BISOPROLOL FUMARATE 1.25MG FILM-COATED TABLETS

Active substance: BISOPROLOL FUMARATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Bisoprolol Fumarate 1.25 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Bisoprolol Fumarate 1.25 mg:
Each film-coated tablet contains 1.25 mg bisoprolol fumarate equivalent to
1.06 mg bisoprolol.
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet
White, circular, biconvex, film-coated tablets debossed with ‘P’ on one side
and ‘1’ on the other side.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Treatment of stable chronic heart failure with reduced systolic left 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
Method of administration
Bisoprolol tablets should be taken in the morning and can be taken with food.
They should be swallowed with liquid and should not be chewed.
Treatment of stable chronic heart failure

Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin
receptor blocker in case of intolerance to ACE inhibitors), a beta-blocking
agent, 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 up titration
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.

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 is generally a longterm treatment.
Renal or liver insufficiency
There is no information regarding pharmacokinetics of bisoprolol in patients
with chronic heart failure and with impaired liver or renal function. Uptitration
of the dose in these populations should therefore be made with additional
caution.
Elderly
No dosage adjustment is required.
Children
There is no experience with bisoprolol in children, therefore its use cannot be
recommended for children.

4.3

Contraindications
Bisoprolol is contra-indicated in patients with:
-

hypersensitivity to bisoprolol or to any of the excipients

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

-

sinoatrial block

-

symptomatic bradycardia

-

symptomatic hypotension

severe bronchial asthma or severe chronic obstructive pulmonary
disease
severe forms of peripheral arterial occlusive disease or severe forms of
Raynaud's syndrome
-

untreated phaeochromocytoma (see 4.4)
metabolic acidosis

4.4

Special warnings and precautions for use
Special Warnings
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).
Precautions
The initiation of treatment of stable chronic heart failure with bisoprolol
necessitates regular monitoring. For the posology and method of
administration please refer to section 4.2.
There is no therapeutic experience of bisoprolol treatment in heart failure in
patients with the following diseases and conditions:
-

insulin dependent diabetes mellitus (type I)

-

severely impaired renal function

-

severely impaired liver function

-

restrictive cardiomyopathy

-

congenital heart disease

-

haemodynamically significant organic valvular disease

-

myocardial infarction within 3 months

Bisoprolol must be used with caution in:
- 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 may not always yield the
expected therapeutic effect.
-

First degree AV block

-

Prinzmetal’s angina

- peripheral arterial occlusive disease. Aggravation of symptoms may occur
especially when starting therapy.

Patients with psoriasis or with a history of psoriasis should only be given betablockers (e.g. bisoprolol) after a careful balancing of benefits against risks.
The symptoms of a thyrotoxicosis may be masked under treatment with
bisoprolol
In patients with phaeochromocytoma bisoprolol must not be administered until
after alpha-receptor blockade.
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 medicinal products, resulting in bradyarrhythmias, attenuation of reflex
tachycardia and 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.
In bronchial asthma or other chronic obstructive lung diseases, which may
cause symptoms, concomitant bronchodilating therapy is recommended.
Occasionally an increase of the airway resistance may occur in patients with
asthma, therefore the dose of beta2-stimulants may have to be increased.
The initiation of treatment with bisoprolol necessitates regular monitoring. For
the posology and method of administration please refer to section 4.2.

4.5

Interaction with other medicinal products and other forms of interaction
Combinations not recommended
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.
Calcium antagonists of the verapamil type and to a lesser extent of the
diltiazem type: negative effect on contractility and atrio-ventricular
conduction. Intravenous administration of verapamil in patients on betablocker treatment may lead to profound hypotension and atrio-ventricular
block.
Centrally-acting antihypertensive drugs (e.g. clonidine, methyldopa,
moxonidine,
rilmenidine):
concomitant
use
of
centrally-acting

antihypertensive drugs may further decrease the central sympathetic tonus and
may thus lead to reduction of heart rate and cardiac output and to
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 medicinal product (e.g. amiodarone): Effect on atrioventricular conduction time may be potentiated.
Parasympathomimetic medicinal products: Concomitant use may increase
atrio-ventricular conduction time and the risk of bradycardia.
Topical beta-blocking agents (e.g. eye drops for glaucoma treatment) may add
to the systemic effects of bisoprolol.
Insulin and oral antidiabetic medicinal products: 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: Increase of atrio-ventricular conduction time, reduction in
heart rate.
Non-steroidal anti-inflammatory medicinal products (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.
norepinephrine, epinephrine): Combination with bisoprolol may unmask the αadrenoceptor-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 medicinal
products 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-blocking agents but also risk for hypertensive
crisis.
Rifampicin: Slight reduction of the half-life of bisoprolol possible due to the
induction of hepatic drug metabolising enzymes. Normally no dosage
adjustment is necessary.
Ergotamine derivatives: Exacerbation of peripheral circulatory disturbances.

