CANDESARTAN TEVA 8 Milligram Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
CANDESARTAN CILEXETIL
Available from:
Teva Pharma B.V.
ATC code:
C09CA06
INN (International Name):
CANDESARTAN CILEXETIL
Dosage:
8 Milligram
Pharmaceutical form:
Tablets
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Angiotensin II antagonists, plain
Authorization status:
Authorised
Authorization number:
PA0749/124/003
Authorization date:
2012-01-06

Teva Pharmaceuticals Europe

Module1.3.1

PatientInformation LeafletText

Package leaflet:Information for the user

Candesartan Teva 8mg Tablets

Candesartan Teva 16mg Tablets

Candesartan cilexetil

Read allofthisleafletcarefully beforeyou starttaking thismedicinebecauseitcontains

important information for you.

- Keep this leaflet. You mayneed to read itagain.

- Ifyou have anyfurtherquestions, askyourdoctororpharmacist.

- This medicine has been prescribed foryouonly. Do notpass iton to others. Itmayharmthem,

even iftheirsigns ofillnessare the same as yours.

- Ifyou getanyside effects,talktoyourdoctororpharmacist.This includesanypossibleside

effects notlisted in this leaflet.See section 4.

What is inthisleaflet

1. WhatCandesartan Teva is and whatitis used for

2. Whatyou need to knowbeforeyou take Candesartan Teva

3. Howto take Candesartan Teva

4. Possible side effects

5. Howto store Candesartan Teva

6. Contents ofthe packandotherinformation

1. WhatCandesartanTeva is and what itis used for

Thename ofyourmedicine isCandesartan Teva.The active ingredientis Candesartan cilexetil.This

belongs to a group ofmedicinescalled Angiotensin IIreceptorantagonists.Itworks bymakingyour

blood vessels relax and widen. This helps to loweryourblood pressure. Italso makesiteasierfor

yourheartto pump blood to allparts ofyourbody.

This medicineisusedfor:

Treatinghighbloodpressure(hypertension)inadultpatientsandinchildrenandadolescents

aged 6 to <18 years.

TreatingadultheartfailurepatientswithreducedheartmusclefunctionwhenAngiotensin

ConvertingEnzyme(ACE)inhibitorscannotbeusedorinadditiontoACE-inhibitorswhen

symptomspersistdespitetreatmentandmineralocorticoidreceptorantagonists(MRA)cannotbe

used. (ACE-inhibitors and MRAs are medicinesused to treatheartfailure).

2. What you need to knowbeforeyou takeCandesartanTeva

Donottake Candesartan Teva

- ifyou are allergic tocandesartan cilexetiloranyofthe otheringredients ofthis medicine(listed

insection 6).

- ifyou are more than 3months pregnant(itisalsobetterto avoid Candesartan Teva in early

pregnancy–see section2:Pregnancyand breast-feeding).

- ifyou have severe liverdisease orbiliaryobstruction (a problemwith the drainage ofthe bile

fromthe gallbladder).

- ifthe patientis achild under1 yearofage.

- ifyou have diabetesorimpaired kidneyfunction and you are treated with a bloodpressure

loweringmedicine containingaliskiren

Ifyouarenotsureifanyoftheseapplytoyou,talktoyourdoctororpharmacistbeforetaking

Candesartan Teva.

Warnings and precautions

Talkto yourdoctororpharmacistbefore takingCandesartan Teva:

- ifyou have heart, liverorkidneyproblems,orare on dialysis.

- ifyou have recentlyhad akidneytransplant.

- ifyou are vomiting, have recentlyhad severe vomiting, orhave diarrhoea.

- ifyou have adisease ofthe adrenalgland called Conn’ssyndrome (also called primary

hyperaldosteronism).

- ifyou have lowblood pressure

- ifyou have everhad astroke.

- you musttellyourdoctorifyou thinkyou are (ormightbecome)pregnant. Candesartan Teva is

notrecommended in earlypregnancy, and mustnotbe taken ifyou are more than 3months

pregnant, asitmaycauseserious harmto yourbabyifused atthatstage (see section2:

Pregnancyand breast-feeding).

- ifyou are takinganyofthe followingmedicinesused to treathigh blood pressure:

-anACE-inhibitor(forexample enalapril, lisinopril, ramipril), in particularifyou have

diabetes-related kidneyproblems.

-aliskiren

- ifyou are takingan ACE-inhibitortogetherwith a medicine which belongs to the class of

medicinesknown asmineralocorticoid receptors antagonists (MRA). These medicinesare for

the treatmentofheartfailure (see ‘Othermedicinesand Candesartan Teva’).

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

potassium)in yourblood atregularintervals.

See also information underthe heading‘Do nottake Candesartan Teva’.

Yourdoctormaywantto see you more often and do some tests ifyou have anyofthese conditions.

Ifyou are goingto have an operation, tellyourdoctorordentistthatyou are takingCandesartan Teva.

This is becauseCandesartan Tevawhen combined with some anaesthetics, maycausea drop in blood

pressure.

Childrenandadolescents

Candesartanhasbeen studied in children. Formore information, talkto yourdoctor.Candesartan

mustnotbe given to children under1 yearofage dueto the potentialriskto the developingkidneys.

Other medicinesandCandesartan Teva

Tellyourdoctororpharmacistifyou are using, have recentlyusedormightuseanyothermedicines,

includingmedicinesobtained withouta prescription.

Candesartan Teva can affectthe waysome othermedicinesworkand some medicinescan have an

effecton Candesartan Teva. Ifyou are usingcertain medicines, yourdoctormayneed to do blood

testsfromtime to time.

In particular, tellyourdoctorifyou areusinganyofthe followingmedicines:

- Othermedicinesto help loweryourblood pressure, includingbeta-blockersanddiazoxide

- Non-steroidalanti-inflammatorydrugs (NSAIDs)such asibuprofen, naproxen, diclofenac,

celecoxib oretoricoxib (medicinesto relieve pain and inflammation).

- Acetylsalicylic acid (ifyou are takingmore than 3 geach day)(medicine to relieve pain and

inflammation).

- Potassiumsupplements orsaltsubstitutescontainingpotassium(medicinesthatincreasethe

amountofpotassiumin yourblood).

- Heparin (a medicine forthinningthe blood).

- Watertablets (diuretics).

- Lithium(a medicine formentalhealth problems).

Yourdoctormayneed to change yourdoseand/orto take otherprecautions:

-Ifyou are takingan ACE-inhibitororaliskiren (see also information underthe headings ‘Do not

take Candesartan Teva’and ‘Warnings and precautions’)

-Ifyou are beingtreated with an ACE-inhibitortogetherwith certain othermedicinesto treat

yourheartfailure, which are known asmineralocorticoid receptors antagonists (MRA)(for

example spironolactone, eplerenone).

Candesartan Teva with food,drinkandalcohol

You can take Candesartan Teva with orwithoutfood.

When you are prescribed Candesartan Teva, discusswith yourdoctorbefore drinkingalcohol.

