CANDESARTAN/HYDROCHLOROTHIAZIDE MYLAN 16/12.5 Milligram Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
CANDESARTAN CILEXETIL, HYDROCHLOROTHIAZIDE
Available from:
McDermott Laboratories Ltd t/a Gerard Laboratories
ATC code:
C09DA06
INN (International Name):
CANDESARTAN CILEXETIL, HYDROCHLOROTHIAZIDE
Dosage:
16/12.5 Milligram
Pharmaceutical form:
Tablets
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Angiotensin II antagonists and diuretics
Authorization status:
Authorised
Authorization number:
PA0577/121/001
Authorization date:
2012-01-27

Packageleaflet:Informationforthe patient

Candesartan/Hydrochlorothiazide Mylan 16mg/12.5mg Tablets

(candesartan cilexetil/hydrochlorothiazide)

Read allofthis leafletcarefully before youstarttaking thismedicinebecauseitcontainsimportant

informationforyou.

Keep thisleaflet. You mayneedto readitagain.

Ifyou have anyfurtherquestions,askyourdoctororpharmacist.

This medicine hasbeen prescribedforyouonly. Do notpass itonto others. Itmay harmthem, even if

theirsigns ofillnessarethesame as yours.

Ifyou getanyside effects, talkto yourdoctororpharmacist.Thisincludesanypossiblesideeffects not

listedinthis leaflet.See section4.

Whatisinthisleaflet

1.WhatCandesartan/HydrochlorothiazideMylanis andwhatitis used for

2.Whatyou needto knowbefore you take Candesartan/HydrochlorothiazideMylan

3.Howto take Candesartan/HydrochlorothiazideMylan

4.Possibleside effects

5.Howto store Candesartan/HydrochlorothiazideMylan

6.Contentsofthe packand otherinformation.

1. What Candesartan/HydrochlorothiazideMylanisandwhatitisusedfor

Thename ofyourmedicineis Candesartan/HydrochlorothiazideMylan. Itis usedfortreatinghigh blood

pressure (hypertension). Itcontainstwo active ingredients:candesartancilexetiland hydrochlorothiazide.

Theseworktogethertoloweryourblood pressure.

Candesartan cilexetilbelongs to a group ofmedicinesknown asangiotensin IIreceptorantagonists.It

makesyourblood vesselsrelaxand widen.Thishelpsto loweryourbloodpressure.

Hydrochlorothiazidebelongs to a group ofmedicinesknown asdiuretics (watertablets).Ithelps your

bodyto getrid ofwaterandsaltslike sodiumin yoururine.Thishelpstoloweryourblood pressure.

YourdoctormayprescribeCandesartan/HydrochlorothiazideMylanifyourbloodpressure hasnotbeen

properlycontrolled bycandesartancilexetilorhydrochlorothiazidealone.

2. What youneedto knowbefore youtake Candesartan/HydrochlorothiazideMylan

Do not take Candesartan/HydrochlorothiazideMylanif:

youare allergicto candesartan,hydrochlorothiazide oranyoftheotheringredientsofthis medicine

(listed insection 6)

youare allergictosulfonamidemedicines(such asco-trimoxazole). Ifyou are notsure ifthis applies

to you, pleaseaskyourdoctor

youare more than 3 months pregnant. (Itisalso betterto avoidCandesartan/Hydrochlorothiazide

Mylaninearlypregnancy–see pregnancysection)

you have severe kidneyproblems

youhave severe liverdiseaseorbiliaryobstruction (aproblemwith the drainage ofthe bilefromthe

gallbladder)

youhave persistentlylowlevels ofpotassiumin yourblooddespite treatmenttoincreasethis

youhave persistentlyhigh levels ofcalciumin yourblooddespitetreatmenttodecreasethis

you have everhad gout

you have diabetesorimpaired kidneyfunction and youaretreated with ablood pressurelowering

medicine containingaliskiren

Ifyou are notsureifanyofthese applyto you, talktoyourdoctororpharmacistbefore taking

Candesartan/HydrochlorothiazideMylan.

Warnings and precautions

Talkto yourdoctororpharmacistbeforetakingCandesartan/HydrochlorothiazideMylanif:

youhave diabetesorareatriskofdevelopingdiabetes

you have heartproblems such as heartfailure (a weakeningofthe heartmuscle)

you have anarrowingofthe valvesofthe heart, orathickeningofthe heartmuscle, whichcanall

affecttheflowofblood fromthe heart

youhaveotherliverorkidneyproblems

youhave recentlyhada kidneytransplant

you have anarrowingofthe kidneyartery

youhave lowlevelsofsodiumin the blood, are verydehydrated orarevomiting, have recentlyhad

severevomiting, orhavediarrhoea

youare beingtreated withhigh dosesofwatertablets(diuretics)orare passinglarge volumesofurine

youhave adiseaseofthe adrenalglandcalled Conn’ssyndrome (alsocalled primary

hyperaldosteronism)

youhave everhad adiseasecalledsystemic lupus erythematosus(SLE)

youhave lowbloodpressure

youhave everhad astroke, heartattackorhave angina(orreduced bloodflowtothe brain)

youhaveeverhadallergyorasthma

youmusttellyourdoctorifyouthinkyou are(ormightbecome)pregnant.

Candesartan/HydrochlorothiazideMylanis notrecommended in earlypregnancy, and mustnotbe

taken ifyou are morethan3 months pregnant, asitmaycauseserious harmto yourbabyifusedatthat

stage (seepregnancysection)

youare takinganyofthefollowingmedicinesusedtotreathigh blood pressure:

-an ACE-inhibitor(forexample enalapril,lisinopril, ramipril), in particularifyou have diabetes-

related kidneyproblems

-aliskiren

Yourdoctormaycheckyourkidneyfunction, blood pressure, and the amountofelectrolytes(e.g. potassium)

in yourblood atregularintervals.

See alsoinformationunderthe heading“Do nottakeCandesartan/HydrochlorothiazideMylan”

During treatment

This medicinecan affectthe resultofcertain bloodtests.Ifyouneed anybloodtests,tellthe doctoror

hospitalstaffthatyou aretakingthis medicine.

Ifyouare goingto have anoperation, tellyourdoctorordentistthatyou are taking

Candesartan/HydrochlorothiazideMylan.Thisis becauseCandesartan/HydrochlorothiazideMylanwhen

combined with someanaesthetics, maycausean excessivedropin blood pressure.

Ifyou need tohave surgicalimagery(to see parts ofyourbody)thentellthe doctororhospitalstaffthatyou

aretakingthis medicine.The useofiodinein the imagingmaterialcanincreasethe riskofside effects

occurring.

Candesartan/HydrochlorothiazideMylanmaycauseincreased sensitivityofthe skin to sun.Ifthisoccurs,do

notuse sunlamps, tanningboothsand usesunscreen orcoverup with clotheswhenin the sun.

Children andadolescents

Thereis no experience withthe useofCandesartan/HydrochlorothiazideMylaninchildren (belowtheage of

18 years).ThereforeCandesartan/HydrochlorothiazideMylanshouldnotbe given to children.

OthermedicinesandCandesartan/HydrochlorothiazideMylan

Tellyourdoctororpharmacistifyou are taking,haverecentlytakenormighttakeanyothermedicines,

includingmedicinesobtained withouta prescription.

Candesartan/HydrochlorothiazideMylancan affectthewaysome othermedicinesworkand some medicines

can have aneffecton Candesartan/HydrochlorothiazideMylan. Ifyou are usingcertain medicines, your

doctormayneed to doblood testsfromtime totime.Yourdoctormayneed to change yourdoseand/orto

take otherprecautions.

