BELLRAMIL

Main information

  • Trade name:
  • BELLRAMIL Capsules Hard 2.5 Milligram
  • Dosage:
  • 2.5 Milligram
  • Pharmaceutical form:
  • Capsules Hard
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BELLRAMIL Capsules Hard 2.5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0408/092/001
  • Authorization date:
  • 07-10-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bellramil2.5mgCapsules,hard

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachhardcapsulecontiansramipril2.5mg.

Excipients:eachcapsulecontainsSunsetyellow(E110)andPonceau4R(E124)

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

HardCapsules.

Size4withorangecap/whitebodyimprintedwith"R"oncapand'2.5'onbody.

Containswhitetooff-whitegranularpowder.

4CLINICALPARTICULARS

4.1TherapeuticIndications

-Treatmentofhypertension.

-Cardiovascularprevention:reductionofcardiovascularmorbidityandmortalityinpatientswith:

omanifestatherothromboticcardiovasculardisease(historyofcoronaryheartdiseaseorstroke,orperipheralvascular

disease)or

odiabeteswithatleastonecardiovascularriskfactor(seesection5.1).

-Treatmentofrenaldisease:

oIncipientglomerulardiabeticnephropathyasdefinedbythepresenceofmicroalbuminuria,

oManifestglomerulardiabeticnephropathyasdefinedbymacroproteinuriainpatientswithatleastonecardiovascular

riskfactor(seesection5.1),

oManifestglomerularnondiabeticnephropathyasdefinedbymacroproteinuria3g/day(seesection5.1).

-Treatmentofsymptomaticheartfailure.

-Secondarypreventionafteracutemyocardialinfarction:reductionofmortalityfromtheacutephaseofmyocardial

infarctioninpatientswithclinicalsignsofheartfailurewhenstarted>48hoursfollowingacutemyocardialinfarction.

4.2Posologyandmethodofadministration

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ItisrecommendedthatBellramilistakeneachdayatthesametimeoftheday.

Bellramilcanbetakenbefore,withoraftermeals,becausefoodintakedoesnotmodifyitsbioavailability(seesection

5.2).Bellramilhastobeswallowedwithliquid.Itmustnotbechewedorcrushed.

Adults

Diuretic-Treatedpatients

HypotensionmayoccurfollowinginitiationoftherapywithBellramil;thisismorelikelyinpatientswhoarebeing

treatedconcurrentlywithdiuretics.Cautionisthereforerecommendedsincethesepatientsmaybevolumeand/orsalt

depleted.

Ifpossible,thediureticshouldbediscontinued2to3daysbeforebeginningtherapywithBellramil(seesection4.4).

Inhypertensivepatientsinwhomthediureticisnotdiscontinued,therapywithBellramilshouldbeinitiatedwitha1.25

mgdose.Renalfunctionandserumpotassiumshouldbemonitored.ThesubsequentdosageofBellramilshouldbe

adjustedaccordingtobloodpressuretarget.

Hypertension

Thedoseshouldbeindividualisedaccordingtothepatientprofile(seesection4.4)andbloodpressurecontrol.

Bellramilmaybeusedinmonotherapyorincombinationwithotherclassesofantihypertensivemedicinalproducts.

Startingdose

Bellramilshouldbestartedgraduallywithaninitialrecommendeddoseof2.5mgdaily.

Patientswithastronglyactivatedrenin-angiotensin-aldosteronesystemmayexperienceanexcessivedropinblood

pressurefollowingtheinitialdose.Astartingdoseof1.25mgisrecommendedinsuchpatientsandtheinitiationof

treatmentshouldtakeplaceundermedicalsupervision(seesection4.4).

Titrationandmaintenancedose

Thedosecanbedoubledatintervaloftwotofourweekstoprogressivelyachievetargetbloodpressure;themaximum

permitteddoseofBellramilis10mgdaily.Usuallythedoseisadministeredoncedaily.

Cardiovascularprevention

Startingdose

Therecommendedinitialdoseis2.5mgofBellramiloncedaily.

Titrationandmaintenancedose

Dependingonthepatient'stolerabilitytotheactivesubstance,thedoseshouldbegraduallyincreased.Itis

recommendedtodoublethedoseafteroneortwoweeksoftreatmentand-afteranothertwotothreeweeks-to

increaseituptothetargetmaintenancedoseof10mgBellramiloncedaily.

