CATASART

Main information

  • Trade name:
  • CATASART Tablets 32 Milligram
  • Dosage:
  • 32 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CATASART Tablets 32 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0711/134/004
  • Authorization date:
  • 04-09-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Catasart32mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains32mgofcandesartancilexetil

Excipient:eachtabletcontains278.27mgoflactosemonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

Pink,mottled,roundbiconvextablet,debossedwith32ononesideandscoredontheotherside.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Catasartisindicatedforthe:

Treatmentofessentialhypertensioninadults.

Treatmentofadultpatientswithheartfailureandimpairedleftventriclesystolicfunction(leftventricular

ejectionfraction 40%)asadd-ontherapytoAngiotensinConvertingEnzyme(ACE)inhibitorsorwhenACE-

inhibitorsarenottolerated(seesection5.1).

4.2Posologyandmethodofadministration

PosologyinHypertension

Therecommendedinitialdoseandusualmaintenancedoseis8mgoncedaily.Mostoftheantihypertensiveeffectis

attainedwithin4weeks.Insomepatientswhosebloodpressureisnotadequatelycontrolled,thedosecanbeincreased

to16mgoncedailyandtoamaximumof32mgoncedaily.Therapyshouldbeadjustedaccordingtobloodpressure

response.

Catasartmayalsobeadministeredwithotherantihypertensiveagents.Additionofhydrochlorothiazidehasbeenshown

tohaveanadditiveantihypertensiveeffectwithvariousdosesofCatasart.

Elderlypopulation

Noinitialdosageadjustmentisnecessaryinelderlypatients.

Patientswithintravascularvolumedepletion

Aninitialdoseof4mgmaybeconsideredinpatientsatriskforhypotension,suchaspatientswithpossiblevolume

depletion(seealso4.4).

Patientswithrenalimpairment

Thestartingdoseis4mginpatientswithrenalimpairment,includingpatientsonhaemodialysis.Thedoseshouldbe

titratedaccordingtoresponse.Thereislimitedexperienceinpatientswithverysevereorend-stagerenalimpairment

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Patientswithhepaticimpairment

Aninitialdoseof4mgoncedailyisrecommendedinpatientswithmildtomoderatehepaticimpairment.Thedose

maybeadjustedaccordingtoresponse.Catasartiscontraindicatedinpatientswithseverehepaticimpairmentand/or

cholestasis(seesections4.3and5.2).

Blackpatients

Theantihypertensiveeffectofcandesartanislessinblackthannon-blackpatients.Consequently,uptitrationofCatasart

andconcomitanttherapymaybemorefrequentlyneededforbloodpressurecontrolinblackthannon-blackpatients

(seesection5.1).

PosologyinHeartFailure

TheusualrecommendedinitialdoseofCatasartis4mgoncedaily.Up-titrationtothetargetdoseof32mgoncedaily

(maximumdose)orthehighesttolerateddoseisdonebydoublingthedoseatintervalsofatleast2weeks(seesection

4.4).Evaluationofpatientswithheartfailureshouldalwayscompriseassessmentofrenalfunctionincluding

monitoringofserumcreatinineandpotassium.

Catasartcanbeadministeredwithotherheartfailuretreatment,includingACEinhibitors,beta-blockers,diureticsand

digitalisoracombinationofthesemedicinalproducts.ThecombinationofanACEinhibitor,apotassium-sparing

diuretic(e.g.spironolactone)andCatasartisnotrecommendedandshouldbeconsideredonlyaftercarefulevaluation

ofthepotentialbenefitsandrisks(see

sections4.4,4.8and5.1).

Specialpatientpopulations

Noinitialdoseadjustmentisnecessaryforelderlypatientsorinpatientswithintravascularvolumedepletion,renal

impairmentormildtomoderatehepaticimpairment.

PaediatricPopulation

ThesafetyandefficacyofCatasartinchildrenagedbetweenbirthand18yearshavenotbeenestablishedinthe

treatmentofhypertensionandheartfailure.Nodataareavailable.

Methodofadministration

Oraluse.

Catasartshouldbetakenoncedailywithorwithoutfood.

Thebioavailabilityofcandesartanisnotaffectedbyfood.

