Bisoprolol Krka 5 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
BISOPROLOL FUMARATE
Available from:
Krka d.d., Novo mesto
ATC code:
C07AB; C07AB07
INN (International Name):
BISOPROLOL FUMARATE
Dosage:
5 milligram(s)
Pharmaceutical form:
Film-coated tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Beta blocking agents, selective; bisoprolol
Authorization status:
Marketed
Authorization number:
PA1347/031/002
Authorization date:
2013-12-13

PACKAGE LEAFLET

Package leaflet: Information for the patient

Bisoprolol Krka 2.5 mg film-coated tablets

Bisoprolol Krka 5 mg film-coated tablets

Bisoprolol Krka 10 mg film-coated tablets

Bisoprolol fumarate

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 Bisoprolol Krka is and what it is used for

What you need to know before you take Bisoprolol Krka

How to take Bisoprolol Krka

Possible side effects

How to store Bisoprolol Krka

Contents of the pack and other information

1.

What Bisoprolol Krka is and what it is used for

The active substance in Bisoprolol Krka is bisoprolol. Bisoprolol belongs to a group of medicines

called beta-blockers. These medicines work by affecting the body`s response to some nerve impulses,

especially in the heart. As a result, bisoprolol slows down the heart rate and makes the heart more

efficient at pumping blood around the body. At the same time bisoprolol reduces the oxygen demand

and blood supply of the heart. Heart failure occurs when the heart muscle is weak and unable to pump

enough blood to supply the body’s needs.

Bisoprolol Krka is used to

treat high blood pressure (hypertension).

treat angina pectoris.

treat stable chronic heart failure. It is used in combination with other medicines suitable for this

condition (such as ACE-inhibitors, diuretics, and heart glycosides).

2.

What you need to know before you take Bisoprolol Krka

Do not take Bisoprolol Krka

Do not take Bisoprolol Krka if you have one of the following conditions:

allergy to the active substance or any of the other ingredients of this medicine (listed in section

severe asthma.

severe blood circulation problems in your limbs (such as Raynaud’s syndrome), which may

cause your fingers and toes to tingle or turn pale or blue.

untreated phaeochromocytoma, which is a rare tumour of the adrenal gland.

metabolic acidosis, which is a condition when there is too much acid in the blood.

Do not take Bisoprolol Krka if you have one of the following heart problems:

acute heart failure.

worsening heart failure requiring an injection of medicines into a vein, that increase the force of

contraction of the heart.

low blood pressure.

certain heart conditions causing a very slow heart rate or irregular heartbeat

cardiogenic shock, which is an acute serious heart condition causing low blood pressure and

circulatory failure.

Warnings and precautions

Talk to your doctor or pharmacist before taking Bisoprolol Krka. If you have any of the following

conditions tell your doctor before taking Bisoprolol Krka tablets; he or she may want to take special

care (for example give additional treatment or perform more frequent checks):

diabetes.

strict fasting.

certain heart diseases such as disturbances in heart rhythm, or severe chest pain at rest

(Prinzmetal’s angina).

kidney or liver problems.

less severe blood circulation problems in your limbs.

less severe asthma or chronic lung disease.

history of a scaly skin rash (psoriasis).

tumour of the adrenal gland (phaeochromocytoma).

thyroid disorder.

first degree heart block (a condition in which nerve signals to the heart are disturbed, possibly

causing it occasionally to skip a beat, or beat irregularly).

In addition, tell your doctor if you are going to have:

desensitization therapy (for example for the prevention of hay fever), because Bisoprolol Krka

tablets may make it more likely that you experience an allergic reaction, or such reaction may

be more severe.

anaesthesia (for example for surgery), because Bisoprolol Krka tablets may influence how your

body reacts to this situation.

Other medicines and Bisoprolol Krka

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

medicines.

Do not take the following medicines with Bisoprolol Krka tablets without special advice from your

doctor:

certain medicines used to treat irregular or abnormal heartbeat (Class I antiarrhythmic

medicines such as quinidine, disopyramide, lidocaine, phenytoin; flecainide, propafenone).

certain medicines used to treat high blood pressure, angina pectoris or irregular heartbeat

(calcium antagonists such as verapamil and diltiazem).

certain medicines used to treat high blood pressure such as clonidine, methyldopa, moxonodine,

rilmenidine. However,

do not stop taking these medicines

without checking with your doctor

first.

