COZAAR COMP 50MG/12.5MG FILM-COATED TABLETS

Main information

  • Trade name:
  • COZAAR COMP 50MG/12.5MG FILM-COATED TABLETS
  • Dosage:
  • 50/12.5 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COZAAR COMP 50MG/12.5MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/109/001A
  • Authorization date:
  • 09-01-2004
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CozaarComp50mg/12.5mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains50mglosartanpotassiumand12.5mghydrochlorothiazide(HCTZ)astheactiveingredients.

Excipients:containsLactoseMonohydrate

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablets

ProductimportedfromItaly:

Yellowoval-shaped,film-coatedtabletmarked‘717’ononesideandasinglescorelineontheother.

ProductimportedfromtheUnitedKingdom:

Yellowoval-shaped,film-coatedtabletmarked‘717’ononesideandplainorscoredontheotherside.

Thescorelineisonlytofacilitatebreakingforeaseofswallowingandnottodivideintoequaldoses.

4CLINICALPARTICULARS

4.1TherapeuticIndications

CozaarCompisindicatedforthetreatmentofessentialhypertensioninpatientswhosebloodpressureisnotadequately

controlledonlosartanorhydrochlorothiazidealone.

4.2Posologyandmethodofadministration

CozaarCompmaybeadministeredwithotherantihypertensiveagents.

CozaarComptabletsshouldbeswallowedwithaglassofwater

CozaarCompmaybeadministeredwithorwithoutfood.

Hypertension

Losartanandhydrochlorothiazideisnotforuseasinitialtherapy,butinpatientswhosebloodpressureisnotadequately

controlledbylosartanpotassiumorhydrochlorothiazidealone.

Dosetitrationwiththeindividualcomponents(losartanandhydrochlorothiazide)isrecommended.

Whenclinicallyappropriatedirectchangefrommonotherapytothefixedcombinationmaybeconsideredinpatients

whosebloodpressureisnotadequatelycontrolled.

TheusualmaintenancedoseofCozaarCompisonetabletofCozaarComp50mg/12.5mg(losartan50mg/HCTZ12.5

mg)oncedaily.ForpatientswhodonotrespondadequatelytoCozaarComp50mg/12.5mg,thedosagemaybe

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doseisonetabletofCozaarComp100mg/25mgoncedaily.Ingeneral,theantihypertensiveeffectisattainedwithin

threetofourweeksafterinitiationoftherapy.CozaarComp100/12.5(losartan100mg/HCTZ12.5mg)isavailablefor

thosepatientstitratedto100mgofCozaarCompwhorequireadditionalbloodpressurecontrol.

Useinpatientswithrenalimpairmentandhaemodialysispatients

Noinitialdosageadjustmentisnecessaryinpatientswithmoderaterenalimpairment(i.e.creatinineclearance30-50

ml/min).Losartanandhydrochlorothiazidetabletsarenotrecommendedforhaemodialysispatients.Losartan/HCTZ

tabletsmustnotbeusedinpatientswithsevererenalimpairment(i.e.creatinineclearance<30ml/min)(seesection

4.3).

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

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Liverfunctionimpairment

Basedonpharmacokineticdatawhichdemonstratesignificantlyincreasedplasmaconcentrationsoflosartanincirrhotic

patients,<CozaarComp>shouldbeusedwithcautioninpatientswithahistoryofmildtomoderatehepatic

impairment.Thereisnotherapeuticexperiencewithlosartaninpatientswithseverehepaticimpairment.Therefore

<CozaarComp>iscontraindicatedinpatientswithseverehepaticimpairment(seesections4.2,4.3and5.2).

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,theuseof<CozaarComp>tabletsisnotrecommended.

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.

Markedhypercalcemiamaybeevidenceofhiddenhyperparathyroidism.Thiazidesshouldbediscontinuedbefore

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Increasesincholesterolandtriglyceridelevelsmaybeassociatedwiththiazidediuretictherapy.

Thiazidetherapymayprecipitatehyperuricemiaand/orgoutincertainpatients.Becauselosartandecreasesuricacid,

losartanincombinationwithhydrochlorothiazideattenuatesthediuretic-inducedhyperuricemia.

