Allen & Hanburys Ltd

Ventolin Concentrate Solution for Intravenous Infusion

Each ampoule contains 5.0mg salbutamol as salbutamol sulphate (1mg/ml).

For excipients, see 6.1.

Concentrate for solution for infusion

A clear colourless to pale straw coloured sterile aqueous solution.

Ventolin Concentrate Solution for Intravenous Infusion is indicated for the management of severe bronchospasm associated with asthma or bronchitis and for the treatment of status asthmaticus.

Management of uncomplicated premature labour in the last trimester of pregnancy.

Salbutamol has a duration of action of 4 to 6 hours in most patients.

Ventolin parenteral preparations are to be used under the direction of a physician.

Increasing use of β₂ agonists may be a sign of worsening asthma. Under these conditions a reassessment of the patient's therapy plan may be required and concomitant glucocorticosteroid therapy should be considered.

As there may be adverse effects associated with excessive dosing, the dosage or frequency of administration should only be increased on medical advice.

Ventolin parenteral preparations should not to be administered in the same syringe or infusion as any other medication.

The contents of the ampoules of Ventolin Concentrate Solution for Intravenous Infusion must not be injected undiluted. The concentration should be reduced by 50% before administration.

Adults:

In bronchospasm and status asthmaticus:

Intravenous slow injection:-

Infusion rates of 3 to 20 micrograms per minute are generally adequate but in patients with respiratory failure, higher dosage has been used with success. A starting dose of 5 micrograms per minute is recommended with appropriate adjustment in dosage according to patient response.

A suitable solution for infusion may be prepared by diluting 5ml of Ventolin Concentrate Solution for Intravenous Infusion in 500ml of an infusion solution such as sodium chloride and dextrose injection BP to provide a salbutamol dose of 10 mcg/ml of solution.

For premature labour (or to control contractions or counteract overdosage of oxytocics):

Intravenous Infusion:-

Infusion rates of 10-45 micrograms per minute are generally adequate. A starting rate of 10 micrograms per minute is recommended, increasing the rate until there is evidence of patient response.

Careful attention should be given to cardio-respiratory function and fluid balance monitoring.

The maternal pulse rate should be monitored regularly and should not be allowed exceed 140 bpm. Treatment discontinuation should be considered should signs of pulmonary oedema or myocardial ischaemiadevelop. (see section 4.4 'Special Warnings and Precautions for Use' and section 4.8 'Undesirable Effects')

Once uterine contractions have ceased the infusion rate should be maintained at the same level for one hour and then reduced by 50% decrements at 6-hourly intervals. Treatment may be continued orally.

Children:-

At present there is insufficient evidence to recommend a dosage regimen for routine use in children.

Ventolin parenteral preparations are contraindicated in patients with a history of hypersensitivity to any of their components.

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, salbutamol presentations should not be used for threatened abortion.

Salbutamol 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.

The management of asthma should normally follow a stepwise programme, and patient response should be monitored clinically and by lung function tests.

Bronchodilators should not be the only or main treatment in patients with severe or unstable asthma. Patients with severe asthma have constant symptoms and frequent exacerbations, with limited physical capacity, and PEF values below 60% predicted at baseline with greater than 30% variability, usually not returning entirely to normal after a bronchodilator. These patients will require high dose inhaled (e.g.>1mg/day beclomethasone dipropionate) or oral corticosteroid therapy. With this primary background corticosteroid treatment, Ventolin provides essential rescue medication for a severe asthmatic in treating acute exacerbations. Failure to respond promptly or fully to such rescue medication signals a need for urgent medical advice and treatment.

Increasing use of short-acting inhaled β₂ agonists to control symptoms indicates deterioration of asthma control. Under these conditions, the patient's therapy plan should be reassessed. Sudden and progressive deterioration in asthma control is potentially life-threatening and consideration should be given to starting or increasing corticosteroid therapy. In patients considered at risk, daily peak flow monitoring may be instituted.