Check with your doctor before taking the following medicines with Bisoprolol Krka tablets; your

doctor may need to check your condition more frequently:

certain medicines used to treat high blood pressure or angina pectoris or abnormal heart beat

(dihydropyridine-type calcium antagonists, such as nifedipine, felodipine and amlodipine).

certain medicines used to treat irregular or abnormal heartbeat (Class III antiarrhythmic

medicines such as amiodarone).

beta-blockers applied locally (such as timolol eye drops for glaucoma treatment).

certain medicines used to treat for example Alzheimer’s disease or glaucoma

(parasympathomimetics, such as tacrine or carbachol) or medicines that are used to treat acute

heart problems (sympathomimetics such as isoprenaline and dobutamine).

antidiabetic medicines including insulin.

anaesthetic agents (for example during surgery).

digitalis, used to treat heart failure.

non-steroidal anti-inflammatory medicines (NSAIDs) used to treat arthritis, pain or

inflammation (for example ibuprofen or diclofenac).

any medicine, which can lower blood pressure as a desired or undesired effect such as

antihypertensives, certain medicines for depression (tricyclic antidepressants such as

imipramine or amitriptyline), certain medicines used to treat epilepsy or during anaesthesia

(barbiturates such as phenobarbital), or certain medicines to treat mental illness characterized

by a loss of contact with reality (phenothiazines such as levomepromazine).

mefloquine, used for prevention or treatment of malaria.

depression treatment medicines called monoamine oxidase inhibitors (except MAO-B

inhibitors) such as moclobemide.

moxisylyte, which is used to treat circulatory problems like Raynaud’s syndrome.

Pregnancy and breast-feeding

There is a risk that use of Bisoprolol Krka during pregnancy may harm the baby. If you are pregnant

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

pharmacist for advice before taking this medicine. He or she will decide whether you can take

Bisoprolol Krka during pregnancy.

It is not known whether bisoprolol passes into human breast milk. Therefore, breastfeeding is not

recommended during therapy with Bisoprolol Krka.

Children and adolescents

Bisoprolol Krka is not recommended for use in children or adolescents.

Driving and using machines

Your ability to drive or use machinery may be affected depending on how well you tolerate the

medicine. Please be especially cautious at the start of treatment, when the dose is increased or the

medication is changed, as well as in combination with alcohol.

Bisoprolol Krka contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially "sodium-

free".

3.

How to take Bisoprolol Krka

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

or pharmacist if you are not sure.

Take the tablet with some water in the morning, with or without food. Do not crush or chew the tablet.

Treatment with Bisoprolol Krka requires regular monitoring by your doctor. This is particularly

necessary at the start of treatment and during dose increase, and when you stop treatment.

Treatment with Bisoprolol Krka is usually long-term.

Hypertension and angina pectoris

Adults including the elderly

The dose should be adjusted individually. The usual daily dose is 10 mg bisoprolol.

Depending on how well you respond to the medicine, your doctor may decide to decrease the dose to

5 mg or he may decide to increase it to 20 mg. The dose should not exceed 20 mg in one day.

Stable chronic heart failure

Adults including the elderly

Treatment with bisoprolol must be started at a low dose and increased gradually.

Your doctor will decide how to increase the dose, and this will normally be done in the following

way:

1.25 mg bisoprolol once daily for one week

2.5 mg bisoprolol once daily for one week

3.75 mg bisoprolol once daily for one week

5 mg bisoprolol once daily for four weeks

7.5 mg bisoprolol once daily for four weeks

10 mg bisoprolol once daily for maintenance (on-going) therapy.

The maximum recommended daily dose is 10 mg bisoprolol.

Depending on how well you tolerate the medicine, your doctor may also decide to lengthen the time

between dose increases. If your condition gets worse or you no longer tolerate the drug, it may be

necessary to reduce the dose again or to interrupt treatment. In some patients a maintenance dose

lower than 10 mg bisoprolol may be sufficient. Your doctor will tell you what to do. If you have to

stop treatment entirely, your doctor will usually advise you to reduce the dose gradually, as otherwise

your condition may become worse.

