CAPOZIDE

Main information

  • Trade name:
  • CAPOZIDE Tablets
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CAPOZIDE Tablets
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/043/001A
  • Authorization date:
  • 25-09-1996
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Capozide50mg/25mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains50mgcaptopriland25mghydrochlorothiazide.

Excipients:Containslactose.ProductimportedfromSpaincontainsSunsetYellow(E110)

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

ProductimportedfromtheU.K.

White,oval,biconvextabletswithabreaklineononesideand‘SQUIBB390’ontheother.

ProductimportedfromSpain

Peach,oval,biconvextabletswithabreaklineononesideand‘390’ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertension.

Thisfixeddosecombinationisindicatedinpatientswhosebloodpressureisnotadequatelycontrolledbycaptopril

aloneorhydrochlorothiazidealone.

4.2Posologyandmethodofadministration

Capozidecanbeadministeredinasingleortwodivideddoses/daywithorwithoutfoodinpatientswhoseblood

pressureisnotadequatelycontrolledbycaptoprilaloneorhydrochlorothiazidealone.Amaximumdailydoseof100mg

captopril/30mghydrochlorothiazideshouldnotbeexceeded.Ifsatisfactoryreductionofbloodpressurehasnotbeen

achieved,additionalantihypertensivemedicationmaybeadded(see4.5).

Adults:Theadministrationofthefixedcombinationofcaptoprilandhydrochlorothiazideisusuallyrecommendedafter

dosagetitrationwiththeindividualcomponents.Theusualmaintenancedoseis50/25mg,onceaday,inthemorning.

Whenclinicallyappropriateadirectchangefrommonotherapytothefixedcombinationmaybeconsidered.

The25/25mg*strengthmaybeusedonceadayforpatientswhosebloodpressureisnotadequatelycontrolledby

hydrochlorothiazide25mgmonotherapyandbeforetitrationofthecaptoprilcomponent.The50/25mgand25/25mg

strengthsareintendedtobeusedoncedaily,astwotabletswouldresultinaninappropriatelyhighdoseof

hydrochlorothiazide(50mg/day).The50/15mgstrengthmaybeadministeredtostartthefixedcombinationinpatients

whosebloodpressureisnotadequatelycontrolledby50mgcaptoprilmonotherapy,and/orwhenalowerdoseof

hydrochlorothiazideispreferred.

Renalimpairment:Creatinineclearancebetween30and80ml/min:theinitialdoseisusually25/12.5mgonceaday,

inthemorning.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 19/04/2011 CRN 2091912 page number: 1

clearance<30ml/min).

Specialpopulations:Insalt/volumedepletedpatients,elderlypatientsanddiabeticpatients,theusualstartingdoseis

25/12.5mgonceaday.

Children:ThesafetyandefficacyofCapozideinchildrenhasnotbeenestablished.

*NotavailableinIreland

4.3Contraindications

Historyofhypersensitivitytocaptopril,toanyoftheexcipientsoranyotherACEinhibitor.

Historyofhypersensitivitytohydrochlorothiazideorothersulphonamide-deriveddrugs.

HistoryofangioedemaassociatedwithprevioustreatmentwithpreviousACEinhibitortherapy.

Hereditary/idiopathicangioneuroticoedema.

Severerenalimpairment(creatinineclearance<30ml/min)

Severehepaticimpairment

Secondandthirdtrimesterofpregnancy(see4.6).

Lactation(see4.6)

4.4Specialwarningsandprecautionsforuse

CAPTOPRIL

Hypotension:Rarelyhypotensionisobservedinuncomplicatedhypertensivepatients.Symptomatichypotensionis

morelikelytooccurinhypertensivepatientswhoarevolumeand/orsodiumdepletedbyvigorousdiuretictherapy,

dietarysaltrestriction,diarrhoea,vomitingorhaemodialysis.Volumeand/orsodiumdepletionshouldbecorrected

beforetheadministrationofanACEinhibitorandalowerstartingdoseshouldbeconsidered.

Aswithanyantihypertensiveagent,excessivebloodpressureloweringinpatientswithischaemiccardiovascularor

cerebrovasculardiseasemayincreasetheriskofmyocardialinfarctionorstroke.Ifhypotensiondevelops,thepatient

shouldbeplacedinasupineposition.Volumerepletionwithintravenousnormalsalinemayberequired.

