COEPRATENZ PLUS

Main information

  • Trade name:
  • COEPRATENZ PLUS
  • Dosage:
  • 600/12.5 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COEPRATENZ PLUS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0108/029/001
  • Authorization date:
  • 10-03-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CoepratenzPlus600mg/12.5mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontainseprosartanmesylateequivalentto600mgeprosartanand12.5mg

hydrochlorothiazide.

Forfulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Butterscotch-coloured,capsule-shapedfilm-coatedtablets

Theinscriptionofthetabletis'5147'ononesideand'SOLVAY'ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Essentialhypertension.CoepratenzPlus600mg/12.5mgisindicatedinpatientswhosebloodpressureisnot

adequatelycontrolledoneprosartanalone.

4.2Posologyandmethodofadministration

TherecommendeddoseisonetabletCoepratenzPlus600mg/12.5mgoncedaily,whichshouldbetakeninthe

morning.Theswitchfromeprosartanmonotherapytothefixedcombinationcanbeconsideredafter8weeksofblood

pressurestabilization.CoepratenzPlus600mg/12.5mgcanbetakenwithorwithoutfood.

Elderly

Nodoseadjustmentisrequiredintheelderly,althoughlimitedinformationisavailableinthispopulation.

Children

Assafetyandefficacyofadministrationtochildrenhavenotbeenestablished,treatmentofchildrenandadolescents<

18yearswithCoepratenzPlus600mg/12.5mgisnotrecommended.

HepaticImpairment

TheuseofCoepratenzPlusinpatientswithmildtomoderatehepaticimpairmentisnotrecommendedsincethereis

currentlyonlylimitedexperienceofeprosartanmesylateinthispatientgroup.Inpatientswithseverehepatic

impairmentCoepratenzPlusiscontraindicated(seesections4.3and4.4).

RenalImpairment

Inpatientswithmildtomoderaterenalimpairment(creatinineclearance 30ml/min)doseadjustmentisnot

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2104774 page number: 1

4.3Contraindications

Historyofhypersensitivitytoeprosartan,sulphonamide-derivedsubstances(ashydrochlorothiazide)ortoanyofthe

excipients.

Secondandthirdtrimestersofpregnancy(seesection4.6).

Severehepaticimpairment.

Severerenalimpairment(creatinineclearance<30ml/min)

Therapyresistanthypokalaemiaorhypercalcaemia

Cholestasisandbiliaryobstructivedisorders

Refractoryhyponatraemia

Symptomatichyperuricaemia/gout

4.4Specialwarningsandprecautionsforuse

Eprosartan

Renovascularhypertension

InpatientswithavasculartoneandrenalfunctionwhichispredominantlydependentontheactivityoftheRenin-

Angiotensin-Aldosteronesystem,e.g.inpatientswithbilateralorunilateralrenalarterystenosiswithsinglefunctioning

kidney,renalfunctionshouldbemonitoredclosely,becausethereisanincreasedriskforseverehypotensionandrenal

insufficiencyinthesepatients.

Hyperkalaemia

DuringtreatmentwithothermedicinalproductswhichaffecttheRenin-Angiotensin-Aldosteronesystem

hyperkalaemiamayoccur,especiallyinthepresenceofrenalimpairmentand/orheartfailure.Cautiousadministration

andadequatemonitoringofserumpotassiumandacid-base-balanceinpatientsatriskfordevelopmentof

hyperkalaemia:patientswithrenalimpairment,diabetesmellitus,concomitantadministrationofpotassium-sparing

diuretics,potassiumsupplementsorpotassium-containingsaltsubstitutes,orothermedicinalproductswhichmaylead

toanincreaseofserumpotassium(seesection4.5)isrecommended.

Aorticandmitralvalvestenosis,obstructivehypertrophiccardiomyopathy

Aswithothervasodilatorspatientswithaorticormitralvalvestenosisorobstructivehypertrophiccardiomyopathy

shouldbetreatedwithcaution.

PrimaryHyperaldosteronism

Patientswithprimaryhyperaldosteronismdonotreactsufficientlyonantihypertensiveswhichactthroughinhibitionof

theRenin-Angiotensin-Aldosteronesystem.Therefore,treatmentwithCoepratenzPlus600mg/12.5mgisnot

recommended.

