Long-acting Beta Agonist

Aka: Long-acting Beta Agonist, Long-Acting Beta-2 Agonist, Long-Acting Inhaled Bronchodilator, Salmeterol, Serevent, Formoterol, Foradil, Indacaterol, Arcapta, Advair, Symbicort, Dulera, Breo Ellipta, Arformoterol, Brovana, Trelegy Ellipta, Single Maintenance and Reliever Therapy, SMART Asthma Management Protocol

1. See Also
   1. Short-acting Beta Agonist
   2. Beta Agonist
2. Indications
   1. Moderate Persistent Asthma
   2. Severe Persistent Asthma
3. Precautions
   1. Adverse outcomes in Asthma with Long-acting Beta Agonist (LABA)
      1. LABA use in Asthma was associated with increased Asthma deaths, increased intubations and hospitalizations
         1. McMahon (2011) Pediatrics 128(5): e1147-54 [PubMed]
      2. However FDA review of more recent studies found similar adverse outcomes with Inhaled Corticosteroids
         1. FDA removed LABA black box warning (see FDA communication link below)
   2. Risk of increased mortality and of more severe and life threatening Asthma Exacerbations
      1. Postulated to mask a patients awareness of severe Asthma Exacerbation
      2. FDA Black Box Warnings placed in 2003, but removed in 2017 (based on newer data as above)
         1. https://www.fda.gov/Drugs/DrugSafety/ucm589587.htm
   3. Not a substitute for Inhaled Corticosteroids
      1. Steroids are key management of persistent Asthma
      2. Long-acting Beta Agonists are in addition to Inhaled Corticosteroids
      3. Lazarus (2001) JAMA 285:2583-93 [PubMed]
   4. Do NOT exceed dosing schedule (e.g. Serevent bid) except Formoterol in SMART Protocol
      1. Use a short acting Beta agonist for rescue use
      2. Exception: See SMART Protocol below
   5. Tolerance over time to Protective effect
      1. Effect diminishes over one month of use
      2. Reference
         1. Simons (1997) Pediatrics 99:655-9 [PubMed]
4. Preparations: Long-acting Beta Agonists (LABA)
   1. Salmeterol (Serevent) Dry Powder Diskus (50 ug/inhale)
      1. One inhalation every 12 hours
   2. Serevent Inhalation aerosol MDI (21 ug/puff)
      1. Adults: 2 puffs every 12 hours
      2. Child: 1-2 puffs every 12 hours
   3. Formoterol (Foradil)
      1. One inhalation every 12 hours
      2. Rapid onset within 5 minutes (contrast 15-30 minutes for other LABAs)
   4. Indacaterol (Arcapta Neohaler)
      1. Once daily dosing
      2. FDA approved for COPD (not proven to prevent COPD exacerbations)
      3. Same cardiovascular risks as other long acting beta agonists
      4. Reference
         1. (2012) presc lett 19(1): 2
   5. Arformoterol (Brovana)
      1. Dose: 15 mcg twice daily
5. Preparations: Combination of Long-acting Beta Agonists with Corticosteroids
   1. Advair Diskus (Fluticasone/Salmeterol: 100/50, 250/50, 500/50)
      1. Dose: One puff twice daily
   2. Wixela Inhub (Fluticasone/Salmeterol)
      1. Released in 2019 at $150/Inhaler
   3. AirDuo (Fluticasone/Salmeterol: 55/14, 113/14, 232/14)
      1. Dose: One puff twice daily
      2. Generic available in 2017 for $90/month (compare with $475/month for Advair)
      3. (2017) Presc Lett 24(7)
   4. Symbicort (Budesonide/Formoterol: 80/4.5, 160/4.5)
      1. Dose: One puff twice daily
   5. Dulera (Mometasone/Formoterol: 50/5, 100/5, 200/5)
      1. Dose: Two puffs twice daily
   6. Breo Ellipta (Fluticasone/Vilanterol: 100/25)
      1. Only indicated for COPD (not Asthma)
      2. Dose: One puff once daily
   7. Trelegy Ellipta (Umeclidinium AND Fluticasone/Vilanterol)
      1. Indicated for severe COPD when an Inhaled Steroid and a LAMA and LABA are both indicated
      2. Indicated in Severe Asthma not controlled on medium to high dose Inhaled Corticosteroid and LABA
      3. Available in 2 strengths of fluticasone component (100 mcg for COPD or Asthma, 200 mcg for Asthma only)
      4. Dosing 1 puff daily of Dry Powder Inhaler
      5. (2020) Presc Lett, 27(11): 62
6. Protocol: Single Maintenance and Reliever Therapy (SMART)
   1. Indications
      1. Moderate to Severe Persistent Asthma
   2. Uses combination Inhaled Corticosteroid with LABA products
      1. Limited to Formoterol due to short onset of action (5 minutes)
   3. Protocol uses combination agent for additional prn dose for exacerbation symptoms
      1. Use 1-2 puffs prn up to maximum based on age (additional doses above the maintenance dose)
         1. Age over 12 years old: Up to 12 puffs per day (including maintenance)
         2. Age 4 o 11 years old: Up to 8 puffs per day (including maintenance)
      2. More than 2 rescue doses per week should prompt reevaluation
   4. Efficacy
      1. Reduced systemic steroids, ED Visits, hospitalizations (NNT 16)
      2. Now a recommended protocol in the NHLBI Asthma Guidelines 2020
   5. Precautions
      1. Extra LABA dosing has been cautioned against in past
      2. Do not use with LABA agents (maintenance or rescue) other than Formoterol
      3. SMART Protocol has been controversial for >10 years
      4. Albuterol rescue Inhaler cost is far less than the combination Corticosteroid/LABA
         1. Extra doses may not be covered by insurance (e.g. early medication refill)
   6. References
      1. (2021) Presc Lett 28(3): 14-5
      2. (2010) Thorax 65(8):747-52 [PubMed]
      3. (2011) Drug Ther Bull 49(11):126-9 [PubMed]
      4. Nalin (2019) Curr Opin Allergy Clin Immunol 19(2):111-7 [PubMed]
      5. Cloutier (2020) J Allergy Clin Immunol 146(6):1217-20 +PMID: 33280709 [PubMed]
7. References
   1. (2013) Presc Lett, 20(8): 43
   2. (2001) Med Clin North Am 43(1104):39-40 [PubMed]
   3. Wilson (2001) Chest 119:2021-6 [PubMed]