SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Salbutamol Inhalation Solution 2.5mg.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Salbutamol Sulphate: 3.0mg/2.5ml (1.2mg/ml) equivalent to Salbutamol 2.5mg/2.5ml (1mg/ml).

International non-proprietary name (INN): Salbutamol Sulphate.

Chemical names: (RS)-1 -(4-hydroxy-3 -hydroxymethylphenyl)-2-(tert-butylamino) ethanol sulphate.

For excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Nebuliser solution.

A clear, colourless or slightly yellow solution, free from visible particles.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Nebulised Salbutamol are indicated in adults, adolescents and children aged 4 years and above, see Section 4.2.

Salbutamol is a selective B2-agonist providing short-acting (4-6 hour) bronchodilation with a fast onset (within 5 minutes) in reversible airways obstruction.

Nebulised Salbutamol are indicated for use in the routine management of chronic bronchospasm unresponsive to conventional therapy, and in the treatment of acute severe asthma.

4.2 Posology and method of administration

Nebulised Salbutamol are for inhalation use only, to be breathed in through the mouth, under the direction of a physician, using a suitable nebuliser.

The solution should not be injected or swallowed.

Adults (including the elderly):

2.5mg to 5mg salbutamol up to four times a day. Up to 40mg per day can be given under strict medical supervision in hospital.

Paediatric Population:

Children aged 12 years and over: Dose as per adult population.

Children aged 4 to 11 years: 2.5mg to 5mg up to four times a day.

Other pharmaceutical forms may be more appropriate for administration in children under 4 years old.

Clinical efficacy of nebulised salbutamol in infants under 18 months is uncertain. As transient hypoxia may occur, supplemental oxygen therapy should be considered.

Salbutamol Inhalation Solution are intended to be used undiluted. However, if a prolonged delivery time is indicated (more than 10 minutes) then dilution with Sodium Chloride Solution (0.9%w/v) for Nebulisation or sterile sodium chloride injection (normal saline) may be required.

4.3 Contraindications

Although intravenous salbutamol, and occasionally salbutamol tablets, are used in the management of premature labour uncomplicated by conditions such as placenta praevia, ante-partum haemorrhage or toxaemia of pregnancy, inhaled salbutamol preparations are not appropriate for managing premature labour. Salbutamol preparations should not be used for threatened abortion.

Salbutamol Inhalation Solution are contra-indicated in patients with a history of hypersensitivity to any of the components.

4.4 Special warnings and precautions for use

Nebulised Salbutamol must only be used by inhalation, to be breathed in through the mouth, and must not be injected or swallowed.

Bronchodilators should not be the only or main treatment in patients with severe or unstable asthma. Severe asthma requires regular medical assessment, including lung-function testing, as patients are at risk of severe attacks and even death. Physicians should consider using the maximum recommended dose of inhaled corticosteroid and/or oral corticosteroid therapy in these patients.

Patients receiving treatment at home should seek medical advice if treatment with Nebulised Salbutamol becomes less effective. The dosage or frequency of administration should only be increased on medical advice.

Patients being treated with Nebulised Salbutamol may also be receiving other dosage forms of short-acting inhaled bronchodilators to relieve symptoms. Increasing use of bronchodilators, in particular short-acting inhaled B2-agonists to relieve symptoms, indicates deterioration of asthma control. The patient should be instructed to seek medical advice if short-acting relief bronchodilator treatment becomes less effective or more inhalations than usual are required. In this situation patients should be assessed and consideration given to the need for increased anti-inflammatory therapy (e.g. higher doses of inhaled corticosteroid or a course of oral corticosteroid).

Severe exacerbations of asthma must be treated in the normal way.

Salbutamol should be administered cautiously to patients suffering from thyrotoxicosis.

Cardiovascular effects may be seen with sympathomimetic drugs, including salbutamol. There is some evidence from post-marketing data and published literature of rare occurrences of myocardial ishaemia associated with salbutamol. Patients with underlying severe heart disease (e.g. Ischaemic heart disease, arrhythmia or severe heart failure) who are receiving salbutamol 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.

Nebulised Salbutamol should be used with care in patients known to have received large doses of other sympathomimetic drugs.

Potentially serious hypokalaemia may result from B2-agonist therapy, mainly from parenteral and nebulised administration. Particular caution is advised in acute severe asthma as this effect may be potentiated by hypoxia and by concomitant treatment with xanthine derivatives, steroids and diuretics. Serum potassium levels should be monitored in such situations.

In common with other B-adrenoceptor agonists, salbutamol can induce reversible metabolic changes such as increased blood glucose levels. Diabetic patients may be unable to compensate for the increase in blood glucose and the development of ketoacidosis has been reported. Concurrent administration of corticosteroids can exaggerate this effect.