Pregnancy

AngiotensinIIreceptorblockersshouldnotbeinitiatedduringpregnancy.UnlesscontinuedAIIRAtherapyis

consideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhich

haveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithAngiotensinII

receptorblockersshouldbestoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted(seesections

4.3and4.6).

Generalinformation

InpatientswhosevasculartoneandrenalfunctionaremainlydependentontheactivityoftheRenin-Angiotensin-

Aldosteronesystem(e.g.patientswithseverecardiacinsufficiencyorexistingrenaldiseaseincludingrenalartery

stenosis)treatmentwithanACE-inhibitororAngiotensin-IIreceptorantagonistwillinfluencethissystemwithacute

hypotension,uraemia,oliguriaandrarelyacuterenalfailure.

AsobservedforallACE-inhibitorsandAngiotensin-IIreceptorantagonists,eprosartanisapparentlylesseffectivein

loweringbloodpressureinblackpeoplethaninnon-blacks.

Aswithallbloodpressureloweringagentsanexcessivedecreaseinbloodpressureinpatientswithischaemic

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2104774 page number: 2

Hydrochlorothiazide

Renalimpairmentandrenaltransplant

Inpatientswithlimitedrenalfunction,aregularmonitoringofserumpotassium,creatinineanduricacidis

recommended.Hydrochlorothiaziderelateduraemiamayoccurinpatientswithimpairedrenalfunction.

HepaticImpairment

Hydrochlorothiazideshouldonlybeusedwithcareinpatientswithmildtomoderatehepaticinsufficiencyasitmay

causeintrahepaticcholestasis.Alterationsoffluidandelectrolytebalancemayprecipitatehepaticcoma.

Metabolicandendocrinedisturbances

Hydrochlorothiazidemayimpairglucosetoleranceandthismayrequiredoseadjustmentofantidiabeticmedication.

LatentdiabetesmaybecomemanifestduringCoepratenzPlus600mg/12.5mgtreatment.

Atdosesof12.5mghydrochlorothiazideinCoepratenzPlus600mg/12.5mgonlymildmetabolicandendocrine

undesirableeffectswereobserved(increaseinserumcholesterolandtriglycerides).

Incertainpatientshydrochlorothiazidetreatmentmaycausehyperuricaemiaorgout.Hydrochlorothiaziderelated

uraemiamayoccurinpatientswithimpairedrenalfunction.

Electrolyteimbalance

Hydrochlorothiazidemaycausefluidorelectrolyteimbalance(hypokalaemia,hyponatraemia,hypercalcaemia,

hypomagnesaemiaandhypochloremicalkalosis).

Asforanypatientsreceivingdiuretictherapy,periodicdeterminationofserumelectrolytesshouldbeconsidered.

Thiazidediureticsmaydecreaserenalcalciumexcretionandtemporarilycauseanincreaseinserumcalcium,evenin

patientswithoutknowncalciummetabolismdisturbances.Pronouncedhypercalcaemiamaybethefirstmanifestation

ofalatenthyperparathyroidism.Thiazidediureticsshouldbestoppedbeforeparathyroidfunctiontesting.Thiazide

diureticsincreaseurinalmagnesiumexcretion.Thismayleadtohypomagnesaemia.

Hypersensitivityreactionstohydrochlorothiazidemayoccurinpatientswithorwithouthistoryofallergyorbronchial

asthma,butaremorelikelyinpatientswithsuchahistory.

Thiazidediureticshavebeenreportedtoexacerbateoractivatesystemiclupuserythematosus.

Hydrochlorothiazidemayleadtoapositiveresultindopingtests.

Eprosartan/Hydrochlorothiazidecombination

Renalimpairmentandrenaltransplant

CoepratenzPlus600mg/12.5mgshouldnotbegiventopatientswithsevererenalimpairment(creatinineclearance<

30ml/min)(seealsosection4.3).

ThereisnoexperiencewithCoepratenzPlus600mg/12.5mginpatientswithrenaltransplants.

