COZAAR INITIATION PACK FOR HEART FAILURE

Main information

  • Trade name:
  • COZAAR INITIATION PACK FOR HEART FAILURE
  • Dosage:
  • 12.5 & 50 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COZAAR INITIATION PACK FOR HEART FAILURE
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0035/082/002
  • Authorization date:
  • 21-12-1998
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0035/082/002

CaseNo:2077446

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

MerckSharpandDohmeLimited

HertfordRoad,Hoddesdon,HertfordshireEN119BU,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

CozaarInitiationPackforHeartFailure

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom21/12/2008.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/05/2010 CRN 2077446 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CozaarInitiationPackforHeartFailure

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachCozaar12.5mgtabletcontains11.5mgoflosartan,presentas12.5mgoflosartanpotassium.

EachCozaar50mgtabletcontains45.8mgoflosartanpresentas50mglosartanpotassium.

Excipients:

EachCozaar12.5mgtabletcontains25.25mgoflactosemonohydrate.

EachCozaar50mgtabletcontains25.5mgoflactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedTablet

Cozaar12.5mg:Blue,oval-shaped,film-coatedtabletmarked‘11’ononesideandplainontheother.

Cozaar50mg:White,oval-shaped,film-coatedtabletwithascore-lineononesideand‘952’ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension

‘Cozaar’isindicatedforthetreatmentofhypertension.

Reductionintheriskofcardiovascularmorbidityinhypertensivepatientswithleftventricularhypertrophy

‘Cozaar’isindicatedtoreducetheriskofcardiovascularmorbidityasmeasuredbythecombinedincidenceof

cardiovasculardeath,stroke,andmyocardialinfarctioninhypertensivepatientswithleftventricularhypertrophy(see

section5.1Pharmacodynamicproperties,LIFEstudy,Race).

Heartfailure

‘Cozaar’isindicatedforthetreatmentofheartfailurewhentreatmentwithanACEinhibitorisnolongerconsidered

appropriate.SwitchingpatientswithheartfailurewhoarestableonanACEinhibitorto‘Cozaar’isnotrecommended

(see5.1‘Pharmacodynamicproperties’).

Renalprotectionintype2diabeticpatientswithproteinuria

‘Cozaar’isindicatedtodelaytheprogressionofrenaldiseaseasmeasuredbyareductioninthecompositeendpointsof

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/05/2010 CRN 2077446 page number: 2

proteinuria.

4.2Posologyandmethodofadministration

‘Cozaar’maybeadministeredwithorwithoutfood.

‘Cozaar’maybeadministeredwithotherantihypertensiveagents.

Hypertension

Thestartingandmaintenancedoseis50mgoncedailyformostpatients.Themaximalantihypertensiveeffectis

attained3-6weeksafterinitiationoftherapy.Somepatientsmayreceiveanadditionalbenefitbyincreasingthedoseto

100mgoncedaily.

Fortheverysmallproportionofpatientswhohaveintravascularvolumedepletion(e.g.thosetreatedwithhigh-dose

diuretics),astartingdoseof25mgoncedailyshouldbeconsidered(see4.4‘Specialwarningsandspecialprecautions

foruse’).

Noinitialdosageadjustmentisnecessaryforelderlypatientsorforpatientswithrenalimpairment,includingpatients

ondialysis.Alowerdoseshouldbeconsideredforpatientswithahistoryofhepaticimpairment(see4.4‘Special

warningsandprecautionsforuse’).

Reductionintheriskofcardiovascularmorbidityinhypertensivepatientswithleftventricularhypertrophy

Theusualstartingdoseis50mgof‘Cozaar’oncedaily.Alowdoseofhydrochlorothiazidemaybeaddedand/orthe

doseof‘Cozaar’maybeincreasedto100mgoncedailybasedonbloodpressure.

Heartfailure

Theinitialdoseof‘Cozaar’inpatientswithheartfailureis12.5mgoncedaily.Thedoseshouldgenerallybetitratedat

weeklyintervalstotheusualmaintenancedoseof50mgoncedaily,astoleratedbythepatient.Therecommended

titrationregimeis12.5mgdailyforsevendays,followedby25mgdailyforafurthersevendays,andthento50mg

oncedaily.‘Cozaar’isusuallygivenincombinationwithdiureticsanddigitalis.Atitrationpackisavailableforthe

firstmonthoftreatment.

