CO-DIOVAN

Main information

  • Trade name:
  • CO-DIOVAN Film Coated Tablet 160/ 12.5 Milligram
  • Dosage:
  • 160/ 12.5 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CO-DIOVAN Film Coated Tablet 160/12.5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1500/059/001
  • Authorization date:
  • 09-07-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PPA1500/059/001

CaseNo:2083758

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ProfindWholesaleLtd.

Unit625,KilshaneAvenue,NorthwestBusinessPark,Dublin15,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Co-Diovan160mg/12.5mgfilm-coatedtablets

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom28/07/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Co-Diovan160mg/12.5mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains160mgvalsartanand12.5mghydrochlorothiazide.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromItaly:

Darkred,ovaloidtabletimprintedwith“HHH”ononesideand“CG”ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertensioninadults.

Co-Diovanfixed-dosecombinationisindicatedinpatientswhosebloodpressureisnotadequatelycontrolledon

valsartanorhydrochlorothiazidemonotherapy.

4.2Posologyandmethodofadministration

Posology

TherecommendeddoseofCo-Diovan160mg/12.5mgisonefilm-coatedtabletoncedaily.Dosetitrationwiththe

individualcomponentsisrecommended.Ineachcase,up-titrationofindividualcomponentstothenextdoseshouldbe

followedinordertoreducetheriskofhypotensionandotheradverseevents.

Whenclinicallyappropriatedirectchangefrommonotherapytothefixedcombinationmaybeconsideredinpatients

whosebloodpressureisnotadequatelycontrolledonvalsartanorhydrochlorothiazidemonotherapy,providedthe

recommendeddosetitrationsequencefortheindividualcomponentsisfollowed.

TheclinicalresponsetoCo-Diovanshouldbeevaluatedafterinitiatingtherapyandifbloodpressureremains

uncontrolled,thedosemaybeincreasedbyincreasingeitheroneofthecomponentstoamaximumdoseofCo-Diovan

320mg/25mg.

Theantihypertensiveeffectissubstantiallypresentwithin2weeks.

Inmostpatients,maximaleffectsareobservedwithin4weeks.However,insomepatients4-8weekstreatmentmaybe

required.Thisshouldbetakenintoaccountduringdosetitration.

Methodofadministration

Co-Diovancanbetakenwithorwithoutfoodandshouldbeadministeredwithwater.

Specialpopulations

Renalimpairment

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Duetothehydrochlorothiazidecomponent,Co-Diovaniscontraindicatedinpatientswithsevererenalimpairment(see

sections4.3,4.4and5.2).

Hepaticimpairment

Inpatientswithmildtomoderatehepaticimpairmentwithoutcholestasisthedoseofvalsartanshouldnotexceed80mg

(seesection4.4).Co-Diovaniscontraindicatedinpatientswithseverehepaticimpairment(seesections4.3,4.4and

5.2).

Elderly

Nodoseadjustmentisrequiredinelderlypatients.

Paediatricpatients

Co-Diovanisnotrecommendedforuseinchildrenbelowtheageof18yearsduetoalackofdataonsafetyand

efficacy.

4.3Contraindications

Hypersensitivitytovalsartan,hydrochlorothiazide,othersulfonamide-derived medicinalproductsortoanyof

theexcipients.

Secondandthirdtrimesterofpregnancy(section4.4and4.6).

Severehepaticimpairment,biliarycirrhosisandcholestasis.

Severerenalimpairment(creatinineclearance<30ml/min),anuria.

Refractoryhypokalaemia,hyponatraemia,hypercalcaemia,andsymptomatichyperuricaemia.

4.4Specialwarningsandprecautionsforuse

Serumelectrolytechanges

Valsartan

Concomitantusewithpotassiumsupplements,potassium-sparingdiuretics,saltsubstitutescontainingpotassium,or

otheragentsthatmayincreasepotassiumlevels(heparin,etc.)isnotrecommended.Monitoringofpotassiumshould

beundertakenasappropriate.

Hydrochlorothiazide

Hypokalaemiahasbeenreportedundertreatmentwiththiazidediuretics,includinghydrochlorothiazide.Frequent

monitoringofserumpotassiumisrecommended.

Treatmentwiththiazidediuretics,includinghydrochlorothiazide,hasbeenassociatedwithhyponatraemiaand

hypochloraemicalkalosis.Thiazides,includinghydrochlorothiazide,increasetheurinaryexcretionofmagnesium,

whichmayresultinhypomagnesaemia.Calciumexcretionisdecreasedbythiazidediuretics.Thismayresultin

hypercalcaemia.

Asforanypatientreceivingdiuretictherapy,periodicdeterminationofserumelectrolytesshouldbeperformedat

appropriateintervals.

Sodiumand/orvolume-depletedpatients

Patientsreceivingthiazidediuretics,includinghydrochlorothiazide,shouldbeobservedforclinicalsignsoffluidor

electrolyteimbalance.