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 blocking
agents 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 blocking agents is necessary, beta1-selective
adrenoceptor blocking agents are preferable.
Bisoprolol is not recommended during pregnancy unless clearly necessary. If
treatment with bisoprolol is considered necessary, the uteroplacental blood
flow and 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.
Lactation:

There are no data on the excretion of bisoprolol in human breast milk or the
safety of bisoprolol exposure in infants. 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, depending on the individual patients response
to treatment an effect on the ability to drive a vehicle or to use machines
cannot be excluded. This needs to be considered particularly at start of
treatment, upon change of medication, or 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, < 1/10)
Uncommon (≥ 1/1,000, < 1/100)
Rare (≥ 1/10,000, < 1/1,000)
Very rare (< 1/10,000)
Not known (can not be estimated from the available data)
Cardiac disorders:
Very common: bradycardia.
Common: worsening of heart failure
Uncommon: AV-conduction disturbances.
Investigations:
Rare: increased triglycerides, increased liver enzymes (ALT, AST).
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
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.
Skin and subcutaneous tissue disorders:
Rare: hypersensitivity reactions such as itching, flush, rash.
Very rare: beta-blocking agents may provoke or worsen psoriasis or induce
psoriasis-like rash, alopecia.
Musculoskeletal and connective tissue disorders:
Uncommon: muscle weakness, muscle cramps.
Vascular disorders:
Common: feeling of coldness or numbness in the extremities, hypotension.
General disorders:
Common: asthenia, fatigue.
Hepatobiliary disorders:
Rare: hepatitis.
Reproductive system and breast disorders:
Rare: potency disorders.
Psychiatric disorders:
Uncommon: sleep disorders, depression.

Rare: nightmares, hallucinations.

4.9

Overdose
The most common signs expected with overdose of a beta-blocker are
bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and
hypoglycaemia. There is limited experience with overdose of bisoprolol, only
a few cases of overdose with bisoprolol have been reported. Bradycardia
and/or hypotension were noted. 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.
In general, if overdose occurs, discontinuation of bisoprolol treatment and
supportive and symptomatic treatment is recommended.
Based on the expected pharmacologic actions and recommendations for other
beta-blocking agents, 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.
AV block (second or third degree): Patients should be carefully monitored and
treated with isoprenaline infusion or temporary pacing.
Acute worsening of heart failure: Administer i.v. diuretics, inotropic agents,
vasodilating agents.
Bronchospasm: Administer bronchodilator therapy such as isoprenaline, beta2sympathomimetic medicinal products and/or aminophylline.
Hypoglycaemia: Administer i.v. glucose.
Limited data suggest that bisoprolol is hardly dialysable.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Beta blocking agents, selective.
ATC Code: C07AB07
Bisoprolol is a highly beta1-selective-adrenoceptor blocking agent, lacking
intrinsic sympathomimetic 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.

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-blocking agents, 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 perprotocol analysis, although the two strategies for initiation of CHF treatment
showed a similar rate of the primary combined endpoint 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 can also be used in elderly chronic heart failure patients with mild
to moderate disease.

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

5.2

Pharmacokinetic properties
Bisoprolol is absorbed and has a biological availability of about 90% after oral
administration. The plasma protein binding of bisoprolol is about 30%. The
distribution volume is 3.5 l/kg. 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.
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. 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.
The kinetics of bisoprolol are linear and independent of age.
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-blocking agents, 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:
Cellulose, Microcrystalline
Calcium Hydrogen Phosphate, Anhydrous
Silica Colloidal Anhydrous
Crospovidone (Type A)
Magnesium Stearate
Tablet coat:
Hypromellose 6cP (E464)
Titanium Dioxide (E171)
Macrogol 400

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years
In use shelf life for HDPE bottle pack [500 tablets]: 6 months

6.4

Special precautions for storage
Store below 25ºC.
Store in the original package in order to protect from light.

6.5

Nature and contents of container
Bisoprolol Fumarate film-coated tablets are available in cold form Aluminum
-Aluminum blisters with pealable lidding foil and HDPE bottle packs.
Pack sizes:

Blister pack: 20, 28, 30, 50, 90, 100 film-coated tablets
Bottle pack: 30, 500 film-coated tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused product or waste material should be disposed of in accordance
with local requirement

7

MARKETING AUTHORISATION HOLDER
Milpharm Limited
Ares, Odyssey Business Park
West End Road
South Ruislip HA4 6QD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 16363/0359

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
26/10/2011

10

DATE OF REVISION OF THE TEXT
04/06/2012

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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