COSARTAL

Main information

  • Trade name:
  • COSARTAL Tablets 25 Milligram
  • Dosage:
  • 25 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COSARTAL Tablets 25 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1380/046/002
  • Authorization date:
  • 11-04-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA1380/046/002

CaseNo:2067457

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ActavisGroupPTCehf

Reykjavikurvegi76-78,220Hafnarfjordur,Iceland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Cosartal25mgFilm-coatedTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom27/08/2009until01/06/2011.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cosartal25mgFilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains25mgoflosartanpotassium

Forexcipients,seeSection6.1

3PHARMACEUTICALFORM

Film-coatedtablet.

White,round,biconvex,film-coatedtablet.

4CLINICALPARTICULARS

4.1TherapeuticIndications

-Treatmentofessentialhypertension.

-Treatmentofrenaldiseaseinpatientswithhypertensionandtype2diabetesmellituswithproteinuria ≥0.5g/dayas

partofanantihypertensivetreatment.

-Treatmentofchronicheartfailure(inpatients ≥60years),whentreatmentwithACEinhibitorsisnotconsidered

suitableduetoincompatibility,especiallycough,orcontraindication.Patientswithheartfailurewhohavebeen

stabilisedwithanACEinhibitorshouldnotbeswitchedtolosartan.Thepatientsshouldhavealeftventricularejection

fraction ≤40%andshouldbestabilisedunderthetreatmentofthechronicheartfailure.

-ReductionintheriskofstrokeinhypertensivepatientswithleftventricularhypertrophydocumentedbyECG(see

section5.1LIFEstudy,RACE).

4.2Posologyandmethodofadministration

Cosartaltabletsshouldbeswallowedwithaglassofwater.

Cosartalmaybeadministeredwithorwithoutfood.

Hypertension

Theusualstartingandmaintenancedoseis50mgoncedailyformostpatients.Themaximalantihypertensiveeffectis

attained3-6weeksafterinitiationoftherapy.Somepatientsmayreceiveanadditionalbenefitbyincreasingthedoseto

100mgoncedaily(inthemorning).

Cosartalmaybeadministeredwithotherantihypertensiveagents,especiallywithdiuretics(e.g.hydrochlorothiazide).

Pediatrichypertension

Therearelimiteddataontheefficacyandsafetyoflosartaninchildrenandadolescentsaged6-16yearsoldforthe

treatmentofhypertension(see5.1:Pharmacodynamicproperties).Limitedpharmacokineticdataareavailablein

hypertensivechildrenaboveonemonthofage(see5.2:Pharmacokineticproperties).

Forpatientswhocanswallowtablets,therecommendeddoseis25mgoncedailyinpatients>20to<50kg.In

exceptionalcasesthedosecanbeincreasedtoamaximumof50mgoncedaily.Dosageshouldbeadjustedaccording

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Inpatients>50kg,theusualdoseis50mgoncedaily.Inexceptionalcasesthedosecanbeadjustedtoamaximumof

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

Losartanisnotrecommendedforuseinchildrenunder6yearsold,aslimiteddataareavailableinthesepatientgroups.

Itisnotrecommendedinchildrenwithglomerularfiltrationrate<30ml/min/1.73m2,asnotdataareavailable(see

alsosection4.4).

Losartanisalsonotrecommendedinchildrenwithhepaticimpairment(seealsosection4.4).

HypertensivetypeIIdiabeticpatientswithproteinuria ≥0.5g/day

Theusualstartingdoseis50mgoncedaily.Thedosemaybeincreasedto100mgoncedailybasedonblodpressure

responsefromonemonthafterinitiationoftherapyonwards.Cosartalmaybeadministeredwithotherantihypertensive

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

insulinandothercommonlyusedhypoglycaemicagents(e.g.sulfonylureas,glitazonesandglucosidaseinhibitors).

Heartfailure

TheusualinitialdoseofCosartalinpatientswithheartfailureis12.5mgoncedaily.Thedoseshouldgenerallybe

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

daily,astoleratedbythepatient.

ReductionintheriskofstrokeinhypertensivepatientswithleftventricularhypertrophydocumentedbyECG

Theusualstartingdoseis50mgofCosartaloncedaily.Alowdoseofhydrochlorothiazideshouldbeaddedand/orthe

doseofCosartalshouldbeincreasedto100mgoncedailybasedonbloodpressureresponse.

