EPLEFA

Main information

  • Trade name:
  • EPLEFA Film Coated Tablet 50 Milligram
  • Dosage:
  • 50 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • EPLEFA Film Coated Tablet 50 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0840/012/002
  • Authorization date:
  • 25-11-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Eplefa50mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains50mgofeplerenone.

Excipient:

Each50mgtabletcontains71.4mgoflactosemonohydrate(seeSection4.4).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

lightyellow,round,biconvexfilm-coatedtablet,debossedwith‘E9RN’ononesideand‘50’ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Eplerenoneisindicated,inadditiontostandardtherapyincludingbeta-blockers,toreducetheriskofcardiovascular

mortalityandmorbidityinstablepatientswithleftventriculardysfunction(LVEF 40%)andclinicalevidenceof

heartfailureafterrecentmyocardialinfarction.

4.2Posologyandmethodofadministration

Fortheindividualadjustmentofdose,thestrengthsof25mgand50mgareavailable.

Therecommendedmaintenancedoseofeplerenoneis50mgoncedaily(OD).Treatmentshouldbeinitiatedat25mg

oncedailyandtitratedtothetargetdoseof50mgoncedailypreferablywithin4weeks,takingintoaccounttheserum

potassiumlevel(seeTable1).Eplerenonetherapyshouldusuallybestartedwithin3-14daysafteranacutemyocardial

infarction.

Patientswithaserumpotassiumof>5.0mmol/Lshouldnotbestartedoneplerenone(seesection4.3).

Serumpotassiumshouldbemeasuredbeforeinitiatingeplerenonetherapy,withinthefirstweekandatonemonthafter

thestartoftreatmentordoseadjustment.Serumpotassiumshouldbeassessedasneededperiodicallythereafter.

Afterinitiation,thedoseshouldbeadjustedbasedontheserumpotassiumlevelasshowninTable1.

Table1:Doseadjustmenttableafterinitiation

Serumpotassium(mmol/L) Action Doseadjustment

<5.0 Increase 25mgEOD*to25mgOD

25mgODto50mgOD

5.0–5.4 Maintain Nodoseadjustment

5.5–5.9 Decrease 50mgODto25mgOD

25mgODto25mgEOD*

25mgEOD*towithhold

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*EOD:EveryOtherDay

Followingwithholdingeplerenoneduetoserumpotassium 6.0mmol/L,eplerenonecanbere-startedatadoseof25

mgeveryotherdaywhenpotassiumlevelshavefallenbelow5.0mmol/L.

Childrenandadolescents

Therearenodatatorecommendtheuseofeplerenoneinthepaediatricpopulation,andtherefore,useinthisagegroup

isnotrecommended.

Elderly

Noinitialdoseadjustmentisrequiredintheelderly.Duetoanage-relateddeclineinrenalfunction,theriskof

hyperkalaemiaisincreasedinelderlypatients.Thisriskmaybefurtherincreasedwhenco-morbidityassociatedwith

increasedsystemicexposureisalsopresent,inparticularmild-to-moderatehepaticimpairment.Periodicmonitoringof

serumpotassiumisrecommended(seesection4.4).

Renalimpairment

Noinitialdoseadjustmentisrequiredinpatientswithmildrenalimpairment.Periodicmonitoringofserumpotassium

isrecommended(seesection4.4).

Eplerenoneisnotdialysable.

Hepaticimpairment

Noinitialdosageadjustmentisnecessaryforpatientswithmild-to-moderatehepaticimpairment.Duetoanincreased

systemicexposuretoeplerenoneinpatientswithmild-to-moderatehepaticimpairment,frequentandregularmonitoring

ofserumpotassiumisrecommendedinthesepatients,especiallywhenelderly(seesection4.4).

Concomitanttreatment

IncaseofconcomitanttreatmentwithmildtomoderateCYP3A4inhibitors,e.g.amiodarone,diltiazemandverapamil,

astartingdoseof25mgODmaybeinitiated.Dosingshouldnotexceed25mgOD(seesection4.5).

Eplerenonemaybeadministeredwithorwithoutfood(seesection5.2).

4.3Contraindications

Hypersensitivitytoeplerenoneoranyoftheexcipients(seesection6.1).

