COZAAR

Main information

  • Trade name:
  • COZAAR Film Coated Tablet 12.5 Milligram
  • Dosage:
  • 12.5 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COZAAR Film Coated Tablet 12.5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1659/017/001
  • Authorization date:
  • 08-10-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cozaar12.5mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachCozaar12.5mgtabletcontains12.5mgoflosartanpotassium.

Excipients:lactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Filmcoatedtablet

ProductimportedfromtheUK:

Blue,ovalfilm-coatedtabletsmarked11ononesideandplainontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertensioninadultsandinchildrenandadolescents6–18yearsofage.

Treatmentofrenaldiseaseinadultpatientswithhypertensionandtype2diabetesmellituswithproteinuria 0.5

g/dayaspartofanantihypertensivetreatment.

TreatmentofchronicheartfailureinadultwhentreatmentwithAngiotensin-convertingenzyme(ACE)

inhibitorsisnotconsideredsuitableduetoincompatibility,especiallycough,orcontraindication.Patientswith

heartfailurewhohavebeenstabilisedwithanACEinhibitorshouldnotbeswitchedtolosartan.Thepatients

shouldhavealeftventricularejectionfraction 40%andshouldbeclinicallystableandonanestablished

treatmentregimenforchronicheartfailure.

Reductionintheriskofstrokeinadulthypertensivepatientswithleftventricularhypertrophydocumentedby

ECG(seesection5.1LIFEstudy,Race).

4.2Posologyandmethodofadministration

Posology

Losartantabletsshouldbeswallowedwithaglassofwater.

COZAARmaybeadministeredwithorwithoutfood.

Hypertension

Theusualstartingandmaintenancedoseis50mgoncedailyformostpatients.Themaximalantihypertensiveeffectis

attained3-6weeksafterinitiationoftherapy.Somepatientsmayreceiveanadditionalbenefitbyincreasingthedoseto

100mgoncedaily(inthemorning).

Losartanmaybeadministeredwithotherantihypertensiveagents,especiallywithdiuretics(e.g.hydrochlorothiazide).

HypertensivetypeIIdiabeticpatientswithproteinuria0.5g/day

Theusualstartingdoseis50mgoncedaily.Thedosemaybeincreasedto100mgoncedailybasedonbloodpressure

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

insulinandothercommonlyusedhypoglycaemicagents(e.g.sulfonylureas,glitazonesandglucosidaseinhibitors).

HeartFailure

Theusualinitialdoseoflosartaninpatientswithheartfailureis12.5mgoncedaily.Thedoseshouldgenerallybe

titratedatweeklyintervals(i.e.12.5mgdaily,25mgdaily,50mgdaily100mgdaily,uptoamaximumdoseof150

mgoncedaily),astoleratedbythepatient.

ReductionintheriskofstrokeinhypertensivepatientswithleftventricularhypertrophydocumentedbyECG

Theusualstartingdoseis50mgoflosartanoncedaily.Alowdoseofhydrochlorothiazideshouldbeaddedand/orthe

doseoflosartanshouldbeincreasedto100mgoncedailybasedonbloodpressureresponse.

Specialpopulations

Useinpatientswithintravascularvolumedepletion:

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

oncedailyshouldbeconsidered(seesection4.4).

Useinpatientswithrenalimpairmentandhaemodialysispatients:

Noinitialdosageadjustmentisnecessaryinpatientswithrenalimpairmentandinhaemodialysispatients.

Useinpatientswithhepaticimpairment:

Alowerdoseshouldbeconsideredforpatientswithahistoryofhepaticimpairment.Thereisnotherapeuticexperience

inpatientswithseverehepaticimpairment.Therefore,losartaniscontraindicatedinpatientswithseverehepatic

impairment(seesections4.3and4.4).

Paediatricpopulation

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/1.73m 2

,asnodataareavailable(see

alsosection4.4).

Losartanisalsonotrecommendedinchildrenwithhepaticimpairment(seealsosection4.4).

UseinElderly

Althoughconsiderationshouldbegiventoinitiatingtherapywith25mginpatientsover75yearsofage,dosage

adjustmentisnotusuallynecessaryfortheelderly.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients(seesection4.4and6.1).

