COZAAR

Main information

  • Trade name:
  • COZAAR Film Coated Tablet 100 Milligram
  • Dosage:
  • 100 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COZAAR Film Coated Tablet 100 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1473/017/002
  • Authorization date:
  • 19-06-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PPA1473/017/002

CaseNo:2059694

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

McDowellPharmaceuticals

4AltonaRoad,Lisburn,N.Ireland,BT275QB

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Cozaar100mgFilm-coatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom19/06/2009.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cozaar100mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains91.6mgofLosartanpresentas100mgofLosartanpotassium.

Excipients-ContainsLactoseMonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

FilmCoatedTablet

ProductimportedfromUK

White,teardrop-shapedtabletwith‘960’ononesideandplainontheother

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertension.

Treatmentofrenaldiseaseinpatientswithhypertensionandtype2diabetesmellituswithproteinuria ≥0.5g/dayas

partofanantihypertensivetreatment.

Treatmentofchronicheartfailure(inpatients 60years),whentreatmentwithACEinhibitorsisnotconsidered

suitableduetoincompatibility,especiallycough,orcontraindication.Patientswithheartfailurewhohavebeen

stabilisedwithanACEinhibitorshouldnotbeswitchedtolosartan.Thepatientsshouldhavealeftventricularejection

fraction ≤40%andshouldbeclinicallystableandonanestablishedtreatmentregimenforchronicheartfailure.

ReductionintheriskofstrokeinhypertensivepatientswithleftventricularhypertrophydocumentedbyECG

(seesection5.1LIFEstudy,Race).

4.2Posologyandmethodofadministration

Losartantabletsshouldbeswallowedwithaglassofwater.

Cozaarmaybeadministeredwithorwithoutfood.

Hypertension

Theusualstartingandmaintenancedoseis50mgoncedailyformostpatients.Themaximalantihypertensiveeffect

isattained3-6weeksafterinitiationoftherapy.Somepatientsmayreceiveanadditionalbenefitbyincreasingthe

doseto100mgoncedaily(inthemorning).

Cozaarmaybeadministeredwithotherantihypertensiveagents,especiallywithdiuretics(e.g.hydrochlorothiazide).

HypertensivetypeIIdiabeticpatientswithproteinuria ≥0.5g/day

Theusualstartingdoseis50mgoncedaily.Thedosemaybeincreasedto100mgoncedailybasedonbloodpressure

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Cozaarmaybeadministeredwithotherantihypertensiveagents(e.g.diuretics,calciumchannelblockers,alpha-or

beta-blockers,andcentrallyactingagents)aswellaswithinsulinandothercommonlyusedhypoglycemicagents(e.g.

sulfonylureas,glitazonesandglucosidaseinhibitors).

HeartFailure

TheusualinitialdoseofCozaarinpatientswithheartfailureis12.5mgoncedaily.Thedoseshouldgenerallybe

titratedatweeklyintervals(i.e.12.5mgdaily,25mgdaily,50mgdaily)totheusualmaintenancedoseof50mgonce

daily,astoleratedbythepatient.

ReductionintheriskofstrokeinhypertensivepatientswithleftventricularhypertrophydocumentedbyECG

Theusualstartingdoseis50mgofCozaaroncedaily.Alowdoseofhydrochlorothiazideshouldbeaddedand/orthe

doseofCozaarshouldbeincreasedto100mgoncedailybasedonbloodpressureresponse.

Useinpatientswithintravascularvolumedepletion:

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

oncedailyshouldbeconsidered(seesection4.4).

Useinpatientswithrenalimpairmentandhaemodialysispatients:

Noinitialdosageadjustmentisnecessaryinpatientswithrenalimpairmentandinhaemodialysispatients.

Useinpatientswithhepaticimpairment:

Alowerdoseshouldbeconsideredforpatientswithahistoryofhepaticimpairment.Thereisnotherapeuticexperience

inpatientswithseverehepaticimpairment.Therefore,losartaniscontraindicatedinpatientswithseverehepatic

impairment(seesections4.3and4.4).

