ATACAND

Main information

  • Trade name:
  • ATACAND Tablets 2 Milligram
  • Dosage:
  • 2 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ATACAND Tablets 2 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0970/030/001
  • Authorization date:
  • 29-04-2002
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0970/030/001

CaseNo:2078949

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

AstraZenecaUKLimited

600CapabilityGreen,Luton,LU13LU,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Atacand2mgtablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom12/05/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Atacand2mgtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains2mgcandesartancilexetil.

Each2mgtabletcontains95.4mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

Atacand2mgareround(diameter7mm),whitetablets.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Essentialhypertension.

Treatmentofpatientswithheartfailureandimpairedleftventriclesystolicfunction(leftventricularejectionfraction

40%)asadd-ontherapytoACEinhibitorsorwhenACEinhibitorsarenottolerated(seesection5.1Pharmacodynamic

properties).

4.2Posologyandmethodofadministration

DosageinHypertension

Therecommendedinitialdoseandusualmaintenancedoseis8mgoncedaily.Thedosemaybeincreasedto16mg

oncedaily.Ifbloodpressureisnotsufficientlycontrolledafter4weeksoftreatmentwith16mgoncedaily,thedose

maybefurtherincreasedtoamaximumof32mgoncedaily(seesection5.1Pharmacodynamicproperties).Ifblood

pressurecontrolisnotachievedwiththisdose,alternativestrategiesshouldbeconsidered.

Therapyshouldbeadjustedaccordingtobloodpressureresponse.Mostoftheantihypertensiveeffectisattainedwithin

4weeksofinitiationoftreatment.

Useintheelderly

Noinitialdosageadjustmentisnecessaryinelderlypatients.

Useinpatientswithintravascularvolumedepletion

Aninitialdoseof4mgmaybeconsideredinpatientsatriskforhypotension,suchaspatientswithpossiblevolume

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Useinimpairedrenalfunction

Thestartingdoseis4mginpatientswithrenalimpairment,includingpatientsonhaemodialysis.Thedoseshouldbe

titratedaccordingtoresponse.Thereislimitedexperienceinpatientswithverysevereorend-stagerenalimpairment

creatinine <15ml/min).(Seesection4.4Specialwarningsandspecialprecautionsforuse.)

Useinimpairedhepaticfunction

Aninitialdoseof2mgoncedailyisrecommendedinpatientswithmildtomoderatehepaticimpairment.Thedose

maybeadjustedaccordingtoresponse.Thereisnoexperienceinpatientswithseverehepaticimpairment.

Concomitanttherapy

Additionofathiazide-typediureticsuchashydrochlorothiazidehasbeenshowntohaveanadditiveantihypertensive

effectwithAtacand.

Useinblackpatients

Theantihypertensiveeffectofcandesartanislessinblackthannon-blackpatients.Consequently,uptitrationof

Atacandandconcomitanttherapymaybemorefrequentlyneededforbloodpressurecontrolinblackthannon-black

patients(seesection5.1Pharmacodynamicproperties).

DosageinHeartFailure

TheusualrecommendedinitialdoseofAtacandis4mgoncedaily.Up-titrationtothetargetdoseof32mgoncedaily

orthehighesttolerateddoseisdonebydoublingthedoseatintervalsofatleast2weeks(seesection4.4Special

warningsandspecialprecautionsforuse).

Specialpatientpopulations

Noinitialdoseadjustmentisnecessaryforelderlypatientsorinpatientswithintravascularvolumedepletion,renal

impairmentormildtomoderatehepaticimpairment.

Concomitanttherapy

Atacandcanbeadministeredwithotherheartfailuretreatment,includingACEinhibitors,beta-blockers,diureticsand

digitalisoracombinationofthesemedicinalproducts(seealsosection4.4Specialwarningsandspecialprecautions

foruseand5.1Pharmacodynamicproperties).

Administration

Atacandshouldbetakenoncedailywithorwithoutfood.

Useinchildrenandadolescents

ThesafetyandefficacyofAtacandhavenotbeenestablishedinchildrenandadolescents(under18years).

4.3Contraindications

Hypersensitivitytocandesartancilexetilortoanyoftheexcipients.

Pregnancyandlactation(seesection4.6Pregnancyandlactation).

Severehepaticimpairmentand/orcholestasis.

