ATACAND

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0970/030/005
  • Authorization date:
  • 22-07-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Atacand32mgtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains32mgcandesartancilexetil.

Each32mgtabletcontains163mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

Atacand32mgareround(diameter9.5mm),pinktabletswithascoreandmarkedA/CLononesideandmarked032

ontheotherside.

Atacand32mgtabletscanbedividedintoequalhalves.

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).

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4.4Specialwarningsandprecautionsforuse

Renalimpairment

Aswithotheragentsinhibitingtherenin-angiotensin-aldosteronesystem,changesinrenalfunctionmaybeanticipated

insusceptiblepatientstreatedwithAtacand.

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

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Aorticandmitralvalvestenosis(obstructivehypertrophiccardiomyopathy)

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromhaemodynamicallyrelevantaorticor

mitralvalvestenosis,orobstructivehypertrophiccardiomyopathy.

Primaryhyperaldosteronism

Patientswithprimaryhyperaldosteronismwillnotgenerallyrespondtoantihypertensivemedicinalproductsacting

throughinhibitionoftherenin-angiotensin-aldosteronesystem.Therefore,theuseofAtacandisnotrecommended.

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

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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.

Thebioavailabilityofcandesartanisnotaffectedbyfood.

4.6Fertility,pregnancyandlactation

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

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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):

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

SystemOrganClass Frequency UndesirableEffect

Infectionsandinfestations Common Respiratoryinfection

Nervoussystemdisorders Common Dizziness/vertigo,headache

SystemOrganClass Frequency UndesirableEffect

Metabolismandnutrition

disorders Common Hyperkalaemia

Vasculardisorders Common Hypotension

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PostMarketing

Thefollowingadversereactionshavebeenreportedinpostmarketingexperience:

4.9Overdose

Symptoms

Basedonpharmacologicalconsiderations,themainmanifestationofanoverdoseislikelytobesymptomatic

hypotensionanddizziness.Inindividualcasereportsofoverdose(ofupto672mgcandesartancilexetil)patient

recoverywasuneventful.

Management

Ifsymptomatichypotensionshouldoccur,symptomatictreatmentshouldbeinstitutedandvitalsignsmonitored.The

patientshouldbeplacedsupinewiththelegselevated.Ifthisisnotsufficient,plasmavolumeshouldbeincreasedby

infusionof,forexample,isotonicsalinesolution.Sympathomimeticmedicinalproductsmaybeadministeredifthe

above-mentionedmeasuresarenotsufficient.

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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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

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

with losartan potassium 100 mg once daily (difference in blood pressure reduction 3.1/1.8 mmHg,

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,

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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

1.06,p=0.19).

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)inpatientswithLVEF 40%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

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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

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.

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

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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

4.2Posologyandmethodofadministration).

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

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6.3ShelfLife

3yearsinHDPEbottles

3yearsinPVC/PVDCblisters

6.4Specialprecautionsforstorage

Donotstoreabove30ºC.

6.5Natureandcontentsofcontainer

PVC/PVDCblisterpacksof7,14,15,20,28,30,50,50x1(singledoseunit),56,98,98x1(singledoseunit),100and

300tablets

HDPEbottlesof100and250tablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

AstraZenecaUKLtd,

600CapabilityGreen

Luton

LU13LU

8MARKETINGAUTHORISATIONNUMBER

PA0970/030/005

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:22July2005

Dateoflastrenewal:29April2007

10DATEOFREVISIONOFTHETEXT

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