Noinitialdosageadjustmentisrequiredforpatientswithrenalorhepaticimpairmentorintravasculardepletion.(See

4.4‘Specialwarningsandprecautionsforuse’).

RenalProtectioninType2DiabeticPatientswithProteinuria.

Theusualstartingdoseis50mgoncedaily.Thedosemaybeincreasedto100mgoncedailybasedonbloodpressure

response.‘Cozaar’maybeadministeredwithotherantihypertensiveagents(e.g.,diuretics,calciumchannelblockers,

alpha-orbeta-blockers,andcentrallyactingagents)aswellaswithinsulinandothercommonlyusedhypoglycaemic

agents(e.g.,sulfonylureas,glitazonesandglucosidaseinhibitors).

4.3Contraindications

‘Cozaar’iscontra-indicatedinpregnancy(see4.6‘Pregnancyandlactation’)andinpatientswhoarehypersensitiveto

anycomponentofthisproduct.

4.4Specialwarningsandprecautionsforuse

Hypersensitivity:Angioedema.See4.8‘Undesirableeffects’.

Hypotensionandelectrolytefluidimbalance:Inpatientswhoareintravascularlyvolumedepleted(e.g.thosetreated

withhigh-dosediuretics),symptomatichypotensionmayoccur.Theseconditionsshouldbecorrectedpriorto

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/05/2010 CRN 2077446 page number: 3

Electrolyteimbalancesarecommoninpatientswithrenalimpairment,withorwithoutdiabetes,andshouldbe

addressed.Inaclinicalstudyconductedintype2diabeticpatientswithproteinuria,theincidenceofhyperkalaemia

washigherinthegrouptreatedwith‘Cozaar’ascomparedtotheplacebogroup;however,fewpatientsdiscontinued

therapyduetohyperkalaemia(see4.8‘Undesirableeffects’andLaboratorytestfindings).

Liverfunctionimpairment:Basedonpharmacokineticdatawhichdemonstratesignificantlyincreasedplasma

concentrationsoflosartanincirrhoticpatients,alowerdoseshouldbeconsideredforpatientswithahistoryofhepatic

impairment(see4.2‘Posologyandmethodofadministration’and5.2‘Pharmacokineticproperties’).

Renalfunctionimpairment:Asaconsequenceofinhibitingtherenin-angiotensin-aldosteronesystem,changesinrenal

functionincludingrenalfailurehavebeenreportedinsusceptibleindividuals;thesechangesinrenalfunctionmaybe

reversibleupondiscontinuationoftherapy.

Otherdrugsthataffecttherenin-angiotensin-aldosteronesystemmayincreaseserumureaandcreatinineinpatients

withbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney.Similareffectshavebeenreportedwith

‘Cozaar’;thesechangesinrenalfunctionmaybereversibleupondiscontinuationoftherapy.

Theuseof‘Cozaar’inpatientswithhaemodynamicallysignificantobstructivevalvulardiseasehasnotbeenadequately

studied.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Inclinicalpharmacokinetictrialsnodruginteractionsofclinicalsignificancehavebeenidentifiedwith

hydrochlorothiazide,digoxin,warfarin,cimetidine,phenobarbital(phenobarbitone),ketoconazoleanderythromycin.

Rifampicinandfluconazolehavebeenreportedtoreducelevelsofactivemetabolite.Theclinicalconsequencesof

theseinteractionshavenotbeenevaluated.

AswithotherdrugsthatblockangiotensinIIoritseffects,concomitantuseofpotassium-sparingdiuretics(e.g.

spironolactone,triamterene,amiloride),potassiumsupplementsorsaltsubstitutescontainingpotassiummayleadto

increasesinserumpotassium.

Aswithotherantihypertensiveagents,theantihypertensiveeffectoflosartanmaybeattenuatedbythenon-steroidal

anti-inflammatorydrugindomethacin.

