DIOVAN

Main information

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

Documents

Localization

  • Available in:
  • DIOVAN Film Coated Tablet 80 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1659/030/001
  • Authorization date:
  • 03-05-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Diovan80mgFilmcoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onefilm-coatedtabletcontains80mgvalsartan.

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablets.

Palered,round,film-coatedtabletwithbevellededges,scoredononeside,withdebossing“D”ononesideofthescore

and“V”ontheothersideofthescoreand“NVR”onthereversesideofthetablet.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension

Treatmentofessentialhypertensioninadults,andhypertensioninchildrenandadolescents6to18yearsofage.

Recentmyocardialinfarction

Treatmentofclinicallystableadultpatientswithsymptomaticheartfailureorasymptomaticleftventricularsystolic

dysfunctionafterarecent(12hours-10days)myocardialinfarction(seesections4.4and5.1).

Heartfailure

TreatmentofsymptomaticheartfailureinadultpatientswhenAngiotensinConvertingEnzyme(ACE)inhibitors

cannotbeused,orasadd-ontherapytoACEinhibitorswhenbetablockerscannotbeused(seesections4.4and5.1).

4.2Posologyandmethodofadministration

Posology

Hypertension

TherecommendedstartingdoseofDiovanis80mgoncedaily.Theantihypertensiveeffectissubstantiallypresent

within2weeks,andmaximaleffectsareattainedwithin4weeks.Insomepatientswhosebloodpressureisnot

adequatelycontrolled,thedosecanbeincreasedto160mgandtoamaximumof320mg.

Diovanmayalsobeadministeredwithotherantihypertensiveagents.Theadditionofadiureticsuchas

hydrochlorothiazidewilldecreasebloodpressureevenfurtherinthesepatients.

Recentmyocardialinfarction

Inclinicallystablepatients,therapymaybeinitiatedasearlyas12hoursafteramyocardialinfarction.Afteraninitial

doseof20mgtwicedaily,valsartanshouldbetitratedto40mg,80mg,and160mgtwicedailyoverthenextfew

weeks.Thestartingdoseisprovidedbythe40mgdivisibletablet.

Thetargetmaximumdoseis160mgtwicedaily.Ingeneral,itisrecommendedthatpatientsachieveadoselevelof80

mgtwicedailybytwoweeksaftertreatmentinitiationandthatthetargetmaximumdose,160mgtwicedaily,be

achievedbythreemonths,basedonthepatient'stolerability.Ifsymptomatichypotensionorrenaldysfunctionoccur,

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Valsartanmaybeusedinpatientstreatedwithotherpost-myocardialinfarctiontherapies,e.g.thrombolytics,

acetylsalicylicacid,betablockers,statins,anddiuretics.ThecombinationwithACEinhibitorsisnotrecommended

(seesections4.4and5.1).

Evaluationofpost-myocardialinfarctionpatientsshouldalwaysincludeassessmentofrenalfunction.

Heartfailure

TherecommendedstartingdoseofDiovanis40mgtwicedaily.Uptitrationto80mgand160mgtwicedailyshouldbe

doneatintervalsofatleasttwoweekstothehighestdose,astoleratedbythepatient.Considerationshouldbegivento

reducingthedoseofconcomitantdiuretics.Themaximumdailydoseadministeredinclinicaltrialsis320mgin

divideddoses.

Valsartanmaybeadministeredwithotherheartfailuretherapies.However,thetriplecombinationofanACEinhibitor,

abetablockerandvalsartanisnotrecommended(seesections4.4and5.1).

Evaluationofpatientswithheartfailureshouldalwaysincludeassessmentofrenalfunction.

Additionalinformationonspecialpopulations

Elderly

Nodoseadjustmentisrequiredinelderlypatients.

Renalimpairment

Nodoseadjustmentisrequiredforadultpatientswithacreatinineclearance>10ml/min(seesections4.4and5.2).

Hepaticimpairment

Diovaniscontraindicatedinpatientswithseverehepaticimpairment,biliarycirrhosisandinpatientswithcholestasis

(seesections4.3,4.4and5.2).Inpatientswithmildtomoderatehepaticimpairmentwithoutcholestasis,thedoseof

valsartanshouldnotexceed80mg.

Paediatricpopulation

Paediatrichypertension

Childrenandadolescents6to18yearsofage

Theinitialdoseis40mgoncedailyforchildrenweighingbelow35kgand80mgoncedailyforthoseweighing35kg

ormore.Thedoseshouldbeadjustedbasedonbloodpressureresponse.Formaximumdosesstudiedinclinicaltrials

pleaserefertothetablebelow.

Doseshigherthanthoselistedhavenotbeenstudiedandarethereforenotrecommended.

Childrenlessthan6yearsofage

Availabledataaredescribedinsections4.8,5.1and5.2.HoweversafetyandefficacyofDiovaninchildrenaged1to

6yearshavenotbeenestablished.

