CANDESARTAN MYLAN

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
CANDESARTAN CILEXETIL
Available from:
McDermott Laboratories Ltd t/a Gerard Laboratories
ATC code:
C09CA06
INN (International Name):
CANDESARTAN CILEXETIL
Dosage:
16 Milligram
Pharmaceutical form:
Tablets
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
candesartan
Authorization status:
Not Marketed
Authorization number:
PA0577/120/003
Authorization date:
2011-08-26

Page 1 of 6

Package leaflet: Information for the patient

Candesartan Mylan 4 mg Tablets

Candesartan Mylan 8 mg Tablets

Candesartan Mylan 16 mg Tablets

candesartan cilexetil

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Candesartan Mylan is and what it is used for

What you need to know before you take Candesartan Mylan

How to take Candesartan Mylan

Possible side effects

How to store Candesartan Mylan

Contents of the pack and other information

1.

What Candesartan Mylan is and what it is used for

Candesartan Mylan contains the active substance candesartan which belongs to a group of medicines

known as angiotensin II receptor antagonists that lower blood pressure. It works by making your blood

vessels relax and widen (which helps to lower your blood pressure). It also makes it easier for your

heart to pump blood to all parts of your body.

Candesartan Mylan is used for:

treating high blood pressure (hypertension) in adult patients and in children and adolescents aged 6

to 18 years.

treating adult heart failure patients with reduced heart muscle function when Angiotensin

Converting Enzyme (ACE) inhibitors cannot be used or in addition to ACE-inhibitors when

symptoms persist despite treatment and mineralocorticoid receptor antagonists (MRA) cannot be

used. (ACE-inhibitors and MRAs are medicines used to treat heart failure).

2.

What you need to know before you take Candesartan Mylan

Do not take Candesartan Mylan:

if you are allergic to candesartan cilexetil or any of the other ingredients of this medicine (listed in

section 6)

if you have severe liver disease or biliary obstruction (a problem with the drainage of the bile from

the gall bladder)

if you are more than 3 months pregnant. (It is also better to avoid Candesartan Mylan in early

pregnancy - see pregnancy section)

if the patient is a child under 1 year of age

if you have diabetes or impaired kidney function and you are treated with a blood pressure

lowering medicine containing aliskiren.

Page 2 of 6

Warnings and precautions

Talk to your doctor or pharmacist before taking Candesartan Mylan:

if you have heart, liver or kidney problems, or are on dialysis

if you have recently had a kidney transplant

if you are vomiting, have recently had severe vomiting, or have diarrhoea

if you have a disease of the adrenal gland called Conn’s syndrome (also called primary

hyperaldosteronism)

if you have low blood pressure

if you have ever had a stroke

if you are taking any of the following medicines used to treat high blood pressure:

an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetes-

related kidney problems

aliskiren

if you are taking an ACE-inhibitor together with a medicine which belongs to the class of

medicines known as mineralocorticoid receptors antagonists (MRA). These medicines are for the

treatment of heart failure (see “Other medicines and Candesartan Mylan”)

you must tell your doctor if you think you are (or might become) pregnant. Candesartan is not

recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant,

as it may cause serious harm to your baby if used at that stage (see pregnancy section).

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g.

potassium) in your blood at regular intervals.

See also information under the heading “Do not take Candesartan Mylan”

If you are going to have an operation, tell your doctor or dentist that you are taking candesartan. This

is because candesartan, when combined with some anaesthetics, may cause a drop in blood pressure.

Children and adolescents

Candesartan has been studied in children. For more information, talk to your doctor. Candesartan must

not be given to children under 1 year of age due to the potential risk to the developing kidneys.

Other medicines and Candesartan Mylan

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines, including medicines obtained without a prescription.

Candesartan Mylan can affect the way some other medicines work and some medicines can have an

effect on Candesartan Mylan. Your doctor may need to change your dose and/or to take other

precautions. If you are using certain medicines, your doctor may need to do blood tests from time to

time. In particular, tell your doctor if you are taking any of the following medicines:

Other medicines to help lower your blood pressure, including beta-blockers, diazoxide, ACE-

inhibitors (such as enalapril, captopril, lisinopril or ramipril) or aliskiren (see also information

under the headings “Do not take Candesartan Mylan” and “Warnings and precautions”).

An ACE-inhibitor together with certain other medicines to treat your heart failure, which are

known as mineralocorticoid receptors antagonists (MRA) (for example spironolactone,

eplerenone).

Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, diclofenac,

celecoxib, or etoricoxib (medicines used to relieve pain and inflammation).

Acetylsalicylic acid (if you are taking more than 3 g each day) (medicine to relieve pain and

inflammation).

Potassium supplements or salt substitutes containing potassium (medicines that increase the

amount of potassium in your blood).

Heparin (a medicine for thinning the blood)

Diuretics (medicines known as ‘water tablets’)

Lithium (a medicine used to treat mental health problems)

Page 3 of 6

Candesartan Mylan with food and alcohol

You can take Candesartan Mylan with or without food.

When you are prescribed candesartan discuss with your doctor before drinking alcohol. Alcohol,

while taking Candesartan Mylan, may make you feel faint and dizzy.

Pregnancy and breast-feeding

Pregnancy

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor or

pharmacist for advice before taking this medicine. Your doctor will normally advise you to stop taking

Candesartan Mylan before you become pregnant or as soon as you know you are pregnant and will

advise you to take another medicine instead of this medicine. Candesartan Mylan is not recommended

in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious

harm to your baby if used after the third month of pregnancy.

Breast-feeding

If you are breast-feeding or about to start breast-feeding ask your doctor or pharmacist for advice

before taking this medicine. Candesartan Mylan is not recommended for mothers who are breast-

feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if

your baby is newborn, or was born prematurely.

Driving and using machines

Some people may feel tired or dizzy when taking this medicine. If this happens to you, do not drive or

use any tools or machines.

Candesartan Mylan contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, such as lactose,

contact your doctor before taking this medicine.

3.

How to take Candesartan Mylan

This is a long-term treatment.

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor

or pharmacist if you are not sure. It is important to keep taking candesartan every day.

You can take Candesartan Mylan with or without food. Swallow the tablet with a drink of water. Try

to take the tablet at the same time each day. This will help you remember to take it.

The tablet can be divided into equal doses.

To treat high blood pressure:

The recommended starting dose is 8 mg once a day. Your doctor may increase this dose up to 32 mg

once a day depending on blood pressure response.

In some patients, such as those with liver problems, kidney problems or those who recently have lost

body fluids, e.g. through vomiting or diarrhoea or by using water tablets, the doctor may prescribe a

lower starting dose.

Some black patients may have a reduced response to this type of medicine when given as the only

treatment; these patients may need a higher dose.

To treat heart failure:

The recommended starting dose of candesartan is 4 mg once a day. Your doctor may increase your

dose by doubling the dose at intervals of at least 2 weeks up to 32 mg once a day. Candesartan can be

taken together with other medicines for heart failure, and your doctor will decide which treatment is

suitable for you.

Page 4 of 6

Use in children and adolescents with high blood pressure:

Children 6 to 18 years of age: The recommended starting dose is 4 mg once daily.

For patients weighing less than 50 kg your doctor may decide the dose needs to be increased to a

maximum of 8 mg once daily.

For patients weighing 50 kg or more your doctor may decide the dose needs to be increased to 8 mg

once daily and then to 16 mg once daily, if needed.

If you take more Candesartan Mylan than you should:

If you take more Candesartan Mylan than prescribed by your doctor, contact a doctor or pharmacist

immediately for advice. Your blood pressure may become low and you may feel dizzy.

If you forget to take Candesartan Mylan:

Do not take a double dose to make up for a forgotten dose. Just take the next dose as normal.

If you stop taking Candesartan Mylan:

If you stop taking this medicine, your blood pressure may increase again. Therefore, do not stop

taking Candesartan Mylan without talking to your doctor first.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

It is important that you are aware of what these side effects may be.

Stop taking Candesartan Mylan and contact your doctor or go to the nearest hospital emergency

department if you have any of the following:

Very rare (may affect less than 1 in 10,000 people):

swelling of the face, lips, tongue and/or throat, which may cause difficulties in breathing or

swallowing.

an increase in the number of infections you may get which causes fever, severe chills, sore

throats, mouth ulcers or chesty coughs. These may be due to a low number of white blood cells.

abnormal liver function including inflammation of the liver (hepatitis) which may be seen as

feeling sick (nausea), being sick (vomiting) loss of appetite, generally feeling unwell, fever,

itching, yellowing of the skin or whites of the eyes with pale stools or dark coloured urine.

