Bisoprolol Fumarate 10 mg Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
BISOPROLOL FUMARATE
Available from:
Chanelle Medical
ATC code:
C07AB; C07AB07
INN (International Name):
BISOPROLOL FUMARATE
Dosage:
10 milligram(s)
Pharmaceutical form:
Tablet
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Beta blocking agents, selective; bisoprolol
Authorization status:
Marketed
Authorization number:
PA0688/014/005
Authorization date:
2008-02-01

ID: PL 130-134M IE

(OLS Clonmel)

Version:

Effective Date:

14/06/2017

Package leaflet: Information for the user

Bisoprolol Fumarate 1.25 mg Tablets

Bisoprolol Fumarate 2.5 mg Tablets

Bisoprolol Fumarate 3.75 mg Tablets

Bisoprolol Fumarate 5 mg Tablets

Bisoprolol Fumarate 10 mg 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 Fumarate Tablets are and what they are used for

What you need to know before you take Bisoprolol Fumarate Tablets

How to take Bisoprolol Fumarate Tablets

Possible side effects

How to store Bisoprolol Fumarate Tablets

Contents of the pack and other information

1.

What Bisoprolol Fumarate Tablets are and what they are used for

The active substance in Bisoprolol Fumarate Tablets is bisoprolol fumarate. It 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.

Heart failure occurs when the heart muscle is weak and unable to pump enough blood to

supply the body’s needs. Bisoprolol fumarate is used to 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 Fumarate Tablets

Do not take Bisoprolol Fumarate Tablets

Do not take Bisoprolol Fumarate Tablets if one of the following conditions applies to you:

ID: PL 130-134M IE

(OLS Clonmel)

Version:

Effective Date:

14/06/2017

allergy (hypersensitive) to bisoprolol fumarate or to any of the other ingredients of this

medicine (listed in section 6)

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 Fumarate Tablets if you have one of the following heart problems:

acute heart failure

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

force of contraction of the heart

slow heart rate

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 Fumarate Tablets.

If you have any of the following conditions tell your doctor before taking Bisoprolol

Fumarate 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

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

desensitisation therapy (for example for the prevention of hay fever), because

Bisoprolol Fumarate 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 Fumarate may influence how

your body reacts to this situation.

If you have chronic lung disease or less severe asthma please inform your doctor

immediately if you start to experience new difficulties in breathing, cough, wheezing after

exercise, etc. when using Bisoprolol Fumarate.

Children and adolescents

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

ID: PL 130-134M IE

(OLS Clonmel)

Version:

Effective Date:

14/06/2017

Other medicines and Bisoprolol Fumarate Tablets

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 Fumarate 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 Fumarate

Tablets; your doctor may need to check your condition more frequently:

certain medicines used to treat high blood pressure or angina pectoris (dihydropyridine-

type calcium antagonists such as 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.

Pregnancy and breast-feeding

Pregnancy

There is a risk that use of Bisoprolol Fumarate Tablets during pregnancy may harm the

baby.

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your

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

Bisoprolol Fumarate during pregnancy.

ID: PL 130-134M IE

(OLS Clonmel)

Version:

Effective Date:

14/06/2017

Breast-feeding

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

is not recommended during therapy with Bisoprolol Fumarate.

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.

3.

How to take Bisoprolol Fumarate Tablets

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

pharmacist if you are not sure.

Treatment with Bisoprolol Fumarate Tablets requires regular monitoring by your doctor.

This is particularly necessary at the start of treatment, during dose increase and when you

stop treatment.

Take Bisoprolol Fumarate Tablets with some water in the morning, with or without food.

Do not crush or chew the tablet. The scored tablets can be divided into two equal doses.

Treatment with Bisoprolol Fumarate Tablets is usually long-term.

dults 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.

If you take more Bisoprolol Fumarate Tablets than you should

If you have taken more Bisoprolol Fumarate tablets than you should, tell your doctor

immediately. Your doctor will decide what measures are necessary.

ID: PL 130-134M IE

(OLS Clonmel)

Version:

Effective Date:

14/06/2017

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 Fumarate Tablets

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

morning.