Renovascularhypertension:Thereisanincreasedriskofhypotensionandrenalinsufficiencywhenpatientswith

bilateralrenalarterystenosisorstenosisofthearterytoasinglefunctioningkidneyaretreatedwithACEinhibitors.

Lossofrenalfunctionmayoccurwithonlymildchangesinserumcreatinine.Inthesepatients,therapyshouldbe

initiatedunderclosemedicalsupervisionwithlowdoses,carefultitrationandmonitoringofrenalfunction.

Angioedema:Angioedemaoftheextremities,face,lips,mucousmembranes,tongue,glottisorlarynxmayoccurin

patientstreatedwithACEinhibitors,particularlyduringthefirstweeksoftreatment.However,inrarecases,severe

angioedemamaydevelopafterlong-termtreatmentwithACEinhibitor.Treatmentshouldbediscontinuedpromptly.

Angioedemainvolvingthetongue,glottisorlarynxmaybefatal.Emergencytherapyshouldbeinstituted.Thepatient

shouldbehospitalisedandobservedforatleast12to24hoursandshouldnotbedischargeduntilcompleteresolution

ofsymptomshasoccurred.

Cough:CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnon-productive,

persistentandresolvesafterdiscontinuationoftherapy.

Hepaticfailure:Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceand

progressestofulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeisnotunderstood.

PatientsreceivingACEinhibitorswhodevelopjaundiceormarkedelevationsofhepaticenzymesshoulddiscontinue

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 19/04/2011 CRN 2091912 page number: 2

Hyperkalaemia:ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,

includingcaptopril.Patientsatriskforthedevelopmentofhyperkalaemiaincludethosewithrenalinsufficiency,

diabetesmellitus,orthoseusingconcomitantpotassium-sparingdiuretics,potassiumsupplementsorpotassium-

containingsaltsubstitutes;orthosepatientstakingotherdrugsassociatedwithincreasedinserumpotassium(e.g.

heparin).Ifconcomitantuseoftheabovementionedagentsisdeemedappropriate,regularmonitoringofserum

potassiumisrecommended.

Aorticandmitralvalvestenosis/Obstructivehypertrophiccardiomyopathy/Cardiogenicshock:ACEinhibitors

shouldbeusedwithcautioninpatientswithleftventricularvalvularandoutflowtractobstructionandavoidedincases

ofcardiogenicshockandhaemodynamicallysignificantobstruction.

Neutropenia/Agranulocytosis:Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedin

patientsreceivingACEinhibitors,includingcaptopril.Inpatientswithnormalrenalfunctionandnoothercomplicating

factors,neutropeniaoccursrarely.

Captoprilshouldbeusedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressanttherapy,

treatmentwithallopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthereispre-

existingimpairedrenalfunction.Someofthesepatientsdevelopedseriousinfectionswhichinafewinstancesdidnot

respondtointensiveantibiotictherapy.

Ifcaptoprilisusedinsuchpatients,itisadvisedthatwhitebloodcellcountanddifferentialcountsshouldbeperformed

priortotherapy,every2weeksduringthefirst3monthsofcaptopriltherapy,andperiodicallythereafter.During

treatmentallpatientsshouldbeinstructedtoreportanysignofinfection(e.g.sorethroat,fever)whenadifferential

whitebloodcellcountshouldbeperformed.Captoprilandotherconcomitantmedication(see4.5)shouldbewithdrawn

ifneutropenia(neutrophilslessthan1000/mm 3

)isdetectedorsuspected

Inmostpatientsneutrophilcountsrapidlyreturntonormalupondiscontinuingcaptopril.

Proteinurea:Proteinureamayoccurparticularlyinpatientswithexistingrenalfunctionimpairmentoronrelatively

highdosesofACEinhibitors.

Totalurinaryproteinsgreaterthan1gperdaywereseeninabout0.7%ofpatientsreceivingcaptopril.Themajorityof

patientshadevidenceofpriorrenaldiseaseorhadreceivedrelativelyhighdosesofcaptopril(inexcessof150mg/day),

orboth.Nephriticsyndromeoccurredinaboutone-fifthofproteinuricpatients.Inmostcases,proteinuriasubsidedor

clearedwithsixmonthswhetherornotcaptoprilwascontinued.Parametersofrenalfunction,suchasBUNand

creatinine,wereseldomalteredinthepatientswithproteinuria.