Use in patients with hepatic and /or renal impairment

In patients with mild to moderate impairment of renal or hepatic function no dosage adjustment is

normally required.

In patients with severe renal impairment (creatinine clearance < 20 ml/min) and in patients with

severe hepatic impairment it is recommended not to exceed a daily dose of 10 mg bisoprolol.

Use in children and adolescents

Bisoprolol Krka is not recommended for use in children.

If you take more Bisoprolol Krka than you should

If you have taken more Bisoprolol Krka than you should, tell your doctor immediately. Your doctor

will decide what measures are necessary.

Symptoms of an overdose may include slowed heart rate, severe difficulty in breathing, feeling dizzy,

or trembling (due to decreased blood sugar).

If you forget to take Bisoprolol Krka

Do not take a double dose to make up for a forgotten tablet dose. Take your usual dose the next

morning.

If you stop taking Bisoprolol Krka

Never stop taking Bisoprolol Krka unless on your doctor’s advice. Otherwise your condition could

become much worse. Especially in patients with ischemic heart disease treatment should not be

stopped abruptly. If you are considering stopping treatment, your doctor will normally advise you to

reduce your dose gradually.

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.

To prevent serious reactions, speak to a doctor immediately if a side effect is severe, occurred

suddenly or gets worse rapidly. The most serious side effects are related to the heart function:

slowing of heart rate (may affect up to 1 in 10 people)

worsening of heart failure (may affect up to 1 in 10 people)

slow or irregular heartbeat (may affect up to 1 in 100 people)

If you feel dizzy or weak, or have breathing difficulties please contact your doctor as soon as

possible.

Further side effects are listed below according to how frequently they may occur:

Common

(may affect up to 1 in 10 people):

tiredness, feeling weak, dizziness, headache

feeling of coldness or numbness in hands or feet

low blood pressure

stomach or intestine problems such as nausea, vomiting, diarrhoea, or constipation.

Uncommon

(may affect up to 1 in 100 people):

sleep disturbances

depression

dizziness when standing up

breathing problems in patients with asthma or chronic lung disease

muscle weakness, muscle cramps.

Rare

(may affect up to 1 in 1,000 people):

hearing problems

allergic runny nose

reduced tear flow (dry eyes)

inflammation of the liver which can cause yellowing of the skin or whites of the eyes

certain blood test results for liver function or fat levels differing from normal

allergy-like reactions such as itching, flush, rash

impaired erection

nightmares, hallucinations

fainting.

Very rare

(may affect up to 1 in 10,000 people):

irritation and redness of the eye (conjunctivitis)

hair loss

appearance or worsening of scaly skin rash (psoriasis); psoriasis-like rash.

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 Bisoprolol 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.

Store in the original package in order to protect from light and moisture.

This medicine does not require any special temperature 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 Bisoprolol Krka contains

The active substance is bisoprolol fumarate.

Each film-coated tablet contains 2.5 mg bisoprolol fumarate.

Each film-coated tablet contains 5 mg bisoprolol fumarate.

Each film-coated tablet contains 10 mg bisoprolol fumarate.

The other ingredients are microcrystalline cellulose, sodium starch glycolate type A, povidone

K30, colloidal anhydrous silica and magnesium stearate (E470b) in the tablet core and

hypromellose 2910, macrogol 400, titanium dioxide (E171), talc, yellow iron oxide (E172) –

only for 5 mg and 10 mg film-coated tablets and red iron oxide (E172) – only for 5 mg and

10 mg film-coated tablets in the film coating.

See section 2 "Bisoprolol Krka contains sodium".

What Bisoprolol Krka looks like and contents of the pack

2.5 mg: White to almost white, oval, slightly biconvex film-coated tablets (tablets), scored on one side

(length: 8.3–8.7 mm, width: 5.5 mm, thickness: 2.8–3.6 mm). The tablet can be divided into equal

doses.

5 mg: Pale brownish yellow, oval, slightly biconvex film-coated tablets (tablets), scored on one side

(length: 8.3–8.7 mm, width: 5.5 mm, thickness: 2.8–3.6 mm). The tablet can be divided into equal

doses.