Inseverelysodium-depletedand/orvolume-depletedpatients,suchasthosereceivinghighdosesofdiuretics,

symptomatichypotensionmayoccurinrarecasesafterinitiationoftherapywithCo-Diovan.Sodiumand/orvolume

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Patientswithseverechronicheartfailureorotherconditionswithstimulationoftherenin-angiotensin-aldosterone-

system

Inpatientswhoserenalfunctionmaydependontheactivityoftherenin-angiotensin-aldosteronesystem(e.g.patients

withseverecongestiveheartfailure),treatmentwithangiotensinconvertingenzymeinhibitorshasbeenassociatedwith

oliguriaand/orprogressiveazotaemia,andinrarecaseswithacuterenalfailure.TheuseofCo-Diovaninpatientswith

severechronicheartfailurehasnotbeenestablished.Henceitcannotbeexcludedthatbecauseoftheinhibitionofthe

renin-angiotensin-aldosteronesystemtheapplicationofCo-Diovanaswellmaybeassociatedwithimpairmentofthe

renalfunction.Co-Diovanshouldnotbeusedinthesepatients.

Renalarterystenosis

Co-Diovanshouldnotbeusedtotreathypertensioninpatientswithunilateralorbilateralrenalarterystenosisor

stenosisofthearterytoasolitarykidney,sincebloodureaandserumcreatininemayincreaseinsuchpatients.

Primaryhyperaldosteronism

PatientswithprimaryhyperaldosteronismshouldnotbetreatedwithCo-Diovanastheirrenin-angiotensinsystemisnot

activated.

Aorticandmitralvalvestenosis,hypertrophicobstructivecardiomyopathy

Aswithallothervasodilators,specialcautionisindicatedinpatientssufferingfromaorticormitralstenosis,or

hypertrophicobstructivecardiomyopathy(HOCM).

Renalimpairment

Nodosageadjustmentisrequiredforpatientswithrenalimpairmentwithacreatinineclearance30ml/min(see

section4.2).Periodicmonitoringofserumpotassium,creatinineanduricacidlevelsisrecommendedwhenCo-Diovan

isusedinpatientswithrenalimpairment.

Kidneytransplantation

ThereiscurrentlynoexperienceonthesafeuseofCo-Diovaninpatientswhohaverecentlyundergonekidney

transplantation.

Hepaticimpairment

Inpatientswithmildtomoderatehepaticimpairmentwithoutcholestasis,Co-Diovanshouldbeusedwithcaution(see

sections4.2and5.2).

Systemiclupuserythematosus

Thiazidediuretics,includinghydrochlorothiazide,havebeenreportedtoexacerbateoractivatesystemiclupus

erythematosus.

Othermetabolicdisturbances

Thiazidediuretics,includinghydrochlorothiazide,mayalterglucosetoleranceandraiseserumlevelsofcholesterol,

triglyceridesanduricacid.Indiabeticpatientsdosageadjustmentsofinsulinororalhypoglycaemicagentsmaybe

required.

Thiazidesmayreduceurinarycalciumexcretionandcauseanintermittentandslightelevationofserumcalciuminthe

absenceofknowndisordersofcalciummetabolism.Markedhypercalcaemiamaybeevidenceofunderlying

hyperparathyroidism.Thiazidesshouldbediscontinuedbeforecarryingouttestsforparathyroidfunction.

Photosensitivity

Casesofphotosensitivityreactionshavebeenreportedwiththiazidediuretics(seesection4.8).Ifphotosensitivity

reactionoccursduringtreatment,itisrecommendedtostopthetreatment.Ifare-administrationofthediureticis

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Pregnancy

AngiotensinIIReceptorAntagonists(AIIRAs)shouldnotbeinitiatedduringpregnancy.UnlesscontinuedAIIRAs

therapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-hypertensive

treatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwith

AIIRAsshouldbestoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted(seesections4.3and

4.6).

General

CautionshouldbeexercisedinpatientswhohaveshownpriorhypersensitivitytootherangiotensinIIreceptor

antagonists.Hypersensitivityreactionstohydrochlorothiazidearemorelikelyinpatientswithallergyandasthma.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Interactionsrelatedtobothvalsartanandhydrochlorothiazide

Concomitantusenotrecommended

Lithium

ReversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcurrentuseofACE

inhibitorsandthiazide,includinghydrochlorothiazide.Duetothelackofexperiencewithconcomitantuseofvalsartan

andlithium,thiscombinationisnotrecommended.Ifthecombinationprovesnecessary,carefulmonitoringofserum

lithiumlevelsisrecommended.

Concomitantuserequiringcaution

Otherantihypertensiveagents

Co-Diovanmayincreasetheeffectsofotheragentswithantihypertensiveproperties(e.g.ACEI,betablockers,calcium

channelblockers).

Pressoramines(e.g.noradrenaline,adrenaline)

Possibledecreasedresponsetopressoraminesbutnotsufficienttoprecludetheiruse.

Non-steroidalanti-inflammatorymedicines(NSAIDs),includingselectiveCOX-2inhibitors,acetylsalicylicacid

>3g/day),andnon-selectiveNSAIDs

NSAIDScanattenuatetheantihypertensiveeffectofbothangiotensinIIantagonistsandhydrochlorothiazidewhen

administeredsimultaneously.Furthermore,concomitantuseofCo-DiovanandNSAIDsmayleadtoworseningofrenal

functionandanincreaseinserumpotassium.Therefore,monitoringofrenalfunctionatthebeginningofthetreatment

isrecommended,aswellasadequatehydrationofthepatient.