4.6Pregnancyandlactation

Useduringpregnancy

Althoughthereisnoexperiencewiththeuseof‘Cozaar’inpregnantwomen,animalstudieswithlosartanpotassium

havedemonstratedfoetalandneonatalinjuryanddeath,themechanismofwhichisbelievedtobepharmacologically

mediatedthrougheffectsontherenin-angiotensin-aldosteronesystem.

Inhumans,foetalrenalperfusion,whichisdependentuponthedevelopmentoftherenin-angiotensin-aldosterone

system,beginsinthesecondtrimester;thus,risktothefoetusincreasesif‘Cozaar’isadministeredduringthesecondor

thirdtrimestersofpregnancy.

Whenusedinpregnancyduringthesecondandthirdtrimesters,drugsthatactdirectlyontherenin-angiotensin-

aldosteronesystemcancauseinjuryandevendeathinthedevelopingfoetus.‘Cozaar’shouldnotbeusedin

pregnancy,andifpregnancyisdetected‘Cozaar’shouldbediscontinuedassoonaspossible.

Useduringlactation

Itisnotknownwhetherlosartanisexcretedinhumanmilk.However,significantlevelsoflosartanandtheactive

metabolitewereshowntobepresentinratmilk.Becauseofthepotentialforadverseeffectsonthenursinginfant,a

decisionshouldbemadewhethertodiscontinuebreast-feedingordiscontinuethedrug,takingintoaccountthe

importanceofthedrugtothemother.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/05/2010 CRN 2077446 page number: 4

Therearenodatatosuggestthat‘Cozaar’affectstheabilitytodriveandusemachines.

4.8Undesirableeffects

‘Cozaar’hasbeenfoundtobegenerallywelltolerated;sideeffectshaveusuallybeenmildandtransientinnatureand

havenotrequireddiscontinuationoftherapy.Theoverallincidenceofsideeffectsreportedwith‘Cozaar’was

comparabletoplacebo.

Incontrolledclinicaltrialsforessentialhypertension,dizzinesswastheonlysideeffectreportedasdrug-relatedthat

occurredwithanincidencegreaterthanplaceboin1%ormoreofpatientstreatedwith‘Cozaar’.Inaddition,dose-

relatedorthostaticeffectswereseeninlessthan1%ofpatients.Rarely,rashwasreported,althoughtheincidencein

controlledclinicaltrialswaslessthanplacebo.

‘Cozaar’wasgenerallywelltoleratedinacontrolledclinicaltrialinhypertensivepatientswithleftventricular

hypertrophy.Themostcommondrug-relatedsideeffectsweredizziness,asthenia/fatigueandvertigo.

‘Cozaar’hasbeenfoundtobegenerallywelltoleratedincontrolledclinicaltrialsinheartfailure.Adverseexperiences

observedweretypicalofthoseexpectedinthispopulation.Themostcommondrug-relatedsideeffectsweredizziness

andhypotension.

‘Cozaar’wasgenerallywelltoleratedinacontrolledclinicaltrialintype2diabeticpatientswithproteinuria.Themost

commondrug-relatedsideeffectswereasthenia/fatigue,dizziness,hypotensionandhyperkalaemia(see4.4‘Special

warningsandprecautionsforuse’,Hypotensionandelectrolyte/fluidimbalance).

Thefollowingadversereactionshavebeenreportedinpost-marketingexperience:

Hypersensitivity:Anaphylacticreactions,angioedemaincludingswellingofthelarynxandglottiscausingairway

obstruction(and/orswellingoftheface,lips,pharynx,and/ortongue)hasbeenreportedrarelyinpatientstreatedwith

losartan;someofthesepatientspreviouslyexperiencedangioedemawithotherdrugsincludingACEinhibitors.

Vasculitis,includingHenoch-Schoenleinpurpurahasbeenreportedrarely.

Gastro-intestinal:Hepatitis(reportedrarely),diarrhoea,liverfunctionabnormalities.

Haematologic:Anaemia,thrombocytopenia(reportedrarely).

Musculoskeletal:Myalgia.

