CUENCA

Main information

  • Trade name:
  • CUENCA Film Coated Tablet 160 Milligram
  • Dosage:
  • 160 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CUENCA Film Coated Tablet 160 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1239/009/003
  • Authorization date:
  • 20-05-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cuenca160mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Oncefilm-coatedtabletcontains160mgofvalsartan.

Excipients:

Eachtabletcontains

sorbitol18.5mg

lactose2.2mg

sodium0.64mg(0.03mmol)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Cylindrical,coated,scoredononeside,ochrefilm-coatedtablets.

Thetabletcanbedividedintoequalhalves.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension

Treatmentofessentialhypertension.

Recentmyocardialinfarction

Treatmentofclinicallystablepatientswithsymptomaticheartfailureorasymptomaticleftventricularsystolic

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

Heartfailure

TreatmentofsymptomaticheartfailurewhenAngiotensinConvertingEnzyme(ACE)inhibitorscannotbeused,oras

add-ontherapytoACEinhibitorswhenbetablockerscannotbeused(seesections4.4and5.1).

4.2Posologyandmethodofadministration

Hypertension

TherecommendedstartingdoseofCuencais80mgoncedaily.Theantihypertensiveeffectissubstantiallypresent

within2weeks,andmaximaleffectsareattainedwithin4weeks.Insomepatientswhosebloodpressureisnot

adequatelycontrolled,thedosecanbeincreasedto160mgandtoamaximumof320mg.

Cuencamayalsobeadministeredwithotherantihypertensiveagents.Theadditionofadiureticsuchas

hydrochlorothiazidewilldecreasebloodpressureevenfurtherinthesepatients.

Recentmyocardialinfarction

Inclinicallystablepatients,therapymaybeinitiatedasearlyas12hoursafteramyocardialinfarction.Afteraninitial

doseof20mgtwicedaily,valsartanshouldbetitratedto40mg,80mg,and160mgtwicedailyoverthenextfew

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mgdivisibletablet.

Thetargetmaximumdoseis160mgtwicedaily.Ingeneral,itisrecommendedthatpatientsachieveadoselevelof80

mgtwicedailybytwoweeksaftertreatmentinitiationandthatthetargetmaximumdose,160mgtwicedaily,be

achievedbythreemonths,basedonthepatient'stolerability.Ifsymptomatichypotensionorrenaldysfunctionoccur,

considerationshouldbegiventoadosagereduction.

Valsartanmaybeusedinpatientstreatedwithotherpost-myocardialinfarctiontherapies,e.g.thrombolytics,

acetylsalicylicacid,betablockers,statins,anddiuretics.ThecombinationwithACEinhibitorsisnotrecommended

(seesections4.4and5.1).

Evaluationofpost-myocardialinfarctionpatientsshouldalwaysincludeassessmentofrenalfunction.

Heartfailure

TherecommendedstartingdoseofCuencais40mgtwicedaily.Uptitrationto80mgand160mgtwicedailyshouldbe

doneatintervalsofatleasttwoweekstothehighestdose,astoleratedbythepatient.Considerationshouldbegivento

reducingthedoseofconcomitantdiuretics.Themaximumdailydoseadministeredinclinicaltrialsis320mgin

divideddoses.

Valsartanmaybeadministeredwithotherheartfailuretherapies.However,thetriplecombinationofanACEinhibitor,

abetablockerandvalsartanisnotrecommended(seesections4.4and5.1).

Evaluationofpatientswithheartfailureshouldalwaysincludeassessmentofrenalfunction.

Methodofadministration

Cuencamaybetakenindependentlyofamealandshouldbeadministeredwithwater.

Additionalinformationonspecialpopulations

Elderly

Nodoseadjustmentisrequiredinelderlypatients.

Renalimpairment

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

Hepaticimpairment

Inpatientswithmildtomoderatehepaticimpairmentwithoutcholestasis,thedoseofvalsartanshouldnotexceed80

mg.Cuencaiscontraindicatedinpatientswithseverehepaticimpairmentandinpatientswithcholestasis(seesections

4.3,4.4and5.2).

Paediatricpatients

Cuencaisnotrecommendedforuseinchildrenbelowtheageof18yearsduetoalackofdataonsafetyandefficacy.

4.3Contraindications

-Hypersensitivitytotheactivesubstanceortoanyoftheexcipients.

-Severehepaticimpairment,biliarycirrhosisandcholestasis.

