Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://emc.medicines.org.uk), or the British National Formulary (BNF) (www.bnf.org).

• Inhaled short-acting beta₂-agonists should be used as required unless an individual has shown to benefit from regular use:
• As-required use of short-acting beta₂-agonists is at least as effective as regular administration [SIGN and BTS, 2009] and is less likely to result in tolerance.
• Inhaled short-acting beta₂-agonists have minimal adverse effects. Overuse can cause tremor, tension, headache, muscle cramps, and palpitations [BNF 53, 2007]. Hypokalaemia may result from high doses of inhaled beta₂-agonists (or oral beta₂-agonists); this may be potentiated by concomitant treatment with theophylline, corticosteroids, diuretics, and by hypoxia. The Committee on the Safety of Medicines has advised that plasma potassium should be monitored in people with severe asthma [CSM, 1990].
• There is some evidence from post-marketing data and published literature of myocardial ischaemia associated with short-acting beta₂-agonists. The MHRA has issued advice that people with a history of heart disease, including angina or rhythm disturbance, should seek medical advice if symptoms such as shortness of breath or chest pain occur, as these may indicate worsening heart disease [MHRA, 2007].

• The various inhaled corticosteroids (ICS) do not seem to differ in efficacy (assuming a potency ratio of beclometasone and fluticasone of 2:1).
• Adverse effects are class effects and do not differ significantly between the different inhaled corticosteroids at either low or high doses. Increased doses of ICS are associated with an increased risk of local and systemic adverse effects.
• CKS recommends beclometasone, budesonide, or fluticasone because they are available in a range of formulations at different doses and for a range of ages.
• Ciclesonide (available as a pressurized metered-dose inhaler) and mometasone (available as a dry-powder inhaler) are once-daily alternatives. Neither drug is licensed for children younger than 12 years. Mometasone has black triangle status and further post-marketing data are needed to confirm its safety.

• Use the lowest dose of inhaled corticosteroid (ICS) that maintains effective control of asthma.
• Start ICS at a dose appropriate to the severity of symptoms [SIGN and BTS, 2009]:
• Suitable starting doses for beclometasone-CFC free as Clenil Modulite^® are:
• Age > 12 years: 200 micrograms twice daily.
• Age 5–12 years: 100 micrograms twice daily.
• Age < 5 years: 100 micrograms twice daily; higher doses may be required to ensure adequate drug delivery.
• If beclometasone CFC-free is started as Qvar^® use half the dose listed above (licensed only for age > 12 years).
• Table 1 and Table 2 show comparable total daily doses of ICS.
• Higher doses of ICS may be needed in people who smoke. At low doses, smokers with mild persistent asthma are less sensitive than non-smokers to the therapeutic effects of ICS treatment. This disparity is reduced at high doses of ICS [Tomlinson et al, 2005].
• Treatment with ICS should initially be twice a day (except ciclesonide, which is licensed for once-a-day use) [SIGN and BTS, 2009]:
• Most ICS are slightly more effective when used twice rather than once a day, but people with milder disease may use them once a day. There is little evidence of benefit for administration more frequently than twice a day.
• Once-daily inhalation of ICS at the same total daily dose, within the product license, may be considered if good control is established.
• Prescribe CFC-free beclometasone inhalers by brand name (Clenil Modulite^® or Qvar^®) [MHRA, 2006a]. They are not equivalent and must not be interchanged.
• When changing from a CFC pMDI to a CFC-free pMDI [BNF 53, 2007; SIGN and BTS, 2009]:
• Clenil Modulite^® may be substituted for beclometasone CFC pMDI at 1:1 dosing.
• Qvar^® may be substituted for beclometasone CFC pMDI at 1:2 dosing if asthma is well controlled, but consider 1:1 dosing if asthma is poorly controlled. Monitor the person closely to ensure that adequate control is maintained.
• CFC-free budesonide may be substituted for budesonide CFC pMDI at 1:1 dosing.

• Comparable doses of inhaled corticosteroids are shown in Table 1 (adults and children > 12 years of age) and Table 2 (children).
• Beclometasone inhalers that contain chlorofluorocarbons (CFC) have been phased out and are no longer available.

• Take into account the use of other systemic or topical corticosteroids when assessing risk.
• Elderly people and children may be particularly susceptible to adverse effects.