2ndand3rdtrimesterofpregnancy(seesection4.4and4.6)

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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

conditionsshouldbecorrectedpriortoadministrationoflosartan,oralowerstartingdoseshouldbeused(seesection

4.2).Thisalsoappliestochildren6to18yearsofage.

Electrolyteimbalances

Electrolyteimbalancesarecommoninpatientswithrenalimpairment,withorwithoutdiabetes,andshouldbe

addressed.Inaclinicalstudyconductedintype2diabeticpatientswithnephropathy,theincidenceofhyperkalemia

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

(seesection4.2).

Renalfunctionshouldberegularlymonitoredduringtreatmentwithlosartanasitmaydeteriorate.Thisapplies

particularlywhenlosartanisgiveninthepresenceofotherconditions(fever,dehydration)likelytoimpairrenal

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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

planningpregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafety

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.

4.6Fertility,pregnancyandlactation

Pregnancy

Theuseoflosartanisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuseoflosartanis

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

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithAngiotensinIIReceptorInhibitors(AIIRAs),similarrisksmayexist

forthisclassofmedicinalproducts.UnlesscontinuedAIIRAtherapyisconsideredessential,patientsplanning

pregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafetyprofilefor

useinpregnancy.Whenpregnancyisdiagnosed,treatmentwithlosartanshouldbestoppedimmediatelyand,if

appropriate,alternativetherapyshouldbestarted.

ExposuretoAIIAtherapyduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

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

hyperkalaemia)(seealso5.3).

Shouldexposuretolosartanhaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

Infantswhosemothershavetakenlosartanshouldbecloselyobservedforhypotension(seealsosection4.3and4.4).

Lactation

Becausenoinformationisavailableregardingtheuseoflosartanduringbreastfeeding,losartanisnotrecommended

andalternativetreatmentswithbetterestablishedsafetyprofilesduringbreastfeedingarepreferable,especiallywhile

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4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,whendriving

vehiclesoroperatingmachinesitmustbeborneinmindthatdizzinessordrowsinessmayoccasionallyoccurwhen

takingantihypertensivetherapy,inparticularduringinitiationoftreatmentorwhenthedoseisincreased.

4.8Undesirableeffects

Losartanhasbeenevaluatedinclinicalstudiesasfollows:

Inacontrolledclinicaltrialin>3000adultpatients18yearsofageandolderforessentialhypertension,

Inacontrolledclinicaltrialin177hypertensivepaediatricpatients6to16yearsofage

Inacontrolledclinicaltrialin>9000hypertensivepatients55to80yearsofagewithleftventricular

hypertrophy

Incontrolledclinicaltrialsin>7700adultpatientswithchronicheartfailure

Inacontrolledclinicaltrialin>1500type2diabeticpatients31yearsofageandolderwithproteinuria

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

*usuallyresolvedupondiscontinuation

Hypertensivepatientswithleft-ventricularhypertrophy

Inacontrolledclinicaltrialin9193hypertensivepatients55to80yearsofagewithleft-ventricularhypertrophythe

Systemorganclass Adversereaction Frequency

Nervoussystemdisorders dizziness,vertigo Common

somnolence,headache,sleepdisorders Uncommon

Cardiacdisorder palpitations,anginapectoris Uncommon

Vasculardisorders symptomatichypotension(especiallyin

patientswithintravascularvolumedepletion,

e.g.patientswithsevereheartfailureorunder

treatmentwithhighdosediuretics),dose-

relatedorthostaticeffects,rash Uncommon

Gastrointestinaldisorders abdominalpain,obstipation Uncommon

Generaldisordersandadministrationsite

conditions asthenia,fatigue,oedema Uncommon

Investigations Hyperkalemia

Increasedalanineaminotransferase(ALT)* Common

Rare

Systemorganclass Adversereaction Frequency

Nervoussystemdisorders dizziness common

Earandlabyrinthdisorders vertigo common

Generaldisordersandadministrationsite

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Chronicheartfailure

Incontrolledclinicaltrialsinpatientswithchronicheartfailure(seeELITEIELITEIIstudy,andHEAALstudy,

section5.1),thefollowingadversereactionswerereported:

*commoninpatientswhoreceived150mglosartaninsteadof50mglosartan

Hypertensionandtype2diabeteswithrenaldisease

Inacontrolledclinicaltrialin1513type2diabeticpatients31yearsofageandolderwithproteinuria(RENAALstudy,

seesection5.1)themostcommondrug-relatedadversereactionswhichwerereportedforlosartanareasfollows:

*Inaclinicalstudyconductedintype2diabeticpatientswithnephropathy,9.9%ofpatientstreatedwithLosartan

tabletsdevelopedhyperkalaemia>5.5mmol/land3.4%ofpatientstreatedwithplacebo

Systemorganclass Adversereaction Frequency

Nervoussystemdisorders dizziness

headache common

uncommon

paraesthesia rare

Cardiacdisorders syncope,atrialfibrillation,cerebrovascular

accident rare

Vasculardisorders hypotension,includingorthostatic

hypotension common

Bloodandlymphaticsystemdisorders anaemia common

Respiratory,thoracicandmediastinal

disorders dyspnoea

cough uncommon

Gastrointestinaldisorders diarrhoea,nausea,vomiting uncommon

Skinandsubcutaneoustissuedisorders urticaria,pruritus,rash uncommon

Generaldisordersandadministrationsite

conditions asthenia/fatigue uncommon

Investigations increaseinbloodurea,serumcreatinineand

serumpotassium common

Metabolismandnutritiondisorders hyperkalaemia uncommon*

Renalandurinarydisorders renalimpairment

renalfailure common

Systemorganclass Adversereaction Frequency

Nervoussystemdisorders dizziness common

Vasculardisorders hypotension common

Generaldisordersandadministrationsite

conditions asthenia/fatigue common

Investigations hypoglycaemia

hyperkalaemia* common

Systemorganclass Adversereaction Frequency

Bloodandlymphaticsystemdisorders anaemia notknown

Cardiacdisorders syncope,palpitations notknown

Vasculardisorders orthostatichypotension notknown

Gastrointestinaldisorders diarrhoea notknown

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Post-marketingexperience

Thefollowingadversereactionshavebeenreportedinpost-marketingexperience:

Renalandurinarydisorders:

Asaconsequenceofinhibitingtherenin-angiotensin-aldosteronesystem,changesinrenalfunctionincludingrenal

failurehavebeenreportedinpatientsatrisk;thesechangesinrenalfunctionmaybereversibleupondiscontinuationof

therapy(seesection4.4)

Paediatricpopulation

Theadversereactionprofileforpaediatricpatientsappearstobesimilartothatseeninadultpatients.Datainthe

disorders

Renalandurinarydisorders urinarytractinfections notknown

Generaldisordersandadministrationsite

conditions flu-likesymptoms notknown

Systemorganclass Adversereaction Frequency

Bloodandlymphaticsystem

disorders anaemia,thrombocytopenia notknown

Earandlabyrinthdisorders tinnitus notknown

Immunesystemdisorders hypersensitivity:anaphylacticreactions,angiooedema

includingswellingofthelarynxandglottiscausing

airwayobstructionand/orswellingoftheface,lips,

pharynx,and/ortongue;insomeofthesepatients

angiooedemahadbeenreportedinthepastinconnection

withtheadministrationofothermedicines,including

ACEinhibitors;vasculitis,includingHenoch-Schonlein

purpura. rare

Nervoussystemdisorders migraine notknown

Respiratory,thoracicand

mediastinaldisorders cough notknown

Gastrointestinaldisorders diarrhoea,pancreatitis notknown

Generaldisordersand

administrationsiteconditions malaise notknown

Hepatobiliarydisorders hepatitis rare

liverfunctionabnormalities notknown

Skinandsubcutaneoustissue

disorders urticaria,pruritus,rash,photosensitivity notknown

Muscoskeletalandconnective

tissuedisorders myalgia,arthralgia,rhabdomyolysis notknown

Reproductivesystemandbreast

disorders erectiledysfunction/impotence notknown

Psychiatricdisorders depression notknown

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4.9Overdose

Symptomsofintoxication

Limiteddataareavailablewithregardtooverdoseinhumans.Themostlikelymanifestationofoverdosewouldbe

hypotensionandtachycardia.Bradycardiacouldoccurfromparasympathetic(vagal)stimulation.

