The Association between drospirenone and hyperkalemia: a comparative-safety study

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Title:
The Association between drospirenone and hyperkalemia: a comparative-safety study
Series Title:
BMC Clinical Pharmacology
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Mixed Material
Language:
English
Creator:
Bird, Steven T.
Pepe, Salvatore R.
Etminan, Mahyar
Liu, Xinyue
Brophy, James M.
Delaney, Joseph A. C.
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BioMed Central
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Background: Drospirenone/ethinyl-estradiol is an oral contraceptive (OC) that possesses unique antimineralocorticoid activity. It is conjectured that drospirenone, taken alone or concomitantly with spironolactone, may be associated with an increased risk of hyperkalemia. Methods: A retrospective cohort study was conducted evaluating women between 18-46 years of age in the Lifelink™ Health Plan Claims Database. The study was restricted to new users of OCs between 1997-2009. Cox proportional hazards models were used to estimate the time to first occurrence of hyperkalemia diagnosis. The main analysis compared OCs containing drospirenone with OCs containing levonorgestrel, a second generation OC not known to impact potassium homeostasis. Logistic regression evaluated concomitant prescribing of drospirenone and spironolactone Results: The cohort included 1,148,183 women, averaging 28.8 years of age and 280 days of OC therapy. 2325 cases of hyperkalemia were identified. The adjusted hazard ratio (HR) for hyperkalemia with drospirenone compared to levonorgestrel was 1.10 (95%CI 0.95-1.26). There was an increased risk of hyperkalemia with norethindrone HR 1.15 (95%CI: 1.00-1.33) and norgestimate HR 1.27 (95%CI: 1.11-1.46). Other OCs were unassociated with hyperkalemia. The odds of receiving spironolactone while taking drospirenone were 2.66 (95%CI 2.53-2.80) times higher than the odds of receiving spironolactone and levonorgestrel. Only 6.5% of patients taking drospirenone and spironolactone had a serum potassium assay within 180 days of starting concomitant therapy. Conclusions: A clinically significant signal for hyperkalemia with drospirenone was not demonstrated in the current study. Despite the bolded warning for hyperkalemia with joint drospirenone and spironolactone administration, physicians are actually using them together preferentially, and are not following the recommended potassium monitoring requirements in the package insert.

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RESEARCHARTICLE OpenAccessTheassociationbetweendrospirenoneand hyperkalemia:acomparative-safetystudyStevenTBird1,2* ,SalvatoreRPepe1,2 ,MahyarEtminan3,XinyueLiu2,JamesMBrophy4and JosephACDelaney2AbstractBackground: Drospirenone/ethinyl-estradiolisanoralcontraceptive(OC)thatpossessesunique antimineralocorticoidactivity.Itisconjecturedthatdrospirenone,takenaloneorconcomitantlywith spironolactone,maybeassociatedwithanincreasedriskofhyperkalemia. Methods: Aretrospectivecohortstudywasconductedevaluatingwomenbetween18-46yearsofageinthe Lifelink HealthPlanClaimsDatabase.ThestudywasrestrictedtonewusersofOCsbetween1997-2009.Cox proportionalhazardsmodelswereusedtoestimatethetimetofirstoccurrenceofhyperkalemiadiagnosis.The