CANDESARTAN TEVA

Main information

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

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/124/001
  • Authorization date:
  • 21-12-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CandesartanTeva2mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains2mgcandesartancilexetil.

Excipients:

Lactose:42.20mglactosemonohydrate/2mgtablet

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

Whitetooffwhite,roundstandardconvextablet.Onesideofthetabletisdebossedwiththenumber"2".Theotherside

ofthetabletisdebossedwith"C".

4CLINICALPARTICULARS

4.1TherapeuticIndications

CandesartanTevaisindicatedforthe:

Treatmentofessentialhypertensioninadults.

Treatmentofadultpatientswithheartfailureandimpairedleftventricularsystolicfunction(leftventricularejection

fraction 40%)asadd-ontherapytoAngiotensinConvertingEnzyme(ACE)inhibitorsorwhenACEinhibitorsarenot

tolerated(seesection5.1).

4.2Posologyandmethodofadministration

PosologyinHypertension

TherecommendedinitialdoseandusualmaintenancedoseofCandesartanTevais8mgoncedaily.Mostofthe

antihypertensiveeffectisattainedwithin4weeks.Insomepatientswhosebloodpressureisnotadequatelycontrolled,

thedosecanbeincreasedto16mgoncedailyandtoamaximumof32mgoncedaily.Therapyshouldbeadjusted

accordingtobloodpressureresponse.CandesartanTevamayalsobeadministeredwithotherantihypertensiveagents.

Additionofhydrochlorothiazidehasbeenshowntohaveanadditiveantihypertensiveeffectwithvariousdosesof

CandesartanTeva.

Elderlypopulation

Noinitialdoseadjustmentisnecessaryinelderlypatients.

Patientswithintravascularvolumedepletion

Aninitialdoseof4mgmaybeconsideredinpatientsatriskforhypotension,suchaspatientswithpossiblevolume

depletion(seesection4.4).

Patientswithrenalimpairment

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titratedaccordingtoresponse.Thereislimitedexperienceinpatientswithverysevereorendstagerenalimpairment

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

Patientswithhepaticimpairment

Aninitialdoseof4mgoncedailyisrecommendedinpatientswithmildtomoderatehepaticimpairment.Thedose

maybeadjustedaccordingtoresponse.CandesartanTevaiscontraindicatedinpatientswithseverehepaticimpairment

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

Blackpatients

Theantihypertensiveeffectofcandesartanislesspronouncedinblackpatientsthaninnon-blackpatients.

Consequently,uptitrationofCandesartanTevaandconcomitanttherapymaybemorefrequentlyneededforblood

pressurecontrolinblackpatientsthaninnon-blackpatients(seesection5.1).

PosologyinHeartFailure

TheusualrecommendedinitialdoseofCandesartanTevais4mgoncedaily.Up-titrationtothetargetdoseof32mg

oncedaily(maximumdose)orthehighesttolerateddoseisdonebydoublingthedoseatintervalsofatleast2weeks

(seesection4.4).Evaluationofpatientswithheartfailureshouldalwayscompriseassessmentofrenalfunction

includingmonitoringofserumcreatinineandpotassium.CandesartanTevacanbeadministeredwithotherheartfailure

treatment,includingACEinhibitors,beta-blockers,diureticsanddigitalisoracombinationofthesemedicinalproducts.

ThecombinationofanACEinhibitor,apotassium-sparingdiuretic(e.g.spironolactone)andCandesartanTevaisnot

recommendedandshouldbeconsideredonlyaftercarefulevaluationofthepotentialbenefitsandrisks(seesections

4.4,4.8and5.1).

Specialpatientpopulations

Noinitialdoseadjustmentisnecessaryforelderlypatientsorinpatientswithintravascularvolumedepletionorrenal

impairmentormildtomoderatehepaticimpairment.

PaediatricPopulation

ThesafetyandefficacyofCandesartanTevainchildrenagedbetweenbirthand18yearshavenotbeenestablishedin

thetreatmentofhypertensionandheartfailure.Nodataareavailable.

Methodofadministration

Oraluse.

CandesartanTevashouldbetakenoncedailywithorwithoutfood.

Thebioavailabilityofcandesartanisnotaffectedbyfood.

4.3Contraindications

Hypersensitivitytocandesartancilexetilortoanyoftheexcipients.

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6).

Severehepaticimpairmentand/orcholestasis.

