BISOPROLOL FUMARATE

Posology Treatment of hypertension and chronic stable angina pectoris:

Adults The dosage should be individually adjusted. It is recommended to start with 5 mg per day. The usual dose is 10 mg once daily with a maximum recommended dose of 20 mg per day. Renal impairment In patients with severe renal impairment (creatinine clearance < 20 ml/min) the dose should not exceed 10 mg once daily.

This dosage may eventually be divided into halves. Severe hepatic impairment No dosage adjustment is required, however careful monitoring is advised. Elderly No dosage adjustment is normally required. It is recommended to start with the lowest possible dose.

Paediatric population There is no experience with bisoprolol in children, therefore its use cannot be recommended for children. 4). The dosage should be diminished slowly by a weekly halving of the dose. Treatment of stable chronic heart failure Adults Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker in case of intolerance to ACE inhibitors), a beta-blocking agent, diuretics, and when appropriate cardiac glycosides.

Patients should be stable (without acute failure) when bisoprolol treatment is initiated. It is recommended that the treating physician should be experienced in the management of chronic heart failure. Transient worsening of heart failure, hypotension, or bradycardia may occur during the titration period and thereafter.

Titration phase The treatment of stable chronic heart failure with bisoprolol requires a titration phase. 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. Special population Hepatic or Renal 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 experience with bisoprolol in children, therefore its use cannot be recommended for children.

Method of administration For oral use 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.

The following definitions apply to the frequency terminology used hereafter:

Very common (≥ 1/10) Common (≥ 1/100 to 1/10) Uncommon (≥ 1/1,000 to 1/100) Rare (≥ 1/10,000 to 1/1,000) Very rare (< 1/10,000) Not known (can not be estimated from the available data) Psychiatric disorders: Uncommon: sleep disorders, depression.

Rare: nightmares, hallucinations.

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 Cardiac disorders: Very common: bradycardia (in patients with chronic heart failure). Common: worsening of pre-existing heart failure (in patients with chronic heart failure).

Uncommon:

AV-conduction disturbances, worsening of pre-existing heart failure (in patients with hypertension or angina pectoris); bradycardia (in patients with hypertension or angina pectoris).

Vascular disorders:

Common: feeling of coldness or numbness in the extremities, hypotension especially in patient with heart failure. Uncommon: orthostatic hypotension.

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.

Hepatobiliary disorders:

Rare: hepatitis.

Skin and subcutaneous tissue disorders:

Rare: hypersensitivity reactions (pruritus, flush, rash and angioedema). Very rare: betablockers may provoke or worsen psoriasis or induce psoriasislike rash, alopecia.

Musculoskeletal and connective tissue disorders:

Uncommon: muscular weakness and cramps.

Reproductive system and breast disorders:

Rare: erectile dysfunction.

General disorders:

Common: asthenia (in patients with chronic heart failure), fatigue*. Uncommon: asthenia (in patients with hypertension or angina pectoris) Investigations: Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT). Applies only to hypertension or angina pectoris: *These symptoms especially occur at the beginning of the therapy.

They are generally mild and usually disappear within 1-2 weeks. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

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2). 2).

Precautions Applies only to hypertension or angina pectoris:

Bisoprolol must be used with caution in patients with hypertension or angina pectoris and accompanying heart failure.

Applies only to chronic heart failure:

The initiation of treatment of stable chronic heart failure with bisoprolol necessitates regular monitoring. 2. 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 Applies to all indications: Bisoprolol must be used with caution in: - bronchospasm (bronchial asthma, obstructive airways diseases).

In bronchial asthma or other chronic obstructive lung diseases, which may cause symptoms, bronchodilating therapy is recommended to 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.

g. tachycardia, palpitations or sweating) can be masked - strict fasting - ongoing desensitisation therapy. As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions.

Epinephrine treatment does not always yield the expected therapeutic effect. - First degree AV block - Prinzmetal’s angina; Cases of coronary vasospasm have been observed. Despite its high beta1-selectivity, angina attacks cannot be completely excluded when bisoprolol is administered to patients with 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 anaesthetist must be aware of beta-blockade because of the potential for interactions with other drugs, resulting in bradyarrhythmias, attenuation of the reflex tachycardia and the decreased reflex ability to compensate for blood loss.

If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia. Combination of bisoprolol 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

v. 4) - metabolic acidosis