BYTRITE

Main information

  • Trade name:
  • BYTRITE Capsule 10 Milligram
  • Dosage:
  • 10 Milligram
  • Pharmaceutical form:
  • Capsule
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BYTRITE Capsule 10 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0915/009/004
  • Authorization date:
  • 22-04-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ByTrite10mgCapsules.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachhardcapsulecontains10mgramipril

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Capsules,hard.

Opaquerichyellowcapandopaquewhitebody,hardgelatincapsules(No.4),printedinblackink93and7212on

opposingcapandbodyportionsofthecapsules.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofhypertension.

Treatmentofrenaldisease:

Incipientglomerulardiabeticnephropathyasdefinedbythepresenceofmicroalbuminuria,

Manifestglomerulardiabeticnephropathyasdefinedbymacroproteinuriainpatientswithatleastone

cardiovascularriskfactor(seesection5.1),

Manifestglomerularnondiabeticnephropathyasdefinedbymacroproteinuria ≥3g/day(seesection

5.1).

Treatmentofsymptomaticheartfailure.

Secondarypreventionafteracutemyocardialinfarction:reductionofmortalityfromtheacutephaseofmyocardial

infarctioninpatientswithclinicalsignsofheartfailurewhenstarted>48hoursfollowingacutemyocardial

infarction.

4.2Posologyandmethodofadministration

Oraluse.

ItisrecommendedthatByTriteistakeneachdayatthesametimeoftheday.

ByTritecanbetakenbefore,withoraftermeals,becausefoodintakedoesnotmodifyitsbioavailability(seesection

5.2).

ByTritehastobeswallowedwithliquid.Itmustnotbechewedorcrushed.

Adults

Diuretic-Treatedpatients:

HypotensionmayoccurfollowinginitiationoftherapywithByTrite;thisismorelikelyinpatientswhoarebeing

treatedconcurrentlywithdiuretics.Cautionisthereforerecommendedsincethesepatientsmaybevolumeand/orsalt

depleted.

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Inhypertensivepatientsinwhomthediureticisnotdiscontinued,therapywithByTriteshouldbeinitiatedwitha1.25

mgdose.Renalfunctionandserumpotassiumshouldbemonitored.ThesubsequentdosageofByTriteshouldbe

adjustedaccordingtobloodpressuretarget.

Hypertension

Thedoseshouldbeindividualisedaccordingtothepatientprofile(seesection4.4)andbloodpressurecontrol.

ByTritemaybeusedinmonotherapyorincombinationwithotherclassesofantihypertensivemedicinalproducts.

Startingdose

ByTriteshouldbestartedgraduallywithaninitialrecommendeddoseof2.5mgdaily.

Patientswithastronglyactivatedrenin-angiotensin-aldosteronesystemmayexperienceanexcessivedropinblood

pressurefollowingtheinitialdose.Astartingdoseof1.25mgisrecommendedinsuchpatientsandtheinitiationof

treatmentshouldtakeplaceundermedicalsupervision(seesection4.4).

Titrationandmaintenancedose

Thedosecanbedoubledatintervaloftwotofourweekstoprogressivelyachievetargetbloodpressure;themaximum

permitteddoseofByTriteis10mgdaily.Usuallythedoseisadministeredoncedaily.

Treatmentofrenaldisease

Inpatientswithdiabetesandmicroalbuminuria:

Startingdose:

Therecommendedinitialdoseis1.25mgofByTriteoncedaily.

Titrationandmaintenancedose

Dependingonthepatient'stolerabilitytotheactivesubstance,thedoseissubsequentlyincreased.Doublingtheonce

dailydoseto2.5mgaftertwoweeksandthento5mgafterafurthertwoweeksisrecommended.

Inpatientswithdiabetesandatleastonecardiovascularrisk

Startingdose:

Therecommendedinitialdoseis2.5mgofByTriteoncedaily.

Titrationandmaintenancedose

Dependingonthepatient’stolerabilitytotheactivesubstance,thedoseissubsequentlyincreased.Doublingthedaily

doseto5mgByTriteafteroneortwoweeksandthento10mgByTriteafterafurthertwoorthreeweeksis

recommended.Thetargetdailydoseis10mg.

Inpatientswithnon-diabeticnephropathyasdefinedbymacroproteinuria3g/day.

