Selective beta 2 agonists

3 Respiratory system

3.1 Bronchodilators

3.1.1 Adrenoceptor agonists (Sympathomimetics)

3.1.1.1 Selective beta 2 agonists

3.1.1

Adrenoceptor agonists

Inhalation A pressurised metered-dose inhaler is an effective method of drug administration in mild to moderate chronic asthma; to deliver the drug effectively particularly in children under 12 years, a spacer device should be used (see also NICE guidance, section 3.1.5). When a pressurised metered-dose inhaler with a spacer is unsuitable or inconvenient, a dry-powder inhaler or breath-actuated inhaler may be used instead if the child is able to use the device effectively. At recommended inhaled doses the duration of action of salbutamol and terbutaline is about 3 to 5 hours and for salmeterol and formoterol is about 12 hours. The dose, the frequency, and the maximum number of inhalations in 24 hours of the beta₂agonist should bestated explicitly to the child and the child’s carer. High doses of beta₂agonists can be dangerous in some children (see Cautions, below).

Excessive use is usually an indication ofinadequately controlled asthma and should be managed with a prophylactic drug such as an inhaled corticosteroid.

The child and the child’s carer should be advised to seek medical advice when the prescribed dose of beta₂agonist fails to provide the usual degree of symptomatic relief because this usually indicates a worsening of the asthma and the child may require alternative medication (see Management of Chronic Asthma, p. 170).

Children and their carers should be advised to follow manufacturers’ instructions on the care and cleansing of inhaler devices.

CFC-free inhalers Chlorofluorocarbon (CFC) propellants in pressurised metered-dose inhalers are being replaced by hydrofluoroalkane (HFA) propellants. Chil-dren receiving CFC-free inhalers and their carers should be reassured about the efficacy of the new inhalers and counselled that the aerosol may feel and taste different to their previous CFC-based inhaler; any difficulty with the new inhaler should be discussed with the doctor or pharmacist.

Nebuliser (or respirator) solutions of salbutamol and terbutaline are used for the treatment of severe acute asthma both in hospital and in general practice.

Children with a severe attack of asthma should have oxygen if possible during nebulisation since beta₂ agonists can increase arterial hypoxaemia, see also section 3.1.5.

Oral Oral preparations of beta₂agonists may be used for children if an inhaler device cannot be used but inhaled beta₂agonists are more effective and have fewer side-effects. A modified-release formulation of salbutamol may be of value in nocturnal asthma as an alternative to modified-release theophylline prepara-tions (section 3.1.3), but an inhaled long-acting beta₂agonist is preferable.

Parenteral Beta₂agonists can be given intravenously in children with severe or life-threatening acute asthma. Chronic asthma unresponsive to stepwise treat-ment (see Managetreat-ment of Chronic Asthma, p. 170) may benefit from continuous subcutaneous infusion of a beta₂agonist but this should be used only under the supervision of a respiratory specialist; the evidence of benefit is uncertain and it may be difficult to withdraw such treatment once started.

Cautions Beta₂ agonists should be used with caution in diabetes—monitor blood glucose (risk of ketoacidosis, especially when a beta2 agonist is given intravenously). Beta₂agonists should also be used with caution in hyperthyroid-ism, cardiovascular disease, arrhythmias, susceptibility to QT-interval prolonga-tion, and hypertension. If high doses of beta₂ agonists are needed during pregnancy they should be given by inhalation because a parenteral beta₂agonist can affect the myometrium and possibly cause cardiac problems; see also Pregnancy and Breast-feeding, section 3.1.Interactions: Appendix 1 (sympatho-mimetics, beta₂).

Hypokalaemia The CSM has advised that potentially serious hypokalaemia may result from beta₂agonist therapy. Particular caution is required in severe asthma, because this effect may be potentiated by concomitant treatment with theo-phylline and its derivatives, corticosteroids, and diuretics, and by hypoxia.

Plasma-potassium concentration should therefore be monitored in severe asthma.

Side-effects Side-effects of the beta₂agonists include fine tremor (particularly in the hands), nervous tension, headache, peripheral dilatation and palpitation.

Other side-effects include tachycardia, arrhythmias, peripheral vasodilation, myo-cardial ischaemia, and disturbances of sleep and behaviour. Muscle cramps and

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hypersensitivity reactions including paradoxical bronchospasm (occasionally severe), urticaria, angioedema, hypotension, and collapse have also been reported. High doses of beta₂ agonists are associated with hypokalaemia (for CSM advice, see Hypokalaemia, p. 173).