10 mg: Pale brownish yellow, round, slightly biconvex film-coated tablets (tablets) with bevelled

edges, scored on one side (diameter: 10.0–10.3 mm, thickness: 2.8–3.6 mm). The tablet can be

divided into equal doses.

Blisters (Alu/Alu foil): 10, 20, 28, 30, 50, 56, 60, 84, 90 and 100 tablets in a box.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

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

Manufacturer

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

TAD Pharma GmbH, Heinz-Lohmann-Straße 5, 27472 Cuxhaven, Germany

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

names:

Czech Republic, Bulgaria,

Estonia, Hungary, Poland, Latvia,

Slovenia, Slovakia

Sobycor

Austria, Denmark, Spain, Finland,

Ireland, Portugal, Sweden

Bisoprolol Krka

France

BISOPROLOL KRKA

Germany

Bisoprolol TAD

Italy

Bisoprololo Krka

Romania

Sobyc

This leaflet was last revised in

Health Products Regulatory Authority

28 August 2020

CRN009VGM

Page 1 of 9

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Bisoprolol Krka 5 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 5 mg bisoprolol fumarate.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet (tablet)

Pale brownish yellow, oval, slightly biconvex film-coated tablets, scored on one side (length: 8.3–8.7 mm, width: 5.5 mm,

thickness: 2.8–3.6 mm). The tablet can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Treatment of hypertension.

Treatment of ischemic heart disease (angina pectoris).

Treatment of stable chronic heart failure with reduced systolic left ventricular function with ACE inhibitors, diuretics, and

optionally cardiac glycosides (for further information see section 5.1).

4.2 Posology and method of administration

Posology

Hypertension and angina pectoris

Adults

The dosage should be individually adjusted. The usual dose is 10 mg once daily with a maximum recommended dose of 20 mg

per day. In some patients 5 mg per day may be adequate.

Renal or hepatic impairment

In patients with mild to moderate impairment of renal or hepatic function no dosage adjustment is normally required.

In patients with final stage impairment of renal function (creatinine clearance < 20 ml/min) or liver function, the dose should

not exceed 10 mg bisoprolol once daily. A lower dose should be used. Experiences with the use of bisoprolol in patients

undergoing dialysis are limited; but there is no evidence supporting a change in dosage.

Elderly

No dosage adjustment is normally required, but 5 mg per day may be adequate in some patients; as for other adults, dosage

may have to be reduced in cases of severe renal or hepatic dysfunction.

Paediatric population

There is no paediatric experience with bisoprolol, therefore its use cannot be recommended in paediatric patients.

Stable chronic heart failure

Health Products Regulatory Authority

28 August 2020

CRN009VGM

Page 2 of 9

Adults

Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker in case of intolerance to ACE

inhibitors), a beta-blocker, diuretics, and when appropriate cardiac glycosides. Patients should be stable (without acute failure)

when bisoprolol treatment is initiated.

It is recommended that the treating physician should be experienced in the management of chronic heart failure.

Transient worsening of heart failure, hypotension, or bradycardia may occur during the titration period and thereafter.

Titration phase

The treatment of stable chronic heart failure with bisoprolol requires a titration phase

The treatment with bisoprolol is to be started with a gradual uptitration according to the following steps:

- 1.25 mg once daily for 1 week, if well tolerated increase to

- 2.5 mg once daily for a further week, if well tolerated increase to

- 3.75 mg once daily for a further week, if well tolerated increase to

- 5 mg once daily for the 4 following weeks, if well tolerated increase to

- 7.5 mg once daily for the 4 following weeks, if well tolerated increase to

- 10 mg once daily for the maintenance therapy.

The maximum recommended dose is 10 mg once daily.

Close monitoring of vital signs (heart rate, blood pressure) and symptoms of worsening heart failure is recommended during

the titration phase. Symptoms may already occur within the first day after initiating the therapy.

Treatment modification

If the maximum recommended dose is not well tolerated, gradual dose reduction may be considered.

In case of transient worsening of heart failure, hypotension, or bradycardia reconsideration of the dosage of the concomitant

medication is recommended. It may also be necessary to temporarily lower the dose of bisoprolol or to consider

discontinuation.