Local adverse effects:

• Oral candidiasis, sore mouth, dysphonia, and hoarseness are commonly recognized problems with inhaled corticosteroid (ICS) use, especially in high doses:
• For people using a pressurized metered-dose inhaler, these effects may be reduced by using a large-volume spacer device (which reduces oropharyngeal deposition by filtering out larger particles) [DTB, 2000; RPSGB, 2006].
• Oral candidiasis can be minimized by rinsing the mouth with water after ICS inhalation.
• Oropharyngeal deposition is high with dry-powder inhalers and autohalers.

Systemic adverse effects — adults:

• Osteoporosis: there are concerns that inhaled corticosteroids may affect bone mineral density, particularly when given in high doses for long periods, but the evidence regarding this is conflicting [SIGN and BTS, 2009]:
• In people who require high doses of ICS for prolonged periods of time, general measures to counteract osteoporosis (such as regular exercise, smoking cessation, and adequate dietary calcium) are prudent.
• Adrenal suppression: evidence indicates that high doses of ICS (equivalent to 1.5 mg/day CFC-containing beclometasone) result in significant adrenal suppression [EBM, 1999]. The risk of adrenal insufficiency is dose related and is largely due to use of oral corticosteroids, although inhaled corticosteroids may have an effect when they are taken at higher doses [Mortimer et al, 2006]:
• Titrate the dose of inhaled steroid to the lowest dose at which effective control of asthma is maintained [SIGN and BTS, 2009].

Systemic adverse effects — children:

• The Committee on Safety of Medicines has 'strongly advised that the paediatric licensed doses of all inhaled corticosteroids should not be exceeded' [CSM, 2002]. Use the lowest dose of ICS that will maintain disease control. If adequate control is not achieved, consider using add-on agents rather than increasing the dose of ICS [SIGN and BTS, 2009].
• Childhood growth: some initial slowing of growth may occur in children who have used ICS, but final adult height does not appear to be affected [Childhood Asthma Management Program Research Group, 2000; MeReC, 2002]:
• All children receiving prolonged treatment with ICS should have their height regularly and accurately monitored using a growth chart [CSM, 1998]. Any slowing of growth should prompt a reduction in dose if possible, or referral to a specialist, or both.
• Bone mineral density: one long-term study in children with chronic asthma treated with ICS suggests no adverse effect of ICS on bone mineral density in children [Agertoft and Pedersen, 2000]. Further long-term studies are needed to confirm this. However, experts suggest that with careful ICS dose adjustment, this risk is likely to be outweighed by the ability of ICS to reduce the need for multiple courses of oral corticosteroids [Kelly et al, 2008].
• Acute adrenal crisis: in a small number of children, doses of inhaled ICS at or above 400 micrograms per day of beclometasone have been associated with growth failure and adrenal suppression. The exact dose and duration of ICS treatment to put a child at risk of adrenal insufficiency is unknown, but it is likely to be 1000 micrograms or more of beclometasone or equivalent daily [SIGN and BTS, 2009]:
• Specific written advice about steroid replacement in the event of a severe intercurrent illness should be part of the management plan for children treated with 800 micrograms or more of beclometasone or equivalent daily.
• Any child receiving this dose should be under the care of a specialist paediatrician for the duration of the treatment.
• Consider use of a steroid treatment card.
• Consider the possibility of adrenal insufficiency in any child maintained on inhaled steroids presenting with shock or decreased consciousness:
• Check serum biochemistry and blood glucose levels urgently.
• Consider whether intramuscular hydrocortisone is required.

• Advise people that smoking can reduce the effectiveness of inhaled corticosteroids (ICS) [SIGN and BTS, 2009].
• Advise people to rinse their mouth with water (or clean children's teeth) after inhalation of a dose of ICS to reduce the risk of oral candidiasis [BNF 53, 2007].
• Advise on general measures to counteract osteoporosis (such as regular exercise, smoking cessation, and adequate calcium intake) in people using high doses of ICS for prolonged periods.
• Advise parents to immediately report non-specific symptoms, such as anorexia, abdominal pain, weight loss, tiredness, headache, nausea, vomiting, decreased consciousness, hypoglycaemia, and seizures, in children using high doses of ICS (400 micrograms or more per day of beclometasone).
• Consider use of a steroid treatment card:
• People using prolonged high doses (off-label high doses, or maximum doses in conjunction with oral corticosteroids) of ICS should be given a steroid treatment card which gives guidance on minimizing risk and provides details of prescriber, drug, dosage, and duration of treatment [CHM, 2006].