FORMOTEROL FUMARATE

(Eformoterol fumarate) Cautions see notes above

Hepatic impairment metabolism possibly reduced in severe cirrhosis

Pregnancy see section 3.1 (manufacturers advise use only if potential benefit outweighs risk) Breast-feeding amount in milk probably too small to be harmful but manufacturers advise avoid Side-effects see notes above; nausea, dizziness,

rash, taste disturbances, and pruritus also reported

Indication and dose

Reversible airways obstruction (including nocturnal asthma and prevention of exercise-induced bronchospasm) in patients requiring long-term regular bronchodilator therapysee also Management of Chronic Asthma, p. 170; for dose see preparations below

CounsellingAdvise children and carers not to exceed prescribed dose, and to follow manufacturer’s directions;

if a previously effective dose of inhaled formoterol fails to provide adequate relief, a doctor’s advice should be obtained as soon as possible

Formoterol(Non-proprietary)A

Dry powder for inhalation, formoterol fumarate 12 micrograms/metered inhalation, net price 120-dose unit = £24.80. Counselling, 120-dose

Brands include Easyhaler^cFormoterol Dose

Chronic asthma . By inhalation of powder

Child 6–18 years12 micrograms twice daily, increased to 24 micrograms twice daily in more severe airways obstruction

Atimos Modulite^c(Chiesi)T A

Aerosol inhalation, formoterol fumarate 12 micr-ograms/metered inhalation, net price 100-dose unit = £31.28. Counselling, dose

Dose

Chronic Asthma . By aerosol inhalation

Child 12–18 years12 micrograms twice daily, increased to max. 24 micrograms twice daily in more severe airways obstruction

Foradil^c(Novartis)A

Dry powder for inhalation, formoterol fumarate 12 micrograms/capsule, net price 60-cap pack (with inhaler device) = £29.23. Counselling, dose Dose

Chronic asthma . By inhalation of powder

Child 5–18 years12 micrograms twice daily, increased to 24 micrograms twice daily in more severe airways obstruction

Oxis^c(AstraZeneca)A

Turbohaler^c(= dry powder inhaler), formoterol fumarate 6 micrograms/inhalation, net price dose unit = £24.80; 12 micrograms/inhalation, 60-dose unit = £24.80. Counselling, 60-dose

Dose

Chronic asthma . By inhalation of powder

Child 6–18 years6–12 micrograms 1–2 times daily;

occasionally up to 48 micrograms daily may be needed (max. single dose 12 micrograms); reassess treatment if additional doses required on more than 2 days a week

Relief of bronchospasm . By inhalation of powder

Child 6–18 years6–12 micrograms

Prevention of exercise-induced bronchospasm . By inhalation of powder

Child 6–18 years6–12 micrograms before exercise

Compound preparations

Forcompound preparations containing formo-terol, see section 3.2

SALBUTAMOL

(Albuterol)

Cautions see notes above Side-effects see notes above

Licensed use not licensed for use in hyperkal-aemia; syrup not licensed for use in children under 2 years; modified-release tablets not licensed for use in children under 3 years; injec-tion not licensed for use in children; Pulvinal^c Salbutamol not licensed for use in children under 6 years

Indication and dose Acute asthma

. By aerosol or nebulised solution inhalation See Management of Acute Asthma, p. 168 . By intravenous injection over 5 minutes (see

also Management of Acute Asthma, p. 168) Child 1 month–2 years5 micrograms/kg as a single dose

Child 2–18 years15 micrograms/kg (max.

250 micrograms) as a single dose

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. By continuous intravenous infusion Child 1 month–18 years1–2 micrograms/kg/

minute, adjusted according to response and heart rate up to 5 micrograms/kg/minute;

doses above 2 micrograms/kg/minute should be given in an intensive care setting

Exacerbations of reversible airways obstruction (including nocturnal asthma) and prevention of allergen- or exercise-induced bronchospasm, see also Management of Chronic Asthma, p. 170 . By aerosol inhalation

Child 1 month–18 years100–200 micrograms (1–2 puffs); for persistent symptoms up to 4 times daily

. By inhalation of powder

(for Asmasal Clickhaler^c, Salbulin Novolizer^c, and Ventolin Accuhaler^cdoses, see under prepara-tions)