The reintroduction and/or uptitration of bisoprolol should always be considered when the patient becomes stable again.

Renal or hepatic impairment

There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired

hepatic or renal function. Uptitration of the dose in these populations should therefore be made with additional caution.

Elderly

No dosage adjustment is required.

Paediatric population

There is no paediatric experience with bisoprolol, therefore its use cannot be recommended in paediatric patients.

Treatment with bisoprolol is usually long-term. Treatment with bisoprolol must not be stopped abruptly as this can lead to

acute deterioration of the patient´s condition. Especially in patients with ischemic heart disease treatment should not be

stopped abruptly. If discontinuation of therapy is considered, gradual dose decrease is recommended.

Method of administration

For oral use.

Health Products Regulatory Authority

28 August 2020

CRN009VGM

Page 3 of 9

Bisoprolol Krka should be taken in morning and can be taken with food. They should be swallowed with liquid and should not

be chewed.

4.3 Contraindications

Bisoprolol is contraindicated in patients with following conditions:

- hypersensitivity to bisoprolol or to any of the excipients listed in section 6.1

- acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy

- cardiogenic shock

- second or third degree AV block (without a pacemaker)

- sick sinus syndrome

- sino-atrial block

- symptomatic bradycardia (heart rate less than 60 beats/min prior to start of therapy)

- symptomatic hypotension (systolic blood pressure < 100 mmHg)

- severe bronchial asthma

- severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's syndrome

- untreated phaeochromocytoma (see section 4.4)

- metabolic acidosis

4.4 Special warnings and precautions for use

The treatment of stable chronic heart failure with bisoprolol has to be initiated with a special titration phase (see section 4.2).

Especially in patients with ischaemic heart disease the cessation of therapy with bisoprolol must not be done abruptly unless

clearly indicated, because this may lead to transitional worsening of heart condition (see section 4.2).

The initiation and cessation of treatment with bisoprolol necessitates regular monitoring.

There is no therapeutic experience of bisoprolol treatment of heart failure in patients with the following diseases and

conditions:

- insulin dependent diabetes mellitus (type I)

- severely impaired renal function

- severely impaired hepatic function

- restrictive cardiomyopathy

- congenital heart disease

- haemodynamically significant organic valvular disease

- myocardial infarction within 3 months.

Bisoprolol must be used with caution in:

- bronchospasm (bronchial asthma, obstructive airways diseases);

- diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia (e.g. tachycardia, palpitations

or sweating) can be masked;

- strict fasting;

- ongoing desensitisation therapy. As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens

and the severity of anaphylactic reactions. Epinephrine treatment does not always yield the expected therapeutic effect.

- first degree AV block;

- Prinzmetal's angina;

- peripheral arterial occlusive disease (intensification of complaints might happen especially during the start of therapy);

- general anaesthesia.

In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias and myocardial ischemia

during induction and intubation, and the post-operative period. It is currently recommended that maintenance beta-blockade

be continued peri-operatively. The anaesthesist must be aware of beta-blockade because of the potential for interactions with

other drugs, resulting in bradyarrhythmias, attenuation of the reflex tachycardia and the decreased reflex ability to compensate

Health Products Regulatory Authority

28 August 2020

CRN009VGM

Page 4 of 9

for blood loss. If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and

completed about 48 hours before anaesthesia.

Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class I antiarrhythmic drugs and

with centrally acting antihypertensive drugs is generally not recommended, for details please refer to section 4.5.

Although cardioselective (beta1) beta-blockers may have less effect on lung function than non-selective beta-blockers, as with

all beta-blockers, these should be avoided in patients with obstructive airways diseases, unless there are compelling clinical

reasons for their use. Where such reasons exist, Bisoprolol Krka may be used with caution. In patients with obstructive airways

diseases, the treatment with bisoprolol should be started at the lowest possible dose and patients should be carefully

monitored for new symptoms (e.g. dyspnea, exercise intolerance, cough). In bronchial asthma or other chronic obstructive lung

diseases, which may cause symptoms, bronchodilating therapy should be given concomitantly. Occasionally an increase of the

airway resistance may occur in patients with asthma, therefore the dose of beta

-stimulants may have to be increased.

Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g.bisoprolol) after carefully balancing

the benefits against the risks.

In patients with phaeochromocytoma bisoprolol must not be administered until after alpha-receptor blockade.

Under treatment with bisoprolol the symptoms of a thyreotoxicosis may be masked.

As other beta-blockers bisoprolol may increase sensitivity to allergens and exacerbate the symptoms of anaphylactic reaction.

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interactions

Combinations not recommended

Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type: Negative influence on contractility and

atrio-ventricular conduction. Intravenous administration of verapamil in patients on β-blocker treatment may lead to profound

hypotension and atrioventricular block.

Class I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone): Effect on

atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.

Centrally acting antihypertensive drugs such as clonidine and others (e.g. methyldopa, moxonodine, rilmenidine): Concomitant

use of centrally acting antihypertensive drugs may worsen heart failure by a decrease in the central sympathetic tonus

(reduction of heart rate and cardiac output, vasodilation). Abrupt withdrawal, particularly if prior to beta-blocker

discontinuation, may increase risk of “rebound hypertension”.

Combinations to be used with caution

Calcium antagonists of the dihydropyridine type such as nifedipine, felodipine and amlodipine: Concomitant use may increase

the risk of hypotension, and an increase in the risk of a further deterioration of the ventricular pump function in patients with

heart failure cannot be excluded.

Class-III antiarrhythmic drugs (e.g. amiodarone): Effect on atrio-ventricular conduction time may be potentiated.

Topical beta-blockers (e.g. eye drops for glaucoma treatment) may add to the systemic effects of bisoprolol.

Parasympathomimetic drugs: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia.

Insulin and oral antidiabetic drugs: Increase of blood sugar lowering effect. Blockade of beta-adrenoreceptors may mask

symptoms of hypoglycaemia.

Health Products Regulatory Authority

28 August 2020

CRN009VGM

Page 5 of 9

Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension (for further information on

general anaesthesia see also section 4.4.).

Digitalis glycosides: Reduction of heart rate, increase of atrio-ventricular conduction time.

Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect of bisoprolol.

β-Sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both agents.

Sympathomimetics that activate both β- and α-adrenoceptors (e.g. noradrenaline, adrenaline): Combination with bisoprolol

may unmask the α-adrenoceptor-mediated vasoconstrictor effects of these agents leading to blood pressure increase and

exacerbated intermittent claudication. Such interactions are considered to be more likely with nonselective β-blockers.

Concomitant use with antihypertensive agents as well as with other drugs with blood pressure lowering potential (e.g. tricyclic

antidepressants, barbiturates, phenothiazines) may increase the risk of hypotension.

Combinations to be considered

Mefloquine: increased risk of bradycardia

Monoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the beta-blockers but also risk for

hypertensive crisis.

4.6 Fertility, pregnancy and lactation

Pregnancy

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn. In general,

beta-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death,

abortion or early labour. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the fetus and newborn infant. If

treatment with beta-adrenoceptor blockers is necessary, beta1-selective adrenoceptor blockers are preferable.

Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary,

the uteroplacental blood flow and the fetal growth should be monitored. In case of harmful effects on pregnancy or the fetus

alternative treatment should be considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and

bradycardia are generally to be expected within the first 3 days.

Breast-feeding

It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not recommended during

administration of bisoprolol.

4.7 Effects on ability to drive and use machines

In a study with coronary heart disease patients bisoprolol did not impair driving performance. However, due to individual

variations in reactions to the drug, the ability to drive a vehicle or to operate machinery may be impaired. This should be

considered particularly at start of treatment and upon change of medication as well as in conjunction with alcohol.

