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:
  • PPA1328/018/003
  • Authorization date:
  • 06-10-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Atacand16mgTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains16mgcandesartancilexetil.

Excipient:Lactose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

ProductimportedfromFrance,GreeceandPortugal:

Pink,roundtabletswithascorelineandmarked‘A/CH’ononesideandmarked‘016’ontheotherside.

ProductimportedfromtheUK:

Pink,roundtabletswithoneconvexsideembossed'16'andoneflatsidewithascoreline.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Atacandisindicatedforthe:

Treatmentofessentialhypertensioninadults.

Treatmentofadultpatientswithheartfailureandimpairedleftventricularsystolicfunction(leftventricularejection

fraction ≤40%)asadd-ontherapytoAngiotensinConvertingEnzyme(ACE)inhibitorsorwhenACEinhibitorsare

nottolerated(seesection5.1Pharmacodynamicproperties).

4.2Posologyandmethodofadministration

PosologyinHypertension

TherecommendedinitialdoseandusualmaintenancedoseofAtacandis8mgoncedaily.Mostoftheantihypertensive

effectisattainedwithin4weeks.Insomepatientswhosebloodpressureisnotadequatelycontrolled,thedosecanbe

increasedto16mgoncedailyandtoamaximumof32mgoncedaily.Therapyshouldbeadjustedaccordingtoblood

pressureresponse.

Atacandmayalsobeadministeredwithotherantihypertensiveagents.Additionofhydrochlorothiazidehasbeenshown

tohaveanadditiveantihypertensiveeffectwithvariousdosesofAtacand.

Elderlypopulation

Noinitialdosageadjustmentisnecessaryinelderlypatients.

Patientswithintravascularvolumedepletion

Aninitialdoseof4mgmaybeconsideredinpatientsatriskforhypotension,suchaspatientswithpossiblevolume

depletion(seealso4.4Specialwarningsandspecialprecautionsforuse).

Patientwithrenalimpairment

Thestartingdoseis4mginpatientswithrenalimpairment,includingpatientsonhaemodialysis.Thedoseshouldbe

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

Patientswithhepaticimpairment

Aninitialdoseof4mgoncedailyisrecommendedinpatientswithmildtomoderatehepaticimpairment.Thedosemay

beadjustedaccordingtoresponse.Atacandiscontraindicatedinpatientswithseverehepaticimpairmentand/or

cholestasis(seesections4.3and5.2).

Blackpatients

Theantihypertensiveeffectofcandesartanislesspronouncedinblackpatientsthaninnon-blackpatients.

Consequently,uptitrationofAtacandandconcomitanttherapymaybemorefrequentlyneededforbloodpressure

controlinblackpatientsthaninnon-blackpatients(seesection5.1Pharmacodynamicproperties).

PosologyinHeartFailure

TheusualrecommendedinitialdoseofAtacandis4mgoncedaily.Up-titrationtothetargetdoseof32mgoncedaily

(maximumdose)orthehighesttolerateddoseisdonebydoublingthedoseatintervalsofatleast2weeks(seesection

4.4Specialwarningsandspecialprecautionsforuse).Evaluationofpatientswithheartfailureshouldalwayscomprise

assessmentofrenalfunctionincludingmonitoringofserumcreatinineandpotassium.Atacandcanbeadministered

withotherheartfailuretreatment,includingACEinhibitors,beta-blockers,diureticsanddigitalisoracombinationof

thesemedicinalproducts.ThecombinationofanACEinhibitors,apotassium-sparingdiuretics(e.g.spironolactone)

andAtacandisnotrecommendedandshouldbeconsideredonlyaftercarefulevaluationofthepotentialbenefitsand

risks(seealsosection4.4,4.8and5.1).

Specialpatientpopulations

Noinitialdoseadjustmentisnecessaryforelderlypatientsorinpatientswithintravascularvolumedepletionorrenal

impairmentormildtomoderatehepaticimpairment.

PaediatricPolpulation

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

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bloodpressure.

Evaluationofpatientswithheartfailureshouldincludeperiodicassessmentsofrenalfunction,especiallyinelderly

patients75yearsorolder,andpatientswithimpairedrenalfunction.DuringdosetitrationofAtacand,monitoringof

serumcreatinineandpotassiumisrecommended.Clinicaltrialsinheartfailuredidnotincludepatientswithserum

creatinine>265µmol/L(>3mg/dL).

ConcomitanttherapywithanACEinhibitorinheartfailure

Theriskofadverseevents,especiallyrenalfunctionimpairmentandhyperkalaemia,mayincreasewhenAtacandis

usedincombinationwithanACEinhibitor(seesection4.8Undesirableeffects).Patientswithsuchtreatmentshouldbe

monitoredregularlyandcarefully.

