This information is intended for use by health professionals

1. Name of the medicinal product

Bricanyl Respules 2.5 mg/ml Nebuliser Solution

2. Qualitative and quantitative composition

Terbutaline sulfate 2.5mg/ml.

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

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Sterile nebuliser solution.

A clear, aqueous, isotonic solution.

4. Clinical particulars
4.1 Therapeutic indications

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.

4.2 Posology and method of administration

Posology

When used as maintenance therapy the patient should also receive optimal anti-inflammatory therapy, e.g. inhaled corticosteroids, leukotriene receptor antagonists.

In most patients, the use of terbutaline sulfate, 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:

Children:

Children:

1 or 2 Respules (5 or 10mg)

(>25kg) 1 Respule (5mg)

(<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

Age

Average kg

weight lb

mg terbutaline

ml undiluted solution

<3

10

22

2.0

0.2

3

15

33

3.0

0.3

6

20

44

4.0

0.4

8+

25+

55+

5.0

0.5

Elderly: Dosage as for adults.

Method of administration

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

4.3 Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

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

Patients with persistent asthma who require maintenance therapy with beta2-agonists should also receive optimal anti-inflammatory therapy e.g. inhaled corticosteroids, leukotriene receptor antagonists. These patients must be advised to continue taking their anti-inflammatory therapy after the introduction of Bricanyl even when symptoms decrease. Should symptoms persist, or if treatment with beta2-agonists needs to be increased, this indicates a worsening of the underlying condition and warrants a reassessment of the therapy. 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). 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 & 4.9). 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.

4.5 Interaction with other medicinal products and other forms of interaction

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.

Halogenated anaesthetics

Halothane anaesthesia should be avoided during Beta2-agonists treatment, since it increases the risk of cardiac arrhythmias. Other halogenated anaesthetics should be used cautiously together with Beta2-agonists.

Potassium depleting agents and hypokalemia

Owing to the hypokalaemic effect of beta-agonists, concurrent administration with Bricanyl 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.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

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.

If used in maintenance therapy for asthma and other pulmonary diseases, Bricanyl respules should be used with caution at the end of pregnancy because of the potential tocolytic effect.

Breast-feeding

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of safety profile

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.

Tabulated list of adverse reaction

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

System Organ Class (SOC)

Frequency Classification

Adverse Drug Reaction

Preferred term (PT)

Immune system disorders

Not known^

Hypersensitivity reactions including angioedema, bronchospasm, hypotension and collapse

Metabolism and nutritional disorders

Common

Hypokalaemia (See section 4.4)

Not known^

Lactic acidosis

Psychiatric disorders

Not known^

Sleep disorder and Behavioural disturbances, such as agitation and restlessness

Nervous system disorders

Very Common

Tremor

Headache

Cardiac disorders

Common

Tachycardia

Palpitations

Not known^

Arrhythmias, e.g. atrial fibrillation, supraventricular tachycardia and extrasystoles

Myocardial ischaemia (See section 4.4)

Vascular disorders

Not known^

Peripheral vasodilation

Respiratory, thoracic and mediastinal Disorders

Not known^

Paradoxical bronchospasm*

Gastrointestinal disorders

Not known^

Nausea

Mouth and throat irritation

Skin and subcutaneous tissue disorders

Not known^

Urticaria

Rash

Musculoskeletal and connective tissue disorders#

Common

Muscle spasms

# 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.

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

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).

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: selective beta2-adrenoreceptor agonists, 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.

5.2 Pharmacokinetic properties

Basic parameters have been evaluated 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 t½ 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 sulfate conjugate and also some glucoronide conjugate can be found in the urine.

5.3 Preclinical safety data

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

6. Pharmaceutical particulars
6.1 List of excipients

Sodium chloride

Disodium edetate

Hydrochloric acid

Water for injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

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.

6.4 Special precautions for storage

Do not store above 30°C.

Store in the original container.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

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

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

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.

7. Marketing authorisation holder

AstraZeneca UK Limited

600 Capability Green,

Luton, LU1 3LUUnited Kingdom

8. Marketing authorisation number(s)

PL 17901/0114

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 7th May 2002

Date of latest renewal: 12th May 2007

10. Date of revision of the text

11th April 2017