Patientswithpriorrenaldiseaseshouldhaveurinaryproteinestimations(dip-stickonfirstmorningurine)priorto

treatment,andperiodicallythereafter.

Anaphylactoidreactionsduringdesensitisation:Sustainedlife-threateninganaphylactoidreactionshavebeenrarely

reportedforpatientsundergoingdesensitisingtreatmentwithhymenopteravenomwhilereceivinganotherACE

inhibitor.Inthesamepatients,thesereactionswereavoidedwhentheACEinhibitorwastemporarilywithheld,but

theyreappeareduponinadvertentrechallenge.Therefore,cautionshouldbeusedinpatientswithACEinhibitors

undergoingsuchdesensitisationprocedures.

Anaphylactoidreactionsduringhigh-fluxdialysis/lipoproteinapheresismembraneexposure:Anaphylactoid

reactionshavebeenreportedinpatientshaemodialysedwithhigh-fluxdialysismembranesorundergoinglow-density

lipoproteinapheresiswithdextransulphateabsorption.Inthesepatients,considerationshouldbegiventousinga

differenttypeofdialysismembraneoradifferentclassofmedication.

Surgery/Anaesthesia:Hypotensionmayoccurinpatientsundergoingmajorsugeryorduringtreatmentwith

anaestheticagentsthatareknowntolowerbloodpressure.Ifhypotensionoccurs,itmaybecorrectedbyvolume

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 19/04/2011 CRN 2091912 page number: 3

Diabeticpatients:Theglycaemialevelsshouldbecloselymonitoredindiabeticpatientspreviouslytreatedwithoral

antidiabeticdrugsorinsulin,namelyduringthefirstmonthoftreatmentwithanACEinhibitor.

Aswithotherangiotensinconvertingenzymeinhibitors,Capozideisapparentlylesseffectiveinloweringblood

pressureinblackpeoplethaninnon-blacks,possiblybecauseofhigherprevalenceoflow-reninstatesintheblack

hypertensivepopulation.

HYDROCHLOROTHIAZIDE

Renalimpairment:Inpatientswithrenaldisease,thiazidesmayprecipitateazotaemia.Cumulativeeffectsofthedrug

maydevelopinpatientswithimpairedrenalfunction.Ifprogressiverenalimpairmentbecomesevident,asindicatedby

arisingnon-proteinnitrogen,carefulreappraisaloftherapyisnecessary,withconsiderationgiventodiscontinuing

diuretictherapy(see4.3)

Hepaticimpairment:Thiazidesshouldbeusedwithcautioninpatientswithimpairedhepaticfunctionorprogressive

liverdisease,sinceminoralterationsoffluidandelectrolytebalancemayprecipitatehepaticcoma(see4.3)

Metabolicandendocrineeffects:Thiazidetherapymayimpairglucosetolerance.Indiabeticpatientsdosage

adjustmentsofinsulinororalhypoglycaemicagentsmayberequired.Latentdiabetesmellitusmaybecomemanifest

duringthiazidetherapy.Increasesincholesterolandtriglyceridelevelshavebeenassociatedwiththiazidediuretic

therapy.

Hyperuricaemiamayoccurorfrankgoutmaybeprecipitatedincertainpatientsreceivingthiazidetherapy.

Electrolyteimbalance:Asforanypatientreceivingdiuretictherapy,periodicdeterminationofserumelectrolytes

shouldeperformedatappropriateintervals.

Thiazides,includinghydochlorothiazide,cancausefluidorelectrolyteimbalance(hypokalaemia,hyponatraemiaand

hypochloraemicalkalosis).Warningsignsoffluidorelectrolyteimbalancearedrynessofmouth,thirst,weakness,

lethargy,drowsiness,restlessness,musclepainorcramps,muscularfatigue,hypotension,oliguria,tachycardiaand

gastrointestinaldisturbancessuchasnauseaorvomiting.Althoughhypokalaemiamaydvelopwiththeuseofthiazide

diuretics,concurrenttherapywithcaptoprilmayreducediuretic-inducedhypokalaemia.

Theriskofhypokalaemiaisgreatestinpatientswithcirrhosisoftheliver,inpatientsexperiencingbriskdiuresis,in

patientswhoarereceivinginadequateoralintakeofelectrolytesandinpatientsreceivingconcomitanttherapywith

corticosteroidsorACTH(see4.5).