4.3Contraindications

Hypersensitivitytocandesartancilexetilortoanyoftheexcipients.

Secondandthirdtrimesterofpregnancy(seesection4.4and4.6)

Severehepaticimpairmentand/orcholestasis.

4.4Specialwarningsandprecautionsforuse

Renalimpairment

Aswithotheragentsinhibitingtherenin-angiotensin-aldosteronesystem,changesinrenalfunctionmaybeanticipated

insusceptiblepatientstreatedwithCatasart.

WhenCatasartisusedinhypertensivepatientswithrenalimpairment,periodicmonitoringofserumpotassiumand

creatininelevelsisrecommended.Thereislimitedexperienceinpatientswithverysevereorend-stagerenal

impairment(Cl creatinine <15ml/min).InthesepatientsCatasartshouldbecarefullytitratedwiththoroughmonitoring

ofbloodpressure.

Evaluationofpatientswithheartfailureshouldincludeperiodicassessmentsofrenalfunction,especiallyinelderly

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serumcreatinineandpotassiumisrecommended.Clinicaltrialsinheartfailuredidnotincludepatientswithserum

creatinine>265µmol/L(>3mg/dL).

ConcomitanttherapywithanACEinhibitorinheartfailureTheriskofadverseevents,especiallyrenalfunction

impairmentandhyperkalaemia,mayincreasewhenCatasartisusedincombinationwithanACEinhibitor(seesection

4.8).Patientswithsuchtreatmentshouldbemonitoredregularlyandcarefully.

Haemodialysis

DuringdialysisthebloodpressuremaybeparticularlysensitivetoAT1-receptorblockadeasaresultofreducedplasma

volumeandactivationoftherenin-angiotensin-aldosteronesystem.ThereforeCatasartshouldbecarefullytitratedwith

thoroughmonitoringofbloodpressureinpatientsonhaemodialysis.

Renalarterystenosis

Medicinalproductsthataffecttherenin-angiotensin-aldosteronesystem,includingangiotensinIIreceptorantagonists

(AIIRAs),mayincreasebloodureaandserumcreatinineinpatientswithbilateralrenalarterystenosisorstenosisof

thearterytoasolitarykidney.

Kidneytransplantation

ThereisnoexperienceregardingtheadministrationofCatasartinpatientswitharecentkidneytransplantation.

Hypotension

HypotensionmayoccurduringtreatmentwithCatasartinheartfailurepatients.Itmayalsooccurinhypertensive

patientswithintravascularvolumedepletionsuchasthosereceivinghighdosediuretics.

Cautionshouldbeobservedwheninitiatingtherapyandcorrectionofhypovolemiashouldbeattempted.

Anaesthesiaandsurgery

HypotensionmayoccurduringanaesthesiaandsurgeryinpatientstreatedwithangiotensinIIantagonistsdueto

blockadeoftherenin-angiotensinsystem.Veryrarely,hypotensionmaybeseveresuchthatitmaywarranttheuseof

intravenousfluidsand/orvasopressors.

Aorticandmitralvalvestenosis(obstructivehypertrophiccardiomyopathy)

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromhaemodynamicallyrelevantaorticor

mitralvalvestenosis,orobstructivehypertrophiccardiomyopathy.

Primaryhyperaldosteronism

Patientswithprimaryhyperaldosteronismwillnotgenerallyrespondtoantihypertensivemedicinalproductsacting

throughinhibitionoftherenin-angiotensin-aldosteronesystem.Therefore,theuseofCatasartisnotrecommended.

Hyperkalaemia

ConcomitantuseofCatasartwithpotassium-sparingdiuretics,potassiumsupplements,saltsubstitutescontaining

potassium,orothermedicinalproductsthatmayincreasepotassiumlevels(e.g.heparin)mayleadtoincreasesinserum

potassiuminhypertensivepatients.Monitoringofpotassiumshouldbeundertakenasappropriate.

InheartfailurepatientstreatedwithCatasart,hyperkalaemiamayoccur.Periodicmonitoringofserumpotassiumis

recommended.