In particular, tellyourdoctorifyou areusinganyofthe followingmedicines:

othermedicinesto helploweryourblood pressure, includingbeta-blockers, diazoxide,ACE inhibitors

such as enalapril,captopril,lisinoprilorramipril,oraliskiren(seealso informationundertheheadings

“Do nottakeCandesartan/HydrochlorothiazideMylan” and “Warnings and precautions”)

non-steroidalanti-inflammatorypainkillers (NSAIDs)such as ibuprofen,naproxen, diclofenac,

celecoxib oretoricoxib (medicinestorelieve pain and inflammation)

acetylsalicylic acid(aspirin)(ifyou are takingmore than 3 geach day)(medicineto relieve pain and

inflammation)

potassiumsupplements orsaltsubstitutescontainingpotassiumorothermedicines thatincrease the

amountofpotassiumin yourbloodsuch as heparin (amedicineforthinningtheblood)

medicinesthatmayaffectthe amountofpotassiumin yourblood(medicinessuchaswatertablets

(diuretics),laxatives, penicillin (an antibiotic),amphotericin(forthe treatmentoffungalinfections),

carbenoxolone(fortreatmentofgulletproblems, ororalulcers), steroidssuch asprednisolone,

pituitaryhormone (ACTH)

calciumorvitamin Dsupplements

medicinestolowercholesterol,suchascolestipolorcolestyramine

medicinesfordiabetes(tabletssuchasmetformin,orinsulin)

medicinestocontrolyourheartbeat(antiarrhythmic agents)such asquinidine,disopyramide,

amiodarone,sotalol,ibutilide,digoxin

othermedicineswhich canaffecttheheartrhythmsuch ascisapride(forstomach problems),

erythromycin, sparfloxacine, pentamidine(antibiotics), halofantrin(formalaria treatment),terfenadine

(antihistamine)

some antipsychoticmedicinesthatcan be affected bypotassiumbloodlevels suchasthioridazine,

chlorpromazine, trifluperazine, haloperidol, amisulpride

lithium(a medicineformentalhealth problems)

medicinestotreatcancer(such as methotrexate (whichcan alsobe used forotherconditions e.g.

psoriasis,arthritis)andcyclophosphamide)

amantadine, (forthetreatmentofParkinson’s diseaseorforseriousinfections caused byviruses)

barbiturates(asedative alsousedto treatepilepsy)

anticholinergicagents suchasatropineand biperiden

ciclosporin, a medicine used fororgan transplantto avoid organ rejection

othermedicinesthatmaylead toenhancementofthe antihypertensive effectsuchasbaclofen(a

medicineforthereliefofspasticity), amifostin (usedincancertreatment)and someanti-depressant

medicines(such as amitriptyline, clomipramine, dosulepin)

adrenaline,ornoradrenaline, sometimesusedto helpincrease bloodpressure or, sometimes, for

treatmentofsevere allergicreactions

Candesartan/HydrochlorothiazideMylanwithalcohol

When you are prescribedCandesartan/Hydrochlorothiazide Mylan, discuss withyourdoctorbefore drinking

alcohol. Alcoholmaymake you feelfaintordizzy.

Pregnancyandbreast-feeding

Ifyou are pregnantorbreast-feeding, thinkyoumaybepregnantorare planningtohave ababy, askyour

doctororpharmacistforadvicebeforetakingthis medicine.

Pregnancy

You musttellyourdoctorifyou thinkyou are (ormightbecome)pregnant. Yourdoctorwillnormallyadvise

you to stop takingCandesartan/HydrochlorothiazideMylanbefore you become pregnantoras soon asyou

knowyou are pregnantandwilladviseyou to take anothermedicineinsteadof

Candesartan/HydrochlorothiazideMylan. Candesartan/HydrochlorothiazideMylanis notrecommended

duringpregnancy, and mustnotbetaken when more than 3 months pregnant,asitmaycauseserious harmto

yourbabyifused afterthethird month ofpregnancy.

Breast-feeding

Tellyourdoctorifyou arebreast-feedingoraboutto startbreast-feeding.Candesartan/Hydrochlorothiazide

Mylanis notrecommended formothers whoarebreast-feeding, and yourdoctormaychoose another

treatmentforyou ifyou wish tobreast-feed,especiallyifyourbabyis newborn,orwasborn prematurely.

Driving andusingmachines

Some people mayfeeltiredordizzywhen takingCandesartan/HydrochlorothiazideMylan. Ifthis happens

to you, do notdrive oruseanytoolsormachines.

Candesartan/HydrochlorothiazideMylancontainslactose

Ifyou have been told byyourdoctorthatyou have anintoleranceto some sugars,such as lactose,contact

yourdoctorbefore takingthis medicine.

3. HowtotakeCandesartan/HydrochlorothiazideMylan

Always takethis medicineexactlyasyourdoctororpharmacisthas told you.Checkwith yourdoctoror

pharmacistifyou are notsure.

Itis importantto keeptakingCandesartan/HydrochlorothiazideMylaneveryday.Therecommendeddoseof

Candesartan/HydrochlorothiazideMylanis one tabletoncedaily.

Swallowthetabletwith a drinkofwater.You maytakeCandesartan/Hydrochlorothiazide Mylan with or

withoutfood.

Trytotake thetabletatthesame time each day, usuallyin the morning.This willhelp you to rememberto

take it.

Ifyoutakemore Candesartan/HydrochlorothiazideMylanthanyou should

Ifyou take moreCandesartan/HydrochlorothiazideMylanthan prescribed byyourdoctor, contacta doctoror

pharmacistimmediatelyforadvice.You mayexperiencealarge dropin blood pressure, which maycause

you to feeldizzy, oryoumaynotice anincreased heartrate orirregularheartbeat,muscle cramps orinsome

cases feelverysleepyorexperience areducedlevelofconsciousness.

Ifyouforgetto take Candesartan/HydrochlorothiazideMylan

Do nottake adouble doseto make up fora forgotten dose.Justtake the nextdoseasnormal.

Ifyoustoptaking Candesartan/HydrochlorothiazideMylan

Ifyou stop takingCandesartan/HydrochlorothiazideMylan, yourblood pressuremayincreaseagain.

Thereforedo notstoptakingthis medicine withoutfirsttalkingto yourdoctor.

Ifyou have anyfurtherquestions onthe useofthis medicine, askyourdoctororpharmacist.

4. Possiblesideeffects

Like allmedicines,this medicinecan causeside effects, although noteverybodygetsthem.Itis important

thatyou areaware ofwhattheseside effects maybe. Some ofthe sideeffects of

Candesartan/HydrochlorothiazideMylanare caused bycandesartancilexetiland some are caused by

hydrochlorothiazide.

Stop taking Candesartan/HydrochlorothiazideMylanandseekmedicalhelpimmediatelyifyou have

any ofthefollowingside effects:

Rare(may affectupto 1in 1,000 people)

difficultybreathing, swellingoftheface, lips,tongue and/orthroat,which maycausedifficulties in

swallowing, severeitchyswollenskin (withraised lumps)

liverproblems, includinginflammation oftheliver(hepatitis).You maynoticetiredness,yellowingof

yourskinandthe whites ofyoureyes, darkurine, palestools orstomach pain

breathingdifficulties (includinglunginflammation andfluidin the lungs)

inflammation ofthe pancreas.This causes moderate tosevere paininthe stomach

a severerash, thatdevelopsquickly, withblisteringorpeelingofthe skinand possiblyblisteringinthe

mouth

occurrenceorworseningofexistinglupuserythematous-like reactions(whichincludesappearanceof

unusualskinreactions,facialrash,jointpain, muscle disorderandfever)

a reductioninyourred orwhite blood cells orplatelets.You maynotice tiredness,more frequent

infections(e.g. sorethroat,mouth ulcers),fever,oreasybruisingorbleeding. Thismaybe dueto

reduced production ofblood cellsinthe bone marrow(bone marrowdepression)

Very rare (mayaffectupto 1 in 10,000people)

kidneyfailure,especiallyifyou alreadyhave kidneyproblems orheartfailure. You maynotice pain in

the back, passlittleornourine orhave cloudyurine orbloodinthe urine.

