COZAAR COMP

Main information

  • Trade name:
  • COZAAR COMP
  • Dosage:
  • 100/ 25 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COZAAR COMP
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1596/038/002
  • Authorization date:
  • 21-01-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CozaarComp100mg/25mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains100mgoflosartanpotassiumand25mgofhydrochlorothiazide(HCTZ).

Excipient:eachtabletcontains126.26mglactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromtheUK:

Lightyellow,ovalfilm-coatedtabletsmarked'747'ononesideandplainontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

CozaarCompisindicatedforthetreatmentofessentialhypertensioninpatientswhosebloodpressureisnot

adequatelycontrolledonlosartanorhydrochlorothiazidealone.

4.2Posologyandmethodofadministration

CozaarCompmaybeadministeredwithotherantihypertensiveagents.

CozaarComptabletsshouldbeswallowedwithaglassofwater

CozaarCompmaybeadministeredwithorwithoutfood.

Hypertension

Losartanandhydrochlorothiazideisnotforuseasinitialtherapy,butinpatientswhosebloodpressureisnotadequately

controlledbylosartanpotassiumorhydrochlorothiazidealone.

Dosetitrationwiththeindividualcomponents(losartanandhydrochlorothiazide)isrecommended.

Whenclinicallyappropriatedirectchangefrommonotherapytothefixedcombinationmaybeconsideredinpatients

whosebloodpressureisnotadequatelycontrolled.

TheusualmaintenancedoseofCozaarCompisonetabletofCozaarComp50mg/12.5mg

(losartan50mg/HCTZ12.5mg)oncedaily.ForpatientswhodonotrespondadequatelytoCozaar

Comp50mg/12.5mg,thedosagemaybeincreasedtoonetabletofCozaarComp100mg/25mg(losartan100mg/

HCTZ25mg)oncedaily.ThemaximumdoseisonetabletofCozaarComp100mg/25mgoncedaily.Ingeneral,

theantihypertensiveeffectisattainedwithinthreetofourweeksafterinitiationoftherapy.

CozaarComp100/12.5(losartan100mg/HCTZ12.5mg)isavailableforthosepatientstitratedto100mgofCozaar

Compwhorequireadditionalbloodpressurecontrol.

Useinpatientswithrenalimpairmentandhaemodialysispatients

Noinitialdosageadjustmentisnecessaryinpatientswithmoderaterenalimpairment(i.e.creatinineclearance

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Losartan/HCTZtabletsmustnotbeusedinpatientswithsevererenalimpairment(i.e.creatinineclearance<30ml/min)

(seesection4.3).

Useinpatientswithintravascularvolumedepletion

Volumeand/orsodiumdepletionshouldbecorrectedpriortoadministrationofLosartan/HCTZtablets.

Useinpatientswithhepaticimpairment

Losartan/HCTZiscontraindicatedinpatientswithseverehepaticimpairment(seesection4.3.).

Useintheelderly

Dosageadjustmentisnotusuallynecessaryfortheelderly.

Useinchildrenandadolescents(<18years)

Thereisnoexperienceinchildrenandadolescents.Therefore,losartan/hydrochlorothiazideshouldnotbeadministered

tochildrenandadolescents.

4.3Contraindications

Hypersensitivitytolosartan,sulphonamide-derivedsubstances(ashydrochlorothiazide)ortoanyofthe

excipients

Therapyresistanthypokalaemiaorhypercalcaemia

Severehepaticimpairment;cholestasisandbiliaryobstructivedisorders

Refractoryhyponatraemia

Symtomatichyperuricaemia/gout

2ndand3rdtrimesterofpregnancy(seesection4.4and4.6)

Severerenalimpairment(i.e.creatinineclearance<30ml/min)

Anuria

4.4Specialwarningsandprecautionsforuse

Losartan

Angiooedema

Patientswithahistoryofangiooedema(swellingoftheface,lips,throat,and/ortongue)shouldbecloselymonitored

(seesection4.8).

HypotensionandIntravascularvolumedepletion

Symptomatichypotension,especiallyafterthefirstdose,mayoccurinpatientswhoarevolume-and/orsodium-

depletedbyvigorousdiuretictherapy,dietarysaltrestriction,diarrhoeaorvomiting.Suchconditionsshouldbe

correctedbeforetheadministrationofCozaarComptablets(seesections4.2.and4.3.).

Electrolyteimbalances

Electrolyteimbalancesarecommoninpatientswithrenalimpairment,withorwithoutdiabetes,andshouldbe

addressed.Therefore,theplasmaconcentrationsofpotassiumandcreatinineclearancevaluesshouldbeclosely

monitored;especiallypatientswithheartfailureandacreatinineclearancebetween30-50ml/minshouldbeclosely

monitored.

Theconcomitantuseofpotassiumsparingdiuretics,potassiumsupplementsandpotassiumcontainingsaltsubstitutes

withlosartan/hydrochlorothiazideisnotrecommended(seesection4.5).

