Candesartan Hydrochlorothiazide Krka 32mg/12.5mg tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Candesartan cilexetil; Hydrochlorothiazide
Available from:
Krka d.d., Novo mesto
ATC code:
C09DA; C09DA06
INN (International Name):
Candesartan cilexetil; Hydrochlorothiazide
Dosage:
32 mg/12.5 milligram(s)
Pharmaceutical form:
Tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Angiotensin II antagonists and diuretics; candesartan and diuretics
Authorization status:
Not marketed
Authorization number:
PA1347/011/003
Authorization date:
2011-08-12

Package leaflet: Information for the user

Candesartan Hydrochlorothiazide Krka 8 mg/12.5 mg tablets

Candesartan Hydrochlorothiazide Krka 16 mg/12.5 mg tablets

Candesartan Hydrochlorothiazide Krka 32 mg/12.5 mg tablets

Candesartan Hydrochlorothiazide Krka 32 mg/25 mg tablets

candesartan cilexetil/hydrochlorothiazide

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 Hydrochlorothiazide Krka is and what it is used for

What you need to know before you take Candesartan Hydrochlorothiazide Krka

How to take Candesartan Hydrochlorothiazide Krka

Possible side effects

How to store Candesartan Hydrochlorothiazide Krka

Contents of the pack and other information

1.

What Candesartan Hydrochlorothiazide Krka is and what it is used for

The name of your medicine is Candesartan Hydrochlorothiazide Krka. It is used for treating high

blood pressure (hypertension) in adult patients. It contains two active ingredients: candesartan

cilexetil and hydrochlorothiazide.

These work together to lower your blood pressure.

Candesartan cilexetil belongs to a group of medicines called angiotensin II receptor antagonists. It

makes your blood vessels relax and widen. This helps to lower your blood pressure.

Hydrochlorothiazide belongs to a group of medicines called diuretics (water tablets). It helps your

body to get rid of water and salts like sodium in your urine. This helps to lower your blood pressure.

Your doctor may prescribe Candesartan Hydrochlorothiazide Krka if your blood pressure has not been

properly controlled by candesartan cilexetil or hydrochlorothiazide alone.

2.

What you need to know before you take Candesartan Hydrochlorothiazide Krka

Do not take Candesartan Hydrochlorothiazide Krka:

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

of this medicine (listed in section 6).

if you are allergic to sulphonamide medicines. If you are not sure if this applies to you, please

ask your doctor.

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

Hydrochlorothiazide Krka in early pregnancy – see pregnancy section).

if you have severe kidney problems.

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

from the gall bladder).

if you have persistently low levels of potassium in your blood.

if you have persistently high levels of calcium in your blood.

if you have ever had gout.

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 Hydrochlorothiazide Krka.

Warnings and precautions

Talk to your doctor or pharmacist before taking Candesartan Hydrochlorothiazide Krka.

if you have diabetes.

if you have heart, liver or kidney problems.

if you have recently had a kidney transplant.

if you are vomiting, 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 ever had a disease called systemic lupus erythematosus (SLE).

if you have low blood pressure.

if you have ever had a stroke.

if you have ever had allergy or asthma.

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

Hydrochlorothiazide 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 have had skin cancer or if you develop an unexpected skin lesion during the treatment.

Treatment with hydrochlorothiazide, particularly long term use with high doses, may increase

the risk of some types of skin and lip cancer (non-melanoma skin cancer). Protect your skin

from sun exposure and UV rays while taking Candesartan Hydrochlorothiazide Krka.

if you experience a decrease in vision or eye pain. These could be symptoms of fluid

accumulation in the vascular layer of the eye (choroidal effusion) or an increase of pressure in

your eye and can happen within hours to weeks of taking Candesartan Hydrochlorothiazide

Krka.. This can lead to permanent vision loss, if not treated. If you earlier have had a

penicillin or sulfonamide allergy, you can be at higher risk of developing this.

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

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

have diabetes-related kidney problems,

aliskiren.

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 Hydrochlorothiazide 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

Hydrochlorothiazide Krka. This is because Candesartan Hydrochlorothiazide Krka, when combined

with some anaesthetics, may cause an excessive drop in blood pressure.

