CANDESARTAN MYLAN

Main information

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

Documents

Localization

  • Available in:
  • CANDESARTAN MYLAN
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0577/120/004
  • Authorization date:
  • 26-08-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CandesartanMylan32mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains32mgcandesartancilexetil.

Each32mgtabletcontains148.0mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

Candesartancilexetil32mgtabletsarewhitetooffwhite,round,biconvextabletdebossedwith“MoverC7”onone

sideandplainwithabreaklineontheotherside.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertensioninadults.

Treatmentofadultpatientswithheartfailureandimpairedleftventricularsystolicfunction(leftventricular

ejectionfraction 40%)asadd-ontherapytoAngiotensinConvertingEnzyme(ACE)inhibitorsorwhenACE

inhibitorsarenottolerated(seesection5.1).

4.2Posologyandmethodofadministration

PosologyinHypertension

TherecommendedinitialdoseandusualmaintenancedoseofCandesartanis8mgoncedaily.Mostofthe

antihypertensiveeffectisattainedwithin4weeks.Insomepatientswhosebloodpressureisnotadequatelycontrolled,

thedosecanbeincreasedto16mgoncedailyandtoamaximumof32mgoncedaily.Therapyshouldbeadjusted

accordingtobloodpressureresponse.

Candesartanmayalsobeadministeredwithotherantihypertensiveagents.Additionofhydrochlorothiazidehasbeen

showntohaveanadditiveantihypertensiveeffectwithvariousdosesofCandesartan.

ElderlyPopulation

Noinitialdosageadjustmentisnecessaryinelderlypatients.

Patientswithintravascularvolumedepletion

Aninitialdoseof4mgmaybeconsideredinpatientsatriskforhypotension,suchaspatientswithpossiblevolume

depletion(seealso4.4).

Patientswithrenalimpairment

Thestartingdoseis4mginpatientswithrenalimpairment,includingpatientsonhaemodialysis.Thedoseshouldbe

titratedaccordingtoresponse.Thereislimitedexperienceinpatientswithverysevereorend-stagerenalimpairment

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Patientswithhepaticimpairment

Aninitialdoseof4mgoncedailyisrecommendedinpatientswithmildtomoderatehepaticimpairment.Thedose

maybeadjustedaccordingtoresponse.Candesartaniscontraindicatedinpatientswithseverehepaticimpairment

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

Blackpatients

TheantihypertensiveeffectofCandesartanislesspronouncedinblackpatientsthaninnon-blackpatients.

Consequently,uptitrationofCandesartanandconcomitanttherapymaybemorefrequentlyneededforbloodpressure

controlinblackpatientsthannon-blackpatients(seesection5.1).

PosologyinHeartFailure

TheusualrecommendedinitialdoseofCandesartanis4mgoncedaily.Up-titrationtothetargetdoseof32mgonce

daily(maximumdose)ortothehighesttolerateddoseisdonebydoublingthedoseatintervalsofatleast2weeks(see

section4.4).Evaluationofpatientswithheartfailureshouldalwayscompriseassessmentofrenalfunctionincluding

monitoringofserumcreatinineandpotassium.Candesartancanbeadministeredwithotherheartfailuretreatment,

includingACEinhibitors,beta-blockers,diureticsanddigitalisoracombinationofthesemedicinalproducts.The

combinationofanACEinhibitor,apotassium-sparingdiuretice.g.spironolactone)andCandesartanisnot

recommendedandshouldbeconsideredonlyaftercarefulevaluationofthepotentialbenefitsandrisks(seesections

4.4,4.8and5.1).

Specialpatientpopulations

Noinitialdoseadjustmentisnecessaryforelderlypatientsorinpatientswithintravascularvolumedepletion,renal

impairmentormildtomoderatehepaticimpairment.

Paediatricpopulations

ThesafetyandefficacyofCandesartaninchildrenagedbetweenbirthand18yearshasnotbeenestablishedinthe

treatmentofhypertensionandheartfailure.Nodataareavailable.

MethodofAdministration

Oraluse

Candesartanshouldbetakenoncedailywithorwithoutfood.

Thebioavailabilityofcandesartanisnotaffectedbyfood.

4.3Contraindications

Hypersensitivitytocandesartancilexetilortoanyoftheexcipients.

