ATACAND PLUS

Main information

  • Trade name:
  • ATACAND PLUS
  • Dosage:
  • 16/ 12.5 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

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

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1447/037/001
  • Authorization date:
  • 28-08-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AtacandPlus16/12.5mgtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

OneAtacandPlustabletcontains16mgcandesartancilexetiland12.5mghydrochlorothiazide.

Eachtabletcontainslactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablets

ProductimportedfromGreece:

AtacandPlusarepeach,oval,biconvextabletswithascoreonbothsidesandengravedA/CSononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

AtacandPlusisindicatedforthe:

Treatmentofessentialhypertensioninadultpatientswhosebloodpressureisnotoptimallycontrolledwith

candersartancilexetilorhydrochlorothiazidemonotherapy.

4.2Posologyandmethodofadministration

Posology

TherecommendeddoseofAtacandPlusisonetabletoncedaily.

Dosetitrationwiththeindividualcomponents(candesartancilexetilandhydrochlorothiazide)isrecommended.When

clinicallyappropriateadirectchangefrommonotherapytoAtacandPlusmaybeconsidered.Dosetitrationof

candesartancilexetilisrecommendedwhenswitchingfromhydrochlorothiazidemonotherapy.AtacandPlusmaybe

administeredinpatientswhosebloodpressureisnotoptimallycontrolledwithcandesartancilexetilor

hydrochlorothiazidemonotherapyorAtacandPlusatlowerdoses.

Mostoftheantihypertensiveeffectisusuallyattainedwithin4weeksofinitiationoftreatment.

Specialpopulations

Elderlypopulation

Nodoseadjustmentisnecessaryinelderlypatients.

Patientswithintravascularvolumedepletion

Dosetitrationofcandesartancilexetilisrecommendedinpatientsatriskforhypotension,suchaspatientswithpossible

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2103060 page number: 1

Patientswithrenalimpairment

Loopdiureticsarepreferredtothiazidesinthispopulation.Dosetitrationofcandesartancilexetilisrecommendedin

patientswithmildtomoderaterenalimpairment(creatinineclearance30ml/min/1.73m 2

BodySurfaceArea(BSA))

beforetreatmentwithAtacandPlus(therecommendedstartingdoseofcandesartancilexetilis4mginthesepatients).

AtacandPlusiscontraindicatedinpatientswithsevererenalimpairment(creatinineclearance<30ml/min/1.73m 2

BSA)(seesection4.3).

Patientswithhepaticimpairment

Dosetitrationofcandesartancilexetilisrecommendedinpatientswithmildtomoderatehepaticimpairmentbefore

treatmentwithAtacandPlus(therecommendedstartingdoseofcandesartancilexetilis4mginthesepatients).

AtacandPlusiscontraindicatedinpatientswithseverehepaticimpairmentand/orcholestasis(seesection4.3).

Paediatricpopulation

ThesafetyandefficacyofAtacandPlusinchildrenagedbetweenbirthand18yearshavenotbeenestablished.Nodata

areavailable.

Methodofadministration

Oraluse.

AtacandPluscanbetakenwithorwithoutfood.

Thebioavailabilityofcandesartanisnotaffectedbyfood.

Thereisnoclinicallysignificantinteractionbetweenhydrochlorothiazideandfood.

4.3Contraindications

Hypersensitivitytotheactivesubstancesortoanyoftheexcipientsortosulfonamidederivedactive

substances.Hydrochlorothiazideisasulfonamidederivedactivesubstances.

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6)

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

Severehepaticimpairmentand/orcholestasis.

Refractoryhypokalaemiaandhypercalcaemia.

Gout.

4.4Specialwarningsandprecautionsforuse

Renalimpairment/Kidneytransplantation

Loopdiureticsarepreferredtothiazidesinthispopulation.WhenAtacandPlusisusedinpatientswithimpairedrenal

function,aperiodicmonitoringofpotassium,creatinineanduricacidlevelsisrecommended.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2103060 page number: 2

Renalarterystenosis

Medicinalproductsthataffecttherenin-angiotensin-aldosteronesystem,includingangiotensinIIreceptorantagonists

(AIIRAs),mayincreasebloodureaandserumcreatinineinpatientswithbilateralrenalarterystenosisorstenosisofthe

arterytoasolitarykidney.