Alcoholmaymake you feelfaintordizzy.

Pregnancy and breast-feeding

Ifyou are pregnantorbreast-feeding, thinkyou maybe pregnantorare planningto have ababy, ask

yourdoctororpharmacistforadvicebefore takingthis medicine.

Pregnancy

You musttellyourdoctorifyou thinkyou are (ormightbecome)pregnant. Yourdoctorwillnormally

adviseyou to stop takingCandesartan Teva before you become pregnantorassoon as you knowyou

are pregnantand willadviseyou to take anothermedicine instead ofCandesartan Teva. Candesartan

Teva is notrecommended in earlypregnancy,and mustnotbe taken when more than 3months

pregnant, asitmaycauseseriousharmto yourbabyifused afterthe third month ofpregnancy.

Breast-feeding

Tellyourdoctorifyou are breast-feedingoraboutto startbreast-feeding. Candesartan Teva is not

recommended formothers who are breast-feeding, and yourdoctormaychoose anothertreatmentfor

you ifyou wish to breast-feed, especiallyifyourbabyis newborn orwasborn prematurely.

Driving and using machines

SomepeoplemayfeeltiredordizzywhentakingCandesartanTeva.Ifthishappenstoyou,donot

drive oruseanytools ormachines.

Candesartan Teva containslactosewhich is atype ofsugar. Ifyou have been told byyourdoctorthat

you have an intolerance to some sugars, contactyourdoctorbefore takingthis medicine.

3. Howto takeCandesartanTeva

Always takethismedicineexactlyasyourdoctororpharmacisthastold you.Checkwith yourdoctor

orpharmacistifyou are notsure.Itis importantto keep takingCandesartan Teva everyday.

You can take Candesartan Teva with orwithoutfood.

Swallowthe tabletwith adrinkofwater.

Tryto take the tabletatthe same time each day. This willhelp you to rememberto take it.

High blood pressure:

The usualdoseofCandesartan Tevais 8mgoncea day. Yourdoctormayincreasethis dose to

16 mgoncea dayand furtherup to 32 mgoncea daydependingon blood pressure response.

In some patients, such as thosewith liverproblems, kidneyproblems orthosewho recently

have lostbodyfluids, e.g., through vomitingordiarrhoeaorbyusingwatertablets, the doctor

mayprescribe alowerstartingdose.

Some blackpatients mayhave areduced responseto this type ofmedicine, when given as the

onlytreatment, and these patients mayneed a higherdose.

Heartfailure

The usualstartingdoseofCandesartan Tevais 4mgonceaday. Yourdoctormayincreaseyour

dosebydoublingthe dose atintervals ofatleast2 weeks up to 32 mgoncea day.Candesartan

Tevacan be taken togetherwith othermedicinesforheartfailure, and yourdoctorwilldecide

which treatmentis suitable foryou.

Usein childrenandadolescentswith high blood pressure:

Children 6 to <18 years ofage:

The recommended startingdoseis 4 mgoncedaily.

For patients weighing< 50 kg:In some patients whose blood pressure is notadequatelycontrolled,

yourdoctormaydecide the dose needsto be increased to a maximumof8 mgoncedaily.

For patients weighing≥50 kg:In some patients whose blood pressure is notadequatelycontrolled,

yourdoctormaydecide the dose needsto be increased to 8 mgoncedailyand to 16mgoncedaily.

Ifyou take moreCandesartan Teva thanyou should

Ifyoutake more Candesartan Teva than prescribed byyourdoctor, contacta doctororpharmacist

immediatelyforadvice.

Ifyou forgetto take Candesartan Teva

Do nottake adouble dose to make up fora forgottentablet.Justtake the nextdoseasnormal.

Ifyoustop taking Candesartan Teva

Ifyou stop takingCandesartan Teva, yourblood pressure mayincreaseagain.Thereforedonotstop

takingCandesartan Teva withoutfirsttalkingto yourdoctor.

Ifyou have anyfurtherquestions on the use ofthismedicine,askyourdoctororpharmacist.

4. Possibleside effects

Like allmedicines,this medicinecan causeside effects, although noteverybodygets them.

Itis importantthatyou are aware ofwhatthese side effects maybe.

Stop takingCandesartan Tevaandseek medicalhelp immediately ifyou have any ofthe

following allergic reactions:

difficultiesin breathing, with orwithoutswellingofthe face, lips, tongue and/orthroat.

swellingofthe face, lips, tongue and/orthroat, which maycausedifficultiesin swallowing.

severe itchingofthe skin(with raised lumps).

Candesartan Tevamaycausea reduction in numberofwhite blood cells. Your resistance to infection

maybe decreased and you maynoticetiredness, an infection ora fever. Ifthis happenscontactyour

doctor. Yourdoctormayoccasionallydo blood tests to checkwhetherCandesartan Tevahashad an

effecton yourblood (agranulocytosis).

Otherpossible side effects include:

Common (may affectupto 1 in 10 people)

Feelingdizzy/spinningsensation.

Headache.

Respiratoryinfection.

Lowblood pressure. This maymake you feelfaintordizzy.

Changesin blood testresults:

- An increased amountofpotassiumin yourblood, especiallyifyou alreadyhave kidney

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

heartbeatorpins and needles.

Effects on how yourkidneys work, especiallyifyou alreadyhave kidneyproblems orheart

failure. In veryrare cases, kidneyfailure mayoccur.

Veryrare(may affectupto1 in 10,000 people)

Swellingofthe face, lips, tongue and/orthroat.

Areduction inyourred orwhite blood cells.You maynoticetiredness, an infection ora fever.

Skin rash, lumpyrash (hives).

Itching.

Cough

Backpain, pain in joints and muscles.

Changesin howyourliveris working, includinginflammation ofthe liver(hepatitis). You may

noticetiredness, yellowingofyourskin and the whitesofyoureyesand flu like symptoms.

Nausea.

Changesin blood testresults:

- Areduced amountofsodiumin yourblood. Ifthis is severe then you maynoticeweakness,

lackofenergy, ormuscle cramps.

Additional side effects in childrenandadolescents

In children treated forhigh blood pressure, side effects appearto be similarto thoseseen inadults,but

theyhappen more often. Sore throatis averycommon side effectin children butnotreported in adults

and runnynose, feverand increased heartrate are common in children butnotreported in adults.

Reporting ofside effects

Ifyou getanyside effects, talkto yourdoctor, pharmacistornurse. This includesanypossible side

effects notlisted in this leaflet. You can also reportside effects directlyvia HPRA

Pharmacovigilance, EarlsfortTerrace, IRL-Dublin 2;Tel:+353 1 6764971;Fax:+353 1 6762517.

Website: www.hpra.ie ;E-mail: medsafety@hpra.ie . Byreportingside effects you can help provide

more information on the safetyofthis medicine.

5. Howto storeCandesartanTeva

Keepthismedicineout ofthesightandreachofchildren.

