CAPOTEN

Main information

  • Trade name:
  • CAPOTEN Tablets 25 Milligram
  • Dosage:
  • 25 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CAPOTEN Tablets 25 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/056/002
  • Authorization date:
  • 10-11-2006
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Capoten25mgtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains25mgcaptopril.

Excipients:lactose

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

ProductimportedfromSpain:

Whitebiconvextablet,squarewithroundedcornersengravedwith‘25’ononesideandwithquadriscentbarsonthe

other.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension:

Capotenisindicatedforthetreatmentofhypertension.

HeartFailure:

Capotenisindicatedforthetreatmentofchronicheartfailurewithreductionofsystolicventricularfunction,in

combinationwithdiureticsandwhenappropriate,digitalisandbeta-blockers.

MyocardialInfarction:

-Short-term(4weeks)treatment:Capotenisindicatedinanyclinicallystablepatientswithinthefirst24hoursofan

infarction.

-Longtermpreventionofsymtomaticheartfailure:Capotenisindicatedinclinicallystablepatientswithasymptomatic

leftventriculardysfunction(ejectionfraction<40%).

TypeIDiabeticNephropathy:

CapotenisindicatedforthetreatmentofmacroproteinuricdiabeticnephropathyinpatientswithtypeIdiabetes.(See

Section5.1).

4.2Posologyandmethodofadministration

Doseshouldbeindividualisedaccordingtopatient'sprofile(see4.4)andbloodpressureresponse.Therecommended

maximumdailydoseis150mg.

Capotenmaybetakenbefore,duringandaftermeals.

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Therecommendedstartingdoseis25-50mgdailyintwodivideddoses.

Thedosemaybeincreasedincrementally,withintervalsofatleast2weeks,to100-150mg/dayintwodivideddosesas

neededtoreachtargetbloodpressure.Captoprilmaybeusedaloneorwithotherantihypertensiveagents,especially

thiazidediuretics.Aonce-dailydosingregimenmaybeappropriatewhenconcomitantantihypertensivemedication

suchasthiazidediureticsisadded.

Inpatientswithastronglyactiverenin-angiotensin-aldosteronesystem(hyovolaemia,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,uptoamaximumof150mgperdayinindividualdoses.The

doseshouldbeincreasedincrementally,withintervalsofatleast2weekstoevaluatepatientsresponse.

MyocardialInfarction:

-Short-termtreatment:Capotentreatmentshouldbegininhospitalassoonaspossiblefollowingtheappearanceofthe

signsand/orsymptomsinpatientswithstablehaemodynamics.A6.25mgtestdoseshouldbeadministered,witha

12.5mgdose12hourslater.Fromthefollowingday,captoprilshouldbeadministeredina100mg/daydose,intwo

dailyadministrations,for4weeks,ifwarrantedbytheabsenceofadversehaemodynamicreactions.Attheendofthe4

weeksoftreatment,thepatient’sstateshouldbereassessedbeforeadecisionistakenconcerningtreatmentforthepost-

myocardialinfarctionstage.

-chronictreatment:Ifcaptopriltreatmenthasnotbegunduringthefirst24hoursoftheacutemyocardialinfarction

stage,itissuggestedthattreatmentbeinstigatedbetweenthe3 rd

and16 th

daypost-infarctiononcethenecessary

treatmentconditionshavebeenattained(stablehaemodynamicsandmanagementofanyresidualischaemia).Treatment

shouldbestartedinhospitalunderstrictsurveillance(particularlyofbloodpressure)untilthe75mgdoseisreached.

Theinitialdosemustbelow(see4.4),particularlyifthepatientexhibitsnormalorlowbloodpressureattheinitiation

oftherapy.Treatmentshouldbeinitiatedwithadoseof6.25mgfollowedby12.5mg3timesdailyfor2daysandthen

25mg3timesdailyifwarrantedbytheabsenceofadversehaemodynamicreactions.Therecommendeddosefor

effectivecardioprotectionduringlong-termtreatmentis75to150mgdailyintwoorthreedoses.Incasesof

symptomatichypotension,asinheartfailure,thedosageofdiureticsand/orotherconcomitantvasodilatorsmaybe

reducedinordertoattainthesteadystatedoseofcaptopril.Wherenecessary,thedoseofcaptoprilshouldbeadjusted

inaccordancewiththepatient’sclinicalreactions.Captoprilmaybeusedincombinationwithothertreatmentsfor

myocardialinfarctionsuchasthrombolyticagents,beta-blockersandacetylsalicylicacid.

