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Medication

Medication Summary

Pharmacologic management includes the use of control agents such as inhaled corticosteroids, inhaled cromolyn or nedocromil, long-acting bronchodilators, theophylline, leukotriene modifiers, and more recent strategies such as the use of anti-immunoglobulin E (IgE) antibodies (omalizumab), IL-5 monoclonal antibodies (mepolizumab, benralizumab), IL-4 receptor alpha monoclonal antibody (dupilumab), and long-acting antimuscarinic agents (LAMA) such as tiotropium. Relief medications include short-acting bronchodilators, systemic corticosteroids, and ipratropium.

In December 2018, FDA approved ProAir Digihaler (albuterol), the first digital and mobile-connected inhaler. The built-in sensors detects when the device is used and measures the strength of the user’s inhalation. The inhaler sends the user’s data to its mobile app companion and their healthcare provider.^[71]

Class Summary

These agents are used to treat bronchospasm in acute asthmatic episodes, and used to prevent bronchospasm associated with exercise-induced asthma or nocturnal asthma. Several studies have suggested that short-acting beta2-agonists such as albuterol may produce adverse outcomes (eg, decreased peak flow or increased risk of exacerbations) in patients homozygous for arginine (Arg/Arg) at the 16th amino acid position of beta-adrenergic receptor gene compared with patients homozygous for glycine (Gly-Gly). Similar findings are reported for long-acting beta2-agonists, such as salmeterol.

Albuterol (AccuNeb, Proventil HFA, Ventolin HFA, ProAir HFA, ProAir RespiClick, ProAir Digihaler)

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This beta2-agonist is the most commonly used bronchodilator that is available in multiple forms (eg, solution for nebulization, MDI, PO solution). This is most commonly used in rescue therapy for acute asthmatic symptoms. Used as needed. Prolonged use may be associated with tachyphylaxis due to beta2-receptor downregulation and receptor hyposensitivity.

Class Summary

This nonracemic form of albuterol offers a significant reduction in the adverse effects associated with racemic albuterol (eg, muscle tremors, tachycardia, hyperglycemia, hypokalemia).

Levalbuterol (Xopenex, Xopenex HFA)

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Nonracemic form of albuterol, levalbuterol (R isomer) is effective in smaller doses and is reported to have fewer adverse effects (eg, tachycardia, hyperglycemia, hypokalemia). The dose may be doubled in acute severe episodes when even a slight increase in the bronchodilator response may make a big difference in the management strategy (eg, in avoiding patient ventilation). It is available as an MDI (45 mcg per actuation) or solution for nebulized inhalation.

Class Summary

Long-acting bronchodilators (LABA) are not used for the treatment of acute bronchospasm. They are used for the preventive treatment of nocturnal asthma or exercise-induced asthmatic symptoms, for example.

Salmeterol is the only single-agent LABA available in the United States that is approved for asthma. Salmeterol and formoterol are available as combination products with inhaled corticosteroids that are approved for asthma in the United States (Advair, Symbicort, Dulera).

LABA may increase the chance of severe asthma episodes and death when those episodes occur. Most cases have occurred in patients with severe and/or acutely deteriorating asthma; they have also occurred in a few patients with less severe asthma.

LABAs are not considered first-line medications to treat asthma. LABAs should not be used as isolated medications and should be added to the asthma treatment plan only if other medicines do not control asthma, including the use of low- or medium-dose corticosteroids. If used as isolated medication, LABAs should be prescribed by a subspecialist (ie, pulmonologist, allergist).

Salmeterol (Serevent)

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This long-acting preparation of a beta2-agonist is used primarily to treat nocturnal or exercise-induced symptoms. It has no anti-inflammatory action and is not indicated in the treatment of acute bronchospastic episodes. It may be used as an adjunct to inhaled corticosteroids to reduce the potential adverse effects of the steroids. The medication is delivered via a Diskus DPI.

Class Summary

Steroids are the most potent anti-inflammatory agents. Inhaled forms are topically active, poorly absorbed, and least likely to cause adverse effects. They are used for long-term control of symptoms and for the suppression, control, and reversal of inflammation. Inhaled forms reduce the need for systemic corticosteroids.

Inhaled steroids block late asthmatic response to allergens; reduce airway hyperresponsiveness; inhibit cytokine production, adhesion protein activation, and inflammatory cell migration and activation; and reverse beta2-receptor downregulation and subsensitivity (in acute asthmatic episodes with LABA use).

Ciclesonide (Alvesco)

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Ciclesonide is an aerosol inhaled corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in adult and adolescent patients aged 12 y and older. Not indicated for relief of acute bronchospasm.

