CANDESARTAN CILEXETIL 8 Milligram Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
CANDESARTAN CILEXETIL
Available from:
Ranbaxy Ireland Limited
INN (International Name):
CANDESARTAN CILEXETIL
Dosage:
8 Milligram
Pharmaceutical form:
Tablets
Prescription type:
Product subject to prescription which may be renewed (B)
Authorization status:
Withdrawn
Authorization number:
PA0408/075/003
Authorization date:
2013-04-16

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Candesartancilexetil8mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains8mgcandesartancilexetil.

Excipient:

75.8mgoflactosemonhydrate/tablet

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

Pinkcapsuleshapedtabletwith‘C’&‘10’debossedoneithersideofbreaklineononesideandbreaklineonotherside.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

CANDESARTANCILEXETILisindicatedforthe:

Treatmentofessentialhypertensioninadults.

Treatmentofadultpatientswithheartfailureandimpairedleftventricularsystolicfunction(leftventricular

ejectionfraction 40%)asadd-ontherapytoAngiotensinConvertingEnzyme(ACE)inhibitorsorwhenACE

inhibitorsarenottolerated(seesection5.1).

4.2Posologyandmethodofadministration

PosologyinHypertension

TherecommendedinitialdoseandusualmaintenancedoseofCANDESARTANCILEXETILis8mgoncedaily.Most

oftheantihypertensiveeffectisattainedwithin4weeks.Insomepatientswhosebloodpressureisnotadequately

controlled,thedosecanbeincreasedto16mgoncedailyandtoamaximumof32mgoncedaily.Therapyshouldbe

adjustedaccordingtobloodpressureresponse.

CANDESARTANCILEXETILmayalsobeadministeredwithotherantihypertensiveagents.Additionof

hydrochlorothiazidehasbeenshowntohaveanadditiveantihypertensiveeffectwithvariousdosesof

CANDESARTANCILEXETIL.

Elderlypopulation

Noinitialdosageadjustmentisnecessaryinelderlypatients.

Patientswithintravascularvolumedepletion

Aninitialdoseof4mgmaybeconsideredinpatientsatriskforhypotension,suchaspatientswithpossiblevolume

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Patientswithrenalimpairment

Thestartingdoseis4mginpatientswithrenalimpairment,includingpatientsonhaemodialysis.

Thedoseshouldbetitratedaccordingtoresponse.

Thereislimitedexperienceinpatientswithverysevereorend-stagerenalimpairment(Cl

creatinine <15ml/min)(See

section4.4).

Patientswithhepaticimpairment

Aninitialdoseof4mgoncedailyisrecommendedinpatientswithmildtomoderatehepaticimpairment.Thedose

maybeadjustedaccordingtoresponse.CANDESARTANCILEXETILiscontraindicatedinpatientswithsevere

hepaticimpairmentand/orcholestasis(seesections4.3and5.2).

Blackpatients

Theantihypertensiveeffectofcandesartanislesspronouncedinblackpatientsthaninnon-blackpatients.

Consequently,uptitrationofCANDESARTANCILEXETILandconcomitanttherapymaybemorefrequentlyneeded

forbloodpressurecontrolinblackpatientsthaninnon-blackpatients(seesection5.1).

PosologyinHeartFailure

TheusualrecommendedinitialdoseofCANDESARTANCILEXETILis4mgoncedaily.Up-titrationtothetarget

doseof32mgoncedaily(maximumdose)orthehighesttolerateddoseisdonebydoublingthedoseatintervalsofat

least2weeks(seesection4.4).Evaluationofpatientswithheartfailureshouldalwayscompriseassessmentofrenal

functionincludingmonitoringofserumcreatinineandpotassium.CANDESARTANCILEXETILcanbeadministered

withotherheartfailuretreatment,includingACEinhibitors,beta-blockers,diureticsanddigitalisoracombinationof

thesemedicinalproducts.ThecombinationofanACEinhibitor,apotassium-sparingdiuretic(e.g.spironolactone)and

CANDESARTANCILEXETILisnotrecommendedandshouldbeconsideredonlyaftercarefulevaluationofthe

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

Specialpatientpopulations

Noinitialdoseadjustmentisnecessaryforelderlypatientsorinpatientswithintravascularvolumedepletion,renal

impairmentormildtomoderatehepaticimpairment.