ThecombinationofanACEinhibitor,apotassium-sparingdiuretic(e.g.spironolactone)andCatasartisnot

recommendedandshouldbeconsideredonlyaftercarefulevaluationofthepotentialbenefitsandrisks.

General

Inpatientswhosevasculartoneandrenalfunctiondependpredominantlyontheactivityoftherenin-angiotensin-

aldosteronesystem(e.g.patientswithseverecongestiveheartfailureorunderlyingrenaldisease,includingrenalartery

stenosis),treatmentwithothermedicinalproductsthataffectthissystemhasbeenassociatedwithacutehypotension,

azotaemia,oliguriaor,rarely,acuterenalfailure.ThepossibilityofsimilareffectscannotbeexcludedwithAIIRAs.As

withanyantihypertensiveagent,excessivebloodpressuredecreaseinpatientswithischaemiccardiopathyorischaemic

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Pregnancy

AngiotensinIIantagonists(AIIRAs)shouldnotbeinitiatedduringpregnancy.UnlesscontinuedAIIRAtherapyis

consideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhich

haveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithAIIRAsshould

bestoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted(seesections4.3and4.6).

Specialwarningsregardingexcipients

Catasartcontainlactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyor

glucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Compoundswhichhavebeeninvestigatedinclinicalpharmacokineticstudiesincludehydrochlorothiazide,warfarin,

digoxin,oralcontraceptives(i.e.ethinylestradiol/levonorgestrel),glibenclamide,nifedipineandenalapril.Noclinically

significantpharmacokineticinteractionswiththesemedicinalproductshavebeenidentified.

Concomitantuseofpotassium-sparingdiuretics,potassiumsupplements,saltsubstitutescontainingpotassium,orother

medicinalproducts(e.g.heparin)mayincreasepotassiumlevels.Monitoringofpotassiumshouldbeundertakenas

appropriate(seesection4.4).

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.AsimilareffectmayoccurwithAIIRAs.Useofcandesartanwith

lithiumisnotrecommended.Ifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsis

recommended.

WhenAIIRAsareadministeredsimultaneouslywithnon-steroidalanti-inflammatorydrugs(i.e.selectiveCOX-2

inhibitors,acetylsalicylicacid>3g/day)andnon-selectiveNSAIDs),attenuationoftheantihypertensiveeffectmay

occur.

AswithACEinhibitors,concomitantuseofAIIRAsandNSAIDsmayleadtoanincreasedriskofworseningofrenal

function,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyinpatientswithpoor

pre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyintheelderly.Patients

shouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunctionafterinitiationof

concomitanttherapy,andperiodicallythereafter.

4.6Fertility,pregnancyandlactation

Pregnancy

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithAIIRAs,similarrisksmayexistforthisclassofdrugs.Unless

continuedAIIRAtherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithAIIRAsshouldbestoppedimmediatelyand,ifappropriate,alternativetherapyshouldbe

started.

ExposuretoAIIRAtherapyduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

renalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,hypotension,

TheuseofAIIRAsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).

TheuseofAIIRAsiscontra-indicatedduringthe2 nd

and3 rd

trimesterofpregnancy(seesection

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ShouldexposuretoAIIRAshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

InfantswhosemothershavetakenAIIRAsshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Lactation

BecausenoinformationisavailableregardingtheuseofCatasartduringbreastfeeding,Catasartisnotrecommended

andalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,especiallywhile

nursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsofcandesartanontheabilitytodriveandusemachineshavebeenperformed.However,it

shouldbetakenintoaccountthatoccasionallydizzinessorwearinessmayoccurduringtreatmentwithCatasart.

4.8Undesirableeffects

TreatmentofHypertension

Incontrolledclinicalstudiesadverseeventsweremildandtransient.Theoverallincidenceofadverseeventsshowedno

associationwithdoseorage.Withdrawalsfromtreatmentduetoadverseeventsweresimilarwithcandesartancilexetil

(3.1%)andplacebo(3.2%).

Inapooledanalysisofclinicaltrialdataofhypertensivepatients,adversereactionswithcandesartancilexetilwere

definedbasedonanincidenceofadverseeventswithcandesartancilexetilatleast1%higherthantheincidenceseen

withplacebo.Bythisdefinition,themostcommonlyreportedadversereactionsweredizziness/vertigo,headacheand

respiratoryinfection.