TypeIDiabeticnephropathy:

InpatientswithtypeIdiabeticnephropathy,therecommendeddailydoseofcaptoprilis75-100mgindivideddoses.

Ifadditionalloweringofbloodpressureisdesired,additionalantihypertensivemedicationsmaybeadded.

Renalimpairment:

Sincecaptoprilisexcretedprimarilyviathekidneys,dosageshouldbereducedorthedosageintervalshouldbe

increasedinpatientswithimpairedrenalfunction.Whenconcomitantdiuretictherapyisrequired,aloopdiuretic(e.g.

furosemide),ratherthanathiazidediuretic,ispreferredinpatientswithsevererenalimpairment.

Inpatientswithimpairedrenalfunction,thefollowingdailydosemayberecommendedtoavoidaccumulationof

captopril.

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(ml/min/1.73m 2

(mg) (mg)

>40 25-50 150

21-40 25 100

10-20 12.5 75

<10 6.25 37.5

Elderlypatients:

Aswithotherantihypertensiveagents,considerationshouldbegiventoiniatingtherapywithalowerstartingdose

(6.25mgbid)inelderlypatientswhomayhavereducedrenalfunctionandotherorgandysfunctions(seeaboveand

section4.4).

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

Ahistoryofprevioushypersensitivitytoanyingredientoftheproduct.

Useinpatientswithaorticstenosisoroutflowtractobstruction.Useinpatientswithbilateralrenalarterystenosisina

singlefunctioningkidney.

UseinpatientswithahistoryofangioneuroticoedemarelatingtoprevioustreatmentwithanACEinhibitor.

Pregnancy:

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6).

4.4Specialwarningsandprecautionsforuse

Hypotension:

Rarelyhypotensionisobservedinuncomplicatedhypertensivepatient.Symptomatichypotensionismorelikelyto

occurinhypertensivepatientswhoarevolumeand/orsodiumdepletedbyvigorousdiuretictherapy,dietarysalt

restriction,diarrhoea,vomitingorhaemodialysis.Volumeand/orsodiumdepletionshouldbecorrectedbeforethe

administrationofanACEinhibitorandalowerstartingdoseshouldbeconsidered.

Patientswithheartfailureareatahighriskofhypotensionandalowerstartingdoseisrecommendedwheninitiating

therapywithanACEinhibitor.Cautionshouldbeusedwheneverthedoseofcaptoprilordiureticisincreasedin

patientswithheartfailure.

Aswithanyantihypertensiveagent,excessivebloodpressureloweringinpatientswithischaemiccardiovascularor

cerebrovasculardiseasemayincreasetheriskofmyocardialinfarctionorstroke.Ifhypotensiondevelops,thepatient

shouldbeplacedinasupineposition.Volumerepletionwithintravenousnormalsalinemayberequired.

Renovascularhypertension:

Thereisanincreasedriskofhypotensionandrenalinsufficiencywhenpatientswithbilateralrenalarterystenosisor

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withonlymildchangesinserumcreatinine.Inthesepatients,therapyshouldbeinitiatedunderclosemedical

supervisionwithlowdoses,carefultitrationandmonitoringofrenalfunction.

Renalimpairment:

Incasesofrenalimpairment(creatinineclearance<40ml/min),theinitialdosageofcaptoprilmustbeadjusted

accordingtothepatient’screatinineclearance(see4.2),andthenasafunctionofthepatient’sresponsetotreatment.

Routinemonitoringofpotassiumandcreatininearepartofnormalmedicalpracticeforthesepatients.

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,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(see4.5)

Aorticandmitralvalvestenos/Obstructivehypertropiccardiomyopathy:

ACEinhibitorsshouldbeusedwithcautioninpatientswithleftventricularvalvularandoutflowtractobstructionand

avoidedincasesofcardiogenicshockandhaemodynamicallysignificantobstruction.

