COVERSYL ARGININE PLUS

Main information

  • Trade name:
  • COVERSYL ARGININE PLUS
  • Dosage:
  • 5/1.25 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • COVERSYL ARGININE PLUS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1562/063/001
  • Authorization date:
  • 04-11-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

CoversylArgininePlus5mg/1.25mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onefilm-coatedtabletcontains3.395mgperindoprilcorrespondingto5mgperindoprilarginineand1.25mg

indapamide.

Excipient:lactosemonohydrate

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedTablets

ProductimportedfromHungary:

White,rod-shapedfilm-coatedtablets

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofessentialhypertension,COVERSYLARGININEPLUS5mg/1.25mgfilm-coatedtabletisindicatedin

patientswhosebloodpressureisnotadequatelycontrolledonperindoprilalone.

4.2Posologyandmethodofadministration

Oralroute

OneCOVERSYLARGININEPLUS5mg/1.25mgfilm-coatedtabletperdayasasingledose,preferablytobetakenin

themorning,andbeforeameal.

Whenpossibleindividualdosetitrationwiththecomponentsisrecommended.COVERSYLARGININEPLUS

5mg/1.25mgfilm-coatedtabletshouldbeusedwhenbloodpressureisnotadequatelycontrolledonCOVERSYL

ARGININEPLUS2.5mg/0.625mgfilm-coatedtablet(whereavailable).Whenclinicallyappropriate,directchange

frommonotherapytoCOVERSYLARGININEPLUS5mg/1.25mgfilm-coatedtabletmaybeconsidered.

Elderly(seesection4.4)

Treatmentshouldbeinitiatedafterconsideringbloodpressureresponseandrenalfunction.

Patientswithrenalimpairment(seesection4.4)

Insevererenalimpairment(creatinineclearancebelow30ml/min),treatmentiscontraindicated.

Inpatientswithmoderaterenalimpairment(creatinineclearance30-60ml/min),itisrecommendedtostarttreatment

withtheadequatedosageofthefreecombination.

Inpatientswithcreatinineclearancegreaterthanorequalto60ml/min,nodosemodificationisrequired.Usual

medicalfollow-upwillincludefrequentmonitoringofcreatinineandpotassium.

Patientswithhepaticimpairment(seesections4.3,4.4and5.2)

Inseverehepaticimpairment,treatmentiscontraindicated.

Inpatientswithmoderatehepaticimpairment,nodosemodificationisrequired.

Childrenandadolescents

COVERSYLARGININEPLUS5mg/1.25mgshouldnotbeusedinchildrenandadolescentsastheefficacyand

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4.3Contraindications

Linkedtoperindopril:

HypersensitivitytoperindopriloranyotherACEinhibitor

Historyofangioedema(Quincke’soedema)associatedwithpreviousACEinhibitortherapy

Hereditary/idiopathicangioedema

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6)

Linkedtoindapamide:

Hypersensitivitytoindapamideortoanyothersulphonamides

Severerenalimpairment(creatinineclearancebelow30ml/min)

Hepaticencephalopathy

Severehepaticimpairment

Hypokalaemia

Asageneralrule,thismedicineisinadvisableincombinationwithnonantiarrhythmicagentscausingtorsadesde

pointes(seesection4.5)

Lactation(seesection4.6).

LinkedtoCOVERSYLARGININEPLUS5mg/1.25mg:

Hypersensitivitytoanyoftheexcipients

Duetothelackofsufficienttherapeuticexperience,COVERSYLARGININEPLUS5mg/1.25mgshouldnotbeused

Dialysispatients

Patientswithuntreateddecompensatedheartfailure.

4.4Specialwarningsandprecautionsforuse

Specialwarnings

Commontoperindoprilandindapamide:

Lithium:

Thecombinationoflithiumandthecombinationofperindoprilandindapamideisusuallynotrecommended(see

section4.5).

Linkedtoperindopril:

Neutropenia/agranulocytosis:

Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedinpatientsreceivingACEinhibitors.

Inpatientswithnormalrenalfunctionandnoothercomplicatingfactors,neutropeniaoccursrarely.Perindoprilshould

beusedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressanttherapy,treatmentwith

allopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthereispre-existingimpaired

renalfunction.Someofthesepatientsdevelopedseriousinfectionswhichinafewinstancesdidnotrespondto

intensiveantibiotictherapy.Ifperindoprilisusedinsuchpatients,periodicalmonitoringofwhitebloodcellcountsis

advisedandpatientsshouldbeinstructedtoreportanysignofinfection(e.g.sorethroat,fever).

Hypersensitivity/angioedema:

Angioedemaoftheface,extremities,lips,tongue,glottisand/orlarynxhasbeenreportedrarelyinpatientstreatedwith

angiotensinconvertingenzymeinhibitors,includingperindopril.Thismayoccuratanytimeduringtreatment.Insuch

casesperindoprilshouldbediscontinuedpromptlyandappropriatemonitoringshouldbeinstitutedtoensurecomplete

resolutionofsymptomspriortodismissingthepatient.Inthoseinstanceswhereswellinghasbeenconfinedtotheface

andlipstheconditiongenerallyresolvedwithouttreatment,althoughantihistamineshavebeenusefulinrelieving

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Angioedemaassociatedwithlaryngealoedemamaybefatal.Wherethereisinvolvementofthetongue,glottisor

larynx,likelytocauseairwayobstruction,appropriatetherapy,whichmayincludesubcutaneousepinephrinesolution

1:1000(0.3mlto0.5ml)and/ormeasurestoensureapatentairway,shouldbeadministeredpromptly.

BlackpatientsreceivingACEinhibitorshavebeenreportedtohaveahigherincidenceofangioedemacomparedto

non-blacks.

PatientswithahistoryofangioedemaunrelatedtoACEinhibitortherapymaybeatincreasedriskofangioedemawhile

receivinganACEinhibitor(seesection4.3).