Nervoussystem/Psychiatric:Migraine.

Respiratory:Cough.

Skin:Urticaria,pruritus.

Laboratorytestfindings

Incontrolledclinicaltrialsforessentialhypertension,clinicallyimportantchangesinstandardlaboratoryparameters

wererarelyassociatedwithadministrationof‘Cozaar’.Hyperkalaemia(serumpotassium>5.5mmol/l)occurredin

1.5%ofpatientsinhypertensionclinicaltrials.Inaclinicalstudyconductedintype2diabeticpatientswith

proteinuria,9.9%ofpatientstreatedwith‘Cozaar’and3.4%ofpatientstreatedwithplacebodevelopedhyperkalaemia

(see4.4‘Specialwarningsandprecautionsforuse’,Hypotensionandelectrolyte/fluidimbalance).ElevationsofALT

occurredrarelyandusuallyresolvedupondiscontinuationoftherapy.

4.9Overdose

Significantlethalitywasobservedinmiceandratsafteroraladministrationof1,000mg/kg(3,000mg/m 2

)and

2,000mg/kg(11,800mg/m 2

)(500and1,000times *

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/05/2010 CRN 2077446 page number: 5

Limiteddataareavailableinregardtooverdosageinhumans.Themostlikelymanifestationofoverdosagewouldbe

hypotensionandtachycardia;bradycardiacouldoccurfromparasympathetic(vagal)stimulation.Ifsymptomatic

hypotensionshouldoccur,supportivetreatmentshouldbeinstituted.

Neitherlosartannortheactivemetabolitecanberemovedbyhaemodialysis.

Basedonapatientweightof50kg.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Losartanisanoral,specificangiotensin-IIreceptor(typeAT

)antagonist.AngiotensinIIbindstotheAT

receptor

foundinmanytissues(e.g.vascularsmoothmuscle,adrenalgland,kidneys,andtheheart)andelicitsseveralimportant

biologicalactions,includingvasoconstrictionandthereleaseofaldosterone.AngiotensinIIalsostimulatessmooth-

muscleproliferation.Basedonbindingandpharmacologicalbioassays,itbindsselectivelytotheAT

receptor.In

vitroandinvivo,bothlosartananditspharmacologicallyactivecarboxylicacidmetabolite(E-3174)blockall

physiologicallyrelevantactionsofangiotensinII,regardlessofthesourceorrouteofsynthesis.

Duringlosartanadministration,removalofangiotensin-IInegativefeedbackonreninsecretionleadstoincreased

plasmareninactivity.IncreasesinplasmareninactivityleadtoincreasesinangiotensinIIinplasma.Evenwiththese

increases,antihypertensiveactivityandsuppressionofplasmaaldosteroneconcentrationaremaintained,indicating

effectiveangiotensin-IIreceptorblockade.

LosartanbindsselectivelytotheAT

receptoranddoesnotbindtoorblockotherhormonereceptorsorionchannels

importantincardiovascularregulation.Furthermore,losartandoesnotinhibitACE(kininaseII),theenzymethat

degradesbradykinin.Consequently,effectsnotdirectlyrelatedtoblockingtheAT

receptor,suchasthepotentiationof

bradykinin-mediatedeffects,thegenerationofoedema(losartan1.7%,placebo1.9%)orfatigue(losartan3.8%,

placebo3.9%),arenotassociatedwithlosartan.

LosartanhasbeenshowntoblockresponsestoangiotensinIandangiotensinIIwithoutaffectingresponsesto

bradykinin,afindingwhichisconsistentwiththespecificmechanismofactionoflosartan.Incontrast,ACEinhibitors

havebeenshowntoblockresponsestoangiotensinIandenhanceresponsestobradykininwithoutalteringthe

responsetoangiotensinII,thusprovidingapharmacodynamicdistinctionbetweenlosartanandACEinhibitors.

Innon-diabetichypertensivepatientswithproteinuria,theadministrationoflosartanpotassiumsignificantlyreduces

proteinuria,fractionalexcretionofalbuminandIgG.Losartanmaintainsglomerularfiltrationrateandreduces

filtrationfraction.Generally,losartancausesadecreaseinserumuricacid(usually<24µmol/l)whichwaspersistent

inchronictherapy.