Candesartan Hydrochlorothiazide Krka may cause increased sensitivity of the skin to sun.

Children and adolescents

There is no experience with the use of Candesartan Hydrochlorothiazide Krka in children (below the

age of 18 years). Therefore Candesartan Hydrochlorothiazide Krka should not be given to children.

Other medicines and Candesartan Hydrochlorothiazide Krka

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

medicines.

Candesartan Hydrochlorothiazide Krka can affect the way some other medicines work and some

medicines can have an effect on Candesartan Hydrochlorothiazide Krka tablets. If you are using

certain medicines, your doctor may need to do blood tests from time to time.

It particular, tell your doctor if you are using any of the following medicines as your doctor may need

to change your dose and/or take other precautions:

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

containing medicines, diazoxide and Angiotensin Converting Enzyme (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).

Calcium or vitamin D supplements.

Medicines to lower your cholesterol such as colestipol or cholestyramine.

Medicines for diabetes (tablets or insulin).

Medicines to control your heart beat (antiarrhythmic agents) such as digoxin and beta-blockers.

Medicines that can be affected by potassium blood levels such as some antipsychotic

medicines.

Heparin (a medicine for thinning the blood).

Water tablets (diuretics).

Laxatives.

Penicillin or co-trimoxazole also known as trimethoprim/sulfamethoxazole (an antibiotic

medicines).

Amphotericin (for the treatment of fungal infections).

Lithium (a medicine for mental health problems).

Steroids such as prednisolone.

Pituitary hormone (ACTH).

Medicines to treat cancer.

Amantadine (for the treatment of Parkinson’s disease or for serious infections caused by

viruses).

Barbiturates (a type of sedative also used to treat epilepsy).

Carbenoxolone (for treatment of oesophageal disease, or oral ulcers).

Anticholinergic agents such as atropine and biperiden.

Cyclosporine, a medicine used for organ transplant to avoid organ rejection.

Other medicines that may lead to enhancement of the antihypertensive effect such as baclofen

(a medicine for relief of spasticity), amifostin (used in cancer treatment) and some

antipsychotic medicines.

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

not take Candesartan Hydrochlorothiazide Krka” and “Warnings and precautions”).

Candesartan Hydrochlorothiazide Krka with food, drink and alcohol

You can take Candesartan Hydrochlorothiazide Krka with or without food.

When you are prescribed Candesartan Hydrochlorothiazide Krka, discuss with your doctor

before drinking alcohol. Alcohol may make you feel faint or dizzy.

Pregnancy and breast-feeding

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 Hydrochlorothiazide Krka before you become pregnant or as

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

Candesartan Hydrochlorothiazide Krka. Candesartan Hydrochlorothiazide 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

Hydrochlorothiazide 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.

Driving and using machines

Some people may feel tired or dizzy when taking Candesartan Hydrochlorothiazide Krka. If this

happens to you, do not drive or use any tools or machines.

Candesartan Hydrochlorothiazide Krka 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 medicinal product.

3.

How to take Candesartan Hydrochlorothiazide Krka

Always take this medicine exactly as described in this leaflet or as your doctor or pharmacist have

told you. Check with your doctor or pharmacist if you are not sure.

It is important to keep taking Candesartan Hydrochlorothiazide Krka every day.

The recommended dose of Candesartan Hydrochlorothiazide Krka is one tablet once a day.

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.

If you take more Candesartan Hydrochlorothiazide Krka than you should

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

doctor or pharmacist immediately for advice.

If you forget to take Candesartan Hydrochlorothiazide 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 Hydrochlorothiazide Krka

If you stop taking Candesartan Hydrochlorothiazide Krka, your blood pressure may increase again.

Therefore do not stop taking Candesartan Hydrochlorothiazide 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. Some of the side effects of

Candesartan Hydrochlorothiazide Krka are caused by candesartan cilexetil and some are caused by

hydrochlorothiazide.

Stop taking Candesartan Hydrochlorothiazide 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 Hydrochlorothiazide 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 tell your doctor. Your doctor may occasionally do blood tests to check whether Candesartan

Hydrochlorothiazide Krka has had any effect on your blood (agranulocytosis).

