ATACAND 16 MG TABLETS

Main information

  • Trade name:
  • ATACAND 16 MG TABLETS
  • Dosage:
  • 16 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ATACAND 16 MG TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/116/002A
  • Authorization date:
  • 06-02-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Atacand16mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains16mgcandesartancilexetil.

EachtabletalsocontainsLactoseMonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

ProductimportedfromItaly:

Pink,roundtabletswithascoreandmarked‘A/CH’ononesideand‘016’ontheotherside.

ProductimportedfromtheUKandItaly:

Lightpinktabletswithoneconvexsideandonescoredflatside,embossed‘16’ontheconvexside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Atacandisindicatedforthe:

Treatmentofessentialhypertensioninadults.

Treatmentofadultpatientswithheartfailureandimpairedleftventricularsystolicfunction(leftventricular

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

inhibitorsarenottolerated(seesection5.1).

4.2Posologyandmethodofadministration

PosologyinHypertension

TherecommendedinitialdoseandusualmaintenancedoseofAtacandis8mgoncedaily.Mostoftheantihypertensive

effectisattainedwithin4weeks.Insomepatientswhosebloodpressureisnotadequatelycontrolled,thedosecanbe

increasedto16mgoncedailyandtoamaximumof32mgoncedaily.Therapyshouldbeadjustedaccordingtoblood

pressureresponse.

Atacandmayalsobeadministeredwithotherantihypertensiveagents.Additionofhydrochlorothiazidehasbeenshown

tohaveanadditiveantihypertensiveeffectwithvariousdosesofAtacand.

Elderlypopulation

Noinitialdoseadjustmentisnecessaryinelderlypatients.

Patientswithintravascularvolumedepletion

Aninitialdoseof4mgmaybeconsideredinpatientsatriskforhypotension,suchaspatientswithpossiblevolume

depletion(seesection4.4).

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2080824 page number: 1

Thestartingdoseis4mginpatientswithrenalimpairment,includingpatientsonhaemodialysis.Thedoseshouldbe

titratedaccordingtoresponse.Thereislimitedexperienceinpatientswithverysevereorend-stagerenalimpairment

creatinine <15ml/min)(seesection4.4).

Patientswithhepaticimpairment

Aninitialdoseof4mgoncedailyisrecommendedinpatientswithmildtomoderatehepaticimpairment.Thedose

maybeadjustedaccordingtoresponse.Atacandiscontraindicatedinpatientswithseverehepaticimpairmentand/or

cholestasis(seesections4.3and5.2).

Blackpatients

Theantihypertensiveeffectofcandesartanislesspronouncedinblackpatientsthaninnon-blackpatients.

Consequently,uptitrationofAtacandandconcomitanttherapymaybemorefrequentlyneededforbloodpressure

controlinblackpatientsthaninnon-blackpatients(seesection5.1).

PosologyinHeartFailure

TheusualrecommendedinitialdoseofAtacandis4mgoncedaily.Up-titrationtothetargetdoseof32mgoncedaily

(maximumdose)orthehighesttolerateddoseisdonebydoublingthedoseatintervalsofatleast2weeks(seesection

4.4).Evaluationofpatientswithheartfailureshouldalwayscompriseassessmentofrenalfunctionincluding

monitoringofserumcreatinineandpotassium.Atacandcanbeadministeredwithotherheartfailuretreatment,

includingACEinhibitors,beta-blockers,diureticsanddigitalisoracombinationofthesemedicinalproducts.The

combinationofanACEinhibitor,apotassium-sparingdiuretic(e.g.spironolactone)andAtacandisnotrecommended

andshouldbeconsideredonlyaftercarefulevaluationofthepotentialbenefitsandrisks(seesections4.4,4.8and5.1).

Specialpatientpopulations

Noinitialdoseadjustmentisnecessaryforelderlypatientsorinpatientswithintravascularvolumedepletionorrenal

impairmentormildtomoderatehepaticimpairment.

PaediatricPopulation

ThesafetyandefficacyofAtacandinchildrenagedbetweenbirthand18yearshavenotbeenestablishedinthe

treatmentofhypertensionandheartfailure.Nodataareavailable.

Methodofadministration

Oraluse.

Atacandshouldbetakenoncedailywithorwithoutfood.

Thebioavailabilityofcandesartanisnotaffectedbyfood.

4.3Contraindications

Hypersensitivitytocandesartancilexetilortoanyoftheexcipients.

