COZAAR

Main information

  • Trade name:
  • COZAAR Film Coated Tablet 50 Milligram
  • Dosage:
  • 50 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COZAAR Film Coated Tablet 50 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1151/005/001A
  • Authorization date:
  • 30-07-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cozaar50mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains50mglosartanpotassium(equivalentto45.8mglosartan).

Excipients:LactoseMonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

ProductimportedfromItalyandtheUK:

White,oval-shaped,film-coatedtabletmarked'952'ononesideandasinglescorelineontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertensioninadultsandinchildrenandadolescents6-18yearsofage.

Treatmentofrenaldiseaseinadultpatientswithhypertensionandtype2diabetesmellituswithproteinuria ≥

0.5g/dayaspartofanantihypertensivetreatment.

Treatmentofchronicheartfailure(inpatients ≥60years),whentreatmentwithAngiotensin-convertingenzyme

(ACE)inhibitorsisnotconsideredsuitableduetoincompatibility,especiallycough,orcontraindication.Patients

withheartfailurewhohavebeenstabilisedwithanACEinhibitorshouldnotbeswitchedtolosartan.Thepatients

shouldhavealeftventricularejectionfraction ≤40%andshouldbeclinicallystableandonanestablishedtreatment

regimenforchronicheartfailure.

ReductionintheriskofstrokeinadulthypertensivepatientswithleftventricularhypertrophydocumentedbyECG

(seesection5.1LIFEstudy,Race).

4.2Posologyandmethodofadministration

Losartantabletsshouldbeswallowedwithaglassofwater.

Cozaarmaybeadministeredwithotherantihypertensiveagents.

Hypertension

Theusualstartingandmaintenancedoseis50mgoncedailyformostpatients.Themaximalantihypertensiveeffectis

attained3-6weeksafterinitiationoftherapy.Somepatientsmayreceiveanadditionalbenefitbyincreasingthedoseto

100mgoncedaily(inthemorning).

Losartanmaybeadministeredwithotherantihypertensiveagents,especiallywithdiuretics(e.g.hydrochlorothiazide).

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Theusualstartingdoseis50mgoncedaily.Thedosemaybeincreasedto100mgoncedailybasedonbloodpressure

responsefromonemonthonwardsafterinitiationoftherapy.Losartanmaybeadministeredwithotherantihypertensive

agents(e.g.diuretics,calciumchannelblockers,alpha-orbeta-blockers,andcentrallyactingagents)aswellaswith

insulinandothercommonlyusedhypoglycaemicagents(e.g.sulfronylureas,glitazonesandglucosidaseinhibitors).

Heartfailure

TheinitialdoseofLosartaninpatientswithheartfailureis12.5mgoncedaily.Thedoseshouldgenerallybetitratedat

weeklyintervals(e.e.12.5mgdaily,25mgdaily,50mgdaily)totheusualmaintenancedoseof50mgoncedaily,as

toleratedbythepatient.

Reductionintheriskofcardiovascularmorbidityinhypertensivepatientswithleftventricularhypertrophy

Theusualstartingdoseis50mgoflosartanoncedaily.Alowdoseofhydrochlorothiazidemaybeaddedand/orthe

doseoflosartanmaybeincreasedto100mgoncedailybasedonbloodpressureresponse.

Specialpopulations

Useinpatientswithintravascularvolumedepletion:

Forpatientswithintravascularvolume-depletion(e.g.thosetreatedwithhigh-dosediuretics),astartingdoseof25mg

oncedailyshouldbeconsidered(seesection4.4).

Useinpatientswithrenalimpairmentandhaemodialysispatients:

Noinitialdosageadjustmentisnecessaryinpatientswithrenalimpairmentandinhaemodialysispatients.

Useinpatientswithhepaticimpairment:

Alowerdoseshouldbeconsideredforpatientswithahistoryofhepaticimpairment.Thereisnotherapeuticexperience

inpatientswithseverehepaticimpairment.Therefore,losartaniscontraindicatedinpatientswithseverehepatic

impairment(seesections4.3and4.4).

Useinpaediatricpatients

Therearelimiteddataontheefficacyandsafetyoflosartaninchildrenandadolescentsaged6-18yearsoldforthe

treatmentofhypertension(seesection5.1).Limitedpharmacokineticdataareavailableinhypertensivechildrenabove

onemonthofage(seesection5.2).

Forpatientswhocanswallowtablets,therecommendeddoseis25mgoncedailyinpatients>20to<50kg.(In

exceptionalcasesthedosecanbeincreasedtoamaximumof50mgoncedaily).Dosageshouldbeadjustedaccording

tobloodpressureresponse.

Inpatients>50kg,theusualdoseis50mgoncedaily.Inexceptionalcasesthedosecanbeadjustedtoamaximumof

100mgoncedaily.Dosesabove1.4mg/kg(orinexcessof100mg)dailyhavenotbeenstudiedinpaediatricpatients.

Losartanisnotrecommendedforuseinchildrenunder6yearsold,aslimiteddataareavailableinthesepatientgroups.

Itisnotrecommendedinchildrenwithglomerularfiltrationrate<30ml/min/1.73m²,asnodataareavailable(seealso

section4.4).