Useinpatientswithintravascularvolumedepletion:

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

oncedailyshouldbeconsidered(seesection4.4).

Useinpatientswithrenalimpairmentandhaemodialysispatients:

Noinitialdosageadjustmentisnecessaryinpatientswithrenalimpairmentandinhaemodialysispatients.

Useinpatientswithhepaticimpairment:

Alowerdoseshouldbeconsideredforpatientswithahistoryofhepaticimpairment.Thereisnotherapeuticexperience

inpatientswithseverehepaticimpairment.Therefore,losartaniscontraindicatedinpatientswithseverehepatic

impairment(seesections4.3and4.4).

UseinElderly

Althoughconsiderationshouldbegiventoinitiatingtherapywith25mginpatientsover75yearsofage,dosage

adjustmentisnotusuallynecessaryfortheelderly.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipients(seesections4.4and6.1).

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6).

Severehepaticimpairment.

4.4Specialwarningsandprecautionsforuse

Hypersensitivity

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

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HypotensionandElectrolyte/FluidImbalance:

Symptomatichypotension,especiallyafterthefirstdoseandafterincreasingofthedose,mayoccurinpatientswhoare

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

conditionsshouldbecorrectedpriortoadministrationofCosartal,oralowerstartingdoseshouldbeused(seesection

4.2).Thisalsoappliestochildren.

Electrolyteimbalances

Electrolyteimbalancesarecommoninpatientswithrenalimpairment,withorwithoutdiabetes,andshouldbe

addressed.Inaclinicalstudyconductedintype2diabeticpatientswithnephropathy,theincidenceofhyperkalaemia

washigherinthegrouptreatedwithlosartanascomparedtotheplacebogroup(seesection4.8,‘Hypertensionandtype

2diabeteswithrenaldisease–Investigations’and‘Post-marketingexperience–Investigations’).Therefore,theplasma

concentrationsofpotassiumaswellascreatinineclearancevaluesshouldbecloselymonitored,especiallypatientswith

heartfailureandaCreatinineClearancebetween30-50ml/minshouldbecloselymonitored.

Theconcomitantuseofpotassiumsparingdiuretics,potassiumsupplementsandpotassiumcontainingsaltsubstitutes

withlosartanisnotrecommended(seesection4.5).

Liverfunctionimpairment:

Basedonpharmacokineticdatawhichdemonstratesignificantlyincreasedplasmaconcentrationsoflosartanincirrhotic

patients,alowerdoseshouldbeconsideredforpatientswithahistoryofhepaticimpairment.Thereisnotherapeutic

experiencewithlosartaninpatientswithseverehepaticimpairment.Thereforelosartanmustnotbeadministeredin

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

Losartanisalsonotrecommendedinchildrenwithhepaticimpairment(seesection4.2).

Renalfunctionimpairment:

Asaconsequenceofinhibitingtherenin-angiotensin-aldosteronesystem,changesinrenalfunctionincludingrenal

failurehavebeenreported(inparticular,inpatientswhoserenalfunctionisdependentonthereninangiotensin

aldosteronesystemsuchasthosewithseverecardiacinsufficiencyorpre-existingrenaldysfunction).Aswithother

drugsthataffecttherenin-angiotensin-aldosteronesystem,increasesinbloodureaandserumcreatininehavealsobeen

reportedinpatientswithbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney;thesechangesin

renalfunctionmaybereversibleupondiscontinuationoftherapy.Losartanshouldbeusedwithcautioninpatientswith

bilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney.

Useinpediatricpatientswithrenalfunctionimpairment

Losartanisnotrecommendedinchildrenwithglomerularfiltrationrate<30ml/min/1.73m2asnodataareavailable

(seesection4.2).

Renalfunctionshouldberegularlymonitoredduringtreatmentwithlosartanasitmaydeteriorate.Thisapplies

particularlywhenlosartanisgiveninthepresenceofotherconditions(fever,dehydration)likelytoimpairrenal

function.

ConcomitantuseoflosartanandACE-inhibitorshasshowntoimpairrenalfunction.Therefore,concomitantuseisnot

recommended.

RenalTransplantation

Thereisnoexperienceinpatientswithrecentkidneytransplantation.

