CO-DIOVAN

Main information

  • Trade name:
  • CO-DIOVAN Film Coated Tablet 80/12.5 Milligram
  • Dosage:
  • 80/12.5 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CO-DIOVAN Film Coated Tablet 80/12.5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1500/059/003
  • Authorization date:
  • 29-10-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Co-Diovan80mg/12.5mgfilm-coatedtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains80mgofvalsartanand12.5mgofhydrochlorothiazide.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromHolland:

Lightorange,ovaloidtabletimprintedwith“HGH”ononesideand“CG”ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertensioninadults.

Co-Diovanfixed-dosecombinationisindicatedinpatientswhosebloodpressureisnotadequatelycontrolledon

valsartanorhydrochlorothiazidemonotherapy.

4.2Posologyandmethodofadministration

Posology

TherecommendeddoseofCo-Diovan80mg/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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 1

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 medicinalproductsortoanyofthe

excipients.

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 2

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

deemednecessary,itisrecommendedtoprotectexposedareastothesunortoartificialUVA.

Pregnancy

AngiotensinIIReceptorAntagonists(AIIRAs)shouldnotbeinitiatedduringpregnancy.UnlesscontinuedAIIRAs

therapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-hypertensive

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 3

Whenpregnancyisdiagnosed,treatmentwithAIIRAsshouldbestoppedimmediately,and,ifappropriate,alternative

therapyshouldbestarted(seesections4.3and4.6).

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-

Diovan(seeinteractionsrelatedtohydrochlorothiazide).

Interactionsrelatedtohydrochlorothiazide

Concomitantuserequiringcaution

Medicinalproductsassociatedwithpotassiumlossandhypokalaemia(e.g.kaliureticdiuretics,corticosteroids,

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

Ifthesemedicinalproductsaretobeprescribedwiththehydrochlorothiazide-valsartancombination,monitoringof

potassiumplasmalevelsisadvised.Thesemedicinalproductsmaypotentiatetheeffectofhydrochlorothiazideon

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 4

Medicinalproductsthatcouldinducetorsadesdepointes

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,mizolastin,pentamidine,

sparfloxacine,terfenadine,vincaminei.v.)

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

myelosuppressiveeffects.

Non-depolarisingskeletalmusclerelaxants(e.g.tubocurarine)

Thiazides,includinghydrochlorothiazide,potentiatetheactionofcurarederivatives.

Ciclosporin

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 5

Alcohol,anaestheticsandsedatives

Potentiationoforthostatichypotensionmayoccur.

Methyldopa

Therehavebeenisolatedreportsofhaemolyticanaemiainpatientsreceivingconcomitanttreatmentwithmethyldopa

andhydrochlorothiazide.

Carbamazepine

Patientsreceivinghydrochlorothiazideconcomitantlywithcarbamazepinemaydevelophyponatremia.Suchpatients

shouldthereforebeadvisedaboutthepossibilityofhyponatraemicreactions,andshouldbemonitoredaccordingly.

Iodinecontrastmedia

Incaseofdiuretic-induceddehydration,thereisanincreasedriskofacuterenalfailure,especiallywithhighdosesof

theiodineproduct.Patientsshouldberehydratedbeforetheadministration.

4.6Fertility,pregnancyandlactation

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

infant.

4.7Effectsonabilitytodriveandusemachines

NostudiesontheeffectofCo-Diovanontheabilitytodriveandusemachineshavebeenperformed.Whendriving

TheuseofAngiotensinIIReceptorAntagonists(AIIRAs)isnotrecommendedduringfirst

trimesterofpregnancy(seesection4.4).TheuseofAIIRAsiscontra-indicatedduringthe

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 6

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

Uncommon Fatigue

Investigations

Notknown Serumuricacidincreased,SerumbilirubinandSerum

creatinineincreased,Hypokalaemia,Hyponatraemia,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 7

Additionalinformationontheindividualcomponents

Adversereactionspreviouslyreportedwithoneoftheindividualcomponentsmaybepotentialundesirableeffectswith

Co-Diovanaswell,evenifnotobservedinclinicaltrialsorduringpostmarketingperiod.

Table2.Frequencyofadversereactionswithvalsartan

Table3:Frequencyofadversereactionswithhydrochlorothiazide

Hydrochlorothiazidehasbeenextensivelyprescribedformanyyears,frequentlyinhigherdosesthanthose

administeredwithCo-Diovan.Thefollowingadversereactionshavebeenreportedinpatientstreatedwith

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

Rare Depression,sleepdisturbances

Nervoussystemdisorders

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 8

4.9Overdose

Symptoms

Overdosewithvalsartanmayresultinmarkedhypotension,whichcouldleadtodepressedlevelofconsciousness,

circulatorycollapseand/orshock.Inaddition,thefollowingsignsandsymptomsmayoccurduetoanoverdoseofthe

hydrochlorothiazidecomponent:nausea,somnolence,hypovolaemia,andelectrolytedisturbancesassociatedwith

cardiacarrhythmiasandmusclespasms.