Neutropenia/Agranulocytosis:

Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedinpatientsreceivingACEinhibitors,

includingcaptopril.Inpatientswithnormalrenalfunctionandnoothercomplicatingfactors,neutropeniaoccurs

rarely.Captoprilshouldbeusedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressant

therapy,treatmentwithallopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthere

isapre-existingimpairedrenalfunction.Someofthesepatientsdevelopedseriousinfectionswhichinafewinstances

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Ifcaptoprilisusedinsuchpatients,itisadvisedthatwhitebloodcellcountanddifferentialcountsshouldbeperformed

priortotherapy,every2weeksduringthefirst3monthsofcaptopriltherapy,andperiodicallythereafter.

Duringtreatmentallpatientsshouldbeinstructedtoreportanysignofinfection(e.g.sorethroat,fever)whena

differentialwhitebloodcellcountshouldbeperformed.Captoprilandotherconcomitantmedication(see4.5)should

bedrawnifneutropenia(neutrophilslessthan1000/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

insulin,namelyduringthefirstmonthoftreatmentwithanACEinhibitor.

Lactose:

Capotencontainslactose,thereforeitshouldnotbeusedincasesofcongenitalgalactosaemia,glucoseandgalactose

malabsorptionorlactasedeficiencysyndromes(raremetabolicdiseases).

Ethnicdifferences:

Aswithotherangiotensinconvertingenzymeinhibitors,captoprilisapparentlylesseffectiveinloweringblood

pressureinblackpeoplethaninnon-blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblack

hypertensivepopulation.

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ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitortherapyisconsidered

essential,patientsplanningpregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhichhavean

establishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbe

stoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted(seesection4.3and4.6).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Potassiumsparingdiureticsorpotassiumsupplements:

ACEinhibitorsattenuatediureticinducedpotassiumloss.Potassiumsparingdiuretics(e.g.spironolactone,triamterene

oramiloride),potassiumsupplements,orpotassium-containingsaltsubstitutesmayleadtosignificantincreasesin

serumpotassium.Ifconcomitantuseisindicatedbecauseofdemonstratedhypokalaemiatheyshouldbeusedwith

cautionandwithfrequentmonitoringofserumpotassium(see4.4)

Diuretics

(Thiazideorloopdiuretics):Priortreatmentwithhighdosediureticsmayresultinvolumedepletionandariskof

hypotensionwheninitiatingtherapywithcaptopril(see4.4)Thehypotensiveeffectscanbereducedbydiscontinuation

ofthediuretic,byincreasingvolumeorsaltintakeorbyinitiatingtherapywithalowdoseofcaptopril.However,no

clinicallysignificantdruginteractionshavebeenfoundinspecificstudieswithhydrochlorothiazideorfurosemide.

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(see4.4).

Tricyclicantidepressants/Antipsychotics:

ACEinhibitorsmayenhancethehypotensiveeffectsofcertaintricyclicantidepressantsandantipsyschotics(see4.4)

Posturalhypotensionmayoccur.

Allopurinol,procainamide,cytostaticorimmuno-suppressiveagents:

ConcomitantadministrationwithACEinhibitorsmayleadtoanincreasedriskforleucopeniaespeciallywhenthelatter

areusedatahigherthancurrentlyrecommendeddoses.

Non-steroidanti-inflammatorymedicinalproducts:

Ithasbeendescribedthatnon-steroidalanti-inflammatorymedicinalproducts(NSAIDs)andACEinhibitorsexertan

additiveeffectontheincreaseinserumpotassiumwhereasrenalfunctionmaydecrease.Theseeffectsareinprinciple,

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elderlyordehydrated.ChronicadministrationofNSAIDsmayreducetheantihypertensiveeffectofanACEinhibitor.

Sympathomimetics:

MayreducetheantihypertensiveeffectsofACEinhibitors;patientsshouldbecarefullymonitored.

Antidiabetics:

PharmacologicalstudieshaveshownthatACEinhibitors,includingcaptopril,canpotentiatethebloodglucose-

reducingeffectsofinsulinandoralantidiabeticssuchassulphonylureaindiabetics.Shouldthisveryrareinteraction

occur,itmaybenecessarytoreducethedoseofantidiabeticduringsimultaneoustreatmentwithACEinhibitors.

ClinicalChemistry:

Captoprilmaycauseafalse-positiveurinetestforacetone.