Useinpaediatricpatientsaged6to18yearswithrenalimpairment

Useinpaediatricpatientswithacreatinineclearance<30ml/minandpaediatricpatientsundergoingdialysishasnot

beenstudied,thereforevalsartanisnotrecommendedinthesepatients.Nodoseadjustmentisrequiredforpaediatric

patientswithacreatinineclearance>30ml/min.Renalfunctionandserumpotassiumshouldbecloselymonitored(see

Weight Maximumdosestudiedinclinicaltrials

≥18kgto<35kg 80mg

≥35kgto<80kg

160mg

≥80kgto≤160kg

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Useinpaediatricpatientsaged6to18yearswithhepaticimpairment

Asinadults,Diovaniscontraindicatedinpaediatricpatientswithseverehepaticimpairment,biliarycirrhosisandin

patientswithcholestasis(seesections4.3,4.4and5.2).ThereislimitedclinicalexperiencewithDiovaninpaediatric

patientswithmildtomoderatehepaticimpairment.Thedoseofvalsartanshouldnotexceed80mginthesepatients.

Paediatricheartfailureandrecentmyocardialinfarction

Diovanisnotrecommendedforthetreatmentofheartfailureorrecentmyocardialinfarctioninchildrenand

adolescentsbelowtheageof18yearsduetothelackofdataonsafetyandefficacy.

Methodofadministration

Diovanmaybetakenindependentlyofamealandshouldbeadministeredwithwater.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

Severehepaticimpairment,biliarycirrhosisandcholestasis.

Secondandthirdtrimesterofpregnancy(seesections4.4and4.6).

4.4Specialwarningsandprecautionsforuse

Hyperkalaemia

Concomitantusewithpotassiumsupplements,potassium-sparingdiuretics,saltsubstitutescontainingpotassium,or

otheragentsthatmayincreasepotassiumlevels(heparin,etc.)isnotrecommended.Monitoringofpotassiumshouldbe

undertakenasappropriate.

Impairedrenalfunction

Thereiscurrentlynoexperienceonthesafeuseinpatientswithacreatinineclearance<10ml/minandpatients

undergoingdialysis,thereforevalsartanshouldbeusedwithcautioninthesepatients.Nodoseadjustmentisrequired

foradultpatientswithcreatinineclearance>10ml/min(seesections4.2and5.2).

Hepaticimpairment

Inpatientswithmildtomoderatehepaticimpairmentwithoutcholestasis,Diovanshouldbeusedwithcaution(see

sections4.2and5.2).

Sodium-and/orvolume-depletedpatients

Inseverelysodium-depletedand/orvolume-depletedpatients,suchasthosereceivinghighdosesofdiuretics,

symptomatichypotensionmayoccurinrarecasesafterinitiationoftherapywithDiovan.Sodiumand/orvolume

depletionshouldbecorrectedbeforestartingtreatmentwithDiovan,forexamplebyreducingthediureticdose.

Renalarterystenosis

Inpatientswithbilateralrenalarterystenosisorstenosistoasolitarykidney,thesafeuseofDiovanhasnotbeen

established.

Short-termadministrationofDiovantotwelvepatientswithrenovascularhypertensionsecondarytounilateralrenal

arterystenosisdidnotinduceanysignificantchangesinrenalhaemodynamics,serumcreatinine,orbloodureanitrogen

(BUN).However,otheragentsthataffecttherenin-angiotensinsystemmayincreasebloodureaandserumcreatininein

patientswithunilateralrenalarterystenosis,thereforemonitoringofrenalfunctionisrecommendedwhenpatientsare

treatedwithvalsartan.

Kidneytransplantation

ThereiscurrentlynoexperienceonthesafeuseofDiovaninpatientswhohaverecentlyundergonekidney

transplantation.

Primaryhyperaldosteronism

PatientswithprimaryhyperaldosteronismshouldnotbetreatedwithDiovanastheirrenin-angiotensinsystemisnot

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Aorticandmitralvalvestenosis,obstructivehypertrophiccardiomyopathy

Aswithallothervasodilators,specialcautionisindicatedinpatientssufferingfromaorticormitralstenosis,or

hypertrophicobstructivecardiomyopathy(HOCM).

Pregnancy

AngiotensinIIReceptorAntagonists(AIIRAs)shouldnotbeinitiatedduringpregnancy.UnlesscontinuedAIIRAs

therapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-hypertensive

treatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwith

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

4.6).

Recentmyocardialinfarction

Thecombinationofcaptoprilandvalsartanhasshownnoadditionalclinicalbenefit,insteadtheriskforadverseevents

increasedcomparedtotreatmentwiththerespectivetherapies(seesections4.2and5.1).Therefore,thecombinationof

valsartanwithanACEinhibitorisnotrecommended.

Cautionshouldbeobservedwheninitiatingtherapyinpost-myocardialinfarctionpatients.Evaluationofpost-

myocardialinfarctionpatientsshouldalwaysincludeassessmentofrenalfunction(seesection4.2).

UseofDiovaninpost-myocardialinfarctionpatientscommonlyresultsinsomereductioninbloodpressure,but

discontinuationoftherapybecauseofcontinuingsymptomatichypotensionisnotusuallynecessaryprovideddosing

instructionsarefollowed(seesection4.2).

HeartFailure

Inpatientswithheartfailure,thetriplecombinationofanACEinhibitor,abetablockerandDiovanhasnotshownany

clinicalbenefit(seesection5.1).Thiscombinationapparentlyincreasestheriskforadverseeventsandisthereforenot

recommended.