Useinpaediatricpatients

Therearelimiteddataontheefficacyandsafetyoflosartaninchildrenandadolescentsaged6-16yearsoldforthe

treatmentofhypertension(see5.1:Pharmacodynamicproperties).Limitedpharmacokineticdataareavailablein

hypertensivechildrenaboveonemonthofage(see5.2:Pharmacokineticproperties).

Forpatientswhocanswallowtablets,therecommendeddoseis25mgoncedailyinpatients>20to<50kg.In

exceptionalcasesthedosecanbeincreasedtoamaximumof50mgoncedaily.Dosageshouldbeadjustedaccording

tobloodpressureresponse.

Inpatients>50kg,theusualdoseis50mgoncedaily.Inexceptionalcasesthedosecanbeadjustedtoamaximumof

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

Losartanisnotrecommendedforuseinchildrenunder6yearsold,aslimiteddataareavailableinthesepatientgroups.

Itisnotrecommendedinchildrenwithglomerularfiltrationrate<30ml/min/1.73m 2

,asnodataareavailable(see

alsosection4.4).

Losartanisalsonotrecommendedinchildrenwithhepaticimpairment(seealsosection4.4).

UseinElderly

Althoughconsiderationshouldbegiventoinitiatingtherapywith25mginpatientsover75yearsofage,dosage

adjustmentisnotusuallynecessaryfortheelderly.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients(seesection4.4and6.1).

2ndand3rdtrimesterofpregnancy(seesection4.4and4.6)

Lactation(seesection4.6)

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4.4Specialwarningsandprecautionsforuse

Hypersensitivity

Angiooedema.Patientswithahistoryofangiooedema(swellingoftheface,lips,throat,and/ortongue)shouldbe

closelymonitored(Seesection4.8).

HypotensionandElectrolyte/FluidImbalance

Symptomatichypotension,especiallyafterthefirstdoseandafterincreasingofthedose,mayoccurinpatientswhoare

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

conditionsshouldbecorrectedpriortoadministrationofCozaar,oralowerstartingdoseshouldbeused(seesection

4.2).Thisalsoappliestochildren.

Electrolyteimbalances

Electrolyteimbalancesarecommoninpatientswithrenalimpairment,withorwithoutdiabetes,andshouldbe

addressed.Inaclinicalstudyconductedintype2diabeticpatientswithnephropathy,theincidenceofhyperkalemia

washigherinthegrouptreatedwithCozaarascomparedtotheplacebogroup(seesection4.8,Hypertension)andtype

2diabeteswithrenaldisease-InvestigationsandPost-marketingexperience-InvestigationsTherefore,theplasma

concentrationsofpotassiumaswellascreatinineclearancevaluesshouldbecloselymonitored,especiallypatientswith

heartfailureandaCreatinineClearancebetween30-50ml/minshouldbecloselymonitored.

Theconcomitantuseofpotassiumsparingdiuretics,potassiumsupplementsandpotassiumcontainingsaltsubstitutes

withlosartanisnotrecommended(seesection4.5).

LiverFunctionImpairment

Basedonpharmacokineticdatawhichdemonstratesignificantlyincreasedplasmaconcentrationsoflosartanincirrhotic

patients,alowerdoseshouldbeconsideredforpatientswithahistoryofhepaticimpairment.

Thereisnotherapeuticexperiencewithlosartaninpatientswithseverehepaticimpairment.Thereforelosartanmust

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

Losartanisalsonotrecommendedinchildrenwithhepaticimpairment(seesection4.2).

RenalFunctionImpairment

Asaconsequenceofinhibitingtherenin-angiotensinsystem,changesinrenalfunctionincludingrenalfailurehave

beenreported(inparticular,inpatientswhoserenalfunctionisdependentonthereninangiotensinaldosteronesystem

suchasthosewithseverecardiacinsufficiencyorpre-existingrenaldysfunction).Aswithotherdrugsthataffectthe

renin-angiotensin-aldosteronesystem,increasesinbloodureaandserumcreatininehavealsobeenreportedinpatients

withbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney;thesechangesinrenalfunctionmaybe

reversibleupondiscontinuationoftherapy.Losartanshouldbeusedwithcautioninpatientswithbilateralrenalartery

stenosisorstenosisofthearterytoasolitarykidney.