4.4Specialwarningsandprecautionsforuse

Renalimpairment

Aswithotheragentsinhibitingtherenin-angiotensin-aldosteronesystem,changesinrenalfunctionmaybeanticipated

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WhenAtacandisusedinhypertensivepatientswithrenalimpairment,periodicmonitoringofserumpotassiumand

creatininelevelsisrecommended.Thereislimitedexperienceinpatientswithverysevereorend-stagerenal

impairment(Cl

creatinine <15ml/min).InthesepatientsAtacandshouldbecarefullytitratedwiththoroughmonitoringof

bloodpressure.

Evaluationofpatientswithheartfailureshouldincludeperiodicassessmentsofrenalfunction,especiallyinelderly

patients75yearsorolder,andpatientswithimpairedrenalfunction.DuringdosetitrationofAtacand,monitoringof

serumcreatinineandpotassiumisrecommended.Clinicaltrialsinheartfailuredidnotincludepatientswithserum

creatinine>265µmol/L(>3mg/dL).

ConcomitanttherapywithanACEinhibitorinheartfailure

Theriskofadverseevents,especiallyrenalfunctionimpairmentandhyperkalaemia,mayincreasewhencandesartanis

usedincombinationwithanACEinhibitor(seesection4.8Undesirableeffects).Patientswithsuchtreatmentshouldbe

monitoredregularlyandcarefully.

Haemodialysis

DuringdialysisthebloodpressuremaybeparticularlysensitivetoAT1-receptorblockadeasaresultofreducedplasma

volumeandactivationoftherenin-angiotensin-aldosteronesystem.Therefore,Atacandshouldbecarefullytitratedwith

thoroughmonitoringofbloodpressureinpatientsonhaemodialysis.

Renalarterystenosis

Othermedicinalproductsthataffecttherenin-angiotensin-aldosteronesystem,i.e.angiotensinconvertingenzyme

(ACE)inhibitors,mayincreasebloodureaandserumcreatinineinpatientswithbilateralrenalarterystenosisor

stenosisofthearterytoasolitarykidney.AsimilareffectmaybeanticipatedwithangiotensinIIreceptorantagonists.

Kidneytransplantation

ThereisnoexperienceregardingtheadministrationofAtacandinpatientswitharecentkidneytransplantation.

Hypotension

HypotensionmayoccurduringtreatmentwithAtacandinheartfailurepatients.Asdescribedforotheragentsactingon

therenin-angiotensin-aldosteronesystem,itmayalsooccurinhypertensivepatientswithintravascularvolume

depletionsuchasthosereceivinghighdosediuretics.Cautionshouldbeobservedwheninitiatingtherapyand

correctionofhypovolemiashouldbeattempted.

Anaesthesiaandsurgery

HypotensionmayoccurduringanaesthesiaandsurgeryinpatientstreatedwithangiotensinIIantagonistsdueto

blockadeoftherenin-angiotensinsystem.Veryrarely,hypotensionmaybeseveresuchthatitmaywarranttheuseof

intravenousfluidsand/orvasopressors.

Aorticandmitralvalvestenosis(obstructivehypertrophiccardiomyopathy)

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromhaemodynamicallyrelevantaorticor

mitralvalvestenosis,orobstructivehypertrophiccardiomyopathy.

Primaryhyperaldosteronism

Patientswithprimaryhyperaldosteronismwillnotgenerallyrespondtoantihypertensivemedicinalproductsacting

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Hyperkalaemia

Basedonexperiencewiththeuseofothermedicinalproductsthataffecttherenin-angiotensin-aldosteronesystem,

concomitantuseofAtacandwithpotassium-sparingdiuretics,potassiumsupplements,saltsubstitutescontaining

potassium,orothermedicinalproductsthatmayincreasepotassiumlevels(e.g.heparin)mayleadtoincreasesinserum

potassiuminhypertensivepatients.

InheartfailurepatientstreatedwithAtacand,hyperkalaemiamayoccur.DuringtreatmentwithAtacandinpatients

withheartfailure,periodicmonitoringofserumpotassiumisrecommended,especiallywhentakenconcomitantlywith

ACEinhibitorsandpotassium-sparingdiureticssuchasspironolactone.