Dilutionalhyponatraemiamayoccurinoedematouspatientsinhotweather.Chloridedeficitisgenerallymildand

usuallydoesnotrequiretreatment.

Thiazidemaydecreaseurinarycalciumexcretionandcauseanintermittentandslightelevationofserumcalciuminthe

absenceofknowndisordersofcalciummetabolism.Markedhypercalcaemiamaybeevidenceofhidden

hyperparathyroidism.Thiazidesshouldbediscontinuedbeforecarryingouttestsforparathyroidfunction.Thiazides

havebeenshowntoincreasetheurinaryexcretionofmagnesium,whichmayresultinhypomagnesaemia.

Anti-dopingtest:Hydrochlorothiazidecontainedinthismedicationcouldproduceapositiveanalyticalresutinananti-

dopingtest.

Other:Sensitivityreactionsmayoccurinpatientswithorwithoutahistoryofallergyorbronchialasthma.The

possibilityofexacerbationoractivationofsystemiclupuserythrematsushasbeenreported.

CAPTOPRIL/HYDROCHLOROTHIAZIDECOMBINATION

Pregnancy:Capozideisnotrecommendedduringthefirsttrimesterofpregnancy(see4.6).Iftreatmentisdiscontinued

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 19/04/2011 CRN 2091912 page number: 4

Riskofhypokalaemia:ThecombinationofanACEinhibitorwithathiazidediureticdoesnotruleouttheoccurrence

ofhypokalaemia.Regularmonitoringofkalaemiashouldbeperformed.

Combinationwithlithium:Capozideisnotrecommendedinassociationwithlithiumduetothepotentiationof

lithiumtoxicity.

Lactose:Capozidecontainslactose.Therefore,itshouldnotbeusedincasesofcongenitalgalactosaemia,glucoseand

galactosemalabsorptionorlactasedeficiencysyndromes(raremetabolicdiseases).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

CAPTOPRIL

Potassiumsparingdiureticsorpotassiumsupplements:ACEinhibitorsattenuatediureticinducedpotassiumloss.

Potassiumsparingdiuretics(e.g.spironolactone,triamereneoramiloride),potassiumsupplements,orpotassium-

containingsaltsubstitutesmayleadtosignificantincreasesinserumpotassium.Ifconcomitantuseisindicatedbecause

ofdemonstratedhypokalaemiatheyshouldbeusedwithcautionandwithfrequentmonitoringofserumpotassium(see

4.4).

Diuretics:(thiazidesorloopdiuretics):Priortreatmentwithhighdosediureticsmayresultinvolumedepletionanda

riskofhypotensionwheninitiatingtherapywithcaptopril(see4.4).Thehypotensiveeffectscanbereducedby

discontinuationofthediuretic,byincreasingvolumeorsaltintakeorbyinitiatingtherapywithalowdoseofcaptopril.

However,noclinicallysignificantdruginteractionshavebeenfoundinspecificstudieswithhydrochlorothizideor

furosemide.

Otherantihypertensiveagents:Captoprilhasbeensafelyco-administeredwithothercommonlyusedanti-

hypertensiveagents(e.g.beta-blockersandlong-actingcalciumchannelblockers).Concomitantuseoftheseagents

mayincreasethehypotensiveeffectsofcaptopril.Nitroglycerineandothernitrates,orothervasodilators,shouldbe

usedwithcaution.

Treatmentofacutemyocardialinfarction:Captoprilmaybeusedconcomitantlywithacetylsalicylicacid(at

cardiologicaldoses),thrombolytics,beta-blockersand/ornitratesinpatientswithmyocardialinfarction.

Tricylicantidepressants/Antipsychotics:ACEinhibitorsmayenhancethehypotensiveeffectsofcertaintricyclic

antidepressantsandantipsychotics(see4.4).Posturalhypotensionmayoccur.

Allopurinol,procainamide,cytostaticorimmuno-suppressantagents:ConcomitantadministrationwithACE

inhibitorsmayleadtoanincreasedriskofleucopenia,especiallywhenthelatterareausedathigherthancurrently

recommendeddoses.

Sympathomimetics:MayreducetheantihypertensiveeffectsofACEinhibitors;patientsshouldbecarefully

monitored.