Seealsoposologyondiuretictreatedpatientsabove.

Treatmentofrenaldisease

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Startingdose:

Therecommendedinitialdoseis1.25mgofBellramiloncedaily.

Titrationandmaintenancedose

Dependingonthepatient'stolerabilitytotheactivesubstance,thedoseissubsequentlyincreased.Doublingtheonce

dailydoseto2.5mgaftertwoweeksandthento5mgafterafurthertwoweeksisrecommended.

Inpatientswithdiabetesandatleastonecardiovascularrisk

Startingdose:

Therecommendedinitialdoseis2.5mgofBellramiloncedaily.

Titrationandmaintenancedose

Dependingonthepatient'stolerabilitytotheactivesubstance,thedoseissubsequentlyincreased.Doublingthedaily

doseto5mgBellramilafteroneortwoweeksandthento10mgBellramilafterafurthertwoorthreeweeksis

recommended.Thetargetdailydoseis10mg.

Inpatientswithnon-diabeticnephropathyasdefinedbymacroproteinuria3g/day.

Startingdose:

Therecommendedinitialdoseis1.25mgofBellramiloncedaily.

Titrationandmaintenancedose

Dependingonthepatient'stolerabilitytotheactivesubstance,thedoseissubsequentlyincreased.Doublingtheonce

dailydoseto2.5mgaftertwoweeksandthento5mgafterafurthertwoweeksisrecommended.

Symptomaticheartfailure

Startingdose

Inpatientsstabilizedondiuretictherapy,therecommendedinitialdoseis1.25mgdaily.

Titrationandmaintenancedose

Bellramilshouldbetitratedbydoublingthedoseeveryonetotwoweeksuptoamaximumdailydoseof10mg.Two

administrationsperdayarepreferable.

Secondarypreventionafteracutemyocardialinfarctionandwithheartfailure

Startingdose

After48hours,followingmyocardialinfarctioninaclinicallyandhaemodynamicallystablepatient,thestartingdoseis

2.5mgtwicedailyforthreedays.Iftheinitial2.5mgdoseisnottoleratedadoseof1.25mgtwiceadayshouldbe

givenfortwodaysbeforeincreasingto2.5mgand5mgtwiceaday.Ifthedosecannotbeincreasedto2.5mgtwicea

daythetreatmentshouldbewithdrawn.

Seealsoposologyondiuretictreatedpatientsabove.

Titrationandmaintenancedose

Thedailydoseissubsequentlyincreasedbydoublingthedoseatintervalsofonetothreedaysuptothetarget

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Themaintenancedoseisdividedin2administrationsperdaywherepossible.

Ifthedosecannotbeincreasedto2.5mgtwiceadaytreatmentshouldbewithdrawn.Sufficientexperienceisstill

lackinginthetreatmentofpatientswithsevere(NYHAIV)heartfailureimmediatelyaftermyocardialinfarction.

Shouldthedecisionbetakentotreatthesepatients,itisrecommendedthattherapybestartedat1.25mgoncedailyand

thatparticularcautionbeexercisedinanydoseincrease.

Specialpopulations

Patientswithrenalimpairment

Dailydoseinpatientswithrenalimpairmentshouldbebasedoncreatinineclearance(seesection5.2):

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

doseis10mg;

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

dailydoseis5mg;

-ifcreatinineclearanceisbetween10-30ml/min,theinitialdoseis1.25mg/dayandthemaximaldailydoseis5mg;

-inhaemodialysedhypertensivepatients:Bellramilisslightlydialysable;theinitialdoseis1.25mg/dayandthe

maximaldailydoseis5mg;themedicinalproductshouldbeadministeredfewhoursafterhaemodialysisisperformed.

Patientswithhepaticimpairment(seesection5.2)

Inpatientswithhepaticimpairment,treatmentwithBellramilmustbeinitiatedonlyunderclosemedicalsupervision

andthemaximumdailydoseis2.5mgBellramil.

Elderly

Initialdosesshouldbelowerandsubsequentdosetitrationshouldbemoregradualbecauseofgreaterchanceof

undesirableeffectsespeciallyinveryoldandfrailpatients.Areducedinitialdoseof1.25mgBellramilshouldbe

considered.

