CANDIST PLUS

Main information

  • Trade name:
  • CANDIST PLUS
  • Dosage:
  • 8/12.5 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CANDIST PLUS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0126/207/001
  • Authorization date:
  • 21-10-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CandistPlus8mg/12.5mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

OneCandistPlus8mg/12.5mgtabletcontains8mgcandesartancilexetiland12.5mghydrochlorothiazide.

Eachtabletcontains117.30mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Tablet.

CandistPlus8mg/12.5mgtabletsarewhite,biconvextabletswithascorelineononesideandanembossingCH8on

thesameside.

Thescorelineisonlytofacilitatebreakingforeaseofswallowingandnottodivideintoequaldoses.

4CLINICALPARTICULARS

4.1TherapeuticIndications

CandistPlusisindicatedforthe:

Treatmentofessentialhypertensioninadultpatientswhosebloodpressureisnotoptimallycontrolledwith

candesartancilexetilorhydrochlorothiazidemonotherapy.

4.2Posologyandmethodofadministration

Posology

TherecommendeddoseofCandistPlusisonetabletoncedaily.

Dosetitrationwiththeindividualcomponents(candesartancilexetilandhydrochlorothiazide)isrecommended.When

clinicallyappropriateadirectchangefrommonotherapytoCandistPlusmaybeconsidered.Dosetitrationof

candesartancilexetilisrecommendedwhenswitchingfromhydrochlorothiazidemonotherapy.CandistPlusmaybe

administeredinpatientswhosebloodpressureisnotoptimallycontrolledwithcandesartancilexetilor

hydrochlorothiazidemonotherapyorCandistPlusatlowerdoses.

Mostoftheantihypertensiveeffectisusuallyattainedwithin4weeksofinitiationoftreatment.

Specialpopulations

Elderlypopulation

Nodoseadjustmentisnecessaryinelderlypatients.

Patientswithintravascularvolumedepletion

Dosetitrationofcandesartancilexetilisrecommendedinpatientsatriskforhypotension,suchaspatientswithpossible

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Patientswithrenalimpairment

Loopdiureticsarepreferredtothiazidesinthispopulation.Dosetitrationofcandesartancilexetilisrecommendedin

patientswithmildtomoderaterenalimpairment(creatinineclearance 30ml/min/1.73m2BodySurfaceArea(BSA))

beforetreatmentwithCandistPlus(therecommendedstartingdoseofcandesartancilexetilis4mginthesepatients).

CandistPlusiscontraindicatedinpatientswithsevererenalimpairment(creatinineclearance<30ml/min/1.73m2

BSA)(seesection4.3).

Patientswithhepaticimpairment

Dosetitrationofcandesartancilexetilisrecommendedinpatientswithmildtomoderatehepaticimpairmentbefore

treatmentwithCandistPlus(therecommendedstartingdoseofcandesartancilexetilis4mginthesepatients).

CandistPlusiscontraindicatedinpatientswithseverehepaticimpairmentand/orcholestasis(seesection4.3).

Paediatricpopulation

ThesafetyandefficacyofCandistPlusinchildrenagedbetweenbirthand18yearshavenotbeenestablished.Nodata

areavailable.

Methodofadministration

Oraluse.

CandistPluscanbetakenwithorwithoutfood.

Thebioavailabilityofcandesartanisnotaffectedbyfood.

Thereisnoclinicallysignificantinteractionbetweenhydrochlorothiazideandfood.

4.3Contraindications

Hypersensitivitytotheactivesubstancesortoanyoftheexcipientsortosulfonamidederivedactivesubstances.

Hydrochlorothiazideisasulfonamidederivedactivesubstance.

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6)

Severerenalimpairment(creatinineclearance<30ml/min/1.73m2BSA).

Severehepaticimpairmentand/orcholestasis.

Refractoryhypokalaemiaandhypercalcaemia.

Gout.

4.4Specialwarningsandprecautionsforuse

Renalimpairment/kidneytransplantation

Loopdiureticsarepreferredtothiazidesinthispopulation.WhenCandistPlusisusedinpatientswithimpairedrenal

function,aperiodicmonitoringofpotassium,creatinineanduricacidlevelsisrecommended.

ThereisnoexperienceregardingtheadministrationofCandistPlusinpatientswitharecentkidneytransplantation.

Renalarterystenosis

Medicinalproductsthataffecttherenin-angiotensin-aldosteronesystem,includingangiotensinIIreceptorantagonists

(AIIRAs),mayincreasebloodureaandserumcreatinineinpatientswithbilateralrenalarterystenosisorstenosisofthe

arterytoasolitarykidney.