Antidiabetics:ParmacologicalstudieshaveshowntheACEinhibitors,includingcaptopril,canpotentiatetheblood

glucose-reducingeffectsofinsulinandoralantidiuretics,suchassulphonylurea,indiabetes.Shouldthisveryrare

interactionoccur,itmaybenecessarytoreducethedoseoftheantidiabeticduringsimultaneoustreatmentwithACE

inhibitors.

HYDROCHLOROTHIAZIDE

AmphotericinB(parenteral),carbenoxolone,corticosteroids,corticotrophin(ACTH)orstimulantlaxative:

hydrocholorothiazidemayintensifyelectrolyteimbalance,particularlyhypokalaemia.

Calciumsalts:Increasedserumcalciumlevelsduetodecreasedexcretionmayoccurwhenadministeredconcurrently

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 19/04/2011 CRN 2091912 page number: 5

Cardiacglycosides:Enhancedpossibilitiyofdigitalistoxicityassociatedwiththiazideinducedhypokalaemia.

Cholestyramineresinandcolestipol:Maydelayordecreaseabsorptionofhydrochlorothiazide.Sulphonamide

diureticsshouldbetakenatleastonehourbeforeorfourtosixhoursafeterthesemedications.

Nondepolarisingmusclerelaxants(e.g.turbocurarinechloride):effectsoftheseagentsmaybepotentiatedby

hydrochlorothiazide.

Drugsassociatedwithtorsadesdepointes:Becauseoftheriskofhypokalaemia,cautionshouldbeusedwen

hydrocjorothiazideiscoadministeredwithdrugsassociatedwithtorsadesdepointes,e.g.someantiarrhythmics,some

antipsychoticsandotherdrugsknowntoinducetorsadesdepointes.

CAPTOPRIL/HYDROCHLOROTHIAZIDECOMBINATION

Lithium:Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.Concomitantuseofthiazidediureticsmayincreasetheriskoflthium

toxicityandenhancethealreadyincreasedriskoflithiumtoxicitywithACEinhibitors.Thecombinationofcaptopril

andhydrochlorothiazidewithlithiumisthereforenotrecommendedandcarefulmonitoringofserumlithiumlevels

shouldbeperformedifthecombinationprovesnecessary.

Non-steroidalanti-inflammatorymedicinalproducts:Ithasbeendescribedthatnon-steroidalanti-inflamatory

medicinalproducts(NSAIDs)andACEinhibitorsexertanadditiveeffectontheincreaseinserumotassium,whereas

renalfunctionmaydecrease.Theseeffectsare,inprinciple,reversible.Rarely,acuterenalfailuremayoccur,

particularlyinpatientswithcompromisedrenalfunctionsuchastheelderlyordehydrated.Chronicadministrationof

NSAIDsmayreducetheantihypertensiveeffectofanACEinhibitor.TheadministrationofNSAIDsmayreducethe

diuretic,natriureticandantihypertensiveeffectsofthiazidediuretics.

Clinicalchemistry

Captoprilmaycauseafalse-positiveurinetestforacetone.Hydrochlorothiazidemaycausediagnosticinterferenceof

thebentiromidetest.ThiazidesmaydecreaseserumPBI(ProteinBoundIodine)levelswithoutsignsofthyroid

disturbance.

4.6Fertility,pregnancyandlactation

Pregnancy:

Capozideisnotrecommendedduringthefirsttrimesterofpregnancy.Whenapregnancyisplannedorconfirmed,an

alternativetreatmentshouldbeinitiatedassoonaspossible.ControlledstudieswithACEinhibitorshavenotbeendone

inhumans,butalimitednumberofcasesoffirsttrimesterexposureshasnowshownmalformations.

Capozideiscontraindicatedduringthesecondandthirdtrimestersofpregnancy.Prolongedcaptoprilexposureduring

thesecondandthirdtrimestersisknowntoinducetoxicityinfoetuses(decreasedrenalfunctionoligohydramnios,skull

ossificationretardation)andinneonates(neonatalrenalfailure,hypotension,hyperkalaemia)(seealso5.3).

Hydrochlorothiazide,incasesofprolongedexposureduringthethirdtrimesterofpregnancy,maycausea

foetoplacentalischaemiaandriskofgrowthhetaidation,moreover,rarecasesofhypoglycaemiaandthrombocytopenia

inneonateshavebeenreportedincaseofexposurenearterm.

