ATACAND PLUS 16/ 12.5MG TABLETS

Main information

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

Documents

Localization

  • Available in:
  • ATACAND PLUS 16/12.5MG TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/117/001A
  • Authorization date:
  • 26-01-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AtacandPlus16/12.5mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains16mgcandesartancilexetiland12.5mghydrochlorothiazide.

Excipients:ContainsLactoseMonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

ProductimportedfromtheNetherlands:

Peach,oval,biconvextabletsmarked‘A/CS’ononesideandscoredonbothsides.

ProductimportedfromItaly:

Pink,ovaltabletsmarked16/CandscoredonbothsidesorPeach,ovalbiconvextabletsmarkedA/CSononesideand

scoredonbothsides.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Essentialhypertension,wheremonotherapywithcandesartancilexetilorhydrochlorothiazideisnotsufficient.

4.2Posologyandmethodofadministration

Dosage

TherecommendeddoseofAtacandPlusis1tabletoncedaily.Thedoseofcandesartancilexetilshouldbetitrated

beforeswitchingtoAtacandPlus.

WhenclinicallyappropriateadirectchangefrommonotherapytoAtacandPlusmaybeconsidered.

Mostoftheantihypertensiveeffectisusuallyattainedwithin4weeksofinitiationoftreatment.

Administration

AtacandPlusshouldbetakenoncedailywithorwithoutfood.

Useintheelderly

Noinitialdosageadjustmentisnecessaryinelderlypatients.

Useinpatientswithintravascularvolumedepletion

Dosetitrationofcandesartancilexetilisrecommendedinpatientsatriskforhypotension,suchaspatientswithpossible

volumedepletion(aninitialdoseofcandesartancilexetilof4mgmaybeconsideredinthesepatients).

Useinimpairedrenalfunction

Nodosageadjustmentisnecessaryinpatientswithmildrenalimpairment.Inpatientswithmoderatetosevererenal

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tolimitedexperience,AtacandPlusshouldnotbeusedinpatientswithsevererenalimpairment(Cl

creatinine <30

ml/min/1.73m 2

BSA).

Useinimpairedhepaticfunction

Dosetitrationofcandesartancilexetilisrecommendedinpatientswithmildtomoderatehepaticimpairmentbefore

treatmentwithAtacandPlus(therecommendedstartingdoseofcandesartancilexetilis2mginthesepatients).Atacand

Plusshouldnotbeusedinpatientswithseverehepaticimpairmentand/orcholestasis.

Useinchildren

ThesafetyandefficacyofAtacandPlushavenotbeenestablishedinchildren.

4.3Contraindications

HypersensitivitytotheactiveingredientsofAtacandPlusortosulfonamidederiveddrugs(hydrochlorothiazideisa

sulfonamidederiveddrug)ortoanyoftheexcipients.

Pregnancyandlactation(seesection4.6PregnancyandLactation).

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

BSA).

Severehepaticimpairmentand/orcholestasis.

Refractoryhypokalaemiaandhypercalcaemia.

Gout.

4.4Specialwarningsandprecautionsforuse

Renalimpairment/Kidneytransplantation

Loopdiureticsarepreferredtothiazidesinthispopulation.WhenAtacandPlusisusedinpatientswithrenal

impairment,periodicmonitoringofpotassium,creatinineanduricacidlevelsisrecommended.Thereisnoexperience

regardingtheadministrationofAtacandPlusinpatientswitharecentkidneytransplantation.

Renalarterystenosis

Otherdrugsthataffecttherenin-angiotensin-aldosteronesystem,i.e.angiotensinconvertingenzyme(ACE)inhibitors,

mayincreasebloodureaandserumcreatinineinpatientswithbilateralrenalarterystenosisorstenosisofthearterytoa

solitarykidney.AsimilareffectmaybeanticipatedwithangiotensinIIreceptorantagonists.

