BLOPRESS PLUS 32/12.5 Milligram Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
CANDESARTAN CILEXETIL, HYDROCHLOROTHIAZIDE
Available from:
Takeda UK Limited
ATC code:
C09DA06
INN (International Name):
CANDESARTAN CILEXETIL, HYDROCHLOROTHIAZIDE
Dosage:
32/12.5 Milligram
Pharmaceutical form:
Tablets
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Angiotensin II antagonists and diuretics
Authorization status:
Authorised
Authorization number:
PA1547/002/003
Authorization date:
2009-06-19

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Blopress Plus 8 mg/12.5 mg tablets

Blopress Plus 16 mg/12.5 mg tablets

Blopress Plus 32 mg/12.5 mg tablets

Blopress Plus 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. This includes any possible side effects not listed

in this leaflet. See section 4.

What is in this leaflet:

What Blopress Plus is and what it is used for

What you need to know before you take Blopress Plus

How to take Blopress Plus

Possible side effects

How to store Blopress Plus

Contents of the pack and other information

1. WHAT BLOPRESS PLUS IS AND WHAT IT IS USED FOR

The name of your medicine is Blopress Plus. 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 Blopress Plus if your blood pressure has not been properly controlled by

candesartan cilexetil or hydrochlorothiazide alone.

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE BLOPRESS PLUS

Do not take Blopress Plus:

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 Blopress Plus 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).

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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

Blopress Plus.

Warnings and precautions

Talk to your doctor before taking Blopress Plus:

if you have diabetes.

if you have heart, liver or kidney problems.

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 ever had a disease called systemic lupus erythaematosus (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. Blopress Plus 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 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.

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 Blopress Plus”.

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 Blopress Plus. This

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

Blopress Plus may cause increased sensitivity of the skin to sun.

Use in children

There is no experience with the use of Blopress Plus in children (below the age of 18 years). Therefore

Blopress Plus should not be given to children.

Other medicines and Blopress Plus

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

Blopress Plus can affect the way some other medicines work and some medicines can have an effect

on Blopress Plus. 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 as your doctor may need

to change your dose and/or take other precautions:

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Other medicines to help lower your blood pressure, including beta-blockers, 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 3g 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 (an antibiotic).

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 heading “Do not

take Blopress Plus:” and “Warnings and precautions”).

Blopress Plus with food, drink and alcohol

You can take Blopress Plus with or without food.

When you are prescribed Blopress Plus, 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 Blopress Plus before you become pregnant or as soon as you know you are

pregnant and will advise you to take another medicine instead of Blopress Plus. Blopress Plus is not

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

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

Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. Blopress Plus 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

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

use any tools or machines.

Blopress Plus contains lactose. Lactose is a type of sugar. If you have been told by your doctor that

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

3. HOW TO TAKE BLOPRESS PLUS

Always take Blopress Plus exactly as your doctor has told you. You should check with your doctor or

pharmacist if you are not sure. It is important to keep taking Blopress Plus every day.

The recommended dose of Blopress Plus 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.

Blopress Plus 8/12.5mg and 16/12.5mg tablets: The tablet can be divided into equal doses.

Blopress Plus 32/12.5mg and 32/25mg tablets: The score line is only there to help you break the tablet

if you have difficulty swallowing it whole.

If you take more Blopress Plus than you should

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

immediately for advice.

If you forget to take Blopress Plus

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

If you stop taking Blopress Plus

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

Blopress Plus without first talking to your doctor.

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

4. POSSIBLE SIDE EFFECTS

Like all medicines, Blopress Plus 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 Blopress

Plus are caused by candesartan cilexetil and some are caused by hydrochlorothiazide.

Stop taking Blopress Plus 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)

Blopress Plus 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 Blopress Plus has had any effect on

your blood (agranulocytosis).

Other possible side effects include:

Common (affects 1 to 10 users in 100)

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.

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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 heartbeat 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 (affects less than 1 user in 100)

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 (affects less than 1 user in 1,000)

Jaundice (yellowing of the 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 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.

Worsening of existing lupus erythaematosus-like reactions or appearance of unusual skin

reactions.

Very rare (affects less than 1 user in 10,000)

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)

Sudden shortsightedness

Sudden eye pain (acute angle-closure glaucoma)

Reporting of side effects

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

Page 6 of 8

medsafety@hpra.ie.

By reporting side effects you can help provide more information on the safety of

this medicine.

5. HOW TO STORE BLOPRESS PLUS

Keep out of the sight and reach of children.