mainanalysiscomparedOCscontainingdrospirenonewithOCscontaininglevonorgestrel,asecondgenerationOC notknowntoimpactpotassiumhomeostasis.Logisticregressionevaluatedconcomitantprescribingof drospirenoneandspironolactone Results: Thecohortincluded1,148,183women,averaging28.8yearsofageand280daysofOCtherapy.2325 casesofhyperkalemiawereidentified.Theadjustedhazardratio(HR)forhyperkalemiawithdrospirenone comparedtolevonorgestrelwas1.10(95%CI0.95-1.26).Therewasanincreasedriskofhyperkalemiawith norethindroneHR1.15(95%CI:1.00-1.33)andnorgestimateHR1.27(95%CI:1.11-1.46).OtherOCswere unassociatedwithhyperkalemia.Theoddsofreceivingspironolactonewhiletakingdrospirenonewere2.66(95%CI 2.53-2.80)timeshigherthantheoddsofreceivingspironolactoneandlevonorgestrel.Only6.5%ofpatientstaking drospirenoneandspironolactonehadaserumpotassiumassaywithin180daysofstartingconcomitanttherapy. Conclusions: Aclinicallysignificantsignalforhyperkalemiawithdrospirenonewasnotdemonstratedinthe currentstudy.Despitetheboldedwarningforhyperkalemiawithjointdrospirenoneandspironolactone administration,physiciansareactuallyusingthemtogetherpreferentially,andarenotfollowingtherecommended potassiummonitoringrequirementsinthepackageinsert.BackgroundDrospirenoneisanovelsyntheticprogestinapprovedin combinationwithethinylestradiolasanoralcontraceptive (OC)[1].MarketedasYasminandYaz,drospirenoneis oneofthemostpopularoralcontraceptivesintheUnited States[2].DrospirenoneisafourthgenerationOCandit possessesantimineralocorticoideffectsnotpresentinpreviousgenerationsofOCs.It santimineralocorticoid potencyisapproximatelyeighttimesgreaterthanspironolactone[3],thusa3mgtabletofdrospirenonehasasimilareffectto20-25mgofspironolactone[4].Thisactivity enhancessodium,chloride,andwaterexcretion,while reducingtheexcretionofpotassium,ammonium,and phosphate[5].Thesimilari tyinchemicalstructure betweendrospirenoneandspironolactoneandtheknown associationbetweenspironolactoneandhyperkalemia bothstrengthentheplausibilitythatclinicallysignificant hyperkalemiamightresultfromdrospirenoneuse. InMayof2001,whendrospirenone/ethinylestradiol (Yasmin)wasfirstapproved,thepackageinsert includedaboldedwarningforhyperkalemia,statingthat Yasminshouldnotbeusedinpatientswithconditions thatpredisposetohyperkalemia [1].Thewarningalso *Correspondence:steven.bird@fda.hhs.gov Contributedequally1DepartmentofHealthandHumanServices/FoodandDrugAdministration/ CenterforDrugEvaluationandResearch(CDER)/OfficeofManagement/ CDERAcademicCollaborationProgram,Bldg22,10903NewHampshire Avenue,SilverSpring,MDUSA20993 FulllistofauthorinformationisavailableattheendofthearticleBird etal BMCClinicalPharmacology 2011, 11 :23 http://www.biomedcentral.com/1472-6904/11/23 2011Birdetal;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommons AttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductionin anymedium,providedtheoriginalworkisproperlycited.