Useinpediatricpatientswithrenalfunctionimpairment

Losartanisnotrecommendedinchildrenwithglomerularfiltrationrate<30ml/min/1.73m 2

asnodataareavailable

(seesection4.2).

Renalfunctionshouldberegularlymonitoredduringtreatmentwithlosartanasitmaydeteriorate.Thisapplies

particularlywhenlosartanisgiveninthepresenceofotherconditions(fever,dehydration)likelytoimpairrenal

function.

ConcomitantuseoflosartanandACE-inhibitorshasshowntoimpairrenalfunction.Therefore,concomitantuseisnot

recommended.

Renaltransplantation

Thereisnoexperienceinpatientswithrecentkidneytransplantation.

Primaryhyperaldosteronism

Patientswithprimaryaldosteronismgenerallywillnotrespondtoantihypertensivedrugsactingthroughinhibitionof

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Coronaryheartdiseaseandcerebrovasculardisease

Aswithanyantihypertensiveagents,excessivebloodpressuredecreaseinpatientswithischaemiccardiovascularand

cerebrovasculardiseasecouldresultinamyocardialinfarctionorstroke.

Heartfailure

Inpatientswithheartfailure,withorwithoutrenalimpairment,thereis-aswithotherdrugsactingontherenin-

angiotensinsystem-ariskofseverearterialhypotension,and(oftenacute)renalimpairment.

Thereisnosufficienttherapeuticexperiencewithlosartaninpatientswithheartfailureandconcomitantsevererenal

impairment,inpatientswithsevereheartfailure(NYHAclassIV)aswellasinpatientswithheartfailureand

symptomaticlifethreateningcardiacarrhythmias.Therefore,losartanshouldbeusedwithcautioninthesepatient

groups.Thecombinationoflosartanwithabeta-blockershouldbeusedwithcaution(seesection5.1).

Aorticandmitralvalvestenosis,obstructivehypertrophiccardiomyopathy

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromaorticormitralstenosis,orobstructive

hypertrophiccardiomyopathy.

Galactoseintolerance,Lapplactasedeficiency,glucose-galactosemalabsorbtion

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

Pregnancy

Losartanshouldnotbeinitiatedduringpregnancy.Unlesscontinuedlosartantherapyisconsideredessential,patients

planningpregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafety

profileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithlosartanshouldbestoppedimmediately,

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

Otherwarningsandprecautions

Asobservedforangiotensinconvertingenzymeinhibitors,losartanandtheotherangiotensinantagonistsareapparently

lesseffectiveinloweringbloodpressureinblackpeoplethaninnon-blacks,possiblybecauseofhigherprevalenceof

low-reninstatesintheblackhypertensivepopulation.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

OtherantihypertensiveagentsmayincreasethehypotensiveactionofLosartan.Othersubstancesinducinghypotension

liketricyclicantidepressants,antipsychotics,baclofene,amifostine:Concomitantusewiththesedrugsthatlowerblood

pressure,asmainorside-effect,mayincreasetheriskofhypotension.

LosartanispredominantlymetabolisedbycytochromeP450(CYP)2C9totheactivecarboxy-acidmetabolite.Ina

clinicaltrialitwasfoundthatfluconazole(inhibitorofCYP2C9)decreasestheexposuretotheactivemetaboliteby

approximately50%.Itwasfoundthatconcomitanttreatmentoflosartanwithrifampicine(inducerofmatabolism

enzymes)gavea40%reductioninplasmaconcentrationoftheactivemetabolite.Theclinicalrelevanceofthiseffectis

unknown.Nodifferenceinexposurewasfoundwithconcomitantlytreatmentwithfluvastatin(weakinhibitorof

CYP2C9).

AswithotherdrugsthatblockangiotensinIIoritseffects,concomitantuseofotherdrugswhichretainpotassium(e.g.

potassium-sparingdiuretics:amiloride,triamterene,spironolactone)ormayincreasepotassiumlevels(e.g.heparin),

potassiumsupplementsorsaltsubstitutescontainingpotassiummayleadtoincreasesinserumpotassium.Co-

medicationisnotadvisable.