This medicinal product does not require any special storage conditions.

Do not use Blopress Plus after the expiry date which is stated on the carton label and blister foil

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

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

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

6. CONTENTS OF THE PACK AND OTHER INFORMATION

What Blopress Plus contains

The active substances of Blopress Plus tablets are candesartan cilexetil and hydrochlorothiazide.

Blopress 8 mg/12.5 mg tablets contain 8 mg of candesartan cilexetil and 12.5 mg of

hydrochlorothiazide.

Blopress Plus 16 mg/12.5 mg tablets contain 16 mg of candesartan cilexetil and 12.5 mg of

hydrochlorothiazide.

Blopress Plus 32 mg/12.5 mg tablets contain 32 mg of candesartan cilexetil and 12.5 mg of

hydrochlorothiazide.

Blopress Plus 32 mg/25 mg tablets contain 32 mg candesartan cilexetil and 25 mg of

hydrochlorothiazide.

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

magnesium stearate, maize starch, macrogol, yellow iron oxide E172 (32 mg/12.5 mg tablet) and

red iron oxide E172 (16 mg/12.5 mg and 32 mg/25 mg tablet).

What Blopress Plus looks like and contents of the pack

Blopress Plus 8 mg/12.5 mg tablets are white to off-white, oval flat tablets approximately 8.5 mm

by 5.1 mm with a score and debossing 8/C on both sides.

Blopress Plus 16 mg/12.5 mg tablets are light pink, oval, flat tablets approximately 8.5 mm by

5.1 mm with a score and debossing 16/C on both sides.

Blopress Plus 32 mg/12.5mg tablets are light yellow, oval, flat tablets approximately 11 mm by

6.5 mm with debossing 32│C1 on both sides.

Blopress Plus 32 mg/25mg tablets are light pink, oval, flat tablets approximately 11 mm by

6.5 mm with debossing 32│C2 on both sides.

Blopress Plus tablets come in blister packs containing 7, 14, 20, 28, 50, 56, 98, 98 x 1 (single dose

unit, only applicable to Blopress 8 mg/12.5 mg), 100 or 300 tablets and calendar packs of 7, 14, 28, 56

and 98 tablets.

Not all pack sizes may be marketed in every country.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

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Takeda UK Limited

Building 3,

Glory Park,

Glory Park Avenue,

Wooburn Green,

BUCKS,

HP10 0DF,

Manufacturer

Delpharm Novara S.r.l, Via Crosa 86, 28065 Cerano (No), Italy or by

Takeda Ireland Ltd., Bray Business Park, Kilruddery, Co. Wicklow, Ireland (only applicable to

Blopress Plus 8 mg/12,5 mg and Blopress Plus 16/12,5 mg).

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

following names:

Name

Member State

Blopress Comp 8 mg/12.5 mg

Blopress Comp 16 mg/12.5 mg

Blopress Comp 32mg/12.5mg

Blopress Comp 32mg/25mg

Sweden

Blopress Plus 8 mg/12,5 mg

Blopress Plus 16 mg/12,5 mg

Blopress Plus 32mg/12,5 mg

Blopress Plus 32mg/25 mg

Austria

Blopress 8 mg Plus 12,5 mg

Blopress 16 mg Plus 12,5 mg

Blopress 32 mg Plus 12,5 mg

Blopress forte 32 mg Plus 25 mg

Germany

Blopress Plus 8 mg/12.5 mg

Blopress Plus 16 mg/12.5 mg

Blopress Plus 32mg/12.5 mg

Blopress Plus 32mg/25 mg

Ireland

Blopresid 8 mg/12,5mg

Blopresid 16 mg/12,5mg

Blopresid 32 mg/12,5mg

Blopresid 32 mg/25mg

Italy

Blopress Plus 16/12,5 mg

Blopress Plus 32/12,5 mg

Blopress Forte 32/25 mg

Spain

Blopress 8 mg + 12,5mg

Blopress 16 mg + 12,5 mg

Blopress 32 mg + 12,5 mg

Blopress 32 mg + 25 mg

Portugal

CoKenzen 8 mg/12,5 mg

CoKenzen 16 mg/12,5 mg

France

This leaflet was last revised in November 2016.

Other sources of information

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Detailed information on this medicine is available on the website of the HPRA.

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Blopress Plus 32 mg/12.5 mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One Blopress Plus 32mg/12.5 mg tablet contains 32 mg candesartan cilexetil and 12.5 mg hydrochlorothiazide.

