BELLRAMIL

Main information

  • Trade name:
  • BELLRAMIL Capsules Hard 1.25 Milligram
  • Dosage:
  • 1.25 Milligram
  • Pharmaceutical form:
  • Capsules Hard
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BELLRAMIL Capsules Hard 1.25 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0967/006/001
  • Authorization date:
  • 27-07-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0967/006/001

CaseNo:2064661

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

Ranbaxy(UK)Limited

20BaldertonStreet,LondonW1K6TL,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Bellramil,1.25Milligram

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom19/05/2009until26/07/2012.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bellramil1.25mgCapsules,hard

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachhardcapsulecontainsramipril1.25mg.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Capsule,hard,Size4withyellowcap/whitebodyimprintedwith‘R’oncapand‘1.25’onbody.Containswhitetooff-

whitegranularpowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Forreducingtheriskofmyocardialinfarction,stroke,cardiovasculardeathorneedforrevascularisationproceduresin

patientsof55yearsormorewhohaveclinicalevidenceofcardiovasculardisease(previousMI,unstableanginaor

multivesselCABGormultivesselPTCA),strokeorperipheralvasculardisease.

Alsoforreducingtheriskofmyocardialinfarction,stroke,cardiovasculardeathorneedforrevascularisation

proceduresindiabeticpatientsof55yearsormorewhohaveoneormoreofthefollowingclinicalfindings:

hypertension(systolicbloodpressure>160mmHgordiastolicbloodpressure>90mmHg);hightotalcholesterol>5.2

mmol/L);lowHDL(<0.9mmol/L);currentsmoker;knownmicroalbuminuria;clinicalevidenceofpreviousvascular

disease.

RamiprilCapsulesareindicatedforthetreatmentofmildtomoderatehypertension.

Congestiveheartfailureasadjunctivetherapytodiureticswithorwithoutcardiacglycosides.

Ramiprilhasbeenshowntoreducemortalitywhengiventopatientssurvivingacutemyocardialinfarctionwithclinical

evidenceofheartfailure.

4.2Posologyandmethodofadministration

DosageandAdministration:

Oraladministration

Reducingtheriskofmyocardialinfarction,strokeorcardiovasculardeathand/ortheneedforrevascularisation

procedures:Therecommendedinitialdoseis2.5mgramiprilonceaday.Dependingonthetolerability,thedoseshould

begraduallyincreased.Itisthereforerecommendedthatthisdoseisdoubledafteraboutoneweekoftreatmentthen,

afterafurther3weeks,itshouldbefinallyincreasedto10mg.Theusualmaintenancedoseis10mgramipriloncea

day.Patientsalreadystabilisedonlowerdosesoframiprilforotherindicationswherepossibleshouldbetitratedto

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Hypertension:Therecommendedinitialdosageinpatientsnotondiureticsandwithoutcongestiveheartfailureis1.25

mgramiprilonceaday.Dosageshouldbeincreasedincrementallyatintervalsof1-2weeks,basedonpatient

response,uptoamaximumof10mgonceaday.

A1.25mgdosewillonlyachieveatherapeuticresponseinaminorityofpatients.Theusualmaintenancedoseis2.5-

5mgasasingledailydose.Ifthepatientresponseisstillunsatisfactoryatadoseof10mgramipril,combination

treatmentisrecommended.

Indiuretictreatedpatients,thediureticshouldbediscontinued2-3daysbeforebeginningtherapywithramiprilto

reducethelikelihoodofsymptomatichypotension.Itmayberesumedlaterifrequired.

Inhypertensivepatientswhoalsohavecongestiveheartfailure,withorwithoutassociatedrenalinsufficiency,

symptomatichypotensionhasbeenobservedaftertreatmentwithACEinhibitors.Inthesepatientstherapyshouldbe

startedatadoseof1.25mgunderclosemedicalsupervisioninhospital.