Lactic acidosis has been reported in association with high therapeutic doses of intravenous and nebulised short-acting beta-agonist therapy, mainly in patients being treated for an acute asthma exacerbation (see Section 4.8). Increase in lactate levels may lead to dyspnoea and compensatory hyperventilation, which could be misinterpreted as a sign of asthma treatment failure and lead to inappropriate intensification of short-acting beta-agonist treatment. It is therefore recommended that patients are monitored for the development of elevated serum lactate and consequent metabolic acidosis in this setting.

A small number of cases of acute angle-closure glaucoma have been reported in patients treated with a combination of nebulised salbutamol and ipratropium bromide. A combination of nebulised salbutamol with nebulised anticholinergics should therefore be used cautiously. Patients should receive adequate instruction in correct administration and be warned not to let the solution or mist enter the eye.

Interaction with other medicinal products and other forms of interaction

Salbutamol and non-selective P-blocking drugs, such as propranolol, should not usually be prescribed together.

Potentially serious hypokalaemia may result from p₂-agonist therapy. Particular caution is advised in acute severe asthma, as this effect may be potentiated by concomitant treatment with xanthine derivatives, theophylline, corticosteroids, diuretics, (including atazolamide, loop diuretics, thiazides and related diuretics) and by hypoxia. It is recommended that serum potassium levels are monitored in such situations. Interactions do not generally apply to corticosteroids used for topical action (including inhalation).

A small number of cases of acute angle-closure glaucoma have been reported in patients treated with a combination of nebulised salbutamol and ipratropium bromide. A combination of nebulised salbutamol with nebulised anticholinergics should therefore be used cautiously. Patients should be warned not to allow the solution or mist to enter the eye.

Salbutamol possibly reduces the plasma concentration of cardiac glycosides, such as digoxin.

4.6 Fertility, pregnancy and lactation

Administration of drugs during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus. As with the majority of drugs, there is little published evidence of the safety of salbutamol in the early stages of human pregnancy, but in animal studies there was evidence of some harmful effects on the fetus at very high dose levels.

As salbutamol is probably secreted in breast milk, its use in nursing mothers requires careful consideration. It is not known whether salbutamol has a harmful effect on the neonate, and so its use should be restricted to situations where it is felt that the expected benefit to the mother is likely to outweigh any potential risk to the neonate.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

Adverse events are listed in the table below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10,000 and <1/1000), very rare (<1/10,000) and unknown (frequency cannot be calculated from available data).

Table 1

Immune system disorders:
Very rare	Hypersensitivity reactions including angioedema, urticaria, bronchospasm, hypotension and collapse.
Metabolism ant	nutrition system disorders:
Rare	Hypokalaemia (see section 4.4). Potentially serious hypokalaemia may result from |32-agonist therapy.
Unknown	Lactic acidosis (see section 4.4)
Nervous system disorders:
Common	Tremor, headache.
Very rare	Hyperactivity. Hyperexcitability and disturbances of sleep and behaviour in children
Cardiac disorders:
Common	Tachycardia. This is not usually accompanied by any changes in the electrocardiogram
Uncommon	Palpitations.
Very rare	Cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia and extrasystoles.
Unknown	Myocardial ischaemia (see section 4.4).
Vascular disorders:
Rare	Peripheral vasodilation.
Respiratory, thoracic and mediastinal disorders:
Very rare	Paradoxical bronchospasm. As with other inhalation therapy, paradoxical bronchospasm may occur with an intermediate increase in wheezing after dosing. This should be treated immediately with an alternative presentation or a different fastacting inhaled bronchodilator. Salbutamol treatment should be discontinued immediately, the patient assessed, and, if necessary, alternative therapy instituted.
Gastrointestina	disorders:
Uncommon	Mouth and throat irritation.
Musculoskeleta	and connective tissue disorders:
Uncommon	Muscle cramps.

4.9 Overdose

The most common signs and symptoms of overdose with salbutamol are transient beta agonist pharmacologically mediated events, including tachycardia, tremor, hyperactivity and metabolic effects including hypokalaemia and lactic acidosis (see sections 4.4 and 4.8).

Hypokalaemia may occur following overdose with salbutamol. Serum potassium levels should be monitored.

Consideration should be given to discontinuation of treatment and appropriate symptomatic therapy such as cardio-selective beta-blocking agents in patients presenting with cardiac symptoms (e.g. tachycardia, palpitations). Beta-blocking drugs should be used with caution in patients with a history of bronchospasm.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic Group: Adrenergics, inhalants; Selective beta-2-adrenoreceptor agonists, ATC code: R03AC02.

