Candesartan 4 mg Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Candesartan cilexetil
Available from:
Actavis Group PTC ehf
ATC code:
C09CA; C09CA06
INN (International Name):
Candesartan cilexetil
Dosage:
4 milligram(s)
Pharmaceutical form:
Tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Angiotensin II antagonists, plain; candesartan
Authorization status:
Marketed
Authorization number:
PA1380/092/001
Authorization date:
2011-04-15

Package leaflet: Information for the user

Candesartan 4 mg tablets

Candesartan 8 mg tablets

Candesartan 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 any 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

1 What Candesartan is and what it is used for

2 What you need to know before you take Candesartan

3 How to take Candesartan

4 Possible side effects

5 How to store Candesartan

6 Contents of the pack and other information

1

What Candesartan is and what it is used for

The name of your medicine is Candesartan. The active ingredient is candesartan cilexetil.

This belongs to a group of medicines called angiotensin II receptor antagonists. It works by

making your blood vessels relax and widen. This helps to lower your blood pressure. It also

makes it easier for your heart to pump blood to all parts of your body.

This medicine 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

Do not take Candesartan:

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

(listed in section 6).

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

pregnancy – see pregnancy section).

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

bile from the gall bladder).

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.

If you are not sure if any of these apply to you, talk to your doctor or pharmacist before

taking Candesartan.

Warnings and precautions

Talk to your doctor before taking Candesartan:

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 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 have ever had a stroke.

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

medicines known as mineralocorticoid receptors antagonist (MRA). These medicines are

for the treatment of heart failure (see “Other medicines and Candesartan”).

You must tell your doctor if you think that 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 under the heading “Do not take Candesartan”.

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

Tell your doctor or pharmacist if you are using, or have recently used or might use any

other medicines.

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

effect on Candesartan. 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 using any of the following medicines:

Other medicines to help lower your blood pressure, including betablockers, diazoxide

and ACE inhibitors such as enalapril, captopril, lisinopril or ramipril.

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

diclofenac, celecoxib or etoricoxib (medicines 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).

Water tablets (diuretics).

Lithium (a medicine for mental health problems).

Your doctor may need to change your dose and/or to take other precautions:

If you are taking an ACE-inhibitor or aliskiren (see also information under the headings

“Do not take Candesartan” and “Warnings and precautions”).

If you are being treated with 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).

Candesartan with food and drink

You can take Candesartan with or without food.

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

Alcohol may make you feel faint or dizzy.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a

baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

You must tell your doctor if you think you are (or might become) pregnant. Your doctor will

normally advise you to stop taking Candesartan before you become pregnant or as soon as

you know you are pregnant and will advise you to take another medicine instead of

Candesartan. Candesartan 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

Tell your doctor if you are breastfeeding or about to start breastfeeding. Candesartan 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 Candesartan. If this happens to you, do not

drive or use any tools or machines.

Candesartan contains lactose

Candesartan contains lactose which is a type of sugar. If you have been told by your doctor

that you have an intolerance to some sugars, contact your doctor before taking this medicine.

3

How to take Candesartan

Always take this medicine exactly as your doctor 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 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 to remember to take it.

High blood pressure:

The recommended dose of Candesartan is 8 mg once a day. Your doctor may increase

this dose to 16 mg once a day and further 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, and these patients may need a higher dose.

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.

Use in children and adolescents with high blood pressure

Children 6 to < 18 years of age:

The recommended starting dose is 4 mg once a day.

For patients weighing < 50 kg: In some patients whose blood pressure is not adequately

controlled, your doctor may decide the dose needs to be increased to a maximum of 8 mg

once a day.

For patients weighing ≥ 50 kg: In some patients whose blood pressure is not adequately

controlled, your doctor may decide the dose needs to be increased to 8 mg once a day or to

16 mg once a day.

If you take more Candesartan than you should

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

immediately for advice.

If you forget to take Candesartan

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

If you stop taking Candesartan

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

stop taking Candesartan without first talking to your doctor.

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 and seek medical help immediately if you have any of the

following allergic reactions:

difficulties in breathing, with or without swelling of the face, lips, tongue and/or throat

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

swallowing

severe itching of the skin (with raised lumps)

Candesartan may cause a reduction in number of white blood cells. Your resistance to

infection may be decreased and you may notice tiredness, an infection or a fever. If this

happens contact your doctor.

Your doctor may occasionally do blood tests to check whether Candesartan has had any

effect on your blood (agranulocytosis).

Other possible side effects include:

Common (may affect up to 1 in 10 users)

Feeling dizzy/ spinning sensation.

Headache.

Respiratory infection.

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

Changes in blood test results:

An increased amount of potassium in your blood, especially if you already have

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

weakness, irregular heart beat or pins and needles.

Effects on how your kidneys work, especially if you already have kidney problems or

heart failure. In very rare cases, kidney failure may occur.

Very rare (may affect up to 1 in 10,000 users)

Swelling of the face, lips, tongue and/ or throat.

A reduction in your red or white blood cells. You may notice tiredness, an infection or a

fever.

