BISOPROLOL FUMARATE

Posology The dose must be individually adjusted.

Adults:

Essential hypertension. The dosage should be individually adjusted. It is recommended to start with the lowest possible dose. In some patients, 5 mg per day may be adequate. Depending on the clinical response, the dose can be increased to 10 mg once daily or to the maximum of 20 mg once daily.

If satisfactory clinical response can not be achieved using monotherapy, another antihypertensive for example a diuretic can be combined to the medication. Chronic, stable angina pectoris The recommended dose is 5 mg once daily. If necessary, this dose can be increased to 10 mg once daily.

In exceptional cases this dosage can be increased to maximally 20 mg once daily. Stable Chronic heart failure Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker in case of intolerance to ACE inhibitors), a beta-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. 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.

Paediatric population:

There is no experience of the use of bisoprolol in children, therefore its use cannot be recommended in patients under 18 years of age.

Elderly:

No dosage adjustment is required. Aging does not affect the dosing, unless patient has renal or hepatic impairment, see below. Renal or hepatic Impairment; In patients with liver or kidney function disorders of mild to moderate severity, no dosage adjustment is normally required.

In patients with severe renal impairment (creatinine clearance < 20 ml/min) and in patients with severe liver function disorders, it is recommended that a daily dose of 10 mg bisoprolol fumarate is not exceeded. Experience with the use of bisoprolol in renal dialysis patients is limited; however, there is no evidence that the dosage regimen needs to be altered.

There is no information about pharmacokinetics of bisoprolol in relation to patients, which have chronic heart failure and impaired renal and hepatic function. In treatment of these patients, the upwards dose titration must be performed with special caution.

Method of Administration:

Bisoprolol Fumarate tablets are taken in the morning with or without food. Tablets are swallowed with some liquid and not to be chewed.

Discontinuation of treatment:

Themust not be stopped suddenly, in particular when patient has ischaemic heart disease, instead the dosage should be reduced step by step for example during 1-2 weeks. Otherwise the symptoms of heart disease may get worse.

The frequency classification of adverse effects is following: • very common (≥ 1/10) • common (≥ 1/100, < 1/10) • uncommon (≥ 1/1 000, < 1/100) • rare (≥ 1/10 000, < /1 000) • very rare (≥ 1/10 000), not known (can not be estimated from the available data).

Psychiatric disorders Uncommon:

Depression, sleep disorders Rare: Nightmares, hallucinations Nervous system disorders Common: Dizziness*, headache* Rare: Syncope Eye disorders Rare: Reduced tear flow (to be considered if the patient uses contact 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 patients with heart failure) Uncommon: Orthostatic hypotension Respiratory, thoracic and mediastinal disorders Uncommon: Bronchospasm in patients with bronchial asthma or a history of obstructive airway 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 such as itching, flush, rash and angioedema Very rare: Alopecia, beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash Musculoskeletal and connective tissue disorders Uncommon: Muscle weakness, muscle cramps Reproductive system and breast disorders Rare: Erectile dysfunction General disorders and administration site conditions Common Asthenia (in patients with chronic heart failure), fatique* Uncommon Asthenia (in patients with hypertension or angina pectoris) Investigations Rare Increased triglycerides, increased liver enzymes (ALAT, ASAT) Applies to hypertension and angina pectoris: *These symptoms especially occur at the beginning of therapy.

They are generally mild and usually disappear within 1 to 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). Bisoprolol must be used with caution in patients with hypertension or angina pectoris and accompanying heart failure. 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 (serum creatinine over 300 mmol/l), - impaired liver function, - restrictive cardiomyopathy, - congenital heart disease, - haemodynamically significant organic valvular disease, - myocardial infarction within 3 months.

Bisoprolol must be used with caution: • stable chronic heart failure (Bisoprolol indicated for treatment after initial titration phase), • Bronchospasm (bronchial asthma, obstructive airways diseases), • diabetes mellitus showing large fluctuations in blood glucose values.

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

Epinephrine treatment may not always yield the expected therapeutic effect, • First degree AV block, • Prinzmetal's angina, 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 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 of 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 reflex tachycardia, and decreased reflex ability to compensate for blood loss.

If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia. Combination of bisoprolol with calcium antagonists of the verapamil and diltiazem type, with Class I antiarrhythmic medicinal products and with centrally acting antihypertensive medicinal products is generally not recommended, for details please refer to section

v. 4, - severe bronchial asthma or other severe symptomatic obstructive pulmonary disease - severe forms of peripheral arterial occlusive disease and Raynaud's syndrome, - metabolic acidosis.