Losartanhasnoeffectonautonomicreflexesandnosustainedeffectonplasmanoradrenaline(norepinephrine)in

hypertensivepatients.

Losartanpotassiumadministeredindosesofupto150mgoncedailydidnotcauseclinicallyimportantchangesin

fastingtriglycerides,totalcholesterolorHDLcholesterolinpatientswithhypertension.Thesamedosesoflosartan

hadnoeffectonfastingglucoselevels.

HypertensionStudies:

Inclinicalstudies,once-dailyadministrationof50mg‘Cozaar’topatientswithmildtomoderateessential

hypertensionproducedstatisticallysignificantreductionsinsystolicanddiastolicbloodpressure;theantihypertensive

effectwasmaintainedinclinicalstudiesforuptooneyear.Measurementofbloodpressureattrough(24hourspost-

dose)relativetopeak(5-6hourspost-dose)demonstratedrelativelysmoothbloodpressurereductionover24hours.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/05/2010 CRN 2077446 page number: 6

intervalwasapproximately70-80%oftheeffectseen5-6hourspost-dose.Discontinuationoflosartaninhypertensive

patientsdidnotresultinanabruptreboundofbloodpressure.Despitethesignificantdecreaseinbloodpressure,

administrationof‘Cozaar’hadnoclinicallysignificanteffectonheartrate.

Theantihypertensiveeffectof‘Cozaar’50mgissimilartoonce-dailyadministrationofenalapril20mg.The

antihypertensiveeffectofonce-dailyadministrationof‘Cozaar’50-100mgiscomparabletoonce-dailyadministration

ofatenolol50-100mg.Theeffectofadministrationof‘Cozaar’50-100mgoncedailyisalsoequivalenttofelodipine

extended-release5-10mginolderhypertensives(65years)after12weeksoftherapy.

Although‘Cozaar’isantihypertensiveinallraces,aswithotherdrugsthataffecttherenin-angiotensin-aldosterone

system,blackhypertensivepatientshaveasmalleraverageresponsetolosartanmonotherapythannon-blackpatients.

If‘Cozaar’isgiventogetherwiththiazide-typediuretics,theblood-pressureloweringeffectsareapproximately

additive.

Theincidenceofcoughfollowingadministrationof‘Cozaar’topatientswithhypertensionissignificantlylessthan

seenwithACEinhibitorsandresultsarecomparabletoresultsseenwithplacebo.

LIFEStudy

TheLosartanInterventionForEndpointreductioninhypertension(LIFE)studywasarandomised,triple-blind,active-

controlledstudyin9,193hypertensivepatientsaged55to80years(mean67years)withECG-documentedleft

ventricularhypertrophy.Patientswererandomisedtoreceiveoncedaily‘Cozaar’50mgoratenolol50mg.Ifgoal

bloodpressure(<140/90mmHg)wasnotreached,hydrochlorothiazide(12.5mg)wasaddedfirstand,ifneeded,the

doseof‘Cozaar’oratenololwasthenincreasedto100mgoncedaily.Ifnecessary,otherantihypertensivetreatments

(e.g.increaseindoseofhydrochlorothiazidetherapyto25mgoradditionofotherdiuretictherapy,calciumchannel

blockers,alpha-blockers,orcentrallyactingagents,butnotACEinhibitors,angiotensinIIantagonists,orbeta-

blockers)wereaddedtothetreatmentregimentoreachthegoalbloodpressure.Themeanlengthoffollowupwas4.8

years.

Theprimaryendpointwasthecompositeofcardiovascularmorbidityandmortalityasmeasuredbyareductioninthe

combinedincidenceofcardiovasculardeath,strokeandmyocardialinfarction.Althoughbloodpressurewas

significantlyloweredtosimilarlevelsinthetwogroups,treatmentwith‘Cozaar’resultedina13.0%riskreduction

(p=0.021,95%confidenceinterval0.77-0.98)ascomparedwithatenololforpatientsreachingtheprimarycomposite

endpoint.Treatmentwith‘Cozaar’reducedtheriskofstrokeby25%relativetoatenolol(p=0.001).Theratesof

cardiovasculardeathandmyocardialinfarctionwerenotsignificantlydifferentbetweenthetreatmentgroups.The

effectof‘Cozaar’ontheprimarycompositeendpointappearedtobeoverandaboveitsbeneficialeffectsonblood

pressurecontrolalone.