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instructsphysicianstomonitorpotassiumlevelsduring thefirstcycleoftreatmentinpatientstakingconcomitant medicationsknowntocausehyperkalemia.Clinicalevidencehoweverhasnotshownastrongassociation betweendrospirenoneandhyperkalemia[6-13].Several studieshaveevaluatedforhyperkalemiainpostmenopausalwomenwithhypertensionordiabeteswhousedrospirenonetotreatvasomotorspasms.Thesestudiesfound noassociationbetweendrospirenoneandhyperkalemia inwomenwithhypertension[6,7]ortype2diabetesmellitus[8];however,allthreestudiesweretwelveorfewer weeksinduration.Largertrialsdesignedtoevaluatethe safetyandefficacyofdrospirenoneeitherdonotevaluate hyperkalemiaorarenotpoweredtodetectit[9-12].Only onelargestudy,mandatedbytheFDAatapproval,has beenperformedevaluatingdrospirenoneforhyperkalemiainyoungerwomen,anditfoundnoassociation betweendrospirenoneandhyperkalemia[13]. Hyperkalemiaisapotential lyseriousconditionthat maybeassociatedwithnumerouspathophysiological conditions.Clinicallysignif icanthyperkalemiareduces membraneexcitabilityanddisturbstheacid-basebalance,manifestingasweakness,flaccidparalysis,hypoventilation,andmetabolicacidosis.Hyperkalemiacan alsoresultincardiactoxicitywithelectrocardiographic changes,whichinseverecasesmayleadtotheterminal eventsofventricularfibrillationorasystole[5]. Theprimaryobjectiveofthecurrentstudyistoinvestigatetheassociationbet weendrospirenoneandthe diagnosisofhyperkalemiainalargeunselectedpopulation.Asecondaryobjectiveistoevaluatetheimpactof thepackageinsertonmedicalprescribingasassessedby anexaminationofthe1)concomitantuseofdrospirenoneandspironolactoneand2)respectforthestated potassiummonitoringrequirements.MethodsDataSourceTheIMSLifelink HealthPlanClaimsDatabasecontainspaidclaimsdatafromover102managedcare plansintheUnitedStates.Thedatabasecontainsfully adjudicatedmedicalandpharmacyclaimsforover68 millionpatients,includinginpatientandoutpatientdiagnosesandprocedures( InternationalClassificationof Diseases,9thRevision,ClinicalModificationformat)in additiontoretailandmailorderprescriptionrecords. Thedataisrepresentativeo fUSresidentswithprivate healthinsuranceintermsofgeography,age,andgender. TheLifelink databaseissubjecttoqualitychecksto ensuredataqualityandtominimizeerrorrates[14].CohortdescriptionAretrospectivecohortwasdeveloped,evaluatingwomen intheLifelink ClaimsdatabasebetweenJanuary1st, 1997andDecember31st,2009.Allwomenbetween1846yearsofagewiththefirstprescriptionforanOC containingethinylestradiol(0.35ugorless)andoneof thefollowingprogestinswereincludedinthecohort: desogestrel,drospirenone,ethynodioldiacetate,levonorgestrel,norethindroneacetate,norethindrone,norgestimate,andnorgestrel .Allpatientswhometthese inclusioncriteriawereanalyzedintheutilizationportion ofthestudy. Forthehyperkalemiaanalysis,inordertoincludeonly newusers,patientswereexcludediftheydidnothave atleast180daysofenrollmenthistorypriortotheir firstclaimforanOC.Patientswerealsoexcludedif theyhadapriordiagnosisofhyperkalemia.Censoring wasperformedifapatientswitchedtoanotherOCduringthestudyperiod,onthefinaldayofOCpossession (determinedfromthefinalprescriptiondateandday supply),beforeagapinOCpossessionof30ormore days,attheeventofhyperkalemia,andattheendofthe studyperiod,December31st,2009.EvaluationofhyperkalemiawasperformedusingadiagnosticICD-9code (276.7).Statisticalanalysis OCsandhyperkalemiaCoxproportionalhazardmodelswereusedtoestimate thetimetofirstoccurrenceofhyperkalemia.Theprimaryanalysisusedanewuserdesignandcompared OCscontainingdrospirenonewithOCscontaininglevonorgestrel.Levonorgestrelwaschosen aprioriasa referencebasedonitshighutilization,lackofassociationwithhyperkalemia,anduseasareferenceinpreviousOCcomparative-saf etystudies[15-21].All estimateswereadjustedbyage,calendartime,chronic