Secondandthirdtrimesterofpregnancy(seesection4.4and4.6).

Severehepaticimpairmentand/orcholestasis.

4.4Specialwarningsandprecautionsforuse

Renalimpairment

Aswithotheragentsinhibitingtherenin-angiotensin-aldosteronesystem,changesinrenalfunctionmaybeanticipated

insusceptiblepatientstreatedwithCandesartan.

WhenCandesartanisusedinhypertensivepatientswithrenalimpairment,periodicmonitoringofserumpotassiumand

creatininelevelsisrecommended.Thereislimitedexperienceinpatientswithverysevereorend-stagerenal

impairment(Cl

creatinine <15ml/min).InthesepatientsCandesartanshouldbecarefullytitratedwiththorough

monitoringofbloodpressure.

Evaluationofpatientswithheartfailureshouldincludeperiodicassessmentsofrenalfunction,especiallyinelderly

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DuringdosetitrationofCandesartan,monitoringofserumcreatinineandpotassiumisrecommended.Clinicaltrialsin

heartfailuredidnotincludepatientswithserumcreatinine>265µmol/L(>3mg/dL).

ConcomitanttherapywithanACEinhibitorinheartfailure

Theriskofadverseevents,especiallyrenalfunctionimpairmentandhyperkalaemia,mayincreasewhenCandesartanis

usedincombinationwithanACEinhibitor(seesection4.8Undesirableeffects).Patientswithsuchtreatmentshouldbe

monitoredregularlyandcarefully.

Haemodialysis

DuringdialysisthebloodpressuremaybeparticularlysensitivetoAT

-receptorblockadeasaresultofreducedplasma

volumeandactivationoftherenin-angiotensin-aldosteronesystem.Therefore,Candesartanshouldbecarefullytitrated

withthoroughmonitoringofbloodpressureinpatientsonhaemodialysis.

Renalarterystenosis

Medicinalproductsthataffecttherenin-angiotensin-aldosteronesystem,includingangiotensinIIreceptorantagonists

(AIIRAs),mayincreasebloodureaandserumcreatinineinpatientswithbilateralrenalarterystenosisorstenosisofthe

arterytoasolitarykidney.

Kidneytransplantation

ThereisnoexperienceregardingtheadministrationofCandesartaninpatientswitharecentkidneytransplantation.

Hypotension

HypotensionmayoccurduringtreatmentwithCandesartaninheartfailurepatients.Itmayalsooccurinhypertensive

patientswithintravascularvolumedepletionsuchasthosereceivinghighdosediuretics.Cautionshouldbeobserved

wheninitiatingtherapyandcorrectionofhypovolemiashouldbeattempted.

Anaesthesiaandsurgery

HypotensionmayoccurduringanaesthesiaandsurgeryinpatientstreatedwithangiotensinIIantagonistsdueto

blockadeoftherenin-angiotensinsystem.Veryrarely,hypotensionmaybeseveresuchthatitmaywarranttheuseof

intravenousfluidsand/orvasopressors.

Aorticandmitralvalvestenosis(obstructivehypertrophiccardiomyopathy)

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromhaemodynamicallyrelevantaorticor

mitralvalvestenosis,orobstructivehypertrophiccardiomyopathy.

Primaryhyperaldosteronism

Patientswithprimaryhyperaldosteronismwillnotgenerallyrespondtoantihypertensivemedicinalproductsacting

throughinhibitionoftherenin-angiotensin-aldosteronesystem.Therefore,theuseofCandesartanisnotrecommended.

Hyperkalaemia

ConcomitantuseofCandesartanwithpotassium-sparingdiuretics,potassiumsupplements,saltsubstitutescontaining

potassium,orothermedicinalproductsthatmayincreasepotassiumlevels(e.g.heparin)mayleadtoincreasesinserum

potassiuminhypertensivepatients.Monitoringofpotassiumshouldbeundertakenasappropriate.

InheartfailurepatientstreatedwithCandesartan,hyperkalaemiamayoccur.Periodicmonitoringofserumpotassiumis

recommended.ThecombinationofanACEinhibitor,apotassium-spargingdiuretic(e.g.spironolactone)and

Candesartanisnotrecommendedandshouldbeconsideredonlyaftercarefulevaluationofthepotentialbenefitsand

risks.