Do notusethis medicineafterthe expirydate which is stated on the blisterfoiland carton after

{EXP}. The expirydate refers to the lastdayofthatmonth.

Do notstoreabove30°C.Store in originalpackagingto protectfrommoisture.

Do notthrowawayanymedicinesvia wastewaterorhousehold waste. Askyourpharmacisthowto

throwawaymedicinesyouno longeruse. These measureswillhelp protectthe environment.

6. Contentsofthe pack and otherinformation

WhatCandesartan Tevacontains

- The active substance isCandesartan cilexetil.

Each Candesartan Teva 8mgTabletcontains 8mgofCandesartan cilexetil.

Each Candesartan Teva 16mgTabletcontains 16mgofCandesartan cilexetil.

- The otheringredients arepregelatinizedmaize starch, povidone K-30, carmellosecalcium,

microcrystalline cellulose(E460), lactosemonohydrate, magnesiumstearate, poloxamer188

and red iron oxide (E172).

What Candesartan Teva looks like andcontents ofthe pack

-Candesartan Teva 8mgTabletis apink, capsule shaped tablet,7.7mmin length and3.5 mmin

width,scored on both sides.One side ofthe tabletis debossed with “C |8” and the otherside is

debossed with “8 |C”.

-Candesartan Teva 16mgTabletis apink, capsule shaped tablet,9.7mmin length and4.3 mmin

width,scored on oneside. One side ofthe tabletis debossed with the number“16”. The otherside

ofthe tabletis debossed with “C|C”.

Candesartan Teva Tabletsare available inOPA/Aluminium/PVC–PVC/PVAC/Aluminium/OPA

blistersinpacksizesof7, 14, 15, 20, 28, 30, 50, 50 x 1 unitdoseblisters (hospitalpack), 56, 60, 84,

90, 98, 100, 250 &300 tablets.

Notallpacksizesmaybe marketed.

Marketing Authorisation Holder

Teva Pharma B.V.

Computerweg10

3542 DRUtrecht

The Netherlands

Manufacturer

Teva PharmaceuticalWorks Private Limited Company

Pallagiút13,

4042 Debrecen,

Hungary

Teva UKLimited

Brampton Road,

Hampden Park,

Eastbourne,

EastSussex,

BN22 9AG, United Kingdom

Pharmachemie B.V.

Swensweg5,

2031 GAHaarlem

The Netherlands

Teva Santé

Rue Bellocier,

89100 Sens

France

Teva Operations Poland Sp. z.o.o.

ul. Mogilska 80,

31-546, Krakow

Poland

Teva Pharma S.L.U.

C/C, n. 4,

Poligono IndustrialMalpica,

50016 Zaragoza

Spain

Teva Operations Poland Sp. z.o.o.

Ul. Sienkiewicza 25,

99-300 Kutno

Poland

Merckle GmbH

Ludwig-Merckle Strasse3,

89143 Blaubeuren-Weiler

Germany

Pliva Hrvatska d.o.o.

Prilazbaruna Filipovića25,

10000 Zagreb,

Croatia

Thismedicinal productis authorised in the Member Statesofthe EEAunder the following

names:

Belgium Candesartan Teva8 mg, 16 mgtabletten

Denmark Cantar8 mg, 16 mg

Estonia Cantar8 mg, 16 mg

Finland Candesartan Teva8 mg, 16 mgtabletti

France Candesartan Teva8 mg, 16 mgcomprimé sécable

Germany Candesartan-ratiopharm8 mg, 16 mgTabletten

Greece Candesartan Cilexetil/Teva Pharma B.V.8 mg, 16 mg

Hungary Candesartan-ratiopharm8 mg, 16 mgtabletta

Ireland Candesartan Teva8 mg, 16 mgTablets

Italy Candesartan Teva Italia8 mg, 16 mg

Latvia Cantar8 mg&16 mgtablets

Luxembourg Candesartan-ratiopharm8 mg, 16 mgTabletten

Netherlands Candesartan cilexetilTeva8 mg, 16 mgtabletten

Norway Candesartan Teva8 mg, 16 mgtabletter

Poland Candesartan cilexetilTeva8 mg, 16 mg

Portugal Candesartan Teva8 mg, 16 mg

Romania Candesartan cilexetilTeva 8 mg, 16 mgcomprimate

Slovakia Kandesartan Teva 8 mg, 16 mg

Spain Candesartan Teva8 mg, 16 mgcomprimidos EFG

Sweden Candesartan Teva 8 mg, 16 mgtabletter

United Kingdom Candesartan cilexetil8 mg, 16 mgTablets

Thisleafletwas lastrevisedinFebruary 2015

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Candesartan Teva 8 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 8 mg candesartan cilexetil.

Excipients with known effects:

Lactose: 43.725 mg lactose monohydrate / 8 mg tablet

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

Pink, capsule shaped tablet, 7.7 mm in length and 3.5 mm in width, scored on both sides. One side of

the tablet is

debossed with " C | 8 " and the other side is debossed with " 8 | C ".

The tablet can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Candesartan cilexetil Teva is indicated for the:

Treatment of essential hypertension in adults.

The treatment of adult patients with heart failure and impaired left ventricular systolic function (left ventricular ejection

fraction

40%)

when ACE-inhibitors are not

tolerated or

as add-on therapy to ACE-inhibitors in patients with

symptomatic heart failure, despite optimal therapy, when mineralocorticoid receptor antagonists are not tolerated (see

sections 4.2, 4.4, 4.5 and 5.1).

Treatment of essential hypertension in children and adolescents aged 6 to <18 years.

4.2 Posology and method of administration

Posology in Hypertension

The recommended initial dose and usual maintenance dose of Candesartan cilexetil Teva is 8 mg once daily. Most of

the antihypertensive effect

is attained within 4 weeks.

In some patients whose blood pressure is not

adequately

controlled, the dose can be increased to 16 mg once daily and to a maximum of 32 mg once daily. Therapy should be

adjusted according to blood pressure response.

Candesartan cilexetil

Teva may also be administered with other

antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1). Addition of hydrochlorothiazide has been shown to have an

additive antihypertensive effect with various doses of Candesartan cilexetil Teva.

Older people

No initial dose adjustment is necessary in older people.

Patients with intravascular volume depletion

An initial dose of 4 mg may be considered in patients at risk for hypotension,

such as patients with possible volume

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

1

depletion (see section 4.4).

Patients with renal impairment

The starting dose is 4 mg in patients with renal impairment, including patients on haemodialysis.

The dose should be

titrated according to response.

There is limited experience in patients with very severe or end-stage renal impairment

creatinine

< 15 ml/min) (see section 4.4).

Patients with hepatic impairment

An initial dose of 4 mg once daily is recommended in patients with mild to moderate hepatic impairment.

The dose

may be adjusted according to response.

Candesartan cilexetil

Teva is contraindicated in patients with severe hepatic

impairment and/or cholestasis (see sections 4.3 and 5.2).

Black patients

antihypertensive

effect

candesartan

less

pronounced

black

patients

than

in non-black

patients.

