CO-TAREG

Main information

  • Trade name:
  • CO-TAREG Film Coated Tablet 320/25 Milligram
  • Dosage:
  • 320/25 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CO-TAREG Film Coated Tablet 320/25 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0013/118/005
  • Authorization date:
  • 01-02-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0013/118/005

CaseNo:2057548

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

NovartisPharmaceuticalsUKLtd

FrimleyBusinessPark,Frimley,Camberley,Surrey,GU167SR,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Co-Tareg320mg/25mgfilm-coatedtablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom26/02/2009until31/01/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Co-Tareg320mg/25mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onefilm-coatedtabletcontains320mgvalsartanand25mghydrochlorothiazide.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Yellow,ovaloidshaped,bevelededge,filmcoatedtablet,imprinted(debossed)with“NVR”ononesideand“CTI”on

thereverseside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertension.

Co-Tareg320mg/25mgfixeddose-combination(valsartan320mg/hydrochlorothiazide25mg)isindicatedinpatients

whosebloodpressureisnotadequatelycontrolledonvalsartanmonotherapy.

4.2Posologyandmethodofadministration

TherecommendeddoseofCo-Tareg320mg/25mgisonefilm-coatedtabletperday.Whenclinicallyappropriate,

directchangefrommonotherapytothefixedcombinationmaybeconsidered.

Co-Tareg320mg/25mgmaybeadministeredinpatientswhosebloodpressureisnotadequatelycontrolledby

valsartanmonotherapyandwhosediastolicbloodpressureis ≥100mmHgfollowingtreatmentwithvalsartan320mg

monotherapy.Treatmentshouldalwaysbeginwiththelowerdosagestrengthofvalsartan320mg/hydrochlorothiazide

12.5mgandbecontinuedforatleast4-8weeksbeforestartingtreatmentwithCo-Tareg320mg/25mg.Individualdose

titrationwiththecomponentsisrecommended.ThemaximumantihypertensiveeffectofCo-Tareg320mg/25mgis

seenwithin4-8weeks.IfnorelevantadditionaleffectisseenwithCo-Tareg320mg/25mgafterthistime,reductionof

thedoseandtreatmentwithanadditionaloralternativeantihypertensivemedicinalproductshouldbeconsidered(see

section5.1).

Co-Tareg320mg/25mgmaybetakenindependentlyofamealandshouldbeadministeredwithfluid.

Renalimpairment

Nodosageadjustmentisrequiredforpatientswithmildtomoderaterenalimpairment(creatinineclearance

30mL/min).

Hepaticimpairment

Inpatientswithmildtomoderatehepaticimpairmentwithoutcholestasisthedoseofvalsartanshouldnotexceed80

mg.ThereforeCo-Tareg320mg/25mgshouldnotbeusedinthesepatients.

Elderly

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Childrenandadolescents(<18years)

Co-Tareg320mg/25mgisnotrecommendedforuseinchildrenbelowtheageof18yearsduetothelackofdataon

safetyandefficacy.

4.3Contraindications

Hypersensitivitytovalsartan,hydrochlorothiazide,othersulfonamide-derivedmedicinalproductsortoanyofthe

excipients.

Pregnancyandlactation(seesection4.6).

Severehepaticimpairment,biliarycirrhosisandcholestasis.

Severerenalimpairment(creatinineclearance<30mL/min),anuriaandpatientsundergoingdialysis.

Refractoryhypokalaemia,hyponatraemia,hypercalcaemia,andsymptomatichyperuricaemia.

4.4Specialwarningsandprecautionsforuse

Serumelectrolytechanges

Concomitantusewithpotassiumsparingdiuretics,potassiumsupplements,saltsubstitutescontainingpotassium,or

othermedicinalproductsthatmayincreaseserumpotassiumlevels(heparin,etc.)shouldbeusedwithcaution.

Hypokalaemiahasbeenreportedundertreatmentwiththiazidediuretics,includinghydrochlorothiazide.Frequent

monitoringofserumpotassiumisrecommended.

Treatmentwiththiazidediuretics,includinghydrochlorothiazide,hasbeenassociatedwithhyponatraemiaand

hypochloraemicalkalosis.Thiazides,includinghydrochlorothiazide,increasetheurinaryexcretionofmagnesium,

whichmayresultinhypomagnesaemia.Calciumexcretionisdecreasedbythiazidediuretics.Thismayresultin

hypercalcaemia.

Periodicdeterminationofserumelectrolytesshouldbeperformedatappropriateintervals.

