Version:1 Colour: Black Size: 400x800 mm Compared toUsersofOralContraceptivesthatContainOtherProgestins Table 1:Estimates(HazardRatios)ofVenous ThromboembolismRiskinCurrentUsersofYasmin agenciesaresummarizedinTableThose thatwererequiredorsponsoredbyregulatory 1. of EEand3mgDRSP)totheriskforusersotherCOCs,includingCOCscontaininglevonorgestrel. A numberofstudieshavecomparedtheriskVTEforusersYasmin (whichcontains0.03mg in Figure1. study [Jick2011]andtheGPRD[Parkin2011]. Theresultsofallthesestudiesarepresented are twonestedcase-controlstudiesthatevaluatedthe riskofnon-fatalidiopathicVTE:thePharMetrics study analysis[vanHylckamaVlieg2009]andthe Germancase-controlstudy[Dinger2010].There Denmark [Lidegaard2009,Lidegaard2011].There aretwocase-controlstudies:theDutchMEGA retrospective cohortstudies:onestudyintheUS fundedbytheFDA(seeTable 1),andtwofrom (LASS), didnotenrolladditionalsubjects,but continued toassessVTErisk.Therearethree Study) [Dinger2007].AnextensionoftheEURAS study, theLong-Term Study ActiveSurveillance Ingenix [Seeger2007],theEuropeanpost-approval safetystudyEURAS(EuropeanActiveSurveillance Overall, therearetwoprospectivecohortstudies (seeTable 1):theUSpost-approvalsafetystudy studies,"otherstudiesofvariousdesignshavebeenconducted. In additiontothese"regulatory contraindicate useofCOCs for VTEincludesmoking,obesity, ofVTE,inadditiontootherfactorsthat andfamily history the risksandbenefitsofaDRSP-containingCOCinlightherriskVTE.Knownfactors COC userorawomanwhoisswitchingfromcontraceptivethatdoesnotcontainDRSP, consider to athree-foldincrease.Beforeinitiatinguseofdrospirenoneandethinylestradioltabletsinnew Epidemiologic studiesthatcomparedtheriskofVTEreportedrangedfromnoincrease thromboembolism (VTE)thanCOCscontainingtheprogestinlevonorgestrelorsomeotherprogestins. (that is,Yasmin), DRSP-containingCOCsmaybeassociatedwithahigherriskofvenous Based onpresentlyavailableinformationDRSP-containingCOCswith0.03mgethinylestradiol Stop drospirenoneandethinylestradioltabletsifanarterialorvenousthrombotic(VTE)eventoccurs. 5.1 5 WARNINGS ANDPRECAUTIONS following: consecutive daysofproductadministration.Instructthepatienttouseanon ethinyl estradioltabletsshouldnotbeconsideredeffectiveasacontraceptiveuntilafterthefirst7 Drospirenone andethinylestradioltabletscanbetakenwithoutregardtomeals. the sametimeeachday, preferablyaftertheeveningmealoratbedtimewithsomeliquid,asneeded. Drospirenone andethinylestradioltabletsshouldbetakenintheorderdirectedonpackageat daily for24consecutivedays,followedbyonewhiteinerttabletonDays25through28. onset ofhermenstrualperiod.Sheshouldtakeonepinkdrospirenoneandethinylestradioltablets one pinkdrospirenoneandethinylestradioltabletsdaily, beginningonthefirstSundayafter During thefirstcycleofdrospirenoneandethinylestradioltabletsuse,instructpatienttotake Sunday Start medication shouldbeconsidered. as back-upduringthefirst7days.Thepossibilityofovulationandconceptionpriortoinitiation The patientshouldbeginhernextandallsubsequent28 medication shouldbeconsidered. as back-upduringthefirst7days.Thepossibilityofovulationandconceptionpriortoinitiation 7 consecutivedaysofproductadministration.Instructthepatienttouseanon-hormonalcontracepti and ethinylestradioltabletsshouldnotbeconsideredeffectiveasacontraceptiveuntilafterthefirst and ethinylestradioltabletsarefirsttakenlaterthanthedayofmenstrualcycle,drospirenone needed. Drospirenoneandethinylestradioltabletscanbetakenwithoutregardtomeals.Ifdrospirenone at thesametimeeachday, preferablyaftertheeveningmealoratbedtimewithsomeliquid,as 28. Drospirenoneandethinylestradioltabletsshouldbetakenintheorderdirectedonpackage tablets dailyfor24consecutivedays,followedbyonewhiteinerttabletonDays25through (The firstdayofmenstruationisDay1.)Sheshouldtakeonepinkdrospirenoneandethinylestradiol one pinkdrospirenoneandethinylestradioltabletsdaily, beginningonDay1ofhermenstrualcycle. During thefirstcycleofdrospirenoneandethinylestradioltabletsuse,instructpatienttotake Day 1Start (Sunday Start). of hermenstrualperiod(Day1Start)oronthefirstSundayafteronset Instruct thepatienttobegintakingdrospirenoneandethinylestradioltabletseitheronfirstday HowtoStartDrospirenoneandEthinylEstradiolTablets 2.2 pills shouldbetakenassoonremembered. tablets mustbetakenexactlyasdirected,intheorderdirectedonblisterpack.Singlemissed To achievemaximumcontraceptiveandPMDDeffectiveness,drospirenoneethinylestradiol missed ortakenincorrectly. Take day. onetabletbymouthatthesametimeevery Thefailureratemayincreasewhenpillsare HowtoTake DrospirenoneandEthinylEstradiolTablets DOSAGEANDADMINISTRATION 2.1 2 treatment ofacneonlyifthepatientdesiresanoralcontraceptiveforbirthcontrol. and haveachievedmenarche. Drospirenoneandethinylestradioltabletsshouldbeusedforthe in womenatleast14yearsofage,whohavenoknowncontraindicationstooralcontraceptivetherapy Drospirenone andethinylestradioltabletsareindicatedforthetreatmentofmoderateacnevulgaris Acne 1.3 syndrome (PMS). Drospirenone andethinylestradioltabletshavenotbeenevaluatedforthetreatmentofpremenstrual In makingthediagnosis,careshouldbetakentoruleoutothercyclicalmooddisorders. to DSM-IVcriteria,withsymptomatologyassessedprospectivelyoveratleasttwomenstrualcycles. social activitiesandrelationshipswithothers.Diagnosisismadebyhealthcareprovidersaccording withworkorschool,usual following onsetofmenses;thedisturbancemarkedlyinterferes In thisdisorder, thesesymptomsoccurregularlyduringthelutealphaseandremitwithinafewdays with PMDDincludebreasttenderness,headache,jointandmusclepain,bloatingweightgain. of energy, changeinappetiteorsleep,andfeelingoutofcontrol.Physicalsymptomsassociated irritability. Otherfeaturesincludedecreasedinterestinusualactivities,difficultyconcentrating,lack IV) includemarkedlydepressedmood,anxietyortension,affectivelability, andpersistentangeror The essentialfeaturesofPMDDaccordingtotheDiagnosticandStatisticalManual-4thedition(DSM- PMDD whenusedformorethanthreemenstrualcycleshasnotbeenevaluated. their methodofcontraception.Theeffectivenessdrospirenoneandethinylestradioltabletsfor premenstrual dysphoricdisorder(PMDD)inwomenwhochoosetouseanoralcontraceptiveas Drospirenone andethinylestradioltabletsarealsoindicatedforthetreatmentofsymptoms PremenstrualDysphoricDisorder(PMDD) 1.2 Drospirenone andethinylestradioltabletsareindicatedforusebywomentopreventpregnancy. OralContraceptive INDICATIONS ANDUSAGE 1.1 1 FULL PRESCRIBINGINFORMATION DRUGINTERACTIONS 7 ADVERSEREACTIONS 6 WARNINGS ANDPRECAUTIONS CONTRAINDICATIONS 5 DOSAGEFORMSANDSTRENGTHS 4 3 DOSAGEANDADMINISTRATION 2 INDICATIONS ANDUSAGE 1 WARNING: CIGARETTESMOKINGANDSERIOUSCARDIOVASCULAR EVENTS FULL PRESCRIBINGINFORMATION: CONTENTS* Pregnancy(4) Livertumorsorliverdisease(4) • Breastcancerorotherestrogen-progestin-sensitive(4) • Undiagnosedabnormaluterinebleeding(4) • Ahighriskofarterialorvenousthromboticdiseases(4) • Adrenalinsufficiency(4) • Renalimpairment(4) • • • 4whiteinerttablets ------CONTRAINDICATIONS------• • order (3): Drosp regarding missedpills,seethe The riskofpregnancyincreaseswitheachactivepinktabletmissed.Foradditionalpatientinstructions Discontinue drospirenoneandethinylestradioltabletsifpregnancyisconfirmed. adhered totheprescribedregimenandmissestwoconsecutiveperiods,ruleoutpregnancy. at thetimeoffirstmissedperiodandtakeappropriatediagnosticmeasures.Ifpatienthas or startedtakingthemonadaylaterthansheshouldhave),considerthepossibilityofpregnancy If thepatienthasnotadheredtoprescribeddosingschedule(missedoneormoreactivetablets according todirections,ifwithdrawalbleedingdoesnotoccur, considerthepossibilityofpregnancy. Although theoccurrenceofpregnancyislowifdrospirenoneandethinylestradioltabletsaretaken her thatifthebleedingispersistentorprolonged,sheshouldconsulthealthcareprovider. Counsel herthatthistypeofbleedingisusuallytransientandwithoutsignificance;however, advise patient tocontinuetakingdrospirenoneandethinylestradioltabletsbytheregimendescribedabove. breakthrough bleedingoccurswhiletakingdrospirenoneandethinylestradioltablets,instructthe Withdrawal bleedingusuallyoccurswithin3daysfollowingthelastpinktablet.Ifspottingor estradiol tabletsshouldbestartedonthedayofremoval. due. Whenswitchingfromanintrauterinecontraceptiveorimplant,drospirenoneandethinyl drospirenone andethinylestradioltabletsshouldbestartedwhenthenextdosewouldhavebeen CONTRAINDICATIONS Do notprescribedrospirenoneandethinylestradioltabletstowomenwhoareknownha 4whiteinerttablets 4 • • Each blisterpack(28film-coatedtablets)containsinthefollowingorder: DOSAGEFORMSANDSTRENGTHS Drospirenone andethinylestradioltabletsUSPareavailableinblisterpacks. 3 regarded asamissedtablet. measures shouldbetaken.Ifvomitingoccurswithin3to4hoursaftertablet-taking,thiscan In caseofseverevomitingordiarrhea,absorptionmaynotbecompleteandadditionalcontraceptive AdviceinCaseofGastrointestinalDisturbances 2.3 days. method ofcontraceptionuntilshehastakendrospirenoneandethinylestradioltabletsfor7consecutive has notyethadaperiod,evaluateforpossiblepregnancy, andinstructhertouseanadditional thromboembolism. Ifthepatientstartsondrospirenoneandethinylestradioltabletspostpartum and ethinylestradioltabletsnoearlierthan4weekspostpartumduetotheincreasedriskof For postpartumwomenwhodonotbreastfeedorafterasecondtrimesterabortion,startdrospirenone against pregnancyprovidedshebeginstakinganewcycleofpinktabletsontheproperday. and ofnoconsequence.Ifthepatientmissesoneormorewhitetablets,sheshouldstillbeprotected Patient Labeling should bestartedwhenthenextapplicationwouldhavebeendue.Whenswitching When switchingfromatransdermalpatchorvaginalring,drospirenoneandethinylestradioltablets When switchingfromamethodotherthanbirthcontrolpill started. be startedonthesamedaythatanewpackofpreviousoralcontraceptivewouldhavebeen When switchingfromanotherbirthcontrolpill,drospirenoneandethinylestradioltabletsshould When switchingfromadifferentbirthcontrolpill she hastakenapinkdrospirenoneandethinylestradioltabletsdailyforsevenconsecutivedays. administration ofthelastwhitetablet,patientshoulduseanothermethodcontraceptionuntil a subsequentcycleofdrospirenoneandethinylestradioltabletsisstartedlaterthanthedayfollowing tablet, regardlessofwhetherornotamenstrualperiodhasoccurredisstillinprogress.Anytime schedule. Sheshouldbegintakingherpinktabletsonthenextdayafteringestionoflastwhite estradiol tabletsonthesamedayofweekthatshebeganherfirstregimen,following Population Studied (Author, Year ofPublication) Epidemiologic Study hormonal contraception) use ofstudycombination (i.e., initiationandcontinuing All users New usersa "FDA-funded study"(2011) new users Initiators, including (Dinger 2007) EURAS users Initiators, includingnew (Seeger 2007) i3 Ingenix by womenwhoareover35yearsofageandsmoke[ of age,andwiththenumbercigarettessmoked.Forthisreason,COCsshouldnotbeused contraceptives (COC)use.Thisriskincreaseswithage,particularlyinwomenover35years Cigarette smokingincreasestheriskofseriouscardiovasculareventsfromcombinationoral WARNING: CIGARETTESMOKINGANDSERIOUSCARDIOVASCULAR EVENTS