Treatmentofintoxication

Ifsymptomatichypotensionshouldoccur,supportivetreatmentshouldbeinstituted.

Measuresaredependingonthetimeofmedicinalproductintakeandkindandseverityofsymptoms.Stabilisationof

thecardiovascularsystemshouldbegivenpriority.Afteroralintaketheadministrationofasufficientdoseofactivated

charcoalisindicated.Afterwards,closemonitoringofthevitalparametersshouldbeperformed.

Vitalparametersshouldbecorrectedifnecessary.

Neitherlosartannortheactivemetabolitecanberemovedbyhaemodialysis.

Symptomsofintoxication

Limiteddataareavailablewithregardtooverdoseinhumans.Themostlikelymanifestationofoverdosewouldbe

hypotensionandtachycardia.Bradycardiacouldoccurfromparasympathetic(vagal)stimulation.

Treatmentofintoxication

Ifsymptomatichypotensionshouldoccur,supportivetreatmentshouldbeinstituted.

Measuresaredependingonthetimeofmedicinalproductintakeandkindandseverityofsymptoms.Stabilisationof

thecardiovascularsystemshouldbegivenpriority.Afteroralintaketheadministrationofasufficientdoseofactivated

charcoalisindicated.Afterwards,closemonitoringofthevitalparametersshouldbeperformed.Vitalparameters

shouldbecorrectedifnecessary.

Neitherlosartannortheactivemetabolitecanberemovedbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

Pharmacotherapeuticgroup:AngiotensinIIantagonists,plain,ATCcode:C09CA01

5.1Pharmacodynamicproperties

Losartanisasyntheticoralangiotensin-IIreceptor(typeAT1)antagonist.AngiotensinII,apotentvasoconstrictor,is

theprimaryactivehormoneoftherenin/angiotensinsystemandanimportantdeterminantofthepathophysiologyof

hypertension.AngiotensinIIbindstotheAT1receptorfoundinmanytissues(e.g.vascularsmoothmuscle,adrenal

gland,kidneysandtheheart)andelicitsseveralimportantbiologicalactions,includingvasoconstrictionandtherelease

ofaldosterone.AngiotensinIIalsostimulatessmoothmusclecellproliferation.

LosartanselectivelyblockstheAT1receptor.Invitroandinvivolosartananditspharmacologicallyactivecarboxylic

acidmetaboliteE-3174blockallphysiologicallyrelevantactionsofangiotensinII,regardlessofthesourceorrouteof

itssynthesis.

Losartandoesnothaveanagonisteffectnordoesitblockotherhormonereceptorsorionchannelsimportantin

cardiovascularregulation.FurthermorelosartandoesnotinhibitACE(kininaseII),theenzymethatdegrades

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Duringadministrationoflosartan,removaloftheangiotensinIInegativefeedbackonreninsecretionleadstoincreased

plasmareninactivity(PRA).IncreaseinthePRAleadstoanincreaseinangiotensinIIinplasma.Despitethese

increases,antihypertensiveactivityandsuppressionofplasmaaldosteroneconcentrationaremaintained,indicating

effectiveangiotensinIIreceptorblockade.AfterdiscontinuationofLosartan,PRAandangiotensinIIvaluesfellwithin

threedaystothebaselinevalues.

BothlosartananditsprincipalactivemetabolitehaveafargreateraffinityfortheAT1-receptorthanfortheAT2-

receptor.Theactivemetaboliteis10-to40-timesmoreactivethanlosartanonaweightforweightbasis.

HypertensionStudies

Incontrolledclinicalstudies,once-dailyadministrationoflosartantopatientswithmildtomoderateessential

hypertensionproducedstatisticallysignificantreductionsinsystolicanddiastolicbloodpressure.Measurementsof

bloodpressure24hourspost-doserelativeto5–6hourspost-dosedemonstratedbloodpressurereductionover24

hours;thenaturaldiurnalrhythmwasretained.Bloodpressurereductionattheendofthedosingintervalwas70–80

%oftheeffectseen5-6hourspost-dose.