These may be signs of serious problems with your liver.

a decrease in kidney function which may be seen as producing little or no urine, cloudy urine or

blood in the urine, pain when passing urine or lower back pain. These may be signs of serious

kidney problems. In very rare cases kidney failure may occur.

Other possible side effects include:

Common (may affect up to 1 in 10 people):

feeling dizzy/spinning sensation when standing still (vertigo)

headache

chest infection

low blood pressure. This may make you feel faint or dizzy

an increased amount of potassium in your blood which can be seen in a blood test, especially if

you already have kidney problems or heart failure. If this is severe you may notice tiredness,

weakness, an irregular heartbeat or pins and needles in your hands or feet

Very rare (may affect less than 1 in 10,000 people):

skin rash, lumpy rash (hives)

Page 5 of 6

itching

cough

back pain, pain in joints and muscles

feeling sick (nausea)

changes in blood test results such as a reduced amount of sodium or an increase in liver enzymes

in your blood.

Not known (frequency cannot be estimated from the available data)

diarrhoea

Additional side effects seen in children and adolescents

In children treated for high blood pressure, side effects appear to be similar to those seen in adults, but

they happen more often. A sore throat is a very common side effect seen in children and a blocked or

runny nose, fever and increased heart rate are common side effects in children but none of these have

been reported in adults.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet.

You can also report side effects directly 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. By reporting side effects you can help provide more information on the safety of

this medicine.

5.

How to store Candesartan Mylan

Keep out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton, blister or bottle after EXP.

The expiry date refers to the last day of that month. After first opening the bottle, use within 100 days.

Do not store above 25˚C. Store in the original package in order to protect from moisture.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Candesartan Mylan contains

The active substance is candesartan cilexetil.

One tablet contains either 4 mg, 8 mg, or 16 mg of candesartan cilexetil.

The other ingredients are carmellose calcium, hydroxypropylcellulose, lactose monohydrate (see

section 2 ‘Candesartan Mylan contains lactose’), magnesium stearate and mannitol.

What Candesartan Mylan looks like and contents of the pack

Candesartan Mylan 4 mg tablets are white to off white, round, biconvex tablet debossed with “C1” on

one side and “M” on one side of the break line on the other side.

Candesartan Mylan 8 mg tablets are white to off white, round, biconvex tablet debossed with “M over

C5” on one side and plain with break line on the other side.

Candesartan Mylan 16 mg tablets are white to off white, round, biconvex tablet debossed with “M

over C6” on one side and plain with break line on the other side.

Page 6 of 6

Candesartan Mylan is available in blisters either inside a carton or inside a pouch of 7, 10, 14, 15, 28,

30, 50, 56, 60, 84, 90, 98 and 100 tablets, and in plastic bottles of 30, 49, 56, 90 and 98 tablets. The

pouch and bottles contain a desiccant. The bottles also contain cotton wool. Do not eat the desiccant.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

McDermott Laboratories Ltd. T/A Gerard Laboratories, 35-36 Baldoyle Industrial Estate, Grange

Road, Dublin 13, Ireland.

Manufacturer

Generics [UK] Ltd., Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom

McDermott Laboratories Ltd. T/A Gerard Laboratories, 35/36 Baldoyle Industrial Estate, Grange

Road, Dublin 13, Ireland

Mylan Hungary Kft, H-2900 Komárom, Mylan utca 1, Hungary

Mylan B.V., Dieselweg 25, 3752 LB Bunschoten, the Netherlands

Mylan S.A.S., 117 Allee des Parcs, 69 800 Saint-Priest, France.

This medicinal product is authorised in the Member States of the EEA under the following

names:

Austria – Candesartan cilexetil Arcana 4 mg, 8 mg, 16 mg, 32 mg Tabletten

Belgium – Candesartan Mylan 8 mg, 16 mg, 32 mg tabletten

Bulgaria – Candesagen 4 mg, 8 mg, 16 mg, 32 mg таблетки

Cyprus – Candesartan/Generics 4 mg, 8 mg, 16 mg, 32 mg Δισκία

Denmark –Kandrozid 4 mg, 8 mg, 16 mg, 32 mg tabletter

Finland – Kandrozid 4 mg, 8 mg, 16 mg, 32 mg tabletit

France – Candesartan Mylan 4 mg, 8 mg, 16 mg, 32 mg Comprimés sécables

Germany – Candesartan cilexetil Mylan 4 mg , 8 mg , 16 mg, 32 mg Tabletten

Hungary – Candesartan Mylan 4 mg, 8 mg, 16 mg, 32 mg tabletta

Ireland – Candesartan Mylan 4 mg , 8 mg , 16 mg, 32 mg Tablets

Luxembourg – Candesartan Mylan 8 mg, 16 mg, 32 mg comprimés

Netherlands – Candesartan cilexetil Mylan 4 mg, 8 mg, 16 mg, 32 mg tabletten

Norway –Kandrozid 4 mg, 8 mg, 16 mg, 32 mg tabletter

Poland – Kangen 8 mg, 16 mg tabletki

Portugal – Candesartan Mylan 4 mg, 8 mg, 16 mg, 32 mg comprimidos

Romania – Candegen 4 mg, 8 mg, 16 mg comprimate

Slovakia – Candesartan Mylan 8 mg, 16 mg, 32 mg tablety

Spain – Candesartan Mylan 4 mg, 8 mg, 16 mg, 32 mg comprimidos EFG

Sweden – Kandrozid 4 mg, 8 mg, 16 mg, 32 mg tabletter

United Kingdom – Candesartan cilexetil 4 mg, 8 mg, 16 mg, 32 mg Tablets

This leaflet was last revised in: May 2018

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Candesartan Mylan 16mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 16 mg candesartan cilexetil.

Excipient with known effect

Each tablet contains 74.0 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

White to off white, round, biconvex tablet debossed with “M over C6” on one side and plain with a break line on the

other side.

The tablet can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Treatment of essential hypertension in adults.

Treatment of adult patients with heart failure and impaired left ventricular systolic function (left ventricular

ejection fraction

40%) when Angiotensin Converting Enzyme (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 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 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 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.

Elderly population

No initial dose adjustment is necessary in elderly patients.

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

depletion (see section 4.4).

Renal impairment

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

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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).

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 is contraindicated in patients with severe hepatic impairment

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

Black patients

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

Consequently, up-titration of candesartan and concomitant therapy may be more frequently needed for blood pressure

control in black patients than 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/1.73 m

(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 is 4 mg once daily. Up-titration to the target dose of 32 mg once

daily (maximum dose) or to 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 can be administered with other heart failure treatment,

including ACE-inhibitors, beta-blockers, diuretics and digitalis or a combination of these medicinal products.

Candesartan 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 is not 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 elderly patients or in patients with intravascular volume depletion, renal

impairment or mild to moderate hepatic impairment.

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Paediatric population

The safety and efficacy of candesartan 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 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 trimester 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 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

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.

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.

When candesartan 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 (Cl

creatinine

<15 ml/min). In these patients candesartan 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, monitoring of

serum creatinine and potassium is recommended. Clinical trials in heart failure did not include patients with serum

creatinine >265

mol/L (>3 mg/dL).

Use in paediatric patients, including patients with renal impairment

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

(see section

4.2).

Concomitant therapy with an ACE-inhibitor in heart failure

The risk of adverse reactions, especially hypotension, hyperkalaemia and decreased renal function (including acute

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renal failure), may increase when candesartan 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

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 should be carefully titrated

with thorough monitoring of blood pressure in patients on haemodialysis.

Renal artery stenosis

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 limited clinical evidence regarding candesartan use in patients who have undergone renal transplant.

Hypotension

Hypotension may occur during treatment with candesartan 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 hypovolaemia should be attempted.

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).

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 not generally respond to antihypertensive medicinal products acting

through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of candesartan is not recommended

in this population.

Hyperkalaemia

Concomitant use of candesartan 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, hyperkalaemia may occur. Periodic monitoring of serum potassium is

recommended.

The combination of an ACE-inhibitor, a potassium-sparing diuretic (e.g. spironolactone) and

candesartan is not recommended and should be considered only after careful evaluation of the potential benefits and

risks.

General

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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

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.

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).

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).

Candesartan Cilexetil contains lactose monohydrate

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose

malabsorption should not take this medicine.

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, nifedipine and enalapril.

No clinically

significant pharmacokinetic interactions with these medicines 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).

Paediatric population

Interaction studies have only been performed in adults.

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4.6 Fertility, pregnancy and lactation

Pregnancy

The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs

is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

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 for 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 foetotoxicity (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).

Breast-feeding

Because no information is available regarding the use of candesartan during breast-feeding, candesartan 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, it

should be taken into account that occasionally dizziness or weariness may occur during treatment with candesartan.

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.