4.6Fertility,pregnancyandlactation

Pregnancy:

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapy

shouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

hypotension,hyperkalaemia).(Seesection5.3.)ShouldexposuretoACEinhibitorshaveoccurredfromthesecond

trimesterofpregnancy,ultrasoundcheckofrenalfunctionandskullisrecommended.Infantswhosemothershave

takenACEinhibitorsshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Lactation:

Limitedpharmacokineticdatademonstrateverylowconcentrationsinbreastmilk(seesection5.2).Althoughthese

concentrationsseemtobeclinicallyirrelevant,theuseofCapoteninbreastfeedingisnotrecommendedforpreterm

infantsandforthefirstfewweeksafterdelivery,becauseofthehypotheticalriskofcardiovascularandrenaleffects

andbecausethereisnotenoughclinicalexperience.

Inthecaseofanolderinfant,theuseofCapoteninabreast-feedingmothermaybeconsideredifthistreatmentis

necessaryforthemotherandthechildisobservedforanyadverseeffect.

4.7Effectsonabilitytodriveandusemachines

Aswithotherantihpertensives,theabilitytodriveandusemachinesmaybereduced,namelyatthestartofthe

treatment,orwhenposologyismodified,andalsowhenusedincombinationwithalcohol,buttheseseffectsdependon

theindividual’ssusceptibility.

4.8Undesirableeffects

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuseof

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Bloodandlymphaticdisorders:

VeryRare: neutropenia/agranulocytosis(see4.4),pancytopeniaparticularlyinpatientswithrenaldysfunction(see

4.4),anaemia(includingaplasticandhaemolytic),thrombocytopenia,lymphadenopathy,eosinophilia,

auto-immunediseasesand/orpositiveANA-titres.

Metabolismandnutritiondisorders:

Rare: Anorexia

VeryRare: Hyperkalaemia,hypoglycaemia(see4.4)

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,cardiogenicshock.

Vasculardisorders

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

Respiratory,thoracicandmediastinaldisorders:

Common: Dry,irritating(nonproductive)cough(see4.4)anddyspnoea.

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: Prurituswithorwithoutarashandalopecia.

Uncommon: Angioedema(see4.4)

VeryRare: Urticaria,StevensJohnsonsyndrome,erythemamultiform,photosensitivity,erythroderma,pemphigoid

reactionsandexfoliativedermatitis.

Musculoskeletal,connectivetissueandbonedisorders:

Veryrare: Myalgia,arthralgia.

Renalandurinarydisorders:

Rare: Renalfunctiondisordersincludingrenalfailure,polyuria,oliguria,increasedurinefrequency.

VeryRare: Nephroticsyndrome.

Reproductivesystemandbreastdisorders:

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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,administrationofabsorbentsand

sodiumsulphatewithin30minutesafterintake)andhasteneliminationshouldbeappliedifingestionisrecent.If

hypotensionoccurs,thepatientshouldbeplacedintheshockpositionandsaltandvolumesupplementsshouldbe

givenrapidly.Treatmentwithangiotension-IIshouldbeconsidered.Bradycardiaorextensivevagalreactionsshould

betreatedbyadministeringatropine.Theuseofapacemakermaybeconsidered.

Captoprilmayberemovedfromcirculationbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup: ACEinhibitors,plain,ATCcode:C09AA01.

Captoprilisahighlyspecific,competitiveinhibitorofangiotensin-Iconvertingenzyme(ACEinhibitors).

ThebeneficialeffectsofACEinhibitorsappeartoresultprimarilyfromthesuppressionoftheplasmarenin-

angiotensin-aldosteronesystem.Reninisanendogenousenzymesynthesizedbythekidneysandreleasedintothe

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

mechanismisinvolvedinthehypotensiveeffectofACEinhibitorsandisresponsibleforcertainadversereactions.

Reductionsofbloodpressureareusuallymaximal60to90minutesafteroraladministrationofindividualdoseof

captopril.Thedurationofeffectisdoserelated.Thereductioninbloodpressuremaybeprogressive,sotoachieve

maximaltherapeuticeffects,severalweeksoftherapymayberequired.Thebloodpressureloweringeffectsof

captoprilandthiazide-typediureticsareadditive.

Inpatientswithhypertension,captoprilcausesareductioninsupineanderectbloodpressure,withoutinducingany

compensatoryincreaseinheartrate,norwaterandsodiumretention.

