CAPOTEN 50 Milligram Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
CAPTOPRIL
Available from:
Bristol-Myers Squibb Pharmaceuticals uc
ATC code:
C09AA01
INN (International Name):
CAPTOPRIL
Dosage:
50 Milligram
Pharmaceutical form:
Tablets
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
ACE inhibitors, plain
Authorization status:
Authorised
Authorization number:
PA0002/039/002
Authorization date:
1981-04-02

Package Leaflet:Informationforthe user

CAPOTEN™50 mgTablets

Captopril

Readallofthisleafletcarefully beforeyoustarttakingthismedicinebecauseitcontains

important informationforyou.

- Keepthis leaflet.Youmayneedtoreaditagain.

- Ifyou haveanyfurtherquestions,askyourdoctororpharmacist.

- Thismedicinehasbeen prescribedforyou only. Do notpassitonto others. Itmay harm

them,eveniftheirsigns ofillness are the same as yours.

- Ifyou getanysideeffects, talkto yourdoctororpharmacist.Thisincludesanypossible

sideeffectsnot listedinthisleaflet.See section4.

Whatisinthisleaflet

1. WhatCapotenisandwhatitisused for

2. Whatyou needto knowbeforeyoutake Capoten

3. Howto takeCapoten

4. Possiblesideeffects

5. Howto storeCapoten

6. Contentsofthepackandotherinformation

1. WhatCapotenisandwhatitisusedfor

Thename ofthis medicineis Capoten.Eachtabletcontains50 mgcaptoprilastheactive

ingredient.

Capotenbelongstothegroup ofmedicinescalled Angiotensin ConvertingEnzyme(ACE)

Inhibitors. ACEinhibitorsworkbyhelpingto widen yourblood vessels, which then makeit

easierforyourhearttopump bloodthrough them.

Capotenisusedtotreathigh bloodpressureand certain heartconditions. Ifhigh blood pressureis

leftuncontrolled itcan increasetheriskofheartdiseaseorstroke. Capoten worksbylowering

yourbloodpressurewhichreduces thisrisk.

Capotencanalso help peoplewhoseheartnolongerpumpsblood aswell asit oncedid.

Thiscondition isknown asheartfailure.

Capotenmayalsobe usedtotreatpatients whorecentlysufferedaheartattack.Aheartattack

happensonceoneofthemajorbloodvesselssupplyingbloodtotheheartmusclebecomes

blocked.Thismeansthatthe heartdoes notreceive theoxygenitneeds andtheheartmuscle

becomes damaged.

In addition, Capoten can beusedforthetreatmentofkidneydiseasein patientswith diabetes.

2. Whatyouneedto knowbeforeyoutakeCapoten

DonottakeCapoten:

-ifyou areallergictocaptopriloranyoftheotheringredientsofthismedicine(listedin section

6).

- ifyou aremorethan3 monthspregnant. (Itisalso betterto avoid Capotenin earlypregnancy–

see pregnancysection).

-ifyou have everhadanallergicreactionto anyingredientsofCapotenorto anyother

medicines, includingotherACEinhibitors.

-ifyouhave everhadareactionwhich included swellingofthehands,lips,faceortonguewhere

thecausewasunknown.

-if you sufferfromanyauto-immune disease(e.g. rheumatoid arthritis, systemiclupus

erythematosusorscleroderma).

-ifyou havediabetesorimpaired kidneyfunction andyou aretreated withablood pressure

loweringmedicinecontainingaliskiren.

Ifanyoftheaboveaffectsyou, oryou areunsureiftheydo, tellyourdoctorwhowillbeableto

adviseyou.

Warningsandprecautions

Talkto yourdoctororpharmacistbeforetakingCapoten.

Ifyou aretakinganyofthefollowingmedicinesusedto treathigh blood pressure:

- an angiotensinIIreceptorblocker(ARBs)(alsoknownas sartans–forexample

valsartan,telmisartan,irbesartan),inparticularifyouhavediabetes-related kidney

problems.

- aliskiren.

Yourdoctormaycheckyourkidneyfunction, bloodpressure,andthe amountofelectrolytes(e.g.

potassium)in yourblood atregularintervals.

Seealsoinformationundertheheading‘Do nottakeCapoten’.

Youmusttellyourdoctorifyou:

-thinkyou are(ormightbecome)pregnant. Capotenisnotrecommended in earlypregnancy, and

mustnotbetaken ifyou aremorethan 3 monthspregnant, asitmaycauseseriousharmto your

babyifusedatthatstage (see pregnancysection).

-sufferfromkidneydisease.

-sufferfromliverdisease.

-areundergoingdialysis.

-sufferfromheartdisease,inparticularproblems withthe valves ofthe heart.

-have diabetes.

-have recentlysufferedfromexcessive vomitingordiarrhoea.

-arereceivingimmuno-suppressanttherapy.

Ifyouare tohave desensitisationtreatmentforwasp orbeestingsyou should tellthedoctorwho

istreatingyou thatyou aretakingCapoten.

Ifyou areaboutto havetreatmentfortheremovalofcholesterolfromyourbloodbyamachine,

(calledLDLapheresis)youshould tellyourdoctoryou aretakingCapoten.

Tellyourdoctoryou aretakingCapoten tabletsbeforeyou haveanyblood orurinetestsas

Capotentablets mayinterfere withtheresults ofsome tests.

SomeAfro-Caribbean patientsmayrequirehigherdosesofCapoten toobtainan adequate

reduction in blood pressure.

Children and adolescents

Safetyand effectivenessinchildren havenotbeen established. Newborns andinfants maybe at

greaterriskto thelowblood pressureside-effectsofCapoten.

Other medicinesandCapoten

Tellyourdoctororpharmacistifyou aretaking, haverecentlytakenormight takeanyother

medicines.Itisespeciallyimportanttotellyourdoctorifyou aretakinganyofthefollowing:

-non steroidalanti-inflammatorypainkillersNSAIDs(e.g. indomethacin, ibuprofen).

-immunosuppressants(e.g. azathioprineand cyclophosphamide).