IntestinalangioedemahasbeenreportedrarelyinpatientstreatedwithACEinhibitors.Thesepatientspresentedwith

abdominalpain(withorwithoutnauseaorvomiting);insomecasestherewasnopriorfacialangioedemaandC-1

esteraselevelswerenormal.TheangioedemawasdiagnosedbyproceduresincludingabdominalCTscan,or

ultrasoundoratsurgeryandsymptomsresolvedafterstoppingtheACEinhibitor.Intestinalangioedemashouldbe

includedinthedifferentialdiagnosisofpatientsonACEinhibitorspresentingwithabdominalpain.

Anaphylactoidreactionsduringdesensitisation:

Therehavebeenisolatedreportsofpatientsexperiencingsustained,life-threateninganaphylactoidreactionswhile

receivingACEinhibitorsduringdesensitisationtreatmentwithhymenoptera(bees,wasps)venom.ACEinhibitors

shouldbeusedwithcautioninallergicpatientstreatedwithdesensitisation,andavoidedinthoseundergoingvenom

immunotherapy.HoweverthesereactionscouldbepreventedbytemporarywithdrawalofACEinhibitorforatleast24

hoursbeforetreatmentinpatientswhorequirebothACEinhibitorsanddesensitisation.

AnaphylactoidreactionsduringLDLapheresis:

Rarely,patientsreceivingACEinhibitorsduringlowdensitylipoprotein(LDL)-apheresiswithdextransulphatehave

experiencedlife-threateninganaphylactoidreactions.ThesereactionswereavoidedbytemporarilywithholdingACE-

inhibitortherapypriortoeachapheresis.

Haemodialysispatients:

Anaphylactoidreactionshavebeenreportedinpatientsdialysedwithhigh-fluxmembranes(e.g.,AN69®)andtreated

concomitantlywithanACEinhibitor.Inthesepatientsconsiderationshouldbegiventousingadifferenttypeof

dialysismembraneoradifferentclassofantihypertensiveagent.

Potassium-sparingdiuretics,potassiumsalts:

Thecombinationofperindoprilandpotassium-sparingdiuretics,potassiumsaltsisusuallynotrecommended(see

section4.5).

Pregnancyandlactation:

ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitortherapyisconsidered

essential,patientsplanningpregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhavean

establishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbe

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

Useofperindoprilisnotrecommendedduringbreastfeeding.

Linkedtoindapamide:

Whenliverfunctionisimpaired,thiazidediureticsandthiazide-relateddiureticsmaycausehepaticencephalopathy.

Administrationofthediureticshouldbestoppedimmediatelyifthisoccurs.

Photosensitivity:

Casesofphotosensitivityreactionshavebeenreportedwiththiazidesandrelatedthiazidesdiuretics(seesection4.8).If

photosensitivityreactionoccursduringtreatment,itisrecommendedtostopthetreatment.Ifare-administrationofthe

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Precautionsforuse

Commontoperindoprilandindapamide:

Renalimpairment:

Incasesofsevererenalimpairment(creatinineclearance<30ml/min),treatmentiscontraindicated.

Incertainhypertensivepatientswithoutpre-existingapparentrenallesionsandforwhomrenalbloodtestsshow

functionalrenalinsufficiency,treatmentshouldbestoppedandpossiblyrestartedeitheratalowdoseorwithone

constituentonly.

Inthesepatientsusualmedicalfollow-upwillincludefrequentmonitoringofpotassiumandcreatinine,aftertwoweeks

oftreatmentandtheneverytwomonthsduringtherapeuticstabilityperiod.Renalfailurehasbeenreportedmainlyin

patientswithsevereheartfailureorunderlyingrenalfailureincludingrenalarterystenosis.

Thedrugisusuallynotrecommendedincaseofbilateralrenalarterystenosisorasinglefunctioningkidney.

Hypotensionandwaterandelectrolytedepletion:

Thereisariskofsuddenhypotensioninthepresenceofpre-existingsodiumdepletion(inparticularinindividualswith

renalarterystenosis).Thereforesystematictestingshouldbecarriedoutforclinicalsignsofwaterandelectrolyte

depletion,whichmayoccurwithanintercurrentepisodeofdiarrhoeaorvomiting.Regularmonitoringofplasma

electrolytesshouldbecarriedoutinsuchpatients.

Markedhypotensionmayrequiretheimplementationofanintravenousinfusionofisotonicsaline.

Transienthypotensionisnotacontraindicationtocontinuationoftreatment.Afterre -establishmentofasatisfactory

bloodvolumeandbloodpressure,treatmentcanbestartedagaineitheratareduceddoseorwithonlyoneofthe

constituents.

Potassiumlevels:

Thecombinationofperindoprilandindapamidedoesnotpreventtheonsetofhypokalaemiaparticularlyindiabetic

patientsorinpatientswithrenalfailure.Aswithanyantihypertensiveagentcontainingadiuretic,regularmonitoringof

plasmapotassiumlevelsshouldbecarriedout.

Excipients:

COVERSYLARGININEPLUS5mg/1.25mgshouldnotbeadministeredtopatientswithrarehereditaryproblemsof

galactoseintolerance,theLapplactasedeficiencyorglucose-galactosemalabsorption.

Linkedtoperindopril:

Cough:

Adrycoughhasbeenreportedwiththeuseofangiotensinconvertingenzymeinhibitors.Itischaracterisedbyits

persistenceandbyitsdisappearancewhentreatmentiswithdrawn.Aniatrogenicaetiologyshouldbeconsideredinthe

eventofthissymptom.Iftheprescriptionofanangiotensinconvertingenzymeinhibitorisstillpreferred,continuation

oftreatmentmaybeconsidered.

Childrenandadolescents:

Theefficacyandtolerabilityofperindoprilinchildrenandadolescents,aloneorincombination,havenotbeen

established.