Paediatricpopulation

Bellramilisnotrecommendedforuseinchildrenandadolescentsbelow18yearsofageduetoinsufficientdataon

safetyandefficacy.

4.3Contraindications

HypersensitivitytoBellramil,toanyoftheexcipientsoranyotherACE(AngiotensinConvertingEnzyme)inhibitors

(seesection6.1).

Historyofangioneuroticoedema(hereditary,idiopathicorduetopreviousangioedemawithACEinhibitorsor

AIIRAs)

Extracorporealtreatmentsleadingtocontactofbloodwithnegativelychargedsurfaces(seesection4.5)

Significantbilateralrenalarterystenosisorrenalarterystenosisinasinglefunctioningkidney

Hypotensiveorhaemodynamicallyunstablepatients.

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4.4Specialwarningsandprecautionsforuse

Specialpopulations

-Pregnancy:ACEinhibitorssuchasBellramil,orAngiotensinIIReceptorAntagonists(AIIRAs)shouldnotbe

initiatedduringpregnancy.UnlesscontinuedACEinhibitor/AIIRAstherapyisconsideredessential,patientsplanning

pregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafetyprofilefor

useinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitors/AIIRAsshouldbestopped

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

-Patientsatparticularriskofhypotension

-Patientswithstronglyactivatedrenin-angiotensin-aldosteronesystem

Patientswithstronglyactivatedrenin-angiotensin-aldosteronesystemareatriskofanacutepronouncedfallinblood

pressureanddeteriorationofrenalfunctionduetoACEinhibition,especiallywhenanACEinhibitororaconcomitant

diureticisgivenforthefirsttimeoratfirstdoseincrease.

Significantactivationofrenin-angiotensin-aldosteronesystemistobeanticipatedandmedicalsupervisionincluding

bloodpressuremonitoringisnecessary,forexamplein:

-patientswithseverehypertension

-patientswithdecompensatedcongestiveheartfailure

-patientswithhaemodynamicallyrelevantleftventricularinfloworoutflowimpediment(e.g.stenosisoftheaorticor

mitralvalve)

-patientswithunilateralrenalarterystenosiswithasecondfunctionalkidney

-patientsinwhomfluidorsaltdepletionexistsormaydevelop(includingpatientswithdiuretics)

-patientswithlivercirrhosisand/orascites

-patientsundergoingmajorsurgeryorduringanaesthesiawithagentsthatproducehypotension.

Generally,itisrecommendedtocorrectdehydration,hypovolaemiaorsaltdepletionbeforeinitiatingtreatment(in

patientswithheartfailure,however,suchcorrectiveactionmustbecarefullyweighedoutagainsttheriskofvolume

overload).

-TransientorpersistentheartfailurepostMI

-Patientsatriskofcardiacorcerebralischemiaincaseofacutehypotension

Theinitialphaseoftreatmentrequiresspecialmedicalsupervision.

-Elderlypatients

Seesection4.2.

-Surgery

ItisrecommendedthattreatmentwithangiotensinconvertingenzymeinhibitorssuchasBellramilshouldbe

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-Monitoringofrenalfunction

Renalfunctionshouldbeassessedbeforeandduringtreatmentanddosageadjustedespeciallyintheinitialweeksof

treatment.Particularlycarefulmonitoringisrequiredinpatientswithrenalimpairment(seesection4.2).Thereisarisk

ofimpairmentofrenalfunction,particularlyinpatientswithcongestiveheartfailureorafterarenaltransplant.

-Angioedema

AngioedemahasbeenreportedinpatientstreatedwithACEinhibitorsincludingBellramil(seesection4.8).

Incaseofangioedema,Bellramilmustbediscontinued.

Emergencytherapyshouldbeinstitutedpromptly.Patientshouldbekeptunderobservationforatleast12to24hours

anddischargedaftercompleteresolutionofthesymptoms.

IntestinalangioedemahasbeenreportedinpatientstreatedwithACEinhibitorsincludingBellramil(seesection4.8).

Thesepatientspresentedwithabdominalpain(withorwithoutnauseaorvomiting).

-Anaphylacticreactionsduringdesensitization

Thelikelihoodandseverityofanaphylacticandanaphylactoidreactionstoinsectvenomandotherallergensare

increasedunderACEinhibition.AtemporarydiscontinuationofBellramilshouldbeconsideredpriorto

desensitization.