-potassiumsupplements,saltsubstitutescontainingpotassiumoranyothermedicines whichcan

increasepotassiumin yourbody, e.g. (amiloride, spironolactone).

-watertablets(diuretics).

-medicines forgout(e.g. allopurinol).

-medicines fordiabetes(astheamountyou needto usemayhaveto bechangedwhiletaking

Capoten).

-medicinesthatcause dilationofthebloodvessels(e.g. minoxidil, clonidine).

-medicines totreatmentalhealthproblemsincludingdepression(such aslithiumor

amitriptyline).

-anyothermedicinestotreathigh blood pressure(e.g.beta-blockerssuch aspropanolol,

atenololorcalciumchannelblockerssuch asamlodipine, nifedipine).

-any medicinethatmaybeused duringand afteraheartattack.

Yourdoctormayneed to changeyourdoseand/orto takeotherprecautions:

Ifyou aretakingan angiotensin IIreceptorblocker(ARB)oraliskiren(seealsoinformation

undertheheadings‘Donottake Capoten’and‘Warnings andprecautions’.

Capoten with foodand drink

Capotencanbetaken withorwithoutfood. Yourdoctormayadviseyou to limittheamountof

saltinyourdietwhile takingCapoten.

ModerateamountsofalcoholwillnotaffectCapoten,however, you should checkwith your

doctorfirstto seeifdrinkingisadvisableforyou.

Pregnancyand breastfeeding

Ifyou arepregnantorbreast-feeding, thinkyoumaybepregnantorareplanningtohaveababy,

askyourdoctororpharmacistforadvicebeforetakingthis medicine.

Pregnancy

You musttellyourdoctorifyou thinkyou are(ormightbecome)pregnant. Yourdoctorwill

normally adviseyoutostop takingCapoten beforeyou becomepregnantorassoonasyou know

you arepregnantand willadviseyou to takeanothermedicineinstead ofCapoten. Capotenisnot

recommended in earlypregnancy, and mustnotbetaken when morethan 3 monthspregnant,asit

maycauseseriousharmtoyourbabyifused afterthethird month ofpregnancy.

Breastfeeding

Tellyourdoctorifyouarebreast-feedingoraboutto startbreast-feeding. Breast-feedingnewborn

babies (firstfewweeks afterbirth),andespeciallypremature babies,isnotrecommendedwhilst

takingCapoten.

Inthe case ofanolderbabyyourdoctorshould adviseyou on thebenefitsand risksoftaking

Capotenwhilstbreast-feeding, compared with othertreatments.

Ifyouare due tohave surgery

Beforesurgeryand anaesthesia(even atthedentist)you should tellyourdoctorordentistthatyou

aretakingCapoten astheremaybeasuddenfallin yourblood pressure.

Drivingandusingmachines

Capotencanaffectyourabilityto drive, usuallywhenyou firststarttakingyourmedicineorif

yourdoctorchangesyourdose. Ifyou do feellight-headed ordizzywhen takingCapoten tablets,

you should notdriveorusemachinery.

Capotencontains lactose

Capotencontains50 mglactosewhichisatypeofsugar. Ifyou havebeen told byyourdoctor

thatyouhave anintolerance tosome sugars,contactyourdoctorbeforetakingthismedicinal

product.

3.HowtotakeCapoten

Always take this medicineexactlyas yourdoctororpharmacisthas toldyou.Checkwithyour

doctororpharmacistifyou arenotsure.

Therecommended dosesare:

Forthe treatmentofhigh blood pressure

Theusualstartingdoseis12.5 – 25 mgtwice a day.Yourdoctormaygraduallyincreasethis dose

to 100– 150 mgaday. You mayalso need to begivenothermedicinestoloweryourblood

pressure.

Olderpatientsand thosewithkidneyproblemsmaybegiven alowerstartingdose.

In heartfailure

Theusualstartingdoseis6.25 – 12.5 mgtwo orthreetimesaday. Yourdoctormaygradually

increasethisdoseto amaximumof150 mg aday.

Aftera heartattack

Theusualstartingdose is6.25 mg, which willthen beincreased byyourdoctortoamaximumof

mga day.

Forthe treatmentofdiabetic patients withkidneydisease

Theusualdose is75– 100 mg aday.

Forchildren

Thestartingdoseis0.3 mg/kgbodyweight, which maybeincreasedgraduallybythedoctor.

Forchildren withkidneyproblems, prematurebabiesand newborn babiesandinfants

Thestartingdoseshould be0.15 mg/kg bodyweight.

Doctors sometimes prescribe differentdosestothe above andifthis appliestoyou,you should

discussitwith yourdoctor.Thetabletscan bebroken in halffora25 mgdose.

Sometimes patients mayfeeldizzyaftertakingthe firstone ortwodoses ofCapoten.Ifthis

happensto you,liedown untilthesesymptomsdisappear.

You shouldtrytotake Capotenataboutthe same time eachmorning.Itcanbetakenbefore,

duringoraftermeals.

Even ifyou feelwellcontinuetotakeCapoten untilyourdoctortellsyou otherwise.

IfyoutakemoreCapotenthanyoushould

Ifyou oranyoneelsetakestoo manytabletsyou should go to yournearesthospitalemergency

departmentortellyourdoctorimmediately.Takethecarton andanyremainingtabletsyou have

with you.

Ifyouforgetto takeCapoten

Ifyoumissadosedonotworry.Justcarryontakingyournormaldosewhen thenextoneisdue.

Do nottakeadoubledoseto makeup foraforgottendose.

Ifyou haveanyfurtherquestionsontheuseofthisproduct,askyourdoctororpharmacist.