If you stop taking Bisoprolol Fumarate Tablets

Never stop taking Bisoprolol Fumarate Tablets unless on your doctor’s advice. Otherwise

your condition could become much worse.

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 more than 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

ID: PL 130-134M IE

(OLS Clonmel)

Version:

Effective Date:

14/06/2017

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 the

national reporting system.

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 Fumarate

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 blister and the carton

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

This medicinal product does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your

pharmacist how to throw away medicines you no longer use. These measures will help

protect the environment.

6.

Contents of the pack and other information

What Bisoprolol Fumarate tablets contain

The active substance is bisoprolol fumarate.

Each 1.25 mg tablet contains 1.25 mg bisoprolol fumarate.

Each 2.5 mg tablet contains 2.5 mg bisoprolol fumarate.

Each 3.75 mg tablet contains 3.75 mg bisoprolol fumarate.

Each 5 mg tablet contains 5 mg bisoprolol fumarate.

ID: PL 130-134M IE

(OLS Clonmel)

Version:

Effective Date:

14/06/2017

Each 10 mg tablet contains 10 mg bisoprolol fumarate.

The other ingredients are microcrystalline cellulose, silica, colloidal anhydrous,

croscarmellose sodium, sodium starch glycolate (type A) and magnesium stearate.

What Bisoprolol Fumarate Tablets look like and contents of the pack

Bisoprolol Fumarate 1.25 mg tablets are white to off white round biconvex tablets.

Bisoprolol Fumarate 2.5 mg tablets are white to off white round biconvex tablets with a

break line on one side.

Bisoprolol Fumarate 3.75 mg tablets are white to off white round biconvex tablets.

Bisoprolol Fumarate 5 mg tablets are white to off white round biconvex tablets with a

break line on one side.

Bisoprolol Fumarate 10 mg tablets are white to off white round biconvex tablets with a

break line on one side.

Each pack contains 20, 28, 30, 50, 56, 60, 90 and 100 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Chanelle Medical, Loughrea, Co. Galway, Ireland.

Distributor

Clonmel Healthcare Ltd, Waterford Road, Clonmel, Co. Tipperary, Ireland

This leaflet was last revised in

06/2017

Health Products Regulatory Authority

19 September 2019

CRN009C31

Page 1 of 9

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Bisoprolol Fumarate 10 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg bisoprolol fumarate

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

Bisoprolol Fumarate 10mg Tablet is a white to off white round biconvex tablet with a breakline on one side.

The tablets can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

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

and optionally cardiac glycosides (for additional information see section 5.1).

4.2 Posology and method of administration

Standard treatment of CHF consist 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.

Posology

Titration phase

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

The treatment with bisoprolol fumarate 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.

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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.

If discontinuation is considered, gradual dose decrease is recommended, since abrupt withdrawal may lead to acute

deterioration of the patients condition.

Treatment of stable chronic heart failure with bisoprolol fumarate is generally a long-term treatment.

Patients with renal or hepatic impairment

There is no information regarding pharmacokinetics of bisoprolol fumarate 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.

Older people

No dosage adjustment is required.

Paediatric population

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

Method of administration

Bisoprolol Fumarate Tablets should be taken in the morning and can be taken with food. They should be swallowed with liquid

and should not be chewed.

4.3 Contraindications

Bisoprolol Fumarate is contraindicated in chronic heart failure patients with:

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

cardiogenic shock

second and third degree AV block

sick sinus syndrome

sinoatrial block

symptomatic bradycardia

symptomatic hypotension

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

hypersensitivity

bisoprolol

excipients

listed

section

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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.

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.

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

There is no therapeutic experience of bisoprolol fumarate 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 Fumarate must be used with caution in:

bronchospasm (bronchial asthma, obstructive airways diseases)

diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia 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. Aggravation of symptoms may occur especially with starting 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 anaesthetist 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

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 fumarate 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 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 fumarate) after carefully

balancing the benefits against the risks.

