DIANETTE

Main information

  • Trade name:
  • DIANETTE Coated Tablets 2 / 0.035 Milligram
  • Dosage:
  • 2 / 0.035 Milligram
  • Pharmaceutical form:
  • Coated Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DIANETTE Coated Tablets 2 / 0.035 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/050/001A
  • Authorization date:
  • 16-10-1998
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Dianette2mg/35microgramCoatedTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains2mgcyproteroneacetateand35microgramsethinyloestradiol.

Excipients:

Lactose

Sucrose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Coatedtablet(Tablet).

Round,beige,sugar-coatedtablets.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Foruseinthemanagementofsevereacnevulgaris,especiallythoseformswhichareaccompaniedbyseborrhoeaorby

inflammationorformationofnodes(acnepapulopustulosa,acnenodulocystica)inwomen.

Oralcontraceptionforthewomansufferingfromtheabove.

AlthoughDianettealsoactsasanoralcontraceptive,itshouldnotbeusedinwomensolelyforcontraception,but

shouldbereservedforthosewomenrequiringtreatmentfortheandrogen-dependentconditionsdescribed.

4.2Posologyandmethodofadministration

HowtotakeDianette

Dianetteistobetakenregularlyinordertoachievethetherapeuticefficacyandtherequiredcontraceptiveprotection.

Combinedoralcontraceptiveswhentakencorrectlyhaveafailurerateofapproximately1%peryear.

Tabletsmustbetakenintheorderdirectedonthepackageeverydayataboutthesametimewithsomeliquidas

needed.Onetabletistobetakendailyfor21consecutivedays.Eachsubsequentpackisstartedaftera7-daytablet-free

interval,duringwhichtimeawithdrawalbleedusuallyoccurs.Thisusuallystartsonday2-3afterthelasttabletand

maynothavefinishedbeforethenextpackisstarted.

HowtostartDianette

Noprecedinghormonalcontraceptiveuse(inthepastmonth)

Tablet-takinghastostartonday1ofthewoman'snaturalcycle(i.e.thefirstdayofhermenstrualbleeding).Startingon

days2-5isallowed,butduringthefirstcycleabarriermethodisrecommendedinadditionforthefirst7daysof

tablet-taking.

Switchingfromacombinedhormonalcontraceptive(combinedoralcontraceptive/COC,vaginalringortransdermal

patch)

ThewomanshouldstartwithDianettepreferablyonthedayafterthelastactivetablet(thelasttabletcontainingthe

activesubstances)ofherCOC,butatthelatestonthedayfollowingtheusualtablet-freeorplacebotabletintervalof

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thedayofremoval,butatthelatestwhenthenextapplicationwouldhavebeendue.

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

system(IUS)

Thewomanmayswitchanydayfromtheminipill(fromanimplantortheIUSonthedayofitsremoval,froman

injectablewhenthenextinjectionwouldbedue),butshouldinallofthesecasesbeadvisedtoadditionallyuseabarrier

methodforthefirst7daysoftablet-taking.

Followingfirst-trimesterabortion

Thewomanmaystartimmediately.Whendoingso,sheneednottakeadditionalcontraceptivemeasures.

Followingdeliveryorsecond-trimesterabortion

Womenshouldbeadvisedtostartatday21to28afterdeliveryorsecond-trimesterabortion.Whenstartinglater,the

womanshouldbeadvisedtoadditionallyuseabarriermethodforthefirst7daysoftablet-taking.However,if

intercoursehasalreadyoccurred,pregnancyshouldbeexcludedbeforetheactualstartofDianetteuseorthewoman

hastowaitforherfirstmenstrualperiod.

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

shouldbetaken.

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

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andthatDianetteisnotcontinuedsolelytoprovideoralcontraception.RepeatcoursesofDianettemaybegivenifthe

androgen-dependentacnerecurs.Inthiscase,anearlyrestartofDianetteshouldbeconsidered.

4.3Contraindications

Combinedoralcontraceptives(COCs)shouldnotbeusedinthepresenceofanyoftheconditionslistedbelow.Should

anyoftheconditionsappearforthefirsttimeduringCOCuse,Dianetteshouldbestoppedimmediately.

Presenceorhistoryofvenousthrombosis(deepvenousthrombosis,pulmonaryembolism).

Presenceorhistoryofarterialthrombosis(myocardialinfarction,cerebrovascularaccident)orprodromal

conditions(e.g.transientischaemicattack,anginapectoris).

Knownpredispositionforvenousorarterialthrombosis,suchasantithrombinIIIdeficiency,proteinC

deficiency,proteinSdeficiency,ActivatedProteinC(APC)resistance(e.g.FactorVLeiden),

hyperhomocysteinaemia,andantiphospholipidantibodies.