-Secondandthirdtrimesterofpregnancy(seesections4.4and4.6).

4.4Specialwarningsandprecautionsforuse

Hyperkalaemia

Concomitantusewithpotassiumsupplements,potassium-sparingdiuretics,saltsubstitutescontainingpotassium,or

otheragentsthatmayincreasepotassiumlevels(heparin,etc.)isnotrecommended.Monitoringofpotassiumshouldbe

undertakenasappropriate.

Sodium-and/orvolume-depletedpatients

Inseverelysodium-depletedand/orvolume-depletedpatients,suchasthosereceivinghighdosesofdiuretics,

symptomatichypotensionmayoccurinrarecasesafterinitiationoftherapywithCuenca.Sodiumand/orvolume

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Renalarterystenosis

Inpatientswithbilateralrenalarterystenosisorstenosistoasolitarykidney,thesafeuseofCuencahasnotbeen

established.

Short-termadministrationofCuencatotwelvepatientswithrenovascularhypertensionsecondarytounilateralrenal

arterystenosisdidnotinduceanysignificantchangesinrenalhaemodynamics,serumcreatinine,orbloodureanitrogen

(BUN).However,otheragentsthataffecttherenin-angiotensinsystemmayincreasebloodureaandserumcreatininein

patientswithunilateralrenalarterystenosis,thereforemonitoringofrenalfunctionisrecommendedwhenpatientsare

treatedwithvalsartan.

Kidneytransplantation

ThereiscurrentlynoexperienceonthesafeuseofCuencainpatientswhohaverecentlyundergonekidney

transplantation.

Primaryhyperaldosteronism

PatientswithprimaryhyperaldosteronismshouldnotbetreatedwithCuencaastheirrenin-angiotensinsystemisnot

activated.

Aorticandmitralvalvestenosis,obstructivehypertrophiccardiomyopathy

Aswithallothervasodilators,specialcautionisindicatedinpatientssufferingfromaorticormitralstenosis,or

hypertrophicobstructivecardiomyopathy(HOCM).

Impairedrenalfunction

Nodosageadjustmentisrequiredforpatientswithacreatinineclearance>10ml/min.Thereiscurrentlynoexperience

onthesafeuseinpatientswithacreatinineclearance<10ml/minandpatientsundergoingdialysis,thereforevalsartan

shouldbeusedwithcautioninthesepatients(seesections4.2and5.2).

Hepaticimpairment

Inpatientswithmildtomoderatehepaticimpairmentwithoutcholestasis,Cuencashouldbeusedwithcaution(see

sections4.2and5.2).

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).

UseofCuencainpost-myocardialinfarctionpatientscommonlyresultsinsomereductioninbloodpressure,but

discontinuationoftherapybecauseofcontinuingsymptomatichypotensionisnotusuallynecessaryprovideddosing

instructionsarefollowed(seesection4.2).

HeartFailure

Inpatientswithheartfailure,thetriplecombinationofanACEinhibitor,abetablockerandCuencahasnotshownany

clinicalbenefit(seesection5.1).Thiscombinationapparentlyincreasestheriskforadverseeventsandisthereforenot

recommended.

Cautionshouldbeobservedwheninitiatingtherapyinpatientswithheartfailure.Evaluationofpatientswithheart

failureshouldalwaysincludeassessmentofrenalfunction(seesection4.2).

UseofCuencainpatientswithheartfailurecommonlyresultsinsomereductioninbloodpressure,butdiscontinuation

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followed(seesection4.2).

Inpatientswhoserenalfunctionmaydependontheactivityoftherenin-angiotensinsystem(e.gpatientswithsevere

congestiveheartfailure),treatmentwithangiotensinconvertingenzymeinhibitorshasbeenassociatedwitholiguria

and/orprogressiveazotaemiaandinrarecaseswithacuterenalfailureand/ordeath.AsvalsartanisanangiotensinII

antagonist,itcannotbeexcludedthattheuseofCuencamaybeassociatedwithimpairmentoftherenalfunction.

Warningaboutexcipients:

Thismedicinecontainssorbitol.Patientswithhereditaryproblemsoffructoseintoleranceshouldnottakethis

medicine.

Thismedicinecontainslactose.Patientswithhereditaryproblemsofgalactoseintolerance,theLapplactasedeficiency

(insufficiencyobservedincertainpopulationsofLaponia)orglucose-galactosemalabsorptionshouldnottakethis

medicine.