Primaryhyperaldosteronism

Patientswithprimaryaldosteronismgenerallywillnotrespondtoantihypertensivedrugsactingthroughinhibitionof

therenin-angiotensinsystem.Therefore,theuseoflosartantabletsisnotrecommended.

Coronaryheartdiseaseandcerebrovasculardisease

Aswithanyantihypertensiveagents,excessivebloodpressuredecreaseinpatientswithischaemiccardiovascularand

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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-galactosemalabsorption

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(inducerofmetabolism

enzymes)gavea40%reductioninplasmaconcentrationoftheactivemetabolite.Theclinicalrelevanceofthiseffectis

unknown.Nodifferenceinexposurewasfoundwithconcomitanttreatmentwithfluvastatin(weakinhibitorof

CYP2C9).

AswithotherdrugsthatblockangiotensinIIoritseffects,concomitantuseofotherdrugswhichretainpotassium(e.g.

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

potassiumsupplementsorsaltsubstitutescontainingpotassiummayleadtoincreasesinserumpotassium.Co-

medicationisnotadvisable.

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.VeryrarecaseshavealsobeenreportedwithangiotensinIIreceptor

antagonists.Co-administrationoflithiumandlosartanshouldbeundertakenwithcaution.Ifthiscombinationproves

essential,serumlithiumlevelmonitoringisrecommendedduringconcomitantuse.

WhenangiotensinIIantagonistsareadministeredsimultaneouslywithNSAIDs(i.e.selectiveCOX-2inhibtors,

acetylsalicylicacidatanti-inflammatorydosesandnon-selectiveNSAIDs),attenuationoftheantihypertensiveeffect

mayoccur.ConcomitantuseofangiotensinIIantagonistsordiureticsandNSAIDsmayleadtoanincreasedriskof

worseningofrenalfunction,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyin

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Thecombinationshouldbeadministeredwithcaution,especiallyintheelderly.Patientsshouldbeadequatelyhydrated

andconsiderationshouldbegiventomonitoringrenalfunctionafterinitiationofconcomitanttherapy,andperiodically

thereafter.

4.6Pregnancyandlactation

Pregnancy:

Theuseoflosartanisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuseoflosartanis

contraindicatedduringthesecondandthirdtrimestersofpregnancy(seesections4.3and4.4).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithAngiotensinIIReceptorInhibitors(AIIRAs),similarrisksmayexist

forthisclassofdrugs.UnlesscontinuedAIIRAtherapyisconsideredessential,patientsplanningpregnancyshouldbe

changedtoalternativeantihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.When

pregnancyisdiagnosed,treatmentwithlosartanshouldbestoppedimmediatelyand,ifappropriate,alternativetherapy

shouldbestarted.

Exposuretolosartantherapyduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

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

hyperkalaemia).(Seesection5.3.)

Shouldexposuretolosartanhaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

Infantswhosemothershavetakenlosartanshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Lactation:

Becausenoinformationisavailableregardingtheuseoflosartanduringbreastfeeding,losartanisnotrecommended

andalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,especiallywhile

nursinganewbornorpreterminfant.

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

eventwasdizziness.

Hypertension

Incontrolledclinicaltrialsforessentialhypertensionwithlosartanthefollowingadverseeventswerereported

Nervoussystemdisorders:

Common:dizziness,vertigo

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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

Skinandsubcutaneoustissuedisorders:

Uncommon:urticaria,pruritus,rash

Generaldisordersandadministrationsiteconditions:

Uncommon:asthenia/fatigue

Hypertensionandtype2diabeteswithrenaldisease

Inacontrolledclinicaltrialintype2diabeticpatientswithproteinuria(RENAALstudy,seesection5.1)themost

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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:

Notknown:migraine

Respiratory,thoracicandmediastinaldisorders:

Notknown:cough

Gastrointestinaldisorders:

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Hepatobiliarydisorders:

Rare:hepatitis

Notknown:liverfunctionabnormalities

Skinandsubcutaneoustissuedisorders:

Notknown:urticaria,pruritus,rash

Muscoskeletalandconnectivetissuedisorders:

Notknown:myalgia,arthralgia

Renaldisorders:

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

Pharmacotherapeuticgroup:AngiotensinIIReceptorAntagonists,ATCcode:C09CA01

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

theprimaryactivehormoneoftherenin/angiotensinsystemandanimportantdeterminantofthepathophysiologyof

hypertension.AngiotensinIIbindstotheAT1receptorfoundinmanytissues(e.g.vascularsmoothmuscle,adrenal

gland,kidneys,andtheheart)andelicitsseveralimportantbiologicalactions,includingvasoconstrictionandtherelease

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LosartanselectivelyblockstheAT1receptor.Invitroandinvivolosartananditspharmacologicallyactivecarboxylic

acidmetabolite(E-3174)blockallphysiologicallyrelevantactionsofangiotensinII,regardlessofthesourceorrouteof

itssynthesis.