Thromboembolic DisordersandOtherVascular Problems d) c) b) a) • • • • • Adrenalinsufficiency Renalimpairment • • . EffectsofCombinedOralContraceptivesonOtherDrugs EffectsofOtherDrugsonCombinedOralContraceptives 7.2 7.1 PostmarketingExperience ClinicalTrials Experience 6.2 6.1 OtherConditions 5.15 Monitoring 5.14 Tests withLaboratory Interference 5.13 Depression 5.12 COCUseBeforeorDuringEarlyPregnancy 5.11 BleedingIrregularities Headache 5.10 CarbohydrateandLipidMetabolicEffects 5.9 GallbladderDisease 5.8 HighBloodPressure 5.7 RiskofLiverEnzymeElevationswithConcomitantHepatitisCTreatment 5.6 LiverDisease 5.5 Carcinoma oftheBreastsandReproductiveOrgans 5.4 Hyperkalemia 5.3 ThromboembolicDisordersandOtherVascular Problems 5.2 5.1 AdviceinCaseofGastrointestinalDisturbances HowtoStartDrospirenoneandEthinylEstradiolTablets 2.3 HowtoTake DrospirenoneandEthinylEstradiolTablets2.2 2.1 Acne PremenstrualDysphoricDisorder(PMDD) 1.3 OralContraceptive 1.2 1.1 with orwithoutdasabuvir(4) Co-administrationwithHepatitisCdrugcombinationscontainingombitasvir, paritaprevir/ritonavir, 24 pinktablets,eachcontaining3mgdrospirenone(DRSP)and0.02ethinylestradiol(EE) contraceptive forbirthcontrol.(1.3) Treat moderateacneforwomenatleast14yearsoldonlyifthepatientdesiresanoral an oralcontraceptiveforcontraception.(1.2) Treat symptomsofpremenstrualdysphoricdisorder(PMDD)forwomenwhochoosetouse 24 pinktabletseachcontaining3mgdrospirenone(DRSP)and0.02ethinylestradiol(EE) • a or levonorgestrel Includes low-doseCOCscontainingthefollowingprogestins: norgestimate,norethindrone, norethindrone dienogest, chlormadinoneacetate,gestodene,cyproterone acetate,norgestimate,or Includes low-doseCOCscontainingthefollowingprogestins:levonorgestrel,desogestrel, levonorgestrel, desogestrel,norgestrel,medroxyprogesterone,orethynodioldiacetate Includes low-doseCOCscontainingthefollowingprogestins:norgestimate,norethindrone, months "New users"-nouseofcombinationhormonalcontraceptionforatleasttheprior6 (5.5) andDrugInteractions(7.3)] or withoutdasabuvirduetothepotentialforALT elevations Use ofHepatitisCdrugcombinationscontainingombitasvir, paritaprevir/ritonavir, with and Precautions(5.10)UseinSpecificPopulations(8.1)] Pregnancy, becausethereisnoreasontouseCOCsduringpregnancy and UseinSpecificPopulations(8.7)] Liver tumors,benignormalignant,liverdisease Warnings andPrecautions(5.3)] Breast cancerorotherestrogen-progestin-sensitivecancer, noworinthepast o o Undiagnosed abnormaluterinebleeding o o o o o o o known to: A highriskofarterialorvenousthromboticdiseases.Examplesincludewomenwhoare a See fullprescribinginformationforcompleteboxedwarning EVENTS WARNING: CIGARETTESMOKINGANDSERIOUSCARDIOVASCULAR . Ifbreakthroughbleedingoccursfollowingmissedtablets,itwillusuallybetransient Have diabetesmellituswithvasculardisease with orwithoutauraifoverage35 Have headacheswithfocalneurologicalsymptomsorhavemigraine Have uncontrolledhypertension (5.1)] Have inheritedoracquiredhypercoagulopathies [see Warnings andPrecautions(5.1)] example, subacutebacterialendocarditiswithvalvulardisease,oratrialfibrillation) Have thrombogenicvalvularorrhythmdiseasesoftheheart(for Have coronary artery disease artery Have coronary Have cerebrovasculardisease Warnings andPrecautions(5.1 embolism,noworinthepast Have deepveinthrombosisorpulmonary Smoke, ifoverage35 • •

contraceptive (COC)use.(4) cardiovascular eventsfromcombinationoral Cigarette smokingincreasestheriskofserious drospirenone andethinylestradioltablets(4). Women over35yearsoldwhosmokeshouldnotuse [see Contraindications(4) " WHAT TODOIFYOUMISSPILLS Levonorgestrel/0.03 mgEE course ofthestudyd Other COCsavailableduringthe Levonorgestrel/0.03 mgEE the courseofstudyd Other COCsavailableduring Levonorgestrel/EE study during theconductof All COCsavailableinEurope study during theconductof All COCsavailableintheUS (all arelow-doseCOCs;with Comparator Product c b £ [see BoxedWarning andWarnings andPrecautions(5.1 0.04mgofEE) . ) ] ] [see Warnings andPrecautions(5.1 [see Warnings andPrecautions(5.1 . [see Warnings andPrecautions(5.5)] - see Contraindications(4) [see Warnings andPrecautions(5.9)] day regimensofdrospirenoneandethinyl [see Warnings andPrecautions(5.8)] [see Warnings andPrecautions(5.7 [see Warnings andPrecautions(5.4) [see Warnings andPrecautions " sectioninthe [see Warnings andPrecautions Hazard Ratio(HR) - hormonal contraceptive (0.5-1.6) HR: 0.9 (1.2-1.8) HR: 1.5 (1.4-2.1) HR: 1.7 (1.1-2.2) HR: 1.6 (1.3-2.4) HR: 1.8 (0.6-1.8) HR: 1 (0.6-1.4) HR: 0.9 (95% CI)