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.VeryrarecaseshavealsobeenreportedwithantiotensinIIreceptor

antagonists.Co-administrationoflithiumandlosartanshouldbeundertakenwithcaution.Ifthiscombinationproves

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WhenangiotensinIIantagonistsareadministeredsimultaneouslywithNSAIDs(i.e.selectiveCOX-2inhibitors,

acetylsalicylicacidatanti-inflammatorydosesandnon-selectiveNSAIDs),attenuationoftheantihypertensiveeffect

mayoccur.ConcomitantuseofangiotensinIIantagonistsordiureticsandNSAIDsmayleadtoanincreasedriskof

worseningofrenalfunction,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyin

patientswithpoorpre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyin

theelderly.Patientsshouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunction

afterinitiationofconcomitanttherapy,andperiodicallythereafter.

4.6Pregnancyandlactation

Pregnancy

Theuseoflosartanisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuseoflosartanis

contra-indicatedduringthe2ndand3rdtrimesterofpregnancy(seesection4.3and4.4).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithAngiotensinIIReceptorInhibitors(AIIRAs),similarrisksmayexist

forthisclassofdrugs.UnlesscontinuedARBtherapyisconsideredessential,patientsplanningpregnancyshouldbe

changedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.

Whenpregnancyisdiagnosed,treatmentwithlosartanshouldbestoppedimmediatelyand,ifappropriate,alternative

therapyshouldbestarted.

Losartantherapyexposureduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

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

hyperkalaemia)(seealso5.3Preclinicalsafetydata).

Shouldexposuretolosartanhaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

Infantswhosemothershavetakenlosartanshouldbecloselyobservedforhypotension(seealsosection4.3and4.4).

Lactation

Itisnotknownwhetherlosartanisexcretedinhumanmilk.However,losartanisexcretedinthemilkoflactatingrats.

Becauseofthepotentialforadverseeffectsonthenursinginfant,losartaniscontraindicatedduringbreast-feeding(see

section4.3).

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,whendriving

vehiclesoroperatingmachineryitmustbeborneinmindthatdizzinessordrowsinessmayoccasionallyoccurwhen

takingantihypertensivetherapy,inparticularduringinitiationoftreatmentorwhenthedoseisincreased.

4.8Undesirableeffects

Thefrequencyofadverseeventslistedbelowisdefinedusingthefollowingconvention:

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

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

Incontrolledclinicaltrialsforessentialhypertension,hypertensivepatientswithleftventricularhypertrophy,chronic

heartfailureaswellasforhypertensionandtype2diabetesmellituswithrenaldisease,themostcommonadverse

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Hypertension

Incontrolledclinicaltrialsforessentialhypertensionwithlosartanthefollowingadverseeventswerereported

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

Hypertensivepatientswithleftventricularhypertrophy

Inacontrolledclinicaltrialinhypertensivepatientswithleftventricularhypertrophythefollowingadverseeventswere

reported:

Nervoussystemdisorders:

common:dizziness

Earandlabyrinthdisorders:

common:vertigo

Generaldisordersandadministrationsiteconditions:

common:asthenia/fatigue

Chronicheartfailure

Inacontrolledclinicaltrialinpatientswithcardiacinsufficiencythefollowingadverseeventswerereported

Nervoussystemdisorders:

uncommon:dizziness,headache

rare:paraesthesia

Cardiacdisorders:

rare:syncope,artrialfibrillation,cerebrovascularaccident

Vasculardisorders:

uncommon:hypotension,includingorthostatichypotension

Respiratory,thoracicandmediastinaldisorders:

uncommon:dyspnoea

Gastrointestinaldisorders:

uncommon:diarrhoea,nausea,vomiting

Skinandsubcutanoustissuedisorders:

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Generaldisordersandadministrationsiteconditions:

uncommon:asthenia/fatigue

Hypertensionandtype2diabeteswithrenaldisease

Inacontrolledclinicaltrialintype2diabeticpatientswithproteinuria(RENAALstudy,seesection5.1)themost

commondrug-relatedadverseeventswhichwerereportedforlosartanareasfollows:

Nervoussystemdisorders:

common:dizziness

Vasculardisorders:

common:hypotension

Generaldisordersandadministrationsiteconditions:

common:asthenia/fatigue

Investigations:

common:hypoglycaemia,hyperkalaemia

Thefollowingadverseeventsoccurredmoreofteninpatientsreceivinglosartanthanplacebo:

Bloodandlymphaticsystemdisorders:

notknown:anaemia

Cardiacdisorders:

notknown:syncope,palpitations

Vasculardisorders:

notknown:orthostatichypotension

Gastrointestinaldisorders:

notknown:diarrhoea

Muscoskeletalandconnectivetissuedisorders:

notknown:backpain

Renalandurinarydisorders:

notknown:urinarytractinfections

Generaldisordersandadministrationsiteconditions:

notknown:flu-likesymptoms

Post-marketingexperience

Thefollowingadverseeventshavebeenreportedinpost-marketingexperience:

Bloodandlymphaticsystemdisorders:

notknown:Anaemia,thrombocytopenia

Immunesystemdisorders:

rare:hypersensitivity:anaphylacticreactions,angiooedemaincludingswellingofthelarynxandglottiscausingairway

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

reportedinthepastinconnectionwiththeadministrationofothermedicines,includingACEinhibitors;vasculitis,

includingHenoch-Schonleinpurpura.

Nervoussystemdisorders:

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Respiratory,thoracicandmediastinaldisorders:

notknown:cough

Gastrointestinaldisorders:

notknown:diarrhoea

Hepatobiliarydisorders:

rare:hepatitis

notknown:liverfunctionabnormalities

Skinandsubcutaneoustissuedisorders:

notknown:urticaria,pruritus,rash

Muscoskeletalandconnectivetissuedisorders:

notknown:myalgia,arthralgia

Asaconsequenceofinhibitingtherenin-angiotensin-aldosteronesystem,changesinrenalfunctionincludingrenal

failurehavebeenreportedinpatientsatrisk;thesechangesinrenalfunctionmaybereversibleupondiscontinuationof

therapy(seesection4.4)

Investigations:

Incontrolledclinicaltrials,clinicallyimportantchangesinstandardlaboratoryparameterswererarelyassociatedwith

administrationofLosartantablets.ElevationsofALToccurredrarelyandusuallyresolvedupondiscontinuationof

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

clinicalstudyconductedintype2diabeticpatientswithnephropathy,9.9%ofpatientstreatedwithLosartantablets

developedhyperkalaemia>5.5mEq/land3.4%ofpatientstreatedwithplacebo(seesection4.4,Electrolyte

imbalances).

Inacontrolledclinicaltrialonpatientswithcardiacinsufficiency,increaseinbloodurea,serumcreatinineandserum

potassiumhasbeenreported.

Theadverseexperienceprofileforpediatricpatientsappearstobesimilartothatseeninadultpatients.Datainthe

pediatricpopulationarelimited.

4.9Overdose

Symptomsofintoxication

Noexperiencewithoverdoseinmanisavailablesofar.Themostlikelysymptoms,dependingontheextentof

overdose,arehypotension,tachycardia,possiblybradycardia.

Treatmentofintoxication

Measuresaredependingonthetimeofdrugintakeandkindandseverityofsymptoms.Stabilisationofthecirculatory

systemshouldbegivenpriority.Afteroralintaketheadministrationofasufficientdoseofactivatedcharcoalis

indicated.Afterwards,closemonitoringofthevitalparametersshouldbeperformed.Vitalparametersshouldbe

correctedifnecessary.

NeitherLosartannortheactivemetabolitecanberemovedbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

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Losartanisasyntheticoralangiotensin-IIreceptor(typeAT

)antagonist.AngiotensinII,apotentvasoconstrictor,is

theprimaryactivehormoneoftherenin/angiotensinsystemandanimportantdeterminantofthepathophysiologyof

hypertension.AngiotensinIIbindstotheAT

receptorfoundinmanytissues(e.g.vascularsmoothmuscle,adrenal

gland,kidneysandtheheart)andelicitsseveralimportantbiologicalactions,includingvasoconstrictionandtherelease

ofaldosterone.AngiotensinIIalsostimulatessmoothmusclecellproliferation.