Liverfunctionimpairment

Basedonpharmacokineticdatawhichdemonstratesignificantlyincreasedplasmaconcentrationsoflosartanincirrhotic

patients,CozaarCompshouldbeusedwithcautioninpatientswithahistoryofmildtomoderatehepaticimpairment.

Thereisnotherapeuticexperiencewithlosartaninpatientswithseverehepaticimpairment.ThereforeCozaarCompis

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Renalfunctionimpairment

Asaconsequenceofinhibitingtherenin-angiotensin-aldosteronesystem,changesinrenalfunction,includingrenal

failure,havebeenreported(inparticular,inpatientswhoserenalfunctionisdependentontherenin-angiotensin-

aldosteronesystem,suchasthosewithseverecardiacinsufficiencyorpre-existingrenaldysfunction).

Aswithotherdrugsthataffecttherenin-angiotensin-aldosteronesystem,increasesinbloodureaandserumcreatinine

havealsobeenreportedinpatientswithbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney;these

changesinrenalfunctionmaybereversibleupondiscontinuationoftherapy.Losartanshouldbeusedwithcautionin

patientswithbilateralrenalarterystenosisorstenosisofthearterytoasolitarykidney.

Renaltransplantation

Thereisnoexperienceinpatientswithrecentkidneytransplantation.

Primaryhyperaldosteronism

Patientswithprimaryaldosteronismgenerallywillnotrespondtoantihypertensivedrugsactingthroughinhibitionof

therenin-angiotensinsystem.Therefore,theuseofCozaarComptabletsisnotrecommended.

Coronaryheartdiseaseandcerebrovasculardisease:

Aswithanyantihypertensiveagents,excessivebloodpressuredecreaseinpatientswithischaemiccardiovascularand

cerebrovasculardiseasecouldresultinamyocardialinfarctionorstroke.

Heartfailure:

Inpatientswithheartfailure,withorwithoutrenalimpairment,thereis–aswithotherdrugsactingontherenin-

angiotensinsystem-ariskofseverearterialhypotension,and(oftenacute)renalimpairment.

Aorticandmitralvalvestenosis,obstructivehypertrophiccardiomyophathy

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromaorticormitralstenosis,orobstructive

hypertrophiccardiomyopathy.

Ethnicdifferences

Asobservedforangiotensinconvertingenzymeinhibitors,losartanandtheotherangiotensinantagonistsareapparently

lesseffectiveinloweringbloodpressureinblackpeoplethaninnon-blacks,possiblybecauseofhigherprevalenceof

low-reninstatesintheblackhypertensivepopulation.

Pregnancy

AIIRAsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedAIIRAtherapyisconsideredessential,patients

planningpregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafety

profileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithAIIRAsshouldbestoppedimmediately,

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

Hydrochlorothiazide

Hypotensionandelectrolyte/fluidimbalance

Aswithallantihypertensivetherapy,symptomatichypotensionmayoccurinsomepatients.Patientsshouldbe

observedforclinicalsignsoffluidorelectrolyteimbalance,e.g.,volumedepletion,hyponatremia,hypochloremic

alkalosis,hypomagnesemiaorhypokalemiawhichmayoccurduringintercurrentdiarrheaorvomiting.Periodic

determinationofserumelectrolytesshouldbeperformedatappropriateintervalsinsuchpatients.Dilutional

hyponatraemiamayoccurinoedematouspatientsinhotweather.

Metabolicandendocrineeffects

Thiazidetherapymayimpairglucosetolerance.Dosageadjustmentofantidiabeticagents,includinginsulin,maybe

required(seesection4.5).

Latentdiabetesmellitusmaybecomemanifestduringthiazidetherapy.

Thiazidesmaydecreaseurinarycalciumexcretionandmaycauseintermittentandslightelevationofserumcalcium.

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carryingouttestsforparathyroidfunction.

Increasesincholesterolandtriglyceridelevelsmaybeassociatedwiththiazidediuretictherapy.

Thiazidetherapymayprecipitatehyperuricemiaand/orgoutincertainpatients.Becauselosartandecreasesuricacid,

losartanincombinationwithhydrochlorothiazideattenuatesthediuretic-inducedhyperuricemia.

Hepaticimpairment

Thiazidesshouldbeusedwithcautioninpatientswithimpairedhepaticfunctionorprogressiveliverdisease,asitmay

causeintrahepaticcholestasis,andsinceminoralterationsoffluidandelectrolytebalancemayprecipitatehepaticcoma.

CozaarCompiscontraindicatedforpatientswithseverehepaticimpairment(seesection4.3and5.2).

Other

Inpatientsreceivingthiazides,hypersensitivityreactionsmayoccurwithorwithoutahistoryofallergyorbronchial

asthma.Exacerbationoractivationofsystemiclupuserythematosushasbeenreportedwiththeuseofthiazides.

Excipient

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Losartan

Rifampicinandfluconazolehavebeenreportedtoreducelevelsofactivemetabolite.Theclinicalconsequencesof

theseinteractionshavenotbeenevaluated.