Historyofmigrainewithfocalneurologicalsymptoms.

Diabetesmellituswithvascularinvolvement.

Thepresenceofasevereormultipleriskfactor(s)forvenousorarterialthrombosismayalsoconstitutea

contraindication(seeundersection4.4,Specialwarningsandprecautionsforuse).

Pancreatitisorahistorythereofifassociatedwithseverehypertriglyceridemia.

Presenceorhistoryofseverehepaticdiseaseaslongasliverfunctionvalueshavenotreturnedtonormal.

Presenceorhistoryoflivertumors(benignormalignant).

Knownorsuspectedsex-steroidinfluencedmalignancies(e.g.ofthegenitalorgansorthebreasts).

Undiagnosedvaginalbleeding.

Knownorsuspectedpregnancy.

Lactation.

Hypersensitivitytotheactivesubstancesortoanyoftheexcipients.

Porphyria.

Uncontrolledhypertension.

4.4Specialwarningsandprecautionsforuse

Warnings

Ifanyoftheconditions/riskfactorsmentionedbelowispresent,thebenefitsoftheuseofDianetteshouldbeweighed

againstthepossibleriskforeachindividualwomananddiscussedwiththewomanbeforeshedecidestostartusingit.

Intheeventofaggravation,exacerbationorfirstappearanceofanyoftheseconditionsorriskfactors,thewoman

shouldcontactherphysician.ThephysicianshouldthendecideonwhetheruseofDianetteshouldbediscontinued.

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

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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

hereditarypredispositionissuspectedthewomanshouldbereferredtoaspecialistforadvicebeforedecidingaboutany

hormonalcontraceptiveuse;

-Obesity(bodymassindexover30kg/m 2

-Prolongedimmobilization,majorsurgery,anysurgerytothelegs,ormajortrauma.Inthesesituationsitisadvisable

todiscontinueCOCuse(inthecaseofelectivesurgeryatleastfourweeksinadvance)andnottoresumeuntiltwo

weeksaftercompleteremobilization;

-Theincreasedriskofvenousthromboembolisminthepuerperiummustbeconsidered(seesection4.6,Pregnancy

andlactation);

-Andpossiblyalsowithsuperficialthrombophlebitisandvaricoseveins.Thereisnoconsensusaboutthepossiblerole

oftheseconditionsintheetiologyofvenousthromboembolism.

TheuseofCOCsingeneralhasbeenassociatedwithanincreasedriskofarterialthrombotic/thromboembolicevents

suchasacutemyocardialinfarction(AMI)orcerebrovascularaccidenti.e.stroke,ariskthatisstronglyinfluencedby

thepresenceofotherriskfactors(e.g.smoking,highbloodpressureandage)(seealsobelow).Theseeventsoccur

rarely.IthasnotbeenstudiedhowDianettemodifiestheriskofAMI.

Theriskofarterialthrombotic/thromboembolicevents(cerebrovascularaccident,myocardialinfarction,peripheral

arterydisease)increaseswith:

-Increasingage;

-Smoking(withheaviersmokingandincreasingagetheriskfurtherincreases,especiallyinwomenover35yearsof

age).Therefore,theCOCusershouldberecommendedtostopsmoking.Inwomenover35yearsofage,analternative

contraceptivemethodshouldbediscussed;

-Apositivefamilyhistory(i.e.venousorarterialthromboembolismeverinasiblingorparentatarelativelyearlyage).

Ifahereditarypredispositionissuspected,thewomanshouldbereferredtoaspecialistforadvicebeforedeciding

aboutanyCOCuse;

-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.Becausebreastcancerisrareinwomenunder40yearsof

age,theexcessnumberofbreastcancerdiagnosesincurrentandrecentCOCusersissmallinrelationtotheoverall

riskofbreastcancer.Thesestudiesdonotprovideevidenceforcausation.

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effectsofCOCsoracombinationofboth.Thebreastcancersdiagnosedinever-userstendtobelessadvanced

clinicallythanthecancersdiagnosedinnever-users.

Inrarecases,benignlivertumors,andevenmorerarely,malignantlivertumorshavebeenreportedinusersofCOCs.

Inisolatedcases,thesetumorshaveledtolife-threateningintra-abdominalhemorrhages.Ahepatictumorshouldbe

consideredinthedifferentialdiagnosiswhensevereupperabdominalpain,liverenlargementorsignsofintra-

abdominalhemorrhageoccurinwomentakingCOCs.

Otherconditions

Womenwithhypertriglyceridemia,orafamilyhistorythereof,maybeatanincreasedriskofpancreatitiswhenusing

COCs.