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.Measurementsof

bloodpressure24hourspost-doserelativeto5–6hourspost-dosedemonstratedbloodpressurereductionover24

hours;thenaturaldiurnalrhythmwasretained.Bloodpressurereductionattheendofthedosingintervalwas70–80

%oftheeffectseen5-6hourspost-dose.

DiscontinuationofLosartaninhypertensivepatientsdidnotresultinanabruptriseinbloodpressure(rebound).

Despitethemarkeddecreaseinbloodpressure,Losartanhadnoclinicallysignificanteffectsonheartrate.

Losartanisequallyeffectiveinmalesandfemales,andinyounger(belowtheageof65years)andolderhypertensive

patients.

LIFE-Study

TheLosartanInterventionForEndpointReductioninHypertension[LIFE]studywasarandomised,triple-blind,

active-controlledstudyin9193hypertensivepatientsaged55to80yearswithECG-documentedleft-ventricular

hypertrophy.PatientswererandomisedtooncedailyLosartan50mgoroncedailyatenolol50mg.Ifgoalblood

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

Losartanoratenololwasthenincreasedto100mgoncedaily.Otherantihypertensives,withtheexceptionofACE-

inhibitors,angiotensinIIantagonistsorbeta-blockerswereaddedifnecessarytoreachthegoalbloodpressure.

Themeanlengthoffollowupwas4.8years.

Theprimaryendpointwasthecompositeofcardiovascularmorbidityandmortalityasmeasuredbyareductioninthe

combinedincidenceofcardiovasculardeath,strokeandmyocardialinfarction.Bloodpressurewassignificantly

loweredtosimilarlevelsinthetwogroups.

Treatmentwithlosartanresultedina13.0%riskreduction(p=0.021,95%confidenceinterval0.77-0.98)compared

withatenololforpatientsreachingtheprimarycompositeendpoint.Thiswasmainlyattributabletoareductionofthe

incidenceofstroke.Treatmentwithlosartanreducedtheriskofstrokeby25%relativetoatenolol(p=0.00195%

confidenceinterval0.63-0.89).Theratesofcardiovasculardeathandmyocardialinfarctionwerenotsignificantly

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Race

IntheLIFE-StudyblackpatientstreatedwithLosartanhadahigherriskofsufferingtheprimarycombinedendpoint,

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

treatedwithatenolol.ThereforetheresultsobservedwithlosartanincomparisonwithatenololintheLIFEstudywith

regardtocardiovascularmorbidity/mortalitydonotapplyforblackpatientswithhypertensionandleftventricular

hypertrophy.

RENAAL-Study

TheReductionofEndpointsinNIDDMwiththeAngiotensinIIReceptorAntagonistLosartanRENAALstudywasa

controlledclinicalstudyconductedworldwidein1513Type2diabeticpatientswithproteinuria,withorwithout

hypertension.751PatientsweretreatedwithLosartan

TheobjectiveofthestudywastodemonstrateanephroprotectiveeffectofLosartanpotassiumoverandabovethe

benefitofabloodloweringpressure.

Patientswithproteinuriaandaserumcreatinineof1.3–3.0mg/dlwererandomisedtoreceiveLosartan50mgoncea

day,titratedifnecessary,toachievebloodpressureresponse,ortoplacebo,onabackgroundofconventional

antihypertensivetherapyexcludingACE-inhibitorsandangiotensionIIantagonists.

Investigatorswereinstructedtotitratethestudymedicationto100mgdailyasappropriate;72%ofpatientswere

takingthe100mgdailydoseforthemajorityofthetime.Otherantihypertensiveagents(diuretics,calciumantagonists,

alpha-andbeta-receptorblockersandalsocentrallyactingantihypertensives)werepermittedassupplementary

treatmentdependingontherequirementinbothgroups.Patientswerefollowedupforupto4.6years(3.4yearson

average).

Theprimaryendpointofthestudywasacompositeendpointofdoublingoftheserumcreatinineend-stagerenalfailure

(needfordialysisortransplantation)ordeath.