from aninjection, ]. FDA Approved [see Warnings 08/2017 08/2017 v e the [see [see v ) ) ) ) e ] ] ] ] pressure checkandforotherindicatedhealthcare. A womanwhoistakingCOCsshouldhaveayearly visitwithherhealthcareproviderforablood Monitoring 5.14 mineralocorticoid activity. DRSP causesanincreaseinplasma globulin increasewithuseofCOCs regular cycles,checkforcausessuchaspregnancyormalignancy. COCs, especiallyduringthefirstthreemonthsofuse.Ifbleedingpersistsoroccursafterpreviously Unscheduled (breakthroughorintracyclic)bleedingandspottingsometimesoccurinpatientson BleedingIrregularities 5.10 cerebrovascular event)maybeareasonforimmediatediscontinuationoftheCOC. may needincreaseddosesofthyroidhormonebecause serumconcentrationsofthyroid lipids, glucosetolerance,andbindingproteins.Women onthyroidhormonereplacement therapy tests,suchascoagulationfactors, The useofCOCsmaychangetheresultssome laboratory Tests InterferencewithLaboratory 5.13 estradiol tabletsdiscontinuedifdepressionrecurstoaseriousdegree. anddrospirenoneethinyl ofdepressionshouldbecarefullyobserved Women withahistory Depression 5.12 (References: Ingenix[Seeger2007] concomitant medication,p)smoking,q)durationofexposure,r)site of inclusion,j)calendaryear, k)education,l)lengthofuse,m)parity, n)chronicdisease,o) hypertension, c)obesity, d)familyhistory, e)age,f)BMI,g)durationofuse,h)VTEhistory, i)period #Some adjustmentfactorsareindicatedbysuperscriptletters:a)Currentheavysmoking,b) † LASSisanextensionoftheEURASstudy *Comparator "OtherCOCs",includingLNG-containingCOCs > 1indicatesanincreasedriskofVTEforDRSP. Risk ratiosdisplayedonlogarithmicscale;riskratio<1indicatesalowerofVTEforDRSP, Figure 1:VTERiskwithYasmin RelativetoLNG-ContainingCOCs(adjustedrisk#) for pregnancy The administrationoforalcontraceptivestoinducewithdrawalbleedingshouldnotbeusedasatest inadvertently duringearlypregnancy. particularly insofarascardiacanomaliesandlimb-reductiondefectsareconcerned,whentaken have usedoralcontraceptivespriortopregnancy. Studiesalsodonotsuggestateratogenic effect, Extensive epidemiologicalstudieshaverevealednoincreasedriskofbirthdefectsinwomenwho COCUseBeforeorDuringEarlyPregnancy 5.11 regimen andmissestwoconsecutiveperiods,ruleoutpregnancy. missed periodandtakeappropriatediagnosticmeasures.Ifthepatienthasadheredtoprescribed on adaylaterthansheshouldhave),considerthepossibilityofpregnancyattimefirst adhered totheprescribeddosingschedule(missedoneormoreactivetabletsstartedtakingthem If withdrawalbleedingdoesnotoccur, considerthepossibilityofpregnancy. Ifthepatienthasnot existent. encounter post-pillamenorrheaoroligomenorrhea,especiallywhensuchaconditionwaspre- 13 cycles,6to10%ofwomenexperiencedcycleswithnowithdrawalbleeding.Somemay bleeding, eveniftheyarenotpregnant.Basedonsubjectdiariesfromcontraceptiontrialsforupto Women whousedrospirenone andethinylestradioltabletsmayexperienceabsenceofwithdrawal menorrhagia, andmetrorrhagia. out of1,056(1.1%)discontinuedduetomenstrualdisordersincludingintermenstrualbleeding, tablets, 8to25%ofwomenexperiencedunscheduledbleedingper28-daycycle.Atotal12subjects Based onpatientdiariesfromtwocontraceptiveclinicaltrialsofdrospirenoneandethinylestradiol excluded, bleedingirregularitiesmayresolveovertimeorwithachangetodifferentCOC. study [Sidney2011] LASS (Long-Term Study)[Dinger, ActiveSurveillance unpublisheddocumentonfile],FDA-funded An increaseinfrequencyorseverityofmigraineduring tablets ifindicated. recurrent, persistent,orsevere,evaluatethecauseanddiscontinuedrospirenoneethinylestradiol If awomantakingdrospirenoneandethinylestradioltabletsdevelopsnewheadachesthatare Headache 5.9 pancreatitis whenusingCOCs. thereof,maybeatanincreasedriskof Women withhypertriglyceridemia,orafamily history of womenwillhaveadverselipidchangeswhileonCOC’s. Consider alternativecontraceptionforwomenwithuncontrolleddyslipidemias.Asmallproportion tablets. COCsmaydecreaseglucoseintoleranceinadose-relatedfashion. Carefully monitorprediabeticanddiabeticwomenwhoaretakingdrospirenoneethinylestradiol CarbohydrateandLipidMetabolicEffects 5.8 Studies suggestasmallincreasedrelativeriskofdevelopinggallbladderdiseaseamongCOCusers. GallbladderDisease 5.7 with increasingconcentrationofprogestin. likely inolderwomenandwithextendeddurationofuse.Theincidencehypertensionincreases An increaseinbloodpressurehasbeenreportedwomentakingCOCs,andthisismore or hypertensionwithvasculardiseaseshouldnotuseCOCs. ethinyl estradioltabletsifbloodpressurerisessignificantly. Women withuncontrolledhypertension For womenwithwell-controlledhypertension,monitorbloodpressureandstopdrospirenone HighBloodPressure 5.6 with theHepatitisCcombinationdrugregimen. and ethinylestradioltabletscanberestartedapproximately2weeksfollowingcompletionoftreatment GPRD study[Parkin2011] boceprevir), andclarithromycin[ antifungals (e.g.ketoconazole,itraconazole,voriconazole),HIV/HCVproteaseinhibitors(e.g.,indinavir, strong CYP3A4inhibitorlong-termandconcomitantly. Strong CYP3A4inhibitorsincludeazole and NSAIDS.Considermonitoringserumpotassiumconcentrationinhigh-riskpatientswhotakea antagonists, potassium-sparingdiuretics,potassiumsupplementation,heparin,aldosterone may increaseserumpotassiumconcentrationincludeACEinhibitors,angiotensin-IIreceptor have theirserumpotassiumconcentrationcheckedduringthefirsttreatmentcycle.Medicationsthat conditions ordiseaseswithmedicationsthatmayincreaseserumpotassiumconcentrationshould impairment,and adrenalinsufficiency).Women receivingdaily, long-termtreatmentforchronic in patientswithconditionsthatpredisposetohyperkalemia(thatis,renalimpairment,hepatic to a25mgdoseofspironolactone.Drospirenoneandethinylestradioltabletsarecontraindicated mineralocorticoid activity, includingthepotentialforhyperkalemiainhigh-riskpatients,comparable Drospirenone andethinylestradioltabletscontain3mgoftheprogestinDRSPwhichhasanti- Hyperkalemia 5.2 [van HylckamaVlieg2009] [ diplopia, papilledema,orretinalvascularlesions.Evaluateforveinthrombosisimmediately. Stop drospirenoneandethinylestradioltabletsifthereisunexplainedlossofvision,proptosis, Oral contraceptivesmustbeusedwithcautioninwomencardiovasculardiseaseriskfactors. with otherunderlyingriskfactors. years ofage),hypertensivewomenwhoalsosmoke.COCsincreasetheriskforstrokein (thrombotic andhemorrhagicstrokes),although,ingeneral,theriskisgreatestamongolder(>35 COCs havebeenshowntoincreaseboththerelativeandattributablerisksofcerebrovascularevents especially inwomenwithotherriskfactorsfortheseevents. Use ofCOCsalsoincreasestheriskarterialthrombosessuchasstrokesandmyocardialinfarctions, week, whereastheriskofovulationincreasesafterthirdpostpartumweek. are notbreastfeeding.Theriskofpostpartumthromboembolismdecreasesafterthethird Start drospirenoneandethinylestradioltabletsnoearlierthan4weeksafterdelivery, inwomenwho orothersurgeriesknowntohaveanelevatedriskofthromboembolism. weeks aftermajorsurgery If feasible,stopdrospirenoneandethinylestradioltabletsatleast4weeksbeforethrough2 women willdevelopaVTE. not pregnantanddouseoralcontraceptivesarefollowedforoneyear, between1and5ofthese postpartum period.To puttheriskofdevelopingaVTEintoperspective:If10,000womenwhoare contraceptives, forwomenwhouseoralpregnantwomen,andinthe Figure 2showstheriskofdevelopingaVTEforwomenwhoarenotpregnantanddouseoral is discontinued. The riskofthromboembolicdiseaseduetooralcontraceptivesgraduallydisappearsafterCOCuse thesameoradifferentCOC. or greaterpill-freeinterval) that thegreatestriskofVTEispresentafterinitiallystartingaCOCorrestarting(following4week COC users,isgreatestduringthefirst6monthsofuse.Datafromthissafetystudyindicate cohort safetystudyofvariousCOCssuggestthatthisincreasedrisk,ascomparedtoinnon- woman-years. TheriskofVTEishighestduringthefirstyearuse.Datafromalarge,prospective (see Figure2).TheriskofVTEinwomenusingCOCshasbeenestimatedtobe39per10,000 non-users, theratesduringpregnancyareevengreater, especiallyduringthepost-partumperiod Although theabsoluteVTEratesareincreasedforusersofhormonalcontraceptivescomparedto ombitasvir/paritaprevir/ritonavir, withorwithoutdasabuvir drospirenone andethinylestradioltabletspriortostartingtherapywiththecombinationdrugregimen more frequentinwomenusingethinylestradiol-containingmedications,suchasCOCs.Discontinue upper limitofnormal(ULN),includingsomecasesgreaterthan20timestheULN,weresignificantly ombitasvir/paritaprevir/ritonavir, withorwithoutdasabuvir, ALT elevationsgreaterthan5timesthe During clinicaltrialswiththeHepatitisCcombinationdrugregimenthatcontains RiskofLiverEnzymeElevationswithConcomitantHepatitisCTreatment 5.5 subsequent COCuse. ofCOC-relatedcholestasismayhavetheconditionrecurwith cholestasis. Women withahistory ofpregnancy-related Oral contraceptive-relatedcholestasismayoccurinwomenwithahistory million users. COC users.However, theattributableriskoflivercancersinCOCusersislessthanonecaseper Studies haveshownanincreasedriskofdevelopinghepatocellularcarcinoma inlong COC users.Ruptureofhepaticadenomasmaycausedeaththroughintra-abdominalhemorrhage. Hepatic adenomasareassociatedwithCOCuse.Anestimateoftheattributableriskis3.3cases/100,000 normal andCOCcausationhasbeenexcluded. function maynecessitatethediscontinuationofCOCuseuntilmarkersliverreturnto be poorlymetabolizedinpatientswithimpairedliverfunction.Acuteorchronicdisturbancesof Discontinue drospirenoneandethinylestradioltabletsifjaundicedevelops.Steroidhormonesmay LiverDisease 5.4 be duetodifferencesinsexualbehaviorandotherfactors. intraepithelial neoplasia.However, thereiscontroversyabouttheextenttowhichthesefindingsmay canceror Some studiessuggestthatCOCsareassociatedwithanincreaseintheriskofcervical recent studieshavenotconfirmedsuchfindings. some paststudieshavesuggestedthatCOCsmightincreasetheincidenceofbreastcancer, more There issubstantialevidencethatCOCsdonotincreasetheincidenceofbreastcancer. Although estradiol tabletsbecausebreastcancerisahormonally-sensitivetumor. Women whocurrentlyhaveorhadbreastcancershouldnotusedrospirenoneandethinyl CarcinomaoftheBreastsandReproductiveOrgans 5.3 See 17forPATIENT COUNSELINGINFORMATION andFDA-approvedpatientlabeling. Nursing Mothers:Notrecommended;candecreasemilkproduction.(8.3) ------USE INSPECIFICPOPULATIONS------alternative methodofcontraceptionwhenenzymeinducersareusedwithCOCs.(7.1) effectiveness ofCOCsorincreasebreakthroughbleeding.Counselpatientstouseaback-up Drugs orherbalproductsthatinducecertainenzymes(forexample,CYP3A4)maydecreasethe ------DRUG INTERACTIONS------FDA at1-800FDA-1088orwww.fda.gov/medwatch To reportSUSPECTEDADVERSEREACTIONS,contactCyndeaPharmaS.L.at858-333-8411or Figure 2:LikelihoodofDevelopingaVTE PATIENT COUNSELINGINFORMATION *Sections orsubsectionsomittedfromthefullprescribinginformationarenotlisted 17 HOWSUPPLIED/STORAGEANDHANDLING REFERENCES 16 15 CLINICALSTUDIES 14 NONCLINICALTOXICOLOGY 13 CLINICALPHARMACOLOGY DESCRIPTION 12 OVERDOSAGE 11 10 USEINSPECIFICPOPULATIONS 8 • • ------ADVERSE REACTIONS------• • • • • • • ------WARNINGS ANDPRECAUTIONS------See AdverseReactions(6). (6.1) irritability (2.8%),decreasedlibidoincreasedweight(2.5%),andaffectlability(2.1%). (24.9%), nausea(15.8%),headache(13%),breasttenderness(10.5%),fatigue(4.2%), 62Storage 16.2 HowSupplied 16.1 AcneClinicalTrials 14.3 PremenstrualDysphoricDisorderClinicalTrials 14.2 OralContraceptiveClinicalTrial 14.1 Carcinogenesis, Mutagenesis,ImpairmentofFertility 13.1 Pharmacokinetics 12.3 Pharmacodynamics 12.2 MechanismofAction 12.1 Race PatientswithHepaticImpairment 8.8 PatientswithRenalImpairment 8.7 GeriatricUse 8.6 PediatricUse 8.5 NursingMothers 8.4 Pregnancy 8.3 8.1 Tests withLaboratory Interference ConcomitantUseofHCVCombinationTherapy–LiverEnzymeElevation 7.4 7.3 of aVTE.(5.1) contain DRSP, considertherisksandbenefitsofaDRSP-containingCOCinlightherrisk tablets inanewCOCuserorwomanwhoisswitchingfromcontraceptivethatdoesnot levonorgestrel orsomeotherprogestins.Beforeinitiatingdrospirenoneandethinylestradiol be associatedwithahigherriskofvenousthromboembolism(VTE)thanCOCscontaining weeks afterdelivery, inwomenwhoarenotbreastfeeding.(5.1)COCscontainingDRSPmay Stop atleast4weeksbeforeandthrough2aftermajorsurgery. Startnoearlierthan4 The mostfrequentadversereactions( Uterine bleeding: Evaluateirregularbleedingoramenorrhea.(5.9) estradiol tabletsifindicated.(5.8) Headache: Evaluatesignificantchangeinheadachesanddiscontinuedrospirenoneethinyl women withuncontrolleddyslipidemia.(5.7) drospirenone andethinylestradioltablets.Consideranalternatecontraceptivemethodfor Carbohydrate andlipidmetab with uncontrolledhypertensionorvasculardisease.(5.5) High bloodpressure: Donotprescribedrospirenoneandethinylestradioltabletsforwomen Liver disease: Discontinuedrospirenoneandethinylestradioltabletsifjaundiceoccurs.(5.4) concentration. (5.2,7.1,7.2) women onlong-termtreatmentwithmedicationsthatmayincreaseserumpotassium to hyperkalemia.Checkserumpotassiumconcentrationduringthefirsttreatmentcyclein Hyperkalemia: DRSPhasanti-mineralocorticoidactivity. Donotuseinpatientspredisposed V The mostfrequentadversereactions( pain/tenderness (4%)andmoodchanges(2.2%).(6.1) headache/migraine (6.7%),menstrualirregularities(4.7%),nausea/vomiting(4.2%),breast ascular risks: Stopdrospirenone andethinylestradioltabletsifathromboticeventoccurs. [see UseinSpecificPopulations(8.1) 3 , Danish[Lidegaard2009] 9 6 ) , GermanCase-Controlstudy[Dinger2010] ] see ClinicalPharmacology(12.3)

[see DrugInteractions(7.2) 1

, EURAS (European Active Surveillance Study)[Dinger2007] , EURAS(EuropeanActiveSurveillance olic effects: Monitorprediabeticanddiabeticwomentaking renin activityandplasmaaldosteroneinducedby itsmildanti ³ 2%) inPMDDclinicaltrialswere:menstrualirregularities ³ 4 2%) incontraceptionandacneclinicaltrialswere: , Danishreanalysis[Lidegaard2011] 10,000 ] .

