Two options for asthma inadequately controlled by a standard dose of an ICS are to (1) double the dose of ICS or (2) combine it with another drug. The addition of theophylline or a leukotriene receptor antagonist modestly increases asthma control, but the most impressive benefits are afforded by addition of a long-acting inhaled β2-receptor agonist (LABA, eg, salmeterol or formoterol). Many studies have shown this combination to be more effective than doubling the dose of the ICS. Combinations of an ICS and an LABA in a single inhaler are now available in fixed-dose preparations (eg, fluticasone and salmeterol [Advair]; budesonide and formoterol [Symbicort]; mometasone and formoterol [Dulera]; fluticasone and vilanterol [Breo]). The rapid onset of action of formoterol enables novel use of its combination with a low dose of budesonide. The combination of 80 mcg of budesonide plus 12.5 mcg of formoterol taken twice daily and additionally for relief of symptoms (ie, taken as both a “controller” and a “reliever”) is as effective an inhalation of a four-times-higher dose of budesonide with albuterol alone taken for relief of symptoms. Use of this flexible dosing strategy is widespread in Europe but is not approved in the USA.
Until recently, a shadow hung over the use of combination ICS-LABA therapy for moderate and severe asthma, generated by evidence of a statistically significant increase in the very low risk of fatal or near-fatal asthma attacks from use of an LABA even when taken in combination with an ICS. This evidence prompted the FDA to require the addition of a “black box” warning to the package insert issued with each ICS-LABA inhaler. The major message of the warning is that a possible increase in risk of a severe rare event, including asthma fatality, from the use of an LABA should be discussed with the patient in presenting options for treatment.
The concerns underlying the “black box” warning have been assuaged by two large, placebo-controlled, double-blind FDA-mandated trials showing no significant increase in severe asthma exacerbations or asthma fatalities from the addition of an LABA to ICS treatment in patients with moderate to severe asthma. Despite these reassuring findings, patients prescribed combination treatment should also be provided with explicit instructions to continue use of a rapid-acting inhaled β agonist, such as albuterol, for relief of acute symptoms and, as for all patients with asthma, to follow an explicit action plan for severe attacks.
A leukotriene pathway antagonist taken as an oral tablet is an alternative to ICS treatment in patients with symptoms occurring more than twice a week or those who are awakened from sleep by asthma more than twice a month. This place in asthma therapy was once held by cromolyn and nedocromil, but neither is now available for asthma in the USA. Although these treatments are not as effective as a low dose of an ICS, both avoid the issue of “steroid phobia” described above and are commonly used in the treatment of children.
The leukotriene receptor antagonist montelukast is the most widely prescribed of these treatments, especially by primary care providers. This drug, taken orally, is easy to administer and is rarely associated with troublesome adverse effects. This maintenance therapy is widely used for treating children in the USA, particularly those who have concurrent symptomatic allergic rhinitis, which is also effectively treated by montelukast.