Consequently, up-titration of Candesartan cilexetil Teva and concomitant therapy may be more frequently needed for

blood pressure control in black patients than in non-black patients (see section 5.1).

Paediatric Population

Children and adolescents aged 6 to <18 years:

The recommended starting dose is 4 mg once daily.

For patients weighing < 50 kg: In patients whose blood pressure is not adequately controlled, the dose can be

increased to a maximum of 8 mg once daily.

For patients weighing

50 kg: In patients whose blood pressure is not adequately controlled, the dose can be

increased to 8 mg once daily and then to 16 mg once daily if needed (see section 5.1).

Doses above 32 mg have not been studied in paediatric patients.

Most of the antihypertensive effect is attained within 4 weeks.

For children with possible intravascular volume depletion (e.g., patients treated with diuretics, particularly those with

impaired renal function), candesartan treatment should be initiated under close medical supervision and a lower starting

dose than the general starting dose above should be considered (see section 4.4).

Candesartan has not been studied in children with glomerular filtration rate less than 30 ml/min/1.73m

(see section

4.4).

Black paediatric patients

The antihypertensive effect of candesartan is less pronounced in black patients than in non

black patients (see section

5.1).

Children aged below 1 year to <6 years

The safety and efficacy in children aged 1 to <6 years of age has not been established. Currently available data are

described in section 5.1 but no recommendation on a posology can be made.

Candesartan is contraindicated in children aged below 1 year (see section 4.3).

Posology in Heart Failure

The usual recommended initial dose of Candesartan cilexetil Teva is 4 mg once daily. Up-titration to the target dose of

32 mg once daily (maximum dose) or the highest tolerated dose is done by doubling the dose at intervals of at least 2

weeks (see section 4.4). Evaluation of patients with heart failure should always comprise assessment of renal function

including monitoring of serum creatinine and potassium.

Candesartan cilexetil

Teva can be administered with other

heart

failure treatment,

including ACE-inhibitors,

beta-blockers,

diuretics and digitalis or

a combination of

these

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

2

medicinal

products.

Candesartan cilexetil

Teva may be co-administered with an ACE-inhibitor

in patients

with

symptomatic heart

failure despite optimal standard heart

failure therapy when mineralocorticoid receptor antagonists

are not tolerated. The combination of an ACE-inhibitor, a potassium-sparing diuretic and Candesartan cilexetil Teva is

recommended and should be considered only after

careful

evaluation of

the potential

benefits and risks (see

sections 4.4, 4.8 and 5.1).

Special patient populations

No initial

dose adjustment

is necessary for older patients or in patients with intravascular volume depletion or renal

impairment or mild to moderate hepatic impairment.

Paediatric Population

The safety and efficacy of Candesartan cilexetil

Teva in children aged between birth and 18 years have not

been

established in the treatment of heart failure. No data are available.

Method of administration

Oral use.

Candesartan cilexetil Teva should be taken once daily with or without food.

The bioavailability of candesartan is not affected by food.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

Severe hepatic impairment and/or cholestasis.

Children aged below 1 year (see section 5.3)

The concomitant

use of Candesartan cilexetil

Teva with aliskiren-containing products is contraindicated in patients

with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m

) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Renal impairment

As with other agents inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated

in susceptible patients treated with Candesartan cilexetil Teva.

When Candesartan cilexetil Teva is used in hypertensive patients with renal impairment, periodic monitoring of serum

potassium and creatinine levels is recommended. There is limited experience in patients with very severe or end-stage

renal

impairment

creatinine

< 15 ml/min).

In these patients Candesartan cilexetil

Teva should be carefully titrated

with thorough monitoring of blood pressure.

Evaluation of patients with heart

failure should include periodic assessments of renal

function,

especially in elderly

patients 75 years or older,

and patients with impaired renal

function.

During dose titration of Candesartan cilexetil

Teva,

monitoring of serum creatinine and potassium is recommended.

Clinical

trials in heart

failure did not

include

patients with serum creatinine > 265 µmol/l (> 3 mg/dl).

Concomitant therapy with an ACE-inhibitor in heart failure

The risk of adverse reactions,

especially hypotension,

hyperkalaemia and decreased renal

function (including acute

renal

failure),

may increase when Candesartan cilexetil

Teva is used in combination with an ACE-inhibitor.

Triple

combination of an ACE-inhibitor,

a mineralocorticoid receptor antagonist

and candesartan is also not

recommended.

Use of these combinations should be under specialist

supervision and subject

to frequent

close monitoring of renal

function, electrolytes and blood pressure.

ACE-inhibitors

and angiotensin II

receptor

blockers

should not

be used concomitantly in patients

with diabetic

nephropathy.

Haemodialysis

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

3

During dialysis the blood pressure may be particularly sensitive to AT

-receptor blockade as a result of reduced plasma

volume and activation of the renin-angiotensin-aldosterone system.

Therefore,

Candesartan cilexetil

Teva should be

carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis.

Renal artery stenosis

Other

medicinal

products

that

affect

the renin-angiotensin-aldosterone system,

including angiotensin II

receptor

antagonists (AIIRAs),

may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or

stenosis of the artery to a solitary kidney.

Kidney transplantation

There is no experience regarding the administration of Candesartan cilexetil

Teva in patients with a recent

kidney

transplantation.

Hypotension

Hypotension may occur during treatment with Candesartan cilexetil Teva in heart failure patients. It may also occur in

hypertensive patients with intravascular volume depletion such as those receiving high dose diuretics. Caution should

be observed when initiating therapy and correction of hypovolemia should be attempted.

Anaesthesia and surgery

Hypotension may occur

during anaesthesia and surgery in patients treated with angiotensin II

antagonists due to

blockade of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of

intravenous fluids and/or vasopressors.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)

As with other vasodilators, special caution is indicated in patients suffering from haemodynamically relevant aortic or

mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism will

generally respond to antihypertensive medicinal

products acting

through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of Candesartan cilexetil Teva is not

recommended in this population.

Hyperkalaemia

Concomitant

Candesartan cilexetil

Teva

with potassium-sparing diuretics,

potassium supplements,

salt

substitutes containing potassium,

or other medicinal

products that

may increase potassium levels (e.g.

heparin) may

lead to increases in serum potassium in hypertensive patients.

Monitoring of

potassium should be undertaken as

appropriate.

In heart

failure patients treated with Candesartan cilexetil

Teva,

hyperkalaemia may occur.

Periodic monitoring of

serum potassium is

recommended.

combination of

an ACE inhibitor,

potassium-sparing diuretic

(e.g.

spironolactone)

and Candesartan cilexetil

Teva is not

recommended and should be considered only after

careful

evaluation of the potential benefits and risks.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the

risk of

hypotension,

hyperkalaemia and decreased renal

function (including acute renal

failure).

Dual

blockade of

RAAS through the combined use of

ACE-inhibitors,

angiotensin II

receptor

blockers or

aliskiren is therefore not

recommended (see sections 4.5 and 5.1).