Cautionshouldbeobservedwheninitiatingtherapyinpatientswithheartfailure.Evaluationofpatientswithheart

failureshouldalwaysincludeassessmentofrenalfunction(seesection4.2).

UseofDiovaninpatientswithheartfailurecommonlyresultsinsomereductioninbloodpressure,butdiscontinuation

oftherapybecauseofcontinuingsymptomatichypotensionisnotusuallynecessaryprovideddosinginstructionsare

followed(seesection4.2).

Inpatientswhoserenalfunctionmaydependontheactivityoftherenin-angiotensinsystem(e.gpatientswithsevere

congestiveheartfailure),treatmentwithangiotensinconvertingenzymeinhibitorshasbeenassociatedwitholiguria

and/orprogressiveazotaemiaandinrarecaseswithacuterenalfailureand/ordeath.AsvalsartanisanangiotensinII

antagonist,itcannotbeexcludedthattheuseofDiovanmaybeassociatedwithimpairmentoftherenalfunction.

Paediatricpopulation

Impairedrenalfunction

Useinpaediatricpatientswithacreatinineclearance<30ml/minandpaediatricpatientsundergoingdialysishasnot

beenstudied,thereforevalsartanisnotrecommendedinthesepatients.Nodoseadjustmentisrequiredforpaediatric

patientswithacreatinineclearance>30ml/min(seesections4.2and5.2).Renalfunctionandserumpotassiumshould

becloselymonitoredduringtreatmentwithvalsartan.Thisappliesparticularlywhenvalsartanisgiveninthepresence

ofotherconditions(fever,dehydration)likelytoimpairrenalfunction

Impairedhepaticfunction

Asinadults,Diovaniscontraindicatedinpaediatricpatientswithseverehepaticimpairment,biliarycirrhosisandin

patientswithcholestasis(seesections4.3and5.2).ThereislimitedclinicalexperiencewithDiovaninpaediatric

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantusenotrecommended

Lithium

ReversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcurrentuseofACE

inhibitors.Duetothelackofexperiencewithconcomitantuseofvalsartanandlithium,thiscombinationisnot

recommended.Ifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsisrecommended.

Potassium-sparingdiuretics,potassiumsupplements,saltsubstitutescontainingpotassiumandothersubstancesthat

mayincreasepotassiumlevels

Ifamedicinalproductthataffectspotassiumlevelsisconsiderednecessaryincombination

Withvalsartan,monitoringofpotassiumplasmalevelsisadvised.

Cautionrequiredwithconcomitantuse

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

>3g/day),andnon-selectiveNSAIDs

WhenangiotensinIIantagonistsareadministeredsimultaneouslywithNSAIDs,attenuationoftheantihypertensive

effectmayoccur.Furthermore,concomitantuseofangiotensinIIantagonistsandNSAIDsmayleadtoanincreased

riskofworseningofrenalfunctionandanincreaseinserumpotassium.Therefore,monitoringofrenalfunctionatthe

beginningofthetreatmentisrecommended,aswellasadequatehydrationofthepatient.

Others

Indruginteractionstudieswithvalsartan,nointeractionsofclinicalsignificancehavebeenfoundwithvalsartanorany

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

amlodipine,glibenclamide.

Paediatricpopulation

Inhypertensioninchildrenandadolescents,whereunderlyingrenalabnormalitiesarecommon,cautionis

recommendedwiththeconcomitantuseofvalsartanandothersubstancesthatinhibitthereninangiotensinaldosterone

systemwhichmayincreaseserumpotassium.Renalfunctionandserumpotassiumshouldbecloselymonitored.

4.6Fertility,pregnancyandlactation

Pregnancy

TheuseofAngiotensinIIReceptorAntagonists(AIIRAs)isnotrecommendedduringthefirsttrimesterofpregnancy

(seesection4.4).TheuseofAIIRAsiscontra-indicatedduringthesecondandthirdtrimesterofpregnancy(see

sections4.3and4.4).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;however,asmallincreaseinriskcannotbeexcluded.Whilstthereis

nocontrolledepidemiologicaldataontheriskwithAIIRAs,similarrisksmayexistforthisclassofdrugs.Unless

continuedAIIRAtherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-

hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,

treatmentwithAIIRAsshouldbestoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted.

AIIRAstherapyexposureduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

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

hyperkalaemia);seealsosection5.3“Preclinicalsafetydata”.

ShouldexposuretoAIIRAshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

TheuseofAngiotensinIIReceptorAntagonists(AIIRAs)isnotrecommendedduringthefirsttrimesterof

pregnancy(seesection4.4).TheuseofAIIRAsiscontra-indicatedduringthesecondandthirdtrimesterof

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InfantswhosemothershavetakenAIIRAsshouldbecloselyobservedforhypotension(seealsosections4.3and4.4).

Lactation

Becausenoinformationisavailableregardingtheuseofvalsartanduringbreastfeeding,Diovanisnotrecommended

andalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,especiallywhile

nursinganewbornorpreterminfant.