Lithium

AswithothermedicinalproductscontainingangiotensinIIantagonistsandthiazideincombination,the

coadministrationofCoepratenzPlusandlithiumisnotrecommended(seesection4.5).

Hepaticimpairment

CoepratenzPlusiscontraindicatedinseverehepaticimpairment(seesection4.3)

Hypotension

Symptomatichypotensionmayoccurinpatientswithsodiumorvolumedepletion,e.g.asaresultofhighdosesof

diuretics,dietarysaltrestriction,diarrhoeaorvomiting.Sodiumand/orvolumedepletionshouldbecorrectedbefore

treatmentwithCoepratenzPlus600mg/12.5mg.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2104774 page number: 3

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Potentialinteractionsrelatedtobotheprosartanandhydrochlorothiazide:

Concomitantusenotrecommended

Lithium:

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithangiotensinconvertingenzymeinhibitorsand,rarely,withangiotensinIIantagonists.In

addition,renalclearanceoflithiumisreducedbythiazidesandconsequentlytheriskoflithiumtoxicitymaybe

increased.

ThereforeuseofCoepratenzPlusandlithiumincombinationisnotrecommended(seesection4.4).Ifuseofthe

combinationprovesnecessary,carefulmonitoringofserumlithiumlevelsisrecommended.

Concomitantuserequiringcaution

Baclofen:

Potentiationofantihypertensiveeffectmayoccur.

Non-steroidalanti-inflammatorymedicinalproducts:

NSAIDs(ieacetylsalicylicacid(>3g/day),COX-2inhibitorsandnon-selectiveNSAIDs)mayreducethe

antihypertensiveeffectofthiazidediureticsandangiotensinIIantagonists.

Insomepatientswithcompromisedrenalfunction(egdehydratedpatientsorelderlypatientswithcompromisedrenal

function)theco-administrationofangiotensinIIantagonistsandagentsthatinhibitcyclo-oxygenasemayresultin

furtherdeteriorationofrenalfunction,includingpossibleacuterenalfailure,whichisusuallyreversible.Therefore,the

combinationshouldbeadministeredwithcaution,especiallyintheelderly.Patientsshouldbeadequatelyhydratedand

considerationshouldbegiventomonitoringofrenalfunctionafterinitiationofconcomitanttherapyandperiodically

thereafter.

Concomitantusetobetakenintoaccount

Amifostine:

Potentiationofantihypertensiveeffectmayoccur.

Otherantihypertensiveagents:

ThebloodpressureloweringeffectofCoepratenzPluscanbeincreasedbyconcomitantuseofotherantihypertensivemedicinal

products.

Alcohol,barbiturates,narcoticsorantidepressants:

Potentiationoforthostatichypotensionmayoccur.

Potentialinteractionsrelatedtoeprosartan:

Concomitantusenotrecommended

Medicinalproductsaffectingpotassiumlevels:

Basedonexperiencewiththeuseofothermedicinalproductsthataffecttherenin-angiotensinsystem,concomitantuseof

potassium-sparingdiuretics,potassiumsupplements,saltsubstitutescontainingpotassiumorothermedicinalproductsthatmay

increaseserumpotassiumlevels(egheparin,ACEinhibitors)mayleadtoincreasesinserumpotassium.Ifmedicinalproduct

whichaffectpotassiumlevelsaretobeprescribedincombinationwithCoepratenzPlus,monitoringofpotassiumplasmalevelsis

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2104774 page number: 4

Potentialinteractionsrelatedtohydrochlorothiazide:

Concomitantusenotrecommended

Medicinalproductsaffectingpotassiumlevels:

Thepotassium-depletingeffectofhydrochlorothiazidemaybepotentiatedbythecoadministrationofothermedicinal

productsassociatedwithpotassiumlossandhypokalaemia(egotherkaliureticdiuretics,laxatives,corticosteroids,

ACTH,amphotericin,carbenoxolone,penicillinGsodiumorsalicylicacidderivatives).Suchconcomitantuseis

thereforenotrecommended(seesection4.4).

Concomitantuserequiringcaution

Calciumsalts:

Thiazidediureticsmayincreaseserumcalciumlevelsduetodecreasedexcretion.Ifcalciumsupplementsmustbe

prescribed,serumcalciumlevelsshouldbemonitoredandcalciumdosageadjustedaccordingly.