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-angitensin-aldosteronesystem.Therefore,theuseofAtacandisnotrecommendedin

thispopulation.

Hyperkalaemia

ConcomitantuseofAtacandwithpotassium-sparingdiuretics,potassiumsupplements,saltsubstitutescontaining

potassium,orothermedicinalproductsthatmayincreasepotassiumlevels(e.g.heparin)mayleadtoincreasesinserum

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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.Thepossibilityofsimilareffectscannotbeexcludedwithangiotensin

IIreceptorantagonists.Aswithanyantihypertensiveagent,excessivebloodpressuredecreaseinpatientswith

ischaemiccardiopathyorischaemiccerebrovasculardiseasecouldresultinamyocardialinfarctionorstroke.

Theantihypertensiveeffectofcandesartanmaybeenhancedbyothermedicinalproductswithbloodpressurelowering

properties,whetherprescribedasanantihypertensiveorprescribedforotherindications.

Atacandcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyor

glucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

Pregnancy

AIIRAsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedAIIRAtherapyisconsideredessential,patients

planningpregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafety

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.AsimilareffectmayoccurwithangiotensinIIreceptorantagonists.Use

ofcandesartanwithlithiumisnotrecommended.Ifthecombinationprovesnecessary,carefulmonitoringofserum

lithiumlevelsisrecommended.

WhenAIIRAsareadministeredsimultaneouslywithnon-steroidalanti-inflammatorydrugs(NSAIDs)(i.e.selective

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

mayoccur.

AswithACEinhibitors,concomitantuseofAIIRAsandNSAIDsmayleadtoanincreasedriskofworseningofrenal

function,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyinpatientswithpoor

pre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyintheelderly.Patients

shouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunctionafterinitiationof

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4.6Fertility,pregnancyandlactation

Pregnancy

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithAngiotensinIIReceptorInhibitors(AIIRAs),similarrisksmayexist

forthisclassofdrugs.UnlesscontinuedAIIRAtherapyisconsideredessential,patientsplanningpregnancyshouldbe

changedtoalternativeantihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.When

pregnancyisdiagnosed,treatmentwithAIIRAsshouldbestoppedimmediatelyand,andifappropriate,alternative

therapyshouldbestarted.

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

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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

receivedothermedicinalproductswhichaffecttherennin-angiotensis-aldosteronesystem,inparticularanACE

inhibitorand/orspironolactone.

SystemOrganClass Frequency UndesirableEffect

Infectionsandinfestations Common Respiratoryinfection

Bloodandlymphaticsystem

disorders Veryrare Leukopenia,neutropeniaand

agranulocytosis

Metabolismandnutritiondisorders Veryrare Hyperkalaemia,hyponatraemia

Nervoussystemdisorders Common Dizziness/vertigo,headache

Gastrointestinaldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,abnormal

hepaticfunctionorhepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,urticaria,pruritus

Musculoskeletalandconnective

tissuedisorders Veryrare Backpain,arthralgia,myalgia

Renalandurinarydisorders Veryrare Renalimpairment,includingrenal

failureinsusceptiblepatients(see

section4.4)

SystemOrganClass Frequency UndesirableEffect

Bloodandlymphaticsystem

disorders Veryrare Leucopenia,neutropeniaand

agranulocytosis

Metabolismandnutritiondisorders Common Hyperkalaemia

Veryrare Hyponatraemia

Nervoussystemdisorders Veryrare Dizziness,headache

Vasculardisorders Common Hypotension

Gastrointestinaldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,abnormal

hepaticfunctionorhepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,urticaria,pruritus

Musculoskeletalandconnective

tissuedisorders Veryrare Backpain,arthralgia,myalgia

Renalandurinarydisorders Common Renalimpairment,includingrenal

failureinsusceptiblepatients(see

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Laboratoryfindings:

HyperkalaemiaandrenalimpairmentarecommoninpatientstreatedwithAtacandfortheindicationofheartfailure.

Periodicmonitoringofserumcreatinineandpotassiumisrecommended(seesection4.4Specialwarningsandspecial

precautionsforuse).

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(AT1)receptor.

Candesartancilexetilisaprodrugsuitablefororaluse.Itisrapidlyconvertedtotheactivesubstance,candesartan,by

esterhydrolysisduringabsorptionfromthegastrointestinaltract.CandesartanisanangiotensinIIreceptorantagonist,

selectiveforAT1receptors,withtightbindingtoandslowdissociationfromthereceptor.Ithasnoagonistactivity.

