UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
BISOPROLOL 1.25 MG, 2.5 MG, 3.75 MG, 5 MG, 7.5 MG AND 10 MG
FILM-COATED TABLETS
PL 21880/0127-32
UKPAR
TABLE OF CONTENTS
Lay Summary
Page 2
Scientific discussion
Page 3
Steps taken for assessment
Page 12
Steps taken after authorisation – summary
Page 13
Summary of Product Characteristics
Page 14
Product Information Leaflet
Page 62
Labelling
Page 64
1
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
BISOPROLOL 1.25 MG, 2.5 MG, 3.75 MG, 5 MG, 7.5 MG AND 10 MG
FILM-COATED TABLETS
PL 21880/0127-32
LAY SUMMARY
On 6th August 2012, the MHRA granted Medreich PLC Marketing Authorisations (licences)
for Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated Tablets.
Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated Tablets contain
the active ingredient, bisoprolol fumarate.
Bisoprolol belongs to a group of medicines called beta-blockers.
Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated Tablets are used
to treat stable chronic heart failure. It is used in combination with other medicines suitable for
this condition (such as ACE (angiotensin-converting-enzyme) inhibitors, diuretics and heart
glycosides).
Heart failure occurs when the heart muscle is weak and unable to pump enough blood to
supply the body’s needs.
Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated Tablets 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.
No new or unexpected safety concerns arose from these applications and it was, therefore,
judged that the benefits of taking Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and
10 mg film-coated Tablets outweigh the risks; hence Marketing Authorisations have been
granted.
2
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
BISOPROLOL 1.25 MG, 2.5 MG, 3.75 MG, 5 MG, 7.5 MG AND 10 MG
FILM-COATED TABLETS
PL 21880/0127-32
SCIENTIFIC DISCUSSION
TABLE OF CONTENTS
Introduction
Page 4
Pharmaceutical assessment
Page 5
Non-clinical assessment
Page 8
Clinical assessment (including statistical assessment)
Page 9
Overall conclusions and risk benefit assessment
Page 11
3
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
INTRODUCTION
The UK granted Medreich PLC Marketing Authorisations for the medicinal products
Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated Tablets
(PL 21880/0127-32) on 6th August 2012.
Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated Tablets are
prescription only medicines (POM) and are indicated for the treatment of stable chronic heart
failure with reduced systolic left ventricular function in addition to ACE inhibitors, and
diuretics, and optionally cardiac glycosides
These applications for Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
film-coated Tablets are submitted under Article 10.1 of Directive 2001/83/EC, claiming to be
generic medicinal products to Cardicor 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
film-coated Tablets, authorised in the UK to E Merck Limited on 24th December 1999
(PL 00493/0179-84). These licences underwent changes of ownership to Merck Serono
Limited on 2nd February 2010 (PL 11648/0071-6).
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 beta2receptors concerned with metabolic regulation.
4
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
PHARMACEUTICAL ASSESSMENT
DRUG SUBSTANCE
INN:
Bisoprolol fumarate
Chemical name:
(RS)-1-[4-[[2-(1-Methylethoxy) ethoxy] methyl] phenoxy]-3-[(1methylethyl) amino] propan-2-ol fumarate
Structure:
Physical form:
A white or almost white, slightly hygroscopic powder.
Solubility:
Very soluble in water and in methanol. Freely soluble in alcohol.
Molecular formula:
Molecular weight:
C40H66N2O12
767
The bisoprolol fumarate used in the product complies with its European Pharmacopoeia
monographs.
The manufacturer of the drug substance holds a valid EDQM (European Directorate for the
Quality of Medicines and Healthcare) Certificate of Suitability. The quality of the substance
is suitably controlled in line with the current edition of the European Pharmacopoeia
Monograph for bisprolol fumarate.
The manufacturing process, control of materials, control of critical steps, validation and
process development for bisprolol fumarate were assessed and approved by the EDQM in
relation to the granting of the Certificate of Suitability and are therefore satisfactory.
An appropriate specification with suitable test methods and limits has been provided for the
drug substance. The methods of testing and limits for residual solvents are in compliance
with current guidelines. Batch analysis data are provided and comply with the proposed
specifications.
Suitable specifications have been provided for all packaging used. The primary packaging
has been shown to comply with current guidelines.
Stability studies have been performed with the drug substance and no significant changes
were observed. On the basis of the results, a suitable re-test period could be approved.
5
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
DRUG PRODUCT
Other ingredients
Other ingredients are pharmaceutical excipients microcrystalline cellulose (PH-102), maize
starch, crospovidone (Type B), colloidal anhydrous silica, magnesium stearate, purified
water, hypromellose, macrogol 400 and titanium dioxide.
Bisoprolol 3.75 mg, 5 mg, 7.5 mg film-coated Tablets have the additional excipient ferric
oxide yellow (E172).
Bisoprolol 10 mg film-coated Tablets has the additional excipients ferric oxide yellow (E172)
and ferric oxide red (E172).
With the exception of ferric oxide yellow (E172) and ferric oxide red (E172), all the
ingredients comply with their relevant European Pharmacopoeia monographs. Ferric oxide
yellow (E172) and ferric oxide red (E172) comply with the United States Pharmacopoeia –
National Forumulary.
None of the excipients used contain material of animal or human origin. The magnesium
stearate used in this product is of plant origin.
Pharmaceutical Development
The objective of the development programme was to produce safe, efficacious products
containing bisoprolol fumarate that could be considered generic medicinal products of
Cardicor 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated Tablets.
Suitable product development information has been provided. Valid justifications for the use
and amounts of each excipient have been provided.
Comparative in vitro dissolution and impurity profiles have been provided for the proposed
and reference products.
Manufacturing Process
Satisfactory batch formulae has been provided for the manufacture of the products, along
with an appropriate account of the manufacturing process. The manufacturing process has
been validated and has shown satisfactory results. In-process controls are satisfactory based
on batch data and controls on the finished products. Process validation data on
commercial-scale batches of each strength have been provided and are satisfactory.
Finished Product Specification
The finished product specifications are acceptable. Test methods have been described and
adequately validated, as appropriate. Batch data have been provided and comply with the
release specifications. Certificates of Analysis have been provided for any working standards
used.
Container-Closure System
The products are packaged in blisters composed of aluminium, polyvinyl chloride (PVC) and
polyvinylidene chloride (PVdC). The blisters are packed in cartons. Pack sizes are 20, 28, 30,
50, 56, 60, 90 and 100 film-coated tablets. Not all pack sizes are marketed.