Corticosteroids have wide range of effects on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (eg, histamines, eicosanoids, leukotrienes, cytokines) involved in inflammation.

Individual patients experience variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 4 wk or longer after initiation of therapy.

After asthma stability is achieved, it is best to titrate to lowest effective dosage to reduce the possibility of adverse effects. For patients who do not adequately respond to the starting dose after 4 wk of therapy, higher doses may provide additional asthma control.

Beclomethasone (QVAR Redihaler)

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Beclomethasone inhibits bronchoconstriction mechanisms; causes direct smooth muscle relaxation; and may decrease the number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness. It is available as 40 mcg/actuation or 80 mcg/actuation.

Fluticasone inhaled (Flovent Diskus, Flovent HFA)

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Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically. It is available as an MDI aerosolized product (HFA) or DPI (Diskus).

Fluticasone furoate inhaled (Arnuity Ellipta)

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Synthetic trifluorinated corticosteroid that elicits anti-inflammatory activity. Has low oral bioavailability owing to extensive first-pass metabolism that is desirable to minimize systemic exposure. Exhibits high binding affinity for human glucocorticoid receptor (~1.7 times higher than fluticasone propionate). It is indicated for once-daily maintenance treatment of asthma as prophylactic therapy in children aged ≥5 years.

Budesonide inhaled (Pulmicort Flexhaler, Pulmicort Respules)

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Budesonide has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically. It is available as a DPI in 90 mcg/actuation (delivers about 80 mcg/actuation) or 180 mcg/actuation (delivers about 160 mcg/actuation). A nebulized susp (ie, Respules) is also available for young children.

Mometasone inhaled (Asmanex HFA, Asmanex Twisthaler)

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Mometasone is a corticosteroid for inhalation. It is indicated for asthma as prophylactic therapy.

Class Summary

These agents are used for short courses (3-10 d) to gain prompt control of inadequately controlled acute asthmatic episodes. They are also used for long-term prevention of symptoms in severe persistent asthma as well as for suppression, control, and reversal of inflammation. Frequent and repetitive use of beta2-agonists has been associated with beta2-receptor subsensitivity and downregulation; these processes are reversed with corticosteroids.

Higher-dose corticosteroids have no advantage in severe asthma exacerbations, and intravenous administration has no advantage over oral therapy, provided that GI transit time or absorption is not impaired. The usual regimen is to continue frequent multiple daily dosing until the FEV₁ or peak expiratory flow (PEF) is 50% of the predicted or personal best values; then, the dose is changed to twice daily. This usually occurs within 48 hours.

Prednisone (Deltasone, Orasone) and prednisolone (Pediapred, Prelone, Orapred)

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An immunosuppressant for the treatment of autoimmune disorders, prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity.

Methylprednisolone (Solu-Medrol)

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Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dexamethasone (Baycadron, Dexamethasone Intensol)

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Dexamethasone in the ED can provide equivalent relief to a 5-day course of prednisone—and without the adverse side effect of vomiting—for acute asthma flare-ups in children. Researchers performed a meta-analysis of 6 studies based in the ED and found that significantly fewer patients receiving dexamethasone vomited in the ED or at home after discharge compared with patients receiving oral prednisone or prednisolone. The data suggest that emergency physicians should consider single or 2-dose dexamethasone regimens over 5-day prednisone/prednisolone regimens for the treatment of acute asthma exacerbations.

Class Summary

Knowledge that leukotrienes cause bronchospasm, increased vascular permeability, mucosal edema, and inflammatory cell infiltration has led to the concept of modifying their action by using pharmacologic agents. These are either 5-lipoxygenase inhibitors or leukotriene-receptor antagonists.

Zafirlukast (Accolate)

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Zafirlukast is a selective competitive inhibitor of LTD4 and LTE4 receptors.

Montelukast (Singulair)

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The last agent introduced in its class, montelukast has the advantages that it is chewable, it has a once-a-day dosing, and it has no significant adverse effects.

Class Summary

These agents are used for long-term control and prevention of symptoms, especially nocturnal symptoms.

Theophylline (Theo-24, Theochron)

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Theophylline is available in short-acting and long-acting formulations. Because of the need to monitor serum concentrations, this agent is used infrequently. The dose and frequency depend on the particular product selected.

Class Summary

These combinations may decrease asthma exacerbations when inhaled short-acting beta2-agonists and corticosteroids have failed. Refer to previous discussion in the LABAs section regarding increased risk of severe asthma episodes and death with LABAs. In a recent study, use of combination therapy using fluticasone propionate and salmeterol prolonged time to first severe asthma exacerbation.^[72]

Budesonide is an inhaled corticosteroid that alters level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in the asthmatic response. Available as MDI in 2 strengths; each actuation delivers formoterol 4.5 mcg with either 80 mcg or 160 mcg.