Sodiumand/orvolume-depletedpatients

Patientsreceivingthiazidediuretics,includinghydrochlorothiazide,shouldbeobservedforclinicalsignsoffluidor

electrolyteimbalance.Warningsignsoffluidorelectrolyteimbalancearedrynessofmouth,thirst,weakness,lethargy,

drowsiness,restlessness,musclepainsorcramps,muscularweakness,hypotension,oliguria,tachycardia,and

gastrointestinaldisturbancessuchasnauseaorvomiting.

Inseverelysodium-depletedand/orvolume-depletedpatients,suchasthosereceivinghighdosesofdiuretics,

symptomatichypotensionmayoccurinrarecasesafterinitiationoftherapywithCo-Tareg320mg/25mg.Electrolyte

and/orvolumedepletionshouldbecorrectedbeforestartingtreatmentwithCo-Tareg320mg/25mg.

Patientswithseverechronicheartfailureorotherconditionswithstimulationoftherenin-angiotensin-

aldosterone-system

Inpatientswhoserenalfunctionmaydependontheactivityoftherenin-angiotensin-aldosteronesystem(e.g.patients

withsevereheartfailure),treatmentwithangiotensinconvertingenzymeinhibitorshasbeenassociatedwitholiguria

and/orprogressiveazotaemiaandinrarecaseswithacuterenalfailure.TheuseofCo-Tareg320mg/25mginpatients

withsevereheartfailurehasnotbeenestablished.Henceitcannotbeexcludedthatbecauseoftheinhibitionofthe

renin-angiotensin-aldosteronesystemtheuseofCo-Tareg320mg/25mgmayaswellbeassociatedwithimpairmentof

therenalfunction.Co-Tareg320mg/25mgshouldnotbeusedinthesepatients.

Renalimpairment

Nodosageadjustmentisrequiredforpatientswithrenalimpairmentwithacreatinineclearance 30mL/min(see

section4.3)

Periodicmonitoringofserumpotassium,creatinineanduricacidlevelsisrecommendedwhenCo-Tareg320mg/25mg

isusedinpatientswithrenalimpairment.

Kidneytransplantation

ThereiscurrentlynoexperienceonthesafeuseofCo-Tareg320mg/25mginpatientswhohaverecentlyundergone

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Renalarterystenosis

Co-Tareg320mg/25mgshouldnotbeusedtotreathypertensioninpatientswithbilateralrenalarterystenosisor

stenosisofthearterytoasinglekidney,sincebloodureaandserumcreatininemayincreaseinsuchpatients.

Primaryhyperaldosteronism

PatientswithprimaryhyperaldosteronismshouldnotbetreatedwithCo-Tareg320mg/25mgastheirrenin-

angiotensin-aldosteronesystemisaffectedbytheprimarydisease.

Aorticandmitralvalvestenosis,hypertrophiccardiomyopathy

SpecialcautionisindicatedwhenusingCo-Tareg320mg/25mginpatientswithaorticormitralstenosis,or

hypertrophiccardiomyopathy.

Hepaticimpairment

Co-Tareg320mg/25mgshouldnotbeusedinthesepatients(seesection4.2).

Systemiclupuserythematosus

Thiazidediuretics,includinghydrochlorothiazide,havebeenreportedtoexacerbateoractivatesystemiclupus

erythematosus.

Ethnicdifferences

Valsartanislesseffectiveinloweringbloodpressureinblackpatientsthaninnon-blacks,possiblybecauseofthe

higherprevalenceoflowreninlevelsintheblackhypertensivepopulation.

Othermetabolicdisturbances

Thiazidediuretics,includinghydrochlorothiazide,mayalterglucosetoleranceandraiseserumlevelsofcholesterol,

triglycerides,anduricacid.

General

CautionshouldbeexercisedinpatientswhohaveshownpriorhypersensitivitytootherangiotensinIIreceptorblocking

agents.

Hypersensitivityreactionstohydrochlorothiazidearemorelikelyinpatientswithallergyandasthma.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Otherantihypertensiveagents:Co-Tareg320mg/25mgmayincreasethehypotensiveeffectofotherantihypertensive

agents.

Lithium:Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcurrentuseof

lithium,ACEinhibitorsand/orthiazidediuretics,includinghydrochlorothiazide.Thereisnoexperiencewith

concomitantuseofvalsartanandlithium.Therefore,regularmonitoringofserumlithiumconcentrationsis

recommendedduringconcurrentuseoflithiumandCo-Tareg320mg/25mg.

