Bricanyl^® Tablets 5mg

Each tablet contains 5mg terbutaline sulphate.

For excipients see Section 6.1.

Tablet.

Off white, circular, biconvex tablet, engraved A/BT and scored on one side, symbol '5' on the reverse.

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

For the management of uncomplicated premature labour.

Use in bronchospasm: Bricanyl Tablets have a duration of action of 7 to 8 hours. The minimum recommended dosage interval is therefore 7 hours.

Adults: During the first 1 - 2 weeks, 2.5mg (half a tablet) 3 times in a 24-hour period is recommended. The dose may then be increased to 5mg (1 tablet) 3 times in a 24hour period to achieve adequate bronchodilation.

Elderly: Dosage as for Adults.

Children 7 - 15 years: The starting dose should normally be 2.5mg (half a tablet) 2 times in 24 hours. However, in some patients, the dose may need to be increased to 2.5mg 3 times in 24 hours.

Use in the management of premature labour: Oral treatment should not be used initially in an attempt to arrest premature labour. After uterine contractions have been controlled by intravenous infusion of Bricanyl Injection, (see Bricanyl Injection Summary of Product Characteristics) or subcutaneous injections (0.25mg, 4 times in a 24-hour period for a few days) maintenance therapy can be continued with oral treatment (5mg, 3 times in a 24-hour period). Oral treatment may be continued for as long as the physician considers it desirable to prolong pregnancy.

Bricanyl Tablets 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 Tablets are used in the management of uncomplicated premature labour, their use in the following conditions is contraindicated:

• any condition of the mother or foetus in which prolongation of the pregnancy is hazardous, e.g. severe toxaemia, ante-partum haemorrhage, intra-uterine infection, severe pre-eclampsia, abruptio placentae, threatened abortion during the 1st and 2nd trimesters, or cord compression.

Bricanyl Tablets 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 beta₂-agonists, these drugs should not be used in patients with hypertrophic cardiomyopathy.

Tocolysis

During infusion treatment in pregnant women with beta₂-stimulants in combination with corticosteroids, a rare complication with a pathological picture resembling pulmonary oedema has been reported.

Increased tendency to uterine bleeding has been reported in connection with Caesarean section. However, this can be effectively stopped by propranolol 12 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 effect on the infant is unlikely at therapeutic doses.

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

None

The intensity of the adverse reactions depends on dosage and route of administration. 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.

Possible symptoms and signs: Headache, anxiety, tremor, nausea, tonic cramp, palpitations, tachycardia, arrhythmia. A fall in blood pressure sometimes occurs. Laboratory findings: hypokalaemia, hyperglycaemia and lactic acidosis sometimes occur.

Treatment:

Mild and moderate cases: Reduce the dose.

Severe cases: Gastric lavage, administration of activated charcoal. Determination of acid-base balance, blood sugar and electrolytes, particularly serum potassium levels. Monitoring of the heart rate and rhythm and blood pressure. Metabolic changes should be corrected. A cardioselective β-blocker (e.g. metoprolol) is recommended for the treatment of arrhythmias causing haemodynamic deterioration. The βblocker 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 the peripheral vascular resistance significantly contributes to the fall in blood pressure, a volume expander should be given.

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 - 2mg 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; increased 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 of 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 beta₂-receptors in the peripheral arteries and in the heart e.g. in healthy subjects, 0.25 - 0.5mg 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

Volume distribution (vss): 114 L

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 iv 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

Lactose monohydrate, maize starch, povidone, microcrystalline cellulose and magnesium stearate.

None known.

4 years.

Do not store above 25°C.

Glass bottles and Securitainers of 100 and 500 tablets.

Not applicable

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

PL 17901/0116

28^th May 2002 / 15^th May 2007

30^th March 2009