Intravascularvolumedepletion

Inpatientswithintravascularvolumeand/orsodiumdepletionsymptomatichypotensionmayoccur,asdescribedfor

otheragentsactingontherenin-angiotensin-aldosteronesystem.Therefore,theuseofCandistPlusisnotrecommended

untilthisconditionhasbeencorrected.

Anaesthesiaandsurgery

HypotensionmayoccurduringanaesthesiaandsurgeryinpatientstreatedwithAIIRAsduetoblockadeoftherenin-

angiotensinsystem.Veryrarely,hypotensionmaybeseveresuchthatitmaywarranttheuseofintravenousfluids

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Hepaticimpairment

Thiazidesshouldbeusedwithcautioninpatientswithimpairedhepaticfunctionorprogressiveliverdisease,since

minoralterationsoffluidandelectrolytebalancemayprecipitatehepaticcoma.Thereisnoclinicalexperiencewith

CandistPlusinpatientswithhepaticimpairment.

Aorticandmitralvalvestenosis(obstructivehypertrophiccardiomyopathy)

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromhaemodynamicallyrelevantaorticor

mitralvalvestenosis,orobstructivehypertrophiccardiomyopathy.

Primaryhyperaldosteronism

Patientswithprimaryhyperaldosteronismgenerallywillnotrespondtoantihypertensiveagentsactingthrough

inhibitionoftherenin-angiotensin-aldosteronesystem.ThereforetheuseofCandistPlusisnotrecommendedinthis

population.

Electrolyteimbalance

Periodicdeterminationofserumelectrolytesshouldbeperformedatappropriateintervals.Thiazides,including

hydrochlorothiazide,cancausefluidorelectrolyteimbalance(hypercalcaemia,hypokalaemia,hyponatraemia,

hypomagnesaemiaandhypochloraemicalkalosis).

Thiazidediureticsmaydecreasetheurinarycalciumexcretionandmaycauseintermittentandslightlyincreasedserum

calciumconcentrations.Markedhypercalcaemiamaybeasignofhiddenhyperparathyroidism.Thiazidesshouldbe

discontinuedbeforecarryingouttestsforparathyroidfunction.

Hydrochlorothiazidedose-dependentlyincreasesurinarypotassiumexcretionwhichmayresultinhypokalaemia.This

effectofhydrochlorothiazideseemstobelessevidentwhencombinedwithcandesartancilexetil.Theriskfor

hypokalaemiamaybeincreasedinpatientswithcirrhosisoftheliver,inpatientsexperiencingbriskdiuresis,inpatients

withaninadequateoralintakeofelectrolytesandinpatientsreceivingconcomitanttherapywithcorticosteroidsor

adrenocorticotropichormone(ACTH).

Treatmentwithcandesartancilexetilmaycausehyperkalaemia,especiallyinthepresenceofheartfailureand/orrenal

impairment.ConcomitantuseofCandistPlusandpotassium-sparingdiuretics,potassiumsupplementsorsalt

substitutesorothermedicinalproductsthatmayincreaseserumpotassiumlevels(e.g.heparinsodium)mayleadto

increasesinserumpotassium.Monitoringofpotassiumshouldbeundertakenasappropriate.

Thiazideshavebeenshowntoincreasetheurinaryexcretionofmagnesium,whichmayresultinhypomagnesaemia.

Metabolicandendocrineeffects

Treatmentwithathiazidediureticmayimpairglucosetolerance.Doseadjustmentofantidiabeticmedicinalproducts,

includinginsulin,mayberequired.Latentdiabetesmellitusmaybecomemanifestduringthiazidetherapy.Increasesin

cholesterolandtriglyceridelevelshavebeenassociatedwiththiazidediuretictherapy.Atthedosescontainedin

CandistPlus,onlyminimaleffectswereobserved.Thiazidediureticsincreaseserumuricacidconcentrationandmay

precipitategoutinsusceptiblepatients.

Photosensitivity

Casesofphotosensitivityreactionshavebeenreportedduringuseofthiazidediuretics(seesection4.8).Ifa

photosensitivityreactionoccurs,itisrecommendedtostoptreatment.Ifre-administrationoftreatmentisessential,itis

recommendedtoprotectareasexposedtothesunortoartificialUVAradiation.