AswithotherdrugsthatblockangiotensinIIoritseffects,concomitantuseofpotassium-sparingdiuretics(e.g.,

spironolactone,triamterene,amiloride),potassiumsupplements,orsaltsubstitutescontainingpotassiummayleadto

increasesinserumpotassium.Co-medicationisnotadvisable.

Aswithothermedicineswhichaffecttheexcretionofsodium,lithiumexcretionmaybereduced.Therefore,serum

lithiumlevelsshouldbemonitoredcarefullyiflithiumsaltsaretobeco-administeredwithangiotensinIIreceptor

antagonists.

WhenangiotensinIIantagonistsareadministeredsimultaneouslywithNSAIDs(i.e.selectiveCOX-2inhibitors,

acetylsalicylicacidatanti-inflammatorydoses)andnon-selectiveNSAIDs,attenuationoftheantihypertensiveeffect

mayoccur.ConcomitantuseofangiotensinIIantagonistsordiureticsandNSAIDsmayleadtoanincreasedriskof

worseningofrenalfunction,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,especiallyin

patientswithpoorpre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,especiallyinthe

elderly.Patientsshouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenalfunctionafter

initiationofconcomitanttherapy,andperiodicallythereafter.

Insomepatientswithcompromisedrenalfunctionwhoarebeingtreatedwithnon-steroidalanti-inflammatorydrugs,

includingselectivecyclooxygenase-2inhibitors,theco-administrationofangiotensinIIreceptorantagonistsmayresult

inafurtherdeteriorationofrenalfunction.Theseeffectsareusuallyreversible.

Othersubstancesinducinghypotensionliketricyclicantidepressants,antipsychotics,baclofene,amifostine:

Concomitantusewiththesedrugsthatlowerbloodpressure,asmainorside-effect,mayincreasetheriskof

hypotension.

Hydrochlorothiazide

Whengivenconcurrently,thefollowingdrugsmayinteractwiththiazidediuretics:

Alcohol,barbiturates,narcoticsorantidepressants:

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Antidiabeticdrugs(oralagentsandinsulin):

Thetreatmentwithathiazidemayinfluencetheglucosetolerance.Dosageadjustmentoftheantidiabeticdrugmaybe

required.Metforminshouldbeusedwithcautionbecauseoftheriskoflacticacidosisinducedbypossiblefunctional

renalfailurelinkedtohydrochlorothiazide.

Otherantihypertensivedrugs

Additiveeffect.

Cholestyramineandcolestipolresins:

Absorptionofhydrochlorothiazideisimpairedinthepresenceofanionicexchangeresins.Singledosesofeither

cholestyramineorcolestipolresinsbindthehydrochlorothiazideandreduceitsabsorptionfromthegastrointestinal

tractbyupto85and43percent,respectively.

Corticosteroids,ACTH

Intensifiedelectrolytedepletion,particularlyhypokalemia.

Pressoramines(e.g.,adrenaline)

Possibledecreasedresponsetopressoraminesbutnotsufficienttoprecludetheiruse.

Skeletalmusclerelaxants,nondepolarizing(e.g.,tubocurarine)

Possibleincreasedresponsivenesstothemusclerelaxant.

Lithium

Diureticagentsreducetherenalclearanceoflithiumandaddahighriskoflithiumtoxicity;concomitantuseisnot

recommended.

Medicinalproductsusedinthetreatmentofgout(probenecid,sulfinpyrazoneandallopurinol)

Dosageadjustmentofuricosuricmedicinalproductsmaybenecessarysincehydrochlorothiazidemayraisethelevelof

serumuricacid.Increaseindosageofprobenecidorsulfinpyrazonemaybenecessary.Coadministrationofathiazide

mayincreasetheincidenceofhypersensitivityreactionstoallopurinol.

Anticholinergicagents(e.g.atropine,biperiden)

Increaseofthebioavailabilitytothiazide-typediureticsbydecreasinggastrointestinalmotilityandstomachemptying

rate.

Cytotoxicagents(egcyclophosphamide,methotrexate)

Thiazidesmayreducetherenalexcretionofcytotoxicmedicinalproductsandpotentiatetheirmyelosuppressiveeffects.

Salicylates

Incaseofhighdosagesofsalicylateshydrochlorothiazidemayenhancethetoxiceffectofthesalicylatesonthecentral

nervoussystem.

Methyldopa

Therehavebeenisolatedreportsofhaemolyticanaemiaoccurringwithconcomitantuseofhydrochlorothiazideand

methyldopa.

Cyclosporine

Concomitanttreatmentwithcyclosporinemayincreasetheriskofhyperuricaemiaandgout-typecomplications.

Digitalisglycosides

Thiazide-inducedhypokalaemiaorhypomagnesaemiamayfavourtheonsetofdigitalis-inducedcardiacarrhythmias.