Fertility

Valsartanhadnoadverseeffectsonthereproductiveperformanceofmaleorfemaleratsatoraldosesupto

200mg/kg/day.Thisdoseis6timesthemaximumrecommendedhumandoseonamg/m 2

basis(calculationsassume

anoraldoseof320mg/dayanda60-kgpatient).

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodrivehavebeenperformed.Whendrivingvehiclesoroperatingmachinesit

shouldbetakenintoaccountthatoccasionallydizzinessorwearinessmayoccur.

4.8Undesirableeffects

Incontrolledclinicalstudiesinadultpatientswithhypertension,theoverallincidenceofadversereactions(ADRs)was

comparablewithplaceboandisconsistentwiththepharmacologyofvalsartan.TheincidenceofADRsdidnotappear

toberelatedtodoseortreatmentdurationandalsoshowednoassociationwithgender,ageorrace.

TheADRsreportedfromclinicalstudies,post-marketingexperienceandlaboratoryfindingsarelistedbelowaccording

tosystemorganclass.

Adversereactionsarerankedbyfrequency,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),includingisolatedreports.Withineachfrequencygrouping,adversereactionsarerankedinorderof

decreasingseriousness.

ForalltheADRsreportedfrompost-marketingexperienceandlaboratoryfindings,itisnotpossibletoapplyanyADR

frequencyandthereforetheyarementionedwitha"notknown"frequency.

Hypertension

Bloodandlymphaticsystemdisorders

Notknown Decreaseinhaemoglobin,Decreasein

haematocrit,Neutropenia,Thrombocytopenia

Immunesystemdisorders

Notknown Hypersensitivityincludingserumsickness

Metabolismandnutritiondisorders

Notknown Increaseofserumpotassium,hyponatraemia

Earandlabyrinthsystemdisorders

Uncommon Vertigo

Vasculardisorders

Notknown Vasculitis

Respiratory,thoracicandmediastinaldisorders

Uncommon Cough

Gastrointestinaldisorders

Uncommon Abdominalpain

Hepato-biliarydisorders

Notknown Elevationofliverfunctionvaluesincluding

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Paediatricpopulation

Hypertension

Theantihypertensiveeffectofvalsartanhasbeenevaluatedintworandomised,double-blindclinicalstudiesin

561paediatricpatientsfrom6to18yearsofage.Withtheexceptionofisolatedgastrointestinaldisorders(like

abdominalpain,nausea,vomiting)anddizziness,norelevantdifferencesintermsoftype,frequencyandseverityof

adversereactionswereidentifiedbetweenthesafetyprofileforpaediatricpatientsaged6to18yearsandthat

previouslyreportedforadultpatients.

Neurocognitiveanddevelopmentalassessmentofpaediatricpatientsaged6to16yearsofagerevealednooverall

clinicallyrelevantadverseimpactaftertreatmentwithDiovanforuptooneyear.

Inadouble-blindrandomizedstudyin90childrenaged1to6years,whichwasfollowedbyaone-yearopen-label

extension,twodeathsandisolatedcasesofmarkedlivertransaminaseselevationswereobserved.Thesecasesoccurred

inapopulationwhohadsignificantcomorbidities.AcausalrelationshiptoDiovanhasnotbeenestablished.Ina

secondstudyinwhich75childrenaged1to6yearswererandomised,nosignificantlivertransaminaseelevationsor

deathoccurredwithvalsartantreatment.

Hyperkalaemiawasmorefrequentlyobservedinchildrenandadolescentsaged6to18yearswithunderlyingchronic

kidneydisease.

Thesafetyprofileseenincontrolled-clinicalstudiesinadultpatientswithpost-myocardialinfarctionand/orheart

failurevariesfromtheoverallsafetyprofileseeninhypertensivepatients.Thismayrelatetothepatientsunderlying

disease.ADRsthatoccurredinadultpatientswithpost-myocardialinfarctionand/orheartfailurepatientsarelisted

below.

Skinandsubcutaneoustissuedisorders

Notknown Angioedema,Rash,Pruritus

Musculoskeletalandconnectivetissuedisorders

Notknown Myalgia

Renalandurinarydisorders

Notknown

Renalfailureandimpairment,Elevationof

serumcreatinine

Generaldisordersandadministrationsiteconditions

Uncommon Fatigue

Bloodandlymphaticsystemdisorders

Notknown Thrombocytopenia

Immunesystemdisorders

Notknown Hypersensitivityincludingserumsickness

Metabolismandnutritiondisorders

Uncommon Hyperkalaemia

Notknown Increaseofserumpotassium,hyponatraemia

Nervoussystemdisorders

Common

Dizziness,Posturaldizziness

Uncommon Syncope,Headache

Earandlabyrinthsystemdisorders

Uncommon Vertigo

Cardiacdisorders

Uncommon Cardiacfailure

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4.9Overdose

Symptoms

OverdosewithDiovanmayresultinmarkedhypotension,whichcouldleadtodepressedlevelofconsciousness,

circulatorycollapseand/orshock.

Treatment

Thetherapeuticmeasuresdependonthetimeofingestionandthetypeandseverityofthesymptoms;stabilisationof

thecirculatoryconditionisofprimeimportance.

Ifhypotensionoccurs,thepatientshouldbeplacedinasupinepositionandbloodvolumecorrectionshouldbe

undertaken.

Valsartanisunlikelytoberemovedbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:AngiotensinIIAntagonists,plain,ATCcode:C09CA03

Valsartanisanorallyactive,potent,andspecificangiotensinII(AngII)receptorantagonist.Itactsselectivelyonthe

receptorsubtype,whichisresponsiblefortheknownactionsofangiotensinII.TheincreasedplasmalevelsofAng

IIfollowingAT

receptorblockadewithvalsartanmaystimulatetheunblockedAT

receptor,whichappearsto

counterbalancetheeffectoftheAT

receptor.ValsartandoesnotexhibitanypartialagonistactivityattheAT

receptor

andhasmuch(about20,000fold)greateraffinityfortheAT

receptorthanfortheAT

receptor.Valsartanisnot

knowntobindtoorblockotherhormonereceptorsorionchannelsknowntobeimportantincardiovascularregulation.

ValsartandoesnotinhibitACE(alsoknownaskininaseII)whichconvertsAngItoAngIIanddegradesbradykinin.

SincethereisnoeffectonACEandnopotentiationofbradykininorsubstanceP,angiotensinIIantagonistsare

unlikelytobeassociatedwithcoughing.InclinicaltrialswherevalsartanwascomparedwithanACEinhibitor,the

incidenceofdrycoughwassignificantly(p<0.05)lessinpatientstreatedwithvalsartanthaninthosetreatedwithan

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

inhibitortherapy,19.5%oftrialsubjectsreceivingvalsartanand19.0%ofthosereceivingathiazidediuretic

Common Hypotension,Orthostatichypotension

Notknown Vasculitis

Respiratory,thoracicandmediastinaldisorders

Uncommon Cough

Gastrointestinaldisorders

Uncommon Nausea,Diarrhoea

Hepato-biliarydisorders

Notknown Elevationofliverfunctionvalues

Skinandsubcutaneoustissuedisorders

Uncommon Angioedema

Notknown Rash,Pruritis

Musculoskeletalandconnectivetissuedisorders

Notknown Myalgia

Renalandurinarydisorders

Common Renalfailureandimpairment

Uncommon Acuterenalfailure,Elevationofserum

creatinine

Notknown

IncreaseinBloodUreaNitrogen

Generaldisordersandadministrationsiteconditions

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Hypertension

AdministrationofDiovantopatientswithhypertensionresultsinreductionofbloodpressurewithoutaffectingpulse

rate.

Inmostpatients,afteradministrationofasingleoraldose,onsetofantihypertensiveactivityoccurswithin2hours,and

thepeakreductionofbloodpressureisachievedwithin4-6hours.Theantihypertensiveeffectpersistsover24hours

afterdosing.Duringrepeateddosing,theantihypertensiveeffectissubstantiallypresentwithin2weeks,andmaximal

effectsareattainedwithin4weeksandpersistduringlong-termtherapy.Combinedwithhydrochlorothiazide,a

significantadditionalreductioninbloodpressureisachieved.

AbruptwithdrawalofDiovanhasnotbeenassociatedwithreboundhypertensionorotheradverseclinicalevents.

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)studyfurtherexaminedtheefficacyofvalsartaninreducingUAEin391

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

preservedrenalfunction(meanserumcreatinine=80µmol/l).Patientswererandomizedtooneof3dosesofvalsartan

(160,320and640mg/od)andtreatedfor30weeks.Thepurposeofthestudywastodeterminetheoptimaldoseof

valsartanforreducingUAEinhypertensivepatientswithtype2diabetes.At30weeks,thepercentagechangeinUAE

wassignificantlyreducedby36%frombaselinewithvalsartan160mg(95%CI:22to47%),andby44%with

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

reductionsinUAEinhypertensivepatientswithtype2diabetes.

Recentmyocardialinfarction

TheVALsartanInAcutemyocardialiNfarcTiontrial(VALIANT)wasarandomised,controlled,multinational,double-

blindstudyin14,703patientswithacutemyocardialinfarctionandsigns,symptomsorradiologicalevidenceof

congestiveheartfailureand/orevidenceofleftventricularsystolicdysfunction(manifestedasanejectionfraction ≤

40%byradionuclideventriculographyor ≤35%byechocardiographyorventricularcontrastangiography).Patients

wererandomisedwithin12hoursto10daysaftertheonsetofmyocardialinfarctionsymptomstovalsartan,captopril,

orthecombinationofboth.Themeantreatmentdurationwastwoyears.Theprimaryendpointwastimetoall-cause

mortality.

Valsartanwasaseffectiveascaptoprilinreducingall-causemortalityaftermyocardialinfarction.All-causemortality

wassimilarinthevalsartan(19.9%),captopril(19.5%),andvalsartan+captopril(19.3%)groups.Combiningvalsartan

withcaptoprildidnotaddfurtherbenefitovercaptoprilalone.Therewasnodifferencebetweenvalsartanandcaptopril

inall-causemortalitybasedonage,gender,race,baselinetherapiesorunderlyingdisease.Valsartanwasalsoeffective

inprolongingthetimetoandreducingcardiovascularmortality,hospitalisationforheartfailure,recurrentmyocardial

infarction,resuscitatedcardiacarrest,andnon-fatalstroke(secondarycompositeendpoint).