PaediatricPopulation

ThesafetyandefficacyofCANDESARTANCILEXETILinchildrenagedbetweenbirthand18yearshavenotbeen

establishedinthetreatmentofhypertensionandheartfailure.Nodataareavailable.

Methodofadministration

ForOraluse.

CANDESARTANCILEXETILshouldbetakenoncedailywithorwithoutfood.

Thebioavailabilityofcandesartanisnotaffectedbyfood.

4.3Contraindications

Hypersensitivitytocandesartancilexetilortoanyoftheexcipients.

Secondandthirdtrimestersofpregnancy(seesection4.4and4.6)

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4.4Specialwarningsandprecautionsforuse

Renalimpairment

Aswithotheragentsinhibitingtherennin-angiotensin-aldesteronesystem,changesinrenalfunctionmaybeanticipated

insusceptiblepatientstreatedwithCANDESARTANCILEXETIL.

WhenCANDESARTANCILEXETILisusedinhypertensivepatientswithrenalimpairment,periodicmonitoringof

serumpotassiumandcreatininelevelsisrecommended.Thereislimitedexperienceinpatientswithverysevereorend-

stagerenalimpairment(Cl

creatinine <15ml/min).InthesepatientsCANDESARTANCILEXETILshouldbecarefully

titratedwiththoroughmonitoringofbloodpressure.

Evaluationofpatientswithheartfailureshouldincludeperiodicassessmentsofrenalfunction,especiallyinelderly

patients75yearsorolder,andpatientswithimpairedrenalfunction.DuringdosetitrationofCANDESARTAN

CILEXETIL,monitoringofserumcreatinineandpotassiumisrecommended.Clinicaltrialsinheartfailuredidnot

includepatientswithserumcreatinine>265µmol/l(>3mg/dl).

ConcomitanttherapywithanACEinhibitorinheartfailure

Theriskofadversereactions,especiallyrenalfunctionimpairmentandhyperkalaemia,mayincreasewhencandesartan

isusedincombinationwithanACEinhibitor(seesection4.8).Patientswithsuchtreatmentshouldbemonitored

regularlyandcarefully.

Haemodialysis

DuringdialysisthebloodpressuremaybeparticularlysensitivetoAT

-receptorblockadeasaresultofreducedplasma

volumeandactivationoftherenin-angiotensin-aldosteronesystem.Therefore,CANDESARTANCILEXETILshould

becarefullytitratedwiththoroughmonitoringofbloodpressureinpatientsonhaemodialysis.

Renalarterystenosis

Medicinalproductsthataffecttherenin-angiotensin-aldosteronesystem,includingangiotensinII

receptorantagonists(AIIRAs),mayincreasebloodureaandserumcreatinineinpatientswithbilateralrenalartery

stenosisorstenosisofthearterytoasolitarykidney.

Kidneytransplantation

ThereisnoexperienceregardingtheadministrationofCANDESARTANCILEXETILinpatientswitharecentkidney

transplantation.

Hypotension

HypotensionmayoccurduringtreatmentwithCANDESARTANCILEXETILinheartfailurepatients.Itmayalso

occurinhypertensivepatientswithintravascularvolumedepletionsuchasthosereceivinghighdosediuretics.Caution

shouldbeobservedwheninitiatingtherapyandcorrectionofhypovolemiashouldbeattempted.

Anaesthesiaandsurgery

HypotensionmayoccurduringanaesthesiaandsurgeryinpatientstreatedwithangiotensinIIantagonistsdueto

blockadeoftherenin-angiotensinsystem.Veryrarely,hypotensionmaybeseveresuchthatitmaywarranttheuseof

intravenousfluidsand/orvasopressors.

Aorticandmitralvalvestenosis(obstructivehypertrophiccardiomyopathy)

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromhaemodynamicallyrelevantaorticor

mitralvalvestenosis,orobstructivehypertrophiccardiomyopathy.

Primaryhyperaldosteronism

Patientswithprimaryhyperaldosteronismwillnotgenerallyrespondtoantihypertensivemedicinalproductsacting

throughinhibitionoftherenin-angiotensin-aldosteronesystem.Therefore,theuseofCANDESARTANCILEXETILis

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Hyperkalaemia

ConcomitantuseofCANDESARTANCILEXETILwithpotassium-sparingdiuretics,potassiumsupplements,salt

substitutescontainingpotassium,orothermedicinalproductsthatmayincreasepotassiumlevels(e.g.heparin)may

leadtoincreasesinserumpotassiuminhypertensivepatients.Monitoringofpotassiumshouldbeundertakenas

appropriate.

