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:
  • PPA1562/076/002
  • Authorization date:
  • 20-04-2012
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

COZAAR100mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachCOZAAR100mgtabletcontains100mgoflosartanpotassium

EachCOZAAR100mgtabletcontains51.0mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablets.

ProductimportedfromtheUK.

White,teardrop-shapedfilm-coatedtabletsmarked960ononesideandplainontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertensioninadultsandinchildrenandadolescents6–18yearsofage.

Treatmentofrenaldiseaseinadultpatientswithhypertensionandtype2diabetesmellituswithproteinuria

0.5g/dayaspartofanantihypertensivetreatment.

Treatmentofchronicheartfailureinadult,whentreatmentwithAngiotensin-convertingenzyme(ACE)inhibitors

isnotconsideredsuitableduetoincompatibility,especiallycough,orcontraindication.Patientswithheartfailure

whohavebeenstabilisedwithanACEinhibitorshouldnotbeswitchedtolosartan.Thepatientsshouldhavea

leftventricularejectionfraction 40%andshouldbeclinicallystableandonanestablishedtreatmentregimenfor

chronicheartfailure.

ReductionintheriskofstrokeinadulthypertensivepatientswithleftventricularhypertrophydocumentedbyECG

(seesection5.1LIFEstudy,Race).

4.2Posologyandmethodofadministration

Posology

Losartantabletsshouldbeswallowedwithaglassofwater.

COZAARmaybeadministeredwithorwithoutfood.

Hypertension

Theusualstartingandmaintenancedoseis50mgoncedailyformostpatients.Themaximalantihypertensiveeffectis

attained3-6weeksafterinitiationoftherapy.Somepatientsmayreceiveanadditionalbenefitbyincreasingthedoseto

100mgoncedaily(inthemorning).

Losartanmaybeadministeredwithotherantihypertensiveagents,especiallywithdiuretics(e.g.hydrochlorothiazide).

HypertensivetypeIIdiabeticpatientswithproteinuria 0.5g/day

Theusualstartingdoseis50mgoncedaily.Thedosemaybeincreasedto100mgoncedailybasedonbloodpressure

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

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

sulfonylureas,glitazonesandglucosidaseinhibitors).

HeartFailure

Theusualinitialdoseoflosartaninpatientswithheartfailureis12.5mgoncedaily.Thedoseshouldgenerallybe

titratedatweeklyintervals(i.e.12.5mgdaily,25mgdaily,50mgdaily,100mgdaily,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)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)

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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,inpatientswhoserenalfunctionisdependentontherenin-angiotensin-aldosteronesystem

suchasthosewithseverecardiacinsufficiencyorpre-existingrenaldysfunction).Aswithothermedicinalproductsthat

affecttherenin-angiotensin-aldosteronesystem,increasesinbloodureaandserumcreatininehavealsobeenreportedin

patientswithbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney;thesechangesinrenalfunction

maybereversibleupondiscontinuationoftherapy.Losartanshouldbeusedwithcautioninpatientswithbilateralrenal

arterystenosisorstenosisofthearterytoasolitarykidney.

Useinpediatricpatientswithrenalimpairment

Losartanisnotrecommendedinchildrenwithglomerularfiltrationrate<30ml/min/1.73m2asnodataareavailable

(seesection4.2).

Renalfunctionshouldberegularlymonitoredduringtreatmentwithlosartanasitmaydeteriorate.Thisapplies

particularlywhenlosartanisgiveninthepresenceofotherconditions(fever,dehydration)likelytoimpairrenal

function.

ConcomitantuseoflosartanandACE-inhibitorshasshowntoimpairrenalfunction.Therefore,concomitantuseisnot

recommended(seesection4.5).

Renaltransplantation

Thereisnoexperienceinpatientswithrecentkidneytransplantation.