AlthoughsmallincreasesinbloodpressurehavebeenreportedinmanywomentakingCOCs,clinicallyrelevant

increasesarerare.However,ifasustainedclinicallysignificanthypertensiondevelopsduringtheuseofaCOCthenit

isprudentforthephysiciantowithdrawtheCOCandtreatthehypertension.Whereconsideredappropriate,COCuse

mayberesumedifnormotensivevaluescanbeachievedwithantihypertensivetherapy.

ThefollowingconditionshavebeenreportedtooccurordeterioratewithbothpregnancyandCOCuse,butthe

evidenceofanassociationwithCOCuseisinconclusive:hemolyticuremicsyndrome;Sydenham'schorea;herpes

gestationis.

Inwomenwithhereditaryangioedema,exogenousoestrogensmayinduceorexacerbatesymptomsofangioedema.

AcuteorchronicdisturbancesofliverfunctionmaynecessitatethediscontinuationofCOCuseuntilmarkersofliver

functionreturntonormal.Recurrenceofcholestaticjaundicewhichoccurredfirstduringpregnancyorprevioususeof

sexsteroidsnecessitatesthediscontinuationofCOCs.

TheuseofCOCsmayhaveaneffectonperipheralinsulinresistanceandglucosetolerance.Therefore,diabeticwomen

shouldbecarefullymonitoredduringthefirstmonthsofCOCuse.

Crohn'sdiseaseandulcerativecolitishavebeenassociatedwithCOCuse.

Chloasmamayoccasionallyoccur,especiallyinwomenwithahistoryofchloasmagravidarum.Womenwitha

tendencytochloasmashouldavoidexposuretothesunorultravioletradiationwhilsttakingCOCs.

HerbalpreparationscontainingSt.John'swort(Hypericumperforatum)shouldnotbeusedwhiletakingDianettedueto

theriskofdecreasedplasmaconcentrationsandreducedclinicaleffectsofDianette(seesection4.5,Interactionwith

othermedicinalproductsandotherformsofinteraction).

Medicalexamination/consultation

AcompletemedicalhistoryandphysicalexaminationshouldbetakenpriortotheinitiationorreinstitutionofDianette,

guidedbythecontraindicationsandwarnings(seesection4.3,Contraindicationsandsection4.4,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

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use.

Ifbleedingirregularitiespersistoroccurafterpreviouslyregularcycles,thennon-hormonalcausesshouldbe

consideredandadequatediagnosticmeasuresareindicatedtoexcludemalignancyandpregnancy.Thesemayinclude

curettage.

Insomewomenwithdrawalbleedingmaynotoccurduringthetablet-freeinterval.IftheCOChasbeentaken

accordingtothedirectionsdescribedinsection4.2,Posologyandmethodofadministrationitisunlikelythatthe

womanispregnant.However,iftheCOChasnotbeentakenaccordingtothesedirectionspriortothefirstmissed

withdrawalbleedoriftwowithdrawalbleedsaremissed,pregnancymustberuledoutbeforeCOCuseiscontinued.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactions

Interactionsbetweenoestrogen-progestogencombinationslikeDianetteandotherdrugsmayleadtobreakthrough

bleedingand/orcontraceptivefailure.Thefollowinginteractionshavebeenreportedintheliterature.

Hepaticmetabolism:Interactionscanoccurwithdrugsthatinducemicrosomalenzymeswhichcanresultinincreased

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

oxcarbazepine,topiramate,felbamate,griseofulvinandproductscontainingSt.John'swort).

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

combinationsofthem,havebeenreportedtopotentiallyaffecthepaticmetabolism.

InterferencewithEnterohepaticCirculation:Someclinicalreportssuggestthatenterohepaticcirculationofoestrogens

maydecreasewhencertainantibioticagentsaregiven,whichmayreduceethinylestradiolconcentrations(e.g.

penicillins,tetracyclines).

WomenontreatmentwithanyofthesedrugsshouldtemporarilyuseabarriermethodinadditiontoDianetteorchoose

anothermethodofcontraception.Withmicrosomalenzyme-inducingdrugs,thebarriermethodshouldbeusedduring

thetimeofconcomitantdrugadministrationandfor28daysaftertheirdiscontinuation.Womenontreatmentwith

antibiotics(exceptrifampicinandgriseofulvin)shouldusethebarriermethoduntil7daysafterdiscontinuation.Ifthe

periodduringwhichthebarriermethodisusedrunsbeyondtheendofthetabletsintheDianettepack,thenextpack

shouldbestartedwithouttheusualtablet-freeinterval.

Oestrogen/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(seesection5.3Preclinicalsafetydata).