-Hyperkalaemia

HyperkalaemiahasbeenobservedinsomepatientstreatedwithACEinhibitorsincludingBellramil.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,Bellramilmaybelesseffectiveinloweringbloodpressureinblackpeoplethaninnon

blackpatients,possiblybecauseofahigherprevalenceofhypertensionwithlowreninlevelintheblackhypertensive

population.

Cough

CoughhasbeenreportedwiththeuseofACEinhibitors.Characteristically,thecoughisnonproductive,persistentand

resolvesafterdiscontinuationoftherapy.ACEinhibitor-inducedcoughshouldbeconsideredaspartofthedifferential

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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)thatmay

reducetheantihypertensiveeffectofBellramil:Bloodpressuremonitoringisrecommended.

Allopurinol,immunosuppressants,corticosteroids,procainamide,cytostaticsandothersubstancesthatmaychangethe

bloodcellcount:Increasedlikelihoodofhaematologicalreactions(seesection4.4).

Lithiumsalts:ExcretionoflithiummaybereducedbyACEinhibitorsandthereforelithiumtoxicitymaybeincreased.

Lithiumlevelmustbemonitored.

Antidiabeticagentsincludinginsulin:Hypoglycaemicreactionsmayoccur.Bloodglucosemonitoringisrecommended.

Non-steroidalanti-inflammatorydrugsandacetylsalicylicacid:ReductionoftheantihypertensiveeffectofBellramilis

tobeanticipated.Furthermore,concomitanttreatmentofACEinhibitorsandNSAIDsmayleadtoanincreasedriskof

worseningofrenalfunctionandtoanincreaseinkalaemia.

4.6Fertility,pregnancyandlactation

Bellramilisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4)andcontraindicatedduringthe

secondandthirdtrimestersofpregnancy(seesection4.3).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternative

antihypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyis

diagnosed,treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapy

shouldbestarted.

ExposuretoACEinhibitor/AngiotensinIIReceptorAntagonist(AIIRA)therapyduringthesecondandthirdtrimesters

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neonataltoxicity(renalfailure,hypotension,hyperkalaemia).(Seesection5.3).ShouldexposuretoACEinhibitors

haveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunctionandskullisrecommended.

NewbornswhosemothershavetakenACEinhibitorsshouldbecloselyobservedforhypotension,oliguriaand

hyperkalaemia(seesections4.3and4.4).

BecauseinsufficientinformationisavailableregardingtheuseofBellramilduringbreastfeeding(seesection5.2),

Bellramilisnotrecommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feeding

arepreferable,especiallywhilenursinganewbornorpreterminfant.

4.7Effectsonabilitytodriveandusemachines

Someadverseeffects(e.g.symptomsofareductioninbloodpressuresuchasdizziness)mayimpairthepatient'sability

toconcentrateandreactand,therefore,constituteariskinsituationswheretheseabilitiesareofparticularimportance

(e.g.operatingavehicleormachinery).

Thiscanhappenespeciallyatthestartoftreatment,orwhenchangingoverfromotherpreparations.Afterthefirstdose

orsubsequentincreasesindoseitisnotadvisabletodriveoroperatemachineryforseveralhours.

4.8Undesirableeffects

ThesafetyprofileofBellramilincludespersistentdrycoughandreactionsduetohypotension.Seriousadverse

reactionsincludeangioedema,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).

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.