4.Possible side effects

Like allmedicines,this medicine cancauseside effects,althoughnoteverybodygetsthem.Ifyou

experience anyofthe followingreactionsstoptakingCapotenandcontactyourdoctor

immediately:

Swellingofthehands,face, lipsortongue

Difficultyinbreathing

Asudden, unexpected rash orburning, red orpeelingskin

Sorethroatorfever

Severedizzinessorfainting

Severe stomachpain

Unusuallyfastorirregularheartbeat

Yellowingoftheskin and/oreyes(jaundice)

Commonsideeffects(affectingbetween1in10 and 1in 100people)

Dizziness Drymouth

Itching Sleep problems

Rashes Diarrhoeaorconstipation

Hairloss Dry, irritatingcough

Changes inthe waythings taste Upsetstomach, feelingsick,vomiting,

Shortnessofbreath abdominalpain

Indigestion Stomach ulcers

Uncommonside effects(affectingbetween 1 in 100and 1 in1000 people)

Headache Pinsand needles, numbnessortingling

Fast,irregular, louderheartbeat Tiredness

Chestpain Generallyfeelingunwell

Lowblood pressure Lookingpale

Reducedblood flowtothehandsandfeet Swellingoftheeyesand lips(angioedema)

(e.g. Raynaud’sphenomenon)

Flushing Loss ofappetite

Muscle weakness

Rare side effects(affectingbetween 1in 1000and 1in10,000 people)

Drowsiness Mouthulcers

Changesinfrequencyofpassingurine Kidneydisordersorfailure

Veryrare side effects(affectingless than 1in 10,000people)

Impaired liverfunctionandraised Liverdamage,inflammation

liverenzymes oftheliverorjaundice

Confusion, depression,fainting Muscle pain

Mini-stroke Joint pain

Blurred vision Wheezingordifficultybreathing

Heartproblemsincluding Rashes orskinreactions

heartattack,andchestinfections

Inflammationofthe pancreas Swellingofbreasttissueinmen

Runnynose Fever

Swollentongue Sensitivityoftheskintolight

Impotence Changes inlevelsofcellsand/orchemicals

Stevens-Johnson syndrome in theblood orlymphaticsystems

(aseriousillnesswith blisteringoftheskin, (e.g. red orwhiteblood cells, potassium,

mouth,eyes andgenitals) sodium, sugars)

Ifanyofthe side effects become serious,orifyounotice anyside effects notlistedinthis leaflet,

pleasetellyourdoctororpharmacistimmediately. Itwillhelp ifyou makeanoteofwhatyou

experienced,when itstarted and howlongitlasted.

Reportingofside effects:

Ifyou getanysideeffects, talkto yourdoctor, pharmacistornurse.Thisincludesanypossible

sideeffects notlistedinthis leaflet.Youcanalsoreportsideeffects directlyvia:

HPRAPharmacovigilance

EarlsfortTerrace

IRL-Dublin 2

Tel:+353 16764971

Fax:+353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Byreportingsideeffects youcanhelpprovidemoreinformation onthesafetyofthismedicine.

5. Howto storeCapoten

Keep thismedicineoutofthesightand reachofchildren.

Do notstoreabove25 °C.Storeintheoriginal package toprotectfrommoisture,andmake sure

theydo notgettoo hotordamp;so do notleaveyourtabletsneararadiator, onawindowsillor

in thebathroom.

Do notusethismedicineaftertheexpirydate whichisstatedonthe carton.Theexpirydate refers

to thelastdayofthatmonth.

Do notthrowawayanymedicines via wastewaterorhouseholdwaste.Askyourpharmacisthow

to throwawaymedicinesyou no longeruse.Thesemeasureswillhelp protecttheenvironment.

6. Contentsofthepackandotherinformation

WhatCapoten contains

-The active substance iscaptopril(50 mg).

-Theotheringredientsarelactose monohydrate,maizestarch,microcrystalline celluloseand

stearic acid.

WhatCapoten lookslikeandcontentsofthepack

Capoten50 mgtablets arewhite,oval,biconvextablets,embossedwith “50”ononesideand

bisected ontheotherside.Thescorelineistofacilitatebreakingfortheeaseofswallowingand

to divideinto equaldosesof25 mg(halftablet).Thetablets come inblisterpacksof28tablets.

MarketingAuthorisation HolderandManufacturer:

Bristol-Myers SquibbPharmaceuticals Ltd

Swords,

CountyDublin, Ireland

Tel:1 800 749 749

Manufacturer:

Bristol-MyersSquibb, S.r.l.

ContradaFontanadelCeraso

03012Anagni(FR)

Italy

Date oflastrevision:

June2016

Document Outline

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Capoten50mgtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains50mgcaptopril

Excipientswithknowneffect:

Lactosemonohydrate50mg

Forthefulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Tablet.

White,oval,biconvextablets,with'50'embossedononesideandscoredontheother.

Thescorelineistofacilitatebreakingforeaseofswallowingandtodivideintoequaldosesof25mg(halftablet).

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension:

Capotenisindicatedforthetreatmentofessentialhypertension.

HeartFailure:

Capotenisindicatedforthetreatmentofchronicheartfailurewithreductionofsystolicventricularfunctionin

combinationwithdiureticsand,whenappropriate,digitalisandbeta-blockers.

MyocardialInfarction:

-Short-term(4weeks)treatment:Capotenisindicatedinanyclinicallystablepatientswithinthefirst24hoursofan

infarction.

-Longtermpreventionofsymptomaticheartfailure:Capotenisindicatedinclinicallystablepatientswith

asymptomaticleftventriculardysfunction(ejectionfraction40%).

TypeIDiabeticNephropathy:

CapotenisindicatedforthetreatmentofmacroproteinuricdiabeticnephropathyinpatientswithTypeIdiabetes.

4.2Posologyandmethodofadministration

Posology:

Doseshouldbeindividualisedaccordingtopatient’sprofile(seesection4.4)andbloodpressureresponse.The

recommendedmaximumdailydoseis150mg.Capotenmaybetakenbefore,duringandaftermeals.

Methodofadministration:

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Hypertension:

Therecommendedstartingdoseis25-50mgdailyintwodivideddoses.Thedosemaybeincreasedincrementally,

withintervalsofatleast2weeks,to100-150mg/dayintwodivideddosesasneededtoreachtargetbloodpressure.

Captoprilmaybeusedaloneorwithotherantihypertensiveagents,especiallythiazidediuretics(seesections4.3,4.4,

4.5and5.1).Aonce-dailydosingregimenmaybeappropriatewhenconcomitantantihypertensivemedicationsuchas

thiazidediureticsisadded.