Patientswithserumpotassiumlevel>5.0mmol/Latinitiation

Patientswithmoderatetosevererenalinsufficiency(creatinineclearance<50mL/min)

Patientswithseverehepaticinsufficiency(Child-PughClassC)

Patientsreceivingpotassium-sparingdiuretics,potassium-supplementsorstronginhibitorsofCYP3A4(eg

itraconazole,ketoconazole,ritonavir,nelfinavir,clarithromycin,telithromycinandnefazodone)(seesection

4.5).

4.4Specialwarningsandprecautionsforuse

Hyperkalaemia

Consistentwithitsmechanismofaction,hyperkalaemiamayoccurwitheplerenone.Serumpotassiumlevelsshouldbe

monitoredinallpatientsatinitiationoftreatmentandwithachangeindosage.Thereafter,periodicmonitoringis

recommendedespeciallyinpatientsatriskforthedevelopmentofhyperkalaemia,suchas(elderly)patientswithrenal

insufficiency(seesection4.2)andpatientswithdiabetes.Theuseofpotassiumsupplementsafterinitiationof

eplerenonetherapyisnotrecommended,duetoanincreasedriskofhyperkalaemia.Dosereductionofeplerenonehas

beenshowntodecreaseserumpotassiumlevels.Inonestudy,theadditionofhydrochlorothiazidetoeplerenone

therapyhasbeenshowntooffsetincreasesinserumpotassium.

Impairedrenalfunction

Potassiumlevelsshouldbemonitoredregularlyinpatientswithimpairedrenalfunction,includingdiabetic

microalbuminuria.Theriskofhyperkalaemiaincreaseswithdecreasingrenalfunction.WhilethedatafromEPHESUS

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observedinthissmallnumberofpatients.Therefore,thesepatientsshouldbetreatedwithcaution.Eplerenoneisnot

removedbyhaemodialysis.

Impairedhepaticfunction

Noelevationsofserumpotassiumabove5.5mmol/Lwereobservedinpatientswithmildtomoderatehepatic

impairment(ChildPughclassAandB).Electrolytelevelsshouldbemonitoredinpatientswithmildtomoderate

hepaticimpairment.Theuseofeplerenoneinpatientswithseverehepaticimpairmenthasnotbeenevaluatedandits

useisthereforecontraindicated(seesection4.3).

CYP3A4inducers

Co-administrationofeplerenonewithstrongCYP3A4inducersisnotrecommended(seesection4.5).

Lithium,cyclosporin,tacromilusshouldbeavoidedduringtreatmentwitheplerenone(seesection4.5).

Lactose

Thetabletscontainlactoseandshouldnotbeadministeredinpatientswithrarehereditaryproblemsofgalactose

intolerance,theLapplactasedeficiencyorglucose-galactosemalabsorption.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Pharmacodynamicinteractions

Potassium-sparingdiureticsandpotassiumsupplements

Duetoincreasedriskofhyperkalaemia,eplerenoneshouldnotbeadministeredtopatientsreceivingpotassium-sparing

diureticsandpotassiumsupplements(seesection4.3).Potassium-sparingdiureticsmaypotentiatetheeffectofanti-

hypertensiveagentsandotherdiuretics.

Lithium

Druginteractionstudiesofeplerenonehavenotbeenconductedwithlithium.However,lithiumtoxicityhasbeen

reportedinpatientsreceivinglithiumconcomitantlywithdiureticsandACEinhibitors(seesection4.4).Co-

administrationofeplerenoneandlithiumshouldbeavoided.Ifthiscombinationappearsnecessary,lithiumplasma

concentrationsshouldbemonitored(seesection4.4).

Cyclosporin,tacrolimus

Cyclosporinandtacromilusmayleadtoimpairedrenalfunctionandincreasetheriskofhyperkalaemia.The

concomitantuseofeplerenoneandcyclosporinortacrolimusshouldbeavoided.Ifthiscombinationappearsnecessary,

closemonitoringofserumpotassiumandrenalfunctionarerecommendedwhencyclosporineandtacrolimusaretobe

administeredduringtreatmentwitheplerenone(seesection4.4).

Non-steroidalanti-inflammatorydrugs(NSAIDs)

TreatmentwithNSAIDsmayleadtoacuterenalfailurebyactingdirectlyonglomerularfiltration,especiallyinat-risk

patients(elderlyand/ordehydratedpatients).PatientsreceivingeplerenoneandNSAIDsshouldbeadequatelyhydrated

andbemonitoredforrenalfunctionpriortoinitiatingtreatment.

