ARPLEXAM 10/2.5/5 Milligram Film Coated Tablet

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
PERINDOPRIL ARGININE, INDAPAMIDE, AMLODIPINE BESILATE
Available from:
Les Laboratoires Servier
ATC code:
C09BX01
INN (International Name):
PERINDOPRIL ARGININE, INDAPAMIDE, AMLODIPINE BESILATE
Dosage:
10/2.5/5 Milligram
Pharmaceutical form:
Film Coated Tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
ACE inhibitors, other combinations
Authorization status:
Authorised
Authorization number:
PA0568/025/004
Authorization date:
2014-03-28

Packageleaflet:Informationforthe patient

Arplexam2.5mg/0.625mg/5mgfilm-coated tablets

Arplexam5mg/1.25mg/5mgfilm-coatedtablets

Arplexam5mg/1.25mg/10mgfilm-coatedtablets

Arplexam10mg/2.5mg/5mgfilm-coatedtablets

Arplexam10mg/2.5mg/10mgfilm-coatedtablets

perindoprilarginine/indapamide/amlodipine

Readallofthisleafletcarefullybeforeyoustarttakingthismedicinebecauseitcontainsimportant

informationforyou.

- Keep thisleaflet. You mayneedto readitagain.

- Ifyou have anyfurtherquestions,askyourdoctor, pharmacistornurse.

- Thismedicinehasbeenprescribedforyouonly.Donotpassitontoothers.Itmayharmthem,evenif

theirsigns ofillnessarethesame as yours.

- Ifyougetanysideeffects,talktoyourdoctor,orpharmacistornurse.Thisincludesanypossibleside

effects notlistedinthis leaflet.Seesection 4.

Whatisinthisleaflet:

1. WhatArplexamis and whatitis usedfor

2. Whatyou needto knowbefore you takeArplexam

3. Howto takeArplexam

4. Possibleside effects

5. Howto storeArplexam

6. Contentofthe packandotherinformation

1. WhatArplexamis andwhat itis usedfor

Arplexamisacombinationofthreeactiveingredients:perindopril,indapamideandamlodipine.Itisananti-

hypertensive medicine usedin the treatmentofhigh blood pressure(hypertension).

Patientsalreadytakingperindopril/indapamideasfixeddosecombinationandamlodipinefromseparate

tabletsmayinsteadreceiveonetabletofArplexamwhichcontainsthethreeactiveingredientsinthesame

strength.

Each ofthe active ingredientsreduces bloodpressureand theyworktogetherto controlyourbloodpressure:

-PerindoprilbelongstoaclassofmedicinescalledAngiotensinConvertingEnzyme(ACE)inhibitors.It

worksbywideningtheblood vessels, which makesiteasierforyourheartto pump bloodthrough them.

-Indapamideisadiuretic(whichbelongstoaclassofmedicinescalledsulphonamidederivativeswithan

indolering).Diureticsincreasetheamountofurineproducedbythekidneys.However,indapamideis

differentfromotherdiuretics, asitonlycauses aslightincreasein the amountofurineproduced.

-Amlodipineisacalciumchannelblockers(whichbelongstoaclassofmedicinescalleddihydropyridines).

Itworks byrelaxingbloodvessels,so blood passesthrough easily.

2. What you needto knowbefore youtakeArplexam

Do not takeArplexam

-ifyouare allergictoperindoprilorotherACE-inhibitors, indapamideorothersulphonamides, amlodipine

orotherdihydropyridines,oranyofthe otheringredients ofthis medicine(listedin Section6),

-ifyouhaveexperiencedsymptomssuchaswheezing,swellingofthefaceortongue,intenseitchingor

severeskinrasheswithpreviousACEinhibitortreatmentorifyouoramemberofyourfamilyhavehad

these symptoms in anyothercircumstances(acondition calledangioedema),

-ifyouhavesevereliverdiseaseorsufferfromaconditioncalledhepaticencephalopathy(diseaseofthe

brain causedbyliverillness),

-ifyouaresuspectedofhavinguntreateddecompensatedheartfailure(severewaterretention,difficultyin

breathing),

-ifyou take non antiarrhythmicmedicinescausinglife-threateningirregularbeat(torsadesde pointes)

-ifyouhavenarrowingoftheaorticheartvalve(aorticstenosis)orcardiogenicshock(aconditionwhere

yourheartis unabletosupplyenough bloodtothe body),

-ifyou sufferfromheartfailure aftera heartattack.

-ifyou have severe lowblood pressure (hypotension),

-ifyou have lowbloodpotassium,

-ifyou have severe kidneyproblems

-ifyou are receivingdialysis

-ifyouhavemoderatekidneyproblems(forArplexamdosescontaining10mg/2.5mg/5mgand

10mg/2.5mg/10mg).

-ifyouaremorethan3monthspregnant(itisalsobettertoavoidArplexaminearlypregnancy–see

pregnancysection.),

-ifyou are breastfeeding.

-ifyou have diabetesmellitus orkidneyproblems and you are treated withaliskiren.

Warning andprecaution

Talkto yourdoctororpharmacistornursebeforetakingArplexam:

- ifyouhavehypertrophiccardiomyopathy(heartmuscledisease)orrenalarterystenosis(narrowing

ofthe arterysupplyingthekidneywith blood),

- ifyou have heartfailureoranyotherheartproblems,

- ifyou havesevere increasein blood pressure (hypertensive crisis),

- ifyou have liverproblems,

- ifyousufferfromacollagendisease(skindisease)suchassystemiclupuserythematosusor

scleroderma,

- ifyou have atherosclerosis(hardeningofthe arteries),

- ifyou need tohave atesttocheckhowwellyourparathyroid glandis working,

- ifyou sufferfromgout,

- ifyou have diabetes,

- ifyouareonasaltrestricteddietorusesaltsubstituteswhichcontainpotassium(awell-balanced

potassiumblood levelisessential),

- ifyoutakelithiumorpotassium-sparingdiuretics(spironolactone,triamterene)astheirusewith

Arplexamshould be avoided (see “Takingothermedicines”),

- ifyou take aliskiren(medicinesusedtotreathypertension)

- ifyou are elderlyand yourdoseneedsto be increased,

- ifyou hadphotosensitivityreactions,

-ifyouareblackpeopleyoumayhavehigherincidenceofangiodema(swellingofthe face,lips,mouth

,tongueorthroatwhichmaycausedifficultyinswallowingorbreathing)andlesseffectivein

loweringbloodpressure,

-ifyou are Haemodialysis patients dialysed withhigh-flux membranes,

-ifyou have kidneyproblems,

-ifyou have too much acidin blood, which maycausean increasedrate ofbreathing,

-ifyou have cerebralcirculatoryinsufficiency(lowblood presure inthebrain),

-ifyouhaveswellingoftheface,lips,mouth,tongueorthroatwhichmaycausedifficultyin

swallowingorbreathing(angioedema),whichcanoccuratanytimeduringtreatment,stopyour

treatmentimmediatelyand directlycontactyourdoctor.

Yourdoctormayprescribeyoubloodteststocheckforlowsodiumorpotassiumlevelsorhighcalcium

levels.

Youmusttellyourdoctorifyouthinkthatyouare(ormightbecome)pregnant.Arplexamisnot

recommendedinearlypregnancy,andmustnotbetakenifyouaremorethan3monthspregnant,asitmay

causeserious harmto yourbabyifused atthatstage (see“Pregnancyand breastfeeding”).

When you are takingArplexam,you shouldalso informyourdoctororthemedicalstaff:

- ifyou are to undergo anaesthesia and/orsurgery,

- ifyou have recentlysuffered fromdiarrhoeaorvomiting, orare dehydrated,

- ifyouaretoundergodialysisorLDLapheresis(whichisremovalofcholesterolfromyourbloodby

a machine),

- ifyouaregoingtohavedesensitisationtreatmenttoreducetheeffectsofanallergytobeeorwasp

stings,

- ifyouareto undergoamedicaltestthatrequiresinjectionofaniodinated contrastagent(a substance

thatmakesorganslike kidneyorstomach visibleon anX-ray).

Children andadolescents

Arplexamshould notbe given to childrenand adolescents.

OthermedicinesandArplexam

Pleasetellyourdoctororpharmacistifyouaretakingorhaverecentlytakenormighttakeanyother

medicines.

Do nottake aliskiren (usedto treathigh bloodpressure)ifyouhave diabetesorkidneyproblems.

You should avoidArplexamwith:

lithium(usedtotreatsomementalhealthdisorderssuchasmania,manicdepressiveillnessandrecurrent

depression),

potassium-sparingdrugs(e.g.triamterene,amiloride),potassiumsupplementsorpotassium-containing

saltsubstitutes,

dantrolene(infusion)isalsousedtotreatmalignanthyperthermiaduringanaesthesia(symptoms

includingveryhigh feverand muscle stiffness),

estramustine (usedin cancertherapy),

othermedicinesusedtotreathighbloodpressure:angiotensin-converting-enzymeinhibitorand

angiotensinreceptorblockers.

TreatmentwithArplexamcanbeaffectedbyothermedicines.Makesuretotellyourdoctorifyouaretaking

anyofthefollowingmedicinesas specialcare maybe required:

othermedicinesfortreatinghighbloodpressure,includingdiuretics(medicineswhichincreasethe

amountofurineproducedbythe kidneys),

potassium-sparingdrugsusedinthetreatmentofheartfailure:eplerenoneandspironolactoneatdoses

between 12.5mgto 50mgperday,

anaesthetic medicines

iodinated contrastagent

bepridil(usedtotreatangina pectoris),

moxifloxacine, sparfloxacine (antibiotic:medicineused totreatinfection),

methadone(usedtotreataddiction)

dofetilide,ibutilide,bretylium,cisapride,diphemamil,procainamide,quinidine,hydroquinidine,

disopyramide, amiodarone,sotalol(forthetreatmentofan irregularheartbeat),

verapamil, diltiazem(heartmedicines)

digoxin orothercardiac glycosides(forthe treatmentofheartproblems),

some antibiotics used totreatinfections, such asrifampicin, erythromycin, clarithromycin,

itraconazole, ketoconazole,amphotericin Bbyinjection (totreatfungaldisease),

allopurinol(forthetreatmentofgout),

mizolastine,terfenadineorastemizole(antihistaminesforhayfeverorallergies),

corticosteroidsusedtotreatvariousconditionsincludingsevereasthmaandrheumatoidarthritis,and

non-steroidalanti-inflammatorydrugs (e.g. ibuprofen)orhigh dosesalicylates(e.g.acetylsalicylic acid),

immunosuppressantsusedforthetreatmentofauto-immunedisordersorfollowingtransplantsurgeryto

preventrejection (e.g. ciclosporin,tacrolimus),

tetracosactide(totreatCrohn’s disease)

gold salts,especiallywith intravenous administration(usedto treatsymptoms ofrheumatoid arthritis),

halofantrine(used totreatcertaintypesofmalaria),

baclofenusedtotreatmuscle stiffnessin diseasessuchasmultiplesclerosis,

medicinestotreatdiabetessuch as insulin ormetformin,

calciumincludingcalciumsupplements,

stimulantlaxatives(e.g. senna),

medicinesforthe treatmentofcancer,

vincamine (used totreatsymptomatic cognitive disordersin elderlyincludingmemoryloss),

medicinestotreatmentalhealthdisorderssuchasdepression,anxiety,schizophrenia…(e.g.tricyclic

antidepressants, antipsychotics, imipramine-like antidepressants, neuroleptics),

pentamidine (usedtotreatpneumonia),

ritonavir,indinavir, nelfinavir(socalledproteaseinhibitors usedto treatHIV).

hypericumperforatum(St.John’s Wort),

trimethoprim(forthetreatmentofinfections),

heparin(medicinesusedtothinblood),

medicinesusedforthetreatmentoflowbloodpressure,shockorasthma(e.g.ephedrine,noradrenaline

oradrenaline),

nitroglycerin and othernitrates, orothervasodilatorsthatmayfurtherreduce blood pressure.