Inpatientswithastronglyactiverenin-angiotensin-aldosteronesystem(hypovolaemia,renovascularhypertension,

cardiacdecompensation)itispreferabletocommencewithasingledoseof6.25mgor12.5mg.Theinaugurationof

thistreatmentshouldpreferablytakeplaceunderclosemedicalsupervision.Thesedoseswillthenbeadministeredata

rateoftwoperday.Thedosagecanbegraduallyincreasedto50mgperdayinoneortwodosesandifnecessaryto

100mgperdayinoneortwodoses.

HeartFailure:

Treatmentwithcaptoprilforheartfailureshouldbeinitiatedunderclosemedicalsupervision.

Theusualstartingdoseis6.25mg-12.5mgBIDorTID.Titrationtothemaintenancedose(75-150mgperday)

shouldbecarriedoutbasedonpatient’sresponse,clinicalstatusandtolerability,uptoamaximumof150mgperday

individeddoses.Thedoseshouldbeincreasedincrementally,withintervalsofatleast2weekstoevaluatepatients

response.

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),particularlyifthepatientexhibitsnormalorlowbloodpressureatthe

initiationoftherapy.Treatmentshouldbeinitiatedwithadoseof6.25mgfollowedby12.5mg3timesdailyfor2

daysandthen25mg3timesdailyifwarrantedbytheabsenceofadversehaemodynamicreactions.Therecommended

doseforeffectivecardioprotectionduringlong-termtreatmentis75to150mgdailyintwoorthreedoses.

Incasesofsymptomatichypotension,asinheartfailure,thedosageofdiureticsand/orotherconcomitantvasodilators

maybereducedinordertoattainthesteadystatedoseofcaptopril.Wherenecessary,thedoseofcaptoprilshouldbe

adjustedinaccordancewiththepatient’sclinicalreactions.Captoprilmaybeusedincombinationwithother

treatmentsformyocardialinfarctionsuchasthrombolyticagents,beta-blockersandacetylsalicylicacid.

TypeIDiabeticNephropathy:

InpatientswithTypeIdiabeticnephropathy,therecommendeddailydoseofcaptoprilis75to100mgindivided

doses.Ifadditionalloweringofbloodpressureisdesired,additionalantihypertensivemedicationsmaybeadded.

Renalimpairment:

Sincecaptoprilisexcretedprimarilyviathekidneys,dosageshouldbereducedorthedosageintervalshouldbe

increasedinpatientswithimpairedrenalfunction.Whenconcomitantdiuretictherapyisrequired,aloopdiuretic(e.g.

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Inpatientswithimpairedrenalfunction,thefollowingdailydosemayberecommendedtoavoidaccumulationof

captopril.

Creatinineclearance DailyStartingdose Dailymaximumdose

(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

Olderpeople:

Aswithotherantihypertensiveagents,considerationshouldbegiventoinitiatingtherapywithalowerstartingdose

(6.25mgBID)inelderlypatientswhomayhavereducedrenalfunctionandotherorgandysfunctions.

Dosageshouldbetitratedagainstthebloodpressureresponseandkeptaslowaspossibletoachieveadequatecontrol.

Paediatricpopulation:

Thesafetyandefficacyofcaptoprilhavenotbeenfullyestablished.Theuseofcaptoprilinchildrenandadolescents

shouldbeinitiatedunderclosemedicalsupervision.Theinitialdoseofcaptoprilisabout0.3mg/kgbodyweight.For

patientsrequiringspecialprecautions(childrenwithrenaldysfunction,prematureinfants,new-bornsandinfants,

becausetheirrenalfunctionisnotthesamewitholderchildrenandadults)thestartingdoseshouldonlybe0.15mg

captopril/kgweight.Generally,captoprilisadministeredtochildren3timesaday,butdoseandintervalofdoseshould

beadaptedindividuallyaccordingtopatient’sresponse.

4.3Contraindications

Hypersensitivitytotheactivesubstanceortoanyoftheexcipientslistedinsection6.1ortoanyotherACEinhibitor.

Useinpatientswithaorticstenosisoroutflowtractobstruction.Useinpatientswithbilateralrenalarterystenosisina

singlefunctioningkidney.

UseinpatientswithahistoryofangioneuroticoedemarelatingtoprevioustreatmentwithanACEinhibitor.

Hereditary/idiopathicangioneuroticoedema.

TheconcomitantuseofCapotenwithaliskiren-containingproductsiscontraindicatedinpatientswithdiabetesmellitus

orrenalimpairment(GFR<60ml/min/1.73m2)(seesections4.5and5.1).

Pregnancy:

Capoteniscontraindicatedinthesecondandthirdtrimestersofpregnancy(seesections4.4and4.6).

Capotenhasbeenshowntobelethaltorabbitandsheepfoetuses.Therewerenofoetotoxiceffectstohamsterorrat

foetuses.

Capotenshouldnotbeusedinwomenofchildbearingpotentialunlessprotectedbyeffectivecontraception.

4.4Specialwarningsandprecautionsforuse

Hypotension:

Rarelyhypotensionisobservedinuncomplicatedhypertensivepatients.Symptomatichypotensionismorelikelyto

occurinhypertensivepatientswhoarevolumeand/orsodiumdepletedbyvigorousdiuretictherapy,dietarysalt

restriction,diarrhoea,vomitingorhaemodialysis.Volumeand/orsodiumdepletionshouldbecorrectedbeforethe

administrationofanACEinhibitorandalowerstartingdoseshouldbeconsidered.

Patientswithheartfailureareatahighriskofhypotensionandalowerstartingdoseisrecommendedwheninitiating

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Themagnitudeofthedecreaseisgreatestearlyinthecourseoftreatment;thiseffectstabiliseswithinaweekortwo,

andgenerallyreturnstopre-treatmentlevels,withoutadecreaseintherapeuticefficacy,withintwomonths.Caution

shouldbeusedwheneverthedoseofcaptoprilordiureticisincreasedinpatientswithheartfailure.