Trimethroprim

Theconcomitantadministrationoftrimethroprimwitheplerenoneincreasestheriskofhyperkalaemia.Monitoringof

serumpotassiumandrenalfunctionshouldbemade,particularlyinpatientswithrenalimpairmentandintheelderly.

ACEinhibitors,angiotensin-IIreceptorsantagonists(AIIA)

EplerenoneandACEinhibitorsorangiotensin-IIreceptorsantagonistsshouldbeco-administeredwithcaution.

Combiningeplerenonewiththesedrugsmayincreaseriskofhyperkalaemiainpatientsatriskforimpairedrenal

function,e.g.theelderly.Aclosemonitoringofserumpotassiumandrenalfunctionisrecommended.

Alpha1blockers(e.g.prazosin,alfuzosine)

Whenalpha-1-blockersarecombinedwitheplerenone,thereisthepotentialforincreasedhypotensiveeffectand/or

posturalhypotension.Clinicalmonitoringforposturalhypotensionisrecommendedduringalpha-1-blockerco-

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Tricyclicanti-depressants,neuroleptics,amifostine,baclofene

Co-administrationofthesedrugswitheplerenonemaypotentiallyincreaseantihypertensiveeffectsandriskofpostural

hypotension.

Glucocorticoides,tetracosactide

Co-administrationofthesedrugswitheplerenonemaypotentiallydecreaseantihypertensiveeffects(sodiumandfluid

retention).

Pharmacokineticinteractions

InvitrostudiesindicatethateplerenoneisnotaninhibitorofCYP1A2,CYP2C19,CYP2C9,CYP2D6orCYP3A4

isozymes.EplerenoneisnotasubstrateoraninhibitorofP-Glycoprotein.

Digoxin

Systemicexposure(AUC)todigoxinincreasesby16%(90%CI:4%-30%)whenco-administeredwitheplerenone.

Cautioniswarrantedwhendigoxinisdosedneartheupperlimitoftherapeuticrange.

Warfarin

Noclinicallysignificantpharmacokineticinteractionshavebeenobservedwithwarfarin.Cautioniswarrantedwhen

warfarinisdosedneartheupperlimitoftherapeuticrange.

CYP3A4substrates

ResultsofpharmacokineticstudieswithCYP3A4probe-substrates,i.e.midazolamandcisapride,showednosignificant

pharmacokineticinteractionswhenthesedrugswereco-administeredwitheplerenone.

CYP3A4inhibitors

-StrongCYP3A4inhibitors:Significantpharmacokineticinteractionsmayoccurwheneplerenoneisco-administered

withdrugsthatinhibittheCYP3A4enzyme.AstronginhibitorofCYP3A4(ketoconazole200mgBID)ledtoa441%

increaseinAUCofeplerenone(seesection4.3).TheconcomitantuseofeplerenonewithstrongCYP3A4inhibitors

suchasketoconazole,itraconazole,ritonavir,nelfinavir,clarithromycin,telithromycinandnefazadone,iscontra-

indicated(seesection4.3).

-MildtomoderateCYP3A4inhibitors:Co-administrationwitherythromycin,saquinavir,amiodarone,diltiazem,

verapamil,andfluconazolehaveledtosignificantpharmacokineticinteractionswithrankorderincreasesinAUC

rangingfrom98%to187%.Eplerenonedosingshouldthereforenotexceed25mgwhenmildtomoderateinhibitorsof

CYP3A4areco-administeredwitheplerenone(seesections4.2).

CYP3A4inducers

Co-administrationofStJohn’sWort(astrongCYP3A4inducer)witheplerenonecauseda30%decreaseineplerenone

AUC.AmorepronounceddecreaseineplerenoneAUCmayoccurwithstrongerCYP3A4inducerssuchasrifampicin.

Duetotheriskofdecreasedeplerenoneefficacy,theconcomitantuseofstrongCYP3A4inducers(rifampicin,

carbamazepine,phenytoin,phenobarbital,StJohn’sWort)witheplerenoneisnotrecommended(seesection4.4).