Inhaemodynamicinvestigations,captoprilcausedamarkedreductioninperipheralarterialresistance.Ingeneralthere

werenoclinicallyrelevantchangesinrenalplasmafloworglomerularfiltrationrate.Inmostpatients,the

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achievedafter60to90minutes.Themaximumreductioninbloodpressureofadefinedcaptoprildosewasgenerally

visibleafterthreetofourweeks.Intherecommendeddailydose,theantihypertensiveeffectpersistsevenduringlong-

termtreatment.Temporarywithdrawalofcaptoprildoesnotcauseanyrapid,excessiveincreaseinbloodpressure

(rebound).Thetreatmentofhypertensionwithcaptoprilleadsalsotoadecreaseinleftventricularhypertrophy.

Haemodynamicinvestigationsinpatientswithheartfailure,showedthatcaptoprilcausedareductioninperipheral

systemicresistanceandariseinvenouscapacity.Thisresultedinareductioninpre-loadandafterloadoftheheart

(reductioninventricularfilingpressure).Inaddition,risesincardiacoutput,workindexandexercisecapacityhave

beenobservedduringtreatmentwithcaptopril.Inalarge,placebo-controlledstudyinpatientswithleftventricular

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

the16 th

dayafterinfarction)prolongedthesurvivaltimeandreducedcardiovascularmortality.Thelatterwas

manifestedasadelayinthedevelopmentofsymptomaticheartfailureandareductioninthenecessityfor

hospitalizationduetoheartfailurecomparedtoplacebo.Therewasalsoareductioninre-infarctionandincardiac

revascularisationproceduresand/orintheneedforadditionalmedicationwithdiureticsand/oranincreaseintheir

dosagecomparedtoplacebo.

Aretrospectiveanalysisshowedthatcaptoprilreducedrecurrentinfarctsandcardiacrevascularisationprocedures

(neitherweretargetcriteriaofthestudy).

Anotherlarge,placebo-controlledstudyinpatientswithmyocardialinfarctionshowedthatcaptopril(givenwithin24

hoursoftheeventandforadurationofonemonth)significantlyreducedoverallmortalityafter5weekscomparedto

placebo.Thefavourableeffectofcaptoprilontotalmortalitywasstilldetectableevenafteroneyear.

Noindicationofanegativeeffectinrelationtoearlymortalityonthefirstdayoftreatmentwasfound.

Captoprilcardioprotectioneffectsareobservedregardlessofthepatient’sageorgender,locationofheinfarctionand

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%.Peakplasmaconcentrationarereachedwith60-90minutes.Thepresenceoffoodinthe

gastrointestinaltractreducesabsorptionbyabout30-40%.Approximately25-30%ofthecirculatingdrugisboundto

plasmaproteins.

Theapparenteliminationhalf-lifeofunchangedcaptoprilinbloodisabout2hours.Greaterthan95%oftheabsorbed

doseiseliminatedintheurinewithin24hours;40-50%isunchangeddrugandtheremainderareinactivedisulphide

metabolites(captoprildisulphideandcaptoprilcysteinedisulphide).Impairedrenalfunctioncouldresultindrug

accumulation.Therefore,inpatientswithimpairedrenalfunctionthedoseshouldbereducedand/ordosageinterval

prolonged(see4.2).

Lactation:

Inthereportoftwelvewomentakingoralcaptopril100mg3timesdaily,theaveragepeakmilklevelwas4.7µg/Land

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lessthanthat0.002%thematernaldailydosage.

Studiesinanimalsindicatethatcaptoprildoesnotcrosstheblood-brainbarriertoanysignificantextent.

5.3Preclinicalsafetydata

Animalstudiesperformedduringorganogenesiswithcaptoprilhavenotshownanyteratogeniceffectbutcaptoprilhas

producedfoetaltoxicityinseveralspecies,includingfoetalmortalityduringlatepregnancy,growthretardationand

postnatalmortalityintherat.Preclinicaldatarevealnootherspecifichazardforhumansbasedonconventionalstudies

ofsafetypharmacology,repeateddosetoxicology,genotoxicityandcarcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactose

Maizestarch

Microcrystallinecellulose

Stearicacid.

6.2Incompatibilities

Notapplicable

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove30°C.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

ThetabletsarepackagedinPVC/aluminiumblistersinpacksof60tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

B&SHealthcare

Unit4

BradfieldRoad

Ruislip

Middlesex

HA40NU

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8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1328/56/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:10thNovember2006

10DATEOFREVISIONOFTHETEXT

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