Aswithanyantihypertensiveagent,excessivebloodpressureloweringinpatientswithischaemiccardiovascularor

cerebrovasculardiseasemayincreasetheriskofmyocardialinfarctionorstroke.Ifhypotensiondevelops,thepatient

shouldbeplacedinasupineposition.Volumerepletionwithintravenousnormalsalinemayberequired.

Infants,especiallynewborns,maybemoresusceptibletotheadversehaemodynamiceffectsofcaptopril.Excessive,

prolongedandunpredictabledecreasesinbloodpressureandassociatedcomplications,includingoliguriaandseizures

havebeenreported.

Renovascularhypertension:

Thereisanincreasedriskofhypotensionandrenalinsufficiencywhenpatientswithbilateralrenalarterystenosisor

stenosisofthearterytoasinglefunctioningkidneyaretreatedwithACEinhibitors.Lossofrenalfunctionmayoccur

withonlymildchangesinserumcreatinine.Inthesepatients,therapyshouldbeinitiatedunderclosemedical

supervisionwithlowdoses,carefultitrationandmonitoringofrenalfunction.

Renalimpairment:

Incasesofrenalimpairment(creatinineclearance<40ml/min),theinitialdosageofcaptoprilmustbeadjusted

accordingtothepatient’screatinineclearance(seesection4.2),andthenasafunctionofthepatient’sresponseto

treatment.Routinemonitoringofpotassiumandcreatininearepartofnormalmedicalpracticeforthesepatients.

Angioedema:

Angioedemaoftheextremities,face,lips,mucousmembranes,tongue,glottisorlarynxmayoccurinpatientstreated

withACEinhibitors,includingCaptopril.Thismayoccuratanytimeduringtreatment.Insuchcases,Captoprilshould

bediscontinuedpromptlyandappropriatemonitoringshouldbeinstitutedtoensurecompleteresolutionofsymptoms

priortodismissingthepatient.Inthoseinstanceswhereswellinghasbeenconfinedtothefaceandlipsthecondition

generallyresolvedwithouttreatment,althoughantihistamineshavebeenusefulinrelievingsymptoms.Angioedema

involvingthetongue,glottisorlarynxmaybefatal.Wherethereisinvolvementofthetongue,glottisorlarynx,likely

tocauseairwayobstruction,appropriatetherapy,whichmayincludesubcutaneousepinephrinesolution1:1000(0.3ml

to0.5ml)and/ormeasurestoensureapatentairway,shouldbeadministeredpromptly.Thepatientshouldbe

hospitalisedandobservedforatleast12to24hoursandshouldnotbedischargeduntilcompleteresolutionof

symptomshasoccurred.

BlackpatientsreceivingACEinhibitorshavebeenreportedtohaveahigherincidenceofangioedemacomparedto

non-blacks.

PatientswithahistoryofangioedemaunrelatedtoACEinhibitortherapymaybeatincreasedriskofangioedemawhile

receivinganACEinhibitor(seesection4.3).

IntestinalangioedemahasalsobeenreportedrarelyinpatientstreatedwithACEinhibitors.Thesepatientspresented

withabdominalpain(withorwithoutnauseaorvomiting);insomecasestherewasnopriorfacialangioedemaandC-1

esteraselevelswerenormal.TheangioedemawasdiagnosedbyproceduresincludingabdominalCTscan,or

ultrasoundoratsurgeryandsymptomsresolvedafterstoppingtheACEinhibitor.Intestinalangioedemashouldbe

includedinthedifferentialdiagnosisofpatientsonACEinhibitorspresentingwithabdominalpain(seesection4.8).

Cough:

CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnon-productive,persistentand

resolvesafterdiscontinuationoftherapy.

Hepaticfailure:

Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceandprogressesto

fulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeisnotunderstood.Patients

receivingACEinhibitorswhodevelopjaundiceormarkedelevationsofhepaticenzymesshoulddiscontinuetheACE

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Hyperkalaemia:

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,includingcaptopril.

Patientsatriskforthedevelopmentofhyperkalaemiaincludethosewithrenalinsufficiency,diabetesmellitus,orthose

usingconcomitantpotassium-sparingdiuretics,potassiumsupplementsorpotassium-containingsaltsubstitutes;or

thosepatientstakingotherdrugsassociatedwithincreasesinserumpotassium(e.g.heparin).Ifconcomitantuseofthe

abovementionedagentsisdeemedappropriate,regularmonitoringofserumpotassiumisrecommended.

Combinationwithlithium:

Capotenisnotrecommendedinassociationwithlithiumduetothepotentiationoflithiumtoxicity(seesection4.5).

Aorticandmitralvalvestenosis/Obstructivehypertropiccardiomyopathy/Cardiogenicshock:

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)shouldbe

withdrawnifneutropenia(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-densitylipoproteinapheresiswithdextransulphateadsorption.Inthesepatients,considerationshould

begiventousingadifferenttypeofdialysis;membraneoradifferentclassofmedication.

Surgery/Anesthesia:

Hypotensionmayoccurinpatientsundergoingmajorsurgeryorduringtreatmentwithanaestheticagentsthatare

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Diabeticpatients:

Theglycaemialevelsshouldbecloselymonitoredindiabeticpatientspreviouslytreatedwithoralantidiabeticdrugsor

insulin,namelyduringthefirstmonthoftreatmentwithanACEinhibitor.

RenalfunctioninpatientswithHeartFailure:

About20%ofpatientsdevelopstableelevationsofBUNandserumcreatinine>20%abovenormalorbaselineupon

long-termtreatmentwithcaptopril.Lessthan5%ofpatients,generallythosewithseverepre-existingrenaldisease,

requireddiscontinuationoftreatmentduetoprogressivelyincreasingcreatinine.

Riskofhypokalaemia:

ThecombinationofanACEinhibitorwithathiazidediureticdoesnotruleouttheoccurrenceofhypokalaemia.

Regularmonitoringofkalaemiashouldbeperformed.

Lactose:

Capotencontainslactose,thereforeitshouldnotbeusedincasesofcongenitalgalactosaemia,glucoseandgalactose

malabsorptionorlactasedeficiencysyndromes(raremetabolicdiseases).