Interactionsrelatedtovalsartan

Concomitantusenotrecommended

Potassium-sparingdiuretics,potassiumsupplements,saltsubstitutescontainingpotassiumandothersubstancesthat

mayincreasepotassiumlevels

Ifamedicinalproductthataffectspotassiumlevelsisconsiderednecessaryincombinationwithvalsartan,monitoring

ofpotassiumplasmalevelsisadvised.

Nointeraction

Indruginteractionstudieswithvalsartan,nointeractionsofclinicalsignificancehavebeenfoundwithvalsartanorany

ofthefollowingsubstances:cimetidine,warfarin,furosemide,digoxin,atenolol,indomethacin,hydrochlorothiazide,

amlodipine,glibenclamide.DigoxinandindomethacincouldinteractwiththehydrochlorothiazidecomponentofCo-

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Interactionsrelatedtohydrochlorothiazide

Concomitantuserequiringcaution

Medicinalproductsassociatedwithpotassiumlossandhypokalaemia(e.g.kaliureticdiuretics,corticosteroids,

laxatives,ACTH,amphotericin,carbenoxolone,penicillinG,salicylicacidandderivatives).

Ifthesemedicinalproductsaretobeprescribedwiththehydrochlorothiazide-valsartancombination,monitoringof

potassiumplasmalevelsisadvised.Thesemedicinalproductsmaypotentiatetheeffectofhydrochlorothiazideon

serumpotassium(seesection4.4).

Medicinalproductsthatcouldinducetorsadesdepointes

Duetotheriskofhypokalaemia,hydrochlorothiazideshouldbeadministeredwithcautionwhenassociatedwith

medicinalproductsthatcouldinducetorsadesdepointes.

Digitalisglycosides

Thiazide-inducedhypokalaemiaorhypomagnesaemiamayoccurasunwantedeffectsfavouringtheonsetofdigitalis-

inducedcardiacarrhythmias.

CalciumsaltsandvitaminD

Administrationofthiazidediuretics,includinghydrochlorothiazide,withvitaminDorwithcalciumsaltsmay

potentiatetheriseinserumcalcium.

Antidiabeticagents(oralagentsandinsulin)

Thetreatmentwithathiazidemayinfluencetheglucosetolerance.Doseadjustmentoftheantidiabeticmedicinal

productmaybenecessary.

Metforminshouldbeusedwithcautionbecauseoftheriskoflacticacidosisinducedbypossiblefunctionalrenal

failurelinkedtohydrochlorothiazide.

Betablockersanddiazoxide

Concomitantuseofthiazidediuretics,includinghydrochlorothiazide,withbetablockersmayincreasetheriskof

hyperglycaemia.Thiazidediuretics,includinghydrochlorothiazide,mayenhancethehyperglycaemiceffectof

diazoxide.

Medicinalproductsusedinthetreatmentofgout(probenecid,sulfinpyrazoneandallopurinol)

Doseadjustmentofuricosuricmedicationsmaybenecessaryashydrochlorothiazidemayraisethelevelofserumuric

acid.Increaseofdosageofprobenecidorsulfinpyrazonemaybenecessary.Co-administrationofthiazidediuretics,

includinghydrochlorothiazide,mayincreasetheincidenceofhypersensitivityreactionstoallopurinol.

Anticholinergicagents(e.g.atropine,biperiden)

Thebioavailabilityofthiazide-typediureticsmaybeincreasedbyanticholinergicagents,apparentlyduetoadecrease

ingastrointestinalmotilityandthestomachemptyingrate.

Amantadine

Thiazides,includinghydrochlorothiazide,mayincreasetheriskofadverseeffectscausedbyamantadine.

Cholestyramineandcholestipolresins

Absorptionofthiazidediuretics,includinghydrochlorothiazide,isimpairedinthepresenceofanionicexchangeresins.

Cytotoxicagents(e.g.cyclophosamide,methotrexate)

Thiazides,includinghydrochlorothiazide,mayreducerenalexcretionofcytotoxicagentsandpotentiatetheir

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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Non-depolarisingskeletalmusclerelaxants(e.g.tubocurarine)

Thiazides,includinghydrochlorothiazide,potentiatetheactionofcurarederivatives.

Ciclosporin

Concomitanttreatmentwithciclosporinmayincreasetheriskofhyperuricaemiaandgout-typecomplications.

Alcohol,anaestheticsandsedatives

Potentiationoforthostatichypotensionmayoccur.

Methyldopa

Therehavebeenisolatedreportsofhaemolyticanaemiainpatientsreceivingconcomitanttreatmentwithmethyldopa

andhydrochlorothiazide.

Carbamazepine

Patientsreceivinghydrochlorothiazideconcomitantlywithcarbamazepinemaydevelophyponatremia.Suchpatients

shouldthereforebeadvisedaboutthepossibilityofhyponatraemicreactions,andshouldbemonitoredaccordingly.

Iodinecontrastmedia

Incaseofdiuretic-induceddehydration,thereisanincreasedriskofacuterenalfailure,especiallywithhighdosesof

theiodineproduct.Patientsshouldberehydratedbeforetheadministration.

4.6Pregnancyandlactation

Pregnancy

Valsartan

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithAngiotensinIIReceptorInhibitors(AIIRAs),similarrisksmayexist

forthisclassofdrugs.UnlesscontinuedAIIRAstherapyisconsideredessential,patientsplanningpregnancyshouldbe

changedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.

