History of Inhaled Corticosteroid Indications in the United States
Beclomethasone dipropionate CFC metered-dose inhaler (MDI) (Vanceril®) was approved by Food and Drug Administration (FDA) in 1976 for the treatment of patients with steroid-dependent asthma. In 1996, fluticasone propionate CFC MDI (Flovent®) was the first inhaled corticosteroid (ICS) approved for initial therapy of persistent asthma. In 2000, the National Heart, Lung, and Blood Institute-funded Childhood Asthma Management Program published the results of a 5-year study demonstrating the efficacy and safety of maintenance ICS in children with mild–moderate persistent asthma. In the same year, FDA approved the combination of fluticasone propionate and salmeterol (Advair® Diskus) as maintenance therapy for patients not controlled on ICS alone. Now the National Asthma Education and Prevention Program (NAEPP) recommends a combination of ICS and the long-acting beta-agonist (LABA) formoterol as single inhaler for maintenance and reliever therapy (SMART) in their 2020 Focused Update of the Asthma Guidelines.1
Efficacy and Safety of SMART
The basis for the recommendations on SMART therapy in the 2020 Asthma Focused Update were derived from a GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodological analysis of the Agency for Healthcare Research and Quality (AHRQ) systematic review.2 The AHRQ meta-analyses included a risk of bias for each individual study.
Low- and medium-dose ICS SMART is recommended as the preferred therapy for the treatment of moderate to severe persistent asthma for ages 4 years and older compared with low- and medium-fixed-dose ICS-LABA, respectively; and low-dose ICS SMART is preferred over medium daily dose ICS alone.1 In 4- to 11-year-old children, SMART reduced the exacerbation composite outcome compared with the same fixed-dose ICS-LABA or daily higher dose ICS alone (Table 1). This is a strong recommendation with moderate certainty of evidence for 4- to 11-year-old children (Table 1) and high certainty of evidence in those ages 12 years and older. Importantly, for patients uncontrolled on a medium-dose of ICS with short acting beta-2-selective agonist (SABA) rescue, it is recommended that SMART therapy with low-dose ICS-formoterol be tried before initiating medium-dose ICS SMART, medium fixed-dose ICS-LABA, or (in those 12 years and older) medium fixed-dose ICS-Long-Acting Muscarinic Antagonist.1 SMART therapy reduces exacerbation rate and corticosteroid use1 but has inconsistent effects on asthma control and quality of life.1,3,4
Table 1.
Evidence Summary: Inhaled Corticosteroid and Long-Acting Beta2-Agonist for Controller and Reliever Therapy in Children Ages 4–11 Years with Persistent Asthma on Exacerbations (Critical Outcome)a
| SMART versus the same ICS dose and long-acting beta2-agonist for controller therapy | |||||
|---|---|---|---|---|---|
| Outcomes | Number of participants (number of studies) | Certainty of evidence (GRADE) | Relative effect (95% CI) | Anticipated absolute effects (95% CI) |
|
| Risk of exacerbation with ICS-LABA controller (at same ICS dose) and SABA quick relief therapy | Risk difference or mean difference with ICS-LABA controller and reliever therapy | ||||
| Composite outcome comprising need for hospitalization, systemic corticosteroids, ED visits, or increased doses of ICS or other medications Follow-up: 52 weeks |
235 (1 RCT) | Moderate | RR: 0.28 (0.14–0.53) | 36/117 (30.8%) |
Favors intervention 10/118 (8.5%), 222 fewer exacerbation per 1,000 patients (from 265 fewer to 145 fewer) |
| SMART versus ICS controller at a higher comparative ICS dose and short-acting beta2-agonist quick relief | |||||
|---|---|---|---|---|---|
| Outcomes | Number of participants (number of studies) | Certainty of evidence (GRADE) | Relative effect (95% CI) | Anticipated absolute effects (95% CI) |
|
| Risk of exacerbation with ICS controller (at higher ICS dose) and SABA quick-relief therapy | Risk difference or mean difference for ICS-LABA controller and reliever therapy | ||||
| Composite outcome measure comprising need for systemic corticosteroids, hospitalizations, ED visits, or increases in ICS or other medication dose Follow-up: 12 months |
224 (1 RCT) | Moderate | RR: 0.43 (0.21–0.87) | 21/106 (19.8%) |
Favors intervention 10/118 (8.5%), 113 fewer exacerbation per 1,000 patients (from 157 fewer to 26 fewer) |
Adapted from references 1 and 5.