kidneydisease,diabetesmellitus,hypertension,inflammatoryboweldisease,obesity[22],polycysticovarysyndrome,premenstrualtensio nsyndrome(premenstrual syndromeandpremenstrualdysphoricdisorder),smokingstatus,andconcomitantmedicationsknownto causehyperkalemia.Thefollowingmedicationswere adjustedfor:angiotensin-convertingenzymeinhibitors (ACE)/angiotensinreceptorblockers(ARB),non-steroidalanti-inflammatorydrugs(NSAID),spironolactone, andothermedications(cyclosporine,diuretics,heparin, penicillinG,tacrolimus,andtrimethoprim).UtilizationConcomitantutilizationofdrospirenoneandspironolactonewasanalyzedduringtheentirestudyperiod.Logisticregressionwasusedtoformoddsratios(OR) comparingtheoddsforreceivingconcomitantspironolactoneanddrospirenonetherapyagainsttheoddsof receivingconcomitantspironolactoneandlevonorgestrel therapy.ORswerealsoformedcalculatingtheoddsof receivingspironolactonewhileonotherprogestin-Bird etal BMCClinicalPharmacology 2011, 11 :23 http://www.biomedcentral.com/1472-6904/11/23 Page2of6

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containingOCscomparedtolevonorgestrel.Toevaluate compliancewithpotassiummonitoringforpatientstakingconcomitantdrospirenoneandspironolactone,the percentageofpatientswhohadabloodserumpotassiumassay(CPT-484132)duringthefirst180daysof concomitanttherapywascalculated. ThisstudywasapprovedbytheUniversityofFlorida IRB.AllcalculationswereperformedinSASsoftware version9.2.ResultsOCsandhyperkalemiaThecohortincluded1,148,183womenexposedtoaprogestin-basedOCand880,014person-yearsoffollow-up time.Patientsinthestudyaveraged28.8yearsofageand hadameanfollowuptimeof280days.Therewere2325 casesofhyperkalemia,representing0.20%ofthepopulation.BaselinecharacteristicsareshowninTable1. Theadjustedhazardratio(HR)forarecordeddiagnosisofhyperkalemiawhileexposedtodrospirenonecomparedtolevonorgestrelwas1.10(95%CI0.95-1.26). OtherOCswereunassociatedwithhyperkalemia:desogestrelHR1.00(95%CI:0.85-1.17),ethynodioldiacetate HR0.71(95%CI:0.49-1.02),norethindroneacetateHR 1.08(95%CI:0.91-1.29),norgestrelHR1.00(95%CI: 0.76-1.33),althoughtherewasanunexpectedsignal withnorethindroneHR1.15(95%CI:1.00-1.33)andnorgestimateHR1.27(95%CI:1.11-1.46)(Table2).Additionally,theanalysisfoundnointeractionbetween drospirenoneandspironolactoneforhyperkalemiain theregressionmodel(HR1.08,95%CI:0.78-1.49).Other interactionswithdrospirenoneintheregressionmodel wereasfollows:ACEI/ARBHR0.78(95%CI0.55-1.10) andNSAIDHR1.09(95%CI0.80-1.48).UtilizationTheutilizationstudyevaluatedall2,925,407patients thatmettheinitialstudyinclusioncriteria.18,869 patientsinthispopulationweretakingbothspironolactoneandanOC.Theoddsofreceivingspironolactone whileondrospirenonewere2.66(95%CI2.53-2.80) timeshigherthantheoddsofreceivingspironolactone whileonlevonorgestrel.TheORsforreceivingspironolactonewhileonotherprogestin-basedOCscompared tolevonorgestrelareasfollows:desogestrel1.46(95%CI 1.38-1.55),ethynodioldiacetate2.85(95%CI2.62-3.11), Table1Characteristicsofwomenincludedinthestudycohortbytypeofprogestinoralcontraceptiveused (n=1,148,183)DesogestrelDrospirenone Ethynodiol Diacetate LevonorgestrelNorethindrone Acetate NorethindroneNorgestimateNorgestrel Numberofpatients139,871224,40817,295180,72093,818234,105228,27629,690 Age28.729.028.829.030.529.726.929.7 Meanfollowup (days) 327272327304240230307249 Numberofcases2674883334920043349956 