Congestiveheartfailure:Recommendedinitialdose:Inpatientsstabilisedondiuretictherapytheinitialdoseis1.25

mgoncedaily.Dependingonthepatient'sresponse,thedosemaybeincreased.Itisrecommendedthatthedose,if

increased,bedoubledatintervalsof1to2weeks.Ifadailydoseof2.5mgormoreisrequired,thismaybetakenasa

singledoseorastwodivideddoses.Maximumpermitteddailydose:10mg.

Inordertominimisethepossibilityofsymptomatichypotension,patientsonprevioushighdosediureticsshouldhave

thediureticdosereducedbeforestartingramipril.

Postmyocardialinfarction:

Initiationoftherapy:Treatmentmustbestartedinhospitalbetweenday3andday10followingmyocardialinfarction.

Thestartingdoseis2.5mgtwiceadayduring2days.Dependinguponthepatient’sresponsetothetherapythedose

maybeincreasedto5mgtwiceadayafter1to3dayinterval.Iftheinitial2.5mgdoseisnottolerated,adoseof1.25

mgtwiceadayshouldbegivenfortwodaysbeforeincreasingto2.5mgand5mgtwiceaday.Ifthedosecannotbe

increasedto2.5mgtwiceaday,treatmentshouldbewithdrawn.Maximumdailydoseis10mg.Maintenancedose:2.5

mg-5mgtwiceaday.’

Dosageadjustmentinrenalimpairment:

Theusualdoseoframiprilisrecommendedforpatientswithacreatinineclearance>30ml/min(serumcreatinine<165

µmol/l).Forpatientswithacreatinineclearance<30ml/min(serumcreatinine>165µmol/l)theinitialdoseis1.25mg

ramipriloncedailyandthemaximumdose5mgramipriloncedaily.

Inpatientswithsevererenalimpairment(creatinineclearance<10ml/minandserumcreatinineof400-650µmol/l),the

recommendedinitialdoseisalso1.25mgramiprilonceaday,butthemaintenancedoseshouldnotexceed2.5mg

ramiprilonceaday.

Dosageinhepaticimpairment:

Inpatientswithimpairedliverfunctionthemetabolismoftheparentcompoundramipril,andthereforetheformationof

thebioactivemetaboliteramiprilat,isdelayedduetoadiminishedactivityofesterasesintheliver,resultinginelevated

plasmaramiprillevels.Treatmentwithramiprilshouldthereforebeinitiatedatadoseof1.25mgunderclosemedical

supervisioninpatientswithimpairedliverfunction.

Elderly:Cautioninelderlypatientswithconcomitantuseofdiuretics,congestiveheartfailureorrenalorhepatic

insufficiency.Thedoseshouldbetitratedaccordingtoneedforthecontrolofbloodpressure.

Children:Ramiprilhasnotbeenstudiedinchildren,andthereforeuseinthisagegroupisnotrecommended.

RamiprilCapsulesshouldbetakenwithaglassofwater.Theabsorptionoframiprilisnotaffectedbyfood.

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4.3Contraindications

Hypersensitivitytoramipriloranyoftheexcipients.

Historyofangioneuroticoedema

Haemodynamicallyrelevantrenalarterystenosis(bilateralorunilateralinsinglekidney).Ramiprilshouldnotbeused

inpatientswithaorticormitralvalvestenosisofoutflowobstruction.

Hypotensiveorhaemodynamicallyunstablepatients.

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6).

4.4Specialwarningsandprecautionsforuse

Warnings:

Ramiprilshouldnotbeusedinpatientswithaorticormitralvalvestenosisoroutflowobstruction.

Precautions:

Assessmentofrenalfunction:Evaluationofthepatientshouldincludeassessmentofrenalfunctionpriortoinitiationof

therapyandduringtreatment.

Impairedrenalfunction:Patientswithrenalinsufficiencymayrequirereducedorlessfrequentdosesoframipril;their

renalfunctionshouldbecloselymonitored.Inthemajority,renalfunctionwillnotalter.Thereisariskofimpairment

ofrenalfunction,particularlyinpatientswithrenalinsufficiency,congestiveheartfailure,bilateralrenalarterystenosis

andunilateralrenalarterystenosisinthesinglekidneyaswellasafterrenaltransplantation.Ifrecognisedearly,such

impairmentofrenalfunctionisreversibleupondiscontinuationoftherapy.