Primaryhyperaldosteronism

Patientswithprimaryaldosteronismgenerallywillnotrespondtoantihypertensivemedicinalproductsactingthrough

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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

amifostine)mayincreasetheriskofhypotension.

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

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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).

Breastfeeding

Becausenoinformationisavailableregardingtheuseoflosartanduringbreastfeeding,losartanisnotrecommended

andalternativetreatmentswithbetterestablishedsafetyprofilesduringbreastfeedingarepreferable,especiallywhile

nursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,whendriving

vehiclesoroperatingmachinesitmustbeborneinmindthatdizzinessordrowsinessmayoccasionallyoccurwhen

takingantihypertensivetherapy,inparticularduringinitiationoftreatmentorwhenthedoseisincreased.

4.8Undesirableeffects

Losartanhasbeenevaluatedinclinicalstudiesasfollows:

Inacontrolledclinicaltrialin>3000adultpatients18yearsofageandolderforessentialhypertension

Inacontrolledclinicaltrialin177hypertensivepediatricpatients6to16yearsofage

Inacontrolledclinicaltrialin>9000hypertensivepatients55to80yearsofagewithleftventricular

hypertrophy

Incontrolledclinicaltrialsin>7700adultpatientswithchronicheartfailure

Inacontrolledclinicaltrialin>1500type2diabeticpatients31yearsofageandolderwithproteinuria

Intheseclinicaltrials,themostcommonadverseeventwasdizziness.

Thefrequencyofadversereactionslistedbelowisdefinedusingthefollowingconvention:

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

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Hypertension

*usuallyresolvedupondiscontinuation

Hypertensivepatientswithleft-ventricularhypertrophy

Inacontrolledclinicaltrialin9193hypertensivepatients55to80yearsofagewithleft-ventricularhypertrophythe

followingadverseeventswerereported:

Chronicheartfailure

Incontrolledclinicaltrialsinpatientswithchronicheartfailure(seeELITEIELITEIIstudy,andHEAALstudy,

Systemorganclass Adversereaction Frequency

Nervoussystemdisorders dizziness,vertigo Common

somnolence,headache,sleep

disorders Uncommon

Cardiacdisorder palpitations,anginapectoris Uncommon

Vasculardisorders symptomatichypotension(especially

inpatientswithintravascularvolume

depletion,e.g.patientswithsevere

heartfailureorundertreatmentwith

highdosediuretics),dose-related

orthostaticeffects,rash Uncommon

Gastrointestinaldisorders abdominalpain,obstipation Uncommon

Generaldisordersand

administrationsite

conditions asthenia,fatigue,oedema Uncommon

Investigations Hyperkalemia

Increasedalanineaminotransferase

(ALT)* Common

Rare

Systemorganclass Adversereaction Frequency

Nervoussystemdisorders dizziness common

Earandlabyrinthdisorders vertigo common

Generaldisordersand

administrationsiteconditions asthenia/fatigue common

Systemorganclass Adversereaction Frequency

Nervoussystemdisorders dizziness

headache common

uncommon

paraesthesia rare

Cardiacdisorders syncope,atrialfibrillation,

cerebrovascularaccident rare

Vasculardisorders hypotension,including

orthostatichypotension common

Bloodandlymphaticsystem

disorders anaemia common

Respiratory,thoracicand

mediastinaldisorders dyspnoea

cough uncommon

Gastrointestinaldisorders diarrhoea,nausea,vomiting uncommon

Skinandsubcutaneoustissue

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*commoninpatientswhoreceived150mglosartaninsteadof50mglosartan

Hypertensionandtype2diabeteswithrenaldisease

Inacontrolledclinicaltrialin1513type2diabeticpatients31yearsofageandolderwithproteinuria(RENAALstudy,

seesection5.1)themostcommondrug-relatedadversereactionswhichwerereportedforlosartanareasfollows:

*Inaclinicalstudyconductedintype2diabeticpatientswithnephropathy,9.9%ofpatientstreatedwithLosartan

tabletsdevelopedhyperkalaemia>5.5mmol/land3.4%ofpatientstreatedwithplacebo

Thefollowingadversereactionsoccurredmoreofteninpatientsreceivinglosartanthanplacebo:

Post-marketingexperience

Generaldisordersand

administrationsiteconditions asthenia/fatigue uncommon

Investigations increaseinbloodurea,

serumcreatinineandserum

potassium common

Metabolismandnutrition

disorders hyperkalaemia uncommon*

Renalandurinarydisorders renalimpairment

renalfailure common

Systemorganclass Adversereaction Frequency

Nervoussystemdisorders dizziness common

Vasculardisorders hypotension common

Generaldisordersand

administrationsiteconditions asthenia/fatigue common

Investigations hypoglycaemia

hyperkalaemia* common

Systemorganclass Adversereaction Frequency

Bloodandlymphaticsystem

disorders anaemia notknown

Cardiacdisorders syncope,palpitations notknown

Vasculardisorders orthostatichypotension notknown

Gastrointestinaldisorders diarrhoea notknown

Musculoskeletalandconnective

tissuedisorders backpain notknown

Renalandurinarydisorders urinarytractinfections notknown

Generaldisordersand

administrationsiteconditions flu-likesymptoms notknown

Systemorganclass Adversereaction Frequency

Bloodandlymphatic

systemdisorders anaemia,thrombocytopenia notknown

Earandlabyrinth

disorders tinnitus notknown

Immunesystemdisorders hypersensitivity:anaphylacticreactions,

angiooedemaincludingswellingofthelarynxand

glottiscausingairwayobstructionand/orswelling

oftheface,lips,pharynx,and/ortongue;insome

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Renalandurinarydisorders:

Asaconsequenceofinhibitingtherenin-angiotensin-aldosteronesystem,changesinrenalfunctionincludingrenal

failurehavebeenreportedinpatientsatrisk;thesechangesinrenalfunctionmaybereversibleupondiscontinuationof

therapy(seesection4.4)

Paediatricpopulation

Theadversereactionprofileforpediatricpatientsappearstobesimilartothatseeninadultpatients.Datainthe

pediatricpopulationarelimited.

4.9Overdose

Symptomsofintoxication

Limiteddataareavailablewithregardtooverdoseinhumans.Themostlikelymanifestationofoverdosewouldbe

hypotensionandtachycardia.Bradycardiacouldoccurfromparasympathetic(vagal)stimulation.

Treatmentofintoxication

Ifsymptomatichypotensionshouldoccur,supportivetreatmentshouldbeinstituted.

Measuresaredependingonthetimeofmedicinalproductintakeandkindandseverityofsymptoms.Stabilisationof

thecardiovascularsystemshouldbegivenpriority.Afteroralintaketheadministrationofasufficientdoseofactivated

charcoalisindicated.Afterwards,closemonitoringofthevitalparametersshouldbeperformed.Vitalparameters

shouldbecorrectedifnecessary.

Neitherlosartannortheactivemetabolitecanberemovedbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Losartanisasyntheticoralangiotensin-IIreceptor(typeAT

)antagonist.AngiotensinII,apotentvasoconstrictor,is

theprimaryactivehormoneoftherenin/angiotensinsystemandanimportantdeterminantofthepathophysiologyof

hypertension.AngiotensinIIbindstotheAT

receptorfoundinmanytissues(e.g.vascularsmoothmuscle,adrenal

gland,kidneysandtheheart)andelicitsseveralimportantbiologicalactions,includingvasoconstrictionandtherelease

inthepastinconnectionwiththeadministration

ofothermedicines,includingACEinhibitors;

vasculitis,includingHenoch-Schonleinpurpura.