Discontinuationoflosartaninhypertensivepatientsdidnotresultinanabruptriseinbloodpressure(rebound).Despite

themarkeddecreaseinbloodpressure,losartanhadnoclinicallysignificanteffectsonheartrate.

Losartanisequallyeffectiveinmalesandfemales,andinyounger(belowtheageof65years)andolderhypertensive

patients.

LIFE-Study

ThelosartanInterventionForEndpointReductioninHypertension[LIFE]studywasarandomised,triple-blind,active-

controlledstudyin9193hypertensivepatientsaged55to80yearswithECG-documentedleft-ventricularhypertrophy.

Patientswererandomisedtooncedailylosartan50mgoroncedailyatenolol50mg.Ifgoalbloodpressure(<140/90

mmHg)wasnotreached,hydrochlorothiazide(12.5mg)wasaddedfirstand,ifneeded,thedoseoflosartanoratenolol

wasthenincreasedto100mgoncedaily.Otherantihypertensives,withtheexceptionofACE-inhibitors,angiotensinII

antagonistsorbeta-blockerswereaddedifnecessarytoreachthegoalbloodpressure.

Themeanlengthoffollowupwas4.8years.

Theprimaryendpointwasthecompositeofcardiovascularmorbidityandmortalityasmeasuredbyareductioninthe

combinedincidenceofcardiovasculardeath,strokeandmyocardialinfarction.Bloodpressurewassignificantly

loweredtosimilarlevelsinthetwogroups.Treatmentwithlosartanresultedina13.0%riskreduction(p=0.021,95%

confidenceinterval0.77-0.98)comparedwithatenololforpatientsreachingtheprimarycompositeendpoint.Thiswas

mainlyattributabletoareductionoftheincidenceofstroke.Treatmentwithlosartanreducedtheriskofstrokeby25%

relativetoatenolol(p=0.00195%confidenceinterval0.63-0.89).Theratesofcardiovasculardeathandmyocardial

infarctionwerenotsignificantlydifferentbetweenthetreatmentgroups.

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

benefitofloweringbloodpressure.

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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.

Inthisstudylosartanwasgenerallywelltolerated,asshownbyatherapydiscontinuationrateonaccountofadverse

reactionsthatwascomparabletotheplacebogroup.

HEAALStudy

TheHeartFailureEndpointEvaluationofAngiotensinIIAntagonistLosartan(HEAAL)studywasacontrolledclinical

studyconductedworldwidein3834patientsaged18to98yearswithheartfailure(NYHAClassII-IV)whowere

intolerantofACEinhibitortreatment.Patientswererandomisedtoreceivelosartan50mgonceadayorlosartan150

mg,onabackgroundofconventionaltherapyexcludingACE-inhibitors.

Patientswerefollowedforover4years(median4.7years).Theprimaryendpointofthestudywasacomposite

endpointofallcausedeathorhospitalizationforheartfailure.

Theresultsshowedthattreatmentwith150mglosartan(828events)ascomparedwith50mglosartan(889events)

resultedina10.1%riskreduction(p=0.02795%confidenceinterval0.82-0.99)inthenumberofpatientsreachingthe

primarycompositeendpoint.Thiswasmainlyattributabletoareductionoftheincidenceofhospitalizationforheart

failure.Treatmentwith150mglosartanreducedtheriskofhospitalizationforheartfailureby13.5%relativeto50mg

losartan(p=0.02595%confidenceinterval0.76-0.98).Therateofallcausedeathwasnotsignificantlydifferent

betweenthetreatmentgroups.Renalimpairment,hypotension,andhyperkalaemiaweremorecommoninthe150mg

groupthaninthe50mggroup,buttheseadverseeventsdidnotleadtosignificantlymoretreatmentdiscontinuationsin

the150mggroup.

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

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therapyonaccountofadversereactionsandasignificantlylowerfrequencyofcough.

AnincreasedmortalitywasobservedinELITEIIinthesmallsubgroup(22%ofallHFpatients)takingbeta-blockers

atbaseline.