If dual

blockade therapy is considered absolutely necessary,

this should only occur under specialist

supervision and

subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors

and angiotensin II

receptor

blockers

should not

be used concomitantly in patients

with diabetic

nephropathy.

General

In patients whose vascular tone and renal

function depend predominantly on the activity of the renin-angiotensin-

aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

4

stenosis),

treatment with other medicinal products that affect this system has been associated with acute hypotension,

azotaemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with AIIRAs. As

with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic

cerebrovascular disease could result in a myocardial infarction or stroke.

The antihypertensive effect of candesartan may be enhanced by other medicinal products with blood pressure lowering

properties, whether prescribed as an antihypertensive or prescribed for other indications.

Candesartan cilexetil Teva contains lactose.

Patients with rare hereditary problems of galactose intolerance,

the Lapp

lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Pregnancy

AIIRAs should not

be initiated during pregnancy.

Unless continued AIIRA therapy is considered essential,

patients

planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety

profile for use in pregnancy.

When pregnancy is diagnosed,

treatment

with AIIRAs should be stopped immediately,

and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Paediatric population, including patients with renal impairment

Candesartan has not been studied in children with a glomerular filtration rate less than 30 ml/min/1.73m

(see section

4.2).

For children with possible intravascular volume depletion (e.g.

patients treated with diuretics,

particularly those with

impaired renal function), candesartan treatment should be initiated under close medical supervision and a lower starting

dose should be considered (see section 4.2).

In post-menarche patients the possibility of pregnancy should be evaluated on a regular basis. Appropriate information

should be given and/or action taken to prevent the risk of exposure during pregnancy (see sections 4.3 and 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin,

digoxin, oral contraceptives (i.e. ethinylestradiol/levonorgestrel), glibenclamide and nifedipine. No clinically

significant pharmacokinetic interactions with these medicinal products have been identified.

Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other

medicinal products (e.g. heparin) may increase potassium levels. Monitoring of potassium should be undertaken as

appropriate (see section 4.4).

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant

administration of lithium with ACE inhibitors. A similar effect may occur with AIIRAs.

Use of candesartan with

lithium is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is

recommended.

When AIIRAs are administered simultaneously with non-steroidal anti-inflammatory drugs (NSAIDs) (i.e. selective

COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive

effect may occur.

As with ACE inhibitors, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of worsening of renal

function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor

pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients

should be adequately hydrated and consideration should be given to monitoring renal function after initiation of

concomitant therapy, and periodically thereafter.

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the

combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of

adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure)

compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

5

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

Epidemiological

evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first

trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no

controlled epidemiological

data on the risk with AIIRAs,

similar

risks may exist

this class of

drugs.

Unless

continued AIIRA therapy is

considered essential,

patients

planning pregnancy should be changed to alternative

antihypertensive treatments

which have an established safety profile for

use in pregnancy.

When pregnancy is

diagnosed,

treatment

with AIIRAs should be stopped immediately and,

if appropriate,

alternative therapy should be

started.

Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity (decreased

renal

function,

oligohydramnios,

skull

ossification retardation)

and neonatal

toxicity (renal

failure,

hypotension,

hyperkalaemia) (see section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy,

ultrasound check of renal

function and skull

is recommended.

Infants whose mothers have taken AIIRAs should be

closely observed for hypotension (see sections 4.3 and 4.4).

Breastfeeding

Because no information is available regarding the use of Candesartan cilexetil Teva during breastfeeding, Candesartan

cilexetil

Teva is not

recommended and alternative treatments with better

established safety profiles during breast-

feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects on ability to drive and use machines

No studies on the effects of candesartan on the ability to drive and use machines have been performed.

However,

should be taken into account

that

occasionally dizziness or weariness may occur during treatment

with Candesartan

Teva.

4.8 Undesirable effects

Treatment of Hypertension

In controlled clinical studies adverse reactions were mild and transient. The overall incidence of adverse events showed

no association with dose or age.

Withdrawals from treatment

due to adverse events were similar with candesartan

cilexetil (3.1%) and placebo (3.2%).

In a pooled analysis of clinical

trial

data of hypertensive patients,

adverse reactions with candesartan cilexetil

were

defined based on an incidence of adverse events with candesartan cilexetil at least 1% higher than the incidence seen

with placebo.

By this definition, the most commonly reported adverse reactions were dizziness/vertigo, headache and

respiratory infection.

Below are presented adverse reactions from clinical trials and post-marketing experience.

The frequencies of adverse events are ranked according to the following: very common (

1/10), common (

1/100 to <

1/10), uncommon (

1/1,000 to < 1/100), rare (

1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be

estimated from the available data).

The use of AIIRAs is not recommended during the first trimester of pregnancy (see

section 4.4). The use of AIIRAs is contra-indicated during the second and third

trimesters of pregnancy (see sections 4.3 and 4.4).

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

6

Infections and infestations

Common:

Respiratory infection

Blood and lymphatic system disorders

Very rare:

Leukopenia, neutropenia and agranulocytosis

Metabolism and nutrition disorders

Very rare:

Hyperkalaemia, hyponatraemia

Nervous system disorders

Common:

Dizziness/vertigo, headache

Respiratory, thoracic and mediastinal disorders

Very rare:

Cough

Gastrointestinal disorders

Very rare:

Nausea

Hepatobiliary disorders

Very rare:

Increased liver enzymes, abnormal hepatic function or hepatitis

Skin and subcutaneous tissue disorders

Very rare:

Angioedema, rash, urticaria, pruritus

Musculoskeletal and connective tissue disorders

Very rare:

Back pain, arthralgia, myalgia

Renal and urinary disorders

Very rare:

Renal impairment, including renal failure in susceptible patients (see section 4.4).

Laboratory findings

In general, there were no clinically important influences of Candesartan cilexetil Teva on routine laboratory variables.

As for other inhibitors of the renin-angiotensin-aldosterone system, small decreases in haemoglobin have been seen. No

routine monitoring of

laboratory variables is usually necessary for

patients receiving Candesartan cilexetil

Teva.

However,

in patients

with renal

impairment,

periodic

monitoring of

serum potassium and creatinine levels

recommended.

Paediatric population

The safety of candesartan cilexetil was monitored in 255 hypertensive children and adolescents, aged 6 to <18 years

old, during a 4 week clinical efficacy study and a 1 year open label study (see section 5.1). In nearly all different

system organ classes, the frequency of adverse events in children are within common/uncommon range. Whilst the

nature and severity of the adverse events are similar to those in adults (see above), the frequency of all adverse events

are higher in children and adolescent, particularly in:

Headache, dizziness and upper respiratory tract infection, are “very common” (ie,

1/10) in children and

common (

1/100 to < 1/10) in adults.

Cough is “very common” (ie,

1/10) in children and very rare (<1/10,000) in adults.

Rash is “common” (ie,

1/100 to <1/10) in children and “very rare” (<1/10,000) in adults.