Whenpregnancyisdiagnosed,treatmentwithAIIRAsshouldbestoppedimmediatelyand,ifappropriate,alternative

therapyshouldbestarted.

AIIRAstherapyexposureduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

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

hyperkalaemia)(seealsosection5.3).

ShouldexposuretoAIIRAshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

InfantswhosemothershavetakenAIIRAsshouldbecloselyobservedforhypotension(seealsosection4.3and4.4).

Hydrochlorothiazide

Thereislimitedexperiencewithhydrochlorothiazideduringpregnancy,especiallyduringthefirsttrimester.Animal

studiesareinsufficient.Hydrochlorothiazidecrossestheplacenta.Basedonthepharmacologicalmechanismofaction

ofhydrochlorothiazideitsuseduringthesecondandthirdtrimestermaycompromisefoeto-placentalperfusionand

maycausefoetalandneonataleffectslikeicterus,disturbanceofelectrolytebalanceandthrombocytopenia.

Lactation

Noinformationisavailableregardingtheuseofvalsartanduringbreastfeeding.Hydrochlorothiazideisexcretedin

humanmilk.ThereforetheuseofCo-Diovanduringbreastfeedingisnotrecommended.Alternativetreatmentswith

betterestablishedsafetyprofilesduringbreast-feedingarepreferable,especiallywhilenursinganewbornorpreterm

TheuseofAngiotensinIIReceptorAntagonists(AIIRAs)isnotrecommendedduringfirst

trimesterofpregnancy(seesection4.4).TheuseofAIIRAsiscontra-indicatedduringthe

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4.7Effectsonabilitytodriveandusemachines

NostudiesontheeffectofCo-Diovanontheabilitytodriveandusemachineshavebeenperformed.Whendriving

vehiclesoroperatingmachinesitshouldbetakenintoaccountthatoccasionallydizzinessorwearinessmayoccur.

4.8Undesirableeffects

Adversereactionsreportedinclinicaltrialsandlaboratoryfindingsoccurringmorefrequentlywithvalsartanplus

hydrochlorothiazideversusplaceboandindividualpostmarketingreportsarepresentedbelowaccordingtosystem

organclass.Adversereactionsknowntooccurwitheachcomponentgivenindividuallybutwhichhavenotbeenseen

inclinicaltrialsmayoccurduringtreatmentwithvalsartan/hydrochlorothiazide.

Adversedrugreactionsarerankedbyfrequency,themostfrequentfirst,usingthefollowingconvention: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),notknown(cannotbeestimatedfromtheavailabledata).Withineachfrequencygrouping,adverse

reactionsarerankedinorderofdecreasingseriousness.

Table1.Frequencyofadversereactionswithvalsartan/hydrochlorothiazide

Metabolismandnutritiondisorders

Uncommon Dehydration

Nervoussystemdisorders

Veryrare Dizziness

Uncommon Paraesthesia

Notknown Syncope

Eyedisorders

Uncommon Visionblurred

Earandlabyrinthdisorders

Uncommon Tinnitus

Vasculardisorders

Uncommon Hypotension

Respiratory,thoracicandmediastinaldisorders

Uncommon Cough

Notknown Noncardiogenicpulmonaryoedema

Gastrointestinaldisorders

Veryrare Diarrhoea

Musculoskeletalandconnectivetissuedisorders

Uncommon Myalgia

Veryrare Arthralgia

Renalandurinarydisorders

Notknown Impairedrenalfunction

Generaldisordersandadministrationsiteconditions

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Additionalinformationontheindividualcomponents

Adversereactionspreviouslyreportedwithoneoftheindividualcomponentsmaybepotentialundesirableeffectswith

Co-Diovanaswell,evenifnotobservedinclinicaltrialsorduringpostmarketingperiod.

Table2.Frequencyofadversereactionswithvalsartan

Table3:Frequencyofadversereactionswithhydrochlorothiazide

Hydrochlorothiazidehasbeenextensivelyprescribedformanyyears,frequentlyinhigherdosesthanthose

administeredwithCo-Diovan.Thefollowingadversereactionshavebeenreportedinpatientstreatedwith

Investigations

Notknown Serumuricacidincreased,SerumbilirubinandSerum

creatinineincreased,Hypokalaemia,Hyponatraemia,

ElevationofBloodUreaNitrogen,Neutropenia

Bloodandlymphaticsystemdisorders

Notknown Decreaseinhaemoglobin,decreaseinhaematocrit,

thrombocytopenia

Immunesystemdisorders

Notknown Otherhypersensitivity/allergicreactionsincluding

serumsickness

Metabolismandnutritiondisorders

Notknown Increaseofserumpotassium

Earandlabyrinthdisorders

Uncommon Vertigo

Vasculardisorders

Notknown Vasculitis

Gastrointestinaldisorders

Uncommon Abdominalpain

Hepatobiliarydisorders

Notknown Elevationofliverfunctionvalues

Skinandsubcutaneoustissuedisorders

Notknown Angioedema,rash,pruritus

Renalandurinarydisorders

Notknown Renalfailure

Bloodandlymphaticsystemdisorders

Rare Thrombocytopeniasometimeswithpurpura

Veryrare Agranulocytosis,leucopenia,haemolytic

anaemia,bonemarrowdepression

Immunesystemdisorders

Veryrare Hypersenstivityreactions

Psychiatricdisorders

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4.9Overdose

Symptoms

Overdosewithvalsartanmayresultinmarkedhypotension,whichcouldleadtodepressedlevelofconsciousness,

circulatorycollapseand/orshock.Inaddition,thefollowingsignsandsymptomsmayoccurduetoanoverdoseofthe

hydrochlorothiazidecomponent:nausea,somnolence,hypovolaemia,andelectrolytedisturbancesassociatedwith

cardiacarrhythmiasandmusclespasms.