Arplexamwithfood anddrink

GrapefruitjuiceandgrapefruitshouldnotbeconsumedbypeoplewhoaretakingArplexam.Thisisbecause

grapefruitandgrapefruitjuicecanleadtoanincreaseinthebloodlevelsoftheactiveingredientamlodipine,

which can causean unpredictableincreasein the bloodpressure loweringeffectofArplexam.

Pregnancyandbreast-feeding

Ifyouarepregnantorbreast-feeding,thinkyoumaybepregnantorareplanningtohaveababy,askyour

doctororpharmacistforadvicebeforetakingthis medicine

Pregnancy

You musttellyourdoctorifyou thinkthatyou are(ormightbecome)pregnant.

YourdoctorwillnormallyadviseyoutostoptakingArplexambeforeyoubecomepregnantorassoonas

youknowyouarepregnantandwilladviseyoutotakeanothermedicineinsteadofArplexam.Arplexamis

notrecommendedinearlypregnancy,andmustnotbetakenwhenmorethan3monthspregnant,asitmay

causeserious harmto yourbabyifused afterthethirdmonth ofpregnancy.

Breast-feeding

Tellyourdoctorifyouarebreast-feedingorabouttostartbreast-feeding.Arplexamisnotrecommendedfor

motherswhoarebreast-feeding,andyourdoctormaychooseanothertreatmentforyouifyouwishtobreast-

feed,especiallyifyourbabyis new-born,orwasbornprematurely.

Driving andusingmachines

Arplexammayaffectyourabilitytodriveorusemachines.Ifthetabletsmakeyoufeelsick,dizzy,tired,or

giveyou a headache,do notdrive orusemachinesandcontactyourdoctorimmediately.

3. HowtotakeArplexam

Alwaystakethismedicineexactlyasyourdoctororpharmacisthastoldyou.Checkwithyourdoctoror

pharmacistifyou are notsure.

Swallowthetabletwithaglassofwaterpreferablyinthemorningandbeforeameal.Yourdoctorwill

decide onthecorrectdoseforyou. Thiswillnormallybe onetabletonce aday.

IfyoutakemoreArplexamthanyou should

Takingtoomanytabletsmaycauseyoubloodpressuretobecomeloworevendangerouslylowsometimes

associatedwithnausea,vomiting,cramps,dizziness,sleepiness,mentalconfusion,oliguria(passingless

urinethanisnormal),anuria(noproductionorpassingofurine).Youmayfelllightheaded,faint,orweak.If

bloodpressuredrop issevereenoughshockcanoccur.Yourskincouldfeelcoolandclaimmyandyoucould

loseconsciousness. Seekimmediate medicalattentionifyou take too manyArplexamtablets.

Ifyouforgetto takeArplexam

Itisimportanttotakeyourmedicine everydayasregulartreatmentismoreeffective.However,Ifyouforget

totakeadoseofArplexam,takethenextdoseattheusualtime.Donottakeadoubledosetomakeupfora

forgotten dose.

IfyoustoptakingArplexam

Asthetreatmentforhighbloodpressureisusuallylife-long,youshoulddiscusswithyourdoctorbefore

stoppingthis medicinalproduct.

Ifyou have anyfurtherquestions onthe useofthismedicine, askyourdoctor, pharmacistornurse.

4. Possiblesideeffects

Like allmedicines,this medicinecan causeside effects, although noteverybodygetsthem.

Stoptakingthemedicinalproductandseeadoctorimmediately,ifyouexperienceanyofthefollowing

sideeffects:

- suddenwheeziness,chestpain,shortnessofbreath,ordifficultyinbreathing,(Uncommon)(may

affectup to 1 in 100 people)

- swellingofeyelids, faceorlips, (Uncommon)(mayaffectup to1 in100 people)

- swellingofthe mouth, tongue and throat, which causesgreatdifficultybreathing, (Uncommon)(may

affectup to 1 in 100 people)

- severeskinreactionsincludingintenseskinrash,hives,reddeningoftheskinoveryourwholebody,

severeitching,blistering,peelingandswellingoftheskin,inflammationofmucousmembranes

(StevensJohnsonSyndrome)orotherallergicreactions,(Veryrare)(mayaffectupto1in10,000

people)

- severe dizziness orfainting,(Common)(mayaffectupto 1in 10 people)

- heartattack,(Veryrare)(mayaffectupto1in10,000peoplelife-threateningirregularbeat.(Not

known)

- inflamedpancreaswhichmaycausesevereabdominalandbackpainaccompaniedwithfeelingvery

unwell(Veryrare)(mayaffectup to1 in10,000people)

In decreasingorderoffrequency, sideeffectscaninclude:

- Common(mayaffectupto1 in 10people):

Headache,dizziness,palpitations(awarenessofyourheartbeat),flushing,vertigo,pinsand

needles,visualimpairment,tinnitus(sensationofnoisesintheears),light-headednessduetolow

bloodpressure,cough,shortnessofbreath,gastro-intestinaldisorders(nausea,vomiting,

abdominalpain,tastedisturbances,,dyspepsiaordifficultyofdigestion,diarrhoea,constipation),

allergicreactions(suchasskinrashes,itching),cramps,feelingoftiredness,somnolence,ankle

swelling(oedema)

- Uncommon (mayaffectupto 1in 100people):

Moodswings,anxiety,depression,sleepdisturbances,trembling,hives,fainting,lossofpain

sensation,rhinitis(blockeduporrunnynose),,changeofbowelhabits,hairloss,purpura(red

pinpointsonskin),skindiscoloration,itchyskin,sweating,chestpain,jointormusclepain,back

pain,pain,feelingunwell(malaise),kidneyproblems,disorderinpassingurine,increasedneedto

urinateatnight,increasednumberoftimesofpassingurine,inabilitytoobtainanerection,fever

orhightemperature,discomfortorenlargementofthebreastsinmen,weightincreaseordecrease,

increaseinsomewhitebloodcells,highpotassiumlevelsintheblood,hypoglycaemia(verylow

bloodsugarlevel),lowsodiumlevelsintheblood,doublevision,rapidheartbeat,vasculitis

(inflammationofbloodvessels),photosensitivityreactions(changeinskinappearance)after

exposuretothesunorartificialUVA,blisterclustersovertheskin,swellingofhands,anklesor

feet, blood creatinine increased and blood ureaincrease, fall, drymouth.

- Rare(mayaffectup to1 in1000 people):

Confusion,changesinlaboratoryparameters:Increasedlevelofliverenzymes,highlevelof

serumbilirubin.

- Veryrare(mayaffectupto1 in 10,000 people):

Decreasednumbersofwhitebloodcells,decreaseinthenumberofplatelets(whichcauseseasy

bruisingandnasalbleeding),anaemia(decreaseinredbloodcells),cardiovasculardisorders

(irregularheartbeat,anginapectoris(painstothechest,jawandback,broughtonbyphysical

effort, and dueto problems with the blood flowto the heart),), eosinophilic pneumonia (a rare type

ofpneumonia),swellingofthegums,severeskinreactionsincludingintenseskinrash,reddening

oftheskinoveryourwholebody,severeitching,blistering,peelingandswellingoftheskin,

erythemamultiforme(askinrashwhichoftenstartswithreditchypatchesonyourface,armsor

legs),bleeding,tenderorenlargedgums,abnormalliverfunction,inflammationoftheliver

(hepatitis),severekidneyproblems,yellowingoftheskin(jaundice),abdominalbloating

(gastritis),disorderofthenerveswhichcancauseweakness,tinglingornumbness,increased

muscletension,hyperglycaemia(veryhighbloodsugarlevel),highlevelofcalciumintheblood,

strokepossiblysecondaryto excessive lowblood pressure.

- Notknown (frequencycannotbeestimatedfromtheavailable data):

Hepaticencephalopathy(diseaseofthebraincausedbyliverillness),abnormalECGhearttracing,

lowpotassiumlevelsintheblood,ifyousufferfromsystemiclupuserythematous(atypeof

collagen disease),this mightgetworse.

Shortsightedness (myopia), blurredvision.

Changesinlaboratoryparameters(bloodtests)canoccur.Yourdoctormayneedtogiveyoubloodteststo

monitoryourcondition.

Reporting ofside effects

Ifyougetanysideeffects,talktoyourdoctor , pharmacist ornurse.Thisincludesanypossiblesideeffects

notlistedinthisleaflet.YoucanalsoreportsideeffectsdirectlyviaHPRAPharmacovigilance,Earlsfort

Terrace,IRL-Dublin2;Tel:+35316764971;Fax:+35316762517.Website: www.hpra.ie ;E-mail:

medsafety@hpra.ie .Byreportingsideeffectsyoucanhelpprovidemoreinformationonthesafetyofthis

medicine.

5. HowtostoreArplexam

Keep this medicineoutofthe sightandreach ofchildren.

Donotusethismedicineaftertheexpirydatewhichisstatedonthecartonandtabletcontainer.Theexpiry

daterefers to the lastdayofthatmonth.

This medicinalproductdoes notrequire anyspecialstorage conditions.

For the containerof30 film-coated tablet, the in-usestabilityafterfirstopeningis30 days.

For the containerof100film-coatedtablet,the in-usestabilityafterfirstopeningis 100 days.

Donotthrowawayanymedicineviawastewaterorhouseholdwaste.Askyourpharmacisthowtothrow

awaymedicinesyou nolongerused.These measureswillhelp toprotectthe environment.

6. Content ofthe packandotherinformation

WhatArplexamcontains

- Theactive substances are perindoprilarginine,indapamide and amlodipine

Onefilm-coatedtabletofArplexam2.5/0.625/5mgcontains1.6975mgperindoprilequivalentto2.5

mgperindoprilarginine,0.625mgindapamideand6.935mgamlodipinebesilateequivalentto5mgof

amlodipine.

Onefilm-coatedtabletofArplexam5/1.25/5mgcontains3.395mgperindoprilequivalentto5mg

perindoprilarginine,1.25mgindapamideand6.935mgamlodipinebesilateequivalentto5mgof

amlodipine.Onefilm-coatedtabletofArplexam5/1.25/10mgcontains3.395mgperindoprilequivalent

to5mgperindoprilarginine,1.25mgindapamideand13.870mgamlodipinebesilateequivalentto10

mgofamlodipine.Onefilm-coatedtabletofArplexam10/2.5/5mgcontains6.790mgperindopril

equivalentto10mgperindoprilarginine,2.5mgindapamideand6.935mgamlodipinebesilate

equivalentto 5 mgofamlodipine.

Onefilm-coatedtabletofArplexam10/2.5/10mgcontains6.790mgperindoprilequivalentto10mg

perindoprilarginine,2.5mgindapamideand13.870mgamlodipinebesilateequivalentto10mgof

amlodipine.

- Theotheringredients are:

-Tabletcore:Calciumcarbonatestarchcompound:Calciumcarbonate90%,Pregelatinisedmaize

starch10%,cellulosemicrocrystalline(E460),croscarmellosesodium(E468),magnesiumstearate

(E572), colloidalanhydrous silica, pregelatinised starch.

-Tabletfilm-coating:Glycerol(E422),hypromellose6mPa.s(E464),macrogol6000,magnesium

stearate(E572), titaniumdioxide(E171).

WhatArplexamlookslike and contents ofthe pack

Arplexam2.5/0.625/5mgtabletsarewhite,oblong,film-coatedtablet,8.5mmlongand4.5mmwide,

engraved with on onefaceand on the otherface.

Arplexam5/1.25/5mgarewhite,oblong,film-coatedtablet,9.75mmlongand5.16mmwide,engraved

with on onefaceand on the otherface.

Arplexam5/1.25/10mgarewhite,oblong,film-coatedtablet,10.7mmlongand5.66mmwide,engraved

with on onefaceand on the otherface.

Arplexam10/2.5/5mgarewhite,oblong,film-coatedtablet,11.5mmlongand6.09mmwide,engraved

with on onefaceand on the otherface.

Arplexam10/2.5/10mgarewhite,oblong,film-coatedtablet,12.2mmlongand6.46mm,engravedwith

on oneface and on the otherface.

Thetabletsareavailableinboxof10,30,60(2tabletcontainersof30),90(3tabletcontainersof30),100

and 500tablets(5 tabletcontainers of100).

