Bisoprolol fumerate 10mg film-coated tablets

1. Name Of The Medicinal Product

Bisoprolol fumerate 10mg film-coated tablets

2. Qualitative And Quantitative Composition

Each film-coated tablet contains 10 mg of bisoprolol fumarate equivalent to 8.48 mg bisoprolol.

For a full list of excipients, see section 6.1

3. Pharmaceutical Form

Film-coated tablet.

Yellow coloured, circular, biconvex, film-coated tablets debossed with 'I and score line' on one side and '13' on the other side. The tablet can be divided into equal halves.

4. Clinical Particulars

4.1 Therapeutic Indications

Hypertension

Chronic stable angina pectoris

4.2 Posology And Method Of Administration

Adults

For both indications the dosage is 5 mg bisoprolol fumarate once daily. If necessary, the dose may be increased to 10 mg bisoprolol fumarate once daily.

The maximum recommended dose is 20 mg once daily.

In all cases the dosage is adjusted individually, in particular according to the pulse rate and therapeutic success.

Renal or liver 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.

Elderly

No dosage adjustment is required.

Children

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

Duration of therapy for all indications

Treatment with bisoprolol is generally a long-term therapy.

The treatment with bisoprolol must not be stopped abruptly since this might lead to a transitory worsening of condition. Especially in patients with ischaemic heart disease, treatment must not be discontinued suddenly. Gradual reduction of the daily dose is recommended.

Administration

BISOPROLOL FUMARATE tablets are taken in the morning with or without food. They are swallowed with some liquid and not to be chewed.

4.3 Contraindications

Bisoprolol is contraindicated 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

• 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

BISOPROLOL FUMARATE is contra-indicated in patients with hypersensitivity to bisoprolol or to any of the excipients

4.4 Special Warnings And Precautions For Use

Special warnings:

Especially in patients with ischaemic heart disease the cessation of therapy with bisoprolol must not be done abruptly unless clearly indicated, because this may lead to transitional worsening of heart condition (see section 4.2).

Precautions:

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

Bisoprolol must be used with caution in:

• diabetes mellitus showing large fluctuations in blood glucose values. Symptoms of hypoglycaemia (e.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,

• peripheral arterial occlusive disease. Aggravation of symptoms may occur especially when starting therapy.

Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g. bisoprolol) after a careful balancing of benefits against risks.

The symptoms of thyrotoxicosis may be masked under treatment with bisoprolol.

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

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.

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.

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.

Centrally-acting antihypertensive drugs (e.g. clonidine methyldopa, moxonodine, rilmenidine): Concomitant use of centrally-acting antihypertensive drugs may further decrease the central sympathetic tonus and may thus lead to reduction of heart rate and cardiac output and to vasodilatation. Abrupt withdrawal, particularly if prior to beta-blocker discontinuation, may increase the risk of 'rebound hypertension'.

Combinations to be used with caution

Class-I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide propafenone): Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.

Calcium antagonists of the dihydropyridine type (e.g. felodipine and amlodipine): 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 (e.g. amiodarone): Effect on atrio-ventricular conduction time may be potentiated.

Parasympathomimetic drugs: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia.

Topical beta-blockers (e.g. eye drops for glaucoma treatment) may add to the systemic effects of bisoprolol.

Insulin and oral antidiabetic drugs: Increase of blood sugar lowering effect. Blockade of beta-adrenoceptors may mask symptoms of hypoglycaemia.

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

Digitalis glycosides: Increase of atrio-ventricular conduction time, reduction in heart rate.

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

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

Sympathomimetics that activate both beta- and alpha-adrenoceptors (e.g. norepinephrine, epinephrine): 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.

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.

Combinations to be considered

Mefloquine: increased risk of bradycardia.

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

Rifampicin: Slight reduction of the half-life of bisoprolol possible due to the induction of hepatic drug -metabolizing enzymes. Normally no dosage adjustment is necessary.

Ergotamine derivatives: Exacerbation of peripheral circulatory disturbances.