Cholestyramineandcolestipolresins:

Absorptionofhydrochlorothiazideisimpairedinthepresenceofanionicexchangeresins.

Digitalisglycosides:

Thiazide-inducedhypokalaemiaorhypomagnesaemiamayfavourtheonsetofdigitalis-inducedcardiacarrhythmias.

Medicinalproductsaffectedbyserumpotassiumdisturbances:

PeriodicmonitoringofserumpotassiumandECGisrecommendedwhenCoepratenzPlusisadministeredwith

medicinalproductsaffectedbyserumpotassiumdisturbances(egdigitalisglycosidesandantiarrhythmics)andwiththe

followingtorsadesdepointes(ventriculartachycardia)-inducingmedicinalproducts(includingsomeantiarrhythmics),

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,vincamine

IV).

Non-depolarizingskeletalmusclerelaxants(egtubocurarine):

Theeffectofnondepolarizingskeletalmusclerelaxantsmaybepotentiatedbyhydrochlorothiazide.

Anticholinergicagents(egatropine,biperiden):

Increaseofthebioavailabilityofthiazide-typediureticsbydecreasinggastrointestinalmotilityandstomachemptying

rate.

Antidiabeticmedicinalproducts(oralagentsandinsulin):

Thetreatmentwithathiazidemayinfluencetheglucosetolerance.Dosageadjustmentoftheantidiabeticmedicinal

productmayberequired(seesection4.4).

Metformin:

Metforminshouldbeusedwithcautionbecauseoftheriskoflacticacidosisinducedbypossiblefunctionalrenal

failurelinkedtohydrochlorothiazide.

Beta-blockersanddiazoxide:

Thehyperglycaemiceffectofbeta-blockersanddiazoxidemaybeenhancedbythiazides.

Pressoramines(egnoradrenaline):

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2104774 page number: 5

Medicinalproductsusedinthetreatmentofgout(probenecid,sulfinpyrazoneandallopurinol):

Dosageadjustmentofuricosuricmedicinalproductsmaybenecessarysincehydrochlorothiazidemayraisethelevelof

serumuricacid.Increaseindosageofprobenecidorsulfinpyrazonemaybenecessary.Coadministrationofathiazide

mayincreasetheincidenceofhypersensitivityreactionstoallopurinol.

Amantadine:

Thiazidesmayincreasetheriskofadverseeffectscausedbyamantadine.

Cytotoxicagents(egcyclophosphamide,methotrexate):

Thiazidesmayreducetherenalexcretionofcytotoxicmedicinalproductsandpotentiatetheirmyelosuppressiveeffects.

Tetracyclines:

Concomitantadministrationoftetracyclinesandthiazidesincreasestheriskoftetracycline-inducedincreaseinurea.

Thisinteractionisprobablynotapplicabletodoxycycline.

4.6Fertility,pregnancyandlactation

Pregnancy:

Duetotheeffectsonthepregnancyofeachoftheactivesubstancesofthismedicinalproduct,theuseofCoepratenz

Plus600mg/12.5mgisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuseof

CoepratenzPlus600mg/12.5mgiscontraindicatedduringthesecondandthirdtrimesterofpregnancy(seesections

4.3and4.4.).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithangiotensinIIreceptorblockers,similarrisksmayexistforthisclass

ofdrugs.UnlesscontinuedangiotensinIIreceptorblockertherapyisconsideredessential,patientsplanningpregnancy

shouldbechangedtoalternativeantihypertensivetreatmentswhichhaveanestablishedsafetyprofileforusein

pregnancy.Whenpregnancyisdiagnosed,treatmentwithangiotensinIIreceptorblockersshouldbestopped

immediatelyand,ifappropriate,alternativetherapyshouldbestarted.

ExposuretoangiotensinIIreceptorblockertherapyduringthesecondandthirdtrimestersisknowntoinducehuman

fetotoxicity(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renal

failure,hypotension,hyperkalaemia).(Seealso5.3‘Preclinicalsafetydata’).ShouldexposuretoangiotensinIIreceptor

blockershaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunctionandskullis

recommended.InfantswhosemothershavetakenangiotensinIIreceptorblockersshouldbecloselyobservedfor

hypotension(seesections4.3and4.4).

