CAPOTEN 12.5 MG TABLETS

Main information

  • Trade name:
  • CAPOTEN 12.5 MG TABLETS
  • Dosage:
  • 12.5 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CAPOTEN 12.5 MG TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0002/039/004
  • Authorization date:
  • 30-09-1986
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0002/039/004

CaseNo:2050595

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

Bristol-MyersSquibbPharmaceuticalsLtd

Swords,Co.Dublin,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Capoten12.5mgTablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom26/03/2009.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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______________________________________________________________________________________________________________________

Date Printed 26/03/2009 CRN 2050595 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Capoten12.5mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontainscaptopril 12.5mg

Excipients:Lactosemonohydrate 33.0mg

Forfulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

Slightlymottled,white,flat-faced,bevel-edged,capsule-shapedtablets,engravedwith‘Squibb’and‘450’ononeside

withabisectingbarontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension:Capotenisindicatedforthetreatmentofhypertension.

HeartFailure:

Capotenisindicatedforthetreatmentofchronicheartfailurewithreductionofsystolicventricularfunction,in

combinationwithdiureticsandwhenappropriate,digitalisandbeta-blockers.

MyocardialInfarction:

-Short-term(4weeks)treatment:Capotenisindicatedinanyclinicallystablepatientswithinthefirst24hoursofan

infarction.

-Longtermpreventionofsymptomaticheartfailure:Capotenisindicatedinclinicallystablepatientswith

asymptomaticleftventriculardysfunction(ejectionfraction<40%).

TypeIDiabeticNephropathy:

CapotenisindicatedforthetreatmentofmacroproteinuricdiabeticnephropathyinpatientswithtypeIdiabetes.

(Seesection5.1,Pharmacodynamicproperties).

4.2Posologyandmethodofadministration

Doseshouldbeindividualisedaccordingtopatient’sprofile(seesection4.4,specialwarningsandprecautionsforuse)

andbloodpressureresponse.Therecommendedmaximumdailydoseis150mg.

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Hypertension:

Therecommendedstartingdoseis25-50mgdailyintwodivideddoses.Thedosemaybeincreasedincrementally,

withintervalsofatleast2weeks,to100-150mg/dayintwodivideddosesasneededtoreachtargetbloodpressure.

Captoprilmaybeusedaloneorwithotherantihypertensiveagents,especiallythiazidediuretics.Aonce-dailydosing

regimenmaybeappropriatewhenconcomitantantihypertensivemedicationsuchasthiazidediureticsisadded.

Inpatientswithastronglyactiverenin-angiotensin-aldosteronesystem(hypovolaemia,renovascularhypertension,

cardiacdecompensation)itispreferabletocommencewithasingledoseof6.25mgor12.5mg.Theinaugurationof

thistreatmentshouldpreferablytakeplaceunderclosemedicalsupervision.Thesedoseswillthenbeadministeredata

rateoftwoperday.Thedosagecanbegraduallyincreasedto50mgperdayinoneortwodosesandifnecessaryto

100mgperdayinoneortwodoses.

HeartFailure:

Treatmentwithcaptoprilforheartfailureshouldbeinitiatedunderclosemedicalsupervision.Theusualstartingdose

is6.25mg-12.5mgBIDorTID.Titrationtothemaintenancedose(75-150mgperday)shouldbecarriedoutbased

onpatient’sresponse,clinicalstatusandtolerability,uptoamaximumof150mgperdayindivideddoses.Thedose

shouldbeincreasedincrementally,withintervalsofatleast2weekstoevaluatepatientsresponse.

MyocardialInfarction:

-Short-termtreatment:Capotentreatmentshouldbegininhospitalassoonaspossiblefollowingtheappearanceofthe

signsand/orsymptomsinpatientswithstablehaemodynamics.A6.25mgtestdoseshouldbeadministered,witha

12.5mgdosebeingadministered2hoursafterwardsanda25mgdose12hourslater.Fromthefollowingday,

captoprilshouldbeadministeredina100mg/daydose,intwodailyadministrations,for4weeks,ifwarrantedbythe

absenceofadversehaemodynamicreactions.Attheendofthe4weeksoftreatment,thepatient’sstateshouldbe

reassessedbeforeadecisionistakenconcerningtreatmentforthepost-myocardialinfarctionstage.