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UseinElderly

Althoughconsiderationshouldbegiventoinitiatingtherapywith25mginpatientsover75yearsofage,dosage

adjustmentisnotusuallynecessaryfortheelderly.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients(seesection4.4and6.1).

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6).

Severehepaticimpairment

4.4Specialwarningsandprecautionsforuse

Hypersensitivity

Angioedema.Patientswithahistoryofangiodema(swellingoftheface,lips,throat,and/ortongue)shouldbeclosely

monitored.(seesection4.8)

Hypotensionandelectrolyte/fluidimbalance

Symptomatichypotension,especiallyafterthefirstdoseandafterincreasingofthedose,mayoccurinpatientswhoare

volume-and/orsodium-depletedbyvigorousdiuretictherapy,dietarysaltrestriction,diarrhoeaorvomiting.These

conditionsshouldbecorrectedpriortoadministrationoflosartan,oralowerstartingdoseshouldbeused(seesection

4.2).Thisalsoappliestochildren6to18yearsofage.

Electrolyteimbalances

Electrolyteimbalancesarecommoninpatientswithrenalimpairment,withorwithoutdiabetes,andshouldbe

addressed.Inaclinicalstudyconductedintype2diabeticpatientswithnephropathy,theincidenceofhyperkalaemia

washigherinthegrouptreatedwithlosartanascomparedtotheplacebogroup(seesection4.8)Therefore,theplasma

concentrationsofpotassiumaswellascreatinineclearancevaluesshouldbecloselymonitored,especiallypatientswith

heartfailureandacreatinineclearancebetween30-50ml/minshouldbecloselymonitored.

Theconcomitantuseofpotassium-sparingdiuretics,potassiumsupplementsandpotassium-containingsaltsubstitutes

withlosartanisnotrecommended(seesection4.5).

Hepaticimpairment

Basedonpharmacokineticdatawhichdemonstratesignificantlyincreasedplasmaconcentrationsoflosartanincirrhotic

patients,alowerdoseshouldbeconsideredforpatientswithahistoryofhepaticimpairment.Thereisnotherapeutic

experiencewithlosartaninpatientswithseverehepaticimpairment.Thereforelosartanmustnotbeadministeredin

patientswithseverehepaticimpairment(seesections4.2,4.3and5.2).

Losartanisnotrecommendedinchildrenwithhepaticimpairment(seesection4.2).

Renalimpairment

Asaconsequenceofinhibitingtherenin-angiotensinsystem,changesinrenalfunctionincludingrenalfailurehave

beenreported(inparticular,inpatientswhoserenalfunctionisdependentontherennin-angiotensin-aldosteronesystem

suchasthosewithseverecardiacinsufficiencyorpre-existingrenaldysfunction).Aswithothermedicinalproductsthat

affecttherenin-angiotensin-aldosteronesystem,increasesinbloodureaandserumcreatininehavealsobeenreportedin

patientswithbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney;thesechangesinrenalfunction

maybereversibleupondiscontinuationoftherapy.Losartanshouldbeusedwithcautioninpatientswithbilateralrenal

arterystenosisorstenosisofthearterytoasolitarykidney.

Useinpediatricpatientswithrenalimpairment

Losartanisnotrecommendedinchildrenwithglomerularfiltrationrate<30ml/min/1.73m 2

asnodataareavailable

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Renalfunctionshouldberegularlymonitoredduringtreatmentwithlosartanasitmaydeteriorate.Thisapplies

particularlywhenlosartanisgiveninthepresenceofotherconditions(fever,dehydration)likelytoimpairrenal

function.

ConcomitantuseoflosartanandACE-inhibitorshasshowntoimpairrenalfunction.Therefore,concomitantuseisnot

recommended(seesection4.5).

Renaltransplantation

Thereisnoexperienceinpatientswithrecentkidneytransplantation.

Primaryhyperaldosteronism

Patientswithprimaryaldosteronismgenerallywillnotrespondtoantihypertensivemedicinalproductsactingthrough

inhibitionoftherenin-angiotensinsystem.Therefore,theuseoflosartanisnotrecommended.

Coronaryheartdiseaseandcerebrovasculardisease

Aswithanyantihypertensiveagents,excessivebloodpressuredecreaseinpatientswithischaemiccardiovascularand

cerebrovasculardiseasecouldresultinamyocardialinfarctionorstroke.

Heartfailure

Inpatientswithheartfailure,withorwithoutrenalimpairment,thereis-aswithothermedicinalproductsactingonthe

renin-angiotensinsystem-ariskofseverearterialhypotension,and(oftenacute)renalimpairment.

Thereisnosufficienttherapeuticexperiencewithlosartaninpatientswithheartfailureandconcomitantsevererenal

impairment,inpatientswithsevereheartfailure(NYHAclassIV)aswellasinpatientswithheartfailureand

symptomaticlifethreateningcardiacarrhythmias.Therefore,losartanshouldbeusedwithcautioninthesepatient

groups.Thecombinationoflosartanwithabeta-blockershouldbeusedwithcaution(seesection5.1).