Other possible side effects include:

Common (

may affect up to 1 in 10 people)

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.

An increased or reduced 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.

An increased amount of cholesterol, sugar, or uric acid in your blood.

Sugar in your urine.

Feeling dizzy/spinning sensation or weak.

Headache.

Respiratory infection.

Uncommon (

may affect up to 1 in 100 people)

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

Loss of appetite, diarrhoea, constipation, stomach irritation.

Skin rash, lumpy rash (hives), rash caused by sensitivity to sunlight.

Rare (

may affect up to 1 in 1,000 people)

Jaundice (yellowing of your skin or the whites of your eyes). If this happens to you, contact

your doctor immediately.

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

failure.

Difficulty in sleeping, depression, being restless.

Tingling or prickling in your arms or legs.

Blurred vision for a short time.

Abnormal heart beat.

Breathing difficulties (including lung inflammation and fluid in the lungs).

High temperature (fever).

Inflammation of the pancreas. This causes moderate to severe pain in the stomach.

Muscle cramps.

Damage to blood vessels causing red or purple dots in the skin.

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

fever or easy bruising.

A severe rash, that develops quickly, with blistering or peeling of the skin and possibly

blistering in the mouth.

Very rare (

may affect up to 1 in 10,000 people)

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

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.

Not known

(frequency cannot be estimated from the available data)

Skin and lip cancer (Non-melanoma skin cancer).

Diarrhoea.

Sudden short-sightedness.

Decrease in vision or pain in your eyes due to high pressure (possible signs of fluid

accumulation in the vascular layer of the eye (choroidal effusion) or acute angle-closure

glaucoma).

Systemic and cutaneous lupus erythaematosus (allergic condition which causes fever, joint

pain, skin rashes which may include redness, blistering, peeling and lumps).

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 Hydrochlorothiazide 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.

Tablets packaged in blisters of PVC/PVDC film and aluminium foil:

Do not store above 30

Tablets packaged in blisters of laminated OPA/Al/PVC foil and aluminium foil:

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 Hydrochlorothiazide Krka contains

The active substances are candesartan cilexetil and hydrochlorothiazide.

Each tablet contains 8 mg candesartan cilexetil and 12.5 mg hydrochlorothiazide.

Each tablet contains 16 mg candesartan cilexetil and 12.5 mg hydrochlorothiazide.

Each tablet contains 32 mg candesartan cilexetil and 25 mg hydrochlorothiazide.

Each tablet contains 32 mg candesartan cilexetil and 12.5 mg hydrochlorothiazide.

The other ingredients are lactose monohydrate, maize starch, macrogol 8000,

hydroxypropylcellulose, carmellose calcium, magnesium stearate,red iron oxide (E172) only

for 16 mg/12.5 mg and 32 mg/25 mg and yellow iron oxide (E172) only for 32 mg/12.5 mg.

What Candesartan Hydrochlorothiazide Krka looks like and contents of the pack

Candesartan Hydrochlorothiazide Krka 8 mg/12.5 mg tablets are white, biconvex, oval, with a score

on one side.

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

Candesartan Hydrochlorothiazide Krka 16 mg/12.5 mg tablets are pale pink, biconvex, oval, with a

score on one side.

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

Candesartan Hydrochlorothiazide Krka 32 mg/12.5 mg tablets are yellowish white, biconvex, oval,

with a score on one side.

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

Candesartan Hydrochlorothiazide Krka 32 mg/25 mg tablets are pale pink, biconvex, oval, with a score

on one side.

The tablet can be divided into equal doses.

Boxes of 14, 15, 28, 30, 56, 60, 84, 90, 98 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

Austria

Candesartan + HCT Krka

Bulgaria, Poland, Romania, Slovak Republic

Karbicombi

Czech Republic

Cancombino

Germany

Candesartan-HCTad

Greece

Candesartan+HCTZ/Krka

Cyprus

Candesartan/Hydrochlorothiazide KRKA

Ireland

Candesartan Hydrochlorothiazide Krka

Slovenia

Candecombi

Lithuania

Canocombi

This leaflet was last revised in

Health Products Regulatory Authority

25 August 2020

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Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Candesartan Hydrochlorothiazide Krka 32mg/12.5mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 32 mg candesartan cilexetil and 12.5 mg hydrochlorothiazide.