Notknown (frequency cannotbe estimatedfromthe available data)

suddeneye painorblurredorlossofvision (acute angle-closure glaucoma)

Other possiblesideeffectsinclude:

Common(mayaffectupto1in10people):

changesin blood testresults:

a reducedamountofsodiumin yourblood. Ifthis issevere then you maynoticeweakness, lackof

energy, ormuscle cramps

an increasedorreducedamountofpotassiumin yourblood, especiallyifyou alreadyhave kidney

problems orheartfailure. Ifthis is severe you maynoticetiredness, weakness, irregularheartbeator

pinsand needles

an increasedamountofcholesterolorfats, sugar,oruric acid inyourblood

sugarin yoururine

feelingdizzy/spinningsensation orweak

headache

lunginfection(which mayinclude signssuchascommon cold, flulike symptoms)

Uncommon(mayaffectup to1in 100people):

lowblood pressure.This maymakeyou feelfaintordizzyespeciallywhen gettingup froma sittingor

lyingposition

lossorlackofappetite,diarrhoea, constipation,stomach irritation

skin rash, rash caused bysensitivitytosunlight.

Rare(mayaffectupto1in 1,000people):

reduced functioningofkidneys, which maybe seeninbloodtests

difficultyin sleeping, depression, beingrestless

tinglingorpricklingin yourarms orlegs

blurred visionfora shortperiod

abnormalheartbeat

high temperature(fever)

muscle cramps

damage to blood vesselscausingredorpurple dotsinthe skin

increase in blood ureanitrogen orcertain proteins (creatinine)in yourblood which maybe seenin blood

tests

Very rare(mayaffectupto1 in 10,000people):

itching

backpain,pain injoints and muscles

changesin howyourliveris working,which maybe seen in blood tests

cough

nausea(feelingsick)

Notknown (frequency cannotbeestimatedfromthe available data)

shortsightedness(inabilityofthe eye tofocus ondistantobjects)

Reporting ofside effects

Ifyou getanyside effects, talkto yourdoctororpharmacist.Thisincludes anypossible sideeffects notlisted

in thisleaflet.You can alsoreportside effectsdirectlyviaHPRAPharmacovigilance, EarlsfortTerrace, IRL

-Dublin 2;Tel:+353 1 6764971;Fax:+353 16762517;website:http://www.hpra.ie;e-mail:

medsafety@hpra.ie.

Byreportingsideeffects you can helpprovide moreinformation onthe safetyofthis medicine.

5.HowtostoreCandesartan/HydrochlorothiazideMylan

Keepthis medicineoutofthesightandreachofchildren.

Do notusethis medicineaftertheexpirydate, which isstated on the carton, blisterorbottle afterEXP.The

expirydaterefers tothe lastdayofthatmonth.

Do notstore above 25°C.

Storeintheoriginalpackage in orderto protectfromlightand moisture.

Thein-useshelflifeoftheproductwhenstored in HDPEbottles is 90 days.Donoteatorremove the

desiccantcontained inthe bottle.

Do notthrowawayanymedicinesvia wastewaterorhousehold waste. Askyourpharmacisthowtothrow

awaymedicinesyounolongeruse.Thesemeasureswillhelpprotectthe environment.

6. Contentsofthe pack andotherinformation

What Candesartan/HydrochlorothiazideMylantablets contain

Theactive substances are candesartan cilexetiland hydrochlorothiazide.

Each tabletcontains 16mgofcandesartan cilexetiland12.5 mgofhydrochlorothiazide.

Theotheringredients arecarmellosecalcium, glycerolmonostearate,hydroxypropylcellulose,lactose

monohydrate, magnesiumstearate, maize starch,iron oxide yellow(E172)andiron oxide red (E172).

What Candesartan/HydrochlorothiazideMylanlooks likeandcontentsofthe pack

Candesartan/Hydrchlorothiazide Mylan16 mg/12.5 mgtablets are peach, mottled, round,biconvex tablets

marked with “M”on one side and“CH2” onthe otherside.

Candesartan/HydrochlorothiazideMylanis availableinblistersof7,10, 14,15, 28, 30, 50, 56, 60, 84, 90,

98, 100tablets andin plastic bottlesof30, 90 tablets.

Notallpacksizesmaybe marketed.

Anyunused productorwaste shouldbe disposed ofinaccordancewithlocalrequirements.

MarketingAuthorisationHolderandManufacturer:

MarketingAuthorisationHolder:

McDermottLaboratoriesLtd t/a Gerard Laboratories, 35/36 Baldoyle IndustrialEstate, Grange Road, Dublin

13, Ireland

Manufacturer:

McDermottLaboratoriesLtd t/a Gerard Laboratories, 35/36 Baldoyle IndustrialEstate, Grange Road, Dublin

13, Ireland

Generics[UK]Ltd., StationClose, Potters Bar, Hertfordshire EN6 1TL, UnitedKingdom

Mylan HungaryLtd. H-2900 Komárom, Mylan utca 1,Hungary

Thismedicinalproductisauthorisedinthe MemberStatesoftheEEAunderthefollowing

names:

Austria Candesartan/HCTArcana 8mg/12.5 mg,16mg/12.5mgTabletten

Belgium Co-CandesartanMylan 16mg/12,5 mgtabletten

Bulgaria CoCandesargen 8 mg/12.5 mg,16mg/12.5 mgtablets

Denmark Kandrozid Comp 8 mg/12.5 mg,16mg/12.5mgtablets

France Candesartan HydrochlorothiazideMylan8 mg/12,5 mg,16 mg/12,5 mgcomprimé

Germany CandesartancilexetilHCTMylan8 mg/12,5 mg,16mg/12,5 mgTabletten

Greece Candesartan + HCTZ/Mylan8 mg/12.5 mg,16 mg/12.5 mgtablets

Ireland Candesartan/HydrochlorothiazideMylan16 mg/12.5 mgTablets

Luxembourg Co-CandesartanMylan 16mg/12,5 mgcomprimés

Netherlands Candesartan cilexetil/Hydrochlorothiazide Mylan8 mg/12,5 mg,16mg/12,5 mg

tabletten

Portugal Candesartan + Hidroclorotiazida Mylan

Romania Candesartan/HidroclorotiazidaMylan8 mg/12,5mg,16 mg/12,5mgcomprimate

Slovakia CandemylCombi16 mg/12.5 mg

Spain Candesartan/HidroclorotiazidaMylan16 mg/12.5 mgcomprimidos EFG

Thisleafletwaslastrevisedin:April2016

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Candesartan/HydrochlorothiazideMylan16mg/12.5mgtablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachCandesartan/HydrochlorothiazideMylan16mg/12.5mgtabletcontains16mgcandesartancilexetiland12.5mg

hydrochlorothiazide.

Excipientwithknowneffect

Eachtabletcontains102.9mglactosemonohydrate.

Forthefulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Tablet.

Candesartan/HydrochlorothiazideMylan16mg/12.5mgtabletsarepeachcolour,mottled,round,biconvextablet

debossedwith“M”ononesideand“CH2”ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Candesartan/HydrochlorothiazideMylanisindicatedfor:

Treatmentofessentialhypertensioninadultpatientswhosebloodpressureisnotoptimallycontrolledwithcandesartan

cilexetilorhydrochlorothiazidemonotherapy.

4.2Posologyandmethodofadministration

Posology

TherecommendeddoseofCandesartan/HydrochlorothiazideMylan16mg/12.5mgtabletis1tabletoncedaily.

Dosetitrationwiththeindividualcomponents(candesartancilexetilandhydrochlorothiazide)isrecommended.When

clinicallyappropriateadirectchangefrommonotherapytocandesartancilexetil/hydrochlorothiazidemaybe

considered.Dosetitrationofcandesartancilexetilisrecommendedwhenswitchingfromhydrochlorothiazide

monotherapy.Candesartancilexetil/hydrochlorothiazidemaybeadministeredinpatientswhosebloodpressureisnot

optimallycontrolledwithcandesartancilexetilorhydrochlorothiazidemonotherapyorcandesartan

cilexetil/hydrochlorothiazideatlowerdoses.

Mostoftheantihypertensiveeffectisusuallyattainedwithin4weeksofinitiationoftreatment.

Specialpopulations

Elderlypopulation

Nodoseadjustmentisnecessaryinelderlypatients.