PaediatricPopulation

PaediatricHypertension

Theantihypertensiveeffectoflosartanwasestablishedinaclinicalstudyinvolving177hypertensivepaediatric

patients6to16yearsofagewithabodyweight>20kgandaglomerularfiltrationrate>30ml/min/1.73m2.Patients

whoweighted>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(p0.001).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

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Distribution

Bothlosartananditsactivemetaboliteare³99%boundtoplasmaproteins,primarilyalbumin.Thevolumeof

distributionoflosartanis34litres.

Biotransformation

About14%ofanintravenously-ororally-administereddoseoflosartanisconvertedtoitsactivemetabolite.Following

oralandintravenousadministrationof14C-labeledlosartanpotassium,circulatingplasmaradioactivityprimarilyis

attributedtolosartananditsactivemetabolite.Minimalconversionoflosartantoitsactivemetabolitewasseenin

aboutonepercentofindividualsstudied.

Inadditiontotheactivemetabolite,inactivemetabolitesareformed.

Elimination

Plasmaclearanceoflosartananditsactivemetaboliteisabout600ml/minand50ml/min,respectively.Renal

clearanceoflosartananditsactivemetaboliteisabout74ml/minand26ml/min,respectively.

Whenlosartanisadministeredorally,about4%ofthedoseisexcretedunchangedintheurine,andabout6%ofthe

doseisexcretedintheurineasactivemetabolite.Thepharmacokineticsoflosartananditsactivemetabolitearelinear

withorallosartanpotassiumdosesupto200mg.

Followingoraladministration,plasmaconcentrationsoflosartananditsactivemetabolitedeclinepolyexponentially

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

losartannoritsactivemetaboliteaccumulatessignificantlyinplasma.

Bothbiliaryandurinaryexcretionscontributetotheeliminationoflosartananditsmetabolites.Followinganoral

dose/intravenousadministrationof14C-labeledlosartaninman,about35%/43%ofradioactivityisrecoveredinthe

urineand58%/50%inthefaeces.

Characteristicsinpatients

Inelderlyhypertensivepatientstheplasmaconcentrationsoflosartananditsactivemetabolitedonotdifferessentially

fromthosefoundinyounghypertensivepatients.

Infemalehypertensivepatientstheplasmalevelsoflosartanwereuptotwiceashighasinmalehypertensivepatients,

whiletheplasmalevelsoftheactivemetabolitedidnotdifferbetweenmenandwomen.

Inpatientswithmildtomoderatealcohol-inducedhepaticcirrhosis,theplasmalevelsoflosartananditsactive

metaboliteafteroraladministrationwererespectively5and1.7timeshigherthaninyoungmalevolunteers(seesection

4.2and4.4).

Plasmaconcentrationsoflosartanarenotalteredinpatientswithacreatinineclearanceabove10ml/minute.Compared

topatientswithnormalrenalfunction,theAUCforlosartanisabout2-timeshigherinhaemodialysisdialysispatients.

Theplasmaconcentrationsoftheactivemetabolitearenotalteredinpatientswithrenalimpairmentorinhaemodialysis

patients.

Neitherlosartannortheactivemetabolitecanberemovedbyhaemodialysis.

Pharmacokineticsinpaediatricpatients

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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

Microcrystallinecellulose(E460)

Lactosemonohydrate

Pregelatinizedmaizestarch

Magnesiumstearate(E572)

Hyprolose(E463)

Hypromellose(E464)

Containcarnaubawax(E903),

Titaniumdioxide(E171),

Indigocarmine(E132)aluminumlake.

Contains1.06mg(0.027mEq),potassium

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownontheblisterstripandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Storeintheoriginalpackageinordertoprotectfromlightandmoisture.

6.5Natureandcontentsofcontainer

Blisterpackageswithaluminumfoilliddingcontaining28film-coatedtablets.Inanover-labelledoutercarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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themtoapharmacyoraskyourpharmacisthowtodisposeoftheminaccordancewiththenationalregulations.These

measureswillhelptoprotecttheenvironment.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse

501MiddletonRoad

Chadderton

Oldham

Lancashire

OL99LY

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/17/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:8thOctober2010

10DATEOFREVISIONOFTHETEXT

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