4.4Specialwarningsandprecautionsforuse

Renalimpairment

Aswithotheragentsinhibitingtherenin-angiotensin-aldosteronesystem,changesinrenalfunctionmaybeanticipated

insusceptiblepatientstreatedwithCandesartanTeva.

WhenCandesartanTevaisusedinhypertensivepatientswithrenalimpairment,periodicmonitoringofserum

potassiumandcreatininelevelsisrecommended.Thereislimitedexperienceinpatientswithverysevereorend-stage

renalimpairment(Cl

creatinine <15ml/min).InthesepatientsCandesartanTevashouldbecarefullytitratedwith

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Evaluationofpatientswithheartfailureshouldincludeperiodicassessmentsofrenalfunction,especiallyinelderly

patients75yearsorolder,andpatientswithimpairedrenalfunction.DuringdosetitrationofCandesartanTeva,

monitoringofserumcreatinineandpotassiumisrecommended.Clinicaltrialsinheartfailuredidnotincludepatients

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

ConcomitanttherapywithanACEinhibitorinheartfailure

Theriskofadversereactions,especiallyrenalfunctionimpairmentandhyperkalaemia,mayincreasewhenCandesartan

TevaisusedincombinationwithanACEinhibitor(seesection4.8).Patientswithsuchtreatmentshouldbemonitored

regularlyandcarefully.

Haemodialysis

DuringdialysisthebloodpressuremaybeparticularlysensitivetoAT

-receptorblockadeasaresultofreducedplasma

volumeandactivationoftherenin-angiotensin-aldosteronesystem.Therefore,CandesartanTevashouldbecarefully

titratedwiththoroughmonitoringofbloodpressureinpatientsonhaemodialysis.

Renalarterystenosis

Othermedicinalproductsthataffecttherenin-angiotensin-aldosteronesystem,includingangiotensinIIreceptor

antagonists(AIIRAs),mayincreasebloodureaandserumcreatinineinpatientswithbilateralrenalarterystenosisor

stenosisofthearterytoasolitarykidney.

Kidneytransplantation

ThereisnoexperienceregardingtheadministrationofCandesartanTevainpatientswitharecentkidney

transplantation.

Hypotension

HypotensionmayoccurduringtreatmentwithCandesartanTevainheartfailurepatients.Itmayalsooccurin

hypertensivepatientswithintravascularvolumedepletionsuchasthosereceivinghighdosediuretics.Cautionshould

beobservedwheninitiatingtherapyandcorrectionofhypovolemiashouldbeattempted.

Anaesthesiaandsurgery

HypotensionmayoccurduringanaesthesiaandsurgeryinpatientstreatedwithangiotensinIIantagonistsdueto

blockadeoftherenin-angiotensinsystem.Veryrarely,hypotensionmaybeseveresuchthatitmaywarranttheuseof

intravenousfluidsand/orvasopressors.

Aorticandmitralvalvestenosis(obstructivehypertrophiccardiomyopathy)

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromhaemodynamicallyrelevantaorticor

mitralvalvestenosis,orobstructivehypertrophiccardiomyopathy.

Primaryhyperaldosteronism

Patientswithprimaryhyperaldosteronismwillnotgenerallyrespondtoantihypertensivemedicinalproductsacting

throughinhibitionoftherenin-angiotensin-aldosteronesystem.Therefore,theuseofCandesartanTevaisnot

recommendedinthispopulation.

Hyperkalaemia

ConcomitantuseofCandesartanTevawithpotassium-sparingdiuretics,potassiumsupplements,saltsubstitutes

containingpotassium,orothermedicinalproductsthatmayincreasepotassiumlevels(e.g.heparin)mayleadto

increasesinserumpotassiuminhypertensivepatients.Monitoringofpotassiumshouldbeundertakenasappropriate.

InheartfailurepatientstreatedwithCandesartanTeva,hyperkalaemiamayoccur.Periodicmonitoringofserum

potassiumisrecommended.ThecombinationofanACEinhibitor,apotassium-sparingdiuretic(e.g.spironolactone)

andCandesartanTevaisnotrecommendedandshouldbeconsideredonlyaftercarefulevaluationofthepotential

benefitsandrisks.

General

Inpatientswhosevasculartoneandrenalfunctiondependpredominantlyontheactivityoftherenin-angiotensin-

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stenosis),treatmentwithothermedicinalproductsthataffectthissystemhasbeenassociatedwithacutehypotension,

azotaemia,oliguriaor,rarely,acuterenalfailure.ThepossibilityofsimilareffectscannotbeexcludedwithAIIRAs.As

withanyantihypertensiveagent,excessivebloodpressuredecreaseinpatientswithischaemiccardiopathyorischaemic

cerebrovasculardiseasecouldresultinamyocardialinfarctionorstroke.