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6).

Severehepaticimpairmentand/orcholestasis.

4.4Specialwarningsandprecautionsforuse

Renalimpairment

Aswithotheragentsinhibitingtherenin-angiotensin-aldosteronesystem,changesinrenalfunctionmaybeanticipated

insusceptiblepatientstreatedwithAtacand.

WhenAtacandisusedinhypertensivepatientswithrenalimpairment,periodicmonitoringofserumpotassiumand

creatininelevelsisrecommended.Thereislimitedexperienceinpatientswithverysevereorend-stagerenal

impairment(Cl

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2080824 page number: 2

ofbloodpressure.

Evaluationofpatientswithheartfailureshouldincludeperiodicassessmentsofrenalfunction,especiallyinelderly

patients75yearsorolder,andpatientswithimpairedrenalfunction.DuringdosetitrationofAtacand,monitoringof

serumcreatinineandpotassiumisrecommended.Clinicaltrialsinheartfailuredidnotincludepatientswithserum

creatinine>265µmol/l(>3mg/dl).

ConcomitanttherapywithanACEinhibitorinheartfailure

Theriskofadversereactions,especiallyrenalfunctionimpairmentandhyperkalaemia,mayincreasewhenAtacandis

usedincombinationwithanACEinhibitor(seesection4.8).Patientswithsuchtreatmentshouldbemonitored

regularlyandcarefully.

Haemodialysis

DuringdialysisthebloodpressuremaybeparticularlysensitivetoAT

-receptorblockadeasaresultofreducedplasma

volumeandactivationoftherenin-angiotensin-aldosteronesystem.Therefore,Atacandshouldbecarefullytitratedwith

thoroughmonitoringofbloodpressureinpatientsonhaemodialysis.

Renalarterystenosis

Medicinalproductsthataffecttherenin-angiotensin-aldosteronesystem,includingangiotensinIIreceptorantagonists

(AIIRAs),mayincreasebloodureaandserumcreatinineinpatientswithbilateralrenalarterystenosisorstenosisofthe

arterytoasolitarykidney.

Kidneytransplantation

ThereisnoexperienceregardingtheadministrationofAtacandinpatientswitharecentkidneytransplantation.

Hypotension

HypotensionmayoccurduringtreatmentwithAtacandinheartfailurepatients.Itmayalsooccurinhypertensive

patientswithintravascularvolumedepletionsuchasthosereceivinghighdosediuretics.Cautionshouldbeobserved

wheninitiatingtherapyandcorrectionofhypovolemiashouldbeattempted.

Anaesthesiaandsurgery

HypotensionmayoccurduringanaesthesiaandsurgeryinpatientstreatedwithangiotensinIIantagonistsdueto

blockadeoftherenin-angiotensinsystem.Veryrarely,hypotensionmaybeseveresuchthatitmaywarranttheuseof

intravenousfluidsand/orvasopressors.

Aorticandmitralvalvestenosis(obstructivehypertrophiccardiomyopathy)

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromhaemodynamicallyrelevantaorticor

mitralvalvestenosis,orobstructivehypertrophiccardiomyopathy.

Primaryhyperaldosteronism

Patientswithprimaryhyperaldosteronismwillnotgenerallyrespondtoantihypertensivemedicinalproductsacting

throughinhibitionoftherenin-angiotensin-aldosteronesystem.Therefore,theuseofAtacandisnotrecommendedin

thispopulation.

Hyperkalaemia

ConcomitantuseofAtacandwithpotassium-sparingdiuretics,potassiumsupplements,saltsubstitutescontaining

potassium,orothermedicinalproductsthatmayincreasepotassiumlevels(e.g.heparin)mayleadtoincreasesinserum

potassiuminhypertensivepatients.Monitoringofpotassiumshouldbeundertakenasappropriate.

InheartfailurepatientstreatedwithAtacand,hyperkalaemiamayoccur.Periodicmonitoringofserumpotassiumis

recommended.ThecombinationofanACEinhibitor,apotassium-sparingdiuretic(e.g.spironolactone)andAtacandis

notrecommendedandshouldbeconsideredonlyaftercarefulevaluationofthepotentialbenefitsandrisks.