Excipients with known effect: lactose (as monohydrate)

Each 32 mg/12.5 mg tablet contains 150.2 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet.

Blopress Plus 32 mg/12.5 mg tablets are light yellow, oval flat tablets approximately 11 mm x 6.5 mm with debossing

C1on both sides.

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

Blopress Plus 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

The recommended dose of Blopress Plus 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 Blopress Plus may be considered. Dose titration of

candesartan cilexetil is recommended when switching from hydrochlorothiazide monotherapy. Blopress Plus may be

administered in patients whose blood pressure is not optimally controlled with candesartan cilexetil or

hydrochlorothiazide monotherapy or Blopress Plus at lower doses.

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

Special populations

Older people

No dose adjustment is necessary in elderly patients.

Patients with intravascular volume depletion

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

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

Patients with renal impairment

Loop diuretics are preferred to thiazides in this population. Dose titration of candesartan cilexetil is recommended in

patients with mild to moderate renal impairment (creatinine clearance

30 ml/min/1.73 m

Body Surface Area (BSA))

before treatment with Blopress Plus (the recommended starting dose of candesartan cilexetil is 4 mg in these patients).

Blopress Plus is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min/1.73 m

BSA) (see section 4.3).

Patients with hepatic impairment

Dose titration of candesartan cilexetil is recommended in patients with mild to moderate hepatic impairment before

treatment with Blopress Plus (the recommended starting dose of candesartan cilexetil is 4 mg in these patients).

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

Paediatric population

The safety and efficacy of Blopress Plus in children aged between birth and 18 years have not been established. No

data are available.

Method of administration

Oral use.

Blopress Plus 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 Blopress Plus with aliskiren-containing products is contraindicated in patients with diabetes

mellitus or renal impairment (GFR <60ml/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 section 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/kidney transplantation

Loop diuretics are preferred to thiazides in this population. When Blopress Plus is used in patients with impaired renal

function, a periodic monitoring of potassium, creatinine and uric acid levels is recommended.

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There is no experience regarding the administration of Blopress Plus in patients with a recent kidney transplantation.

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 Blopress Plus is not

recommended until this condition has been corrected.

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

Blopress Plus 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 agents acting through

inhibition of the renin-angiotensin-aldosterone system. Therefore the use of Blopress Plus 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 Blopress Plus and potassium-sparing diuretics, potassium supplements or salt

substitutes or other medicinal products that may increase serum potassium levels (e.g. heparin sodium) 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 medicinal products,

including insulin, may be required. Latent diabetes mellitus may become manifest during thiazide therapy. Increases in

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

Blopress Plus, 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 medicinal products that 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. 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 erythaematosus has been reported with the use of thiazide diuretics.

The antihypertensive effect of Blopress Plus may be enhanced by other antihypertensives.

This medicinal product contains lactose, as an excipient, and patients with rare hereditary problems of galactose

intolerance, the Lapp 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).

4.5 Interaction with other medicinal products and other forms of interaction

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 Blopress Plus and potassium-sparing diuretics, potassium supplements or salt substitutes or other

medicinal products that may increase serum potassium levels (e.g. heparin sodium) 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 Blopress Plus 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)

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

sparfloxacine, terfenadine, vincamine iv)

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 drugs (NSAIDs) (i.e. selective

COX-2 inhibitors, acetylsalicylic acid (>3g/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 of nondepolarising 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

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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

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 Blopress Plus during breastfeeding, Blopress Plus 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 Blopress Plus during breast-feeding is not recommended.

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 Blopress Plus.

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4.8 Undesirable effects

In controlled clinical studies with candesartan cilexetil/hydrochlorothiazide adverse reactions were mild and transient.

Withdrawals from treatment due to adverse events were similar with candesartan cilexetil/hydrochlorothiazide (2.3-

3.3%) and placebo (2.7-4.3%).

In clinical trials with candesartan cilexetil/hydrochlorothiazide, 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.

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) and not known (cannot be

estimated from the available data).

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

higher.

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

Hepatobiliary disorders

Very rare

Increased liver enzymes, abnormal

hepatic function or hepatitis

Skin and subcutaneous

tissue disorders

Very rare

Angioedema, rash, urticaria,

pruritus

Musculoskeletal

andconnective 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)

System Organ Class

Frequency

Undesirable Effect

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

Common

Light-headedness, vertigo

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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

disorders

Rare

Paraesthesia

Eye disorders

Rare

Transient blurred vision

Not known

Acute myopia, acute angle-closure

glaucoma

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,

cutaneous lupus erythaematosus-like

reactions, reactivation of cutaneous

lupus erythaematosus

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

Investigations

Common

Increases in cholesterol and

triglycerides

Rare

Increases in BUN and serum

creatinine

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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 overdose with Blopress Plus. The following measures are,

however, suggested in case of overdose.