Hydrochlorothiazidecanreduceplasmavolumeaswellastheuteroplacentalbloodflow.

ShouldexposuretoCapozidehaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

Lactation:

Capozideiscontraindicatedinthelactationperiod.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 19/04/2011 CRN 2091912 page number: 6

havebeenassociatedwithadecreaseorevensuppressionoflactation.Hypersensitivitytosulphonamide-deriveddrugs,

hypokalaemiaandnuclearicterusmightoccur.

Becauseofthepotentialforseriousadverseeffectsinnursinginfantsfrombothdrugs,adecisionshouldbemade

whethertodiscontinuenursingortodiscontinuetherapy,takingintoaccounttheimportanceofthistherapytothe

mother.

4.7Effectsonabilitytodriveandusemachines

Aswithotherantihypertensives,theabilitytodriveandusemachinesmaybereduced,e.g.atthestartofthetreatment

orwhenthedoseismodified,andalsowhenusedincombinationwithalcohol,buttheseeffectsdependonthe

individual’ssusceptibility.

4.8Undesirableeffects

CAPTOPRIL

Undesirableeffectsreportedforcaptopriland/orACEinhibitortherapyinclude:

Bloodandlymphaticdisorders:

Veryrare: Neutropenia/agranulocytosis(see4.4),pancytopenia,particularlyinpatientswithrenaldysfunction

(see4.4),anaemia(includingaplasticandhaemolytic),thrombocytopenia,lymphadenopathy,

eosinophilia,auto-immunediseasesand/orpositiveANA-titres.

Metabolismandlymphaticdisorders:

Rare: Anorexia

Veryrare: Hyperkalaemiahypoglycaemia(see4.4)

Psychiatricdisorders:

Common: Sleepdisorders

Veryrare: Confusion,depression

Nervoussystemdisorders:

Common: Tasteimpairment,dizziness

Rare: Drowsiness,headacheandparaesthesia

Veryrare: Cerebrovascularincidents,incldingstroke,andsyncope

Eyedisorders:

Veryrare: Blurredvision

Cardiacdisorder:

Uncommon Tachycardiaortachyarrhythmia,anginapectoris,palpitations

Veryrare: Cardiacarrest,cardiogenicshock

Vasculardisorders:

Uncommon Hypotension(see4.4),Raynaudsyndrome,flush,pallor

Respiratory,thoracicandmediastinaldisorders:

Common: Dry,irritating(non-productive)cough(see4.4)anddyspnoea

Veryrare: Bronchospasm,rhinitis,allergicalveolitis/eosinophilicpneumonia

Gastrointestinaldisorders:

Common: Nausea,vomiting,gastricirritations,abdominalpain,diarrhoea,constipation,drymouth

Rare: Stomatitis/aphthousulcerations

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 19/04/2011 CRN 2091912 page number: 7

Hepato-biliarydisorders:

Veryrare: Impairedhepaticfunctionandcholestasis(includingjaundice),hepatitisincludingnecrosis,elevated

liverenzymesandbilirubin.

Skinandsubcutaneoustissuedisorders:

Common: Prurituswithorwithoutarash,rashandalopecia

Uncommon: Angioedema(see4.4)

Veryrare: Uticaria,StevensJohnsonsyndrome,erythemamultiforme,photosensitivity,erythroderma,

pemphigoidreactionsandexfoliativedermatitis.

Musculoskeletal,connectivetissueandbonedisorders:

Veryrare: Myalgia,arthralgia

Renalandurinarydisorders:

Rare: Renalfunctiondisorders,includingrenalfailure,polyuria,oliguria,increasedurinefrequency

Veryrare: Nephriticsyndrome

Reprodutivesystemandbreastdisorders:

Veryrare: Impotence,gynaecomastia

Generaldisorders:

Uncommon Chestpain,fatigue,malaise

Veryrare: Fever

Investigations:

Veryrare: Proteinuria,eosinophilia,increaseofserumpotassium,decreaseofserumsodium,elevationof

BUN,serumcreatinineandserumbilirubin,decreasesinhaemoglobin,haematocrit,leucocytes,

thrombocytes,positiveANA-titre,elevatedESR.

HYDROCHLOROTHIAZIDE

Infectionsandinfestations:Sialadenitis

Bloodandlympharicsystemdisorders:Leucopenia,neutropenia/agranulocytosis,thrombocytopenia,aplastic

anaemia,haemolyticanaemia,bonemarrowdepression.