Patientswithintravascularvolumedepletion

Dosetitrationofcandesartancilexetilisrecommendedinpatientsatriskforhypotension,suchaspatientswithpossible

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Renalimpairment

Inpatientswithmildtomoderaterenalimpairment(creatinineclearance30-80ml/min/1.73m2BSA)adosetitrationis

recommended.

Candesartancilexetil/hydrochlorothiazideiscontraindicatedinpatientswithsevererenalimpairment(creatinine

clearance<30ml/min/1.73m 2

BSA)(seesection4.3).

Hepaticimpairment

Dosetitrationofcandesartancilexetilisrecommendedinpatientswithmildtomoderatechronicliverdisease.

Candesartancilexetil/hydrochlorothiazideiscontraindicatedinpatientswithseverehepaticimpairmentand/or

cholestasis(seesection4.3).

Paediatricpopulation

Thesafetyandefficacyofcandesartancilexetil/hydrochlorothiazideinchildrenagedbetweenbirthand18yearshave

notbeenestablished.Nodataareavailable.

Methodofadministration

Oraluse.

Candesartan/HydrochlorothiazideMylancanbetakenwithorwithoutfood.

Thebioavailabilityofcandesartanisnotaffectedbyfood.

Thereisnoclinicallysignificantinteractionbetweenhydrochlorothiazideandfood.

4.3Contraindications

Hypersensitivitytotheactivesubstances,toanyoftheexcipientslistedinsection6.1ortosulfonamidederived

activesubstances.Hydrochlorothiazideisasulfonamide-derivedactivesubstance.

Secondandthirdtrimestersofpregnancy(seesections4.4and4.6).

Severerenalimpairment(creatinineclearance<30ml/min/1.73m 2

BSA).

Severehepaticimpairmentand/orcholestasis.

Refractoryhypokalaemiaandhypercalcaemia.

Gout.

TheconcomitantuseofCandesartanCilexetil/Hydrochlorothiazidewithaliskiren-containingproductsis

contraindicatedinpatientswithdiabetesmellitusorrenalimpairment(GFR<60ml/min/1.73m 2

)(seesections

4.5and5.1).

4.4Specialwarningsandprecautionsforuse

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.

Renalimpairment

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insusceptiblepatientstreatedwithcandesartancilexetil/hydrochlorothiazide(seesection4.3).

Kidneytransplantation

Thereisnoexperienceregardingtheadministrationofcandesartancilexetil/hydrochlorothiazideinpatientswitha

recentkidneytransplantation.

Renalarterystenosis

Medicinalproductsthataffecttherenin-angiotensin-aldosteronesystem,includingangiotensinIIreceptorantagonists

(AIIRAs),mayincreasebloodureaandserumcreatinineinpatientswithbilateralrenalarterystenosisorstenosisofthe

arterytoasolitarykidney.

Intravascularvolumedepletion

Inpatientswithintravascularvolumeand/orsodiumdepletionsymptomatichypotensionmayoccur,asdescribedfor

otheragentsactingontherenin-angiotensin-aldosteronesystem.Therefore,theuseofcandesartan

cilexetil/hydrochlorothiazideisnotrecommendeduntilthisconditionhasbeencorrected.

Anaesthesiaandsurgery

HypotensionmayoccurduringanaesthesiaandsurgeryinpatientstreatedwithangiotensinIIreceptorantagonistsdue

toblockadeoftherenin-angiotensinsystem.Veryrarely,hypotensionmaybeseveresuchthatitmaywarranttheuseof

intravenousfluidsand/orvasopressors.

Hepaticimpairment

Thiazidesshouldbeusedwithcautioninpatientswithimpairedhepaticfunctionorprogressiveliverdisease,since

minoralterationsoffluidandelectrolytebalancemayprecipitatehepaticcoma.Thereisnoclinicalexperiencewith

candesartancilexetil/hydrochlorothiazideinpatientswithhepaticimpairment.

Aorticandmitralvalvestenosis(obstructivehypertrophiccardiomyopathy)

Aswithothervasodilators,specialcautionisindicatedinpatientssufferingfromhaemodynamicallyrelevantaorticor

mitralvalvestenosis,orobstructivehypertrophiccardiomyopathy.

Primaryhyperaldosteronism

Patientswithprimaryhyperaldosteronismgenerallywillnotrespondtoantihypertensiveagentsactingthrough

inhibitionoftherenin-angiotensin-aldosteronesystem.Thereforetheuseofcandesartancilexetil/hydrochlorothiazideis

notrecommendedinthispopulation.

Electrolyteimbalance

Periodicdeterminationofserumelectrolytesshouldbeperformedatappropriateintervals.

Thiazides,includinghydrochlorothiazide,cancausefluidorelectrolyteimbalance

(hypercalcaemia,hypokalaemia,hyponatraemia,hypomagnesaemiaandhypochloraemicalkalosis).

Thiazidediureticsmaydecreasetheurinarycalciumexcretionandmaycauseintermittentandslightlyincreasedserum

calciumconcentrations.

Markedhypercalcaemiamaybeasignofhiddenhyperparathyroidism.Thiazidesshouldbediscontinuedbefore

carryingouttestsforparathyroidfunction.

Hydrochlorothiazidedose-dependentlyincreasesurinarypotassiumexcretionwhichmayresultinhypokalaemia.This

effectofhydrochlorothiazideseemstobelessevidentwhencombinedwithcandesartancilexetil.Theriskfor

hypokalaemiamaybeincreasedinpatientswithcirrhosisoftheliver,inpatientsexperiencingbriskdiuresis,inpatients

withaninadequateoralintakeofelectrolytesandinpatientsreceivingconcomitanttherapywithcorticosteroidsor

adrenocorticotropichormone(ACTH).

Treatmentwithcandesartancilexetilmaycausehyperkalaemia,especiallyinthepresenceofheartfailureand/orrenal

impairment.Concomitantuseofcandesartancilexetil/hydrochlorothiazideandACEinhibitors,aliskiren,potassium-

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potassiumlevels(e.g.heparinsodium)mayleadtoincreasesinserumpotassium.Monitoringofpotassiumshouldbe

undertakenasappropriate.

Thiazideshavebeenshowntoincreasetheurinaryexcretionofmagnesium,whichmayresultinhypomagnesaemia.

Metabolicandendocrineeffects

Treatmentwithathiazidediureticmayimpairglucosetolerance.Doseadjustmentofantidiabeticmedicinalproducts,

includinginsulin,mayberequired.Latentdiabetesmellitusmaybecomemanifestduringthiazidetherapy.Increasesin

cholesterolandtriglyceridelevelshavebeenassociatedwiththiazidediuretictherapy.Atthedosescontainedin

candesartancilexetil/hydrochlorothiazideonlyminimaleffectswereobserved.Thiazidediureticsincreaseserumuric

acidconcentrationandmayprecipitategoutinsusceptiblepatients.

Photosensitivity

Casesofphotosensitivityreactionshavebeenreportedduringuseofthiazidediuretics(seesection4.8).Ifa

photosensitivityreactionoccurs,itisrecommendedtostoptreatment.Ifre-administrationoftreatmentisessentialitis

recommendedtoprotectareasexposedtothesunortoartificialUVAradiation.

General

Inpatientswhosevasculartoneandrenalfunctiondependpredominantlyontheactivityoftherenin-angiotensin-

aldosteronesystem(e.g.patientswithseverecongestiveheartfailureorunderlyingrenaldisease,includingrenalartery

stenosis),treatmentwithothermedicinalproductsthataffectthissystemincludingAIIRA’shasbeenassociatedwith

acutehypotension,azotaemia,oliguriaor,rarely,acuterenalfailure.Aswithanyantihypertensiveagent,excessive

bloodpressuredecreaseinpatientswithischaemicheartdiseaseoratheroscleroticcerebrovasculardiseasecouldresult

inamyocardialinfarctionorstroke.

Hypersensitivityreactionstohydrochlorothiazidemayoccurinpatientswithorwithoutahistoryofallergyorbronchial

asthma,butaremorelikelyinpatientswithsuchahistory.