Theexperienceoftheuseofhydrochlorothiazideduringpregnancyislimited,inparticularduringthefirsttrimester.

Animalstudiesareinsufficient.Hydrochlorothiazidecrossestheplacentalbarrier.Consideringthemechanismofaction

ofhydrochlorothiazidetheuseofthisproductduringthesecondandthirdtrimestersmaycompromisethe

foetoplacentalperfusionandmaycauseneonatalandfoetaleffects,suchasjaundice,electrolytedisturbancesand

thrombocytopenia.Hydrochlorothiazideshouldnotbeusedforgestationaloedema,hypertensioninpregnancyorpre-

eclampsiaduetotheriskoftheplasmavolumereductionandplacentalhypoperfusionwithoutanybenefitsduringthe

courseofthedisease.Hydrochlorothiazideshouldnotbeusedforessentialhypertensioninpregnantwomen,unlessin

raresituationwherethereisnotherapeuticalternative.

Lactation:

BecausenoinformationisavailableregardingtheuseofCoepratenzPlus600mg/12.5mgduringbreast-feeding,

CoepratenzPlus600mg/12.5mgisnotrecommendedandalternativetreatmentswithbetterestablishedsafetyprofiles

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2104774 page number: 6

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheabilitytodriveandusemachineshavebeenperformed,butbasedonitspharmacodynamicproperties,

CoepratenzPlus600mg/12.5mgisunlikelytoaffectthisability.Whendrivingvehiclesoroperatingmachines,it

shouldbetakenintoaccount,thatoccasionallydizzinessorwearinessmayoccurduringtreatmentofhypertension.

4.8Undesirableeffects

Inplacebo-controlledclinicaltrialsin628patients,ofwhich268weretreatedwitheprosartanincombinationwith

hydrochlorothiazide,thefollowingundesirableeffectswerereportedwiththefollowingfrequencies:verycommon

(>1/10);common(>1/100,<1/10);uncommon(>1/1000,<1/100);rare(>1/10000,<1/1000);veryrare<1/10000),

includingisolatedreports.

Psychiatricdisorders:

Common:restlessness,insomnia,depression

Uncommon:anxiety,nervousness

Nervoussystemdisorders:

Common:dizziness,headache,neuralgia,paraesthesia,fatigue.

Cardiacdisorders:

Uncommon:arrhythmia

Vasculardisorders:

Veryrare:hypotension,includingorthostatichypotension

Respiratory,thoracicandmediastinaldisorders:

Common:bronchitis.

Uncommon:cough,epistaxis,pharyngitis,rhinitis,upperrespiratorytractinfection

Gastrointestinaldisorders:

Common:abdominalpain

Uncommon:gastroenteritis,nausea

Skinandsubcutaneoustissuedisorders:

Uncommon:rash

Veryrare:pruritis

Musculoskeletalandconnectivetissuedisorders:

Common:osteoarthritis,backpain

Uncommon:arthralgia,arthritis

Renalandurinarydisorders:

Common:albuminuria,urinarytractinfections

Generaldisordersandadministrativesiteconditions:

Uncommon:oedemaperipheral,pyrexia,drymouth,hyperhydrosis

Laboratoryfindings

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2104774 page number: 7

Eprosartan

Thefollowingfindingswereobservedduringeprosartanmonotherapy:Inplacebocontrolledclinicaltrialsadverse

eventswereobservedduringeprosartantreatmentwithafrequencycomparabletoplacebotreatment.Undesirable

effectswereusuallymildandtransientinnatureandledtowithdrawaloftreatmentduetoadversereactionsin4.1%of

thecasesduringeprosartantreatmentincomparisonto6.5%duringplacebotreatment.Duringeprosartantreatment

1.2%ofthepatientsreporteddyspneaincontrolledclinicaltrials(placebo0.6%).Inplacebocontrolledclinicaltrials

significantlyincreasedserumpotassiumlevelswereobservedin0.9%ofthepatientstreatedwitheprosartanandin

0.3%ofthepatientstreatedwithplacebo.Hypertriglyceridaemiawasobservedin1.2%oftheeprosartantreated

patients(placebo0%).Chestpainandpalpitationwerecommonlyreported.