Theantihypertensiveeffectofcandesartanmaybeenhancedbyothermedicinalproductswithbloodpressurelowering

properties,whetherprescribedasanantihypertensiveorprescribedforotherindications.

CandesartanTevacontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

Pregnancy

AIIRAsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedAIIRAtherapyisconsideredessential,patients

planningpregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhichhaveanestablishedsafety

profileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithAIIRAsshouldbestoppedimmediately,

and,ifappropriate,alternativetherapyshouldbestarted(seesections4.3and4.6).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Compoundswhichhavebeeninvestigatedinclinicalpharmacokineticstudiesincludehydrochlorothiazide,warfarin,

digoxin,oralcontraceptives(i.e.ethinylestradiol/levonorgestrel),glibenclamide,nifedipineandenalapril.Noclinically

significantpharmacokineticinteractionswiththesemedicinalproductshavebeenidentified.

Concomitantuseofpotassium-sparingdiuretics,potassiumsupplements,saltsubstitutescontainingpotassium,orother

medicinalproducts(e.g.heparin)mayincreasepotassiumlevels.Monitoringofpotassiumshouldbeundertakenas

appropriate(seesection4.4).

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.AsimilareffectmayoccurwithAIIRAs.Useofcandesartanwith

lithiumisnotrecommended.Ifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsis

recommended.

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

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

effectmayoccur.

AswithACEinhibitors,concomitantuseofAIIRAsandNSAIDsmayleadtoanincreasedriskofworseningofrenal

function,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyinpatientswithpoor

pre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyintheelderly.Patients

shouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunctionafterinitiationof

concomitanttherapy,andperiodicallythereafter.

4.6Fertility,pregnancyandlactation

Pregnancy

TheuseofAIIRAsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).TheuseofAIIRAsis

contra-indicatedduringthesecondandthirdtrimestersofpregnancy(seesections4.3and4.4).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithAIIRAs,similarrisksmayexistforthisclassofdrugs.Unless

continuedAIIRAtherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithAIIRAsshouldbestoppedimmediatelyand,ifappropriate,alternativetherapyshouldbe

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ExposuretoAIIRAtherapyduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

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

hyperkalaemia)(seesection5.3).ShouldexposuretoAIIRAshaveoccurredfromthesecondtrimesterofpregnancy,

ultrasoundcheckofrenalfunctionandskullisrecommended.InfantswhosemothershavetakenAIIRAsshouldbe

closelyobservedforhypotension(seesections4.3and4.4).

Lactation

BecausenoinformationisavailableregardingtheuseofCandesartanTevaduringbreastfeeding,CandesartanTevais

notrecommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsofcandesartanontheabilitytodriveandusemachineshavebeenperformed.However,it

shouldbetakenintoaccountthatoccasionallydizzinessorwearinessmayoccurduringtreatmentwithCandesartan

Teva.

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),

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,neutropenia

andagranulocytosis

Metabolismandnutritiondisorders Veryrare Hyperkalaemia,

hyponatraemia

Nervoussystemdisorders Common Dizziness/vertigo,

headache

Gastrointestinaldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,

abnormalhepaticfunction

orhepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,

urticaria,pruritus

Musculoskeletalandconnective

tissuedisorders Veryrare Backpain,arthralgia,

myalgia

Renalandurinarydisorders Veryrare Renalimpairment,

includingrenalfailurein

susceptiblepatients(see

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Laboratoryfindings

Ingeneral,therewerenoclinicallyimportantinfluencesofCandesartanTevaonroutinelaboratoryvariables.Asfor

otherinhibitorsoftherenin-angiotensin-aldosteronesystem,smalldecreasesinhaemoglobinhavebeenseen.No

routinemonitoringoflaboratoryvariablesisusuallynecessaryforpatientsreceivingCandesartanTeva.However,in

patientswithrenalimpairment,periodicmonitoringofserumpotassiumandcreatininelevelsisrecommended.

TreatmentofHeartFailure

TheadverseexperienceprofileofCandesartanTevainheartfailurepatientswasconsistentwiththepharmacologyof

thedrugandthehealthstatusofthepatients.IntheCHARMclinicalprogramme,comparingCandesartanindosesup

to32mg(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

HyperkalaemiaandrenalimpairmentarecommoninpatientstreatedwithCandesartanTevafortheindicationofheart

failure.Periodicmonitoringofserumcreatinineandpotassiumisrecommended(seesection4.4).