General

Inpatientswhosevasculartoneandrenalfunctiondependpredominantlyontheactivityoftherenin-angiotensin-

aldosteronesystem(e.g.patientswithseverecongestiveheartfailureorunderlyingrenaldisease,includingrenalartery

stenosis),treatmentwithothermedicinalproductsthataffectthissystemhasbeenassociatedwithacutehypotension,

azotaemia,oliguriaor,rarely,acuterenalfailure.Thepossibilityofsimilareffectscannotbeexcludedwithangiotensin

IIreceptorantagonists.Aswithanyantihypertensiveagent,excessivebloodpressuredecreaseinpatientswith

ischaemiccardiopathyorischaemiccerebrovasculardiseasecouldresultinamyocardialinfarctionorstroke.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicinalproduct

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Nodruginteractionsofclinicalsignificancehavebeenidentified.

Compoundswhichhavebeeninvestigatedinclinicalpharmacokineticstudiesincludehydrochlorothiazide,warfarin,

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

Candesartaniseliminatedonlytoaminorextentbyhepaticmetabolism(CYP2C9).Availableinteractionstudies

indicatenoeffectonCYP2C9andCYP3A4buttheeffectonothercytochromeP450isoenzymesispresently

unknown.

Theantihypertensiveeffectofcandesartanmaybeenhancedbyothermedicinalproductswithbloodpressurelowering

properties,whetherprescribedasanantihypertensiveorprescribedforotherindications.

Basedonexperiencewiththeuseofothermedicinalproductsthataffecttherenin-angiotensin-aldosteronesystem,

concomitantuseofpotassium-sparingdiuretics,potassiumsupplements,saltsubstitutescontainingpotassium,orother

medicinalproductsthatmayincreasepotassiumlevels(e.g.heparin)mayleadtoincreasesinserumpotassium.

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.AsimilareffectmayoccurwithangiotensinIIreceptorantagonistsand

carefulmonitoringofserumlithiumlevelsisrecommendedduringconcomitantuse.

WhenangiotensinIIreceptorantagonistsareadministeredsimultaneouslywithnon-steroidalanti-inflammatorydrugs

(i.e.selectiveCOX-2inhibitors,acetylsalicylicacid(>3g/day)andnon-selectiveNSAIDs),attenuationofthe

antihypertensiveeffectmayoccur.

AswithACEinhibitors,concomitantuseofangiotensinIIreceptorantagonistsandNSAIDsmayleadtoanincreased

riskofworseningofrenalfunction,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,

especiallyinpatientswithpoorpre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,

especiallyintheelderly.Patientsshouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenal

functionafterinitiationofconcomitanttherapy,andperiodicallythereafter.

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4.6Pregnancyandlactation

Useinpregnancy

ThereareverylimiteddatafromtheuseofAtacandinpregnantwomen.Thesedataareinsufficienttoallow

conclusionsaboutpotentialriskforthefetuswhenusedduringthefirsttrimester.Inhumans,foetalrenalperfusion,

whichisdependentuponthedevelopmentoftherenin-angiotensin-aldosteronesystem,beginsinthesecondtrimester.

ThusrisktothefoetusincreasesifAtacandisadministeredduringthesecondorthirdtrimestersofpregnancy.

Whenusedinpregnancyduringthesecondandthirdtrimesters,medicinalproductsthatactdirectlyontherenin-

angiotensinsystemcancausefetalandneonatalinjury(hypotension,renaldysfunction,oliguriaand/oranuria,

oligohydramnios,skullhypoplasia,intrauterinegrowthretardation)anddeath.Casesoflunghypoplasia,facial

abnormalitiesandlimbcontractureshavealsobeendescribed.

Animalstudieswithcandesartancilexetilhavedemonstratedlatefoetalandneonatalinjuryinthekidney.The

mechanismisbelievedtobepharmacologicallymediatedthrougheffectsontherenin-angiotensin-aldosteronesystem.

Basedontheaboveinformation,Atacandshouldnotbeusedinpregnancy.Ifpregnancyisdetectedduringtreatment,

Atacandshouldbediscontinued(seesection4.3Contraindications).

Useinlactation

Itisnotknownwhethercandesartanisexcretedinhumanmilk.However,candesartanisexcretedinthemilkof

lactatingrats.Becauseofthepotentialforadverseeffectsonthenursinginfant,Atacandshouldnotbegivenduring

breast-feeding(seesection4.3Contraindications).

4.7Effectsonabilitytodriveandusemachines

Theeffectofcandesartanontheabilitytodriveandusemachineshasnotbeenstudied,butbasedonits

pharmacodynamicpropertiescandesartanisunlikelytoaffectthisability.Whendrivingvehiclesoroperating

machines,itshouldbetakenintoaccountthatdizzinessorwearinessmayoccurduringtreatment.