Treatment

Thetherapeuticmeasuresdependonthetimeofingestionandthetypeandseverityofthesymptoms,stabilisationof

thecirculatoryconditionbeingofprimeimportance.

Ifhypotensionoccurs,thepatientshouldbeplacedinthesupinepositionandsaltandvolumesupplementationshould

begivenrapidly.

Valsartancannotbeeliminatedbymeansofhaemodialysisbecauseofitsstrongplasmabindingbehaviourwhereas

Nervoussystemdisorders

Rare Headache

Cardiacdisorders

Rare Cardiacarrhythmias

Vasculardisorders

Common Posturalhypotension

Respiratory,thoracicandmediastinaldisorders

Veryrare Respiratorydistressincludingpneumonitisand

pulmonaryoedema

Gastrointestinaldisorders

Common Lossofappetite,mildnauseaandvomiting

Rare Constipation,gastrointestinaldiscomfort

Veryrare Pancreatitis

Hepatobiliarydisorders

Rare Intrahepaticcholestasisorjaundice

Skinandsubcutaneoustissuedisorders

Common Urticariaandotherformsofrash

Rare Photosensitisation

Veryrare Necrotisingvasculitisandtoxicepidermal

necrolysis,cutaneouslupuserythematosus-like

reactions,reactivationofcutaneouslupus

erythematosus

Reproductivesystemandbreastdisorders

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:AngiotensinIIantagonistsanddiuretics,valsartananddiuretics;ATCcode:C09DA03.

Valsartan/hydrochlorothiazide

Inadouble-blind,randomised,active-controlledtrialinpatientsnotadequatelycontrolledonhydrochlorothiazide

12.5mg,significantlygreatermeansystolic/diastolicBPreductionswereobservedwiththecombinationof

valsartan/hydrochlorothiazide160/12.5mg(12.4/7.5mmHg)comparedtohydrochlorothiazide25mg(5.6/2.1mmHg).

Inaddition,asignificantlygreaterpercentageofpatientsresponded(BP<140/90mmHgorSBPreduction ≥20mmHg

orDPBreduction ≥10mmHg)withvalsartan/hydrochlorothiazide160/12.5mg(50%)comparedtohydrochlorothiazide

25mg(25%).

Inadouble-blind,randomisedactive-controlledtrialinpatientsnotadequatelycontrolledonvalsartan160mg,

significantlygreatermeansystolic/diastolicBPreductionswereobservedwithboththecombinationof

valsartan/hydrochlorothiazide 160/25mg (14.6/11.9mmHg) and valsartan/hydrochlorothiazide 160/12.5mg

(12.4/10.4mmHg)comparedtovalsartan160mg(8.7/8.8mmHg).ThedifferenceinBPreductionsbetweenthe

160/25mgand160/12.5mgdosesalsoreachedstatisticalsignificance.Inaddition,asignificantlygreaterpercentageof

patientsresponded(diastolicBP<90mmHgorreduction ≥10mmHg)withvalsartan/hydrochlorothiazide160/25mg

(68%)and160/12.5mg(62%)comparedtovalsartan160mg(49%).

Inadoubleblind,randomised,placebo-controlled,factorialdesigntrialcomparingvariousdosecombinationsof

valsartan/hydrochlorothiazidetotheirrespectivecomponents,significantlygreatermeansystolic/diastolicBP

reductionswereobservedwiththecombinationofvalsartan/hydrochlorothiazide160/12.5mg(17.8/13.5mmHg)and

160/25mg(22.5/15.3mmHg)comparedtoplacebo(1.9/4.1mmHg)andtherespectivemonotherapies,i.e.,

hydrochlorothiazide12.5mg(7.3/7.2mmHg),hydrochlorothiazide25mg(12.7/9.3mmHg)andvalsartan160mg

(12.1/9.4mmHg).Inaddition,asignificantlygreaterpercentageofpatientsresponded(diastolicBP<90mmHgor

reduction ≥10mmHg)withvalsartan/hydrochlorothiazide160/25mg(81%)andvalsartan/hydrochlorothiazide

160/12.5mg(76%)comparedtoplacebo(29%)andtherespectivemonotherapies,i.e.hydrochlorothiazide12.5mg

(41%),hydrochlorothiazide25mg(54%),andvalsartan160mg(59%).

Dose-dependentdecreasesinserumpotassiumoccurredincontrolledclinicalstudieswithvalsartan+

hydrochlorothiazide. Reduction in serum potassium occurred more frequently inpatients given 25mg

hydrochlorothiazidethan in those given12.5mghydrochlorothiazide.Incontrolledclinical trials with

valsartan/hydrochlorothiazidethepotassiumloweringeffectofhydrochlorothiazidewasattenuatedbythepotassium-

sparingeffectofvalsartan.

