Long-acting bronchodilators: their properties and place in treatment

Long-acting bronchodilators: their properties and place in treatment Steve Chaplin MSc, MRPharmS and Paul Walker BMedSci (Hons), MD, FRCP Steve Chaplin and Dr Paul KEY POINTS Walker provide an overview there are 3 long-acting bronchodilators currently available: the longacting beta 2 -agonists (LABAs) formoterol, indacaterol and salmeterol, of the properties of long-acting bronchodilators and their and the antimuscarinic tiotropium they are all licensed for maintenance treatment of COPD; formoterol current recommended place and salmeterol also licensed for asthma in combination with an inhaled steroid in treating asthma and formoterol and salmeterol are taken twice daily, indacaterol and COPD. tiotropium once daily; both formoterol and indacaterol have a rapid onset of action there is a wide variety of delivery devices, providing greater choice for patients LABA side-effects include hand tremor, anxiety, headache, muscle cramps and palpitations; tiotropium may cause dry mouth, other sideeffects uncommon LABAs should be used with caution in patients with thyrotoxicosis and cardiovascular disease; tiotropium with caution in patients with narrow-angle glaucoma, prostatic hyperplasia, bladder-neck obstruction and cardiac rhythm disorders The BNF includes four long-acting inhaled bronchodilators: three are selective beta 2 -agonists (LABAs) formoterol, indacaterol (Onbrez Breezhaler) and salmeterol (Sere- vent) and one is an antimuscarinic tiotropium (Spiriva). Indacaterol and tiotropium are licensed only as maintenance therapy of COPD whereas formoterol and salmeterol are also licensed, in combination with an inhaled steroid, as maintenance therapy of chronic asthma. Formoterol is also available in combination with beclometasone (Fostair) and with budesonide (Symbicort), and salmeterol with fluticasone (Seretide). Age The age range of patients with asthma who use a LABA is wide but, confusingly, not all brands are licensed for the same ages. The minimum licensed ages for formoterol are five years for Foradil, six for Oxis and Formoterol Easyhaler and 12 for Atimos Modulite; for salmeterol, the limit is four years. Whether any differences between these brands, eg ease of using the device, is clinically significant at these ages seems unlikely, but the age limits are stated on the package inserts and this may cause confusion unless explained. Onset and duration of action The bronchodilator effects of formoterol and salmeterol last for 12 hours and twice-daily administration is required. Formoterol has a rapid onset of action (one to three minutes), making it suitable as a reliever therapy, whereas the onset of action of salmeterol is approximately 30 minutes. The effects of indacaterol and tiotropium persist for 24 hours, allowing once-daily dosing. Indacaterol has a rapid onset of action (less than five minutes), though whether this is important in the maintenance therapy of COPD is unclear; the onset of action of tiotropium is 30 minutes. Devices All four long-acting bronchodilators are available as dr y-powder inhalers that require loading for each dose (tiotropium Handihaler, indacaterol Breezhaler, formoterol 28 Prescriber 19 September 2011 www.prescriber.co.uk