General

Inpatientswhosevasculartoneandrenalfunctiondependpredominantlyontheactivityoftherenin-angiotensin-

aldosteronesystem(e.g.patientswithseverecongestiveheartfailureorunderlyingrenaldisease,includingrenalartery

stenosis),treatmentwithothermedicinalproductsthataffectthissystemhasbeenassociatedwithacutehypotension,

azotaemia,oliguriaor,rarely,acuterenalfailure.ThepossibilityofsimilareffectscannotbeexcludedwithAIIRAs.As

withanyantihypertensiveagent,excessivebloodpressuredecreaseinpatientswithischaemiccardiopathyorischaemic

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TheantihypertensiveeffectofCandesartanmaybeenhancedbyothermedicinalproductswithbloodpressurelowering

properties,whetherprescribedasanantihypertensiveorprescribedforotherindications.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-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

significantpharmacokineticinteractionswiththesemedicineshavebeenidentified.

Concomitantuseofpotassium-spargingdiuretics,potassiumsupplements,saltsubstitutescontainingpotassium,or

othermedicinalproducts(e.g.heparin)mayincreasepotassiumlevels.Monitoringofpotassiumshouldbeundertaken

asappropriate(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

mayoccur.

AswithACEinhibitors,concomitantuseofAIIRAsandNSAIDsmayleadtoanincreasedriskofworseningofrenal

function,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyinpatientswithpoor

pre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyintheelderly.Patients

shouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunctionafterinitiationof

concomitanttherapy,andperiodicallythereafter.

4.6Fertility,pregnancyandlactation

Pregnancy

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithAngiotensinIIReceptorInhibitors(AIIRAs),similarrisksmayexist

forthisclassofdrugs.UnlesscontinuedAIIRAtherapyisconsideredessential,patientsplanningpregnancyshouldbe

changedtoalternativeantihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.When

pregnancyisdiagnosed,treatmentwithAIIRAsshouldbestoppedimmediatelyand,ifappropriate,alternativetherapy

TheuseofAIIRAsisnotrecommendedduringthefirsttrimesterofpregnancy(see

section4.4).TheuseofAIIRAsiscontraindicatedduringthesecondandthirdtrimesters

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ExposuretoAIIRAtherapyduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

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

hyperkalaemia).(Seesection5.3.)

ShouldexposuretoAIIRAshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

InfantswhosemothershavetakenAIIRAsshouldbecloselyobservedforhypotension(seesection4.3and4.4).

Lactation

BecausenoinformationisavailableregardingtheuseofCandesartanMylanduringbreastfeeding,CandesartanMylan

isnotrecommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingare

preferable,especiallywhilenursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsofcandesartanontheabilitytodriveandusemachineshavebeenperformed.However,it

shouldbetakenintoaccountthatdizzinessorwearinessmayoccurduringtreatmentwithcandesartan.

4.8Undesirableeffects

TreatmentofHypertension

Incontrolledclinicalstudiesadversereactionsweremildandtransient.Theoverallincidenceofadverseevents

showednoassociationwithdoseorage.Withdrawalsfromtreatmentduetoadverseeventsweresimilarwith

candesartancilexetil(3.1%)andplacebo(3.2%).

Inapooledanalysisofclinicaltrialdataofhypertensivepatients,adversereactionswithcandesartancilexetilwere

definedbasedonanincidenceofadverseeventswithcandesartancilexetilatleast1%higherthantheincidenceseen

withplacebo.Bythisdefinition,themostcommonlyreportedadversereactionsweredizziness/vertigo,headacheand

respiratoryinfection.

Thetablebelowpresentsadversereactionsfromclinicaltrialsandpost-marketingexperience.