General

Inpatientswhosevasculartoneandrenalfunctiondependpredominantlyontheactivityoftherenin-angiotensin-

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2080824 page number: 3

stenosis),treatmentwithothermedicinalproductsthataffectthissystemhasbeenassociatedwithacutehypotension,

azotaemia,oliguriaor,rarely,acuterenalfailure.ThepossibilityofsimilareffectscannotbeexcludedwithAIIRAs.As

withanyantihypertensiveagent,excessivebloodpressuredecreaseinpatientswithischaemiccardiopathyorischaemic

cerebrovasculardiseasecouldresultinamyocardialinfarctionorstroke.

Theantihypertensiveeffectofcandesartanmaybeenhancedbyothermedicinalproductswithbloodpressurelowering

properties,whetherprescribedasanantihypertensiveorprescribedforotherindications.

Atacandcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyor

glucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

Pregnancy

AIIRAsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedAIIRAtherapyisconsideredessential,patients

planningpregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhichhaveanestablishedsafety

profileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithAIIRAsshouldbestoppedimmediately,

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

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(NSAIDs)(i.e.selective

COX-2inhibitors,acetylsalicylicacid(>3g/day)andnon-selectiveNSAIDs),attenuationoftheantihypertensive

effectmayoccur.

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

TheuseofAIIRAsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).

TheuseofAIIRAsiscontraindicatedduringthesecondandthirdtrimestersofpregnancy(see

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2080824 page number: 4

diagnosed,treatmentwithAIIRAsshouldbestoppedimmediatelyand,ifappropriate,alternativetherapyshouldbe

started.

ExposuretoAIIRAtherapyduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

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

hyperkalaemia)(seesection5.3).

ShouldexposuretoAIIRAshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

InfantswhosemothershavetakenAIIRAsshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Lactation

BecausenoinformationisavailableregardingtheuseofAtacandduringbreastfeeding,Atacandisnotrecommended

andalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,especiallywhile

nursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsofcandesartanontheabilitytodriveandusemachineshavebeenperformed.However,it

shouldbetakenintoaccountthatoccasionallydizzinessorwearinessmayoccurduringtreatmentwithAtacand.

4.8Undesirableeffects

TreatmentofHypertension

Incontrolledclinicalstudiesadversereactionsweremildandtransient.Theoverallincidenceofadverseeventsshowed

noassociationwithdoseorage.Withdrawalsfromtreatmentduetoadverseeventsweresimilarwithcandesartan

cilexetil(3.1%)andplacebo(3.2%).

Inapooledanalysisofclinicaltrialdataofhypertensivepatients,adversereactionswithcandesartancilexetilwere

definedbasedonanincidenceofadverseeventswithcandesartancilexetilatleast1%higherthantheincidenceseen

withplacebo.Bythisdefinition,themostcommonlyreportedadversereactionsweredizziness/vertigo,headacheand

respiratoryinfection.

Thetablebelowpresentsadversereactionsfromclinicaltrialsandpost-marketingexperience.

Thefrequenciesusedinthetablesthroughoutsection4.8are:verycommon( ≥1/10),common(≥1/100to<1/10),

uncommon( ≥1/1,000to<1/100),rare(≥1/10,000to<1/1,000)andveryrare(<1/10,000).

SystemOrganClass Frequency UndesirableEffect

Infectionsandinfestations Common Respiratoryinfection

Bloodandlymphaticsystemdisorders Veryrare Leukopenia,neutropenia

andagranulocytosis

Metabolismandnutritiondisorders Veryrare Hyperkalaemia,

hyponatraemia

Nervoussystemdisorders Common Dizziness/vertigo,

headache

Gastrointestinaldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,

abnormalhepaticfunction

orhepatitis

Skinandsubcutaneoustissuedisorders Veryrare Angioedema,rash,

urticaria,pruritus

Musculoskeletalandconnectivetissue

disorders Veryrare Backpain,arthralgia,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2080824 page number: 5

Laboratoryfindings

Ingeneral,therewerenoclinicallyimportantinfluencesofAtacandonroutinelaboratoryvariables.Asforother

inhibitorsoftherenin-angiotensin-aldosteronesystem,smalldecreasesinhaemoglobinhavebeenseen.Noroutine

monitoringoflaboratoryvariablesisusuallynecessaryforpatientsreceivingAtacand.However,inpatientswithrenal

impairment,periodicmonitoringofserumpotassiumandcreatininelevelsisrecommended.