Patientshaemodialysedusinghighfluxpolyacrylonitrile('AN69')membranesarehighlylikelytoexperience

anaphylactoidreactionsiftheyaretreatedwithACEinhibitors.Thiscombinationshouldthereforebeavoided,either

byuseofalternativeantihypertensivedrugsoralternativemembranesfordialysis.

Similarreactionshavebeenobservedduringlow-densitylipoproteinapheresiswithdextransulphate.Thismethod

should,therefore,notbeusedinpatientstreatedwithACEinhibitors.

Somehypertensivepatientswithnoapparentpre-existingrenaldisease,maydevelopminorandusuallytransient

increasesinbloodureanitrogenandserumcreatininewhenramiprilisgiven,inparticularconcomitantlywitha

diuretic.Dosagereductionoframipriland/ordiscontinuationofthediureticmayberequired.Additionally,inpatients

withrenalinsufficiency,thereisariskofhyperkalaemia.

Impairedliverfunction:Asramiprilisaprodrugmetabolisedtoitsactivemoietyintheliver,particularcautionand

closemonitoringshouldbeappliedtopatientswithimpairedliverfunction.Themetabolismoftheparentcompound,

andthereforetheformationofthebioactivemetaboliteramiprilat,maybediminishedresultinginmarkedlyelevated

plasmalevelsoftheparentcompound(duetothereducedactivityofesterasesintheliver).

Symptomatichypotension:Inpatientswithuncomplicatedhypertension,symptomatichypotensionhasbeenobserved

rarelyaftertheinitialdoseoframiprilaswellasafterincreasingthedoseoframipril.Itismorelikelytooccurin

patientswhohavebeenvolume-andsalt-depletedbyprolongeddiuretictherapy,dietarysaltrestriction,dialysis,

diarrhoea,vomitingorpatientswithsevereheartfailure.Therefore,inthesepatients,diuretictherapyshouldbe

discontinuedandvolumeand/orsaltdepletionshouldbecorrectedbeforeinitiatingtherapywithramipril.

Ifsymptomatichypotensionoccurs,thepatientshouldbeplacedinasupinepositionand,ifnecessary,receivean

intravenousinfusionofphysiologicalsaline.Intravenousatropinemaybenecessaryifthereisassociatedbradycardia.

Treatmentwithramiprilmayusuallybecontinuedfollowingrestorationofeffectivebloodvolumeandbloodpressure.

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mayblockangiotensinIIformationsecondarytocompensatoryreninrelease.Ifhypotensionoccursandisconsidered

tobeduetothismechanism,itcanbecorrectedbyappropriatetreatment.

Agranulocytosisandbonemarrowdepression:Inpatientsonangiotensinconvertingenzymeinhibitorsagranulocytosis

andbonemarrowdepressionhavebeenseenrarely,aswellasareductioninredcellcount,haemoglobincontentand

plateletcount.Thesearemorefrequentinpatientswithrenalimpairment,especiallyiftheyhaveacollagenvascular

disease.Regularmonitoringofwhitebloodcellcountsandproteinlevelsinurineshouldbeconsideredinpatientswith

collagenvasculardisease(e.g.lupuserythematosusandscleroderma),especiallyassociatedwithimpairedrenal

functionandconcomitanttherapyparticularlywithcorticosteroidsandantimetabolites.Patientsonallopurinol,

immunosuppressantsandothersubstancesthatmaychangethebloodpicturealsohaveincreasedlikelihoodofother

bloodpicturechanges.

Hyperkalaemia:Elevatedserumpotassiumhasbeenobservedveryrarelyinhypertensivepatients.Riskfactorsforthe

developmentofhyperkalaemiaincluderenalinsufficiency,potassiumsparingdiureticsandtheconcomitantuseof

agentstotreathypokalaemia.