LABA Indications Dosage regimen and cost per 30 days Comment Formoterol asthma, COPD 12 24µg twice daily also available with budesonide as dry powder: 11.88 23.75 (Formoterol combined inhaler for COPD and Easyhaler) asthma (Symbicort), and with MDI: 18.04 36.07 (Atimos Modulite) beclometasone for asthma (Fostair) Idacaterol COPD 150 300µg once daily dry powder: 29.26 (Onbrez Breezhaler) Salmeterol asthma, COPD 50 100µg twice daily max. 50µg twice daily for COPD Serevent Accuhaler dry powder, aerosol: also available with fluticasone as 29.26 58.52 combined inhaler for COPD and Serevent Diskhaler: 35.79 71.58 + refill asthma (Seretide) 35.15 70.30 Serevent Evohaler MDI: 29.26 58.52 Tiotropium COPD dry powder: 18µg once daily use with caution if egfr less than Spiriva 30-cap pack plus HandiHaler: 50ml/min/1.73m 2 34.87; 30-cap refill: 31.89 Spiriva Respimat solution: 5µg once daily 60-dose unit (30 days supply): 36.27 Table 1. Dosage and cost of long-acting bronchodilators (prices MIMS July 2011) Foradil inhaler) or several doses (salmeterol Diskhaler, Accuhaler). Salmeterol is also formulated as a CFC-free metered-dose inhaler (Serevent Evohaler). Formoterol is also available as a dry powder in a Turbohaler (Oxis) and an Easyhaler (Easyhaler Formoterol), neither of which needs loading, and in a CFC-free metered-dose aerosol (Atimos Modulite). Tiotropium also comes as a solution for administration by a specific device (Respimat), which is useful for patients with poor manual dexterity who cannot use the inhaler. There is also a choice of devices for combined steroid/ long-acting bronchodilator inhalers for asthma: a Turbohaler for Symbi - cort, a CFC-free aerosol for Fostair and an Accuhaler or CFC-free Evohaler aerosol for Seretide. Adverse effects LABAs have a common mechanism of action and share a similar profile of dose-dependent adverse effects due to stimulation of beta 2 - receptors. These include hand tremor, anxiety, headache, muscle cramps and palpitations. Other cardiovascular effects include tachycardia, arrhythmias, peripheral vasodilatation and myocardial ischaemia. Behavioural disturbance and sleep disruption may also occur. Tiotropium may cause dr y mouth and, uncommonly, oro - pharyngeal candidosis, dysphagia and constipation. Adverse respiratory effects are uncommon and include epistaxis, dysphonia, pharyngitis and cough. Cardio vascular effects (atrial fibrillation, palpitations, supra - ventricular tachycardia and tachycardia) are also uncommon, as are dizziness, headache, rash and pruritus. The Respimat formulation has been associated with a 40 50 per cent increase in the risk of mortality compared with placebo (though the absolute increase in risk is 0.8 per cent). 1 No increase in risk has been associated with the inhaler. Cautions Caution is recommended when prescribing a beta 2 -agonist for patients with hyperthyroidism or cardiovascular disease (including arrhythmias, susceptibility to QTinterval prolongation or hypertension). In patients with diabetes, increased blood glucose and (mainly after intravenous administration) ketoacidosis have rarely been reported. Tiotropium should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia, bladder-neck obstruction or cardiac rhythm dis - orders. Patients should be advised to avoid getting the spray into their eyes because this may precipitate or worsen narrow-angle glaucoma and cause eye redness, discomfort and blurred vision. www.prescriber.co.uk Prescriber 19 September 2011 29

Drug interactions Potent CYP3A4 inhibitors, eg ketoconazole, itraconazole, telithro - mycin and ritonavir, inhibit the metabolism of salmeterol and indacaterol; this could increase the risk of QTc interval prolongation and palpitations. Additive cardiac effects are possible with concurrent use of antiarrhythmic agents, tricyclic antidepressants, MAOIs, antihistamines and pheno thiazines. In high doses, beta 2 -agonists can cause hypokalaemia; this may be potentiated by concurrent treatment with theophyllines, oral steroids and diuretics, and by hypoxia. The BNF recommends monitoring plasma potassium in patients with severe asthma. Beta-blockers antagonise the effects of adrenergic LABAs. Tiotropium is not associated with clinically significant drug interactions but concurrent use of other antimuscarinic agents may increase the risk of adverse effects. Reference 1. National Prescribing Centre. Increased risk of mortality associated with tiotropium Respimat in COPD. MeReC Rapid Review. July 2011. Declaration of interests Steve Chaplin has undertaken paid writing work for a number of companies including Novo Nordisk, Bayer, Novartis, Roche, Astra Zeneca, GlaxoSmithKline and Pfizer. Steve Chaplin is a pharmacist who specialises in writing on therapeutics

