CAPOTEN 50 MG TABLETS

Main information

  • Trade name:
  • CAPOTEN 50 MG TABLETS
  • Dosage:
  • 50 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CAPOTEN 50 MG TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/002/002A
  • Authorization date:
  • 28-09-1988
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Capoten50mgTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletscontains50mgofcaptopril.

Excipients:containslactose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

ProductimportedfromtheUK:

Slightlymottled,white,ovalandbiconvex,engravedwith‘Squibb’and‘482’ononeside,withabreaklineonthe

other.

ProductimportedfromSpain:

Slightlymottled,white,ovalandbiconvex,engravedwith‘Squibb’and‘482’ononeside,withabreaklineontheother

orwhite,oval,biconvextabletswith"50"embossedononesideandscoredontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension:

Capotenisindicatedforthefirstlinetreatmentofhypertension.

HeartFailure:

Capotenisindicatedforthetreatmentofchronicheartfailurewithreductionofsystolicventricularfunction,in

combinationwithdiureticsand,whenappropriate,digitalisandbeta-blockers.

MyocardialInfarction:

Short-term(4weeks)treatment:Capotenisindicatedinanyclinicallystablepatientswithinthefirst24hoursofan

infarction.

Long-termpreventionofsymptomaticheartfailure:Capotenisindicatedinclinicallystablepatientswithasymptomatic

leftventriculardysfunction(ejectionfraction40%).

TypeIDiabeticNephropathy:

CapotenisindicatedforthetreatmentofmacroproteinuricdiabeticnephropathyinpatientswithTypeIdiabetes.(See

section5.1,Pharmacodynamicproperties).

4.2Posologyandmethodofadministration

Doseshouldbeindividualisedaccordingtopatient’sprofile(seesection4.4,Specialwarningsandprecautionsforuse)

andbloodpressureresponse.Therecommendedmaximumdailydoseis150mg.Capotenmaybetakenbefore,during

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Hypertension:

Therecommendedstartingdoseis25-50mgdailyintwodivideddoses.Thedosemaybeincreasedincrementally,with

intervalsofatleast2weeks,to100-150mg/dayintwodivideddosesasneededtoreachtargetbloodpressure.Captopril

maybeusedaloneorwithotherantihypertensiveagents,especiallythiazidediuretics.Aonce-dailydosingregimen

maybeappropriatewhenconcomitantantihypertensivemedicationsuchasthiazidediureticsisadded.

Inpatientswithastrongactiverennin-angiotensin-aldosteronesystem(hypovolaemia,renovascularhypertension,

cardiacdecompensation)itispreferabletocommencewithasingledoseof6.25mgor12.5mg.Theinaugurationof

thistreatmentshouldpreferablytakeplaceunderclosemedicalsupervision.Thesedoseswillthenbeadministeredata

rateoftwoperday.Thedosagecanbegraduallyincreasedto50mgperdayinoneortwodosesandifnecessaryto

100mgperdayinoneortwodoses.

Heartfailure:

Treatmentwithcaptoprilforheartfailureshouldbeinitiatedunderclosemedicalsupervision.Theusualstartingdoseis

6.25mgor12.5mgBIDorTID.Titrationtothemaintenancedose(75–150mgperday)shouldbecarriedoutbasedon

patient’sresponse,clinicalstatusandtolerability,uptoamaximumof150mgperdayindivideddoses.Thedose

shouldbeincreasedincrementally,withintervalsofatleast2weekstoevaluatepatientsresponse.

MyocardialInfarction:

Short-termtreatment:

Capotentreatmentshouldbegininhospitalassoonaspossiblefollowingtheappearanceofthesignsand/orsymptoms

inpatientswithstablehaemodynamics.A6.25mgtestdoseshouldbeadministered,witha12.5mgdosebeing

administered2hoursafterwardsanda25mgdose12hourslater.Fromthefollowingday,captoprilshouldbe

administeredina100mg/daydose,intwodailyadministrations,for4weeks,ifwarrantedbytheabsenceofadverse

haemodynamicreactions.Attheendofthe4weeksoftreatment,thepatient’sstateshouldbereassessedbefore

adecisionistakenconcerningtreatmentforthepost-myocardialinfarctionstage.

