SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Emcor 10 mg film coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg bisoprolol fumarate.

For excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

Pale orange - light orange, heart-shaped, scored and film-coated tablets

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

In the management of hypertension and the management of angina pectoris.

4.2    Posology and method of administration

Adults: The usual dose is 10 mg once daily with a maximum recommended dose of 20 mg per day. In some patients 5 mg per day may be adequate.

Administration

Emcor 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 populations

Elderly: No dosage adjustment is normally required, but 5 mg per day may be adequate in some patients; as for other adults, dosage may have to be reduced in cases of severe renal or hepatic dysfunction.

Children: There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for children.

Renal or hepatic impairment: In patients with final stage impairment of renal function (creatinine clearance < 20 ml/min) or liver function, the dose should not exceed 10 mg bisoprolol once daily.

4.3 Contraindications

Bisoprolol is contra-indicated in 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 (heart rate less than 60 beats/min prior to start of therapy).

•    hypotension (systolic blood pressure < 100mmHg).

•    severe bronchial asthma or severe chronic obstructive pulmonary disease.

•    severe forms of peripheral arterial occlusive disease and Raynaud’s syndrome.

•    untreated phaeochromocytoma (see section 4.4).

•    metabolic acidosis.

•    hypersensitivity to bisoprolol or to any of the excipients.

4.4 Special warnings and precautions for use

Bisoprolol must be used with caution in:

•    heart failure

The treatment of stable chronic heart failure with bisoprolol has to be initiated with a special titration phase (for details, see SPC for bisoprolol indicated for the treatment of stable chronic heart failure).

•    bronchospasm (bronchial asthma, obstructive airways diseases).

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.

•    For patients with severe renal impairment and patients with severe liver function disorders please refer to section 4.2.

•    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 of 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 or with centrally acting antihypertensive drugs is generally not recommended, for details please refer to section 4.5.

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 thyrotoxicosis may be masked.

Treatment with bisoprolol should not be stopped abruptly unless clearly indicated, especially in patients with ischaemic heart disease.

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 influence on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients on beta-blocker treatment may lead to profound hypotension and atrioventricular block.

•    Centrally acting antihypertensive drugs such as clonidine and others (e.g. methyldopa, moxonodine, rilmenidine): Concomitant use of centrally acting antihypertensive drugs may further decrease 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 nifedipine: 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-I antiarrhythmic drugs (e.g. disopyramide, quinidine): Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased

•    Class-III antiarrhythmic drugs (e.g. amiodarone): Effect on atrioventricular 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 atrioventricular conduction time and the risk of bradycardia.

•    Insulin and oral antidiabetic drugs: Intensification 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 (for further information on general anaesthesia see also section 4.4).

•    Digitalis glycosides: Reduction of heart rate, increase of atrioventricular conduction time.

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

•    Beta-sympathomimetic agents (e.g. isoprenaline, dobutamine): Combination with bisoprolol may reduce the effect of both agents.

•    Sympathomimetics that activate both beta- and alpha-adrenoceptors (e.g. noradrenaline, adrenaline): Combination with bisoprolol may unmask the alpha-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 beta-blockers. Higher doses of adrenaline may be necessary for treatment of allergic reactions.

•    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.

•    Moxisylyte: Possibly causes severe postural 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

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn. In general, P-adrenoreceptor 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 P-adrenoreceptor blockers is necessary, p₁- selective adrenoreceptor 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.

Lactation

It is not known whether this drug is excreted in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol.

4.7 Effects on ability to drive and use machines

In a study of 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 the start of treatment and upon change of medication as well as in conjunction with alcohol.

4.8 Undesirable effects

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:

Uncommon: AV-conduction disturbances, worsening of pre-existing heart failure, bradycardia.

Vascular disorders:

Common: feeling of coldness or numbness in the extremities, hypotension. Uncommon: Orthostatic hypotension.

Metabolism and nutrition disorders:

Rare: Increased triglycerides.

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.

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: increased liver enzymes (ALAT, ASAT), hepatitis.

Skin and subcutaneous tissue disorders:

Rare: hypersensitivity reactions (itching, flush, rash).

Very rare: beta-blockers 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: potency disorders.

General disorders:

Common: fatigue*.

Uncommon: asthenia.

*These symptoms especially occur at the beginning of the therapy. They are generally mild and often disappear within 1-2 weeks.

The most common signs expected with overdosage of a B-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. Bradycardia and/or hypotension were noted. All patients recovered. There is a wide interindividual variation in sensitivity to one single high dose of bisoprolol.

In general, 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 pharmacological actions and recommendations for other B-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, B2-sympathomimetic drugs and/or aminophylline.

Hypoglycaemia: Administer i.v. glucose.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Bisoprolol is a potent, highly ^-selective adrenoreceptor blocking agent devoid of intrinsic sympathomimetic activity and without relevant membrane stabilising activity.

As with other ^-blocking agents, the mode of action in hypertension is

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

In patients with angina, the blockade of ^-receptors reduces heart

action and thus reduces oxygen demand. Hence bisoprolol is effective in eliminating or reducing the symptoms.

5.2 Pharmacokinetic properties

Bisoprolol is absorbed almost completely from the gastrointestinal tract. Together with the very small first pass effect in the liver, this results in a high bioavailability of approximately 90%. The drug is cleared equally by the liver and kidney.

The plasma elimination half-life (10-12 hours) provides 24 hours efficacy following a once daily dosage. About 95% of the drug substance is excreted through the kidney, half of this is as unchanged bisoprolol. There are no active metabolites in man.

Not applicable.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core: silica, colloidal anhydrous; magnesium stearate; crospovidone; cellulose, microcrystalline; maize starch; calcium hydrogen phosphate, anhydrous.

Film coating: iron oxide red (E172); iron oxide yellow (E172); dimeticone; macrogol 400; titanium dioxide (E171); hypromellose.

6.2 Incompatibilities

None.

6.3 Shelf life

4 years

6.4 Special precautions for storage

This product does not require any special storage conditions.

6.5 Nature and contents of container

Cartons containing blister packs of 4, 14 or 28 tablets.

6.6 Special precautions for disposal

None.

7    MARKETING AUTHORISATION HOLDER

Merck Serono Ltd Bedfont Cross, Stanwell Road Feltham, Middlesex,

TW14 8NX, UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 11648/0070

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11 February 1993

DATE OF REVISION OF THE TEXT

25/10/2012