Satisfactory specifications and Certificates of Analysis have been provided for all packaging
components. All primary product packaging complies with current legislation and the EU
directives regarding contact with food stuffs.
6
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
Stability of the product
Stability studies were performed on batches of the finished products in the packaging
proposed for marketing and in accordance with current guidelines. These data support a
shelf-life of 24 months with no special requirements for storage.
Summary of Product Characteristics (SmPCs), Patient Information Leaflet (PIL) and
Labelling
The SmPCs, PIL and labelling are pharmaceutically acceptable. The UK approved SmPCs,
PIL and labelling are included in modules 2, 3 and 4 of this report.
User testing results have been submitted for the PIL for these products. The results indicate
that the PIL is in accordance with Article 59 of Council Directive 2001/83/EC, as amended
and is well-structured and organised, easy to understand and written in a comprehensive
manner. The test shows that the patients/users are able to act upon the information that it
contains.
MAA Forms
These are pharmaceutically satisfactory.
Quality Overall Summary
The quality overall summary has been written by an appropriately qualified person and is a
suitable summary of the pharmaceutical dossier.
Conclusion
From a quality point of view, it is recommended that Marketing Authorisations are granted
for these applications.
7
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
NON-CLINICAL ASSESSMENT
The pharmacodynamics, pharmacokinetics and toxicological properties of bisoprolol
fumarate are well-known. As bisoprolol fumarate is a widely used, well-known drug
substance, no new non-clinical data have been provided and none are required. An overview
based on literature is therefore appropriate.
Non-Clinical Overview
The non-clinical overview has been written by an appropriately qualified person and is a
suitable summary of the non-clinical aspects of the dossier.
Environmental Risk Assessment
A satisfactory justification for the absence of an Environmental Risk Assessment was
provided.
Conclusion
From a non-clinical point of view, it is recommended that Marketing Authorisations are
granted for these applications.
8
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
CLINICAL ASSESSMENT
CLINICAL PHARMACOLOGY
To support the applications, a single bioequivalence study has been provided:
A single dose, two-period, crossover bioequivalence study comparing the
pharmacokinetics of the test product Bisoprolol 10 mg film-coated Tablets versus the
reference product Cardicor (bisoprolol fumarate) 10 mg film-coated Tablets (Merck
Serono) in healthy volunteers under fasted conditions.
Blood sampling was performed pre-dose and up to 72 hours post dose in each treatment
period. There was a washout period of 8 days. Pharmacokinetic parameters were calculated
and statistically analysed.
Results from this study are presented below as log-transformed values:
Geometric Least Mean Squares and 90% Confidence Interval
Pharmacokinetic parameters of bisoprolol fumarate
Treatment
AUC0-t
AUC0-∞
(ng.hr/ml)
(ng.hr/ml)
Cmax
(ng/ml)
571.098
582.449
36.257
36.971
Test
Reference
585.682
598.095
98.1
97.9
98.1
94.08 – 102.18
94.03 – 101.98
94.47 – 101.81
area under the plasma concentration-time curve from time zero to infinity
area under the plasma concentration-time curve from time zero to t hours
maximum plasma concentration
Ratio (90% CI)
AUC0-∞
AUC0-t
Cmax
The results for the primary variables indicated that the 90% confidence intervals
test/reference ratio of geometric means for AUC0-t and Cmax for bisoprolol fumarate lie within
the normal 80-125% limits. Thus, bioequivalence has been shown between the test and
reference products.
The applicant provided a satisfactory justification for the application of a biowaiver for the
other strengths, which was accepted. Therefore, the results and conclusions of the
bioequivalence study on the 10 mg tablet strength can be extrapolated to Bisoprolol 1.25 mg,
2.5 mg, 3.75 mg, 5 mg and 7.5 mg film-coated Tablets.
Efficacy
These are generic applications based on demonstration of bioequivalence and new data
relating to efficacy are not required as per EU legislation once bioequivalence has been
demonstrated.
Safety
With the exception of the data submitted during the bioequivalence study, no new safety data
were submitted with these generic applications and none were required. No new or
unexpected safety concerns were raised during the bioequivalence study.
9
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
The Pharmacovigilance System and the Risk Management Plan
The pharmacovigilance system as described by the Marketing Authorisation Holder (MAH)
fulfils the requirements and provides adequate evidence that the MAH has the services of a
qualified person responsible for pharmacovigilance and has the necessary means for the
notification of any adverse reaction suspected of occurring.
A satisfactory justification for the absence of a Risk Management Plan has been provided.
Summary of Product Characteristics (SmPCs), Patient Information Leaflet (PIL) and
Labelling
The SmPCs, PIL and labelling are clinically satisfactory and consistent with those for the
reference products.
MAA Forms
The MAA forms are clinically satisfactory.
Clinical Overview
The clinical overview has been written by a suitably qualified person and is satisfactory.
Conclusion
The bioequivalence study has shown that Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg
and 10 mg film-coated Tablets can be considered as generic medicinal products to the
reference products Cardicor 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg film-coated
Tablets.
From a clinical point of view, it is recommended that Marketing Authorisations are granted
for these applications.
10
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
OVERALL CONCLUSIONS AND RISK BENEFIT ASSESSMENT
QUALITY
The important quality characteristics of Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg
and 10 mg film-coated Tablets are well-defined and controlled. The specifications and batch
analytical results indicate consistency from batch to batch. There are no outstanding quality
issues that would have a negative impact on the benefit/risk balance.
NON-CLINICAL
No new non-clinical data were submitted and none are required for applications of this type.
EFFICACY
Bioequivalence has been demonstrated between the applicant’s Bisoprolol 10 mg film-coated
Tablets and the reference product, Cardicor 10 mg film-coated Tablets.
This conclusion can be extrapolated to Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg and
7.5 mg film-coated Tablets.
No new or unexpected safety concerns arise from these applications.
The SmPCs, PIL and labelling are satisfactory and consistent with those for the reference
products.
RISK BENEFIT ASSESSMENT
The quality of the products is acceptable and no new non-clinical or clinical safety concerns
have been identified. The bioequivalence studies support the claim that the applicant’s
products and the reference products are interchangeable. Clinical experience with bisoprolol
fumarate is considered to have demonstrated the therapeutic value of the compound. The
benefit/risk is, therefore, considered to be positive.
