Bricanyl^® Respules^® 2.5 mg/ml Nebuliser Solution

Terbutaline sulphate 2.5mg/ml.

Each single dose respule contains 2ml (5mg).

For excipients see Section 6.1.

Sterile nebuliser solution.

A clear, aqueous, isotonic solution.

Terbutaline is a selective beta₂-adrenergic agonist recommended for the relief of severe bronchospasm in bronchial asthma and in chronic bronchitis and other bronchopulmonary disorders in which bronchospasm is a complicating factor.

In most patients, the use of terbutaline sulphate, based on the doses below, given 2-4 times daily will be sufficient to relieve bronchospasm. In acute, severe asthma, additional doses may be necessary.

Bricanyl Respules:

Adults: 1 or 2 Respules (5 or 10mg)

Children: (>25kg) 1 Respule (5mg)

Children: (<25kg) use multidose bottles.

Multidose Bottles:

Adults: 0.5 to 1 ml (5 to 10mg) diluted to required nebuliser volume with sterile physiological saline.

Children: 0.2 to 0.5ml (2 to 5mg), see table, diluted to required nebuliser volume with sterile physiological saline.

Table illustrating ml undiluted solution from multidose bottle required for administration to children

Elderly: Dosage as for adults.

Instructions for use and cleaning are provided in the Patient Information Leaflet which can be found in each pack.

Bricanyl preparations are contra-indicated in patients with a history of hypersensitivity to any of their constituents.

Patients should be instructed in proper use and their inhalation technique checked regularly.

If a previously effective dosage regimen no longer gives the same symptomatic relief, the patient should urgently seek further medical advice. Consideration should be given to the requirements for additional therapy (including increased dosages of anti-inflammatory medication). Severe exacerbations of asthma should be treated as an emergency in the usual manner.

As for all beta₂-agonists caution should be observed in patients with thyrotoxicosis.

Due to the positive inotropic effect of the beta₂-agonists, these drugs should not be used in patients with hypertrophic cardiomyopathy.

Cardiovascular effects may be seen with sympathomimetic drugs, including Bricanyl. 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 Bricanyl 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.

Due to the hyperglycaemic effects of beta₂-agonists, additional blood glucose controls are recommended initially in diabetic patients.

Potentially serious hypokalaemia may result from beta₂-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, Interactions). It is recommended that serum potassium levels are monitored in such situations.

Lactic acidosis has been reported in association with high therapeutic doses of parenteral and nebulised short-acting beta-agonist therapy, mainly in patients being treated for an acute asthma exacerbation (see Section 4.8 Undesirable effects & 4.9 Overdose). In patients not adequately responding to acute Bricanyl therapy, consideration should be given to the presence of lactic acidosis as a possible contributing factor to ongoing respiratory symptoms.

Beta-blocking agents (including eye drops), especially the non-selective ones such as propranolol, may partially or totally inhibit the effect of beta-stimulants. Therefore, Bricanyl preparations and non-selective beta-blockers should not normally be administered concurrently. Bricanyl should be used with caution in patients receiving other sympathomimetics.

Hypokalaemia may result from beta₂-agonist therapy and may be potentiated by concomitant treatment with xanthine derivatives, corticosteroids and diuretics (see Section 4.4, Special Warnings and Precautions for use).

Although no teratogenic effects have been observed in animals or in patients, Bricanyl should only be administered with caution during the first trimester of pregnancy.

Terbutaline is secreted via breast milk, but effect on the infant is unlikely at therapeutic doses.

None Known

The frequency of adverse reactions is low at the recommended dose. Terbutaline given by inhalation is unlikely to produce significant systemic effects when given in recommended doses. Most of the adverse reactions are characteristic of sympathomimetic amines. The majority of these effects have reversed spontaneously within the first 1-2 weeks of treatment.

The frequency of side-effects is low at the recommended doses.

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 (>1/1,000 and <1/100), rare (>1/10,000 and <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

# A few patients feel tense; this is also due to the effects on skeletal muscle and not to direct CNS stimulation.

^ Reported spontaneously in post-marketing data and therefore frequency regarded as unknown

* In rare cases, through unspecified mechanisms, paradoxical bronchospasm may occur, with wheezing immediately after inhalation. This should be immediately treated with a rapid-onset bronchodilator. Bricanyl therapy should be discontinued and after assessment, an alternative therapy initiated.

i) Possible symptoms and signs

Headache, anxiety, tremor, nausea, tonic cramp, palpitations, tachycardia and arrhythmia. A fall in blood pressure sometimes occurs. Laboratory findings; hypokalaemia, hyperglycaemia and metabolic acidosis sometimes occur (see Section 4.4. Special warnings and special precautions for use).

ii) Treatment

Mild and moderate cases: Reduce the dose.