Medicinalproductsthatmayincreasepotassiumlevelsorinducehyperkalaemia:Concomitantusewithpotassium-

sparingdiuretics,potassiumsupplements,saltsubstitutescontainingpotassium,orothermedicinalproductsthatmay

increasepotassiumlevels(e.g.ACEinhibitors,heparin,cyclosporin)shouldbeusedwithcautionandwithfrequent

monitoringofpotassiumlevels(seesection4.4).

ThefollowingpotentialdruginteractionsmayoccurduetothethiazidecomponentofCo-Tareg320mg/25mg:

Medicinalproductsassociatedwithpotassiumlossandhypokalaemia(e.g.kaliureticdiuretics,corticosteroids,

laxantia,ACTH,amphotericin,carbenoxolone,penicillinG,salicylicacidandsalicylates).Ifthesemedicinalproducts

aretobeprescribedwiththehydrochlorothiazide-valsartancombination,monitoringofpotassiumplasmalevelsis

advised.Thesemedicinalproductsmaypotentiatetheeffectofhydrochlorothiazideonserumpotassium(seesection

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Medicinalproductsaffectedbyserumpotassiumdisturbances:PeriodicmonitoringofserumpotassiumandECGis

recommendedwhenCo-Tareg320mg/25mgisadministeredwithmedicinalproductsaffectedbyserumpotassium

disturbances(e.g.digitalisglycosides,antiarrhythmics)andthefollowingtorsadesdepointesinducingmedicinal

products(whichincludesomeantiarrhythmics),hypokalaemiabeingapredisposingfactortotorsadesdepointes.

Digitalisglycosides:Thiazide-inducedhypokalaemiaorhypomagnesaemiamayoccurasunwantedeffectfavoringthe

onsetofdigitalis-inducedcardiacarrhythmias.

CalciumsaltsandvitaminD:Concomitantuseofthiazidediuretics,includinghydrochlorothiazide,withvitaminDor

withcalciumsaltsmaypotentiatetheriseinserumcalcium.

Antidiabeticmedicinalproducts(insulinandoralmedicinalproducts):Doseadjustmentoftheantidiabeticmedicinal

productmaybenecessary.

Beta-blockersanddiazoxide:Concomitantuseofthiazidediuretics,includinghydrochlorothiazide,withbeta-blockers

mayincreasetheriskofhyperglycaemia.Thiazidediuretics,includinghydrochlorothiazide,mayenhancethe

hyperglycaemiceffectofdiazoxide.

Medicinalproductsusedinthetreatmentofgout(probenecid,sulfinpyrazoneandallopurinol):Dosageadjustmentof

uricosuricmedicinalproductsmaybenecessaryashydrochlorothiazidemayraisethelevelofserumuricacid.Increase

ofdosageofprobenecidorsulfinpyrazonemaybenecessary.Co-administrationofthiazidediuretics,including

hydrochlorothiazide,mayincreasetheincidenceofhypersensitivityreactionstoallopurinol.

Anticholinergicagents(e.g.atropine,biperiden):Thebioavailabilityofthiazide-typediureticsmaybeincreasedby

anticholinergicagentsduetoadecreaseingastrointestinalmotilityandthestomachemptyingrate.

Pressoramines(e.g.noradrenaline,adrenaline):Theeffectofpressoraminesmaybedecreased.

Amantadine:Thiazides,includinghydrochlorothiazide,mayincreasetheriskofundesirableeffectscausedby

amantadine.

Cholestyramineandcholestipolresins:Absorptionofthiazidediuretics,includinghydrochlorothiazide,isimpairedin

thepresenceofanionicexchangeresins.

Cytotoxicagents(e.g.cyclophosamide,methotrexate):Thiazides,includinghydrochlorothiazide,mayreducerenal

excretionofcytotoxicmedicinalproductsandpotentiatetheirmyelosuppressiveeffects.

Non-steroidalanti-inflammatoryagents:WhenangiotensinIIantagonistsareadministeredsimultaneouslywith

nonsteroidalanti-inflammatoryagents(e.g.selectiveCOX-2inhibitors,acetylsalicylicacid>3g/dayandnon-selective

NSAIDs),attenuationoftheantihypertensiveeffectmayoccur.Furthermore,concomitantuseofangiotensinII

antagonistsandNSAIDsmayleadtoanincreasedriskofdeteriorationofrenalfunctionandanincreaseinserum

potassium.Therefore,monitoringofrenalfunctionatthebeginningofthetreatmentshouldberecommended,aswell

asadequatehydrationofthepatient.

Nondepolarizingskeletalmusclerelaxants(e.g.tubocurarine):Thiazidediuretics,includinghydrochlorothiazide,

potentiatetheactionofcurarederivatives.

