Bricanyl^® Injection, 0.5 mg/ml, solution for injection or infusion.

Terbutaline sulphate 0.5 mg/ml.

For excipients see Section 6.1.

Solution for injection or infusion.

A clear aqueous solution.

Bronchodilation

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

For the management of uncomplicated premature labour

To arrest labour between 24 and 33 weeks of gestation in patients with no medical or obstetric contraindication to tocolytic therapy. The main effect of tocolytic therapy is a delay in delivery of up to 48 hours; no statistically significant effect on perinatal mortality or morbidity has as yet been observed in randomised, controlled trials. The greatest benefit from tocolytic therapy is gained by using the delay in delivery to administer glucocorticoids or to implement other measures known to improve perinatal health.

Routes of administration

Parenteral - subcutaneous, intramuscular, intravenous.

The dosage should be individualised.

For bronchodilation

When a rapid therapeutic response is required, Bricanyl can be administered by any of the three standard parenteral routes: subcutaneous, intramuscular, or i.v. bolus. The preferred routes will usually be subcutaneous or intramuscular. When given as an i.v. bolus the injection must be made slowly noting patient response.

Adults:0.5 - 1 ml (0.25 - 0.5 mg) up to four times a day.

Children 2 - 15 years: 0.01 mg/kg body weight to a maximum of 0.3 mg total.

By infusion: 3 - 5 ml (1.5 - 2.5 mg) in 500 ml 5% dextrose, saline or dextrose/saline given by continuous intravenous infusion at a rate of 10 - 20 drops (0.5 - 1 ml) per minute for 8 to 10 hours. A corresponding reduction in dosage should be made for children.

Elderly: Dosage as for adults.

For the management of premature labour

Procedure: To be administered as early as possible after the diagnosis of premature labour, and after evaluation of the patient to rule out contraindications to the use of terbutaline (see Section 4.3, Contraindications).

Initially, 5 mcg/min should be infused during the first 20 minutes increasing by 2.5 mcg/min at 20 minute intervals until the contractions stop. More than 10 mcg/min should seldom be given, 20 mcg/min should not be exceeded.

The infusion should be stopped if labour progresses despite treatment at the maximum dose.

If successful, the infusion should continue for 1 hour at the chosen rate and then be decreased by 2.5 mcg/min every 20 minutes to the lowest dose that produces suppression of contractions. Keep the infusion at this rate for 12 hours and then continue with oral maintenance therapy.

As an alternative, subcutaneous injections of 250 mcg should be given four times a day for a few days before oral treatment is commenced. Oral treatment may be continued for as long as the physician considers it desirable to prolong pregnancy.

Special cautions for infusion: The dose must be individually titrated with reference to suppression of contractions, increase in pulse rate and changes in blood pressure, which are limiting factors. These parameters should be carefully monitored during treatment. A maternal heart rate of more than 135 beats/min should be avoided.

Careful control of the level of hydration is essential to avoid the risk of maternal pulmonary oedema (see Section 4.8, Undesirable effects). The volume of fluid in which the drug is administered should thus be kept to a minimum. A controlled infusion device should be used, preferably a syringe pump.

Dilution:

The recommended infusion fluid is 5% dextrose. If a syringe pump is available, the concentration of the drug infused should be 0.1 mg/ml (10 ml Bricanyl Injection should be added to 40 ml of 5% dextrose).

At this dilution:

5 mcg/min 0.05 ml/min and

10 mcg/min 0.1 ml/min

If no syringe pump is available, the concentration of the drug should be 0.01 mg/ml (10 ml Bricanyl Injection should be added to 490 ml of 5% dextrose).

At this dilution:

5 mcg/min 0.5 ml/min and

10 mcg/min 1 ml/min.

Bricanyl solution for injection 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.

Although Bricanyl solution for injection is used in the management of uncomplicated premature labour, use in the following conditions is contra-indicated: -

Bricanyl solution for injection should not be used in patients with a history of hypersensitivity to any of the ingredients.

