4.1. Therapeutic indications

Management of asthma, bronchospasm and/or reversible airways obstruction.

4.2. Posology and method of administration

Posology

Bambec is formulated as a tablet and should be taken once daily, shortly before bedtime. The dose should be individualised.

Patients must receive optimal anti-inflammatory therapy (e.g. inhaled corticosteroids, leukotriene receptor antagonists) when using Bambec for management of asthma.

Adults:

The recommended starting doses are 10 mg–20 mg. The 10 mg dose may be increased to 20 mg if necessary after 1–2 weeks, depending on the clinical effect.

In patients who have previously tolerated β2-agonists well, the recommended starting dose, as well as maintenance dose, is 20 mg.

Elderly:

Dose adjustment is not required in the elderly.

Hepatic Impairment:

Significant hepatic dysfunction: Not recommended because of unpredictable conversion to terbutaline.

Renal impairment:

Moderate to severely impaired renal function (GFR < 50 ml/min): It is recommended that the starting dose of Bambec should be halved in these patients.

Paediatric population:

Until the clinical documentation has been completed, Bambec should not be used in children.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Bambec is presently not recommended for children due to limited clinical data in this age group.

4.4. Special warnings and precautions for use

As terbutaline is excreted mainly via the kidneys, the dose of Bambec should be halved in patients with an impaired renal function (GFR ≤ 50 mL/min).

In patients with liver cirrhosis, and probably in patients with other causes of severely impaired liver function, the daily dose must be individualised, taking into account the possibility that the individual patient could have an impaired ability to metabolise bambuterol to terbutaline. Therefore, from a practical point of view, the direct use of the active metabolite, terbutaline (Bricanyl™), is preferable in these patients.

As for all β2-agonists, caution should be observed in patients with thyrotoxicosis.

Cardiovascular effects may be seen with sympathomimetic drugs, including Bambec. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ischaemia associated with beta agonists. Patients with underlying severe heart disease (e.g. ischaemic heart disease, arrhythmia or severe heart failure) who are receiving Bambec should be warned to seek medical advice if they experience chest pain or other symptoms of worsening heart disease. Attention should be paid to assessment of symptoms such as dyspnoea and chest pain, as they may be of either respiratory or cardiac origin.

Although Bambec is not indicated for the treatment of premature labour it should be noted that bambuterol is metabolised to terbutaline and that terbutaline should not be used as a tocolytic agent in patients with pre-existing ischaemic heart disease or those patients with significant risk factors for ischaemic heart disease.

Due to the hyperglycaemic effects of β2-agonists, additional blood glucose controls are recommended initially in diabetic patients.

Due to the positive inotropic effects of β2-agonists these drugs should not be used in patients with hypertrophic cardiomyopathy.

β2-agonists may be arrhythmogenic and this must be considered in the treatment of the individual patient.

Unpredictable inter-individual variation in the metabolism of bambuterol to terbutaline has been shown in subjects with liver cirrhosis. The use of an alternative β2-agonist is recommended in patients with cirrhosis and other forms of severely impaired liver function.

Potentially serious hypokalaemia may result from β2-agonist therapy. Particular caution is recommended in acute severe asthma as the associated risk may be augmented by hypoxia. The hypokalaemic effect may be potentiated by concomitant treatments (see section 4.5). It is recommended that serum potassium levels are monitored in such situations.

Asthma patients who require treatment with Bambec must have optimum anti-inflammatory treatment, e.g. inhaled corticosteroids, leukotriene receptor antagonists. The patients must be instructed to continue taking their anti-inflammatory medication after the start of treatment with Bambec, even if the asthma symptoms diminish. If a previously effective dosage regimen no longer gives the same symptomatic relief this suggests that the underlying disease has worsened. The patient should urgently seek further medical advice and a re-evaluation of the asthma treatment must be carried out. Consideration should be given to the requirements for additional therapy (including increased dosages of anti-inflammatory medication). Treatment with Bambec must not be begun or the dose increased during an acute exacerbation of the asthma. Severe exacerbations of asthma should be treated as an emergency in the usual manner.

Precaution should be applied when treating patients predisposed to angle closure glaucoma.

Bambec tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

Halogenated anaesthetics

Halothane anaesthesia should be avoided during β2-agonists treatment, since it increases the risk of cardiac arrhythmias. Other halogenated anaesthetics should be used cautiously together with β2-agonists.

Bambuterol prolongs the muscle-relaxing effect of suxamethonium (succinylcholine). A prolongation of the muscle-relaxing effect of suxamethonium of up to 2-fold has been observed in some patients after taking Bambec 20 mg on the evening prior to surgery. The inhibition is dose-dependent and fully reversible after cessation of treatment with bambuterol. This is due to the fact that plasma cholinesterase, which inactivates suxamethonium, is partly inhibited by bambuterol. Studies on the effects on plasma cholinesterase showed that bambuterol inhibited activity, but that this was reversible. However in extreme situations, the interaction may result in a prolonged apnoea time which may be of clinical importance. This interaction should also be considered with other muscle relaxants, which are metabolised by plasma cholinesterase.

