III. 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]

IV. 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

V. 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

VI. Protocol: Single Maintenance and Reliever Therapy (SMART)

  1. Indications
    1. Moderate to Severe Persistent Asthma in age 4 years and older
  2. Uses combination Inhaled Corticosteroid with LABA products
    1. Limited to Formoterol (Symbicort or Dulera) due to short onset of action (5 minutes)
  3. Protocol uses combination agent for additional prn dose for exacerbation symptoms
    1. Maintenance base dosing as above
      1. Dose 1-2 puffs (1 puff if under age 12 years) daily or twice daily
    2. 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 (Symbicort) or 10 puffs (Dulera) per day (including maintenance)
      2. Age 4 to 11 years old: Up to 8 puffs (Symbicort) or 7 puffs (Dulera) per day (including maintenance)
    3. Indications for medical evaluation
      1. Red Zone Symptoms (call 911, and use rescue puffs every 1-3 minutes up to 6 puffs until EMS arrival)
      2. Yellow zone symptoms for 2-3 days (>4 rescue puffs/day in age <12 years, >6 rescue puffs/day if older)
        1. See Asthma Exacerbation
        2. Consider Corticosteroid burst (e.g. Prednisone 40 mg daily for 5 to 7 days)
        3. Consider increasing maintenance therapy
  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. (2022) Presc Lett, August Issue, accessed online 8/2/2022
    3. (2010) Thorax 65(8):747-52 [PubMed]
    4. (2011) Drug Ther Bull 49(11):126-9 [PubMed]
    5. Nalin (2019) Curr Opin Allergy Clin Immunol 19(2):111-7 [PubMed]
    6. Cloutier (2020) J Allergy Clin Immunol 146(6):1217-20 +PMID: 33280709 [PubMed]

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Cost: Medications

serevent (on 1/1/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
SEREVENT DISKUS 50 MCG $6.79 each
formoterol (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
FORMOTEROL 20 MCG/2 ML NEB VL Generic $5.08 per ml
advair (on 2/23/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
ADVAIR 100-50 DISKUS Generic $1.41 each
ADVAIR 250-50 DISKUS Generic $1.63 each
ADVAIR 500-50 DISKUS Generic $2.89 each
ADVAIR HFA 115-21 MCG INHALER $32.46 per gram
ADVAIR HFA 230-21 MCG INHALER $42.69 per gram
ADVAIR HFA 45-21 MCG INHALER $26.18 per gram
symbicort (on 1/1/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
SYMBICORT 160-4.5 MCG INHALER Generic $22.80 per gram
SYMBICORT 80-4.5 MCG INHALER Generic $19.81 per gram
dulera (on 1/14/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
DULERA 100 MCG-5 MCG INHALER $24.20 per gram
DULERA 200 MCG-5 MCG INHALER $24.12 per gram
DULERA 50 MCG-5 MCG INHALER $24.16 per gram
breo ellipta (on 1/1/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
BREO ELLIPTA 100-25 MCG INH Generic $3.75 each
BREO ELLIPTA 200-25 MCG INH Generic $3.70 each
arformoterol (on 12/21/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
ARFORMOTEROL 15 MCG/2 ML SOLN Generic $1.53 per ml
brovana (on 11/23/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
BROVANA 15 MCG/2 ML SOLUTION Generic $1.20 per ml
trelegy ellipta (on 1/1/2022 at Medicaid.Gov Survey of pharmacy drug pricing)
TRELEGY ELLIPTA 100-62.5-25 $9.93 each
TRELEGY ELLIPTA 200-62.5-25 $9.95 each