General

Inpatientswhosevasculartoneandrenalfunctiondependpredominantlyontheactivityoftherenin-angiotensin-

aldosteronesystem(e.g.patientswithseverecongestiveheartfailureorunderlyingrenaldisease,includingrenalartery

stenosis),treatmentwithmedicinalproductsthataffectthissystemincludingAIIRAs,hasbeenassociatedwithacute

hypotension,azotaemia,oliguriaor,rarely,acuterenalfailure.Aswithanyantihypertensiveagent,excessiveblood

pressuredecreaseinpatientswithischaemicheartdiseaseoratheroscleroticcerebrovasculardiseasecouldresultina

myocardialinfarctionorstroke.

Hypersensitivityreactionstohydrochlorothiazidemayoccurinpatientswithorwithoutahistoryofallergyorbronchial

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Exacerbationoractivationofsystemiclupuserythaematosushasbeenreportedwiththeuseofthiazidediuretics.

TheantihypertensiveeffectofCandistPlusmaybeenhancedbyotherantihypertensives.

Thismedicinalproductcontainslactose,asanexcipient,andpatientswithrarehereditaryproblemsofgalactose

intolerance,theLapplactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

Pregnancy

AIIRAsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedAIIRAtherapyisconsideredessential,patients

planningpregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhichhaveanestablishedsafety

profileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithAIIRAsshouldbestoppedimmediately,

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

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Compoundswhichhavebeeninvestigatedinclinicalpharmacokineticstudiesincludewarfarin,digoxin,oral

contraceptives(i.e.ethinylestradiol/levonorgestrel),glibenclamideandnifedipine.Nopharmacokineticinteractionsof

clinicalsignificancewereidentifiedinthesestudies.

Thepotassiumdepletingeffectofhydrochlorothiazidecouldbeexpectedtobepotentiatedbyothermedicinalproducts

associatedwithpotassiumlossandhypokalaemia(e.g.otherkaliureticdiuretics,laxatives,amphotericin,

carbenoxolone,penicillinGsodium,salicylicacidderivates,steroids,ACTH).

ConcomitantuseofCandistPlusandpotassium-sparingdiuretics,potassiumsupplementsorsaltsubstitutesorother

medicinalproductsthatmayincreaseserumpotassiumlevels(e.g.heparinsodium)mayleadtoincreasesinserum

potassium.Monitoringofpotassiumshouldbeundertakenasappropriate(seesection4.4).

Diuretic-inducedhypokalaemiaandhypomagnesaemiapredisposestothepotentialcardiotoxiceffectsofdigitalis

glycosidesandantiarrhythmics.PeriodicmonitoringofserumpotassiumisrecommendedwhenCandistPlusis

administeredwithsuchmedicinalproducts,andwiththefollowingmedicinalproductsthatcouldinducetorsadesde

pointes:

ClassIaantiarrhythmics(e.g.quinidine,hydroquinidine,disopyramide)

ClassIIIantiarrhythmics(e.g.amiodarone,sotalol,dofetilide,ibutilide)

Someantipsychotics(e.g.thioridazine,chlorpromazine,levomepromazine,trifluoperazine,cyamemazine,

sulpiride,sultopride,amisulpride,tiapride,pimozide,haloperidol,droperiodol)

Others(e.g.bepridil,cisapride,diphemanil,erythromyciniv,halofantrin,ketanserin,mizolastin,pentamidine,

sparfloxacine,terfenadine,vincamineiv)

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithAngiotensinConvertingEnzyme(ACE)inhibitorsorhydrochlorothiazide.Asimilar

effecthasalsobeenreportedwithAIIRAs.Useofcandesartanandhydrochlorothiazidewithlithiumisnot

recommended.Ifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsisrecommended.

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.

Thediuretic,natriureticandantihypertensiveeffectofhydrochlorothiazideisbluntedbyNSAIDs.

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Theeffectofnondepolarisingskeletalmusclerelaxants(e.g.tubocurarine)maybepotentiatedbyhydrochlorothiazide.

Thiazidediureticsmayincreaseserumcalciumlevelsduetodecreasedexcretion.IfcalciumsupplementsorVitaminD

mustbeprescribed,serumcalciumlevelsshouldbemonitoredandthedoseadjustedaccordingly.

Thehyperglycaemiceffectofbeta-blockersanddiazoxidemaybeenhancedbythiazides.

Anticholinergicagents(e.g.atropine,biperiden)mayincreasethebioavailabilityofthiazide-typediureticsby

decreasinggastrointestinalmotilityandstomachemptyingrate.