Aorticandmitralvalvestenosis,obstructivehypertrophiccardiomyopathy

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromaorticormitralstenosis,orobstructive

hypertrophiccardiomyopathy.

Excipients

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

Pregnancy

Losartanshouldnotbeinitiatedduringpregnancy.Unlesscontinuedlosartantherapyisconsideredessential,patients

planningpregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhichhaveanestablishedsafety

profileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithlosartanshouldbestoppedimmediately,

and,ifappropriate,alternativetherapyshouldbestarted(seesections4.3and4.6).

Otherwarningsandprecautions

Asobservedforangiotensinconvertingenzymeinhibitors,losartanandtheotherangiotensinantagonistsareapparently

lesseffectiveinloweringbloodpressureinblackpeoplethaninnon-blacks,possiblybecauseofhigherprevalenceof

low-reninstatesintheblackhypertensivepopulation.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Otherantihypertensiveagentsmayincreasethehypotensiveactionoflosartan.Concomitantusewithothersubstances

whichmayinducehypotensionasanadversereaction(liketricyclicantidepressants,antipsychotics,baclofene,and

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LosartanispredominantlymetabolisedbycytochromeP450(CYP)2C9totheactivecarboxy-acidmetabolite.Ina

clinicaltrialitwasfoundthatfluconazole(inhibitorofCYP2C9)decreasestheexposuretotheactivemetaboliteby

approximately50%.Itwasfoundthatconcomitanttreatmentoflosartanwithrifampicine(inducerofmetabolism

enzymes)gavea40%reductioninplasmaconcentrationoftheactivemetabolite.Theclinicalrelevanceofthiseffectis

unknown.Nodifferenceinexposurewasfoundwithconcomitanttreatmentwithfluvastatin(weakinhibitorof

CYP2C9).

AswithothermedicinalproductsthatblockangiotensinIIoritseffects,concomitantuseofothermedicinalproducts

whichretainpotassium(e.g.potassium-sparingdiuretics:amiloride,triamterene,spironolactone)ormayincrease

potassiumlevels(e.g.heparin),potassiumsupplementsorsaltsubstitutescontainingpotassiummayleadtoincreasesin

serumpotassium.Co-medicationisnotadvisable.

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.VeryrarecaseshavealsobeenreportedwithangiotensinIIreceptor

antagonists.Co-administrationoflithiumandlosartanshouldbeundertakenwithcaution.Ifthiscombinationproves

essential,serumlithiumlevelmonitoringisrecommendedduringconcomitantuse.

WhenangiotensinIIantagonistsareadministeredsimultaneouslywithNSAIDs(i.e.selectiveCOX-2inhibitors,

acetylsalicylicacidatanti-inflammatorydosesandnon-selectiveNSAIDs),attenuationoftheantihypertensiveeffect

mayoccur.ConcomitantuseofangiotensinIIantagonistsordiureticsandNSAIDsmayleadtoanincreasedriskof

worseningofrenalfunction,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyin

patientswithpoorpre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyinthe

elderly.Patientsshouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunctionafter

initiationofconcomitanttherapy,andperiodicallythereafter.

4.6Pregnancyandlactation

Pregnancy

TheuseofLosartanisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).TheuseofLosartanis

contraindicatedduringthesecondandthirdtrimestersofpregnancy(seesections4.3and4.4).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithAngiotensinIIReceptorInhibitors(AIIRAs),similarrisksmayexist

forthisclassofmedicinalproducts.UnlesscontinuedAIIRAtherapyisconsideredessential,patientsplanning

pregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuse

inpregnancy.Whenpregnancyisdiagnosed,treatmentwithLosartanshouldbestoppedimmediatelyand,if

appropriate,alternativetherapyshouldbestarted.

ExposuretoAIIRAtherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity(decreased

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

hyperkalaemia).(Seesection5.3.)

ShouldexposuretoLosartanhaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

InfantswhosemothershavetakenLosartanshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Lactation

BecausenoinformationisavailableregardingtheuseofLosartanduringbreastfeeding,Losartanisnotrecommended

andalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,especiallywhile

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4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,whendriving

vehiclesoroperatingmachinesitmustbeborneinmindthatdizzinessordrowsinessmayoccasionallyoccurwhen

takingantihypertensivetherapy,inparticularduringinitiationoftreatmentorwhenthedoseisincreased.

4.8Undesirableeffects

Losartanhasbeenevaluatedinclinicalstudiesasfollows:

incontrolledclinicaltrialsinapproximately3300adultpatients18yearsofageandolderforessentialhypertension,

inacontrolledclinicaltrialin9193hypertensivepatients55to80yearsofagewithleftventricularhypertrophy

inacontrolledclinicaltrialinapproximately3900patients20yearsofageandolderwithchronicheartfailure

inacontrolledclinicaltrialin1513type2diabeticpatients31yearsofageandolderwithproteinuria

inacontrolledclinicaltrialin177hypertensivepediatricpatients6to16yearsofage

Intheseclinicaltrials,themostcommonadversereactionwasdizziness.