Thedesiccantispresentin the stopperofthetabletcontainers.

Notallpacksizesmaybe marketed.

MarketingAuthorisationHolderandManufacturer

MarketingAuthorisationHolder:

Les LaboratoiresServier

50, rueCarnot

92284 Suresnescedex–France

Manufacturers:

Servier(Ireland)IndustriesLtd

GoreyRoad

Arklow-Co. Wicklow–Ireland

and

Les LaboratoiresServierIndustrie

905 route de Saran

45520 Gidy–France

and

AnpharmPrzedsiebiorstwoFarmaceutyczne S.A.

03-236 Warszawa

ul. Annopol6b–Poland

and

EGIS Pharmaceuticals PLC

H-9900 Körmend, Mátyáskirályu.65

Hungary

Thismedicinalproductisauthorisedinthe MemberStatesoftheEEAunderthefollowing names:

Austria ARPLEXAM, Filmtabletten

Belgium ARPLEXAM, comprimé pelliculé

Bulgaria ARPLEXAM,филмиранитаблетки

Cyprus ARPLEXAM, επικαλυμμένα μελεπτό υμένιο δισκία

Czech Republic ARPLEXAM, potahovanétablety

Estonia ARPLEXAM

Finland ARPLEXAM, kalvopäällysteinentabletti

France ARPLEXAM, comprimé pelliculé

Greece ARPLEXAM, επικαλυμμένα μελεπτό υμένιο δισκία

Hungary ARPLEXAMfilmtabletták

Ireland ARPLEXAMfilm-coated tablets

Italy TRIPLIAM, compresserivestite confilm

Latvia ARPLEXAM, apvalkotāstabletes

Lithuania ARPLEXAM, plėvele dengtostabletės

Luxembourg ARPLEXAM, comprimé pelliculé

Malta ARPLEXAMfilm-coated tablets

Netherlands ARPLEXAM, filmomhulde tabletten

Poland ARPLEXAM

Portugal ARPLEXAM

Romania ARPLEXAMcomprimatefilmate

Slovakia ARPLEXAM, filmomobalenétablety

Slovenia ARPLEXAMfilmsko obloženetablete

Spain ARPLEXAMcomprimidos recubiertoscon película

Thisleafletwaslastrevised inSeptember2015

Other sources ofinformation

Detailedinformation onthis medicineisavailable onthe Medicines Authorityweb site:

www.medicinesauthority.gov.mt

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Arplexam10mg/2.5mg/5mgfilm-coatedtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onefilm-coatedtabletcontains6.790mgperindoprilequivalentto10mgperindoprilarginine,2.5mgindapamideand

6.935mgamlodipinebesilateequivalentto5mgofamlodipine.

Forthefulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

White,oblong,film-coatedtablet,11.5mmlongand6.09mmwideengravedwith ononefaceand ontheother

face.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Arplexamisindicatedassubstitutiontherapyfortreatmentofessentialhypertension,inpatientsalreadycontrolledwith

perindopril/indapamidefixeddosecombinationandamlodipine,takenatthesamedoselevel.

4.2Posologyandmethodofadministration

Posology

OneArplexamfilm-coatedtabletperdayasasingledose,preferablytobetakeninthemorningandbeforeameal.

Thefixeddosecombinationisnotsuitableforinitialtherapy.

Ifachangeoftheposologyisrequired,titrationshouldbedonewiththeindividualcomponents.

Specialpopulation

Renalimpairment(seesection4.3and4.4)

Insevererenalimpairment(creatinineclearancebelow30mL/min),treatmentiscontraindicated.

Inpatientswithmoderaterenalimpairment(creatinineclearance30-60mL/min),Arplexamatthedoses

10mg/2.5mg/5mgand10mg/2.5mg/10mgiscontraindicated.Itisrecommendedtostarttreatmentwiththeadequate

dosageofthefreecombination.

Usualmedicalfollow-upwillincludefrequentmonitoringofcreatinineandpotassium.

Concomitantuseofperindoprilwithaliskireniscontraindicatedinpatientswithrenalimpairment(GFR<60

ml/min/1.73m2)(seesection4.3).

Hepaticimpairment(seesections4.3,4.4and5.2)

Inseverehepaticimpairment,Arplexamiscontraindicated.

Inpatientswithmildtomoderatehepaticimpairment,Arplexamshouldbeadministratedwithcaution,asdosage

recommendationsforamlodipineinthesepatientshavenotbeenestablished.

Elderly(seesection4.4)

Health Products Regulatory Authority

______________________________________________________________________________________________________________________

Date Printed 12/11/2015 CRN 2170072 page number: 1

ElderlycanbetreatedwithArplexamaccordingtorenalfunction(seeSection4.3).

Paediatricpopulation

ThesafetyandefficacyofArplexaminchildrenandadolescentshavenotbeenestablished.Nodataareavailable.

Methodofadministration

Oraluse.

4.3Contraindications

Dialysispatients

Patientswithuntreateddecompensatedheartfailure

Severerenalimpairment(creatinineclearancebelow30mL/min)

Moderaterenalimpairment(creatinineclearancebelow60mL/min)forArplexamdosescontaining10mg/2.5mgof

perindopril/indapamidecombination(i.e.,Arplexam10mg/2.5mg/5mgand10mg/2.5mg/10mg)

-Hypersensitivitytotheactivesubstances,toothersulphonamides,todihydropyridinederivatives,anyotherACE-

inhibitorortoanyoftheexcipientslistedinsection6.1.

Historyofangioedema(Quincke’soedema)associatedwithpreviousACEinhibitortherapy(seesection4.4)

Hereditary/idiopathicangioedema

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6)

Lactation(seesection4.6)

Hepaticencephalopathy

Severehepaticimpairment

Hypokalaemia

Severehypotension

Shock,includingcardiogenicshock

Obstructionoftheoutflow-tractoftheleftventricle(e.g.highgradeaorticstenosis)

Haemodynamicallyunstableheartfailureafteracutemyocardialinfarction

ConcomitantuseofArplexamwithaliskiren-containingproductsinpatientswithdiabetesmellitusorrenal

impairment(GFR<60mL/min/1.73m 2

)(Seesections4.5and5.1)

4.4Specialwarningsandprecautionsforuse

Allwarningsrelatedtoeachcomponent,aslistedbelow,shouldapplyalsotothefixedcombinationofArplexam.

Specialwarnings

Lithium

Thecombinationoflithiumandthecombinationofperindopril/indapamideisusuallynotrecommended(seesection

4.5).

Dualblockadeoftherenin-angiotensin-aldosteronesystem(RAAS)

ThereisevidencethattheconcomitantuseofACE-inhibitors,angiotensinIIreceptorblockersoraliskirenincreasesthe

riskofhypotension,hyperkalaemiaanddecreasedrenalfunction(includingacuterenalfailure).Dualblockadeof

RAASthroughthecombineduseofACE-inhibitors,angiotensinIIreceptorblockersoraliskirenisthereforenot

recommended(seesections4.5and5.1).

Ifdualblockadetherapyisconsideredabsolutelynecessary,thisshouldonlyoccurunderspecialistsupervisionand

subjecttofrequentclosemonitoringofrenalfunction,electrolytesandbloodpressure.

ACE-inhibitorsandangiotensinIIreceptorblockersshouldnotbeusedconcomitantlyinpatientswithdiabetic

nephropathy.

Potassium-sparingdrugs,potassiumsupplementsorpotassium-containingsaltsubstitutes

Thecombinationofperindoprilandpotassium-sparingdrugs,potassiumsupplementsorpotassium-containingsalt

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Neutropenia/agranulocytosis/thrombocytopenia/anaemia

Neutropenia/agranulocytosis,thrombocytopeniaandanaemiahavebeenreportedinpatientsreceivingACEinhibitors.

Inpatientswithnormalrenalfunctionandnoothercomplicatingfactors,neutropeniaoccursrarely.Perindoprilshould

beusedwithextremecautioninpatientswithcollagenvasculardisease,immunosuppressanttherapy,treatmentwith

allopurinolorprocainamide,oracombinationofthesecomplicatingfactors,especiallyifthereispre-existingimpaired

renalfunction.Someofthesepatientsdevelopedseriousinfectionswhichinafewinstancesdidnotrespondto

intensiveantibiotictherapy.Ifperindoprilisusedinsuchpatients,periodicalmonitoringofwhitebloodcellcountsis

advisedandpatientsshouldbeinstructedtoreportanysignofinfection(e.g.sorethroat,fever)(seesection4.8).

Hypersensitivity/angioedema

Angioedemaoftheface,extremities,lips,tongue,glottisand/orlarynxhasbeenreportedrarelyinpatientstreatedwith

angiotensinconvertingenzymeinhibitors,includingperindopril.Thismayoccuratanytimeduringtreatment.Insuch

casesperindoprilshouldbediscontinuedpromptlyandappropriatemonitoringshouldbeinstitutedtoensurecomplete

resolutionofsymptomspriortodismissingthepatient.Inthoseinstanceswhereswellinghasbeenconfinedtotheface

andlipstheconditiongenerallyresolvedwithouttreatment,althoughantihistamineshavebeenusefulinrelieving

symptoms.

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.

Anaphylactoidreactionsduringdesensitization

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.

Pregnancy

ACEinhibitorsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedACEinhibitortherapyisconsidered

essential,patientsplanningpregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhavean

establishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithACEinhibitorsshouldbe

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

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Whenliverfunctionisimpaired,thiazidediureticsandthiazide-relateddiureticsmaycausehepaticencephalopathy.

Administrationofthediureticshouldbestoppedimmediatelyifthisoccurs.

Photosensitivity

Casesofphotosensitivityreactionshavebeenreportedwiththiazidesandrelatedthiazidesdiuretics(seesection4.8).If

photosensitivityreactionoccursduringtreatment,itisrecommendedtostopthetreatment.Ifare-administrationofthe

diureticisdeemednecessary,itisrecommendedtoprotectexposedareastothesunortoartificialUVA.

Precautionsforuse

Renalfunction

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

Forpatientswithamoderaterenalimpairment(creatinineclearance<60mL/min),treatmentiscontraindicatedwith

Arplexamdosescontaining10mg/2.5mgofperindopril/indapamidecombination(i.e.,Arplexam10mg/2.5mg/5mg

and10mg/2.5mg/10mg).

Incertainhypertensivepatientswithoutpre-existingapparentrenallesionsandforwhomrenalbloodtestsshow

functionalrenalinsufficiency,treatmentshouldbestoppedandpossiblyrestartedeitheratalowdoseorwithone

constituentonly.

Inthesepatientsusualmedicalfollow-upwillincludefrequentmonitoringofpotassiumandcreatinine,aftertwo

weeksoftreatmentandtheneverytwomonthsduringtherapeuticstabilityperiod.Renalfailurehasbeenreported

mainlyinpatientswithsevereheartfailureorunderlyingrenalfailureincludingrenalarterystenosis.

Thedrugisusuallynotrecommendedincaseofbilateralrenalarterystenosisorasinglefunctioningkidney.

Riskofarterialhypotensionand/orrenalinsufficiency(incasesofcardiacinsufficiency,waterandelectrolyte

depletion,etc…):Markedstimulationoftherenin-angiotensin-aldosteronesystemhasbeenobservedwith

perindoprilparticularlyduringmarkedwaterandelectrolytedepletions(strictsodiumrestricteddietorprolonged

diuretictreatment),inpatientswhosebloodpressurewasinitiallylow,incasesofrenalarterystenosis,congestive

heartfailureorcirrhosiswithoedemaandascites.

Theblockingofthissystemwithanangiotensinconvertingenzymeinhibitormaythereforecause,particularlyatthe

timeofthefirstadministrationandduringthefirsttwoweeksoftreatment,asuddendropinbloodpressureand/or

anincreaseinplasmalevelsofcreatinine,showingafunctionalrenalinsufficiency.Occasionallythiscanbeacutein

onset,althoughrare,andwithavariabletimetoonset.

