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.
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 special 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
- 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.
4.8 Undesirable effects
The following definitions apply to the frequency terminology used hereafter:
Very common (³ 1/10)
Common (³ 1/100, < 1/10)
Uncommon (³ 1/1,000, < 1/100)
Rare (³ 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 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
5.1 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 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 ³65 years with mild to moderate chronic heart failure (CHF; NYHA class II or III) and left ventricular ejection fraction £35%, who had not been treated previously with ACE inhibitors, beta-blockers, or angiotensin receptor blockers. Patients were treated with a combination of bisoprolol and enalapril for 6 to 24 months after an initial 6 months treatment with either bisoprolol or enalapril.
There was a trend toward higher frequency of chronic heart failure worsening when bisoprolol was used as the initial 6 months treatment. Non inferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis, although the two strategies for initiation of CHF treatment showed a similar rate of the primary combined endpoint death and 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.