Chronic:

Ifcaptopriltreatmenthasnotbegunduringthefirst24hoursoftheacutemyocardialinfarctionstage,itissuggested

thattreatmentbeinstigatedbetweenthe3 rd

and16 th

daypost-infarctiononcethenecessarytreatmentconditionshave

beenattained(stablehaemodynamicsandmanagementofanyresidualischaemia).

Treatmentshouldbestartedinhospitalunderstrictsurveillance(particularlyofbloodpressure)untilthe75mgdoseis

reached.Theinitialdosemustbelow(seesection4.4,Specialwarningsandprecautionsforuse),particularlyifthe

patientexhibitsnormalorlowbloodpressureattheinitiationoftherapy.Treatmentshouldbeinitiatedwithadoseof

6.25mgfollowedby12.5mg3timesdailyfor2daysandthen25mg3timesdailyifwarrantedbytheabsenceof

adversehaemodynamicreactions.Therecommendeddoseforeffectivecardioprotectionduringlong-termtreatmentis

75to150mgdailyintwoorthreedoses.Incasesofsymptomatichypotension,asinheartfailure,thedosageof

diureticsand/orotherconcomitantvasodilatorsmaybereducedinordertoattainthesteadystatedoseofcaptopril.

Wherenecessary,thedoeofcaptoprilshouldbeadjustedinaccordancewiththepatient’sclinicalreactions.Captopril

maybeusedincombinationwithothertreatmentsformyocardialinfarctionsuchasthrombolyticagents,beta-blockers

andacetylsalicylicacid.

TypeIDiabeticNephropathy:

InpatientswithtypeIdiabeticnephropathy,therecommendeddailydoseofcaptoprilis75-100mgindivideddoses.If

additionalloweringofbloodpressureisdesired,additionalantihypertensivemedicationsmaybeadded.

RenalImpairment:

Sincecaptoprilisexcretedprimarilyviathekidneys,dosageshouldbereducedorthedosageintervalshouldbe

increasedinpatientswithimpairedrenalfunction.Whenconcomitantdiuretictherapyisrequired,aloopdiuretic(e.g.

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Inpatientswithimpairedrenalfunction,thefollowingdailydosemayberecommendedtoavoidaccumulationof

captopril.

ElderlyPatients:

Aswithotherantihypertensiveagents,considerationshouldbegiventoinitiatingtherapywithalowerstartingdose

(6.25mgbid)inelderlypatientswhomayhavereducedrenalfunctionandotherorgandysfunctions(seeaboveand

section4.4,Specialwarningsandprecautionsforuse).

Dosagemaybetitratedagainstthebloodpressureresponseandkeptaslowaspossibletoachieveadequatecontrol.

Childrenandadolescents:

Theefficacyandsafetyofcaptoprilhavenotbeenfullyestablished.Theuseofcaptoprilinchildrenandadolescents

shouldbeinitiatedunderclosemedicalsupervision.Theinitialdoseofcaptoprilisabout0.3mg/kgbodyweight.For

patientsrequiringspecialprecautions(childrenwithrenaldysfunction,prematureinfants,new-bornsandinfants)the

startingdoseshouldonlybe0.15mgcaptopril/kgweightbecausetheirrenalfunctionisnotthesameasolderchlidren

andadults.Generally,captoprilisadministeredtochildren3timesaday,butdoseandintervalofdoseshouldbe

adaptedindividuallyaccordingtopatient’sresponse.

4.3Contraindications

1.Historyofprevioushypersensitivitytocaptopril,toanyoftheexcipientsoranyotherACEinhibitor.

2.Useinpatientswithaorticstenosisoroutflowtractobdtruction.Useinpatientswithbilateralrenalarterystenosis,or

unilateralrenalarterystenosisinasinglefunctioningkidney.

3.HistoryofangioedemaassociatedwithpreviousACEinhibitortherapy.