Thefrequencyofadversereactionslistedbelowisdefinedusingthefollowingconvention:

verycommon( ≥1/10);common(≥1/100,to<1/10);uncommon(≥1/1,000,to<1/100);rare(≥1/10,000,to<1/1,000);

veryrare(<1/10,000),notknown(cannotbeestimatedfromtheavailabledata).

Hypertension

Incontrolledclinicaltrialsofapproximately3300adultpatients18yearsofageandolder,foressentialhypertension

withlosartan,thefollowingadversereactionswerereported

Nervoussystemdisorders:

common:dizziness,vertigo

uncommon:somnolence,headache,sleepdisorders

Cardiacdisorder:

uncommon:palpitations,anginapectoris

Vasculardisorders:

uncommon:symptomatichypotension(especiallyinpatientswithintravascularvolumedepletion,e.g.patientswith

severeheartfailureorundertreatmentwithhighdosediuretics),dose-relatedorthostaticeffects,rash.

Gastrointestinaldisorders:

uncommon:abdominalpain,obstipation

Generaldisordersandadministrationsiteconditions:

uncommon:asthenia,fatigue,oedema

Investigations:

Incontrolledclinicaltrials,clinicallyimportantchangesinstandardlaboratoryparameterswererarelyassociatedwith

administrationofLosartantablets.ElevationsofALToccurredrarelyandusuallyresolvedupondiscontinuationof

therapy.Hyperkalaemia(serumpotassium>5.5mmol/l)occurredin1.5%ofpatientsinhypertensionclinicaltrials.

Hypertensivepatientswithleftventricularhypertrophy

Inacontrolledclinicaltrialin9193hypertensivepatients55to80yearsofage,withleftventricularhypertrophy,the

followingadversereactionswerereported:

Nervoussystemdisorders:

common:dizziness

Earandlabyrinthdisorders:

common:vertigo

Generaldisordersandadministrationsiteconditions:

common:asthenia/fatigue

Chronicheartfailure

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followingadversereactionswerereported:

Nervoussystemdisorders:

uncommon:dizziness,headache

rare:paraesthesia

Cardiacdisorders:

rare:syncope,atrialfibrillation,cerebrovascularaccident

Vasculardisorders:

uncommon:hypotension,includingorthostatichypotension

Respiratory,thoracicandmediastinaldisorders:

uncommon:dyspnoea

Gastrointestinaldisorders:

uncommon:diarrhoea,nausea,vomiting

Skinandsubcutaneoustissuedisorders:

uncommon:urticaria,pruritus,rash

Generaldisordersandadministrationsiteconditions:

uncommon:asthenia/fatigue

Investigations:

uncommon:increaseinbloodurea,serumcreatinineandserumpotassiumhasbeenreported.

Hypertensionandtype2diabeteswithrenaldisease

Inacontrolledclinicaltrialin1513type2diabeticpatients31yearsofageandolder,withproteinuria(RENAAL

study,seesection5.1),themostcommondrug-relatedadversereactionswhichwerereportedforlosartanareas

follows:

Nervoussystemdisorders:

common:dizziness

Vasculardisorders:

common:hypotension

Generaldisordersandadministrationsiteconditions:

common:asthenia/fatigue

Investigations:

common:hypoglycaemia,hyperkalaemia

Thefollowingadversereactionsoccurredmoreofteninpatientsreceivinglosartanthanplacebo:

Bloodandlymphaticsystemdisorders:

notknown:anaemia

Cardiacdisorders:

notknown:syncope,palpitations

Vasculardisorders:

notknown:orthostatichypotension

Gastrointestinaldisorders:

notknown:diarrhoea

Muscoskeletalandconnectivetissuedisorders:

notknown:backpain

Renalandurinarydisorders:

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Generaldisordersandadministrationsiteconditions:

notknown:flu-likesymptoms

Investigations:

Inaclinicalstudyconductedintype2diabeticpatientswithnephropathy,9.9%ofpatientstreatedwithLosartantablets

developedhyperkalaemia>5.5mEq/land3.4%ofpatientstreatedwithplacebo

Post-marketingexperience

Thefollowingadversereactionshavebeenreportedinpost-marketingexperience:

Bloodandlymphaticsystemdisorders:

notknown:anaemia,thrombocytopenia

Earandlabyrinthdisorders:

notknown:tinnitus

Immunesystemdisorders:

rare:hypersensitivity:anaphylacticreactions,angiooedemaincludingswellingofthelarynxandglottiscausingairway

obstructionand/orswellingoftheface,lips,pharynx,and/ortongue;insomeofthesepatientsangiooedemahadbeen

reportedinthepastinconnectionwiththeadministrationofothermedicines,includingACEinhibitors;vasculitis,

includingHenoch-Schonleinpurpura.