Cyclosporin:Concomitanttreatmentwithcyclosporinmayincreasetheriskofhyperuricaemiaandgout-type

complications.

Tetracyclines:Concomitantadministrationoftetracyclinesandthiazidediureticsincreasestheriskfortetracycline-

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,

droperidol)

Others(e.g.bepridil,cisapride,diphemanil,erythromycini.v.,halofantrin,ketanserin,

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Alcohol,anaestheticsandsedatives:Potentiationoforthostatichypotensionmayoccur.

Methyldopa:Therehavebeenisolatedreportsofhaemolyticanaemiainpatientsreceivingconcomitanttreatmentwith

methyldopaandhydrochlorothiazide.

4.6Pregnancyandlactation

AngiotensinIIantagonistscancausefetalinjurywhichmaybesimilartothefetaleffectsofACEinhibitors.Inutero

exposuretoangiotensinconvertingenzyme(ACE)inhibitorsgiventopregnantwomenduringthesecondandthird

trimestershasbeenreportedtocauseinjuryanddeathtothedevelopingfetus.

Hydrochlorothiazidecrossestheplacentaandtheintrauterineexposuretothiazidediuretics,including

hydrochlorothiazide,isassociatedwithfetalorneonatalthrombocytopenia,andmaybeassociatedwithotheradverse

reactionsthathaveoccurredinadults.

Therehavebeenreportsofspontaneousabortion,oligohydramniosandnewbornrenaldysfunction,whenpregnant

womenhaveinadvertentlytakenvalsartan.

Likeothermedicinalproductsthatactdirectlyontherenin-angiotensin-aldosteronesystem(RAAS),Co-

Tareg320mg/25mgshouldnotbeusedduringpregnancy.Ifpregnancyisdetectedduringtherapy,Co-

Tareg320mg/25mgshouldbediscontinuedassoonaspossible.

Itisnotknownwhethervalsartanisexcretedinhumanmilk.Valsartanwasexcretedinthemilkoflactatingrats.

Hydrochlorothiazideisexcretedinhumanmilk.ThusitisnotadvisabletouseCo-Tareg320mg/25mginlactating

mothers(seesection4.3).

4.7Effectsonabilitytodriveandusemachines

NostudiesontheeffectofCo-Tareg320mg/25mgontheabilitytodriveandusemachineshavebeenperformed.

Whendrivingvehiclesoroperatingmachinesitshouldbetakenintoaccountthatoccasionallydizzinessorweariness

mayoccur.

4.8Undesirableeffects

Fixed-dosecombination

Adversereactionsreportedinclinicaltrialsandoccurringmorefrequentlywithvalsartanplushydrochlorothiazidethan

withplaceboorfromindividualreportsarepresentedbelowaccordingtosystemorganclass.Adversereactionsknown

tooccurwitheachcomponentgivensinglybutwhichhavenotbeenseeninclinicaltrialsmayoccurduringtreatment

withCo-Tareg320mg/25mg.

AdversereactionshavebeenrankedusingtheMedDRAfrequencyconvention:verycommon( ≥1/10);common(≥

1/100,<1/10);uncommon( ≥1/1.000,<1/100);rare(≥1/10.000,<1/1.000);veryrare(<1/10.000),notknown(cannot

beestimatedfromtheavailabledata).

Investigations

Bloodandlymphaticsystemdisorders

Uncommon: Serumuricacidincreased,BilirubinandCreatinine

increase,Hypokalaemia,Hyponatremia

CardiacDisorders

Uncommon: ChestPain

Rare: Hypotension

Veryrare: Arrhythmia

Veryrare: Thrombocytopenia,Anaemia

Nervoussystemdisorders

Uncommon: Dizziness

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Gastrointestinaldisorders

Generaldisordersandadministrationsiteconditions

Immunesystemdisorders

Additionalinformationonindividualcomponents

Undesirableeffectspreviouslyreportedwithoneoftheindividualcomponentsmaybepotentialundesirableeffects

withCo-Tareg320mg/25mg,evenifnotobservedinclinicaltrialswiththismedicinalproduct.

Valsartan

Uncommon:backpain,conjunctivitis,depression,epistaxis,insomnia,musclecramps,sinusitis,vertigo.

Rare:neuralgia.

Veryrare:arthralgia,gastroentritis.

Post-marketingdatarevealedrarecasesofangioedema,rash,pruritusandotherallergicreactionsincludingserum

sickness,andvasculitis,veryrarecasesofimpairedrenalfunction;insomecasespre-existingrenalimpairmentwas

temporarilyintensified.

Uncommonelevationsofliverfunctionvalueswerereportedinpatientstreatedwithvalsartan.