InheartfailurepatientstreatedwithCANDESARTANCILEXETIL,hyperkalaemiamayoccur.Periodicmonitoringof

serumpotassiumisrecommended.ThecombinationofanACEinhibitor,apotassium-sparingdiuretic(e.g.

spironolactone)andCANDESARTANCILEXETILisnotrecommendedandshouldbeconsideredonlyaftercareful

evaluationofthepotentialbenefitsandrisks.

General

Inpatientswhosevasculartoneandrenalfunctiondependpredominantlyontheactivityoftherenin-angiotensin-

aldosteronesystem(e.g.patientswithseverecongestiveheartfailureorunderlyingrenaldisease,includingrenalartery

stenosis),treatmentwithothermedicinalproductsthataffectthissystemhasbeenassociatedwithacutehypotension,

azotaemia,oliguriaor,rarely,acuterenalfailure.ThepossibilityofsimilareffectscannotbeexcludedwithAIIRAs.As

withanyantihypertensiveagent,excessivebloodpressuredecreaseinpatientswithischaemiccardiopathyorischaemic

cerebrovasculardiseasecouldresultinamyocardialinfarctionorstroke.

Theantihypertensiveeffectofcandesartanmaybeenhancedbyothermedicinalproductswithbloodpressurelowering

properties,whetherprescribedasanantihypertensiveorprescribedforother

indications.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

Pregnancy

AIIRAsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedAIIRAstherapyisconsideredessential,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)thatmayincreasepotassiumlevels.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),attenuationoftheantihypertensiveeffect

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AswithACEinhibitors,concomitantuseofAIIRAsandNSAIDsmayleadtoanincreasedriskofworseningofrenal

function,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyinpatientswithpoor

pre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyintheelderly.Patients

shouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunctionafterinitiationof

concomitanttherapy,andperiodicallythereafter.

4.6Fertility,pregnancyandlactation

Pregnancy

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithAIIRAs,similarrisksmayexistforthisclassofdrugs.Unless

continuedAIIRAtherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithAIIRAsshouldbestoppedimmediatelyand,ifappropriate,alternativetherapyshouldbe

started.

ExposuretoAIIRAtherapyduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

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

hyperkalaemia)(seealsosection5.3).

ShouldexposuretoAIIRAshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

InfantswhosemothershavetakenAIIRAsshouldbecloselyobservedforhypotension(seealsosections4.3and4.4).

Lactation

BecausenoinformationisavailableregardingtheuseofCANDESARTANBASICSduringbreastfeeding,

CANDESARTANBASICSisnotrecommendedandalternativetreatmentswithbetterestablishedsafetyprofiles

duringbreastfeedingarepreferable,especiallywhilenursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsofcandesartanontheabilitytodriveandusemachineshavebeenperformed.However,it

shouldbetakenintoaccountthatoccasionallydizzinessorwearinessmayoccurduringtreatmentwith

CANDESARTANCILEXETIL.

4.8Undesirableeffects

TreatmentofHypertension

Incontrolledclinicalstudiesadversereactionsweremildandtransient.Theoverallincidenceofadverseeventsshowed

noassociationwithdoseorage.Withdrawalsfromtreatmentduetoadverseeventsweresimilarwithcandesartan

TheuseofAngiotensinIIReceptorInhibitorsisnotrecommendedduringthefirsttrimesterof

pregnancy(seesection4.4).TheuseofAIIRAsiscontraindicatedduringthesecondandthird

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Inapooledanalysisofclinicaltrialdataofhypertensivepatients,adversereactionswithcandesartancilexetilwere

definedbasedonanincidenceofadverseeventswithcandesartancilexetilatleast1%higherthantheincidenceseen

withplacebo.Bythisdefinition,themostcommonlyreportedadversereactionsweredizziness/vertigo,headacheand

respiratoryinfection.

Thetablebelowpresentsadversereactionsfromclinicaltrialsandpost-marketingexperience.