• The long-acting beta₂-agonists (LABAs), salmeterol and formoterol, are well tolerated and have few adverse effects.
• There has been concern regarding LABAs and an increase in asthma-related adverse events. On the basis of current evidence, the Medicines and Healthcare products Regulatory Agency has issued the following recommendations [MHRA, 2005]:
• Long-acting beta₂-agonists (LABAs) should not be prescribed for someone who is not already using an inhaled corticosteroid.
• Inhaled corticosteroid treatment should not be stopped whilst the person is using a LABA.
• People with acutely deteriorating asthma should not be started on LABA therapy.
• People should be monitored closely, especially during the first 3 months of treatment.
• Treatment with LABAs should be continued only if they have shown benefit.
• Stepping-down therapy should be considered when good long-term asthma control has been achieved.
• Salmeterol has a slower onset of action than salbutamol or terbutaline and should not be used to relieve an acute exacerbation of asthma [BNF 53, 2007].
• A daily dose of 24 micrograms formoterol should be sufficient for most children, particularly younger age groups. Higher doses should be used rarely, and only when control is not maintained on the lower dose [MHRA, 2010].

• There has been concern regarding the safety of long-acting beta₂-agonist (LABA) therapy.
• The Salmeterol Multi-Centre Asthma Research Trial (SMART) [Nelson et al, 2006] was a large randomized controlled trial (n = 26,355) that compared salmeterol with placebo in older children and adults. The study was stopped prematurely because the incidence of asthma-related adverse effects (such as severe asthma exacerbations and asthma-related deaths) was higher in people who had used salmeterol without an inhaled corticosteroid (ICS):
• The risk of adverse effects was higher in African-American people than in the white population.
• The authors could not determine whether the negative outcomes in the trial were due to the physiological effect of the drug, genetic factors, behavioural factors, or combinations of these factors.
• A meta-analysis pooled the results from 19 trials (n = 33,826 including the SMART study), and similarly concluded that LABA therapy increases severe and life-threatening asthma exacerbations, and risk of asthma-related death [Salpeter et al, 2006].

• Advise people who are starting treatment with a long-acting beta₂-agonist (LABA) to report any deterioration in symptoms [BNF 53, 2007].
• Advise people using a LABA that they must not stop using their ICS.
• Advise people who have been prescribed salmeterol that they should not use it to relieve an acute asthma attack.

• The margin between therapeutic and toxic doses of theophylline is narrow. Most people require plasma concentrations between 10 and 20 mg/L for satisfactory bronchodilation, although a lower concentration may be effective.
• Once a maintenance dose has been reached, check serum theophylline concentration every 6 to 12 months, or if the person is experiencing adverse effects that might suggest toxicity [UKMI, 2002].
• Adverse effects, including nausea, vomiting, tremor, palpitations, and arrhythmias, can occur at plasma concentrations of 10–20 mg/L. The frequency and severity of adverse effects increase with concentrations greater than 20 mg/L.
• Serum levels of theophylline are increased (because of an increase in the half-life of theophylline) in people with heart failure or hepatic impairment, in elderly people, and by drugs that inhibit hepatic enzymes (e.g. cimetidine, ciprofloxacin, erythromycin, fluvoxamine, St John's Wort):
• If people whose disease is stable during theophylline therapy begin to take one of these drugs, a reduction of the theophylline dose is recommended.
• Serum levels of theophylline are decreased (because of a decrease in the half-life of theophylline) in people who smoke, in chronic alcohol misuse, and by drugs that induce hepatic enzymes (e.g. phenytoin, carbamazepine, rifampicin):
• If people whose disease is stable during theophylline therapy begin to take one of those drugs, the theophylline dose may need to be increased.
• If people whose disease is stable during theophylline therapy stop smoking, plasma levels of theophylline may increase, and a reduction in dose may be necessary.
• When prescribing theophylline, the brand should be specified on the prescription. Because of differences in bioavailability among brands, people should be maintained on the same brand of theophylline.