11
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
BISOPROLOL 1.25 MG, 2.5 MG, 3.75 MG, 5 MG, 7.5 MG AND 10 MG
FILM-COATED TABLETS
PL 21880/0127-32
STEPS TAKEN FOR ASSESMENT
1
The MHRA received the Marketing Authorisation Applications on 9th June
2011.
2
Following standard checks and communication with the applicant the MHRA
considered the applications valid on 7th July 2011.
3
The applicant responded to the MHRA’s requests, providing further information
on 13th July 2012 and 30th July 2012 for the quality section.
The applicant responded to the MHRA’s requests, providing further information
on 1st June 2012 and 8th June 2012 for the clinical section.
4
The applications were determined on 6th August 2012.
12
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
BISOPROLOL 1.25 MG, 2.5 MG, 3.75 MG, 5 MG, 7.5 MG AND 10 MG
FILM-COATED TABLETS
PL 21880/0127-32
STEPS TAKEN AFTER AUTHORISATION - SUMMARY
Date
Application
submitted type
Scope
Outcome
13
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
SUMMARY OF PRODUCT CHARACTERISTICS
1
NAME OF THE MEDICINAL PRODUCT
Bisoprolol 1.25mg film-coated Tablets
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Film coated tablet contains Bisoprolol Fumarate 1.25mg
For list of excipients refer 6.1
3
PHARMACEUTICAL FORM
Film-coated tablet.
White colored round, biconvex, film coated tablets, plain on both sides
4
4.1
CLINICAL PARTICULARS
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
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.
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 long-term treatment.
14
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
Special population
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.
Children
There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for
children.
4.3
CONTRAINDICATIONS
Bisoprolol 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 or third degree AV block (without a pacemaker)
- sick sinus syndrome
- sinoatrial block
- bradycardia with less than 60 beats/min before the start of therapy
- hypotension (systolic blood pressure less than 100 mm Hg)
- severe bronchial asthma or severe chronic obstructive pulmonary disease
- late stages of peripheral arterial occlusive disease and Raynaud's syndrome
- untreated phaeochromocytoma (see 4.4)
- metabolic acidosis
- hypersensitivity to bisoprolol or to any of the excipients
4.4
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
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 can be
masked
- strict fasting
- ongoing desensitisation therapy
- 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
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.
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
15
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
- congenital heart disease
- haemodynamically significant organic valvular disease
- myocardial infarction within 3 months
Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class I
antiarrhytmic drugs and with centrally acting antihypertensive drugs is generally not recommended, for
details please refer to section 4.5.
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 beta2-stimulants may have to be
increased.
As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the
severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic
effect.
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.
The initiation of treatment with bisoprolol necessitates regular monitoring. For the posology and
method of administration please refer to section 4.2.
The cessation of therapy with bisoprolol should not be done abruptly unless clearly indicated. For
further information please refer to section 4.2.
4.5
INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF
INTERACTION
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 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.
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UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
Insulin and oral antidiabetic drugs: Intensification of blood sugar lowering effect. Blockade of betaadrenoreceptors 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 betablockers but also risk for hypertensive crisis.
4.6
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 betaadrenoceptor 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.
Lactation:
It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not
recommended during administration of bisoprolol.
Fertility:
In reproduction toxicology studies Bisoprolol had no influence on fertility or on general reproduction
performance (see section 5.3).
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
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)
17
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
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.
Gastrointestinal disorders:
Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.
Skin and subcutaneous tissue disorders:
Rare: hypersensitivity reactions (itching, flush, rash).
Very rare: beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.
Musculoskeletal and connective tissue disorders:
Uncommon: muscular weakness and 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: sleep disorders, depression.
Rare: nightmares, hallucinations.
4.9
OVERDOSE
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 betablocker 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.
18
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
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
5.1
PHARMACOLOGICAL PROPERTIES
PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: Beta blocking agents, selective
ATC Code: C07AB07
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 beta2mediated 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-blockers, or angiotensin receptor blockers. The trial
compared the efficacy and safety of an initial six-month monotherapy with bisoprolol (target dose 10
mg once daily), to which the ACE inhibitor enalapril (target dose 10 mg twice daily) was added for
further 6 to 24 months, with the opposite sequence of treatment initiation. Each group comprised 505
patients.
The two strategies were blindly compared with regard to the combined primary endpoint of all-cause
mortality or hospitalisation, and each of these components individually. In the intention-to-treat
population the primary endpoint occurred in 178 patients (35.2%) in the bisoprolol-first group vs. 186
(36.8%) in the enalapril-first group, showing bisoprolol-first treatment to be comparably effective
(non-inferior) as enalapril-first treatment. With bisoprolol-first, 65 patients died vs. 73 with enalaprilfirst (between-group difference p=0.44), and 151 vs. 157 patients were hospitalisised (p=0.66). The
number of serious and total adverse events was similar in the two groups. Analysis of data from the
19
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
first year showed a non-significant trend of the bisoprolol-first strategy to reduce all-cause mortality by
31% compared with the enalapril-first strategy. Mainly the statistically significant risk-reduction of
sudden death by 46% (p=0.049) during the first year contributed to the better survival in the bisoprololfirst group.
The two strategies for initiation of CHF treatment showed a similar rate of combined death and
hospitalization, and a trend towards prolonged survival, particularly by reduction of sudden death, was
observed in the bisoprolol-first group. The results indicate that it is as safe and efficacious to initiate
treatment for CHF with bisoprolol as with enalapril.
Bisoprolol is also used for the treatment of hypertension and angina.
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-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
6.1
PHARMACEUTICAL PARTICULARS
LIST OF EXCIPIENTS
Microcrystalline Cellulose (PH-102)
Maize Starch
Crospovidone (Type B)
Colloidal Anhydrous Silica
Magnesium Stearate
Purified Water
Film coating (1.25mg tablets and 2.5mg tablets): Hypromellose, Macrogol 400 and Titanium dioxide
(E171).
Film coating (3.75mg tablets, 5 mg tablets and 7.5mg tablets): Hypromellose, Macrogol 400, Titanium
dioxide (E171) and Ferric oxide yellow (E172)
Film coating (10 mg tablets): Hypromellose, Macrogol 400, Titanium dioxide (E171),
Ferric oxide yellow (E172), Ferric oxide red (E172)
6.2
INCOMPATIBILITIES
Not applicable.