Intravascularvolumedepletion

Inpatientswithintravascularvolumeand/orsodiumdepletionsymptomatichypotensionmayoccur,asdescribedfor

otheragentsactingontherenin-angiotensin-aldosteronesystem.Therefore,theuseofAtacandPlusisnot

recommendeduntilthisconditionhasbeencorrected.

Hepaticimpairment

Thiazidesshouldbeusedwithcautioninpatientswithimpairedhepaticfunctionorprogressiveliverdisease,since

minoralterationsoffluidandelectrolytebalancemayprecipitatehepaticcoma.Thereisnoclinicalexperiencewith

AtacandPlusinpatientswithhepaticimpairment.

Aorticandmitralvalvestenosis(obstructivehypertrophiccardiomyopathy)

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromhaemodynamicallyrelevantaorticor

mitralvalvestenosis,orobstructivehypertrophiccardiomyopathy.

Primaryhyperaldosteronism

Patientswithprimaryhyperaldosteronismwillnotgenerallyrespondtoantihypertensivedrugsactingthrough

inhibitionoftherenin-angiotensin-aldosteronesystem.ThereforetheuseofAtacandPlusisnotrecommended.

Electrolyteimbalance

Asforanypatientreceivingdiuretictherapy,periodicdeterminationofserumelectrolytesshouldbeperformedat

appropriateintervals.

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hyponatraemia,hypomagnesaemiaandhypochloraemicalkalosis).

Thiazidediureticsmaydecreasetheurinarycalciumexcretionandmaycauseintermittentandslightlyincreasedserum

calciumconcentrations.

Markedhypercalcaemiamaybeasignofhiddenhyperparathyroidism.Thiazidesshouldbediscontinuedbefore

carryingouttestsforparathyroidfunction.

Hydrochlorothiazidedose-dependentlyincreasesurinarypotassiumexcretionwhichmayresultinhypokalaemia.This

effectofhydrochlorothiazideseemstobelessevidentwhencombinedwithcandesartancilexetil.

Theriskforhypokalaemiamaybeincreasedinpatientswithcirrhosisoftheliver,inpatientsexperiencingbrisk

diuresis,inpatientswithaninadequateoralintakeofelectrolytesandinpatientsreceivingconcomitanttherapywith

corticosteroidsoradrenocorticotropichormone(ACTH).

Basedonexperiencewiththeuseofotherdrugsthataffecttherenin-angiotensin-aldosteronesystem,concomitantuse

ofpotassium-sparingdiuretics,potassiumsupplementsorsaltsubstitutesorotherdrugsthatmayincreaseserum

potassiumlevels(e.g.heparinsodium)mayleadtoincreasesinserumpotassium.

AlthoughnotdocumentedwithAtacandPlustreatmentwithangiotensinconvertingenzymeinhibitorsorangiotensin-

II-receptorinhibitorsmaycausehyperkalaemia,especiallyinthepresenceofheartfailureand/orrenalimpairment.

Thiazideshavebeenshowntoincreasetheurinaryexcretionofmagnesium,whichmayresultinhypomagnesaemia.

Metabolicandendocrineeffects

Treatmentwithathiazidediureticmayimpairglucosetolerance.Dosageadjustmentofanti-diabeticdrugs,including

insulin,mayberequired.Latentdiabetesmellitusmaybecomemanifestduringthiazidetherapy.Increasesin

cholesterolandtriglyceridelevelshavebeenassociatedwiththiazidediuretictherapy;howeveratthe12.5mgdose

containedinAtacandPlusminimalornoeffectswerereported.Thiazidediureticsincreaseserumuricacid

concentrationandmayprecipitategoutinsusceptiblepatients.