TheresultsshowedthatthetreatmentwithLosartan(327events)ascomparedwithplacebo(359events)resultedina

16.1%riskreduction(p=0.022)inthenumberofpatientsreachingtheprimarycompositeendpoint.

Forthefollowingindividualandcombinedcomponentsoftheprimaryendpoint,theresultsshowedasignificantrisk

reductioninthegrouptreatedwithLosartan:25.3%riskreductionfordoublingoftheserumcreatinine(p=0.006);

28.6%riskreductionforend-stagerenalfailure(p=0.002);19.9%riskreductionforend-stagerenalfailureordeath

(p=0.009);21.0%riskreductionfordoublingofserumcreatinineorend-stagerenalfailure(p=0.01).

All-causemortalityratewasnotsignificantlydifferentbetweenthetwotreatmentgroups.

Inthisstudylosartanwasgenerallywelltolerated,asshownbyatherapydiscontinuationrateonaccountofadverse

eventsthatwascomparabletotheplacebogroup.

ELITEIandELITEIIStudy

IntheELITEStudycarriedoutover48weeksin722patientswithheartfailure(NYHAClassII-IV),nodifferencewas

observedbetweenthepatientstreatedwithLosartanandthosetreatedwithcaptoprilwasobservedwithregardtothe

primaryendpointofalong-termchangeinrenalfunction.TheobservationoftheELITEIStudy,that,comparedwith

captopril,Losartanreducedthemortalityrisk,wasnotconfirmedinthesubsequentELITEIIStudy,whichisdescribed

inthefollowing.

IntheELITEIIStudyLosartan50mgoncedaily(startingdose12.5mg,increasedto25mg,then50mgoncedaily)

wascomparedwithcaptopril50mgthreetimesdaily(startingdose12.5m,increasedto25mgandthento50mgthree

timesdaily).Theprimaryendpointofthisprospectivestudywastheall-causemortality.

Inthisstudy3152patientswithheartfailure(NYHAClassII-IV)werefollowedforalmosttwoyears(median:1.5

years)inordertodeterminewhetherLosartanissuperiortocaptoprilinreducingallcausemortality.Theprimary

endpointdidnotshowanystatisticallysignificantdifferencebetweenLosartanandcaptoprilinreducingall-cause

mortality.

Inbothcomparator-controlled(notplacebo-controlled)clinicalstudiesonpatientswithheartfailurethetolerabilityof

Losartanwassuperiortothatofcaptopril,measuredonthebasisofasignificantlylowerrateofdiscontinuationsof

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AnincreasedmortalitywasobservedinELITEIIinthesmallsubgroup(22%ofallHFpatients)takingbeta-blockers

atbaseline.

Paediatricpopulation

PaediatricHypertension

TheantihypertensiveeffectofCozaarwasestablishedinaclinicalstudyinvolving177hypertensivepediatricpatients6

to16yearsofagewithabodyweight>20kgandaglomerularfilrationrate>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)wererandomizedto

receiveeitherlosartan(n=122)orplacebo(n=124).Losartanwasgivenatdosesof0.7mg/kgto1.4mg/kg(upto

maximumdoseof100mgperday).Amlodipinewasgivenatdosesof0.05mg/kgto0.2mg/kg(uptoamaximumdose

of5mgperday).

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

childrenasmalldecreaseinbloodpressurewasobservedinthelosartangroup(-3.7/-3.4mmHg)comparedtoplacebo.

Nosignificantcorrelationbetweenthedeclineinproteinuriaandbloodpressurewasnoted,howeveritispossiblethat

thedeclineinbloodpressurewasresponsible,inpart,forthedeclineinproteinuriainthelosartantreatedgroup.Long-

termeffectsofreductionofproteinuriainchildrenhavenotbeenstudied.

5.2Pharmacokineticproperties

Absorption

Followingoraladministration,losartaniswellabsorbedandundergoesfirst-passmetabolism,forminganactive

carboxylicacidmetaboliteandotherinactivemetabolites.Thesystemicbioavailabilityoflosartantabletsis

approximately33%.Meanpeakconcentrationsoflosartananditsactivemetabolitearereachedin1hourandin3-4

hours,respectively.