Covariates(%) CKD 0.150.090.080.090.120.150.080.19 Diabetes4.104.104.413.934.134.123.375.43 Hypertension8.348.478.538.629.788.896.5510.82 IBD*0.941.031.221.001.030.850.750.98 Obesity11.5912.5312.4411.2210.7510.089.5013.60 PCOS 4.475.785.002.112.802.812.213.48 PTS(PMS/ PMDD) 3.635.533.043.013.261.951.692.73 Smoking6.625.948.487.366.436.496.979.00 ACEI/ARB0.500.470.560.600.750.670.420.80 NSAIDS 5.674.845.795.565.135.904.776.09 Spironolactone0.430.740.840.280.320.190.320.29 Other Medications 0.460.360.560.460.370.350.270.44*Inflammatoryboweldisease CKD=ChronicKidneyDisease PCOS=PolycysticOvarySyndrome PTS(PMS/PMDD)=premenstrualtensionsyndrome(premenstrualsyndromeandpremenstrualdysphoricdisorder) ACE/ARB=angiotensin-convertingenzymeinhibitors/angiotensinreceptorblockers NSAID=non-steroidalanti-inflammatorydrugs Othermedications=diuretics,heparin,cyclosporine,tacrolimus,trimethoprim,andpenicillinGBird etal BMCClinicalPharmacology 2011, 11 :23 http://www.biomedcentral.com/1472-6904/11/23 Page3of6

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norethindroneacetate1.01(95%CI0.93-1.08),norethindrone0.78(95%CI0.74-0.83),norgestimate1.34(95%CI 1.27-1.41),andnorgestrel0.98(95%CI0.89-1.08).The YasminandYazpackageinsertsrecommendpotassiummonitoringwithinthefirsttreatmentcyclefor patienttakingothermedicationsknowntocausehyperkalemia.Ofthe5,752patientswhotookdrospirenone andspironolactoneconcomitantly,only376(6.5%) patientsunderwentaserumpotassiumassaywithin180 daysofstartingconcomitanttherapy.DiscussionThecurrentstudydidnotfindasubstantialandmeaningfulassociationbetweendrospirenoneuseandhyperkalemiacomparedtopatientstakinglevonorgestrel.Itis interestingtonotethatnorethindroneandnorgestimate arebothassociatedwithahigherriskforhyperkalemia comparedtolevonorgestrel.Thesehoweverwerenot a priori hypothesesandmaybechancefindingsdueto multipletesting. Theseresultsmustalsobetakeninto contextwiththelowabsoluteriskforhyperkalemiain OCusers.TheincreasedHRfornorethindroneof1.16 resultsinanumberneedtoharm(NNH)of3086 patients,whiletheHRfornorgestimateof1.27results inaNNHof1829patients. Thenullassociationbetweendrospirenoneandhyperkalemiaisconcordantwiththeresultsfromprevious studies[13,23].Toourknowledge,onlyonepriorcohort studyhasbeenconductedwiththeprimaryaimtoevaluatedrospirenoneandhyperkalemia[13].Thisstudy had67,287OCusers,identified378casesofhyperkalemia,andfoundaRRcomparingdrospirenonetoother OCsof0.9(95%CI0.7-1.1).Ourstudypopulationhas approximatelyseventeentimestheOCuserpopulation ofthisprioranalysis,allowinggreaterdetectionfor hyperkalemiaandprovidingin creasedstatisticalprecision.Anotherstudyidentified102casesofdrug-associatedhyperkalemiaanddidnotattributeanycasesto useofdrospirenone[23].Inourstudy,thecomparison amongOCusersinouranalysisminimizestheriskof confoundingbyindication,andthenewuserdesign eliminatesthesurvivoreffectthatlongtermOCusers aretoleranttothetherapyandhealthierthanshort termusers.Thetotalityoftheevidencesuggeststhat hyperkalemiawhileondrospirenoneisnotofclinical importance.UtilizationWefoundthatdrospirenoneusersare2.66timesmore likelytoreceivespironolactonecomparedwithlevonorgestrelusers.AnORofthismagnitudesuggeststhat physiciansarenotavoidingtheconcomitantuseofdrospirenoneandspironolactone,butprescribingthem together.Thisisaparticularlyinterestingfinding