TreatmentofHeartFailure

TheadverseexperienceprofileofAtacandinheartfailurepatientswasconsistentwiththepharmacologyofthedrug

andthehealthstatusofthepatients.IntheCHARMclinicalprogramme,comparingAtacandindosesupto32mg

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

treatmentbecauseofadverseevents.Themostcommonlyreportedadversereactionswerehyperkalaemia,hypotension

andrenalimpairment.Theseeventsweremorecommoninpatientsover70yearsofage,diabetics,orsubjectswho

receivedothermedicinalproductswhichaffecttherenin-angiotensin-aldosteronesystem,inparticularanACEinhibitor

and/orspironolactone.

Thetablebelowpresentsadversereactionsfromclinicaltrialsandpost-marketingexperience.

Laboratoryfindings

HyperkalaemiaandrenalimpairmentarecommoninpatientstreatedwithAtacandfortheindicationofheartfailure.

Periodicmonitoringofserumcreatinineandpotassiumisrecommended(seesection4.4).

4.9Overdose

Symptoms

Basedonpharmacologicalconsiderations,themainmanifestationofanoverdoseislikelytobesymptomatic

Renalandurinarydisorders Veryrare Renalimpairment,

includingrenalfailurein

susceptiblepatients(see

section4.4)

SystemOrganClass Frequency UndesirableEffect

Bloodandlymphaticsystem

disorders Veryrare Leukopenia,neutropenia

andagranulocytosis

Metabolismandnutrition

disorders Common Hyperkalaemia

Veryrare Hyponatraemia

Nervoussystemdisorders Veryrare Dizziness,headache

Vasculardisorders Common Hypotension

Gastrointestinaldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,

abnormalhepaticfunction

orhepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,

urticaria,pruritus

Musculoskeletalandconnective

tissuedisorders Veryrare Backpain,arthralgia,

myalgia

Renalandurinarydisorders Common Renalimpairment,

includingrenalfailurein

susceptiblepatients(see

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2080824 page number: 6

recoverywasuneventful.

Management

Ifsymptomatichypotensionshouldoccur,symptomatictreatmentshouldbeinstitutedandvitalsignsmonitored.The

patientshouldbeplacedsupinewiththelegselevated.Ifthisisnotsufficient,plasmavolumeshouldbeincreasedby

infusionof,forexample,isotonicsalinesolution.Sympathomimeticdrugsmaybeadministerediftheabove-mentioned

measuresarenotsufficient.

Candesartanisnotremovedbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:

AngiotensinIIantagonists,plain,ATCcode:C09CA06

AngiotensinIIistheprimaryvasoactivehormoneoftherenin-angiotensin-aldosteronesystemandplaysaroleinthe

pathophysiologyofhypertension,heartfailureandothercardiovasculardisorders.Italsohasaroleinthepathogenesis

ofendorganhypertrophyanddamage.ThemajorphysiologicaleffectsofangiotensinII,suchasvasoconstriction,

aldosteronestimulation,regulationofsaltandwaterhomeostasisandstimulationofcellgrowth,aremediatedviathe

type1(AT

)receptor.

Candesartancilexetilisaprodrugsuitablefororaluse.Itisrapidlyconvertedtotheactivesubstance,candesartan,by

esterhydrolysisduringabsorptionfromthegastrointestinaltract.CandesartanisanAIIRA,selectiveforAT

receptors,

withtightbindingtoandslowdissociationfromthereceptor.Ithasnoagonistactivity.

CandesartandoesnotinhibitACE,whichconvertsangiotensinItoangiotensinIIanddegradesbradykinin.Thereisno

effectonACEandnopotentiationofbradykininorsubstanceP.Incontrolledclinicaltrialscomparingcandesartan

withACEinhibitors,theincidenceofcoughwaslowerinpatientsreceivingcandesartancilexetil.Candesartandoesnot

bindtoorblockotherhormonereceptorsorionchannelsknowntobeimportantincardiovascularregulation.The

antagonismoftheangiotensinII(AT

)receptorsresultsindoserelatedincreasesinplasmareninlevels,angiotensinI

andangiotensinIIlevels,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

bloodpressurereductionover24hours,withlittledifferencebetweenmaximumandtrougheffectsduringthedosing

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

increasedantihypertensiveeffectisalsoseenwhencandesartancilexetiliscombinedwithamlodipineorfelodipine.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2080824 page number: 7

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

openlabelclinicalexperiencetrialin5,156patientswithdiastolichypertension,thebloodpressurereductionduring

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

p<0.0001/p<0.0001).