Thesafetyprofileofvalsartanwasconsistentwiththeclinicalcourseofpatientstreatedinthepost-myocardial

infarctionsetting.Regardingrenalfunction,doublingofserumcreatininewasobservedin4.2%ofvalsartan-treated

patients,4.8%ofvalsartan+captopril-treatedpatients,and3.4%ofcaptopril-treatedpatients.Discontinuationsdueto

varioustypesofrenaldysfunctionoccurredin1.1%ofvalsartan-treatedpatients,1.3%invalsartan+captoprilpatients,

and0.8%ofcaptoprilpatients.Anassessmentofrenalfunctionshouldbeincludedintheevaluationofpatientspost-

myocardialinfarction.

Therewasnodifferenceinall-causemortality,cardiovascularmortalityormorbiditywhenbetablockerswere

administeredtogetherwiththecombinationofvalsartan+captopril,valsartanalone,orcaptoprilalone.Irrespectiveof

treatment,mortalitywaslowerinthegroupofpatientstreatedwithabetablocker,suggestingthattheknownbeta

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Heartfailure

Val-HeFTwasarandomised,controlled,multinationalclinicaltrialofvalsartancomparedwithplaceboonmorbidity

andmortalityin5,010NYHAclassII(62%),III(36%)andIV(2%)heartfailurepatientsreceivingusualtherapywith

LVEF<40%andleftventricularinternaldiastolicdiameter(LVIDD)>2.9cm/m 2

.BaselinetherapyincludedACE

inhibitors(93%),diuretics(86%),digoxin(67%)andbetablockers(36%).Themeandurationoffollow-upwasnearly

twoyears.ThemeandailydoseofDiovaninVal-HeFTwas254mg.Thestudyhadtwoprimaryendpoints:allcause

mortality(timetodeath)andcompositemortalityandheartfailuremorbidity(timetofirstmorbidevent)definedas

death,suddendeathwithresuscitation,hospitalisationforheartfailure,oradministrationofintravenousinotropicor

vasodilatoragentsforfourhoursormorewithouthospitalisation.

Allcausemortalitywassimilar(p=NS)inthevalsartan(19.7%)andplacebo(19.4%)groups.Theprimarybenefitwas

a27.5%(95%CI:17to37%)reductioninriskfortimetofirstheartfailurehospitalisation(13.9%vs.18.5%).Results

appearingtofavourplacebo(compositemortalityandmorbiditywas21.9%inplacebovs.25.4%invalsartangroup)

wereobservedforthosepatientsreceivingthetriplecombinationofanACEinhibitor,abetablockerandvalsartan.

InasubgroupofpatientsnotreceivinganACEinhibitor(n=366),themorbiditybenefitsweregreatest.Inthissubgroup

all-causemortalitywassignificantlyreducedwithvalsartancomparedtoplaceboby33%(95%CI:–6%to58%)

(17.3%valsartanvs.27.1%placebo)andthecompositemortalityandmorbidityriskwassignificantlyreducedby44%

(24.9%valsartanvs.42.5%placebo).

InpatientsreceivinganACEinhibitorwithoutabeta-blocker,allcausemortalitywassimilar(p=NS)inthevalsartan

(21.8%)andplacebo(22.5%)groups.Compositemortalityandmorbidityriskwassignificantlyreducedby18.3%

(95%CI:8%to28%)withvalsartancomparedwithplacebo(31.0%vs.36.3%).

IntheoverallVal-HeFTpopulation,valsartantreatedpatientsshowedsignificantimprovementinNYHAclass,and

heartfailuresignsandsymptoms,includingdyspnoea,fatigue,oedemaandralescomparedtoplacebo.Patientstreated

withvalsartanhadabetterqualityoflifeasdemonstratedbychangeintheMinnesotaLivingwithHeartFailure

QualityofLifescorefrombaselineatendpointthanplacebo.Ejectionfractioninvalsartantreatedpatientswas

significantlyincreasedandLVIDDsignificantlyreducedfrombaselineatendpointcomparedtoplacebo.

Paediatricpopulation

Hypertension

Theantihypertensiveeffectofvalsartanhavebeenevaluatedinfourrandomized,double-blindclinicalstudiesin

561paediatricpatientsfrom6to18yearsofageand165paediatricpatients1to6yearsofage.Renalandurinary

disorders,andobesitywerethemostcommonunderlyingmedicalconditionspotentiallycontributingtohypertensionin

thechildrenenrolledinthesestudies.

Clinicalexperienceinchildrenatorabove6yearsofage

Inaclinicalstudyinvolving261hypertensivepaediatricpatients6to16yearsofage,patientswhoweighed<35kg

received10,40or80mgofvalsartantabletsdaily(low,mediumandhighdoses),andpatientswhoweighed ≥35kg

received20,80,and160mgofvalsartantabletsdaily(low,mediumandhighdoses).Attheendof2weeks,valsartan

reducedbothsystolicanddiastolicbloodpressureinadose-dependentmanner.Overall,thethreedoselevelsof

valsartan(low,mediumandhigh)significantlyreducedsystolicbloodpressureby8,10,12mmHgfromthebaseline,

respectively.Patientswerere-randomizedtoeithercontinuereceivingthesamedoseofvalsartanorwereswitchedto

placebo.Inpatientswhocontinuedtoreceivethemediumandhighdosesofvalsartan,systolicbloodpressureattrough

was-4and-7mmHglowerthanpatientswhoreceivedtheplacebotreatment.Inpatientsreceivingthelowdoseof

valsartan,systolicbloodpressureattroughwassimilartothatofpatientswhoreceivedtheplacebotreatment.Overall,

thedose-dependentantihypertensiveeffectofvalsartanwasconsistentacrossallthedemographicsubgroups.