Losartandoesnothaveanagonisteffectnordoesitblockotherhormonereceptorsorionchannelsimportantin

cardiovascularregulation.FurthermorelosartandoesnotinhibitACE(kininaseII),theenzymethatdegrades

bardykinin.Consequently,thereisnopotentiationofundesirablebradykininmediatedeffects.

Duringlosartanadministration,removalofangiotensin-IInegativefeedbackonreninsecretionleadstoincreased

plasmareninactivity(PRA).IncreaseinthePRAleadstoanincreaseinangiotensinIIinplasma.Despitethese

increases,antihypertensiveactivityandsuppressionofplasmaaldosteroneconcentrationaremaintained,indicating

effectiveangiotensin-IIreceptorblockade.Afterdiscontinuationoflosartan,PRAandangiotensinIIvaluesfellwithin

threedaystothebaselinevalues.

BothlosartananditsprincipalactivemetabolitehaveafargreateraffinityfortheAT1-receptorthanfortheAT2-

receptor.Theactivemetaboliteis10-to40-timesmoreactivethanlosartanonaweightforweightbasis.

HypertensionStudies:

Incontrolledclinicalstudies,once-dailyadministrationofLosartantopatientswithmildtomoderateessential

hypertensionproducedstatisticallysignificantreductionsinsystolicanddiastolicbloodpressure.Measurementof

bloodpressure24hourspost-doserelativeto5-6hourspost-dosedemonstratedbloodpressurereductionover24hours;

thenaturaldiurnalrhythmwasmaintained.Blood-pressurereductionattheendofthedosingintervalwas

approximately70-80%oftheeffectseen5-6hourspost-dose.

Discontinuationoflosartaninhypertensivepatientsdidnotresultinanabruptriseinbloodpressure(rebound).Despite

themarkeddecreaseinbloodpressure,administrationofLosartanhadnoclinicallysignificanteffectonheartrate.

Losartanisequallyeffectiveinmalesandfemales,andinyounger(belowtheageof65years)andolderhypertensive

patients.

LIFE-Study

TheLosartanInterventionForEndpointReductioninHypertension(LIFE)studywasarandomised,triple-blind,

active-controlledstudyin9,193hypertensivepatientsaged55to80yearswithECG-documentedleftventricular

hypertrophy.PatientswererandomisedtoreceiveoncedailyLosartan50mgoroncedailyatenolol50mg.Ifgoal

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

doseofLosartanoratenololwasthenincreasedto100mgoncedaily.Otherantihypertensiveswiththeexceptionof

ACE-inhibitors,angiotensinIIantagonistsorbetablockerswereaddedifnecessarytoreachthegoalbloodpressure.

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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RENAALStudy:

TheReductionofEndpointsinNIDDMwiththeAngiotensinIIReceptorAntagonistLosartan(RENAAL)studywasa

controlledclinicalstudyconductedworldwidein1513Type2diabeticpatientswithproteinuriawithorwithout

hypertension.751patientsweretreatedwithLosartan.

Theobjectiveofthestudywastodemonstrateanephroprotectiveeffectoflosartanpotassiumoverandabovethe

benefitofabloodloweringpressure.

Patientswithproteinuriaandserumcreatinineof1.3-3.0mg/dlwererandomisedtoreceiveLosartan50mgoncedaily,

titratedifnecessary,toachievebloodpressureresponse,ortoplacebo,onabackgroundofconventional

antihypertensivetherapyexcludingACEinhibitorsandangiotensinIIantagonists.Investigatorswereinstructedto

titratethestudymedicationto100mgdailyasappropriate;72%ofpatientsweretakingthe100mgdailydoseforthe

majorityofthetime.Otherantihypertensiveagents(diuretics,calciumantagonists,alpha-andbeta-receptorblockers

andalsocentrallyactingantihypertensives)werepermittedassupplementarytreatmentdependingontherequirement

inbothgroups.Patientswerefollowedforupto4.6years(3.4yearsonaverage).