Hydrochlorothiazide

Thefollowingadversereactionshavebeenreportedinpatientstreatedwiththiazidediureticsalone,including

hydrochlorothiazide,frequentlyathigherdosesthanthosecontainedinCo-Tareg320mg/25mg.

Common:urticariaandotherformsofrash,lossofappetite,mildnauseaandvomiting,posturalhypotension,

impotence.

Rare:photosensitisation,constipation,diarrhoea,gastrointestinaldiscomfort,intrahepaticcholestasisorjaundice,

cardiacarrhythmias,headache,dizzinessorlight-headedness,sleepdisturbances,depression,paraesthesias,

disturbancesofvision,thrombocytopeniasometimeswithpurpura.

Veryrare:necrotisingvasculitisandtoxicepidermalnecrolysis,cutaneouslupuserythematosus-likereactions,

reactivationofcutaneouslupuserythematosus,pancreatitis,leucopenia,agranulocytosis,bonemarrowdepression,

haemolyticanaemia,hypersensitivityreactions,respiratorydistressincludingpneumonitisandpulmonaryoedema.

Earandlabyrinthdisorders

Rare: Vertigo,Tinnitus

Respiratory,thoriacicandmediastinal

disorders

Uncommon: Cough

Common:

Uncommon: Diarrhoea

Nausea,Dyspepsia,Abdominalpain

Renalandurinarydisorders

Uncommon: Pollakiuria

Skinandsubcutaneoustissuedisorders

Veryrare: Angiodema,Rash,Pruritus,Cutaneousvasculitis

Musculoskeletalandconnectivetissue

disorder

Uncommon: Paininextremity,ligamentsprain,Arthritis

Rare: Myalgia,Muscularweakness

Infectionsandinfestations

Common: Nasopharyngitis

Uncommon: Upperrespiratorytractinfections,Urinarytract

infections,Viralinfections,Rhinitis

Common:

Rare:

Veryrare: Fatigue

Hyperhydrosis

Hemorrhage,Oedema,Alopecia

Veryrare: Hypersensitivityandallergicreactions,Serum

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4.9Overdose

Symptoms

Overdosewithvalsartanmayresultinmarkedhypotensionwhichcouldleadtodepressedlevelofconsciousness,

circulatorycollapseand/orshock.Inaddition,thefollowingsignsandsymptomsmayoccurduetoanoverdoseofthe

hydrochlorothiazidecomponent:nausea,somnolence,hypovolaemia,andelectrolytedisturbancesassociatedwith

cardiacarrhythmiasandmusclespasms.

Treatment

Thetherapeuticmeasuresdependonthetimeofingestionandthetypeandseverityofthesymptoms,stabilisationof

thecirculatoryconditionbeingofprimeimportance.

Thepatientshouldbegivenasufficientamountofactivatedcharcoal.Ifhypotensionoccurs,thepatientshouldbe

placedinthesupinepositionandsaltandvolumesupplementationshouldbegivenrapidly.

Valsartancannotbeeliminatedbymeansofhaemodialysisbecauseofitsstrongplasmabindingbehaviourwhereas

clearanceofhydrochlorothiazidecanbeachievedbydialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:angiotensinIIantagonistsanddiuretics,valsartanandhydrochlorothiazide;ATCcode:

C09DA03.

Valsartan

ValsartanisanorallyactiveandspecificangiotensinII(AngII)receptorantagonist.Itactsselectivelyonthe

ATreceptorsubtype,whichisresponsiblefortheknownactionsofangiotensinII.TheincreasedplasmalevelsofAng

IIfollowingAT

receptorblockadewithvalsartanmaystimulatetheunblockedAT

receptor,whichappearsto

counterbalancetheeffectoftheAT

receptor.ValsartandoesnotexhibitanypartialagonistactivityattheATreceptor

andhasmuch(about20,000fold)greateraffinityfortheATreceptorthanfortheATreceptor.

ValsartandoesnotinhibitACE,alsoknownaskininaseII,whichconvertsAngItoAngIIanddegradesbradykinin.

Nopotentiationofbradykininrelatedundesirableeffectsshouldbeexpected.

InclinicaltrialswherevalsartanwascomparedwithanACEinhibitor,theincidenceofdrycoughwassignificantly

(P<0.05)lessinpatientstreatedwithvalsartanthaninthosetreatedwithanACEinhibitor(2.6%versus7.9%

respectively).InaclinicaltrialofpatientswithahistoryofdrycoughduringACEinhibitortherapy,19.5%oftrial

subjectsreceivingvalsartanand19.0%ofthosereceivingathiazidediureticexperiencedcoughcomparedwith68.5%

ofthosetreatedwithanACEinhibitor(P<0.05).Valsartandoesnotbindtoorblockotherhormonereceptorsorion

channelsknowntobeimportantincardiovascularregulation.