Common Uncommon Rare Veryrare Notknown

Cardiac

disorders Myocardial

ischaemia

including

anginapectoris

ormyocardial

infarction,

tachycardia,

arrhythmia,

palpitations,

oedema

peripheral

Bloodand

lymphaticsystem

disorders Eosinophilia Whitebloodcell

countdecreased

(including

neutropeniaor

agranulocytosis),

redbloodcell

countdecreased,

haemoglobin

decreased,

Bonemarrow

failure,

pancytopenia,

haemolytic

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decreased

Nervoussystem

disorders Headache,

dizziness Vertigo,

paraesthesia,

ageusia,

dysgeusia, Tremor,balance

disorder Cerebral

ischaemia

including

ischaemic

strokeand

transient

ischaemic

attack,

psychomotor

skillsimpaired,

burning

sensation,

parosmia

Eyedisorders Visual

disturbance

including

blurredvision Conjunctivitis

Earand

labyrinth

disorders Hearing

impaired,tinnitus

Respiratory,

thoracicand

mediastinal

disorders Non-productive

ticklingcough,

bronchitis,

sinusitis,

dyspnoea Bronchospasm

including

asthma

aggravated,

nasal

congestion

Gastrointestinal

disorders Gastrointestinal

inflammation,

digestive

disturbances,

abdominal

discomfort,

dyspepsia,

diarrhoea,

nausea,

Pancreatitis

(casesoffatal

outcomehave

beenvery

exceptionally

reportedwith

inhibitors),

pancreatic

enzymes

increased,

smallbowel

angioedema,

abdominalpain

upperincluding

gastritis,

constipation,

Glossitis Aphtous

stomatitis

Renaland

urinary

disorders Renal

impairment

includingrenal

failureacute,

urineoutput

increased,

worseningofa

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proteinuria,

bloodurea

increased,

blood

creatinine

increased

Skinand

subcutaneous

tissuedisorders Rashin

particular

maculo-papular Angioedema;

very

exceptionally,

theairway

obstruction

resultingfrom

angioedema

mayhavea

fataloutcome;

pruritus,

Exfoliative

dermatitis,

urticaria,

onycholysis, Photosensitivity

reaction Toxic

epidermal

necrolysis,

Stevens-

Johnson

syndrome,

erythema

multiforme,

pemphigus,

psoriasis

aggravated,

dermatitis

psoriasiform,

pemphigoidor

lichenoid

exanthemaor

enanthema,

alopecia

Musculoskeletal

andconnective

tissuedisorders Musclespasms,

myalgia Arthralgia

Metabolismand

nutrition

disorders Blood

potassium

increased Anorexia,

decreased

appetite, Bloodsodium

decreased

Vascular

disorders Hypotension,

orthostatic

bloodpressure

decreased,

syncope Flushing Vascular

stenosis,

hypoperfusion,

vasculitis Raynaud's

phenomenon

General

disordersand

administration

siteconditions Chestpain,

fatigue Pyrexia Asthenia

Immunesystem

disorders Anaphylacticor

anaphylactoid

reactions,

antinuclear

antibody

increased

Hepatobiliary

disorders Hepatic

enzymesand/or Jaundice

cholestatic, Acutehepatic

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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

Bellramilispoorlyremovedfromthegeneralcirculationbyhaemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Thepharmacotherapeuticgroup:ACEInhibitors,plain,ATC-codeC09AA05

Mechanismofaction

Ramiprilat,theactivemetaboliteoftheprodrugBellramil,inhibitstheenzymedipeptidylcarboxypeptidaseI

(synonyms:angiotensin-convertingenzyme;kininaseII).Inplasmaandtissuethisenzymecatalysestheconversionof

angiotensinItotheactivevasoconstrictorsubstanceangiotensinII,aswellasthebreakdownoftheactivevasodilator

bradykinin.ReducedangiotensinIIformationandinhibitionofbradykininbreakdownleadtovasodilatation.

SinceangiotensinIIalsostimulatesthereleaseofaldosterone,ramiprilatcausesareductioninaldosteronesecretion.

TheaverageresponsetoACEinhibitormonotherapywaslowerinblack(Afro-Caribbean)hypertensivepatients

(usuallyalow-reninhypertensivepopulation)thaninnon-blackpatients.

Pharmacodynamiceffects

Antihypertensiveproperties:

AdministrationofBellramilcausesamarkedreductioninperipheralarterialresistance.Generally,therearenomajor

bilirubin

conjugated

increased, hepatocellular

damage cholestaticor

cytolytic

hepatitis(fatal

outcomehas

beenvery

exceptional).

Reproductive

systemand

breastdisorders Transient

erectile

impotence,

libido

decreased Gynaecomastia

Psychiatric

disorders Depressed

mood,anxiety,

nervousness,

restlessness,

sleepdisorder

including

somnolence Confusionalstate Disturbancein

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leadstoareductioninsupineandstandingbloodpressurewithoutacompensatoryriseinheartrate.

Inmostpatientstheonsetoftheantihypertensiveeffectofasingledosebecomesapparent1to2hoursafteroral

administration.Thepeakeffectofasingledoseisusuallyreached3to6hoursafteroraladministration.The

antihypertensiveeffectofasingledoseusuallylastsfor24hours.