Excipient with known effect: Lactose 142.79 mg

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

Candesartan Hydrochlorothiazide Krka 32 mg/12.5 mg tablets are yellowish white, biconvex, oval, with a score on one side.

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

Candesartan Hydrochlorothiazide Krka is indicated for the:

Treatment of essential hypertension in adult patients whose blood pressure is not optimally controlled with candesartan

cilexetil or hydrochlorothiazide monotherapy.

4.2 Posology and method of administration

Posology in hypertension

The recommended dose of Candesartan Hydrochlorothiazide Krka is one tablet once daily.

Dose titration with the individual components (candesartan cilexetil and hydrochlorothiazide) is recommended. When clinically

appropriate a direct change from monotherapy to Candesartan Hydrochlorothiazide Krka may be considered. Dose titration of

candesartan cilexetil is recommended when switching from hydrochlorothiazide monotherapy. Candesartan

Hydrochlorothiazide Krka may be administered in patients whose blood pressure is not optimally controlled with candesartan

cilexetil or hydrochlorothiazide monotherapy or Candesartan Hydrochlorothiazide Krka at lower doses.

Most of the antihypertensive effect is usually attained within 4 weeks of initiation of treatment.

Special populations

Elderly

No dose adjustment is necessary in elderly patients.

Intravascular volume depletion

Dose titration of candesartan cilexetil is recommended in patients at risk for hypotension such as patients with possible volume

depletion (an initial dose of candesartan cilexetil of 4 mg may be considered in these patients).

Renal impairment

In patients with mild to moderate renal impairment (creatinine clearance is ≥30‑80 ml/min/1.73 m

BSA) a dose titration is

recommended.

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Candesartan Hydrochlorothiazide Krka is contraindicated in patients with severe renal impairment (creatinine clearance

<30 ml/min/1.73 m

BSA) (see section 4.3).

Hepatic impairment

Dose titration of candesartan cilexetil is recommended in patients with mild to moderate chronic liver disease. Candesartan

Hydrochlorothiazide Krka is contraindicated in patients with severe hepatic impairment and/or cholestasis (see section 4.3).

Paediatric population

The safety and efficacy of Candesartan Hydrochlorothiazide Krka in children aged between birth and 18 years have not been

established. No data are available.

Method of administration

Oral use.

Candesartan Hydrochlorothiazide Krka can be taken with or without food.

The bioavailability of candesartan is not affected by food.

There is no clinically significant interaction between hydrochlorothiazide and food.

4.3 Contraindications

- Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 or to sulfonamide derived active

substances. Hydrochlorothiazide is a sulfonamide derived active substance.

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

- Severe renal impairment (creatinine clearance <30 ml/min/1.73 m

BSA).

- Severe hepatic impairment and/or cholestasis.

- Refractory hypokalaemia and hypercalcaemia.

- Gout.

- The concomitant use of Candesartan Hydrochlorothiazide 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

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

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

hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the

combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5

and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to

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

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

Renal impairment

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

susceptible patients treated with Candesartan Hydrochlorothiazide Krka (see section 4.3).

Kidney transplantation

There is limited clinical evidence regarding Candesartan Hydrochlorothiazide Krka use in patients who have undergone renal

transplant.

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.

Intravascular volume depletion

In patients with intravascular volume and/or sodium depletion symptomatic hypotension may occur, as described for other

agents acting on the renin-angiotensin-aldosterone system. Therefore, the use of Candesartan Hydrochlorothiazide Krka is not

recommended until this condition has been corrected.

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Anaesthesia and surgery

Hypotension may occur during anaesthesia and surgery in patients treated with AIIRAs 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.

Hepatic impairment

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor

alterations of fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with Candesartan

Hydrochlorothiazide Krka in patients with hepatic impairment.

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 generally will not respond to antihypertensive medicine acting through inhibition of

the renin-angiotensin-aldosterone system. Therefore, the use of Candesartan Hydrochlorothiazide Krka is not recommended in

this population.