Theprimaryendpointofthestudywasacompositeendpointofdoublingoftheserumcreatinineendstagerenalfailure

(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%riskreduction

forend-stagerenalfailure(p=0.002);19.9%riskreductionforend-stagerenalfailureordeath(p=0.009);21.0%risk

reductionfordoublingofserumcreatinineorend-stagerenalfailure(p=0.01).

All-causemortalityratewasnotsignificantlydifferentbetweenthetwotreatmentgroups.

Inthisstudy,Losartanwasgenerallywelltolerated,asshownbyatherapydiscontinuationrateonaccountofadverse

eventsthatwascomparabletotheplacebogroup.

ELITEIandELITEIIstudy

IntheELITEStudycarriedoutover48weeksin722patientswithheartfailure(NYHAClassII-IV),nodifferencewas

observedbetweenthepatientstreatedwithlosartanandthosetreatedwithcaptoprilwithregardtotheprimaryendpoint

ofalong-termchangeinrenalfunction.TheobservationoftheELITEIStudy,that,comparedwithcaptopril,losartan

reducedthemortalityrisk,wasnotconfirmedinthesubsequentELITEIIStudy,whichisdescribedinthefollowing.

IntheELITEIIStudyLosartan50mgoncedaily(startingdose12.5mg,increasedto25mg,then50mgoncedaily)

wascomparedwithcaptopril50mgthreetimesdaily(startingdose12.5mg,increasedto25mgandthento50mg

threetimesdaily).Theprimaryendpointofthisprospectivestudywastheall-causemortality.

Inthisstudy3152patientswithheartfailure(NYHAClassII-IV)werefollowedforalmosttwoyears(median:1.5

years)inordertodeterminewhetherlosartanissuperiortocaptoprilinreducingallcausemortality.Theprimary

endpointdidnotshowanystatisticallysignificantdifferencebetweenlosartanandcaptoprilinreducingall-cause

mortality.

Inbothcomparator-controlled(notplacebo-controlled)clinicalstudiesonpatientswithheartfailurethetolerabilityof

losartanwassuperiortothatofcaptopril,measuredonthebasisofasignificantlylowerrateofdiscontinuationsof

therapyonaccountofadverseeventsandasignificantlylowerfrequencyofcough.

AnincreasedmortalitywasobservedinELITEIIinthesmallsubgroup(22%ofallHFpatients)takingbeta-blockers

atbaseline.

PediatricHypertension

Theantihypertensiveeffectoflosartanwasestablishedinaclinicalstudyinvolving177hypertensivepediatricpatients

6to16yearsofagewithabodyweight>20kgandaglomerularfiltrationrate>30ml/min/1.73m2.Patientswho

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

receivedeither5,50or100mgoflosartandaily.Attheendofthreeweeks,losartanadministrationoncedailylowered

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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,didnotappeartoofferconsistentantihypertensive

efficacy.

TheseresultswereconfirmedduringperiodIIofthestudywherepatientswererandomisedtocontinuelosartanor

placebo,afterthreeweeksoftreatment.Thedifferenceinbloodpressureincreaseascomparedtoplacebowaslargestin

themiddledosegroup(6.7mmHgmiddledosevs.5.38mmHGhighdose).Theriseintroughdiastolicbloodpressure

wasthesameinpatientsreceivingplaceboandinthosecontinuinglosartanatthelowestdoseineachgroup,again

suggestingthatthelowestdoseineachgroupdidnothavesignificantantihypertensiveeffect.

Long-termeffectsoflosartanongrowth,pubertyandgeneraldevelopmenthavenotbeenstudied.Thelong-term

efficacyofantihypertensivetherapywithlosartaninchildhoodtoreducecardiovascularmorbidityandmortalityhas

alsonotbeenestablished.

5.2Pharmacokineticproperties

Absorption

Followingoraladministration,losartaniswellabsorbedandundergoesfirst-passmetabolism,forminganactive

carboxylicacidmetaboliteandotherinactivemetabolites.Thesystemicbioavailabilityoflosartantabletsis

approximately33%.Meanpeakconcentrationsoflosartananditsactivemetabolitearereachedin1hourandin3-4

hours,respectively.