Administrationofvalsartantopatientswithhypertensionresultsinreductionofbloodpressurewithoutaffectingpulse

rate.

Inmostpatients,afteradministrationofasingleoraldose,onsetofantihypertensiveactivityoccurswithin2hours,and

thepeakreductionofbloodpressureisachievedwithin4-6hours.Theantihypertensiveeffectpersistsover24hours

afterdosing.Duringrepeateddosing,themaximumreductioninbloodpressurewithanydoseisgenerallyattained

within4-8weeksandissustainedduringlong-termtherapy.Combinedwithhydrochlorothiazide,asignificant

additionalreductioninbloodpressureisachieved.

Hydrochlorothiazide

Thesiteofactionofthiazidediureticsisprimarilyintherenaldistalconvolutedtubule.Ithasbeenshownthatthereisa

high-affinityreceptorintherenalcortexastheprimarybindingsiteforthethiazidediureticactionandinhibitionof

NaCl(Sodiumchloride)transportinthedistalconvolutedtubule.Themechanismofactionofthiazidesisthrough

inhibitionoftheNa +

symporterperhapsbycompetingfortheCl -

site,therebyaffectingelectrolytereabsorption

mechanisms:directlybyincreasingsodiumandchlorideexcretiontoanapproximatelyequalextent,andindirectlyby

theirdiureticactionreducingplasmavolume,withconsequentincreasesinplasmareninactivity,aldosteronesecretion

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Therenin-aldosteronelinkismediatedbyangiotensinII,sowithco-administrationofvalsartanthereductioninserum

potassiumislesspronouncedasobservedundermonotherapywithhydrochlorothiazide.

Valsartan/hydrochlorothiazide

Amulticentre,randomiseddoubleblind,activecontrolled,parallelgrouptrialhasshownanormalisationofblood

pressure(definedastroughsittingdiastolicBP<90mmHg)withCo-Diovan80mg/12.5mgin42.6%ofthepatients

(non-responderstohydrochlorothiazide)attheendofthetrial.

Asecondrandomiseddoubleblind,activecontrolled,parallelgrouptrialhasshownthatthefixedcombinationof

valsartan160mgwithHCTZ(Hydrochlorothiazide)12.5mgor25mgimprovedbloodpressurecontrolinahigher

proportionofpatientsthanmonotherapywithvalsartan160mg.Furthermore,thefixedcombinationwithHCTZ25mg

wassignificantlymoreeffectivethanthefixedcombinationwiththelowerdoseofHCTZ.Thefollowingresponder

rateswereobserved:valsartan160mg:49%;valsartan160mg+HCTZ12.5mg:61.7%;valsartan160mg+HCTZ

25mg:68%.

Anotherrandomiseddoubleblind,activecontrolled,parallelgrouptrialinpatientsnotadequatelycontrolledwith

valsartanmonotherapy320mghasshownthatthefixedcombinationsofvalsartan/HCTZ320mg/25mgand

320mg12.5mgweremoreeffectivethanvalsartan320mg.Thefollowingresponderrateswereobserved:valsartan

320mg:52.7%;valsartan320mg+HCTZ12.5mg:68.8%;valsartan320mg+HCTZ25mg:74.9%.Anadditional

analysisshowedthatmoreseverepatients(MSDBPatbaseline ≥100mmHg)achievedhigherresponderrateswith

valsartan320mg/HCTZ25mg(69.2%)comparedtovalsartan320mg/HCTZ12.5mg(56.1%).

ArandomiseddoubleblindmultifactorialtrialcomparedvariousdosagecombinationsofvalsartanandHCTZtotheir

respectivecomponentsandplacebo.ThefollowingMSSBP/MSDBPreductionswereobserved:-24.7/16.6mmHgfor

valsartan/HCTZ320mg/25mg;-21.7/-15.0mmHgforvalsartan/HCTZ320mg/12.5mg;-20.3/-15.2mmHgfor

valsartan/HCTZ160mg/12.5mg.

Dose-dependenthypokalaemiaoccurredincontrolledclinicalstudieswithvalsartan+HCTZ.Hypokalaemiaoccurred

morefrequentlyinpatientsgiven25mgHCTZthaninthosegiven12.5mgHCTZ.