Child 5–12 years200 micrograms; for persis-tent symptoms up to 4 times daily Child 12–18 years200–400 micrograms; for persistent symptoms up to 4 times daily . By mouth (but use by inhalation preferred)

Child 1 month–2 years100 micrograms/kg (max. 2 mg) 3–4 times daily

Child 2–6 years1–2 mg 3–4 times daily Child 6–12 years2 mg 3–4 times daily Child 12–18 years4 mg (sensitive patients initially 2 mg) 3–4 times daily; max. single dose 8 mg (but unlikely to provide extra benefit or to be tolerated)

Severe hyperkalaemia (section 9.2.1.1) . By intravenous injection over 5 minutes

Neonate4 micrograms/kg as a single dose;

repeat if necessary

Child 1 month–18 years4 micrograms/kg as a single dose; repeat if necessary

. By inhalation of nebulised solution (but intra-venous injection preferred)

Neonate2.5–5 mg as a single dose; repeat if necessary

Child 1 month–18 years2.5–5 mg as a single dose; repeat if necessary

Administration for continuous intravenous infusion, dilute to a concentration of 200 micrograms/mL with Glucose 5%, Sodium Chloride 0.9%, or Water for injections; if fluid-restricted, can be given undiluted through central venous catheter.

For intravenous injection, dilute to a concentration of 50 micrograms/mL with Glucose 5%, Sodium Chloride 0.9%, or Water for injections For nebulisation, dilute nebuliser solution with a suitable volume of sterile Sodium Chloride 0.9%

solution according to nebuliser type and duration of administration; salbutamol and ipratropium bromide solutions are compatible and can be mixed for nebulisation.

Oral

Salbutamol(Non-proprietary)A

Tablets, salbutamol (as sulphate) 2 mg, net price 28-tab pack = £12.71; 4 mg, 28-tab pack = £12.20 Oral solution, salbutamol (as sulphate) 2 mg/5 mL, net price 150 mL = £1.27

Brands include Salapin^c(sugar-free)

Ventmax^cSR(Chiesi)A

Capsules, m/r, salbutamol (as sulphate) 4 mg (green/grey), net price 56-cap pack = £8.57; 8 mg (white), 56-cap pack = £10.28. Label: 25 Dose

Chronic asthma(but see notes above) . By mouth

Child 3–12 years4 mg twice daily Child 12–18 years8 mg twice daily

Ventolin^c(A&H)A

Syrup, sugar-free, salbutamol (as sulphate) 2 mg/

5 mL, net price 150 mL = 60p

Parenteral Ventolin^c(A&H)A

Injection, salbutamol (as sulphate) 500 micr-ograms/mL, net price 1-mL amp = 40p Solution for intravenous infusion, salbutamol (as sulphate) 1 mg/mL. Dilute before use. Net price 5-mL amp = £2.58

Inhalation

CounsellingAdvise children and carers not to exceed prescribed dose and to follow manufacturer’s directions; if a previously effective dose of inhaled salbutamol fails to provide at least 3 hours relief, a doctor’s advice should be obtained as soon as possible.

Patients receiving CFC-free inhalers should be reassured about their efficacy and counselled that aerosol may feel and taste different (see notes above)

Salbutamol(Non-proprietary)A

Aerosol inhalation, salbutamol 100 micrograms/

metered inhalation, net price 200-dose unit = £2.88.

Counselling, dose Excipientsinclude CFC propellants

Aerosol inhalation, salbutamol (as sulphate) 100 micrograms/metered inhalation, net price 200-dose unit = £2.99. Counselling, 200-dose, change to CFC-free inhaler

Excipientsinclude HFA-134a (a non-CFC propellant) Brands include Salamol^c

NoteCan be supplied against a generic prescription but if CFC-free not specified will be reimbursed at price for CFC-containing inhaler

Dry powder for inhalation, salbutamol 100 micr-ograms/metered inhalation, net price 200-dose unit = £3.46; 200 micrograms/metered inhalation, 100-dose unit = £5.05, 200-dose unit = £6.92.