Intravascularvolumedepletion

Inpatientswithintravascularvolumeand/orsodiumdepletionsymptomatichypotensionmayoccur,asdescribedfor

otheragentsactingontherenin-angiotensin-aldosteronesystem.Therefore,theuseofAtacandPlusisnot

recommendeduntilthisconditionhasbeencorrected.

Anaesthesiaandsurgery

HypotensionmayoccurduringanaesthesiaandsurgeryinpatientstreatedwithAIIRAsduetoblockadeoftherenin-

angiotensinsystem.Veryrarely,hypotensionmaybeseveresuchthatitmaywarranttheuseofintravenousfluids

and/orvasopressors.

Hepaticimpairment

Thiazidesshouldbeusedwithcautioninpatientswithimpairedhepaticfunctionorprogressiveliverdisease,since

minoralterationsoffluidandelectrolytebalancemayprecipitatehepaticcoma.Thereisnoclinicalexperiencewith

AtacandPlusinpatientswithhepaticimpairment.

Aorticandmitralvalvestenosis(obstructivehypertrophiccardiomyopathy)

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromhaemodynamicallyrelevantaorticor

mitralvalvestenosis,orobstructivehypertrophiccardiomyopathy.

Primaryhyperaldosteronism

Patientswithprimaryhyperaldosteronismgenerallywillnotrespondtoantihypertensivedrugsactingthrough

inhibitionoftherenin-angiotensin-aldosteronesystem.ThereforetheuseofAtacandPlusisnotrecommended.

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.ConcomitantuseofAtacandPlusandpotassium-sparingdiuretics,potassiumsupplementsorsalt

substitutesorothermedicinalproductsthatmayincreaseserumpotassiumlevels(e.g.heparinsodium)mayleadto

increasesinserumpotassium.Monitoringofpotassiumshouldbeundertakenasappropriate.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2103060 page number: 3

Metabolicandendocrineeffects

Treatmentwithathiazidediureticmayimpairglucosetolerance.Doseadjustmentofantidiabeticmedicinalproducts,

includinginsulin,mayberequired.Latentdiabetesmellitusmaybecomemanifestduringthiazidetherapy.Increasesin

cholesterolandtriglyceridelevelshavebeenassociatedwiththiazidediuretictherapy.Atthedosescontainedin

AtacandPlus,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

asthma,butaremorelikelyinpatientswithsuchahistory.

Exacerbationoractivationofsystemiclupuserythematosushasbeenreportedwiththeuseofthiazidediuretics.

TheantihypertensiveeffectofAtacandPlusmaybeenhancedbyotherantihypertensives.

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).

ConcomitantuseofAtacandPlusandpotassium-sparingdiuretics,potassiumsupplementsorsaltsubstitutesorother

medicinalproductsthatmayincreaseserumpotassiumlevels(e.g.heparinsodium)mayleadtoincreasesinserum

potassium.Monitoringofpotassiumshouldbeundertakenasappropriate(seesection4.4).

Diuretic-inducedhypokalaemiaandhypomagnesaemiapredisposestothepotentialcardiotoxiceffectsofdigitalis

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2103060 page number: 4

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),attenuationoftheantihypertensiveeffect

mayoccur.

AswithACEinhibitors,concomitantuseofAIIRAsandNSAIDsmayleadtoanincreasedriskofworseningofrenal

function,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyinpatientswithpoor

pre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyintheelderly.Patients

shouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunctionafterinitiationof

concomitanttherapy,andperiodicallythereafter.

Thediuretic,natriureticandantihypertensiveeffectofhydrochlorothiazideisbluntedbyNSAIDs.

Theabsorptionofhydrochlorothiazideisreducedbycolestipolorcholestyramine.