-chronictreatment:Ifcaptopriltreatmenthasnotbegunduringthefirst24hoursoftheacutemyocardialinfarction

stage,itissuggestedthattreatmentbeinstigatedbetweenthe3 rd

and16 th

daypost-infarctiononcethenecessary

treatmentconditionshavebeenattained(stablehaemodynamicsandmanagementofanyresidualischaemia).Treatment

shouldbestartedinhospitalunderstrictsurveillance(particularlyofbloodpressure)untilthe75mgdoseisreached.

Theinitialdosemustbelow(seesection4.4,Specialwarningsandprecautionsforuse),particularlyifthepatient

exhibitsnormalorlowbloodpressureattheinitiationoftherapy.Treatmentshouldbeinitiatedwithadoseof6.25mg

followedby12.5mg3timesdailyfor2daysandthen25mg3timesdailyifwarrantedbytheabsenceofadverse

haemodynamicreactions.Therecommendeddoseforeffectivecardioprotectionduringlong-termtreatmentis75to

150mgdailyintwoorthreedoses.

Incasesofsymptomatichypotension,asinheartfailure,thedosageofdiureticsand/orotherconcomitantvasodilators

maybereducedinordertoattainthesteadystatedoseofcaptopril.Wherenecessary,thedoseofcaptoprilshouldbe

adjustedinaccordancewiththepatient’sclinicalreactions.Captoprilmaybeusedincombinationwithother

treatmentsformyocardialinfarctionsuchasthrombolyticagents,beta-blockersandacetylsalicylicacid.

TypeIDiabeticnephropathy:

InpatientswithtypeIdiabeticnephropathy,therecommendeddailydoseofcaptoprilis75-100mgindivideddoses.

Ifadditionalloweringofbloodpressureisdesired,additionalantihypertensivemedicationsmaybeadded.

Renalimpairment:

Sincecaptoprilisexcretedprimarilyviathekidneys,dosageshouldbereducedorthedosageintervalshouldbe

increasedinpatientswithimpairedrenalfunction.Whenconcomitantdiuretictherapyisrequired,aloopdiuretic(e.g.

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Inpatientswithimpairedrenalfunction,thefollowingdailydosemayberecommendedtoavoidaccumulationof

captopril.

Elderlypatients:

Aswithotherantihypertensiveagents,considerationshouldbegiventoiniatingtherapywithalowerstartingdose

(6.25mgBID)inelderlypatientswhomayhave

reducedrenalfunctionandotherorgandysfunctions(seeaboveandsection4.4,specialwarningsandprecautionsfor

use).

Dosageshouldbetitratedagainstthebloodpressureresponseandkeptaslowaspossibletoachieveadequatecontrol.

Childrenandadolescents:

Theefficacyandsafetyofcaptoprilhavenotbeenfullyestablished.Theuseofcaptoprilinchildrenandadolescents

shouldbeinitiatedunderclosemedicalsupervision.Theinitialdoseofcaptoprilisabout0.3mg/kgbodyweight.For

patientsrequiringspecialprecautions(childrenwithrenaldysfunction,prematureinfants,new-bornsandinfants,

becausetheirrenalfunctionisnotthesamewitholderchildrenandadults)thestartingdoseshouldonlybe0.15mg

captopril/kgweight.Generally,catoprilisadministeredtochildren3timesaday,butdoseandintervalofdoseshould

beadaptedindividuallyaccordingtopatient’sresponse.

4.3Contraindications

Ahistoryofprevioushypersensitivitytoanyingredientsoftheproduct.

Useinpatientswithaorticstenosisoroutflowtractobstruction.Useinpatientswithbilateralrenalarterystenosisina

singlefunctioningkidney.

UseinpatientswithahistoryofanfioneuroticoedemarelatingtoprevioustreatmentwithanACEinhibitor.

Pregnancy:

Capotenhasbeenshowntobelethaltorabbitandsheepfoetuses.Therewerenofoetotoxiceffectstohamsterorrat

foetuses.

Capoteniscontraindicatiedinpregnancyandshouldnotbeusedinwomenofchildbearingpotentialunlessprotected

byeffectivecontraception.

Exposureofthemotherinthesecondandthirdtrimesterofpregnancyhasbeenassociatedwitholigohydramniosand

neonatalhypertensionand/oranuria.