Metabolismandnutritiondisorders:Anorexia,hyperglycaemia,glycosuria,hyperuricaemia,electrolyteimbalance

(includinghyponatraemiaandhypokalaemia),increasesincholesterolandtriglycerides.

Psychiatricdisorders:Restlessness,depression,sleepdisturbances

Nervoussystemdisorders:Lossofappetite,paraesthesia,light-headedness

Eyedisorders:Xanthopsia,transientblurredvision

Earandlabyrinthdisorders:Vertigo

Cardiacdisorders:Posturalhypotension,cardiacarrhythmias

Vasculardisease:Necrotisingangiitis(vasculitis,cutaneousvasculitis)

Respiratory,thoracicandmediastinaldisorders:Respiratorydistress(includingpneumonitisandpulmonary

oedema).

Gastrointestinaldisorders:Gastricirritation,diarrhoea,constipation,pancreatitis.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 19/04/2011 CRN 2091912 page number: 8

4.9Overdose

Symptomsofoverdosageare:increaseddiuresis,electrolyteimbalance,severehypotension,depressionof

consciousness(includingcoma),convulsions,paresis,cardiacarrhythmias,bradycardia,renalfailure.

Measurestopreventabsorption(e.g.gastriclavage,administrationofabsorbingagentsandsodiumsulphatewithin30

minutesofintake)andtohasteneliminationshouldbeappliedifingestionisrecent.Ifhypotensionoccurs,thepatient

shouldbeplacedintheshockpositionandsodiumchlorideandvolumesupplementationshouldbegivenrapidly.

Treatmentwithangiotensin-IIcanbeconsidered.Bradycardiaorextensivevagalreactionsshouldbetreatedby

administeringatropine.Theuseofapacemakermaybeconsidered.Constantmonitoringofwater,electrolyteandacid

basebalance,andbloodglucoseisessential.Intheeventofhypokalaemia,potassiumsubstitutionisnecessary.

Captoprilmayberemovedfromcirculationbyhaemodialysis.Thedegreetowhichhydrochlorothiazideisremovedby

haemolysishasnotbeenestablished.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeticgroup:ACE(Angiotensin-Converting-Enzyme)inhibitors,combinations,

ATCcode:C09BA01.

CapozideisacombinationofanACEinhibitor,captopril,andanantihypertensivediuretic,hydrochlorothiazide.The

combinationoftheseagentshasanadditiveantihypertensiveeffect,reducingbloodpressuretoagreaterdegreethan

eitheralone.

Captoprilisanangiotensinconvertingenzyme(ACE)inhibitor,i.e.itinhibitsACE,theenzymeinvolvedinthe

conversionofangiotensinItoangiotensinII-avasoconstrictorwhichalsostmulatesaldosteronesecretionbythe

adrenalcortex.

Suchinhibitionleadsto:

Reducedaldosteronesecretionincreasedplasmarenninactivity,sincealdosteronenolongerexertsnegativefeedback,a

dropintotalperipheralresistance(withapreferentialeffectonmusclesandkidneys)whichisnotaccompaniedby

waterandsodiumretentionorreflextachycardiaduringlong-termtreatment.Captoprilalsoexertsitsantihypertensive

effectinsubjectswithlowornormalrenninconcentrations.

Captopriliseffectiveatallstagesofhypertension,i.e.mild,moderateorsevere.Areductioninsupineandstanding

systolicanddiastolicbloodpressuresisobserved.

Afterasingledose,theantihypertensiveeffectisevidentfifteenminutespost-doseandreachesamaximumbetween1h

and1.5hafteradministrationofthedrug.Itsdurationofactionisdose-dependentandvariesfrom6to12hours.

Bloodpressurebecomesnormalised(seatedDBP<90mmHg)inpatientsaftertwoweekstoonemonthoftreatmentand

thedrugretainsitseffectivenessoverthecourseoftime.PatientsarealsoclassifiedasrespondersifseatedDBP

decreasedby10%ormorefrombaseline-BP.

Skinandsubcutaneoustissuedisorders:Photosensitivityreactions,rash,cutaneouslupuserythematosus-like

reactions,reactivationofcutaneouslupuserythematosus-likereactions,reactivationofcutaneouslupus

erythematosus,uticaria,anaphylacticreactions,toxicepidermalnecrolysis.