4.8Undesirableeffects

TreatmentofHypertension

Incontrolledclinicalstudiesadverseeventsweremildandtransientandcomparabletoplacebo.Theoverallincidence

ofadverseeventsshowednoassociationwithdoseorage.Withdrawalsfromtreatmentduetoadverseeventswere

similarwithcandesartancilexetil(3.1%)andplacebo(3.2%).

Inapooledanalysisofclinicaltrialdata,thefollowingadversereactionswithcandesartancilexetilwerereportedbased

onanincidenceofadverseeventswithcandesartancilexetilatleast1%higherthantheincidenceseenwithplacebo.

Thefrequenciesusedinthetablesthroughoutthissectionare:verycommon( ≥1/10)common(≥1/100<1/10),

uncommon( ≥1/1000,<1/100),rare(≥1/10000,<1/1000)andveryrare(<1/10000):

SystemOrganClass Frequency UndesirableEffect

Infectionsandinfestations Common Respiratoryinfection

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Laboratoryfindings

Ingeneral,therewerenoclinicallyimportantinfluencesofAtacandonroutinelaboratoryvariables.Asforother

inhibitorsoftherenin-angiotensin-aldosteronesystem,smalldecreasesinhaemoglobinhavebeenseen.Increasesin

creatinine,ureaorpotassiumanddecreaseinsodiumhavebeenobserved.IncreasesinS-ALAT(S-GPT)werereported

asadverseeventsslightlymoreoftenwithAtacandthanwithplacebo(1.3%vs0.5%).Noroutinemonitoringof

laboratoryvariablesisusuallynecessaryforpatientsreceivingAtacand.However,inpatientswithrenalimpairment,

periodicmonitoringofserumpotassiumandcreatininelevelsisrecommended.

TreatmentofHeartFailure

TheadverseexperienceprofileofAtacandinheartfailurepatientswasconsistentwiththepharmacologyofthedrug

andthehealthstatusofthepatients.IntheCHARMclinicalprogramme,comparingAtacandindosesupto32mg

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

treatmentbecauseofadverseevents.Adversereactionsseenwere:

Laboratoryfindings

Increasesincreatinine,ureaandpotassium.Periodicmonitoringofserumcreatinineandpotassiumisrecommended

(seesection4.4Specialwarningsandspecialprecautionsforuse).

PostMarketing

SystemOrganClass Frequency UndesirableEffect

Metabolismandnutrition

disorders Common Hyperkalaemia

Vasculardisorders Common Hypotension

Renalandurinarydisorders Common Renalimpairment

SystemOrganClass Frequency UndesirableEffect

Bloodandlymphaticsystem

disorders Veryrare Leukopenia,neutropeniaand

agranulocytosis

Metabolismandnutrition

disorders Veryrare Hyperkalaemia,hyponatraemia

Nervoussystemdisorders Veryrare Dizziness,headache

Gastrointestinaldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,abnormal

hepaticfunctionorhepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,urticaria,pruritus

Musculoskeletal,connective

tissueandbonedisorders Veryrare Backpain,arthralgia,myalgia

Renalandurinarydisorders Veryrare Renalimpairment,includingrenal

failureinsusceptiblepatients

(seesection4.4Specialwarningsand

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4.9Overdose

Symptoms

Basedonpharmacologicalconsiderations,themainmanifestationofanoverdoseislikelytobesymptomatic

hypotensionanddizziness.Inindividualcasereportsofoverdose(ofupto672mgcandesartancilexetil)patient

recoverywasuneventful.

Management

Ifsymptomatichypotensionshouldoccur,symptomatictreatmentshouldbeinstitutedandvitalsignsmonitored.The

patientshouldbeplacedsupinewiththelegselevated.Ifthisisnotsufficient,plasmavolumeshouldbeincreasedby

infusionof,forexample,isotonicsalinesolution.Sympathomimeticmedicinalproductsmaybeadministeredifthe

above-mentionedmeasuresarenotsufficient.

Candesartanisnotremovedbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:

AngiotensinIIantagonists(candesartan),ATCcodeC09CA06.

AngiotensinIIistheprimaryvasoactivehormoneoftherenin-angiotensin-aldosteronesystemandplaysaroleinthe

pathophysiologyofhypertension,heartfailureandothercardiovasculardisorders.Italsohasaroleinthepathogenesis

ofendorganhypertrophyanddamage.ThemajorphysiologicaleffectsofangiotensinII,suchasvasoconstriction,

aldosteronestimulation,regulationofsaltandwaterhomeostasisandstimulationofcellgrowth,aremediatedviathe

type1(AT

)receptor.