Exacerbationoractivationofsystemiclupuserythematosushasbeenreportedwiththeuseofthiazidediuretics.

Theantihypertensiveeffectofcandesartancilexetil/hydrochlorothiazidemaybeenhancedbyotherantihypertensives.

Pregnancy

AIIRAsshouldnotbeinitiatedduringpregnancy.UnlesscontinuedAIIRAtherapyisconsideredessential,patients

planningpregnancyshouldbechangedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafety

profileforuseinpregnancy.Whenpregnancyisdiagnosed,treatmentwithAIIRAsshouldbestoppedimmediately,

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

Thismedicinalproductcontainslactose,asanexcipient,andpatientswithrarehereditaryproblemsofgalactose

intolerance,theLapplactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Compoundswhichhavebeeninvestigatedinclinicalpharmacokineticstudiesincludewarfarin,digoxin,oral

contraceptives(i.e.ethinylestradiol/levonorgestrel),glibenclamideandnifedipine.Nopharmacokineticinteractionsof

clinicalsignificancewereidentifiedinthesestudies.

Thepotassiumdepletingeffectofhydrochlorothiazidecouldbeexpectedtobepotentiatedbyothermedicinalproducts

associatedwithpotassiumlossandhypokalaemia(e.g.otherkaliureticdiuretics,laxatives,amphotericin,

carbenoxolone,penicillinGsodium,salicylicacidderivates,steroids,ACTH).

Concomitantuseofcandesartancilexetil/hydrochlorothiazideandpotassium-sparingdiuretics,potassiumsupplements

orsaltsubstitutes,orothermedicinalproductsthatmayincreaseserumpotassiumlevels(e.g.heparinsodium)maylead

toincreasesinserumpotassium.Monitoringofpotassiumshouldbeundertakenasappropriate(seesection4.4).

Diuretic-inducedhypokalaemiaandhypomagnesaemiapredisposestothepotential

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recommendedwhencandesartancilexetil/hydrochlorothiazideisadministeredwithsuchmedicinalproducts,andwith

thefollowingmedicinalproductsthatcouldinducetorsadesdepointes:

ClassIaantiarrhythmics(e.g.quinidine,hydroquinidine,disopyramide)

ClassIIIantiarrhythmics(e.g.amiodarone,sotalol,dofetilide,ibutilide)

Someantipsychotics(e.g.thioridazine,chlorpromazine,levomepromazine,trifluoperazine,cyamemazine,

sulpiride,sultopride,amisulpride,tiapride,pimozide,haloperidol,droperiodol)

Others(e.g.bepridil,cisapride,diphemanil,erythromyciniv,halofantrin,ketanserin,mizolastin,pentamidine,

sparfloxacine,terfenadine,vincamineiv)

Reversibleincreasesinserumlithiumconcentrationsandtoxicityhavebeenreportedduringconcomitant

administrationoflithiumwithAngiotensinConvertingEnzyme(ACE)inhibitorsorhydrochlorothiazide.Asimilar

effecthasalsobeenreportedwithAIIRAs.Useofcandesartanandhydrochlorothiazidewithlithiumisnot

recommended.Ifthecombinationprovesnecessary,carefulmonitoringofserumlithiumlevelsisrecommended.

WhenAIIRAsareadministeredsimultaneouslywithnon-steroidalanti-inflammatorydrugs(NSAIDs)(i.e.selective

COX-2inhibitors,acetylsalicylicacid(>3g/day)andnon-selectiveNSAIDs),attenuationoftheantihypertensiveeffect

mayoccur.

AswithACEinhibitors,concomitantuseofangiotensinIIreceptorantagonistsandNSAIDsmayleadtoanincreased

riskofworseningofrenalfunction,includingpossibleacuterenalfailure,andanincreaseinserumpotassium,

especiallyinpatientswithpoorpre-existingrenalfunction.Thecombinationshouldbeadministeredwithcaution,

especiallyintheelderly.Patientsshouldbeadequatelyhydratedandconsiderationshouldbegiventomonitoringrenal

functionafterinitiationofconcomitanttherapy,andperiodicallythereafter.

Thediuretic,natriureticandantihypertensiveeffectofhydrochlorothiazideisbluntedbyNSAIDs.

Clinicaltrialdatahasshownthatdualblockadeoftherenin-angiotensin-aldosterone-system(RAAS)throughthe

combineduseofACE-inhibitors,angiotensinIIreceptorblockersoraliskirenisassociatedwithahigherfrequencyof

adverseeventssuchashypotension,hyperkalaemiaanddecreasedrenalfunction(includingacuterenalfailure)

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

Theabsorptionofhydrochlorothiazideisreducedbycolestipolorcholestyramine.

Theeffectofnondepolarisingskeletalmusclerelaxants(e.g.tubocurarine)maybepotentiatedbyhydrochlorothiazide.

Thiazidediureticsmayincreaseserumcalciumlevelsduetodecreasedexcretion.IfcalciumsupplementsorVitaminD

mustbeprescribed,serumcalciumlevelsshouldbemonitoredandthedoseadjustedaccordingly.

Thehyperglycaemiceffectofbeta-blockersanddiazoxidemaybeenhancedbythiazides.

Anticholinergicagents(e.g.atropine,biperiden)mayincreasethebioavailabilityofthiazidetypediureticsby

decreasinggastrointestinalmotilityandstomachemptyingrate.

Thiazidemayincreasetheriskofadverseeffectscausedbyamantadine.

Thiazidesmayreducetherenalexcretionofcytotoxicmedicinalproducts(e.g.cyclophosphamide,methotrexate)and

potentiatetheirmyelosuppressiveeffects.

Posturalhypotensionmaybecomeaggravatedbysimultaneousintakeofalcohol,barbituratesoranaesthetics.

Treatmentwithathiazidediureticmayimpairglucosetolerance.Doseadjustmentofantidiabeticmedicinalproducts,

includinginsulin,mayberequired.Metforminshouldbeusedwithcautionbecauseoftheriskoflacticacidosis

inducedbypossiblefunctionalrenalfailurelinkedtohydrochlorothiazide.

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excludeapressoreffect.

Hydrochlorothiazidemayincreasetheriskofacuterenalinsufficiencyespeciallywithhighdosesofiodinatedcontrast

media.

Concomitanttreatmentwithciclosporinmayincreasetheriskofhyperuricaemiaandgouttypecomplications.

Concomitanttreatmentwithbaclofen,amifostin,tricyclicantidepressantsorneurolepticsmayleadtoenhancementof

theantihypertensiveeffectandmayinducehypotension.

4.6Fertility,pregnancyandlactation

Pregnancy

AngiotensinIIReceptorAntagonists(AIIRAs):

TheuseofAIIRAsisnotrecommendedduringthefirsttrimesterofpregnancy(seesection4.4).TheuseofAIIRAsis

contra-indicatedduringthesecondandthirdtrimestersofpregnancy(seesections4.3and4.4).

EpidemiologicalevidenceregardingtheriskofteratogenicityfollowingexposuretoACEinhibitorsduringthefirst

trimesterofpregnancyhasnotbeenconclusive;howeverasmallincreaseinriskcannotbeexcluded.Whilstthereisno

controlledepidemiologicaldataontheriskwithangiotensinIIreceptorinhibitors(AIIRAs),similarrisksmayexistfor

thisclassofdrugs.UnlesscontinuedAIIRAtherapyisconsideredessential,patientsplanningpregnancyshouldbe

changedtoalternativeanti-hypertensivetreatmentswhichhaveanestablishedsafetyprofileforuseinpregnancy.

Whenpregnancyisdiagnosed,treatmentwithAIIRAsshouldbestoppedimmediatelyand,ifappropriate,alternative

therapyshouldbestarted.

ExposuretoAIIRAtherapyduringthesecondandthirdtrimestersisknowntoinducehumanfetotoxicity(decreased

renalfunction,oligohydramnios,skullossificationretardation)andneonataltoxicity(renalfailure,hypotension,

hyperkalaemia)(seesection5.3).