4.Hereditary/idiopathicangioneuroticoedema.

5.Secondandthirdtrimesterorpregnancy(see4.6,PregnancyandLactation).

6.Lactation(see4.6,Pregnancy&Lactation).

4.4Specialwarningsandprecautionsforuse

Hypotension:

Rarelyhypotensionisobservedinuncomplicatedhypertensivepatient.Symptomatichypotensionismorelikelyto

occurinhypertensivepatientswhoarevolumeand/orsodiumdepletedbyvigorousdiuretictherapy,dietarysalt

restriction,diarrhoea,vomitingorhaemodialysis.Volumeand/orsodiumdepletionshouldbecorrectedbeforethe

administrationofanACEinhibitorandalowerstartingdoseshouldbeconsidered.

Patientswithheartfailureareatahighriskofhypotensionandalowerstartingdoseisrecommendedwheninitiating

therapywithanACEinhibitor.Cautionshouldbeusedwheneverthedoseofcaptoprilordiureticisincreasedin

patientswithheartfailure.

Aswithanyantihypertensiveagent,excessivebloodpressureloweringinpatientswithischaemiccardiovascularor

cerebrovasculardiseasemayincreasetheriskofmyocardialinfarctionorstroke.Ifhypotensiondevelops,thepatient

Creatinineclearance

(ml/min/1.73m 2

Dailystartingdose(mg) Dailymaximumdose(mg)

>40

21-40 25-50

10-20

<10 12.5

6.25 75

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Renovascularhypertension:

Thereisanincreasedriskofhypotensionandrenalinsufficiencywhenpatientswithbilateralrenalarterystenosisor

stenosisofthearterytoasinglefunctioningkidneyaretreatedwithACEinhibitors.Lossofrenalfunctionmayoccur

withonlymildchangesinserumcreatinine.Inthesepatients,therapyshouldbeinitiatedunderclosemedical

supervisionwithlowdoses,carefultitrationandmonitoringofrenalfunction.

RenalImpairment:

Incasesofrenalimpairment(creatinineclearance 40ml/min),theinitialdasageofcaptoprilmustbeadjusted

accordingtothepatient’screatinineclearance(see4.2,Posologyandmethodofadministration),andthenasafunction

ofthepatient’screatinineclearance(see4.2Posologyandmethodofadministration),andthenasafunctionofthe

patient’sresponsetotreatment.Routinemonitoringofpotassiumandcreatininearepartofnormalmedicalpractisefor

thesepatients.

Angioedema:

Angioedemaoftheextremities,face,lips,mucousmembranes,tongue,glottisorlarynxmayoccurinpatientstreated

withACEinhibitorsparticularlyduringthefirstweeksoftreatment.However,inrarecases,severeangioedemamay

developafterlong-termtreatmentwithanACEinhibitor.Treatmentshouldbediscontinuedpromptly.Angioedema

involvingthetongue,glottisorlarynxmaybefatal.Emergencytherapyshouldbeinstituted.Thepatientshouldbe

hospitalizedandobservedforatleast12to24hoursandshouldnotbedischargeduntilcompleteresolutionof

symptomshasoccurred.

Cough:

CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnon-productive,persistentand

resolvesafterdiscontinuationoftherapy.

HepaticFailure:

Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceandprogressesto

fulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeisnotunderstood.Patients

receivingACEinhibitorswhodevelopjaundiceormarkedelevationsofhepaticenzymesshoulddiscontinuetheACE

inhibitorandreceiveappropriatemedicalfollowup.

Hyperkalaemia:

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,includingcaptopril.

Patientsatriskforthedevelopmentofhyperkalaemiaincludethosewithrenalinsufficiency,diabetesmellitus,orthose

usingconcomitantpotassium-sparingdiuretics,potassiumsupplementsorthoseusingconcomitantpotassium-sparing

diuretics,potassiumsupplementsorpotassium-containingsaltsubstitutes;orthosepatientstakingotherdrugs

associatedwithincreasesinserumpotassium(e.g.heparin).Ifconcomitantuseoftheabovementionedagentsis

deemedappropriate,regularmonitoringofserumpotassiumisrecommended.

