Candesartan Krka 4 mg Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Candesartan cilexetil
Available from:
Krka d.d., Novo mesto
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:
PA1347/026/001
Authorization date:
2012-03-09

Package leaflet: Information for the user

Candesartan Krka 4 mg tablets

Candesartan Krka 8 mg tablets

Candesartan Krka 16 mg tablets

Candesartan Krka 32 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

What Candesartan Krka is and what it is used for

What you need to know before you take Candesartan Krka

How to take Candesartan Krka

Possible side effects

How to store Candesartan Krka

Contents of the pack and other information

1.

What Candesartan Krka is and what it is used for

The name of your medicine is Candesartan Krka. 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 under 18 years.

treating Candesartan Krka can be used to treat 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 Krka

Do not take Candesartan Krka:

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 Krka 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 Krka.

Warnings and precautions

Talk to your doctor or pharmacist before taking Candesartan Krka.

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,

you must tell your doctor if you think that you are (or might become) pregnant. Candesartan

Krka 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).

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 Krka”).

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 Krka”.

Your doctor may want to see you more often and do some tests if you have any of these conditions.

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

Krka. This is because Candesartan Krka, when combined with some anaesthetics, may cause a drop in

blood pressure.

Children and adolescents

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

Candesartan Krka must not be given to children under 1 year of age due to the potential risk to the

developing kidneys.

Other medicines and Candesartan Krka

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

medicines.

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

effect on Candesartan Krka. 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 beta-blockers, diazoxide and ACE

inhibitors such as enalapril, captopril, lisinopril or ramipril.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen or 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 Krka ” 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 Krka with food and drink and alcohol

Candesartan Krka can be taken with or without food.

When you are prescribed Candesartan Krka, 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 Krka before you become pregnant or as soon as you know you

are pregnant and will advise you to take other medicines instead of Candesartan Krka. Candesartan

Krka 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.

Breastfeeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. Candesartan Krka 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 Krka. If this happens to you, do not

drive or use any tools or machines.

Candesartan Krka contains lactose.

If you have been told by your doctor that you have an intolerance to some sugars, contact your

doctor before taking this product.

3.

How to take Candesartan Krka

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 Krka every day.

You can take Candesartan Krka 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 Krka 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.

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 < 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 daily.

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 daily and to 16 mg once daily.

Heart failure in adults

The recommended starting dose of Candesartan Krka 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

Krka can be taken together with other medicines for heart failure, and your doctor will decide which

treatment is suitable for you.

If you take more Candesartan Krka than you should

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

immediately for advice.

If you forget to take Candesartan Krka

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 Krka

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

taking Candesartan Krka 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 Krka 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 Krka 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 Krka has had any

effect on your blood (agranulocytosis).

Other possible side effects include:

Common (affects 1 to 10 users in 100)

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 (affects less than 1 user in 10,000)

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.

Cough.

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.

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 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: 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 Krka

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 packaging after EXP. The expiry

date refers to the last day of that month.

Do not store above 30

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 Krka contains

The active substance is candesartan cilexetil. Each tablet contains 4 mg, 8 mg, 16 mg or 32 mg

candesartan cilexetil.

The other ingredients are lactose monohydrate, maize starch, dibutyl sebacate, sodium

laurilsulfate, hydroxypropylcellulose, carmellose calcium, magnesium stearate and iron oxide

red (E172) – (8 mg, 16 mg and 32 mg tablets only)

What Candesartan Krka looks like and contents of the pack

4 mg tablets are round, white, biconvex, one side scored.

8 mg tablets are round, pinkish-white, biconvex, one side scored.

16 mg tablets are round, slightly pink, biconvex, one side scored.

32 mg tablets are round, slightly pink, biconvex, one side scored.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

Boxes of 7, 10, 14, 28, 30, 50, 56, 60, 84, 90, 98, 100 tablets in blisters are available.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

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

Name of the member state

Name of the medicinal product

United Kingdom

Candesartan cilexetil

Austria, Belgium, Cyprus, Denmark,

Finland, Greece, Hungary, Ireland,

Norway, Portugal, Sweden

Candesartan Krka

France, Italy, Spain

Karbis

This leaflet was last revised in 02/2015

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Candesartan Krka 4 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 4 mg candesartan cilexetil.

Excipient with known effect:

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

Round, white, biconvex, one side scored tablets.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Treatment of essential hypertension in adults.

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

Treatment of adult patients with heart failure and impaired left ventricle 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 Krka 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 Krka may also be administered with other antihypertensive agents. Addition of hydrochlorothiazide has

been shown to have an additive antihypertensive effect with various doses of Candesartan Krka.

Older people

No initial dosage adjustment is necessary in older people.

Patients with intravascular volume depletion

An initial dose of 4 mg may be considered in patients at risk for hypotension, such as patients with possible volume

depletion (see section 4.4).