Budesonide/formoterol (Symbicort)

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Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with asthma. Budesonide is an inhaled corticosteroid that alters the level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in the asthmatic response. This combination is available as an MDI in 2 strengths; each actuation delivers formoterol 4.5-mcg with either 80-mcg or 160-mcg of budesonide. The 80/4.5 mcg strength is approved for use in children aged 6-12 y, whereas, either strength is approved for children aged ≥12 y.

Mometasone and formoterol (Dulera)

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This is a combination corticosteroid and LABA metered-dose inhaler. Mometasone elicits local anti-inflammatory effects in the respiratory tract with minimal systemic absorption. Formoterol elicits bronchial smooth muscle relaxation.

This combination is indicated for prevention and maintenance of asthma symptoms in patients inadequately controlled with other asthma controller medications (eg, low-dose to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, including a LABA. Available in 3 strengths; each actuation delivers mometasone/formoterol 50 mcg/5 mcg,100 mcg/5 mcg, or 200 mcg/5 mcg.

Salmeterol/fluticasone inhaled (Advair)

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This is a combination corticosteroid and LABA metered-dose inhaler. Fluticasone inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, in turn decreasing airway hyper-responsiveness. It also has vasoconstrictive activity. Salmeterol relaxes the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis and can relieve bronchospasms. Its effect may also facilitate expectoration. Adverse effects are more likely to occur when administered at high or more frequent doses than recommended. Two delivery mechanisms are available (ie, powder for inhalation [Diskus], metered-dose inhaler [MDI]). Diskus is available as a combination of salmeterol 50 mcg with fluticasone 100 mcg, 250 mcg, or 500 mcg. The MDI is available as 21 mcg salmeterol with fluticasone 45 mcg, 115 mcg, or 230 mcg.

Vilanterol/fluticasone furoate inhaled (Breo Ellipta)

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Fluticasone furoate is a long-acting inhaled trifluorinated corticosteroid with potent anti-inflammatory activity. Vilanterol is a long-acting beta2-agonist. It is indicated as once daily maintenance treatment of asthma in patients aged 5 years and older.

Class Summary

The long-acting anticholinergic agent, tiotropium, may be considered for long-term maintenance therapy, but not for acute treatment of asthma exacerbations.

Tiotropium (Spiriva Respimat)

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Tiotropium is a long-acting antimuscarinic agent, often referred to as an anticholinergic. Inhibits M₃-receptors at smooth muscle, leading to bronchodilation. It is indicated for long-term, once-daily, maintenance treatment of asthma in patients aged ≥6 years.

Ipratropium (Atrovent)

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Chemically related to atropine, ipratropium has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. The MDI delivers 17 mcg/actuation. Solution for inhalation contains 500 mcg/2.5 mL (ie, 0.02% solution for nebulization). It is not approved for asthma, but off-label use for acute exacerbations of asthma in addition to beta2-agonist therapy has been described in the literature. It is a short-acting anticholinergic agent with an onset of 15 minutes.

Class Summary

Monoclonal antibody effects vary depending on their receptor target. Omalizumab binds to IG-E on the surface of mast cells and basophils. It reduces release of these mediators that promote an allergic response. Mepolizumab and benralizumab inhibit IL-5 binding to eosinophils and results in reduced blood, tissue, and sputum eosinophil levels. Dupilumab inhibits IL-4 receptor alpha, and thereby blocks IL-4 and IL-13 signaling. This in turn reduces cytokine-induced inflammatory response.

Mepolizumab approval was based on 3 key phase 3 trials (DREAM, MENSA, and SIRIUS). Each trial demonstrated statistically significant improvement in decreasing asthma exacerbations and emergency department visits or hospitalization. Mean reduction in glucocorticoid use was 50% in the mepolizumab group, while also reducing the asthma exacerbation rate. Significant improvement in FEV₁ was also observed compared with placebo.^{[73, 74, 75]}

Benralizumab approval was based on results from the WINDWARD clinical trial program, including the phase 3 exacerbation trials, SIROCCO and CALIMA, and the phase 3 oral corticosteroid (OCS)-sparing trial, ZONDA.^{[76, 77, 78]}Results for the 8-week benralizumab dosing regimen from these trials showed significantly reduced annual asthma exacerbation rate (AAER), improved FEV₁, and a 75% median reduction in daily OCS use and discontinuation of OCS use in 52% of eligible patients compared with placebo.