Lithium:

Thecombinationoflithiumandcaptoprilisnotrecommended(seesection4.5,Interactionswithothermedicamentsand

otherformsofinteraction)).

Aorticandmitralvalvestenos/Obstructivehypertropiccardiomyopathy:

ACEinhibitorsshouldbeusedwithcautioninpatientswithleftventricularvalvularandoutflowtractobstructionand

avoidedincasesofcardiogenicshockandhaemodynamicallysignificantobstruction.

Neutropenia/Agranulocytosis:

Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedinpatientsreceivingACEinhibitors,

includingcaptopril.Inpatientswithnormalrenalfunctionandnoothercomplicatingfactors,neutropeniaoccursrarely.

Captoprilshouldbeusedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressanttherapy,

treatmentwithallopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthereisapre-

existingimpairedrenalfunction.Someofthesepatientsdevelopedseriousinfectionswhichinafewinstancesdidnot

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Ifcaptoprilisusedinsuchpatients,itisadvisedthatwhitebloodcellcountanddifferentialcountsshouldbeperformed

priortotherapy,every2weeksduringthefirst3monthsofcaptopriltherapy,andperiodicallytereafter.Dring

treatmentallpatientsshouldbeinstructedtoreportanysignofinfection(e.g.sorethroat,fever)whenadifferential

whitebloodcellcountshouldbeperformed.Captoprilandotherconcomitantmedication(seesection4.5,Interactions

withothermedicamentsandotherformsofinteraction)shouldnotbedrawnifneutropenia(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

undergoinglowdensitylipoproteinapheresiswithdextransulphateabsorption.Inthesepatients,considerationshould

begiventousingadifferenttypeofdialysismembraneoradifferentclassofmedication.

Surgery/Anaesthesia:

Hypotensionmayoccurinpatientsundergoingmajorsurgeryorduringtreatmentwithanaestheticagentsthatare

knowntolowerbloodpressure.Ifhypotensionoccurs,itmaybecorrected.

Diabeticpatients:

Theglycaemialevelsshouldbecloselymonitoredindiabeticpatientspreviouslytreatedwithoralantidiabeticdrugsor

insulin,namelyduringthefirstmonthoftreatmentwithanACEinhibitor.

Lactose:

Capotencontainslactose,thereforepatientswithrarehereditaryproblrmsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

Ethnicdifferences:

Aswithotherangiotensinconvertingenzymeinhibitors,captoprilisapparentlylesseffectiveinloweringblood

pressureinblackpeoplethaninnon-blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblack

hypertensivepopulation.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Potassiumsparingdiureticsorpotassiumsupplements:

ACEinhibitorsattenuatediureticinducedpotassiumloss.Potassiumsparingdiuretics(e.g.spironolactone,triamterene

oramiloride),potassiumsupplements,orpotassium-containingsaltsubstitutesmayleadtosignificantincreasesin

serumpotassium.Ifconcomitantuseisindicatedbecauseofdemonstratedhypokalaemiatheyshouldbeusedwith

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Diuretics:

(Thiazideorloopdiuretics):Priortreatmentwithhighdosediureticsmayresultinvolumedepletionandariskof

hypotensionwheninitiatingtherapywithcaptopril(seesection4.4,Specialwarningsandprecautionsforuse).The

hypotensiveeffectscanbereducedbydiscontinuationofthediuretic,byincreasingvolumeorsaltintakeorby

initiatingtherapywithalowdoseofcaptopil.However,noclinicallysignificantdruginteractionshavebeenfoundin

specificstudieswithhydrochlorothiazideorfurosemide.

Otherhypertensiveagents:

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

long-actingcalciumchannelblockers).Concomitantuseoftheseagentsmayincreasethehypotensiveeffectsof

captopril.Treatmentwithnitroglycerineandothernitrates,orothervasodilators,shouldbeusedwithcaution.