Distribution

Bothlosartananditsactivemetaboliteare ≥99%boundtoplasmaproteins,primarilyalbumin.Thevolumeof

distributionoflosartanis34litres.

Biotransformation

About14%ofanintravenouslyororallyadministereddoseoflosartanisconvertedtoitsactivemetabolite.Following

oralandintravenousadministrationof14C-labelledlosartanpotassium,circulatingplasmaradioactivityprimarilyis

attributedtolosartananditsactivemetabolite.Minimalconversionoflosartantoitsactivemetabolitewasseenin

aboutonepercentofindividualsstudied.

Inadditiontotheactivemetabolite,inactivemetabolitesareformed.

Elimination

Plasmaclearanceoflosartananditsactivemetaboliteisabout600ml/minand50ml/min,respectively.Renalclearance

oflosartananditsactivemetaboliteisabout74ml/minand26ml/min,respectively.Whenlosartanisadministered

orally,about4%ofthedoseisexcretedunchangedintheurine,andabout6%ofthedoseisexcretedintheurineas

activemetabolite.Thepharmacokineticsoflosartananditsactivemetabolitearelinearwithorallosartanpotassium

dosesupto200mg.

Followingoraladministration,plasmaconcentrationsoflosartananditsactivemetabolitedeclinepolyexponentially

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

losartannoritsactivemetaboliteaccumulatessignificantlyinplasma.

Bothbiliaryandurinaryexcretioncontributetotheeliminationoflosartananditsmetabolites.Followinganoraldose/

intravenousadministrationof14C-labelledlosartaninman,about35%/43%ofradioactivityisrecoveredintheurine

and58%/50%inthefaeces.

Characteristicsinpatients

Inelderlyhypertensivepatientstheplasmaconcentrationsoflosartananditsactivemetabolitedonotdifferessentially

fromthosefoundinyounghypertensivepatients.

Infemalehypertensivepatientstheplasmalevelsoflosartanwereuptotwiceashighasinmalehypertensivepatients,

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Inpatientswithmildtomoderatealcohol-inducedhepaticcirrhosis,theplasmalevelsoflosartananditsactive

metaboliteafteroraladministrationwere,respectively,5and1.7timeshigherthaninyoungmalevolunteers(see

section4.2and4.4).

Plasmaconcentrationsoflosartanarenotalteredinpatientswithcreatinineclearanceabove10ml/min.Comparedto

patientswithnormalrenalfunction,theAUCforlosartanisapproximately2-timeshigherinhaemodialysispatients.

Theplasmaconcentrationsoftheactivemetabolitearenotalteredinpatientswithrenalimpairmentorinhaemodialysis

patients.

Neitherlosartannortheactivemetabolitecanberemovedbyhaemodialysis.

Pharmacokineticsinpediatricpatients

Thepharmacokineticsoflosartanhavebeeninvestigatedin50hypertensivepediatricpatients>1monthto<16yearsof

agefollowingoncedailyoraladministrationofapproximately0.54to0.77mg/kgoflosartan(meandoses).

Theresultsshowedthattheactivemetaboliteisformedfromlosartaninallagegroups.Theresultsshowedroughly

similarpharmacokineticparametersoflosartanfollowingoraladministrationininfantsandtoddlers,preschool

children,schoolagechildrenandadolescents.Thepharmacokineticparametersforthemetabolitedifferedtoagreater

extentbetweentheagegroups.Whencomparingpreschoolchildrenwithadolscentsthesedifferencesbecame

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

Mannitol

Microcrystallinecellulose

Croscarmellosesodium

Povidon

Magnesiumstearate

Hypromellose

Titaniumdioxide(E171)

Talc

Propyleneglycol

6.2Incompatibilities

Notapplicable

6.3ShelfLife

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6.4Specialprecautionsforstorage

Donotstoreabove25ºC.

6.5Natureandcontentsofcontainer

PVC/PVdC/AlStrip

Packsizes:5,7,10,14,15,20,21,28,30,50,56,60,84,90,98,100,120,

210,280or500tablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

ActavisGroupPTCehf

Reykjavikurvegi76-78

220Hafnarfjordur

Iceland

8MARKETINGAUTHORISATIONNUMBER

PA1380/46/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:2ndJune2006

10DATEOFREVISIONOFTHETEXT

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