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Bisoprolol Fumarate 3.75 Mg Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Bisoprolol Fumarate 3.75 mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 3.75 mg bisoprolol fumarate For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Tablet

White to off white round biconvex tablet

4    CLINICAL PARTICULARS

4.1    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.

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:

-    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.

Renal or liver impairment:

There is no information regarding pharmacokinetics of bisoprolol fumarate in patients with chronic heart failure and with impaired liver 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

Bisoprolol Fumarate Tablets should be taken in the morning and can be taken with food. They should be swallowed with liquid and should not be chewed.

4.3 Contraindications

Bisoprolol Fumarate is contraindicated in chronic heart failure patients with:

-    hypersensitivity to bisoprolol or to any of the excipients listed in section 6.1

-    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 (see section 4.4)

-    metabolic acidosis

4.4 Special warnings and precautions for use

The treatment of stable chronic heart failure with bisoprolol has to be initiated with a special titration phase.

Bisoprolol Fumarate must be used with caution in:

-    bronchospasm (bronchial asthma, obstructive airways diseases)

-    diabetes mellitus showing 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 may 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

In patients undergoing general anaesthesia the anaesthetist must be aware of beta-blockade. 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 fumarate treatment in heart failure in patients with the following diseases and conditions:

-    insulin dependent diabetes mellitus (type I)

-    severely impaired renal function

-    severely impaired liver function

-    restrictive cardiomyopathy

-    congenital heart disease

-    haemodynamically significant organic valvular disease

-    myocardial infarction within 3 months

Combination of bisoprolol fumarate 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 4.5.

In bronchial asthma or other chronic obstructive pulmonary diseases, which may cause symptoms, concomitant bronchodilating therapy is recommended. 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-blocking agents bisoprolol fumarate 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 fumarate) after a careful balancing of benefits against risks.

The symptoms of thyreotoxicosis may be masked under treatment with bisoprolol fumarate.

In patients with phaeochromocytoma bisoprolol must not be administered until after alpha-receptor blockade.

The initiation and cessation of treatment of stable chronic heart failure with bisoprolol fumarate necessitates regular monitoring. For the posology and method of administration please refer to section 4.2.

Especially in patients with ischaemic heart disease the cessation of therapy with bisoprolol fumarate must not be done abruptly unless clearly indicated, , because this may lead to transitional worsening of heart condition. 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 effect on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients on beta-blocker treatment may lead to profound hypotension and atrio-ventricular block.

Class I antiarrhythmic drugs: Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.

Centrally acting antihypertensive drugs: Concomitant use of centrally-acting antihypertensive drugs may lead to reduction of heart rate and cardiac output and to vasodilatation. Abrupt withdrawal may increase risk of “rebound hypertension”.

Combinations to be used with caution

Calcium antagonists of the dihydropyridine type: 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: 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 beta-adrenoreceptors may mask symptoms of hypoglycaemia.

Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension (see also section 4.4.).

Digitalis glycosides: Reduction in heart rate, increase of atrio-ventricular conduction time.

Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect of bisoprolol.

Beta-sympathomimetics : Combination with bisoprolol may reduce the effect of both agents.

Sympathomimetics that activate both beta- and alpha-adrenoceptors: Combination with bisoprolol may lead to blood pressure increase.

Concomitant use with antihypertensive agents as well as with other drugs with blood pressure lowering potential may increase the risk of hypotension.

Moxixylate: Possibly causes severe postural hypertension

Combinations to be considered

Mefloquine: increased risk of bradycardia

Monoamine oxidase inhibitors (except MAO-B inhibitors): Enhanced hypotensive effect of the beta-blocking agents but also risk for hypertensive crisis.

4.6 Fertility, pregnancy and lactation

Pregnancy

Bisoprolol Fumarate is not recommended during pregnancy unless clearly necessary. If treatment is considered necessary, monitoring of the uteroplacental blood flow and the foetal growth is recommended. In case of harmful effects on pregnancy or the foetus consideration of alternative treatment is recommended. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.

Breast-feeding

Breastfeeding is not recommended during administration of bisoprolol fumarate.

4.7 Effects on ability to drive and use machines

Depending on the individual patients response to treatment the ability to drive a vehicle or to use machines may be impaired. This needs to be considered particularly at start of treatment, upon change of medication, or in conjunction with alcohol.

4.8 Undesirable effects

The following terminologies have been used in order to classify the occurrence of undesirable effects:

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 (cannot be estimated from the available data)

Cardiac disorders:

Very common: bradycardia.

Common: worsening of pre-existing 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.

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 such as itching, flush, rash.

Very rare: Beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.

Musculoskeletal and connective tissue disorders:

Uncommon: muscle weakness and muscle 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.

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

The most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is a wide inter-individual variation in sensitivity to one single high dose of bisoprolol and patients with heart failure are probably very sensitive.

Management

In general, if overdose occurs, discontinuation of bisoprolol treatment and supportive and symptomatic treatment is recommended.

Limited data suggest that bisoprolol is hardly dialysable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Beta blocking agents, selective

ATC Code: C07AB07

Bisoprolol fumarate 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 fumarate 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-blocking agents, 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 fumarate is already used for the treatment of hypertension and angina. As with other P 1-blocking agents, the mode of action in hypertension

is not clear but it is known that bisoprolol markedly depresses plasma renin levels.

In acute administration in patients with coronary heart disease without chronic heart failure bisoprolol fumarate reduces the heart rate and stroke volume and thus the cardiac output and oxygen consumption. In chronic administration the initially elevated peripheral resistance decreases. Hence bisoprolol is effective in eliminating or reducing the symptoms.

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-blocking agents, bisoprolol fumarate 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 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Cellulose, Microcrystalline Silica, colloidal anhydrous Croscarmellose sodium Sodium Starch glycolate (Type A) Magnesium Stearate

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years.

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of container

Blister of white PVC/PVDC/Aluminium Packsizes of 20, 21, 28, 30, 50, 56, 60, 90 and 100 Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements.

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

ratiopharm GmbH, Graf-Arco-Str.3, D-89079 Ulm, Germany

8    MARKETING AUTHORISATION NUMBER(S)

PL 15773/0676

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 26/11/2009

10 DATE OF REVISION OF THE TEXT

12/04/2016