4.6 Pregnancy And Lactation

Pregnancy:

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/newborn. In general, β-adrenoceptor blocking agents reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse reactions (e.g. hypoglycaemia, bradycardia) may occur in the fetus and newborn infant. If treatment with β-adrenoceptor blocking agents is necessary, β₁-adrenoceptor blocking agents are preferable.

Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, the uteroplacental blood flow and 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:

There are no data on the excretion of bisoprolol in human breast milk or the safety of bisoprolol exposure in infants. Therefore, breastfeeding is not recommended during administration of {Tradename}.

4.7 Effects On Ability To Drive And Use Machines

In a study with coronary heart disease patients, bisoprolol did not impair driving performance. However, depending on the individual patients response to treatment an effect on the ability to drive a vehicle or to use machines cannot be excluded. 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 undesirable effects have been observed during treatment with bisoprolol with the following frequencies:

Very common (

common (

uncommon (

rare (

very rare (<0.01%)

Investigations

Rare:

increased triglycerides, increased liver enzymes (ALT, AST)

Cardiac disorders

Uncommon:

AV-conduction disturbances; worsening of pre-existing heart failure; bradycardia

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

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

Skin and subcutaneous tissue disorders

Rare:	hypersensitivity reactions such as itching, flush, rash
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

Vascular disorders

Common:

feeling of coldness or numbness in the extremities, hypotension especially in patients with heart failure

General disorders

Common:	fatigue*
Uncommon:	asthenia

Hepatobiliary disorders

Rare:

hepatitis.

Reproductive system and breast disorders

Rare:

potency disorders

Psychiatric disorders

Uncommon:	depression, sleep disorders
Rare:	nightmares, hallucinations

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

4.9 Overdose

The most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is limited experience with overdose of bisoprolol, only a few cases of overdose with bisoprolol have been reported. Bradycardia and/or hypotension were noted. All patients recovered. 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.

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

Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following general measures may 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 temporary pacing.

Acute worsening of heart failure: Administer i.v. diuretics, inotropic agents, vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as isoprenaline, beta2-sympathomimetic drugs and/or aminophylline.

Hypoglycaemia: Administer i.v. glucose.

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 is a highly beta1-selective-adrenoceptor blocking agent, lacking intrinsic sympathomimetic 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.

Bisoprolol is used for the treatment of hypertension and angina pectoris. As with other Beta-1-blocking agents, the method of acting in hypertension is unclear. However, it is known that Bisoprolol reduces plasma renin activity markedly.

Antianginal mechanism: Bisoprolol by inhibiting the cardiac beta receptors inhibits the response given to sympathetic activation. That results in the decrease of heart rate and contractility this way decreasing the oxygen demand of the cardiac muscle.

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.

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 plasma protein binding of bisoprolol is about 30 %. The distribution volume is 3.5 l/kg. The total clearance is approximately 15 l/h

The plasma elimination half-life (10-12 hours) provides 24 hours efficacy following a once daily dosage.

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 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 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 β-blocking agents, bisoprolol 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

Tablet core:

Cellulose, microcrystalline

Calcium Hydrogen Phosphate, Anhydrous

Silica Colloidal Anhydrous

Crospovidone (Type A)

Magnesium stearate

Tablet coat:

Hypromellose 6cP (E464)

Titanium Dioxide (E171)

Macrogol 400

Iron Oxide Yellow (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

2 years.

6.4 Special Precautions For Storage

Store in the original package in order to protect from light.

6.5 Nature And Contents Of Container

BISOPROLOL FUMARATE film-coated tablets are available in –Polyamide/Aluminium/PVC/Paper/Polyester/Aluminium blisters and HDPE container with PP closure containing silica gel sachet.

Pack sizes:

Blister pack: 20, 28, 30, 50, 90, 100 film-coated tablets

HDPE container pack: 30, 500 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

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

7. Marketing Authorisation Holder

Aurobindo Pharma (Malta) Limited

Vault 14, Level 2, Valletta Waterfront

Floriana FRN 1913

Malta

8. Marketing Authorisation Number(S)

PL 32256/0090

9. Date Of First Authorisation/Renewal Of The Authorisation

23/05/2011

10. Date Of Revision Of The Text

23/05/2011