ThemaximumantihypertensiveeffectofcontinuedtreatmentwithBellramilisgenerallyapparentafter3to4weeks.It

hasbeenshownthattheantihypertensiveeffectissustainedunderlongtermtherapylasting2years.

AbruptdiscontinuationofBellramildoesnotproducearapidandexcessivereboundincreaseinbloodpressure.

Heartfailure:

Inadditiontoconventionaltherapywithdiureticsandoptionalcardiacglycosides,Bellramilhasbeenshowntobe

effectiveinpatientswithfunctionalclassesII-IVoftheNew-YorkHeartAssociation.Thedrughadbeneficialeffects

oncardiachaemodynamics(decreasedleftandrightventricularfillingpressures,reducedtotalperipheralvascular

resistance,increasedcardiacoutputandimprovedcardiacindex).Italsoreducedneuroendocrineactivation.

Clinicalefficacyandsafety

Cardiovascularprevention/Nephroprotection;

Apreventiveplacebo-controlledstudy(theHOPE-study),wascarriedoutinwhichBellramilwasaddedtostandard

therapyinmorethan9,200patients.Patientswithincreasedriskofcardiovasculardiseasefollowingeither

atherothromboticcardiovasculardisease(historyofcoronaryheartdisease,strokeorperipheralvasculardisease)or

diabetesmellituswithatleastoneadditionalriskfactor(documentedmicroalbuminuria,hypertension,elevatedtotal

cholesterollevel,lowhigh-densitylipoproteincholesterollevelorcigarettesmoking)wereincludedinthestudy.

ThestudyshowedthatBellramilstatisticallysignificantlydecreasestheincidenceofmyocardialinfarction,deathfrom

cardiovascularcausesandstroke,aloneandcombined(primarycombinedevents).

TheHOPEStudy:MainResults;

Bellramil 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

Deathfromcardiovascular

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

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TheMICRO-HOPEstudy,apredefinedsubstudyfromHOPE,investigatedtheeffectoftheadditionofBellramil10

mgtothecurrentmedicalregimenversusplaceboin3,577patientsatleast 55yearsold(withnoupperlimitofage),

withamajorityoftype2diabetes(andatleastanotherCVriskfactor),normotensiveorhypertensive.

Theprimaryanalysisshowedthat117(6.5%)participantsonBellramiland149(8.4%)onplacebodevelopedovert

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

TheREINstudy,amulticenterrandomized,double-blindparallelgroup,placebo-controlledstudyaimedatassessing

theeffectoftreatmentwithBellramilontherateofdeclineofglomerularfunctionrate(GFR)in352normotensiveor

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

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

stratified.

Themainanalysisofpatientswiththemostsevereproteinuria(stratumprematurelydisruptedduetobenefitin

Bellramilgroup)showedthatthemeanrateofGFRdeclinepermonthwaslowerwithBellramilthanwithplacebo;-

0.54(0.66)vs.-0.88(1.03)ml/min/month,p=0.038.Theintergroupdifferencewasthus0.34[0.03-0.65]permonth,

andaround4ml/min/year;23.1%ofthepatientsintheBellramilgroupreachedthecombinedsecondaryendpointof

doublingofbaselineserumcreatinineconcentrationand/orend-stagerenaldisease(ESRD)(needfordialysisorrenal

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

Secondarypreventionafteracutemyocardialinfarction

TheAIREstudyincludedmorethan2,000patientswithtransient/persistentclinicalsignsofheartfailureafter

documentedmyocardialinfarction.TheBellramiltreatmentwasstarted3to10daysaftertheacutemyocardial

infarction.Thestudyshowedthatafteranaveragefollow-uptimeof15monthsthemortalityinBellramil-treated

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

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

5.2Pharmacokineticproperties

PharmacokineticsandMetabolism

Absorption

FollowingoraladministrationBellramilisrapidlyabsorbedfromthegastrointestinaltract:peakplasmaconcentrations

ofBellramilarereachedwithinonehour.Basedonurinaryrecovery,theextentofabsorptionisatleast56%andisnot

significantlyinfluencedbythepresenceoffoodinthegastrointestinaltract.Thebioavailabilityoftheactivemetabolite

ramiprilatafteroraladministrationof2.5mgand5mgBellramilis45%.