Approval for dupilumab was based on the LIBERTY QUEST (n=1902) and VENTURE (n=210) phase 3 clinical trials. In the LIBERTY QUEST trial, patients with moderate-to-severe uncontrolled asthma were administered dupilumab add-on therapy to current maintenance therapy every 2 weeks or matched placebo. Those receiving a 200-mg dose demonstrated a 47.7% lower rate of annualized severe asthma exacerbations compared with placebo add-on (P<0.001). The 300-mg dose showed a similar response.^[79]

In the LIBERTY VENTURE trial, patients with oral corticosteroid-dependent severe asthma were administered dupilumab add-on therapy or matched placebo to current maintenance therapy every 2 weeks for 24 weeks or matched placebo. Corticosteroid doses were gradually decreased from week 4 to week 20 and then maintained for 4 weeks. Patients receiving dupilumab had a 70.1% greater corticosteroid dose reduction compared with 41.9% for placebo add-on (P<0.001). Additionally, patients receiving dupilumab had a 59% (95% [CI], 37 to 74) lower rate of severe asthma exacerbations than those taking placebo add-on.^[80]

Approval of tezepelumab was based on the NAVIGATOR phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (aged 12 to 80 years) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. Among 1061 patients who underwent randomization, 529 were assigned to receive tezepelumab and 532 to receive placebo. The annualized rate of asthma exacerbations was 0.93 with tezepelumab and 2.10 with placebo (P<0.001). Additionally, among patients with a blood eosinophil count of less than 300 cells per microliter, the annualized rate was 1.02 with tezepelumab and 1.73 with placebo (P<0.001). At week 52, improvements were greater with tezepelumab than with placebo with respect to the prebronchodilator FEV₁ (0.23 vs 0.09 liters; P<0.001).<ref>81</ref>

Omalizumab (Xolair)

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Omalizumab is a recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE on surface of mast cells and basophils. It reduces mediator release, which promotes allergic response. It is indicated for moderate-to-severe persistent asthma in patients aged 6 years or older who react to perennial allergens in whom symptoms are not controlled by inhaled corticosteroids.

Mepolizumab (Nucala)

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Mepolizumab is a humanized IgG1 kappa monoclonal antibody specific for interleukin-5 (IL-5). Mepolizumab binds to IL-5, and therefore stops IL-5 from binding to its receptor on the surface of eosinophils. It is indicated for add-on maintenance treatment of patients with severe asthma aged 6 years or older, and with an eosinophilic phenotype.

Benralizumab (Fasenra)

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Benralizumab is a humanized monoclonal antibody (IgG1/kappa-class) selective for the IL-5 alpha subunit of basophils and eosinophils. It is indicated for add-on maintenance treatment of severe asthma in patients aged 12 years or older who have an eosinophilic phenotype.

Dupilumab (Dupixent)

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Inhibits IL-4 receptor alpha, and thereby blocks IL-4 and IL-13 signaling. This in turn reduces cytokine-induced inflammatory response. It is indicated as an add-on maintenance treatment for moderate-to-severe asthma in patients aged 12 years or older with eosinophilic phenotype or PO corticosteroid dependent asthma.

Tezepelumab (Tezspire)

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Human monoclonal antibody immunoglobulin G2-lambda that inhibits thymic stromal lymphopoietin (TSLP), a key epithelial cytokine involved in multiple inflammatory cascades and initiates an over reactive immune response to allergic, eosinophilic, and other types of airway inflammation associated with severe asthma. Tezepelumab is indicated as add-on maintenance treatment for severe asthma in adults and adolescents aged 12 years and older.

Questions

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Table 1. Stepwise Approach to Asthma Medications

Table 1. Stepwise Approach to Asthma Medications

Intermittent Asthma		Persistent Asthma: Daily Medication
Age	Step 1	Step 2	Step 3	Step 4	Step 5	Step 6
< 5 y	Rapid-acting beta2-agonist prn	Low-dose inhaled corticosteroid (ICS)	Medium-dose ICS	Medium-dose ICS plus either long-acting beta2-agonist (LABA) or montelukast	High-dose ICS plus either LABA or montelukast	High-dose ICS plus either LABA or montelukast; Oral systemic corticosteroid
		Alternate regimen: cromolyn or montelukast
5-11 y	Rapid-acting beta2-agonist prn	Low-dose ICS	Either low-dose ICS plus either LABA, LTRA, or theophylline OR Medium-dose	Medium-dose ICS plus LABA	High-dose ICS plus LABA	High-dose ICS plus LABA plus oral systemic corticosteroid
		Alternate regimen: cromolyn, leukotriene receptor antagonist (LTRA), or theophylline		Alternate regimen: medium-dose ICS plus either LTRA or theophylline	Alternate regimen: high-dose ICS plus either LABA or theophylline	Alternate regimen: high-dose ICS plus LRTA or theophylline plus systemic corticosteroid
12 y or older	Rapid-acting beta2-agonist as needed	Low-dose ICS	Low-dose ICS plus LABA OR Medium-dose ICS	Medium-dose ICS plus LABA	High-dose ICS plus LABA (and consider omalizumab for patients with allergies)	High-dose ICS plus either LABA plus oral corticosteroid (and consider omalizumab for patients with allergies)
		Alternate regimen: cromolyn, LTRA, or theophylline	Alternate regimen: low-dose ICS plus either LTRA, theophylline, or zileuton	Alternate regimen: medium-dose ICS plus either LTRA, theophylline, or zileuton