Treatmentofacutemyocardialinfarction:

Captoprilmaybeusedconcomitantlywithacetylsalicylicacid(atcardiologicdoses),thrombolytics,beta-blockers

and/ornitratesinpatientswithmyocardialinfarction.

Lithium:

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreprtedduringconcomitantadministration

oflithiumwithACEinhibitors.Concomitantuseofthiazidediureticsmayincreasetheriskoflithiumtoxicityand

enhancethealreadyincreasedriskoflithiumtoxicitywithACEinhibitors.Useofcaptoprilwithlithiumisnot

recommended,butifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsshouldbe

performed(seesection4.4,Specialwarningsandprecautionsforuse).

Tricyclicantidepressants/Antipsychotics:

ACEinhibitorsmayenhancethehypotensiveeffectsofcertaintricyclicantidepressantsandantipsychotics(seesection

4.4,Specialwarningsandprecautionsforuse).Posturaltensionmayoccur.

Allopurinol,procainamide,cytostaticorimmuno-suppressiveagents:

ConcomitantadministrationwithACEinhibitorsmayleadtoanincreasedriskofleucopeniaespeciallywhenthelatter

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.

4.6Fertility,pregnancyandlactation

Pregnancy:

Capotenhasbeenshowntobelethaltorabbitandsheepfoetuses.Therewerenofoetotoxiceffectstohamsterorrat

foetuses.

Capoteniscontraindicatedinpregnancyandshouldnotbeusedinwomenofchildbearingpotentialunlessprotected

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Exposureofthemotherinthesecondandthirdtrimestersofpregnancyhasbeenassociatedwitholigohydramniosand

neonatalhypertensionand/oranuria.

Lactation:

Capoteniscontraindicatedinthelactationperiod.

4.7Effectsonabilitytodriveandusemachines

Aswithotherantihypertensives,theabilitytodriveandusemachinesmaybereduced,namelyatthestartofthe

treatment,orwhenposologyismodified,andalsowhenusedincombinationwithalcohol,buttheseeffectsdependon

theindividual’ssusceptibility.

4.8Undesirableeffects

Verycommon(1/10);

Common(1/100to<1/10);

Uncommon(1/1,000to1/100);

Rare(1/10,000to1/1,000);

Veryrare(1/10,000),

Notknown(cannotbeestimatedformtheavailabledata).

Undesirableeffectsreportedforcaptopriland/orACEinhibitorinclude:

Bloodandlymphaticdisorders:

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

particularlyinpatientswithrenaldysfunction(seesection4.4,Specialwarningsandprecautionsforuse),anaemia

(incudingaplasticandhaemolytic),thrombocytopenia,lymphadenopathy,eosinophilia,auto-immunediseasesand/r

positiveANA-titres.

Metabolicandnutritiondisorders:

Rare: Anorexia

Veryrare: Hyperkalaemia,hypoglycaemia(seesection4.4Specialwarningsandprecautionsforuse)

Psychiatricdisorders:

Common: Sleepdisorders.

VeryRare: Confusion,depression.

Nervoussystemdisorders:

Common: Tasteimpairment,dizziness.

Rare: Drowsiness,headacheandparaesthesia.

Veryrare: Cerebrovascularincidents,includingstroke,andsyncope.

Eyedisorders:

Veryrare: Blurredvision.

Cardiacdisorders:

Uncommon: Tachycardiaortachyarrhythmias,anginapectoris,palpitations.

Veryrare: Cardiacarrest.

Vasculardisorders:

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

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Respiratory,thoracicandmediastinaldisorders:

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

dyspnoea.

Veryrare: Bronchospasm,rhinitis,allergicalveoltis/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: Prurituswithorwithoutarashandalopecia.

Uncommon: Angioedema(seesection4.4,Specialwarningsandprecautionsforuse)

Veryrare: Uticaria,stevensJohnsonsyndrome,erythemamultiform,photosensitivity,erythroderma,pemphigoid

reactionsandexfoliativedermatitis.

Musculoskeletal,connectivetissueandbonedisorders:

Veryrare: Myalgia,arthralgia.