4.4Specialwarningsandprecautionsforuse

Hypotension:

Rarelyhypotensionisobservedinuncomplicatedhypertensivepatients.Symptomatichypotensionismorelikelyto

occurinhypertensivepatientswhoarevolumeand/orsodiumdepletedbyvigorousdiuretictherapy,dietarysalt

restriction,diarrhoea,vomitingorhaemodialysis.Volumeand/orsodiumdepletionshouldbecorrectedbeforethe

Creatinineclearance

(ml/min/1.73m 2

DailyStartingdose

(mg) Dailymaximumdose

(mg)

>40 25-50 150

21-40 25 100

10-20 12.5 75

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Patientswithheartfailureareatahighriskofhypotensionandalowerstartingdoseisrecommendedwheninitiating

therapywithanACEinhibitor.Cautionshouldbeusedwheneverthedoseofcaptoprilordiureticisincreasedin

patientswithheartfailure.

Aswithanyantihypertensiveagent,excessivebloodpressureloweringinpatientswithischaemiccardiovascularor

cerebrovasculardiseasemayincreasetheriskofmyocardialinfarctionorstroke.Ifhypotensiondevelops,thepatient

shouldbeplacedinasupineposition.Volumerepletionwithintravenousnormalsalinemayberequired.

Renovascularhypertension:

Thereisanincreasedriskofhypotensionandrenalinsufficiencywhenpatientswithbilateralrenalarterystenosisor

stenosisofthearterytoasinglefunctioningkidneyaretreatedwithACEinhibitors.Lossofrenalfunctionmayoccur

withonlymildchangesinserumcreatinine.Inthesepatients,therapyshouldbeinitiatedunderclosemedical

supervisionwithlowdoses,carefultitrationandmonitoringofrenalfunction.

Renalimpairment:

Incasesofrenalimpairment(creatinineclearance<40ml/min),theinitialdosageofcaptoprilmustbeadjusted

accordingtothepatient’screatinineclearance(seesection4.2,Posologyandmethodofadministration),andthenasa

functionofthepatient’sresponsetotreatment.Routinemonitoringofpotassiumandcreatininearepartofnormal

medicalpracticeforthesepatients.

Angioedema:

Angioedemaoftheextremities,face,lips,mucousmembranes,tongue,glottisorlarynxmayoccurinpatientstreated

withACEinhibitorsparticularlyduringthefirstweeksoftreatment.However,inrarecases,severeangioedemamay

developafterlong-termtreatmentwithanACEinhibitor.Treatmentshouldbediscontinuedpromptly.Angioedema

involvingthetongue,glottisorlarynxmaybefatal.Emergencytherapyshouldbeinstituted.

Thepatientshouldbehospitalisedandobservedforatleast12to24hoursandshouldnotbedischargeduntilcomplete

resolutionofsymptomshasoccurred.

Cough:

CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnon-productive,persistent

andresolvesafterdiscontinuationoftherapy.

Hepaticfailure:

Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceandprogressesto

fulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeisnotunderstood.Patients

receivingACEinhibitorswhodevelopjaundiceormarkedelevationsofhepaticenzymesshoulddiscontinuetheACE

inhibitorandreceiveappropriatemedicalfollowup.

Hyperkalaemia:

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,includingcaptopril.

Patientsatriskforthedevelopmentofhyperkalaemiaincludethosewithrenalinsufficiency,diabetesmellitus,orthose

usingconcomitantpotassium-sparingdiuretics,potassiumsupplementsorpotassium-containingsaltsubstitutes;or

thosepatientstakingotherdrugsassociatedwithincreasesinserumpotassium(e.g.heparin).Ifconcomitantuseofthe

abovementionedagentsisdeemedappropriate,regularmonitoringofserumpotassiumisrecommended.

Lithium:

Thecombinationoflithiumandcaptoprilisnotrecommended(seesection4.5,Interactionwithothermedicinal

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Aorticandmitralvalvestenos/Obstructivehypertropiccardiomyopathy:

ACEinhibitorsshouldbeusedwithcautioninpatientswithleftventricularvalvularandoutflowtractobstructionand

avoidedincasesofcardiogenicshockandhaemodynamicallysignificantobstruction.