4.9Overdose

Symptoms

Basedonpharmacologicalconsiderations,themainmanifestationofanoverdoseislikelytobesymptomatic

hypotensionanddizziness.Inindividualcasereportsofoverdose(ofupto672mgCandesartancilexetil)patient

recoverywasuneventful.

Management

Ifsymptomatichypotensionshouldoccur,symptomatictreatmentshouldbeinstitutedandvitalsignsmonitored.The

SystemOrganClass Frequency UndesirableEffect

Bloodandlymphaticsystem

disorders Veryrare Leukopenia,neutropenia

andagranulocytosis

Metabolismandnutritiondisorders Common Hyperkalaemia

Veryrare Hyponatraemia

Nervoussystemdisorders Veryrare Dizziness,headache

Vasculardisorders Common Hypotension

Gastrointestinaldisorders Veryrare Nausea

Hepato-biliarydisorders Veryrare Increasedliverenzymes,

abnormalhepaticfunction

orhepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,

urticaria,pruritus

Musculoskeletalandconnective

tissuedisorders Veryrare Backpain,arthralgia,

myalgia

Renalandurinarydisorders Common Renalimpairment,

includingrenalfailurein

susceptiblepatients(see

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infusionof,forexample,isotonicsalinesolution.Sympathomimeticmedicinalproductsmaybeadministeredifthe

above-mentionedmeasuresarenotsufficient.Candesartanisnotremovedbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:AngiotensinIIantagonists,plain,ATCcodeC09CA06.

AngiotensinIIistheprimaryvasoactivehormoneoftherenin-angiotensinaldosteronesystemandplaysaroleinthe

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

andangiotensinIIlevels,andadecreaseinplasmaaldosteroneconcentration.

Hypertension

Inhypertension,candesartancausesadose-dependent,long-lastingreductioninarterialbloodpressure.The

antihypertensiveactionisduetodecreasedsystemicperipheralresistance,withoutreflexincreaseinheartrate.Thereis

noindicationofseriousorexaggeratedfirstdosehypotensionorreboundeffectaftercessationoftreatment.

Afteradministrationofasingledoseofcandesartancilexetil,onsetofantihypertensiveeffectgenerallyoccurswithin2

hours.Withcontinuoustreatment,mostofthereductioninbloodpressurewithanydoseisgenerallyattainedwithin

fourweeksandissustainedduringlong-termtreatment.Accordingtoameta-analysis,theaverageadditionaleffectofa

doseincreasefrom16mgto32mgoncedailywassmall.Takingintoaccounttheinter-individualvariability,amore

thanaverageeffectcanbeexpectedinsomepatients.Candesartancilexetiloncedailyprovideseffectiveandsmooth

bloodpressurereductionover24hours,withlittledifferencebetweenmaximumandtrougheffectsduringthedosing

interval.Theantihypertensiveeffectandtolerabilityofcandesartanandlosartanwerecomparedintworandomised,

double-blindstudiesinatotalof1,268patientswithmildtomoderatehypertension.Thetroughbloodpressure

reduction(systolic/diastolic)was13.1/10.5mmHgwithcandesartancilexetil32mgoncedailyand10.0/8.7mmHg

withlosartanpotassium100mgoncedaily(differenceinbloodpressurereduction3.1/1.8mmHg,p<0.0001/p<0.0001).

Whencandesartancilexetilisusedtogetherwithhydrochlorothiazide,thereductioninbloodpressureisadditive.An

increasedantihypertensiveeffectisalsoseenwhencandesartancilexetiliscombinedwithamlodipineorfelodipine.

Medicinalproductsthatblocktherenin-angiotensin-aldosteronesystemhavelesspronouncedantihypertensiveeffectin

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

openlabelclinicalexperiencetrialin5,156patientswithdiastolichypertension,thebloodpressurereductionduring

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

p<0.0001/p<0.0001).

Candesartanincreasesrenalbloodflowandeitherhasnoeffecton,orincreasesglomerularfiltrationratewhilerenal

vascularresistanceandfiltrationfractionarereduced.Ina3-monthclinicalstudyinhypertensivepatientswithtype2

diabetesmellitusandmicroalbuminuria,antihypertensivetreatmentwithcandesartancilexetilreducedurinaryalbumin

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candesartanontheprogressiontodiabeticnephropathy.