Riskofarterialhypotensionand/orrenalinsufficiency(incasesofcardiacinsufficiency,waterandelectrolyte

depletion,etc...):

Markedstimulationoftherenin-angiotensin-aldosteronesystemhasbeenobservedparticularlyduringmarkedwater

andelectrolytedepletions(strictsodium-freedietorprolongeddiuretictreatment),inpatientswhosebloodpressure

wasinitiallylow,incasesofrenalarterystenosis,congestiveheartfailureorcirrhosiswithoedemaandascites.

Theblockingofthissystemwithanangiotensinconvertingenzymeinhibitormaythereforecause,particularlyatthe

timeofthefirstadministrationandduringthefirsttwoweeksoftreatment,asuddendropinbloodpressureand/oran

increaseinplasmalevelsofcreatinine,showingafunctionalrenalinsufficiency.Occasionallythiscanbeacutein

onset,althoughrare,andwithavariabletimetoonset.

Insuchcases,thetreatmentshouldthenbeinitiatedatalowerdoseandincreasedprogressively.

Elderly:

Renalfunctionandpotassiumlevelsshouldbetestedbeforethestartoftreatment.Theinitialdoseissubsequently

adjustedaccordingtobloodpressureresponse,especiallyincasesofwaterandelectrolytedepletion,inordertoavoid

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Patientswithknownatherosclerosis:

Theriskofhypotensionexistsinallpatientsbutparticularcareshouldbetakeninpatientswithischaemicheartdisease

orcerebralcirculatoryinsufficiency,withtreatmentbeingstartedatalowdose.

Renovascularhypertension:

Thetreatmentforrenovascularhypertensionisrevascularisation.Nonetheless,angiotensinconvertingenzyme

inhibitorscanbebeneficialinpatientspresentingwithrenovascularhypertensionwhoareawaitingcorrectivesurgery

orwhensuchasurgeryisnotpossible.

IfCOVERSYLARGININEPLUS5mg/1.25mgisprescribedtopatientswithknownorsuspectedrenalarterystenosis,

treatmentshouldbestartedinahospitalsettingatalowdoseandrenalfunctionandpotassiumlevelsshouldbe

monitored,sincesomepatientshavedevelopedafunctionalrenalinsufficiencywhichwasreversedwhentreatmentwas

stopped.

Otherpopulationsatrisk:

Inpatientswithseverecardiacinsufficiency(gradeIV)orinpatientswithinsulindependentdiabetesmellitus

(spontaneoustendencytoincreasedlevelsofpotassium),treatmentshouldbestartedundermedicalsupervisionwitha

reducedinitialdose.Treatmentwithbeta-blockersinhypertensivepatientswithcoronaryinsufficiencyshouldnotbe

stopped:theACEinhibitorshouldbeaddedtothebeta-blocker.

Diabeticpatients:

Theglycaemialevelsshouldbecloselymonitoredindiabeticpatientspreviouslytreatedwithoralantidiabeticdrugsor

insulin,namelyduringthefirstmonthoftreatmentwithanACEinhibitor.

Ethnicdifferences:

Aswithotherangiotensinconvertingenzymeinhibitors,perindoprilisapparentlylesseffectiveinloweringblood

pressureinblackpeoplethaninnon -blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblack

hypertensivepopulation.

Surgery/anaesthesia:

Angiotensinconvertingenzymeinhibitorscancausehypotensionincasesofanaesthesia,especiallywhenthe

anaestheticadministeredisanagentwithhypotensivepotential.

Itisthereforerecommendedthattreatmentwithlong-actingangiotensinconvertingenzymeinhibitorssuchas

perindoprilshouldbediscontinuedwherepossibleonedaybeforesurgery.

Aorticormitralvalvestenosis/hypertrophiccardiomyopathy:

ACEinhibitorsshouldbeusedwithcautioninpatientwithanobstructionintheoutflowtractoftheleftventricle.

Hepaticfailure:

Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceandprogressesto

fulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeisnotunderstood.Patients

receivingACEinhibitorswhodevelopjaundiceormarkedelevationsofhepaticenzymesshoulddiscontinuetheACE

inhibitorandreceiveappropriatemedicalfollow-up(seesection4.8).

Hyperkalaemia:

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,includingperindopril.

Riskfactorsforthedevelopmentofhyperkalemiaincludethosewithrenalinsufficiency,worseningofrenalfunction,

age(>70years),diabetesmellitus,intercurrentevents,inparticulardehydration,acutecardiacdecompensation,

metabolicacidosisandconcomitantuseofpotassium-sparingdiuretics(e.g.,spironolactone,eplerenone,triamterene,or

amiloride),potassiumsupplementsorpotassium-containingsaltsubstitutes;orthosepatientstakingotherdrugs

associatedwithincreasesinserumpotassium(e.g.heparin).Theuseofpotassiumsupplements,potassium-sparing

diuretics,orpotassium-containingsaltsubstitutesparticularlyinpatientswithimpairedrenalfunctionmayleadtoa

significantincreaseinserumpotassium.Hyperkalemiacancauseserious,sometimesfatalarrhythmias.Ifconcomitant

useoftheabove-mentionedagentsisdeemedappropriate,theyshouldbeusedwithcautionandwithfrequent

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Linkedtoindapamide:

Waterandelectrolytebalance:

Sodiumlevels:

Theseshouldbetestedbeforetreatmentisstarted,thenatregularintervals.Alldiuretictreatmentcancauseareduction

insodiumlevels,whichmayhaveseriousconsequences.Reductioninsodiumlevelscanbeinitiallyasymptomaticand

regulartestingisthereforeessential.Testingshouldbemorefrequentinelderlyandcirrhoticpatients(seesections4.8

and4.9).