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Author

Girish D Sharma, MD, FCCP, FAAP Professor of Pediatrics, Rush Medical College; Director, Section of Pediatric Pulmonology and Rush Cystic Fibrosis Center, Rush Children's Hospital, Rush University Medical Center

Girish D Sharma, MD, FCCP, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, Royal College of Physicians of Ireland

Disclosure: Nothing to disclose.

Coauthor(s)

Payel Gupta, MD Department of Allergy and Immunology, ENT Faculty Practice

Payel Gupta, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Charles Callahan, DO Professor, Chief, Department of Pediatrics and Pediatric Pulmonology, Tripler Army Medical Center

Charles Callahan, DO is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American College of Osteopathic Pediatricians, American Thoracic Society, The Society of Federal Health Professionals (AMSUS), Christian Medical and Dental Associations

Disclosure: Nothing to disclose.

Chief Editor

Kenan Haver, MD Associate Professor of Pediatrics, Harvard Medical School; Director of Asthma Program, Director of Flexible Bronchoscopy Program, Director of Pulmonary Division Asthma Program, Co-Director of Primary Ciliary Dyskinesia, Co-Leader of Empyema Standardized Clinical Assessment and Management Plans (SCAMP), Boston Children’s Hospital

Kenan Haver, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society

Disclosure: Author for: UptoDate.

Additional Contributors

Thomas Scanlin, MD Chief, Division of Pulmonary Medicine and Cystic Fibrosis Center, Department of Pediatrics, Rutgers Robert Wood Johnson Medical School

Thomas Scanlin, MD is a member of the following medical societies: American Association for the Advancement of Science, Society for Pediatric Research, American Society for Biochemistry and Molecular Biology, American Thoracic Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Pediatric Asthma Medication

Medication Summary

Bronchodilators, Beta2-Agonists

Class Summary

Albuterol (AccuNeb, Proventil HFA, Ventolin HFA, ProAir HFA, ProAir RespiClick, ProAir Digihaler)

Nonracemic Form of the Beta2-Agonist Albuterol

Class Summary

Levalbuterol (Xopenex, Xopenex HFA)

Long-Acting Beta2-Agonists

Class Summary

Salmeterol (Serevent)

Inhaled Corticosteroids

Class Summary

Ciclesonide (Alvesco)

Beclomethasone (QVAR Redihaler)

Fluticasone inhaled (Flovent Diskus, Flovent HFA)

Fluticasone furoate inhaled (Arnuity Ellipta)

Budesonide inhaled (Pulmicort Flexhaler, Pulmicort Respules)

Mometasone inhaled (Asmanex HFA, Asmanex Twisthaler)

Systemic Corticosteroids

Class Summary

Prednisone (Deltasone, Orasone) and prednisolone (Pediapred, Prelone, Orapred)

Methylprednisolone (Solu-Medrol)

Dexamethasone (Baycadron, Dexamethasone Intensol)

Leukotriene Modifiers

Class Summary

Zafirlukast (Accolate)

Montelukast (Singulair)

Methylxanthines

Class Summary

Theophylline (Theo-24, Theochron)

Combination Inhaled Steroids/Long-Acting Beta2-Agonists

Class Summary

Budesonide/formoterol (Symbicort)

Mometasone and formoterol (Dulera)

Salmeterol/fluticasone inhaled (Advair)

Vilanterol/fluticasone furoate inhaled (Breo Ellipta)

Anticholinergic Agents

Class Summary

Tiotropium (Spiriva Respimat)

Ipratropium (Atrovent)

Monoclonal Antibodies, Anti-asthmatics

Class Summary

Omalizumab (Xolair)

Mepolizumab (Nucala)

Benralizumab (Fasenra)

Dupilumab (Dupixent)

Tezepelumab (Tezspire)

References

Tables

Contributor Information and Disclosures

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