Pregnancy:ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitortherapyis

consideredessential,patientsplanningpregnancyshouldbechangedtoalternativeantihypertensivetreatmentswhich

haveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitors

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

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Combinationwithdiureticsorotherantihypertensiveagentsmaypotentiatetheantihypertensiveresponsetoramipril.

Adrenergic-blockingdrugsshouldonlybecombinedwithramiprilundercarefulsupervision.

Potassiumsparingdiuretics(spironolactone,amiloride,triamterene)orpotassiumsupplementsmayincreasetheriskof

hyperkalaemia.Ifconcomitantuseoftheseagentsisindicated,theyshouldbegivenwithcautionandserumpotassium

shouldbemonitoredregularly.Ramiprilmayattenuatethepotassiumlosscausedbythiazide-typediuretics.

Whenantidiabeticagents(insulinandsulphonylureaderivatives)areusedconcurrently,thepossibilityofincreased

blood-sugarreductionmustbeconsidered.

WhenACEinhibitorsareadministeredsimultaneouslywithnon-steroidalanti-inflammatorydrugs(e.g.acetylsalicylic

acidandindomethacin),attenuationoftheantihypertensiveeffectmayoccur.

Iframiprilisgivenwithlithium,anincreaseinserumlithiumconcentrationmayoccur.

Patientsonallopurinol,immunosuppressantsandothersubstancesthatmaychangethebloodpicturealsohave

increasedlikelihoodofotherbloodpicturechanges.

Patientshaemodialysedusinghighfluxpolyacrylonitrile('AN69')membranesarehighlylikelytoexperience

anaphylactoidreactionsiftheyaretreatedwithACEinhibitors.Thiscombinationshouldthereforebeavoided,either

byuseofalternativeantihypertensivedrugsoralternativemembranesfordialysis.

4.6Pregnancyandlactation

Pregnancy:

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(see

section4.4).TheuseofACEinhibitorsiscontraindicatedduringthesecondandthird

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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:

Becauseinsufficientinformationisavailableregardingtheuseoframiprilduringbreastfeeding(seesection5.2),

ramiprilisnotrecommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingare

preferable,especiallywhilenursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Inindividualcases,asaresultofareductioninbloodpressure,treatmentwithramiprilmayaffecttheabilitytodrive

andoperatemachinery.Thisoccursespeciallyatthestartoftreatment,whenchangingoverfromotherpreparations

andduringconcomitantuseofalcohol.Afterthefirstdoseorsubsequentincreasesindoseitisnotadvisabletodriveor

operatemachineryforseveralhours.

4.8Undesirableeffects

Generally,adversereactionshavebeenmildandtransient,anddonotrequirediscontinuationoftherapy.Themost

frequentlyreportedadversereactionsarenausea,dizzinessandheadache.

Bloodandlymphaticdisorders

Veryrare,includingisolatedcases

Rare Agranulocytosisandbonemarrowdepression

Reductioninredbloodcellcountand

haemoglobincontent,reductioninthewhite

bloodcellorbloodplateletcount

Immunesystemdisorders

Common

Rare Hypertensitivityreactionsaccompaniedby

pruritus,rash,shortnessofbreath,fevermay

occur,

Eosinophilia.Raisedtitresofantinuclear

antibodies

Angioneuroticoedema

Psychiatricdisorders

Common Sleepdisorders,Depressedmood,feelingof

anxiety

Nervoussystemdisorders

Common Dizziness,disturbancesofbalance,nervousness,

restlessness,tremor,confusion,lossofappetite,

paraesthesiae.

Eyedisorders

Common Conjunctivitis

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Common

Rare Symptomatichypotensionaccompaniedby

dizziness,weaknessandnausea

Ithasbeenrarelyobserved,butmayoccurin

severelysalt/volume-depletedpatientssuchas

thosetreatedwithdiuretics,patientsondialysis

andinpatientswithseverecongestiveheart

failure.