Antacids

Basedontheresultsofapharmacokineticclinicalstudy,nosignificantinteractionisexpectedwhenantacidsareco-

administeredwitheplerenone.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedataontheuseofeplerenoneinpregnantwomen.Animalstudiesdidnotindicatedirector

indirectadverseeffectswithrespecttopregnancy,embryofoetaldevelopment,parturitionandpostnataldevelopment

(seesection5.3).Cautionshouldbeexercisedprescribingeplerenonetopregnantwomen.

Lactation

Itisunknownifeplerenoneisexcretedinhumanbreastmilkafteroraladministration.However,preclinicaldatashow

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normally.Becauseoftheunknownpotentialforadverseeffectsonthebreastfedinfant,adecisionshouldbemade

whethertodiscontinuebreast-feedingordiscontinuethedrug,takingintoaccounttheimportanceofthedrugtothe

mother.

Fertility

Noimpactonfertilitywasdetectedinratstudiesatdosagesupto300mg/kg.Noclinicaldataareavailable,potential

riskforhumanisunknown.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectofeplerenoneontheabilitytodriveorusemachineshavebeenperformed.Eplerenonedoes

notcausedrowsinessorimpairmentofcognitivefunctionbutwhendrivingvehiclesoroperatingmachinesitshouldbe

takenintoaccountthatdizzinessmayoccurduringtreatment.

4.8Undesirableeffects

Intheeplerenonepost-acutemyocardialinfarctionheartfailureefficacyandsurvivalstudy(EPHESUS),theoverall

incidenceofadverseeventsreportedwitheplerenone(78.9%)wassimilartoplacebo(79.5%).Thediscontinuationrate

duetoadverseeventsinthesestudieswas4.4%forpatientsreceivingeplerenoneandfor4.3%patientsreceiving

placebo.

AdverseeventsreportedbelowareeithertakenfromEPHESUSandarethosewithsuspectedrelationshiptotreatment

andinexcessofplaceboorareseriousandsignificantlyinexcessofplacebo,orhavebeenobservedduringpost

marketingsurveillance.Adverseeventsarelistedbybodysystemandabsolutefrequency.Frequenciesaredefinedas:

common(1/100to<1/10),uncommon(1/1,000to<1/100)andnotknown(cannotbeestimatedfromtheavailable

data).

Infectionsandinfestations

Uncommon:pyelonephritis

Bloodandlymphaticsystemdisorders

Uncommon:eosinophilia

Metabolismandnutritiondisorders

Common:hyperkalaemia

Uncommon:hyponatraemia,dehydration,hypercholesterolaemia,hypertriglyceridaemia,

Psychiatricdisorders

Uncommon:insomnia

Nervoussystemdisorders

Common:dizziness

Uncommon:headache

Cardiacdisorders

Uncommon:myocardialinfarction,cardiacfailureleft,fibrillationatrial,

Vasculardisorders

Common:hypotension

Uncommon:thrombosisarterialleg,hypotensionpostural,

Respiratory,thoracicandmediastinaldisorders

Uncommon:pharyngitis

Gastrointestinaldisorders

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Uncommon:vomiting,flatulence,

Skinandsubcutaneoustissuedisorders

Common:rash

Uncommon:pruritus,sweatingincreased

Notknown:angioneuroticoedema

Musculoskeletalandconnectivetissuedisorders

Uncommon:backpain,cramplegs

Renalandurinarydisorders

Common:renalfunctionabnormal

Reproductivesystemandbreastdisorders

Uncommon:gynecomastia

Generaldisordersandadministrationsiteconditions

Uncommon:asthenia,malaise

Investigations

Uncommon:BUNincreased,creatinineincrease

InEPHESUS,therewerenumericallymorecasesofstrokeintheelderlygroup(75yearsold).Therewashoweverno

statisticalsignificantdifferencebetweentheoccurrenceofstrokeintheeplerenone(30)vsplacebo(22)groups.

4.9Overdose

Nocasesofhumanoverdosagewitheplerenonehavebeenreported.Themostlikelymanifestationofhuman

overdosagewouldbeanticipatedtobehypotensionorhyperkalaemia.Eplerenonecannotberemovedby

haemodialysis.Eplerenonehasbeenshowntobindextensivelytocharcoal.Ifsymptomatichypotensionshouldoccur,

supportivetreatmentshouldbeinitiated.Ifhyperkalaemiadevelops,standardtreatmentshouldbeinitiated.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:aldosteroneantagonists,ATCcode:C03DA04

Eplerenonehasrelativeselectivityinbindingtorecombinanthumanmineralocorticoidreceptorscomparedtoits

bindingtorecombinanthumanglucocorticoid,progesteroneandandrogenreceptors.Eplerenonepreventsthebinding

ofaldosterone,akeyhormoneintherenin-angiotensin-aldosterone-system(RAAS),whichisinvolvedintheregulation

ofbloodpressureandthepathophysiologyofcardiovasculardisease.