20
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
6.3
SHELF LIFE
24 months.
6.4
SPECIAL PRECAUTIONS FOR STORAGE
No special requirements
6.5
NATURE AND CONTENTS OF CONTAINER
20, 28, 30, 50, 56, 60, 90, or 100 tablets
Not all pack sizes are marketed.
Tablets are packed in Aluminium (0.02mm thickness) and PVC (0.25mm)/ PVDC (120 gsm) blisters.
Blisters are packed in cartons.
6.6
SPECIAL PRECAUTIONS FOR DISPOSAL
No special requirements.
7
MARKETING AUTHORISATION HOLDER
Medreich Plc
9 Royal Parade
Kew Gardens
Surrey TW9 3QD
UK
8
MARKETING AUTHORISATION NUMBER(S)
PL 21880/0127
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
06/08/2012
10
DATE OF REVISION OF THE TEXT
06/08/2012
21
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
1
NAME OF THE MEDICINAL PRODUCT
Bisoprolol 2.5 mg film-coated Tablets
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Film coated tablet contains Bisoprolol Fumarate 2.5mg
For list of excipients refer 6.1
3
PHARMACEUTICAL FORM
Film-coated tablet.
White and heart-shaped with a break-line on both sides.
4
4.1
CLINICAL PARTICULARS
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
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.
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 long-term treatment.
22
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
Special population
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.
Children
There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for
children.
4.3
CONTRAINDICATIONS
Bisoprolol 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 or third degree AV block (without a pacemaker)
- sick sinus syndrome
- sinoatrial block
- bradycardia with less than 60 beats/min before the start of therapy
- hypotension (systolic blood pressure less than 100 mm Hg)
- severe bronchial asthma or severe chronic obstructive pulmonary disease
- late stages of peripheral arterial occlusive disease and Raynaud's syndrome
- untreated phaeochromocytoma (see 4.4)
- metabolic acidosis
- hypersensitivity to bisoprolol or to any of the excipients
4.4
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
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 can be
masked
- strict fasting
- ongoing desensitisation therapy
- 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
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.
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
23
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
- congenital heart disease
- haemodynamically significant organic valvular disease
- myocardial infarction within 3 months
Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class I
antiarrhytmic drugs and with centrally acting antihypertensive drugs is generally not recommended, for
details please refer to section 4.5.
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 beta2-stimulants may have to be
increased.
As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the
severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic
effect.
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.
The initiation of treatment with bisoprolol necessitates regular monitoring. For the posology and
method of administration please refer to section 4.2.
The cessation of therapy with bisoprolol should not be done abruptly unless clearly indicated. For
further information please refer to section 4.2.
4.5
INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF
INTERACTION
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 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.
24
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
Insulin and oral antidiabetic drugs: Intensification of blood sugar lowering effect. Blockade of betaadrenoreceptors 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 betablockers but also risk for hypertensive crisis.
4.6
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 betaadrenoceptor 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.
Lactation:
It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not
recommended during administration of bisoprolol.
Fertility:
In reproduction toxicology studies Bisoprolol had no influence on fertility or on general reproduction
performance (see section 5.3).
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
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)
25
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
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.
Gastrointestinal disorders:
Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.
Skin and subcutaneous tissue disorders:
Rare: hypersensitivity reactions (itching, flush, rash).
Very rare: beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.
Musculoskeletal and connective tissue disorders:
Uncommon: muscular weakness and 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: sleep disorders, depression.
Rare: nightmares, hallucinations.
4.9
OVERDOSE
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 betablocker 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.
26
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
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
5.1
PHARMACOLOGICAL PROPERTIES
PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: Beta blocking agents, selective
ATC Code: C07AB07
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 beta2mediated 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-blockers, or angiotensin receptor blockers. The trial
compared the efficacy and safety of an initial six-month monotherapy with bisoprolol (target dose 10
mg once daily), to which the ACE inhibitor enalapril (target dose 10 mg twice daily) was added for
further 6 to 24 months, with the opposite sequence of treatment initiation. Each group comprised 505
patients.
The two strategies were blindly compared with regard to the combined primary endpoint of all-cause
mortality or hospitalisation, and each of these components individually. In the intention-to-treat
population the primary endpoint occurred in 178 patients (35.2%) in the bisoprolol-first group vs. 186
(36.8%) in the enalapril-first group, showing bisoprolol-first treatment to be comparably effective
(non-inferior) as enalapril-first treatment. With bisoprolol-first, 65 patients died vs. 73 with enalaprilfirst (between-group difference p=0.44), and 151 vs. 157 patients were hospitalisised (p=0.66). The
number of serious and total adverse events was similar in the two groups. Analysis of data from the
27
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
first year showed a non-significant trend of the bisoprolol-first strategy to reduce all-cause mortality by
31% compared with the enalapril-first strategy. Mainly the statistically significant risk-reduction of
sudden death by 46% (p=0.049) during the first year contributed to the better survival in the bisoprololfirst group.
The two strategies for initiation of CHF treatment showed a similar rate of combined death and
hospitalization, and a trend towards prolonged survival, particularly by reduction of sudden death, was
observed in the bisoprolol-first group. The results indicate that it is as safe and efficacious to initiate
treatment for CHF with bisoprolol as with enalapril.
Bisoprolol is also used for the treatment of hypertension and angina.
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-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
6.1
PHARMACEUTICAL PARTICULARS
LIST OF EXCIPIENTS
Microcrystalline Cellulose (PH-102)
Maize Starch
Crospovidone (Type B)
Colloidal Anhydrous Silica
Magnesium Stearate
Purified Water
Film coating (1.25mg tablets and 2.5mg tablets): Hypromellose, Macrogol 400 and Titanium dioxide
(E171).
Film coating (3.75mg tablets, 5 mg tablets and 7.5mg tablets): Hypromellose, Macrogol 400, Titanium
dioxide (E171) and Ferric oxide yellow (E172)
Film coating (10 mg tablets): Hypromellose, Macrogol 400, Titanium dioxide (E171),
Ferric oxide yellow (E172), Ferric oxide red (E172)
6.2
INCOMPATIBILITIES
Not applicable.
28
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
6.3
SHELF LIFE
24 months.