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.

4.9Overdose

Symptomsofoverdosageareseverehypotension,shock,stupor,bradycardia,electrolytedisturbancesandrenalfailure.

Measurestopreventabsorption(e.g.gastriclavage,administrationofabsorbentsandsodiumsulphatewithin30

minutesafterintake)andhasteneliminationshouldbeappliedifingestionisrecent.Ifhypotensinoccurs,thepatient

shouldbeplacedintheshockpositionandsaltandvolumesupplementsshouldbegivenrapidly.Treatmentwith

angiotension-IIshouldbeconsidered.Bradycardiaorextensivevagalreactionsshouldbetreatedbyadministering

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:ACEinhibitors,plain,ATCcode:C09AA01.

CaptoprilisahighlyspecificcompetitiveinhibitorofangiotensinI-convertingenzyme(ACEinhibitors).

ThebeneficialeffectsofAceinhibitorsappeartoresultfromthesuppressionoftheplasmarennin-angiotensin-

aldosteronesystem.Reninisanendogenousenzymesynthesizedbythekidneysandreleasedintothecirculationwhere

itconvertsangiotensinogentoangiotensin-Iarelativelyinactivedecapeptide.

Angiotensin-Iisthenconvertedbyangiotensinconvertingenzyme,apeptidyldipeptidase,toangiotensin-II.

Angiotensin-IIisapotentvasoconstrictorresponsibleforarterialvasoconstrictionandincreasedbloodpressure,aswell

asforstimulationoftheadrenalglandtosecretealdosterone.InhibitionofACEresultsindecreasedplasma

angiotensin-IIwhichleadstodecreasedvasopressoractivityandtoreducedaldosteronesecretion.Althoughthelatter

decreaseissmall,smallincreasesinserumpotassiumconcentrationsmayoccur,alongwithsodiumandfluidloss.

Thecessationofthenegativefeedbackofangiotensin-IIontherenninsecretionresultsinanincreaseoftheplasma

renninactivity.

Anotherfunctionoftheconvertingenzymeistodegradethepotentvasodepressivekininpeptidebradykinintoinactive

metabolites.Therefore,inhibitionofACEresultsinanincreasedactivityofcirculatingandlocalkallikrein-kinin-

systemwhichcontributestoperipheralvasodilationbyactivatingtheprostaglandinsystem;itispossiblethatthis

mechanismisinvolvedinthehypotensiveeffectofACEinhibitorsandisresponsibleforcertainadversereactions.

Reductionsofbloodpressureareusuallymaximal60to90minutesafteroraladministrationofindividualdoseof

captopril.Thedurationofeffectisdoserelated.Thereductioninbloodpressuremaybeprogressive,sotoachieve

maximaltherapeuticeffects,severalweeksoftherapymayberequired.Thebloodpressureloweringeffectsof

captoprilandthiazide-typediureticsareadditive.

Inpatientswithhypertension,captoprilcausesareductioninsupineanderectbloodpressure,withoutinducingany

compensatoryincreaseinheartrate,norwaterandsodiumretention.

Inhaemodynamicinvestigations,captoprilcausedamarkedreductioninperipheralarterialresistanceIngeneralthere

werenoclinicallyrelevantchangesinperipheralarterialresistance.Ingeneraltherewerenoclinicallyrelevantchanges

inrenalplasmafloworglomerularfiltrationrate.Inmostpatients,theantihypertensiveeffectbeganabout15to30

minutesafteroraladministrationofcaptopril;thepeakeffectwasachievedafter60to90minutes.Themaximum

reductioninbloodpressureofadefinedcaptoprildosewasgenerallyvisibleafterthreetofourweeks.Inthe

recommendeddailydose,theantihypertensiveeffectpersistsevenduringlong-termtreatment.Temporarywithdrawal

ofcaptoprildoesnotcauseanyrapid,excessiveincreaseinbloodpressure(rebound).Thetreatmentofhypertension

withcaptoprilleadsalsotoadecreaseinleftventricularhypertrophy.