Nervoussystemdisorders:

notknown:migraine

Respiratory,thoracicandmediastinaldisorders:

notknown:cough

Gastrointestinaldisorders:

notknown:diarrhoea,pancreatitis

Generaldisordersandadministrationsiteconditions:

notknown:malaise

Hepatobiliarydisorders:

rare:hepatitis

notknown:liverfunctionabnormalities

Skinandsubcutaneoustissuedisorders:

notknown:urticaria,pruritus,rash,photosensitivity

Muscoskeletalandconnectivetissuedisorders:

notknown:myalgia,arthralgia,rhabdomyolysis

Reproductivesystemandbreastdisorders:

notknown:erectiledysfunction/impotence

Renalandurinarydisorders:

Asaconsequenceofinhibitingtherenin-angiotensin-aldosteronesystem,changesinrenalfunctionincludingrenal

failurehavebeenreportedinpatientsatrisk;thesechangesinrenalfunctionmaybereversibleupondiscontinuationof

therapy(seesection4.4)

Psychiatricdisorders:

notknown:depression

Investigations:

notknown:hyponatraemia

Paediatricpopulation

Theadversereactionprofileforpaediatricpatientsappearstobesimilartothatseeninadultpatients.Datainthe

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4.9Overdose

Symptomsofintoxication

Limiteddataareavailablewithregardtooverdoseinhumans.Themostlikelymanifestationofoverdosewouldbe

hypotensionandtachycardia.Bradycardiacouldoccurfromparasympathetic(vagal)stimulation.

Treatmentofintoxication

Ifsymptomatichypotensionshouldoccur,supportivetreatmentshouldbeinstituted.

Measuresaredependingonthetimeofmedicinalproductintakeandkindandseverityofsymptoms.Stabilisationof

thecardiovascularsystemshouldbegivenpriority.Afteroralintake,theadministrationofasufficientdoseofactivated

charcoalisindicated.Afterwards,closemonitoringofthevitalparametersshouldbeperformed.Vitalparameters

shouldbecorrectedifnecessary.

Neitherlosartannortheactivemetabolitecanberemovedbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacothetherapeuticgroup:AngiotensinIIantagoinists,plain,ATCcode:C09CA01

Losartanisasyntheticoral,specificangiotensin-IIreceptor(typeAT1)antagonist.

AngiotensinII,apotentvasoconstrictor,istheprimaryactivehormoneoftherenin/angiotensinsystemandan

importantdeterminantofthepathophysiologyofhypertension.AngiotensinIIbindstotheAT

receptorfoundinmany

tissues(e.g.vascularsmoothmuscle,adrenalgland,kidneysandtheheart)andelicitsseveralimportantbiological

actions,includingvasoconstrictionandthereleaseofaldosterone.AngiotensinIIalsostimulatessmoothmusclecell

proliferation.

LosartanselectivelyblockstheAT

receptor.Invitroandinvivolosartananditspharmacologicallyactivecarboxylic

acidmetaboliteE-3174blockallphysiologicallyrelevantactionsofangiotensinII,regardlessofthesourceorrouteof

itssynthesis.

Losartandoesnothaveanagonisteffectnordoesitblockotherhormonereceptorsorionchannelsimportantin

cardiovascularregulation.FurthermoreLosartandoesnotinhibitACE(kininaseII),theenzymethatdegrades

bradykinin.Consequently,thereisnopotentiationofundesirablebradykinin-mediatedeffects.

DuringadministrationofLosartan,removaloftheangiotensinIInegativefeedbackonreninsecretionleadsto

increasedplasmareninactivity(PRA).IncreaseinthePRAleadstoanincreaseinangiotensinIIinplasma.Despite

theseincreases,antihypertensiveactivityandsuppressionofplasmaaldosteroneconcentrationaremaintained,

indicatingeffectiveangiotensinIIreceptorblockade.AfterdiscontinuationofLosartan,PRAandangiotensinIIvalues

fellwithinthreedaystothebaselinevalues.

BothLosartananditsprincipalactivemetabolitehaveafargreateraffinityfortheAT

-receptorthanfortheAT

receptor.Theactivemetaboliteis10-to40-timesmoreactivethanLosartanonaweightforweightbasis.

HypertensionStudies

Incontrolledclinicalstudies,once-dailyadministrationofLosartantopatientswithmildtomoderateessential

hypertensionproducedstatisticallysignificantreductionsinsystolicanddiastolicbloodpressure.Measurementof

bloodpressureat24hourspost-doserelativetopeak5-6hourspost-dosedemonstratedrelativelysmoothblood

pressurereductionover24hours;thenaturaldiurnalrhythmwasretained.Blood-pressurereductionattheendofthe

dosingintervalwas70-80%oftheeffectseen5-6hourspost-dose.Discontinuationoflosartaninhypertensivepatients

didnotresultinanabruptriseinbloodpressure.Despitethemarkeddecreaseinbloodpressure,Losartanhadno

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Losartanisequallyeffectiveinmalesandfemales,andinyounger(belowtheageof65years)andolderhypertensive

patients.

LIFEStudy

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

controlledstudyin9,193hypertensivepatientsaged55to80years(mean67years)withECG-documentedleft

ventricularhypertrophy.PatientswererandomisedtoreceiveoncedailyLosartan50mgoratenolol50mg.

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

thedoseofLosartanoratenololwasthenincreasedto100mgoncedaily.Otherantihypertensives,withtheexception

ofACEinhibitors,angiotensinIIantagonists,orbeta-blockerswereaddedifnecessarytoreachthegoalbloodpressure.