Startingdose:

Therecommendedinitialdoseis1.25mgofByTriteoncedaily.

Titrationandmaintenancedose

Dependingonthepatient’stolerabilitytotheactivesubstance,thedoseissubsequentlyincreased.Doublingtheonce

dailydoseto2.5mgaftertwoweeksandthento5mgafterafurthertwoweeksisrecommended.

Symptomaticheartfailure

Startingdose

Inpatientsstabilizedondiuretictherapy,therecommendedinitialdoseis1.25mgdaily.

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ByTriteshouldbetitratedbydoublingthedoseeveryonetotwoweeksuptoamaximumdailydoseof10mg.Two

administrationsperdayarepreferable.

Secondarypreventionafteracutemyocardialinfarctionandwithheartfailure

Startingdose

After48hours,followingmyocardialinfarctioninaclinicallyandhaemodynamicallystablepatient,thestartingdoseis

2.5mgtwicedailyforthreedays.Iftheinitial2.5mgdoseisnottoleratedadoseof1.25mgtwiceadayshouldbe

givenfortwodaysbeforeincreasingto2.5mgand5mgtwiceaday.Ifthedosecannotbeincreasedto2.5mgtwicea

daythetreatmentshouldbewithdrawn.

Seealsoposologyondiuretictreatedpatientsabove.

Titrationandmaintenancedose

Thedailydoseissubsequentlyincreasedbydoublingthedoseatintervalsofonetothreedaysuptothetarget

maintenancedoseof5mgtwicedaily.

Themaintenancedoseisdividedin2administrationsperdaywherepossible.

Ifthedosecannotbeincreasedto2.5mgtwiceadaytreatmentshouldbewithdrawn.Sufficientexperienceisstill

lackinginthetreatmentofpatientswithsevere(NYHAIV)heartfailureimmediatelyaftermyocardialinfarction.

Shouldthedecisionbetakentotreatthesepatients,itisrecommendedthattherapybestartedat1.25mgoncedailyand

thatparticularcautionbeexercisedinanydoseincrease.

Specialpopulations

Patientswithrenalimpairment

Dailydoseinpatientswithrenalimpairmentshouldbebasedoncreatinineclearance(seesection5.2):

-ifcreatinineclearanceis ≥60ml/min,itisnotnecessarytoadjusttheinitialdose(2.5mg/day);themaximal

dailydoseis10mg;

-ifcreatinineclearanceisbetween30-60ml/min,itisnotnecessarytoadjusttheinitialdose(2.5mg/day);the

maximaldailydoseis5mg;

-ifcreatinineclearanceisbetween10-30ml/min,theinitialdoseis1.25mg/dayandthemaximaldailydoseis5

-inhaemodialysedhypertensivepatients:ramiprilisslightlydialysable;theinitialdoseis1.25mg/dayandthe

maximaldailydoseis5mg;themedicinalproductshouldbeadministeredfewhoursafterhaemodialysisis

performed.

Patientswithhepaticimpairment(seesection5.2)

Inpatientswithhepaticimpairment,treatmentwithByTritemustbeinitiatedonlyunderclosemedicalsupervisionand

themaximumdailydoseis2.5mgByTrite.

Elderly

Initialdosesshouldbelowerandsubsequentdosetitrationshouldbemoregradualbecauseofgreaterchanceof

undesirableeffectsespeciallyinveryoldandfrailpatients.Areducedinitialdoseof1.25mgramiprilshouldbe

considered.

Paediatricpopulation

ByTriteisnotrecommendedforuseinchildrenandadolescentsbelow18yearsofageduetoinsufficientdataonsafety

andefficacy.

4.3Contraindications

Hypersensitivitytotheactivesubstance,toanyoftheexcipientsoranyotherACE

(AngiotensinConvertingEnzyme)inhibitors(seesection6.1)

Historyofangioedema(hereditary,idiopathicorduetopreviousangioedemawith

ACEinhibitorsorAIIRAs)

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Significantbilateralrenalarterystenosisorrenalarterystenosisinasinglefunctioningkidney

and3 rd

trimesterofpregnancy(seesections4.4and4.6)

Ramiprilmustnotbeusedinpatientswithhypotensiveorhaemodynamicallyunstablestates.