Patientstreatedwith‘Cozaar’hadsignificantlygreaterreductioninECGindicesofleftventricularhypertrophyas

comparedtopatientstreatedwithatenolol.Inthesubgroupsofpatientswithabaselinehistoryofdiabetesmellitus

(n=1,195)orisolatedsystolichypertension(ISH)(n=1,326),theresultsoftreatmentwith‘Cozaar’wereconsistentwith

benefitoftherapywith‘Cozaar’seenintheoverallstudypopulation:indiabeticpatients,a24%reduction(p=0.06%)

wasobservedandinpatientswithISH,a25%riskreduction(p=0.06)wasobserved.Consistentwithresultsseeninthe

overallpopulation,areductioninstrokewasanimportantcontributortothebenefitobservedinpatientswithdiabetes

orISH.

IntheLIFEstudy,amongpatientswithoutdiabetesatbaseline,therewasalowerincidenceofnewonsetdiabetes

mellituswith‘Cozaar’ascomparedtoatenolol(242patientsversus320patientsrespectively,p<0.001).Becausethere

wasnoplacebogroupincludedinthestudy,itisnotknownifthisrepresentsabeneficialeffectof‘Cozaar’oran

adverseeffectofatenolol.

Race:BasedontheLIFEstudy,thebenefitsof‘Cozaar’oncardiovascularmorbidityandmortalitycomparedto

atenololdonotapplytoBlackpatientswithhypertensionandleftventricularhypertrophy,althoughbothtreatment

regimenseffectivelyloweredbloodpressureinBlackpatients.IntheLIFEstudy,‘Cozaar’decreasedtheriskof

cardiovascularmorbidityandmortalitycomparedtoatenololinnon-Black,hypertensivepatientswithleftventricular

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/05/2010 CRN 2077446 page number: 7

andmyocardialinfarction(p=0.003).Inthisstudy,however,Blackpatientstreatedwithatenololwereatlowerriskof

experiencingtheprimarycompositeendpointcomparedwithBlackpatientstreatedwith‘Cozaar’(p=0.03).Inthe

subgroupofBlackpatients(n=533;6%oftheLIFEstudypatients),therewere29primaryendpointsamong263

patientsonatenolol(11%,25.9per1,000patient-years)and46primaryendpointsamong270patients(17%,41.8per

1,000patient-years)on‘Cozaar’.

Inthisstudy,‘Cozaar’wasgenerallywelltolerated,andthetolerabilityprofileof‘Cozaar’wassuperiortoatenololas

evidencedbyasignificantlylowerincidenceofdiscontinuationsduetosideeffects.

Heartfailure

Inthe48-weekELITEstudyinpatients(n=722)withheartfailure(NYHAClassII-IV),nodifferencewasobservedin

theprimaryendpointofpersistentrenaldysfunctionbetweenthosepatientstreatedwith‘Cozaar’andthosetreatedwith

captopril.Theunexpectedobservationofsuperiorbenefitof‘Cozaar’inreducingtheriskofdeathrelativetocaptopril

observedintheELITEstudywasnotconfirmedinthedefinitiveELITEIIsurvivalstudy [1] asdescribedbelow.