Themeanlengthoffollowupwas4.8years.

Theprimaryendpointwasthecompositeofcardiovascularmorbidityandmortalityasmeasuredbyareductioninthe

combinedincidenceofcardiovasculardeath,strokeandmyocardialinfarction.Bloodpressurewassignificantly

loweredtosimilarlevelsinthetwogroupsTreatmentwithlosartanresultedina13.0%riskreduction(p=0.021,95%

confidenceinterval0.77-0.98)ascomparedwithatenololforpatientsreachingtheprimarycompositeendpoint.This

wasmainlyattributabletoareductionoftheincidenceofstroke.Treatmentwithlosartanreducedtheriskofstrokeby

25%relativetoatenolol(p=0.001,95%confidenceinterval0.63-0.89).Theratesofcardiovasculardeathand

myocardialinfarctionwerenotsignificantlydifferentbetweenthetreatmentgroups.

Race

IntheLIFE-StudyblackpatientstreatedwithLosartanhadahigherriskofsufferingtheprimarycombinedendpoint,

i.e.acardiovascularevent(e.g.cardiacinfarction,cardiovasculardeath)andespeciallystroke,thentheblackpatients

treatedwithatenolol.ThereforetheresultsobservedwithlosartanincomparisonwithatenololintheLIFEstudywith

regardtocardiovascularmorbidity/mortalitydonotapplyforblackpatientswithhypertensionandleftventricular

hypertrophy.

RENAALStudy

TheReductionofEndpointsinNIDDMwiththeAngiotensinIIReceptorAntagonistLosartan(RENAAL)studywasa

controlledclinicalstudyconductedworldwidein1513Type2diabeticpatientswithproteinuria,withorwithout

hypertension.751PatientsweretreatedwithLosartan

TheobjectiveofthestudywastodemonstrateanephroprotectiveeffectofLosartanpotassiumoverandabovethe

benefitofloweringbloodpressure.

Patientswithproteinuriaandaserumcreatinineof1.3–3.0mg/dlwererandomisedtoreceiveLosartan50mgoncea

day,titratedifnecessary,toachievebloodpressureresponse,ortoplacebo,onabackgroundofconventional

antihypertensivetherapyexcludingACE-inhibitorsandangiotensinIIantagonists.

Investigatorswereinstructedtotitratethestudymedicationto100mgdailyasappropriate;72%ofpatientswere

takingthe100mgdailydoseforthemajorityofthetime.Otherantihypertensiveagents(diuretics,calciumantagonists,

alpha-andbeta-receptorblockersandalsocentrallyactingantihypertensives)werepermittedassupplementary

treatmentdependingontherequirementinbothgroups.Patientswerefollowedupforupto4.6years(3.4yearson

average).Theprimaryendpointofthestudywasacompositeendpointofdoublingoftheserumcreatinineend-stage

renalfailure(needfordialysisortransplantation)ordeath.

TheresultsshowedthatthetreatmentwithLosartan(327events)ascomparedwithplacebo(359events)resultedina

16.1%riskreduction(p=0.022)inthenumberofpatientsreachingtheprimarycompositeendpoint.Forthefollowing

individualandcombinedcomponentsoftheprimaryendpoint,theresultsshowedasignificantriskreductioninthe

grouptreatedwithLosartan:25.3%riskreductionfordoublingoftheserumcreatinine(p=0.006);28.6%risk

reductionforend-stagerenalfailure(p=0.002);19.9%riskreductionforend-stagerenalfailureordeath(p=0.009);

21.0%riskreductionfordoublingofserumcreatinineorend-stagerenalfailure(p=0.01).

All-causemortalityratewasnotsignificantlydifferentbetweenthetwotreatmentgroups.

Inthisstudy,Losartanwasgenerallywelltoleratedasevidencedbyasimilarincidenceofdiscontinuationsduetoside

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ELITEIandELITEIIStudy

IntheELITEStudycarriedoutover48weeksin722patientswithheartfailure(NYHAClassII-IV),nodifferencewas

observedbetweenthepatientstreatedwithLosartanandthosetreatedwithcaptoprilwasobservedwithregardtothe

primaryendpointofalong-termchangeinrenalfunction.TheobservationoftheELITEIStudy,that,comparedwith

captopril,Losartanreducedthemortalityrisk,wasnotconfirmedinthesubsequentELITEIIStudy,whichisdescribed

inthefollowing.

IntheELITEIIStudyLosartan50mgoncedaily(startingdose12.5mg,increasedto25mg,then50mgoncedaily)

wascomparedwithcaptopril50mgthreetimesdaily(startingdose12.5mg,increasedto25mgandthento50mg

threetimesdaily).Theprimaryendpointofthisprospectivestudywastheall-causemortality.

Inthisstudy3152patientswithheartfailure(NYHAClassII-IV)werefollowedforalmosttwoyears(median:1.5

years)inordertodeterminewhetherLosartanissuperiortocaptoprilinreducingallcausemortality.Theprimary

endpointdidnotshowanystatisticallysignificantdifferencebetweenLosartanandcaptoprilinreducingall-cause

mortality.