Thiazidemayincreasetheriskofadverseeffectscausedbyamantadine.

Thiazidesmayreducetherenalexcretionofcytotoxicmedicinalproducts(e.g.cyclophosphamide,methotrexate)and

potentiatetheirmyelosuppressiveeffects.

Posturalhypotensionmaybecomeaggravatedbysimultaneousintakeofalcohol,barbituratesoranaesthetics.

Treatmentwithathiazidediureticmayimpairglucosetolerance.Doseadjustmentofantidiabeticmedicinalproducts,

includinginsulin,mayberequired.Metforminshouldbeusedwithcautionbecauseoftheriskoflacticacidosis

inducedbypossiblefunctionalrenalfailurelinkedtohydrochlorothiazide.

Hydrochlorothiazidemaycausethearterialresponsetopressoramines(e.g.adrenaline)todecreasebutnotenoughto

excludeapressoreffect.

Hydrochlorothiazidemayincreasetheriskofacuterenalinsufficiencyespeciallywithhighdosesofiodinatedcontrast

media.

Concomitanttreatmentwithcyclosporinemayincreasetheriskofhyperuricaemiaandgout-typecomplications.

Concomitanttreatmentwithbaclofen,amifostin,tricyclicantidepressantsorneurolepticsmayleadtoenhancementof

theantihypertensiveeffectandmayinducehypotension.

4.6Fertility,pregnancyandlactation

Pregnancy

AngiotensinIIReceptorAntagonists(AIIRAs):

TheuseofAIIRAsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).TheuseofAIIRAs

iscontraindicatedduringthesecondandthirdtrimestersofpregnancy(seesections4.3and4.4).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithAIIRAs,similarrisksmayexistforthisclassofdrugs.Unless

continuedAIIRAtherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithAIIRAsshouldbestoppedimmediatelyand,ifappropriate,alternativetherapyshouldbe

started.

ExposuretoAIIRAtherapyduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

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

hyperkalaemia)(seesection5.3).

ShouldexposuretoAIIRAshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

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Hydrochlorothiazide:

Thereislimitedexperiencewithhydrochlorothiazideduringpregnancy,especiallyduringthefirsttrimester.Animal

studiesareinsufficient.

Hydrochlorothiazidecrossestheplacenta.Basedonthepharmacologicalmechanismofactionofhydrochlorothiazide

itsuseduringthesecondandthirdtrimestersmaycompromisefoeto-placentalperfusionandmaycausefoetaland

neonataleffectslikeicterus,disturbanceofelectrolytebalanceandthrombocytopenia.

Hydrochlorothiazideshouldnotbeusedforgestationaloedema,gestationalhypertensionor

preeclampsiaduetotheriskofdecreasedplasmavolumeandplacentalhypoperfusion,

withoutabeneficialeffectonthecourseofthedisease.

Hydrochlorothiazideshouldnotbeusedforessentialhypertensioninpregnantwomenexcept

inraresituationswherenoothertreatmentcouldbeused.

Lactation

AngiotensinIIReceptorAntagonists(AIIRAs):

BecausenoinformationisavailableregardingtheuseofCandistPlusduringbreastfeeding,CandistPlusisnot

recommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

Hydrochlorothiazide:

Hydrochlorothiazideisexcretedinhumanmilkinsmallamounts.Thiazidesinhighdosescausingintensediuresiscan

inhibitthemilkproduction.TheuseofCandistPlusduringbreast-feedingisnotrecommended.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Whendrivingvehiclesor

operatingmachines,itshouldbetakenintoaccountthatoccasionallydizzinessorwearinessmayoccurduring

treatmentwithCandistPlus.

4.8Undesirableeffects

Incontrolledclinicalstudieswithcandesartancilexetil/hydrochlorothiazideadversereactionsweremildandtransient.

Withdrawalsfromtreatmentduetoadverseeventsweresimilarwithcandesartancilexetil/hydrochlorothiazide(2.3-

3.3%)andplacebo(2.7-4.3%).

Inclinicaltrialswithcandesartancilexetil/hydrochlorothiazide,adversereactionswerelimitedtothosethatwere

reportedpreviouslywithcandesartancilexetiland/orhydrochlorothiazide.

Thetablebelowpresentsadversereactionswithcandesartancilexetilfromclinicaltrialsandpostmarketingexperience.

Inapooledanalysisofclinicaltrialdataofhypertensivepatients,adversereactionswithcandesartancilexetilwere

definedbasedonanincidenceofadverseeventswithcandesartancilexetilatleast1%higherthantheincidenceseen

withplacebo.

