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

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II. Indications

  1. Moderate Persistent Asthma
  2. Severe Persistent Asthma

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]

VII. 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]

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Related Studies

Cost: Medications

serevent (on 2/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
SEREVENT DISKUS 50 MCG $5.61 each
arcapta (on 4/1/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
ARCAPTA NEOHALER 75 MCG CAP $7.56 each
advair (on 2/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
ADVAIR 100-50 DISKUS $4.66 each
ADVAIR 250-50 DISKUS $5.79 each
ADVAIR 500-50 DISKUS $7.62 each
ADVAIR HFA 115-21 MCG INHALER $28.91 per gram
ADVAIR HFA 230-21 MCG INHALER $38.04 per gram
ADVAIR HFA 45-21 MCG INHALER $23.25 per gram
symbicort (on 2/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
SYMBICORT 160-4.5 MCG INHALER $29.11 per gram
SYMBICORT 80-4.5 MCG INHALER $25.45 per gram
dulera (on 2/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
DULERA 100 MCG/5 MCG INHALER $21.47 per gram
DULERA 200 MCG/5 MCG INHALER $21.48 per gram
breo ellipta (on 2/22/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
BREO ELLIPTA 100-25 MCG INH $5.16 each
BREO ELLIPTA 200-25 MCG INH $5.16 each
brovana (on 4/19/2017 at Medicaid.Gov Survey of pharmacy drug pricing)
BROVANA 15 MCG/2 ML SOLUTION $6.98 per ml
FPNotebook does not benefit financially from showing this medication data or their pharmacy links. This information is provided only to help medical providers and their patients see relative costs. Insurance plans negotiate lower medication prices with suppliers. Prices shown here are out of pocket, non-negotiated rates. See Needy Meds for financial assistance information.

Ontology: formoterol (C0060657)

Definition (NCI) A long-acting beta-adrenergic receptor agonist with bronchodilator activity. Formoterol selectively binds to beta-2 adrenergic receptors in bronchial smooth muscle, thereby activating intracellular adenyl cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cAMP). Increased cAMP levels cause relaxation of bronchial smooth muscle, relieve bronchospasms, improve mucociliary clearance and reduce mediator substance release from inflammatory cells, especially from mast cells.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C012629
SnomedCT 320260000, 395969001, 386171009, 414289007
English N-(2-hydroxy-5-(1-hydroxy-2-((2-(4-methoxyphenyl)-1-methylethyl)amino)ethyl)phenyl)formamide, (E)-2-butenedioate (2:1) (salt), eformoterol, formoterol [Chemical/Ingredient], Eformoterol (product), Eformoterol (substance), FORMOTEROL, Formoterol (product), Formoterol, Eformoterol, Formoterol (substance), formoterol
Spanish eformoterol, eformoterol (producto), eformoterol (sustancia), formoterol (producto), formoterol, formoterol (sustancia)
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: salmeterol (C0073992)

Definition (NCI) A highly selective, long-acting beta-2 adrenergic agonist with bronchodilatory activity. Salmeterol's benzene moiety resembles the structure of catecholamines, and occupies the active site of beta-2 adrenergic receptor, while the long, lipophilic side chain of salmeterol, binds to the so called 'exosite' near the beta-2 adrenergic receptors. The binding at the exosite allows the active portion of the molecule to remain at the receptor site and continually engage and disengage with the receptor, therefore providing a long duration of action. This agent stimulates intracellular adenyl cyclase to catalyze the conversion of adenosine triphosphate to cyclic-3',5'-adenosine monophosphate (cAMP). Increased cAMP levels result in relaxation of bronchiolar smooth muscle, bronchodilation and increased bronchial airflow.
Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C057823
SnomedCT 108605008, 372515005
English salmeterol, salmeterol (medication), salmeterol [Chemical/Ingredient], SALMETEROL, Salmeterol, Salmeterol product, Salmeterol (product), Salmeterol (substance)
Spanish salmeterol (producto), salmeterol (sustancia), salmeterol
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Selective beta-2 adrenoceptor stimulants (C0354671)

Concepts Pharmacologic Substance (T121)
SnomedCT 320073005, 373215002
English Selective beta-2 stimulants, Selective beta-2 adrenoceptor stimulants, Selective beta-2 agonists, Selective beta-2 adrenoceptor stimulants (product), Selective beta-2 adrenoceptor stimulants (substance)
Spanish estimulantes selectivos de receptores adrenérgicos beta 2 (sustancia), estimulantes selectivos de receptores adrenérgicos beta 2, estimulantes selectivos beta 2 adrenérgicos (producto), estimulantes selectivos beta 2 adrenérgicos (sustancia), estimulantes selectivos beta 2 adrenérgicos
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Foradil (C0592533)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C012629
English Foradil, Schering brand of formoterol fumarate, foradil
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Serevent (C0700491)

Concepts Pharmacologic Substance (T121) , Organic Chemical (T109)
MSH C057823
English Serevent, Glaxo Wellcome brand of salmeterol xinafoate, serevent
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Arcapta (C3162477)

Concepts Organic Chemical (T109) , Pharmacologic Substance (T121)
English Arcapta
Derived from the NIH UMLS (Unified Medical Language System)

Related Topics in Pharmacology

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