Hyperkalemia, hyponatraemia and abnormal liver function are uncommon (

1/1,000 to < 1/100) in children and

very rare (< 1/10,000) in adults.

Sinus arrhythmia, Nasopharyngitis, pyrexia are “common” (ie,

1/100 to <1/10) and oropharyngeal pain is “very

common” (ie,

1/10) in children; but none are reported in adults. However these are temporary and widespread

childhood illnesses.

The overall safety profile for candesartan cilexetil in paediatric patients does not differ significantly from the safety

profile in adults.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

7

Treatment of Heart Failure

The adverse experience profile of

Candesartan cilexetil

Teva in heart

failure patients

consistent

with the

pharmacology of

the drug and the health status of

the patients.

In the CHARM clinical

programme,

comparing

Candesartan in doses up to 32 mg (n=3,803) to placebo (n=3,796), 21.0% of the candesartan cilexetil group and 16.1%

of the placebo group discontinued treatment because of adverse events. The most commonly reported adverse reactions

were hyperkalaemia, hypotension and renal impairment. These events were more common in patients over 70 years of

age,

diabetics,

subjects who received other

medicinal

products which affect

the renin-angiotensin-aldosterone

system, in particular an ACE inhibitor and/or spironolactone.

Below are presented adverse reactions from clinical trials and post-marketing experience.

Blood and lymphatic system disorders

Very rare:

Leukopenia, neutropenia and agranulocytosis

Metabolism and nutrition disorders

Common:

Hyperkalaemia

Very rare:

Hyponatraemia

Nervous system disorders

Very rare:

Dizziness, headache

Vascular disorders

Common:

Hypotension

Gastrointestinal disorders

Very rare:

Nausea

Hepatobiliary disorders

Very rare:

Increased liver enzymes, abnormal hepatic function or hepatitis

Skin and subcutaneous tissue disorders

Very rare:

Angioedema, rash, urticaria, pruritus

Musculoskeletal and connective tissue disorders

Very rare:

Back pain, arthralgia, myalgia

Renal and urinary disorders

Common:

Renal impairment, including renal failure in susceptible patients (see section 4.4).

Laboratory findings

Hyperkalaemia and renal impairment are common in patients treated with Candesartan cilexetil Teva for the indication

of heart failure. Periodic monitoring of serum creatinine and potassium is recommended (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued

monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any

suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;

Fax: +353 1 6762517. Website: http://www.hpra.ie/; E-mail:medsafety@hpra.ie.

4.9 Overdose

Symptoms

Based on pharmacological

considerations,

the main manifestation of

an overdose is

likely to be symptomatic

hypotension and dizziness.

In individual

case reports of

overdose (of

up to 672 mg Candesartan cilexetil)

patient

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

8

recovery was uneventful.

Management

If symptomatic hypotension should occur,

symptomatic treatment should be instituted and vital signs monitored.

patient should be placed supine with the legs elevated. If this is not sufficient, plasma volume should be increased by

infusion of,

for example,

isotonic saline solution.

Sympathomimetic medicinal

products may be administered if the

above-mentioned measures are not sufficient. Candesartan is not removed by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin II antagonists, plain, ATC code C09CA06.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the

pathophysiology of hypertension, heart failure and other cardiovascular disorders. It also has a role in the pathogenesis

of end organ hypertrophy and damage. The major physiological effects of angiotensin II, such as vasoconstriction,

aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth, are mediated via the

type 1 (AT

) receptor.

Candesartan cilexetil is a prodrug suitable for oral use. It is rapidly converted to the active substance, candesartan, by

ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an AIIRA, selective for AT

receptors,

with tight binding to and slow dissociation from the receptor. It has no agonist activity.

Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and degrades bradykinin. There is no

effect on ACE and no potentiation of bradykinin or substance P. In controlled clinical trials comparing candesartan

with ACE inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil. Candesartan does not

bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. The

antagonism of the angiotensin II (AT

) receptors results in dose related increases in plasma renin levels, angiotensin I

and angiotensin II levels, and a decrease in plasma aldosterone concentration.

Hypertension

In hypertension, candesartan causes a dose-dependent, long-lasting reduction in arterial blood pressure. The

antihypertensive action is due to decreased systemic peripheral resistance, without reflex increase in heart rate. There is

no indication of serious or exaggerated first dose hypotension or rebound effect after cessation of treatment.

After administration of a single dose of candesartan cilexetil, onset of antihypertensive effect generally occurs within 2

hours. With continuous treatment, most of the reduction in blood pressure with any dose is generally attained within

four weeks and is sustained during long-term treatment. According to a meta-analysis, the average additional effect of a

dose increase from 16 mg to 32 mg once daily was small. Taking into account the inter-individual variability, a more

than average effect can be expected in some patients. Candesartan cilexetil once daily provides effective and smooth

blood pressure reduction over 24 hours, with little difference between maximum and trough effects during the dosing

interval. The antihypertensive effect and tolerability of candesartan and losartan were compared in two randomised,

double-blind studies in a total of 1,268 patients with mild to moderate hypertension. The trough blood pressure

reduction (systolic/diastolic) was 13.1/10.5 mmHg with candesartan cilexetil 32 mg once daily and 10.0/8.7 mmHg

with losartan potassium 100 mg once daily (difference in blood pressure reduction 3.1/1.8 mmHg, p<0.0001/p<0.0001).

When candesartan cilexetil is used together with hydrochlorothiazide, the reduction in blood pressure is additive. An

increased antihypertensive effect is also seen when candesartan cilexetil is combined with amlodipine or felodipine.

Medicinal products that block the renin-angiotensin-aldosterone system have less pronounced antihypertensive effect in

black patients (usually a low-renin population) than in non-black patients. This is also the case for candesartan. In an

open label clinical experience trial in 5,156 patients with diastolic hypertension, the blood pressure reduction during

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

9

candesartan treatment was significantly less in black than non-black patients (14.4/10.3 mmHg vs 19.0/12.7 mmHg,

p<0.0001/p<0.0001).

Candesartan increases renal blood flow and either has no effect on, or increases glomerular filtration rate while renal

vascular resistance and filtration fraction are reduced. In a 3-month clinical study in hypertensive patients with type 2

diabetes mellitus and microalbuminuria, antihypertensive treatment with candesartan cilexetil reduced urinary albumin

excretion (albumin/creatinine ratio, mean 30%, 95%CI 15

42%). There is currently no data on the effect of

candesartan on the progression to diabetic nephropathy.

The effects of candesartan cilexetil 8-16 mg (mean dose 12 mg), once daily, on cardiovascular morbidity and mortality

were evaluated in a randomised clinical trial with 4,937 elderly patients (aged 70-89 years; 21% aged 80 or above) with

mild to moderate hypertension followed for a mean of 3.7 years (Study on COgnition and Prognosis in the Elderly).