The use of Ventolin parenteral preparations in the treatment of severe bronchospasm or status asthmaticus does not obviate the requirement for glucocorticoid steroid therapy as appropriate.

When practicable, administration of oxygen concurrently with parenteral Ventolin is recommended particularly when it is given by intravenous infusion to hypoxic patients.

In common with other β-adrenoceptor agonists, Ventolin can induce reversible metabolic changes such as reversible hypokalaemia and increased blood glucose levels. The diabetic patient may be unable to compensate for this and the development of ketoacidosis has been reported. Concurrent administration of corticosteroids can exaggerate this effect.

Potentially serious hypokalaemia may result from β₂ agonist therapy mainly from parenteral and nebulised administration. Particular caution is advised in acute severe asthma as this effect may be potentiated by concomitant treatment with xanthine derivatives, steroids, diuretics and by hypoxia. It is recommended that serum potassium levels are monitored in such situations.

Diabetic patients and those concurrently receiving corticosteroids should be monitored frequently during intravenous infusion of Ventolin so that remedial steps (e.g. an increase in insulin dosage) can be taken to counter any metabolic change occurring. For these patients Ventolin Concentrate Solution for Intravenous Infusion should be diluted with Sodium Chloride Injection BP, rather than Sodium Chloride and Dextrose Injection BP.

Lactic acidosis has been reported very rarely 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 Adverse Reaction section). 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.

Salbutamol causes peripheral vasodilation which may result in reflex tachycardia and increased cardiac output. Caution should be used in patients with angina, severe tachycardia or thyrotoxicosis.

As maternal pulmonary oedema and myocardial ischaemia havebeen reported during or following treatment of premature labour with β₂ agonists, careful attention should be given to fluid balance and cardio-respiratory function, including ECG, should be monitored. If signs of pulmonary oedema or myocardial ischaemia develop, discontinuation of treatment should be considered. (See section 4.2 'Posology and Method of Administration' and section 4.8 'Undesirable Effects').

In the treatment of premature labour by intravenous infusion of salbutamol increases in maternal heart rate of the order 20 to 50 beats per minute usually accompany the infusion. The maternal pulse rate should be monitored and not normally allowed to exceed a steady rate of 140 beats per minute.

Maternal blood pressure may fall slightly during the infusion; the effect being greater on diastolic than on systolic pressure. Falls in diastolic pressure are usually within the range of 10 to 20mmHg. The effect of infusion on foetal rate is less marked but increases of up to 20 beats per minute may occur.

In the treatment of premature labour, before Ventolin parenteral preparations are given to any patient with known heart disease, an adequate assessment of the patient's cardiovascular status should be made by a physician experienced in cardiology.

Cardiovascular effects may be seen with sympathomimetic drugs, including salbutamol. There is some evidence from post-marketing data and published literature of myocardial ischaemia associated with salbutamol.

Tocolysis

Salbutamol should be used with caution in tocolysis and supervision of cardiorespiratory function, including ECG monitoring, should be considered. Treatment should be discontinued if signs of myocardial ischaemia (such as chest pain or ECG changes) develop. Salbutamol should not be used as a tocolytic agent in patients with significant risk factors for or pre-existing heart disease (see section 4.3).

Respiratory indications

Patients with underlying severe heart disease (e.g. ischaemic heart disease, arrhythmia or severe heart failure) who are receiving salbutamol for respiratory disease, 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.

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

Salbutamol is not contra-indicated in patients under treatment with monoamine oxidase inhibitors (MAOIs), however the effects of salbutamol may be altered by guanethidine, reserpine, methyldopa and tricyclic antidepressants.

Caution should be exercised in it's use with anaesthetic agents such as chloroform, cyclopropane, halothane and other halogenated agents.

The use of the drug will inhibit the effects of oxytocic drugs.

Salbutamol will inhibit the effects of non-selective β-adrenoceptor blockers.

Administration of drugs during pregnancy should only be considered if the expected benefit to the mother is greater than any possible risk to the foetus.