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).

SystemOrganClass Frequency UndesirableEffect

Infectionsandinfestations Common Respiratoryinfection

Bloodandlymphaticsystemdisorders Veryrare Leukopenia,neutropenia

andagranulocytosis

Metabolismandnutritiondisorders Veryrare Hyperkalaemia,

hyponatraemia

Nervoussystemdisorders Common Dizziness/vertigo,

headache

Respiratory,thoracicandmediastinal

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Thetablebelowpresentsadversereactionswithhydrochlorothiazidemonotherapyusuallywithdosesof25mgor

Gastrointestinaldisorders Veryrare Nausea

Hepatobiliarydisorders Veryrare Increasedliverenzymes,

abnormalhepaticfunction

orhepatitis

Skinandsubcutaneoustissuedisorders Veryrare Angioedema,rash,

urticaria,pruritus

Musculoskeletalandconnectivetissue

disorders Veryrare Backpain,arthralgia,

myalgia

Renalandurinarydisorders Veryrare Renalimpairment,

includingrenalfailurein

susceptiblepatients(see

section4.4)

SystemOrganClass Frequency UndesirableEffect

Bloodandlymphaticsystemdisorders Rare Leukopenia,

neutropenia/agranulocytosis,

thrombocytopenia,aplastic

anaemia,bonemarrow

depression,haemolytic

anaemia

Immunesystemdisorders Rare Anaphylacticreactions

Metabolismandnutritiondisorders Common Hyperglycaemia,

hyperuricaemia,electrolyte

imbalance(including

hyponatraemiaand

hypokalaemia)

Psychiatricdisorders Rare Sleepdisturbances,

depression,restlessness

Nervoussystemdisorders Common Light-headedness,vertigo

Rare Paraesthesia

Eyedisorders Rare Transientblurredvision

Cardiacdisorders Rare Cardiacarrhythmias

Vasculardisorders Uncommon Posturalhypotension

Rare Necrotisingangiitis

(vasculitis,cutaneous

vasculitis)

Respiratory,thoracicandmediastinal

disorders Rare Respiratorydistress

(includingpneumonitis

andpulmonaryoedema)

Gastrointestinaldisorders Uncommon Anorexia,lossofappetite,

gastricirritation,diarrhoea,

constipation

Rare Pancreatitis

Hepatobiliarydisorders Rare Jaundice(intrahepatic

cholestaticjaundice)

Skinandsubcutaneoustissuedisorders Uncommon Rash,urticaria,

photosensitivityreactions

Rare Toxicepidermal

necrolysis,cutaneous

lupuserythaematosus-like

reactions,reactivationof

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4.9Overdose

Symptoms

Basedonpharmacologicalconsiderations,themainmanifestationofanoverdoseofcandesartancilexetilislikelytobe

symptomatichypotensionanddizziness.Inindividualcasereportsofoverdose(ofupto672mgcandesartancilexetil)

patientrecoverywasuneventful.

Themainmanifestationofanoverdoseofhydrochlorothiazideisacutelossoffluidandelectrolytes.Symptomssuchas

dizziness,hypotension,thirst,tachycardia,ventriculararrhythmias,sedation/impairmentofconsciousnessandmuscle

crampscanalsobeobserved.

Management

NospecificinformationisavailableonthetreatmentofoverdosewithCandistPlus.Thefollowingmeasuresare,

however,suggestedincaseofoverdose.

Whenindicated,inductionofvomitingorgastriclavageshouldbeconsidered.Ifsymptomatichypotensionshould

occur,symptomatictreatmentshouldbeinstitutedandvitalsignsmonitored.Thepatientshouldbeplacedsupinewith

thelegselevated.Ifthisisnotsufficient,plasmavolumeshouldbeincreasedbyinfusionofisotonicsalinesolution.

Serumelectrolyteandacidbalanceshouldbecheckedandcorrected,ifneeded.Sympathomimeticmedicinalproducts

maybeadministerediftheabove-mentionedmeasuresarenotsufficient.

Candesartancannotberemovedbyhaemodialysis.Itisnotknowntowhatextenthydrochlorothiazideisremovedby

haemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmaco-therapeuticgroup:AngiotensinIIantagonists+diuretics,ATCcode:C09DA06

AngiotensinIIistheprimaryvasoactivehormoneoftherenin-angiotensin-aldosteronesystemandplaysaroleinthe

pathophysiologyofhypertensionandothercardiovasculardisorders.Italsohasaroleinthepathogenesisoforgan

hypertrophyandendorgandamage.ThemajorphysiologicaleffectsofangiotensinII,suchasvasoconstriction,

aldosteronestimulation,regulationofsaltandwaterhomeostasisandstimulationofcellgrowth,aremediatedviathe

type1(AT1)receptor.

