestiondrugserumlevels

increaseabout2.5-foldreachingsteady-stateconditionsduringthesecondhalfofatreatmentcycle.

Ethinylestradiol

Absorption

Orallyadministeredethinylestradiolisrapidlyandcompletelyabsorbed.Peakserumconcentrationsofabout71pg/ml

arereachedat1.6hours.Duringabsorptionandfirst-liverpassage,ethinylestradiolismetabolizedextensively,

resultinginameanoralbioavailabilityofabout45%withalargeinterindividualvariationofabout20-65%.

Distribution

Ethinylestradiolishighlybutnon-specificallyboundtoserumalbumin(approximately98%),andinducesanincrease

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Metabolism

Ethinylestradiolissubjecttopresystemicconjugationinbothsmallbowelmucosaandtheliver.Ethinylestradiolis

primarilymetabolizedbyaromatichydroxylationbutawidevarietyofhydroxylatedandmethylatedmetabolitesare

formed,andthesearepresentasfreemetabolitesandasconjugateswithglucuronidesandsulfate.Theclearancerate

wasreportedtobeabout2.3–7ml/min/kg.

Elimination

Ethinylestradiolserumlevelsdecreaseintwodispositionphasescharacterizedbyhalf-livesofabout1hourand10–20

hours,respectively.Unchangeddrugisnotexcreted,ethinylestradiolmetabolitesareexcretedataurinarytobiliary

ratioof4:6.Thehalf-lifeofmetaboliteexcretionisabout1day.

Steady-stateconditions

Steady-stateconditionsarereachedduringthesecondhalfofatreatmentcyclewhenserumdruglevelsarehigherby

60%ascomparedtosingledose.

5.3Preclinicalsafetydata

Ethinylestradiol

Thetoxicityprofileofethinylestradioliswellknown.Therearenopreclinicaldataofrelevancetotheprescriberthat

provideadditionalsafetyinformationtothosealreadyincludedinothersectionsoftheproductinformation.

Cyproteroneacetate

Systemictoxicity

Preclinicalsafetydatarevealnospecificriskforhumansbasedonconventionalstudiesofrepeateddosetoxicity.

Embryotoxicity/teratogenicity

Investigationsintoembryotoxicityusingthecombinationofthetwoactiveingredientsshowednoeffectsindicativeof

ateratogeniceffectfollowingtreatmentduringorganogenesisbeforedevelopmentoftheexternalgenitalorgans.

Administrationofcyproteroneacetateduringthehormone-sensitivedifferentiationphaseofthegenitalorgansledto

signsoffeminizationinmalefetusesfollowinghigherdoses.Observationofmalenewbornchildrenwhohadbeen

exposedinuterotocyproteroneacetatedidnotshowanysignsoffeminization.However,pregnancyisa

contraindicationfortheuseofDianette.

Genotoxicityandcarcinogenicity

Recognizedfirst-linetestsofgenotoxicitygavenegativeresultswhenconductedwithcyproteroneacetate.However,

furthertestsshowedthatcyproteroneacetatewascapableofproducingadductswithDNA(andanincreaseinDNA

repairactivity)inlivercellsfromratsandmonkeysandalsoinfreshlyisolatedhumanhepatocytes,theDNA-adduct

levelindoglivercellswasextremelylow.

ThisDNA-adductformationoccurredatsystemicexposuresthatmightbeexpectedtooccurintherecommendeddose

regimensforcyproteroneacetate.Invivoconsequencesofcyproteroneacetatetreatmentweretheincreasedincidence

offocal,possiblypre-neoplastic,liverlesionsinwhichcellularenzymeswerealteredinfemalerats,andanincreaseof

mutationfrequencyintransgenicratscarryingabacterialgeneastargetformutations.

Clinicalexperienceandwellconductedepidemiologicaltrialstodatewouldnotsupportanincreasedincidenceof

hepatictumorsinman.Nordidinvestigationsintothetumorigenicityofcyproteroneacetateinrodentsrevealany

indicationofaspecifictumorigenicpotential.

However,itmustbeborneinmindthatsexualsteroidscanpromotethegrowthofcertainhormone-dependenttissues

andtumors.

Onthewhole,theavailablefindingsdonotraiseanyobjectiontotheuseofDianetteinhumansifusedinaccordance

Irish Medicines Board

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

Povidone

Talc

Magnesiumstearate

Sucrose

Polyethyleneglycol6000

Calciumcarbonate

Glycerol

Titaniumdioxide(E171)

Yellowferricoxidepigment(E172)

Montanglycolwax

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25 °

6.5Natureandcontentsofcontainer

OutercartoncontainsaluminiumfoilandPVCblistercalenderpackcontaining21tablets.Eachcartoncontainsone

blistercalenderpack.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7PARALLELPRODUCTAUTHORISATIONHOLDER

McDowellPharmaceuticals

4AltonaRoad

Lisburn

N.Ireland

BT275QB

8PARALLELPRODUCTAUTHORISATIONNUMBER

Irish Medicines Board

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:29thofOctober2010

Irish Medicines Board

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