Salbutamol has been in widespread use for many years in human beings without apparent ill consequence; this indicates its well established use in the management of premature labour. However, as with the majority of drugs, there is little published evidence of its safety in the early stages of human pregnancy, but in animal studies there was evidence of some harmful effects on the foetus at very high dose levels.

During worldwide marketing experience, rare cases of various congenital anomalies, including cleft palate and limb defects have been reported in the offspring of patients being treated with salbutamol. Some of the mothers were taking multiple medications during their pregnancies. Because no consistent pattern of defects can be discerned, and baseline rate for congenital anomalies is 2-3%, a relationship with salbutamol use cannot be established.

As salbutamol is probably secreted in breast milk its use in nursing mothers is not recommended unless the expected benefits outweigh any potential risk. It is not known whether salbutamol in breast milk has a harmful effect on the neonate.

None reported.

Adverse events are listed 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) and very rare (<1/10,000) including isolated reports. Very common and common events were generally determined from clinical trial data. Rare and very rare events were generally determined from spontaneous data.

Symptoms and Signs

The most common signs and symptoms of overdose with salbutamol are transient beta agonist pharmacologically mediated events (see Special Warnings and Precautions for Use and Undesirable Effects).

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

Nausea, vomiting and hyperglycaemia have been reported, predominantly in children and when salbutamol overdose has been taken via the oral route.

Treatment

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.

Pharmacotherapeutic group: Selective β₂ -adrenoceptor agonist

ATC code: R03A C02

Salbutamol is a selective β₂ adrenoceptor agonist. At therapeutic doses it acts on the β₂ adrenoceptors of bronchial muscle, with little or no action on the β-1 adrenoceptors of the heart.

Salbutamol administered intravenously has a half-life of 4 to 6 hours and is cleared partly renally and partly by metabolism to the inactive 4'-O-sulphate (phenolic sulphate) which is also excreted primarily in the urine. The faeces are a minor route of excretion. The majority of a dose of salbutamol given intravenously, orally or by inhalation is excreted within 72 hours. Salbutamol is bound to plasma proteins to the extent of 10%.

In common with other potent selective β₂ receptor agonists, salbutamol has been shown to be teratogenic in mice when given subcutaneously. In a reproductive study, 9.3% of foetuses were found to have cleft palate, at 2.5mg/kg, 4 times the maximum human oral dose. In rats, treatment at the levels of 0.5, 2.32, 10.75 and 50mg/kg/day orally throughout pregnancy resulted in no significant foetal abnormalities. The only toxic effect was an increase in neonatal mortality at the highest dose level as the result of lack of maternal care. A reproductive study in rabbits revealed cranial malformations in 37% of foetuses at 50mg/kg/day, 78 times the maximum human oral dose.

Sodium chloride

Dilute sulphuric acid

Sodium hydroxide

Water for injections

Ventolin Concentrate Solution for Intravenous Infusion should only be admixed with those infusion solutions which are recommended (see Section 6.6 Instructions for Use and Handling).

Unopened: 3 years.

Chemical and physical in-use stability has been demonstrated for 24 hours at 20-25°C.

From a microbiological point of view, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

Do not store above 30°C. Keep the ampoules in the outer carton.

Ventolin Concentrate Solution for Intravenous Infusion is presented in a 5 ml colourless, neutral Type 1 glass ampoule and is available in boxes of 10 ampoules.

Dilute before use. Discard any unused contents.

The following infusion fluids are compatible with Ventolin Concentrate Solution for Intravenous Infusion:

5% w/v Dextrose Injection BP

0.9% w/v Sodium Chloride Injection BP

0.3% Potassium Chloride

0.18% Sodium Chloride and

4% w/v Dextrose Intravenous Infusion BP

Chemical and physical in-use stability has been demonstrated for 24 hours at 20-25°C.

From a microbiological point of view, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

GlaxoSmithKline (Ireland) Ltd.,

Stonemasons Way,

Rathfarnham,

Dublin 16

Trading as: Allen & Hanburys

PA 1077/49/2

5^th August 1983/5^th August 2003

July 2007