CI, confidence interval; ED, emergency department; GRADE, Grading of Recommendations, Assessment, Development, and Evaluation; ICS-LABA, inhaled corticosteroid-long-acting beta-agonist; RCT, randomized controlled trial; RR, risk ratio; SABA, short acting beta-2-selective agonist; SMART, single inhaler for maintenance and reliever therapy.
The maximum daily dose of ICS-formoterol in children 4–11 years is 8 inhalations containing 4.5 μg/inhalation of formoterol.1 The maintenance dose in ages 12 years and older is 1–2 puffs once or twice daily plus a rescue dose of 1–2 puffs as needed up to a combined maximum of 12 puffs per day (total dose max, 54 μg formoterol).1
The study in children ages 4–11 years evaluated growth for a period of 1 year.5 Patients received budesonide-formoterol dry powder inhaler 80/4.5 μg once daily with up to seven additional inhalations per day for relief (SMART) or budesonide alone 320 μg per day with short-acting beta2-selective agonist (SABA) for relief (budesonide maintenance) or budesonide-formoterol 80/4.5 μg once daily with SABA for rescue (fixed-dose budesonide-formoterol). SMART was associated with significant reductions in exacerbations requiring medical intervention (P < 0.001), a clinically relevant lower mean daily dose of ICS (126 μg) compared with daily budesonide (320 μg) and a significantly improved growth rate (mean difference of 1 cm) (P = 0.005).
Treatment with SMART in patients ≥12 years versus the same dose of ICS-LABA fixed-dose controller therapy reduced the risk of the composite exacerbation outcome (exacerbations requiring systemic corticosteroids, hospitalization, or emergency department visits) with an overall risk ratio (95% confidence interval) of 0.68 (0.58–0.80). In comparison, with patients receiving a higher fixed-ICS dose with LABA controller therapy the overall risk ratio of the composite exacerbation outcome with SMART was 0.75 (0.59–0.96).1
Budesonide-formoterol dry powder inhaler (Symbicort® Turbuhaler®) is approved for SMART in Australia, Canada, and New Zealand in children ≥12 years and in the EU and UK in patients ≥18 years.
Obstacles to SMART in the United States
The lack of FDA approval for SMART is likely to slow adoption of this mode of therapy. In addition, it is unclear whether either of the two ICS-formoterol hydrofluoroalkane (HFA) MDI products available in the United States (Symbicort HFA MDI or Dulera® HFA MDI) would provide the same efficacy as the products included in the Systematic Review with Meta-Analysis, relied upon by the NAEPP.6 There were 16 randomized controlled trials in that analysis, but only 1 employed the budesonide-formoterol MDI available in the United States (Symbicort HFA MDI).7 Another of the 16 studies employed a beclomethasone-formoterol combination available in Europe, whereas the remaining 14 studies employed the budesonide-formoterol dry powder inhaler (Symbicort Turbuhaler) that delivers twice as much budesonide to the airways as the MDI8,9 but is not available in the United States. There are no studies of SMART listed in PubMed or ClinicalTrials.gov on the other ICS-formoterol combination product in the United States, mometasone-formoterol HFA MDI (Dulera).
FDA requires the following statement in the official labeling, manufacturer supplied patient counseling information, and in TV and print advertisements: “SYMBICORT should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not SYMBICORT, should be used to relieve acute symptoms such as shortness of breath.” This precaution will create confusion for parents and patients as it contradicts a SMART prescription.