Thefrequenciesusedinthetablesthroughoutsection4.8are:Verycommon(1/10),Common(1/100to<1/10),

Uncommon(1/1,000to<1/100),Rare(1/10,000to<1/1,000),Veryrare(<1/10,000).

Laboratoryfindings

Ingeneral,therewerenoclinicallyimportantinfluencesofCANDESARTANCILEXETILonroutinelaboratory

variables.Asforotherinhibitorsoftherenin-angiotensin-aldosteronesystem,smalldecreasesinhaemoglobinhave

beenseen.NoroutinemonitoringoflaboratoryvariablesisusuallynecessaryforpatientsreceivingCANDESARTAN

CILEXETIL.However,inpatientswithrenalimpairment,periodicmonitoringofserumpotassiumandcreatinine

levelsisrecommended.

TreatmentofHeartFailure

Theadverseexperienceprofileofcandesartaninheartfailurepatientswasconsistentwiththepharmacologyofthe

drugandthehealthstatusofthepatients.IntheCHARMclinicalprogramme,comparingcandesartancilexetilindoses

upto32mg(n=3,803)toplacebo(n=3,796),21,0%ofthecandesartancilexetilgroupand16,1%oftheplacebogroup

discontinuedtreatmentbecauseofadverseevents.Themostcommonlyreportedadversereactionswerehyperkalaemia,

hypotensionandrenalimpairment.Theseeventsweremorecommoninpatientsover70yearsofage,diabetics,or

subjectswhoreceivedothermedicinalproductswhichaffecttherenin-angiotensin-aldosteronesystem,inparticularan

ACEinhibitorand/orspironolactone.

SystemOrganClass Frequency UndesirableEffect

Infectionsandinfestations Common Respiratoryinfection

Bloodandlymphaticsystem

disorders Veryrare Leukopenia,neutropeniaand

agranulocytosis

Metabolismandnutrition

disorders Veryrare Hyperkalaemia,hyponatraemia

Nervoussystemdisorders Common Dizziness/vertigo,headache

Gastrointestianldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,abnormal

hepaticfunctionorhepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,urticaria,pruritus

Musculoskeletaland

connectivetissuedisorders Veryrare Backpain,arthralgia,myalgia

Renalandurinarydisorders Veryrare Renalimpairment,includingrenalfailure

insusceptiblepatients(seesection4.4)

SystemOrganClass Frequency UndesirableEffect

Bloodandlymphaticsystem

disorders Veryrare Leukopenia,neutropeniaand

agranulocytosis

Metabolismandnutrition

disorders Common Hyperkalaemia

Veryrare Hyponatraemia

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Laboratoryfindings

HyperkalaemiaandrenalimpairmentarecommoninpatientstreatedwithCANDESARTANCILEXETILforthe

indicationofheartfailure.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

bindtoorblockotherhormonereceptorsorionchannelsknowntobeimportantincardiovascularregulation.The

antagonismoftheangiotensinII(AT

)receptorsresultsindoserelatedincreasesinplasmareninlevels,angiotensinI

Vasculardisorders Common Hypotension

Gastrointestianldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,abnormal

hepaticfunctionorhepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,urticaria,pruritus

Musculoskeletalandconnective

tissuedisorders Veryrare Backpain,arthralgia,myalgia

Renalandurinarydisorders Common Renalimpairment,includingrenalfailure

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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

bloodpressurereductionover24hourswithlittledifferencebetweenmaximumandtrougheffectsduringthedosing

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

increasedantihypertensiveeffectisalsoseenwhencandesartancilexetiliscombined

withamlodipineorfelodipine.

Medicinalproductsthatblocktherenin-angiotensin-aldosteronesystemhavelesspronouncedantihypertensiveeffectin

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

open-labelclinicalexperiencetrialin5,156patientswithdiastolichypertension,thebloodpressurereductionduring

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

p<0.0001/p<0.0001).

Candesartanincreasesrenalbloodflowandeitherhasnoeffecton,orincreasesglomerularfiltrationratewhilerenal

vascularresistanceandfiltrationfractionarereduced.Ina3-monthclinicalstudyinhypertensivepatientswithtype2

diabetesmellitusandmicroalbuminuria,antihypertensivetreatmentwithcandesartancilexetilreducedurinaryalbumin

excretion(albumin/creatinineratio,mean30%,95%confidencelevelinterval15-42%).Therearecurrentlynodataon

theeffectofcandesartanontheprogressiontodiabeticnephropathy.