Insuchcases,thetreatmentshouldthenbeinitiatedatalowerdoseandincreasedprogressively.Inpatientswith

ischaemicheartorcerebrovasculardiseaseanexcessivefallinbloodpressurecouldresultinamyocardialinfarction

orcerebrovascularaccident.

Thiazidediureticsandthiazide-relateddiureticsareonlyfullyeffectivewhenrenalfunctionisnormaloronly

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

Intheelderlythevalueofplasmacreatininelevelsshouldbeadjustedinrelationtoage,weightandgender.

Hypovolaemia,secondarytothelossofwaterandsodiumcausedbythediureticatthestartoftreatment,causesa

reductioninglomerularfiltration.Itmayresultinanincreaseinbloodureaandcreatininelevels.Thistransitory

functionalrenalinsufficiencyisofnoadverseconsequenceinpatientswithnormalrenalfunctionbutmayhowever

worsenapre-existingrenalimpairment.

Amlodipinemaybeusedatnormaldosesinpatientswithrenalfailure.Changesinamlodipineplasma

concentrationsarenotcorrelatedwithdegreeofrenalimpairment.

TheeffectofthecombinationArplexamhasnotbeentestedinrenaldysfunction.Inrenalimpairment,Arplexam

dosesshouldrespectthoseoftheindividualcomponentstakenseparately.

Hypotensionandwaterandsodiumdepletion

Thereisariskofsuddenhypotensioninthepresenceofpre-existingsodiumdepletion(inparticularinindividuals

withrenalarterystenosis).Thereforesystematictestingshouldbecarriedoutforclinicalsignsofwaterand

electrolytedepletion,whichmayoccurwithanintercurrentepisodeofdiarrhoeaorvomiting.Regularmonitoringof

plasmaelectrolytesshouldbecarriedoutinsuchpatients.

Markedhypotensionmayrequiretheimplementationofanintravenousinfusionofisotonicsaline.

Transienthypotensionisnotacontraindicationtocontinuationoftreatment.Afterre -establishmentofasatisfactory

bloodvolumeandbloodpressure,treatmentcanbestartedagaineitheratareduceddoseorwithonlyoneofthe

constituents.

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sodiumlevelscanbeinitiallyasymptomaticandregulartestingisthereforeessential.Testingshouldbemorefrequent

inelderlyandcirrhoticpatients(seesections4.8and4.9).

Potassiumlevels

Thecombinationofindapamidewithperindoprilandamlodipinedoesnotpreventtheonsetofhypokalaemia

particularlyindiabeticpatientsorinpatientswithrenalfailure.Aswithanyantihypertensiveagentincombination

withadiuretic,regularmonitoringofplasmapotassiumlevelsshouldbecarriedout.

ElevationsinserumpotassiumhavebeenobservedinsomepatientstreatedwithACEinhibitors,including

perindopril.Riskfactorsforthedevelopmentofhyperkalemiaincludethosewithrenalinsufficiency,worseningof

renalfunction,age(>70years),diabetesmellitus,intercurrentevents,inparticulardehydration,acutecardiac

decompensation,metabolicacidosisandconcomitantuseofpotassium-sparingdiuretics(e.g.,spironolactone,

eplerenone,triamterene,oramiloride),potassiumsupplementsorpotassium-containingsaltsubstitutes;orthose

patientstakingotherdrugsassociatedwithincreasesinserumpotassium(e.g.heparin).Theuseofpotassium

supplements,potassium-sparingdiuretics,orpotassium-containingsaltsubstitutesparticularlyinpatientswith

impairedrenalfunctionmayleadtoasignificantincreaseinserumpotassium.Hyperkalemiacancauseserious,

sometimesfatalarrhythmias.Ifconcomitantuseoftheabove-mentionedagentsisdeemedappropriate,theyshould

beusedwithcautionandwithfrequentmonitoringofserumpotassium(seesection4.5).

Potassiumdepletionwithhypokalaemiaisamajorriskwiththiazidediureticsandthiazide-relateddiuretics.The

riskofonsetofloweredpotassiumlevels(<3.4mmol/l)shouldbepreventedinsomehighriskpopulationssuchas

elderlyand/ormalnourishedsubjects,whetherornottheyaretakingmultiplemedications,cirrhoticpatientswith

oedemaandascites,coronarypatientsandpatientswithheartfailure.

Insuchcaseshypokalaemiaincreasesthecardiactoxicityofcardiacglycosidesandtheriskofrhythmdisorders.

SubjectspresentingwithalongQTintervalarealsoatrisk,whethertheoriginiscongenitaloriatrogenic.

Hypokalaemia,aswithbradycardia,actsasafactorwhichfavourstheonsetofsevererhythmdisorders,inparticular

torsadesdepointes,whichmaybefatal.

Inallcasesmorefrequenttestingofpotassiumlevelsisnecessary.Thefirstmeasurementofplasmapotassiumlevels

shouldbecarriedoutduringthefirstweekfollowingthestartoftreatment.

Iflowpotassiumlevelsaredetected,correctionisrequired.

Calciumlevels

Thiazidediureticsandthiazide-relateddiureticsmayreduceurinaryexcretionofcalciumandcauseamildandtransient

increaseinplasmacalciumlevels.Markedlyraisedlevelsofcalciummayberelatedtoundiagnosed

hyperparathyroidism.Insuchcasesthetreatmentshouldbestoppedbeforeinvestigatingtheparathyroidfunction(see

section4.8).

Renovascularhypertension

Thetreatmentforrenovascularhypertensionisrevascularisation.Nonetheless,angiotensinconvertingenzyme

inhibitorscanbebeneficialinpatientspresentingwithrenovascularhypertensionwhoareawaitingcorrectivesurgery

orwhensuchasurgeryisnotpossible.

IfArplexamisprescribedtopatientswithknownorsuspectedrenalarterystenosis,treatmentshouldbestartedina

hospitalsettingatalowdoseandrenalfunctionandpotassiumlevelsshouldbemonitored,sincesomepatientshave

developedafunctionalrenalinsufficiencywhichwasreversedwhentreatmentwasstopped.

Cough

Adrycoughhasbeenreportedwiththeuseofangiotensinconvertingenzymeinhibitors.Itischaracterisedbyits

persistenceandbyitsdisappearancewhentreatmentiswithdrawn.Aniatrogenicaetiologyshouldbeconsideredinthe

eventofthissymptom.Iftheprescriptionofanangiotensinconvertingenzymeinhibitorisstillpreferred,continuation

oftreatmentmaybeconsidered.

Atherosclerosis

Theriskofhypotensionexistsinallpatientsbutparticularcareshouldbetakeninpatientswithischaemicheartdisease

orcerebralcirculatoryinsufficiency,withtreatmentbeingstartedatalowdose.

Hypertensivecrisis

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Cardiacfailure/severecardiacinsufficiency

Patientswithheartfailureshouldbetreatedwithcaution.

Inalong-term,placebocontrolledstudyinpatientswithsevereheartfailure(NYHAclassIIIandIV)thereported

incidenceofpulmonaryoedemawashigherintheamlodipinetreatedgroupthanintheplacebogroup.Calciumchannel

blockers,includingamlodipine,shouldbeusedwithcautioninpatientswithcongestiveheartfailure,astheymay

increasetheriskoffuturecardiovasculareventsandmortality.

Inpatientswithseverecardiacinsufficiency(gradeIV)treatmentshouldbestartedundermedicalsupervisionwitha

reducedinitialdose.Treatmentwithbeta-blockersinhypertensivepatientswithcoronaryinsufficiencyshouldnotbe

stopped:theACEinhibitorshouldbeaddedtothebeta-blocker.

Aorticormitralvalvestenosis/hypertrophiccardiomyopathy

ACEinhibitorsshouldbeusedwithcautioninpatientwithanobstructionintheoutflowtractoftheleftventricle.

Diabeticpatients

Inpatientswithinsulindependentdiabetesmellitus(spontaneoustendencytoincreasedlevelsofpotassium),treatment

shouldbestartedundermedicalsupervisionwithareducedinitialdose.

Theglycaemialevelsshouldbecloselymonitoredindiabeticpatientspreviouslytreatedwithoralantidiabeticdrugsor

insulin,namelyduringthefirstmonthoftreatmentwithanACEinhibitor.

Monitoringofbloodglucoseisimportantindiabeticpatients,particularlywhenpotassiumlevelsarelow.

Ethnicdifferences

Aswithotherangiotensinconvertingenzymeinhibitors,perindoprilisapparentlylesseffectiveinloweringblood

pressureinblackpeoplethaninnon -blacks,possiblybecauseofahigherprevalenceoflow-reninstatesintheblack

hypertensivepopulation.

Surgery/anaesthesia

Angiotensinconvertingenzymeinhibitorscancausehypotensionincasesofanaesthesia,especiallywhenthe

anaestheticadministeredisanagentwithhypotensivepotential.

Itisthereforerecommendedthattreatmentwithlong-actingangiotensinconvertingenzymeinhibitorssuchas

perindoprilshouldbediscontinuedwherepossibleonedaybeforesurgery.

Hepaticimpairment

Rarely,ACEinhibitorshavebeenassociatedwithasyndromethatstartswithcholestaticjaundiceandprogressesto

fulminanthepaticnecrosisand(sometimes)death.Themechanismofthissyndromeisnotunderstood.Patients

receivingACEinhibitorswhodevelopjaundiceormarkedelevationsofhepaticenzymesshoulddiscontinuetheACE

inhibitorandreceiveappropriatemedicalfollow-up(seesection4.8).

Thehalf-lifeofamlodipineisprolongedandAUCvaluesarehigherinpatientswithimpairedliverfunction;dosage

recommendationshavenotbeenestablished.Amlodipineshouldthereforebeinitiatedatthelowerendofthedosing

rangeandcautionshouldbeused,bothoninitialtreatmentandwhenincreasingthedose.Slowdosetitrationand

carefulmonitoringmayberequiredinpatientswithseverehepaticimpairment.

TheeffectofthecombinationArplexamhasnotbeentestedinhepaticdysfunction.Takingintoaccounttheeffectof

eachindividualcomponentofthiscombination,Arplexamiscontraindicatedinpatientswithseverehepatic

impairment,andcautionshouldbeexercisedinpatientswithmildtomoderatehepaticimpairment.

Uricacid

Tendencytogoutattacksmaybeincreasedinhyperuricaemicpatients.

Elderly

Renalfunctionandpotassiumlevelsshouldbetestedbeforethestartoftreatment.Theinitialdoseissubsequently

adjustedaccordingtobloodpressureresponse,especiallyincasesofwaterandelectrolytedepletion,inordertoavoid

suddenonsetofhypotension.

Intheelderlyincreaseofthedosageofamlodipineshouldtakeplacewithcare(seesections4.2and5.2).

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Clinicaltrialdatahasshownthatdualblockadeoftherenin-angiotensin-aldosterone-system(RAAS)throughthe

combineduseofACE-inhibitors,angiotensinIIreceptorblockersoraliskirenisassociatedwithahigherfrequencyof

adverseeventssuchashypotension,hyperkalaemiaanddecreasedrenalfunction(includingacuterenalfailure)

comparedtotheuseofasingleRAAS-actingagent(seesections4.3,4.4and5.1).

Drugsinducinghyperkalaemia:

Somedrugsortherapeuticclassesmayincreasetheoccurrenceofhyperkalaemia:aliskiren,potassiumsalts,potassium-

sparingdiuretics,ACEinhibitors,angiotensin-IIreceptorsantagonists,NSAIDs,heparins,immunosuppressantagents

suchasciclosporinortacrolimus,trimethoprim.Thecombinationofthesedrugsincreasestheriskofhyperkalaemia.

Concomitantusecontraindicated(Seesection4.3):

Aliskiren:Indiabeticorimpairedrenalpatients,riskofhyperkalaemia,worseningofrenalfunctionandcardiovascular

morbidityandmortalityincrease.