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

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

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

antiarrhythmic

drugs

(e.g.

quinidine,

disopyramide;

lidocaine,

phenytoin;

flecainide,

propafenone):

Effect

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 vasodilatation). Abrupt withdrawal, particularly if prior to beta-blocker

discontinuation, may increase the risk of 'rebound hypertension'.

Combinations to be used with caution

Calcium antagonists of the dihydropyridine type such as 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.

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

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19 September 2019

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Pregnancy

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

general,

beta-adrenoceptor

blockers

reduce

placental

perfusion,

which

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.

treatment

with

beta-adrenoceptor

blockers

necessary,

beta1-selective

adrenoceptor

blockers

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

known

whether

this

drug

excreted

human

milk.

Therefore,

breastfeeding

recommended

during

administration of bisoprolol fumarate.

4.7 Effects on ability to drive and use machines

In a study with coronary heart disease patients bisoprolol fumarate 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

The following definitions apply to the frequency terminology used hereafter:

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)

Frequency not known (cannot be estimated from available data)

Cardiac disorders:

Very common: bradycardia

Common: worsening of heart failure

Uncommon: AV-conduction disturbances,

Investigations

Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT)

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 impairment.

Respiratory, thoracic and mediastinal disorders:

Uncommon: Bronchospasm in patients with bronchial asthma or a history of obstructive airways disease.

Rare: allergic rhinitis.

Health Products Regulatory Authority

19 September 2019

CRN009C31

Page 6 of 9

Gastrointestinal disorders:

Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.

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: muscle weakness, muscle cramps

Vascular disorders:

Common: feeling of coldness or numbness in the extremities, hypotension.

Uncommon: orthostatic hypotension.

General disorders:

Common: asthenia, fatigue

Hepatobiliary disorders:

Rare: hepatitis.

Reproductive system and breast disorders:

Rare: Potency disorders.

Psychiatric disorders

Uncommon: depression, sleep disorders

Rare: nightmares, hallucinations

Reporting of suspected adverse reactions

Reporting

suspected

adverse

reactions

after

authorisation

medicinal

product

important.

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

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 fumarate 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.

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.

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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, beta

-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

fumarate

highly

beta

-selective-adrenoceptor

blocking

agent,

lacking

intrinsic

stimulating

relevant

membrane stabilising activity. It only shows low affinity to the beta

-receptor of the smooth muscles of bronchi and vessels as

well as to the beta

-receptors concerned with metabolic regulation. Therefore, bisoprolol fumarate is generally not to be

expected to influence the airway resistance and beta

-mediated metabolic effects. Its beta

-selectivity extends beyond the

therapeutic dose range.

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 ≥ 65years 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

angiotens inreceptor blockers. Patients were treated with a combination of Bisoprolol Fumarate and enalapril for 6 to 24

months after an initial 6 months treatment with either Bisoprolol Fumarate or enalapril.

There was a trend toward higher frequency of chronic heart failure worsening when Bisoprolol Fumarate 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 end point

death and 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 Fumarate can also be used in elderly chronic heart failure patients with mild to

moderate disease.

Bisoprolol fumarate is also used for the treatment of hypertension and angina.

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

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

elevated peripheral resistance decreases.

5.2 Pharmacokinetic properties

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Absorption

Bisoprolol fumarate 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 fumarate is about 30%.

Biotransformation and Elimination

Bisoprolol fumarate 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 fumarate are linear and independent of age.

Special populations

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.

Patients with chronic heart failure (NYHA stage III) t

he 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 fumarate 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

Microcrystalline Cellulose

Silica Colloidal Anhydrous

Croscarmellose sodium

Sodium Starch glycolate (Type A)

Magnesium Stearate

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

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Blister of white PVC/PVDC 250/60 sealed with 20 um Aluminium foil. Cartons of 20, 28, 30, 50, 56, 60, 90 and 100.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Chanelle Medical

Dublin Road

Loughrea

Co. Galway

Ireland

8 MARKETING AUTHORISATION NUMBER

PA0688/014/005

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of First Authorisation: 1 February 2008

Date of Latest Renewal: 1 February 2013

10 DATE OF REVISION OF THE TEXT

July 2017

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