Thetablebelowpresentsadversereactionsfromclinicaltrialsandpost-marketingexperience.

Thefrequenciesusedinthetablesthroughoutthissectionare:

Verycommon(1/10);common(1/100,<1/10);uncommon(1/1000,<1/100);rare(1/10000,<1/1000);veryrare

(<1/10000),includingisolatedreports.

SystemOrganClass Frequency UndesirableEffect

Infectionsandinfestations Common Respiraoryinfection

Bloodandlymphaticsystem

disorders Veryrare Leukopenia,neutropeniaand

agranulocytosis

Metabolismandnutrition

disorders Veryrare Hyperkalaemia,hyponatraemia

Nervoussystemdisorders Common Dizzyness/vertigo,headache

Gastrointestinaldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,abnormal

hepaticfunctionorhepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,urticaria,

pruritus

Musculoskeletaland

connectivetissuedisorders Veryrare Backpain,arthralgia,myalgia

Renalandurinarydisorders Veryrare Renalimpairment,includingrenal

failureinsusceptiblepatients(see

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Laboratoryfindings

Ingeneral,therewerenoclinicallyimportantinfluencesofcandesartancilexetilonroutinelaboratoryvariables.Asfor

otherinhibitorsoftherenin-angiotensin-aldosteronesystem,smalldecreasesinhaemoglobinhavebeenseen.No

routinemonitoringoflaboratoryvariablesisusuallynecessaryforpatientsreceivingCatasart.However,inpatients

withrenalimpairment,periodicmonitoringofserumpotassiumandcreatininelevelsisrecommended.

TreatmentofHeartFailure

Theadverseexperienceprofileofcandesartancilexetilinheartfailurepatientswasconsistentwiththepharmacologyof

thedrugandthehealthstatusofthepatients.IntheCHARMclinicalprogramme,comparingcandesartancilexetilin

dosesupto32mg(n=3,803)toplacebo(n=3,796),21.0%ofthecandesartancilexetilgroupand16.1%oftheplacebo

groupdiscontinuedtreatmentbecauseofadverseevents.Themostcommonlyreportedadversereactionswere

hyperkalaemia,hypotensionandrenalimpairment.Theseeventsweremorecommoninpatientsover70yearsofage,

diabetics,orsubjectswhoreceivedothermedicinalproductswhichaffecttherenin-angiotensin-aldosteronesystem,in

particularanACEinhibitorand/orspironolactone.

Thetablebelowpresentsadversereactionsfromclinicaltrialsandpost-marketingexperience.

Laboratoryfindings:

HyperkalaemiaandrenalimpairmentarecommoninpatientstreatedwithCatasartfortheindicationofheartfailure.

Periodicmonitoringofserumcreatinineandpotassiumisrecommended(seesection4.4).Periodicmonitoringofserum

creatinineandpotassiumisrecommended(seesection4.4).

SystemOrganClass Frequency UndesirableEffect

Bloodandlymphaticsystem

disorders Veryrare Leukopenia,neutropeniaand

agranulocytosis

Metabolismandnutrition

disorders Common Hyperkalaemia

Veryrare Hyponatraemia

Nervoussystemdisorders Veryrare Dizziness,headache

Vasculardisorders Common Hypotension

Gastrointestinaldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,abnormal

hepaticfunctionorhepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,urticaria,pruritus

Musculoskeletalandconnective

tissuedisorders Veryrare Backpain,arthralgia,myalgia

Renalandurinarydisorders Common Renalimpairment,includingrenal

failureinsusceptiblepatients(see

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Symptoms

Basedonpharmacologicalconsiderations,themainmanifestationofanoverdoseislikelytobesymptomatic

hypotensionanddizziness.Inindividualcasereportsofoverdose(ofupto672mgcandesartancilexetil),patient

recoverywasuneventful.

Management

Ifsymptomatichypotensionshouldoccur,symptomatictreatmentshouldbeinstitutedandvitalsignsmonitored.The

patientshouldbeplacedsupinewiththelegselevated.Ifthisisnotsufficient,plasmavolumeshouldbeincreasedby

infusionof,forexample,isotonicsalinesolution.Sympathomimeticmedicinalproductsmaybeadministeredifthe

above-mentionedmeasuresarenotsufficient.

Candesartancilexetilisnotremovedbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:

AngiotensinIIantagonists,plain,ATCcode:C09CA06.

AngiotensinIIistheprimaryvasoactivehormoneoftherenin-angiotensin-aldosteronesystemandplaysaroleinthe

pathophysiologyofhypertension,heartfailureandothercardiovasculardisorders.Italsohasaroleinthepathogenesis

ofendorganhypertrophyanddamage.ThemajorphysiologicaleffectsofangiotensinII,suchasvasoconstriction,

aldosteronestimulation,regulationofsaltandwaterhomeostasisandstimulationofcellgrowth,aremediatedviathe

type1(AT1)receptor.

Candesartancilexetilisaprodrugsuitablefororaluse.Itisrapidlyconvertedtotheactivesubstance,candesartan,by

esterhydrolysisduringabsorptionfromthegastrointestinaltract.CandesartanisanAIIRA,selectiveforAT1receptors,

withtightbindingtoandslowdissociationfromthereceptor.Ithasnoagonistactivity.

CandesartandoesnotinhibitACE,whichconvertsangiotensinItoangiotensinIIanddegradesbradykinin.Thereisno

effectonACEandnopotentiationofbradykininorsubstanceP.Incontrolledclinicaltrialscomparingcandesartan

cilexetilwithACEinhibitors,theincidenceofcoughwaslowerinpatientsreceivingcandesartancilexetil.Candesartan

doesnotbindtoorblockotherhormonereceptorsorionchannelsknowntobeimportantincardiovascularregulation.

TheantagonismoftheangiotensinII(AT1)receptorsresultsindoserelatedincreasesinplasmareninlevels,

angiotensinIandangiotensinIIlevels,andadecreaseinplasmaaldosteroneconcentration.

Hypertension

Inhypertension,candesartancausesadose-dependent,long-lastingreductioninarterialbloodpressure.The

antihypertensiveactionisduetodecreasedsystemicperipheralresistance,withoutreflexincreaseinheartrate.Thereis

noindicationofseriousorexaggeratedfirstdosehypotensionorreboundeffectaftercessationoftreatment.

Afteradministrationofasingledoseofcandesartancilexetil,onsetofantihypertensiveeffectgenerallyoccurswithin2

hours.Withcontinuoustreatment,mostofthereductioninbloodpressurewithanydoseisgenerallyattainedwithin

fourweeksandissustainedduringlong-termtreatment.Accordingtoameta-analysis,theaverageadditionaleffectofa

doseincreasefrom16mgto32mgoncedailywassmall.Takingintoaccounttheinter-individualvariability,amore

thanaverageeffectcanbeexpectedinsomepatients.Candesartancilexetiloncedailyprovideseffectiveandsmooth

bloodpressurereductionover24hourswithlittledifferencebetweenmaximumandtrougheffectsduringthedosing

interval.Theantihypertensiveeffectandtolerabilityofcandesartanandlosartanwerecomparedintworandomised,

double-blindstudiesinatotalof1,268patientswithmildtomoderatehypertension.Thetroughbloodpressure

reduction(systolic/diastolic)was13.1/10.5mmHgwithcandesartancilexetil32mgoncedailyand10.0/8.7mmHg

withlosartanpotassium100mgoncedaily(differenceinbloodpressurereduction3.1/1.8mmHg,

p<0.0001/p<0.0001).

Whencandesartancilexetilisusedtogetherwithhydrochlorothiazide,thereductioninbloodpressureisadditive.An

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Medicinalproductsthatblocktherenin-angiotensin-aldosteronesystemhavelesspronouncedantihypertensiveeffectin

blackpatients(usuallyalow-reninpopulation)thaninnon-blackpatients.Thisisalsothecaseforcandesartan.Inan

open-labelclinicalexperiencetrialin5,156patientswithdiastolichypertension,thebloodpressurereductionduring

candesartantreatmentwassignificantlylessinblackthannon-blackpatients(14.4/10.3mmHgvs19.0/12.7mmHg,

p<0.0001/p<0.0001).