Inbothcomparator-controlled(notplacebo-controlled)clinicalstudiesonpatientswithheartfailurethetolerabilityof

Losartanwassuperiortothatofcaptopril,measuredonthebasisofasignificantlylowerrateofdiscontinuationsof

therapyonaccountofadversereactionsandasignificantlylowerfrequencyofcough.

AnincreasedmortalitywasobservedinELITEIIinthesmallsubgroup(22%ofallHFpatients)takingbeta-blockers

atbaseline.

PaediatricPopulation

PaediatricHypertension

Theantihypertensiveeffectoflosartanwasestablishedinaclinicalstudyinvolving177hypertensivepediatricpatients

6to16yearsofagewithabodyweight>20kgandaglomerularfiltrationrate>30ml/min/1.73m 2

.Patientswho

weighted>20kgto<50kgreceivedeither2.5,25or50mgoflosartandailyandpatientswhoweighted>50kg

receivedeither5,50or100mgoflosartandaily.Attheendofthreeweeks,losartanadministrationoncedailylowered

troughbloodpressureinadose-dependentmanner.

Overall,therewasadose-response.Thedose-responserelationshipbecameveryobviousinthelowdosegroup

comparedtothemiddledosegroup(periodI:-6.2mmHgvs.-11.65mmHg),butwasattenuatedwhencomparingthe

middledosegroupwiththehighdosegroup(periodI:-11.65mmHgvs.-12.21mmHg).Thelowestdosesstudied,2.5

mgand5mg,correspondingtoanaveragedailydoseof0.07mg/kg,didnotappeartoofferconsistent

antihypertensiveefficacy.

TheseresultswereconfirmedduringperiodIIofthestudywherepatientswererandomizedtocontinuelosartanor

placebo,afterthreeweeksoftreatment.Thedifferenceinbloodpressureincreaseascomparedtoplacebowaslargestin

themiddledosegroup(6.70mmHgmiddledosevs.5.38mmHghighdose).Theriseintroughdiastolicbloodpressure

wasthesameinpatientsreceivingplaceboandinthosecontinuinglosartanatthelowestdoseineachgroup,again

suggestingthatthelowestdoseineachgroupdidnothavesignificantantihypertensiveeffect.

Long-termeffectsoflosartanongrowth,pubertyandgeneraldevelopmenthavenotbeenstudied.Thelong-term

efficacyofantihypertensivetherapywithlosartaninchildhoodtoreducecardiovascularmorbidityandmortalityhas

alsonotbeenestablished.

Inhypertensive(N=60)andnormotensive(N=246)childrenwithproteinuria,theeffectoflosartanonproteinuriawas

evaluatedina12-weekplacebo-andactive-controlled(amlodipine)clinicalstudy.Proteinuriawasdefinedasurinary

protein/creatinineratioof ≥0.3.Thehypertensivepatients(ages6through18years)wererandomizedtoreceiveeither

losartan(n=30)oramlodipine(n=30).Thenormotensivepatients(ages1through18years)wererandomizedtoreceive

eitherlosartan(n=122)orplacebo(n=124).Losartanwasgivenatdosesof0.7mg/kgto1.4mg/kg(uptomaximum

doseof100mgperday).Amlodipinewasgivenatdosesof0.05mg/kgto0.2mg/kg(uptoamaximumdoseof5mg

perday).

Overall,after12weeksoftreatment,patientsreceivinglosartanexperiencedastatisticallysignificantreductionfrom

baselineinproteinuriaof36%versus1%increaseinplacebo/amlodipinegroup(p ≤0.001).Hypertensivepatients

receivinglosartanexperiencedareductionfrombaselineproteinuriaof-41.5%(95%CI-29.9;-51.1)versus+2.4%

(95%CI-22.2;14.1)intheamlodipinegroup.Thedeclineinbothsystolicbloodpressureanddiastolicbloodpressure

wasgreaterinthelosartangroup(-5.5/-3.8mmHg)versustheamlodipinegroup(-0.1/+0.8mmHg).Innormotensive

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Nosignificantcorrelationbetweenthedeclineinproteinuriaandbloodpressurewasnoted,howeveritispossiblethat

thedeclineinbloodpressurewasresponsible,inpart,forthedeclineinproteinuriainthelosartantreatedgroup.Long-

termeffectsofreductionofproteinuriainchildrenhavenotbeenstudied.

5.2Pharmacokineticproperties

Absorption

Followingoraladministration,losartaniswellabsorbedandundergoesfirst-passmetabolism,forminganactive

carboxylicacidmetaboliteandotherinactivemetabolites.

Thesystemicbioavailabilityoflosartantabletsisapproximately33%.Meanpeakconcentrationsoflosartanandits

activemetabolitearereachedin1hourandin3-4hours,respectively.Therewasnoclinicallysignificanteffectonthe

plasmaconcentrationprofileoflosartanwhenthedrugwasadministeredwithastandardisedmeal.

Distribution

Bothlosartananditsactivemetaboliteare ≥99%boundtoplasmaproteins,primarilyalbumin.Thevolumeof

distributionoflosartanis34litres.Studiesinratsindicatethatlosartancrossestheblood-brainbarrierpoorly,ifatall.