Theeffectonnondepolarizingskeletalmusclerelaxants(e.g.tubocurarine)maybepotentiatedbyhydrochlorothiazide.

Thiazidediureticsmayincreaseserumcalciumlevelsduetodecreasedexcretion.IfcalciumsupplementsorVitaminD

mustbeprescribed,serumcalciumlevelsshouldbemonitoredanddosageadjustedaccordingly.

Thehyperglycaemiceffectofbeta-blockersanddiazoxidemaybeenhancedbythiazides.

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

decreasinggastrointestinalmotilityandstomachemptyingrate.

Thiazidemayincreasetheriskofadverseeffectscausedbyamantadine.

Thiazidesmayreducetherenalexcretionofcytotoxicmedicinalproducts(e.g.cyclophosphamide,methotrexate)and

potentiatetheirmyelosuppressiveeffects.

Posturalhypotensionmaybecomeaggravatedbysimultaneousintakeofalcohol,barbituratesoranaesthetics.

Treatmentwithathiazidediureticmayimpairglucosetolerance.Dosageadjustmentofantidiabeticmedicinal

products,includinginsulin,mayberequired.Metforminshouldbeusedwithcautionbecauseoftheriskoflactic

acidosisinducedbypossiblefunctionalrenalfailurelinkedtohydrochlorothiazide.

Hydrochlorothiazidemaycausethearterialresponsetopressoramines(e.g.adrenaline)todecreasebutnotenoughto

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2103060 page number: 5

Hydrochlorothiazidemayincreasetheriskofacuterenalinsufficiencyespeciallywithhighdosesofiodinatedcontrast

media.

Concomitanttreatmentwithcyclosporinemayincreasetheriskofhyperuricaemiaandgout-typecomplications.

Concomitanttreatmentwithbaclofen,amifostin,tricyclicantidepressantsorneurolepticsmayleadtoenhancementof

theantihypertensiveeffectandmayinducehypotension.

4.6Fertility,pregnancyandlactation

Pregnancy

AngiotensinIIReceptorAntagonists(AIIRAs):

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.

InfantswhosemothershavetakenAIIRAsshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Hydrochlorothiazide:

Thereislimitedexperiencewithhydrochlorothiazideduringpregnancy,especiallyduringthefirsttrimester.Animal

studiesareinsufficient.

Hydrochlorothiazidecrossestheplacenta.Basedonthepharmacologicalmechanismofactionofhydrochlorothiazide

itsuseduringthesecondandthirdtrimestersmaycompromisefoeto-placentalperfusionandmaycausefoetaland

neonataleffectslikeicterus,disturbanceofelectrolytebalanceandthrombocytopenia.

Hydrochlorothiazideshouldnotbeusedforgestationaloedema,gestationalhypertensionorpreeclampsiaduetothe

riskofdecreasedplasmavolumeandplacentalhypoperfusion,withoutabeneficialeffectonthecourseofthedisease.

Hydrochlorothiazideshouldnotbeusedforessentialhypertensioninpregnantwomenexceptinraresituationswhere

noothertreatmentcouldbeused.

Lactation

AngiotensinIIReceptorAntagonists(AIIRAs):

TheuseofAIIRAsisnotrecommendedduringthefirsttrimesterofpregnancy(see

section4.4).TheuseofAIIRAsiscontraindicatedduringthesecondandthird

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2103060 page number: 6

recommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

Hydrochlorothiazide:

Hydrochlorothiazideisexcretedinhumanmilkinsmallamounts.Thiazidesinhighdosescausingintensediuresiscan

inhibitthemilkproduction.TheuseofAtacandPlusduringbreast-feedingisnotrecommended.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.Whendrivingvehiclesor

operatingmachines,itshouldbetakenintoaccountthatoccasionallydizzinessorwearinessmayoccurduring

treatmentwithAtacandPlus.

4.8Undesirableeffects

Incontrolledclinicalstudieswithcandesartancilexetil/hydrochlorothiazideadverseeventsweremildandtransient.