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

uncommon(1/1,000to<1/100),rare(1/10,000to<1/1,000)andveryrare(<1/10,000):

SystemOrganClass Frequency UndesirableEffect

Infectionsandinfestations Common Respiratoryinfection

Bloodandlymphaticsystem

disorders Veryrare Leukopenia,neutropeniaand

agranulocytosis

Metabolismandnutrition

disorders Veryrare Hyperkalaemia,hyponatraemia

Nervoussystemdisorders Common Dizziness/vertigo,headache

Gastrointestinaldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,abnormal

hepaticfunctionorhepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,urticaria,pruritus

Musculoskeletaland

connectivetissuedisorders Veryrare Backpain,arthralgia,myalgia

Renalandurinarydisorders Veryrare Renalimpairment,includingrenal

failureinsusceptiblepatients(see

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Laboratoryfindings

Ingeneral,therewerenoclinicallyimportantinfluencesofCandesartanonroutinelaboratoryvariables.Asforother

inhibitorsoftherenin-angiotensin-aldosteronesystem,smalldecreasesinhaemoglobinhavebeenseen.Noroutine

monitoringoflaboratoryvariablesisusuallynecessaryforpatientsreceivingCandesartan.However,inpatientswith

renalimpairment,periodicmonitoringofserumpotassiumandcreatininelevelsisrecommended.

TreatmentofHeartFailure

TheadverseexperienceprofileofCandesartaninheartfailurepatientswasconsistentwiththepharmacologyofthe

drugandthehealthstatusofthepatients.IntheCHARMclinicalprogramme,comparingCandesartanindosesupto32

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

discontinuedtreatmentbecauseofadverseevents.Themostcommonlyreportedadversereactionswerehyperkalaemia,

hypotensionandrenalimpairment.Theseeventsweremorecommoninpatientsover70yearsofage,diabetics,or

subjectswhoreceivedothermedicinalproductswhichaffecttherenin-angiotensin-aldosteronesystem,inparticularan

ACEinhibitorand/orspironolactone.

Thetablebelowpresentsadversereactionsfromclinicaltrialsandpost-marketingexperience.

Laboratoryfindings

HyperkalaemiaandrenalimpairmentarecommoninpatientstreatedwithCandesartanfortheindicationofheart

failure.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.

SystemOrganClass Frequency UndesirableEffect

Bloodandlymphaticsystem

disorders Veryrare Leukopenia,neutropeniaand

agranulocytosis

Metabolismandnutrition

disorders Common Hyperkalaemia

Veryrare Hyponatraemia

Nervoussystemdisorders Veryrare Dizziness,headache

Vasculardisorders Common Hypotension

Gastrointestinaldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,

abnormalhepaticfunctionor

hepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,urticaria,

pruritus

Musculoskeletaland

connectivetissuedisorders Veryrare Backpain,arthralgia,

myalgia

Renalandurinarydisorders Common Renalimpairment,including

renalfailureinsusceptible

patients

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:AngiotensinIIantagonists(candesartan).

ATCcode:C09CA06.

AngiotensinIIistheprimaryvasoactivehormoneoftherenin-angiotensin-aldosteronesystemandplaysaroleinthe

pathophysiologyofhypertension,heartfailureandothercardiovasculardisorders.Italsohasaroleinthe

pathogenesisofendorganhypertrophyanddamage.ThemajorphysiologicaleffectsofangiotensinII,suchas

vasoconstriction,aldosteronestimulation,regulationofsaltandwaterhomeostasisandstimulationofcellgrowth,are

mediatedviathetype1(AT

)receptor.

Candesartancilexetilisaprodrugsuitablefororaluse.Itisrapidlyconvertedtotheactivesubstance,candesartan,by

esterhydrolysisduringabsorptionfromthegastrointestinaltract.CandesartanisanangiotensinIIreceptor

antagonist,selectiveforAT

receptors,withtightbindingtoandslowdissociationfromthereceptor.Ithasno

agonistactivity.

CandesartandoesnotinhibitACE,whichconvertsangiotensinItoangiotensinIIanddegradesbradykinin.Thereis

noeffectonACEandnopotentiationofbradykininorsubstanceP.Incontrolledclinicaltrialscomparing

candesartanwithACEinhibitors,theincidenceofcoughwaslowerinpatientsreceivingcandesartancilexetil.

Candesartandoesnotbindtoorblockotherhormonereceptorsorionchannelsknowntobeimportantin

cardiovascularregulation.TheantagonismoftheangiotensinII(AT1)receptorsresultsindoserelatedincreasesin

plasmareninlevels,angiotensinIandangiotensinIIlevels,andadecreaseinplasmaaldosteroneconcentration.