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–

AssessmentofReductioninMortalityandmorbidity(CHARM)programme.

Thisplacebocontrolled,double-blindstudyprogrammeinchronicheartfailure(CHF)patientswithNYHAfunctional

classIItoIVconsistedofthreeseparatestudies:CHARM-Alternative(n=2,028)inpatientswithLVEF 40%not

treatedwithanACEinhibitorbecauseofintolerance(mainlyduetocough,72%),CHARM-Added(n=2,548)in

patientswithLVEF 40%andtreatedwithanACEinhibitor,andCHARM-Preserved(n=3,023)inpatientswith

LVEF>40%.PatientsonoptimalCHFtherapyatbaselinewererandomisedtoplaceboorcandesartancilexetil(titrated

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)and

ofplacebopatients40.0%(95%CI:37.0to43.1)experiencedthisendpoint,absolutedifference7.0%(95%CI:11.2to

2.8).Fourteenpatientsneededtobetreatedforthedurationofthestudytopreventonepatientfromdyingofa

cardiovasculareventorbeinghospitalisedfortreatmentofheartfailure.Thecompositeendpointofall-causemortality

orfirstCHFhospitalisationwasalsosignificantlyreducedwithcandesartan,HR0.80(95%CI:0.70to0.92,p=0.001).

Ofcandesartanpatients36.6%(95%CI:33.7to39.7)andofplacebopatients42.7%(95%CI:39.6to45.8)experienced

thisendpoint,absolutedifference6.0%(95%CI:10.3to1.8).Boththemortalityandmorbidity(CHFhospitalisation)

componentsofthesecompositeendpointscontributedtothefavourableeffectsofcandesartan.Treatmentwith

candesartancilexetilresultedinimprovedNYHAfunctionalclass(p=0.008).

InCHARM-Added,thecompositeendpointofcardiovascularmortalityorfirstCHFhospitalisationwassignificantly

reducedwithcandesartanincomparisonwithplacebo,HR0.85(95%CI:0.75to0.96,p=0.011).Thiscorrespondstoa

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

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

neededtobetreatedforthedurationofthestudytopreventonepatientfromdyingofacardiovasculareventorbeing

hospitalisedfortreatmentofheartfailure.Thecompositeendpointofall-causemortalityorfirstCHFhospitalisation

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

42.2%(95%CI:39.5to45.0)andofplacebopatients46.1%(95%CI:43.4to48.9)experiencedthisendpoint,absolute

difference3.9%(95%CI:7.8to0.1).Boththemortalityandmorbiditycomponentsofthesecompositeendpoints

contributedtothefavourableeffectsofcandesartan.TreatmentwithcandesartancilexetilresultedinimprovedNYHA

functionalclass(p=0.020).

InCHARM-Preserved,nostatisticallysignificantreductionwasachievedinthecompositeendpointofcardiovascular

mortalityorfirstCHFhospitalisation,HR0.89(95%CI:0.77to1.03,p=0.118).

All-causemortalitywasnotstatisticallysignificantwhenexaminedseparatelyineachofthethreeCHARMstudies.

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

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Thebeneficialeffectsofcandesartanwereconsistentirrespectiveofage,genderandconcomitantmedication.

Candesartanwaseffectivealsoinpatientstakingbothbeta-blockersandACEinhibitorsatthesametime,andthe

benefitwasobtainedwhetherornotpatientsweretakingACEinhibitorsatthetargetdoserecommendedbytreatment

guidelines.

InpatientswithCHFanddepressedleftventricularsystolicfunction(leftventricularejectionfraction,LVEF 40%),

candesartandecreasessystemicvascularresistanceandpulmonarycapillarywedgepressure,increasesplasmarenin

activityandangiotensinIIconcentration,anddecreasesaldosteronelevels.

5.2Pharmacokineticproperties

Absorptionanddistribution

Followingoraladministration,candesartancilexetilisconvertedtotheactivesubstancecandesartan.Theabsolute

bioavailabilityofcandesartanisapproximately40%afteranoralsolutionofcandesartancilexetil.Therelative

bioavailabilityofthetabletformulationcomparedwiththesameoralsolutionisapproximately34%withverylittle

variability.Theestimatedabsolutebioavailabilityofthetabletistherefore14%.Themeanpeakserumconcentration

)isreached3-4hoursfollowingtabletintake.Thecandesartanserumconcentrationsincreaselinearlywith

increasingdosesinthetherapeuticdoserange.Nogenderrelateddifferencesinthepharmacokineticsofcandesartan

havebeenobserved.Theareaundertheserumconcentrationversustimecurve(AUC)ofcandesartanisnot

significantlyaffectedbyfood.Candesartanishighlyboundtoplasmaprotein(morethan99%).Theapparentvolume

ofdistributionofcandesartanis0.1l/kg.