Inanotherclinicalstudyinvolving300hypertensivepaediatricpatients6to18yearsofage,eligiblepatientswere

randomizedtoreceivevalsartanorenalapriltabletsfor12weeks.Childrenweighingbetween ≥18kgand<35kg

receivedvalsartan80mgorenalapril10mg;thosebetween ≥35kgand<80kgreceivedvalsartan160mgorenalapril

20mg;those ≥80kgreceivedvalsartan320mgorenalapril40mg.Reductionsinsystolicbloodpressurewere

comparableinpatientsreceivingvalsartan(15mmHg)andenalapril(14mmHg)(non-inferiorityp-value<0.0001).

Consistentresultswereobservedfordiastolicbloodpressurewithreductionsof9.1mmHgand8.5mmHgwith

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Clinicalexperienceinchildrenlessthan6yearsofage

Twoclinicalstudieswereconductedinpatientsaged1to6yearswith90and75patients,respectively.Nochildren

belowtheageof1yearwereenrolledinthesestudies.Inthefirststudy,theefficacyofvalsartanwasconfirmed

comparedtoplacebobutadose-responsecouldnotbedemonstrated.Inthesecondstudy,higherdosesofvalsartan

wereassociatedwithgreaterBPreductions,butthedoseresponsetrenddidnotachievestatisticalsignificanceandthe

treatmentdifferencecomparedtoplacebowasnotsignificant.Becauseoftheseinconsistencies,valsartanisnot

recommendedinthisagegroup(seesection4.8).

TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswithDiovaninallsubsets

ofthepaediatricpopulationinheartfailureandheartfailureafterrecentmyocardialinfarction.Seesection4.2for

informationonpaediatricuse.

5.2Pharmacokineticproperties

Absorption:

Followingoraladministrationofvalsartanalone,peakplasmaconcentrationsofvalsartanarereachedin2–4hourswith

tabletsand1–2hourswithsolutionformulation.Meanabsolutebioavailabilityis23%and39%withtabletsand

solutionformulation,respectively.Fooddecreasesexposure(asmeasuredbyAUC)tovalsartanbyabout40%andpeak

plasmaconcentration(C

)byabout50%,althoughfromabout8hpostdosingplasmavalsartanconcentrationsare

similarforthefedandfastedgroups.ThisreductioninAUCisnot,however,accompaniedbyaclinicallysignificant

reductioninthetherapeuticeffect,andvalsartancanthereforebegiveneitherwithorwithoutfood.

Distribution:

Thesteady-statevolumeofdistributionofvalsartanafterintravenousadministrationisabout17litres,indicatingthat

valsartandoesnotdistributeintotissuesextensively.Valsartanishighlyboundtoserumproteins(94–97%),mainly

serumalbumin.

Biotransformation:

Valsartanisnotbiotransformedtoahighextentasonlyabout20%ofdoseisrecoveredasmetabolites.Ahydroxy

metabolitehasbeenidentifiedinplasmaatlowconcentrations(lessthan10%ofthevalsartanAUC).Thismetaboliteis

pharmacologicallyinactive.

Excretion:

Valsartanshowsmultiexponentialdecaykinetics(t

<1handt

½ß about9h).Valsartanisprimarilyeliminatedby

biliaryexcretioninfaeces(about83%ofdose)andrenallyinurine(about13%ofdose),mainlyasunchangeddrug.

Followingintravenousadministration,plasmaclearanceofvalsartanisabout2l/handitsrenalclearanceis0.62l/h

(about30%oftotalclearance).Thehalf-lifeofvalsartanis6hours.

Inheartfailurepatients

Theaveragetimetopeakconcentrationandeliminationhalf-lifeofvalsartaninheartfailurepatientsaresimilartothat

observedinhealthyvolunteers.AUCandC

valuesofvalsartanarealmostproportionalwithincreasingdoseover

theclinicaldosingrange(40to160mgtwiceaday).Theaverageaccumulationfactorisabout1.7.Theapparent

clearanceofvalsartanfollowingoraladministrationisapproximately4.5l/h.Agedoesnotaffecttheapparentclearance

inheartfailurepatients.

Specialpopulations

Elderly

Asomewhathighersystemicexposuretovalsartanwasobservedinsomeelderlysubjectsthaninyoungsubjects;

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Impairedrenalfunction

Asexpectedforacompoundwhererenalclearanceaccountsforonly30%oftotalplasmaclearance,nocorrelationwas

seenbetweenrenalfunctionandsystemicexposuretovalsartan.Doseadjustmentisthereforenotrequiredinpatients

withrenalimpairment(creatinineclearance>10ml/min).Thereiscurrentlynoexperienceonthesafeuseinpatients

withacreatinineclearance<10ml/minandpatientsundergoingdialysis,thereforevalsartanshouldbeusedwith

cautioninthesepatients(seesections4.2and4.4).