Eplerenonehasbeenshowntoproducesustainedincreasesinplasmareninandserumaldosterone,consistentwith

inhibitionofthenegativeregulatoryfeedbackofaldosteroneonreninsecretion.Theresultingincreasedplasmarenin

activityandaldosteronecirculatinglevelsdonotovercometheeffectsofeplerenone.

Indose-rangingstudiesofchronicheartfailure(NYHAclassificationII-IV),theadditionofeplerenonetostandard

therapyresultedinexpecteddose-dependentincreasesinaldosterone.Similarly,inacardiorenalsubstudyof

EPHESUS,therapywitheplerenoneledtoasignificantincreaseinaldosterone.Theseresultsconfirmtheblockadeof

themineralocorticoidreceptorinthesepopulations.

Eplerenonewasstudiedintheeplerenonepost-acutemyocardialinfarctionheartfailureefficacyandsurvivalstudy

(EPHESUS).EPHESUSwasadouble-blind,placebo-controlledstudy,of3yearduration,in6632patientswithacute

myocardialinfarction(MI),leftventriculardysfunction(asmeasuredbyleftventricularejectionfraction[LVEF]

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eplerenoneorplaceboinadditiontostandardtherapiesataninitialdose25mgoncedailyandtitratedtothetargetdose

of50mgoncedailyafter4weeksifserumpotassiumwas<5.0mmol/L.Duringthestudypatientsreceivedstandard

careincludingacetylsalicylicacid(92%),ACEinhibitors(90%),ß-blockers(83%),nitrates(72%),loopdiuretics

(66%),orHMGCoAreductaseinhibitors(60%).

InEPHESUS,theco-primaryendpointswereall-causemortalityandthecombinedendpointofCVdeathorCV

hospitalisation;14.4%ofpatientsassignedtoeplerenoneand16.7%ofpatientsassignedtoplacebodied(allcauses),

while26.7%ofpatientsassignedtoeplerenoneand30.0%assignedtoplacebometthecombinedendpointofCVdeath

orhospitalisation.Thus,inEPHESUS,eplerenonereducedtheriskofdeathfromanycauseby15%(RR0.85;95%CI,

0.75-0.96;p=0.008)comparedtoplacebo,primarilybyreducingcardiovascular(CV)mortality.TheriskofCVdeath

orCVhospitalisationwasreducedby13%witheplerenone(RR0.87;95%CI,0.79-0.95;p=0.002).Theabsoluterisk

reductionsfortheendpointsallcausemortalityandCVmortality/hospitalisationwere2.3and3.3%,respectively.

Clinicalefficacywasprimarilydemonstratedwheneplerenonetherapywasinitiatedinpatientsaged<75yearsold.

Thebenefitsoftherapyinthosepatientsovertheageof75areunclear.NYHAfunctionalclassificationimprovedor

remainedstableforastatisticallysignificantlygreaterproportionofpatientsreceivingeplerenonecomparedtoplacebo.

Theincidenceofhyperkalaemiawas3.4%intheeplerenonegroupvs2.0%intheplacebogroup(p<0.001).The

incidenceofhypokalaemiawas0.5%intheeplerenonegroupvs1.5%intheplacebogroup(p<0.001).

Noconsistenteffectsofeplerenoneonheartrate,QRSduration,orPRorQTintervalwereobservedin147normal

subjectsevaluatedforelectrocardiographicchangesduringpharmacokineticstudies.

5.2Pharmacokineticproperties

AbsorptionandDistribution

Theabsolutebioavailabilityofeplerenoneisunknown.Maximumplasmaconcentrationsarereachedafterabout2

hours.Bothpeakplasmalevels(Cmax)andareaunderthecurve(AUC)aredoseproportionalfordosesof10to100

mgandlessthanproportionalatdosesabove100mg.Steadystateisreachedwithin2days.Absorptionisnotaffected

byfood.