Potassiumlevels:

Potassiumdepletionwithhypokalaemiaisamajorriskwiththiazidediureticsandthiazide-relateddiuretics.Theriskof

onsetofloweredpotassiumlevels(<3.4mmol/l)shouldbepreventedinsomehighriskpopulationssuchaselderly

and/ormalnourishedsubjects,whetherornottheyaretakingmultiplemedications,cirrhoticpatientswithoedemaand

ascites,coronarypatientsandpatientswithheartfailure.

Insuchcaseshypokalaemiaincreasesthecardiactoxicityofcardiacglycosidesandtheriskofrhythmdisorders.

SubjectspresentingwithalongQTintervalarealsoatrisk,whethertheoriginiscongenitaloriatrogenic.

Hypokalaemia,aswithbradycardia,actsasafactorwhichfavourstheonsetofsevererhythmdisorders,inparticular

torsadesdepointes,whichmaybefatal.

Inallcasesmorefrequenttestingofpotassiumlevelsisnecessary.Thefirstmeasurementofplasmapotassiumlevels

shouldbecarriedoutduringthefirstweekfollowingthestartoftreatment.

Iflowpotassiumlevelsaredetected,correctionisrequired.

Calciumlevels:

Thiazidediureticsandthiazide-relateddiureticsmayreduceurinaryexcretionofcalciumandcauseamildandtransient

increaseinplasmacalciumlevels.Markedlyraisedlevelsofcalciummayberelatedtoundiagnosed

hyperparathyroidism.Insuchcasesthetreatmentshouldbestoppedbeforeinvestigatingtheparathyroidfunction.

Bloodglucose:

Monitoringofbloodglucoseisimportantindiabeticpatients,particularlywhenpotassiumlevelsarelow.

Uricacid:

Tendencytogoutattacksmaybeincreasedinhyperuricaemicpatients.

Renalfunctionanddiuretics:

Thiazidediureticsandthiazide-relateddiureticsareonlyfullyeffectivewhenrenalfunctionisnormaloronlyslightly

impaired(creatininelevelslowerthanapproximately25mg/l,i.e.220µmol/lforanadult).

Intheelderlythevalueofplasmacreatininelevelsshouldbeadjustedtotakeaccountoftheage,weightandsexofthe

patient,accordingtotheCockroftformula:

=(140-age)xbodyweight/0.814xplasmacreatininelevelwith:

ageexpressedinyears

bodyweightinkg

plasmacreatininelevelinmicromol/l

Thisformulaissuitableforanelderlymaleandshouldbeadaptedforwomenbymultiplyingtheresultby0.85.

Hypovolaemia,resultingfromthelossofwaterandsodiumcausedbythediureticatthestartoftreatment,causesa

reductioninglomerularfiltration.Itmayresultinanincreaseinbloodureaandcreatininelevels.Thistransitory

functionalrenalinsufficiencyisofnoadverseconsequenceinpatientswithnormalrenalfunctionbutmayhowever

worsenapre-existingrenalimpairment.

Athletes:

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Commontoperindoprilandindapamide:

Concomitantusenotrecommended:

Lithium:reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithACEinhibitors.Concomitantuseofthiazidediureticsmayfurtherincreaselithiumlevels

andenhancetheriskoflithiumtoxicitywithACEinhibitors.Useofperindoprilcombinedwithindapamidewith

lithiumisnotrecommended,butifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevels

shouldbeperformed(seesection4.4).

Concomitantusewhichrequiresspecialcare:

Baclofen:Potentiationofantihypertensiveeffect.Monitoringofbloodpressureandrenalfunction,anddose

adaptationoftheantihypertensiveifnecessary.

Non-steroidalanti-inflammatorymedicinalproducts(includedacetylsalicylicacidathighdoses):whenACE-

inhibitorsareadministeredsimultaneouslywithnon-steroidalanti-inflammatorydrugs(i.e.acetylsalicylicacidat

anti-inflammatorydosageregimens,COX-2inhibitorsandnon-selectiveNSAIDs),attenuationofthe

antihypertensiveeffectmayoccur.ConcomitantuseofACE-inhibitorsandNSAIDsmayleadtoanincreasedrisk

ofworseningofrenalfunction,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,

especiallyinpatientswithpoorpre-existingrenalfunction.Thecombinationshouldbeadministeredwith

caution,especiallyintheelderly.Patientsshouldbeadequatelyhydratedandconsiderationshouldbegivento

monitoringrenalfunctionafterinitiationofconcomitanttherapy,andperiodicallythereafter.

Concomitantusewhichrequiressomecare:

Imipramine-likeantidepressants(tricyclics),neuroleptics:Increasedantihypertensiveeffectandincreasedriskof

orthostatichypotension(additiveeffect).

Corticosteroids,tetracosactide:Reductioninantihypertensiveeffect(saltandwaterretentiondueto

corticosteroids).

otherantihypertensiveagents:useofotherantihypertensivemedicinalproductswithperindopril/indapamide

couldresultinadditionalbloodpressureloweringeffect.

Linkedtoperindopril:

Concomitantusenotrecommended:

Potassium-sparingdiuretics(spironolactone,triamterene,aloneorincombination),potassium(salts):ACE

inhibitorsattenuatediureticinducedpotassiumloss.Potassiumsparingdiureticse.g.spironolactone,triamterene,

oramiloride,potassiumsupplements,orpotassium-containingsaltsubstitutesmayleadtosignificantincreasesin

serumpotassium(potentiallylethal).Ifconcomitantuseisindicatedbecauseofdocumentedhypokalemiathey

shouldbeusedwithcautionandwithfrequentmonitoringofserumpotassiumandbyECG.

Concomitantusewhichrequiresspecialcare:

Antidiabeticagents(insulin,hypoglycaemicsulphonamides):Reportedwithcaptoprilandenalapril.