Beta-receptor blocking agents (including eye-drops), especially those which are non-selective, may partly or totally inhibit the effect of beta-stimulants. Therefore, Bambec tablets and non-selective β-blockers should not normally be administered concurrently.

Potassium depleting agents and hypokalaemia

Owing to the hypokalaemic effect of beta agonists, concurrent administration of serum potassium depleting agents known to exacerbate the risk of hypokalaemia, such as diuretics, methyl xanthines and corticosteroids, should be administered cautiously after careful evaluation of the benefits and risks with special regard to the increased risk of cardiac arrhythmias arising as a result of hypokalaemia (see Section 4.4). Hypokalaemia also predisposes to digoxin toxicity.

Bambec should be used with caution in patients receiving other sympathomimetics.

Six cases have been reported where concomitant treatment with salbutamol and ipratropium, used in asthma (nebuliser), has caused narrow angle glaucoma. Terbutaline is likely to interact, similar to salbutamol, with ipratropium when administered in a nebuliser. The combination is discouraged in predisposed patients.

4.6. Fertility, pregnancy and lactation

Pregnancy

Although no teratogenic effects have been observed in animals after administration of bambuterol, caution is recommended during the first trimester of pregnancy.

Beta-agonists for asthma and other pulmonary diseases should be used with caution at the end of pregnancy because of the tocolytic effect.

Transient hypoglycaemia has been reported in newborn preterm infants after maternal β2-agonist treatment.

Breast-feeding

It is unknown whether bambuterol or intermediary metabolites are excreted in human breast milk. Terbutaline, the active metabolite of bambuterol, is excreted in breast milk, but at therapeutic doses of terbutaline no effect on breastfed newborns/infants are anticipated. A decision must be made whether to discontinue breast-feeding or to discontinue Bambec therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

4.7. Effects on ability to drive and use machines

Bambec has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Most of the adverse reactions are characteristic of sympathomimetic amines. The intensity of the adverse reactions is dose-dependent. Tolerance to these effects has usually developed within 1-2 weeks.

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to < 1/100), Rare (≥1/10,000 to < 1/1,000), Very rare (<1/10,000) and Not known (cannot be estimated from available data).

System Organ Class (SOC)

Frequency Classification

Adverse Drug Reaction

Immune system disorders

Not known

Hypersensitivity reactions including Angioedema, Urticaria, Exanthema, Bronchospasm, Hypotension and Collapse.

Metabolism and nutrition disorders

Not known

Hypokalemia

Hyperglycaemia

Psychiatric disorders

Very Common

Behavioural Disturbances, such as Restlessness

Common

Sleep disturbances

Uncommon

Behavioural Disturbances, such as Agitation

Not known

Dizziness

Hyperactivity

Nervous system disorders

Very common

Tremor, Headache

Cardiac disorders

Common

Palpitations

Uncommon

Tachycardia

Cardiac arrhythmias, e.g. Atrial Fibrillation, Supraventricular tachycardia and Extrasystoles

Not known

Myocardial ischemia (see section 4.4)

Respiratory, thoracic and mediastinal disorders

Unknown

Paradoxical bronchospasm

Gastrointestinal disorders

Not known

Nausea

Musculoskeletal, connective tissue and bone disorders

Common

Muscle cramps

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.

Website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Symptoms

Overdosing may result in high levels of terbutaline and therefore the same symptoms and signs as recorded after overdosage with Bricanyl: Headache, anxiety, tremor, nausea, tonic muscle cramps, palpitations, tachycardia and cardiac arrhythmias.

A fall in blood pressure sometimes occurs after terbutaline overdosage.

Laboratory findings: Hyperglycaemia and lactic acidosis sometimes occur. High doses of β2-agonists may cause hypokalemia as a result of redistribution of potassium.

Overdosage with Bambec is likely to cause a considerable inhibition of plasma cholinesterase, that may last for days (see also section 4.5).

Management

Usually no treatment is required. In particularly severe cases of overdosage, the following measures may be considered on a case-by-case basis: Gastric lavage and activated charcoal.

Determine acid-base balance, blood glucose and electrolytes. Monitor heart rate and rhythm and blood pressure. The preferred antidote for haemodynamically significant cardiac arrhythmias is a cardioselective beta-blocking agent, but beta-blocking drugs should be used with caution in patients with a history of bronchospasm. If the β2-mediated reduction in peripheral vascular resistance significantly contributes to the fall in blood pressure, a volume expander should be given.