Inrarecasesanincreaseofserumureawasreportedduringtreatmentwitheprosartan.Increasesinliverfunctionvalues

wererarelyobserved,butwerenotconsideredtoberelatedtoeprosartantreatment.Headache,dizziness,restlessness

andskineffects(rash,pruritis,urticaria)wererarelyreported.Hypotension,includingorthostatichypotension,swollen

faceand/orangioedemawereveryrarelyreported.

Hydrochlorothiazide

Thefollowingundesirableeffectswerereportedinpatientstreatedsolelywiththiazidediuretics(including

hydrochlorothiazide),mostlyathigherdosesthaninCoepratenzPlus600mg/12.5mg:lossofappetite,gastric

irritation,nausea,vomiting,abdominalcramps,diarrhoea,constipation,icterus(intrahepaticcholestasis),pancreatitis,

somnolence,dizziness,visiondisturbances,paraesthesia,headache,restlessness,sleepdisturbances,hypotension,

includingorthostatichypotension,arrhythmia,leucopenia,agranulocytosis,thrombocytopenia,aplasticanaemia,

haemolyticanaemia,hyperglycaemia,hyperuricaemia,gout,hyponatraemia,hypokalaemia,hypochloraemia,

hypercalcaemia,hypomagnesaemia,hypercholesterolaemia,hypertriglyceridaemia,renaldysfunction,interstitial

nephritis,acuterenalfailure,pneumonitis,pulmonaryoedema,photosensitivity,rash,vasculitis,toxicepidermal

necrosis,systemiclupuserythematosus,musclespasms,weakness,sexualdysfunction,and/orlibidochanges,fever,

anaphylacticreactions.

4.9Overdose

ForCoepratenzPlus600mg/12.5mglimiteddataareavailableinregardtooverdoseinhumansanditstreatment.The

mostlikelymanifestationofoverdosewouldbehypotension.

Othersymptomsmaybeduetodehydrationandelectrolytedepletion(hypokalaemia,hypochloraemia,hyponatraemia)

andwillmostlikelypresentasnauseaandsomnolence.

Treatmentshouldbesymptomaticandsupportive.Dependingonthetimesinceingestion,emesis,gastriclavageand/or

applicationofactivatedcharcoalshouldbeinduced.Incaseofhypotensionthepatientshouldbeplacedinsupine

positionandsaltsandvolumereplacementshouldbegiven.Eprosartanisnotexcretedbyhaemodialysis.Thedegreeto

whichhydrochlorothiazideisexcretedbyhaemodialysishasnotbeenestablished.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Eprosartananddiuretics:ATC-code:C09DA02.

Eprosartan

Eprosartanisanon-peptide,orallyactivenon-biphenylnon-tetrazoleangiotensinIIreceptorantagonist,whichselectivelybindsto

theAT

-receptor.

AngiotensinIIplaysamajorroleinthepathophysiologyofhypertension.Itistheprimaryactivehormoneofthe

Renin-Angiotensin-Aldosteronesystemandapotentvasoconstrictor.

EprosartanantagonisedtheeffectofangiotensinIIonbloodpressure,renalbloodflowandaldosteronesecretionin

man.Bloodpressurecontrolismaintainedovera24hourperiodwithnofirstdoseposturalhypotensionorreflex

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2104774 page number: 8

Eprosartandoesnotcompromiserenalautoregulatorymechanisms.Inhealthyadultmaleseprosartanhasbeenshown

toincreasemeaneffectiverenalplasmaflow.

Eprosartandoesnotpotentiateeffectsrelatingtobradykinin(ACEmediated)e.g.cough.

Hydrochlorothiazide

Hydrochlorothiazideisanestablishedthiazidediuretic.Thiazidesaffecttherenaltubularmechanismsofelectrolytere-

absorption,increasingexcretionoffluid,sodiumandchloride.Thediureticactionofhydrochlorothiazidereduces

plasmavolume,increasesplasmareninactivity,increasesaldosteronesecretion,withconsequentialincreasesinurinary

potassiumandbicarbonatelossanddecreasesinserumpotassium.Theantihypertensiveactionofhydrochlorothiazide

appearstobeduetocombineddiureticanddirectvascularactivity(reductionofvascularresistance)mechanism.