Theuseofangiotensinconvertingenzymeinhibitorsmayincreasethehypoglycaemiceffectindiabeticsreceiving

treatmentwithinsulinorwithhypoglycaemicsulphonamides.Theonsetofhypoglycaemicepisodesisveryrare

(improvementinglucosetolerancewitharesultingreductionininsulinrequirements).

Concomitantusewhichrequiressomecare:

Allopurinol,cytostaticorimmunosuppressiveagents,systemiccorticosteroidsorprocainamide:Concomitant

administrationwithACEinhibitorsmayleadtoanincreasedriskforleucopenia.

Anaestheticdrugs:ACEinhibitorsmayenhancethehypotensiveeffectsofcertainanaestheticdrugs.

Diuretics(thiazideorloopdiuretics):Priortreatmentwithhighdosediureticsmayresultinvolumedepletionand

inariskofhypotensionwheninitiatingtherapywithperindopril.

Gold:Nitritoidreactions(symptomsincludefacialflushing,nausea,vomitingandhypotension)havebeen

reportedrarelyinpatientsontherapywithinjectablegold(sodiumaurothiomalate)andconcomitantACE

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Linkedtoindapamide:

Concomitantusewhichrequiresspecialcare:

Torsadesdepointesinducingdrugs:Duetotheriskofhypokalemia,indapamideshouldbeadministeredwith

cautionwhenassociatedwithmedicinalproductsthatinducedtorsadesdepointessuchasclassIAantiarrhythmic

agents(quinidine,hydroquinidine,disopyramide);classIIIantiarrhythmicagents(amiodarone,dofetilide,ibutilide,

bretylium,sotalol);someneuroleptics(chlorpromazine,cyamemazine,levomepromazine,thioridazine,

trifluoperazine),benzamides(amisulpride,sulpiride,sultopride,tiapride),butyrophenones(droperidol,haloperidol),

otherneuroleptics(pimozide);othersubstancessuchasbepridil,cisapride,diphemanil,IVerythromycin,

halofantrine,mizolastine,moxifloxacin,pentamidine,sparfloxacin,IVvincamine,methadone,astemizole,

terfenadine.Preventionoflowpotassiumlevelsandcorrectionifnecessary:monitoringoftheQTinterval.

Potassium-loweringdrugs:amphotericinB(IVroute),glucocorticoidsandmineralocorticoids(systemicroute),

tetracosactide,stimulantlaxatives:Increasedriskoflowpotassiumlevels(additiveeffect).Monitoringof

potassiumlevels,andcorrectionifnecessary;particularconsiderationrequiredincasesoftreatmentwithcardiac

glycosides.Nonstimulantlaxativesshouldbeused.

Cardiacglycosides:Lowpotassiumlevelsfavourthetoxiceffectsofcardiacglycosides.Potassiumlevelsand

ECGshouldbemonitoredandtreatmentreconsideredifnecessary.

Concomitantusewhichrequiressomecare:

Metformin:Lacticacidosisduetometformincausedbypossiblefunctionalrenalinsufficiencylinkedtodiuretics

andinparticulartoloopdiuretics.Donotusemetforminwhenplasmacreatininelevelsexceed15mg/l

(135micromol/l)inmenand12mg/l(110micromol/l)inwomen.

Iodinatedcontrastmedia:Incasesofdehydrationcausedbydiuretics,thereisanincreasedriskofacuterenal

insufficiency,particularlywhenhighdosesofiodinatedcontrastmediaareused.Rehydrationshouldbecarried

outbeforetheiodinatedcompoundisadministered.

Calcium(salts):Riskofincreasedlevelsofcalciumduetoreducedeliminationofcalciumintheurine.

Ciclosporin:Riskofincreasedcreatininelevelswithnochangeincirculatinglevelsofciclosporin,evenwhen

thereisnosaltandwaterdepletion.

4.6Fertility,pregnancyandlactation

Giventheeffectsoftheindividualcomponentsinthiscombinationproductonpregnancyandlactation,

COVERSYLARGININEPLUS5mg/1.25mgisnotrecommendedduringthefirsttrimesterofpregnancy.

COVERSYLARGININEPLUS5mg/1.25mgiscontraindicatedduringthesecondandthirdtrimestersofpregnancy.

COVERSYLARGININEPLUS5mg/1.25mgiscontraindicatedduringlactation.Adecisionshouldthereforebemade

whethertodiscontinuenursingortodiscontinueCOVERSYLARGININEPLUS5mg/1.25mgtakingaccountthe

importanceofthistherapyforthemother.

Pregnancy:

Linkedtoperindopril:

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-

hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,

treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

hypotension,hyperkalaemia)(seesection5.3).

ShouldexposuretoACEinhibitorshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenal

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy

(seesection4.4).TheuseofACEinhibitorsiscontra-indicatedduringthesecondand

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InfantswhosemothershavetakenACEinhibitorsshouldbecloselyobservedforhypotension(seesections4.3and

4.4).

Linkedtoindapamide:

Prolongedexposuretothiazideduringthethirdtrimesterofpregnancycanreducematernalplasmavolumeaswellas

uteroplacentalbloodflow,whichmaycauseafeto-placentalischemiaandgrowthretardation.Moreover,rarecasesof

hypoglycemiaandthrombocytopeniainneonateshavebeenreportedfollowingexposurenearterm.

Lactation:

COVERSYLARGININEPLUS5mg/1.25mgiscontraindicatedduringlactation.

Linkedtoperindopril:

Becausenoinformationisavailableregardingtheuseofperindoprilduringbreastfeeding,perindoprilisnot

recommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

Linkedtoindapamide:

Indapamideisexcretedinhumanmilk.Indapamideiscloselyrelatedtothiazidediureticswhichhavebeenassociated,

duringbreast-feeding,withdecreaseorevensuppressionofmilklactation.Hypersensitivitytosulfonamide-derived

drugs,hypokalaemiaandnuclearicterusmightoccur.