becausedrospirenoneistheonlyOCwithabolded warningforhyperkalemia.Thesemedicationshaveno overlapinlabeledindications;however,drospirenone doeshaveanindicationforacnevulgaris,whilespironolactonehasanoff-labeluseforitstreatment.Another likelyexplanationintherecentliteratureisthatdrospirenoneandspironolactonearebothseenasbeneficialfor treatmentofweightgainand bloatingexperiencedby patientswithpostmenstrualdysphoricdisorderandin reducinghirsutismandacneinpatientswithpolycystic ovariansyndrome(PCOS)[24-28]. Itwasrecentlyreportedthat,among11,019drospirenoneusers,17.6%ofpatientsaretakinganothermedicationknowntoinducehyperkalemia[29].Inthisstudy, spironolactoneaccountedfor11.1%ofthisconcomitant utilization.Ourstudyfoundthatonly6.5%ofpatients takingdrospirenoneandspironolactoneunderwent potassiummonitoring.Thisraisesconcernthatfewphysiciansarefollowingtherecommendationsformonitoringserumpotassiumasstatedinthepackageinsert. Althoughwefoundanon-significantinteractionfor hyperkalemiawithconcomitantuseofdrospirenoneand spironolactone,thisdoesnotassurethesafecombined useofthesetwomedications.Particularly,patientswith PCOSgenerallyexpresscharacteristicsofmetabolicsyndrome,areatanincreasedriskfordruginducedliver injury[30],andwarrantcarefulmonitoring.LimitationsTheuseofICD-9-CMcodesforthedetectionofhyperkalemiaprovidesahighspec ificityfordiagnosedcases becausethisdiagnosisismadefromanassayofserum potassium.Thismeasurement howeverlackssensitivity duetoalackofpotassiumtestinginthegeneralpopulation.InadequaciesindocumentingICD-9-CMcodes Table2Riskforhyperkalemia*withuseofcommonly usedoralcontraceptivesCrudeHR(95%CI)AdjustedHR (95%CI) Levonorgestrel1.0(reference)1.0 Desogestrel 0.93(0.79-1.09)1.00(0.85-1.17) Drospirenone 1.26(1.10-1.44)1.10(0.95-1.26) Ethynodioldiacetate0.96(0.67-1.38)0.71(0.49-1.02) Norethindroneacetate1.41(1.18-1.68)1.08(0.91-1.29) Norethindrone 1.27(1.11-1.47)1.15(1.00-1.33) Norgestimate 1.13(0.98-1.29)1.27(1.11-1.46) Norgestrel 1.13(0.85-1.49)1.00(0.76-1.33)*HyperkalemiadeterminedfromadiagnosticICD-9code(276.7) Adjustedbyage,calendartime,chronickidneydisease,diabetesmellitus, hypertension,inflammatoryboweldisease,obesity,polycysticovarysyndrome, premenstrualtensionsyndrome(premenstrualsyndromeandpremenstrual dysphoricdisorder),smokingstatus,angiotensin-convertingenzyme inhibitors/angiotensinreceptorblockers,non-steroidalanti-inflammatory drugs,spironolactone,andothermedicationsknowntocausehyperkalemia (cyclosporine,diuretics,heparin,penicillinG,tacrolimus,andtrimethoprim).Bird etal BMCClinicalPharmacology 2011, 11 :23 http://www.biomedcentral.com/1472-6904/11/23 Page4of6

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couldalsoleadtounderreportingofhyperkalemia.To determineifthiswaslikelytobeproblematic,weinterrogatedtheLifelink databasetoinvestigatecontrol drugswithknownassociationstohyperkalemia.Amiloride,apotassium-sparingdiuretic,spironolactone,an aldosteroneantagonist,andallACEinhibitorswere selectedaspositiveco ntrols.TheLifelink database wasabletoreplicatethreekn ownpositiveassociations: amilorideHR7.94(95%CI1.96-32.08),spironolactone HR3.46(95%CI2.97-4.02),andACEinhibitorsHR1.90 (95%CI1.70-2.11).Negativecontrolsselectedwereloratadine,anon-drowsyantihistamine,topicalhydrocortisone,andallstatins.Allnegativeassociationswere replicated:loratadineHR0.84(95%CI0.60-1.20),topical