COC use(whichmaybeprodromalofa [see Contraindications(4)] ] . ].

If pathologyandpregnancyare 7 , PharMetrics[Jick2011] Revised: 02/2019 - term (>8years) . Drospirenone 5 , MEGAstudy - binding 2 8 , , 24 pink DESCRIPTION Drosperinone andethinylestradioltabletsUSPprovideanoralcontraceptiveregimenconsistingof 11 overdose. of potassiumandsodium,evidencemetabolicacidosis,shouldbemonitoredincases DRSP isaspironolactoneanaloguewhichhasanti-mineralocorticoidproperties.Serumconcentration Overdosage maycausewithdrawalbleedinginfemalesandnausea. OVERDOSAGE There havebeennoreportsofseriousilleffectsfromoverdose,includingingestionbychildren. 10 dioxide. cellulose,polyvinylalcohol,talc,titanium macrogol/PEG, magnesiumstearate,microcrystalline dioxide, yellowironoxide.Thewhiteinertfilm-coatedtabletscontainlactosemonohydrate, monohydrate, macrogol/PEG,magnesiumstearate,polyvinylalcohol,redironoxide,talc,titanium The inactiveingredientsinthepinktabletsarecornstarch, colloidalsilicondioxide,lactose estradiol and4whiteinertfilmcoatedtablets. Japanese versusCaucasianwomen betweenthepharmacokineticsofDRSPorEEin No clinicallysignificantdifferencewasobserved Race 8.8 with severehepaticimpairment. with normalliverfunction.Drospirenoneandethinylestradioltabletshavenotbeenstudiedinwomen with moderateliverimpairmentisapproximatelythreetimeshigherthantheexposureinwomen drug in theclinicaltrialsofadrugcannotbedirectlycomparedtoratesanother conditions,adversereactionratesobserved Because clinicaltrialsareconductedunderwidelyvarying ClinicalTrials Experience 6.1 Adverse reactionscommonlyreportedbyCOCusersare: Contraindications (4)andWarnings andPrecautions(5.4) Drospirenone andethinylestradioltabletsarecontraindicatedinpatientswithhepaticdisease[ PatientswithHepaticImpairment 8.7 For contraception,aPhase3,multicenter, multinational,open vulgaris (N=536). in theadequateandwell-controlledstudiesforcontraception(N=1,056)moderateacne The dataprovidedreflecttheexperiencewithuseofdrospirenoneandethinylestradioltablets Contraception andAcneClinicalTrials Clinical Pharmacology(12.3 is intheupperreferencerange,andwhoareconcomitantlyusingpotassiumsparingdrugs is apotentialtodevelophyperkalemiainsubjectswithrenalimpairmentwhoseserumpotassium DRSP concentrationswereonaverage37%higherthanthoseinthecontrolgroup.Inaddition,there safety andefficacyuptooneyearin1,027womenaged1736whotook women, oncedailyco or theprogestinboth.Inaclinicaldrug-druginteractionstudyconductedinpremenopausal diltiazem,andgrapefruitjuicecanincreasetheplasmaconcentrationsofestrogen erythromycin), ketoconazole, itraconazole,voriconazole,fluconazole),verapamil,macrolides(e.g.,clarithromycin, Concomitant administrationofmoderateorstrongCYP3A4inhibitorssuchasazoleantifungals(e.g., aceta certain COCscontainingEE Substances increasingtheplasmaconcentrationsofCOCs: discontinuing theenzymeinducertoensurecontraceptivereliability. enzyme inducersareusedwithCOCs,andtocontinueback-upcontraceptionfor28daysafter active-controlled studytoevaluatetheeffectof728 drospirenone andethinylestradioltablets.AsecondPhase3studywasasinglecenter, open-label, DRSP systemicexposure.TheexposureofEEwasincreasedmildly CYP3A4 inhibitor, ketoconazole200mgtwicedailyfor10daysresultedinamoderateincreaseof weight (2.5%),andaffectlability(2.1%). breast tenderness(10.5%),fatigue(4.2%),irritability(2.8%),decreasedlibidoincreased hemorrhage [primarilyspotting]andmetrorrhagia)(24.9%),nausea(15.8%),headache(13%), (1.1%), andirritability(1.1%). and metrorrhagia)(4.2%),fatigue(1.8%),breasttenderness(1.4%),depressionheadache irregularity (includingvaginalhemorrhage,menorrhagia,menstrualdisorder, menstruationirregular frequent adversereactionsleadingtodiscontinuationwere:nausea/vomiting(4.6%),menstrual Of 285women,11.6%discontinuedfromtheclinicaltrialsduetoanadversereaction;most PMDD ClinicalTrials menometrorrhagia, menorrhagia,metrorrhagiaandvaginalhemorrhage)(2.2%). frequent adversereactionleadingtodiscontinuationwasmenstrualirregularities(including Of 536women,5.4%discontinuedfromtheclinicaltrialsduetoanadversereaction;most Acne ClinicalTrials nausea/vomiting (1.0%). frequent adversereactionsleadingtodiscontinuationwereheadache/migraine(1.6%)and Of 1,056women,6.6%discontinuedfromtheclinicaltrialsduetoanadversereaction;most Contraception ClinicalTrials failure. Counselwomentouseanalternativemethodofcontraceptionoraback between oralcontraceptivesandotherdrugsmayleadtobreakthroughbleedingand/orcontraceptive griseofulvin, oxcarbazepine,rifampin,topiramateandproductscontainingSt.John’s wort.Interactions hormonal contraceptivesincludephenytoin,barbiturates,carbamazepine,bosentan,felbamate, breakthrough bleeding.Somedrugsorherbalproductsthatmaydecreasetheeffectivenessof including cytochromeP4503A4(CYP3A4),maydecreasetheeffectivenessofCOCsorincrease Substances diminishingtheefficacyofCOCs: EffectsofOtherDrugsonCombinedOralContraceptives 7.1 with hormonalcontraceptivesorthepotentialforenzymealterations DRUGINTERACTIONS Consult thelabelingofallconcurrently-useddrugstoobtainfurtherinformationaboutinteractions 7 Musculoskeletal andconnectivetissuedisorders:Systemiclupuserythematosus boweldisease Gastrointestinal disorders:Inflammatory multiforme nodosum,erythema Skin andsubcutaneoustissuedisorders:Chloasma,angioedema,erythema or effectonperipheralinsulinresistance(includingdiabetesmellitus) Metabolism andnutritiondisorders:Hyperkalemia,hypertriglyceridemia,changesinglucosetolerance Immune systemdisorders:Hypersensitivity(includinganaphylacticreaction) disorders:Gallbladderdisease,liverfunctiondisturbances,tumors Hepatobiliary hypertension (includinghypertensivecrisis) vein thrombosis,cerebralretinalmyocardialinfarction andstroke), Vascular emboli,deep disorders:Venous andarterialthromboembolicevents(includingpulmonary Adverse reactionsaregroupedintoSystemOrganClasses,andorderedbyfrequency. relationship todrugexposure. uncertain size,itisnotalwayspossibletoreliablyestimatetheirfrequencyorestablishacausal ethinyl estradioltablets.Becausethesereactionsarereportedvoluntarilyfromapopulationof The followingadversereactionshavebeenidentifiedduringpostapprovaluseofdrospirenoneand PostmarketingExperience 6.2 PMDD ClinicalTrials Acne ClinicalTrials: Contraception ClinicalTrials Serious AdverseReactions Adverse Reactions( and efficacyofdrospirenoneethinylestradioltabletsduringupto3 indicationoftreatingthesymptomsPMDDevaluatedsafety controlled trialsforthesecondary Two (oneparallelandonecrossoverdesigned)multicenter, double-blind,randomized,placebo design andsettingintheContraceptionAcnestudiesascomparedtoPMDDclinicalprogram. Safety datafromtrialsfortheindicationofPMDDarereportedseparatelyduetodifferencesinstudy PMDD ClinicalTrials depression, depressedmoodandaffectlability)(2.2%). (4.7%), nausea/vomiting(4.2%),breastpain/tenderness(4%)andmoodchanges(moodswings, (6.7%), menstrualirregularities(includingvaginalhemorrhage[primarilyspotting]andmetrorrhagia of 366.5andamolecularformulaC 17,2’(5H)-furan]-3,5’(2H)-dione) isasyntheticprogestationalcompoundandhasmolecularweight hexadecahydro-10,13-dimethylspiro-[17H-dicyclopropa- [6,7:15,16]cyclopenta[a]phenanthrene- Drospirenone (6R,7R,8R,9S,10R,13S,14S,15S,16S,17S)-1,3’,4’,6,6a,7,8,9,10,11,12,13,14,15,15a,16- two multicenter, double-blind,randomized,placebo tablets oncarbohydratemetabolism,lipidsandhemostasisin29womenaged18to35.Foracne, ADVERSEREACTIONS The followingseriousadversereactionswiththeuseofCOCsarediscussedelsewhereinlabeling: 6 radiation whiletakingCOCs. gravidarum. Women withatendencytochloasmashouldavoidexposurethesunorultraviolet of angioedema.Chloasmamayoccasionallyoccur, ofchloasma especially inwomenwithahistory angioedema,exogenousestrogensmayinduceorexacerbatesymptoms In womenwithhereditary OtherConditions 5.15 The structuralformulasareasfollows: plasma concentrationsofestrogenandprogestinhavebeennotedinsomecases nucleoside reversetranscriptaseinhibitors: Human immunodeficiencyvirus(HIV)/HepatitisC(HCV)proteaseinhibitorsandnon- (5.2) andClinicalPharmacology(12.3) Common adversereactions( estradiol tablets. aged 18to42,diagnosedwithPMDDandwhotookatleastonedoseofdrospirenoneethinyl concentrations 1 to10mg.Followingdailydosingofdrospirenone andethinylestradioltablets,steadystateDRSP The pharmacokineticsofDRSParedoseproportional followingsingledosesrangingfrom 2 hoursafteradministrationofdrospirenoneand ethinyl estradiol. it isdosedasafreesteroid.Serumconcentrations ofDRSPandEEreachedpeaklevelswithin1to The bioavailabilityofEEissimilarwhendosedvia a betadexclathrateformulationcomparedtowhen and EEstabilizedbybetadexasaclathrate(molecular inclusioncomplex),hasnotbeenevaluated. absolute bioavailabilityofdrospirenoneandethinyl estradiol,whichisacombinationtabletofDRSP of EEisapproximately40%asaresultpresystemic conjugationandfirst-passmetabolism.The The absolutebioavailabilityofDRSPfromasingleentity tabletisabout76%.Theabsolutebioavailability Absorption Pharmacokinetics 12.3 established. Theimpactoftheantiandrogenicactivity ofDRSPonacneisnotknown. healthy womenwiththisskinconditionhasnotbeen in theseverityoffacialacneotherwise (SHBG) anddecreasesfreetestosterone,therelationshipbetweenthesechangesadecrease sebum production.WhilethecombinationofEEandDRSPincreasessexhormonebindingglobulin Acne vulgarisisaskinconditionwithmultifactorialetiologyincludingandrogenstimulationof Acne 21-day regimen. (1/49, 2%)takingthe24-dayregimenwhoovulatedcomparedto4subjects(4/50,8%)using errors (3missedactivetabletsonDays1to3)duringthesecondtreatmentcycle,therewassubject compared to1subject(1/50,2%)usingthe21-dayregimen.Afterintentionallyintroduceddosing the firsttreatmentcycle,therewerenosubjects(0/49,0%)taking24-dayregimenwhoovulated 7-day pill-freeperiod)onthesuppressionofovarianactivityduringtwotreatmentcycles.During regimens (24-dayactivetabletperiodplus4-daypill-freevs.21-day inhibition. Onestudycomparedtheeffectof3mgDRSP/0.02EEcombinationswithtwodifferent period plus7-daypill-freeperiod).Morethan90%ofsubjectsinthesestudiesdemonstratedovulation hormone (progesteroneandestradiol)analysesduringtwotreatmentcycles(21-dayactivetablet ovarian activityasassessedbymeasurementoffolliclesizeviatransvaginalultrasoundandserum Two studies evaluatedtheeffectof3mgDRSP/0.02EEcombinationsonsuppression Contraception The estrogenindrospirenoneandethinylestradioltabletsisestradiol. Drospirenone isaspironolactoneanaloguewithanti-mineralocorticoidandantiandrogenicactivity. Pharmacodynamics 12.2 changes thatreducethelikelihoodofimplantation. mucuschanges thatinhibitspermpenetrationandtheendometrial mechanisms mayincludecervical COCs lowertheriskofbecomingpregnantprimarilybysuppressingovulation.Otherpossible MechanismofAction CLINICALPHARMACOLOGY 12.1 12 Meets USPDissolutionTest 3. Ethinyl estradiol(19-nor-17 compound andhasamolecularweightof296.4formulaC from thepooleddataset.Themostcommonadversereactions( The adversereactionsseenacrossthe2indicationsoverlapped,andarereportedusingfrequencies tablets, evaluatedthesafetyandefficacyduringupto6cycles. 45 withmoderateacnevulgariswhotookatleastonedoseofdrospirenoneandethinylestradiol COCs IncreasingthePlasmaConcentrationsofCYP450Enzymes interactions withCOCsorthepotentialforenzymealterations. be necessary. Consultthelabelingofconcurrently-useddrugtoobtainfurtherinformationabout glucuronidation. Thismayreduceseizurecontrol;therefore,dosageadjustmentsoflamotrigine significantly decreaseplasmaconcentrationsoflamotrigine,likelyduetoinductionlamotrigine COCs containingEEmayinhibitthemetabolismofothercompounds.havebeenshownto EffectsofCombinedOralContraceptivesonOtherDrugs 7.2 plasma concentrationsofsyntheticsteroids. antibiotics, butclinicalpharmacokineticstudieshavenotshownconsistenteffectsofantibioticson Antibiotics with HIV/HCVproteaseinhibitorsornon-nucleosidereversetranscriptaseinhibitors. clinically relevantconcentrations potentialofDRSPtowardshumanCYPenzymesat Clinical studiesdidnotindicateaninhibitory and tizanidine)canhaveaweakormoderateincrease. CYP2C19 substrates(e.g.,omeprazoleandvoriconazole)CYP1A2theophylline in plasmaconcentrationsofCYP3A4substrates(e.g.,midazolam)while of ahormonalcontraceptivecontainingEEdidnotleadtoanyincreaseoronlyweak Potential toIncreaseSerumPotassiumConcentration because serumconcentrationofthyroid-bindingglobulinincreaseswithuseCOCs. Women onthyroidhormonereplacementtherapymayneedincreaseddosesof elevations containing ombitasvir/paritaprevir/ritonavir, withorwithoutdasabuvir, duetopotentialforALT Do notco-administerdrospirenoneandethinylestradioltabletswithHCVdrugcombinations ConcomitantUsewithHCVCombinationTherapy–LiverEnzymeElevation 7.3 Pharmacology (12.3 that mayincreaseserumpotassiumconcentration potassium concentrationinwomentakingdrospirenoneandethinylestradioltabletswithotherdrugs plasma reninactivityandaldosteroneinducedbyitsmildanti-mineralocorticoidactivity. coagulation factors,lipids,glucosetolerance,andbindingproteins.DRSPcausesanincreasein tests,suchas The useofcontraceptivesteroidsmayinfluencetheresultscertainlaboratory Tests InterferencewithLaboratory 7.4 non-genital birthdefects(includingcardiacanomaliesandlimb pregnancy. Epidemiologicstudiesandmeta-analyseshavenotfoundanincreasedriskofgenitalor There islittleornoincreasedriskofbirthdefectsinwomenwhoinadvertentlyuseCOCsduringearly Pregnancy USEINSPECIFICPOPULATIONS 8.1 8 Warnings andPrecautions(5.12)DrugInteractions(7.2).] her child.Estrogen-containingCOCscanreducemilkproductioninbreastfeedingmothers. When possible,advisethenursingmothertouseotherformsofcontraceptionuntilshehasweaned NursingMothers 8.3 Women whodonotbreastfeedmaystartCOCsnoearlierthanfourweekspostpartum. COCs shouldnotbeusedduringpregnancytotreatthreatenedorhabitualabortion. The administrationofCOCstoinducewithdrawalbleedingshouldnotbeusedasatestforpregnancy. to lowdoseCOCspriorconceptionorduringearlypregnancy. to thoseinacontrolgroupwithCLcr In subjectswithcreatinineclearance(CLcr)of50to79mL/min,serumDRSPlevelswerecomparable Contraindications (4)andWarnings andPrecautions(5.2) Drospirenone andethinylestradioltabletsarecontraindicatedinpatientswithrenalimpairment[ PatientswithRenalImpairment 8.6 not indicatedinthispopulation. Drospirenone andethinylestradioltabletshavenotbeenstudiedinpostmenopausalwomenis GeriatricUse 8.5 of 18andforusersyearsolder. Useofthisproductbeforemenarche isnotindicated. of reproductiveage.Efficacyisexpectedtobethesameforpostpubertaladolescentsunderage Safety andefficacyofdrospirenoneethinylestradioltabletshavebeenestablishedinwomen PediatricUse 8.4 maximal dailydoseofabout0.003mgDRSPinaninfant. dose wasexcretedintothebreastmilkofpostpartumwomenwithin24hours.Thisresultsina After oraladministrationof3mgDRSP/0.03EE(Yasmin) tablets,about0.02%oftheDRSP women. Smallamountsoforalcontraceptivesteroidsand/ormetabolitesarepresentinbreastmilk. less likelytooccuroncebreastfeedingiswell-established;however, itcanoccuratanytimeinsome