The table below presents adverse reactions from clinical trials and post-marketing experience.

The frequencies used in the tables throughout this section are: 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) and not known (cannot be

estimated from the available data):

System organ class

Frequency

Undesirable effect

Infections and infestations

Common

Respiratory infection

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Laboratory findings

In general, there were no clinically important influences of candesartan 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. However, in patients with

renal impairment, periodic monitoring of serum potassium and creatinine levels is 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 the table above), the frequency of all adverse

events are higher in children and adolescents, particularly in:

Headache, dizziness and upper respiratory tract infection, are “very common” (i.e.

1/10) in children and

common (

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

Cough is “very common” (i.e. > 1/10) in children and very rare (< 1/10,000) in adults.

Rash is “common” (i.e.

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

Hyperkalaemia, 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” (i.e.

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

“very common” (i.e.

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.

Treatment of heart failure

The adverse experience profile of candesartan in adult heart failure patients was 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, or

subjects who received other medicinal products which affect the renin-angiotensin-aldosterone system, in particular an

ACE-inhibitor and/or spironolactone.

The table below presents adverse reactions from clinical trials and post-marketing experience.

Blood and lymphatic system disorders

Very rare

Leucopenia, 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

Not known

Diarrhoea

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)

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Laboratory findings

Hyperkalaemia and renal impairment are common in patients treated with candesartan for the indication of heart

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

Reporting 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: 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) in an adult

patient recovery was uneventful.

Management

If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital signs monitored. The

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.

Mechanism of action

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,

System organ class

Frequency

Undesirable effect

Blood and lymphatic system disorders

Very rare

Leucopenia, neutropenia and

agranulocytosis

Metabolism and nutrition disorders

Common

Hyperkalaemia

Very rare

Hyponatraemia

Nervous system disorders

Very rare

Dizziness, headache

Vascular disorders

Common

Hypotension

Respiratory, thoracic and mediastinal

disorders

Very rare

Cough

Gastrointestinal disorders

Very rare

Nausea

Not known

Diarrhoea

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).

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

type 1 (AT

) receptor.

Pharmacodynamic effects

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 angiotensin II receptor antagonist,

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 (AT1) receptors results in dose related increases in plasma renin levels, angiotensin I

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

Clinical efficacy and safety

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

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% confidence interval 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).

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

Global Endpoint Trial) and VA NEPHRON-0 (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.

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 10.2 mmHg (P< 0.0001) and SiDBP (P=0.0029) by 6.6

mmHg, from the base line. In the placebo group, there was also a reduction of 3.7 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

children below and above 50 kg was reached at 8 mg 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.

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

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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 0.67-0.89,

p<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 0.70-0.92, 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 0.75-0.96, 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 0.78-0.98, 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 0.77-1.03, 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 0.79-0.98, p=0.018) and all three studies, HR 0.91 (95% CI 0.83-1.00, 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.

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

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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 on 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.

Pharmacokinetics in 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 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 t½ 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 t½ 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

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

years in two single dose PK studies.

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

There was no correlation between C

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

and AUC with age. However weight seems to significantly correlate with C

(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

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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 to alterations of renal perfusion.

Furthermore, candesartan induced hyperplasia/hypertrophy of the

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.

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.

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.

The renin-angiotensin-aldosterone system plays a critical role in kidney development in utero. Renin-angiotensin-

aldosterone system blockade has 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 should not receive candesartan cilexetil (see section 4.3).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Carmellose calcium

Hydroxypropylcellulose

Lactose monohydrate

Magnesium stearate

Mannitol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

The in-use shelf life of the product when stored in HDPE bottles is 100 days.

6.4 Special precautions for storage

Do not store above 25˚C. Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

OPA-Aluminium-PVC / Aluminium blister contained within a laminated pouch, together with a desiccant bag, or a

PVC / Aluminium blister: pack of 7, 10, 14, 15, 28, 30, 50, 56, 60, 84, 90, 98 and 100 tablets.

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White opaque HDPE bottles with screw cap with desiccant and absorbent cotton: pack of 30, 49, 56, 90 and 98 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

McDermott Laboratories Ltd

t/a Gerard Laboratories

35/36 Baldoyle Industrial Estate

Grange Road

Dublin 13

Ireland

8 MARKETING AUTHORISATION NUMBER

PA0577/120/003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26th August 2011

Date of last renewal: 26th January 2016

10 DATE OF REVISION OF THE TEXT

July 2018

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