hydrocortisoneHR1.37(95%CI0.92-2.05),andstatins HR1.06(95%CI0.92-1.22).Apositiveassociationwas notfoundbetweenNSAIDSandhyperkalemia(HR0.93 (95%CI0.81-1.06)).Theabovepositiveandnegative controlsarereassuringfortheabilityofthisclaimsdatabasetodetectclinicallyre levanthyperkalemiaandto findanullresultwhennoassociationisknown. Theboldedwarningfordrospirenoneandhyperkalemiaalsohasthepotentialtointroduceameasurement bias.Thiswarningmakespotassiummonitoringinthe drospirenonegroupmorelikely,inducingabiasaway fromthenull.Thisanti-conservativebiasprovidesadditionalconfidenceinournullresult.Ifchannelingbiasis presentinourstudypopulation,steeringpatientsat highriskforhyperkalemiaawayfromdrospirenone wouldprovideabiastowardthenull.Anotherinterpretationofthestudyresultsisthat,basedontheregulatoryframework,currentclinicalpracticeissufficientto mitigatetheriskofhyperkalemiainthispopulation. Duetothenatureofaclaimsdatabase,residualconfoundingisalwayspresent.Alcoholconsumption,ethnicity,anddietareallpotentialunadjustedconfoundersin ourstudy.Twocovariatesintheanalysis,smokingand obesity,arereportedonlyto justifytreatment(suchas bariatricsurgeryorsmokingcessationtherapy)andare notcompletelycontrolled.FutureimplicationsAlthoughaclinicallysignificantincreaseinthediagnosisofhyperkalemiawasnotfoundinouranalysis,a subclinicalincreaseinserumpotassiuminthispopulationcannotberuledout.Incr easedutilizationofspironolactoneinpatientstakingdrospirenoneandpoor compliancewiththerequir ementforpotassiummonitoringinthepackageinsertsuggestsalackofattention tothepossibilityofhyperkalemia.Spironolactonehoweverhasastrongassociationwithhyperkalemia,and, forpatientstakingbothspironolactoneanddrospirenone,itisconcerningthatsofewphysiciansfollowthe packageinsertmonitoringrecommendations.This suggeststhatpackageinse rtsmaynotbeaneffective mechanismforthecommunicationofdrugsafety information.Ifanincreaseinhyperkalemiahadbeen foundinpatientstakingdrospirenone,thiscurrent monitoringpracticemaynothavebeensufficientto detectit.ConclusionsInalargecohortofyoungwomen,drospirenonedidnot causeaclinicallysignificantincreaseinriskforhyperkalemiawhencomparedwithotherprogestin-containing OCs.Itishoweverconcerningthat,despitethebolded warningforhyperkalemia,drospirenoneandspironolactoneareusedtogetherpreferentially.Thislikelydemonstratesachannelingofpa tientswithpremenstrual dysphoricdisorderandpolycysticovarysyndrometo useofdrospirenone.Furthermore,physiciansarenot followingthemonitoringrequirementsforserumpotassiumassaysinthepackageinsertforpatientstaking thesetwomedications.AuthordetailSTBandSRPworkattheCenterforDrugEvaluation andResearchintheFoodandDrugAdministration. JMBisaprofessorofmedicineandepidemiologyat McGillUniversity;MEisanassistantprofessorofmedicineinthePharmaceuticalOutcomesProgrammeatthe UniversityofBritishColumbia;andJACDisanassistant professorofPharmaceuticalOutcomes&Policyatthe UniversityofFlorida.XLisagraduatestudentinthe departmentofPharmaceuticalOutcomes&Policyatthe UniversityofFlorida.Acknowledgements Thisstudywassupportedbyanunrestrictedoperatinggrant,fundedinpart bytheMcGillUniversityHealthCenter,FondsdelaRechercheenSantdu Qubec,andtheMinistredelaSantetdesServicesSociaux.Thesources offundinghadnoroleinthecollection,analysis,andinterpretationofdata; inthewritingofthemanuscript;andinthedecisiontosubmitthe