Medicinalproductsaffectedbyserumpotassiumdisturbances

PeriodicmonitoringofserumpotassiumandECGisrecommendedwhenlosartan/hydrochlorothiazideisadministered

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withthefollowingtorsadesdepointes(ventriculartachycardia)-inducingmedicinalproducts(includingsome

antiarrhythmics),hypokalaemiabeingapredisposingfactortotorsadesdepointes(ventriculartachycardia):

ClassIaantiarrythmics(egquinidine,hydroquinidine,disopyramide).

ClassIIIantiarrythmics(egamiodarone,sotalol,dofetilide,ibutilide).

Someantipsychotics(egthioridazine,chlorpromazine,levomepromazine,trifluoperazine,cyamemazine,

sulpiride,sultopride,amisulpride,tiapride,pimozide,haloperidol,droperidol).

Others(egbepridil,cisapride,diphemanil,erythromycinIV,halofantrin,mizolastin,pentamidine,terfenadine,

vincamineIV).

Calciumsalts

Thiazidediureticsmayincreaseserumcalciumlevelsduetodecreasedexcretion.Ifcalciumsupplementsmustbe

prescribed,serumcalciumlevelsshouldbemonitoredandcalciumdosageshouldbeadjustedaccordingly.

LaboratoryTestInteractions

Becauseoftheireffectsoncalciummetabolism,thiazidesmayinterferewithtestsforparathyroidfunction(seesection

4.4).

Carbamazepine

Riskofsymptomatichyponatremia.Clinicalandbiologicalmonitoringisrequired.

IodineContrastMedia

Incaseofdiuretic-induceddehydration,thereisanincreasedriskofacuterenalfailure,especiallywithhighdosesof

theiodineproduct.Patientsshouldberehydratedbeforetheadministration.

AmphotericinB(parenteral),corticosteroids,ACTH,stimulantlaxatives,orglycyrrhizin(foundinliquorice)

Hydrochlorothiazidemayintensifyelectrolyteimbalance,particularlyhypokalaemia.

4.6Fertility,pregnancyandlactation

Pregnancy

TheuseofAIIRAsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).TheuseofAIIRAsis

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

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithAngiotensinIIReceptorInhibitors(AIIRAs),similarrisksmayexist

forthisclassofdrugs.

UnlesscontinuedAIIRAtherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

anti-hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithAIIRAsshouldbestoppedimmediatelyand,ifappropriate,alternativetherapyshouldbe

started.

ExposuretoAIIRAtherapyduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

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

hyperkalaemia)(seesection5.3).

ShouldexposuretoAIIRAshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

InfantswhosemothershavetakenAIIRAsshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Thereislimitedexperiencewithhydrochlorothiazideduringpregnancy,especiallyduringthefirsttrimester.Animal

studiesareinsufficient.

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itsuseduringsecondandthirdtrimestersmaycompromisefoeto-placentalperfusionandmaycausefoetalandneonatal

effectslikeicterus,disturbanceofelectrolytebalanceandthrombocytopenia.

Hydrochlorothiazideshouldnotbeusedforgestationaloedema,gestationalhypertensionorpreeclampsiaduetothe

riskofdecreasedplasmavolumeandplacentalhypoperfusion,withoutabeneficialeffectonthecourseofthedisease.

Hydrochlorothiazideshouldnotbeusedforessentialhypertensioninpregnantwomen,exceptinraresituationswhere

nootheralternativetreatmentcouldbeused.

Lactation

NoinformationisavailableregardingtheuseofCozaarCompduringbreastfeeding.Hydrochlorothiazideisexcretedin

humanmilk.Therefore,theuseofCozaarCompduringbreastfeedingisnotrecommended.Alternativetreatmentswith

betterestablishedsafetyprofilesduringbreastfeedingarepreferable,especiallywhilenursinganewbornorpreterm

infant.

4.7Effectsonabilitytodriveandusemachines

Nostudiesonthereactionsontheabilitytodriveandusemachineshavebeenperformed.However,whendriving

vehiclesoroperatingmachineryitmustbeborneinmindthatdizzinessordrowsinessmayoccasionallyoccurwhen

takingantihypertensivetherapy,inparticularduringinitiationoftreatmentorwhenthedoseisincreased.

4.8Undesirableeffects

Theadversereactionsbelowareclassifiedwhereappropriatebysystemorganclassandfrequencyaccordingtothe

followingconvention:

Verycommon: 1/10

Common: 1/100,<1/10

Uncommon: 1/1,000, 1/100

Rare: 1/10,000, 1/1,000

Veryrare: 1/10,000

Notknown: 1/10,000

(cannotbeestimatedfromtheavailabledata)

Inclinicaltrialswithlosartanpotassiumsaltandhydrochlorothiazide,noadversereactionspeculiartothiscombination

ofsubstanceswereobserved.Theadversereactionswererestrictedtothosewhichwereformerlyobservedwith

losartanpotassiumsaltand/orhydrochlorothiazide.

Incontrolledclinicaltrialsforessentialhypertension,dizzinesswastheonlyadversereactionreportedassubstance-

relatedthatoccurredwithanincidencegreaterthanplaceboin1%ormoreofpatientstreatedwithlosartanand

hydrochlorothiazide.