Candesartancilexetilisaprodrugsuitablefororaluse.Itisrapidlyconvertedtotheactivesubstance,candesartan,by

esterhydrolysisduringabsorptionfromthegastrointestinaltract.CandesartanisanangiotensinIIreceptorantagonist,

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

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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).Themostcommonadverseeventswererespiratoryinfection(candesartan6.6%,losartan8.9%),

headache(candesartan5.8%,losartan5.6%)anddizziness(candesartan4.4%,losartan1.9%).

Whencandesartancilexetilisusedtogetherwithhydrochlorothiazide,thereductioninbloodpressureisadditive.

Concomitantadministrationofcandesartancilexetilwithhydrochlorothiazideoramlodipineiswelltolerated.

Candesartanissimilarlyeffectiveinpatientsirrespectiveofageandgender.

Medicinalproductsthatblocktherenin-angiotensin-aldosteronesystemhavelesspronouncedantihypertensiveeffectin

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%confidenceinterval15-42%).Thereiscurrentlynodataonthe

effectofcandesartanontheprogressiontodiabeticnephropathy.InhypertensivepatientswithtypeIIdiabetesmellitus,

12weekstreatmentwithcandesartancilexetil8mgto16mghadnoadverseeffectsonbloodglucoseorlipidprofile.

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(cardiovascular

mortality,non-fatalstrokeandnon-fatalmyocardialinfarction).Therewere26.7eventsper1000patient-yearsinthe

candesartangroupversus30.0eventsper1000patient-yearsinthecontrolgroup(relativerisk0.89,95%CI0.75to

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HeartFailure

Treatmentwithcandesartancilexetilreducesmortality,reduceshospitalisationduetoheartfailure,andimproves

symptomsinpatientswithleftventricularsystolicdysfunctionasshownintheCandesartaninHeartfailure–

AssessmentofReductioninMortalityandmorbidity(CHARM)programme.

Thismultinational,placebocontrolled,double-blindstudyprogrammeinchronicheartfailure(CHF)patientswith

NYHAfunctionalclassIItoIVconsistedofthreeseparatestudies:CHARM-Alternative(n=2,028)inpatientswith

LVEF40%nottreatedwithanACEinhibitorbecauseofintolerance(mainlyduetocough,72%),CHARM-Added

(n=2,548)inpatientswithLVEF40%andtreatedwithanACEinhibitor,andCHARM-Preserved(n=3,023)in

patientswithLVEF>40%.PatientsonoptimalCHFtherapyatbaselinewererandomisedtoplaceboorcandesartan

cilexetil(titratedfrom4mgor8mgoncedailyto32mgoncedailyorthehighesttolerateddose,meandose24mg)

andfollowedforamedianof37.7months.After6monthsoftreatment63%ofthepatientsstilltakingcandesartan

cilexetil(89%)wereatthetargetdoseof32mg.

InCHARM-Alternative,thecompositeendpointofcardiovascularmortalityorfirstCHFhospitalisationwas

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

p<0.001).Thiscorrespondstoarelativeriskreductionof23%.Fourteenpatientsneededtobetreatedfortheduration

ofthestudytopreventonepatientfromdyingofacardiovasculareventorbeinghospitalisedfortreatmentofheart

failure.Thecompositeendpointofall-causemortalityorfirstCHFhospitalisationwasalsosignificantlyreducedwith

candesartan(HR0.80,95%CI0.70-0.92,p=0.001).Boththemortalityandmorbidity(CHFhospitalisation)

componentsofthesecompositeendpointscontributedtothefavourableeffectsofcandesartan.Treatmentwith

candesartancilexetilresultedinimprovedNYHAfunctionalclass(p=0.008).

InCHARM-Added,thecompositeendpointofcardiovascularmortalityorfirstCHFhospitalisationwassignificantly

reducedwithcandesartanincomparisonwithplacebo(HR0.85,95%CI0.75-0.96,p=0.011).Thiscorrespondstoa

relativeriskreductionof15%.Twenty-threepatientsneededtobetreatedforthedurationofthestudytopreventone

patientfromdyingofacardiovasculareventorbeinghospitalisedfortreatmentofheartfailure.Thecomposite

endpointofall-causemortalityorfirstCHFhospitalisationwasalsosignificantlyreducedwithcandesartan(HR0.87,

95%CI0.78-0.98,p=0.021).