Althoughlowdoseexposuretocyproteroneacetateduringpregnancyhasnotbeenassociatedwithteratogeniceffects

ormalformations,clinicaldataonfetaloutcomesfollowingexposuretocyproteroneacetateislimited.

Animalstudieshaverevealedthatfeminizationofmalefetusesmayoccurifcyproteroneacetateisadministeredduring

thephaseofembryogenesisatwhichdifferentiationoftheexternalgenitaliaoccurs.Althoughtheresultsofthesetests

arenotnecessarilyrelevanttoman,thepossibilitymustbeconsideredthatadministrationofDianettetowomenafter

the45 th

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contra-indicationfortreatmentwithDianette,andmustbeexcludedbeforesuchtreatmentisbegun(seesection5.3

Preclinicalsafetydata).

TheadministrationofDianetteisalsocontraindicatedduringlactation.Cyproteroneacetateistransferredintothemilk

oflactatingwomen.About0.2%ofthematernaldosewillreachthenewbornviamilkcorrespondingtoadoseof

about1mcg/kg.0.02%ofthedailymaternaldoseofethinylestradiolcouldbetransferredtothenewbornviamilk

duringestablishedlactation.

4.7Effectsonabilitytodriveandusemachines

Notapplicable

4.8Undesirableeffects

ThemostseriousundesirableeffectsassociatedwiththeuseofCOCsarelistedinsection4.4,Specialwarningsand

precautionsforuse.

OthersideeffectsthathavebeenreportedinusersofDianettebutforwhichtheassociationhasbeenneitherconfirmed

norrefutedare:

*ThemostappropriateMedDRAterm(version7.0)todescribeacertainadversereactionislisted.Synonymsorrelated

conditionsarenotlisted,butshouldbetakenintoaccountaswell.

Inwomenwithhereditaryangioedema,exogenousoestrogensmayinduceorexacerbatesymptomsofangioedema.

4.9Overdose

Therehavebeennoreportsofseriousdeleteriouseffectfromoverdose.Symptomsthatmayoccurinthiscaseare:

nausea,vomitingand,inyounggirls,slightvaginalbleeding.

Therearenoantidotesandfurthertreatmentshouldbesymptomatic.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

SystemOrganClass

Common( ≥1/100)

Uncommon( ≥1/1000

and<1/100) Rare(<1/1000)

Eyedisorders contactlensintolerance

Gastrointestinal

disorders nausea,abdominalpain vomiting,diarrhea

Immunesystem

disorders hypersensitivity

Investigations weightincreased weightdecreased

Metabolismand

nutritiondisorders fluidretention

Nervoussystem

disorders headache migraine

Psychiatricdisorders depressedmood,mood

altered libidodecreased libidoincreased

Reproductivesystem

andbreastdisorders Breastpain,breast

tenderness breasthypertrophy vaginaldischarge,

breastdischarge

Skinandsubcutaneous

tissuedisorders rash,urticaria erythemanodosum,

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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

Absorption

Orallyadministeredcyproteroneacetateisrapidlyandcompletelyabsorbed.Peakserumconcentrationsof15ng/mlare

reachedatabout1.6hoursaftersingleingestion.

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,resulting

inameanoralbioavailabilityofabout45%withalargeinterindividualvariationofabout20–65%.

Distribution

Ethinylestradiolishighlybutnon-specificallyboundtoserumalbumin(approximately98%),andinducesanincrease

intheserumconcentrationsofSHBG.Anapparentvolumeofdistributionofabout2.8–8.6l/kgwasdetermined.

Metabolism

Ethinylestradiolissubjecttopresystemicconjugationinbothsmallbowelmucosaandtheliver.Ethinylestradiolis

primarilymetabolizedbyaromatichydroxylationbutawidevarietyofhydroxylatedandmethylatedmetabolitesare

formed,andthesearepresentasfreemetabolitesandasconjugateswithglucuronidesandsulfate.Theclearancerate

wasreportedtobeabout2.3–7ml/min/kg.

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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

withthedirectionsforthegivenindicationandattherecommendeddose.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactose

Maizestarch

Povidone

Talc

Magnesiumstearate(E572)

Sucrose

Macrogol6000

Calciumcarbonate(E170)

Titaniumdioxide(E171)

Irish Medicines Board

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Date Printed 19/04/2011 CRN 2091912 page number: 9

Montanglycolwax

Yellowferricoxidepigment(E172)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelflifeexpirydateforthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25 °

6.5Natureandcontentsofcontainer

Dianettetabletscomeinblisterpacksof21and63(3x21)tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8PARALLELPRODUCTAUTHORISATIONNUMBER

PA465/50/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:16October1998

Dateoflastrenewal:16October2007

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 19/04/2011 CRN 2091912 page number: 10