Thismedicinecontainslessthan23mgofsodiumperdose;thatis,essentially“sodiumfree”.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantusenotrecommended

Lithium

ReversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcurrentuseofACE

inhibitors.Duetothelackofexperiencewithconcomitantuseofvalsartanandlithium,thiscombinationisnot

recommended.Ifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsisrecommended.

Potassium-sparingdiuretics,potassiumsupplements,saltsubstitutescontainingpotassiumandothersubstancesthat

mayincreasepotassiumlevels

Ifamedicinalproductthataffectspotassiumlevelsisconsiderednecessaryincombinationwithvalsartan,monitoring

ofpotassiumplasmalevelsisadvised.

Cautionrequiredwithconcomitantuse

Non-steroidalanti-inflammatorymedicines(NSAIDs),includingselectiveCOX-2inhibitors,acetylsalicylicacid>3

g/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.

4.6Fertility,pregnancyandlactation

Pregnancy:

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;however,asmallincreaseinriskcannotbeexcluded.Whilstthereis

nocontrolledepidemiologicaldataontheriskwithAIIRAs,similarrisksmayexistforthisclassofdrugs.Unless

continuedAIIRAtherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-

hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.

TheuseofAngiotensinIIReceptorAntagonists(AIIRAs)isnotrecommendedduringthefirst

trimesterofpregnancy(seesection4.4).TheuseofAIIRAsiscontra-indicatedduringthe

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therapyshouldbestarted.

AIIRAstherapyexposureduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

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

hyperkalemia);seealsosection5.3“Preclinical

safetydata”.

ShouldexposuretoAIIRAshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

InfantswhosemothershavetakenAIIRAsshouldbecloselyobservedforhypotension(seealsosections4.3and4.4).

Lactation

Becausenoinformationisavailableregardingtheuseofvalsartanduringbreastfeeding,Cuencaisnotrecommended

andalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,especiallywhile

nursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodrivehavebeenperformed.Whendrivingvehiclesoroperatingmachinesit

shouldbetakenintoaccountthatoccasionallydizzinessorwearinessmayoccur.

4.8Undesirableeffects

Incontrolledclinicalstudiesinpatientswithhypertension,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)

Notknown(cannotbeestimatedfromtheavailabledata)

.Withineachfrequencygrouping,adversereactionsarerankedinorderofdecreasingseriousness.

ForalltheADRsreportedfrompost-marketingexperienceandlaboratoryfindings,itisnotpossibletoapplyanyADR

frequencyandthereforetheyarementionedwitha"notknown"frequency.

Hypertension

Bloodandlymphaticsystemdisorders

Notknown Decreaseinhaemoglobin,Decreasein

haematocrit,Neutropenia,Thrombocytopenia

Immunesystemdisorders

Notknown Hypersensitivityincludingserumsickness

Metabolismandnutritiondisorders

Notknown Increaseofserumpotassium

Earandlabyrinthsystemdisorders

Uncommon Vertigo

Vasculardisorders

Notknown Vasculitis

Respiratory,thoracicandmediastinaldisorders

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Thesafetyprofileseenincontrolled-clinicalstudiesinpatientswithpost-myocardialinfarctionand/orheartfailure

variesfromtheoverallsafetyprofileseeninhypertensivepatients.Thismayrelatetothepatientsunderlyingdisease.

ADRsthatoccurredinpost-myocardialinfarctionand/orheartfailurepatientsarelistedbelow:

Gastrointestinaldisorders

Uncommon Abdominalpain

Hepato-biliarydisorders

Notknown Elevationofliverfunctionvaluesincluding

increaseofserumbilirubin

Skinandsubcutaneoustissuedisorders

Notknown Angioedema,Rash,Pruritus

Musculoskeletalandconnectivetissuedisorders

Notknown Myalgia

Renalandurinarydisorders

Notknown Renalfailureandimpairment,Elevationof

serumcreatinine

Generaldisordersandadministrationsiteconditions

Uncommon Fatigue

Bloodandlymphaticsystemdisorders

Notknow Thrombocytopenia

Immunesystemdisorders

Notknown Hypersensitivityincludingserumsickness

Metabolismandnutritiondisorders

Uncommon Hyperkalaemia

Notknown Increaseofserumpotassium

Nervoussystemdisorders

Common Dizziness,Posturaldizziness

Uncommon Syncope,Headache

Earandlabyrinthsystemdisorders

Uncommon Vertigo

Cardiacdisorders

Uncommon Cardiacfailure

Vasculardisorders

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

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4.9Overdose

Symptoms

ACuencaoverdosecouldpossiblycauseamarkedhypotensionthatundercertaincircumstancescouldleadto

depressedlevelofconsciousness,circulatorycollapseand/orshock.