Neutropenia/Agranulocytosis:

Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedinpatientsreceivingACEinhibitors,

includingcaptopril.Inpatientswithnormalrenalfunctionandnoothercomplicatingfactors,neutropeniaoccurs

rarely.Captoprilshouldbeusedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressant

therapy,treatmentwithallopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthere

isapre-existingimpairedrenalfunction.Someofthesepatientsdevelopedseriousinfectionswhichinafewinstances

didnotrespondtointensiveantibiotictherapy.

Ifcaptoprilisusedinsuchpatients,itisadvisedthatwhitebloodcellcountanddifferentialcountsshouldbeperformed

priortotherapy,every2weeksduringthefirst3monthsofcaptopriltherapy,andperiodicallythereafter.During

treatmentallpatientsshouldbeinstructedtoreportanysignofinfection(e.g.sorethroat,fever)whenadifferential

whitebloodcellcountshouldbeperformed.Captoprilandotherconcomitantmedication(seesection4.5,Interaction

withothermedicinalproductsandotherformsofinteraction)shouldbewithdrawnifneutropenia(neutrophilslessthan

1000/mm 3

)isdetectedorsuspected.

Inmostpatientsneutrophilcountsrapidlyreturntonormalupondiscontinuingcaptopril.

Proteinuria:

Proteinuriamayoccurparticularlyinpatientswithexistingrenalfunctionimpairmentoronrelativelyhighdosesof

ACEinhibitors.

Totalurinaryproteinsgreaterthan1gperdaywereseeninabout0.7%ofpatientsreceivingcaptopril.Themajorityof

patientshadevidenceofpriorrenaldiseaseorhadreceivedrelativelyhighdosesofcaptopril(inexcessof150mg/day),

orboth.Nephroticsyndromeoccurredinaboutone-fifthofproteinuricpatients.Inmostcases,proteinuriasubsidedor

clearedwithinsixmonthswhetherornotcaptoprilwascontinued.Parametersofrenalfunction,suchasBUNand

creatinine,wereseldomalteredinthepatientswithproteinuria.Patientswithpriorrenaldiseaseshouldhaveurinary

proteinestimations(dip-stickonfirstmorningurine)priortotreatment,andperiodicallythereafter.

Anaphylactoidreactionsduringdesensitisation:

Sustainedlife-threateninganaphylactoidreactionshavebeenrarelyreportedforpatientsundergoingdesensitising

treatmentwithhymenopteravenomwhilereceivinganotherACEinhibitor.Inthesamepatients,thesereactionswere

avoidedwhentheACEinhibitorwastemporarilywithheld,buttheyreappeareduponinadvertentrechallenge.

Therefore,cautionshouldbeusedinpatientstreatedwithACEinhibitorsundergoingsuchdesensitisationprocedures.

Anaphylactoidreactionsduringhigh-fluxdialysis/lipoproteinapheresismembraneexposure:

Anaphylactoidreactionshavebeenreportedinpatientshaemodialysedwithhigh-fluxdialysismembranesor

undergoinglow-densitylipoproteinapheresiswithdextransulphateabsorption.Inthesepatients,considerationshould

begiventousingadifferenttypeofdialysis;membraneoradifferentclassofmedication.

Surgery/Anesthesia:

Hypotensionmayoccurinpatientsundergoingmajorsurgeryorduringtreatmentwithanaestheticagentsthatare

knowntolowerbloodpressure.Ifhypotensionoccurs,itmaybecorrectedbyvolumeexpansion.

Diabeticpatients:

Theglycaemialevelsshouldbecloselymonitoredindiabeticpatientspreviouslytreatedwithoralantidiabeticdrugsor

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Lactose:

Capotencontainslactose,thereforeitshouldnotbeusedincasesofcongenitalgalactosaemia,glucoseandgalactose

malabsorptionorlactasedeficiencysyndromes(raremetabolicdiseases).

Ethnicdifferences:

Aswithotherangiotensinconvertingenzymeinhibitors,captoprilisapparentlylesseffectiveinloweringblood

pressureinblackpeoplethaninnon-blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblack

hypertensivepopulation.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Potassiumsparingdiureticsorpotassiumsupplements:

ACEinhibitorsattenuatediureticinducedpotassiumloss.Potassiumsparingdiuretics(e.g.spironolactone,triamterene

oramiloride),potassiumsupplements,orpotassium-containingsaltsubstitutesmayleadtosignificantincreasesin

serumpotassium.Ifconcomitantuseisindicatedbecauseofdemonstratedhypokalaemiatheyshouldbeusedwith

cautionandwithfrequentmonitoringofserumpotassium(seesection4.4,Specialwarningsandprecautionsforuse).

