BYTRITE

Main information

  • Trade name:
  • BYTRITE Capsule 5 Milligram
  • Dosage:
  • 5 Milligram
  • Pharmaceutical form:
  • Capsule
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BYTRITE Capsule 5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0915/009/003
  • Authorization date:
  • 22-04-2005
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ByTrite5mgCapsules.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachhardcapsulecontains5.0mgramipril

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Capsules,hard.

Opaquerichyellowcapandopaquewhitebody,hardgelatincapsules(No.4),printedinblackink93and7211on

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

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Ifpossible,thediureticshouldbediscontinued2to3daysbeforebeginningtherapywithByTrite(seesection4.4).

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

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Titrationandmaintenancedose

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

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Extracorporealtreatmentsleadingtocontactofbloodwithnegativelychargedsurfaces(seesection4.5)

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.

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anddischargedaftercompleteresolutionofthesymptoms.

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

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Allopurinol,immunosuppressants,corticosteroids,procainamide,cytostaticsandothersubstancesthatmaychangethe

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

ischaemiaincluding

anginapectorisor

myocardial

infarction,

tachycardia,

arrhythmia,

palpitations,

oedemaperipheral

Bloodandlymphatic

systemdisorders Eosinophilia Whitebloodcellcount

decreased(including

neutropeniaor

agranulocytosis),red

bloodcellcount

decreased,

haemoglobin

decreased,platelet

countdecreased Bonemarrow

failure,

pancytopenia,

haemolyticanaemia

Nervoussystem

disorders Headache,

dizziness Vertigo,

paraesthesia,

ageusia,dysgeusia, Tremor,balance

disorder Cerebralischaemia

includingischaemic

strokeandtransient

ischaemicattack,

psychomotorskills

impaired,burning

sensation,parosmia

Eyedisorders Visualdisturbance

includingblurred

vision Conjunctivitis

Earandlabyrinth

disorders Hearingimpaired,

tinnitus

Respiratory,thoracic

andmediastinal

disorders Non-productive

ticklingcough,

bronchitis,

sinusitis,dyspnoea Bronchospasm

includingasthma

aggravated,nasal

congestion

Gastrointestinal

disorders Gastrointestinal

inflammation,

digestive

disturbances,

abdominal Pancreatitis(cases

offataloutcome

havebeenvery

exceptionally

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discomfort,

dyspepsia,

diarrhoea,nausea,

vomiting inhibitors),

pancreaticenzymes

increased,small

bowelangioedema,

abdominalpain

upperincluding

gastritis,

constipation,dry

mouth

Renalandurinary

disorders Renalimpairment

includingrenal

failureacute,urine

outputincreased,

worseningofapre-

existingproteinuria,

bloodurea

increased,blood

creatinineincreased

Skinand

subcutaneoustissue

disorders Rashinparticular

maculo-papular Angioedema;very

exceptionally,the

airwayobstruction

resultingfrom

angioedemamay

haveafatal

outcome;pruritus,

hyperhidrosis Exfoliativedermatitis,

urticaria,onycholysis, Photosensitivity

reaction Toxicepidermal

necrolysis,Stevens-

Johnsonsyndrome,

erythema

multiforme,

pemphigus,psoriasis

aggravated,

dermatitis

psoriasiform,

pemphigoidor

lichenoidexanthema

orenanthema,

alopecia

Musculoskeletaland

connectivetissue

disorders Musclespasms,

myalgia Arthralgia

Metabolismand

nutritiondisorders Bloodpotassium

increased Anorexia,decreased

appetite, Bloodsodium

decreased

Vasculardisorders Hypotension,

orthostaticblood Flushing Vascularstenosis,

hypoperfusion, 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.

pressuredecreased,

syncope vasculitis

Generaldisordersand

administrationsite

conditions Chestpain,fatigue Pyrexia Asthenia

Immunesystem

disorders Anaphylacticor

anaphylactoid

reactions,

antinuclearantibody

increased

Hepatobiliary

disorders Hepaticenzymes

and/orbilirubin

conjugated

increased, Jaundicecholestatic,

hepatocellulardamage Acutehepatic

failure,cholestaticor

cytolytichepatitis

(fataloutcomehas

beenvery

exceptional).

Reproductivesystem

andbreastdisorders Transienterectile

impotence,libido

decreased Gynaecomastia

Psychiatricdisorders Depressedmood,

anxiety,

nervousness,

restlessness,sleep

disorderincluding

somnolence Confusionalstate Disturbancein

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TheaverageresponsetoACEinhibitormonotherapywaslowerinblack(Afro-Caribbean)hypertensivepatients

(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

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

amajorityoftype2diabetes(andatleastanotherCVriskfactor),normotensiveorhypertensive.

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

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Patientswithrenalimpairment(seesection4.2)

Renalexcretionoframiprilatisreducedinpatientswithimpairedrenalfunction,andrenalramiprilatclearanceis

proportionallyrelatedtocreatinineclearance.Thisresultsinelevatedplasmaconcentrationsoframiprilat,which

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)

Redironoxide(E172)

Gelatin

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

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

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

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6.4Specialprecautionsforstorage

Donotstoreabove25°C.

Storeintheoriginalpackageinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

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

Notallpacksizesmaybemarketed

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

HelsinnBirexTherapeuticsLtd

Damastown

Mulhuddart

Dublin15

Ireland

8MARKETINGAUTHORISATIONNUMBER

PA915/9/3

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:22April2005

Dateoflastrenewal:22April2010

10DATEOFREVISIONOFTHETEXT

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