Hepaticimpairment

Thiazidesshouldbeusedwithcautioninpatientswithimpairedhepaticfunctionorprogressiveliverdisease,asitmay

causeintrahepaticcholestasis,andsinceminoralterationsoffluidandelectrolytebalancemayprecipitatehepatic

coma.

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:

Potentiationoforthostatichypotensionmayoccur.

Antidiabeticdrugs(oralagentsandinsulin):

Thetreatmentwithathiazidemayinfluencetheglucosetolerance.Dosageadjustmentoftheantidiabeticdrugmaybe

required.Metforminshouldbeusedwithcautionbecauseoftheriskoflacticacidosisinducedbypossiblefunctional

renalfailurelinkedtohydrochlorothiazide.

Otherantihypertensivedrugs

Additiveeffect.

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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

withmedicinalproductsaffectedbyserumpotassiumdisturbances(e.g.digitalisglycosidesandantiarrhythmics)and

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

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LaboratoryTestInteractions

Becauseoftheireffectsoncalciummetabolism,thiazidesmayinterferewithtestsforparathyroidfunction(seesection

4.4).

Carbamazepine

Riskofsymptomatichyponatremia.Clinicalandbiologicalmonitoringisrequired.

IodineContrastMedia

Incaseofdiuretic-induceddehydration,thereisanincreasedriskofacuterenalfailure,especiallywithhighdosesof

theiodineproduct.Patientsshouldberehydratedbeforetheadministration.

AmphotericinB(parenteral),corticosteroids,ACTHorstimulantlaxatives

Hydrochlorothiazidemayintensifyelectrolyteimbalance,particularlyhypokalaemia.

4.6Fertility,pregnancyandlactation

Pregnancy

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EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithAngiotensinIIReceptorInhibitors(AIIRAs),similarrisksmayexist

forthisclassofdrugs.UnlesscontinuedAIIRAtherapyisconsideredessential,patientsplanningpregnancyshouldbe

changedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.

Whenpregnancyisdiagnosed,treatmentwithAIIRAsshouldbestoppedimmediatelyand,ifappropriate,alternative

therapyshouldbestarted.

ExposuretoAIIRAtherapyduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

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

hyperkalaemia)(seesection5.3).

ShouldexposuretoAIIRAshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

InfantswhosemothershavetakenAIIRAsshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Thereislimitedexperiencewithhydrochlorothiazideduringpregnancy,especiallyduringthefirsttrimester.Animal

studiesareinsufficient.

Hydrochlorothiazidecrossestheplacenta.Basedonthepharmacologicalmechanismofactionofhydrochlorothiazide,

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:

Inclinicaltrialswithlosartanpotassiumsaltandhydrochlorothiazide,noadversereactionspeculiartothiscombination

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

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losartanpotassiumsaltand/orhydrochlorothiazide.

Incontrolledclinicaltrialsforessentialhypertension,dizzinesswastheonlyadversereactionreportedassubstance-

relatedthatoccurredwithanincidencegreaterthanplaceboin1%ormoreofpatientstreatedwithlosartanand

hydrochlorothiazide.

Nexttotheseeffects,therearefurtheradversereactionsreportedaftertheintroductionoftheproducttothemarketas

follows:

Hepato-biliarydisorders

rare: Hepatitis

Investigations

rare: Hyperkalaemia,elevationofALT

Additionaladversereactionsthathavebeenseenwithoneoftheindividualcomponentsandmaybepotentialadverse

reactionswithlosartanpotassium/hydrochlorothiazidearethefollowing:

Losartan

Bloodandlymphaticsystemdisorders

uncommon:Anaemia,Henoch-Schönleinpurpura,ecchymosis,haemolysis

Immunesystemdisorders

rare: Anaphylacticreactions,angioedema,urticaria

Metabolismandnutritiondisorders

uncommon:Anorexia,gout

Psychiatricdisorders

common: Insomnia

uncommon:Anxiety,anxietydisorder,panicdisorder,confusion,depression,abnormaldreams,sleepdisorder,

somnolence,memoryimpairment

Nervoussystemdisorders

common: Headache,dizziness

uncommon:Nervousness,paraesthesia,peripheralneuropathy,tremor,migraine,syncope

Eyedisorders

uncommon:Blurredvision,burning/stingingintheeye,conjunctivitis,decreaseinvisualacuity