4.4Specialwarningsandprecautionsforuse

Specialpopulations

Pregnancy:ACEinhibitorssuchasramipril,orAngiotensinIIReceptorAntagonists(AIIRAs)shouldnotbeinitiated

duringpregnancy.UnlesscontinuedACEinhibitor/AIIRAstherapyisconsideredessential,patientsplanning

pregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafetyprofilefor

useinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitors/AIIRAsshouldbestopped

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

Patientsatparticularriskofhypotension

Patientswithstronglyactivatedrenin-angiotensin-aldosteronesystem

Patientswithstronglyactivatedrenin-angiotensin-aldosteronesystemareatriskofanacutepronouncedfallin

bloodpressureanddeteriorationofrenalfunctionduetoACEinhibition,especiallywhenanACEinhibitorora

concomitantdiureticisgivenforthefirsttimeoratfirstdoseincrease.

Significantactivationofrenin-angiotensin-aldosteronesystemistobeanticipatedandmedicalsupervision

includingbloodpressuremonitoringisnecessary,forexamplein:

patientswithseverehypertension

patientswithdecompensatedcongestiveheartfailure

patientswithhaemodynamicallyrelevantleftventricularinfloworoutflowimpediment(e.g.stenosisofthe

aorticormitralvalve)

patientswithunilateralrenalarterystenosiswithasecondfunctionalkidney

patientsinwhomfluidorsaltdepletionexistsormaydevelop(includingpatientswithdiuretics)

patientswithlivercirrhosisand/orascites

patientsundergoingmajorsurgeryorduringanaesthesiawithagentsthatproducehypotension.

Generally,itisrecommendedtocorrectdehydration,hypovolaemiaorsaltdepletionbeforeinitiatingtreatment(in

patientswithheartfailure,however,suchcorrectiveactionmustbecarefullyweighedoutagainsttheriskofvolume

overload).

-TransientorpersistentheartfailurepostMI

-Patientsatriskofcardiacorcerebralischemiaincaseofacutehypotension

Theinitialphaseoftreatmentrequiresspecialmedicalsupervision.

Elderlypatients

Seesection4.2.

Surgery

Itisrecommendedthattreatmentwithangiotensinconvertingenzymeinhibitorssuchasramiprilshouldbe

discontinuedwherepossibleonedaybeforesurgery.

Monitoringofrenalfunction

Renalfunctionshouldbeassessedbeforeandduringtreatmentanddosageadjustedespeciallyintheinitialweeksof

treatment.Particularlycarefulmonitoringisrequiredinpatientswithrenalimpairment(seesection4.2).Thereisarisk

ofimpairmentofrenalfunction,particularlyinpatientswithcongestiveheartfailureorafterarenaltransplant.

Angioedema

AngioedemahasbeenreportedinpatientstreatedwithACEinhibitorsincludingramipril(seesection4.8).

Incaseofangioedema,ByTritemustbediscontinued.

Emergencytherapyshouldbeinstitutedpromptly.Patientshouldbekeptunderobservationforatleast12to24hours

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IntestinalangioedemahasbeenreportedinpatientstreatedwithACEinhibitorsincludingByTrite(seesection4.8).

Thesepatientspresentedwithabdominalpain(withorwithoutnauseaorvomiting).

Anaphylacticreactionsduringdesensitization

Thelikelihoodandseverityofanaphylacticandanaphylactoidreactionstoinsectvenomandotherallergensare

increasedunderACEinhibition.AtemporarydiscontinuationofByTriteshouldbeconsideredpriortodesensitization.

Hyperkalaemia

HyperkalaemiahasbeenobservedinsomepatientstreatedwithACEinhibitorsincludingByTrite.Patientsatriskfor

developmentofhyperkalaemiaincludethosewithrenalinsufficiency,age(>70years),uncontrolleddiabetesmellitus,

orthoseusingpotassiumsalts,potassiumretainingdiureticsandotherplasmapotassiumincreasingactivesubstances,

orconditionssuchasdehydration,acutecardiacdecompensation,metabolicacidosis.Ifconcomitantuseoftheabove

mentionedagentsisdeemedappropriate,regularmonitoringofserumpotassiumisrecommended(seesection4.5).