Nexttotheseeffects,therearefurtheradversereactionsreportedaftertheintroductionoftheproducttothemarketas

follows:

Systemorganclass Adversereaction Frequency

Hepato-biliary

disorders Hepatitis rare

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Theadversereactionsthathavebeenseenwithoneoftheindividualcomponentsandmaybepotentialadverse

reactionswithlosartanpotassium/hydrochlorothiazidearethefollowing:

Losartan

Thefollowingadversereactionshavebeenreportedforlosartaninclinicalstudiesandinpost-marketingexperience:

Systemorganclass Adversereaction Frequency

Bloodandlymphatic

systemdisorders anaemia,Henoch-Schönleinpurpura,

ecchymosis,haemolysis uncommon

thrombocytopenia notknown

Cardiacdisorders hypotension,orthostatichypotension,

sternalgia,anginapectoris,gradeIIAV

block,cerebrovascularevent,

myocardial

infarction,palpitation,arrhythmias

(atrialfibrillations,sinusbradycardia,

tachycardia,

ventriculartachycardia,ventricular

uncommon

Earandlabyrinth

disorders vertigo,tinnitus uncommon

Eyedisorders blurredvision,burning/stinginginthe

eye,conjunctivitis,decreaseinvisual

acuity uncommon

Gastrointestinal

disorders abdominalpain,nausea,diarrhea,

dyspepsia common

constipation,dentalpain,drymouth,

flatulence,gastritis,vomiting,

obstipation uncommon

pancreatitis notknown

Generaldisordersand

administrationsite

conditions asthenia,fatigue,chestpain common

facialoedema,oedema,fever uncommon

flu-likesymptoms,malaise notknown

Hepatobiliarydisorders liverfunctionabnormalities notknown

Immunesystem

disorders hypersensitivity:

anaphylacticreactions,angiooedema

including

swellingofthelarynxandglottis

causingairwayobstructionand/or

swellingoftheface,lips,pharynx,

and/ortongue;insomeofthesepatients

angiooedemahadbeen

reportedinthepastinconnectionwith

theadministrationofother

rare

Metabolismand

nutritiondisorders anorexia,gout uncommon

Musculoskeletaland

connectivetissue

disorders musclecramp,backpain,legpain,

myalgia common

armpain,jointswelling,kneepain,

musculoskeletalpain,shoulderpain,

stiffness,arthralgia,arthritis,coxalgia,

fibromyalgia,muscleweakness uncommon

rhabdomyolysis notknown

Nervoussystem

disorders headache,dizziness common

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neuropathy,tremor,migraine,syncope

Psychiatricdisorders insomnia common

anxiety,anxietydisorder,panic

disorder,confusion,depression,

abnormaldreams,sleepdisorder,

somnolence,memoryimpairment uncommon

Renalandurinary

disorders renalimpairment,renalfailure common

nocturia,urinaryfrequency,urinary

tractinfection uncommon

Reproductivesystem

andbreastdisorders decreasedlibido,erectile

dysfunction/impotence uncommon

Respiratory,thoracic

andmediastinal

disorders cough,upperrespiratoryinfection,

nasalcongestion,sinusitis,sinus

disorder common

pharyngealdiscomfort,pharyngitis,

laryngitis,dyspnoea,bronchitis,

epistaxis,rhinitis,respiratory

congestion uncommon

Skinandsubcutaneous

tissuedisorders alopecia,dermatitis,dryskin,

erythema,flushing,photosensitivity,

pruritus,rash,urticaria,sweating uncommon

Vasculardisorders vasculitis uncommon

Investigations hyperkalaemia,mildreductionof

haematocritandhaemoglobin,

hypoglycaemia common

mildincreaseinureaandcreatinine

serumlevels uncommon

increaseinhepaticenzymesand

bilirubin veryrare

hyponatraemia nonknown

Systemorganclass Adversereaction Frequency

Bloodandlymphatic

systemdisorders Agranulocytosis,aplasticanaemia,

haemolyticanaemia,leukopenia,

purpura,thrombocytopenia uncommon

Immunesystem

disorders Anaphylacticreaction rare

Metabolismand

nutritiondisorders Anorexia,hyperglycaemia,

hyperuricaemia,hypokalaemia,

hyponatraemia uncommon

Psychiatricdisorders Insomnia uncommon

Nervoussystem

disorders Cephalalgia common

Eyedisorders Transientblurredvision,xanthopsia uncommon

Vasculardisorders Necrotizingangiitis(vasculitis,

cutaneousvasculitis) uncommon

Respiratory,thoracic

andmediastinal

disorders Respiratorydistressincluding

pneumonitisandpulmonaryoedema uncommon

Gastrointestinal

disorders Sialoadenitis,spasms,stomach

irritation,nausea,vomiting,diarrhoea,

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4.9Overdose

NospecificinformationisavailableonthetreatmentofoverdosagewithCozaarComp.Treatmentissymptomaticand

supportive.TherapywithCozaarCompshouldbediscontinuedandthepatientobservedclosely.Suggestedmeasures

includeinductionofemesisifingestionisrecent,andcorrectionofdehydration,electrolyteimbalance,hepaticcoma

andhypotensionbyestablishedprocedures.