Inastudyinpatientswithheartfailurethatwasprospectivelydesignedtoevaluatethemortality(ELITEII),aregimen

of‘Cozaar’50mgoncedaily(startingdoseof12.5mgtitratedto25mgand50mgoncedaily)wascomparedto

captopril50mgthreetimesdaily(startingdoseof12.5mgtitratedto25mgand50mgthreetimesdaily).Inthisstudy

(n=3,152),patientswithheartfailure(NYHAClassII-IV)werefollowedforapproximatelytwoyears(median

follow-up1.5years)toevaluatewhether‘Cozaar’wassuperiortocaptoprilinreducingtotalmortality.Theprimary

endpointshowednostatisticallysignificantdifferencebetween‘Cozaar’andcaptoprilintotalmortality(17.7%for

‘Cozaar’and15.9%forcaptopril,p=0.16).Thesecondaryendpointshowednostatisticallysignificantdifferencein

suddencardiacdeathand/orresuscitatedcardiacarrest(9.0%for‘Cozaar’and7.3%forcaptopril,p=0.08).Thetertiary

endpointofall-causemortalityand/orallcausehospitalisationshowednostatisticallysignificantdifferencebetween

‘Cozaar’andcaptopril(47.7%for‘Cozaar’and44.9%forcaptopril,p=0.18).Ingeneral,othermorbidityandmortality

endpointsincludingimprovementinNYHAClasswerenotdifferentbetweenthetreatmentgroups.

Inbothofthesecontrolledclinicaltrialsinpatientswithheartfailure,‘Cozaar’wasgenerallywelltolerated,andthe

tolerabilityprofileof‘Cozaar’wassuperiortocaptoprilasmeasuredbysignificantlylowerincidenceof

discontinuationsduetosideeffectsandsignificantlylowerincidenceofcough.

RENAALStudy:

TheReductionofEndpointsinNIDDMwiththeAngiotensinIIReceptorAntagonistLosartan(RENAAL)studywasa

multicentre,randomised,placebo-controlled,double-blindstudyin1513type2diabeticpatientswithproteinuria(751

treatedwith‘Cozaar’),withorwithouthypertension.Patientswithproteinuriaandserumcreatinineof115-265

micromol/lwererandomisedtoreceive‘Cozaar’50mgoncedaily,titratedaccordingtobloodpressureresponse,or

placebo,onabackgroundofconventionalantihypertensivetherapyexcludingACEinhibitorsandangiotensinII

antagonists.Investigatorswereinstructedtotitratestudydrugto100mgdailyasappropriate;72%ofpatientswere

takingthe100mgdailydosethemajorityofthetimetheywereonstudydrug.Patientswerefollowedfor

approximately5years(meanof3.4years).

Theresultsshowedthattreatmentwith‘Cozaar’(327events)ascomparedwithplacebo(359events)resultedina

16.1%riskreduction(p=0.022)inthenumberofpatientsreachingtheprimarycompositeendpointofdoublingof

serumcreatinine,endstagerenaldisease(needfordialysisortransplantation),ordeath.Thebenefitexceededthat

attributabletochangesinbloodpressurealone.Theresultsalsoshowedsignificantriskreductioninthegrouptreated

with‘Cozaar’:25.3%riskreductionindoublingofserumcreatinine(p=0.006);28.6%riskreductioninend-stagerenal

disease(p=0.002);therewasnosignificanteffectontherateofdeath.Forcombinedcomponentstherewasa19.9%

riskreductioninend-stagerenaldiseaseordeath(p=0.009);21.0%riskreductionindoublingofserumcreatinineor

end-stagerenaldisease(p=0.010).

Forthesecondaryendpointstheresultsshowedanaveragereductionof34.3%inthelevelofproteinuriainthegroup

treatedwith‘Cozaar’(p<0.001)overthemeanof3.4years.Treatmentwith‘Cozaar’reducedtherateofdeclinein

renalfunctionduringthechronicphaseofthestudyby13.9%,p=0.003(medianrateofdeclineof18.5%,p=0.01)as

measuredbythereciprocaloftheserumcreatinineconcentration timecurve.Therewasnosignificantdifference

betweenthegrouptreatedwith‘Cozaar’(247events)andtheplacebogroup(268events)inthecompositeendpointof

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/05/2010 CRN 2077446 page number: 8

Inthisstudy,‘Cozaar’wasgenerallywelltoleratedasevidencedbyasimilarincidenceofdiscontinuationsduetoside

effectscomparedtoplacebo.