Neutropenia/agranulocytosis

Neutropenia/agranulocytosis,aswellasthrombocytopeniaandanaemia,havebeenrarelyseenandbonemarrow

depressionhasalsobeenreported.Itisrecommendedtomonitorthewhitebloodcellcounttopermitdetectionofa

possibleleucopoenia.Morefrequentmonitoringisadvisedintheinitialphaseoftreatmentandinpatientswith

impairedrenalfunction,thosewithconcomitantcollagendisease(e.g.lupuserythematosusorscleroderma),andall

thosetreatedwithothermedicinalproductsthatcancausechangesinthebloodpicture(seesections4.5and4.8).

Ethnicdifferences

ACEinhibitorscausehigherrateofangioedemainblackpatientsthaninnonblackpatients.

AswithotherACEinhibitors,ramiprilmaybelesseffectiveinloweringbloodpressureinblackpeoplethaninnon

blackpatients,possiblybecauseofahigherprevalenceofhypertensionwithlowreninlevelintheblackhypertensive

population.

Cough

CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnon-productive,persistentand

resolvesafterdiscontinuationoftherapy.ACEinhibitor-inducedcoughshouldbeconsideredaspartofthedifferential

diagnosisofcough.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Contra-indicatedcombinations

Extracorporealtreatmentsleadingtocontactofbloodwithnegativelychargedsurfacessuchasdialysisor

haemofiltrationwithcertainhigh-fluxmembranes(e.g.polyacrylonitrilmembranes)andlowdensitylipoprotein

apheresiswithdextransulphateduetoincreasedriskofsevereanaphylactoidreactions(seesection4.3).Ifsuch

treatmentisrequired,considerationshouldbegiventousingadifferenttypeofdialysismembraneoradifferentclass

ofantihypertensiveagent.

Precautionsforuse

Potassiumsalts,heparin,potassium-retainingdiureticsandotherplasmapotassiumincreasingactivesubstances

(includingAngiotensinIIantagonists,trimethoprim,tacrolimus,ciclosporin):Hyperkalaemiamayoccur,therefore

closemonitoringofserumpotassiumisrequired.

Antihypertensiveagents(e.g.diuretics)andothersubstancesthatmaydecreasebloodpressure(e.g.nitrates,tricyclic

antidepressants,anaesthetics,acutealcoholintake,baclofen,alfuzosin,doxazosin,prazosin,tamsulosin,terazosin):

Potentiationoftheriskofhypotensionistobeanticipated(seesection4.2fordiuretics)

Vasopressorsympathomimeticsandothersubstances(e.g.isoproterenol,dobutamine,dopamine,epinephrine)that

mayreducetheantihypertensiveeffectofByTrite:Bloodpressuremonitoringisrecommended.

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bloodcellcount:Increasedlikelihoodofhaematologicalreactions(seesection4.4).

Lithiumsalts:ExcretionoflithiummaybereducedbyACEinhibitorsandthereforelithiumtoxicitymaybeincreased.

Lithiumlevelmustbemonitored.

Antidiabeticagentsincludinginsulin:Hypoglycaemicreactionsmayoccur.Bloodglucosemonitoringis

recommended.

Non-steroidalanti-inflammatorydrugsandacetylsalicylicacid:ReductionoftheantihypertensiveeffectofByTriteis

tobeanticipated.Furthermore,concomitanttreatmentofACEinhibitorsandNSAIDsmayleadtoanincreasedriskof

worseningofrenalfunctionandtoanincreaseinkalaemia.

4.6Fertility,pregnancyandlactation

ByTriteisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4)andcontraindicatedduringthe

secondandthirdtrimestersofpregnancy(seesection4.3).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-

hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,

treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted.

ACEinhibitor/AngiotensinIIReceptorAntagonist(AIIRA)therapyexposureduringthesecondandthirdtrimestersis

knowntoinducehumanfetotoxicity(decreasedrenalfunction,oligohydramnios,skullossificationretardation)and

neonataltoxicity(renalfailure,hypotension,hyperkalaemia).(Seealso5.3'Preclinicalsafetydata').Shouldexposure

toACEinhibitorhaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunctionandskullis

recommended.NewbornswhosemothershavetakenACEinhibitorsshouldbecloselyobservedforhypotension,

oliguriaandhyperkalaemia(seealsosections4.3and4.4).

