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

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.
Posology:
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:
- 2.5 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
- 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.
Renal or hepatic impairment
There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart
failure and with impaired hepatic or renal function. Uptitration of the dose in these populations
should therefore be made with additional caution.
Elderly
No dosage adjustment is required.
Paediatric population
There is no paediatric experience with bisoprolol, therefore its use cannot be recommended in
paediatric patients.

Method of administration:
Bisoprolol tablets should be taken in the morning and can be taken with food. They should be
swallowed with liquid and should not be chewed.

 

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 • sick sinus syndrome • sinoatrial block • symptomatic bradycardia • symptomatic hypotension • severe bronchial asthma or severe chronic obstructive pulmonary disease • severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's syndrome • untreated phaeochromocytoma • metabolic acidosis • hypersensitivity to bisoprolol or to any of the excipients listed in section 6.1

The treatment of stable chronic heart failure with bisoprolol has to be initiated with a special
titration phase.
Especially in patients with ischaemic heart disease the cessation of therapy with bisoprolol must
not be done abruptly unless clearly indicated, because this may lead to transitional worsening of
heart condition.
The initiation and cessation of treatment with bisoprolol necessitates regular monitoring.

There is no therapeutic experience of bisoprolol treatment of heart failure in patients with the
following diseases and conditions:
• insulin dependent diabetes mellitus (type I)
• severely impaired renal function
• severely impaired hepatic function
• restrictive cardiomyopathy
• congenital heart disease
• haemodynamically significant organic valvular disease
• myocardial infarction within 3 months
Bisoprolol must be used with caution in:
• bronchospasm (bronchial asthma, obstructive airways diseases)
• diabetes mellitus with large fluctuations in blood glucose values; Symptoms of hypoglycaemia
can be masked
• strict fasting
• ongoing desensitisation therapy As with other beta-blockers, bisoprolol may increase both the
sensitivity towards allergens and the severity of anaphylactic reactions. Epinephrine treatment
does not always yield the expected therapeutic effect.
• first degree AV block
• Prinzmetal's angina
• peripheral arterial occlusive disease. Aggravation of symptoms may occur especially when
starting therapy.
• general anaesthesia
In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias
and myocardial ischemia during induction and intubation, and the post-operative period.

It is currently recommended that maintenance beta-blockade be continued peri-operatively. The
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.
Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with
Class I antiarrhythmic drugs and with centrally acting antihypertensive drugs is generally not
recommended, for details please refer to section 4.5.
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.
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 alphareceptor
blockade.
Under treatment with bisoprolol the symptoms of a thyreotoxicosis may be masked.

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.
Insulin and oral antidiabetic drugs: Increase 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.
Digitalis glycosides: Reduction of heart rate, increase of atrio-ventricular conduction time.

Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect of
bisoprolol.
β-Sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may
reduce the effect of both agents.
Sympathomimetics that activate both β- and α-adrenoceptors (e.g. noradrenaline, adrenaline):
Combination with bisoprolol may unmask the α-adrenoceptor-mediated vasoconstrictor effects
of these agents leading to blood pressure increase and exacerbated intermittent claudication.
Such interactions are considered to be more likely with nonselective β-blockers.
Concomitant use with antihypertensive agents as well as with other drugs with blood pressure
lowering potential (e.g. tricyclic antidepressants, barbiturates, phenothiazines) may increase the
risk of hypotension.
Combinations to be considered Mefloquine: increased risk of bradycardia
Monoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the
beta-blockers but also risk for hypertensive crisis.

Pregnancy Category C
Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the
fetus/newborn. In general, beta-adrenoceptor blockers reduce placental perfusion, which has
been associated with growth retardation, intrauterine death, abortion or early labour. Adverse
effects (e.g. hypoglycaemia and bradycardia) may occur in the fetus and newborn infant. If
treatment with beta-adrenoceptor blockers is necessary, beta1-selective adrenoceptor blockers
are preferable.
Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with
bisoprolol is considered necessary, the uteroplacental blood flow and the fetal growth should be
monitored. In case of harmful effects on pregnancy or the fetus alternative treatment should be
considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and
bradycardia are generally to be expected within the first 3 days.
Breast-feeding
It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not
recommended during administration of bisoprolol.

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.

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)
Cardiac disorders:
Very common: bradycardia.
Common: worsening of heart failure.
Uncommon: AV-conduction disturbances
Investigations:
Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT).
Nervous system disorders:
Common: dizziness, headache.
Rare: syncope
Eye disorders:
Rare: reduced tear flow (to be considered if the patient uses lenses).
Very rare: conjunctivitis.
Ear and labyrinth disorders:
Rare: hearing disorders.