Electrolyte imbalance

Periodic determination of serum electrolytes should be performed at appropriate intervals. Thiazides, including

hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypercalcaemia, hypokalaemia, hyponatraemia,

hypomagnesaemia and hypochloraemic alkalosis).

Thiazide diuretics may decrease the urinary calcium excretion and may cause intermittent and slightly increased serum calcium

concentrations. Marked hypercalcaemia may be a sign of hidden hyperparathyroidism. Thiazides should be discontinued

before carrying out tests for parathyroid function.

Hydrochlorothiazide dose-dependently increases urinary potassium excretion which may result in hypokalaemia. This effect of

hydrochlorothiazide seems to be less evident when combined with candesartan cilexetil. The risk for hypokalaemia may be

increased in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients with an inadequate oral intake

of electrolytes and in patients receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH).

Treatment with candesartan cilexetil may cause hyperkalaemia, especially in the presence of heart failure and/or renal

impairment. Concomitant use of Candesartan Hydrochlorothiazide Krka and ACE inhibitors, aliskiren, potassium-sparing

diuretics, potassium supplements or salt substitutes or other medicinal products that may increase serum potassium levels (e.g.

heparin sodium, co‑trimoxazole also known as trimethoprim/sulfamethoxazole) may lead to increases in serum potassium.

Monitoring of potassium should be undertaken as appropriate. Thiazides have been shown to increase the urinary excretion of

magnesium, which may result in hypomagnesaemia.

Metabolic and endocrine effects

Treatment with a thiazide diuretic may impair glucose tolerance. Dose adjustment of antidiabetic medicines, including insulin,

may be required. Latent diabetes mellitus may become manifest during thiazide therapy. Increases in cholesterol and

triglyceride levels have been associated with thiazide diuretic therapy. At the doses contained in Candesartan

Hydrochlorothiazide Krka, only minimal effects were observed.. Thiazide diuretics increase serum uric acid concentration and

may precipitate gout in susceptible patients.

Photosensitivity

Cases of photosensitivity reactions have been reported during use of thiazide diuretics (see section 4.8). If a photosensitivity

reaction occurs, it is recommended to stop treatment. If re‑administration of treatment is essential, it is recommended to

protect areas exposed to the sun or to artificial UVA radiation.

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 productsthat affect this system including AIIRAs, has been associated with acute hypotension, azotaemia,

oliguria or, rarely, acute renal failure. As with any antihypertensive agent, excessive blood pressure decrease in patients with

ischaemic heart disease or atherosclerotic cerebrovascular disease could result in a myocardial infarction or stroke.

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Page 4 of 12

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma,

but are more likely in patients with such a history.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

The antihypertensive effect of Candesartan Hydrochlorothiazide Krka may be enhanced by other antihypertensives.

Candesartan Hydrochlorothiazide Krka tablets contain lactose. Patients with rare hereditary problems of galactose intolerance,

total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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).

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with

increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based

on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and

promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and

in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer.

Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of

HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

Choroidal effusion, acute myopia and secondary angle-closure glaucoma

Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in choroidal effusion with visual field

defect, transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular

pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to

permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical

treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute

angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

4.5 Interaction with other medicinal products and other forms of interactions

Compounds which have been investigated in clinical pharmacokinetic studies include warfarin, digoxin, oral contraceptives (i.e.

ethinylestradiol/levonorgestrel), glibenclamide and nifedipine. No pharmacokinetic interactions of clinical significance were

identified in these studies.

The potassium depleting effect of hydrochlorothiazide could be expected to be potentiated by other medicinal products

associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone,

penicillin G sodium, salicylic acid derivates, steroids, ACTH).

Concomitant use of Candesartan Hydrochlorothiazide Krka and potassium-sparing diuretics, potassium supplements or salt

substitutes or other medicinal products that may increase serum potassium levels (e.g. heparin sodium, co-trimoxazole also

known as trimethoprim/sulfamethoxazole) may lead to increases in serum potassium. Monitoring of potassium should be

undertaken as appropriate (see section 4.4).

Diuretic-induced hypokalaemia and hypomagnesaemia predisposes to the potential cardiotoxic effects of digitalis glycosides

and antiarrhythmics. Periodic monitoring of serum potassium is recommended when Candesartan Hydrochlorothiazide Krka is

administered with such medicinal products, and with the following medicinal products that could induce torsades de pointes:

- Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide).

- Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide).

- Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride,

amisulpride, tiapride, pimozide, haloperidol, droperiodol).

- Others (e.g. bepridil, cisapride, diphemanil, erythromycin iv, halofantrin, ketanserin, mizolastin, pentamidine, sparfloxacine,

terfenadine, vincamine iv).

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

lithium with Angiotensin Converting Enzyme (ACE) inhibitors or hydrochlorothiazide. A similar effect has also been reported

with AIIRAs. Use of candesartan and hydrochlorothiazide 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 medicines (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.

The diuretic, natriuretic and antihypertensive effect of hydrochlorothiazide is blunted by NSAIDs.

The absorption of hydrochlorothiazide is reduced by colestipol or cholestyramine.

The effect on non‑depolarizing skeletal muscle relaxants (e.g. tubocurarine) may be potentiated by hydrochlorothiazide.

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements or Vitamin D must be

prescribed, serum calcium levels should be monitored and the dose adjusted accordingly.

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-type diuretics by decreasing

gastrointestinal motility and stomach emptying rate.

Thiazide may increase the risk of adverse effects caused by amantadine.

Thiazides may reduce the renal excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and

potentiate their myelosuppressive effects.

Postural hypotension may become aggravated by simultaneous intake of alcohol, barbiturates or anaesthetics.

Treatment with a thiazide diuretic may impair glucose tolerance. Dose adjustment of antidiabetic medicinal products, including

insulin, may be required. Metformin should be used with caution because of the risk of lactic acidosis induced by possible

functional renal failure linked to hydrochlorothiazide.

Hydrochlorothiazide may cause the arterial response to pressor amines (e.g. adrenaline) to decrease but not enough to exclude

a pressor effect.

Hydrochlorothiazide may increase the risk of acute renal insufficiency especially with high doses of iodinated contrast media.

Concomitant treatment with cyclosporine may increase the risk of hyperuricaemia and gout-type complications.

Concomitant treatment with baclofen, amifostin, tricyclic antidepressants or neuroleptics may lead to enhancement of the

antihypertensive effect and may induce hypotension.

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).

4.6 Fertility, pregnancy and lactation

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Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs):

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

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

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

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

epidemiological data on the risk with AIIRAs, similar risks may exist for this class of drugs. Unless continued AIIRA therapy is

considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an

established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped

immediately and if appropriate, alternative therapy should be started.

Exposure to AIIRA therapy during the second and third trimesters is known to induce human 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).

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are

insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use

during the second and third trimesters may compromise foeto-placental perfusion and may cause foetal and neonatal effects

like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of

decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other

treatment could be used.

Breastfeeding

Angiotensin II Receptor Antagonists (AIIRAs):

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

Candesartan Hydrochlorothiazide 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.

Hydrochlorothiazide

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit

the milk production. The use of Candesartan Hydrochlorothiazide Krka during breast feeding is not recommended. If

Candesartan Hydrochlorothiazide Krka is used during breast feeding, doses should be kept as low as possible.

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. When driving vehicles or operating

machines, it should be taken into account that occasionally dizziness or weariness may occur during treatment

with Candesartan Hydrochlorothiazide Krka.

4.8 Undesirable effects

In controlled clinical studies with Candesartan Hydrochlorothiazide Krka adverse reactions were mild and transient.

Withdrawals from treatment due to adverse events were similar with Candesartan Hydrochlorothiazide Krka (2.3-3.3%) and

placebo (2.7-4.3%).

In clinical trials with Candesartan Hydrochlorothiazide Krka, adverse reactions were limited to those that were reported

previously with candesartan cilexetil and/or hydrochlorothiazide.

The table below presents adverse reactions with candesartan cilexetil from clinical trials and post marketing experience. 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:

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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)

Very rare (<1/10,000)

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.

Hepatobiliary disorders

Very rare

Increased liver enzymes, abnormal hepatic function or hepatitis.

Skin and subcutaneous tissue disorders

Very rare

Angioedema, rash, urticaria, pruritus.