Earandlabyrinthdisorders

uncommon:Vertigo,tinnitus

Cardiacdisorders

uncommon:Hypotension,orthostatichypotension,sternalgia,anginapectoris,gradeII-AVblock,cerebrovascular

event,myocardialinfarction,palpitation,arrhythmias(atrialfibrillations,sinusbradycardia,tachycardia,

ventriculartachycardia,ventricularfibrillation)

Vasculardisorders

uncommon:Vasculitis

Respiratory,thoracicandmediastinaldisorders

common: Cough,upperrespiratoryinfection,nasalcongestion,sinusitis,sinusdisorder

uncommon:Pharyngealdiscomfort,pharyngitis,laryngitis,dyspnoea,bronchitis,epistaxis,rhinitis,respiratory

congestion

Gastrointestinaldisorders

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uncommon:Constipation,dentalpain,drymouth,flatulence,gastritis,vomiting

Hepato-biliarydisorders

notknown:Liverfunctionabnormalities

Skinandsubcutaneoustissuedisorders

uncommon:Alopecia,dermatitis,dryskin,erythema,flushing,photosensitivity,pruritus,rash,urticaria,sweating

Musculoskeletalandconnectivetissuedisorders

common: Musclecramp,backpain,legpain,myalgia

uncommon:Armpain,jointswelling,kneepain,musculoskeletalpain,shoulderpain,stiffness,arthralgia,arthritis,

coxalgia,fibromyalgia,muscleweakness

Renalandurinarydisorders

uncommon:Nocturia,urinaryfrequency,urinarytractinfection

Reproductivesystemandbreastdisorders

uncommon:Decreasedlibido,impotence

Generaldisordersandadministrationsiteconditions

common: Asthenia,fatigue,chestpain

uncommon:Facialoedema,fever

Investigations

common: Hyperkalaemia,mildreductionofhaematocritandhaemoglobin

uncommon:Mildincreaseinureaandcreatinineserumlevels

veryrare: Increaseinhepaticenzymesandbilirubin.

Hydrochlorothiazide

Bloodandlymphaticsystemdisorders

uncommon:Agranulocytosis,aplasticanaemia,haemolyticanaemia,leukopenia,purpura,thrombocytopenia

Immunesystemdisorders

rare: Anaphylacticreaction

Metabolismandnutritiondisorders

uncommon:Anorexia,hyperglycaemia,hyperuricaemia,hypokalaemia,hyponatraemia

Psychiatricdisorders

uncommon:Insomnia

Nervoussystemdisorders

common: Cephalalgia

Eyedisorders

uncommon:Transientblurredvision,xanthopsia

Vasculardisorders

uncommon:Necrotizingangiitis(vasculitis,cutaneousvasculitis)

Respiratory,thoracicandmediastinaldisorders

uncommon:Respiratorydistressincludingpneumonitisandpulmonaryoedema

Gastrointestinaldisorders

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4.9Overdose

Nospecificinformationisavailableonthetreatmentofoverdosagewith'Cozaar'-Comp.Treatmentissymptomaticand

supportive.Therapywith'Cozaar'-Compshouldbediscontinuedandthepatientobservedclosely.Suggestedmeasures

includeinductionofemesisifingestionisrecent,andcorrectionofdehydration,electrolyteimbalance,hepaticcoma,

andhypotensionbyestablishedprocedures.

Losartan

Limiteddataareavailableinregardtooverdosageinhumans.Themostlikelymanifestationofoverdosagewouldbe

hypotensionandtachycardia;bradycardiacouldoccurfromparasympathetic(vagal)stimulation.Ifsymptomatic

hypotensionshouldoccur,supportivetreatmentshouldbeinstituted.

Neitherlosartannortheactivemetabolitecanberemovedbyhaemodialysis.