Beneficialeffectsofvalsartanincombinationwithhydrochlorothiazideoncardiovascularmortalityandmorbidityare

currentlyunknown.

Epidemiologicalstudieshaveshownthatlong-termtreatmentwithhydrochlorothiazidereducestheriskof

cardiovascularmortalityandmorbidity.

Valsartan

ValsartanisanorallyactiveandspecificangiotensinII(AngII)receptorantagonist.Itactsselectivelyonthe

ATreceptorsubtype,whichisresponsiblefortheknownactionsofangiotensinII.TheincreasedplasmalevelsofAng

IIfollowingAT

receptorblockadewithvalsartanmaystimulatetheunblockedAT

receptor,whichappearsto

counterbalancetheeffectoftheAT

receptor.ValsartandoesnotexhibitanypartialagonistactivityattheATreceptor

andhasmuch(about20,000-fold)greateraffinityfortheATreceptorthanfortheATreceptor.Valsartanisnot

knowntobindtoorblockotherhormonereceptorsorionchannelsknowntobeimportantincardiovascular

regulation. 1

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ValsartandoesnotinhibitACE,alsoknownaskininaseII,whichconvertsAngItoAngIIanddegradesbradykinin.

SincethereisnoeffectonACEandnopotentiationofbradykininorsubstanceP,angiotensinIIantagonistsare

unlikelytobeassociatedwithcoughing.InclinicaltrialswherevalsartanwascomparedwithanACEinhibitor,the

incidenceofdrycoughwassignificantly(P<0.05)lowerinpatientstreatedwithvalsartanthaninthosetreatedwithan

ACEinhibitor(2.6%versus7.9%,respectively).InaclinicaltrialofpatientswithahistoryofdrycoughduringACE

inhibitortherapy,19.5%oftrialsubjectsreceivingvalsartanand19.0%ofthosereceivingathiazidediuretic

experiencedcoughcomparedto68.5%of.thosetreatedwithanACEinhibitoro(P<0.05).

Administrationofvalsartantopatientswithhypertensionresultsinreductionofbloodpressurewithoutaffectingpulse

rate.Inmostpatients,afteradministrationofasingleoraldose,onsetofantihypertensiveactivityoccurswithin2

hours,andthepeakreductionofbloodpressureisachievedwithin4–6hours.Theantihypertensiveeffectpersistsover

24hoursafterdosing.Duringrepeateddosing,themaximumreductioninbloodpressurewithanydoseisgenerally

attainedwithin2–4weeksandissustainedduringlong-termtherapy.Combinedwithhydrochlorothiazide,asignificant

additionalreductioninbloodpressureisachieved.

Abruptwithdrawalofvalsartanhasnotbeenassociatedwithreboundhypertensionorotheradverseclinicalevents.

Inhypertensivepatientswithtype2diabetesandmicroalbuminuria,valsartanhasbeenshowntoreducetheurinary

excretionofalbumin.TheMARVAL(MicroAlbuminuriaReductionwithValsartan)studyassessedthereductionin

urinaryalbuminexcretion(UAE)withvalsartan(80-160mg/od)versusamlodipine(5-10mg/od),in332type2

diabeticpatients(meanage:58years;265men)withmicroalbuminuria(valsartan:58µg/min;amlodipine:

55.4µg/min),normalorhighbloodpressureandwithpreservedrenalfunction(bloodcreatinine<120µmol/l).At

24weeks,UAEwasreduced(p<0.001)by42%(–24.2µg/min;95%CI:–40.4to–19.1)withvalsartanand

approximately3%(–1.7µg/min;95%CI:–5.6to14.9)withamlodipinedespitesimilarratesofbloodpressure

reductioninbothgroups.

TheDiovanReductionofProteinuria(DROP)studyfurtherexaminedtheefficacyofvalsartaninreducingUAEin

391hypertensivepatients(BP=150/88mmHg)withtype2diabetes,albuminuria(mean=102µg/min;20-700µg/min)

andpreservedrenalfunction(meanserumcreatinine=80µmol/l).Patientswererandomisedtooneof3dosesof

valsartan(160,320and640mg/od)andtreatedfor30weeks.Thepurposeofthestudywastodeterminetheoptimal

doseofvalsartanforreducingUAEinhypertensivepatientswithtype2diabetes.At30weeks,thepercentagechange

inUAEwassignificantlyreducedby36%frombaselinewithvalsartan160mg(95%CI:22to47%),andby44%with

valsartan320mg(95%CI:31to54%).Itwasconcludedthat160-320mgofvalsartanproducedclinicallyrelevant

reductionsinUAEinhypertensivepatientswithtype2diabetes.

Hydrochlorothiazide

Thesiteofactionofthiazidediureticsisprimarilyintherenaldistalconvolutedtubule.Ithasbeenshownthatthereisa

high-affinityreceptorintherenalcortexastheprimarybindingsiteforthethiazidediureticactionandinhibitionof

NaCltransportinthedistalconvolutedtubule.ThemodeofactionofthiazidesisthroughinhibitionoftheNa +

symporterperhapsbycompetingfortheCl -

site,therebyaffectingelectrolytereabsorptionmechanisms:directly

increasingsodiumandchlorideexcretiontoanapproximatelyequalextent,andindirectlybythisdiureticaction

reducingplasmavolume,withconsequentincreasesinplasmareninactivity,aldosteronesecretionandurinary

potassiumloss,andadecreaseinserumpotassium.Therenin-aldosteronelinkismediatedbyangiotensinII,sowith

co-administrationofvalsartanthereductioninserumpotassiumislesspronouncedasobservedundermonotherapy

withhydrochlorothiazide.