ShouldexposuretoAIIRAshaveoccurredfromthesecondtrimesterofpregnancy,ultrasoundcheckofrenalfunction

andskullisrecommended.

InfantswhosemothershavetakenAIIRAsshouldbecloselyobservedforhypotension(seesections4.3and4.4).

Hydrochlorothiazide:

Thereislimitedexperiencewithhydrochlorothiazideduringpregnancy,especiallyduringthefirsttrimester.Animal

studiesareinsufficient.

Hydrochlorothiazidecrossestheplacenta.Basedonthepharmacologicalmechanismofactionofhydrochlorothiazide

itsuseduringthesecondandthirdtrimestersmaycompromisefoeto-placentalperfusionandmaycausefoetaland

neonataleffectslikeicterus,disturbanceofelectrolytebalanceandthrombocytopenia.

Hydrochlorothiazideshouldnotbeusedforgestationaloedema,gestationalhypertensionorpreeclampsiaduetothe

riskofdecreasedplasmavolumeandplacentalhypoperfusion,withoutabeneficialeffectonthecourseofthedisease.

Hydrochlorothiazideshouldnotbeusedforessentialhypertensioninpregnantwomenexceptinraresituationswhere

noothertreatmentcouldbeused.

Breast-feeding

AngiotensinIIReceptorAntagonists(AIIRAs):

Becausenoinformationisavailableregardingtheuseofcandesartancilexetil/hydrochlorothiazideduring

breastfeeding,candesartancilexetil/hydrochlorothiazideisnotrecommendedandalternativetreatmentswithbetter

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Hydrochlorothiazide:

Hydrochlorothiazideisexcretedinhumanmilkinsmallamounts.Thiazidesinhighdosescausingintensediuresiscan

inhibitthemilkproduction.Theuseofcandesartancilexetil/hydrochlorothiazideduringbreastfeedingisnot

recommended.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.

Whendrivingvehiclesoroperatingmachines,itshouldbetakenintoaccountthatoccasionallydizzinessorweariness

mayoccurduringtreatmentwithcandesartancilexetil/hydrochlorothiazide.

4.8Undesirableeffects

Incontrolledclinicalstudieswithcandesartancilexetil/hydrochlorothiazideadversereactionsweremildandtransient.

Withdrawalsfromtreatmentduetoadverseeventsweresimilarwithcandesartancilexetil/hydrochlorothiazide(2.3-

3.3%)andplacebo(2.7–4.3%).

Inclinicaltrialswithcandesartancilexetil/hydrochlorothiazide,adversereactionswerelimitedtothosethatwere

reportedpreviouslywithcandesartancilexetiland/orhydrochlorothiazide.

Thetablebelowpresentsadversereactionswithcandesartancilexetilfromclinicaltrialsandpostmarketingexperience.

Inapooledanalysisofclinicaltrialdataofhypertensivepatients,adversereactionswithcandesartancilexetilwere

definedbasedonanincidenceofadverseeventswithcandesartancilexetilatleast1%higherthantheincidenceseen

withplacebo:

Thefrequenciesusedinthetablesthroughoutsection4.8are: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)andnotknown(cannotbe

estimatedfromtheavailabledata):

Thetablebelowpresentsadversereactionswithhydrochlorothiazidemonotherapy,usuallywithdosesof25mgor

SystemOrganClass Frequency UndesirableEffect

Infectionsandinfestations Common Respiratoryinfection

Bloodandlymphaticsystem

disorders Veryrare Leukopenia,neutropeniaand

agranulocytosis

Metabolismandnutrition

disorders Veryrare Hyperkalaemia,hyponatraemia

Nervoussystemdisorders Common Dizziness/vertigo,headache

Respiratory,thoracicand

mediastinaldisorders Veryrare Cough

Gastrointestinaldisorders Veryrare Nausea

Hepatobiliarydisorders Veryrare Increasedliverenzymes,abnormalhepatic

functionorhepatitis

Skinandsubcutaneoustissue

disorders Veryrare Angioedema,rash,urticaria,pruritus

Musculoskeletaland

connectivetissuedisorders Veryrare Backpain,arthralgia,myalgia

Renalandurinarydisorders Veryrare Renalimpairment,includingrenalfailurein

susceptiblepatients(seesection4.4)

SystemOrganClass Frequency UndesirableEffect

Bloodandlymphaticsystem

disorders Rare Leucopenia,neutropenia/agranulocytosis,

thrombocytopenia,aplasticanaemia,bone

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Reportingofsuspectedadversereactions

Reportingsuspectedadversereactionsafterauthorisationofthemedicinalproductisimportant.Itallowscontinued

monitoringofthebenefit/riskbalanceofthemedicinalproduct.Healthcareprofessionalsareaskedtoreportany

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

Fax:+35316762517;website:http://www.hpra.ie;e-mail: medsafety@hpra.ie .

4.9Overdose

Symptoms

Basedonpharmacologicalconsiderations,themainmanifestationofanoverdoseofcandesartancilexetilislikelytobe

symptomatichypotensionanddizziness.Inindividualcasereportsofoverdose(ofupto672mgcandesartancilexetil)

patientrecoverywasuneventful.

Immunesystemdisorders Rare Anaphylacticreactions

Metabolismandnutrition

disorders Common Hyperglycaemia,hyperuricaemia,electrolyte

imbalance(includinghyponatraemiaand

hypokalaemia)

Psychiatricdisorders Rare Sleepdisturbances,depression,restlessness

Nervoussystemdisorders

Common

Rare Light-headedness,vertigo

Paraesthesia

Eyedisorders Rare

Notknown Transientblurredvision

Acutemyopia,acuteangle-closureglaucoma

Cardiacdisorders Rare Cardiacarrhythmias

Vasculardisorders Uncommon

Rare Posturalhypotension

Necrotisingangiitis(vasculitis,cutaneous

vasculitis)

Respiratory,thoracicand

mediastinaldisorders Rare Respiratorydistress(includingpneumonitis

andpulmonaryoedema)

Gastrointestinaldisorders Uncommon

Rare Anorexia,lossofappetite,gastricirritation,

diarrhoea,constipation

Pancreatitis

Hepatobiliarydisorders Rare Jaundice(intrahepaticcholestaticjaundice)

Skinandsubcutaneoustissue

disorders Uncommon

Rare

Notknown Rash,urticaria,photosensitivityreactions

Toxicepidermalnecrolysis,cutaneouslupus

erythematosus-likereactions,reactivationof

cutaneouslupuserythematosus

Systemiclupuserythematosus

Musculoskeletaland

connectivetissuedisorders Rare Musclespasm

Renalandurinarydisorders

Common

Rare Glycosuria

Renaldysfunctionandinterstitialnephritis

Generaldisordersand

administrationsite

conditions Common

Rare Weakness

Fever

Investigations Common

Rare Increasesincholesteroland

Triglycerides

IncreasesinBUNandserum

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dizziness,hypotension,thirst,tachycardia,ventriculararrhythmias,sedation/impairmentofconsciousnessandmuscle

crampscanalsobeobserved.

Management

Nospecificinformationisavailableonthetreatmentofoverdosewithcandesartancilexetil/hydrochlorothiazide.The

followingmeasuresare,however,suggestedincaseofoverdose.

Whenindicated,inductionofvomitingorgastriclavageshouldbeconsidered.Ifsymptomatichypotensionshould

occur,symptomatictreatmentshouldbeinstitutedandvitalsignsmonitored.Thepatientshouldbeplacedsupinewith

thelegselevated.Ifthisisnotsufficient,plasmavolumeshouldbeincreasedbyinfusionofisotonicsalinesolution.

Serumelectrolyteandacidbalanceshouldbecheckedandcorrected,ifneeded.Sympathomimeticmedicinalproducts

maybeadministerediftheabove-mentionedmeasuresarenotsufficient.

Candesartancannotberemovedbyhaemodialysis.Itisnotknowntowhatextenthydrochlorothiazideisremovedby

haemodialysis.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:AngiotensinIIantagonists+diuretics

ATCcode:C09DA06.