Becauseinsufficientinformationisavailableregardingtheuseoframiprilduringbreastfeeding(seesection5.2),

ramiprilisnotrecommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingare

preferable,especiallywhilenursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Someadverseeffects(e.g.symptomsofareductioninbloodpressuresuchasdizziness)mayimpairthepatient’s

abilitytoconcentrateandreactand,therefore,constituteariskinsituationswheretheseabilitiesareofparticular

importance(e.g.operatingavehicleormachinery).

Thiscanhappenespeciallyatthestartoftreatment,orwhenchangingoverfromotherpreparations.Afterthefirstdose

orsubsequentincreasesindoseitisnotadvisabletodriveoroperatemachineryforseveralhours.

4.8Undesirableeffects

Thesafetyprofileoframiprilincludespersistentdrycoughandreactionsduetohypotension.Seriousadversereactions

includeangioedema,hyperkalaemia,renalorhepaticimpairment,pancreatitis,severeskinreactionsand

neutropenia/agranulocytosis.

Adversereactionsfrequencyisdefinedusingthefollowingconvention:

Verycommon( ≥1/10);common(≥1/100to<1/10);uncommon(≥1/1,000to<1/100);

rare( ≥1/10,000to<1/1,000);veryrare(<1/10,000);

notknown(cannotbeestimatedfromtheavailabledata).

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Common Uncommon Rare Veryrare Notknown

Cardiacdisorders Myocardial

ischaemia

includingangina

pectorisor

myocardial

infarction,

tachycardia,

arrhythmia,

palpitations,

oedema

peripheral

Bloodand

lymphaticsystem

disorders Eosinophilia Whitebloodcell

countdecreased

(including

neutropeniaor

agranulocytosis),

redbloodcell

countdecreased,

haemoglobin

decreased,platelet

countdecreased Bonemarrow

failure,

pancytopenia,

haemolytic

anaemia

Nervoussystem

disorders Headache,

dizziness Vertigo,

paraesthesia,

ageusia,

dysgeusia, Tremor,balance

disorder Cerebral

ischaemia

including

ischaemicstroke

andtransient

ischaemicattack,

psychomotor

skillsimpaired,

burning

sensation,

parosmia

Eyedisorders Visual

disturbance

including

blurredvision Conjunctivitis

Earandlabyrinth

disorders Hearingimpaired,

tinnitus

Respiratory,

thoracicand

mediastinal

disorders Non-productive

ticklingcough,

bronchitis,

sinusitis,

dyspnoea Bronchospasm

including

asthma

aggravated,

nasalcongestion

Gastrointestinal

disorders Gastrointestinal

inflammation,

digestive

disturbances,

abdominal

discomfort, Pancreatitis

(casesoffatal

outcomehave

beenvery

exceptionally

reportedwith Glossitis Aphtous

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dyspepsia,

diarrhoea,

nausea,vomiting ACEinhibitors),

pancreatic

enzymes

increased,small

bowel

angioedema,

abdominalpain

upperincluding

gastritis,

constipation,dry

mouth

Renalandurinary

disorders Renal

impairment

includingrenal

failureacute,

urineoutput

increased,

worseningofa

pre-existing

proteinuria,

bloodurea

increased,blood

creatinine

increased

Skinand

subcutaneous

tissuedisorders Rashin

particular

maculo-papular Angioedema;

very

exceptionally,

theairway

obstruction

resultingfrom

angioedemamay

haveafatal

outcome;

pruritus,

Exfoliative

dermatitis,

urticaria,

onycholysis, Photosensitivity

reaction Toxicepidermal

necrolysis,

Stevens-Johnson

syndrome,

erythema

multiforme,

pemphigus,

psoriasis

aggravated,

dermatitis

psoriasiform,

pemphigoidor

lichenoid

exanthemaor

enanthema,

alopecia

Musculoskeletal

andconnective

tissuedisorders Musclespasms,

myalgia Arthralgia

Metabolismand

nutritiondisorders Bloodpotassium

increased Anorexia,

decreased

appetite, Bloodsodium

decreased

Vascular

disorders Hypotension,

orthostaticblood

pressure Flushing Vascularstenosis,

hypoperfusion,

vasculitis Raynaud’s

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4.9Overdose

SymptomsassociatedwithoverdosageofACEinhibitorsmayincludeexcessiveperipheralvasodilatation(withmarked