Counselling, dose

Brands include Easyhaler^cSalbutamol, Pulvinal^c Salbut-amol

Inhalation powder, hard capsule (for use with Cyclohaler^cdevice), salbutamol 200 micrograms, net price 120-cap pack = £8.99; 400 micrograms, 120-cap pack = £12.99. Counselling, dose Brands include Salbutamol Cyclocaps^c

SALBUTAMOL (continued)

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Nebuliser solution, salbutamol (as sulphate) 1 mg/

mL, net price 20 2.5 mL (2.5 mg) = £1.99; 2 mg/

mL, 20 2.5 mL (5 mg) = £3.98. May be diluted with sterile sodium chloride 0.9%

Brands include Salamol Steri-Neb^c

Airomir^c(IVAX)A

Aerosol inhalation, salbutamol (as sulphate) 100 micrograms/metered inhalation, net price 200-dose unit = £1.97. Counselling, 200-dose, change to CFC-free inhaler

Excipientsinclude HFA-134a (a non-CFC propellant) NoteCan be supplied against a generic prescription but if

‘CFC-free’ not specified will be reimbursed at price for CFC-containing inhaler

Autohaler(breath-actuated aerosol inhalation), salbutamol (as sulphate) 100 micrograms/metered inhalation, net price 200-dose unit = £6.02. Coun-selling, dose, change to CFC-free inhaler Excipientsinclude HFA-134a (a non-CFC propellant),

Asmasal Clickhaler^c(UCB Pharma)A

Dry powder for inhalation, salbutamol (as sulphate) 95 micrograms/metered inhalation, net price 200-dose unit = £5.88. Counselling, 200-dose

Dose

Acute bronchospasm . By inhalation of powder

Child 5–18 years1–2 puffs; for persistent symptoms up to 4 times daily (but see also Management of Chronic Asthma, p. 170)

Prophylaxis of allergen- or exercise-induced bron-chospasm

. By inhalation of powder Child 5–18 years1–2 puffs

Salamol Easi-Breathe^c(IVAX)A

Aerosol inhalation, salbutamol 100 micrograms/

metered inhalation, net price 200-dose breath-actuated unit = £6.30. Counselling, dose Excipientsinclude HFA-134a (a non-CFC propellant)

Salbulin Novolizer^c(Meda)A

Dry powder for inhalation, salbutamol (as sulphate) 100 micrograms/metered inhalation, net price refillable 200-dose unit = £4.95; 200-dose refill =

£2.75. Counselling, dose Dose

Acute bronchospasm . By inhalation of powder

Child 6–12 years100-200 micrograms; for persistent symptoms up to 400 micrograms daily (but see also Management of Chronic Asthma, p. 170) Child 12–18 years100-200 micrograms; for persistent symptoms up to 800 micrograms daily (but see also Management of Chronic Asthma, p. 170)

Prophylaxis of allergen- or exercise-induced bron-chospasm

. By inhalation of powder

Child 6–12 years100–200 micrograms Child 12–18 years200 micrograms

Ventolin^c(A&H)A

Accuhaler^c(dry powder for inhalation), disk con-taining 60 blisters of salbutamol (as sulphate) 200 micrograms/blister with Accuhaler^cdevice, net price = £5.12. Counselling, dose

Dose

Acute bronchospasm . By inhalation of powder

Child 5–18 years200 micrograms; for persistent symptoms up to 4 times daily but see also Manage-ment of Chronic Asthma, p. 170

Prophylaxis of allergen- or exercise-induced bron-chospasm

. By inhalation of powder Child 5–18 years200 micrograms

Evohaler^caerosol inhalation, salbutamol (as sul-phate) 100 micrograms/metered inhalation, net price 200-dose unit = £1.50. Counselling, dose, change to CFC-free inhaler

Excipientsinclude HFA-134a (a non-CFC propellant) NoteCan be supplied against a generic prescription but if CFC-free not specified will be reimbursed at price for CFC-containing inhaler

Nebules^c(for use with nebuliser), salbutamol (as sulphate) 1 mg/mL, net price 20 2.5 mL (2.5 mg)

= £1.75; 2 mg/mL, 20 2.5 mL (5 mg) = £2.95. May be diluted with sterile sodium chloride 0.9%

Respirator solution(for use with a nebuliser or ventilator), salbutamol (as sulphate) 5 mg/mL. Net price 20 mL = £2.27 (hosp. only). May be diluted with sterile sodium chloride 0.9%

SALMETEROL

NoteNot for immediate relief of acute attacks; existing corticosteroid therapy should not be reduced or with-drawn

Cautions see notes above

Side-effects see notes above; nausea, dizziness, arthralgia, and rash also reported