5.2Pharmacokineticproperties

Valsartan/hydrochlorothiazide

Thesystemicavailabilityofhydrochlorothiazideisreducedbyabout30%whenco-administeredwithvalsartan.The

kineticsofvalsartanarenotmarkedlyaffectedbytheco-administrationofhydrochlorothiazide.Thisobserved

interactionhasnoimpactonthecombineduseofvalsartanandhydrochlorothiazide,sincecontrolledclinicaltrialshave

shownaclearanti-hypertensiveeffect,greaterthanthatobtainedwitheitheractivesubstancegivenalone,orplacebo.

Valsartan

Absorption

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Meanabsolutebioavailabilityis23%.Fooddecreasesexposure(asmeasuredbyAUC)tovalsartanbyabout40%and

peakplasmaconcentration(C

)byabout50%,althoughfromabout8hpostdosingplasmavalsartanconcentrations

aresimilarforthefedandfastedgroups.ThisreductioninAUCisnot,however,accompaniedbyaclinically

significantreductioninthetherapeuticeffect,andvalsartancanthereforebegiveneitherwithorwithoutfood.

Distribution

Thesteady-statevolumeofdistributionofvalsartanafterintravenousadministrationisabout17litres,indicatingthat

valsartandoesnotdistributeintotissuesextensively.Valsartanishighlyboundtoserumproteins(94–97%),mainly

serumalbumin.

Biotransformation

Valsartanisnotbiotransformedtoahighextentasonlyabout20%ofdoseisrecoveredasmetabolites.Ahydroxy

metabolitehasbeenidentifiedinplasmaatlowconcentrations(lessthan10%ofthevalsartanAUC).Thismetaboliteis

pharmacologicallyinactive.

Elimination

Valsartanshowsmultiexponentialdecaykinetics(t

<1handt

½ß about9h).Valsartanisprimarilyeliminatedin

faeces(about83%ofdose)andurine(about13%ofdose),mainlyasunchangeddrug.Followingintravenous

administration,plasmaclearanceofvalsartanisabout2l/handitsrenalclearanceis0.62l/h(about30%oftotal

clearance).Thehalf-lifeofvalsartanis6hours.

Hydrochlorothiazide

Absorption

Theabsorptionofhydrochlorothiazide,afteranoraldose,israpid(t

about2h),withsimilarabsorption

characteristicsforbothsuspensionandtabletformulations.Absolutebioavailabilityofhydrochlorothiazideis60–80%

afteroraladministration.Concomitantadministrationwithfoodhasbeenreportedtobothincreaseanddecreasethe

systemicavailabilityofhydrochlorothiazidecomparedwiththefastedstate.Themagnitudeoftheseeffectsissmalland

hasminimalclinicalimportance.TheincreaseinmeanAUCislinearanddoseproportionalinthetherapeuticrange.

Thereisnochangeinthekineticsofhydrochlorothiazideonrepeateddosing,andaccumulationisminimalwhendosed

oncedaily.

Distribution

Thedistributionandeliminationkineticshavegenerallybeendescribedbyabi-exponentialdecayfunction.The

apparentvolumeofdistributionis4–8l/kg.

Circulatinghydrochlorothiazideisboundtoserumproteins(40–70%),mainlyserumalbumin.Hydrochlorothiazide

alsoaccumulatesinerythrocytesatapproximately1.8timesthelevelinplasma.

Elimination

Forhydrochlorotiazide,>95%oftheabsorbeddosebeingexcretedasunchangedcompoundintheurine.Therenal

clearanceiscomposedofpassivefiltrationandactivesecretionintotherenaltubule.Theterminalhalf-lifeis6-15h.

Specialpopulations

Elderly

Asomewhathighersystemicexposuretovalsartanwasobservedinsomeelderlysubjectsthaninyoungsubjects;

however,thishasnotbeenshowntohaveanyclinicalsignificance.

Limiteddatasuggestthatthesystemicclearanceofhydrochlorothiazideisreducedinbothhealthyandhypertensive

elderlysubjectscomparedtoyounghealthyvolunteers.

Renalimpairment

AttherecommendeddoseofCo-Diovannodoseadjustmentisrequiredforpatientswithacreatinineclearanceof30–

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Inpatientswithsevererenalimpairment(creatinineclearance<30ml/min)andpatientsundergoingdialysisnodataare

availableforCo-Diovan.Valsartanishighlyboundtoplasmaproteinandisnottoberemovedbydialysis,whereas

clearanceofhydrochlorothiazidewillbeachievedbydialysis.

Renalclearanceofhydrochlorothiazideiscomposedofpassivefiltrationandactivesecretionintotherenaltubule.As

expectedforacompoundwhichisclearedalmostexclusivelyviathekidneys,renalfunctionhasamarkedeffectonthe

kineticsofhydrochlorothiazide(seesection4.3).