Peakplasmaconcentrationsoframiprilat,thesoleactivemetaboliteofBellramilarereached2-4hoursafterBellramil

intake.SteadystateplasmaconcentrationsoframiprilatafteroncedailydosingwiththeusualdosesofBellramilare

reachedbyaboutthefourthdayoftreatment.

Distribution

TheserumproteinbindingofBellramilisabout73%andthatoframiprilatabout56%.

Hospitalisationforunstable

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

Complicationsrelatedto

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Bellramilisalmostcompletelymetabolisedtoramiprilat,andtothediketopiperazineester,thediketopiperazineacid,

andtheglucuronidesofBellramilandramiprilat.

Elimination

Excretionofthemetabolitesisprimarilyrenal.

Plasmaconcentrationsoframiprilatdeclineinapolyphasicmanner.Becauseofitspotent,saturablebindingtoACE

andslowdissociationfromtheenzyme,ramiprilatshowsaprolongedterminaleliminationphaseatverylowplasma

concentrations.

Aftermultipleonce-dailydosesofBellramil,theeffectivehalf-lifeoframiprilatconcentrationswas13-17hoursforthe

5-10mgdosesandlongerforthelower1.25-2.5mgdoses.Thisdifferenceisrelatedtothesaturablecapacityofthe

enzymetobindramiprilat.

AsingleoraldoseofBellramilproducedanundetectablelevelofBellramilanditsmetaboliteinbreastmilk.However

theeffectofmultipledosesisnotknown.

Patientswithrenalimpairment(seesection4.2)

Renalexcretionoframiprilatisreducedinpatientswithimpairedrenalfunction,andrenalramiprilatclearanceis

proportionallyrelatedtocreatinineclearance.Thisresultsinelevatedplasmaconcentrationsoframiprilat,which

decreasemoreslowlythaninsubjectswithnormalrenalfunction.

Patientswithhepaticimpairment(seesection4.2)

Inpatientswithimpairedliverfunction,themetabolismofBellramiltoramiprilatwasdelayed,duetodiminished

activityofhepaticesterases,andplasmaBellramillevelsinthesepatientswereincreased.Peakconcentrationsof

ramiprilatinthesepatients,however,arenotdifferentfromthoseseeninsubjectswithnormalhepaticfunction.

5.3Preclinicalsafetydata

OraladministrationofBellramilhasbeenfoundtobedevoidofacutetoxicityinrodentsanddogs.

Studiesinvolvingchronicoraladministrationhavebeenconductedinrats,dogsandmonkeys.

Indicationsofplasmaelectrolyteshiftsandchangesinbloodpicturehavebeenfoundinthe3species.

AsanexpressionofthepharmacodynamicactivityofBellramil,pronouncedenlargementofthejuxtaglomerular

apparatushasbeennotedinthedogandmonkeyfromdailydosesof250mg/kg/d.

Rats,dogsandmonkeystolerateddailydosesof2,2.5and8mg/kg/drespectivelywithoutharmfuleffects.

Reproductiontoxicologystudiesintherat,rabbitandmonkeydidnotdiscloseanyteratogenicproperties.

Fertilitywasnotimpairedeitherinmaleorinfemalerats.

TheadministrationofBellramiltofemaleratsduringthefetalperiodandlactationproducedirreversiblerenaldamage

(dilatationoftherenalpelvis)intheoffspringatdailydosesof50mg/kgbodyweightorhigher.

ExtensivemutagenicitytestingusingseveraltestsystemshasyieldednoindicationthatBellramilpossessesmutagenic

orgenotoxicproperties.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Capsulecontents

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CapsulesShell

Orange/Whitebody,size‘4

CapShell

Gelatin

Sunsetyellow(E110)

Ponceau4R(E124)

Titaniumdioxide(E171)

PrintingInk

Shellac

Propyleneglycol

Potassiumhydroxide

Blackironoxide(E172)

6.2Incompatibilities

Notapplicable

6.3Shelflife

2Years

6.4Specialprecautionsforstorage

Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

AluminiumstripscomprisingofaluminiumfoillaminatedwithLDPE.Thestripsareenclosedinacardboardcartonin

packsizesof21,28,30,56or60capsules.Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

RanbaxyIrelandLimited

SpaField

CorkRoad

Cashel

Co.Tipperary

8MARKETINGAUTHORISATIONNUMBER

PA0408/092/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:27 th

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10DATEOFREVISIONOFTHETEXT

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