Candesartanincreasesrenalbloodflowandeitherhasnoeffectonorincreasesglomerularfiltrationratewhilerenal

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

pressurewasreducedfrom166/90to145/80mmHginthecandesartangroup,andfrom167/90to149/82mmHginthe

controlgroup.Therewasnostatisticallysignificantdifferenceintheprimaryendpoint,majorcardiovascularevents

(cardiovascularmortality,non-fatalstrokeandnon-fatalmyocardialinfarction).Therewere26.7eventsper1000

patient-yearsinthecandesartangroupversus30.0eventsper1000patient-yearsinthecontrolgroup(relativerisk0.89,

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

HeartFailure

Treatmentwithcandesartancilexetilreducesmortality,reduceshospitalisationduetoheartfailure,andimproves

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

(titratedfrom4mgor8mgoncedailyto32mgoncedailyorthehighesttolerateddose,meandose24mg)and

followedforamedianof37.7months.After6monthsoftreatment63%ofthepatientsstilltakingcandesartancilexetil

(89%)wereatthetargetdoseof32mg.

InCHARM-Alternative,thecompositeendpointofcardiovascularmortalityorfirstCHFhospitalisationwas

significantlyreducedwithcandesartanincomparisonwithplacebo,hazardratio(HR)0.77(95%CI:0.67to0.89,p<

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

ofplacebopatients40.0%(95%CI:37.0to43.1)experiencedthisendpoint,absolutedifference7.0%(95%CI:11.2to

2.8).Fourteenpatientsneededtobetreatedforthedurationofthestudytopreventonepatientfromdyingofa

cardiovasculareventorbeinghospitalisedfortreatmentofheartfailure.Thecompositeendpointofall-causemortality

orfirstCHFhospitalisationwasalsosignificantlyreducedwithcandesartan,HR0.80(95%CI:0.70to0.92,p=0.001).

Ofcandesartanpatients36.6%(95%CI:33.7to39.7)andofplacebopatients42.7%(95%CI:39.6to45.8)experienced

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

componentsofthesecompositeendpointscontributedtothefavourableeffectsofcandesartan.Treatmentwith

candesartancilexetilresultedinimprovedNYHAfunctionalclass(p=0.008).

InCHARM-Added,thecompositeendpointofcardiovascularmortalityorfirstCHFhospitalisationwassignificantly

reducedwithcandesartanincomparisonwithplacebo,HR0.85(95%CI:0.75to0.96,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

neededtobetreatedforthedurationofthestudytopreventonepatientfromdyingofacardiovasculareventorbeing

hospitalisedfortreatmentofheartfailure.Thecompositeendpointofall-causemortalityorfirstCHFhospitalisation

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2080824 page number: 8

42.2%(95%CI:39.5to45.0)andofplacebopatients46.1%(95%CI:43.4to48.9)experiencedthisendpoint,absolute

difference3.9%(95%CI:7.8to0.1).Boththemortalityandmorbiditycomponentsofthesecompositeendpoints

contributedtothefavourableeffectsofcandesartan.TreatmentwithcandesartancilexetilresultedinimprovedNYHA

functionalclass(p=0.020).

InCHARM-Preserved,nostatisticallysignificantreductionwasachievedinthecompositeendpointofcardiovascular

mortalityorfirstCHFhospitalisation,HR0.89(95%CI:0.77to1.03,p=0.118).

All-causemortalitywasnotstatisticallysignificantwhenexaminedseparatelyineachofthethreeCHARMstudies.

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

0.88(95%CI:0.79to0.98,p=0.018)andallthreestudies,HR0.91(95%CI:0.83to1.00,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.

Pharmacokineticsinspecialpopulations

Intheelderly(over65years)C

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2080824 page number: 9

respectivelyincomparisontoyoungsubjects.However,thebloodpressureresponseandtheincidenceofadverse

eventsaresimilarafteragivendoseofAtacandinyoungandelderlypatients(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(seesection4.6PregnancyandLactation).

Datafrominvitroandinvivomutagenicitytestingindicatethatcandesartanwillnotexertmutagenicorclastogenic

activitiesunderconditionsofclinicaluse.Therewasnoevidenceofcarcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Carmellosecalcium

Hyprolose

Lactosemonohydrate

Magnesiumstearate

Maizestarch

Macrogol

Ironoxidered(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2080824 page number: 10

6.5Natureandcontentsofcontainer

Blisterpackcontaining28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA465/116/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorizations:6 th

February2004

Dateoflastrenewal:6 th

February2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/05/2011 CRN 2080824 page number: 11