6.4
SPECIAL PRECAUTIONS FOR STORAGE
No special requirements
6.5
NATURE AND CONTENTS OF CONTAINER
20, 28, 30, 50, 56, 60, 90, or 100 tablets
Not all pack sizes are marketed.
Tablets are packed in Aluminium (0.02mm thickness) and PVC (0.25mm)/ PVDC (120 gsm) blisters.
Blisters are packed in cartons.
6.6
SPECIAL PRECAUTIONS FOR DISPOSAL
No special requirements.
7
MARKETING AUTHORISATION HOLDER
Medreich Plc
9 Royal Parade
Kew Gardens
Surrey TW9 3QD
UK
8
MARKETING AUTHORISATION NUMBER(S)
PL 21880/0128
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
06/08/2012
10
DATE OF REVISION OF THE TEXT
06/08/2012
29
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
1
NAME OF THE MEDICINAL PRODUCT
Bisoprolol 3.75mg film-coated Tablets
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Film coated tablet contains Bisoprolol Fumarate 3.75mg
For list of excipients refer 6.1
3
PHARMACEUTICAL FORM
Film-coated tablet.
Off-white and heart-shaped with a break-line on both sides
4
4.1
CLINICAL PARTICULARS
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
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.
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 long-term treatment.
30
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
Special population
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.
Children
There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for
children.
4.3
CONTRAINDICATIONS
Bisoprolol 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 or third degree AV block (without a pacemaker)
- sick sinus syndrome
- sinoatrial block
- bradycardia with less than 60 beats/min before the start of therapy
- hypotension (systolic blood pressure less than 100 mm Hg)
- severe bronchial asthma or severe chronic obstructive pulmonary disease
- late stages of peripheral arterial occlusive disease and Raynaud's syndrome
- untreated phaeochromocytoma (see 4.4)
- metabolic acidosis
- hypersensitivity to bisoprolol or to any of the excipients
4.4
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
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 can be
masked
- strict fasting
- ongoing desensitisation therapy
- 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
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.
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
31
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
- congenital heart disease
- haemodynamically significant organic valvular disease
- myocardial infarction within 3 months
Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class I
antiarrhytmic drugs and with centrally acting antihypertensive drugs is generally not recommended, for
details please refer to section 4.5.
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 beta2-stimulants may have to be
increased.
As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the
severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic
effect.
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.
The initiation of treatment with bisoprolol necessitates regular monitoring. For the posology and
method of administration please refer to section 4.2.
The cessation of therapy with bisoprolol should not be done abruptly unless clearly indicated. For
further information please refer to section 4.2.
4.5
INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF
INTERACTION
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 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.
32
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
Insulin and oral antidiabetic drugs: Intensification of blood sugar lowering effect. Blockade of betaadrenoreceptors 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 betablockers but also risk for hypertensive crisis.
4.6
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 betaadrenoceptor 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.
Lactation:
It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not
recommended during administration of bisoprolol.
Fertility:
In reproduction toxicology studies Bisoprolol had no influence on fertility or on general reproduction
performance (see section 5.3).
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
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)
33
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
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.
Gastrointestinal disorders:
Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.
Skin and subcutaneous tissue disorders:
Rare: hypersensitivity reactions (itching, flush, rash).
Very rare: beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.
Musculoskeletal and connective tissue disorders:
Uncommon: muscular weakness and 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: sleep disorders, depression.
Rare: nightmares, hallucinations.
4.9
OVERDOSE
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 betablocker 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.
34
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
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
5.1
PHARMACOLOGICAL PROPERTIES
PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: Beta blocking agents, selective
ATC Code: C07AB07
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 beta2mediated 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-blockers, or angiotensin receptor blockers. The trial
compared the efficacy and safety of an initial six-month monotherapy with bisoprolol (target dose 10
mg once daily), to which the ACE inhibitor enalapril (target dose 10 mg twice daily) was added for
further 6 to 24 months, with the opposite sequence of treatment initiation. Each group comprised 505
patients.
The two strategies were blindly compared with regard to the combined primary endpoint of all-cause
mortality or hospitalisation, and each of these components individually. In the intention-to-treat
population the primary endpoint occurred in 178 patients (35.2%) in the bisoprolol-first group vs. 186
(36.8%) in the enalapril-first group, showing bisoprolol-first treatment to be comparably effective
(non-inferior) as enalapril-first treatment. With bisoprolol-first, 65 patients died vs. 73 with enalaprilfirst (between-group difference p=0.44), and 151 vs. 157 patients were hospitalisised (p=0.66). The
number of serious and total adverse events was similar in the two groups. Analysis of data from the
35
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
first year showed a non-significant trend of the bisoprolol-first strategy to reduce all-cause mortality by
31% compared with the enalapril-first strategy. Mainly the statistically significant risk-reduction of
sudden death by 46% (p=0.049) during the first year contributed to the better survival in the bisoprololfirst group.
The two strategies for initiation of CHF treatment showed a similar rate of combined death and
hospitalization, and a trend towards prolonged survival, particularly by reduction of sudden death, was
observed in the bisoprolol-first group. The results indicate that it is as safe and efficacious to initiate
treatment for CHF with bisoprolol as with enalapril.
Bisoprolol is also used for the treatment of hypertension and angina.
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-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
6.1
PHARMACEUTICAL PARTICULARS
LIST OF EXCIPIENTS
Microcrystalline Cellulose (PH-102)
Maize Starch
Crospovidone (Type B)
Colloidal Anhydrous Silica
Magnesium Stearate
Purified Water
Film coating (1.25mg tablets and 2.5mg tablets): Hypromellose, Macrogol 400 and Titanium dioxide
(E171).
Film coating (3.75mg tablets, 5 mg tablets and 7.5mg tablets): Hypromellose, Macrogol 400, Titanium
dioxide (E171) and Ferric oxide yellow (E172)
Film coating (10 mg tablets): Hypromellose, Macrogol 400, Titanium dioxide (E171),
Ferric oxide yellow (E172), Ferric oxide red (E172)
6.2
INCOMPATIBILITIES
Not applicable.
36
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
6.3
SHELF LIFE
24 months.
6.4
SPECIAL PRECAUTIONS FOR STORAGE
No special requirements
6.5
NATURE AND CONTENTS OF CONTAINER
20, 28, 30, 50, 56, 60, 90, or 100 tablets
Not all pack sizes are marketed.
Tablets are packed in Aluminium (0.02mm thickness) and PVC (0.25mm)/ PVDC (120 gsm) blisters.