and may not reflect the rates observed inpractice. and maynotreflecttheratesobserved m Headache Breasttenderness • Nausea • Irregularuterinebleeding • • Vascular events • Liverdisease • Seriouscardiovasculareventsandstroke • inophen mayincreaseplasmaEEconcentrations,possiblybyinhibitionofconjugation.

active film-coatedtabletseachcontaining3mgofdrospirenoneand0.02ethinyl [see Warnings andPrecautions(5.5)] : Precautions (5.1 There havebeenreportsofpregnancywhiletakinghormonalcontraceptivesand ³ none reportedintheclinicaltrials : cervical dysplasia : cervical ) ] 1%) LeadingtoStudyDiscon . - administration ofDRSP3mg/EE0.02mgcontainingtabletswithstrong [see Warnings andPrecautions(5.4

: migraine and cervical dysplasia : migraineandcervical ) increase AUCvaluesforEEbyapproximately20%.Ascorbicacidand a [see Warnings andPrecautions(5.1 ) ] ] . -pregna ³ 2%ofusers)were:menstrualirregularities(includingvaginal

[see ClinicalPharmacology(12.3)

[see ClinicalPharmacology(12.3) 934-2019-02 ³

24 80 mL/min.InsubjectswithCLcrof30to49mL/min,serum 1,3,5(10)-triene-20-yne-3, 17-diol)isasyntheticestrogenic ] H . 30 O 3 . Drugs orherbalproductsthatinducecertainenzymes,

Significant changes(increaseordecrease)inthe DROSPIRENONE AND . [see Warnings andPrecautions(5.2)Clinical tinuation: - day cyclesofdrospirenoneandethinylestradiol -

controlled studies,in536womenaged14to ETHINYL ESTRADIOL [see BoxedWarning andWarnings and : There isapotentialforanincreaseinserum

] TABLETS ]. . The meanexposuretoDRSPinwomen ³ - - label studywasconductedtoevaluate Co-administration of atorvastatin and Co-administration ofatorvastatin ) 2% ofusers)were:headache/migraine reduction defects)followingexposure ] ) ] : In clinicalstudies,administration

]. [see Warnings andPrecautions

. 2xxxxxx ] .

cycles among285women 20

at leastonedoseof of co-administration H 24 - up methodwhen O 2 .