Indication and dose

Reversible airways obstruction (including nocturnal asthma and prevention of exercise-induced bronchospasm) in patients requiring long-term regular bronchodilator therapysee also Management of Chronic Asthma, p. 170 . By inhalation

Child 5–12 years50 micrograms (2 puffs or 1 blister) twice daily

SALBUTAMOL (continued)

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Child 12–18 years50 micrograms (2 puffs or 1 blister) twice daily; up to 100 micrograms (4 puffs or 2 blisters) twice daily in more severe airways obstruction

CounsellingAdvise children and carers that sal-meterol shouldnot be used for relief of acute attacks, not to exceed prescribed dose, and to follow manu-facturer’s directions; if a previously effective dose of inhaled salmeterol fails to provide adequate relief, a doctor’s advice should be obtained as soon as possible

Serevent^c(A&H)A

Accuhaler^c(dry powder for inhalation), disk con-taining 60 blisters of salmeterol (as xinafoate) 50 micrograms/blister with Accuhaler^cdevice, net price = £29.26. Counselling, dose

Evohaler^caerosol inhalation, salmeterol (as xinafoate) 25 micrograms/metered inhalation, net price 120-dose unit = £29.26. Counselling, dose, change to CFC-free inhaler

Excipientsinclude HFA-13Ha (a non-CFC propellant) Diskhaler^c(dry powder for inhalation), disks con-taining 4 blisters of salmeterol (as xinafoate) 50 micrograms/blister, net price 15 disks with Dis-khaler^cdevice = £35.79, 15-disk refill = £35.15.

Counselling, dose, change to CFC-free inhaler Compound preparations

Forcompound preparations containing sal-meterol, see section 3.2

TERBUTALINE SULPHATE

Cautions see notes above Side-effects see notes above

Licensed use tablets not licensed for use in chil-dren under 7 years; injection not licensed for use in children under 2 years

Indication and dose Acute asthma

. By inhalation of nebulised solution see Management of Acute Asthma, p. 168 . By subcutaneous or slow intravenous injection

Child 2–15 years10 micrograms/kg (max.

300 micrograms) up to 4 times daily Child 15–18 years250–500 micrograms up to 4 times daily

. By continuous intravenous infusion Child 1 month–18 yearsinitially 2–4 ograms/kg as a loading dose, then 1–10 micr-ograms/kg/hour according to response and heart rate (doses above 10 micrograms/kg/

hour with close monitoring)

Exacerbations of reversible airways obstruction (including nocturnal asthma) and prevention of exercise-induced bronchospasmsee Manage-ment of Chronic Asthma, p. 170

. By inhalation of powder

Child 5–18 years500 micrograms (1 inhalation) up to 4 times daily (for occasional use only) . By mouth (but not recommended)

Child 1 month–7 years75 micrograms/kg (max. 2.5 mg) 3 times daily

Child 7–15 years2.5 mg 2–3 times daily Child 15–18 yearsinitially 2.5 mg 3 times daily, increased if necessary to 5 mg 3 times daily

Administration For continuous intravenous infusion, dilute to a concentration of 5 micrograms/mL with Glucose 5% or Sodium Chloride 0.9%; if fluid-restricted, dilute to a concentration of 100 micrograms/mL

For nebulisation, dilute nebuliser solution with sterile Sodium Chloride 0.9% solution according to nebuliser type and duration of administration;

terbutaline and ipratropium bromide solutions are compatible and may be mixed for nebulisa-tion.

Oral and parenteral Bricanyl^c(AstraZeneca)A

Tablets, scored, terbutaline sulphate 5 mg, net price 20 = 82p

Syrup, sugar-free, terbutaline sulphate 1.5 mg/

5 mL, net price 100 mL = £2.00

Injection, terbutaline sulphate 500 micrograms/

mL, net price 1-mL amp = 30p; 5-mL amp = £1.40 Inhalation

CounsellingAdvise children and carers not to exceed prescribed dose and to follow manufacturer’s directions; if a previously effective dose of inhaled terbutaline fails to provide at least 3 hours relief, a doctor’s advice should be obtained as soon as possible

Bricanyl^c(AstraZeneca)A

Turbohaler^c(= dry powder inhaler), terbutaline sulphate 500 micrograms/metered inhalation, net price 100-dose unit = £6.92. Counselling, dose Respules^c(= single-dose units for nebulisation), terbutaline sulphate 2.5 mg/mL, net price 20 2-mL units (5-mg) = £4.04