Blisters are packed in cartons.
6.6
SPECIAL PRECAUTIONS FOR DISPOSAL
No special requirements.
7
MARKETING AUTHORISATION HOLDER
Medreich Plc
9 Royal Parade
Kew Gardens
Surrey TW9 3QD
UK
8
MARKETING AUTHORISATION NUMBER(S)
PL 21880/0129
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
06/08/2012
10
DATE OF REVISION OF THE TEXT
06/08/2012
37
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
1
NAME OF THE MEDICINAL PRODUCT
Bisoprolol 5mg film-coated Tablets
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Film coated tablet contains Bisoprolol Fumarate 5mg
For list of excipients refer 6.1
3
PHARMACEUTICAL FORM
Film-coated tablet.
White-yellow, heart-shaped with a break-line on both sides.
4
4.1
CLINICAL PARTICULARS
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
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.
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 long-term treatment.
38
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
Special population
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.
Children
There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for
children.
4.3
CONTRAINDICATIONS
Bisoprolol 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 or third degree AV block (without a pacemaker)
- sick sinus syndrome
- sinoatrial block
- bradycardia with less than 60 beats/min before the start of therapy
- hypotension (systolic blood pressure less than 100 mm Hg)
- severe bronchial asthma or severe chronic obstructive pulmonary disease
- late stages of peripheral arterial occlusive disease and Raynaud's syndrome
- untreated phaeochromocytoma (see 4.4)
- metabolic acidosis
- hypersensitivity to bisoprolol or to any of the excipients
4.4
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
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 can be
masked
- strict fasting
- ongoing desensitisation therapy
- 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
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.
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
39
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
- congenital heart disease
- haemodynamically significant organic valvular disease
- myocardial infarction within 3 months
Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class I
antiarrhytmic drugs and with centrally acting antihypertensive drugs is generally not recommended, for
details please refer to section 4.5.
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 beta2-stimulants may have to be
increased.
As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the
severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic
effect.
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.
The initiation of treatment with bisoprolol necessitates regular monitoring. For the posology and
method of administration please refer to section 4.2.
The cessation of therapy with bisoprolol should not be done abruptly unless clearly indicated. For
further information please refer to section 4.2.
4.5
INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF
INTERACTION
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 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.
40
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
Insulin and oral antidiabetic drugs: Intensification of blood sugar lowering effect. Blockade of betaadrenoreceptors 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 betablockers but also risk for hypertensive crisis.
4.6
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 betaadrenoceptor 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.
Lactation:
It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not
recommended during administration of bisoprolol.
Fertility:
In reproduction toxicology studies Bisoprolol had no influence on fertility or on general reproduction
performance (see section 5.3).
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
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)
41
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
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.
Gastrointestinal disorders:
Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.
Skin and subcutaneous tissue disorders:
Rare: hypersensitivity reactions (itching, flush, rash).
Very rare: beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.
Musculoskeletal and connective tissue disorders:
Uncommon: muscular weakness and 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: sleep disorders, depression.
Rare: nightmares, hallucinations.
4.9
OVERDOSE
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 betablocker 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.
42
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
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
5.1
PHARMACOLOGICAL PROPERTIES
PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: Beta blocking agents, selective
ATC Code: C07AB07
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 beta2mediated 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-blockers, or angiotensin receptor blockers. The trial
compared the efficacy and safety of an initial six-month monotherapy with bisoprolol (target dose 10
mg once daily), to which the ACE inhibitor enalapril (target dose 10 mg twice daily) was added for
further 6 to 24 months, with the opposite sequence of treatment initiation. Each group comprised 505
patients.
The two strategies were blindly compared with regard to the combined primary endpoint of all-cause
mortality or hospitalisation, and each of these components individually. In the intention-to-treat
population the primary endpoint occurred in 178 patients (35.2%) in the bisoprolol-first group vs. 186
(36.8%) in the enalapril-first group, showing bisoprolol-first treatment to be comparably effective
(non-inferior) as enalapril-first treatment. With bisoprolol-first, 65 patients died vs. 73 with enalaprilfirst (between-group difference p=0.44), and 151 vs. 157 patients were hospitalisised (p=0.66). The
number of serious and total adverse events was similar in the two groups. Analysis of data from the
43
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
first year showed a non-significant trend of the bisoprolol-first strategy to reduce all-cause mortality by
31% compared with the enalapril-first strategy. Mainly the statistically significant risk-reduction of
sudden death by 46% (p=0.049) during the first year contributed to the better survival in the bisoprololfirst group.
The two strategies for initiation of CHF treatment showed a similar rate of combined death and
hospitalization, and a trend towards prolonged survival, particularly by reduction of sudden death, was
observed in the bisoprolol-first group. The results indicate that it is as safe and efficacious to initiate
treatment for CHF with bisoprolol as with enalapril.
Bisoprolol is also used for the treatment of hypertension and angina.
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-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
6.1
PHARMACEUTICAL PARTICULARS
LIST OF EXCIPIENTS
Microcrystalline Cellulose (PH-102)
Maize Starch
Crospovidone (Type B)
Colloidal Anhydrous Silica
Magnesium Stearate
Purified Water
Film coating (1.25mg tablets and 2.5mg tablets): Hypromellose, Macrogol 400 and Titanium dioxide
(E171).
Film coating (3.75mg tablets, 5 mg tablets and 7.5mg tablets): Hypromellose, Macrogol 400, Titanium
dioxide (E171) and Ferric oxide yellow (E172)
Film coating (10 mg tablets): Hypromellose, Macrogol 400, Titanium dioxide (E171),
Ferric oxide yellow (E172), Ferric oxide red (E172)
6.2
INCOMPATIBILITIES
Not applicable.
44
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
6.3
SHELF LIFE
24 months.
6.4
SPECIAL PRECAUTIONS FOR STORAGE
No special requirements
6.5
NATURE AND CONTENTS OF CONTAINER
20, 28, 30, 50, 56, 60, 90, or 100 tablets
Not all pack sizes are marketed.
Tablets are packed in Aluminium (0.02mm thickness) and PVC (0.25mm)/ PVDC (120 gsm) blisters.
Blisters are packed in cartons.
6.6
SPECIAL PRECAUTIONS FOR DISPOSAL
No special requirements.
