A Benefit-Risk Assessment of Inhaled Long-Acting ??2-Agonists in the Management of Obstructive Pulmonary Disease

Abstract

The two inhaled long-acting beta2-adrenoceptor agonists, salmeterol and formoterol, have been studied extensively since their introduction in the early 1990s. In this review we consider the evidence for their efficacy and safety in adults with asthma and chronic obstructive pulmonary disease (COPD), by reviewing long-term prospective studies in which these drugs have been compared with placebo or an alternative bronchodilator. We have also assessed safety, including data from postmarketing surveillance studies and case-control studies using large databases. In patients with asthma, salmeterol and formoterol increase lung function, reduce asthmatic symptoms and improve quality of life when compared with placebo. Both drugs protect against exercise-induced asthma, although some tolerance develops with regular use. Tolerance to the bronchodilator effects of formoterol has also been seen, although this is small and most of the beneficial effects are maintained long-term. Both drugs have been shown to reduce asthma exacerbations but only in studies in which most patients were taking an inhaled corticosteroid. Adding a long-acting beta2-agonist provided better control than increasing the dose of inhaled corticosteroid in several studies. Long-acting beta2-agonists also provide better asthma control than use of regular short-acting beta2-agonists and theophylline. Their relative efficacy compared with leukotriene antagonists is uncertain as yet. Formoterol appears to be at least as safe and effective as a short-acting beta2-agonist when used on an 'as required' basis. In patients with COPD, both salmeterol and formoterol offer improved lung function and reduced COPD symptoms compared with placebo, and quality of life has been improved in some studies. Some tolerance to the bronchodilating effect of salmeterol was seen in one study. Most studies have not found a significant reduction in exacerbations in COPD. Both drugs have provided greater benefit than ipratropium bromide or theophylline; there are limited data on tiotropium bromide. The long-acting beta2-agonists cause predictable adverse effects including headache, tremor, palpitations, muscle cramps and a fall in serum potassium concentration. Salmeterol can also cause paradoxical bronchospasm. There is some evidence that serious adverse events including dysrhythmias and life-threatening asthma episodes can occur; however, the incidence of such events is very low but may be increased in patients not taking an inhaled corticosteroid. Salmeterol 50 microg twice daily and formoterol 12 microg twice daily are effective and safe in treating patients with asthma and COPD. Higher doses cause more adverse effects, although serious adverse events are rare.

Co-morbidities of COPD in primary care: frequency, relation to COPD, and treatment consequences

“…Furthermore, the progressive decline in lung function, the identification of co-morbid conditions, and advancing age in elderly patients, typically necessitates the introduction of additional therapies. 1 Table 4 lists the possible drug interactions in patients receiving different types of therapy for COPD; [61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] these should be borne in mind, particularly when treating elderly patients with multiple co-morbidities.…”

“…This may impact on treatment of chronic heart failure in patients with COPD β2-agonists used in COPD may precipitate cardiac rhythm disturbances (rare) 69 Hypokalaemia may be seen when β2-agonists are coadministered with thiazide diuretics or corticosteroids 75 Acute hypotension may be seen when salbutamol is coadministered with methyldopa, 61 and coadministration with salbutamol may reduce plasma concentrations of digoxin 64 …”

Pharmacological Characterization of Olodaterol, a Novel Inhaled β2-Adrenoceptor Agonist Exerting a 24-Hour-Long Duration of Action in Preclinical Models

“…In addition, a higher therapeutic index would be desirable for the new generation of inhaled ␤ 2 -AR agonists, because doubling the dose of currently marketed drugs, e.g., salmeterol and formoterol, causes a significant increase in the incidence of adverse effects, including headache, tremor, palpitations, muscle cramps, and a fall in serum potassium concentration (Sovani et al, 2004).…”

In Vitro and in Vivo Pharmacological Characterization of 5-[(R)-2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (Indacaterol), a Novel Inhaled β2Adrenoceptor Agonist with a 24-h Duration of Action

“…These adverse events are minimized when these drugs are given by inhalation; salbutamol, salmeterol, and formoterol are perceived to be safe at the recommended clinical doses. However, the therapeutic margin of these drugs is rather small, such that doubling the dose of, e.g., salmeterol and formoterol, can result in a significant increase in the incidence of side effects (Guhan et al, 2000;Sovani et al, 2004). Furthermore, such undesirable side effects have been linked to reduced compliance to treatment (White and Sander, 1999).…”