Losartan

Limiteddataareavailableinregardtooverdosageinhumans.Themostlikelymanifestationofoverdosagewouldbe

hypotensionandtachycardia;bradycardiacouldoccurfromparasympathetic(vagal)stimulation.Ifsymptomatic

hypotensionshouldoccur,supportivetreatmentshouldbeinstituted.

Neitherlosartannortheactivemetabolitecanberemovedbyhemodialysis.

Hydrochlorothiazide

Themostcommonsignsandsymptomsobservedarethosecausedbyelectrolytedepletion(hypokalemia,

hypochloremia,hyponatremia)anddehydrationresultingfromexcessivediuresis.Ifdigitalishasalsobeen

administered,hypokalemiamayaccentuatecardiacarrhythmias.

Thedegreetowhichhydrochlorothiazideisremovedbyhemodialysishasnotbeenestablished.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:AngiotensinIIantagonistsanddiuretics,ATCcode:C09DA01

Losartan-Hydrochlorothiazide

ThecomponentsofCozaarComphavebeenshowntohaveanadditiveeffectonbloodpressurereduction,reducing

bloodpressuretoagreaterdegreethaneithercomponentalone.Thiseffectisthoughttobearesultofthe

complimentaryactionsofbothcomponents.Further,asaresultofitsdiureticeffect,hydrochlorothiazideincreases

plasmareninactivity,increasesaldosteronesecretion,decreasesserumpotassium,andincreasesthelevelsof

angiotensinII.AdministrationoflosartanblocksallthephysiologicallyrelevantactionsofangiotensinIIandthrough

inhibitionofaldosteronecouldtendtoattenuatethepotassiumlossassociatedwiththediuretic.

Losartanhasbeenshowntohaveamildandtransienturicosuriceffect.Hydrochlorothiazidehasbeenshowntocause

modestincreasesinuricacid;thecombinationoflosartanandhydrochlorothiazidetendstoattenuatethediuretic-

inducedhyperuricemia.

TheantihypertensiveeffectofCozaarCompissustainedfora24-hourperiod.Inclinicalstudiesofatleastoneyear's

Hepato-biliary

disorders Icterus(intrahepaticcholestatis),

pancreatitis uncommon

Skinandsubcutaneous

tissuedisorders Photosensitivity,urticaria,toxic

epidermalnecrolysis uncommon

Musculoskeletaland

connectivetissue

disorders Musclecramps uncommon

Renalandurinary

disorders Glycosuria,interstitialnephritis,renal

dysfunction,renalfailure uncommon

Generaldisordersand

administrationsite

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pressure,administrationofCozaarComphadnoclinicallysignificanteffectonheartrate.Inclinicaltrials,after12

weeksoftherapywithlosartan50mg/hydrochlorothiazide12.5mg,troughsittingdiastolicbloodpressurewasreduced

byanaverageofupto13.2mmHg.

CozaarCompiseffectiveinreducingbloodpressureinmalesandfemales,blacksandnon-blacksandinyounger(<65

years)andolder(65years)patientsandiseffectiveinalldegreesofhypertension.

Losartan

Losartanisasyntheticallyproducedoralangiotensin-IIreceptor(typeAT

)antagonist.AngiotensinII,apotent

vasoconstrictor,istheprimaryactivehormonoftherenin-angiotensinsystemandanimportantdeterminantofthe

pathophysiologyofhypertension.AngiotensinIIbindstotheAT

receptorfoundinmanytissues(e.g.vascularsmooth

muscle,adrenalgland,kidneysandtheheart)andelicitsseveralimportantbiologicalactions,including

vasoconstrictionandthereleaseofaldosterone.AngiotensinIIalsostimulatessmooth-musclecellproliferation.

LosartanselectivelyblockstheAT

receptor.Invitroandinvivolosartananditspharmacologicallyactivecarboxylic

acidmetaboliteE-3174blockallphysiologicallyrelevantactionsofangiotensinII,regardlessofthesourceorrouteof

itssynthesis.

Losartandoesnothaveanagonisteffectnordoesitblockotherhormonereceptorsorionchannelsimportantin

cardiovascularregulation.Furthermore,losartandoesnotinhibitACE(kininaseII),theenzymethatdegrades

bradykinin.Consequently,thereisthusnoincreaseinbradykinin-mediatedundesirableeffects.

DuringtheadministrationoflosartantheremovaloftheangiotensinIInegativefeedbackonreninsecretionleadsto

increasedplasma-reninactivity(PRA).IncreaseinthePRAleadstoanincreaseinangiotensinIIinplasma.Despite

theseincreases,antihypertensiveactivityandsuppressionoftheplasmaaldosteroneconcentrationaremaintained,

indicatingeffectiveangiotensinIIreceptorblockade.Afterthediscontinuationoflosartan,PRAandangiotensinII

valuesfellwithin3daystothebaselinevalues.