Therapy

Therapeuticmeasuresdependonwhenthemedicinewastaken,aswellasthetypeandseverityofthesymptoms.Here

restorationofstablecirculatoryconditionsshouldbethemainconcern.

Afteranoverdose,thepatientsshouldreceiveasufficientquantityofactivatedcharcoal.

Incaseofhypotensionthepatientshouldbeplacedinahorizontalposition.Saltandplasmareplacementpreparations

shouldberapidlyadministered.

Valsartancannotberemovedbyhaemodialysisduetoitsstrongplasma-proteinbonding.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:AngiotensinIIAntagonists,plain,ATCcode:C09CA03

Valsartanisanorallyactive,potent,andspecificangiotensinII(AngII)receptorantagonist.Itactsselectivelyonthe

AT1receptorsubtype,whichisresponsiblefortheknownactionsofangiotensinII.TheincreasedplasmalevelsofAng

IIfollowingAT1receptorblockadewithvalsartanmaystimulatetheunblockedAT2receptor,whichappearsto

counterbalancetheeffectoftheAT1receptor.ValsartandoesnotexhibitanypartialagonistactivityattheAT1

receptorandhasmuch(about20,000fold)greateraffinityfortheAT1receptorthanfortheAT2receptor.Valsartanis

notknowntobindtoorblockotherhormonereceptorsorionchannelsknowntobeimportantincardiovascular

regulation.

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

experiencedcoughcomparedto68.5%ofthosetreatedwithanACEinhibitor(P<0.05).

Hypertension

AdministrationofCuencatopatientswithhypertensionresultsinreductionofbloodpressurewithoutaffectingpulse

rate.

Inmostpatients,afteradministrationofasingleoraldose,onsetofantihypertensiveactivityoccurswithin2hours,and

thepeakreductionofbloodpressureisachievedwithin4-6hours.Theantihypertensiveeffectpersistsover24hours

afterdosing.Duringrepeateddosing,theantihypertensiveeffectissubstantiallypresentwithin2weeks,andmaximal

effectsareattainedwithin4weeksandpersistduringlong-termtherapy.Combinedwithhydrochlorothiazide,a

significantadditionalreductioninbloodpressureisachieved.

AbruptwithdrawalofCuencahasnotbeenassociatedwithreboundhypertensionorotheradverseclinicalevents.

Inhypertensivepatientswithtype2diabetesandmicroalbuminuria,valsartanhasbeenshowntoreducetheurinary

excretionofalbumin.TheMARVAL(MicroAlbuminuriaReductionwithValsartan)studyassessedthereductionin

Notknown IncreaseinBloodUreaNitrogen

Generaldisordersandadministrationsiteconditions

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diabeticpatients(meanage:58years;265men)withmicroalbuminuria(valsartan:58µg/min;amlodipine:55.4

µg/min),normalorhighbloodpressureandwithpreservedrenalfunction(bloodcreatinine<120µmol/l).At24weeks,

UAEwasreduced(p<0.001)by42%(–24.2µg/min;95%CI:–40.4to–19.1)withvalsartanandapproximately3%(–

1.7µg/min;95%CI:–5.6to14.9)withamlodipinedespitesimilarratesofbloodpressurereductioninbothgroups.

TheCuencaReductionofProteinuria(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

blockerbenefitinthispopulationwasmaintainedinthistrial.

Heartfailure

Val-HeFTwasarandomised,controlled,multinationalclinicaltrialofvalsartancomparedwithplaceboonmorbidity

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

LVEF<40%andleftventricularinternaldiastolicdiameter(LVIDD)>2.9cm/m2.BaselinetherapyincludedACE

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

twoyears.ThemeandailydoseofCuencainVal-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).

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(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.

5.2Pharmacokineticproperties

Absorption:

Followingoraladministrationofvalsartanalone,peakplasmaconcentrationsofvalsartanarereachedin2–4hours.

Meanabsolutebioavailabilityis23%.Fooddecreasesexposure(asmeasuredbyAUC)tovalsartanbyabout40%and

peakplasmaconcentration(Cmax)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.