Nervoussystemdisorders migraine notknown

Respiratory,thoracicand

mediastinaldisorders cough notknown

Gastrointestinaldisorders diarrhoea,pancreatitis notknown

Generaldisordersand

administrationsite

conditions malaise notknown

Hepatobiliarydisorders hepatitis rare

liverfunctionabnormalities notknown

Skinandsubcutaneous

tissuedisorders urticaria,pruritus,rash,photosensitivity notknown

Muscoskeletaland

connectivetissue

disorders myalgia,arthralgia,rhabdomyolysis notknown

Reproductivesystemand

breastdisorders erectiledysfunction/impotence notknown

Psychiatricdisorders depression notknown

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LosartanselectivelyblockstheAT

receptor.Invitroandinvivolosartananditspharmacologicallyactivecarboxylic

acidmetaboliteE-3174blockallphysiologicallyrelevantactionsofangiotensinII,regardlessofthesourceorrouteof

itssynthesis.

Losartandoesnothaveanagonisteffectnordoesitblockotherhormonereceptorsorionchannelsimportantin

cardiovascularregulation.FurthermorelosartandoesnotinhibitACE(kininaseII),theenzymethatdegrades

bradykinin.Consequently,thereisnopotentiationofundesirablebradykinin-mediatedeffects.

Duringadministrationoflosartan,removaloftheangiotensinIInegativefeedbackonreninsecretionleadstoincreased

plasmareninactivity(PRA).IncreaseinthePRAleadstoanincreaseinangiotensinIIinplasma.Despitethese

increases,antihypertensiveactivityandsuppressionofplasmaaldosteroneconcentrationaremaintained,indicating

effectiveangiotensinIIreceptorblockade.Afterdiscontinuationoflosartan,PRAandangiotensinIIvaluesfellwithin

threedaystothebaselinevalues.

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).Despite

themarkeddecreaseinbloodpressure,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)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

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RENAAL-Study

TheReductionofEndpointsinNIDDMwiththeAngiotensinIIReceptorAntagonistLosartanRENAALstudywasa

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.

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

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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

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/creatinineratioof0.3.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(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

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Long-termeffectsofreductionofproteinuriainchildrenhavenotbeenstudied.

5.2Pharmacokineticproperties

Absorption

Followingoraladministration,losartaniswellabsorbedandundergoesfirst-passmetabolism,forminganactive

carboxylicacidmetaboliteandotherinactivemetabolites.Thesystemicbioavailabilityoflosartantabletsis

approximately33%.Meanpeakconcentrationsoflosartananditsactivemetabolitearereachedin1hourandin3-4

hours,respectively.

Distribution

Bothlosartananditsactivemetaboliteare99%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.Whenlosartanis

administeredorally,about4%ofthedoseisexcretedunchangedintheurine,andabout6%ofthedoseisexcretedin

theurineasactivemetabolite.Thepharmacokineticsoflosartananditsactivemetabolitearelinearwithorallosartan

potassiumdosesupto200mg.

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-timeshigherinhaemodialysispatients.

Theplasmaconcentrationsoftheactivemetabolitearenotalteredinpatientswithrenalimpairmentorinhaemodialysis

patients.

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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,losartanhasbeenshowntoinduceadversereactionsonthelatefoetaldevelopment,resulting

infoetaldeathandmalformations.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose(E460)

Lactosemonohydrate

Pregelatinizedmaizestarch

Magnesiumstearate(E572)

Hyprolose(E463)

Hypromellose(E464)

Carnaubawax(E903)

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateforthisproductshallbethedateshownontheblisterandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Storeintheoriginalpackageinordertoprotectfromlightandmoisture.

6.5Natureandcontentsofcontainer

PVC/PE/PVDCblisterpackageswithaluminumfoilliddingincartonscontaining28tablets

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

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7PARALLELPRODUCTAUTHORISATIONHOLDER

LTTPharmaLimited

Unit18

OxleasowRoad

EastMoonsMoat

Redditch

Worcestershire

B980RE

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1562/76/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:20thApril2012

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