General

Inpatientswhosevasculartoneandrenalfunctiondependpredominantlyontheactivityoftherenin-angiotensin-

aldosteronesystem(e.g.patientswithseverecongestiveheartfailureorunderlyingrenaldisease,includingrenalartery

stenosis),treatmentwithotherdrugsthataffectthissystemhasbeenassociatedwithacutehypotension,azotaemia,

oliguriaor,rarely,acuterenalfailure.AlthoughthepossibilityofsimilareffectscannotbeexcludedwithangiotensinII

receptorantagoniststheseeffectsarenotreportedwithAtacand.Aswithanyantihypertensiveagent,excessiveblood

pressuredecreaseinpatientswithischaemiccardiopathyorischaemiccerebrovasculardiseasecouldresultina

myocardialinfarctionorstroke.

Hypersensitivityreactionstohydrohlorothiazidemayoccurinpatientswithorwithoutahistoryofallergyorbronchial

asthma,butaremorelikelyinpatientswithsuchahistory.

Exacerbationoractivationofsystemiclupuserythematosushasbeenreportedwiththeuseofthiazidediuretics.

Containslactosemonohydrate.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Nodruginteractionsofclinicalsignificancehavebeenidentifiedforcandesartancilexitil.Compoundswhichhavebeen

investigatedinclinicalpharmacokineticstudiesincludehydrochlorothiazide,warfarin,digoxin,oralcontraceptives(i.e.

ethinylestradiol/levonorgestrel),glibenclamideandnifedipine.

Thebioavailabilityofcandesartanisnotaffectedbyfood.

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Thepotassiumdepletingeffectofhydrochlorothiazidecouldbeexpectedtobepotentiatedbyotherdrugsassociated

withpotassiumlossandhypokalaemia(e.g.otherkaliureticdiuretics,laxatives,amphoteracin,carbenoxolone,

penicillinGsodium,salicylicacidderivatives).

Basedonexperiencewiththeuseofotherdrugsthataffecttherenin-angiotensin-aldosteronesystem,concomitantuse

ofAtacandPlusandpotassium-sparingdiuretics,potassiumsupplementsorsaltsubstitutesorotherdrugsthatmay

increasepotassiumlevels(e.g.heparinsodium)mayleadtoincreasesinserumpotassium.

Diuretic-inducedhypokalaemiaandhypomagnesaemiapredisposestothepotentialcardiotoxiceffectsofdigitalis

glycosidesandantiarrhythmic.PeriodicmonitoringofserumpotassiumisrecommendedwhenAtacandPlusis

administeredwithsuchdrugs.

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitorsorhydrochlorothiazide.AsimilareffectmayoccurwithangiotensinII

receptorantagonistsandcarefulmonitoringofserumlithiumlevelsisrecommendedduringconcomitantuse.

Thediuretic,natriureticandanti-hypertensiveeffectofhydrochlorothiazideisbluntedbyNSAIDs.

Theabsorptionofhydrochlorothiazideisreducedbycolestipolorcholestyramine.

Theeffectonnondepolarizingskeletalmusclerelaxants(e.g.tubocurarine)maybepotentiatedbyhydrochlorothiazide.

Thiazidediureticsmayincreaseserumcalciumlevelsduetodecreaseexcretion.IfcalciumsupplementsorVitaminD

mustbeprescribed,serumcalciumlevelsshouldbemonitoredanddosageadjustedaccordingly.

Thehyperglycaemiceffectofbeta-blockersanddiazoxidemaybeenhancedbythiazides.

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

decreasinggastrointestinalmotilityandstomachemptyingrate.

Thiazidemayincreasetheriskofadverseeffectscausedbyamantadine.

Thiazidesmayreducetherenalexcretionofcytotoxicdrugs(e.g.cyclophosphamide,methotrexate)andpotentiatetheir

myelosuppressiveeffects.

Theriskforhypokalaemiamaybeincreasedduringconcomitantuseofsteroidsoradrenocorticotropichormone

(ACTH).

Posturalhypotensionmaybecomeaggravatedbysimultaneousintakeofalcohol,barbituratesoranaesthetics.

Treatmentwithathiazidediureticmayimpairglucosetolerance.Dosageadjustmentofantidiabeticdrugs,including

insulin,mayberequired.