4.7Effectsonabilitytodriveandusemachines

Linkedtoperindopril,indapamideandCOVERSYLARGININEPLUS5mg/1.25mg:

NeitherthetwoactivesubstancesnorCOVERSYLARGININEPLUS5mg/1.25mgaffectalertnessbutindividual

reactionsrelatedtolowbloodpressuremayoccurinsomepatients,particularlyatthestartoftreatmentorin

combinationwithanotherantihypertensivemedication.

Asaresulttheabilitytodriveoroperatemachinerymaybeimpaired.

4.8Undesirableeffects

Theadministrationofperindoprilinhibitstherenin-angiotensin-aldosteroneaxisandtendstoreducethepotassiumloss

causedbyindapamide.FourpercentofthepatientsontreatmentwithCOVERSYLARGININEPLUS5mg/1.25mg

experiencehypokalaemia(potassiumlevel<3.4mmol/l).

Thefollowingundesirableeffectscouldbeobservedduringtreatmentandrankedunderthefollowingfrequency:

Verycommon(1/10);common(1/100,<1/10);uncommon(1/1000,<1/100);rare(1/10000,<1/1000),veryrare

(<1/10000),notknown(cannotbeestimatedfromtheavailabledata).

Bloodandthelymphaticsystemdisorders:

Veryrare:

Thrombocytopenia,leucopenia/neutropenia,agranulocytosis,aplasticanaemia,haemolyticanaemia.

Anaemia(seesection4.4)hasbeenreportedwithangiotensinconvertingenzymeinhibitorsinspecific

circumstances(patientswhohavehadkidneytransplants,patientsundergoinghaemodialysis).

Psychiatricdisorders:

Uncommon: moodorsleepdisturbances.

Nervoussystemdisorders:

Common: Paresthesia,headache,asthenia,feelingsofdizziness,vertigo.

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Eyedisorders:

Common: Visiondisturbance.

Earandlabyrinthdisorders:

Common: Tinnitus.

Vasculardisorders:

Common: Hypotensionwhetherorthostaticornot(seesection4.4).

Cardiacdisorders:

Veryrare: Arrhythmiaincludingbradycardia,ventriculartachycardia,atrialfibrillation,anginapectorisand

myocardialinfarctionpossiblysecondarytoexcessivehypotensioninhigh-riskpatients(seesection

4.4).

Respiratory,thoracicandmediastinaldisorders:

Common:

Adrycoughhasbeenreportedwiththeuseofangiotensinconvertingenzymeinhibitors.Itis

characterisedbyitspersistenceandbyitsdisappearancewhentreatmentiswithdrawn.Aniatrogenic

aetiologyshouldbeconsideredinthepresenceofthissymptom.Dyspnoea.

Uncommon: Bronchospasm.

Veryrare: Eosinophilicpneumonia,rhinitis.

Gastrointestinaldisorders:

Common: Constipation,drymouth,nausea,epigastricpain,anorexia,vomiting,abdominalpain,tastedisturbance,

dyspepsia,diarrhoea.

Veryrare: Pancreatitis.

Hepato-biliarydisorders:

Veryrare: Hepatitiseithercytolyticorcholestatic(seesection4.4).

Notknown: Incaseofhepaticinsufficiency,thereisapossibilityofonsetofhepaticencephalopathy(seesections

4.3and4.4).

Skinandsubcutaneoustissuedisorders:

Common: Rash,pruritus,maculopapulareruptions.

Uncommon:

Angioedemaofface,extremities,lips,mucousmembranes,tongue,glottisand/orlarynx,urticaria(see

section4.4).

Hypersensitivityreactions,mainlydermatological,insubjectswithapredispositiontoallergicand

asthmaticreactions.

Purpura.

Possibleaggravationofpre-existingacutedisseminatedlupuserythematosus.

Veryrare: erythemamultiforme,toxicepidermicnecrolysis,StevenJohnsonsyndrome.

Casesofphotosensitivityreactionshavebeenreported(seesection4.4).

Musculoskeletal,connectivetissueandbonedisorders:

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Renalandurinarydisorders:

Uncommon: Renalinsufficiency.

Veryrare: Acuterenalfailure.

Reproductivesystemandbreastdisorders:

Uncommon: Impotence.

Generaldisordersandadministrationsiteconditions:

Common: Asthenia.

Uncommon: Sweating.

Investigations:

Potassiumdepletionwithparticularlyseriousreductioninlevelsofpotassiuminsomeatrisk

populations(seesection4.4).

Reducedsodiumlevelswithhypovolaemiacausingdehydrationandorthostatichypotension.

Increaseinuricacidlevelsandinbloodglucoselevelsduringtreatment.

Slightincreaseinureaandinplasmacreatininelevels,reversiblewhentreatmentisstopped.This

increaseismorefrequentincasesofrenalarterystenosis,arterialhypertensiontreatedwithdiuretics,

renalinsufficiency.

Increasedlevelsofpotassium,usuallytransitory.

Rare: Raisedplasmacalciumlevels.

4.9Overdose

Themostlikelyadversereactionincasesofoverdoseishypotension,sometimesassociatedwithnausea,vomiting,

cramps,dizziness,sleepiness,mentalconfusion,oliguriawhichmayprogresstoanuria(duetohypovolaemia).Saltand

waterdisturbances(lowsodiumlevels,lowpotassiumlevels)mayoccur.

Thefirstmeasurestobetakenconsistofrapidlyeliminatingtheproduct(s)ingestedbygastriclavageand/or

administrationofactivatedcharcoal,thenrestoringfluidandelectrolytebalanceinaspecialisedcentreuntiltheyreturn

tonormal.

Ifmarkedhypotensionoccurs,thiscanbetreatedbyplacingthepatientinasupinepositionwiththeheadlowered.If

necessaryanintravenousinfusionofisotonicsalinemaybegiven,oranyothermethodofvolaemicexpansionmaybe

used.