Boththemortalityandmorbiditycomponentsofthesecompositeendpointscontributedtothefavourableeffectsof

candesartan.TreatmentwithcandesartancilexetilresultedinimprovedNYHAfunctionalclass(p=0.020).

InCHARM-Preserved,nostatisticallysignificantreductionwasachievedinthecompositeendpointofcardiovascular

mortalityorfirstCHFhospitalisation(HR0.89,95%CI0.77-1.03,p=0.118).Thenumericalreductionwasattributable

toreducedCHFhospitalisation.Therewasnoevidenceofeffectonmortalityinthisstudy.

All-causemortalitywasnotstatisticallysignificantwhenexaminedseparatelyineachofthethreeCHARMstudies.

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

0.88,95%CI0.79-0.98,p=0.018)andallthreestudies(HR0.91,95%CI0.83-1.00,p=0.055).

ThebeneficialeffectsofcandesartanoncardiovascularmortalityandCHFhospitalisationwereconsistentirrespective

ofage,genderandconcomitantmedication.Candesartanwaseffectivealsoinpatientstakingbothbeta-blockersand

ACEinhibitorsatthesametime,andthebenefitwasobtainedwhetherornotpatientsweretakingACEinhibitorsatthe

targetdoserecommendedbytreatmentguidelines.

InpatientswithCHFanddepressedleftventricularsystolicfunction(leftventricularejectionfraction,LVEF40%),

candesartandecreasessystemicvascularresistanceandpulmonarycapillarywedgepressure,increasesplasmarenin

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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.

Metabolismandelimination

Candesartanismainlyeliminatedunchangedviaurineandbileandonlytoaminorextenteliminatedbyhepatic

metabolism.Theterminalhalf-lifeofcandesartanisapproximately9hours.Thereisnoaccumulationfollowing

multipledoses.

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

renaleliminationofcandesartanisbothbyglomerularfiltrationandactivetubularsecretion.Followinganoraldoseof

C-labelledcandesartancilexetil,approximately26%ofthedoseisexcretedintheurineascandesartanand7%asan

inactivemetabolitewhileapproximately56%ofthedoseisrecoveredinthefaecesascandesartanand10%asthe

inactivemetabolite.

Pharmacokineticsinspecialpopulations

Intheelderly(over65years)C

andAUCofcandesartanareincreasedbyapproximately50%and80%,

respectivelyincomparisontoyoungsubjects.However,thebloodpressureresponseandtheincidenceofadverse

eventsaresimilarafteragivendoseofAtacandinyoungandelderlypatients(seesection4.2Posologyandmethodof

administration).

InpatientswithmildtomoderaterenalimpairmentC

andAUCofcandesartanincreasedduringrepeateddosingby

approximately50%and70%,respectively,butt

wasnotaltered,comparedtopatientswithnormalrenalfunction.

Thecorrespondingchangesinpatientswithsevererenalimpairmentwereapproximately50%and110%,respectively.

Theterminalt

ofcandesartanwasapproximatelydoubledinpatientswithsevererenalimpairment.TheAUCof

candesartaninpatientsundergoinghaemodialysiswassimilartothatinpatientswithsevererenalimpairment.

Inpatientswithmildtomoderatehepaticimpairment,therewasa23%increaseintheAUCofcandesartan(seesection

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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).

Datafrominvitroandinvivomutagenicitytestingindicatesthatcandesartanwillnotexertmutagenicorclastogenic

activitiesunderconditionsofclinicaluse.

Therewasnoevidenceofcarcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Carmellosecalcium

Hydroxypropylcellulose

Ironoxidereddish-brownE172(only8mg,16mgand32mgtablets)

Lactosemonohydrate

Magnesiumstearate

Maizestarch

Macrogol

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2yearsinPVC/PVDCblisters

3yearsinpolypropylene(PP)blisters

6.4Specialprecautionsforstorage

Donotstoreabove30ºC.

6.5Natureandcontentsofcontainer

PPorPVC/PVDCblisterpacksof7and14tablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7MARKETINGAUTHORISATIONHOLDER

AstraZenecaUKLtd,

600CapabilityGreen

Luton

LU13LU

8MARKETINGAUTHORISATIONNUMBER

PA0970/030/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:23January1998

Dateoflastrenewal:29April2007

10DATEOFREVISIONOFTHETEXT

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