BothlosartananditsprincipalactivemetabolitehaveafargreateraffinityfortheAT

receptorthanfortheAT

receptor.Theactivemetaboliteis10-to40-timesmoreactivethanlosartanonaweightforweightbasis.

Inastudyspecificallydesignedtoassesstheincidenceofcoughinpatientstreatedwithlosartanascomparedto

patientstreatedwithACEinhibitors,theincidenceofcoughreportedbypatientsreceivinglosartanor

hydrochlorothiazidewassimilarandwassignificantlylessthaninpatientstreatedwithanACEinhibitor.Inaddition,

inanoverallanalysisof16double-blindclinicaltrialsin4131patients,theincidenceofspontaneouslyreportedcough

inpatientstreatedwithlosartanwassimilar(3.1%)tothatofpatientstreatedwithplacebo(2.6%)or

hydrochlorothiazide(4.1%),whereastheincidencewithACEinhibitorswas8.8%.

Innondiabetichypertensivepatientswithproteinuria,theadministrationoflosartanpotassiumsignificantlyreduces

proteinuria,fractionalexcretionofalbuminandIgG.Losartanmaintainsglomerularfiltrationrateandreducesfiltration

fraction.Generallylosartancausesadecreaseinserumuricacid(usually<0.4mg/dL)whichwaspersistentinchronic

therapy.

Losartanhasnoeffectonautonomicreflexesandnosustainedeffectonplasmanorepinephrine.

Inpatientswithleftventricularfailure,25mgand50mgdosesoflosartanproducedpositivehemodynamicand

neurohormonaleffectscharacterizedbyanincreaseincardiacindexanddecreasesinpulmonarycapillarywedge

pressure,systemicvascularresistance,meansystemicarterialpressureandheartrateandareductionincirculating

levelsofaldosteroneandnorepinephrine,respectively.Theoccurrenceofhypotensionwasdoserelatedintheseheart

failurepatients.

HypertensionStudies

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hypertensionproducedstatisticallysignificantreductionsinsystolicanddiastolicbloodpressure.

Measurementofbloodpressure24hourspost-doserelativeto5–6hourspost-dosedemonstratedbloodpressure

reductionover24hours;thenaturaldiurnalrhythmwasretained.Bloodpressurereductionattheendofthedosing

intervalwas70–80%oftheeffectseen5-6hourspost-dose.

Discontinuationoflosartaninhypertensivepatientsdidnotresultinanabruptriseinbloodpressure(rebound).Despite

themarkeddecreaseinbloodpressure,losartanhadnoclinicallysignificanteffectonheartrate.

Losartanisequallyeffectiveinmalesandfemales,andinyounger(belowtheageof65years)andolderhypertensive

patients.

LIFEStudy

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

controlledstudyin9193hypertensivepatientsaged55to80yearswithECG-documentedleftventricularhypertrophy.

Patientswererandomisedtooncedailylosartan50mgoroncedailyatenolol50mg.Ifgoalbloodpressure

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

oratenololwasthenincreasedto100mgoncedaily.Otherantihypertensives,withtheexceptionofACEinhibitors,

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.

Hydrochlorothiazide

Hydrochlorothiazideisathiazidediuretic.Themechanismoftheantihypertensiveeffectofthiazidediureticsisnot

fullyknown.Thiazidesaffecttherenaltubularmechanismsofelectrolytereabsorption,directlyincreasingexcretionof

sodiumandchlorideinapproximatelyequivalentamounts.Thediureticactionofhydrochlorothiazidereducesplasma

volume,increasesplasmareninactivityandincreasesaldosteronesecretion,withconsequentincreasesinurinary

potassiumandbicarbonateloss,anddecreasesinserumpotassium.Therenin-aldosteronelinkismediatedby

angiotensinIIandthereforecoadministrationofanangiotensinIIreceptorantagonisttendstoreversethepotassium

lossassociatedwiththiazidediuretics.

Afteroraluse,diuresisbeginswithin2hours,peaksinabout4hoursandlastsabout6to12hourstheantihypertensive

effectpersistsforupto24hours.

5.2Pharmacokineticproperties

Absorption

Losartan

Followingoraladministration,losartaniswellabsorbedandundergoesfirst-passmetabolism,forminganactive

carboxylicacidmetaboliteandotherinactivemetabolites.Thesystemicbioavailabilityoflosartantabletsis

approximately33%.Meanpeakconcentrationsoflosartananditsactivemetabolitearereachedin1hourandin3-4

hours,respectively.Therewasnoclinicallysignificanteffectontheplasmaconcentrationprofileoflosartanwhenthe

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Distribution

Losartan

Bothlosartananditsactivemetaboliteare99%boundtoplasmaproteins,primarilyalbumin.Thevolumeof

distributionoflosartanis34liters.Studiesinratsindicatethatlosartancrossestheblood-brainbarrierpoorly,ifatall.

Hydrochlorothiazide

Hydrochlorothiazidecrossestheplacentalbutnottheblood-brainbarrierandisexcretedinbreastmilk.