Concomitantusenotrecommended:

Component Known interaction

with the following

product Interactionwithothermedicinalproduct

perindopril/

indapamide Lithium Reversibleincreasesinserumlithiumconcentrationsandtoxicity

havebeenreportedduringconcomitantadministrationoflithium

with ACEinhibitors. Use of perindopril combined with

indapamidewithlithiumisnotrecommended,butifthe

combinationprovesnecessary,carefulmonitoringofserumlithium

levelsshouldbeperformed(seesection4.4).

perindopril Aliskiren .Inpatientsotherthandiabeticorimpairedrenalpatients,riskof

hyperkalaemia,worseningofrenalfunctionandcardiovascular

morbidityandmortalityincrease.(Seesection4.4)

Concomitant therapy

withACEinhibitorand

angiotensin-receptor

blocker Ithasbeenreportedintheliteraturethatinpatientswith

establishedatheroscleroticdisease,heartfailure,orwithdiabetes

withendorgandamage,concomitanttherapywithACEinhibitor

andangiotensin-receptorblockerisassociatedwithahigher

frequencyofhypotension,syncope,hyperkalaemia,andworsening

renalfunction(includingacuterenalfailure)ascomparedtouseof

single renin-angiotensin-aldosterone system agent. Dual

blockade(e.g,bycombininganACE-inhibitorwithanangiotensin

IIreceptorantagonist)shouldbelimitedtoindividuallydefined

caseswithclosemonitoringofrenalfunction,potassiumlevels,

andbloodpressure.(Seesection4.4)

Estramustine Riskofincreasedadverseeffectssuchasangioneuroticoedema

(angioedema).

Potassium-sparing

drugs (e.g

triamterene,amiloride,

…),potassium(salts), Hyperkalaemia(potentiallylethal),especiallyinconjunctionwith

renal impairment (additive hyperkalaemic effects). The

combinationofperindoprilwiththeabove-mentioneddrugsisnot

recommended(seesection4.4).Ifconcomitantuseisnonetheless

indicated,theyshouldbeusedwithcautionandwithfrequent

monitoringofserumpotassium.Foruseofspironolactoneinheart

failure,see“Concomitantusewhichrequiresspecialcare”.

amlodipine Dantrolene(infusion) Inanimals,lethalventricularfibrillationandcardiovascular

collapseareobservedinassociationwithhyperkalemiaafter

administrationofverapamilandintravenousdantrolene.Dueto

riskofhyperkalemia,itisrecommendedthattheco-administration

ofcalciumchannelblockerssuchasamlodipinebeavoidedin

patientssusceptibletomalignanthyperthermiaandinthe

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Concomitantusewhichrequiresspecialcare: Grapefruitorgrapefruit

juice Thebioavailabilitymaybeincreasedinsomepatientsresultingin

increasedbloodpressureloweringeffects

Component Knowninteraction

withthefollowing

product Interactionwithothermedicinalproduct

perindopril /

indapamide/ Baclofen

Increasedantihypertensiveeffect.Monitorbloodpressure

andadaptantihypertensivedosageifnecessary.

Non-steroidalanti-

inflammatory

medicinalproducts

(includedacetylsalicylic

acidathighdoses) WhenACE-inhibitorsareadministeredsimultaneously

with non-steroidal anti-inflammatory drugs (i.e.

acetylsalicylicacidatanti-inflammatorydosageregimens,

COX-2inhibitorsandnon-selectiveNSAIDs),attenuation

oftheantihypertensiveeffectmayoccur.Concomitantuse

ofACE-inhibitorsandNSAIDsmayleadtoanincreased

riskofworseningofrenalfunction,includingpossible

acuterenalfailure,andanincreaseinserumpotassium,

especiallyinpatientswithpoorpre-existingrenalfunction.

Thecombinationshouldbeadministeredwithcaution,

especiallyintheelderly.Patientsshouldbeadequately

hydratedandconsiderationshouldbegiventomonitoring

renalfunctionafterinitiationofconcomitanttherapy,and

periodicallythereafter.

perindopril Antidiabetic

agents (insulin,

oral

hypoglycaemic

agents) Epidemiologicalstudieshavesuggestedthatconcomitant

administration of ACE inhibitors and antidiabetic

medicines(insulins,oralhypoglycaemicagents)maycause

anincreasedblood-glucoseloweringeffectwithriskof

hypoglycaemia.Thisphenomenonappearedtobemore

likelytooccurduringthefirstweeksofcombined

treatmentandinpatientswithrenalimpairment.

Non-potassium-

sparingdiuretics Patientsondiuretics,andespeciallythosewhoarevolume

and/orsaltdepleted,mayexperienceexcessivereductionin

bloodpressureafterinitiationoftherapywithanACE

inhibitor.Thepossibilityofhypotensiveeffectscanbe

reducedbydiscontinuationofthediuretic,byincreasing

volumeorsaltintakepriortoinitiatingtherapywithlow

andprogressivedosesofperindopril.

Inarterialhypertension,whenpriordiuretictherapycan

havecausedsalt/volumedepletion,eitherthediureticmust

bediscontinuedbeforeinitiatingtheACEinhibitor,in

whichcaseanon-potassium-sparingdiureticcanbe

thereafterreintroducedortheACEinhibitormustbe

initiatedwithalowdosageandprogressivelyincreased.

Indiuretic-treatedcongestiveheartfailure,theACE

inhibitorshouldbeinitiatedataverylowdosage,possibly

afterreducingthedosageoftheassociatednon-potassium-

sparingdiuretic.

Inallcases,renalfunction(creatininelevels)mustbe

monitoredduringthefirstfewweeksofACEinhibitor

therapy.

Potassium-sparing

diuretics

(eplerenone,

spironolactone) Witheplerenoneorspironolactoneatdosesbetween12.5

mgto50mgbydayandwithlowdosesofACEinhibitors:

InthetreatmentofclassII-IVheartfailure(NYHA)with

anejectionfraction<40%,andpreviouslytreatedwith

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potentiallylethal,especiallyincaseofnon-observanceof

theprescriptionrecommendationsonthiscombination.

Beforeinitiatingthecombination,checktheabsenceof

hyperkalaemiaandrenalimpairment.

Aclosemonitoringofthekalaemiaandcreatinemiais

recommendedinthefirstmonthofthetreatmentoncea

weekatthebeginningand,monthlythereafter.

indapamide Torsades de

pointes inducing

drugs Duetotheriskofhypokalemia,indapamideshouldbe

administeredwithcautionwhenassociatedwithmedicinal

productsthatinducedtorsadesdepointessuchas:

-classIAantiarrhythmicagents(quinidine,hydroquinidine,

disopyramide);

-classIIIantiarrhythmicagents(amiodarone,dofetilide,

ibutilide,bretylium,sotalol);

some neuroleptics (chlorpromazine, cyamemazine,

levomepromazine,thioridazine,trifluoperazine),benzamides

(amisulpride,sulpiride,sultopride,tiapride),butyrophenones

(droperidol,haloperidol),otherneuroleptics(pimozide);

-othersubstancessuchasbepridil,cisapride,diphemanil,IV

erythromycin, halofantrine, mizolastine, moxifloxacin,

pentamidine, sparfloxacin, IV vincamine, methadone,

astemizole,terfenadine.

Preventionoflowpotassiumlevelsandcorrectionif

necessary:monitoringoftheQTinterval

Amphotericin B

route),

glucocorticoids

mineralocorticoids

(systemic route),

tetracosactide,

stimulantlaxatives Increasedriskoflowpotassiumlevels(additiveeffect).

Monitoring of potassium levels, and correction if

necessary;particularconsiderationrequiredincasesof

treatmentwithcardiacglycosides.Nonstimulantlaxatives

shouldbeused.

Cardiacglycosides Lowpotassiumlevelsfavourthetoxiceffectsofcardiac

glycosides. Potassium levels and ECG should be

monitoredandtreatmentreconsideredifnecessary.

Allopurinol Concomitanttreatmentwithindapamidemayincreasethe

incidenceofhypersensitivityreactionstoallopurinol.

amlodipine CYP3A4inducers ThereisnodataavailableregardingtheeffectofCYP3A4

inducersonamlodipine.TheconcomitantuseofCYP3A4

inducers(e.g.,rifampicin,hypericumperforatum)may

give a lower plasma concentration of amlodipine.

Amlodipineshouldbeusedwithcautiontogetherwith

CYP3A4inducers

CYP3A4

inhibitors Concomitantuseofamlodipinewithstrongormoderate

CYP3A4inhibitors(proteaseinhibitors,azoleantifungals,

macrolideslikeerythromycinorclarithromycin,verapamil

ordiltiazem)maygiverisetosignificantincreasein

amlodipineexposure.TheclinicaltranslationofthesePK

variationsmaybemorepronouncedintheelderly.Clinical

monitoringanddoseadjustmentmaythusberequired

Component Knowninteraction

withthefollowing

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perindopril/

indapamide/

amlodipine Imipramine-like

antidepressants

(tricyclics),

neuroleptics Increasedantihypertensiveeffectandincreasedriskoforthostatic

hypotension(additiveeffect).

other

antihypertensive

agents Useofotherantihypertensivemedicinalproductscouldresultin

additionalbloodpressureloweringeffect

Corticosteroids,

tetracosactide Reductioninantihypertensiveeffect(saltandwaterretentiondue

tocorticosteroids).

perindopril Antihypertensive

agentsand

vasodilators Concomitantusewithnitroglycerinandothernitrates,orother

vasodilators,mayfurtherreducebloodpressure

Allopurinol,

cytostatic or

immunosuppressive

agents, systemic

corticosteroids or

procainamide ConcomitantadministrationwithACEinhibitorsmayleadtoan

increasedriskforleucopenia

Anaestheticdrugs ACEinhibitorsmayenhancethehypotensiveeffectsofcertain

anaestheticdrugs

Diuretics(thiazide

orloopdiuretics) Priortreatmentwithhighdosediureticsmayresultinvolume

depletionandinariskofhypotensionwheninitiatingtherapywith

perindopril.

Gliptines

(linagliptine,

saxagliptine,

sitagliptine,

vildagliptine) Increasedriskofangio-oedema,duetodipeptidylpeptidaseIV

(DPP-IV)decreasedactivitybythegliptine,inpatientsco-treated

withanACEinhibitor.

Sympathomimetics Sympathomimeticsmayreducetheantihypertensiveeffectsof

ACEinhibitors

Gold Nitritoidreactions(symptomsincludefacialflushing,nausea,

vomitingandhypotension)havebeenreportedrarelyinpatientson

therapy with injectable gold (sodium aurothiomalate) and

concomitantACEinhibitortherapyincludingperindopril.

indapamide Metformin Lacticacidosisduetometformincausedbypossiblefunctional

renalinsufficiencylinkedtodiureticsandinparticulartoloop

diuretics.Donotusemetforminwhenplasmacreatininelevels

exceed 15mg/l (135micromol/l) in men and 12mg/l

(110micromol/l)inwomen.

Iodinatedcontrast

media Incasesofdehydrationcausedbydiuretics,thereisanincreased

riskofacuterenalinsufficiency,particularlywhenhighdosesof

iodinatedcontrastmediaareused.Rehydrationshouldbecarried

outbeforetheiodinatedcompoundisadministered

Calcium(salts) Riskofincreasedlevelsofcalciumduetoreducedeliminationof

calciumintheurine

Ciclosporin Riskofincreasedcreatininelevelswithnochangeincirculating

levelsofciclosporin,evenwhenthereisnosaltandwaterdepletion

amlodipine Atorvastatin,

digoxin, warfarin

orciclosporin Inclinicalinteractionstudies,amlodipinedidnotaffectthe

pharmacokineticsofatorvastatin,digoxin,warfarin,orciclosporin.

Simvastatin Co-administrationofmultipledosesof10mgofamlodipinewith

80mgsimvastatinresultedina77%increaseinexposureto

simvastatincomparedtosimvastatinalone.Limitthedoseof

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4.6Fertility,pregnancyandlactation

Giventheeffectsoftheindividualcomponentsinthiscombinationproductonpregnancyandlactation,

Arplexamisnotrecommendedduringthefirsttrimesterofpregnancy.Arplexamiscontraindicatedduringthesecond

andthirdtrimestersofpregnancy.

Arplexamiscontraindicatedduringlactation.Adecisionshouldthereforebemadewhethertodiscontinuenursingorto

discontinueArplexamtakingaccounttheimportanceofthistherapyforthemother.