Place in therapy Since their introduction in the early 1990s long-acting bronchodilators beta 2 -agonists (LABAs) and antimuscarinics (LAMAs) have taken an increasingly important place in the management of asthma and COPD, while the addition of new agents and deliver y devices provides greater choice for prescriber and patient. LABAs work by a direct effect on airway smooth muscle via airway beta-adrenoceptors, while LAMAs reduce vagomotor tone. Both have been shown to reduce static and dynamic hyperinflation in COPD, 1,2 while LABAs appear to have some synergy of effect with inhaled corticosteroids in patients with asthma. Asthma Inhaled steroids are the first-line treatment of asthma, but where adequate control is not achieved by modest doses alone the addition of a LABA produces superior outcomes compared with increasing the steroid dose. 3 This forms the basis of step 3 of the British Thoracic Society adult asthma guidelines. 4 LAMAs have always played a relatively small role in the management of moderate asthma, but a recent study suggests similar results when tiotropium is used at this step. 5 It is important that LABAs are only ever prescribed for asthmatic patients already taking inhaled steroids to avoid the risk of serious adverse events seen in patients treated with only beta-agonists. 6 The formoterol/budesonide

combination Symbicort can be used as adjustable maintenance therapy with evidence of similar control achieved with lower inhaled steroid exposure. 7 The short onset of action of formoterol allows this to be used as a reliever both as a combination inhaler (Symbicort) or alone (in patients taking separate inhaled steroids). COPD In contrast to asthma, long-acting bronchodilators can be safely prescribed in COPD without use of inhaled steroids. LABAs and LAMAs are superior to their shortacting equivalents with respect to improvements in breathlessness, health status, exercise capacity and exacerbation frequency. 8,9 The 2010 revision of the National Institute for Health and Clinical Excellence (NICE) COPD guidelines promotes early use of long-acting bronchodilators in any patient who is symptomatic or suffering exacerbations on short-acting agents. 10 Optim isation of bronchodilator therapy before pulmonary rehabilitation is important as it increases benefit gained. 11 The newly licensed ultra-longacting beta 2 -agonist indacaterol 12 is attractive due to its ability to be used with tiotropium to provide once-daily maintenance therapy, though many COPD patients, including those with an FEV 1 (forced expiratory volume in one second) less than 50 per cent of predicted and those with frequent exacerbations, are likely to benefit from a twice-daily inhaled steroid/laba inhaler. References 1. O Donnell DE, et al. Eur Respir J 2004; 23:832 40. 2. O Donnell DE, et al. Eur Respir J 2004; 24:86 94. 3. Pauwels RA, et al. N Engl J Med 1997; 337:1405 11. 4.: www.brit-thoracic.org.uk/portals/0/ Clinical%20Information/Asthma/ Guidelines/sign101%20revised%20 June%2009.pdf. Last accessed 26 January 2011. 5. Peters SP et al, for the National Heart, Lung, and Blood Institute Asthma Clinical Research Network. N Engl J Med 2010;363:1715 26. 6. Salpeter SR, et al. Ann Intern Med 2006;144:904 12. 7. Bousquet J, et al. Respir Med 2007; 101:2437 46. 8. Tashkin DP, et al; UPLIFT Study Investigators. N Engl J Med 2008; 359:1543 54. 9. Calverley PM, et al; TORCH investigators. N Engl J Med 2007;356:775 89. 10. www.nice.org.uk/nicemedia/live/ 13029/49425/49425.pdf. Last viewed 26 January 2011. 11. Casaburi R, et al. Chest 2005; 127:809 17. 12. Dahl R, et al, on behalf of the INVOLVE Study Investigators. Thorax 2010;65:473 9. Declaration of interests Dr Paul Walker has received honoraria from Boehringer Ingelheim, Pfizer, Novartis and GlaxoSmith - Kline, and his department has received payment from Bayer, Profile Pharma and Pharmaxis for delivery of phase 3 clinical trials. Dr Walker is consultant in respiratory medicine at University Hospital Aintree, Liverpool 32 Prescriber 19 September 2011 www.prescriber.co.uk