Respiratory, thoracic and mediastinal disorders:
Uncommon: bronchospasm in patients with bronchial asthma or a history of
obstructive airways disease.
Rare: allergic rhinitis.
Gastrointestinal disorders:
Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.
Skin and subcutaneous tissue disorders:
Rare: hypersensitivity reactions (itching, flush, rash).
Very rare: alopecia. Beta-blockers may provoke or worsen psoriasis or induce
psoriasis-like rash.
Musculoskeletal and connective tissue disorders:
Uncommon: muscular weakness and cramps.
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

To reports any side effect(s):
• Saudi Arabia
-The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2340.
o Toll free phone: 19999
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

With overdose (e.g. daily dose of 15 mg instead of 7.5 mg) third degree AV-block, bradycardia,
and dizziness have been reported. In general the most common signs expected with overdosage
of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and
hypoglycaemia. To date a few cases of overdose (maximum: 2000 mg) with bisoprolol have
been reported in patients suffering from hypertension and/or coronary heart disease showing
bradycardia and/or hypotension; all patients recovered. There is a wide interindividual variation
in sensitivity to one single high dose of bisoprolol and patients with heart failure are probably
very sensitive. Therefore it is mandatory to initiate the treatment of these patients with a gradual
uptitration according to the scheme given in section 4.2.
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.

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 beta2-mediated metabolic effects. Its beta1-selectivity extends beyond the
therapeutic dose range.
In total 2647 patients were included in the CIBIS II trial. 83% (n = 2202) were in NYHA class
III and 17% (n = 445) were in NYHA class IV. They had stable symptomatic systolic heart
failure (ejection fraction ≤35%, based on echocardiography). Total mortality was reduced from
17.3% to 11.8% (relative reduction 34%). A decrease in sudden death (3.6% vs 6.3%, relative
reduction 44%) and a reduced number of heart failure episodes requiring hospital admission
(12% vs 17.6%, relative reduction 36%) was observed. Finally, a significant improvement of the
functional status according to NYHA classification has been shown. During the initiation and
titration of bisoprolol hospital admission due to bradycardia (0.53%), hypotension (0.23%), and
acute decompensation (4.97%) were observed, but they were not more frequent than in the
placebo-group (0%, 0.3% and 6.74%). The numbers of fatal and disabling strokes during the
total study period were 20 in the bisoprolol group and 15 in the placebo group.
The CIBIS III trial investigated 1010 patients aged ≥65 years with mild to moderate chronic
heart failure (CHF; NYHA class II or III) and left ventricular ejection fraction ≤35%, who had
not been treated previously with ACE inhibitors, beta-blockers, or angiotensin receptor blockers.
Patients were treated with a combination of bisoprolol and enalapril for 6 to 24 months after an
initial 6 months treatment with either bisoprolol or enalapril.

There was a trend toward higher frequency of chronic heart failure worsening when bisoprolol
was used as the initial 6 months treatment. Non inferiority of bisoprolol-first versus enalaprilfirst
treatment was not proven in the per-protocol analysis, although the two strategies for
initiation of CHF treatment showed a similar rate of the primary combined endpoint death and
hospitalization at study end (32.4% in the bisoprolol-first group vs. 33.1 % in the enalapril-first
group, per-protocol population). The study shows that bisoprolol can also be used in elderly
chronic heart failure patients with mild to moderate disease.
Bisoprolol is also used for the treatment of hypertension and angina.
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.

Absorption
Bisoprolol is absorbed and has a biological availability of about 90% after oral administration.
Distribution
The distribution volume is 3.5 l/kg. The plasma protein binding of bisoprolol is about 30%.
Biotransformation and Elimination
Bisoprolol is excreted from the body by two routes. 50% is metabolised by the liver to inactive
metabolites which are then excreted by the kidneys. The remaining 50% is excreted by the
kidneys in an unmetabolised form. Total clearance is approximately 15 l/h. The half-life in
plasma of 10-12 hours gives a 24 hour effect after dosing once daily.
Linearity
The kinetics of bisoprolol are linear and independent of age.

Special population
Since the elimination takes place in the kidneys and the liver to the same extent a dosage
adjustment is not required for patients with impaired liver function or renal insufficiency. The pharmacokinetics in patients with stable chronic heart failure and with impaired liver or renal
function has not been studied. In patients with chronic heart failure (NYHA stage III) the plasma
levels of bisoprolol are higher and the half-life is prolonged compared to healthy volunteers.
Maximum plasma concentration at steady state is 64±21 ng/ml at a daily dose of 10 mg and the
half-life is 17±5 hours.

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.

 

Maize starch
Microcrystalline Cellulose PH 102
Crospovidone NF
Anhydrous Dibasic Calcium Phosphate
Colloidal Silicone Dioxide (Aerosil 200)
Magnesium Stearate
Opadry White 03H28604
Purified Water

Not applicable.

2 years

Do not store above 30 °C.

Immediate Container: Alu-Alu blister.

No special requirements.