Hydrochlorothiazide

Themostcommonsignsandsymptomsobservedarethosecausedbyelectrolytedepletion(hypokalaemia,

hypochloraemia,hyponatraemia)anddehydrationresultingfromexcessivediuresis.Ifdigitalishasalsobeen

administered,hypokalaemiamayaccentuatecardiacarrhythmias.

Thedegreetowhichhydrochlorothiazideisremovedbyhaemodialysishasnotbeenestablished.

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.

Hepato-biliarydisorders

uncommon:Icterus(intrahepaticcholestatis),pancreatitis

Skinandsubcutaneoustissuedisorders

uncommon:Photosensitivity,urticaria,toxicepidermalnecrolysis

Musculoskeletalandconnectivetissuedisorders

uncommon:Musclecramps

Renalandurinarydisorders

uncommon:Glycosuria,interstitialnephritis,renaldysfunction,renalfailure

Generaldisordersandadministrationsiteconditions

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duration,theantihypertensiveeffectwasmaintainedwithcontinuedtherapy.Despitethesignificantdecreaseinblood

pressure,administrationofCozaarComphadnoclinicallysignificanteffectonheartrate.Inclinicaltrials,after12

weeksoftherapywithlosartan50mg/hydrochlorothiazide12.5mg,troughsittingdiastolicbloodpressurewasreduced

byanaverageofupto13.2mmHg.

CozaarCompiseffectiveinreducingbloodpressureinmalesandfemales,blacksandnon-blacksandinyounger(<65

years)andolder(>65years)patientsandiseffectiveinalldegreesofhypertension.

Losartan

Losartanisasyntheticallyproducedoralangiotensin-IIreceptor(typeAT1)antagonist.AngiotensinII,apotent

vasoconstrictor,istheprimaryactivehormonoftherenin-angiotensinsystemandanimportantdeterminantofthe

pathophysiologyofhypertension.AngiotensinIIbindstotheAT1receptorfoundinmanytissues(e.g.vascularsmooth

muscle,adrenalgland,kidneysandtheheart)andelicitsseveralimportantbiologicalactions,including

vasoconstrictionandthereleaseofaldosterone.AngiotensinIIalsostimulatessmooth-musclecellproliferation.

LosartanselectivelyblockstheAT1receptor.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.

BothlosartananditsprincipalactivemetabolitehaveafargreateraffinityfortheAT1receptorthanfortheAT2

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

Incontrolledclinicalstudies,once-dailyadministrationoflosartantopatientswithmildtomoderateessential

hypertensionproducedstatisticallysignificantreductionsinsystolicanddiastolicbloodpressure.Measurementof

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hours;thenaturaldiurnalrhythmwasretained.Bloodpressurereductionattheendofthedosingintervalwas70–80

%oftheeffectseen5-6hourspost-dose.

Discontinuationoflosartaninhypertensivepatientsdidnotresultinanabruptriseinbloodpressure(rebound).Despite

themarkeddecreaseinbloodpressure,losartanhadnoclinicallysignificanteffectonheartrate.

Losartanisequallyeffectiveinmalesandfemales,andinyounger(belowtheageof65years)andolderhypertensive

patients.

LIFEStudy

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

controlledstudyin9193hypertensivepatientsaged55to80yearswithECG-documentedleftventricularhypertrophy.

Patientswererandomisedtooncedailylosartan50mgoroncedailyatenolol50mg.Ifgoalbloodpressure(<140/90

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

wasthenincreasedto100mgoncedaily.Otherantihypertensives,withtheexceptionofACEinhibitors,angiotensinII

antagonistsorbeta-blockerswereaddedifnecessarytoreachthegoalbloodpressure.

Themeanlengthoffollowupwas4.8years.

Theprimaryendpointwasthecompositeofcardiovascularmorbidityandmortalityasmeasuredbyareductioninthe

combinedincidenceofcardiovasculardeath,strokeandmyocardialinfarction.Bloodpressurewassignificantly

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

confidenceinterval0.77-0.98)comparedwithatenololforpatientsreachingtheprimarycompositeendpoint.Thiswas

mainlyattributabletoareductionoftheincidenceofstroke.Treatmentwithlosartanreducedtheriskofstrokeby25%

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

infarctionwerenotsignificantlydifferentbetweenthetreatmentgroups.