4.8 Undesirable effects

- 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)

Health Products Regulatory Authority

28 August 2020

CRN009VGM

Page 6 of 9

Psychiatric disorders

Uncommon

sleep disorders, depression

Rare

nightmares, hallucinations

Nervous system disorders

Common

dizziness, headache

Rare

syncope

Eye disorders

Rare

reduced tear flow (to be considered if the patient uses

lenses)

Very rare

conjunctivitis

Ear and labyrinth disorders

Rare

hearing disorders

Cardiac disorders

Very common

bradycardia

Common

worsening of heart failure

Uncommon

AV-conduction disturbances

Vascular disorders

Common

feeling of coldness or numbness in the extremities,

hypotension

Uncommon

orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon

bronchospasm in patients with bronchial asthma or a

history of obstructive airways disease

Rare

allergic rhinitis

Gastrointestinal disorders

Common

gastrointestinal complaints such as nausea, vomiting,

diarrhoea, constipation

Hepatobiliary disorders

Rare

hepatitis

Skin and subcutaneous tissue disorders

Rare

hypersensitivity reactions (itching, flush, rash)

Very rare

alopecia, beta-blockers may provoke or worsen psoriasis

or induce psoriasis-like rash

Musculoskeletal and connective tissue disorders

Uncommon

muscular weakness and cramps

Reproductive system and breast disorders

Rare

potency disorders

General disorders and administration site conditions

Common

asthenia, fatigue

Investigations

Rare

increased triglycerides, increased liver enzymes (ALAT,

ASAT).

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 the national reporting system:

HPRA Pharmacovigilance

Website: www.hpra.ie

4.9 Overdose

Symptoms

With overdose (e.g. daily dose of 15 mg instead of 7.5 mg) third degree AV-block, bradycardia, and dizziness have been

reported. In general the most common signs expected with overdosage of a beta-blocker are bradycardia, hypotension,

bronchospasm, acute cardiac insufficiency and hypoglycaemia. To date a few cases of overdose (maximum: 2000 mg) with

bisoprolol have been reported in patients suffering from hypertension and/or coronary heart disease showing bradycardia

and/or hypotension; all patients recovered. There is a wide interindividual variation in sensitivity to one single high dose of

bisoprolol and patients with heart failure are probably very sensitive. Therefore it is mandatory to initiate the treatment of

these patients with a gradual uptitration according to the scheme given in section 4.2.

Management

If overdose occurs, bisoprolol treatment should be stopped and supportive and symptomatic treatment should be provided.

Limited data suggest that bisoprolol is hardly dialysable. Based on the expected pharmacologic actions and recommendations

for other beta-blockers, the following general measures should be considered when clinically warranted.

Health Products Regulatory Authority

28 August 2020

CRN009VGM

Page 7 of 9

Bradycardia: Administer intravenous atropine. If the response is inadequate, isoprenaline or another agent with positive

chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be

necessary.

Hypotension: Intravenous fluids and vasopressors should be administered. Intravenous glucagon may be useful.

AV block (second or third degree): Patients should be carefully monitored and treated with isoprenaline infusion or

transvenous cardiac pacemaker insertion.

Acute worsening of heart failure: Administer i.v. diuretics, inotropic agents, vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as isoprenaline, beta2-sympathomimetic drugs and/or aminophylline.

Hypoglycaemia: Administer i.v. glucose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: beta blocking agents, selective, ATC code: C07AB07.

Mechanism of action

Bisoprolol is a highly beta1-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and relevant membrane

stabilising activity. It only shows low affinity to the beta2-receptor of the smooth muscles of bronchi and vessels as well as to

the beta2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the

airway resistance and beta2‑mediated metabolic effects. Its beta1-selectivity extends beyond the therapeutic dose range.

Pharmacodynamic effects

As with other β1-blocking agents, the mode of action in hypertension is not clear but it is known that bisoprolol markedly

depresses plasma renin levels.

In patients with angina, the blockade of β1-receptors reduces heart action and thus reduces oxygen demand. Hence bisoprolol

is effective in eliminating or reducing the symptoms.

In acute administration in patients with coronary heart disease without chronic heart failure bisoprolol reduces the heart rate

and stroke volume and thus the cardiac output and oxygen consumption. In chronic administration the initially elevated

peripheral resistance decreases.