[Baxter, 2006; BNF 53, 2007]

• The leukotriene receptor antagonists montelukast and zafirlukast are well tolerated and have few class-related adverse effects [GINA, 2006].
• Zafirlukast has been associated with liver toxicity. If clinical symptoms or signs suggestive of liver dysfunction occur (e.g. anorexia, nausea, vomiting, right upper quadrant pain, fatigue, lethargy, flu-like symptoms, enlarged liver, pruritus, or jaundice), stop zafirlukast and immediately measure serum transaminases (in particular, serum alanine aminotransferase). Routine monitoring of liver function is not recommended [ABPI Medicines Compendium, 2004].
• Use in children: montelukast is the only leukotriene receptor antagonist licensed for use in children (aged 6 months and older). A paediatric granule formulation is available, which can be swallowed or mixed with cold or room-temperature soft food and taken immediately [ABPI Medicines Compendium, 2007].
• Use in pregnancy: do not start a leukotriene receptor antagonist during pregnancy. However, if a woman is already taking a leukotriene receptor antagonist and it is considered essential, treatment can be continued during pregnancy [SIGN and BTS, 2009].
• In two small prospective studies no increase in the rates of congenital malformation, preterm birth, or low-birthweight was found. There have been several case reports of limb defects in women taking a leukotriene receptor antagonist during pregnancy, but a causal relationship has not been established [Schaefer et al, 2007].

• Advise people taking zafirlukast to seek medical advice in the event of persistent nausea, vomiting, malaise, or jaundice [BNF 53, 2007].
• Advise the person that montelukast should not be used to relieve symptoms of an acute asthma exacerbation.

• Advise people that inhaled sodium cromoglicate or nedocromil sodium should be used regularly, usually four times a day.
• Cromone inhalers should not be used to relieve an acute attack of asthma.
• If inhalation of the dry powder form of sodium cromoglicate causes bronchospasm, advise the person to use their short-acting beta₂-agonist inhaler (salbutamol or terbutaline) a few minutes prior to using the sodium cromoglicate inhaler.

[BNF 53, 2007]

• Adverse effects are uncommon with infrequent, short courses of oral corticosteroids.
• Table 1 in Managing people not needing admission shows the dose of oral prednisolone recommended in an acute exacerbation of asthma:
• In adults, oral corticosteroids should be continued for at least 5 days, until recovery.
• In children, oral corticosteroids should be continued for at least 3 days, until recovery.
• Prescribe soluble prednisolone tablets for children who cannot swallow tablets.
• Repeat the dose of prednisolone in children who vomit.
• After recovery from the acute exacerbation, therapy with prednisolone can be stopped abruptly, without tapering the dose, unless the course was longer than 3 weeks or the person was previously receiving maintenance oral corticosteroid treatment.

[SIGN and BTS, 2009]

• The risk and severity of adverse effects with oral corticosteroids increase with the dose and the duration of treatment. People receiving long-term oral corticosteroids (more than 3 months) or those needing frequent courses of an oral corticosteroid (three to four per year) are at risk of systemic adverse effects.
• Systemic adverse effects include osteoporosis, hypertension, diabetes, hypothalamic–pituitary–adrenal axis suppression, weight gain, cataracts, glaucoma, skin-thinning, easy bruising, and muscle weakness.
• Aim to prevent, minimize, or quickly detect adverse effects of long-term corticosteroids. General and lifestyle recommendations to minimize adverse effects include the following:
• Encourage adequate dietary calcium intake and good nutrition.
• Maintain normal body weight where possible.
• Advise on smoking cessation.
• Advise on moderate alcohol consumption.
• Encourage physical exercise within the limits imposed by the underlying disease.
• Perform a falls risk assessment, where appropriate, and advise those at increased risk of fractures from falling.
• Monitor, prevent, and treat the systemic adverse effects of continuous or frequent courses of oral corticosteroids:
• Blood pressure: monitor regularly and treat if necessary.
• Diabetes mellitus: screen regularly and treat if necessary.
• Osteoporosis: see the CKS topic on Osteoporosis - preventing steroid-induced for details on when to prescribe prophylactic bisphosphonate therapy.
• Growth suppression: record height of children regularly and accurately.
• Cataracts: screen children periodically through community optometric services.
• Children who frequently use courses of oral corticosteroids should have regular checks for signs of adrenal suppression. Refer to a paediatrician who can arrange Synacthen^® testing, where appropriate.
• Document the person's history of chickenpox (fatal disseminated chickenpox may occur in non-immune people). Advise all people without a history of chickenpox who are taking systemic prednisolone to avoid close contact with people who have chickenpox or shingles, and to seek urgent medical advice if they are exposed.

[GINA, 2006; BNF 53, 2007; SIGN and BTS, 2009]