1. Name Of The Medicinal Product
Bambec Tablets 20 mg
2. Qualitative And Quantitative Composition
Each tablet contains 20 mg Bambuterol hydrochloride
For excipients, see Section 6.1
3. Pharmaceutical Form
Tablet
4. Clinical Particulars
4.1 Therapeutic Indications
Management of asthma, bronchospasm and/or reversible airways obstruction.
4.2 Posology And Method Of Administration
Bambec is formulated as a tablet and should be taken once daily, shortly before bedtime. The dose should be individualised.
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.
Children: Until the clinical documentation has been completed, Bambec should not be used in children.
Elderly: Dose adjustment is not required in the elderly.
Significant hepatic dysfunction: Not recommended because of unpredictable conversion to terbutaline.
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.
4.3 Contraindications
Bambec tablets are contraindicated in patients with a history of hypersensitivity to any of their ingredients. 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
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 with corticosteroids. 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.
Bambec tablets contains 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
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. 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.
Hypokalemia may result from β2-agonist therapy and may be potentiated by concomitant treatment with xanthine derivatives, steroids and diuretics (see section 4.4).
Bambec should be used with caution in patients receiving other sympathomimetics.
4.6 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 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.
Lactation
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
None stated.
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 (
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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).
Treatment of overdosage
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: selective β2-agonists, bambuterol, ATC code: R03C C12.
Bambuterol is an active precursor of the selective β2-adrenergic agonist terbutaline. Bambuterol is the bis-dimethylcarbamate of terbutaline, and is present in the formulation as a 1:1 racemate.
Pharmacodynamic studies have shown that after oral administration of bambuterol to guinea pigs, a sustained protective effect was achieved against histamine-induced bronchoconstriction. At equipotent doses, the duration of the relaxing activity was more prolonged than after plain terbutaline. Bambuterol, or the monocarbamate ester, did not exert any smooth muscle relaxing properties. The bronchoprotective effects seen after oral administration of bambuterol are related to the generation of terbutaline, as were the secondary effects (effects on other organs).
Pharmacodynamic studies have been conducted in asthmatics and healthy volunteers. The effects observed were bronchodilation, tremor and increases in heart rate. The metabolic effects included a small increase in blood glucose, while the effect on serum potassium was negligible. In short-term studies on lipoprotein metabolism, an increase in HDL cholesterol, has been observed. In conclusion, all pharmacodynamic effects observed can be ascribed to the active metabolite terbutaline.
5.2 Pharmacokinetic Properties
On average, 17.5% of an oral dose is absorbed. Approximately 70–90% of the absorption occurs in the first 24 hours.
Bambuterol is metabolised in the liver and terbutaline is formed by both hydrolysis and oxidation. After absorption from the gut, about 2/3 of terbutaline is first-pass metabolised, bambuterol escapes this first-pass metabolism. Of the absorbed amount, about 65% reaches the circulation. Bambuterol therefore has a bioavailability of about 10%.
Protein binding of bambuterol is low, 40–50% at therapeutic concentrations.
The terminal half-life of bambuterol after an oral dose is 9–17 hours.
Studies on the effects on plasma cholinesterase showed that bambuterol inhibited activity, but that this was reversible.
All categories of subjects studied were able to form terbutaline in a predictive way except for liver cirrhotics.
5.3 Preclinical Safety Data
Bambuterol has not revealed any adverse effects which pose a risk to man at therapeutic dosages in the toxicity studies.
Bambuterol is given as a racemate: (-)-bambuterol is responsible for the pharmacodynamic effects via generation of (-)-terbutaline. (+)-bambuterol generates the pharmacodynamic inactive (+)-terbutaline. Both (+) and (-)-bambuterol are equally active as plasma cholinesterase inhibitors. This inhibition is reversible.
The toxicity studies showed that bambuterol has β2-stimulatory effects, expressed as cardiotoxicity in dogs, and at high doses, observed in the acute toxicity studies, cholinergic effects.
There is no evidence from the preclinical safety data to indicate that bambuterol cannot be used in man for the intended indications with sufficient safety.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose monohydrate; maize starch; povidone; microcrystalline cellulose; magnesium stearate; water, purified.
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
Do not store above 30°C.
6.5 Nature And Contents Of Container
Amber glass bottle with LD-polyethene cap: 7, 14, 28, 30, 56 or 100 tablets.
HDPE container with LD-polyethene cap: 7, 14, 28, 30, 56 or 100 tablets.
HDPE container with polypropylene cap: 7, 14, 28, 30, 56 or 100 tablets.
PVC blisters: 7, 14, 28, 30, 56 or 100 tablets.
6.6 Special Precautions For Disposal And Other Handling
None.
7. Marketing Authorisation Holder
AstraZeneca UK Ltd.,
600 Capability Green,
Luton, LU1 3LU, UK.
8. Marketing Authorisation Number(S)
PL 17901/0104
9. Date Of First Authorisation/Renewal Of The Authorisation
21st May 2002
10. Date Of Revision Of The Text
21st March 2011
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