Dose-dependentorthostaticreactionswerereportedin<1%ofpatientsgivenacombinationofvalsartan+HCTZ.A

dose-dependentincreaseinthefrequencyof“dizziness”wasreportedinpatientstreatedwithdosesrangingfrom

valsartan80mg+HCTZ12.5mgtovalsartan160mg+HCTZ25mg.Inanon-controlledstudyinwhichCo-

Tareg160mg/25mgwasgivenfor4weekstopatientswhohadnotbeenadequatelytreatedwithvalsartan160mgand

HCTZ12.5mg,totalcholesterolrosefrom209to220mg/dl.

Beneficialeffectsofvalsartanincombinationwithhydrochlorothiazideoncardiovascularmortalityandmorbidityare

currentlyunknown.Epidemiologicalstudieshaveshownthatlong-termtreatmentwithhydrochlorothiazidereducesthe

riskofcardiovascularmortalityandmorbidity.Studiesareongoingtoinvestigatetheeffectsofvalsartanandvalsartan

incombinationwithhydrochlorothiazideoncardiovascularmortalityandmorbidity.

5.2Pharmacokineticproperties

Valsartan

Absorptionofvalsartanafteroraladministrationisrapid,althoughtheamountabsorbedvarieswidely.Meanabsolute

bioavailabilityforvalsartanis23%.Valsartanshowsmultiexponentialdecaykinetics(t

<1handt

ßabout9h).

Thepharmacokineticsofvalsartanarelinearinthedoserangetested.Thereisnochangeinthekineticsofvalsartanon

repeatedadministration,andlittleaccumulationwhendosedoncedaily.Plasmaconcentrationsweresimilarinmales

andfemales.

Valsartanishighlyboundtoserumprotein(94-97%),mainlyserumalbumin.Steady-statevolumeofdistributionis

about17Litres.Plasmaclearanceisabout2L/h.Valsartanismainlyeliminatedasunchangedcompoundinthebile

andintheurine.Atnormalglomerularfiltrationrate(120mL/min),renalclearanceaccountsforabout30%oftotal

plasmaclearance.Ahydroxymetabolitehasbeenidentifiedinplasmaatlowconcentrations(lessthan10%ofthe

valsartanAUC).Thismetaboliteispharmacologicallyinactive.Afteroraldosingofvalsartan83%isexcretedinthe

faecesand13%intheurine,mainlyasunchangedcompound.

Whenvalsartanisgivenwithfood,theareaundertheplasmaconcentrationcurve(AUC)ofvalsartanisreducedby

48%,althoughfromabout8hpostdosingplasmavalsartanconcentrationsaresimilarforthefedandfastedgroup.

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Hydrochlorothiazide

Theabsorptionofhydrochlorothiazide,afteranoraldose,israpid(t

about2h),withsimilarabsorption

characteristicsforbothsuspensionandtabletformulations.Thedistributionandeliminationkineticshavegenerally

beendescribedbyabi-exponentialdecayfunction,withaterminalhalf-lifeof6-15h.

TheincreaseinmeanAUCislinearanddoseproportionalinthetherapeuticrange.Thereisnochangeinthekineticsof

hydrochlorothiazideonrepeateddosing,andaccumulationisminimalwhendosedoncedaily.Theapparentvolumeof

distributionis4-8L/kg.Circulatinghydrochlorothiazideisboundtoserumproteins(40-70%),mainlyserumalbumin.

Hydrochlorothiazidealsoaccumulatesinerythrocytesatapproximately1.8timesthelevelinplasma.

Absolutebioavailabilityofhydrochlorothiazideis60-80%afteroraladministration,with>95%oftheabsorbeddose

beingexcretedasunchangedcompoundintheurine.

Concomitantadministrationwithfoodhasbeenreportedtobothincreaseanddecreasethesystemicavailabilityof

hydrochlorothiazidecomparedwiththefastedstate.Themagnitudeoftheseeffectsissmallandhaslittleclinical

importance.

Valsartan/hydrochlorothiazide

Thesystemicavailabilityofhydrochlorothiazideisreducedbyabout30%whenco-administeredwithvalsartan.The

kineticsofvalsartanarenotmarkedlyaffectedbytheco-administrationofhydrochlorothiazide.Thisobserved

interactionhasnoimpactonthecombineduseofvalsartanandhydrochlorothiazide,sincecontrolledclinicaltrialshave

shownaclearanti-hypertensiveeffect,greaterthanthatobtainedwitheithermedicinalproductgivenalone,orwith

placebo.

SpecialPopulations

Elderly

Asomewhathighersystemicexposuretovalsartanwasobservedinsomeelderlysubjectsthaninyoungsubjects;

however,thishasnotbeenshowntohaveanyclinicalsignificance.