Perindoprilat,theactiveformofperindopril,canbedialysed(seesection5.2).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:perindoprilanddiuretics,ATCcode:C09BA04

COVERSYLARGININEPLUS5mg/1.25mgisacombinationofperindoprilargininesalt,anangiotensinconverting

enzymeinhibitor,andindapamide,achlorosulphamoyldiuretic.Itspharmacologicalpropertiesarederivedfromthose

ofeachofthecomponentstakenseparately,inadditiontothoseduetotheadditivesynergicactionofthetwoproducts

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Pharmacologicalmechanismofaction

LinkedtoCOVERSYLARGININEPLUS5mg/1.25mg:

COVERSYLARGININEPLUS5mg/1.25mgproducesanadditivesynergyoftheantihypertensiveeffectsofthetwo

components.

Linkedtoperindopril:

Perindoprilisaninhibitoroftheangiotensinconvertingenzyme(ACEinhibitor)whichconvertsangiotensinIto

angiotensinII,avasoconstrictingsubstance;inadditiontheenzymestimulatesthesecretionofaldosteronebythe

adrenalcortexandstimulatesthedegradationofbradykinin,avasodilatorysubstance,intoinactiveheptapeptides.

Thisresultsin:

areductioninaldosteronesecretion,

anincreaseinplasmareninactivity,sincealdosteronenolongerexercisesnegativefeedback,

areductionintotalperipheralresistancewithapreferentialactiononthevascularbedinmuscleandthekidney,

withnoaccompanyingsaltandwaterretentionorreflextachycardia,withchronictreatment.

Theantihypertensiveactionofperindoprilalsooccursinpatientswithlowornormalreninconcentrations.

Perindoprilactsthroughitsactivemetabolite,perindoprilat.Theothermetabolitesareinactive.

Perindoprilreducestheworkoftheheart:

byavasodilatoryeffectonveins,probablycausedbychangesinthemetabolismofprostaglandins:reductionin

pre-load,

byreductionofthetotalperipheralresistance:reductioninafterload.

Studiescarriedoutonpatientswithcardiacinsufficiencyhaveshown:

areductioninleftandrightventricularfillingpressures,

areductionintotalperipheralvascularresistance,

anincreaseincardiacoutputandanimprovementinthecardiacindex,

anincreaseinregionalbloodflowinmuscle.

Exercisetestresultsalsoshowedimprovement.

Linkedtoindapamide:

Indapamideisasulphonamidederivativewithanindolering,pharmacologicallyrelatedtothethiazidegroupof

diuretics.Indapamideinhibitsthereabsorptionofsodiuminthecorticaldilutionsegment.Itincreasestheurinary

excretionofsodiumandchloridesand,toalesserextent,theexcretionofpotassiumandmagnesium,therebyincreasing

urineoutputandhavinganantihypertensiveaction.

Characteristicsofantihypertensiveaction

LinkedtoCOVERSYLARGININEPLUS5mg/1.25mg:

Inhypertensivepatientsregardlessofage,COVERSYLARGININEPLUS5mg/1.25mgexertsadose-dependent

antihypertensiveeffectondiastolicandsystolicarterialpressurewhilstsupineorstanding.Thisantihypertensiveeffect

lastsfor24hours.Thereductioninbloodpressureisobtainedinlessthanonemonthwithouttachyphylaxis;stopping

treatmenthasnoreboundeffect.Duringclinicaltrials,theconcomitantadministrationofperindoprilandindapamide

producedantihypertensiveeffectsofasynergicnatureinrelationtoeachoftheproductsadministeredalone.

PICXEL,amulticenter,randomised,doubleblindactivecontrolledstudyhasassessedonechocardiographytheeffect

ofperindopril/indapamidecombinationonLVHversusenalaprilmonotherapy.

InPICXEL,hypertensivepatientswithLVH(definedasleftventricularmassindex(LVMI)>120g/m 2

inmaleand>

100g/m 2

infemale)wererandomisedeithertoperindopriltert-butylamine2mg(equivalentto2.5mgperindopril

arginine)/indapamide0.625mgortoenalapril10mgonceadayforaone-yeartreatment.Thedosewasadapted

accordingtobloodpressurecontrol,uptoperindopriltert-butylamine8mg(equivalentto10mgperindoprilarginine)

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Only34%ofthesubjectsremainedtreatedwithperindopriltert-butylamine2mg(equivalentto2.5mgperindopril

arginine)/indapamide0.625mg(versus20%withEnalapril10mg).

Attheendoftreatment,LVMIhaddecreasedsignificantlymoreintheperindopril/indapamidegroup(-10.1g/m²)than

intheenalaprilgroup(-1.1g/m²)intheallrandomisedpatientspopulation.ThebetweengroupdifferenceinLVMI

changewas-8.3(95%CI(-11.5,-5.0),p<0.0001).

AbettereffectonLVMIwasreachedwithhigherperindopril/indapamidedosesthanthoselicensedforPRETERAX

ARGININE2.5mg/0.625mgandCOVERSYLARGININEPLUS5mg/1.25mg.

Regardingbloodpressure,theestimatedmeanbetween-groupdifferencesintherandomisedpopulationwere-5.8

mmHg(95%CI(-7.9,-3.7),p<0.0001)forsystolicbloodpressureand-2.3mmHg(95%CI(-3.6,-0.9),p=0.0004)

fordiastolicbloodpressurerespectively,infavouroftheperindopril/indapamidegroup.

Linkedtoperindopril:

Perindoprilisactiveinallgradesofhypertension:mildtomoderateorsevere.Areductioninsystolicanddiastolic

arterialpressureisobservedinthelyingandstandingposition.

Theantihypertensiveactivityafterasingledoseismaximalatbetween4and6hoursandismaintainedover24hours.