Theplasmaproteinbindingofeplerenoneisabout50%andisprimarilyboundtoalpha1-acidglycoproteins.The

apparentvolumeofdistributionatsteadystateisestimatedat50(±7)L.Eplerenonedoesnotpreferentiallybindtored

bloodcells.

MetabolismandExcretion

EplerenonemetabolismisprimarilymediatedviaCYP3A4.Noactivemetabolitesofeplerenonehavebeenidentifiedin

humanplasma.

Lessthan5%ofaneplerenonedoseisrecoveredasunchangeddrugintheurineandfaeces.Followingasingleoral

doseofradiolabeleddrug,approximately32%ofthedosewasexcretedinthefaecesandapproximately67%was

excretedintheurine.Theeliminationhalf-lifeofeplerenoneisapproximately3to5hours.Theapparentplasma

clearanceisapproximately10L/hr.

SpecialPopulations

Age,Gender,andRace

Thepharmacokineticsofeplerenoneatadoseof100mgoncedailyhavebeeninvestigatedintheelderly(65years),

inmalesandfemales,andinblacks.Thepharmacokineticsofeplerenonedidnotdiffersignificantlybetweenmalesand

females.Atsteadystate,elderlysubjectshadincreasesinCmax(22%)andAUC(45%)comparedwithyounger

subjects(18to45years).Atsteadystate,Cmaxwas19%lowerandAUCwas26%lowerinblacks.(seesection4.2.)

RenalInsufficiency

Thepharmacokineticsofeplerenonewereevaluatedinpatientswithvaryingdegreesofrenalinsufficiencyandin

patientsundergoinghaemodialysis.Comparedwithcontrolsubjects,steady-stateAUCandCmaxwereincreasedby

38%and24%,respectively,inpatientswithsevererenalimpairmentandweredecreasedby26%and3%,respectively,

inpatientsundergoinghaemodialysis.Nocorrelationwasobservedbetweenplasmaclearanceofeplerenoneand

creatinineclearance.Eplerenoneisnotremovedbyhaemodialysis(seesection4.4.).

HepaticInsufficiency

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hepaticimpairmentandcomparedwithnormalsubjects.Steady-stateCmaxandAUCofeplerenonewereincreasedby

3.6%and42%,respectively(seesection4.2).Sincetheuseofeplerenonehasnotbeeninvestigatedinpatientswith

severehepaticimpairment,eplerenoneiscontraindicatedinthispatients’group(seesection4.3).

HeartFailure

Thepharmacokineticsofeplerenone50mgwereevaluatedinpatientswithheartfailure(NYHAclassificationII-IV).

Comparedwithhealthysubjectsmatchedaccordingtoage,weightandgender,steadystateAUCandCmaxinheart

failurepatientswere38%and30%higher,respectively.Consistentwiththeseresults,apopulationpharmacokinetic

analysisofeplerenonebasedonasubsetofpatientsfromEPHESUSindicatesthatclearanceofeplerenoneinpatients

withheartfailurewassimilartothatinhealthyelderlysubjects.

5.3Preclinicalsafetydata

Preclinicalstudiesonsafetypharmacology,genotoxicity,carcinogenicpotentialandtoxicitytoreproductionrevealed

nospecialhazardforhumans.

Inrepeateddosetoxicitystudies,prostateatrophywasobservedinratsanddogsatexposurelevelsslightlyabove

clinicalexposurelevels.Theprostaticchangeswerenotassociatedwithadversefunctionalconsequences.Theclinical

relevanceofthesefindingsisunknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

Lactosemonohydrate

Cellulose,microcrystalline(E460)

Croscarmellosesodium(E468)

Hypromellose(E464)

Sodiumlaurilsulfate

Talc(E553b)

Magnesiumstearate

Tabletcoating

Hypromellose(E464)

Polysorbate80(E433)

Macrogol400

Titaniumdioxide(E171)

Ironoxideyellow(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC/Aluminiumblisters

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unitdoseof10x1,14x1,20x1,28x1,30x1,50x1,56x1,60x1,84x1,90x1,98x1,or100x1tablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

SynthonBV

Microweg22,

6545CMNijmegen,

Netherlands

8MARKETINGAUTHORISATIONNUMBER

PA0840/012/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:25thNovember2011

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