Haemodynamicinvestigationsinpatientswithheartfailure,showedthatcaptoprilcausedareductioninperipheral

systemicresistanceandariseinvenouscapacity.Thisresultedinareductioninpre-loadandafterloadoftheheart

(reductioninventricularfilingpressure).

Inaddition,risesincardiacoutput,workindexandexercisecapacityhavebeenobservedduringtreatmentwith

captopril.Inalarge,placebo-controlledstudyinpatientswithleftventriculardysfunction(LVEF 40%)following

myocardialinfarction,itwasshownthatcaptopril(initiatedbetweenthe3 rd

tothe16 th

dayafterinfarction)prolonged

thesurvivaltimeandreducedcardiovascularmortality.Thelatterwasmanifestedasadelayinthedevelopmentof

symptomaticheartfailureandareductioninthenecessityforhospitalizationduetoheartfailureandareductioninthe

necessityforhospitalizationduetoheartfailureandareductioninthenecessityforhospitalizationduetoheartfailure

comparedtoplacebo.Therewasalsoareductioninre-infarctionandincardiacrevascularisationproceduresand/orin

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Aretrospectiveanalysisshowedthatcaptoprilreducedrecurrentinfarctsandcardiacrevascularisationprocedures

(neitherweretargetcriteriaofthestudy).

Anotherlarge,placebo-controlledstudyinpatientswithmyocardialinfarctionshowedthatcaptopril(givenwithin24

hoursoftheeventandforadurationofonemonth)significantlyreducedoverallmortalityafter5weekscomparedto

placebo.Thefavourableeffectofcaptoprilontotalmortalitywasstilldetectableevenafteroneyear.Noindicationofa

negativeeffectinrelationtoearlymortalityonthefirstdayoftreatmentwasfound.

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,treatmentwith

captoprilreducedalbuminexcretionwithintwoyears.

Theeffectsoftreatmentwithcaptoprilonthepreservationofrenalfunctionareinadditiontoanybenefitthatmayhave

beenderivedfromthereductioninbloodpressure.

5.2Pharmacokineticproperties

Captoprilisanorallyactiveagentthatdoesnotrequirebiotransformationforactivity.Theaverageminimalabsorption

isapproximately75%.Peakplasmaconcentrationsarereachedwith60-90minutes.Thepresenceoffoodinthe

gastrointestinaltractreducesabsorptionbyabout30-40%.Approximately25-30%ofthecirculatingdrugisboundto

plasmaproteins.

Theapparenteliminationhalf-lifeofunchangedcaptoprilinbloodisabout2hours.Greaterthan95%oftheabsorbed

doseiseliminatedintheurinewithin24hours;40-50%isunchangeddrugandtheremainderareinactivedisulphide

metabolites(captoprildisulphideandcaptoprilcysteinedisulphide).Impairedrenalfunctioncouldresultindrug

accumulation.Thereforeinpatientswithimpairedrenalfunctionthedoseshouldbereducedand/ordosageinterval

prolonged(seesection4.2,Posologyandmethodofadministration).

Studiesinanimalsindicatethatcaptoprildoesnotcrosstheblood-brainbarriertoanysignificantextent.

5.3Preclinicalsafetydata

Animalstudiesperformedduringorganogenesiswithcaptoprilhavenotshownanyteratogeniceffectbutcaptoprilhas

producedfoetaltoxicityinseveralspecies,includingfoetalmortalityduringlatepregnancy,growthretardationand

postnatalmortalityintherat.Preclinicaldatarevealnootherspecifichazardforhumansbasedonconventionalstudies

ofsafetypharmacology,repeateddosetoxicology,genotoxicityandcarcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactose

Maizestarch

Microcrystallinecellulose

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6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateforthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.

Storeintheoriginalcontainer.

6.5Natureandcontentsofcontainer

Blisterpackscontaining30and56tabletscontainedinanoutercardboardcarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA465/2/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28September1988

Dateoflastrenewal:28September2008

10DATEOFREVISIONOFTHETEXT

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