Candesartancilexetilisaprodrugwhichisrapidlyconvertedtotheactivedrug,candesartan,byesterhydrolysisduring

absorptionfromthegastrointestinaltract.CandesartanisanAIIRA,selectiveforAT1receptors,withtightbindingto

andslowdissociationfromthereceptor.Ithasnoagonistactivity.

erythaematosus

Musculoskeletalandconnectivetissue

disorders Rare Musclespasm

Renalandurinarydisorders Common Glycosuria

Rare Renaldysfunctionand

interstitialnephritis

Generaldisordersandadministrationsite

conditions Common Weakness

Rare Fever

Investigations Common Increasesincholesterol

andtriglycerides

Rare IncreasesinBUNand

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thereisnoeffectonthedegradationofkinins,oronthemetabolismofothersubstances,suchassubstanceP,AIIRAs

areunlikelytobeassociatedwithcough.IncontrolledclinicaltrialscomparingcandesartancilexetilwithACE

inhibitors,theincidenceofcoughwaslowerinpatientsreceivingcandesartancilexetil.Candesartandoesnotbindtoor

blockotherhormonereceptorsorionchannelsknowntobeimportantincardiovascularregulation.Theantagonismof

theAT1receptorsresultsindoserelatedincreasesinplasmareninlevels,angiotensinIandangiotensinIIlevels,anda

decreaseinplasmaaldosteroneconcentration.

Theeffectsofcandesartancilexetil8-16mg(meandose12mg)oncedailyoncardiovascularmorbidityandmortality

wereevaluatedinarandomisedclinicaltrialwith4,937elderlypatients(aged70-89years,21%aged80orabove)with

mildtomoderatehypertensionfollowedforameanof3.7years(StudyonCOgnitionandPrognosisintheElderly).

Patientsreceivedcandesartanorplacebowithotherantihypertensivetreatmentaddedasneeded.Thebloodpressure

wasreducedfrom166/90to145/80mmHginthecandesartangroup,andfrom167/90to149/82mmHginthecontrol

group.Therewasnostatisticallysignificantdifferenceintheprimaryendpoint,majorcardiovascularevents

(cardiovascularmortality,non-fatalstrokeandnon-fatalmyocardialinfarction).Therewere26.7eventsper1000

patient-yearsinthecandesartangroupversus30.0eventsper1000patient-yearsinthecontrolgroup(relativerisk0.89,

95%CI0.75to1.06,p=0.19).

Hydrochlorothiazideinhibitstheactivereabsorptionofsodium,mainlyinthedistalkidneytubules,andpromotesthe

excretionofsodium,chlorideandwater.Therenalexcretionofpotassiumandmagnesiumincreasesdose-dependently,

whilecalciumisreabsorbedtoagreaterextent.Hydrochlorothiazidedecreasesplasmavolumeandextracellularfluid

andreducescardiacoutputandbloodpressure.Duringlong-termtherapy,reducedperipheralresistancecontributesto

thebloodpressurereduction.

Largeclinicalstudieshaveshownthatlong-termtreatmentwithhydrochlorothiazidereducestheriskforcardiovascular

morbidityandmortality.

Candesartanandhydrochlorothiazidehaveadditiveantihypertensiveeffects.

Inhypertensivepatients,Candesartan/Hydrochlorothiazideresultsinadose-dependentandlong-lastingreductionin

arterialbloodpressurewithoutreflexincreaseinheartrate.Thereisnoindicationofseriousorexaggeratedfirstdose

hypotensionorreboundeffectaftercessationoftreatment.AfteradministrationofasingledoseofCandesartan/

Hydrochlorothiazide,onsetoftheantihypertensiveeffectgenerallyoccurswithin2hours.Withcontinuoustreatment,

mostofthereductioninbloodpressureisattainedwithinfourweeksandissustainedduringlong-termtreatment.

Candesartan/Hydrochlorothiazideoncedailyprovideseffectiveandsmoothbloodpressurereductionover24hours,

withlittledifferencebetweenmaximumandtrougheffectsduringthedosinginterval.Inadouble-blindrandomised

study,Candesartan/Hydrochlorothiazide16mg/12.5mgoncedailyreducedbloodpressuresignificantlymore,and

controlledsignificantlymorepatients,thanthecombinationlosartan/hydrochlorothiazide50mg/12.5mgoncedaily.