Skin rash, lumpy rash (hives).

Itching.

Back pain, pain in joints and muscles.

Changes in how your liver is working, including inflammation of the liver (hepatitis).

You may notice tiredness, yellowing of your skin and the whites of your eyes and flu like

symptoms.

Nausea.

Changes in blood test results:

A reduced amount of sodium in your blood. If this is severe then you may notice

weakness, lack of energy, or muscle cramps.

Cough.

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

Diarrhoea

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

adults, but they happen more often. Sore throat is a very common side effect in children but

not reported in adults and runny nose, fever and increased heart rate are common in children

but not reported in adults.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. 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: 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

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and on the blister

pack after EXP. The expiry date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

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 contains

The active substance is candesartan cilexetil. Each tablet contains 4 mg, 8 mg or 16 mg of

candesartan cilexetil.

The other ingredients are lactose monohydrate, maize starch, hydroxypropylcellulose,

croscarmellose sodium, magnesium stearate and triethyl citrate.

What Candesartan looks like and contents of the pack

Candesartan 4 mg tablets are white, biconvex tablets with a score line on one side and

embossing C4 on the same side.

Candesartan 8 mg tablets are white, biconvex tablets with a score line on one side and

embossing C8 on the same side.

Candesartan 16 mg tablets are white, biconvex tablets with a score line on one side and

embossing C16 on the same side.

The tablet can be divided into equal halves.

Pack sizes: 7, 14, 28, 30, 56, 70, 90, 98, 100 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Actavis Group PTC ehf.

Reykjavikurvegur 76-78

220 Hafnarfjordur

Iceland

Manufacturers

Siegfried Malta Ltd

HHF070 Hal Far Industrial Estate

P.O. box 14

Hal Far BBG 3000

Malta

Actavis Group PTC ehf.

Reykjavikurvegur 76-78

220 Hafnarfjordur

Iceland

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

following names:

Ireland

Candesartan 4 mg / 8 mg / 16 mg Tablets

UK

Candesartan tablets

This leaflet was last revised in February 2019

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Candesartan 4 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 4 mg candesartan cilexetil.

Each tablet contains 133.80 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

Candesartan 4 mg tablets are white biconex tablets, 8 x 3mm with a score line on one side and embossing C4 on the same side.

The tablet can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Candesartan is indicated for the:

- Treatment of essential hypertension in adults.

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

- 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).

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).

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 (Cl

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 Actavis is contraindicated in patients with severe hepatic impairment and/or

cholestasis (see sections 4.3 and 5.2).

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Black patients

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

uptitration of Candesartan 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 nonblack patients (see section 5.1).

Children aged below 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 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 (e.g. spironolactone) 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.

Paediatric Population

The safety and efficacy of Candesartan in children aged between birth and 18 years have not been established in the treatment

of hypertension and heart failure. No data are available.

Method of administration

Oral use.

Candesartan should be taken once daily with or without food.

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The bioavailability of candesartan is not affected by food.

4.3 Contraindications

- Hypersensitivity to candesartan cilexetil or to any of the excipientslisted 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 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.

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

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 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 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 no experience regarding the administration of Candesartan in patients with a recent kidney transplantation.

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 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)

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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

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, uraemia, 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 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).

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).

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.

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/1.73m

(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).

4.5 Interaction with other medicinal products and other forms of interactions

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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 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).

Paediatric population

Interaction studies have only been performed in adults.

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 Angiotensin II Receptor Inhibitors (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 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).

Breast-feeding

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

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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 section 4.8 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) and 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

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

Not known

Diarrhoea

Hepato-biliary 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 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 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.

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- 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” (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.

Treatment of Heart Failure

The adverse experience profile of Candesartan in 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.

System Organ Class

Frequency

Undesirable Effect

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

Respiratory, thoracic and mediastinal disorders

Very rare

Cough

Gastrointestinal disorders

Very rare

Nausea

Not known

Diarrhoea

Hepato-biliary 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 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: 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 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

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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

) receptors results in dose related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in

plasma aldosterone concentration.

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.

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

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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% 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).

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 randomized to receive an oral dose of

candesartan 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. 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 in a ratio of 1:2:2:2. For children who weighed< 50 kg, the doses of candesartan were 2, 8, or 16 mg once daily. In

children who weighed > 50 kg, the candesartan 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.

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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< 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.

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 (C

) 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.

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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 14C-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 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

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 weighting 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 C

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 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.

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

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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 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 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 (see section 4.3).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Maize starch

Hydroxypropylcellulose

Croscarmellose sodium

Magnesium stearate

Triethyl Citrate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC-PVDC/ Alu blister.

Pack sizes: 7, 14, 28, 30, 56, 70, 90, 98 and 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf

Reykjavikurvegi 76-78

220 Hafnarfjördur

Iceland

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8 MARKETING AUTHORISATION NUMBER

PA1380/092/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of First Authorisation: 15th April 2011

Date of Last Renewal: 5th February 2016

10 DATE OF REVISION OF THE TEXT

May 2019

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