Pregnancy

Perindopril:

TheuseofACEinhibitorsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).The

useofACEinhibitorsiscontra-indicatedduringthesecondandthirdtrimestersofpregnancy(seesections4.3

and4.4).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Unlesscontinued

ACEinhibitortherapyisconsideredessential,patientsplanningpregnancyshouldbechangedtoalternativeanti-

hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.Whenpregnancyisdiagnosed,

treatmentwithACEinhibitorsshouldbestoppedimmediately,and,ifappropriate,alternativetherapyshouldbestarted.

ExposuretoACEinhibitortherapyduringthesecondandthirdtrimestersisknowntoinducehumanfoetotoxicity

(decreasedrenalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,

hypotension,hyperkalaemia)(seesection5.3).

ShouldexposuretoACEinhibitorshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenal

functionandskullisrecommended.

InfantswhosemothershavetakenACEinhibitorsshouldbecloselyobservedforhypotension(seesections4.3and

4.4).

Indapamide:

Therearenoorlimitedamountofdata(lessthan300pregnancyoutcomes)fromtheuseofindapamideinpregnant

women.Prolongedexposuretothiazideduringthethirdtrimesterofpregnancycanreducematernalplasmavolumeas

wellasuteroplacentalbloodflow,whichmaycauseafeto-placentalischemiaandgrowthretardation.Moreover,rare

casesofhypoglycemiaandthrombocytopeniainneonateshavebeenreportedfollowingexposurenearterm.

Animalstudiesdonotindicatedirectorindirectharmfuleffectswithrespecttoreproductivetoxicity(seesection5.3).

Amlodipine:

Thesafetyofamlodipineinhumanpregnancyhasnotbeenestablished.

Inanimalstudies,reproductivetoxicitywasobservedathighdoses(seesection5.3).

Breastfeeding

Arplexamiscontraindicatedduringlactation.

Perindopril:

Becausenoinformationisavailableregardingtheuseofperindoprilduringbreastfeeding,perindoprilisnot

recommendedandalternativetreatmentswithbetterestablishedsafetyprofilesduringbreast-feedingarepreferable,

especiallywhilenursinganewbornorpreterminfant.

Indapamide:

Thereisinsufficientinformationontheexcretionofindapamide/metabolitesinhumanmilk.Arisktothe

newborns/infantscannotbeexcluded.

Indapamideiscloselyrelatedtothiazidediureticswhichhavebeenassociated,duringbreast-feeding,withdecreaseor

evensuppressionofmilklactation.Hypersensitivitytosulfonamide-deriveddrugs,hypokalaemiamightoccur.

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Itisnotknownwhetheramlodipineisexcretedinbreastmilk.

Fertility

Commontoperindoprilandindapamide:

Reproductivetoxicitystudiesshowednoeffectonfertilityinfemaleandmalerats(seesection5.3).Noeffectson

humanfertilityareanticipated.

Amlodipine

Reversiblebiochemicalchangesintheheadofspermatozoahavebeenreportedinsomepatientstreatedbycalcium

channelblockers.Clinicaldataareinsufficientregardingthepotentialeffectofamlodipineonfertility.Inoneratstudy,

adverseeffectswerefoundonmalefertility(seesection5.3).

4.7Effectsonabilitytodriveandusemachines

NostudiesontheeffectsofArplexamontheabilitytodriveandusemachineshavebeenperformed.

Perindopirilandindapamidehavenoinfluenceontheabilitytodriveandusemachinesbutindividualreactionsrelated

tolowbloodpressuremayoccurinsomepatients.

Amlodipinecanhaveminorormoderateinfluenceontheabilitytodriveandusemachines.Ifpatientssufferfrom

dizziness,headache,fatigue,wearinessornausea,theabilitytoreactmaybeimpaired.

Asaresulttheabilitytodriveoroperatemachinerymaybeimpaired.Cautionisrecommendedespeciallyatthestartof

treatment.

4.8Undesirableeffects

Summaryofthesafetyprofile

Themostcommonlyreportedadversereactionswithperindopril,indapamideandamlodipinegivenseparatelyare:

dizziness,headache,paraesthesia,vertigo,somnolence,visualimpairment,tinnitus,palpitations,flushing,hypotension

(andeffectsrelatedtohypotension),cough,dyspnea,gastro-intestinaldisorders(abdominalpain,constipation,

diarrhoea,dysgeusia,nausea,dyspepsia,vomiting),pruritus,rash,maculopapularrashes,musclespasms,ankle

swelling,asthenia,oedemaandfatigue.

Tabulatedlistofadversereactions

Thefollowingundesirableeffectshavebeenobservedwithperindopril,indapamideoramlodipineduringtreatmentand

rankedunderthefollowingfrequency:

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).

MedDRA

SystemOrgan

Class UndesirableEffects Frequency

Infectionsand

infestations Rhinitis Veryrare - Uncommon

Bloodand

lymphaticSystem

Disorders Eosinophilia Uncommon* - -

Agranulocytosis(seesection4.4) Veryrare Veryrare -

Aplasticanaemia - Veryrare

Pancytopenia Veryrare - -

Leukopenia(seesection4.4) Veryrare Veryrare Veryrare

Neutropenia(seesection4.4) Veryrare - -

Haemolyticanaemia Veryrare Veryrare -

Thrombocytopenia(seesection4.4) Veryrare Veryrare Veryrare

ImmuneSystem

Disorders Hypersensitivity Uncommon Veryrare

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Metabolismand

Nutrition

Disorders Hyperkalaemiareversibleondiscontinuation

(seesection4.4) Uncommon* - -

Hyponatraemia(seesection4.4) Uncommon* Notknow

Hyperglycaemia - - Veryrare

Hypercalcaemia - Veryrare -

Potassiumdepletionwithhypokalaemia,

particularlyseriousincertainhighrisk

populations(seesection4.4) - Notknown -

Psychiatric

disorders Insomnia - - Uncommon

Moodaltered(includinganxiety) Uncommon - Uncommon

Depression - - Uncommon

Sleepdisorder Uncommon - -

Confusion Veryrare - Rare

NervousSystem

Dizziness Common - Common

Headache Common Rare Common

Paraesthesia Common Rare Uncommon

Vertigo Common Rare -

Somnolence Uncommon* - Common

Hypoesthaesia - - Uncommon

Dysgeusia Common - Uncommon

Tremor - - Uncommon

Syncope Uncommon* Notknown Uncommon

Hypertonia - - Veryrare

Peripheralneuropathy - - Veryrare

Extrapyramidaldisorder(extrapyramidal

syndrome) - - Notknown

Strokepossiblysecondarytoexcessive

hypotensioninhigh-riskpatients(seesection

4.4) Veryrare - -

EyeDisorders Visualimpairment Common Notknown Uncommon

Diplopia - - Uncommon

Myopia - Notknown -

Blurredvision - Notknown -

Earandlabyrinth

disorders Tinnitus Common - Uncommon

CardiacDisorders Palpitations Uncommon* - Common

Tachycardia Uncommon* - -

Anginapectoris(seesection4.4) Veryrare - -

Arrhythmia(includingbradycardia,

ventriculartachycardiaandatrialfibrillation) Veryrare Veryrare Veryrare

Myocardialinfarction,possiblysecondaryto

excessivehypotensioninhighriskpatients

(seesection4.4) Veryrare - Veryrare

Torsadedepointes(potentiallyfatal)(see

sections4.4and4.5) - Notknown -

Vascular

Disorders Flushing - - Common

Hypotension(andeffectsrelatedto

hypotension)(seesection4.4) Common Veryrare Uncommon

Vasculitis Uncommon* - Veryrare

Respiratory,

Thoracicand

Mediastinal Cough(seesection4.4) Common - Veryrare

Dyspnoea Common - Uncommon

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Disorders Eosinophilicpneumonia Veryrare - -

Gastro-intestinal

Disorders Abdominalpain Common - Common

Constipation Common Rare Uncommon

Diarrhoea Common - Uncommon

Dyspepsia Common - Uncommon

Nausea Common Rare Common

Vomiting Common Uncommon Uncommon

Drymouth Uncommon Rare Uncommon

Changeofbowelhabit - - Uncommon

Gingivalhyperplasia - - Veryrare

Pancreatitis Veryrare Veryrare Veryrare

Gastritis - - Veryrare

Hepato-biliary

Disorders Hepatitis(seesection4.4) Veryrare Notknown Veryrare

Jaundice - - Veryrare

Hepaticfunctionabnormal - Veryrare -

Possibilityofonsetofhepaticencephalopathy

incaseofhepaticinsufficiency(seesections

4.3and4.4) - Notknown -

Skinand

Subcutaneous

Pruritus Common - Uncommon

Rash Common - Uncommon

Rashmaculo-papular Common- -

Urticaria(seesection4.4) Uncommon Veryrare Veryrare

Angioedema(seesection4.4) Uncommon Veryrare Veryrare

Alopecia - - Uncommon

Purpura - Uncommon Uncommon

Skindiscoloration - - Uncommon

Hyperhidrosis Uncommon - Uncommon

Exanthema - - Uncommon

Photosensitivityreaction Uncommon* Notknown

(seesection

4.4) Veryrare

Pemphigoid Uncommon*

Erythemamultiforme Veryrare - Veryrare

Stevens-JohnsonSyndrome - Veryrare Veryrare

Exfoliativedermatitis - - Veryrare

Toxicepidermalnecrolysis - Veryrare -

Quincke’soedema - - Veryrare

Possibleworseningofpre-existingacute

disseminatedlupuserythematosus - Notknown -

Musculoskeletal

AndConnective

TissueDisorders Musclespasms Common - Uncommon

Ankleswelling - - Common

Arthralgia Uncommon* - Uncommon

Myalgia Uncommon* - Uncommon

Backpain - - Uncommon

Renaland

UrinaryDisorders Micturitiondisorder,nocturia,pollakiuria - - Uncommon

Acuterenalfailure Veryrare - -

Renalfailure Uncommon Veryrare -

Reproductive

Systemand

BreastDisorders Erectiledysfunction Uncommon - Uncommon

Gynaecomastia - - Uncommon

GeneralDisorders Asthenia Common - Uncommon

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*Frequencycalculatedfromclinicaltrialsforadverseeventsdetectedfromspontaneousreport

Reportingofsuspectedadversereactions

Reportingsuspectedadversereactionsafterauthorisationofthemedicinalproductisimportant.Itallowscontinued

monitoringofthebenefit/riskbalanceofthemedicinalproduct.Healthcareprofessionalsareaskedtoreportany

suspectedadversereactionsviaHPRAPharmacovigilance,EarlsfortTerrace,IRL-Dublin2;Tel:+35316764971;

Fax:+35316762517.Website: www.hpra.ie ;E-mail: medsafety@hpra.ie .

4.9Overdose

ThereisnoinformationonoverdosagewithArplexaminhumans.

Forperindopril/indapamidecombination

Symptoms

Themostlikelyadversereactionincasesofoverdoseishypotension,sometimesassociatedwithnausea,vomiting,

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

waterdisturbances(lowsodiumlevels,lowpotassiumlevels)mayoccur.

Management

Thefirstmeasurestobetakenconsistofrapidlyeliminatingtheproduct(s)ingestedbygastriclavageand/or

administrationofactivatedcharcoal,thenrestoringfluidandelectrolytebalanceinaspecialisedcentreuntiltheyreturn

tonormal.

Ifmarkedhypotensionoccurs,thiscanbetreatedbyplacingthepatientinasupinepositionwiththeheadlowered.If

necessaryanintravenousinfusionofisotonicsalinemaybegiven,oranyothermethodofvolaemicexpansionmaybe

used.

Perindoprilat,theactiveformofperindopril,canbedialysed(seesection5.2).

Foramlodipine

Experiencewithintentionaloverdoseinhumansislimited.