Hydrochlorothiazidemaycausethearterialresponseonpresoramines(e.g.adrenaline)todecreasebutnotenoughto

excludeapressoreffect.

Hydrochlorothiazidemayincreasetheriskofacuterenalinsufficiencyespeciallywithhighdosesofiodinatedcontrast

media.

Thereisnoclinicallysignificantinteractionbetweenhydrochlorothiazideandfood.

4.6Fertility,pregnancyandlactation

Pregnancy

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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):

BecausenoinformationisavailableregardingtheuseofAtacandPlusduringbreastfeeding,AtacandPlusisnot

recommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

Hydrochlorothiazide:

Hydrochlorothiazideisexcretedinhumanmilkinsmallamounts.Thiazidesinhighdosescausingintensediuresiscan

inhibitthemilkproduction.TheuseofAtacandPlusduringbreast-feedingisnotrecommended.

4.7Effectsonabilitytodriveandusemachines

TheeffectofAtacandPlusontheabilitytodriveandusemachineshasnotbeenstudiedbutbasedonits

pharmacodynamicproperties,AtacandPlusisunlikelytoaffectthisability.Whendrivingvehiclesoroperating

machinesitshouldbetakenintoaccountthatoccasionallydizzinessorwearinessmayoccurduringtreatmentof

hypertension.

4.8Undesirableeffects

Incontrolledclinicalstudieswithcandesartancilexetil/hydrochlorothiazideadversereactionsweremildandtransient.

Withdrawalsfromtreatmentduetoadverseeventsweresimilarwithcandesartancilexetil/hydrochlorothiazide(2.3-

TheuseofAIIRAsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).TheuseofAIIRAsis

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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).

Thetablebelowpresentsadversereactionswithhydrochlorothiazidemonotherapyusuallywithdosesof25mgor

SystemOrganClass Frequency UndesirableEffect

Infectionsandinfestations Common Respiratoryinfection

Bloodandlymphaticsystemdisorders Veryrare Leukopenia,neutropeniaand

agranulocytosis

Metabolismandnutritiondisorders Veryrare Hyperkalaemia,hyponatraemia

Nervoussystemdisorders Common Dizziness/vertigo,headache

Respiratory,thoracicandmediastinal

disorders Veryrare Cough

Gastrointestinaldisorders Veryrare Nausea

Hepatobiliarydisorders Veryrare Increasedliverenzymes,abnormal

hepaticfunctionorhepatitis

Skinandsubcutaneoustissuedisorders Veryrare Angioedema,rash,urticaria,pruritus

Musculoskeletalandconnectivetissue

disorders Veryrare Backpain,arthralgia,myalgia

Renalandurinarydisorders Veryrare Renalimpairment,includingrenal

failureinsusceptiblepatients(see

section4.4)

SystemOrganClass Frequency UndesirableEffect

Bloodandlymphaticsystemdisorders Rare Leukopenia,

neutropenia/agranulocytosis,

thrombocytopenia,aplasticanaemia,

bonemarrowdepression,haemolytic

anaemia

Immunesystemdisorders Rare Anaphylacticreactions

Metabolismandnutritiondisorders Common Hyperglycaemia,hyperuricaemia,

electrolyteimbalance(including

hyponatraemiaandhypokalaemia)

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)

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disorders pneumonitisandpulmonaryoedema)

Gastrointestinaldisorders Uncommon Anorexia,lossofappetite,gastric

irritation,diarrhoea,constipation

Rare Pancreatitis

Hepatobiliarydisorders Rare Jaundice(intrahepaticcholestatic

jaundice)

Skinandsubcutaneoustissuedisorders Uncommon Rash,urticaria,photosensitivityreactions

Rare Toxicepidermalnecrolysis,cutaneous

lupuserythaematosus-likereactions,

reactivationofcutaneouslupus

erythaematosus

Musculoskeletalandconnectivetissue

disorders Rare Musclespasm

Renalandurinarydisorders Common Glycosuria

Rare Renaldysfunctionandinterstitial

nephritis

Generaldisordersandadministration

siteconditions Common Weakness

Rare Fever

Investigations Common Increasesincholesterolandtriglycerides

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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.