Ethnicdifferences:

Aswithotherangiotensinconvertingenzymeinhibitors,captoprilisapparentlylesseffectiveinloweringblood

pressureinblackpeoplethaninnon-blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblack

hypertensivepopulation.

Pregnancy:

ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitortherapyisconsidered

essential,patientsplanningpregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhichhavean

establishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbe

stoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted(seesections4.3and4.6).

Dualblockadeoftherenin-angiotensin-aldosteronesystem(RAAS):

ThereisevidencethattheconcomitantuseofACE-inhibitors,angiotensinIIreceptorblockersoraliskirenincreasesthe

riskofhypotension,hyperkalaemiaanddecreasedrenalfunction(includingacuterenalfailure).Dualblockadeof

RAASthroughthecombineduseofACE-inhibitors,angiotensinIIreceptorblockersoraliskirenisthereforenot

recommended(seesections4.5and5.1).

Ifdualblockadetherapyisconsideredabsolutelynecessary,thisshouldonlyoccurunderspecialistsupervisionand

subjecttofrequentclosemonitoringofrenalfunction,electrolytesandbloodpressure.

ACE-inhibitorsandangiotensinIIreceptorblockersshouldnotbeusedconcomitantlyinpatientswithdiabetic

nephropathy.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Potassiumsparingdiureticsorpotassiumsupplements:

ACEinhibitorsattenuatediureticinducedpotassiumloss.Potassiumsparingdiuretics(e.g.spironolactone,triamterene

oramiloride),potassiumsupplements,orpotassium-containingsaltsubstitutesmayleadtosignificantincreasesin

serumpotassium.Ifconcomitantuseisindicatedbecauseofdemonstratedhypokalaemiatheyshouldbeusedwith

cautionandwithfrequentmonitoringofserumpotassium(seesection4.4).

Diuretics(Thiazideorloopdiuretics):

Priortreatmentwithhighdosediureticsmayresultinvolumedepletionandariskofhypotensionwheninitiating

therapywithcaptopril(seesection4.4).Thehypotensiveeffectscanbereducedbydiscontinuationofthediuretic,by

increasingvolumeorsaltintakeorbyinitiatingtherapywithalowdoseofcaptopril.However,noclinicallysignificant

druginteractionshavebeenfoundinspecificstudieswithhydrochlorothiazideorfurosemide.

Otherantihypertensiveagents:

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

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Concomitantuseoftheseagentsmayincreasethehypotensiveeffectsofcaptopril.Treatmentwithnitroglycerineand

othernitrates,orothervasodilators,shouldbeusedwithcaution.

Alphablockingagents:

Concomitantuseofalphablockingagentsmayincreasetheantihypertensiveeffectsofcaptoprilandincreasetheriskof

orthostatichypotension.

Treatmentsofacutemyocardialinfarction:

Captoprilmaybeusedconcomitantlywithacetylsalicylicacid(atcardiologicdoses),thrombolytics,beta-blockers

and/ornitratesinpatientswithmyocardialinfarction.

Lithium:

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.Concomitantuseofthiazidediureticsmayincreasetheriskoflithium

toxicityandenhancethealreadyincreasedriskoflithiumtoxicitywithACEinhibitors.Useofcaptoprilwithlithiumis

notrecommended,butifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsshouldbe

performed(seesection4.4).

Tricyclicantidepressants/Antipsychotics:

ACEinhibitorsmayenhancethehypotensiveeffectsofcertaintricyclicantidepressantsandantipsyschotics(see

section4.4).Posturalhypotensionmayoccur.

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.

Clinicaltrialdatahasshownthatdualblockadeoftherenin-angiotensin-aldosterone-system(RAAS)throughthe

combineduseofACE-inhibitors,angiotensinIIreceptorblockersoraliskirenisassociatedwithahigherfrequencyof

adverseeventssuchashypotension,hyperkalaemiaanddecreasedrenalfunction(includingacuterenalfailure)

comparedtotheuseofasingleRAAS-actingagent(seesections4.3,4.4and5.1).

4.6Fertility,pregnancyandlactation

Pregnancy:

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).Theuseof

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EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.

Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,

alternativetherapyshouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andinneonataltoxicity(renalfailure,

hypotension,hyperkalaemia)(seesection5.3).ShouldexposuretoACEinhibitorshaveoccurredfromthesecond

trimesterofpregnancy,ultrasoundcheckofrenalfunctionandskullisrecommended.Infantswhosemothershave

takenACEinhibitorsshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Breastfeeding:

Limitedpharmacokineticdatademonstrateverylowconcentrationsinbreastmilk(seesection5.2).Althoughthese

concentrationsseemtobeclinicallyirrelevant,theuseofCapoteninbreastfeedingisnotrecommendedforpreterm

infantsandforthefirstfewweeksafterdelivery,becauseofthehypotheticalriskofcardiovascularandrenaleffects

andbecausethereisnotenoughclinicalexperience.

Inthecaseofanolderinfant,theuseofCapoteninabreast-feedingmothermaybeconsideredifthistreatmentis

necessaryforthemotherandthechildisobservedforanyadverseeffect.

4.7Effectsonabilitytodriveandusemachines

Aswithotherantihypertensives,theabilitytodriveandusemachinesmaybereduced,namelyatthestartofthe

treatment,orwhenposologyismodified,andalsowhenusedincombinationwithalcohol,buttheseeffectsdependon

theindividual’ssusceptibility.

4.8Undesirableeffects

Frequencyisdefinedusingthefollowingconvention:common(>1/100,<1/10),uncommon(>1/1,000,<1/100),rare

(>1/10,000,<1/1,000)andveryrare(<1/10,000).

Undesirableeffectsreportedforcaptopriland/orACEinhibitorinclude:

Bloodandlymphaticdisorders:

VeryRare: Neutropenia/agranulocytosis(seesection4.4),pancytopeniaparticularlyinpatientswithrenal

dysfunction(seesection4.4),anaemia(includingaplasticandhaemolytic),thrombocytopenia,lymphadenopathy,

eosinophilia,auto-immunedisorder.

Metabolismandnutritiondisorders:

Uncommon: Decreasedappetite

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

Psychiatricdisorders:

Common: Insomnia.