Diuretics(ThiazideorloopDiuretics)

Priortreatmentwithhighdosediureticsmayresultinvolumedepletionandariskofhypotensionwheninitiating

therapywithcaptopril(seesection4.4,Specialwarningsandprecautionsforuse)Thehypotensiveeffectscanbe

reducedbydiscontinuationofthediuretic,byincreasingvolumeorsaltintakeorbyinitiatingtherapywithalowdose

ofcaptopril.However,noclinicallysignificantdruginteractionshavebeenfoundinspecificstudieswith

hydrochlorothiazideorfurosemide.

Otherantihypertensiveagents:

Captoprilhasbeensafelyco-administeredwithothercommonlyusedanti-hypertensiveagents(e.g.beta-blockersand

long-actingcalciumchannelblockers).Concomitantuseoftheseagentsmayincreasethehypotensiveeffectsof

captopril.Treatmentwithnitroglycerineandothernitrates,orothervasodilators,shouldbeusedwithcaution.

Treatmentsofacutemyocardialinfarction:

Captoprilmaybeusedconcomitantlywithacetylsalicylicacid(atcardiologicdoses),thrombolytics,beta-blockers

and/ornitratesinpatientswithmyocardialinfarction.

Lithium:

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.Concomitantuseofthiazidediureticsmayincreasetheriskoflithium

toxicityandenhancethealreadyincreasedriskoflithiumtoxicitywithACEinhibitors.Useofcaptoprilwithlithiumis

notrecommended,butifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsshouldbe

performed(seesection4.4,Specialwarningsandprecautionsforuse).

Tricyclicantidepressants/Antipsychotics:

ACEinhibitorsmayenhancethehypotensiveeffectsofcertaintricyclicantidepressantsandantipsyschotics(seesection

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Allopurinol,procainamide,cytostaticorimmuno-suppressiveagents:

ConcomitantadministrationwithACEinhibitorsmayleadtoanincreasedriskforleucopeniaespeciallywhenthelatter

areusedatahigherthancurrentlyrecommendeddoses.

Non-steroidalanti-inflammatorymedicinalproducts:

Ithasbeendescribedthatnon-steroidalanti-inflammatorymedicinalproducts(NSAIDs)andACEinhibitorsexertan

additiveeffectontheincreaseinserumpotassiumwhereasrenalfunctionmaydecrease.Theseeffectsareinprinciple,

reversible.Rarely,acuterenalfailuremayoccur,particularlyinpatientswithcompromisedrenalfunctionsuchasthe

elderlyordehydrated.ChronicadministrationofNSAIDsmayreducetheantihypertensiveeffectofanACEinhibitor.

Sympathomimetics:

MayreducetheantihypertensiveeffectsofACEinhibitors;patientsshouldbecarefullymonitored.

Antidiabetics:

PharmacologicalstudieshaveshownthatACEinhibitors,includingcaptopril,canpotentiatethebloodglucose-

reducingeffectsofinsulinandoralantidiabeticssuchassulphonylureaindiabetics.Shouldthisveryrareinteraction

occur,itmaybenecessarytoreducethedoseofantidiabeticduringsimultaneoustreatmentwithACEinhibitors.

ClinicalChemistry:

Captoprilmaycauseafalse-positiveurinetestforacetone.

4.6Pregnancyandlactation

Pregnancy:

Capotenisnotrecommendedduringthefirsttrimesterofpregnancy.Whenapregnancyisplannedorconfirmed,the

switchtoanalternativetreatmentshouldbeinitiatedassoonaspossible.ControlledstudieswithACEinhibitorshave

notbeendoneinhumans,butlimitednumberofcasesoffirsttrimesterexposureshavenotshownmalformations.

Capoteniscontraindicatedduringthesecondandthirdtrimestersofpregnancy.Prolongedcaptoprilexposureduring

thesecondandthirdtrimesterisknowntoinducetoxicityinfoetuses(decreasedrenalfunction,oligohydramnios,skull

ossificationretardation)andinneonates(neonatalrenalfailure,hypotension,hyperkalaemia)(seealsosection5.3,

Preclinicalsafetydata)

Lactation:

Capoteniscontraindicatedinthelactationperiod.