7
MARKETING AUTHORISATION HOLDER
Medreich Plc
9 Royal Parade
Kew Gardens
Surrey TW9 3QD
UK
8
MARKETING AUTHORISATION NUMBER(S)
PL 21880/0130
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
06/08/2012
10
DATE OF REVISION OF THE TEXT
06/08/2012
45
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
1
NAME OF THE MEDICINAL PRODUCT
Bisoprolol 7.5mg film-coated Tablets
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Film coated tablet contains Bisoprolol Fumarate 7.5mg
For list of excipients refer 6.1
3
PHARMACEUTICAL FORM
Film-coated tablet.
Pale yellow and heart-shaped with a break-line on both sides.
4
4.1
CLINICAL PARTICULARS
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
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.
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 long-term treatment.
46
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
Special population
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.
Children
There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for
children.
4.3
CONTRAINDICATIONS
Bisoprolol 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 or third degree AV block (without a pacemaker)
- sick sinus syndrome
- sinoatrial block
- bradycardia with less than 60 beats/min before the start of therapy
- hypotension (systolic blood pressure less than 100 mm Hg)
- severe bronchial asthma or severe chronic obstructive pulmonary disease
- late stages of peripheral arterial occlusive disease and Raynaud's syndrome
- untreated phaeochromocytoma (see 4.4)
- metabolic acidosis
- hypersensitivity to bisoprolol or to any of the excipients
4.4
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
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 can be
masked
- strict fasting
- ongoing desensitisation therapy
- 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
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.
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
47
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
- congenital heart disease
- haemodynamically significant organic valvular disease
- myocardial infarction within 3 months
Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class I
antiarrhytmic drugs and with centrally acting antihypertensive drugs is generally not recommended, for
details please refer to section 4.5.
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 beta2-stimulants may have to be
increased.
As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the
severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic
effect.
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.
The initiation of treatment with bisoprolol necessitates regular monitoring. For the posology and
method of administration please refer to section 4.2.
The cessation of therapy with bisoprolol should not be done abruptly unless clearly indicated. For
further information please refer to section 4.2.
4.5
INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF
INTERACTION
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 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.
48
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
Insulin and oral antidiabetic drugs: Intensification of blood sugar lowering effect. Blockade of betaadrenoreceptors 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 betablockers but also risk for hypertensive crisis.
4.6
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 betaadrenoceptor 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.
Lactation:
It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not
recommended during administration of bisoprolol.
Fertility:
In reproduction toxicology studies Bisoprolol had no influence on fertility or on general reproduction
performance (see section 5.3).
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
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)
49
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
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.
Gastrointestinal disorders:
Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.
Skin and subcutaneous tissue disorders:
Rare: hypersensitivity reactions (itching, flush, rash).
Very rare: beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.
Musculoskeletal and connective tissue disorders:
Uncommon: muscular weakness and 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: sleep disorders, depression.
Rare: nightmares, hallucinations.
4.9
OVERDOSE
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 betablocker 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.
50
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
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
5.1
PHARMACOLOGICAL PROPERTIES
PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: Beta blocking agents, selective
ATC Code: C07AB07
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 beta2mediated 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-blockers, or angiotensin receptor blockers. The trial
compared the efficacy and safety of an initial six-month monotherapy with bisoprolol (target dose 10
mg once daily), to which the ACE inhibitor enalapril (target dose 10 mg twice daily) was added for
further 6 to 24 months, with the opposite sequence of treatment initiation. Each group comprised 505
patients.
The two strategies were blindly compared with regard to the combined primary endpoint of all-cause
mortality or hospitalisation, and each of these components individually. In the intention-to-treat
population the primary endpoint occurred in 178 patients (35.2%) in the bisoprolol-first group vs. 186
(36.8%) in the enalapril-first group, showing bisoprolol-first treatment to be comparably effective
(non-inferior) as enalapril-first treatment. With bisoprolol-first, 65 patients died vs. 73 with enalaprilfirst (between-group difference p=0.44), and 151 vs. 157 patients were hospitalisised (p=0.66). The
number of serious and total adverse events was similar in the two groups. Analysis of data from the
51
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
first year showed a non-significant trend of the bisoprolol-first strategy to reduce all-cause mortality by
31% compared with the enalapril-first strategy. Mainly the statistically significant risk-reduction of
sudden death by 46% (p=0.049) during the first year contributed to the better survival in the bisoprololfirst group.
The two strategies for initiation of CHF treatment showed a similar rate of combined death and
hospitalization, and a trend towards prolonged survival, particularly by reduction of sudden death, was
observed in the bisoprolol-first group. The results indicate that it is as safe and efficacious to initiate
treatment for CHF with bisoprolol as with enalapril.
Bisoprolol is also used for the treatment of hypertension and angina.
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-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
6.1
PHARMACEUTICAL PARTICULARS
LIST OF EXCIPIENTS
Microcrystalline Cellulose (PH-102)
Maize Starch
Crospovidone (Type B)
Colloidal Anhydrous Silica
Magnesium Stearate
Purified Water
Film coating (1.25mg tablets and 2.5mg tablets): Hypromellose, Macrogol 400 and Titanium dioxide
(E171).
Film coating (3.75mg tablets, 5 mg tablets and 7.5mg tablets): Hypromellose, Macrogol 400, Titanium
dioxide (E171) and Ferric oxide yellow (E172)
Film coating (10 mg tablets): Hypromellose, Macrogol 400, Titanium dioxide (E171),
Ferric oxide yellow (E172), Ferric oxide red (E172)
6.2
INCOMPATIBILITIES
Not applicable.
52
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
6.3
SHELF LIFE
24 months.
6.4
SPECIAL PRECAUTIONS FOR STORAGE
No special requirements
6.5
NATURE AND CONTENTS OF CONTAINER
20, 28, 30, 50, 56, 60, 90, or 100 tablets
Not all pack sizes are marketed.
Tablets are packed in Aluminium (0.02mm thickness) and PVC (0.25mm)/ PVDC (120 gsm) blisters.
Blisters are packed in cartons.
6.6
SPECIAL PRECAUTIONS FOR DISPOSAL
No special requirements.
7
MARKETING AUTHORISATION HOLDER
Medreich Plc
9 Royal Parade
Kew Gardens
Surrey TW9 3QD
UK
8
MARKETING AUTHORISATION NUMBER(S)
PL 21880/0131
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
06/08/2012
10
DATE OF REVISION OF THE TEXT
06/08/2012
53
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
1
NAME OF THE MEDICINAL PRODUCT
Bisoprolol 10mg film-coated Tablets
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each Film coated tablet contains Bisoprolol Fumarate 10mg
For list of excipients refer 6.1
3
PHARMACEUTICAL FORM
Film-coated tablet.