Musculoskeletal,connectivetissueandbonedisorders:Musclespasm

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 19/04/2011 CRN 2091912 page number: 9

Thetreatmentofhypertensionwithcaptoprilleadstoanincreaseinarterialcompliance,ariseinrenalbloodflow

withoutanysignificantdropintheglomerularfiltrationrateandadecreaseinleftventricularhypertrophy.

Hydrochlorothiazideisathiazidediureticwhichactsbyinhibitingthereabsorptonofsodiuminthecorticaldiluting

segmentofrenaltubules.Itincreasestheexcretionofsodiumandchlorideinurineand,toalesserextent,theexcretion

ofpotassiumandmagnesiumtherebyincreasingurinaryoutputandexertinganantihypertensiveeffect.

Thetimetoonsetofdiureticactivityisapproximately2hours.Diureticactivityreachesapeakafter4hoursandis

maintainedfor6to12hours.Aboveacertaindose,thiazidediureticsreachaplateauintermsoftherapeuticeffect

whereasadversereactionscontinuetomultiply.Whentreatmentisineffective,increasingthedosebeyond

recommendeddosesservesnousefulpurposeandoftengivesrisetoadversereactions.

Theconcomitantadministrationofcaptoprilandhydrochlorothiazideinclinicaltrialsledtogreaterreductionsinblood

pressurethanwhenetheroftheproductswasadministeredalone.

Theadministrationofcaptoprilinhibitstherenninangiotensinaldosteronesystemandtendstoreduce

hydrochlorothiazide-inducedpotassiumloss.

CombinationofanACEinhibitorwithathiazidediureticproducesasynergisticeffectandalsolessenstheriskof

hypokalaemiaprovokedbythediureticalone.

5.2Pharmacokineticproperties

Captoprilisquicklyabsorbedafteroraladministrationandmaximumserumconcentrationsareobtainedaroundone

hourafteradministration.Minimummeanabsorptionisapproximately75%.Peakplasmaconcentrationsarereached

within60-90minutes.Thepreenceoffoodinthegastrointestinaltractreducesabsorptionbyabout30-40%.

Approximately25-30%ofthecirculatingdrugisboundtoplasmaproteins.Theapparenteliminationhalf-lifeof

unchangedcaptoprilinbloodisabout2hours.Greaterthan95%oftheabsorptiondoseiseliminatedintheurinewithin

24hours;40-50%isunchangeddrugandtheremainderareinactivedisulphidemetabolites(captoprildisulphideand

captoprilcysteinedisulphide).Impairedrenalfunctioncouldresultindrugaccumulation.Studiesinanimalsindicate

thatcaptoprildoesnotcrosstheblood-brainbarriertoanysignificantextent.Oralabsorptionofhydrochlorothiazideis

relativelyrapid.Themeanplasmahalf-lifeinfastedindividualshasbeenreportedtobe5to15hours.

Hydochlorothiazideiseliminatedrapidlybythekidneyandexcretedunchanged(>95%)intheurine.

5.3Preclinicalsafetydata

Animalstudiesperformedduringorganogenesiswithcaptopriland/orhydrochlorothiazidehavenotshownany

teratogeniceffectbutcaptoprilasproducedfoetaltoxicityinseveralspecies,includingfoetalmortalityduringlate

pregnancy,growthretardationandpostnatalmortalityintherat.Preclinicaldatarevealnootherspecifichazardfor

humansbasedonconventionalstudiesofsafetypharmacology,repeateddosetoxicology,genotoxicityand

carcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

ExcipientspresentintheproductimportedfromtheUK:

Lactose

Magnesiumstearate

Pregelatinisedmaizestarch

Microcrystallinecellulose

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 19/04/2011 CRN 2091912 page number: 10

ExcipientspresentintheproductimportedfromSpain:

Lactose

Magnesiumstearate

Pregelatinisedmaizestarch

Microcrystallinecellulose

Stearicacid

Sunsetyellowcolouringagent(E110)

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelflifeexpirydateforthisproductshallbethedateonthecontainerandouterpackageoftheproductinthe

countryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

Blisterspacksof28or30tabletscontainedinanoutercardboardcarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA0465/043/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:25September1996

Dateoflastrenewal:25September2006

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 19/04/2011 CRN 2091912 page number: 11