Mechanismofaction

AngiotensinIIistheprimaryvasoactivehormoneoftherenin-angiotensin-aldosteronesystemandplaysaroleinthe

pathophysiologyofhypertensionandothercardiovasculardisorders.Italsohasaroleinthepathogenesisoforgan

hypertrophyandendorgandamage.ThemajorphysiologicaleffectsofangiotensinII,suchasvasoconstriction,

aldosteronestimulation,regulationofsaltandwaterhomeostasisandstimulationofcellgrowth,aremediatedviathe

type1(AT1)receptor.

Pharmacodynamiceffects

Candesartancilexetilisaprodrugwhichisrapidlyconvertedtotheactivedrug,candesartan,byesterhydrolysisduring

absorptionfromthegastrointestinaltract.CandesartanisanAIIRAselectiveforAT1receptors,withtightbindingto

andslowdissociationfromthereceptor.Ithasnoagonistactivity.

Clinicalefficacyandsafety

CandesartandoesnotinfluenceACEorotherenzymesystemsusuallyassociatedwiththeuseofACEinhibitors.Since

thereisnoeffectonthedegradationofkinins,oronthemetabolismofothersubstances,suchassubstanceP,AIIRAs

areunlikelytobeassociatedwithcough.IncontrolledclinicaltrialscomparingcandesartancilexetilwithACE

inhibitors,theincidenceofcoughwaslowerinpatientsreceivingcandesartancilexetil.Candesartandoesnotbindtoor

blockotherhormonereceptorsorionchannelsknowntobeimportantincardiovascularregulation.Theantagonismof

theAT1receptorsresultsindoserelatedincreasesinplasmareninlevels,angiotensinIandangiotensinIIlevels,anda

decreaseinplasmaaldosteroneconcentration.

Theeffectsofcandesartancilexetil8-16mg(meandose12mg)oncedailyoncardiovascularmorbidityandmortality

wereevaluatedinarandomisedclinicaltrialwith4937elderlypatients(aged70-89years,21%aged80orabove)with

mildtomoderatehypertensionfollowedforameanof3.7years(StudyonCOgnitionandPrognosisintheElderly).

Patientsreceivedcandesartanorplacebowithotherantihypertensivetreatmentaddedasneeded.Thebloodpressure

wasreducedfrom166/90to145/80mmHginthecandesartangroup,andfrom167/90to149/82mmHginthecontrol

group.Therewasnostatisticallysignificantdifferenceintheprimaryendpoint,majorcardiovascularevents

(cardiovascularmortality,non-fatalstrokeandnon-fatalmyocardialinfarction).Therewere26.7eventsper1000

patient-yearsinthecandesartangroupversus30.0eventsper1000patient-yearsinthecontrolgroup(relativerisk0.89,

95%CI0.75to1.06,p=0.19).

Hydrochlorothiazideinhibitstheactivereabsorptionofsodium,mainlyinthedistalkidneytubules,andpromotesthe

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whilecalciumisreabsorbedtoagreaterextent.Hydrochlorothiazidedecreasesplasmavolumeandextracellularfluid

andreducescardiacoutputandbloodpressure.Duringlong-termtherapy,reducedperipheralresistancecontributesto

thebloodpressurereduction.

Largeclinicalstudieshaveshownthatlong-termtreatmentwithhydrochlorothiazidereducestheriskforcardiovascular

morbidityandmortality.

Candesartanandhydrochlorothiazidehaveadditiveantihypertensiveeffects.

Inhypertensivepatients,candesartancilexetil/hydrochlorothiazideresultsinadose-dependentandlong-lasting

reductioninarterialbloodpressurewithoutreflexincreaseinheartrate.Thereisnoindicationofseriousorexaggerated

firstdosehypotensionorreboundeffectaftercessationoftreatment.Afteradministrationofasingledoseof

candesartancilexetil/hydrochlorothiazide,onsetoftheantihypertensiveeffectgenerallyoccurswithin2hours.With

continuoustreatment,mostofthereductioninbloodpressureisattainedwithinfourweeksandissustainedduring

long-termtreatment.Candesartancilexetil/hydrochlorothiazideoncedailyprovideseffectiveandsmoothblood

pressurereductionover24hours,withlittledifferencebetweenmaximumandtrougheffectsduringthedosinginterval.

Inadouble-blindrandomisedstudy,candesartancilexetil/hydrochlorothiazide16mg/12.5mgoncedailyreducedblood

pressuresignificantlymore,andcontrolledsignificantlymorepatients,thanthecombination

losartan/hydrochlorothiazide50mg/12.5mgoncedaily.

Indouble-blind,randomisedstudies,theincidenceofadverseevents,especiallycough,waslowerduringtreatment

withcandesartancilexetil/hydrochlorothiazidethanduringtreatmentwithcombinationsofACEinhibitorsand

hydrochlorothiazide.

Intwoclinicalstudies(randomised,double-blind,placebocontrolled,parallelgroup)including275and1524

randomisedpatients,respectively,thecandesartancilexetil/hydrochlorothiazidecombinations32mg/12.5mgand32

mg/25mgresultedinbloodpressurereductionsof22/15mmHgand21/14mmHg,respectively,andweresignificantly

moreeffectivethantherespectivemonocomponents.

Inarandomised,double-blind,parallelgroupclinicalstudyincluding1975randomisedpatientsnotoptimally

controlledon32mgcandesartancilexetiloncedaily,theadditionof12.5mgor25mghydrochlorothiazideresultedin

additionalbloodpressurereductions.Thecandesartancilexetil/hydrochlorothiazidecombination32mg/25mgwas

significantlymoreeffectivethanthe32mg/12.5mgcombination,andtheoverallmeanbloodpressurereductionswere

16/10mmHgand13/9mmHg,respectively.

Candesartancilexetil/hydrochlorothiazideissimilarlyeffectiveinpatientsirrespectiveofageandgender.

Currentlytherearenodataontheuseofcandesartancilexetil/hydrochlorothiazideinpatientswithrenal

disease/nephropathy,reducedleftventricularfunction/congestiveheartfailureandpostmyocardialinfarction.

Twolargerandomised,controlledtrials(ONTARGET(ONgoingTelmisartanAloneandincombinationwithRamipril

GlobalEndpointTrial)andVANEPHRON-D(TheVeteransAffairsNephropathyinDiabetes))haveexaminedtheuse

ofthecombinationofanACE-inhibitorwithanangiotensinIIreceptorblocker.

ONTARGETwasastudyconductedinpatientswithahistoryofcardiovascularorcerebrovasculardisease,ortype2

diabetesmellitusaccompaniedbyevidenceofend-organdamage.VANEPHRON-Dwasastudyinpatientswithtype

2diabetesmellitusanddiabeticnephropathy.

Thesestudieshaveshownnosignificantbeneficialeffectonrenaland/orcardiovascularoutcomesandmortality,while

anincreasedriskofhyperkalaemia,acutekidneyinjuryand/orhypotensionascomparedtomonotherapywasobserved.

Giventheirsimilarpharmacodynamicproperties,theseresultsarealsorelevantforotherACE-inhibitorsand

angiotensinIIreceptorblockers.ACE-inhibitorsandangiotensinIIreceptorblockersshouldthereforenotbeused

concomitantlyinpatientswithdiabeticnephropathy.

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designedtotestthebenefitofaddingaliskirentoastandardtherapyofanACE-inhibitororanangiotensinIIreceptor

blockerinpatientswithtype2diabetesmellitusandchronickidneydisease,cardiovasculardisease,orboth.Thestudy

wasterminatedearlybecauseofanincreasedriskofadverseoutcomes.Cardiovasculardeathandstrokewereboth

numericallymorefrequentinthealiskirengroupthanintheplacebogroupandadverseeventsandseriousadverse

eventsofinterest(hyperkalaemia,hypotensionandrenaldysfunction)weremorefrequentlyreportedinthealiskiren

groupthanintheplacebogroup.