Candesartanincreasesrenalbloodflowandeitherhasnoeffecton,orincreasesglomerularfiltrationratewhilerenal

vascularresistanceandfiltrationfractionarereduced.Ina3-monthclinicalstudyinhypertensivepatientswithtype2

diabetesmellitusandmicroalbuminuria,antihypertensivetreatmentwithcandesartancilexetilreducedurinaryalbumin

excretion(albumin/creatinineratio,mean30%,95%CI15-42%).Thereiscurrentlynodataontheeffectofcandesartan

ontheprogressiontodiabeticnephropathy.

Theeffectsofcandesartancilexetil8-16mg(meandose12mg)oncedaily,oncardiovascularmorbidityandmortality

wereevaluatedinarandomisedclinicaltrialwith4,937elderlypatients(aged70-89years;21%aged80orabove)with

mildtomoderatehypertensionfollowedforameanof3.7years(StudyonCOgnitionandPrognosisintheElderly).

Patientsreceivedcandesartancilexetilorplacebowithotherantihypertensivetreatmentaddedasneeded.Theblood

pressurewasreducedfrom166/90to145/80mmHginthecandesartancilexetilgroup,andfrom167/90to

149/82mmHginthecontrolgroup.Therewasnostatisticallysignificantdifferenceintheprimaryendpoint,major

cardiovascularevents(cardiovascularmortality,non-fatalstrokeandnon-fatalmyocardialinfarction).Therewere26.7

eventsper1000patient-yearsinthecandesartangroupversus30.0eventsper1000patient-yearsinthecontrolgroup

(relativerisk0.89,95%CI0.75to1.06,p=0.19).

HeartFailure

Treatmentwithcandesartancilexetilreducesmortality,reduceshospitalisationduetoheartfailureandimproves

symptomsinpatientswithleftventricularsystolicdysfunctionasshownintheCandesartaninHeartfailure–

AssessmentofReductioninMortalityandmorbidity(CHARM)programme.

Thisplacebocontrolled,double-blindstudyprogrammeinchronicheartfailure(CHF)patientswithNYHAfunctional

classIItoIVconsistedofthreeseparatestudies:CHARM-Alternative(n=2,028)inpatientswithLVEF ≤40%not

treatedwithanACEinhibitorbecauseofintolerance(mainlyduetocough,72%),CHARM-Added(n=2,548)in

patientswithLVEF ≤40%andtreatedwithanACEinhibitor,andCHARM-Preserved(n=3,023)inpatientswith

LVEF>40%.PatientsonoptimalCHFtherapyatbaselinewererandomisedtoplaceboorcandesartancilexetil(titrated

from4mgor8mgoncedailyto32mgoncedailyorthehighesttolerateddose,meandose24mg)andfollowedfora

medianof37.7months.After6monthsoftreatment63%ofthepatientsstilltakingcandesartancilexetil(89%)wereat

thetargetdoseof32mg.

InCHARM-Alternative,thecompositeendpointofcardiovascularmortalityorfirstCHFhospitalisationwas

significantlyreducedwithcandesartanincomparisonwithplacebo,hazardratio(HR)0.77(95%CI0.67-0.89,

p<0.001).Thiscorrespondstoarelativeriskreductionof23%.Ofcandesartanpatients33.0%(95%CI:30.1to36.0)

andofplacebopatients40.0%(95%CI:37.0to43.1)experiencedthisendpoint,absolutedifference7.0%(95%CI:11.2

to2.8).Fourteenpatientsneededtobetreatedforthedurationofthestudytopreventonepatientfromdyingofa

cardiovasculareventorbeinghospitalisedfortreatmentofheartfailure.Thecompositeendpointofall-causemortality

orfirstCHFhospitalisationwasalsosignificantlyreducedwithcandesartanHR0.80(95%CI:0.70-0.92,p=0.001).Of

candesartanpatients36.6%(95%CI:33.7to39.7)andofplacebopatients42.7%(95%CI:39.6to45.8)experienced

thisendpoint,absolutedifference6.0%(95%CI:10.3to1.8).