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 medicinal products

may be administered if the above-mentioned measures are not sufficient.

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

haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Angiotensin II antagonists + 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 (AT

) 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 AIIRA, selective for AT

receptors, with tight binding to

and slow dissociation from the receptor. It has no agonist activity.

Clinical efficacy and safety

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 channels known to be important in cardiovascular regulation. The antagonism of

the AT

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

decrease in plasma aldosterone concentration.

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 reabsorption 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,

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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.

Candesartan and hydrochlorothiazide have additive antihypertensive effects.

In hypertensive patients, Blopress Plus 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 Blopress Plus, 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. Blopress Plus 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, Blopress Plus 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 Blopress Plus 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 cilexetil/hydrochlorothiazide combinations 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 cilexetil/hydrochlorothiazide 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 cilexetil/hydrochlorothiazide is similarly effective in patients irrespective of age and gender.

Currently there are no data on the use of candesartan cilexetil/hydrochloro-thiazide 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 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

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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 alsikiren

group than in the placebo group.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Blopress Plus in all

subsets of the paediatric population in essential hypertension (see section 4.2 for information on paediatric use)

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 substance

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 (C

) is reached 3-4

hours following tablet intake. The candesartan serum concentrations increase linearly with increasing doses in the

therapeutic dose range. No gender related differences in the pharmacokinetics of candesartan have been observed. The

area under the serum concentration versus time curve (AUC) of candesartan is not significantly affected by food.

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

0.1 l/kg.

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.

Biotransformation 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 medicinal products whose metabolism is dependent upon

cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal

half-life (t

) 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.

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.

Hydrochlorothiazide

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Hydrochlorothiazide is not metabolised and is excreted almost entirely as unchanged drug by glomerular filtration and

active tubular secretion. The terminal t

of hydrochlorothiazide is approximately 8 hours. Approximately 70% of an

oral dose is eliminated in the urine within 48 hours. The half-life of hydrochlorothiazide remains unchanged

(approximately 8 h) after administration of hydrochlorothiazide in combination with candesartan cilexetil. No

additional accumulation of hydrochlorothiazide occurs after repeated doses of the combination compared to

monotherapy.

Pharmacokinetics in special populations

Candesartan cilexetil

In elderly subjects (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 Blopress Plus 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 the terminal 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

pharmacokinetics in patients undergoing haemodialysis were similar to those 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.

Hydrochlorothiazide

The terminal t

of hydrochlorothiazide is prolonged in patients with renal impairment.

5.3 Preclinical safety data

There were no qualitative new toxic findings with the combination compared to that observed for each component. In

preclinical safety studies candesartan itself 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 regeneration, dilatation and basophilia in 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. Addition of hydrochlorothiazide potentiates the nephrotoxicity of candesartan.

Furthermore, candesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells. These changes were

considered to be caused by the pharmacological action of candesartan and to be of little clinical relevance.

Foetotoxicity has been observed in late pregnancy with candesartan. The addition of hydrochlorothiazide did not

significantly affect the outcome of foetal development studies in rats, mice or rabbits (see section 4.6).

Candesartan and hydrochlorothiazide both show genotoxic activity at very high concentrations/doses. Data from in

vitro and in vivo genotoxicity testing indicate that candesartan and hydrochlorothiazide are unlikely to exert any

mutagenic or clastogenic activity under conditions of clinical use.

There was no evidence that either compound is carcinogenic.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

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Carmellose calcium

Hydroxypropylcellulose

Iron oxide yellow E 172

Lactose monohydrate

Magnesium stearate

Maize starch

Macrogol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Aluminium blister packs of 7, 14, 20, 28, 50, 56, 98, 100, 300 tablets and calendar packs of 7, 14, 28, 56 and 98 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Takeda UK Limited

Building 3

Glory Park,

Glory Park Avenue

Wooburn Green

BUCKS

HP10 0DF

8 MARKETING AUTHORISATION NUMBER

PA1547/002/003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 19th June 2009

Date of first renewal: 6th February 2014

10 DATE OF REVISION OF THE TEXT

February 2017

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