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.Therewasnoclinicallysignificanteffectontheplasma-concentrationprofileoflosartanwhenthe

drugwasadministeredwithastandardisedmeal.

Distribution

Losartan:

Bothlosartananditsactivemetaboliteare99%boundtoplasmaproteins,primarilyalbumin.Thevolumeof

distributionoflosartanis34litres.Studiesinratsindicatethatlosartancrossestheblood-brainbarrierpoorly,ifatall.

Hydrochlorothiazide:

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Biotransformation

Losartan:

About14%ofanintravenouslyororallyadministereddoseoflosartanisconvertedtoitsactivemetabolite.Following

oralandintravenousadministrationof14C-labelledlosartanpotassium,circulatingplasmaradioactivityprimarilyis

attributedtolosartananditsactivemetabolite.Minimalconversionoflosartantoitsactivemetabolitewasseenin

about1%ofindividualsstudied.

Inadditiontotheactivemetabolite,inactivemetabolitesareformed,includingtwomajormetabolitesformedby

hydroxylationofthebutylsidechainandaminormetabolite,anN-2tetrazoleglucuronide.

Elimination

Losartan:

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

of14C-labelledlosartaninman,about35%ofradioactivityisrecoveredintheurineand58%inthefaeces.

Hydrochlorothiazide:

Hydrochlorothiazideisnotmetabolisedbutiseliminatedrapidlybythekidney.Whenplasmalevelshavebeen

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

oftheoraldoseiseliminatedunchangedwithin24hours.

CharacteristicsinPatients

Losartan-hydrochlorothiazide

Theplasmaconcentrationsoflosartananditsactivemetaboliteandtheabsorptionofhydrochlorothiazideinelderly

hypertensivesarenotsignificantlydifferentfromthoseinyounghypertensives.

Losartan:

Followingoraladministrationinpatientswithmildtomoderatealcoholiccirrhosisoftheliver,plasmaconcentrations

oflosartananditsactivemetabolitewere,respectively,fivefoldand1.7-foldgreaterthanthoseseeninyoungmale

volunteers.

Neitherlosartannortheactivemetabolitecanberemovedbyhaemodialysis.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofgeneralpharmacology,

genotoxicityandcarcinogenicpotential.Thetoxicpotentialofthecombinationoflosartan/hydrochlorothiazidewas

evaluatedinchronictoxicitystudiesforuptosixmonthsdurationinratsanddogsafteroraladministration,andthe

changesobservedinthesestudieswiththecombinationweremainlyproducedbythelosartancomponent.The

administrationofthelosartan/hydrochlorothiazidecombinationinducedadecreaseintheredbloodcellparameters

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

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

Therewasnoevidenceofteratogenicityinratsorrabbitstreatedwiththelosartan/hydrochlorothiazidecombination.

Foetaltoxicityinrats,asevidencedbyaslightincreaseinsupernumeraryribsintheF1generation,wasobservedwhen

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neonatalreactions,includingrenaltoxicityandfoetaldeath,occurredwhenpregnantratsweretreatedwiththe

losartan/hydrochlorothiazidecombinationduringlategestationand/orlactation.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Hydroxypropylcellulose(E463)

Hypromellose(E464)

Lactosemonohydrate

Magnesiumstearate(E572)

Microcrystallinecellulose(E460)

Pregelatinisedmaizestarch

Titaniumdioxide(E171)

QuinolineYellowaluminiumlake(E104)

Carnaubawax(E903)

Contains4.24mg(0.108mmol)ofpotassium

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateforthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Storeintheoriginalpackageinordertoprotectfromlightandmoisture.

6.5Natureandcontentsofcontainer

Blisterpacksof14tabletsinanover-labelledoutercarton.

Packsize:28tablets

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,

AshbourneBusinessPark

Rath,Ashbourne

Co.Meath

Ireland

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PPA465/109/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:9 th

January2004

Dateoflastrenewal: 9 th

January2009

10DATEOFREVISIONOFTHETEXT

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