Common Syncope

Myocardialinfractionorcerebrovascularaccident

possiblysecondarytoseverehypotension,chest

pain,palpitations,rhythmdisturbances,angina

pectoris

Vasculardisorders

Common Vasculitis

Respiratory,thoracicand

mediastinaldisorders

Common Dryticklingcough

Rhinitis,sinusitis,bronchitisandespeciallyin

patientswithticklingcough,bronchspasm

Gastrointestinaldisorders

Common

Drynessofthemouth,irritationorinflammation

oftheoralmucosa,digestivedisturbances,

constipation,diarrhoea,nausea,andvomiting,

(gastritis-like)stomachpain,upperabdominal

discomfort(sometimeswithincreasedlevelsof

pancreaticenzymes),increasesinhepatic

enzymesand/orserumbilirubin,jaundicedueto

impairedexcretionofbilepigment(cholestatic

jaundice),otherformsofimpairedliver

function,andhepatitis.

Pancreatitis

Skinandaubcutaneoustissue

disorder

Common Cutaneousandmucosalreactions:reddeningof

skinareaswithaccompanyingheatsensation,

itching,urticaria,otherskinormucosaleruptions

(maculo-papularandlichenoidexanthemaand

enanthema,erythemamultiforme),sometimes

pronouncedhairloss,andprecipitationor

intensificationofRaynaud'sphenomenon.

WithotherACEinhibitorspsoriasiformand

pemphigoidexanthemaandenanthema,

hypersensitivityoftheskintolightand

onycholysis

Musculoskeletalandconnective

tissuedisorders

Common Musclecramps,muscleandjointpains

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4.9Overdose

Incaseofoverdosageprolongedhypotensionistobeexpected.Treatmentwithanintravenousinfusionof

physiologicalsalineand/orangiotensinIImayberequired.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATC-code:C09AA05

Thepharmacotherapeuticgroup:ACEinhibitors,plain

Ramiprilisaprodrugwhich,afterabsorptionfromthegastrointestinaltract,ishydrolysedinthelivertoformtheactive

angiotensinconvertingenzyme(ACE)inhibitor,ramiprilatwhichisapotentandlongactingACEinhibitor.

Administrationoframiprilcausesanincreaseinplasmareninactivityandadecreaseinplasmaconcentrationsof

angiotensinIIandaldosterone.ThebeneficialhaemodynamiceffectsresultingfromACEinhibitionareaconsequence

ofthereductioninangiotensinIIcausingdilatationofperipheralvesselsandreductioninvascularresistance.Thereis

evidencesuggestingthattissueACEparticularlyinthevasculature,ratherthancirculatingACE,istheprimaryfactor

determiningthehaemodynamiceffects.

AngiotensinconvertingenzymeisidenticalwithkininaseII,oneoftheenzymesresponsibleforthedegradationof

bradykinin.ThereisevidencethatACEinhibitionbyramiprilatappearstohavesomeeffectsonthekallikrein-kinin-

prostaglandinsystems.Itisassumedthateffectsonthesesystemscontributetothehypotensiveandmetabolicactivity

oframipril.

Administrationoframipriltohypertensivepatientsresultsinreductionofbothsupineandstandingbloodpressure.The

antihypertensiveeffectisevidentwithinonetotwohoursafterthedrugintake;peakeffectoccurs3-6hoursafterdrug

intakeandhasbeenshowntobemaintainedforatleast24hoursafterusualtherapeuticdoses.

Inalargeendpointstudy–HOPE-ramiprilsignificantlyreducedtheincidenceofstroke,myocardialinfarctionand/or

cardiovasculardeathwhencomparedwithplacebo.Thesebenefitsoccurredlargelyinnormotensivepatientsandwere

shown,usingstandardregressionanalysistechniques,tobeonlypartiallyduetotherelativelymodestreductionsin

bloodpressuredemonstratedinthestudy.The10mgdose,currentlythehighestsafedoselevelapproved,wasselected

bytheHOPEinvestigatorsfrompreviousdose-rangingstudies(SECURE,HEART)andwasconsideredtobethemost

Common

Reproductivesystemandbreast

disorders

Common Impotence,decreasedlibido

Generaldisordersand

administrationsiteconditions

Common Tastechange,tastereductionandsometimes

lossoftaste,

Fever,headache,fatigue,malaise

Investigations

Common Increasesinbloodureanitrogenandserum

creatininemayoccur,inparticularwithrenal

insufficiencyorinpatientspretreatedwitha

diuretic.Pre-existingproteinuriamay

deteriorate.