Symptoms

Availabledatasuggestthatgrossoverdosagecouldresultinexcessiveperipheralvasodilatationandpossiblyreflex

tachycardia.Markedandprobablyprolongedsystemichypotensionuptoandincludingshockwithfataloutcomehave

and

Administration

SiteCondition Oedema - - Common

Chestpain Uncommon* - Uncommon

Pain - - Uncommon

Malaise Uncommon* - Uncommon

Oedemaperipheral Uncommon* - -

GeneralDisorders

and

Administration

SiteCondition Pyrexia Uncommon* - -

Investigations Weightincrease,weightdecrease - - Uncommon

Bloodureaincreased Uncommon* - -

Bloodcreatinineincreased Uncommon* - -

Bloodbilirubinincreased Rare - -

Hepaticenzymeincreased Rare Notknown Veryrare

Haemoglobindecreasedandhaematocrit

decreased(seesection4.4) Veryrare - -

ElectrocardiogramQTprolonged(see

sections4.4and4.5) - Notknown -

Bloodglucoseincreased - Notknown -

Blooduricacidincreased - Notknown -

Injury,poisoning

andprocedural

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Management

Clinicallysignificanthypotensionduetoamlodipineoverdosagecallsforactivecardiovascularsupportincluding

frequentmonitoringofcardiacandrespiratoryfunction,elevationofextremitiesandattentiontocirculatingfluid

volumeandurineoutput.

Avasoconstrictormaybehelpfulinrestoringvasculartoneandbloodpressure,providedthatthereisno

contraindicationtoitsuse.Intravenouscalciumgluconatemaybebeneficialinreversingtheeffectsofcalciumchannel

blockade.

Gastriclavagemaybeworthwhileinsomecases.Inhealthyvolunteerstheuseofcharcoalupto2hoursafter

administrationofamlodipine10mghasbeenshowntoreducetheabsorptionrateofamlodipine.

Sinceamlodipineishighlyprotein-bound,dialysisisnotlikelytobeofbenefit.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:ACEinhibitors,combinations.ACEinhibitors,calciumchannelblockersanddiuretics.

ATCcode:C09BX01

Arplexamisacombinationofthreeantihypertensivecomponentswithcomplementarymechanismstocontrolblood

pressureinpatientwithhypertension.Perindoprilargininesaltisanangiotensinconvertingenzymeinhibitor,

indapamide,achlorosulphamoyldiureticandamlodipine,acalciumionfluxinhibitorofthedihydropyridinegroup.

ThepharmacologicalpropertiesofArplexamarederivedfromthoseofeachofthecomponentstakenseparately.In

addition,thecombinationofperindopril/indapamideproducesanadditivesynergyoftheantihypertensiveeffectsof

thetwocomponents.

Mechanismofaction

Perindopril:

Perindoprilisaninhibitoroftheangiotensinconvertingenzyme(ACEinhibitor)whichconvertsangiotensinIto

angiotensinII,avasoconstrictingsubstance;inadditiontheenzymestimulatesthesecretionofaldosteronebythe

adrenalcortexandstimulatesthedegradationofbradykinin,avasodilatorysubstance,intoinactiveheptapeptides.

Thisresultsin:

-areductioninaldosteronesecretion,

-anincreaseinplasmareninactivity,sincealdosteronenolongerexercisesnegativefeedback,

-areductionintotalperipheralresistancewithapreferentialactiononthevascularbedinmuscleandthekidney,with

noaccompanyingsaltandwaterretentionorreflextachycardia,withchronictreatment.

Theantihypertensiveactionofperindoprilalsooccursinpatientswithlowornormalreninconcentrations.

Perindoprilactsthroughitsactivemetabolite,perindoprilat.Theothermetabolitesareinactive.

Perindoprilreducestheworkoftheheart:

-byavasodilatoryeffectonveins,probablycausedbychangesinthemetabolismofprostaglandins:reductioninpre-

load,

-byreductionofthetotalperipheralresistance:reductioninafterload.

Studiescarriedoutonpatientswithcardiacinsufficiencyhaveshown:

-areductioninleftandrightventricularfillingpressures,

-areductionintotalperipheralvascularresistance,

-anincreaseincardiacoutputandanimprovementinthecardiacindex,

-anincreaseinregionalbloodflowinmuscle.

Exercisetestresultsalsoshowedimprovement.

Indapamide:

Indapamideisasulphonamidederivativewithanindolering,pharmacologicallyrelatedtothethiazidegroupof

diuretics.Indapamideinhibitsthereabsorptionofsodiuminthecorticaldilutionsegment.Itincreasestheurinary

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urineoutputandhavinganantihypertensiveaction.

Amlodipine:

Amlodipineisacalciumioninfluxinhibitorofthedihydropyridinegroup(slowchannelblockerorcalciumion

antagonist)andinhibitsthetransmembraneinfluxofcalciumionsintocardiacandvascularsmoothmuscle.

Pharmacodynamiceffects

Perindopril/indapamide:

Inhypertensivepatientsregardlessofage,theperindopril/indapamidecombinationexertsadose-dependent

antihypertensiveeffectondiastolicandsystolicarterialpressurewhilstsupineorstanding.Duringclinicaltrials,the

concomitantadministrationofperindoprilandindapamideproducedantihypertensiveeffectsofasynergicnaturein

relationtoeachoftheproductsadministeredalone.

Perindopril:

Perindoprilisactiveinallgradesofhypertension:mildtomoderateorsevere.Areductioninsystolicanddiastolic

arterialpressureisobservedinthelyingandstandingposition.

Theantihypertensiveactivityafterasingledoseismaximalatbetween4and6hoursandismaintainedover24hours.

Thereisahighdegreeofresidualblockingofangiotensinconvertingenzymeat24hours,approximately80%.

Inpatientswhorespond,normalisedbloodpressureisreachedafteronemonthandismaintainedwithout

tachyphylaxis.

Withdrawaloftreatmenthasnoreboundeffectonhypertension.

Perindoprilhasvasodilatorypropertiesandrestoreselasticityofthemainarterialtrunks,correctshistomorphometric

changesinresistancearteriesandproducesareductioninleftventricularhypertrophy.

Ifnecessary,theadditionofathiazidediureticleadstoanadditivesynergy.

Thecombinationofanangiotensinconvertingenzymeinhibitorwithathiazidediureticdecreasesthehypokalaemia

riskassociatedwiththediureticalone.

Indapamide:

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.

Amlodipine:

Themechanismoftheantihypertensiveactionofamlodipineisduetoadirectrelaxanteffectonvascularsmooth

muscle.Theprecisemechanismbywhichamlodipinerelievesanginahasnotbeenfullydeterminedbutamlodipine

reducestotalischaemicburdenbythefollowingtwoactions:

Amlodipinedilatesperipheralarteriolesandthus,reducesthetotalperipheralresistance(afterload)againstwhichthe

heartworks.Sincetheheartrateremainsstable,thisunloadingoftheheartreducesmyocardialenergyconsumption

andoxygenrequirements.

Themechanismofactionofamlodipinealsoprobablyinvolvesdilatationofthemaincoronaryarteriesandcoronary

arterioles,bothinnormalandischaemicregions.Thisdilatationincreasesmyocardialoxygendeliveryinpatientswith

coronaryarteryspasm(Prinzmetal'sorvariantangina).

Inpatientswithhypertension,oncedailydosingprovidesclinicallysignificantreductionsofbloodpressureinboththe

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afeatureofamlodipineadministration.

Amlodipinehasnotbeenassociatedwithanyadversemetaboliceffectsorchangesinplasmalipidsandissuitablefor

useinpatientswithasthma,diabetes,andgout.

Clinicalefficacyandsafety

Arplexamhasnotbeenstudiedonmorbidityandmortality.

Perindopril/indapamide:

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)

andindapamide2.5mgorenalapril40mgonceaday.Only34%ofthesubjectsremainedtreatedwithperindopriltert-

butylamine2mg(equivalentto2.5mgperindoprilarginine)/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/indapamidedosesthanthoselicensedfor

perindopril/indapamide2.5mg/0.625mgandperindopril/indapamide5mg/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.

TheADVANCEstudywasamulticentre,international,randomised,2x2factorialdesignedtrialaimedatdetermining

thebenefitsofBloodPressureloweringwiththefixedcombinationperindopril/indapamidevsplaceboontopof

currentstandardtherapy(doubleblindcomparison)andofgliclazideMRbasedintensiveglucosecontrolstrategy

(HbA1ctargetof6.5%orlower)vsstandardglucosecontrol(PROBE[ProspectiveRandomisedOpenstudywith

BlindedEvaluation]design)onmajormacrovascularandmicrovasculareventsintype2diabeticpatients.

Theprimaryend-pointwasacompositeofmajormacrovascular(cardiovasculardeath,non-fatalmyocardialinfarction,

non-fatalstroke)andmicrovascular(neworworseningnephropathyandeyedisease)events.

Overall,11140type2diabeticpatients(meanvalues:age66years,BMI28kg/m 2

,durationofdiabetes8years,

HbA1c7.5%andSBP/DBP145/81mmHg)wereinvolvedinthetrial.Amongthem,83%werehypertensive,32%and

10%presentedahistoryofmacro-ormicro-vasculardiseaserespectivelyand27%hadmicroalbuminuria.

ConcomitanttherapiesincludedBPloweringagents(75%),lipidloweringagents(35%mainlystatins28%),aspirinor

otherantiplatelets(47%).

Followinga6-weekrun-inperiodonopenperindopril/indapamidecombinationandusualglucoseloweringtreatment,

patientswererandomlyassignedtoplacebo(n=5571)orperindopril/indapamidecombination(n=5569).

Afterameandurationoffollow-upof4.3years,thetreatmentwithperindopril/indapamideresultedinasignificant

relativeriskreductionof9%intheprimaryendpoint(95%CI[0.828;0.996],p=0.041).

Thisbenefitwasdrivenbyasignificantrelativeriskreductionof14%intotalmortality(95%CI[0.75;0.98],p=0.025),

of18%incardiovasculardeaths(95%CI[0.68;0.98],p=0.027)andof21%intotalrenalevents(95%CI[0.74;0.86],

p<0.001)intheperindopril/indapamidegroupcomparedtotheplacebogroup.

Inthesub-groupofinterestofhypertensivepatients,therewasarelativeriskreductionof9%inthecombinedmajor

macrovascularandmicrovasculareventsintheperindopril/indapamidegroupcomparedtotheplacebogroup(95%CI

[0.82;1.00],p=0.052).

Therewerealsoasignificantrelativeriskreductionof16%intotalmortality(95%CI[0.73;0.97],p=0.019),of20%in

cardiovasculardeaths(95%CI[0.66;0.97],p=0.023)andof20%intotalrenalevents(95%CI[0.73;0.87],p<0.001)in

theperindopril/indapamidegroupcomparedtotheplacebogroup.

ThebenefitsoftheBPloweringinterventionwereindependentofthoseobservedwiththeintensiveglucosecontrol

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Amlodipine:

Arandomizeddouble-blindmorbidity-mortalitystudycalledtheAntihypertensiveandLipid-LoweringTreatmentto

PreventHeartAttackTrial(ALLHAT)wasperformedtocomparenewerdrugtherapies:amlodipine2.5-10mg/d

(calciumchannelblocker)orlisinopril10-40mg/d(ACE-inhibitor)asfirst-linetherapiestothatofthethiazide-diuretic,

chlorthalidone12.5-25mg/dinmildtomoderatehypertension.”

Atotalof33,357hypertensivepatientsaged55orolderwererandomizedandfollowedforameanof4.9years.The

patientshadatleastoneadditionalCHDriskfactor,including:previousmyocardialinfarctionorstroke(>6months

priortoenrollment)ordocumentationofotheratheroscleroticCVD(overall51.5%),type2diabetes(36.1%),HDL-C<

35mg/dL(11.6%),leftventricularhypertrophydiagnosedbyelectrocardiogramorechocardiography(20.9%),current

cigarettesmoking(21.9%).