Hepaticimpairment

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

wasincreasedapproximately2-foldcomparedwithhealthyvolunteers.Thereisnodataavailableontheuseof

valsartaninpatientswithseverehepaticdysfunction(seesection4.3).

Hepaticdiseasedoesnotsignificantlyaffectthepharmacokineticsofhydrochlorothiazide.

5.3Preclinicalsafetydata

Thepotentialtoxicityofthevalsartan-hydrochlorothiazidecombinationafteroraladministrationwasinvestigatedin

ratsandmarmosetsinstudieslastinguptosixmonths.Nofindingsemergedthatwouldexcludetheuseoftherapeutic

dosesinman.

Thechangesproducedbythecombinationinthechronictoxicitystudiesaremostlikelytohavebeencausedbythe

valsartancomponent.Thetoxicologicaltargetorganwasthekidney,thereactionbeingmoremarkedinthemarmoset

thantherat.Thecombinationledtokidneydamage(nephropathywithtubularbasophilia,risesinplasmaurea,plasma

creatinineandserumpotassium,increasesinurinevolumeandurinaryelectrolytesfrom30mg/kg/dayvalsartan+

9mg/kg/dayhydrochlorothiazideinratsand10+3mg/kg/dinmarmosets),probablybywayofalteredrenal

haemodynamics.Thesedosesinrat,respectively,represent0.9and3.5-timesthemaximumrecommendedhumandose

(MRHD)ofvalsartanandhydrochlorothiazideonamg/m 2

basis.Thesedosesinmarmoset,respectively,represent0.3

and1.2-timesthemaximumrecommendedhumandose(MRHD)ofvalsartanandhydrochlorothiazideonamg/m 2

basis.(Calculationsassumeanoraldoseof320mg/dayvalsartanincombinationwith25mg/dayhydrochlorothiazide

anda60-kgpatient.)

Highdosesofthevalsartan-hydrochlorothiazidecombinationcausedfallsinredbloodcellindices(redcellcount,

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

respectively,represent3.0and12timesthemaximumrecommendedhumandose(MRHD)ofvalsartanand

hydrochlorothiazideonamg/m 2

basis.Thesedosesinmarmoset,respectively,represent0.9and3.5timesthe

maximumrecommendedhumandose(MRHD)ofvalsartanandhydrochlorothiazideonamg/m 2

basis.(Calculations

assumeanoraldoseof320mg/dayvalsartanincombinationwith25mg/dayhydrochlorothiazideanda60-kgpatient).

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

kidneytohyperplasiaoftheafferentaterioles(at600+188mg/kg/dinratsandfrom30+9mg/kg/dinmarmosets).

Thesedosesinmarmoset,respectively,represent0.9and3.5timesthemaximumrecommendedhumandose(MRHD)

ofvalsartanandhydrochlorothiazideonamg/m 2

basis.Thesedosesinrat,respectively,represent18and73timesthe

maximumrecommendedhumandose(MRHD)ofvalsartanandhydrochlorothiazideonamg/m 2

basis.(Calculations

assumeanoraldoseof320mg/dayvalsartanincombinationwith25mg/dayhydrochlorothiazideanda60-kgpatient).

Theabovementionedeffectsappeartobeduetothepharmacologicaleffectsofhighvalsartandoses(blockadeof

angiotensinII-inducedinhibitionofreninrelease,withstimulationoftherenin-producingcells)andalsooccurwith

ACEinhibitors.Thesefindingsappeartohavenorelevancetotheuseoftherapeuticdosesofvalsartaninhumans.

Thevalsartan-hydrochlorothiazidecombinationwasnottestedformutagenicity,chromosomalbreakageor

carcinogenicity,sincethereisnoevidenceofinteractionbetweenthetwosubstances.However,thesetestswere

performedseparatelywithvalsartanandhydrochlorothiazide,andproducednoevidenceofmutagenicity,chromosomal

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Inrats,maternallytoxicdosesofvalsartan(600mg/kg/day)duringthelastdaysofgestationandlactationledtolower

survival,lowerweightgainanddelayeddevelopment(pinnadetachmentandear-canalopening)intheoffspring(see

section4.6).Thesedosesinrats(600mg/kg/day)areapproximately18timesthemaximumrecommendedhumandose

onamg/m2basis(calculationsassumeanoraldoseof320mg/dayanda60-kgpatient).Similarfindingswereseen

withvalsartan/hydrochlorothiazideinratsandrabbitsInembryo-fetaldevelopment(SegmentII)studieswith

valsartan/hydrochlorothiazideinratandrabbit,therewasnoevidenceofteratogenicity;however,fetotoxicity

associatedwithmaternaltoxicitywasobserved.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Microcrystallinecellulose

Colloidalanhydroussilica

Crospovidone

Magnesiumstearate

Coating:

Hypromellose

Macrogol8000

Talc

Redironoxide(E172)

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable

6.3ShelfLife

Theshelflifeexpirydateofthisproductisthedateshownontheblisterstripsandoutercartonoftheproductas

marketedinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Over-labelledcardboardcartoncontainingblisterstrips(14tabletsperblister).Packsize28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7PARALLELPRODUCTAUTHORISATIONHOLDER

ProfindWholesaleLtd

Unit625,KilshaneAvenue

NorthwestBusinessPark

Dublin15

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8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1500/59/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:9 th

July2010

10DATEOFREVISIONOFTHETEXT

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