Biotransformation

About14%ofanintravenouslyororally-administereddoseoflosartanisconvertedtoitsactivemetabolite.Following

oralandintravenousadministrationof14C-labelledlosartanpotassium,circulatingplasmaradioactivityprimarilyis

attributedtolosartananditsactivemetabolite.Minimalconversionoflosartantoitsactivemetabolitewasseenin

aboutonepercentofindividualsstudied.

Inadditiontotheactivemetabolite,inactivemetabolitesareformed.

Elimination

Plasmaclearanceoflosartananditsactivemetaboliteisabout600ml/minand50ml/min,respectively.Renalclearance

oflosartananditsactivemetaboliteisabout74ml/minand26ml/min,respectively.Whenlosartanisadministered

orally,about4%ofthedoseisexcretedunchangedintheurine,andabout6%ofthedoseisexcretedintheurineas

activemetabolite.Thepharmacokineticsoflosartananditsactivemetabolitearelinearwithorallosartanpotassium

dosesupto200mg.

Followingoraladministration,plasmaconcentrationsoflosartananditsactivemetabolitedeclinepolyexponentially

withaterminalhalf-lifeofabout2hoursand6to9hours,respectively.Duringonce-dailydosingwith100mg,neither

losartannoritsactivemetaboliteaccumulatessignificantlyinplasma.

Bothbiliaryandurinaryexcretioncontributetotheeliminationoflosartananditsmetabolites.Followinganoraldose

of14C-labelledlosartaninman,about35%/43%ofradioactivityisrecoveredintheurineand50%/58%inthe

faeces.

Characteristicsinpatients

Inelderlyhypertensivepatientstheplasmaconcentrationsoflosartananditsactivemetabolitedonotdifferessentially

fromthosefoundinyounghypertensivepatients.

Infemalehypertensivepatientstheplasmalevelsoflosartanwereuptotwiceashighasinmalehypertensivepatients,

whiletheplasmalevelsoftheactivemetabolitedidnotdifferbetweenmenandwomen.

Inpatientswithmildtomoderatealcohol-inducedhepaticcirrhosis,theplasmalevelsoflosartananditsactive

metaboliteafteroraladministrationwererespectively5and1.7timeshigherthaninyoungmalevolunteers(seesection

4.2and4.4).

Plasmaconcentrationsoflosartanarenotalteredinpatientswithcreatinineclearanceabove10ml/min.Comparedto

patientswithnormalrenalfunction,theAUCforlosartanisapproximately2-foldgreaterinhaemodialysispatients.

Plasmaconcentrationsoftheactivemetabolitearenotalteredinpatientswithrenalimpairmentorinhaemodialysis

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NeitherLosartannortheactivemetabolitecanberemovedbyhaemodialysis.

Pharmacokineticsinpaediatricpatients

Thepharmacokineticsoflosartanhavebeeninvestigatedin50hypertensivepaediatricpatients>1monthto<16years

ofagefollowingoncedailyoraladministrationofapproximately0.54to0.77mg/kgoflosartan(meandoses).

Theresultsshowedthattheactivemetaboliteisformedfromlosartaninallagegroups.Theresultsshowedroughly

similarpharmacokineticparametersoflosartanfollowingoraladministrationininfantsandtoddlers,preschool

children,schoolagechildrenandadolescents.Thepharmacokineticparametersforthemetabolitedifferedtoagreater

extentbetweentheagegroups.Whencomparingpreschoolchildrenwithadolescentsthesedifferencesbecame

statisticallysignificant.Exposureininfants/toddlerswascomparativelyhigh.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofgeneralpharmacology,

genotoxicityandcarcinogenicpotential.Inrepeateddosetoxicitystudies,theadministrationoflosartaninduceda

decreaseintheredbloodcellparameters(erythrocytes,haemoglobin,haematocrit),ariseinurea-Nintheserumand

occasionalrisesinserumcreatinine,adecreaseinheartweight(withoutahistologicalcorrelate)andgastrointestinal

changes(mucousmembranelesions,ulcers,erosions,haemorrhages).Likeothersubstancesthatdirectlyaffectthe

renin-angiotensinsystem,losartanhasbeenshowntoinduceadverseeffectsonthelatefoetaldevelopment,resultingin

foetaldeathandmalformations.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Hyprolose

Hypromellose

Lactosemonohydrate

Magnesiumstearate

Microcrystallinecellulose

Pregelatinisedstarch

Titaniumdioxide(E171)

Carnaubawax

‘Cozaar’50mgalsocontains4.24mg(0.108mmol)ofpotassium.

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelflifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.Storeintheoriginalpackageinordertoprotectfromlightandmoisture.

6.5Natureandcontentsofcontainer

Cardboardoutercontainingblisterstrips.

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ImbatLimited

UnitL2

NorthRingBusinessPark

Santry

Dublin9

8MARKETINGAUTHORISATIONNUMBER

PPA1151/5/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:30 th

July2004

Dateoflastrenewal:30 th

July2009

10DATEOFREVISIONOFTHETEXT

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