VeryRare: Confusionalstate,depression.

Nervoussystemdisorders:

Common: Dysgeusia,dizziness

Uncommon: Headache,paraesthesia.

Rare: Somnolence.

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Eyedisorders:

VeryRare: Visionblurred.

Cardiacdisorders:

Uncommon: Tachycardia,arrhythmia,anginapectoris,palpitations.

VeryRare: Cardiacarrest,cardiogenicshock.

Vasculardisorders

Uncommon: Hypotension(seesection4.4),Raynaud’sphenomenon,flushing,pallor,orthostatichypotension.

Respiratory,thoracicandmediastinaldisorders:

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

VeryRare: Bronchospasm,rhinitis,alveolitisallergic/eosinophilicpneumonia.

Gastrointestinaldisorders:

Common: Nausea,vomiting,epigastricdiscomfort,abdominalpain,diarrhoea,constipation,drymouth,peptic

ulcer,dyspepsia.

Rare: Stomatitis/aphthousstomatitis,smallbowelangioedema(seesection4.4).

VeryRare: Glossitis,pancreatitis.

Hepato-biliarydisorders:

VeryRare: Hepaticfunctionabnormal,cholestasis,jaundice,hepatitis,hepaticnecrosis,hepaticenzyme

increased,bloodbilirubinincreased,transaminaseincreased,bloodalkalinephosphataseincreased.

Skinandsubcutaneoustissuedisorders:

Common: Prurituswithorwithoutarash,rashandalopecia.

Uncommon: Angioedema(seesection4.4).

VeryRare: Urticaria,StevensJohnsonsyndrome,erythemamultiforme,photosensitivityreactions,pemphigoid,

dermatitisexfoliative.

Musculoskeletal,connectivetissueandbonedisorders:

VeryRare: Myalgia,arthralgia.

Renalandurinarydisorders:

Rare: Renalimpairment,renalfailure,polyuria,oliguria,pollakiuria.

VeryRare: Nephroticsyndrome.

Reproductivesystemandbreastdisorders:

VeryRare: Erectiledysfunction,gynaecomastia.

Generaldisordersandadministrationsiteconditions:

Uncommon: Chestpain,fatigue,malaise,asthenia.

VeryRare: Pyrexia.

Investigations:

VeryRare: Proteinuria,eosinophilia,bloodpotassiumincreased,bloodsodiumdecreased,bloodureaincreased,

bloodcreatinineincreased,bloodbilirubinincreased,haemoglobindecreased,haematocritdecreased,whiteblood

cellcountdecreased,plateletcountdecreased,antinuclearantibodypositiveredbloodcellsedimentationrate

increased.

Reportingofsuspectedadversereactions

Reportingsuspectedadversereactionsafterauthorisationofthemedicinalproductisimportant.Itallowscontinued

monitoringofthebenefit/riskbalanceofthemedicinalproduct.Healthcareprofessionalsareaskedtoreportany

suspectedadversereactionsvia:HPRAPharmacovigilance,EarlsfortTerrace,IRL-Dublin2.Tel:+35316764971;

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4.9Overdose

Symptomsofoverdosageareseverehypotension,shock,stupor,bradycardia,electrolytedisturbancesandrenalfailure.

Measurestopreventabsorption(e.g.gastriclavage,administrationofadsorbentsandsodiumsulphatewithin30

minutesafterintake)andhasteneliminationshouldbeappliedifingestionisrecent.Ifhypotensionoccurs,thepatient

shouldbeplacedintheshockpositionandsaltandvolumesupplementsshouldbegivenrapidly.Treatmentwith

angiotensin-IIshouldbeconsidered.Bradycardiaorextensivevagalreactionsshouldbetreatedbyadministering

atropine.Theuseofapacemakermaybeconsidered.

Captoprilmayberemovedfromadultcirculationbyhaemodialysis.Captoprilisnotadequatelyclearedbyperitoneal

dialysis.

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.InhibitionofACEresultsindecreasedplasmaangiotensin-IIwhichleadsto

decreasedvasopressoractivityandtoreducedaldosteronesecretion.Althoughthelatterdecreaseissmall,small

increasesinserumpotassiumconcentrationsmayoccur,alongwithsodiumandfluidloss.Thecessationofthe

negativefeedbackofangiotensin-IIonthereninsecretionresultsinanincreaseoftheplasmareninactivity.

Anotherfunctionoftheconvertingenzymeistodegradethepotentvasodepressivekininpeptidebradykinintoinactive

metabolites.Therefore,inhibitionofACEresultsinanincreasedactivityofcirculatingandlocalkallikrein-kinin-

systemwhichcontributestoperipheralvasodilationbyactivatingtheprostaglandinsystem;itispossiblethatthis

mechanismisinvolvedinthehypotensiveeffectofACEinhibitorsandisresponsibleforcertainadversereactions.

Reductionsofbloodpressureareusuallymaximal60to90minutesafteroraladministrationofanindividualdoseof

captopril.Thedurationofeffectisdoserelated.Thereductioninbloodpressuremaybeprogressive,sotoachieve

maximaltherapeuticeffects,severalweeksoftherapymayberequired.Thebloodpressureloweringeffectsof

captoprilandthiazide-typediureticsareadditive.

Inpatientswithhypertension,captoprilcausesareductioninsupineanderectbloodpressure,withoutinducingany

compensatoryincreaseinheartrate,norwaterandsodiumretention.

Inhaemodynamicinvestigations,captoprilcausedamarkedreductioninperipheralarterialresistance.Ingeneralthere

werenoclinicallyrelevantchangesinrenalplasmafloworglomerularfiltrationrate.Inmostpatients,the

antihypertensiveeffectbeganabout15to30minutesafteroraladministrationofcaptopril;thepeakeffectwasachieved

after60to90minutes.Themaximumreductioninbloodpressureofadefinedcaptoprildosewasgenerallyvisible

afterthreetofourweeks.