hypotension,shock),bradycardia,electrolytedisturbances,andrenalfailure.Thepatientshouldbecloselymonitored

andthetreatmentshouldbesymptomaticandsupportive.Suggestedmeasuresincludeprimarydetoxification(gastric

lavage,administrationofadsorbents)andmeasurestorestorehaemodynamicstability,including,administrationof

alpha1adrenergicagonistsorangiotensinII(angiotensinamide)administration.Ramiprilat,theactivemetaboliteof

ramiprilispoorlyremovedfromthegeneralcirculationbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:ACEInhibitors,plain,ATCcodeC09AA05.

Mechanismofaction

Ramiprilat,theactivemetaboliteoftheprodrugramipril,inhibitstheenzymedipeptidylcarboxypeptidaseI(synonyms:

angiotensin-convertingenzyme;kininaseII).InplasmaandtissuethisenzymecatalysestheconversionofangiotensinI

totheactivevasoconstrictorsubstanceangiotensinII,aswellasthebreakdownoftheactivevasodilatorbradykinin.

ReducedangiotensinIIformationandinhibitionofbradykininbreakdownleadtovasodilatation.

SinceangiotensinIIalsostimulatesthereleaseofaldosterone,ramiprilatcausesareductioninaldosteronesecretion.

decreased,

syncope

Generaldisorders

andadministration

siteconditions Chestpain,

fatigue Pyrexia Asthenia

Immunesystem

disorders Anaphylacticor

anaphylactoid

reactions,

antinuclear

antibody

increased

Hepatobiliary

disorders Hepaticenzymes

and/orbilirubin

conjugated

increased, Jaundice

cholestatic,

hepatocellular

damage Acutehepatic

failure,

cholestaticor

cytolytic

hepatitis(fatal

outcomehas

beenvery

exceptional).

Reproductive

systemandbreast

disorders Transient

erectile

impotence,

libidodecreased Gynaecomastia

Psychiatric

disorders Depressed

mood,anxiety,

nervousness,

restlessness,

sleepdisorder

including

somnolence Confusionalstate Disturbancein

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(usuallyalow-reninhypertensivepopulation)thaninnon-blackpatients.

Pharmacodynamiceffects

Antihypertensiveproperties:

Administrationoframiprilcausesamarkedreductioninperipheralarterialresistance.Generally,therearenomajor

changesinrenalplasmaflowandglomerularfiltrationrate.Administrationoframipriltopatientswithhypertension

leadstoareductioninsupineandstandingbloodpressurewithoutacompensatoryriseinheartrate.

Inmostpatientstheonsetoftheantihypertensiveeffectofasingledosebecomesapparent1to2hoursafteroral

administration.Thepeakeffectofasingledoseisusuallyreached3to6hoursafteroraladministration.The

antihypertensiveeffectofasingledoseusuallylastsfor24hours.

Themaximumantihypertensiveeffectofcontinuedtreatmentwithramiprilisgenerallyapparentafter3to4weeks.It

hasbeenshownthattheantihypertensiveeffectissustainedunderlongtermtherapylasting2years.

Abruptdiscontinuationoframiprildoesnotproducearapidandexcessivereboundincreaseinbloodpressure.

Heartfailure:

Inadditiontoconventionaltherapywithdiureticsandoptionalcardiacglycosides,ramiprilhasbeenshowntobe

effectiveinpatientswithfunctionalclassesII-IVoftheNew-YorkHeartAssociation.Thedrughadbeneficialeffects

oncardiachaemodynamics(decreasedleftandrightventricularfillingpressures,reducedtotalperipheralvascular

resistance,increasedcardiacoutputandimprovedcardiacindex).Italsoreducedneuroendocrineactivation.

Clinicalefficacyandsafety

Cardiovascularprevention/Nephroprotection;

Apreventiveplacebo-controlledstudy(theHOPE-study),wascarriedoutinwhichramiprilwasaddedtostandard

therapyinmorethan9,200patients.Patientswithincreasedriskofcardiovasculardiseasefollowingeither

atherothromboticcardiovasculardisease(historyofcoronaryheartdisease,strokeorperipheralvasculardisease)or

diabetesmellituswithatleastoneadditionalriskfactor(documentedmicroalbuminuria,hypertension,elevatedtotal

cholesterollevel,lowhigh-densitylipoproteincholesterollevelorcigarettesmoking)wereincludedinthestudy.