TheprimaryendpointwasacompositeoffatalCHDornon-fatalmyocardialinfarction.Therewasnosignificant

differenceintheprimaryendpointbetweenamlodipine-basedtherapyandchlorthalidone-basedtherapy:RR0.98(95%

CI(0.90-1.07)p=0.65.Amongsecondaryendpoints,theincidenceofheartfailure(componentofacomposite

combinedcardiovascularendpoint)wassignificantlyhigherintheamlodipinegroupascomparedtothechlorthalidone

group(10.2%vs.7.7%,RR1.38,(95%CI[1.25-1.52]p<0.001)).However,therewasnosignificantdifferenceinall-

causemortalitybetweenamlodipine-basedtherapyandchlorthalidone-basedtherapy.RR0.96(95%CI[0.89-1.02]

p=0.20).

Dualblockadeoftherenin-angiotensin-aldosteronesystem(RAAS)clinicaltrialdata:

Twolargerandomised,controlledtrials(ONTARGET(ONgoingTelmisartanAloneandincombinationwithRamipril

GlobalEndpointTrial)andVANEPHRON-D(TheVeteransAffairsNephropathyinDiabetes))haveexaminedtheuse

ofcombinationofanACE-inhibitorwithanangiotensinIIreceptorblocker.

ONTARGETwasastudyconductedinpatientswithahistoryofcardiovascularorcerebrovasculardisease,ortype2

diabetesmellitusaccompaniedbyevidenceofend-organdamage.VANEPHRON-Dwasastudyinpatientswithtype

2diabetesmellitusanddiabeticnephropathy.

Thesestudieshaveshownnosignificantbeneficialeffectonrenaland/orcardiovascularoutcomesandmortality,while

anincreasedriskofhyperkalaemia,acutekidneyinjuryand/orhypotensionascomparedtomonotherapywasobserved.

Giventheirsimilarpharmacodynamicproperties,theseresultsarealsorelevantforotherACE-inhibitorsand

angiotensinIIreceptorblockers.

ACE-inhibitorsandangiotensinIIreceptorblockersshouldthereforenotbeusedconcomitantlyinpatientswith

diabeticnephropathy.

ALTITUDE(AliskirenTrialinType2DiabetesUsingCardiovascularandRenalDiseaseEndpoints)wasastudy

designedtotestthebenefitofaddingaliskirentoastandardtherapyofanACE-inhibitororanangiotensinIIreceptor

blockerinpatientswithtype2diabetesmellitusandchronickidneydisease,cardiovasculardisease,orboth.Thestudy

wasterminatedearlybecauseofanincreasedriskofadverseoutcomes.Cardiovasculardeathandstrokewereboth

numericallymorefrequentinthealiskirengroupthanintheplacebogroupandadverseeventsandseriousadverse

eventsofinterest(hyperkalaemia,hypotensionandrenaldysfunction)weremorefrequentlyreportedinthealiskiren

groupthanintheplacebogroup.

Paediatricpopulation:

NodataareavailablewithArplexaminchildren.

TheEuropeanMedicinesAgencyhaswaivedtheobligationtosubmittheresultsofstudieswithArplexaminall

subsetsofthepaediatricpopulationinhypertension(seesection4.2forinformationonpaediatricuse).

5.2Pharmacokineticproperties

Arplexam:

Theco-administrationofperindopril/indapamideandamlodipinedoesnotchangetheirpharmacokineticpropertiesby

comparisontoseparateadministration.

Perindopril:

Absorptionandbioavailability

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(perindoprilisaprodrugandperindoprilattheactivemetabolite).Theplasmahalf-lifeofperindoprilisequalto1hour.

Asingestionoffooddecreasesconversiontoperindoprilat,hencebioavailability,perindoprilarginineshouldbe

administeredorallyinasingledailydoseinthemorningbeforeameal.

Distribution

Thevolumeofdistributionisapproximately0.2L/kgforunboundperindoprilat.Proteinbindingofperindoprilatto

plasmaproteinsis20%,principallytoangiotensinconvertingenzyme,butisconcentration-dependent.

Biotransformation

Perindoprilisaprodrug.Twentysevenpercentoftheadministeredperindoprildosereachesthebloodstreamasthe

activemetaboliteperindoprilat.Inadditiontoactiveperindoprilat,perindoprilyieldsfivemetabolites,allinactive.The

peakplasmaconcentrationofperindoprilatisachievedwithin3to4hours.

Elimination

Perindoprilatiseliminatedintheurineandtheterminalhalf-lifeoftheunboundfractionisapproximately17hours,

resultinginsteady-statewithin4days.

Linearity/non-linearity

Ithasbeendemonstratedalinearrelationshipbetweenthedoseofperindoprilanditsplasmaexposure.

SpecialPopulations

-Elderly:Eliminationofperindoprilatisdecreasedintheelderly,andalsoinpatientswithheartorrenalfailure.

-Renalimpairment:Dosageadjustmentinrenalinsufficiencyisdesirabledependingonthedegreeofimpairment

(creatinineclearance).

-Incaseofdialysis:clearanceofperindoprilatisequalto70mL/min.

-Inpatientswithcirrhosis:Perindoprilpharmacokineticsismodified,hepaticclearanceoftheparentmoleculeis

reducedbyhalf.However,thequantityofperindoprilatformedisnotreducedandthereforenodosageadjustmentis

required(seesections4.2and4.4).

Indapamide:

Absorption

Indapamideisrapidlyandcompletelyabsorbedfromthedigestivetract.

Thepeakplasmalevelisreachedinhumansapproximatelyonehourafteroraladministrationoftheproduct.

Distribution

Plasmaproteinbindingis79%.

MetabolismandElimination

Theeliminationhalf-lifeisbetween14and24hours(average18hours).Repeatedadministrationdoesnotproduce

accumulation.

Eliminationismainlyintheurine(70%ofthedose)andfaeces(22%)intheformofinactivemetabolites.

Specialpopulations

Thepharmacokineticsisunchangedinpatientswithrenalinsufficiency.

Amlodipine:

AbsorptionandBioavailability

Afteroraladministrationoftherapeuticdoses,amlodipineiswellabsorbedwithpeakbloodlevelsbetween6-12hours

postdose.Absolutebioavailabilityhasbeenestimatedtobebetween64and80%.

Thebioavailabilityofamlodipineisnotaffectedbyfoodintake.

Distribution

Thevolumeofdistributionisapproximately21L/kg.Invitrostudieshaveshownthatapproximately97.5%of

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Metabolism

Amlodipineisextensivelymetabolisedbythelivertoinactivemetaboliteswith10%oftheparentcompoundand60%

ofmetabolitesexcretedintheurine.

Elimination

Theterminalplasmaeliminationhalf-lifeisabout35-50hoursandisconsistentwithoncedailydosing.

Specialpopulations

-Useintheelderly:thetimetoreachpeakplasmaconcentrationsofamlodipineissimilarinelderlyandyounger

subjects.AmlodipineclearancetendstobedecreasedwithresultingincreasesinAUCandeliminationhalf-lifein

elderlypatients.IncreasesinAUCandeliminationhalf-lifeinpatientswithcongestiveheartfailurewereasexpected

forthepatientagegroupstudied.

-Useinpatientswithimpairedhepaticfunction:Verylimitedclinicaldataareavailableregardingamlodipine

administrationinpatientswithhepaticimpairment.Patientswithhepaticinsufficiencyhavedecreasedclearanceof

amlodipineresultinginalongerhalf-lifeandanincreaseinAUCofapproximately40-60%.

5.3Preclinicalsafetydata

Perindopril:

Inthechronicoraltoxicitystudies(ratsandmonkeys),thetargetorganisthekidney,withreversibledamage.

Nomutagenicityhasbeenobservedininvitroorinvivostudies.

Reproductiontoxicologystudies(rats,mice,rabbitsandmonkeys)showednosignofembryotoxicityorteratogenicity.

However,angiotensinconvertingenzymeinhibitors,asaclass,havebeenshowntoinduceadverseeffectsonlatefetal

development,resultinginfetaldeathandcongenitaleffectsinrodentsandrabbits:renallesionsandanincreaseinperi-

andpostnatalmortalityhavebeenobserved.Fertilitywasnotimpairedeitherinmaleorinfemalerats.

Nocarcinogenicityhasbeenobservedinlongtermstudiesinratsandmice.

Indapamide:

Thehighestdosesadministeredorallytodifferentanimalspecies(40to8000timesthetherapeuticdose)haveshown

anexacerbationofthediureticpropertiesofindapamide.Themajorsymptomsofpoisoningduringacutetoxicity

studieswithindapamideadministeredintravenouslyorintraperitoneallywererelatedtothepharmacologicalactionof

indapamide,i.e.bradypnoeaandperipheralvasodilation.

Indapamidehasbeentestednegativeconcerningmutagenicandcarcinogenicproperties.

Reproductivetoxicitystudieshavenotshownanyembryotoxicorteratogeniceffectinrat,miceandrabbit.

Fertilitywasnotimpairedeitherinmaleorfemalerats.

Perindopril/indapamide:

Theperindopril/indapamidecombinationhasslightlyincreasedtoxicitythanthatofitscomponents.Renal

manifestationsdonotseemtobepotentiatedintherat.However,thecombinationproducesgastro-intestinaltoxicityin

thedogandthetoxiceffectsonthemotherseemtobeincreasedintherat(comparedtoperindopril).

Nonetheless,theseadverseeffectsappearatdoselevelscorrespondingtoaverymarkedsafetymarginbycomparison

tothetherapeuticdosesused.

Preclinicalstudiesperformedseparatelywithperindoprilandindapamidedidnotshowgenotoxic,carcinogenicor

teratogenicpotential.

Amlodipine:

Reproductivestudiesinratsandmicehaveshowndelayeddateofdelivery,prolongeddurationoflabouranddecreased

pupsurvivalatdosagesapproximately50timesgreaterthanthemaximumrecommendeddosageforhumansbasedon

mg/kg.

Therewasnoeffectonthefertilityofratstreatedwithamlodipine(malesfor64daysandfemales14dayspriorto

mating)atdosesupto10mg/kg/day(8times*themaximumrecommendedhumandoseof10mgonamg/m2basis).

Inanotherratstudyinwhichmaleratsweretreatedwithamlodipinebesilatefor30daysatadosecomparablewiththe

humandosebasedonmg/kg,decreasedplasmafollicle-stimulatinghormoneandtestosteronewerefoundaswellas

decreasesinspermdensityandinthenumberofmaturespermatidsandSertolicells.

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levelsof0.5,1.25,and2.5mg/kg/dayshowednoevidenceofcarcinogenicity.Thehighestdose(formice,similarto,

andforratstwice*themaximumrecommendedclinicaldoseof10mgonamg/m2basis)wasclosetothemaximum

tolerateddoseformicebutnotforrats.

Mutagenicitystudiesrevealednodrugrelatedeffectsateitherthegeneorchromosomelevels.

*Basedonpatientweightof50kg

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Core:

Calciumcarbonatestarchcompound:Calciumcarbonate90%,Pregelatinisedmaizestarch10%

Cellulosemicrocrystalline(E460),

Croscarmellosesodium(E468),

Magnesiumstearate(E572),

Colloidalanhydroussilica,

Pregelatinisedstarch

Film-coating:

Glycerol(E422),

Hypromellose6mPa.s(E464),

Macrogol6000,

Magnesiumstearate(E572),

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable

6.3Shelflife

2years

Forthecontainerof30film-coatedtablet,thein-usestabilityafterfirstopeningis30days.

Forthecontainerof100film-coatedtablet,thein-usestabilityafterfirstopeningis100days.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions

6.5Natureandcontentsofcontainer

10or30film-coatedtabletsinpolypropylenetabletcontainerequippedwithalowdensitypolyethyleneflowreducer

andalowdensitypolyethylenestoppercontainingadesiccant.

100film-coatedtabletsinahighdensitypolyethylenetabletcontainerequippedwithapolypropylenestopper

containingadesiccant.

Boxof10,30,60(2tabletcontainersof30),90(3tabletcontainersof30),100,500tablets(5tabletcontainersof100).

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

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7MARKETINGAUTHORISATIONHOLDER

LesLaboratoiresServier

50RueCarnot

92284SuresnesCedex

France

8MARKETINGAUTHORISATIONNUMBER

PA0568/025/004

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:28thMarch2014

10DATEOFREVISIONOFTHETEXT

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