Indouble-blind,randomisedstudies,theincidenceofadverseevents,especiallycough,waslowerduringtreatment

withCandesartan/HydrochlorothiazidethanduringtreatmentwithcombinationsofACEinhibitorsand

hydrochlorothiazide.

Intwoclinicalstudies(randomised,double-blind,placebocontrolled,parallelgroup)including275and1524

randomisedpatients,respectively,thecandesartancilexetil/hydrochlorothiazidecombinations32mg/12.5mgand32

mg/25mgresultedinbloodpressurereductionsof22/15mmHgand21/14mmHg,respectively,andweresignificantly

moreeffectivethantherespectivemonocomponents.

Inarandomised,double-blind,parallelgroupclinicalstudyincluding1975randomisedpatientsnotoptimally

controlledon32mgcandesartancilexetiloncedaily,theadditionof12.5mgor25mghydrochlorothiazideresultedin

additionalbloodpressurereductions.Thecandesartancilexetil/hydrochlorothiazidecombination32mg/25mgwas

significantlymoreeffectivethanthe32mg/12.5mgcombination,andtheoverallmeanbloodpressurereductionswere

16/10mmHgand13/9mmHg,respectively.

Candesartancilexetil/hydrochlorothiazideissimilarlyeffectiveinpatientsirrespectiveofageandgender.

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disease/nephropathy,reducedleftventricularfunction/congestiveheartfailureandpostmyocardialinfarction.

5.2Pharmacokineticproperties

Concomitantadministrationofcandesartancilexetilandhydrochlorothiazidehasnoclinicallysignificanteffectonthe

pharmacokineticsofeithermedicinalproduct.

Absorptionanddistribution

Candesartancilexetil

Followingoraladministration,candesartancilexetilisconvertedtotheactivesubstancecandesartan.Theabsolute

bioavailabilityofcandesartanisapproximately40%afteranoralsolutionofcandesartancilexetil.Therelative

bioavailabilityofatabletformulationofcandesartancilexetilcomparedwiththesameoralsolutionisapproximately

34%withverylittlevariability.Themeanpeakserumconcentration(Cmax)isreached3-4hoursfollowingtablet

intake.Thecandesartanserumconcentrationsincreaselinearlywithincreasingdosesinthetherapeuticdoserange.No

genderrelateddifferencesinthepharmacokineticsofcandesartanhavebeenobserved.Theareaundertheserum

concentrationversustimecurve(AUC)ofcandesartanisnotsignificantlyaffectedbyfood.

Candesartanishighlyboundtoplasmaprotein(morethan99%).Theapparentvolumeofdistributionofcandesartanis

0.1l/kg.

Hydrochlorothiazide

Hydrochlorothiazideisrapidlyabsorbedfromthegastrointestinaltractwithanabsolutebioavailabilityof

approximately70%.Concomitantintakeoffoodincreasestheabsorptionbyapproximately15%.Thebioavailability

maydecreaseinpatientswithcardiacfailureandpronouncedoedema.

Theplasmaproteinbindingofhydrochlorothiazideisapproximately60%.Theapparentvolumeofdistributionis

approximately0.8l/kg.

Biotransformationandelimination

Candesartancilexetil

Candesartanismainlyeliminatedunchangedviaurineandbileandonlytoaminorextenteliminatedbyhepatic

metabolism(CYP2C9).AvailableinteractionstudiesindicatenoeffectonCYP2C9andCYP3A4.Basedoninvitro

data,nointeractionwouldbeexpectedtooccurinvivowithmedicinalproductswhosemetabolismisdependentupon

cytochromeP450isoenzymesCYP1A2,CYP2A6,CYP2C9,CYP2C19,CYP2D6,CYP2E1orCYP3A4.Theterminal

half-life(t½)ofcandesartanisapproximately9hours.Thereisnoaccumulationfollowingmultipledoses.Thehalf-life

ofcandesartanremainsunchanged(approximately9h)afteradministrationofcandesartancilexetilincombinationwith

hydrochlorothiazide.Noadditionalaccumulationofcandesartanoccursafterrepeateddosesofthecombination

comparedtomonotherapy.