Thebioavailabilityofcandesartanisnotaffectedbyfood.

Biotransformationandelimination

Candesartanismainlyeliminatedunchangedviaurineandbileandonlytoaminorextenteliminatedbyhepatic

metabolism(CYP2C9).AvailableinteractionstudiesindicatenoeffectonCYP2C9andCYP3A4.Basedoninvitro

data,nointeractionwouldbeexpectedtooccurinvivowithdrugswhosemetabolismisdependentuponcytochrome

isoenzymesCYP1A2,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

eventsaresimilarafteragivendoseofCandesartanTevainyoungandelderlypatients(seesection4.2).

InpatientswithmildtomoderaterenalimpairmentC

andAUCofcandesartanincreasedduringrepeateddosingby

approximately50%and70%,respectively,butt

wasnotaltered,comparedtopatientswithnormalrenalfunction.

Thecorrespondingchangesinpatientswithsevererenalimpairmentwereapproximately50%and110%,respectively.

Theterminalt

ofcandesartanwasapproximatelydoubledinpatientswithsevererenalimpairment.TheAUCof

candesartaninpatientsundergoinghaemodialysiswassimilartothatinpatientswithsevererenalimpairment.

Intwostudies,bothincludingpatientswithmildtomoderatehepaticimpairment,therewasanincreaseinthemean

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experienceinpatientswithseverehepaticimpairment.

5.3Preclinicalsafetydata

Therewasnoevidenceofabnormalsystemicortargetorgantoxicityatclinicallyrelevantdoses.Inpreclinicalsafety

studiescandesartanhadeffectsonthekidneysandonredcellparametersathighdosesinmice,rats,dogsand

monkeys.Candesartancausedareductionofredbloodcellparameters(erythrocytes,haemoglobin,haematocrit).

Effectsonthekidneys(suchasinterstitialnephritis,tubulardistension,basophilictubules;increasedplasma

concentrationsofureaandcreatinine)wereinducedbycandesartanwhichcouldbesecondarytothehypotensiveeffect

leadingtoalterationsofrenalperfusion.Furthermore,candesartaninducedhyperplasia/hypertrophyofthe

juxtaglomerularcells.Thesechangeswereconsideredtobecausedbythepharmacologicalactionofcandesartan.For

therapeuticdosesofcandesartaninhumans,thehyperplasia/hypertrophyoftherenaljuxtaglomerularcellsdoesnot

seemtohaveanyrelevance.

Foetotoxicityhasbeenobservedinlatepregnancy(seesection4.6).

Datafrominvitroandinvivomutagenicitytestingindicatesthatcandesartanwillnotexertmutagenicorclastogenic

activitiesunderconditionsofclinicaluse.Therewasnoevidenceofcarcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Pregelatinizedmaizestarch

PovidoneK-30

Carmellosecalcium

Microcrystallinecellulose(E460)

Lactosemonohydrate

Magnesiumstearate

L-Leucine

6.2Incompatibilities

Notapplicable.

6.3Shelflife

OPA/Aluminium/PVC–PVC/PVAC/Aluminiumblisters:

12months.

OPA/Aluminium/PEwithdesiccantagent/PE–PE/Aluminiumblisters:

2years.

6.4Specialprecautionsforstorage

OPA/Aluminium/PVC–PVC/PVAC/Aluminiumblisters:

Storebelow25°C.Storeintheoriginalpackageinordertoprotectfrommoisture.

OPA/Aluminium/PEwithdesiccantagent/PE–PE/Aluminiumblisters:

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

OPA/Aluminium/PVC–PVC/PVAC/AluminiumblistersorOPA/Aluminium/PEwithdesiccantagent/PE–

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Packsizes:7,14,15,20,28,30,50,50x1unitdoseblisters(hospitalpack),56,60,84,90,98,100,250&300tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V.

Computerweg10,

P.O.Box43028,

3540AAUtrecht,

Netherlands

8MARKETINGAUTHORISATIONNUMBER

PA749/124/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:21stDecember2011

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