CoepratenzPlus600mg/12.5mg

Inaplacebo-controlled,8weeksclinicaltrialin473patientswithessentialhypertensionitwasshownthatthe

combinationof600mgeprosartanand12.5mghydrochlorothiazideiswelltoleratedandefficacious.CoepratenzPlus

600mg/12.5mgreducedsystolicanddiastolicbloodpressuretoaclinicallyrelevantdegreeandwasstatistically

significantsuperiortobothindividualcomponentsandplacebo,despiteahighplaceboresponse(p=0.08for

comparisonofeprosartanaloneandplacebo).Tolerabilitywasequalforbotheprosartan/hydrochlorothiazide600

mg/12.5mg,eprosartanandplacebo.

Inanotherclinicaltrialpatientswithadiastolicbloodpressurebetween98and114mmHg,whowerenottreated

sufficientlywitha3-weekstreatmentofeprosartan600mgalone,weregiveneithereprosartan/hydrochlorothiazde600

mg/12.5mgor600mgeprosartanalonefor8weeks.Thecombinationcausedastatisticallysignificantandclinically

relevantadditionaldecreaseinsystolicanddiastolicbloodpressureinpatientsnotreactingsufficientlytoeprosartan

monotherapy.Tolerabilitywasequallysatisfactoryforboththecombinationandmonotherapy.

Onlylimiteddataisavailableinpatientsover80yearsofage.

Theeffectofthecombinationofeprosartanandhydrochlorothiazideonmorbidityandmortalitywasnotinvestigated.

Epidemiologicalstudiesshowedthatlongtermtreatmentwithhydrochlorothiazidereducestheriskforcardiovascular

mortalityandmorbidity.

5.2Pharmacokineticproperties

Eprosartan

Absolutebioavailabilityfollowingoraladministrationofeprosartanisapprox.13%.Eprosartanplasmaconcentrations

peakat1to2hoursafterdosinginthefastedstate.Theterminaleliminationhalf-lifeofeprosartanistypically5to9

hours.Aslightaccumulation(14%)isseenwithchronicuseofeprosartan.Administrationofeprosartanwithfood

delaysabsorption,butdoesnotdecreasethebioavailability.

Inthedoserangebetween100to800mgthereisaslightlessthandose-proportionalincreaseinexposureto

eprosartan,mostlikelyduetothephysicochemicalpropertiesofthedrug.

Plasmaproteinbindingofeprosartanis98%andisnotinfluencedbygender,age,hepaticdysfunctionormild-to

moderaterenalimpairment.Plasmaproteinbindingisdecreasedinasmallnumberofpatientswithsevererenal

impairment.

Thevolumeofdistributionofeprosartanisapprox.13litres.Totalplasmaclearanceisapprox.130ml/min.Afteroral

administrationof[ 14

C]eprosartanapproximately90%ofradioactivitywasrecoveredfromfaeces.Approximately7%

wasexcretedinurine,80%ofwhichaseprosartan.BothAUCandC

valuesforeprosartanarehigherintheelderly

(onaveragetwofold),butdoseadjustmentisnotnecessary.AUCvalues(butnotC

)foreprosartanareincreasedon

averageby40%inpatientswithhepaticimpairment,butthisdoesnotnecessitatedoseadjustment.

ComparedtosubjectswithnormalrenalfunctionmeanAUCandC

valueswereapproximately30%higherin

patientswithmoderaterenalimpairment(creatinineclearance30-59ml/min),approximately50%higherinpatients

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2104774 page number: 9

betweenmalesandfemales.

ItwasshowninvitrothateprosartandoesnotinhibithumanCytochromeP450isoenzymesCYP1A,2A6,2C9/8,2C19,

2D6,2Eand3A.