4.7Effectsonabilitytodriveandusemachines

Aswithotherantihpertensives,theabilitytodriveandusemachinesmaybereduced,namelyatthestartofthe

treatment,orwhenposologyismodified,andalsowhenusedincombinationwithalcohol,buttheseseffectsdependon

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4.8Undesirableeffects

Undesirableeffectsreportedforcaptopriland/orACEinhibitorinclude:

Bloodandlymphaticdisorders:

VeryRare: neutropenia/agranulocytosis(seesection4.4,Specialwarningsandprecautionsforuse),pancytopenia

particularlyinpatientswithrenaldysfunction(seesection4.4,Specialwarningsandprecautionsforuse),anaemia

(includingaplasticandhaemolytic),thrombocytopenia,lymphadenopathy,eosinophilia,auto-immunediseasesand/or

positiveANA-titres.

Metabolismandnutritiondisorders:

Rare: Anorexia

VeryRare: Hyperkalaemia,hypoglycaemia(seesection4.4,Specialwarningsandprecautionsforuse)

Psychiatricdisorders:

Common: Sleepdisorders.

VeryRare: Confusion,depression.

Nervoussystemdisorders:

Common: Tasteimpairment,dizziness.

Rare: Drowsiness,headacheandparaesthesia.

VeryRare: Cerebrovascularincidents,includingstroke,andsyncope.

Eyedisorders:

VeryRare: Blurredvision.

Cardiacdisorders:

Uncommon: Tachycardiaortachyarrhythmia,anginapectoris,palpitations.

VeryRare: Cardiacarrest,cardiogenicshock.

Vasculardisorders

Uncommon: Hypotension(seesection4.4,Specialwarningsandprecautionsforuse),Raynaudsyndrome,flush,

pallor.

Respiratory,thoracicandmediastinaldisorders:

Common: Dry,irritating(nonproductive)cough(seesection4.4,Specialwarningsandprecautionsforuse)and

dyspnoea.

VeryRare: Bronchospasm,rhinitis,allergicalveolitis/eosinophilicpneumonia.

Gastrointestinaldisorders:

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

Rare: Stomatitis/aphthousulcerations.

VeryRare: Glossitis,pepticulcer,pancreatitis.

Hepato-biliarydisorders:

VeryRare: Impairedhepaticfunctionandcholestasis.(includingjaundice),hepatitisincludingnecrosis,elevated

liverenzymesandbilirubin.

Skinandsubcutaneoustissuedisorders:

Common: Prurituswithorwithoutarash,rashandalopecia.

Uncommon: Angioedema(seesection4.4,Specialwarningsandprecautionsforuse)

VeryRare: Urticaria,StevensJohnsonsyndrome,erythemamultiforme,photosensitivity,erythroderma,

pemphigoidreactionsandexfoliativedermatitis.

Musculoskeletal,connectivetissueandbonedisorders:

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Renalandurinarydisorders:

Rare: Renalfunctiondisordersincludingrenalfailure,polyuria,oliguria,increasedurinefrequency.

VeryRare: Nephroticsyndrome.

Reproductivesystemandbreastdisorders:

VeryRare: Impotence,gynaecomastia.

Generaldisorders:

Uncommon: Chestpain,fatigue,malaise.

VeryRare: Fever

Investigations:

VeryRare: Proteinuria,eosinophilia,increaseofserumpotassium,decreaseofserumsodium,elevationofBUN,

serumcreatinineandserumbilirubin,decreasesinhaemoglobin,haematocrit,leucocytes,thrombocytes,positiveANA-

titre,elevatedESR.

IntestinalangioedemahasalsobeereportedveryrarelyinpatientswithACEinhibitorsandshouldbeincludedinthe

differentialdiagnosisofpatientsonACEinhibitorspresentingwithabdominalpain.

4.9Overdose

Symptomsofoverdosageareseverehypotension,shock,stupor,bradycardia,electrolytedisturbancesandrenalfailure.