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

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

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

Tocolysis

Bricanyl 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. Bricanyl should not be used as a tocolytic agent in patients with significant risk factors for or pre-existing heart disease (see section 4.3, Contraindications).

In premature labour in a patient with known or suspected cardiac disease, a physician experienced in cardiology should assess the suitability of treatment before intravenous infusion with Bricanyl.

In order to minimise the risk of hypotension associated with tocolytic therapy, special care should be taken to avoid caval compression by keeping the patient in the left or right lateral positions throughout the infusion.

In treatment of premature labour, hyperglycaemia and ketoacidosis have been found in pregnant women with diabetes after treatment with beta₂-agonists. It may therefore be necessary to adjust the insulin dose when beta₂-agonists are used in the treatment.

Increased tendency to uterine bleeding has been reported in connection with Caesarian section. However, this can be effectively stopped by propranolol 1-2 mg injected intravenously.

Respiratory indications

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.

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.

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 into breast milk, but any effects on the infant are unlikely at therapeutic doses.

Transient hypoglycaemia has been reported in newborn preterm infants after maternal beta₂-agonist treatment.

Bricanyl does not affect the ability to drive or use machines.

The intensity of the adverse reactions depends on dosage and route of administration. An initial dose titration will often reduce the adverse reactions. 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).

Bronchial asthma. Chronic bronchitis, emphysema and other lung diseases where bronchospasm is a complicating factor.

^# 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.

Preterm labour

# 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.

During treatment of preterm labour, when high doses of Bricanyl are used, diabetic mothers may develop hyperglycaemia and lactacidosis. In these patients glucose and acid-base balance should be carefully monitored. High doses of beta₂-stimulants may cause hypokalaemia as a result of redistribution of potassium. Symptoms of pulmonary oedema have also been reported following treatment of preterm labour, in some cases this has proved fatal. Predisposing factors include fluid overload, multiple pregnancy, pre-existing cardiac disease and maternal infection. Close monitoring of the patient's state of hydration is essential. If signs of pulmonary oedema develop (e.g. cough, shortness of breath), treatment should be discontinued immediately and diuretic therapy instituted.

An increased tendency to bleeding has been described in connection with caesarean section (give propranolol, 1-2 mg i.v.) in patients treated with Bricanyl for preterm labour

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 lactic acidosis sometimes occur.

ii) Treatment:

Mild and moderate cases: Reduce the dose.

Severe cases: 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 beta₂-mediated reduction in peripheral vascular resistance significantly contributes to the fall in blood pressure, a volume expander should be given.

In preterm labour:

Pulmonary oedema: discontinue administration of Bricanyl. A normal dose of loop diuretic (e.g. frusemide) should be given intravenously.

Increased bleeding in connection with Caesarian section: propranolol, 1 - 2 mg intravenously.

Pharmaco-therapeutic group: selective beta₂-agonist, terbutaline, ATC code: R03C 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 CNS: low penetration into the blood-brain barrier at therapeutic doses, due to the highly hydrophilic nature of the molecule.

v) In the CVS: administration of terbutaline results in cardiovascular effects mediated through β₂-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 evaluated in man after i.v. and oral administration of therapeutic doses, e.g.

i.v. single dose

Oral dose

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 glucuronide 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, hydrochloric acid and water for injection.

Bricanyl solution for injection should not be mixed with alkaline solutions, i.e. solutions with a pH higher than 7.0.

24 months

Do not store above 25°C. Keep in the outer carton.

Packs of 5 x 1ml glass ampoules

Packs of 10 x 5ml glass ampoules

Bronchodilation: the recommended diluent is 5% dextrose, saline or dextrose/saline.

In the management of premature labour, the recommended infusion fluid is 5% dextrose. Saline should be avoided due to the risk of pulmonary oedema. If saline is used, the patient should be carefully monitored.

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

PL 17901/0112

7^th May 2002 / 12^th May 2007

30^th March 2009