Treatment

Thetherapeuticmeasuresdependonthetimeofingestionandthetypeandseverityofthesymptoms,stabilisationof

thecirculatoryconditionbeingofprimeimportance.

Ifhypotensionoccurs,thepatientshouldbeplacedinthesupinepositionandsaltandvolumesupplementationshould

begivenrapidly.

Valsartancannotbeeliminatedbymeansofhaemodialysisbecauseofitsstrongplasmabindingbehaviourwhereas

clearanceofhydrochlorothiazidewillbeachievedbydialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 9

Valsartan/hydrochlorothiazide

Inadouble-blind,randomised,active-controlledtrialinpatientsnotadequatelycontrolledonhydrochlorothiazide

12.5mg,significantlygreatermeansystolic/diastolicBPreductionswereobservedwiththecombinationof

valsartan/hydrochlorothiazide80/12.5mg(14.9/11.3mmHg)comparedtohydrochlorothiazide12.5mg

(5.2/2.9mmHg)andhydrochlorothiazide25mg(6.8/5.7mmHg).

Inaddition,asignificantlygreaterpercentageofpatientsresponded(diastolicBP<90mmHgorreduction ≥10mmHg)

withvalsartan/hydrochlorothiazide80/12.5mg(60%)comparedtohydrochlorothiazide12.5mg(25%)and

hydrochlorothiazide25mg(27%).

Inadouble-blind,randomised,active-controlledtrialinpatientsnotadequatelycontrolledonvalsartan80mg,

significantlygreatermeansystolic/diastolicBPreductionswereobservedwiththecombinationof

valsartan/hydrochlorothiazide80/12.5mg(9.8/8.2mmHg)comparedtovalsartan80mg(3.9/5.1mmHg)andvalsartan

160mg(6.5/6.2mmHg).Inaddition,asignificantlygreaterpercentageofpatientsresponded(diastolicBP<90mmHg

orreduction ≥10mmHg)withvalsartan/hydrochlorothiazide80/12.5mg(51%)comparedtovalsartan80mg(36%)

andvalsartan160mg(37%).

Inadouble-blind,randomised,placebo-controlled,factorialdesigntrialcomparingvariousdosecombinationsof

valsartan/hydrochlorothiazidetotheirrespectivecomponents,significantlygreatermeansystolic/diastolicBP

reductionswereobservedwiththecombinationofvalsartan/hydrochlorothiazide80/12.5mg(16.5/11.8mmHg)

comparedtoplacebo(1.9/4.1mmHg)andbothhydrochlorothiazide12.5mg(7.3/7.2mmHg)andvalsartan80mg

(8.8/8.6mmHg).Inaddition,asignificantlygreaterpercentageofpatientsresponded(diastolicBP<90mmHgor

reduction ≥10mmHg)withvalsartan/hydrochlorothiazide80/12.5mg(64%)comparedtoplacebo(29%)and

hydrochlorothiazide(41%).

Dose-dependentdecreasesinserumpotassiumoccurredincontrolledclinicalstudieswithvalsartan+

hydrochlorothiazide.Reductioninserumpotassiumoccurredmorefrequentlyinpatientsgiven25mg

hydrochlorothiazidethaninthosegiven12.5mghydrochlorothiazide.Incontrolledclinicaltrialswith

valsartan/hydrochlorothiazidethepotassiumloweringeffectofhydrochlorothiazidewasattenuatedbythepotassium-

sparingeffectofvalsartan.

Beneficialeffectsofvalsartanincombinationwithhydrochlorothiazideoncardiovascularmortalityandmorbidityare

currentlyunknown.

Epidemiologicalstudieshaveshownthatlong-termtreatmentwithhydrochlorothiazidereducestheriskof

cardiovascularmortalityandmorbidity.

Valsartan

ValsartanisanorallyactiveandspecificangiotensinII(AngII)receptorantagonist.ItactsselectivelyontheAT

receptorsubtype,whichisresponsiblefortheknownactionsofangiotensinII.TheincreasedplasmalevelsofAngII

followingAT

receptorblockadewithvalsartanmaystimulatetheunblockedAT

receptor,whichappearsto

counterbalancetheeffectoftheAT

receptor.ValsartandoesnotexhibitanypartialagonistactivityattheAT

receptor

andhasmuch(about20,000-fold)greateraffinityfortheAT

receptorthanfortheAT

receptor.Valsartanisnot

knowntobindtoorblockotherhormonereceptorsorionchannelsknowntobeimportantincardiovascularregulation.