Withdrawalsfromtreatmentduetoadverseeventsweresimilarwithcandesartancilexetil/hydrochlorothiazide(2.3-

3.3%)andplacebo(2.7–4.3%).

Inclinicaltrialswithcandesartancilexetil/hydrochlorothiazide,adversereactionswerelimitedtothosethatwere

reportedpreviouslywithcandesartancilexetiland/orhydrochlorothiazide.

Thetablebelowpresentsadversereactionswithcandesartancilexetilfromclinicaltrialsandpostmarketingexperience.

Inapooledanalysisofclinicaltrialdataofhypertensivepatients,adversereactionswithcandesartancilexetilwere

definedbasedonanincidenceofadverseeventswithcandesartancilexetilatleast1%higherthantheincidenceseen

withplacebo.

Thefrequenciesusedinthetablesthroughoutthissection4.8are:verycommon(>1/10)common(>1/100to<1/10),

uncommon(>1/1000to<1/100),rare(>1/10000to<1/1000)andveryrare(<1/10000):

SystemOrganClass Frequency UndesirableEffect

Infectionsandinfestations Common Respiratoryinfection

Bloodandlymphaticsystem

disorders Veryrare Leukopena,neutropeniaand

agranulocytosis

Metabolismandnutrition

disorders Veryrare Hyperkalaemia,

hyponatraemia

Nervoussystemdisorders Common Dizziness/vertigo,headache

Respiratory,thoracicand

mediastinaldisorders Veryrare Cough

Gastrointestinaldisorders Veryrare Nausea

Hepatobiliarydisorders Veyrare Increasedliverenzyme,

abnormalhepaticfunctionor

hepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,uticaria,

pruritus

Muskuloskeletal,connective

tissueandbonedisorders Veryrare Backpain,arthralgia,

myalgia

Renalandurinarydisorders Veryrare Renalimpairment,including

renalfailureinsusceptible

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2103060 page number: 7

Thetablebelowpresentsadversereactionswithhydrochlorothiazidemonotherapyusuallywithdosesof25mgor

higher.

SystemOrganClass Frequency UndesirableEffects

BloodandlymphaticSytem

disorders Rare Leucopenia,

neutropenia/agranulocytosis,

thrombocytopenia,aplastic

anaemia,bonemarrow

depression,haemolytic

anaemia

ImmuneSystemdisorders Rare Anaphylacticreactions

Metabolismandnutrition

disorders Common Hyperglycaemia,

hyperruricaemia,electrolyte

imbalance(including

hyponatraemiaand

hypokalaemia

Psychiatricdisorders Rare Sleepdisturbances,

depression,restlessness

Nervoussystemdisorders Common Light-headedness,vertigo

Rare Paraesthesia

Eyedisorders Rare Transientblurredvision

Cardiacdisorders Rare Cardiacarrhytmias

Vasculardisorders Uncommon Posturalhypotension

Rare Necrotisingangiitis

(vasculitis,cutaneous

vasculitis)

Respiratory,thorasicand

mediastinaldisorders Rare Respiratorydistress

(includingpneumonitisand

pulmonaryoedema)

Gastrointestinaldisorders Uncommon Anorexia,lossofappetite,

gastricirritation,diarrhoea,

constipation

Rare Pancreatitis

Hepatobiliarydisorders Rare Jaundice(intrahepatic

cholestaticjaundice)

Skinandsubcutaneoustissue

disorders Uncommon Rash,uticaria,

photosensitivityreactions

Rare Toxicepidermalnecrolysis,

cutaneouslupus

erythematosus-likereactions,

reactivationofcutaneous

lupuserythematosus

Musculoskeletal,connective

tissueandbonedisorders Rare Musclespasm

Renalandurinarydisorders Common Glycosuria

Rare Renaldysfunctionand

interstitialnephritis

Generaldisordersand

administrationsiteconditions Common Weakness

Rare Fever

Investigations Common Increaseincholesteroland

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2103060 page number: 8

4.9Overdose

Symptoms

Basedonpharmacologicalconsiderations,themainmanifestationofanoverdoseofcandesartancilexetilislikelytobe

symptomatichypotensionanddizziness.Inindividualcasereportsofoverdose(ofupto672mgcandesartancilexetil)

patientrecoverywasuneventful.