This contradiction in labeling also may impact dispensing of a prescription for SMART since it is “off label.” If a health care provider prescribes SMART with either formoterol-containing combination product (i.e., Symbicort or Dulera), with, for example, an instruction of “2 puffs BID and PRN,” the pharmacist may question the prescription and call the prescriber, which will delay dispensing and many third-party payers may deny coverage unless the prescriber goes through the appeal process. In contrast, if the prescription is approved for payment and dispensed, patients who are adherent to SMART are likely to run out of medication early since most insurance plans will only pay for one canister per month.
Finally, it is important to point out to prescribers that the NAEPP recommendations for SMART do not include fluticasone propionate-salmeterol combination products (Advair, AirDuo® and their generic equivalents). Salmeterol has a much slower bronchodilator onset than formoterol,10 a flat dose–response curve in the airways,11 can only be used twice daily, and may be more likely to prolong the QTc interval.
Conclusion
Although there is substantial scientific data on the efficacy and general safety of SMART,1 particularly in patients >11 years old, it is unlikely that there will be widespread adoption of this mode of therapy unless it is approved by FDA. That will require demonstration of effectiveness and safety with the products available in the United States or new products and may include additional proof of cardiovascular safety that is lacking from current studies.
The findings, discussions, comments, or opinions expressed in “My Corner” are those of the author(s), and do not reflect those of the Editor-in-Chief, the journal publisher, or any of its affiliates.
References
- 1. National Heart, Lung, and Blood Institute. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol 2020; 146:1217–1270 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Sobieraj DM, Baker WL, Weeda ER, et al. Intermittent Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists for Asthma. Comparative Effectiveness Review No. 194. (Prepared by the University of Connecticut Evidence-based Practice Center under Contract No. 290-2015-00012-I.) AHRQ Publication No. 17(18)-EHC027-EF. Rockville, MD: Agency for Healthcare Research and Quality, 2018. Posted final reports are located on the Effective Health Care Program search page. DOI: 10.23970/AHRQEPCCER194 [DOI] [PubMed]
- 3. Bousquet J, Boulet LP, Peters MJ, et al. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs high-dose salmeterol/fluticasone. Respir Med 2007; 101:2437–2446 [DOI] [PubMed] [Google Scholar]
- 4. Kuna P, Peters MJ, Manjra AI, et al. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract 2007; 61:725–736 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Bisgaard H, Le Roux P, Bjamer D, et al. Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. Chest 2006; 130:1733–1743 [DOI] [PubMed] [Google Scholar]
- 6. Sobieraj DM, Weeda ER, Nguyen E, et al. Association of inhaled corticosteroids and long-acting β-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma. A systematic review and meta-analysis. JAMA 2018; 319:1485–1496 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Patel M, Pilcher J, Pritchard A, et al. Efficacy and safety of maintenance and reliever combination budesonide-formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomized controlled trial. Lancet Respir Med 2013; 1:32–42 [DOI] [PubMed] [Google Scholar]
- 8. Thorsson L, Edsbäcker S, Conradson TB. Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler P-MDI. Eur Respir J 1994; 7:1839–1844 [DOI] [PubMed] [Google Scholar]
- 9. Thorsson L, Kenyon C, Newman SP, et al. Lung deposition of budesonide in asthmatics: a comparison of different formulations. Int J Pharm 1998; 168:119–127 [Google Scholar]
- 10. Palmqvist M, Persson G, Lazer L, et al. Inhaled dry-powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect and potency. Eur Respir J 1997; 10:2484–2489 [DOI] [PubMed] [Google Scholar]
- 11. Palmqvist M, Ibsen T, Mellen A, et al. Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients. Am J Respir Crit Care Med 1999; 160:244–249 [DOI] [PubMed] [Google Scholar]