Patients received Candesartan cilexetil or placebo with other antihypertensive treatment added as needed. The blood

pressure was reduced from 166/90 to 145/80 mmHg in the candesartan group, and from 167/90 to 149/82 mmHg in the

control group. There was no statistically significant difference in the primary endpoint, major cardiovascular events

(cardiovascular mortality, non-fatal stroke and non-fatal myocardial infarction). There were 26.7 events per 1000

patient-years in the candesartan group versus 30.0 events per 1000 patient-years in the control group (relative risk 0.89,

95%CI 0.75 to 1.06, p=0.19).

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril

Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use

of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2

diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type

2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while

an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed.

Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and

angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with

diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study

designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor

blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study

was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both

numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse

events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren

group than in the placebo group.

Heart Failure

Treatment with candesartan cilexetil reduces mortality, reduces hospitalisation due to heart failure and improves

symptoms in patients with left ventricular systolic dysfunction as shown in the Candesartan in Heart failure –

Assessment of Reduction in Mortality and morbidity (CHARM) programme.

This placebo controlled, double-blind study programme in chronic heart failure (CHF) patients with NYHA functional

class II to IV consisted of three separate studies: CHARM-Alternative (n=2,028) in patients with LVEF

40% not

treated with an ACE inhibitor because of intolerance (mainly due to cough, 72%), CHARM-Added (n=2,548) in

patients with LVEF

40% and treated with an ACE inhibitor, and CHARM-Preserved (n=3,023) in patients with

LVEF > 40%. Patients on optimal CHF therapy at baseline were randomised to placebo or candesartan cilexetil (titrated

from 4 mg or 8 mg once daily to 32 mg once daily or the highest tolerated dose, mean dose 24 mg) and followed for a

median of 37.7 months. After 6 months of treatment 63% of the patients still taking candesartan cilexetil (89%) were at

the target dose of 32 mg.

In CHARM-Alternative, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was

significantly reduced with candesartan in comparison with placebo, hazard ratio (HR) 0.77 (95%CI: 0.67 to 0.89, p<

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

1

0

0.001). This corresponds to a relative risk reduction of 23%. Of candesartan patients 33.0% (95%CI: 30.1 to 36.0) and

of placebo patients 40.0% (95%CI: 37.0 to 43.1) experienced this endpoint, absolute difference 7.0% (95%CI: 11.2 to

2.8). Fourteen patients needed to be treated for the duration of the study to prevent one patient from dying of a

cardiovascular event or being hospitalised for treatment of heart failure. The composite endpoint of all-cause mortality

or first CHF hospitalisation was also significantly reduced with candesartan, HR 0.80 (95%CI: 0.70 to 0.92, p=0.001).

Of candesartan patients 36.6% (95%CI: 33.7 to 39.7) and of placebo patients 42.7% (95%CI: 39.6 to 45.8) experienced

this endpoint, absolute difference 6.0% (95%CI: 10.3 to 1.8). Both the mortality and morbidity (CHF hospitalisation)

components of these composite endpoints contributed to the favourable effects of candesartan. Treatment with

candesartan cilexetil resulted in improved NYHA functional class (p=0.008).

In CHARM-Added, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly

reduced with candesartan in comparison with placebo, HR 0.85 (95%CI: 0.75 to 0.96, p=0.011). This corresponds to a

relative risk reduction of 15%. Of candesartan patients 37.9% (95%CI: 35.2 to 40.6) and of placebo patients 42.3%

(95%CI: 39.6 to 45.1) experienced this endpoint, absolute difference 4.4% (95%CI: 8.2 to 0.6). Twenty-three patients

needed to be treated for the duration of the study to prevent one patient from dying of a cardiovascular event or being

hospitalised for treatment of heart failure. The composite endpoint of all-cause mortality or first CHF hospitalisation

was also significantly reduced with candesartan, HR 0.87 (95%CI: 0.78 to 0.98, p=0.021). Of candesartan patients

42.2% (95%CI: 39.5 to 45.0) and of placebo patients 46.1% (95%CI: 43.4 to 48.9) experienced this endpoint, absolute

difference 3.9% (95%CI: 7.8 to 0.1). Both the mortality and morbidity components of these composite endpoints

contributed to the favourable effects of candesartan. Treatment with candesartan cilexetil resulted in improved NYHA

functional class (p=0.020).

In CHARM-Preserved, no statistically significant reduction was achieved in the composite endpoint of cardiovascular

mortality or first CHF hospitalisation, HR 0.89 (95%CI: 0.77 to 1.03, p=0.118).

All-cause mortality was not statistically significant when examined separately in each of the three CHARM studies.

However, all-cause mortality was also assessed in pooled populations, CHARM-Alternative and CHARM-Added, HR

0.88 (95%CI: 0.79 to 0.98, p=0.018) and all three studies, HR 0.91 (95%CI: 0.83 to 1.00, p=0.055).

The beneficial effects of candesartan were consistent irrespective of age, gender and concomitant medication.

Candesartan was effective also in patients taking both beta-blockers and ACE inhibitors at the same time, and the

benefit was obtained whether or not patients were taking ACE inhibitors at the target dose recommended by treatment

guidelines.

In patients with CHF and depressed left ventricular systolic function (left ventricular ejection fraction, LVEF

40%),

candesartan decreases systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin

activity and angiotensin II concentration, and decreases aldosterone levels.

Paediatric population - hypertension

The antihypertensive effects of candesartan were evaluated in hypertensive children aged 1 to <6 years and 6 to <17

years in two randomised, double-blind multicentre, 4 week dose ranging studies.

In children aged 1 to <6 years, 93 patients, 74% of whom had renal disease, were randomised to receive an oral dose of

candesartan cilexetil suspension 0.05, 0.20 or 0.40 mg/kg once daily.

The primary method of analysis was slope of the change in systolic blood pressure (SBP) as a function of dose. SBP

and diastolic blood pressure (DBP) decreased 6.0/5.2 to 12.0/11.1 mmHg from baseline across the three doses of

candesartan cilexetil. However, since there was no placebo group, the true magnitude of blood pressure effect remains

uncertain which makes a conclusive assessment of benefit-risk balance difficult in this age group.

In children aged 6 to <17 years, 240 patients were randomised to receive either placebo or low, medium, or high doses

of candesartan cilexetil in a ratio of 1: 2: 2: 2. For children who weighed < 50 kg, the doses of candesartan cilexetil

were 2, 8, or 16 mg once daily. In children who weighed > 50 kg, the candesartan cilexetil doses were 4, 16 or 32 mg

once daily. Candesartan at pooled doses reduced SiSBP by 10.22 mmHg (P< 0.0001) and SiDBP (P=0.0029) by 6.56

mmHg, from the base line. In the placebo group, there was also a reduction of 3.667 mmHg in SiSBP (p=0.0074) and

1.80 mmHg for SiDBP (p=0.0992) from the baseline. Despite the large placebo effect, all individual candesartan doses

(and all doses pooled) were significantly superior to placebo. Maximum response in reduction of blood pressure in

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

1

1

children below and above 50 kg was reached at 8mg and 16 mg doses, respectively and the effect plateaued after that

point.