Hypertension

Inhypertension,candesartancausesadose-dependent,long-lastingreductioninarterialbloodpressure.The

antihypertensiveactionisduetodecreasedsystemicperipheralresistance,withoutreflexincreaseinheartrate.There

isnoindicationofseriousorexaggeratedfirstdosehypotensionorreboundeffectaftercessationoftreatment.

Afteradministrationofasingledoseofcandesartancilexetil,onsetofantihypertensiveeffectgenerallyoccurswithin

2hours.Withcontinuoustreatment,mostofthereductioninbloodpressurewithanydoseisgenerallyattained

withinfourweeksandissustainedduringlong-termtreatment.Accordingtoameta-analysis,theaverageadditional

effectofadoseincreasefrom16mgto32mgoncedailywassmall.Takingintoaccounttheinter-individual

variability,amorethanaverageeffectcanbeexpectedinsomepatients.Candesartancilexetiloncedailyprovides

effectiveandsmoothbloodpressurereductionover24hours,withlittledifferencebetweenmaximumandtrough

effectsduringthedosinginterval.Theantihypertensiveeffectandtolerabilityofcandesartanandlosartanwere

comparedintworandomised,double-blindstudiesinatotalof1,268patientswithmildtomoderatehypertension.

Thetroughbloodpressurereduction(systolic/diastolic)was13.1/10.5mmHgwithcandesartancilexetil32mgonce

dailyand10.0/8.7mmHgwithlosartanpotassium100mgoncedaily(differenceinbloodpressurereduction3.1/1.8

mmHg,p<0.0001/p<0.0001).

Whencandesartancilexetilisusedtogetherwithhydrochlorothiazide,thereductioninbloodpressureisadditive.An

increasedantihypertensiveeffectisalsoseenwhencandesartancilexetiliscombinedwithamlodipineorfelodipine.

Medicinalproductsthatblocktherenin-angiotensin-aldosteronesystemhavelesspronouncedantihypertensiveeffect

inblackpatients(usuallyalow-reninpopulation)thaninnon-blackpatients.Thisisalsothecaseforcandesartan.In

anopenlabelclinicalexperiencetrialin5,156patientswithdiastolichypertension,thebloodpressurereduction

duringcandesartantreatmentwassignificantlylessinblackthannon-blackpatients(14.4/10.3mmHgvs.19.0/12.7

mmHg,p<0.0001/p<0.0001).

Candesartanincreasesrenalbloodflowandeitherhasnoeffectonorincreasesglomerularfiltrationratewhilerenal

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Ina3-monthclinicalstudyinhypertensivepatientswithtype2diabetesmellitusandmicroalbuminuria,

antihypertensivetreatmentwithcandesartancilexetilreducedurinaryalbuminexcretion(albumin/creatinineratio,

mean30%,95%confidenceinterval15-42%).Thereiscurrentlynodataontheeffectofcandesartanonthe

progressiontodiabeticnephropathy.

Theeffectsofcandesartancilexetil8-16mg(meandose12mg),oncedaily,oncardiovascularmorbidityand

mortalitywereevaluatedinarandomisedclinicaltrialwith4,937elderlypatients(aged70-89years;21%aged80or

above)withmildtomoderatehypertensionfollowedforameanof3.7years(StudyonCognitionandPrognosisin

theElderly).Patientsreceivedcandesartancilexetilorplacebowithotherantihypertensivetreatmentaddedas

needed.Thebloodpressurewasreducedfrom166/90to145/80mmHginthecandesartangroup,andfrom167/90to

149/82mmHginthecontrolgroup.Therewasnostatisticallysignificantdifferenceintheprimaryendpoint,major

cardiovascularevents(cardiovascularmortality,non-fatalstrokeandnon-fatalmyocardialinfarction).Therewere

26.7eventsper1000patient-yearsinthecandesartangroupversus30.0eventsper1000patient-yearsinthecontrol

group(relativerisk0.89,95%CI0.75to1.06,p=0.19).

HeartFailure

Treatmentwithcandesartancilexetilreducesmortality,reduceshospitalisationduetoheartfailure,andimproves

symptomsinpatientswithleftventricularsystolicdysfunctionasshownintheCandesartaninHeartfailure–

AssessmentofReductioninMortalityandmorbidity(CHARM)programme.