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,reduceshospitalisationduetoheartfailureandimproves

symptomsinpatientswithleftventricularsystolicdysfunctionasshownintheCandesartaninHeartfailure–

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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

from4mgor8mgoncedailyto32mgoncedailyorthehighesttolerateddose,meandose24mg)andfollowedfora

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)

andofplacebopatients40.0%(95%CI:37.0to43.1)experiencedthisendpoint,absolutedifference7.0%(95%CI:11.2

to2.8).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-threepatientsneededtobetreatedforthedurationofthestudy

topreventonepatientfromdyingofacardiovasculareventorbeinghospitalisedfortreatmentofheartfailure.The

compositeendpointofall-causemortalityorfirstCHFhospitalisationwasalsosignificantlyreducedwithcandesartan,

HR0.87(95%CI:0.78to0.98,p=0.021).Ofcandesartanpatients42.2%(95%CI:39.5to45.0)andofplacebopatients

46.1%

(95%CI:43.4to48.9)experiencedthisendpoint,absolutedifference3.9%(95%CI:7.8to0.1).Boththemortalityand

morbiditycomponentsofthesecompositeendpointscontributedtothefavourableeffectsofcandesartan.Treatment

withcandesartancilexetilresultedinimprovedNYHAfunctionalclass(p=0.020).

InCHARM-Preserved,nostatisticallysignificantreductionwasachievedinthecompositeendpointofcardiovascular

mortalityorfirstCHFhospitalization,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

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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

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

eventsaresimilarafteragivendoseofcandesartaninyoungandelderlypatients(seesection4.2).

InpatientswithmildtomoderaterenalimpairmentC

andAUCofcandesartanincreasedduringrepeateddosingby

approximately50%and70%,respectively,butt

wasnotaltered,comparedtopatientswithnormalrenalfunction.

Thecorrespondingchangesinpatientswithsevererenalimpairmentwereapproximately50%and110%,respectively.

Theterminalt

ofcandesartanwasapproximatelydoubledinpatientswithsevererenalimpairment.TheAUCof

candesartaninpatientsundergoinghaemodialysiswassimilartothatinpatientswithsevererenalimpairment.

Intwostudies,bothincludingpatientswithmildtomoderatehepaticimpairment,therewasanincreaseinthemean

AUCofcandesartanofapproximately20%inonestudyand80%intheotherstudy(seesection4.2).Thereisno

experienceinpatientswithseverehepaticimpairment.

5.3Preclinicalsafetydata

Therewasnoevidenceofabnormalsystemicortargetorgantoxicityatclinicallyrelevantdoses.Inpreclinicalsafety

studiescandesartanhadeffectsonthekidneysandonredcellparametersathighdosesinmice,rats,dogsand

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Effectsonthekidneys(suchasinterstitialnephritis,tubulardistension,basophilictubules;increasedplasma

concentrationsofureaandcreatinine)wereinducedbycandesartanwhichcouldbesecondarytothehypotensiveeffect

leadingtoalterationsofrenalperfusion.Furthermore,candesartaninducedhyperplasia/hypertrophyofthe

juxtaglomerularcells.Thesechangeswereconsideredtobecausedbythepharmacologicalactionofcandesartan.For

therapeuticdosesofcandesartaninhumans,thehyperplasia/hypertrophyoftherenaljuxtaglomerularcellsdoesnot

seemtohaveanyrelevance.

Foetotoxicityhasbeenobservedinlatepregnancy(seesection4.6).

Datafrominvitroandinvivomutagenicitytestingindicatethatcandesartanwillnotexertmutagenicorclastogenic

activitiesunderconditionsofclinicaluse.

Therewasnoevidenceofcarcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Carmellosecalcium

Hyprolose

Ironoxidered(E172)

Lactosemonohydrate

Magnesiumstearate

Maizestarch

Macrogol6000

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

PVC/PE/PVDC/Aluminiumblister

Packsizes7,14,15,20,28,30,50,56,90,98,100tablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

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7MARKETINGAUTHORISATIONHOLDER

RanbaxyIrelandLimited

Spafield

CorkRoad

Cashel

Co.Tipperary

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA408/75/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:5November2010

10DATEOFREVISIONOFTHETEXT

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