Musculoskeletal and connective tissue disorders

Very rare

Back pain, arthralgia, myalgia.

Renal and urinary disorders

Very rare

Renal impairment, including renal failure in susceptible

patients (see section 4.4).

The table below presents adverse reactions with hydrochlorothiazide monotherapy usually with doses of 25 mg or higher.

System Organ Class

Frequency

Undesirable Effect

Neoplasms benign, malignant and unspecified (incl cysts

and polyps)

Not known

Non‑melanoma skin cancer (Basal cell carcinoma

and Squamous cell carcinoma)

Blood and lymphatic system disorders

Rare

Leukopenia, neutropenia/agranulocytosis,

thrombocytopenia, aplastic anaemia, bone marrow

depression, haemolytic anaemia.

Immune system disorders

Rare

Anaphylactic reactions.

Metabolism and nutrition disorders

Common

Hyperglycaemia, hyperuricaemia, electrolyte

imbalance (including hyponatraemia and

hypokalaemia).

Psychiatric disorders

Rare

Sleep disturbances, depression, restlessness.

Nervous system disorders

Common

Light-headedness, vertigo.

Rare

Paraesthesia.

Eye disorders ​

Rare

Transient blurred vision.

Not known

Acute myopia, acute angle-closure glaucoma,

choroidal effusion.

Cardiac disorders

Rare

Cardiac arrhythmias.

Vascular disorders

Uncommon

Postural hypotension.

Rare

Necrotising angiitis (vasculitis, cutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders

Rare

Respiratory distress (including pneumonitis and

pulmonary oedema).

Gastrointestinal disorders

Uncommon

Anorexia, loss of appetite, gastric irritation, diarrhoea,

constipation.

Rare

Pancreatitis.

Hepatobiliary disorders

Rare

Jaundice (intrahepatic cholestatic jaundice).

Skin and subcutaneous tissue disorders

Uncommon

Rash, urticaria, photosensitivity reactions.

Rare

Toxic epidermal necrolysis.

Not known

Systemic lupus erythematosus, Cutaneous lupus

erythematosus.

Musculoskeletal and connective tissue disorders

Rare

Muscle spasm.

Renal and urinary disorders

Common

Glycosuria.

Rare

Renal dysfunction and interstitial nephritis.

General disorders and administration site conditions ​

Common

Weakness.

Rare

Fever.

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Investigations

Common

Increases in cholesterol and triglycerides.

Rare

Increases in BUN and serum creatinine.

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association

between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

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 of candesartan cilexetil 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.

The main manifestation of an overdose of hydrochlorothiazide is acute loss of fluid and electrolytes. Symptoms such as

dizziness, hypotension, thirst, tachycardia, ventricular arrhythmias, sedation/impairment of consciousness and muscle cramps

can also be observed.

Management

No specific information is available on the treatment of overdosage with Candesartan Hydrochlorothiazide Krka. The following

measures are, however, suggested in case of overdosage.

When indicated, induction of vomiting or gastric lavage should be considered. 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 isotonic saline solution. Serum electrolyte

and acid balance should be checked and corrected, if needed. Sympathomimetic drugs may be administered if the

above-mentioned measures are not sufficient.

Candesartan cannot be removed by haemodialysis. It is not known to what extent hydrochlorothiazide is removed by

haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, angiotensin II antagonists and diuretics, ATC code:

C09DA06.

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 and other cardiovascular disorders. It also has a role in the pathogenesis of organ

hypertrophy and end organ 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 (AT1) receptor.

Pharmacodynamic effects

Candesartan cilexetil is a prodrug which is rapidly converted to the active drug, candesartan, by ester hydrolysis during

absorption from the gastrointestinal tract. Candesartan is an angiotensin II receptor antagonist, selective for AT1 receptors,

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

Candesartan does not influence ACE or other enzyme systems usually associated with the use of ACE inhibitors. Since there is

no effect on the degradation of kinins, or on the metabolism of other substances such as substance P, AIIRAs are unlikely to be

associated with cough. In controlled clinical trials comparing candesartan cilexetil 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

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channels known to be important in cardiovascular regulation. The antagonism of the AT1 receptors results in dose related

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

Clinical efficacy and safety

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 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).