Thestudyshowedthatramiprilstatisticallysignificantlydecreasestheincidenceofmyocardialinfarction,deathfrom

cardiovascularcausesandstroke,aloneandcombined(primarycombinedevents).

TheHOPEstudy:Mainresults

TheMICRO-HOPEstudy,apredefinedsubstudyfromHOPE,investigatedtheeffectoftheadditionoframipril10mg

tothecurrentmedicalregimenversusplaceboin3,577patientsatleast ≥55yearsold(withnoupperlimitofage),with

Ramipril Placebo relativerisk

(95% confidence

interval) p-value

Allpatients n=4,645 N=4,652

Primarycombinedevents 14.0 17.8 0.78(0.70-0.86) <0.001

Myocardialinfarction 9.9 12.3 0.80(0.70-0.90) <0.001

Death from cardiovascular

causes 6.1 8.1 0.74(0.64-0.87) <0.001

Stroke 3.4 4.9 0.68(0.56-0.84) <0.001

Secondaryendpoints

Deathfromanycause 10.4 12.2 0.84(0.75-0.95) 0.005

NeedforRevascularisation 16.0 18.3 0.85(0.77-0.94) 0.002

Hospitalisation for unstable

angina 12.1 12.3 0.98(0.87-1.10) NS

Hospitalisationforheartfailure 3.2 3.5 0.88(0.70-1.10) 0.25

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Theprimaryanalysisshowedthat117(6.5%)participantsonramipriland149(8.4%)onplacebodevelopedovert

nephropathy,whichcorrespondstoaRRR24%;95%CI[3-40],p=0.027.

TheREINstudy,amulticenterrandomized,double-blindparallelgroup,placebo-controlledstudyaimedatassessing

theeffectoftreatmentwithramiprilontherateofdeclineofglomerularfunctionrate(GFR)in352normotensiveor

hypertensivepatients(18-70yearsold)sufferingfrommild(i.e.meanurinaryproteinexcretion>1and<3g/24h)or

severeproteinuria( ≥3g/24h)duetochronicnon-diabeticnephropathy.Bothsubpopulationswereprospectively

stratified.

Themainanalysisofpatientswiththemostsevereproteinuria(stratumprematurelydisruptedduetobenefitinramipril

group)showedthatthemeanrateofGFRdeclinepermonthwaslowerwithramiprilthanwithplacebo;-0.54(0.66)vs.

-0.88(1.03)ml/min/month,p=0.038.Theintergroupdifferencewasthus0.34[0.03-0.65]permonth,andaround4

ml/min/year;23.1%ofthepatientsintheramiprilgroupreachedthecombinedsecondaryendpointofdoublingof

baselineserumcreatinineconcentrationand/orend-stagerenaldisease(ESRD)(needfordialysisorrenal

transplantation)vs.45.5%intheplacebogroup(p=0.02).

Secondarypreventionafteracutemyocardialinfarction

TheAIREstudyincludedmorethan2,000patientswithtransient/persistentclinicalsignsofheartfailureafter

documentedmyocardialinfarction.Theramipriltreatmentwasstarted3to10daysaftertheacutemyocardial

infarction.Thestudyshowedthatafteranaveragefollow-uptimeof15monthsthemortalityinramipril-treated

patientswas16.9%andintheplacebotreatedpatientswas22.6%.Thismeansanabsolutemortalityreductionof5.7

%andarelativeriskreductionof27%(95%CI[11-40%]).

5.2Pharmacokineticproperties

PharmacokineticsandMetabolismAbsorption

Followingoraladministrationramiprilisrapidlyabsorbedfromthegastrointestinaltract:peakplasmaconcentrations

oframiprilarereachedwithinonehour.Basedonurinaryrecovery,theextentofabsorptionisatleast56%andisnot

significantlyinfluencedbythepresenceoffoodinthegastrointestinaltract.Thebioavailabilityoftheactivemetabolite

ramiprilatafteroraladministrationof2.5mgand5mgramiprilis45%.