Thisplacebocontrolled,double-blindstudyprogrammeinchronicheartfailure(CHF)patientswithNYHA

functionalclassIItoIVconsistedofthreeseparatestudies:CHARM-Alternative(n=2,028)inpatientswithLVEF

40%nottreatedwithanACEinhibitorbecauseofintolerance(mainlyduetocough,72%),CHARM-Added

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

patientswithLVEF>40%.PatientsonoptimalCHFtherapyatbaselinewererandomisedtoplaceboorcandesartan

cilexetil(titratedfrom4mgor8mgoncedailyto32mgoncedailyorthehighesttolerateddose,meandose24mg)

andfollowedforamedianof37.7months.After6monthsoftreatment63%ofthepatientsstilltakingcandesartan

cilexetil(89%)wereatthetargetdoseof32mg.

InCHARM-Alternative,thecompositeendpointofcardiovascularmortalityorfirstCHFhospitalisationwas

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

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

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

11.2to2.8).Fourteenpatientsneededtobetreatedforthedurationofthestudytopreventonepatientfromdyingof

acardiovasculareventorbeinghospitalisedfortreatmentofheartfailure.Thecompositeendpointofall-cause

mortalityorfirstCHFhospitalisationwasalsosignificantlyreducedwithcandesartan(HR0.80,95%CI0.70-0.92,

p=0.001).Ofcandesartanpatients36.6%(95%CI:33.7to39.7)andofplacebopatients42.7%(95%CI:39.6to

45.8)experiencedthisendpoint,absolutedifference6.0%(95%CI:10.3to1.8).Boththemortalityandmorbidity

(CHFhospitalisation)componentsofthesecompositeendpointscontributedtothefavourableeffectsofcandesartan.

TreatmentwithcandesartancilexetilresultedinimprovedNYHAfunctionalclass(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-three

patientsneededtobetreatedforthedurationofthestudytopreventonepatientfromdyingofacardiovascularevent

orbeinghospitalisedfortreatmentofheartfailure.Thecompositeendpointofall-causemortalityorfirstCHF

hospitalisationwasalsosignificantlyreducedwithcandesartan(HR0.87,95%CI0.78-0.98,p=0.021).Of

candesartanpatients42.2%(95%CI:39.5to45.0)andofplacebopatients46.1%(95%CI:43.4to48.9)experienced

thisendpoint,absolutedifference3.9%(95%CI:7.8to0.1).Boththemortalityandmorbiditycomponentsofthese

compositeendpointscontributedtothefavourableeffectsofcandesartan.Treatmentwithcandesartancilexetil

resultedinimprovedNYHAfunctionalclass(p=0.020).

InCHARM-Preserved,nostatisticallysignificantreductionwasachievedinthecompositeendpointof

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

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However,all-causemortalitywasalsoassessedinpooledpopulations,CHARM-AlternativeandCHARM-Added

(HR0.88,95%CI0.79-0.98,p=0.018)andallthreestudies(HR0.91,95%CI0.83-1.00,p=0.055).

Thebeneficialeffectsofcandesartanwereconsistentirrespectiveofage,genderandconcomitantmedication.

Candesartanwaseffectivealsoinpatientstakingbothbeta-blockersandACEinhibitorsatthesametime,andthe

benefitwasobtainedwhetherornotpatientsweretakingACEinhibitorsatthetargetdoserecommendedby

treatmentguidelines.

InpatientswithCHFanddepressedleftventricularsystolicfunction(leftventricularejectionfraction,LVEF40%),

candesartandecreasessystemicvascularresistanceandpulmonarycapillarywedgepressure,increasesplasmarenin

activityandangiotensinIIconcentration,anddecreasesaldosteronelevels.