Hydrochlorothiazide inhibits the active re-absorption of sodium, mainly in the distal kidney tubules, and promotes the

excretion of sodium, chloride and water. The renal excretion of potassium and magnesium increases dose-dependently, while

calcium is reabsorbed to a greater extent. Hydrochlorothiazide decreases plasma volume and extracellular fluid and reduces

cardiac output and blood pressure. During long-term therapy, reduced peripheral resistance contributes to the blood pressure

reduction.

Large clinical studies have shown that long-term treatment with hydrochlorothiazide reduces the risk for cardiovascular

morbidity and mortality.

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association

between HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629

cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCTZ use (≥50,000 mg cumulative) was

associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative

dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip

cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set

sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6)

increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg)

(see also section 4.4).

Candesartan and hydrochlorothiazide have additive antihypertensive effects.

In hypertensive patients, Candesartan Hydrochlorothiazide Krka results in a dose-dependent and long-lasting reduction in

arterial blood pressure 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

Hydrochlorothiazide Krka, onset of the antihypertensive effect generally occurs within 2 hours. With continuous treatment,

most of the reduction in blood pressure is attained within four weeks and is sustained during long-term treatment.

Candesartan Hydrochlorothiazide Krka once daily provides effective and smooth blood pressure reduction over 24 hours, with

little difference between maximum and trough effects during the dosing interval. In a double-blind randomised study,

Candesartan Hydrochlorothiazide Krka 16 mg/12.5 mg once daily reduced blood pressure significantly more, and controlled

significantly more patients, than the combination losartan/hydrochlorothiazide 50 mg/12.5 mg once daily. In double-blind,

randomised studies, the incidence of adverse events, especially cough, was lower during treatment with Candesartan

Hydrochlorothiazide Krka than during treatment with combinations of ACE inhibitors and hydrochlorothiazide.

In two clinical studies (randomised, double-blind, placebo controlled, parallel group) including 275 and 1524 randomised

patients, respectively, the Candesartan Hydrochlorothiazide Krka 32 mg/12.5 mg and 32 mg/25 mg resulted in blood pressure

reductions of 22/15 mmHg and 21/14 mmHg, respectively, and were significantly more effective than the respective

monocomponents.

In a randomised, double-blind, parallel group clinical study including 1975 randomised patients not optimally controlled on

32 mg candesartan cilexetil once daily, the addition of 12.5 mg or 25 mg hydrochlorothiazide resulted in additional blood

pressure reductions. The Candesartan Hydrochlorothiazide Krka combination 32 mg/25 mg was significantly more effective

than the 32 mg/12.5 mg combination, and the overall mean blood pressure reductions were 16/10 mmHg and 13/9 mmHg,

respectively.

Candesartan Hydrochlorothiazide Krka is similarly effective in patients irrespective of age and gender.

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Currently there are no data on the use of Candesartan Hydrochlorothiazide Krka in patients with renal disease/nephropathy,

reduced left ventricular function/congestive heart failure and post myocardial infarction.

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.

5.2 Pharmacokinetic properties

Concomitant administration of candesartan cilexetil and hydrochlorothiazide has no clinically significant effect on the

pharmacokinetics of either medicinal product.

Absorption and distribution

Candesartan cilexetil

Following oral administration, candesartan cilexetil is converted to the active drug candesartan. The absolute bioavailability of

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

formulation of candesartan cilexetil compared with the same oral solution is approximately 34% with very little variability. The

mean peak serum concentration (Cmax) 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.

Hydrochlorothiazide

Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of approximately 70%.

Concomitant intake of food increases the absorption by approximately 15%. The bioavailability may decrease in patients with

cardiac failure and pronounced oedema.

The plasma protein binding of hydrochlorothiazide is approximately 60%. The apparent volume of distribution is approximately

0.8 l/kg.

Metabolism and elimination

Candesartan cilexetil

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 (t½) of candesartan is approximately 9 hours. There is no

accumulation following multiple doses. The half-life of candesartan remains unchanged (approximately 9 h) after

administration of candesartan cilexetil in combination with hydrochlorothiazide. No additional accumulation of candesartan

occurs after repeated doses of the combination compared to monotherapy.

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