Boththemortalityandmorbidity(CHFhospitalisation)componentsofthesecompositeendpointscontributedtothe

favourableeffectsofcandesartan.TreatmentwithcandesartancilexetilresultedinimprovedNYHAfunctionalclass

(p=0.008).

InCHARM-Added,thecompositeendpointofcardiovascularmortalityorfirstCHFhospitalisationwassignificantly

reducedwithcandesartanincomparisonwithplacebo,HR0.85(95%CI:0.75-0.96,p=0.011).Thiscorrespondstoa

relativeriskreductionof15%.Ofcandesartanpatients37.9%(95%CI:35.2to40.6)andofplacebopatients42.3%

(95%CI:39.6to45.1)experiencedthisendpoint,absolutedifference4.4%(95%CI:8.2to0.6).Twenty-threepatients

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hospitalisedfortreatmentofheartfailure.Thecompositeendpointofall-causemortalityorfirstCHFhospitalisation

wasalsosignificantlyreducedwithcandesartan,HR0.87(95%CI:0.78-0.98,p=0.021).Ofcandesartanpatients42.2%

(95%CI:39.5to45.0)andofplacebopatients46.1%

(95%CI:43.4to48.9)experiencedthisendpoint,absolutedifference3.9%(95%CI:7.8to0.1).Boththemortalityand

morbiditycomponentsofthesecompositeendpointscontributedtothefavourableeffectsofcandesartan.Treatment

withcandesartancilexetilresultedinimprovedNYHAfunctionalclass(p=0.020).

InCHARM-Preserved,nostatisticallysignificantreductionwasachievedinthecompositeendpointofcardiovascular

mortalityorfirstCHFhospitalisation,HR0.89(95%CI:0.77-1.03,p=0.118).

All-causemortalitywasnotstatisticallysignificantwhenexaminedseparatelyineachofthethreeCHARMstudies.

However,all-causemortalitywasalsoassessedinpooledpopulations,CHARM-AlternativeandCHARM-Added,HR

0.88(95%CI:0.79-0.98,p=0.018)andallthreestudies,HR0.91(95%CI:0.83-1.00,p=0.055).

Thebeneficialeffectsofcandesartanwereconsistentirrespectiveofage,genderandconcomitantmedication.

Candesartanwaseffectivealsoinpatientstakingbothbeta-blockersandACEinhibitorsatthesametime,andthe

benefitwasobtainedwhetherornotpatientsweretakingACEinhibitorsatthetargetdoserecommendedbytreatment

guidelines.

InpatientswithCHFanddepressedleftventricularsystolicfunction(leftventricularejectionfraction,LVEF ≤40%),

candesartandecreasessystemicvascularresistanceandpulmonarycapillarywedgepressure,increasesplasmarenin

activityandangiotensinIIconcentration,anddecreasesaldosteronelevels.

5.2Pharmacokineticproperties

Absorptionanddistribution

Followingoraladministration,candesartancilexetilisconvertedtotheactivesubstancecandesartan.Theabsolute

bioavailabilityofcandesartanisapproximately40%afteranoralsolutionofcandesartancilexetil.Therelative

bioavailabilityofthetabletformulationcomparedwiththesameoralsolutionisapproximately34%withverylittle

variability.Theestimatedabsolutebioavailabilityofthetabletistherefore14%.Themeanpeakserumconcentration

)isreached3-4hoursfollowingtabletintake.Thecandesartanserumconcentrationsincreaselinearlywith

increasingdosesinthetherapeuticdoserange.Nogenderrelateddifferencesinthepharmacokineticsofcandesartan

havebeenobserved.Theareaundertheserumconcentrationversustimecurve(AUC)ofcandesartanisnot

significantlyaffectedbyfood.

Candesartanishighlyboundtoplasmaprotein(morethan99%).Theapparentvolumeofdistributionofcandesartanis

0.1l/kg.

Thebioavailabilityofcandesartanisnotaffectedbyfood.