Excretion:

Valsartanshowsmultiexponentialdecaykinetics(t½<1handt½ßabout9h).Valsartanisprimarilyeliminatedby

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

Followingintravenousadministration,plasmaclearanceofvalsartanisabout2l/handitsrenalclearanceis0.62l/h

(about30%oftotalclearance).Thehalf-lifeofvalsartanis6hours.

InHeartfailurepatients:

Theaveragetimetopeakconcentrationandeliminationhalf-lifeofvalsartaninheartfailurepatientsaresimilartothat

observedinhealthyvolunteers.AUCandCmaxvaluesofvalsartanarealmostproportionalwithincreasingdoseover

theclinicaldosingrange(40to160mgtwiceaday).Theaverageaccumulationfactorisabout1.7.Theapparent

clearanceofvalsartanfollowingoraladministrationisapproximately4.5l/h.Agedoesnotaffecttheapparentclearance

inheartfailurepatients.

Specialpopulations

Elderly

Asomewhathighersystemicexposuretovalsartanwasobservedinsomeelderlysubjectsthaninyoungsubjects;

however,thishasnotbeenshowntohaveanyclinicalsignificance.

Impairedrenalfunction

Asexpectedforacompoundwhererenalclearanceaccountsforonly30%oftotalplasmaclearance,nocorrelationwas

seenbetweenrenalfunctionandsystemicexposuretovalsartan.Doseadjustmentisthereforenotrequiredinpatients

withrenalimpairment(creatinineclearance>10ml/min).Thereiscurrentlynoexperienceonthesafeuseinpatients

withacreatinineclearance<10ml/minandpatientsundergoingdialysis,thereforevalsartanshouldbeusedwith

cautioninthesepatients(seesections4.2and4.4).Valsartanishighlyboundtoplasmaproteinandisunlikelytobe

removedbydialysis.

Hepaticimpairment

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notundergoanynoteworthybiotransformation.Adoublingofexposure(AUC)wasobservedinpatientswithmildto

moderatehepaticimpairmentcomparedtohealthysubjects.However,nocorrelationwasobservedbetweenplasma

valsartanconcentrationversusdegreeofhepaticdysfunction.Cuencahasnotbeenstudiedinpatientswithsevere

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

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/m2basis(calculationsassumeanoraldoseof320mg/dayanda60-kgpatient).

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

bloodcellparameters(erythrocytes,haemoglobin,haematocrit)andevidenceofchangesinrenalhaemodynamics

(slightlyraisedplasmaurea,andrenaltubularhyperplasiaandbasophiliainmales).Thesedosesinrats(200and600

mg/kg/day)areapproximately6and18timesthemaximumrecommendedhumandoseonamg/m2basis(calculations

assumeanoraldoseof320mg/dayanda60-kgpatient).

Inmarmosetsatsimilardoses,thechangesweresimilarthoughmoresevere,particularlyinthekidneywherethe

changesdevelopedtoanephropathywhichincludedraisedureaandcreatinine.

Hypertrophyoftherenaljuxtaglomerularcellswasalsoseeninbothspecies.Allchangeswereconsideredtobecaused

bythepharmacologicalactionofvalsartanwhichproducesprolongedhypotension,particularlyinmarmosets.For

therapeuticdosesofvalsartaninhumans,thehypertrophyoftherenaljuxtaglomerularcellsdoesnotseemtohaveany

relevance.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

Cellulose,microcrystalline(E460)

Silica,colloidalanhydrous(E551)

Sorbitol(E-420)

Magnesiumcarbonate(E504)

Maizestarch,pregelatinised

PovidoneK-25(E1201)

Sodiumstearylfumarate

Sodiumlaurylsulphate

CrospovidoneTypeA(E1202)

Filmcoating

Lactosemonohydrate

Hypromellose(E464)

Titaniumdioxide(E171)

Macrogol

Yellowironoxide(E172)

Brownironoxide(E172)

6.2Incompatibilities

Notapplicable

6.3Shelflife

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6.4Specialprecautionsforstorage

Donotstoreabove30°C.Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

PVC/PE/PVDC/aluminiumblister.

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

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

Anyunusedproductorwasteshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

LaboratoriosLiconsa,S.A.

GranVíaCarlosIII,98,7thfloor

08028Barcelona,SPAIN

8MARKETINGAUTHORISATIONNUMBER

PA1239/9/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:20 th

May2011

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