Distribution

Bothlosartananditsactivemetaboliteare 99%boundtoplasmaproteins,primarilyalbumin.Thevolumeof

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Biotransformation

About14%ofanintravenously-ororally-administereddoseoflosartanisconvertedtoitsactivemetabolite.Following

oralandintravenousadministrationof C-labeledlosartanpotassium,circulatingplasmaradioactivityprimarilyis

attributedtolosartananditsactivemetabolite.Minimalconversionoflosartantoitsactivemetabolitewasseenin

aboutonepercentofindividualsstudied.

Inadditiontotheactivemetabolite,inactivemetabolitesareformed.

Elimination

Plasmaclearanceoflosartananditsactivemetaboliteisabout600mL/minand50mL/min,respectively.Renal

clearanceoflosartananditsactivemetaboliteisabout74mL/minand26mL/min,respectively.Whenlosartanis

administeredorally,about4%ofthedoseisexcretedunchangedintheurine,andabout6%ofthedoseisexcretedin

theurineasactivemetabolite.Thepharmacokineticsoflosartananditsactivemetabolitearelinearwithorallosartan

potassiumdosesupto200mg.

Followingoraladministration,plasmaconcentrationsoflosartananditsactivemetabolitedeclinepolyexponentially

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

losartannoritsactivemetaboliteaccumulatessignificantlyinplasma.

Bothbiliaryandurinaryexcretioncontributetotheeliminationoflosartananditsmetabolites.Followinganoral

dose/intravenousadministrationof C-labeledlosartaninman,about35%/43%ofradioactivityisrecoveredinthe

urineand58%/50%inthefaeces.

CharacteristicsinPatients

Inelderlyhypertensivepatientstheplasmaconcentrationsoflosartananditsactivemetabolitedonotdifferessentially

fromthosefoundinyounghypertensivepatients.

Infemalehypertensivepatientstheplasmalevelsoflosartanwereuptotwiceashighasinmalehypertensivepatients,

whiletheplasmalevelsoftheactivemetabolitedidnotdifferbetweenmenandwomen.

Inpatientswithmildtomoderatealcohol-inducedhepaticcirrhosis,theplasmalevelsoflosartananditsactive

metaboliteafteroraladministrationwererespectively5and1.7timeshigherthaninyoungmalevolunteers(seesection

4.2and4.4).

PlasmaconcentrationsofLosartanarenotalteredinpatientswithacreatinineclearanceabove10ml/minute.

Comparedtopatientswithnormalrenalfunction,theAUCforLosartanisabout2-timeshigherinhaemodialysis

dialysispatients.

Theplasmaconcentrationsoftheactivemetabolitearenotalteredinpatientswithrenalimpairmentorinheamodialysis

patients.

NeitherLosartannortheactivemetabolitecanberemovedbyhaemodialysis.

Pharmacokineticsinpaediatricpatients

Thepharmacokineticsoflosartanhavebeeninvestigatedin50hypertensivepaediatricpatients>1monthto<16years

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

Theresultsshowedthattheactivemetaboliteisformedfromlosartaninallagegroups.Theresultsshowedroughly

similarpharmacokineticparametersoflosartanfollowingoraladministrationininfantsandtoddlers,preschool

children,schoolagechildrenandadolescents.

Thepharmacokineticparametersforthemetabolitedifferedtoagreaterextentbetweentheagegroups.When

comparingpreschoolchildrenwithadolescentsthesedifferencesbecamestatisticallysignificant.Exposureininfants/

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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(E463)

Hypromellose(E464)

LactoseMonohydrate

MagnesiumStearate(E572)

Microcrystallinecellulose(E460)

PregelatinisedStarch

TitaniumDioxide(E171)

Carnaubawax

6.2Incompatibilities

Notapplicable

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30 °

Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

WhiteopaquePVC/PE/PVDCblisterswithaluminiumfoilliddinginanoverlabelledoutercarton.

Packof28Tablets

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7ParallelProductAuthorisationHolder

McDowellPharmaceuticals

4AltonaRoad

Lisburn

NIreland

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8ParallelProductAuthorisationNumber

PPA1473/17/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:19thJune2009

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