Pale to light orange, heart-shaped with a break-line on both sides.
4
4.1
CLINICAL PARTICULARS
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
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.
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 long-term treatment.
54
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
Special population
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.
Children
There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for
children.
4.3
CONTRAINDICATIONS
Bisoprolol 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 or third degree AV block (without a pacemaker)
- sick sinus syndrome
- sinoatrial block
- bradycardia with less than 60 beats/min before the start of therapy
- hypotension (systolic blood pressure less than 100 mm Hg)
- severe bronchial asthma or severe chronic obstructive pulmonary disease
- late stages of peripheral arterial occlusive disease and Raynaud's syndrome
- untreated phaeochromocytoma (see 4.4)
- metabolic acidosis
- hypersensitivity to bisoprolol or to any of the excipients
4.4
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
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 can be
masked
- strict fasting
- ongoing desensitisation therapy
- 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
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.
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
55
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
- congenital heart disease
- haemodynamically significant organic valvular disease
- myocardial infarction within 3 months
Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with Class I
antiarrhytmic drugs and with centrally acting antihypertensive drugs is generally not recommended, for
details please refer to section 4.5.
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 beta2-stimulants may have to be
increased.
As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the
severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic
effect.
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.
The initiation of treatment with bisoprolol necessitates regular monitoring. For the posology and
method of administration please refer to section 4.2.
The cessation of therapy with bisoprolol should not be done abruptly unless clearly indicated. For
further information please refer to section 4.2.
4.5
INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF
INTERACTION
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 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.
56
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
Insulin and oral antidiabetic drugs: Intensification of blood sugar lowering effect. Blockade of betaadrenoreceptors 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 betablockers but also risk for hypertensive crisis.
4.6
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 betaadrenoceptor 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.
Lactation:
It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not
recommended during administration of bisoprolol.
Fertility:
In reproduction toxicology studies Bisoprolol had no influence on fertility or on general reproduction
performance (see section 5.3).
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
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)
57
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
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.
Gastrointestinal disorders:
Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.
Skin and subcutaneous tissue disorders:
Rare: hypersensitivity reactions (itching, flush, rash).
Very rare: beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.
Musculoskeletal and connective tissue disorders:
Uncommon: muscular weakness and 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: sleep disorders, depression.
Rare: nightmares, hallucinations.
4.9
OVERDOSE
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 betablocker 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.
58
UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
Film-Coated Tablets
PL 21880/0127-32
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.
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
5.1
PHARMACOLOGICAL PROPERTIES
PHARMACODYNAMIC PROPERTIES
Pharmacotherapeutic group: Beta blocking agents, selective
ATC Code: C07AB07
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 beta2mediated 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-blockers, or angiotensin receptor blockers. The trial
compared the efficacy and safety of an initial six-month monotherapy with bisoprolol (target dose 10
mg once daily), to which the ACE inhibitor enalapril (target dose 10 mg twice daily) was added for
further 6 to 24 months, with the opposite sequence of treatment initiation. Each group comprised 505
patients.
The two strategies were blindly compared with regard to the combined primary endpoint of all-cause
mortality or hospitalisation, and each of these components individually. In the intention-to-treat
population the primary endpoint occurred in 178 patients (35.2%) in the bisoprolol-first group vs. 186
(36.8%) in the enalapril-first group, showing bisoprolol-first treatment to be comparably effective
(non-inferior) as enalapril-first treatment. With bisoprolol-first, 65 patients died vs. 73 with enalaprilfirst (between-group difference p=0.44), and 151 vs. 157 patients were hospitalisised (p=0.66). The
number of serious and total adverse events was similar in the two groups. Analysis of data from the
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UKPAR Bisoprolol 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg
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first year showed a non-significant trend of the bisoprolol-first strategy to reduce all-cause mortality by
31% compared with the enalapril-first strategy. Mainly the statistically significant risk-reduction of
sudden death by 46% (p=0.049) during the first year contributed to the better survival in the bisoprololfirst group.
The two strategies for initiation of CHF treatment showed a similar rate of combined death and
hospitalization, and a trend towards prolonged survival, particularly by reduction of sudden death, was
observed in the bisoprolol-first group. The results indicate that it is as safe and efficacious to initiate
treatment for CHF with bisoprolol as with enalapril.
Bisoprolol is also used for the treatment of hypertension and angina.
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-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
6.1
PHARMACEUTICAL PARTICULARS
LIST OF EXCIPIENTS
Microcrystalline Cellulose (PH-102)
Maize Starch
Crospovidone (Type B)
Colloidal Anhydrous Silica
Magnesium Stearate
Purified Water
Film coating (1.25mg tablets and 2.5mg tablets): Hypromellose, Macrogol 400 and Titanium dioxide
(E171).
Film coating (3.75mg tablets, 5 mg tablets and 7.5mg tablets): Hypromellose, Macrogol 400, Titanium
dioxide (E171) and Ferric oxide yellow (E172)
Film coating (10 mg tablets): Hypromellose, Macrogol 400, Titanium dioxide (E171),
Ferric oxide yellow (E172), Ferric oxide red (E172)
6.2
INCOMPATIBILITIES
Not applicable.
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6.3
SHELF LIFE
24 months.
6.4
SPECIAL PRECAUTIONS FOR STORAGE
No special requirements
6.5
NATURE AND CONTENTS OF CONTAINER
20, 28, 30, 50, 56, 60, 90, or 100 tablets
Not all pack sizes are marketed.
Tablets are packed in Aluminium (0.02mm thickness) and PVC (0.25mm)/ PVDC (120 gsm) blisters.
Blisters are packed in cartons.
6.6
SPECIAL PRECAUTIONS FOR DISPOSAL
No special requirements.
7
MARKETING AUTHORISATION HOLDER
Medreich Plc
9 Royal Parade
Kew Gardens
Surrey TW9 3QD
UK
8
MARKETING AUTHORISATION NUMBER(S)
PL 21880/0132
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
06/08/2012
10
DATE OF REVISION OF THE TEXT
06/08/2012
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PATIENT INFORMATION LEAFLET
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LABELLING
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69