Biotransformation

Losartan

About14%ofanintravenously-ororally-administereddoseoflosartanisconvertedtoitsactivemetabolite.Following

oralandintravenousadministrationof14C-labelledlosartanpotassium,circulatingplasmaradioactivityprimarilyis

attributedtolosartananditsactivemetabolite.Minimalconversionoflosartantoitsactivemetabolitewasseenin

aboutonepercentofindividualsstudied.

Inadditiontotheactivemetabolite,inactivemetabolitesareformed,includingtwomajormetabolitesformedby

hydroxylationofthebutylsidechainandaminormetabolite,anN-2tetrazoleglucuronide.

Elimination

Losartan

Plasmaclearanceoflosartananditsactivemetaboliteisabout600ml/minand50ml/min,respectively.Renalclearance

oflosartananditsactivemetaboliteisabout74ml/minand26ml/min,respectively.Whenlosartanisadministered

orally,about4%ofthedoseisexcretedunchangedintheurine,andabout6%ofthedoseisexcretedintheurineas

activemetabolite.

Thepharmacokineticsoflosartananditsactivemetabolitearelinearwithorallosartanpotassiumdosesupto200mg.

Followingoraladministration,plasmaconcentrationsoflosartananditsactivemetabolitedeclinepolyexponentially

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

losartannoritsactivemetaboliteaccumulatessignificantlyinplasma.

Bothbiliaryandurinaryexcretioncontributetotheeliminationoflosartananditsmetabolites.Followinganoraldose

of14C-labeledlosartaninman,about35%ofradioactivityisrecoveredintheurineand58%inthefeces.

Hydrochlorothiazide

Hydrochlorothiazideisnotmetabolizedbutiseliminatedrapidlybythekidney.Whenplasmalevelshavebeen

followedforatleast24hours,theplasmahalf-lifehasbeenobservedtovarybetween5.6and14.8hours.Atleast61

percentoftheoraldoseiseliminatedunchangedwithin24hours.

CharacteristicsinPatients

Losartan-Hydrochlorothiazide

Theplasmaconcentrationsoflosartananditsactivemetaboliteandtheabsorptionofhydrochlorothiazideinelderly

hypertensivesarenotsignificantlydifferentfromthoseinyounghypertensives.

Losartan

Followingoraladministrationinpatientswithmildtomoderatealcoholiccirrhosisoftheliver,plasmaconcentrations

oflosartananditsactivemetabolitewere,respectively,5-foldand1.7-foldgreaterthanthoseseeninyoungmale

volunteers.

PharmacokineticstudiesshowedthattheAUCoflosartaninJapaneseandnon-Japanesehealthymalesubjectsisnot

different.However,theAUCofthecarboxylicacidmetabolite(E-3174)appearstobedifferentbetweenthetwo

groups,withanapproximately1.5foldhigherexposureinJapanesesubjectsthaninnon-Japanesesubjects.Theclinical

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Neitherlosartannortheactivemetabolitecanberemovedbyhemodialysis.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofgeneralpharmacology,

genotoxicityandcarcinogenicpotential.Thetoxicpotentialofthecombinationoflosartan/hydrochlorothiazidewas

evaluatedinchronictoxicitystudiesforuptosixmonthsdurationinratsanddogsafteroraladministration,andthe

changesobservedinthesestudieswiththecombinationweremainlyproducedbythelosartancomponent.

Theadministrationofthelosartan/hydrochlorothiazidecombinationinducedadecreaseintheredbloodcellparameters

(erythrocytes,haemoglobin,haematocrit),ariseinurea-Nintheserum,adecreaseinheartweight(withouta

histologicalcorrelate)andgastrointestinalchanges(mucousmembranelesions,ulcers,erosions,haemorrhages).

Therewasnoevidenceofteratogenicityinratsorrabbitstreatedwiththelosartan/hydrochlorothiazidecombination.

Foetaltoxicityinrats,asevidencedbyaslightincreaseinsupernumeraryribsintheF

generation,wasobservedwhen

femalesweretreatedpriortoandthroughoutgestation.Asobservedinstudieswithlosartanalone,adversefoetaland

neonatalreactions,includingrenaltoxicityandfoetaldeath,occurredwhenpregnantratsweretreatedwiththe

losartan/hydrochlorothiazidecombinationduringlategestationand/orlactation

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Lactosemonohydrate

Pregelatinizedmaizestarch

Magnesiumstearate

Hydroxypropylcellulose

Hypromellose

Titaniumdioxide(E171)

Quinolineyellowaluminumlake(E104)

Carnaubawax(E903)

Contains8.48mg(0.216mEq)ofpotassium.

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackagingoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.Storeintheoriginalpackageinordertoprotectfromlightandmoisture.Donotopenthe

blisterpackuntilyouarereadytotakethemedicine.

6.5Natureandcontentsofcontainer

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6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ClearPharmacy

157-173RodenStreet

BelfastBT125QA

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1596/038/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:21stJanuary2011

10DATEOFREVISIONOFTHETEXT

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