This is [See [see see see - been pregnant,andyouhavenothadaperiodsinceyourpregnancy. (7 days).Thisalsoappliesifyoustartdrospirenoneandethinylestradioltabletsafterhaving method ifyouhavesexanytimefromtheSundaystartyourfirstpackuntilnext 2. Useanothermethodofbirthcontrol(suchasacondomandspermicide)back-up are stillbleeding.IfyourperiodbeginsonSunday, startthepackthatsameday. 1. Take thefirstpinkpillofpackonSundayafteryourperiodstarts,evenifyou Sunday Start: as acondomandspermicide)back-upmethoduntilyouhavetaken7pinkpills. later thanthefirstdayofyourperiod,youshoulduseanothermethodbirthcontrol(such at thebeginningofyourperiod.However, ifyoustartdrospirenoneandethinylestradioltablets 2. You willnotneedtouseaback-upmethodofbirthcontrol,sinceyouarestartingthePill 1. Take thefirstpinkpillofpackduring24hoursyourperiod. Day 1Start: have beenstarted. should bestartedonthesamedaythatanewpackofpreviousbirthcontrolpillwould W If youmiss3ormorepinkpillsinarow period twomonthsinarow, callyourhealthcare providerbecauseyoumightbepregnant. 3. You maynothave yourperiodthismonthbutisexpected.However, ifyoumissyour those 7days. must useanotherbirthcontrolmethod(suchasacondom and spermicide)asaback-upfor 2. You couldbecome pregnantifyouhavesexinthe7daysafterrestartyourpills.You start anewpackofpillsthatsameday. dayuntilSunday.Keep takingonepillevery OnSunday, throwouttherestofpackand If youareaSundayStarter: Throw outtherestofpillpackandstarta newpackthatsameday. 1. IfyouareaDay1Starter: If youmiss2pinkpillsinarowWeek 3orWeek 4ofyourpack: those 7days. must useanotherbirthcontrolmethod(suchasacondom and spermicide)asaback-upfor 3. You couldbecome pregnantifyouhavesexinthe7daysafterrestartyourpills.You 2. Thentakeonepilladayuntilyoufinishthepack. 1. Take twopillsonthedayyourememberandnextday. If youmiss2pinkpillsinarowWeek 1orWeek 2ofyourpack: 2. You donotneed touseaback-upbirthcontrolmethodifyouhavesex. may taketwopillsinoneday. 1. Take itas soonasyouremember. Take thenextpill atyourregulartime.Thismeansyou If youmiss1pinkpillofyourpack: 2. often. Do notskippillsevenifyoudohavesexvery your stomach(nausea). Do notskippillsevenifyouarespottingorbleedingbetweenmonthlyperiodsfeelsickto 1. Take dayuntilthepackisempty. onepillatthesametimeevery W W W W not waitanydaysbetweenpacks. If youmissany 3. Callyourhealthcareprovider ifyoumissyourperiod,becausemightbepregnant. those 7days. must useanotherbirthcontrol method(suchascondomsandspermicides)aback-up for 2. You couldbecomepregnantifyouhavesexin the 7daysafteryourestartyourpills.You a newpackofpillsthatsame day. dayuntilSunday.Keep taking1pillevery OnSunday, throwouttherestofpackandstart If youareaSundayStarter: Throw outtherestofpillpackandstarta newpackthatsameday. 1. IfyouareaDay1Starter: You donotneedaback-upmethod. Keep takingonepilleachday until thepackisempty. Throw awaythepillsyoumissed. tablets shouldbestartedwhenthenextapplicationwouldhavebeendue. W dose wouldhavebeendue. from aninjection,drospirenoneandethinylestradioltabletsshouldbestartedwhenthenext drospirenone andethinylestradioltabletsshouldbestartedonthedayofremoval. healthcare provider. 7. Ifyouhaveanyquestionsorareunsureabouttheinformationinthisleaflet,callyour to makepill-takingeasieroraboutusinganothermethodofbirthcontrol. 6. Ifyouhavetroublerememberingtotakethepill,talkyourhealthcareproviderabouthow provider. Use aback-upmethod(suchascondomsandspermicides)untilyoucheckwithyourhealthcare your pillsmaynotworkaswell. medicines, includingsomeantibioticsandherbalproductssuchasSt.John'sWort, instructions for"WHAT TODOIFYOUMISSPILLS."Ifyouhavediarrheaoriftakecertain 5. Ifyouhavevomiting(within3to4hoursaftertakeyourpill),shouldfollowthe your stomach. On thedaysyoutaketwopills,tomakeupformissedcouldalsofeelalittlesick pills. 4. Missingpillscanalsocausespottingorlightbleeding,evenwhenyoumakeupthesemissed provider. pill. Theproblemwillusuallygoaway. Ifitdoesnotgoaway, checkwithyourhealthcare If youdohavespottingorlightbleedingfeelsicktoyourstomach,notstoptakingthe stomach duringthefirst1-3packsofpills. 3. Manywomenhavespottingorlightbleedingatunexpectedtimes,mayfeelsicktotheir togetpregnant. and aretrying of thechartshowschancegettingpregnantforwomenwhodonotusebirthcontrol in effectiveness.Themosteffectivemethodsareatthetopofchart.boxonbottom of birthcontrol.Eachboxonthechartcontainsalistcontrolmethodsthataresimilar The followingchartshowsthechanceofgettingpregnantforwomenwhousedifferentmethods during thefirstyeartheyusedrospirenoneandethinylestradioltablets. Based ontheresultsofoneclinicalstudy, 1to2womenoutof100women,maygetpregnant pregnant. birth controlpills.Thebetteryoufollowthedirections,lesschancehaveofgetting Your chanceofgettingpregnantdependsonhowwellyoufollowthedirectionsfortakingyour How Well DoDrospirenoneandEthinylEstradiolTablets Work? You wanttouseabirthcontrolpillpreventpregnancy. You havestartedhavingmenstrualperiods. • You areatleast14yearsold. • • • the followingaretrue: Drospirenone andethinylestradioltabletsmayalsobetakentotreatmoderateacneifallof PMS. ethinyl estradioltabletsonlyifyouwanttopreventpregnancy;andnotforthetreatmentof If youoryourhealthcareproviderbelievehavePMS,shouldtakedrospirenoneand of premenstrualsyndrome(PMS),alessserioussetsymptomsoccurringbeforemenstruation. Drospirenone andethinylestradioltabletshavenotbeenshowntobeeffectiveforthetreatment HavebeendiagnosedwithPMDDbyyourhealthcareprovider. Havealreadydecidedtouseoralcontraceptivesforbirthcontrol,and • • You shouldonlyusedrospirenoneandethinylestradioltabletsfortreatmentofPMDDifyou: should bemadebyhealthcareproviders. starts andgoawaywithinafewdaysfollowingthestartofperiod.DiagnosisPMDD and musclepain,bloatingweightgain.Thesesymptomsoccurregularlybeforemenstruation Physical symptomsassociatedwithPMDDmayincludebreasttenderness,headache,joint difficulty concentrating,lackofenergy, changeinappetiteorsleep,andfeelingoutofcontrol. and persistentangerorirritability. Otherfeaturesincludedecreasedinterestinusualactivities, with others.Symptomsincludemarkedlydepressedmood,anxietyortension,moodswings, withworkorschool,usualsocialactivitiesandrelationships significantly interferes same risksasthePill.PMDDisamooddisorderrelatedtomenstrualcycle. to treatyourPMDDbecausethereareothermedicaltherapiesforthatdonothavethe to usethePillforbirthcontrol,youshouldnotstartdrospirenoneandethinylestradioltablets disorder (PMDD)ifyouchoosetousethePillforbirthcontrol.Unlesshavealreadydecided Drospirenone andethinylestradioltabletsmayalsobetakentotreatpremenstrualdysphoric Aldosteroneantagonists Heparin • Angiotensin-IIreceptorantagonists(Cozaar, Diovan,Avapro andothers) • ACEinhibitors(Capoten,Vasotec, Zestrilandothers) • Potassiumsupplementation • Potassium-sparingdiuretics(spironolactoneandothers) • • • ethinyl estradioltablets,youshouldhaveabloodtesttocheckyourpotassiumlevel. estradiol tabletsarerightforyou,andduringthefirstmonththatyoutakedrospirenone below, youshouldconsult your healthcareprovideraboutwhetherdrospirenoneandethinyl are currentlyondaily, long-termtreatmentforachronicconditionwithanyofthemedications cause seriousheartandhealthproblems.Otherdrugsmayalsoincreasepot The drospirenoneandethinylestradioltabletspillpackhas 2. LookatYour PillPack-Ithas28Pills to meals. some liquid,asneeded.Drospirenoneandethinylestradioltabletscanbetakenwithoutregard day,package atthesametimeevery preferablyaftertheeveningmealoratbedtime,with It isimportanttotakedrospirenoneandethinylestradioltabletsintheorderdirectedon 1. DecideWhatTime ofDayYou Want toTake Your Pill Before Y Guide forUsingDrospirenoneandEthinylEstradiolTablets FDA ApprovedPatientLabeling b) Inwhatordertotakethepills(followarrows) a) Whereonthepacktostarttakingpills, 3. 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during any See "WHAT TODOIFYOUMISSPILLS"below. you miss,themorelikelyaretogetpregnant. includes startingthepacklate.Themorepills If youmisspillscouldgetpregnant.This meals. estradiol tabletscanbetakenwithoutregardto liquid, asneeded.Drospirenoneandethinyl after theeveningmealoratbedtime,withsome directed onthepackage.Preferably, takethepill dayatthesametimeinorder pill every 2. Therightwaytotakethepillisone sure whattodo. start takingyourpillsoranytimeyouarenot 1. Besuretoreadthesedirections Estradiol Tablets? How DoITake DrospirenoneandEthinyl easy toremember. day foryou.Pickatimeofwhichwillbe your healthcareproviderwhichisthebest taking yourfirstpackofpills.Decidewith You haveachoiceforwhichdaytostart W full pillpack. up incaseyoumisspills,and(b)anextra, condoms andspermicides)touseasaback- another kindofbirthcontrol(suchas 4. Besureyouhavereadyatalltimes(a) hen T