Limiteddatasuggestthatthesystemicclearanceofhydrochlorothiazideisreducedinbothhealthyandhypertensive

elderlysubjectscomparedtoyounghealthyvolunteers.

Renalimpairment

AttherecommendeddoseofCo-Tareg320mg/25mgnodoseadjustmentisrequiredforpatientswithacreatinine

clearanceof30-70mL/min.Inpatientswithsevererenalimpairment(creatinineclearance<30mL/min)andinpatients

undergoingdialysisnodataareavailableforCo-Tareg320mg/25mg.

Valsartanishighlyboundtoplasmaproteinandisnottoberemovedbydialysiswhereasclearanceof

hydrochlorothiazidewillbeachievedbydialysis.

Renalclearanceofhydrochlorothiazideiscomposedofpassivefiltrationandactivesecretionintotherenaltubule.As

expectedforacompoundwhichisclearedalmostexclusivelyviathekidneys,renalfunctionhasamarkedeffectonthe

kineticsofhydrochlorothiazide(seesection4.3).

Hepaticimpairment

Inapharmacokineticstrialinpatientswithmild(n=6)tomoderate(n=5)hepaticdysfunction,exposuretovalsartanhas

shownanapproximately2-foldincreaseinAUCandC

valuescomparedwithhealthyvolunteers.Therefore,Co-

Tareg320mg/25mgshouldnotbeusedinthesepatients(seesection4.2).Thereisnodataavailableontheuseof

valsartaninpatientswithseverehepaticdysfunction(seesection4.3).

Hepaticdiseasedoesnotsignificantlyaffectthepharmacokineticsofhydrochlorothiazide.

5.3Preclinicalsafetydata

Thepotentialtoxicityofthevalsartan+hydrochlorothiazidecombinationafteroraladministrationwasinvestigatedin

ratsandmarmosetsinstudieslastinguptosixmonths.Nofindingsemergedthatwouldexcludetheuseoftherapeutic

dosesinman.

Thechangesproducedbythecombinationinthechronictoxicitystudiesaremostlikelytohavebeencausedbythe

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Thetoxicologicaltargetorganwasthekidney,thereactionbeingmoremarkedinthemarmosetthantherat.The

combinationledtokidneydamage(nephropathywithtubularbasophilia,risesinplasmaurea,plasmacreatinineand

serumpotassium,increasesinurinevolumeandurinaryelectrolytesfrom30mg/kg/dvalsartan+9mg/kg/d

hydrochlorothiazideinratsand10+3mg/kg/dinmarmosets),probablybywayofalteredrenalhaemodynamics.

Highdosesofthevalsartan+hydrochlorothiazidecombinationcausedfallsinredbloodcellindices(redcellcount,

haemoglobin,haematocrit,from100+31mg/kg/dinratsand30+9mg/kg/dinmarmosets).

Inmarmosets,damagewasobservedinthegastricmucosa(from30+9mg/kg/d).

Thecombinationalsoledinthekidneytohyperplasiaoftheafferentaterioles(at600+188mg/kg/dinratsandfrom

30+9mg/kg/dinmarmosets).

Theabovementionedeffectsappeartobeduetothepharmacologicaleffectsofhighvalsartandoses(blockadeof

angiotensinII-inducedinhibitionofreninrelease,withstimulationoftherenin-producingcells)andalsooccurwith

ACEinhibitors.Thesefindingsappeartohavenorelevancetotheuseoftherapeuticdosesofvalsartaninhumans.

Thevalsartan+hydrochlorothiazidecombinationwasnottestedformutagenicity,chromosomalbreakageor

carcinogenicity,sincethereisnoevidenceofinteractionbetweenthetwosubstances.However,thesetestswere

performedseparatelywithvalsartanandhydrochlorothiazide,andproducednoevidenceofmutagenicity,chromosomal

breakageorcarcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Microcrystallinecellulose

Silica,Colloidalanhydrous

Crospovidone

Magnesiumstearate

Coating:

Hypromellose

Macrogol4000

Talc

Titaniumdioxide(E171)

Yellowironoxide(E172)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

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6.5Natureandcontentsofcontainer

PVC/PVDC/Alublisters

7,14,28,56,98,280film-coatedtablets

PVC/PVDC/Aluperforatedunitdoseblisters

56x1,98x1,280x1film-coatedtablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

NovartisPharmaceuticalsUKLtd.

FrimleyBusinessPark

Frimley

Camberley

Surrey

GU167SR

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA0013/118/005

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

1stFebruary2008

10DATEOFREVISIONOFTHETEXT

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