Intherecommendeddailydose,theantihypertensiveeffectpersistsevenduringlong-termtreatment.Temporary

withdrawalofcaptoprildoesnotcauseanyrapid,excessiveincreaseinbloodpressure(rebound).Thetreatmentof

hypertensionwithcaptoprilleadsalsotoadecreaseinleftventricularhypertrophy.

Haemodynamicinvestigationsinpatientswithheartfailure,showedthatcaptoprilcausedareductioninperipheral

systemicresistanceandariseinvenouscapacity.Thisresultedinareductioninpre-loadandafterloadoftheheart

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Inaddition,risesincardiacoutput,workindexandexercisecapacityhavebeenobservedduringtreatmentwith

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

myocardialinfarction,itwasshownthatcaptopril(initiatedbetweenthe3 rd

tothe16 th

dayafterinfarction)prolonged

thesurvivaltimeandreducedcardiovascularmortality.Thelatterwasmanifestedasadelayinthedevelopmentof

symptomaticheartfailureandareductioninthenecessityforhospitalisationduetoheartfailurecomparedtoplacebo.

Therewasalsoareductioninre-infarctionandincardiacrevascularisationproceduresand/orintheneedforadditional

medicationwithdiureticsand/oranincreaseintheirdosagecomparedtoplacebo.

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.

Twolargerandomised,controlledtrials(ONTARGET(ONgoingTelmisartanAloneandincombinationwithRamipril

GlobalEndpointTrial)andVANEPHRON-D(TheVeteransAffairsNephropathyinDiabetes))haveexaminedtheuse

ofthecombinationofanACE-inhibitorwithanangiotensinIIreceptorblocker.

ONTARGETwasastudyconductedinpatientswithahistoryofcardiovascularorcerebrovasculardisease,ortype2

diabetesmellitusaccompaniedbyevidenceofend-organdamage.VANEPHRON-Dwasastudyinpatientswithtype

2diabetesmellitusanddiabeticnephropathy.

Thesestudieshaveshownnosignificantbeneficialeffectonrenaland/orcardiovascularoutcomesandmortality,while

anincreasedriskofhyperkalaemia,acutekidneyinjuryand/orhypotensionascomparedtomonotherapywasobserved.

Giventheirsimilarpharmacodynamicproperties,theseresultsarealsorelevantforotherACE-inhibitorsand

angiotensinIIreceptorblockers.

ACE-inhibitorsandangiotensinIIreceptorblockersshouldthereforenotbeusedconcomitantlyinpatientswith

diabeticnephropathy.

ALTITUDE(AliskirenTrialinType2DiabetesUsingCardiovascularandRenalDiseaseEndpoints)wasastudy

designedtotestthebenefitofaddingaliskirentoastandardtherapyofanACE-inhibitororanangiotensinIIreceptor

blockerinpatientswithtype2diabetesmellitusandchronickidneydisease,cardiovasculardisease,orboth.The

studywasterminatedearlybecauseofanincreasedriskofadverseoutcomes.Cardiovasculardeathandstrokewere

bothnumericallymorefrequentinthealiskirengroupthanintheplacebogroupandadverseeventsandserious

adverseeventsofinterest(hyperkalaemia,hypotensionandrenaldysfunction)weremorefrequentlyreportedinthe

aliskirengroupthanintheplacebogroup.

5.2Pharmacokineticproperties

Captoprilisanorallyactiveagentthatdoesnotrequirebiotransformationforactivity.Theaverageminimalabsorption

isapproximately75%.Peakplasmaconcentrationsarereachedwithin60-90minutes.Thepresenceoffoodinthe

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Approximately25-30%ofthecirculatingdrugisboundtoplasmaproteins.

Theapparenteliminationhalf-lifeofunchangedcaptoprilinbloodisabout2hours.Greaterthan95%oftheabsorbed

doseiseliminatedintheurinewithin24hours;40-50%isunchangeddrugandtheremainderareinactivedisulphide

metabolites(captoprildisulphideandcaptoprilcysteinedisulphide).Impairedrenalfunctioncouldresultindrug

accumulation.Therefore,inpatientswithimpairedrenalfunctionthedoseshouldbereducedand/ordosageinterval

prolonged(seesection4.2).

Studiesinanimalsindicatethatcaptoprildoesnotcrosstheblood-brainbarriertoanysignificantextent.

Lactation:

Inthereportoftwelvewomentakingoralcaptopril100mg3timesdaily,theaveragepeakmilklevelwas4.7µg/Land

occurred3.8hoursafterthedose.Basedonthesedata,themaximumdailydosagethatanursinginfantwouldreceiveis

lessthan0.002%ofthematernaldailydosage.

5.3Preclinicalsafetydata

Animalstudiesperformedduringorganogenesiswithcaptoprilhavenotshownanyteratogeniceffectbutcaptoprilhas

producedfoetaltoxicityinseveralspecies,includingfoetalmortalityduringlatepregnancy,growthretardationand

postnatalmortalityintherat.Preclinicaldatarevealnootherspecifichazardforhumansbasedonconventionalstudiesof

safetypharmacology,repeateddosetoxicology,genotoxicityandcarcinogenicity.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Maizestarch

Microcrystallinecellulose

Stearicacid50

6.2Incompatibilities

Notapplicable.

6.3Shelflife

PVC/Alfoil:4years

PVC/PVdC/Alfoil:3years

6.4Specialprecautionsforstorage

PVC/Alfoilblister:

Donotstoreabove30°C.

Storeintheoriginalpackage.

PVC/PVdC/Alfoilblister:

Donotstoreabove25°C.

Storeintheoriginalpackagetoprotectfrommoisture.

6.5Natureandcontentsofcontainer

ThetabletsarepackagedinPVC/aluminiumblisters,orPVC/PVdC/aluminiumblistersinpacksof28or56tablets.

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6.6Specialprecautionsfordisposal

Nospecialrequirementsfordisposal.

Anyunusedmedicinalproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

Bristol–MyersSquibbPharmaceuticalsLtd.

Swords

CountyDublin

8MARKETINGAUTHORISATIONNUMBER

PA0002/039/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:2 nd

April1981

Dateoflastrenewal:2 nd

April2006

10DATEOFREVISIONOFTHETEXT

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