manuscriptforpublication.Publicationofthisarticlewasfundedinpartby theUniversityofFloridaOpen-AccessPublishingFund. Authordetails1DepartmentofHealthandHumanServices/FoodandDrugAdministration/ CenterforDrugEvaluationandResearch(CDER)/OfficeofManagement/ CDERAcademicCollaborationProgram,Bldg22,10903NewHampshire Avenue,SilverSpring,MDUSA20993.2UniversityofFlorida,Collegeof Pharmacy,PharmaceuticalOutcomes&Policy,101S.NewellDrive(HPNP), POBox100496,GainesvilleFL,USA32611.3UniversityofBritishColumbia, PharmaceuticalOutcomesProgramme,709-828West10thAvenue, Vancouver,BritishColumbia,CanadaV5Z1M9.4McGillUniversity,Royal VictoriaHospital,687PineStreetWest,Montreal,QuebecH3A1A1,Canada. Authors contributions JMB,JACD,andMEacquireddataforthisanalysis.Allauthorscontributedto thestudydesign.ThestatisticalanalysiswascompletedbySTBandJACD, andallauthorscontributedtotheinterpretationofthedata.STBwrotethe draftmanuscriptandallauthorscontributedtocriticalrevisionofthe manuscriptforimportantintellectualcontent.JACDisthestudyguarantor. Allauthorsreadandapprovedthefinalmanuscriptforpublication.Bird etal BMCClinicalPharmacology 2011, 11 :23 http://www.biomedcentral.com/1472-6904/11/23 Page5of6

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Competinginterests Thismanuscriptrepresentstheopinionsoftheauthorsandnotthoseofthe FoodandDrugAdministration.JMBisaphysicianscientistwhoreceives peerreviewfinancialsupportfromleFondsdelaRechercheenSantdu Qubec.Theauthorshavenoothercompetinginterests. Received:3October2011Accepted:30December2011 Published:30December2011 References1.Yasmin[packageinsert],WayneNJ:BayerHealthcarePharmaceuticals,Inc.; 2010. 2.TheWorldHealthOrganization: Cardiovasculardiseaseandsteroid hormonecontraception. TechnicalReportSeries877 Geneva:The Organization;1998. 3.MuhnP,FuhrmannU,FritzemeierKH,KrattenmacherR,SchillingerE: Drospirenone:anovelprogestogenwithantimineralocorticoidand antiandrogenicactivity. AnnNYAcadSci 1995, 761 :311-335. 4.HeinemannLA,DingerJ: Safetyofaneworalcontraceptivecontaining drospirenone. DrugSaf 2004, 27(13) :1001-1018. 5. Disordersoftheadrenalcortex. 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ActaObstetGynecolScand 1995, 74(10) :803-808. 28.SahaL,KaurS,SahaPK: Pharmacotherapyofpolycysticovarysyndromeanupdate. FundamClinPharmacol 29.McAdamsM,StaffaJA,DalPanGJ: Theconcomitantprescribingofethinyl estradiol/drospirenoneandpotentiallyinteractingdrugs. Contraception 2007, 76(4) :278-281. 30.TarantinoG,ConcaP,BasileV,GentileA,CaponeD,PolichettiG,LeoE: A prospectivestudyofacutedrug-inducedliverinjuryinpatientssuffering fromnon-alcoholicfattyliverdisease. HepatolRes 2007, 37(6) :410-415.Pre-publicationhistory Thepre-publicationhistoryforthispapercanbeaccessedhere: http://www.biomedcentral.com/1472-6904/11/23/prepubdoi:10.1186/1472-6904-11-23 Citethisarticleas: Bird etal .: Theassociationbetweendrospirenone andhyperkalemia:acomparative-safetystudy. BMCClinical Pharmacology 2011 11 :23. Submit your next manuscript to BioMed Central and take full advantage of: Convenient online submission Thorough peer review No space constraints or color gure charges Immediate publication on acceptance Inclusion in PubMed, CAS, Scopus and Google Scholar Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Bird etal BMCClinicalPharmacology 2011, 11 :23 http://www.biomedcentral.com/1472-6904/11/23 Page6of6