The bronchodilatory effects of salbutamol reside in its ability to bind to the p₂-adrenoceptor. The p₂-adrenoceptor is a member of the gene family of seven-transmembrane G protein-linked receptors. Stimulation results in G-protein activation leading to activation of adenylate cyclase and increased levels of cyclic AMP. This in turn activates protein kinase A, which catalyses phosphorylation of serine residues. ^-receptors are expressed on bronchial smooth muscle, on airways epithelium and on submucosal mucus glands. Mucus hypersecretion occurs in response to p₂-agonists in vitro, but does not seem to be a prominent effect of the compounds in vivo. Mast cells and leukocytes also express ^-receptors and p₂-agonists are potent inhibitors of mast cell degranulation. In theory, the compounds could be thought to have anti-inflammatory action, but there is no evidence of this in vivo. An important feature of p₂-receptor function is desensitisation - this exposure leads to cells becoming unresponsive to further challenge. There are two phases to the development of unresponsiveness. Acute unresponsiveness occurs after about 60 minutes of exposure to 0.01pM isoprenaline and results from phosphorylation of the receptor which becomes uncoupled from adenylate cyclase. This abates fairly quickly. The more chronic unresponsiveness seen at higher concentrations of agonist is due to decreased expression of the receptor. The extent to which this occurs in vivo and its relevance to p₂-agonist treatment in asthmatics is uncertain. Asthmatics appear to be less prone to p₂-agonist tachyphylaxis than non-asthmatics. There is no evidence that expression of the p₂-receptor is reduced in airways smooth muscle in asthmatics.

The onset of effect after inhalation is observed within seconds of administration. Maximal effects are reached shortly after and are sustained over a period of about 3-6 hours.

5.2 Pharmacokinetic properties

Studies with radiolabelled salbutamol (0.1mg by inhalation and 10mg orally) show that the drug is relatively more slowly excreted after inhalation than oral administration. Blood levels were negligible after aerosol inhalation. Any salbutamol swallowed following aerosol inhalation will not be inactivated by conjugation in the gut wall and may continue to exert a pharmacological effect.

Between 1% and 20% of a nebulised dose of salbutamol enters the systemic circulation. Deposition of particles tends to be greater in central than peripheral airways. The plasma salbutamol concentrations achieved after conventional nebuliser therapy in acute asthma are less than the concentrations achieved after oral or intravenous therapy with salbutamol. Plasma levels with therapeutic doses of intravenous salbutamol are 200-500ng/ml compared with the accepted target range for plasma salbutamol of 10-20ng/ml in patients with stable asthma. Frequent high dose nebulised salbutamol (every 20-30 mins or even continuously) in acute severe asthma leads to plasma levels as high as 40ng/ml.

The main metabolite of salbutamol in humans is the sulphate conjugate. Salbutamol has a terminal half-life of around 3-4 hours. The elimination rate of the sulphate conjugate is similar to that of unchanged salbutamol, indicating that the kinetics of elimination of the metabolite are formation rate-limited. In humans, salbutamol and metabolites are rapidly excreted in urine and faeces.

5.3 Preclinical safety data

The LD₅₀ in the mouse following intravenous administration was 70.5mg/kg (males), 75.3mg/kg (females) and, following oral administration, greater than 2,000mg/kg. In rats, the values were 61.5mg/kg (males), 59mg/kg (females) intravenously and greater than 2,000mg/kg orally.

No signs of toxicity were observed in dogs following the administration of 0.15mg/kg daily by aerosol for 12 weeks or in rats which inhaled 3.3mg/kg over a period of 3 hours daily for 6 weeks.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride Dilute sulphuric acid Sodium hydroxide solution Water for injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

Special precautions for storage

Store in a dry place below 25°C; protect from light. Discard any remaining solution after use.

6.5 Nature and contents of container

Strips of 10 Low Density Polyethylene (LDPE) plastic ampoules wrapped in an aluminium bag, each ampoule containing 2.5ml of a clear, colourless or slightly yellow solution. Cartons containing 20 ampoules.

6.6 Special precautions for disposal

Preparing the nebuliser and Salbutamol Inhalation Solution:

Ensure you are fully familiar with the operation of your nebuliser. Your doctor will instruct you in how to correctly use the nebuliser and Salbutamol Inhalation Solution. You should also carefully read the instructions provided with the nebuliser.

Prepare the nebuliser for use.

Separate an ampoule from the strip by carefully pulling and twisting. Never use one that is already open.

Hold the ampoule upright and twist off the tab. Use the contents of the ampoule immediately after opening.

Squeeze all the ampoule contents into the nebuliser reservoir. If dilution is necessary, this should be carried out using only sterile normal saline solution as instructed by the doctor.

Assemble the nebuliser and use it as instructed by the doctor. Care should be taken to ensure that the nebuliser mist (or the solution) does not enter your eyes.

After nebulisation throw away any solution remaining in the nebuliser and clean the nebuliser as instructed.

7    MARKETING AUTHORISATION HOLDER

Focus Pharmaceuticals Limited Unit 5 Faraday Court First Avenue, Centrum 100 Burton upon Trent

Staffordshire DE14 2WX United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 20046/0093

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/10/2005

10    DATE OF REVISION OF THE TEXT

02/07/2015