Peakplasmaconcentrationsoframiprilat,thesoleactivemetaboliteoframiprilarereached2-4hoursafterramipril

intake.Steadystateplasmaconcentrationsoframiprilatafteroncedailydosingwiththeusualdosesoframiprilare

reachedbyaboutthefourthdayoftreatment.

Distribution

Theserumproteinbindingoframiprilisabout73%andthatoframiprilatabout56%.

Metabolism

Ramiprilisalmostcompletelymetabolisedtoramiprilat,andtothediketopiperazineester,thediketopiperazineacid,

andtheglucuronidesoframiprilandramiprilat.

Elimination

Excretionofthemetabolitesisprimarilyrenal.

Plasmaconcentrationsoframiprilatdeclineinapolyphasicmanner.Becauseofitspotent,saturablebindingtoACE

andslowdissociationfromtheenzyme,ramiprilatshowsaprolongedterminaleliminationphaseatverylowplasma

concentrations.

Aftermultipleonce-dailydosesoframipril,theeffectivehalf-lifeoframiprilatconcentrationswas13-17hoursforthe

5-10mgdosesandlongerforthelower1.25-2.5mgdoses.Thisdifferenceisrelatedtothesaturablecapacityofthe

enzymetobindramiprilat.

Asingleoraldoseoframiprilproducedanundetectableleveloframiprilanditsmetaboliteinbreastmilk.Howeverthe

effectofmultipledosesisnotknown.

Patientswithrenalimpairment(seesection4.2)

Renalexcretionoframiprilatisreducedinpatientswithimpairedrenalfunction,andrenalramiprilatclearanceis

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decreasemoreslowlythaninsubjectswithnormalrenalfunction.

Patientswithhepaticimpairment(seesection4.2)

Inpatientswithimpairedliverfunction,themetabolismoframipriltoramiprilatwasdelayed,duetodiminished

activityofhepaticesterases,andplasmaramiprillevelsinthesepatientswereincreased.Peakconcentrationsof

ramiprilatinthesepatients,however,arenotdifferentfromthoseseeninsubjectswithnormalhepaticfunction.

5.3Preclinicalsafetydata

Oraladministrationoframiprilhasbeenfoundtobedevoidofacutetoxicityinrodentsanddogs.

Studiesinvolvingchronicoraladministrationhavebeenconductedinrats,dogsandmonkeys.Indicationsofplasma

electrolyteshiftsandchangesinbloodpicturehavebeenfoundinthe3species.

Asanexpressionofthepharmacodynamicactivityoframipril,pronouncedenlargementofthejuxtaglomerular

apparatushasbeennotedinthedogandmonkeyfromdailydosesof250mg/kg/d.Rats,dogsandmonkeystolerated

dailydosesof2,2.5and8mg/kg/drespectivelywithoutharmfuleffects.

Reproductiontoxicologystudiesintherat,rabbitandmonkeydidnotdiscloseanyteratogenicproperties.Fertilitywas

notimpairedeitherinmaleorinfemalerats.

Theadministrationoframipriltofemaleratsduringthefetalperiodandlactationproducedirreversiblerenaldamage

(dilatationoftherenalpelvis)intheoffspringatdailydosesof50mg/kgbodyweightorhigher.

Extensivemutagenicitytestingusingseveraltestsystemshasyieldednoindicationthatramiprilpossessesmutagenicor

genotoxicproperties

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core

Pregelatinisedstarch

Calciumphosphate

Magnesiumhydroxide

Collodialanhydroussilica

Magnesiumstearate

CapsuleShell

Titaniumdioxide(E171)

Indigotine(E132)

Gelatin

Printingink(blackprintinginkSW–9008/SW–9009)contains:shellac,dehydratedalcohol,n-butylalcohol,purified

water,strongammoniasolution,potassiumhydroxide,propyleneglycol,blackironoxide(E172),isopropylalcohol.

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

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Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

TransparentPVC/Aclar254µm/51µmandaluminium20µmfoil,packof28,30and50capsules.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

HelsinnBirexTherapeuticsLtd

Damastown

Mulhuddart

Dublin15

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA915/9/4

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateofauthorisation:22 nd

April2005.

Dateoflastrenewal:22 nd

April2010

10DATEOFREVISIONOFTHETEXT

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