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 10

Administrationofvalsartantopatientswithhypertensionresultsinreductionofbloodpressurewithoutaffectingpulse

rate.Inmostpatients,afteradministrationofasingleoraldose,onsetofantihypertensiveactivityoccurswithin

2hours,andthepeakreductionofbloodpressureisachievedwithin4–6hours.Theantihypertensiveeffectpersists

over24hoursafterdosing.Duringrepeateddosing,themaximumreductioninbloodpressurewithanydoseis

generallyattainedwithin2–4weeksandissustainedduringlong-termtherapy.Combinedwithhydrochlorothiazide,a

significantadditionalreductioninbloodpressureisachieved.

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)studyfurtherexaminedtheefficacyof

valsartaninreducingUAEin391hypertensivepatients(BP=150/88mmHg)withtype2diabetes,albuminuria

(mean=102µg/min;20-700µg/min)andpreservedrenalfunction(meanserumcreatinine=80µmol/l).Patientswere

randomisedtooneof3dosesofvalsartan(160,320and640mg/od)andtreatedfor30weeks.Thepurposeofthestudy

wastodeterminetheoptimaldoseofvalsartanforreducingUAEinhypertensivepatientswithtype2diabetes.

At30weeks,thepercentagechangeinUAEwassignificantlyreducedby36%frombaselinewithvalsartan160mg

(95%CI:22to47%),andby44%withvalsartan320mg(95%CI:31to54%).Itwasconcludedthat160-320mgof

valsartanproducedclinicallyrelevantreductionsinUAEinhypertensivepatientswithtype2diabetes.

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

Followingoraladministrationofvalsartanalone,peakplasmaconcentrationsofvalsartanarereachedin2–4hours.

Meanabsolutebioavailabilityis23%.Fooddecreasesexposure(asmeasuredbyAUC)tovalsartanbyabout40%and

peakplasmaconcentration(C

)byabout50%,althoughfromabout8hpostdosingplasmavalsartanconcentrations

aresimilarforthefedandfastedgroups.ThisreductioninAUCisnot,however,accompaniedbyaclinically

significantreductioninthetherapeuticeffect,andvalsartancanthereforebegiveneitherwithorwithoutfood.

Distribution

Thesteady-statevolumeofdistributionofvalsartanafterintravenousadministrationisabout17litres,indicatingthat

valsartandoesnotdistributeintotissuesextensively.Valsartanishighlyboundtoserumproteins(94–97%),mainly

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 11

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.Thereisnochangeinthekineticsof

hydrochlorothiazideonrepeateddosing,andaccumulationisminimalwhendosedoncedaily.

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–

70ml/min.

Inpatientswithsevererenalimpairment(creatinineclearance<30ml/min)andpatientsundergoingdialysisnodataare

availableforCo-Diovan.Valsartanishighlyboundtoplasmaproteinandisnottoberemovedbydialysis,whereas

clearanceofhydrochlorothiazidewillbeachievedbydialysis.

Renalclearanceofhydrochlorothiazideiscomposedofpassivefiltrationandactivesecretionintotherenaltubule.As

expectedforacompoundwhichisclearedalmostexclusivelyviathekidneys,renalfunctionhasamarkedeffectonthe

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 12

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,represent0.3and1.2-timesthemaximumrecommendedhumandose(MRHD)

ofvalsartanandhydrochlorothiazideonamg/m 2

basis.(Calculationsassumeanoraldoseof320mg/dayvalsartanin

combinationwith25mg/dayhydrochlorothiazideanda60-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

breakageorcarcinogenicity.

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 13

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Microcrystallinecellulose

Colloidalanhydroussilica

Crospovidone

Magnesiumstearate

Coating:

Hypromellose

Macrogol8000

Talc

Redironoxide(El72)

Yellowironoxide(El72)

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelflifeexpirydateofthisproductisthedateshownontheblisterstripsandoutercartonoftheproductas

marketedinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30·C.

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Anover-labelledcartoncontainingtwoblisterstrips(14tabletsperblister).

Packsize:28capsules.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7PARALLELPRODUCTAUTHORISATIONHOLDER

ProfindWholesaleLtd.

Unit625,KilshaneAvenue

NorthwestBusinessPark

Ballycoolin

Dublin15

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 14

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:29thofOctober2010

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/10/2010 CRN 2086784 page number: 15