Measurestopreventabsorption(e.g.gastriclavage,administrationofabsorbentsandsodiumsulphatewithin30

minutesafterintake)andhasteneliminationshouldbeappliedifingestionisrecent.Ifhypotensionoccurs,thepatient

shouldbeplacedintheshockpositionandsaltandvolumesupplementsshouldbegivenrapidly.Treatmentwith

angiotension-IIshouldbeconsidered.Bradycardiaorextensivevagalreactionsshouldbetreatedbyadministering

atropine.Theuseofapacemakermaybeconsidered.

Captoprilmayberemovedfromcirculationbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup: ACEinhibitors,plain,ATCcode:C09AA01.

Captoprilisahighlyspecific,competitiveinhibitorofangiotensin-Iconvertingenzyme(ACEinhibitors).

ThebeneficialeffectsofACEinhibitorsappeartoresultprimarilyfromthesuppressionoftheplasmarenin-

angiotensin-aldosteronesystem.Reninisanendogenousenzymesynthesisedbythekidneysandreleasedintothe

circulationwhereitconvertsangiotensinogentoangiotensin-Iarelativelyinactivedecapeptide.Angiotensin-Iisthen

convertedbyangiotensinconvertingenzyme,apeptidyldipeptidase,toangiotensin-II.Angiotensin-IIisapotent

vasoconstrictorresponsibleforarterialvasoconstrictionandincreasedbloodpressure,aswellasforstimulationofthe

adrenalglandtosecretealdosterone.InhibitionofACEresultsindecreasedplasmaangiotension-IIwhichleadsto

decreasedvasopressoractivityandtoreducedaldosteronesecretion.Althoughthelatterdecreaseissmall,small

increasesinserumpotassiumconcentrationsmayoccur,alongwithsodiumandfluidloss.Thecessationofthe

negativefeedbackofangiotensin-IIonthereninsecretionresultsinanincreaseoftheplasmareninactivity.

Anotherfunctionoftheconvertingenzymeistodegradethepotentvasodepressivekininpeptidebradykinintoinactive

metabolites.Therefore,inhibitionofACEresultsinanincreasedactivityofcirculatingandlocalkallikrein-kinin-

systemwhichcontributestoperipheralvasodilationbyactivatingtheprostaglandinsystem;itispossiblethatthis

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Reductionsofbloodpressureareusuallymaximal60to90minutesafteroraladministrationofanindividualdoseof

captopril.Thedurationofeffectisdoserelated.Thereductioninbloodpressuremaybeprogressive,sotoachieve

maximaltherapeuticeffects,severalweeksoftherapymayberequired.Thebloodpressureloweringeffectsof

captoprilandthiazide-typediureticsareadditive.

Inpatientswithhypertension,captoprilcausesareductioninsupineanderectbloodpressure,withoutinducingany

compensatoryincreaseinheartrate,norwaterandsodiumretention.

Inhaemodynamicinvestigations,captoprilcausedamarkedreductioninperipheralarterialresistance.Ingeneralthere

werenoclinicallyrelevantchangesinrenalplasmafloworglomerularfiltrationrate.Inmostpatients,the

antihypertensiveeffectbeganabout15to30minutesafteroraladministrationofcaptopril;thepeakeffectwas

achievedafter60to90minutes.Themaximumreductioninbloodpressureofadefinedcaptoprildosewasgenerally

visibleafterthreetofourweeks.Intherecommendeddailydose,theantihypertensiveeffectpersistsevenduringlong-

termtreatment.Temporarywithdrawalofcaptoprildoesnotcauseanyrapid,excessiveincreaseinbloodpressure

(rebound).Thetreatmentofhypertensionwithcaptoprilleadsalsotoadecreaseinleftventricularhypertrophy.

Haemodynamicinvestigationsinpatientswithheartfailureshowedthatcaptoprilcausedareductioninperipheral

systemicresistanceandariseinvenouscapacity.Thisresultedinareductioninpre-loadandafterloadoftheheart

(reductioninventricularfilingpressure).Inaddition,risesincardiacoutput,workindexandexercisecapacityhave

beenobservedduringtreatmentwithcaptopril.Inalarge,placebo-controlledstudyinpatientswithleftventricular

dysfunction(LVEF<40%)followingmyocardialinfarction,itwasshownthatcaptopril(initiatedbetweenthe3 rd

the16 th

dayafterinfarction)prolongedthesurvivaltimeandreducedcardiovascularmortality.Thelatterwas

manifestedasadelayinthedevelopmentofsymptomaticheartfailureandareductioninthenecessityfor

hospitalisationduetoheartfailurecomparedtoplacebo.Therewasalsoareductioninre-infarctionandincardiac

revascularisationproceduresand/orintheneedforadditionalmedicationwithdiureticsand/oranincreaseintheir

dosagecomparedtoplacebo.

