ATACAND

Main information

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

Documents

Localization

  • Available in:
  • ATACAND Tablets 16 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1447/038/001
  • Authorization date:
  • 21-08-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Atacand16mgtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains16mgcandesartancilexetil.

Eachtabletcontainslactosemonohydrate.

Forafulllistofexcipients,see6.1.

3PHARMACEUTICALFORM

Tablets

ProductimportedfromGreece:

Atacand16mgareround(diameter7mm),pinktabletswithascoreandmarkedA/CHononesideandmarked016on

theotherside.

Atacand16mgcanbedividedintoequalhalves.

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).

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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

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WhenAtacandisusedinhypertensivepatientswithrenalimpairment,periodicmonitoringofserumpotassiumand

creatininelevelsisrecommended.Thereislimitedexperienceinpatientswithverysevereorend-stagerenal

impairment(Cl

creatinine <15ml/min).InthesepatientsAtacandshouldbecarefullytitratedwiththoroughmonitoring

ofbloodpressure.

Evaluationofpatientswithheartfailureshouldincludeperiodicassessmentsofrenalfunction,especiallyinelderly

patients75yearsorolder,andpatientswithimpairedrenalfunction.DuringdosetitrationofAtacand,monitoringof

serumcreatinineandpotassiumisrecommended.Clinicaltrialsinheartfailuredidnotincludepatientswithserum

creatinine>265µmol/l(>3mg/dl).

ConcomitanttherapywithanACEinhibitorinheartfailure

Theriskofadversereactions,especiallyrenalfunctionimpairmentandhyperkalaemia,mayincreasewhenAtacandis

usedincombinationwithanACEinhibitor(seesection4.8).Patientswithsuchtreatmentshouldbemonitored

regularlyandcarefully.

Haemodialysis

DuringdialysisthebloodpressuremaybeparticularlysensitivetoAT1-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

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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-

aldosteronesystem(e.g.patientswithseverecongestiveheartfailureorunderlyingrenaldisease,includingrenalartery

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

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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,

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),

TheuseofAIIRAsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).

TheuseofAIIRAsiscontraindicatedduringthesecondandthirdtrimestersofpregnancy(see

sections4.3and4.4).

SystemOrganClass Frequency UndesirableEffect

Infectionsandinfestations Common Respiratoryinfection

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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.

andagranulocytosis

Metabolismandnutritiondisorders Veryrare Hyperkalaemia,

hyponatraemia

Nervoussystemdisorders Common Dizziness/vertigo,

headache

Respiratory,thoracicandmediastinal

disorders Veryrare Cough

Gastrointestinaldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,

abnormalhepaticfunction

orhepatitis

Skinandsubcutaneoustissuedisorders Veryrare Angioedema,rash,

urticaria,pruritus

Musculoskeletalandconnectivetissue

disorders Veryrare Backpain,arthralgia,

myalgia

Renalandurinarydisorders Veryrare Renalimpairment,

includingrenalfailurein

susceptiblepatients(see

section4.4)

SystemOrganClass Frequency UndesirableEffect

Bloodandlymphaticsystemdisorders Veryrare Leukopenia,neutropenia

andagranulocytosis

Metabolismandnutritiondisorders Common Hyperkalaemia

Veryrare Hyponatraemia

Nervoussystemdisorders Veryrare Dizziness,headache

Vasculardisorders Common Hypotension

Respiratory,thoracicandmediastinal

disorders Veryrare Cough

Gastrointestinaldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,

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Laboratoryfindings

HyperkalaemiaandrenalimpairmentarecommoninpatientstreatedwithAtacandfortheindicationofheartfailure.

Periodicmonitoringofserumcreatinineandpotassiumisrecommended(seesection4.4).

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,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

orhepatitis

Skinandsubcutaneoustissuedisorders Veryrare Angioedema,rash,

urticaria,pruritus

Musculoskeletalandconnectivetissue

disorders Veryrare Backpain,arthralgia,

myalgia

Renalandurinarydisorders Common Renalimpairment,

includingrenalfailurein

susceptiblepatients(see

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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.

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%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(titrated

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

thetargetdoseof32mg.

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

wasalsosignificantlyreducedwithcandesartan,HR0.87(95%CI:0.78to0.98,p=0.021).Ofcandesartanpatients

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

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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

andAUCofcandesartanareincreasedbyapproximately50%and80%,

respectivelyincomparisontoyoungsubjects.However,thebloodpressureresponseandtheincidenceofadverse

eventsaresimilarafteragivendoseofAtacandinyoungandelderlypatients(seesection4.2).

InpatientswithmildtomoderaterenalimpairmentC

andAUCofcandesartanincreasedduringrepeateddosingby

approximately50%and70%,respectively,butt

wasnotaltered,comparedtopatientswithnormalrenalfunction.

Thecorrespondingchangesinpatientswithsevererenalimpairmentwereapproximately50%and110%,respectively.

Theterminalt½ofcandesartanwasapproximatelydoubledinpatientswithsevererenalimpairment.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).

Datafrominvitroandinvivomutagenicitytestingindicatesthatcandesartanwillnotexertmutagenicorclastogenic

activitiesunderconditionsofclinicaluse.

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Carmellosecalcium

Hydroxypropylcellulose

Ironoxide(E172)

Lactosemonohydrate

Magnesiumstearate

Maizestarch

Macrogol

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateofthisproductisthedateshownontheblisterfoilandoutercartonoftheproductas

marketedincountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30 0

6.5Natureandcontentsofcontainer

Blisterpacksof14tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

G&ALicensingLtd

Ballymurray

CoRoscommon

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1447/038/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:21stAugust2009

10DATEOFREVISIONOFTHETEXT

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