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W hen switching beforeyou Finally, if you are still not sure what to do about the pills you have missed: were observed after 8 days. There was about 2 to 3 fold accumulation in serum Cmax and 16.2 Storage AUC (0-24h) values of DRSP following multiple dose administration of drospirenone and ethinyl estradiol Store at 20° to 25°C (68°-77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Use a back-up method (such as condoms and spermicides) anytime you have sex. tablets (see Table 2). Room Temperature]. Contact your healthcare provider and continue taking one active pink pill each day until For EE, steady-state conditions are reported during the second half of a treatment cycle. Following 17 PATIENT COUNSELING INFORMATION otherwise directed. daily administration of drospirenone and ethinyl estradiol tablets, serum Cmax and AUC (0 to 24h) values Advise the patient to read the FDA-approved patient labeling (Patient Information). of EE accumulate by a factor of about 1.5 to 2 (see Table 2). • Counsel patients that cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs. WHO SHOULD NOT TAKE DROSPIRENONE AND ETHINYL ESTRADIOL TABLETS? Table 2: Pharmacokinetic Parameters Of Drospirenone and ethinyl estradiol tablets (DRSP 3 mg • Counsel patients that the increased risk of VTE compared to non-users of COCs is greatest and EE 0.02 mg) Your healthcare provider will not give you drospirenone and ethinyl estradiol tablets if you: after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the • Ever had blood clots in your legs (deep vein thrombosis), lungs (pulmonary embolism), DRSP same or a different COC. a b a a Cycle / No. of Cmax Tmax AUC (0-24h) t1/2 • Counsel patients about the information regarding the risk of VTE with DRSP-containing COCs or eyes (retinal thrombosis) Day Subjects (ng/mL) (h) (ng•h/mL) (h) compared to COCs that contain levonorgestrel or some other progestins. • Counsel patients that drospirenone and ethinyl estradiol tablets do not protect against HIV- • Ever had a stroke 1/1 23 38.4 (25) 1.5 (1 to 2) 268 (19) NAc infection (AIDS) and other sexually transmitted diseases. • Ever had a heart attack 1/21 23 70.3 (15) 1.5 (1 to 2) 763 (17) 30.8 (22) • Counsel patients on Warnings and Precautions associated with COCs. • Have certain heart valve problems or heart rhythm abnormalities that can cause blood EE • Counsel patients that drospirenone and ethinyl estradiol tablets contain DRSP. Drospirenone a b a a Cycle / No. of Cmax Tmax AUC (0-24h) t1/2 may increase potassium. Patients should be advised to inform their healthcare provider if they clots to form in the heart Day Subjects (pg/mL) (h) (pg•h/mL) (h) have kidney, liver or adrenal disease because the use of drospirenone and ethinyl estradiol • Have an inherited problem with your blood that makes it clot more than normal 1/1 23 32.8 (45) 1.5 (1 to 2) 108 (52) NAc tablets in the presence of these conditions could cause serious heart and health problems. They should also inform their healthcare provider if they are currently on daily, long-term • c Have high blood pressure that medicine can’t control 1/21 23 45.1 (35) 1.5 (1 to 2) 220 (57) NA treatment (NSAIDs, potassium-sparing diuretics, potassium supplementation, ACE inhibitors, • Have diabetes with kidney, eye, nerve, or blood vessel damage a) geometric mean (geometric coefficient of variation) angiotensin-II receptor antagonists, heparin or aldosterone antagonists) for a chronic condition • Ever had certain kinds of severe migraine headaches with aura, numbness, weakness or b) median (range) or taking strong CYP3A4 inhibitors. c) NA = Not available • Inform patients that drospirenone and ethinyl estradiol tablets are not indicated during pregnancy. changes in vision If pregnancy occurs during treatment with drospirenone and ethinyl estradiol tablets, instruct Food Effect • Ever had breast cancer or any cancer that is sensitive to female hormones the patient to stop further intake. The rate of absorption of DRSP and EE following single administration of a formulation similar to • Counsel patients to take one tablet daily by mouth at the same time every day. Instruct patients • Have liver disease, including liver tumors drospirenone and ethinyl estradiol tablets was slower under fed (high fat meal) conditions with the what to do in the event pills are missed. See “What to Do if You Miss Pills” section in FDA- • Take any Hepatitis C drug combination containing ombitasvir/paritaprevir/ritonavir, with serum Cmax being reduced about 40% for both components. The extent of absorption of DRSP, Approved Patient Labeling. however, remained unchanged. In contrast, the extent of absorption of EE was reduced by about • Counsel patients to use a back-up or alternative method of contraception when enzyme inducers or without dasabuvir. This may increase levels of the liver enzyme “alanine aminotransferase” 20% under fed conditions. are used with COCs. (ALT) in the blood. Distribution • Counsel patients who are breastfeeding or who desire to breastfeed that COCs may reduce • Have kidney disease DRSP and EE serum concentrations decline in two phases. The apparent volume of distribution of breast milk production. This is less likely to occur if breastfeeding is well established. DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4 to 5 L/kg. • Counsel any patient who starts COCs postpartum, and who has not yet had a period, to use • Have adrenal disease an additional method of contraception until she has taken a pink tablet for 7 consecutive days. DRSP does not bind to SHBG or corticosteroid binding globulin (CBG) but binds about 97% to other Also, do not take birth control pills if you: • Counsel patients that amenorrhea may occur. Rule out pregnancy in the event of amenorrhea serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured in two or more consecutive cycles. • Smoke and are over 35 years old at trough concentrations). EE is reported to be highly but non-specifically bound to serum albumin • Are or suspect you are pregnant (approximately 98.5 %) and induces an increase in the serum concentrations of both SHBG and CBG. EE induced effects on SHBG and CBG were not affected by variation of the DRSP dosage in Birth control pills may not be a good choice for you if you have ever had jaundice (yellowing the range of 2 to 3 mg. of the skin or eyes) caused by pregnancy (also called cholestasis of pregnancy). Metabolism The two main metabolites of DRSP found in human plasma were identified to be the acid form of Tell your healthcare provider if you have ever had any of the above conditions (your DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate, formed by reduction and subsequent sulfation. These metabolites were shown not to be pharmacologically healthcare provider can recommend another method of birth control). Manufactured by: active. Drospirenone is also subject to oxidative metabolism catalyzed by CYP3A4. Cyndea Pharma, S.L., What Else Should I Know about Taking Drospirenone and Ethinyl Estradiol Tablets? EE has been reported to be subject to significant gut and hepatic first-pass metabolism. Metabolism S.L., Ólvega (Soria), 42110 Birth control pills do not protect you against any sexually transmitted disease, including HIV, of EE and its oxidative metabolites occur primarily by conjugation with glucuronide or sulfate. CYP3A4 Spain the virus that causes AIDS. in the liver is responsible for the 2-hydroxylation which is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal Distributed by: Do not skip any pills, even if you do not have sex often. excretion. If you miss a period, you could be pregnant. However, some women miss periods or have Excretion ® DRSP serum concentrations are characterized by a terminal disposition phase half-life of approximately light periods on birth control pills, even when they are not pregnant. Contact your healthcare 30 hours after both single and multiple dose regimens. Excretion of DRSP was nearly complete after provider for advice if you: ten days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively Camber Pharmaceuticals, Inc. • Think you are pregnant metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least Piscataway, USA 20 different metabolites were observed in urine and feces. About 38 to 47% of the metabolites in • Miss one period and have not taken your birth control pills every day urine were glucuronide and sulfate conjugates. In feces, about 17 to 20% of the metabolites were Revised: 02/2019 • Miss two periods in a row excreted as glucuronides and sulfates. 2xxxxxx Birth control pills should not be taken during pregnancy. However, birth control pills For EE the terminal disposition phase half-life has been reported to be approximately 24 hours. EE is not excreted unchanged. EE is excreted in the urine and feces as glucuronide and sulfate conjugates taken by accident during pregnancy are not known to cause birth defects. and undergoes enterohepatic circulation. You should stop drospirenone and ethinyl estradiol tablets at least four weeks before you have Use in Specific Populations major surgery and not restart it until at least two weeks after the surgery due to an increased Pediatric Use: Safety and efficacy of drospirenone and ethinyl estradiol tablets have been established risk of blood clots. in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 and for users 18 years and older. Use of this product before menarche is not If you are breastfeeding, consider another birth control method until you are ready to stop indicated. breastfeeding. Birth control pills that contain estrogen, like drospirenone and ethinyl estradiol Geriatric Use: Drospirenone and ethinyl estradiol tablets have not been studied in postmenopausal tablets, may decrease the amount of milk you make. A small amount of the pill's hormones women and is not indicated in this population. pass into breast milk. Race: No clinically significant difference was observed between the pharmacokinetics of DRSP or If you have vomiting or diarrhea, your birth control pills may not work as well. Use another EE in Japanese versus Caucasian women (age 25 to 35) when 3 mg DRSP/0.02 mg EE was birth control method, like condoms and a spermicide, until you check with your healthcare administered daily for 21 days. Other ethnic groups have not been specifically studied. Renal Impairment: Drospirenone and ethinyl estradiol tablets are contraindicated in patients with provider. renal impairment. If you are scheduled for any laboratory tests, tell your doctor you are taking birth-control pills. The effect of renal impairment on the pharmacokinetics of DRSP (3 mg daily for 14 days) and the Certain blood tests may be affected by birth-control pills. effect of DRSP on serum potassium concentrations were investigated in three separate groups of female subjects (n=28, age 30 to 65). All subjects were on a low potassium diet. During the study, Tell your healthcare provider about all the medicines you take, including prescription 7 subjects continued the use of potassium-sparing drugs for the treatment of their underlying illness. and overthe-counter medicines, vitamins and herbal supplements. On the 14th day (steady-state) of DRSP treatment, the serum DRSP concentrations in the group with CLcr of 50 to 79 mL/min were comparable to those in the control group with CLcr ³80 mL/min. Drospirenone and ethinyl estradiol tablets may affect the way other medicines work, and other The serum DRSP concentrations were on average 37% higher in the group with CLcr of 30 to 49 medicines may affect how well drospirenone and ethinyl estradiol tablets work. Know the mL/min compared to those in the control group. DRSP treatment did not show any clinically significant medicines you take. effect on serum potassium concentration. Although hyperkalemia was not observed in the study, in five of the seven subjects who continued use of potassium-sparing drugs during the study, mean Keep a list of them to show your healthcare provider and pharmacist when you get a new serum potassium concentrations increased by up to 0.33 mEq/L. [See Contraindications (4) and medicine. Warnings and Precautions (5.2).] What are the Most Serious Risks of Taking Birth Control Pills? Hepatic Impairment: Drospirenone and ethinyl estradiol tablets are contraindicated in patients with Like pregnancy, birth control pills increase the risk of serious blood clots (see following graph), hepatic disease. The mean exposure to DRSP in women with moderate liver impairment is approximately three times especially in women who have other risk factors, such as smoking, obesity, or age greater higher than the exposure in women with normal liver function. Drospirenone and ethinyl estradiol than 35. This increased risk is highest when you first start taking birth control pills and when tablets have not been studied in women with severe hepatic impairment. [See Contraindications (4) you restart the same or different birth control pills after not using them for a month or more. and Warnings and Precautions (5.4).] Women who use birth control pills with drospirenone (like drospirenone and ethinyl estradiol Drug Interactions Consult the labeling of all concurrently used drugs to obtain further information about interactions tablets) may have a higher risk of getting a blood clot. Some studies reported that the risk of with oral contraceptives or the potential for enzyme alterations. blood clots was higher for women who use birth control pills that contain drospirenone than Effects of Other Drugs on Combined Oral Contraceptives for women who use birth control pills that do not contain drospirenone. Substances diminishing the efficacy of COCs: Drugs or herbal products that induce certain enzymes, Talk with your healthcare provider about your risk of getting a blood clot before deciding including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. which birth control pill is right for you. Substances increasing the plasma concentrations of COCs: Co-administration of atorvastatin and certain COCs containing EE increase AUC values for EE by approximately 20%. Ascorbic acid and It is possible to die or be permanently disabled from a problem caused by a blood clot, such acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. In a clinical drug-drug interaction study conducted in 20 premenopausal women, co-administration of as a heart attack or a stroke. Some examples of serious clots are blood clots in the: a DRSP (3 mg)/EE (0.02 mg) COC with the strong CYP3A4 inhibitor ketoconazole (200 mg twice • Legs (deep vein thrombosis or DVT) daily) for 10 days increased the AUC(0 to 24h) of DRSP and EE by 2.68-fold (90% CI: 2.44, 2.95) and • Lungs (pulmonary embolus or PE) 1.40-fold (90% CI: 1.31, 1.49), respectively. The increases in Cmax were 1.97-fold (90% CI: 1.79, • 2.17) and 1.39-fold (90% CI: 1.28, 1.52) for DRSP and EE, respectively. Although no clinically Eyes (loss of eyesight) relevant effects on safety or laboratory parameters including serum potassium were observed, this • Heart (heart attack) study only assessed subjects for 10 days. The clinical impact for a patient taking a DRSP-containing • Brain (stroke) COC concomitantly with chronic use of a CYP3A4/5 inhibitor is unknown [see Warnings and Precautions (5.2)]. To put the risk of developing a blood clot into perspective: If 10,000 women who are not HIV/HCV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant pregnant and do not use birth control pills are followed for one year, between 1 and 5 of these changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been women will develop a blood clot. The figure below shows the likelihood of developing a serious noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside blood clot for women who are not pregnant and do not use birth control pills, for women who reverse transcriptase inhibitors. use birth control pills, for pregnant women, and for women in the first 12 weeks after delivering Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on a baby. plasma concentrations of synthetic steroids. Effects of Combined Oral Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Consult the labeling of the concurrently-used drug to obtain further information about interactions with COCs or the potential for enzyme alterations. In vitro, EE is a reversible inhibitor of CYP2C19, CYP1A1 and CYP1A2 as well as a mechanism-based inhibitor of CYP3A4/5, CYP2C8, and CYP2J2. Metabolism of DRSP and potential effects of DRSP on hepatic CYP enzymes have been investigated in in vitro and in vivo studies. In in vitro studies DRSP did not affect turnover of model substrates of CYP1A2 and CYP2D6, but had an inhibitory influence on the turnover of model substrates of CYP1A1, CYP2C9, CYP2C19, and CYP3A4, with CYP2C19 being the most sensitive enzyme. The potential effect of DRSP on CYP2C19 activity was investigated in a clinical pharmacokinetic study using omeprazole as a marker substrate. In the study with 24 postmenopausal women [including 12 women with homozygous (wild type) CYP2C19 genotype and 12 women with heterozygous CYP2C19 genotype] the daily oral administration of 3 mg DRSP for 14 days did not affect the oral clearance of omeprazole (40 mg, single oral dose) and the CYP2C19 product 5-hydroxy omeprazole. Furthermore, no significant effect of DRSP on the systemic clearance of the CYP3A4 product omeprazole sulfone was found. These results demonstrate that DRSP did not inhibit CYP2C19 and CYP3A4 in vivo. Two additional clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4 were each performed in 24 healthy postmenopausal women. The results of 10,000 these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady state DRSP concentrations achieved after administration of 3 mg DRSP/day. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs. Interactions With Drugs That Have the Potential to Increase Serum Potassium Concentration: A few women who take birth control pills may get: There is a potential for an increase in serum potassium concentration in women taking drospirenone and ethinyl estradiol tablets with other drugs that may increase serum potassium concentration [see • High blood pressure Warnings and Precautions (5.2)]. • Gallbladder problems A drug-drug interaction study of DRSP 3 mg/estradiol (E2) 1 mg versus placebo was performed in • Rare cancerous or noncancerous liver tumors 24 mildly hypertensive postmenopausal women taking enalapril maleate 10 mg twice daily. Potassium concentrations were obtained every other day for a total of 2 weeks in all subjects. Mean serum All of these events are uncommon in healthy women. potassium concentrations in the DRSP/E2 treatment group relative to baseline were 0.22 mEq/L Call your healthcare provider right away if you have: higher than those in the placebo group. Serum potassium concentrations also were measured at • Persistent leg pain multiple time points over 24 hours at baseline and on Day 14. On Day 14, the ratios for serum potassium Cmax and AUC in the DRSP/E2 group to those in the placebo group were 0.955 (90% CI: • Sudden shortness of breath 0.914, 0.999) and 1.010 (90% CI: 0.944, 1.08), respectively. No patient in either treatment group • Sudden blindness, partial or complete developed hyperkalemia (serum potassium concentrations > 5.5 mEq/L). • Severe pain in your chest 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility • Sudden, severe headache unlike your usual headaches In a 24 month oral carcinogenicity study in mice dosed with 10 mg/kg/day DRSP alone or 1 + 0.01, • Weakness or numbness in an arm or leg, or trouble speaking 3 + 0.03 and 10 + 0.1 mg/kg/day of DRSP and EE, 0.1 to 2 times the exposure (AUC of DRSP) of • Yellowing of the skin or eyeballs women taking a contraceptive dose, there was an increase in carcinomas of the harderian gland in the group that received the high dose of DRSP alone. In a similar study in rats given 10 mg/kg/day What are the Common Side Effects of Birth Control Pills? DRSP alone or 0.3 + 0.003, 3 + 0.03 and 10 + 0.1 mg/kg/day DRSP and EE, 0.8 to 10 times the The most common side effects of birth control pills are: exposure of women taking a contraceptive dose, there was an increased incidence of benign and total (benign and malignant) adrenal gland pheochromocytomas in the group receiving the high dose • Spotting or bleeding between menstrual periods of DRSP. Mutagenesis studies for DRSP were conducted in vivo and in vitro and no evidence of • Nausea mutagenic activity was observed. • Breast tenderness 14 CLINICAL STUDIES • Headache 14.1 Oral Contraceptive Clinical Trial In the primary contraceptive efficacy study of drospirenone and ethinyl estradiol tablets (3 mg These side effects are usually mild and usually disappear with time. DRSP/0.02 mg EE) of up to 1 year duration, 1,027 subjects were enrolled and completed 11,480 Less common side effects are: 28-day cycles of use. The age range was 17 to 36 years. The racial demographic was: 87.8% Caucasian, 4.6% Hispanic, 4.3% Black, 1.2% Asian, and 2.1% other. Women with a BMI greater • Acne than 35 were excluded from the trial. The pregnancy rate (Pearl Index) was 1.41 (95% CI [0.73, • Less sexual desire 2.47]) per 100 woman-years of use based on 12 pregnancies that occurred after the onset of treatment • Bloating or fluid retention and within 14 days after the last dose of drospirenone and ethinyl estradiol tablets in women 35 • Blotchy darkening of the skin, especially on the face years of age or younger during cycles in which no other form of contraception was used. 14.2 Premenstrual Dysphoric Disorder Clinical Trials • High blood sugar, especially in women who already have diabetes Two multicenter, double-blind, randomized, placebo-controlled studies were conducted to evaluate • High fat (cholesterol; triglyceride) levels in the blood the effectiveness of drospirenone and ethinyl estradiol tablets in treating the symptoms of PMDD. • Depression, especially if you have had depression in the past. Call your healthcare provider Women aged 18–42 who met DSM-IV criteria for PMDD, confirmed by prospective daily ratings of their symptoms, were enrolled. Both studies measured the treatment effect of drospirenone and immediately if you have any thoughts of harming yourself. ethinyl estradiol tablets using the Daily Record of Severity of Problems scale, a patient-rated instrument • Problems tolerating contact lenses that assesses the symptoms that constitute the DSM-IV diagnostic criteria. The primary study was • Weight changes a parallel group design that included 384 evaluable reproductive-aged women with PMDD who were randomly assigned to receive drospirenone and ethinyl estradiol tablets or placebo treatment for 3 This is not a complete list of possible side effects. Talk to your healthcare provider if you menstrual cycles. The supportive study, a crossover design, was terminated prematurely prior to develop any side effects that concern you. You may report side effects to the FDA at 1-800- achieving recruitment goals due to enrollment difficulties. A total of 64 women of reproductive age with PMDD were treated initially with drospirenone and ethinyl estradiol tablets or placebo for up FDA-1088. to 3 cycles followed by a washout cycle and then crossed over to the alternate medication for No serious problems have been reported from a birth control pill overdose, even when 3 cycles. accidentally taken by children. Efficacy was assessed in both studies by the change from baseline during treatment using a scoring system based on the first 21 items of the Daily Record of Severity of Problems. Each of the 21 items Do Birth Control Pills Cause Cancer? was rated on a scale from 1 (not at all) to 6 (extreme); thus a maximum score of 126 was possible. In both trials, women who received drospirenone and ethinyl estradiol tablets had statistically Birth control pills do not seem to cause breast cancer. However, if you have breast cancer significantly greater improvement in their Daily Record of Severity of Problems scores. In the primary now, or have had it in the past, do not use birth control pills because some breast cancers study, the average decrease (improvement) from baseline was 37.5 points in women taking are sensitive to hormones. drospirenone and ethinyl estradiol tablets, compared to 30.0 points in women taking placebo. Women who use birth control pills may have a slightly higher chance of getting cervical cancer. 14.3 Acne Clinical Trials In two multicenter, double-blind, randomized, placebo-controlled studies, 889 subjects, ages 14 to However, this may be due to other reasons such as having more sexual partners. 45 years, with moderate acne received drospirenone and ethinyl estradiol tablets or placebo for six What Should I Know about My Period when Taking Drospirenone and Ethinyl Estradiol 28-day cycles. The primary efficacy endpoints were the percent change in inflammatory lesions, non-inflammatory lesions, total lesions, and the percentage of subjects with a "clear" or "almost clear" Tablets? rating on the Investigator's Static Global Assessment (ISGA) scale on day 15 of cycle 6, as presented Irregular vaginal bleeding or spotting may occur while you are taking drospirenone and ethinyl in Table 3: estradiol tablets. Irregular bleeding may vary from slight staining between menstrual periods Table 3: Efficacy Results for Acne Trials* to breakthrough bleeding, which is a flow much like a regular period. Irregular bleeding occurs Study 1 Study 2 most often during the first few months of oral contraceptive use, but may also occur after you DRSP/EE Placebo DRSP/EE Placebo have been taking the pill for some time. Such bleeding may be temporary and usually does Tablets N=230 Tablets N=213 not indicate any serious problems. It is important to continue taking your pills on schedule. N=228 N=218 If the bleeding occurs in more than one cycle, is unusually heavy, or lasts for more than a few ISGA Success Rate 35 (15%) 10 (4%) 46 (21%) 19 (9%) Inflammatory Lesions days, call your healthcare provider. Mean Baseline Count 33 33 32 32 Some women may not have a menstrual period but this should not be cause for alarm as long Mean Absolute (%) 15 (48%) 11 (32%) 16 (51%) 11 (34%) has you have taken the pills according to direction. Reduction Non-inflammatory What if I Miss My Scheduled Period when Taking Drospirenone and Ethinyl Estradiol Tablets? Lesions Mean Baseline 47 47 44 44 It is not uncommon to miss your period. However, if you miss two periods in a row or miss Count 18 (39%) 10 (18%) 17 (42%) 11 (26%) one period when you have not taken your birth control pills according to directions, call your Mean Absolute (%) Reduction healthcare provider. Also notify your healthcare provider if you have symptoms of pregnancy Total lesions such as morning sickness or unusual breast tenderness. It is important that your healthcare Mean Baseline Count 80 80 76 76 provider checks you to find out if you are pregnant. Stop taking drospirenone and ethinyl Mean Absolute (%) 33 (42%) 21 (25%) 33 (46%) 22 (31%) estradiol tablets if you are pregnant. Reduction What If I Want to Become Pregnant? * Evaluated at day 15 of cycle 6, last observation carried forward for the Intent to treat population You may stop taking the pill whenever you wish. Consider a visit with your healthcare 15 REFERENCES provider for a pre-pregnancy checkup before you stop taking the pill. 1. Seeger, J.D., Loughlin, J., Eng, P.M., Clifford, C.R., Cutone, J., and Walker, A.M. (2007). Risk of thromboembolism in women taking ethinylestradiol/drospirenone and other oral contraceptives. General Advice about Drospirenone and Ethinyl Estradiol Tablets Obstet Gynecol 110, 587-593. Your healthcare provider prescribed drospirenone and ethinyl estradiol tablets for you. Please 2. Dinger, J.C., Heinemann, L.A., and Kuhl-Habich, D. (2007). The safety of a drospirenone-containing do not share drospirenone and ethinyl estradiol tablets with anyone else. Keep drospirenone oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives and ethinyl estradiol tablets out of the reach of children. based on 142,475 women- years of observation. Contraception 75, 344-354. 3. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular endpoints. Sidney, S. (primary author) http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf accessed Oct If you have concerns or questions, ask your healthcare provider. You may also ask your 27, 2011. healthcare provider for a more detailed label written for medical professionals. 4. Lidegaard, O., Lokkegaard, E., Svendsen, A.L., and Agger, C. (2009). Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 339, b2890. 5. Lidegaard, O., Nielsen, L.H., Skovlund, C.W., Skjeldestad, F.E., and Lokkegaard, E. (2011). Risk Manufactured by: of venous thromboembolism from use of oral contraceptives containing different progestogens and Cyndea Pharma, oestrogen doses: Danish cohort study, 2001-9. BMJ 343, d6423. S.L., Ólvega (Soria), 42110 6. van Hylckama Vlieg, A., Helmerhorst, F.M., Vandenbroucke, J.P., Doggen, C.J., and Rosendaal, F.R. (2009). The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and Spain progestogen type: results of the MEGA case- control study. BMJ 339, b2921. 7. Dinger, J., Assmann, A., Mohner, S., and Minh, T.D. (2010). Risk of venous thromboembolism and the use of dienogest- and drospirenone-containing oral contraceptives: results from a German Distributed by: case-control study. J Fam Plann Reprod Health Care 36, 123-129. 8. Jick, S.S., and Hernandez, R.K. (2011). Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives ® containing levonorgestrel: case-control study using United States claims data. BMJ 342, d2151. 9. Parkin, L., Sharples, K., Hernandez, R.K., and Jick, S.S. (2011). Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database. BMJ 342, d2139. Camber Pharmaceuticals, Inc. 16 HOW SUPPLIED/STORAGE AND HANDLING Piscataway, USA 16.1 How Supplied Drospirenone and ethinyl estradiol tablets, USP are available in packages of one blister pack (NDC 31722-934-31) and three blister packs (NDC 31722-934-32). The active film-coated tablets are rounded with biconvex faces, one side is debossed with 20. The Revised: 02/2019 placebo film-coated tablets are rounded with biconvex faces, one side is debossed with PL. Each blister pack (28 film-coated tablets) contains in the following order: • 24 active pink round, unscored, film-coated tablets debossed with a "20" on one side, each containing 3 mg drospirenone and 0.02 mg ethinyl estradiol • 4 inert white round, unscored, film-coated tablets debossed with a "PL".