Totalplasmaclearanceofcandesartanisabout0.37ml/min/kg,witharenalclearanceofabout0.19ml/min/kg.The

renaleliminationofcandesartanisbothbyglomerularfiltrationandactivetubularsecretion.Followinganoraldoseof

14C-labelledcandesartancilexetil,approximately26%ofthedoseisexcretedintheurineascandesartanand7%asan

inactivemetabolitewhileapproximately56%ofthedoseisrecoveredinthefaecesascandesartanand10%asthe

inactivemetabolite.

Hydrochlorothiazide

Hydrochlorothiazideisnotmetabolisedandisexcretedalmostentirelyasunchangeddrugbyglomerularfiltrationand

activetubularsecretion.Theterminalt½ofhydrochlorothiazideisapproximately8hours.Approximately70%ofan

oraldoseiseliminatedintheurinewithin48hours.Thehalf-lifeofhydrochlorothiazideremainsunchanged

(approximately8h)afteradministrationofhydrochlorothiazideincombinationwithcandesartancilexetil.No

additionalaccumulationofhydrochlorothiazideoccursafterrepeateddosesofthecombinationcomparedto

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Pharmacokineticsinspecialpopulations

Candesartancilexetil

Inelderlysubjects(over65years),CmaxandAUCofcandesartanareincreasedbyapproximately50%and80%,

respectivelyincomparisontoyoungsubjects.However,thebloodpressureresponseandtheincidenceofadverse

eventsaresimilarafteragivendoseofCandesartan/Hydrochlorothiazideinyoungandelderlypatients(seesection

4.2).

Inpatientswithmildtomoderaterenalimpairment,CmaxandAUCofcandesartanincreasedduringrepeateddosing

byapproximately50%and70%,respectively,buttheterminalt½wasnotaltered,comparedtopatientswithnormal

renalfunction.Thecorrespondingchangesinpatientswithsevererenalimpairmentwereapproximately50%and

110%,respectively.Theterminalt½ofcandesartanwasapproximatelydoubledinpatientswithsevererenal

impairment.Thepharmacokineticsinpatientsundergoinghaemodialysisweresimilartothoseinpatientswithsevere

renalimpairment.

Intwostudies,bothincludingpatientswithmildtomoderatehepaticimpairment,therewasanincreaseinthemean

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

experienceinpatientswithseverehepaticimpairment.

Hydrochlorothiazide

Theterminalt½ofhydrochlorothiazideisprolongedinpatientswithrenalimpairment.

5.3Preclinicalsafetydata

Therewerenoqualitativenewtoxicfindingswiththecombinationcomparedtothatobservedforeachcomponent.In

preclinicalsafetystudiescandesartanitselfhadeffectsonthekidneysandonredcellparametersathighdosesinmice,

rats,dogsandmonkeys.Candesartancausedareductionofredbloodcellparameters(erythrocytes,haemoglobin,

haematocrit).Effectsonthekidneys(suchasregeneration,dilatationandbasophiliaintubules;increasedplasma

concentrationsofureaandcreatinine)wereinducedbycandesartanwhichcouldbesecondarytothehypotensiveeffect

leadingtoalterationsofrenalperfusion.Additionofhydrochlorothiazidepotentiatesthenephrotoxicityofcandesartan.

Furthermore,candesartaninducedhyperplasia/hypertrophyofthejuxtaglomerularcells.

Thesechangeswereconsideredtobecausedbythepharmacologicalactionofcandesartanandtobeoflittleclinical

relevance.

Foetotoxicityhasbeenobservedinlatepregnancywithcandesartan.Theadditionofhydrochlorothiazidedidnot

significantlyaffecttheoutcomeoffoetaldevelopmentstudiesinrats,miceorrabbits(seesection4.6).

Candesartanandhydrochlorothiazidebothshowgenotoxicactivityatveryhighconcentrations/doses.Datafromin

vitroandinvivogenotoxicitytestingindicatethatcandesartanandhydrochlorothiazideareunlikelytoexertany

mutagenicorclastogenicactivityunderconditionsofclinicaluse.

Therewasnoevidencethateithercompoundiscarcinogenic.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

Hydroxypropylcellulose

Croscarmellosesodium

Magnesiumstearate

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6.2Incompatibilities

Notapplicable

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Donotstoreabove25°C

6.5Natureandcontentsofcontainer

PVC-PVDC/Alublister

Packsizes:7,10,14,28,30,56,98,100tablets

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

ClonmelHealthcareLtd,

WaterfordRoad,

Clonmel,

Co.Tipperary

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA126/207/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:21stOctober2011

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