Of those enrolled, 47% were black patients and 29% were female; mean age +/- SD was 12.9 +/- 2.6 years. In children

aged 6 to < 17 years there was a trend for a lesser effect on blood pressure in black patients compared to non-black

patients.

5.2 Pharmacokinetic properties

Absorption and distribution

Following oral administration, candesartan cilexetil is converted to the active substance candesartan. The absolute

bioavailability of candesartan is approximately 40% after an oral solution of candesartan cilexetil. The relative

bioavailability of the tablet formulation compared with the same oral solution is approximately 34% with very little

variability. The estimated absolute bioavailability of the tablet is therefore 14%. The mean peak serum concentration

) is reached 3-4 hours following tablet intake. The candesartan serum concentrations increase linearly with

increasing doses in the therapeutic dose range. No gender related differences in the pharmacokinetics of candesartan

have been observed. The area under the serum concentration versus time curve (AUC) of candesartan is not

significantly affected by food. Candesartan is highly bound to plasma protein (more than 99%). The apparent volume

of distribution of candesartan is 0.1 l/kg.

The bioavailability of candesartan is not affected by food.

Biotransformation and elimination

Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated by hepatic

metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and CYP3A4. Based on in vitro

data, no interaction would be expected to occur in vivo with drugs whose metabolism is dependent upon cytochrome

P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal half-life of

candesartan is approximately 9 hours. There is no accumulation following multiple doses.

Total plasma clearance of candesartan is about 0.37 ml/min/kg, with a renal clearance of about 0.19 ml/min/kg. The

renal elimination of candesartan is both by glomerular filtration and active tubular secretion. Following an oral dose of

C-labelled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an

inactive metabolite while approximately 56% of the dose is recovered in the faeces as candesartan and 10% as the

inactive metabolite.

Special populations

In the elderly (over 65 years) C

and AUC of candesartan are increased by approximately 50% and 80%,

respectively in comparison to young subjects. However, the blood pressure response and the incidence of adverse

events are similar after a given dose of Candesartan cilexetil Teva in young and elderly patients (see section 4.2).

In patients with mild to moderate renal impairment C

and AUC of candesartan increased during repeated dosing by

approximately 50% and 70%, respectively, but t

was not altered, compared to patients with normal renal function.

The corresponding changes in patients with severe renal impairment were approximately 50% and 110%, respectively.

The terminal t

of candesartan was approximately doubled in patients with severe renal impairment. The AUC of

candesartan in patients undergoing haemodialysis was similar to that in patients with severe renal impairment.

In two studies, both including patients with mild to moderate hepatic impairment, there was an increase in the mean

AUC of candesartan of approximately 20% in one study and 80% in the other study (see section 4.2). There is no

experience in patients with severe hepatic impairment.

Paediatric population

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

1

2

The Pharmacokinetic properties of candesartan were evaluated in hypertensive children aged1 to <6 years and 6 to <17

years in two single dose PK studies.

In children aged 1 to <6 years, 10 children weighting 10 to <25 kg received a single dose of 0.2mg/kg, oral suspension.

There was no correlation between Cmax and AUC with age or weight. No clearance data has been collected; therefore

the possibility of a correlation between clearance and weight/age in this population is unknown.

In children aged 6 to <17 years, 22 children received a single dose of 16 mg tablet. There was no correlation between

Cmax and AUC with age. However weight seems to significantly correlate with Cmax (p=0.012) and AUC (p=0.011).

No clearance data, has been collected, therefore the possibility of a correlation between clearance and weight/age in this

population is unknown.

Children >6 years of age had exposure similar to adults given the same dose.

The pharmacokinetics of candesartan cilexetil have not been investigated in paediatric patients <1 year of age.

5.3 Preclinical safety data

There was no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In preclinical safety

studies candesartan had effects on the kidneys and on red cell

parameters at

high doses in mice,

rats,

dogs and

monkeys.

Candesartan caused a reduction of

red blood cell

parameters (erythrocytes,

haemoglobin,

haematocrit).

Effects

on the

kidneys

(such as

interstitial

nephritis,

tubular

distension,

basophilic

tubules;

increased plasma

concentrations of urea and creatinine) were induced by candesartan which could be secondary to the hypotensive effect

leading

alterations

renal

perfusion.

Furthermore,

candesartan

induced

hyperplasia/hypertrophy

juxtaglomerular cells. These changes were considered to be caused by the pharmacological action of candesartan. For

therapeutic doses of candesartan in humans,

the hyperplasia/hypertrophy of the renal

juxtaglomerular cells does not

seem to have any relevance.

Foetotoxicity has been observed in late pregnancy (see section 4.6).

Data from in vitro and in vivo mutagenicity testing indicates that candesartan will not exert mutagenic or clastogenic

activities under conditions of clinical use. There was no evidence of carcinogenicity.

In preclinical studies in normotensive neonatal and juvenile rats,

candesartan caused a reduction in body weight and

heart weight. As in adult animals, these effects are considered to result from the pharmacological action of candesartan.

At the lowest dose of 10 mg/kg exposure to candesartan was between 12 and 78 times the levels found in children aged

1 to <6 who received candesartan cilexetil at a dose of 0.2 mg/kg and 7 to 54 times those found in children aged 6 to

<17 who received candesartan cilexetil at a dose of 16 mg.

As a no observed effect level was not identified in these

studies, the safety margin for the effects on heart weight and the clinical relevance of the finding is unknown.

The renin-angiotensin-aldosterone system plays a critical

role in kidney development

in utero.

Renin-angiotensin-

aldosterone

system blockade

been shown to lead to abnormal

kidney development

in very young mice.

Administering drugs that act directly on the renin-angiotensin-aldosterone system can alter normal renal development.

Therefore, children aged less than 1 year must should not receive candesartan (see section 4.3).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Pregelatinized maize starch

Povidone K-30

Carmellose calcium

Microcrystalline cellulose (E460)

Lactose monohydrate

Magnesium stearate

Poloxamer 188

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

1

3

Red iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Do not store above 30°C. Store in original packaging to protect from moisture.

6.5 Nature and contents of container

OPA/Aluminium/PVC – PVC/PVAC/Aluminium/OPA blisters.

Pack sizes: 7, 14, 15, 20, 28, 30, 50, 50 x 1 unit dose blisters (hospital pack), 56, 60, 84, 90, 98, 100, 250 & 300 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Teva Pharma B.V.

Swansweg 5

2031GA Haarlem

Netherlands

8 MARKETING AUTHORISATION NUMBER

PA0749/124/003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 6

January 2012

Date of last renewal: 30

December 2015

10 DATE OF REVISION OF THE TEXT

May 2018

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

1

/

0

6

/

2

0

1

8

C

R

N

2

1

6

3

9

9

2

p

a

g

e

n

u

m

b

e

r

:

1

4

Similar products

Search alerts related to this product

View documents history

Share this information