Hydrochlorothiazide

Afteroraladministrationabsorptionofhydrochlorothiazideisrelativelyrapid.Whengiveninfastedstatethemean

eliminationhalf-lifeis5-15hours.Hydrohlorothiazideisnotmetabolizedandisrapidlyexcretedbythekidneys.At

least61%ofanoraldoseisexcretedunchangedwithin24hours.Hydrochlorothiazidecrossestheplacentalbutnotthe

blood-brainbarrierandisexcretedinbreastmilk.

CoepratenzPlus600mg/12.5mg

Co-administrationofeprosartanandhydrochlorothiazidehasnoclinicalsignificanteffectonthepharmacokineticsof

eitheractivesubstance.Thebioavailabilityofeprosartanandhydrochlorothiazideisnotinfluencedbyfood,but

absorptionisdelayed.Peakplasmaconcentrationsarereachedafter4hoursforeprosartanandafter3hoursfor

hydrochlorothiazide.

5.3Preclinicalsafetydata

Thepotentialtoxicityofthecombinationeprosartan/hydrochlorothiazideafteroraladministrationwasinvestigatedin

ratsanddogsinstudieslastingupto3months.Nofindingsemergedthatwouldexcludetheuseoftherapeuticdosesin

man.

Thetoxicologictargetorganwasthekidney.Thecombinationeprosartan/hydrochlorothiazideinducedfunctionalrenalchanges

(increasesinserumureaandinserumcreatinine).Furthermore,tubularde-andregenerationinthekidneyswereinducedathigher

dosesinmiceanddogs,probablybywayofalteredrenalhaemodynamics(reducedrenalperfusionasaconsequenceof

hypotensionleadingtotubularhypoxiawithtubularcellulardegeneration).

Furthermore,thecombinationinducedjuxtaglomerularcellhyperplasia,decreasesinredbloodcellparametersandadecreasein

heartweight.TheseeffectsappeartobeduetothepharmacologicaleffectsofhighdoseseprosartanandalsooccurwithACE-

inhibitors.Therelevanceofthesefindingstotheuseoftherapeuticdosesofthecombinationeprosartan/hydrochlorothiazidein

humansisunknown.

Findingsfrominvitroandinvivostudieswitheprosartanandhydrochlorothiazidebothaloneandincombinationdid

notrevealarelevantgenotoxicpotential.

Carcinogenicitystudieswerenotperformedwiththecombinationeprosartan/hydrochlorothiazide.Carcinogenicitywas

notobservedinratsandmice,administeredeprosartanupto600mgor2000mg/kgdailyrespectivelyfor2years.The

extensivehumanexperiencewithhydrochlorothiazidehasfailedtoshowanassociationbetweenitsuseandanincrease

inneoplasms.

Inpregnantrabbits,eprosartanhasbeenshowntoproducematernalandfetalmortalityat10mg/kgperdayduringlate

pregnancyonly.Hydrochlorothiazidedidnotenhancematernalandembryo-fetaltoxicityofeprosartan.The

combination eprosartan/hydrochlorothiazide administered orally at doses up to 3/1 mg/kg/day

(eprosartan/hydrochlorothiazide)resultedinneithermaternalnorfetaldevelopmentallytoxiceffects.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Microcrystallinecellulose

Pregelatinisedstarch(frommaize)

Crospovidone

Magnesiumstearate

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2104774 page number: 10

Filmcoat:

Polyvinylalcohol

Talc

Titaniumdioxide(E171)

Macrogol3350

Ironoxideyellow(E172)

Ironoxideblack(E172).

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Nospecialprecautionsforstorage

6.5Natureandcontentsofcontainer

WhitePVC/PCTFE/Aluminiumfoilblistersor

WhitePVC/PVDC/Aluminiumfoilblister

Blisterpacks: 28film-coatedtablets

56film-coatedtablets

98film-coatedtablets

280(10x28)film-coatedtablets

Sample:film-coated14tablets

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

AbbottHealthcareProductsLtd

MansbridgeRoad,

WestEnd,

Southampton,

SO183JD,

England.

8MARKETINGAUTHORISATIONNUMBER

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2104774 page number: 11

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:10thMarch2006

Dateoflastrenewal:1stNovember2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/08/2011 CRN 2104774 page number: 12