5.2Pharmacokineticproperties

Concomitantadministrationofcandesartancilexetilandhydrochlorothiazidehasnoclinicallysignificanteffectonthe

pharmacokineticsofeithermedicinalproduct.

Absorptionanddistribution

Candesartancilexetil

Followingoraladministration,candesartancilexetilisconvertedtotheactivesubstancecandesartan.Theabsolute

bioavailabilityofcandesartanisapproximately40%afteranoralsolutionofcandesartancilexetil.Therelative

bioavailabilityofatabletformulationofcandesartancilexetilcomparedwiththesameoralsolutionisapproximately

34%withverylittlevariability.Themeanpeakserumconcentration(Cmax)isreached3-4hoursfollowingtablet

intake.Thecandesartanserumconcentrationsincreaselinearlywithincreasingdosesinthetherapeuticdoserange.No

genderrelateddifferencesinthepharmacokineticsofcandesartanhavebeenobserved.Theareaundertheserum

concentrationversustimecurve(AUC)ofcandesartanisnotsignificantlyaffectedbyfood.

Candesartanishighlyboundtoplasmaprotein(morethan99%).Theapparentvolumeofdistributionofcandesartanis

0.1l/kg.

Hydrochlorothiazide

Hydrochlorothiazideisrapidlyabsorbedfromthegastrointestinaltractwithanabsolutebioavailabilityof

approximately70%.Concomitantintakeoffoodincreasestheabsorptionbyapproximately15%.Thebioavailability

maydecreaseinpatientswithcardiacfailureandpronouncedoedema.

Theplasmaproteinbindingofhydrochlorothiazideisapproximately60%.Theapparentvolumeofdistributionis

approximately0.8l/kg.

Biotransformationandelimination

Candesartancilexetil

Candesartanismainlyeliminatedunchangedviaurineandbileandonlytoaminorextenteliminatedbyhepatic

metabolism(CYP2C9).AvailableinteractionstudiesindicatenoeffectonCYP2C9andCYP3A4.Basedoninvitro

data,nointeractionwouldbeexpectedtooccurinvivowithmedicinalproductswhosemetabolismisdependentupon

cytochromeP450isoenzymesCYP1A2,CYP2A6,CYP2C9,CYP2C19,CYP2D6,CYP2E1orCYP3A4.Theterminal

half-life(t½)ofcandesartanisapproximately9hours.Thereisnoaccumulationfollowingmultipledoses.Thehalf-life

ofcandesartanremainsunchanged(approximately9h)afteradministrationofcandesartancilexetilincombinationwith

hydrochlorothiazide.Noadditionalaccumulationofcandesartanoccursafterrepeateddosesofthecombination

comparedtomonotherapy.

Totalplasmaclearanceofcandesartanisabout0.37ml/min/kg,witharenalclearanceofabout0.19ml/min/kg.The

renaleliminationofcandesartanisbothbyglomerularfiltrationandactivetubularsecretion.Followinganoraldoseof

14C-labelledcandesartancilexetil,approximately26%ofthedoseisexcretedintheurineascandesartanand7%asan

inactivemetabolitewhileapproximately56%ofthedoseisrecoveredinthefaecesascandesartanand10%asthe

inactivemetabolite.

Hydrochlorothiazide

Hydrochlorothiazideisnotmetabolisedandisexcretedalmostentirelyasunchangeddrugbyglomerularfiltrationand

activetubularsecretion.Theterminalt½ofhydrochlorothiazideisapproximately8hours.Approximately70%ofan

oraldoseiseliminatedintheurinewithin48hours.Thehalf-lifeofhydrochlorothiazideremainsunchanged

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additionalaccumulationofhydrochlorothiazideoccursafterrepeateddosesofthecombinationcomparedto

monotherapy.

Pharmacokineticsinspecialpopulations

Candesartancilexetil

Inelderlysubjects(over65years),CmaxandAUCofcandesartanareincreasedbyapproximately50%and80%,

respectivelyincomparisontoyoungsubjects.However,thebloodpressureresponseandtheincidenceofadverse

eventsaresimilarafteragivendoseofcandesartancilexetil/hydrochlorothiazideinyoungandelderlypatients(see

section4.2).

Inpatientswithmildtomoderaterenalimpairment,CmaxandAUCofcandesartanincreasedduringrepeateddosing

byapproximately50%and70%,respectively,buttheterminalt½wasnotaltered,comparedtopatientswithnormal

renalfunction.Thecorrespondingchangesinpatientswithsevererenalimpairmentwereapproximately50%and

110%,respectively.Theterminalt½ofcandesartanwasapproximatelydoubledinpatientswithsevererenal

impairment.Thepharmacokineticsinpatientsundergoinghaemodialysisweresimilartothoseinpatientswithsevere

renalimpairment.

Intwostudies,bothincludingpatientswithmildtomoderatehepaticimpairment,therewasanincreaseinthemean

AUCofcandesartanofapproximately20%inonestudyand80%intheotherstudy(seesection4.2).Thereisno

experienceinpatientswithseverehepaticimpairment.

Hydrochlorothiazide

Theterminalt½ofhydrochlorothiazideisprolongedinpatientswithrenalimpairment.

5.3Preclinicalsafetydata

Therewerenoqualitativenewtoxicfindingswiththecombinationcomparedtothatobservedforeachcomponent.In

preclinicalsafetystudiescandesartanitselfhadeffectsonthekidneysandonredcellparametersathighdosesinmice,

rats,dogsandmonkeys.Candesartancausedareductionofredbloodcellparameters(erythrocytes,haemoglobin,

haematocrit).Effectsonthekidneys(suchasregeneration,dilatationandbasophiliaintubules;increasedplasma

concentrationsofureaandcreatinine)wereinducedbycandesartan,whichcouldbesecondarytothehypotensiveeffect

leadingtoalterationsofrenalperfusion.Additionofhydrochlorothiazidepotentiatesthenephrotoxicityofcandesartan.

Furthermore,candesartaninducedhyperplasia/hypertrophyofthejuxtaglomerularcells.Thesechangeswere

consideredtobecausedbythepharmacologicalactionofcandesartanandtobeoflittleclinicalrelevance.

Foetotoxicityhasbeenobservedinlatepregnancywithcandesartan.Theadditionofhydrochlorothiazidedidnot

significantlyaffecttheoutcomeoffoetaldevelopmentstudiesinrats,miceorrabbits(seesection4.6).

Candesartanandhydrochlorothiazidebothshowgenotoxicactivityatveryhighconcentrations/doses.Datafromin

vitroandinvivogenotoxicitytestingindicatethatcandesartanandhydrochlorothiazideareunlikelytoexertany

mutagenicorclastogenicactivityunderconditionsofclinicaluse.

Therewasnoevidencethateithercompoundiscarcinogenic.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate,

Carmellosecalcium,

Glycerolmonostearate,

Hydroxypropylcellulose,

IronOxideYellow(E172),

IronOxideRed(E172),

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Magnesiumstearate

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years.

Thein-useshelflifeoftheproductwhenstoredinHDPEbottlesis90days.

6.4Specialprecautionsforstorage

Donotstoreabove25C.

Storeintheoriginalpackageinordertoprotectfromlightandmoisture.

Donotremovethedesiccantcontainedinthebottle.

6.5Natureandcontentsofcontainer

OPA-Aluminium-PVC/Aluminiumblister,orPVC/Aluminiumblisterinthefollowingpacksizes:7,10,14,15,28,

30,50,56,60,84,90,98,100tablets.

WhiteopaqueHDPEbottlewithwhiteopaquescrewcapwithabsorbentcottonanddesiccant,inthefollowingpack

sizes:30and90tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Anyunusedmedicinalproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

McDermottLaboratoriesLtdt/aGerardLaboratories,

35/36BaldoyleIndustrialEstate,

GrangeRoad,

Dublin13,

Ireland.

8MARKETINGAUTHORISATIONNUMBER

PA0577/121/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateofthefirstauthorisation:27thJanuary2012

10DATEOFREVISIONOFTHETEXT

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