4 mg tablets

Lactose

monohydrate

94.050 mg

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Patients with renal impairment

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

titrated according to response. There is limited experience in patients with very severe or end-stage renal impairment

creatinine

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

Patients with hepatic impairment

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

may be adjusted according to response. Candesartan Krka 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, uptitration of Candesartan Krka and concomitant therapy may be more frequently needed for blood

pressure control in black 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 some 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 some 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 Krka 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 Krka has not been studied in children with glomerular filtration rate less than 30 ml/min/1.73m2 (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 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 Krka is contraindicated in children aged below 1 year (see section 4.3).

Posology in heart failure

The usual recommended initial dose of Candesartan Krka 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 Krka can be administered with other heart failure treatment, including ACE-inhibitors, beta-blockers,

diuretics and digitalis or a combination of these medicinal products. Candesartan Krka 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

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diuretic and Candesartan Krka 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 Krka 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 Krka 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 Krka 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 Krka.

When Candesartan Krka 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 Krka 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 Krka,

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 Krka 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

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volume and activation of the renin-angiotensin-aldosterone system. Therefore Candesartan Krka 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 Krka in patients with a recent kidney

transplantation.

Hypotension

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

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

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

Anaesthesia and surgery

Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II antagonists due to

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

intravenous fluids and/or vasopressors.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)

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

mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism will not generally respond to antihypertensive medicinal products acting

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

recommended.

Hyperkalaemia

Concomitant use of Candesartan Krka 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 Krka, 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 Krkais 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,

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.

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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 angiotensin II receptor antagonists should

be stopped immediately, and, if appropriate, alternative therapy should be started (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.

Paediatric population

Use in paediatric patients including patients with renal impairment

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

(see

section 4.2).

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

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

dose should be considered (see section 4.2).

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

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

This medicinal product contains lactose monohydrate.

Patients with rare hereditary problems of galactose intolerance, total 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 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 (> 3g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect

may occur.

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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 are

no controlled epidemiological data on the risk with AIIRAs, similar risks may exist for this class of drug. Unless

continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-

hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed,

treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.

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

renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension,

hyperkalaemia) (See section 5.3).

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function

and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4).

Breastfeeding

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

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, the following 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.

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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), not known (cannot be estimated from the available data)

Laboratory findings

In general, there were no clinically important influences of candesartan cilexetil on routine laboratory variables. As for

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

routine monitoring of laboratory variables is usually necessary for patients receiving candesartan cilexetil. 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.

Hyperkalemia, hyponatraemia and abnormal liver function are uncommon (

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

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

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 disorder

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)

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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 cilexetil 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 cilexetil 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.

Laboratory findings

Hyperkalaemia and renal impairment are common in patients treated with Candesartan Krkafor 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

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

Gastrointestinal disorders

Very rare

Nausea

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)

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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 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,

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 AIIRA, selective for AT

receptors,

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

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

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

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

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

antagonism of the angiotensin II (AT

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

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

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).

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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 are 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 149/82mmHg 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 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 8mg and 16 mg doses, respectively and the effect plateaued after that

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

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

non-black patients.

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

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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 0.67-0.89,

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% CI0.70-0.92, 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.

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

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

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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.

5.2 Pharmacokinetic properties

Absorption and distribution

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

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

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

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

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

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

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

significantly affected by food.

Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution of candesartan is

0.1 l/kg.

The bioavailability of candesartan is not affected by food.

Biotransformation and elimination

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

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

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

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

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

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

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

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

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

inactive metabolite.

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 cilexetil in young and elderly patients (see section 4.2).

In patients with mild to moderate renal impairment C

and AUC of candesartan increased during repeated dosing by

approximately 50% and 70%, respectively, but t

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

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

The terminal t

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

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

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

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

experience in patients with severe hepatic impairment.

Paediatric population

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.

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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 Cmax and AUC with age or weight. No clearance data has been collected; therefore

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

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

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

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

population is unknown.

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

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

5.3 Preclinical safety data

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

studies candesartan had effects on the kidneys and on red cell parameters at high doses in mice, rats, dogs and

monkeys. Candesartan caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit).

Effects on the kidneys (such as interstitial nephritis, tubular distension, basophilic tubules; increased plasma

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

leading 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.

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

Data from in vitro and in vivo mutagenicity testing indicate 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 (see section 4.3).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate

Maize starch

Dibutyl sebacate

Sodium laurilsulfate

Hydroxypropylcellulose

Carmellose calcium

Magnesium stearate

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6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 30

6.5 Nature and contents of container

Blister PVC/PVDC/Aluminium

Pack sizes: 7, 10, 14, 28, 30, 50, 56, 60, 84, 90, 98, 100 tablets in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Krka d.d. Novo mesto

Šmarješka cesta 6

8501 Novo mesto

Slovenia

8 MARKETING AUTHORISATION NUMBER

PA1347/026/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of First Authorisation: 9th March 2012

Date of Last Renewal: 29th December 2015

10 DATE OF REVISION OF THE TEXT

July 2018

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