Biotransformationandelimination

Candesartanismainlyeliminatedunchangedviaurineandbileandonlytoaminorextenteliminatedbyhepatic

metabolism(CYP2C9).AvailableinteractionstudiesindicatenoeffectonCYP2C9andCYP3A4.Basedoninvitro

data,nointeractionwouldbeexpectedtooccurinvivowithdrugswhosemetabolismisdependentuponcytochrome

P450isoenzymesCYP1A2,CYP2A6,CYP2C9,CYP2C19,CYP2D6,CYP2E1orCYP3A4.Theterminalhalf-lifeof

candesartanisapproximately9hours.Thereisnoaccumulationfollowingmultipledoses.

Totalplasmaclearanceofcandesartanisabout0.37ml/min/kg,witharenalclearanceofabout0.19ml/min/kg.The

renaleliminationofcandesartanisbothbyglomerularfiltrationandactivetubularsecretion.Followinganoraldoseof

C-labelledcandesartancilexetil,approximately26%ofthedoseisexcretedintheurineascandesartanand7%asan

inactivemetabolitewhileapproximately56%ofthedoseisrecoveredinthefaecesascandesartanand10%asthe

inactivemetabolite.

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Intheelderly(over65years)C

andAUCofcandesartanareincreasedbyapproximately50%and80%,

respectivelyincomparisontoyoungsubjects.However,thebloodpressureresponseandtheincidenceofadverse

eventsaresimilarafteragivendoseofCatasartinyoungandelderlypatients(seesection4.2).

InpatientswithmildtomoderaterenalimpairmentC

andAUCofcandesartanincreasedduringrepeateddosingby

approximately50%and70%,respectively,butt

wasnotaltered,comparedtopatientswithnormalrenalfunction.

Thecorrespondingchangesinpatientswithsevererenalimpairmentwereapproximately50%and110%,respectively.

Theterminalt

ofcandesartanwasapproximatelydoubledinpatientswithsevererenalimpairment.TheAUCof

candesartaninpatientsundergoinghaemodialysiswassimilartothatinpatientswithsevererenalimpairment.

Intwostudies,bothincludingpatientswithmildtomoderatehepaticimpairment,therewasanincreaseinthemean

AUCofcandesartanofapproximately20%inonestudyand80%intheotherstudy(seesection4.2).Thereisno

experienceinpatientswithseverehepaticimpairment.

5.3Preclinicalsafetydata

Therewasnoevidenceofabnormalsystemicortargetorgantoxicityatclinicallyrelevantdoses.Inpreclinicalsafety

studiescandesartanhadeffectsonthekidneysandonredcellparametersathighdosesinmice,rats,dogsand

monkeys.Candesartancausedareductionofredbloodcellparameters(erythrocytes,haemoglobin,haematocrit).

Effectsonthekidneys(suchasinterstitialnephritis,tubulardistension,basophilictubules;increasedplasma

concentrationsofureaandcreatinine)wereinducedbycandesartanwhichcouldbesecondarytothehypotensiveeffect

leadingtoalterationsofrenalperfusion.Furthermore,candesartaninducedhyperplasia/hypertrophyofthe

juxtaglomerularcells.Thesechangeswereconsideredtobecausedbythepharmacologicalactionofcandesartan.For

therapeuticdosesofcandesartaninhumans,thehyperplasia/hypertrophyoftherenaljuxtaglomerularcellsdoesnot

seemtohaveanyrelevance.

Foetotoxicityhasbeenobservedinlatepregnancy(seesection4.6).

Datafrominvitroandinvivomutagenicitytestingindicatethatcandesartanwillnotexertmutagenicorclastogenic

activitiesunderconditionsofclinicaluse.

Therewasnoevidenceofcarcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

PovidoneK-30

Carrageenan

Croscarmellosesodium

Magnesiumstearate

Ironoxide,red(E172)

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable

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2years

HDPEbottles:usewithin3monthsafterfirstopening

6.4Specialprecautionsforstorage

Storeintheoriginalplaceinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Al/AlBlister:7,10,14,28,30,56,98,100,300tablets

Al/AlBlisterwithdesiccant:7,10,14,28,30,56,98,100,300tablets

HDPEbottlewithPPcapandsilicageldesiccant:30,100,500tablets

Notice!HDPEbottlecontainsdesiccant.Donotswallow.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

RowexLtd

Bantry

Co.Cork

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA711/134/4

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:4September2009

10DATEOFREVISIONOFTHETEXT

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