CandesartandoesnotinhibitACE,whichconvertsangiotensinItoangiotensinIIanddegradesbradykinin.Thereisno

effectonACEandnopotentiationofbradykininorsubstanceP.Incontrolledclinicaltrialscomparingcandesartan

withACEinhibitors,theincidenceofcoughwaslowerinpatientsreceivingcandesartancilexetil.Candesartandoesnot

bindtoorblockotherhormonereceptorsorionchannelsknowntobeimportantincardiovascularregulation.The

antagonismoftheangiotensinII(AT1)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

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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

increasedantihypertensiveeffectsisalsoseenwhencandesartancilexetileiscombinedwithamlodipineorfelodipine.

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%Cl15-42%).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:0.67-0.89,

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

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

11.2to2.8).Fourteenpatientsneededtobetreatedforthedurationofthestudytopreventonepatientfromdyingofa

cardiovasculareventorbeinghospitalisedfortreatmentofheartfailure.Thecompositeendpointofall-causemortality

orfirstCHFhospitalisationwasalsosignificantlyreducedwithcandesartan,HR0.80(95%CI0.70-0.92,p=0.001).Of

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

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componentsofthesecompositeendpointscontributedtothefavourableeffectsofcandesartan.Treatmentwith

candesartancilexetilresultedinimprovedNYHAfunctionalclass(p=0.008).

InCHARM-Added,thecompositeendpointofcardiovascularmortalityorfirstCHFhospitalisationwassignificantly

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

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

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

neededtobetreatedforthedurationofthestudytopreventonepatientfromdyingofacardiovasculareventorbeing

hospitalisedfortreatmentofheartfailure.Thecompositeendpointofall-causemortalityorfirstCHFhospitalisation

wasalsosignificantlyreducedwithcandesartan(HR0.87,95%CI0.78-0.98,p=0.021).Boththemortalityand

morbiditycomponentsofthesecompositeendpointscontributedtothefavourableeffectsofcandesartan.Treatment

withcandesartancilexetilresultedinimprovedNYHAfunctionalclass(p=0.020).

InCHARM-Preserved,nostatisticallysignificantreductionwasachievedinthecompositeendpointofcardiovascular

mortalityorfirstCHFhospitalisationHR0.89(95%CI:0.77to1.03,p=0.118).

All-causemortalitywasnotstatisticallysignificantwhenexaminedseparatelyineachofthethreeCHARMstudies.

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

0.88(95%CI0.79-0.98,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

(Cmax)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

P450isoenzymeCYP1A2,CYP2A6,CYP2C9,CYP2C19,CYP2D6,CYP2E3orCYP3A4.Theterminalhalf-lifeof

candesartanisapproximately9hours.Thereisnoaccumulationfollowingmultipledoses.

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renaleliminationofcandesartanisbothbyglomerularfiltrationandactivetubularsecretion.Followinganoraldoseof

C-labelledcandesartancilexetil,approximately26%ofthedoseisexcretedintheurineascandesartanand7%asan

inactivemetabolitewhileapproximately56%ofthedoseisrecoveredinthefaecesascandesartanand10%asthe

inactivemetabolite.

Pharmacokineticsinspecialpopulations

Intheelderly(over65years)CmaxandAUCofcandesartanareincreasedbyapproximately50%and80%,

respectivelyincomparisontoyoungsubjects.However,thebloodpressureresponseandtheincidenceofadverse

eventsaresimilarafteragivendoseofAtacandinyoungandelderlypatients(seesection4.2Posologyandmethodof

administration).

InpatientswithmildtomoderaterenalimpairmentCmaxandAUCofcandesartanincreasedduringrepeateddosingby

approximately50%and70%,respectively,butt

wasnotaltered,comparedtopatientswithnormalrenalfunction.

Thecorrespondingchangesinpatientswithsevererenalimpairmentwereapproximately50%and110%,respectively.

Theterminalt½ofcandesartanwasapproximatelydoubledinpatientswithsevererenalimpairment.TheAUCof

candesartaninpatientsundergoinghaemodialysiswassimilartothatinpatientswithsevererenalimpairment.

Intwostudies,bothincludingpatientswithmildtomoderatehepaticimpairment,therewasanincreaseinthemean

AUCofcandesartanofapproximately20%inonestudyand80%intheotherstudy(seesection4.2Posologyand

methodofadministration).Thereisnoexperienceinpatientswithseverehepaticimpairment.

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

Hyprolose

Lactosemonohydrate

Magnesiumstearate

Maizestarch

Macrogol

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6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

PVC/PVDCblisterpacksof14and28tablets

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

B&SHealthcare

Unit4

BradfieldRoad

Ruislip

Middlesex

HA40NU

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1328/18/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:6thOctober2006.

10DATEOFREVISIONOFTHETEXT

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