5.2Pharmacokineticproperties

Absorptionanddistribution

Followingoraladministration,candesartancilexetilisconvertedtotheactivesubstance

candesartan.Theabsolutebioavailabilityofcandesartanisapproximately40%afteranoralsolutionofcandesartan

cilexetil.Therelativebioavailabilityofthetabletformulationcomparedwiththesameoralsolutionisapproximately

34%withverylittlevariability.Theestimatedabsolutebioavailabilityofthetabletistherefore14%.Themeanpeak

serumconcentration(C

)isreached3-4hoursfollowingtabletintake.Thecandesartanserumconcentrations

increaselinearlywithincreasingdosesinthetherapeuticdoserange.Nogenderrelateddifferencesinthe

pharmacokineticsofcandesartanhavebeenobserved.Theareaundertheserumconcentrationversustimecurve(AUC)

ofcandesartanisnotsignificantlyaffectedbyfood.

Candesartanishighlyboundtoplasmaprotein(morethan99%).Theapparentvolumeofdistributionofcandesartanis

0.1l/kg.

Thebioavailabilityofcandesartanisnotaffectedbyfood.

Metabolismandelimination

Candesartanismainlyeliminatedunchangedviaurineandbileandonlytoaminorextenteliminatedbyhepatic

metabolism(CYP2C9).AvailableinteractionstudiesindicatenoeffectonCYP2C9andCYP3A4.Basedoninvitro

data,nointeractionwouldbeexpectedtooccurinvivowithdrugswhosemetabolismisdependantoncytochromeP450

isoenzymesCYP1A2,CYP2A6,CYP2C9,CYP2C19,CYP2D6,CYP2E1,ORCYP3A4.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,butt½wasnotaltered,comparedtopatientswithnormalrenalfunction.

Thecorrespondingchangesinpatientswithsevererenalimpairmentwereapproximately50%and110%,respectively.

Theterminalt½ofcandesartanwasapproximatelydoubledinpatientswithsevererenalimpairment.TheAUCof

candesartaninpatientsundergoinghaemodialysiswassimilartothatinpatientswithsevererenalimpairment.

Intwostudies,bothincludingpatientswithmildtomoderatehepaticimpairment,therewasanincreaseinthemean

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Thereisnoexperienceinpatientswithseverehepaticimpairment.

5.3Preclinicalsafetydata

Therewasnoevidenceofabnormalsystemicortargetorgantoxicityatclinicallyrelevantdoses.Inpreclinicalsafety

studiescandesartanhadeffectsonthekidneysandonredcellparametersathighdosesinmice,rats,dogsand

monkeys.Candesartancausedareductionofredbloodcellparameters(erythrocytes,haemoglobin,haematocrit).

Effectsonthekidneys(suchasinterstitialnephritis,tubulardistension,basophilictubules;increasedplasma

concentrationsofureaandcreatinine)wereinducedbycandesartan,whichcouldbesecondarytothehypotensiveeffect

leadingtoalterationsofrenalperfusion.Furthermore,candesartaninducedhyperplasia/hypertrophyofthe

juxtaglomerularcells.Thesechangeswereconsideredtobecausedbythepharmacologicalactionofcandesartan.For

therapeuticdosesofcandesartaninhumans,thehyperplasia/hypertrophyoftherenaljuxtaglomerularcellsdoesnot

seemtohaveanyrelevance.

Foetotoxicityhasbeenobservedinlatepregnancy(seesection4.6).

Datafrominvitroandinvivomutagenicitytestingindicatesthatcandesartanwillnotexertmutagenicorclastogenic

activitiesunderconditionsofclinicaluse.Therewasnoevidenceofcarcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Carmellosecalcium

Hyprolose

Lactosemonohydrate

MagnesiumStearate

Mannitol

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years

Thein-useshelflifeoftheproductwhenstoredinHDPEbottlesis90days.

6.4Specialprecautionsforstorage

Donotstoreabove25˚C.Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

OPA-Aluminium-PVC/Aluminiumblistercontainedwithinalaminatedpouch,togetherwithadesiccantbag:packof

7,10,14,15,28,30,50,56,60,84,90,98and100tablets.

WhiteopaqueHDPEbottleswithwhiteopaquescrewcap(madeofpropylene)withdesiccantandabsorbentcotton:

packof30and90tablets.

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6.6Specialprecautionsfordisposal

Nospecialrequirements.

Anyunusedproductorwasteshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

McDermottLaboratoriesLtd

t/aGerardLaboratories

35/36BaldoyleIndustrialEstate

GrangeRoad

Dublin13

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA577/120/4

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:26thAugust2011

10DATEOFREVISIONOFTHETEXT

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