Aretrospectiveanalysisshowedthatcaptoprilreducedrecurrentinfarctsandcardiacrevascularisationprocedures

(neitherweretargetcriteriaofthestudy).

Anotherlarge,placebo-controlledstudyinpatientswithmyocardialinfarctionshowedthatcaptopril(givenwithin24

hoursoftheeventandforadurationofonemonth)significantlyreducedoverallmortalityafter5weekscomparedto

placebo.Thefavourableeffectofcaptoprilontotalmortalitywasstilldetectableevenafteroneyear.Noindicationof

anegativeeffectinrelationtoearlymortalityonthefirstdayoftreatmentwasfound.

Captoprilcardioprotectioneffectsareobservedregardlessofthepatient’sageorgender,locationoftheinfarctionand

concomitanttreatmentswithprovenefficacyduringthepost-infarctionperiod(thrombolyticagents,beta-blockersand

acetylsalicylicacid).

TypeIdiabeticnephropathy

Inaplacebo-controlled,multicentredoubleblindclinicaltrialininsulin-dependent(TypeI)diabeteswithproteinuria,

withorwithouthypertension(simultaneousadministrationofotherantihypertensivestocontrolbloodpressurewas

allowed),captoprilsignificantlyreduced(by51%)thetimetodoublingofthebaselinecreatinineconcentration

comparedtoplacebo;theincidenceofterminalrenalfailure(dialysis,transplantation)ordeathwasalsosignificantly

lesscommonundercaptoprilthanunderplacebo(51%).Inpatientswithdiabetesandmicroalbuminuria,treatment

withcaptoprilreducedalbuminexcretionwithintwoyears.

Theeffectsoftreatmentwithcaptoprilonthepreservationofrenalfunctionareinadditiontoanybenefitthatmayhave

beenderivedfromthereductioninbloodpressure.

5.2Pharmacokineticproperties

Captoprilisanorallyactiveagentthatdoesnotrequirebiotransformationforactivity.Theaverageminimalabsorption

isapproximately75%.Peakplasmaconcentrationsarereachedwithin60-90minutes.Thepresenceoffoodinthe

gastrointestinaltractreducesabsorptionbyabout30-40%.Approximately25-30%ofthecirculatingdrugisboundto

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Theapparenteliminationhalf-lifeofunchangedcaptoprilinbloodisabout2hours.Greaterthan95%oftheabsorbed

doseiseliminatedintheurinewithin24hours;40-50%isunchangeddrugandtheremainderareinactivedisulphide

metabolites(captoprildisulphideandcaptoprilcysteinedisulphide).Impairedrenalfunctioncouldresultindrug

accumulation.Therefore,inpatientswithimpairedrenalfunctionthedoseshouldbereducedand/ordosageinterval

prolonged(seesection4.2,Posologyandmethodofadministration).

Studiesinanimalsindicatethatcaptoprildoesnotcrosstheblood-brainbarriertoanysignificantextent.

5.3Preclinicalsafetydata

Animalstudiesperformedduringorganogenesiswithcaptoprilhavenotshownanyteratogeniceffectbutcaptoprilhas

producedfoetaltoxicityinseveralspecies,includingfoetalmortalityduringlatepregnancy,growthretardationand

postnatalmortalityintherat.Preclinicaldatarevealnootherspecifichazardforhumansbasedonconventionalstudies

ofsafetypharmacology,repeateddosetoxicology,genotoxicityandcarcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

Microcrystallinecellulose

Stearicacid50

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

4years.

6.4Specialprecautionsforstorage

Forblisterpacks:

Donotstoreabove30°C.

Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

ThetabletsarepackagedinPVC/aluminiumblisters,inpacksof56tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

Bristol–MyersSquibbPharmaceuticalsLtd.,

Swords,

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8MARKETINGAUTHORISATIONNUMBER

PA0002/039/004

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:30September1986

Dateoflastrenewal:30September2006

10DATEOFREVISIONOFTHETEXT

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