Serumsodiumlevelsmaydecrease.Elevationof

serumpotassiummayoccur,sinceramipril

leadstoadecreaseinaldosteronesecretion;

potassium-sparingdiuretics(spironolactone,

amiloride,triamterene)orpotassium

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inhibitorslikeramiprilarelikelytohaveotherdirecteffectsonthecardiovascularsystem.Thesemayincludethe

antagonismofangiotensinIImediatedvasoconstriction,theinhibitionofproliferatingvascularsmoothmuscleand

plaquerupture,theenhancementofendothelialfunction,thereductionofleftventricularhypertrophyandpositive

effectsonfibrinolysis.Additionaleffectsindiabeticpatientsmayalsocontributee.g.effectsoninsulinclearanceand

pancreaticbloodflow.

5.2Pharmacokineticproperties

Followingoraladministrationramiprilisrapidlyabsorbedfromthegastrointestinaltract;peakplasmaconcentrations

oframiprilarereachedwithinonehour.Peakplasmaconcentrationsoftheactivemetabolite,ramiprilat,arereached

within2–4hours.

Plasmaconcentrationsoframiprilatdeclineinapolyphasicmanner.Theeffectivehalf-lifeoframiprilataftermultiple

oncedailyadministrationoframiprilis13–17hoursfor5–10mgramiprilandmarkedlylongerforlowerdoses,1.25

–2.5mgramipril.Thisdifferenceisrelatedtothelongterminalphaseoftheramiprilatconcentrationtimecurve

observedatverylowplasmaconcentrations.Thisterminalphaseisindependentofthedose,indicatingasaturable

capacityoftheenzymetobindramiprilat.Steady-stateplasmaconcentrationsoframiprilatafteroncedailydosingwith

theusualdosesoframiprilarereachedbyaboutthefourthdayoftreatment.

Ramiprilisalmostcompletelymetabolisedandthemetabolitesareexcretedmainlyviathekidneys.Inadditiontothe

bioactivemetabolite,ramiprilat,other,inactivemetaboliteshavebeenidentified,includingdiketopiperazineester,

diketopiperazineacidandconjugates.

Theproteinbindingoframiprilisabout73%andoframiprilatabout56%.

Lactation:

Onesingle10mgoraldoseoframiprilproducedanundetectablelevelinbreastmilk.Howevertheeffectofmultiple

dosesisnotknown.

5.3Preclinicalsafetydata

Reproductiontoxicologystudiesintherat,rabbitandmonkeydidnotdiscloseanyteratogenicproperties.Fertilitywas

notimpairedeitherinmaleorinfemalerats.Theadministrationoframipriltofemaleratsduringthefetalperiodand

lactationproducedirreversiblerenaldamage(dilatationoftherenalpelvis)intheoffspringatdailydosesof50mg/kg

bodyweightandhigher.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontents

Pregelatinisedstarch(Maize)

CapsulesShell

Yellowcap/Whitebody,size‘4

CapShell

Gelatin

Quinolineyellow(E104)

Ponceau4R(E124)

Titaniumdioxide(E171)

PrintingInk

Shellac

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Potassiumhydroxide

Blackironoxide(E172)

6.2Incompatibilities

Notapplicable

6.3ShelfLife

2Years

6.4Specialprecautionsforstorage

Storeintheoriginalpackeage.

6.5Natureandcontentsofcontainer

AluminiumstripscomprisingofaluminiumfoillaminatedwithLDPE.Thestripsareenclosedinacardboardcartonin

packsizesof21,28,30,56or60capsules.Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

Ranbaxy(UK)Limited

20BaldertonStreet

LondonW1K6TL

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA967/6/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:27 th

July2007

10DATEOFREVISIONOFTHETEXT

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