Themainmanifestationofanoverdoseofhydrochlorothiazideisacutelossoffluidandelectrolytes.Symptomssuchas

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

crampscanalsobeobserved.

Management

NospecificinformationisavailableonthetreatmentofoverdosagewithAtacandPlus.Thefollowingmeasuresare,

however,suggestedincaseofoverdosage.

Whenindicated,inductionofvomitingorgastriclavageshouldbeconsidered.Ifsymptomatichypotensionshould

occur,symptomatictreatmentshouldbeinstitutedandvitalsignsmonitored.Thepatientshouldbeplacedsupinewith

thelegselevated.Ifthisisnotsufficient,plasmavolumeshouldbeincreasedbyinfusionofisotonicsalinesolution.

Serumelectrolyteandacidbalanceshouldbecheckedandcorrected,ifneeded.Sympathomimeticmedicinalproducts

maybeadministerediftheabove-mentionedmeasuresarenotsufficient.

Candesartancannotberemovedbyhaemodialysis.Itisnotknowntowhatextenthydrochlorothiazideisremovedby

haemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmaco-therapeuticgroup:AngiotensinIIantagonists+diuretics,ATCcodeC09DA06.

AngiotensinIIistheprimaryvasoactivehormoneoftherenin-angiotensin-aldosteronesystemandplaysaroleinthe

pathophysiologyofhypertensionandothercardiovasculardisorders.Italsohasaroleinthepathogenesisoforgan

hypertrophyandendorgandamage.ThemajorphysiologicaleffectsofangiotensinII,suchasvasoconstriction,

aldosteronestimulation,regulationofsaltandwaterhomeostasisandstimulationofcellgrowth,aremediatedviathe

type1(AT

)receptor.

Candesartancilexetilisaprodrugwhichisrapidlyconvertedtotheactivedrug,candesartan,byesterhydrolysisduring

absorptionfromthegastrointestinaltract.CandesartanisanAIIRA,selectiveforAT1receptors,withtightbindingto

andslowdissociationfromthereceptor.Ithasnoagonistactivity.

CandesartandoesnotinfluenceACEorotherenzymesystemsusuallyassociatedwiththeuseofACEinhibitors.Since

thereisnoeffectonthedegradationofkinins,oronthemetabolismofothersubstances,suchassubstanceP,AIIRAs

areunlikelytobeassociatedwithcough.IncontrolledclinicaltrialscomparingcandesartancilexetilwithACE

inhibitors,theincidenceofcoughwaslowerinpatientsreceivingcandesartancilexetil.Candesartandoesnotbindtoor

blockotherhormonereceptorsorionchannelsknowntobeimportantincardiovascularregulation.Theantagonismof

theAT

receptorsresultsindoserelatedincreasesinplasmareninlevels,angiotensinIandangiotensinIIlevels,anda

Rare IncreaseBUNandserum

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2103060 page number: 9

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).

Hydrochlorothiazideinhibitstheactivere-absorptionofsodium,mainlyinthedistalkidneytubules,andpromotesthe

excretionofsodium,chlorideandwater.Therenalexcretionofpotassiumandmagnesiumincreasesdose-dependently,

whilecalciumisreabsorbedtoagreaterextent.Hydrochlorothiazidedecreasesplasmavolumeandextracellularfluid

andreducescardiacoutputandbloodpressure.Duringlong-termtherapy,reducedperipheralresistancecontributesto

thebloodpressurereduction.

Largeclinicalstudieshaveshownthatlong-termtreatmentwithhydrochlorothiazidereducestheriskforcardiovascular

morbidityandmortality.

Candesartanandhydrochlorothiazidehaveadditiveantihypertensiveeffects.