5.2Pharmacokineticproperties

Absorption

Followingoraladministration,losartaniswellabsorbedandundergoesfirst-passmetabolism,forminganactive

carboxylicacidmetaboliteandotherinactivemetabolites.Thesystemicbioavailabilityoflosartantabletsis

approximately33%.Meanpeakconcentrationsoflosartananditsactivemetabolitearereachedin1hourandin3-4

hours,respectively.Therewasnoclinicallysignificanteffectontheplasmaconcentrationprofileoflosartanwhenthe

drugwasadministeredwithastandardisedmeal.

Distribution

Bothlosartananditsactivemetaboliteare 99%boundtoplasmaproteins,primarilyalbumin.Thevolumeof

distributionoflosartanis34litres.Studiesinratsindicatethatlosartancrossestheblood-brainbarrierpoorly,ifatall.

Biotransformation

About14%ofanintravenouslyororallyadministereddoseoflosartanisconvertedtoitsactivemetabolite.Following

oralandintravenousadministrationof 14

C-labelledlosartanpotassium,circulatingplasmaradioactivityprimarilyis

attributedtolosartananditsactivemetabolite.

Inadditiontotheactivemetabolite,inactivemetabolitesareformed,includingtwomajormetabolitesformedby

hydroxylationofthebutylsidechainandaminormetabolite,anN-2tetrazoleglucuronide.

Elimination

Plasmaclearanceoflosartananditsactivemetaboliteisabout600ml/minand50ml/min,respectively.Renalclearance

oflosartananditsactivemetaboliteisabout74ml/minand26ml/min,respectively.Whenlosartanisadministered

orally,about4%ofthedoseisexcretedunchangedintheurine,andabout6%ofthedoseisexcretedintheurineas

activemetabolite.Thepharmacokineticsoflosartananditsactivemetabolitearelinearwithorallosartanpotassium

dosesupto200mg.

Followingoraladministration,plasmaconcentrationsoflosartananditsactivemetabolitedeclinepolyexponentially

withaterminalhalf-lifeofabout2hoursand6-9hours,respectively.Duringonce-dailydosingwith100mg,neither

losartannoritsactivemetaboliteaccumulatessignificantlyinplasma.

Bothbiliaryandurinaryexcretioncontributetotheeliminationoflosartananditsmetabolites.Followinganoraldose

C-labelledlosartaninman,about35%ofradioactivityisrecoveredintheurineand58%inthefaeces.

Characteristicsinpatients

Followingoraladministrationinpatientswithmildtomoderatealcoholiccirrhosisoftheliver,plasmaconcentrations

oflosartananditsactivemetabolitewere,respectively,5-foldand1.7-foldgreaterthanthoseseeninyoungmale

volunteers.

Plasmaconcentrationsoflosartanarenotalteredinpatientswithcreatinineclearanceabove10ml/min.Comparedto

patientswithnormalrenalfunction,theAUCforlosartanisapproximately2-foldgreaterinhaemodialysispatients.

Plasmaconcentrationsoftheactivemetabolitearenotalteredinpatientswithrenalimpairmentorinhaemodialysis

patients.Neitherlosartannortheactivemetabolitecanberemovedbyhaemodialysis.

5.3Preclinicalsafetydata

Notapplicable.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/05/2010 CRN 2077446 page number: 9

6.1Listofexcipients

EachCozaar12.5mgtabletandeachCozaar50mgtabletcontains:

Hyprolose(E463)

Hypromellose(E464)

Lactosemonohydrate

Magnesiumstearate(E572)

Microcrystallinecellulose(E460)

Pregelatinisedstarch

Titaniumdioxide(E171)

Carnaubawax

EachCozaar12.5mgtabletalsocontainsIndigocarminealuminiumlake(E132).

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

3years.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

White,opaquePVC/PE/PVDCblisterswithaluminium-foillidding.

Initiationpackforheartfailure:35tabletsasfollows:

12.5mgx21

50mgx14

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

MerckSharp&DohmeLimited

HertfordRoad

Hoddesdon

HertfordshireEN119BU

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA35/82/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/05/2010 CRN 2077446 page number: 10

Dateoflastrenewal:21December2008

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 18/05/2010 CRN 2077446 page number: 11