Ifsymptomatichypotensionshouldoccur,symptomatictreatmentshouldbeinstitutedandvitalsignsmonitored.The

patientshouldbeplacedsupinewiththelegselevated.Ifthisisnotsufficient,plasmavolumeshouldbeincreasedby

infusionofisotonicsalinesolution.Sympathomimeticdrugsmaybeadministerediftheabove-mentionedmeasuresare

notsufficient.

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.

CandesartandoesnotinfluenceACEorotherenzymesystemsusuallyassociatedwiththeuseofACEinhibitors.Since

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).

Therewere26.7eventsper1000patient-yearsinthecandesartangroupversus30.0eventsper1000patient-yearsinthe

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Hydrochlorothiazideinhibitstheactivereabsorptionofsodium,mainlyinthedistalkidneytubules,andpromotesthe

excretionofsodium,chlorideandwater.Therenalexcretionofpotassiumandmagnesiumincreasesdose-dependently,

whilecalciumisreabsorbedtoagreaterextent.Hydrochlorothiazidedecreasesplasmavolumeandextracellularfluid

andreducescardiacoutputandbloodpressure.Duringlong-termtherapy,reducedperipheralresistancecontributesto

thebloodpressurereduction.

Largeclinicalstudieshaveshownthatlong-termtreatmentwithhydrochlorothiazidereducestheriskforcardiovascular

morbidityandmortality.

Candesartanandhydrochlorothiazidehaveadditiveantihypertensiveeffects.

Inhypertensivepatients,AtacandPlusresultsinadose-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

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.

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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

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

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5.3Preclinicalsafetydata

Therewerenoqualitativenewtoxicfindingswiththecombinationcomparedtothatobservedforeachcomponent.In

preclinicalsafetystudiescandesartanhadeffectsonthekidneysandonredcellparametersathighdosesinmice,rats,

dogsandmonkeys.Candesartancausedareductionofredbloodcellparameters(erythrocytes,haemoglobin,

haematocrit).Effectsonthekidneys(suchasregeneration,dilatationandbasophiliaintubules;increasedplasma

concentrationsofureaandcreatinine)wereinducedbycandesartanwhichcouldbesecondarytothehypotensiveeffect

leadingtoalterationsofrenalperfusion.Additionofhydrochlorothiazidepotentiatesthenephrotoxicityofcandesartan.

Furthermore,candesartaninducedhyperplasia/hypertrophyofthejuxtaglomerularcells.Thesechangeswere

consideredtobecausedbythepharmacologicalactionofcandesartanandtobeoflittleclinicalrelevance.

Foetotoxicityhasbeenobservedinlatepregnancywithcandesartan.Theadditionofhydrochlorothiazidedidnot

significantlyaffecttheoutcomeoffoetaldevelopmentstudiesinrats,miceorrabbits(seesection4.6Pregnancyand

Lactation).

Candesartanandhydrochlorothiazidebothshowgenotoxicactivityatveryhighconcentration/doses.Datafrominvitro

andinvivogenotoxicitytestingindicatethatcandesartanwillnotexertmutagenicorclastogenicactivitiesunder

conditionsofclinicaluse.

Therewasnoevidencethateithercompoundiscarcinogenic.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Carmellosecalcium

Hyprolose

Lactosemonohydrate

Magnesiumstearate

Maizestarch

Macrogol

IronOxide(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductisthedateshownontheblisterandoutercartonoftheproductonthemarket

inthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

Blisterpackcontaining28or30tabletscontainedinanoverlabelledoutercardboardcarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA465/117/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorizations:26 th

January2004

Dateoflastrenewal:26 th

January2009

10DATEOFREVISIONOFTHETEXT

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