Severe cases: Gastric lavage, administration of activated charcoal, (where suspected that significant amounts have been swallowed). Determination of acid-base balance, blood sugar and electrolytes, particularly serum potassium levels. Monitoring of heart rate and rhythm and blood pressure. Metabolic changes should be corrected. A cardioselective beta-blocker (e.g. metoprolol) is recommended for the treatment of arrhythmias causing haemodynamic deterioration. The beta-blocker should be used with care because of the possibility of inducing bronchoconstriction: use with caution in patients with a history of bronchospasm. If the beta-mediated reduction in peripheral vascular resistance significantly contributes to the fall in blood pressure, a volume expander should be given.

Pharmaco-therapeutic group: selective beta₂-agonist, terbutaline, ATC code: R03A C03.

Terbutaline is a selective beta₂-adrenergic stimulant, having the following pharmacological effects:-

i) In the lung: bronchodilation; increase in mucociliary clearance; suppression of oedema and anti-allergic effects.

ii) In skeletal muscle: stimulates Na⁺/K⁺ transport and also causes depression of subtetanic contractions in slow-contracting muscle.

iii) In uterine muscle: Inhibition of uterine contractions.

iv) In the C.N.S: Low penetration into the blood-brain barrier at therapeutic doses, due to the highly hydrophilic nature of the molecule.

v) In the C.V.S.: Administration of terbutaline results in cardiovascular effects mediated through beta₂-receptors in the peripheral arteries and in the heart e.g. in healthy subjects, 0.25 - 0.5 mg injected s.c., is associated with an increase in cardiac output (up to 85% over controls) due to an increase in heart rate and a larger stroke volume. The increase in heart rate is probably due to a combination of a reflex tachycardia, via a fall in peripheral resistance, and a direct positive chronotropic effect of the drug.

Basic parameters have been eva luated in man after i.v. and oral administration of therapeutic doses, e.g.

I.V. single dose

Volume distribution (VSS) - 114L

Total body clearance (CL) - 213 ml/min.

Mean residence time (MRT) - 9.0 h.

Renal clearance (CLR) - 149 ml/min.(males)

Oral dose

Renal clearance (CLR) - 1.925 ml/min. (males)

Renal clearance (CLR) - 2.32 ml/min. (females)

The plasma concentration/time curve after i.v. administration is characterised by a fast distribution phase, an intermediate elimination phase and a late elimination phase.

Terminal half-life t_½ has been determined after single and multiple dosing (mean values varied between 16-20 h.).

Bioavailability

Food reduces bioavailability following oral dosing (10% on average) fasting values of 14-15% have been obtained.

Metabolism

The main metabolite after oral dosing is the sulphate conjugate and also some glucoronide conjugate can be found in the urine.

The major toxic effect of terbutaline, observed in toxicological studies in rats and dogs at exposures in excess of maximum human exposure, is focal myocardial necrosis. This type of cardiotoxicity is a well known pharmacological manifestation seen after the administration of high doses of beta₂-agonists.

In rats, an increase in the incidence of benign uterine leiomyomas has been observed. This effect is looked upon as a class-effect observed in rodents after long term exposure to high doses of beta₂-agonists

Sodium chloride, disodium edetate, hydrochloric acid, water for injections.

None known.

36 months

Single dose units in an opened foil envelope should be used within 3 months.

Each single dose unit must be used within 24 hours after it is opened. Once the container has been opened, any remaining product cannot be regarded as sterile. This must be considered if the intention is to use the remaining content at a later occasion.

Do not store above 30°C.

Store in the original container.

Single dose, plastic units (Respules) in cartons of 20 Respules, as 4 strips of 5 units, each wrapped in a foil envelope.

Bricanyl Respules will not normally require dilution at recommended doses. The pH of Bricanyl Respules is 3-4.5.

If dilution is required use sterile normal saline.

AstraZeneca UK Limited

600 Capability Green

Luton

LU1 3LU

United Kingdom

PL 17901/0114

7^th May 2002 / 12^th May 2007

20^th November 2013