Over-the-counter Dispensing: Widening Access to Inhaled Corticosteroid/Formoterol Reliever Therapy

The limited availability of low-dose inhaled corticosteroid (ICS)/formoterol reliever therapy in many countries is an issue of international concern. As recommended by the GINA (Global Initiative for Asthma) strategy, ICS/formoterol is preferred to short-acting β₂ agonists (SABA) as reliever therapy in adolescents and adults with asthma across the range of asthma severity (1, 2). As-needed ICS/formoterol reduces the risk of severe exacerbations by between 55% and 32% compared with SABA reliever therapy when taken alone in mild asthma (3) or together with maintenance ICS/long-acting β₂-agonist (LABA) therapy in moderate or severe asthma, respectively (4). It reduces the risk of β₂ agonist overuse in the situation of worsening asthma and the associated delay in seeking medical review, both key risk factors for asthma mortality (5). It allows titration of ICS use according to changes in asthma severity through the vehicle of bronchodilator use and ensures delivery of ICS therapy in patients not prescribed or nonadherent to maintenance ICS-based medication. It is simple to use, requiring only one inhaler device regardless of severity and is the regimen preferred by most patients (6).

However, as discussed in an authoritative review in this issue of the Journal, Krings and colleagues (pp. 390–405) note numerous barriers to implementing this approach in real-world practice, particularly in the United States (7). As the authors outline, despite the evidence above and the ICS/formoterol SMART (Single Maintenance And Reliever Therapy) regimen being recommended by the U.S.-based NAEPP (National Asthma Education and Prevention Program) guidelines (as well as by GINA) and approved by regulators in more than 120 countries, budesonide/formoterol (the specific ICS/formoterol product for which almost all the evidence of benefit and safety exists) is not currently approved by the U.S. Food and Drug Administration for reliever use.

The authors make a number of recommendations to overcome the inevitable downstream effects of this lack of regulatory approval, including the paradigm shift to make budesonide/formoterol available as an over-the-counter (OTC) medication. A strong case is made that this regulatory action would have the potential to markedly improve the availability of budesonide/formoterol, particularly for disadvantaged populations, and thereby lead to better outcomes in asthma and reduce the burden of disease, enhance patient safety, reduce the mortality risk with SABA monotherapy, and substantially reduce inhaler and healthcare costs. Importantly, in the United States, such an action would provide a much-needed safer and more effective choice to the current OTC availability of aerosolized epinephrine, an α and β agonist, for which there is only low-quality evidence that it has similar efficacy as a β₂-selective agonist (8). ICS/formoterol reliever alone would overcome the real concerns with the use of epinephrine taken without concomitant ICS therapy, ensuring that all patients received an ICS at the same time that their reliever was administered, titrating the dose of ICS according to changes in asthma severity.

Although the case in favor of OTC budesonide/formoterol is convincingly made, are there any outstanding issues that inform these considerations? The first relates to the use of ICS/formoterol as a reliever alone: how does it compare with other treatment regimens recommended for mild or moderate asthma, although presumably not available to patients accessing OTC medication? In a network meta-analysis of clinical trials in adolescents and adults with asthma, ICS/formoterol reliever alone was ranked higher than low-dose maintenance ICS/LABA plus SABA reliever or low- or medium-dose maintenance ICS plus SABA reliever in terms of exacerbation risk reduction (9). SABA reliever therapy alone ranked the lowest of the 10 inhaled therapeutic regimens included in the analysis.

The second issue relates to the use of ICS/formoterol according to the SMART regimen: how does it compare with other treatment regimens recommended for moderate or severe asthma, likewise not otherwise available to patients seeking OTC medications? The network analysis reported that low- and medium-dose ICS/formoterol, according to the SMART regimen, ranked higher than all 8 other inhaled therapeutic regimens, including low-, medium- and high-dose ICS/LABA maintenance plus SABA reliever therapy (9).

Although these data are reassuring, the issue of safety with repeated use in the situation of a severe attack of asthma also needs consideration. The recent randomized controlled trial of cumulative high doses of albuterol and budesonide/formoterol, as would be used in the treatment of a severe attack resulting in hospital admission, is informative (10). There were significantly more adverse events during the albuterol regimen compared with budesonide/formoterol when administered repeatedly in the ratio of 200 μg versus 200/6 μg, respectively, with 5% of participants withdrawn because of safety concerns after albuterol use. At 180 minutes, albuterol resulted in a 0.26 mmol/L greater reduction in serum potassium and a 10 beats/min greater heart rate, indicating greater systemic β₂ and β₁/β₂ effects, respectively. The acute increase in FEV₁ was greater with albuterol initially, without a difference in perception of breathlessness, and budesonide/formoterol achieved a greater FEV₁ later in the time course.

Although the clinical relevance of differences in bronchodilator efficacy in the community setting is a moot point, as the patient can simply take an additional dose if needed to relieve symptoms, the lesser β₁- and β₂-agonist systemic adverse effects of ICS/formoterol compared with albuterol, when given in these comparative doses, is likely of clinical relevance. Furthermore, as asthma mortality epidemics have been associated with high-dose preparations of poorly selective β₂ agonists, the relatively lower β₂-agonist dose of ICS/formoterol may have a potential safety advantage when compared with albuterol, and the greater β₂-agonist selectivity a potential safety advantage compared with epinephrine. The observation that as-needed ICS/formoterol reduces the risk of asthma-related hospital admission or emergency department or urgent care visit by 65% compared with as-needed albuterol is consistent with potentially reduced mortality risk (4, 11).

Finally, despite the above evidence demonstrating the efficacy and safety of ICS/formoterol reliever therapy in adults and adolescents, there is a worrying lack of evidence in children under 12 years of age to support its prescribed, let alone OTC, use. Randomized controlled trials in this age group across the spectrum of asthma severity are an urgent priority.

In summary, the review makes a persuasive case for attention to move from the evidence base for the efficacy/safety profile of ICS/formoterol reliever therapy in asthma to measures needed to ensure affordable access to this regimen. Although this may require different initiatives in different healthcare systems, OTC availability for adolescents and adults with asthma should be seriously considered. It is not a matter of whether there are no risks with this approach but rather whether the potential benefits outweigh the potential risks (Figure 1). We propose that this is the case but submit that it would be crucial for the outcome of such a regulatory action to be closely assessed in different jurisdictions to guide its implementation more widely.

Figure 1.

Over-the-counter dispensing of inhaled corticosteroid/formoterol: balancing the pros and cons. OTC = over-the-counter.