Clinical efficacy and safety

In total 2647 patients were included in the CIBIS II trial. 83% (n = 2202) were in NYHA class III and 17% (n = 445) were in NYHA

class IV. They had stable symptomatic systolic heart failure (ejection fraction ≤ 35%, based on echocardiography). Total

mortality was reduced from 17.3% to 11.8% (relative reduction 34%). A decrease in sudden death (3.6% vs 6.3%, relative

reduction 44%) and a reduced number of heart failure episodes requiring hospital admission (12% vs 17.6%, relative reduction

36%) was observed. Finally, a significant improvement of the functional status according to NYHA classification has been

shown. During the initiation and titration of bisoprolol hospital admission due to bradycardia (0.53%), hypotension (0.23%),

and acute decompensation (4.97%) were observed, but they were not more frequent than in the placebo-group (0%, 0.3% and

6.74%). The numbers of fatal and disabling strokes during the total study period were 20 in the bisoprolol group and 15 in the

placebo group.

The CIBIS III trial investigated 1010 patients aged ≥ 65 years with mild to moderate chronic heart failure (CHF; NYHA class II or

III) and left ventricular ejection fraction ≤ 35%, who had not been treated previously with ACE inhibitors, beta-blockers, or

angiotensin receptor blockers. Patients were treated with a combination of bisoprolol and enalapril for 6 to 24 months after an

initial 6 months treatment with either bisoprolol or enalapril.

There was a trend toward higher frequency of chronic heart failure worsening when bisoprolol was used as the initial 6 months

treatment. Non inferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis,

although the two strategies for initiation of CHF treatment showed a similar rate of the primary combined endpoint death and

Health Products Regulatory Authority

28 August 2020

CRN009VGM

Page 8 of 9

hospitalization at study end (32.4% in the bisoprolol-first group vs. 33.1% in the enalapril-first group, per-protocol population).

The study shows that bisoprolol can also be used in elderly chronic heart failure patients with mild to moderate disease.

5.2 Pharmacokinetic properties

Absorption

Bisoprolol is absorbed and has a biological availability of about 90% after oral administration.

Distribution

The distribution volume is 3.5 l/kg. The plasma protein binding of bisoprolol is about 30%.

Biotransformation and elimination

Bisoprolol is excreted from the body by two routes. 50% is metabolised by the liver to inactive metabolites which are then

excreted by the kidneys. The remaining 50% is excreted by the kidneys in an unmetabolised form. Total clearance is

approximately 15 l/h. The half-life in plasma of 10-12 hours gives a 24 hour effect after dosing once daily.

Linearity

The kinetics of bisoprolol are linear and independent of age.

Special population

Since the elimination takes place in the kidneys and the liver to the same extent a dosage adjustment is not required for

patients with impaired liver function or renal insufficiency. The pharmacokinetics in patients with stable chronic heart failure

and with impaired liver or renal function has not been studied. In patients with chronic heart failure (NYHA stage III) the plasma

levels of bisoprolol are higher and the half-life is prolonged compared to healthy volunteers. Maximum plasma concentration

at steady state is 64±21 ng/ml at a daily dose of 10 mg and the half-life is 17±5 hours.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose

toxicity, genotoxicity or carcinogenicity. Like other beta-blockers, bisoprolol caused maternal (decreased food intake and

decreased body weight) and embryo/fetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring,

retarded physical development) at high doses but was not teratogenic.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Microcrystalline cellulose

Sodium starch glycolate type A

Povidone K30

Silica, colloidal anhydrous

Magnesium stearate (E470b)

Film coating

Hypromellose 2910

Macrogol 400

Titanium dioxide (E171)

Talc

Iron oxide, yellow (E172)

Iron oxide, red (E172)

6.2 Incompatibilities

Not applicable.

Health Products Regulatory Authority

28 August 2020

CRN009VGM

Page 9 of 9

6.3 Shelf life

5 years

6.4 Special precautions for storage

Store in the original package in order to protect from light and moisture.

This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

Blisters (Alu/Alu foil): 10, 20, 28, 30, 50, 56, 60, 84, 90 and 100 tablets in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

Krka d.d., Novo mesto

Šmarješka cesta 6

8501 Novo mesto

Slovenia

8 MARKETING AUTHORISATION NUMBER

PA1347/031/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13

December 2013

Date of last renewal: 12

November 2018

10 DATE OF REVISION OF THE TEXT

August 2020

Similar products

Search alerts related to this product

View documents history

Share this information