Thereisahighdegreeofresidualblockingofangiotensinconvertingenzymeat24hours,approximately80%.

Inpatientswhorespond,normalisedbloodpressureisreachedafteronemonthandismaintainedwithout

tachyphylaxis.

Withdrawaloftreatmenthasnoreboundeffectonhypertension.

Perindoprilhasvasodilatorypropertiesandrestoreselasticityofthemainarterialtrunks,correctshistomorphometric

changesinresistancearteriesandproducesareductioninleftventricularhypertrophy.

Ifnecessary,theadditionofathiazidediureticleadstoanadditivesynergy.

Thecombinationofanangiotensinconvertingenzymeinhibitorwithathiazidediureticdecreasesthehypokalaemia

riskassociatedwiththediureticalone.

Linkedtoindapamide:

Indapamide,asmonotherapy,hasanantihypertensiveeffectwhichlastsfor24hours.Thiseffectoccursatdosesat

whichthediureticpropertiesareminimal.

Itsantihypertensiveactionisproportionaltoanimprovementinarterialcomplianceandareductionintotaland

arteriolarperipheralvascularresistance.

Indapamidereducesleftventricularhypertrophy.

Whenadoseofthiazidediureticandthiazide-relateddiureticsisexceeded,theantihypertensiveeffectreachesa

plateau,whereastheadverseeffectscontinuetoincrease.Ifthetreatmentisineffective,thedoseshouldnotbe

increased.

Furthermore,ithasbeenshownthatintheshort-term,mid-termandlong-terminhypertensivepatients,indapamide:

hasnoeffectonlipidmetabolism:triglycerides,LDL-cholesterolandHDL-cholesterol,

hasnoeffectoncarbohydratemetabolism,evenindiabetichypertensivepatients.

5.2Pharmacokineticproperties

LinkedtoCOVERSYLARGININEPLUS5mg/1.25mg:

Theco-administrationofperindoprilandindapamidedoesnotchangetheirpharmacokineticpropertiesbycomparison

toseparateadministration.

Linkedtoperindopril:

Afteroraladministration,theabsorptionofperindoprilisrapidandthepeakconcentrationisachievedwithin1hour.

Theplasmahalf-lifeofperindoprilisequalto1hour.

Perindoprilisaprodrug.Twentysevenpercentoftheadministeredperindoprildosereachesthebloodstreamasthe

activemetaboliteperindoprilat.Inadditiontoactiveperindoprilat,perindoprilyieldsfivemetabolites,allinactive.The

peakplasmaconcentrationofperindoprilatisachievedwithin3to4hours.

Asingestionoffooddecreasesconversiontoperindoprilat,hencebioavailability,perindoprilarginineshouldbe

administeredorallyinasingledailydoseinthemorningbeforeameal.

Ithasbeendemonstratedalinearrelationshipbetweenthedoseofperindoprilanditsplasmaexposure.

Thevolumeofdistributionisapproximately0.2l/kgforunboundperindoprilat.Proteinbindingofperindoprilatto

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Perindoprilatiseliminatedintheurineandtheterminalhalf-lifeoftheunboundfractionisapproximately17hours,

resultinginsteady-statewithin4days.

Eliminationofperindoprilatisdecreasedintheelderly,andalsoinpatientswithheartorrenalfailure.Dosage

adjustmentinrenalinsufficiencyisdesirabledependingonthedegreeofimpairment(creatinineclearance).

Dialysisclearanceofperindoprilatisequalto70ml/min.

Perindoprilkineticsaremodifiedinpatientswithcirrhosis:hepaticclearanceoftheparentmoleculeisreducedbyhalf.

However,thequantityofperindoprilatformedisnotreducedandthereforenodosageadjustmentisrequired(see

sections4.2and4.4).

Linkedtoindapamide:

Indapamideisrapidlyandcompletelyabsorbedfromthedigestivetract.

Thepeakplasmalevelisreachedinhumansapproximatelyonehourafteroraladministrationoftheproduct.Plasma

proteinbindingis79%.

Theeliminationhalf-lifeisbetween14and24hours(average18hours).Repeatedadministrationdoesnotproduce

accumulation.Eliminationismainlyintheurine(70%ofthedose)andfaeces(22%)intheformofinactive

metabolites.

Thepharmacokineticsareunchangedinpatientswithrenalinsufficiency.

5.3Preclinicalsafetydata

COVERSYLARGININEPLUS5mg/1.25mghasslightlyincreasedtoxicitythanthatofitscomponents.Renal

manifestationsdonotseemtobepotentiatedintherat.However,thecombinationproducesgastro-intestinaltoxicityin

thedogandthetoxiceffectsonthemotherseemtobeincreasedintherat(comparedtoperindopril).

Nonetheless,theseadverseeffectsareshownatdoselevelscorrespondingtoaverymarkedsafetymarginby

comparisontothetherapeuticdosesused.

Preclinicalstudiesperformedseparatelywithperindoprilandindapamidedidnotshowgenotoxic,carcinogenicor

teratogenicpotential.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Lactosemonohydrate

Magnesiumstearate(E470B)

Maltodextrin

Silicacolloidalanhydrous(E551)

Sodiumstarchglycolate(typeA)

FilmCoating:

Glycerol(E422)

Hypromellose(E464)

Macrogol6000

Magnesiumstearate(E470B)

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateforthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

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6.4Specialprecautionsforstorage

Keepthecontainertightlyclosedinordertoprotectfrommoisture.

6.5Natureandcontentsofcontainer

30tabletsinpolypropylenewhitecontainerequippedwithalowdensitypolyethyleneflowreducerandalowdensity

polyethylenewhiteopaquestoppercontainingawhitedesiccantgel.

Packsize:1x30

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

LTTPharma

Unit18OxleasowRoad

EastMoonsMoat

Redditch

WorcestershireB980RE

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1562/063/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:4 th

November2011

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