Inhypertensivepatients,AtacandPlusresultinadose-dependentandlong-lastingreductioninarterialbloodpressure

withoutreflexincreaseinheartrate.Thereisnoindicationofseriousorexaggeratedfirstdosehypotensionorrebound

effectaftercessationoftreatment.AfteradministrationofasingledoseofAtacandPlus,onsetoftheantihypertensive

effectgenerallyoccurswithin2hours.Withcontinuoustreatment,mostofthereductioninbloodpressureisattained

withinfourweeksandissustainedduringlong-termtreatment.AtacandPlusoncedailyprovideseffectiveandsmooth

bloodpressurereductionover24hours,withlittledifferencebetweenmaximumandtrougheffectsduringthedosing

interval.Inadouble-blindrandomisedstudy,AtacandPlus16mg/12.5mgoncedailyreducedbloodpressure

significantlymore,andcontrolledsignificantlymorepatients,thanthecombinationlosartan/hydrochlorothiazide50

mg/12.5mgoncedaily.

Indouble-blind,randomisedstudies,theincidenceofadverseevents,especiallycough,waslowerduringtreatment

withAtacandPlusthanduringtreatmentwithcombinationsofACEinhibitorsandhydrochlorothiazide.

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.

Currentlytherearenodataontheuseofcandesartancilexetil/hydrochlorothiazideinpatientswithrenal

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2103060 page number: 10

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

C-labelledcandesartancilexetil,approximately26%ofthedoseisexcretedintheurineascandesartanand7%asan

inactivemetabolitewhileapproximately56%ofthedoseisrecoveredinthefaecesascandesartanand10%asthe

inactivemetabolite.

Hydrochlorothiazide

Hydrochlorothiazideisnotmetabolizedandisexcretedalmostentirelyasunchangeddrugbyglomerularfiltrationand

activetubularsecretion.Theterminalt½ofhydrochlorothiazideisapproximately8hours.Approximately70%ofan

oraldoseiseliminatedintheurinewithin48hours.Thehalf-lifeofhydrochlorothiazideremainsunchanged

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2103060 page number: 11

additionalaccumulationofhydrochlorothiazideoccursafterrepeateddosesofthecombinationcomparedto

monotherapy.

Pharmacokineticsinspecialpopulations

Candesartancilexetil

Inelderlysubjects(over65years),CmaxandAUCofcandesartanareincreasedbyapproximately50%and80%,

respectivelyincomparisontoyoungsubjects.However,thebloodpressureresponseandtheincidenceofadverse

eventsaresimilarafteragivendoseofAtacandPlusinyoungandelderlypatients(seesection4.2).

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.Thesechangeswere

consideredtobecausedbythepharmacologicalactionofcandesartanandtobeoflittleclinicalrelevance.

Foetotoxicityhasbeenobservedinlatepregnancywithcandesartan.Theadditionofhydrochlorothiazidedidnot

significantlyaffecttheoutcomeoffoetaldevelopmentstudiesinrats,miceorrabbits(seesection4.6).

Candesartanandhydrochlorothiazidebothshowgenotoxicactivityatveryhighconcentrations/doses.Datafromin

vitroandinvivogenotoxicitytestingindicatethatcandesartanandhydrochlorothiazideareunlikelytoexertany

mutagenicorclastogenicactivityunderconditionsofclinicaluse.

Therewasnoevidencethateithercompoundiscarcinogenic.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Carmellosecalcium

Hydroxypropycellulose

Ironoxidereddish-brown(E172)

Ironoxideyellow(E172)

Lactosemonohydrate

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2103060 page number: 12

Maizestarch

Macrogol

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateofthisproductisthedateshownontheblisterfoilandtheoutercartonoftheproductas

marketedinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30 o

6.5Natureandcontentsofcontainer

Blisterpacksof14tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

G&ALicensingLtd.

Ballymurray

Co.Roscommon

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1447/037/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28thAugust2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2103060 page number: 13