Valsartanishighlyboundtoplasmaproteinandisunlikelytoberemovedbydialysis.

Hepaticimpairment

Approximately70%ofthedoseabsorbediseliminatedinthebile,essentiallyintheunchangedform.Valsartandoes

notundergoanynoteworthybiotransformation.Adoublingofexposure(AUC)wasobservedinpatientswithmildto

moderatehepaticimpairmentcomparedtohealthysubjects.However,nocorrelationwasobservedbetweenplasma

valsartanconcentrationversusdegreeofhepaticdysfunction.Diovanhasnotbeenstudiedinpatientswithsevere

hepaticdysfunction(seesections4.2,4.3and4.4).

Paediatricpopulation

Inastudyof26paediatrichypertensivepatients(aged1to16years)givenasingledoseofasuspensionofvalsartan

(mean:0.9to2mg/kg,withamaximumdoseof80mg),theclearance(litres/h/kg)ofvalsartanwascomparableacross

theagerangeof1to16yearsandsimilartothatofadultsreceivingthesameformulation.

Impairedrenalfunction

Useinpaediatricpatientswithacreatinineclearance<30ml/minandpaediatricpatientsundergoingdialysishasnot

beenstudied,thereforevalsartanisnotrecommendedinthesepatients.Nodoseadjustmentisrequiredforpaediatric

patientswithacreatinineclearance>30ml/min.Renalfunctionandserumpotassiumshouldbecloselymonitored(see

sections4.2and4.4).

5.3Preclinicalsafetydata

Non-clinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicity,carcinogenicpotential.

Inrats,maternallytoxicdoses(600mg/kg/day)duringthelastdaysofgestationandlactationledtolowersurvival,

lowerweightgainanddelayeddevelopment(pinnadetachmentandear-canalopening)intheoffspring(seesection

4.6).Thesedosesinrats(600mg/kg/day)areapproximately18timesthemaximumrecommendedhumandoseona

mg/m 2

basis(calculationsassumeanoraldoseof320mg/dayanda60-kgpatient).

Innon-clinicalsafetystudies,highdosesofvalsartan(200to600mg/kgbodyweight)causedinratsareductionofred

bloodcellparameters(erythrocytes,haemoglobin,haematocrit)andevidenceofchangesinrenalhaemodynamics

(slightlyraisedplasmaurea,andrenaltubularhyperplasiaandbasophiliainmales).Thesedosesinrats(200and

600mg/kg/day)areapproximately6and18timesthemaximumrecommendedhumandoseonamg/m 2

basis

(calculationsassumeanoraldoseof320mg/dayanda60-kgpatient).

Inmarmosetsatsimilardoses,thechangesweresimilarthoughmoresevere,particularlyinthekidneywherethe

changesdevelopedtoanephropathywhichincludedraisedureaandcreatinine.

Hypertrophyoftherenaljuxtaglomerularcellswasalsoseeninbothspecies.Allchangeswereconsideredtobecaused

bythepharmacologicalactionofvalsartanwhichproducesprolongedhypotension,particularlyinmarmosets.For

therapeuticdosesofvalsartaninhumans,thehypertrophyoftherenaljuxtaglomerularcellsdoesnotseemtohaveany

relevance.

Paediatricpopulation

Dailyoraldosingofneonatal/juvenilerats(fromapostnatalday7topostnatalday70)withvalsartanatdosesaslowas

1mg/kg/day(about10-35%ofthemaximumrecommendedpaediatricdoseof4mg/kg/dayonsystemicexposure

basis)producedpersistent,irreversiblekidneydamage.Theseeffectsabovementionedrepresentanexpected

exaggeratedpharmacologicaleffectofangiotensinconvertingenzymeinhibitorsandangiotensinIItype1blockers;

sucheffectsareobservedifratsaretreatedduringthefirst13daysoflife.Thisperiodcoincideswith36weeksof

gestationinhumans,whichcouldoccasionallyextendupto44weeksafterconceptioninhumans.Theratsinthe

juvenilevalsartanstudyweredoseduptoday70,andeffectsonrenalmaturation(postnatal4-6weeks)cannotbe

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Functionalrenalmaturationisanongoingprocesswithinthefirstyearoflifeinhumans.Consequently,aclinical

relevanceinchildren<1yearofagecannotbeexcluded,whilepreclinicaldatadonotindicateasafetyconcernfor

childrenolderthan1year.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

TabletCore

Microcrystallinecellulose

Crospovidone

Colloidalanhydroussilica

Magnesiumstearate

Filmcoat

Hypromellose

Titaniumdioxide(E171)

Macrogol8000

Ironoxidered(E172)

Ironoxideyellow(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownontheblisterandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

Blisterpackcontaining28tablets.Inanover-labelledoutercarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse

501MiddletonRoad,

Chadderton,Oldham

Lancashire

OL99LY

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8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/30/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:3rdMay2011

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