View the Comparison Chart: Some Inhaled Drugs for Treatment of Asthma

View the Comparison Chart: Correct Use of Inhalers for Asthma

The goal of asthma treatment is to control symptoms, prevent exacerbations, and maintain normal lung function. Management of acute exacerbations in the emergency department is not discussed here.

The FDA has approved Airsupra (AstraZeneca), a metered-dose inhaler containing the short-acting beta₂-agonist (SABA) albuterol and the inhaled corticosteroid (ICS) budesonide, for use as needed for treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in patients ≥18 years old with asthma. Airsupra is the first combination of a SABA and an ICS to become available in the US. It is not approved for use as maintenance therapy.

Tezepelumab-ekko (Tezspire – AstraZeneca/Amgen), a subcutaneously administered thymic stromal lymphopoietin (TSLP) blocker, has been approved by the FDA for add-on maintenance treatment of severe asthma in patients ≥12 years old. It is the first TSLP blocker to become available in the US and the first biologic drug to be approved for treatment of severe asthma without phenotypic or biomarker limitations.

The goal of asthma treatment is to control symptoms, prevent exacerbations, and maintain normal lung function. Management of acute exacerbations of asthma in the emergency department is not discussed here.

View the table: Some Inhaled Drugs for Treatment of Asthma

View the table: Correct Use of Inhalers for Asthma

The short-acting beta₂-agonist albuterol sulfate has recently become available as a large-volume (20 mL), preservative-free concentrate (albuterol inhalation solution 0.5% – Nephron Pharmaceuticals) that can be used to prepare solutions for administration of continuous nebulized albuterol (CNA). CNA is commonly used (off-label) for acute treatment of severe asthma exacerbations in hospitalized patients, particularly children. Many hospitals have been using a 20-mL multidose bottle of 0.5% albuterol that contains the preservative benzalkonium chloride (BAC) for this purpose. Until now, preservative-free albuterol was only available in 0.5-mL single-dose vials.

View the Table: Correct Use of Inhalers for COPD

The FDA is requiring stronger warnings in the labeling of the leukotriene receptor antagonist montelukast (Singulair, and generics) about the risk of suicidal behavior and other serious neuropsychiatric events associated with its use.

The FDA has approved over-the-counter (OTC) sale of inhaled epinephrine (Primatene Mist – Amphastar), a nonselective alpha and beta agonist, for temporary relief of mild symptoms of intermittent asthma in patients ≥12 years old who have been diagnosed with mild intermittent asthma by a healthcare professional. The original version of Primatene Mist, which was approved by the FDA in 1967, was removed from the market in 2011 because the metered-dose inhaler (MDI) contained ozone-depleting chlorofluorocarbon (CFC) propellants; the new MDI contains hydrofluoroalkane (HFA) propellants.

The FDA has approved the subcutaneously injected monoclonal antibody dupilumab (Dupixent – Sanofi/Regeneron) for add-on maintenance treatment of patients ≥12 years old with moderate to severe asthma with an eosinophilic phenotype or with oral corticosteroid-dependent asthma. Dupilumab was approved earlier to treat adults with moderate to severe atopic dermatitis inadequately controlled with topical therapies.

The FDA has approved benralizumab (Fasenra – AstraZeneca), a humanized monoclonal antibody selective for the interleukin-5 (IL-5) receptor, for add-on maintenance treatment of severe asthma in patients ≥12 years old with an eosinophilic phenotype. Benralizumab is the third anti-IL-5 antibody to be approved for treatment of severe eosinophilic asthma; mepolizumab (Nucala) and reslizumab (Cinqair), which target IL-5 itself, were approved earlier.

The goal of asthma treatment is to control symptoms and prevent exacerbations. Management of acute exacerbations of asthma is not discussed here.

View the Comparison Table: Some Inhaled Drugs for Treatment of Asthma

View the Comparison Table: Correct Use of Inhalers

Allergic rhinitis can be classified as seasonal, perennial, or episodic. It is often associated with allergic conjunctivitis, rhinosinusitis, and asthma.

H₁-ANTIHISTAMINES — Oral – Oral second-generation H₁-antihistamines are the preferred first-line treatment for relief of the itching, sneezing, and rhinorrhea that characterize mild-to-moderate allergic rhinitis. They are less effective for nasal congestion.

The FDA has approved reslizumab (Cinqair – Teva), a humanized interleukin-5 (IL-5) antagonist monoclonal antibody, for add-on maintenance treatment of severe asthma in adults who have an eosinophilic phenotype. It is the second IL-5 antagonist to be approved in the US; mepolizumab (Nucala) was approved for the same indication in 2015.

The FDA has approved mepolizumab (Nucala - GSK), a subcutaneously injected humanized interleukin-5 (IL-5) antagonist monoclonal antibody, for maintenance treatment of severe asthma in patients ≥12 years old who have an eosinophilic phenotype.

The short-acting beta₂-agonist albuterol sulfate is now available as a dry powder for inhalation (ProAir RespiClick – Teva) for prevention and treatment of broncho spasm in patients ≥12 years old. ProAir RespiClick is the only short-acting beta₂-agonist dry powder inhaler available in the US.



Metered-dose inhalers (MDIs) use a hydrofluoroalkane (HFA) propellant. They require coordination of inhalation with actuation; using them with a valved holding chamber minimizes this need, but decreases portability because of the size of the chamber. Dry powder inhalers such as ProAir RespiClick, which are breath-actuated, do not require a propellant and do not have to be primed before use. They do not require coordination of inhalation with actuation, but patients must be capable of performing a rapid, deep inhalation, which might be difficult during a severe asthma attack.

The recommended dose of ProAir RespiClick for treatment of bronchospasm is 2 inhalations, but 1 inhalation may be sufficient for some patients. The dose can be repeated every 4-6 hours as needed. For prevention of exercise-induced bronchospasm, the recommended dosage is 2 inhalations 15-30 minutes before exercise.

Each ProAir RespiClick inhaler includes a dose counter. Opening the mouthpiece cap readies a dose for administration and causes the counter to count down by 1; closing the cap without inhaling the medication wastes that dose. The inhaler should be cleaned with a dry cloth as needed.

ProAir RespiClick may contain trace levels of milk proteins; it is contraindicated for use in patients with a history of a severe hypersensitivity reaction to milk proteins.

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The FDA has approved Arnuity Ellipta (GSK), a single-agent inhaler containing the corticosteroid fluticasone furoate, for once-daily maintenance treatment of asthma in patients ≥12 years old. Fluticasone furoate is also available in combination with the long-acting beta₂-agonist vilanterol as Breo Ellipta for treatment of asthma and COPD.

INHALATION DEVICES — Metered-dose inhalers (MDIs) require coordination of inhalation with hand-actuation of the device. Valved holding chambers (VHCs) or spacers help some patients, especially young children and the elderly, use MDIs effectively. VHCs have one-way valves that prevent the patient from exhaling into the device, minimizing the need for coordinated actuation and inhalation. Spacers are tubes or chambers placed between the canister and a face mask or mouthpiece, which also avoids the need to coordinate actuation and inhalation. Both VHCs and spacers retain the larger particles emitted from the MDI, decreasing their deposition in the oropharynx and leading to a higher proportion of small respirable particles being inhaled.

Inhalation is the preferred route of delivery for most asthma drugs. Chlorofluorocarbons (CFCs), which have ozone-depleting properties, are being phased out as propellants in metered-dose inhalers. Non-chlorinated hydrofluoroalkane (HFA) propellants, which do not deplete the ozone layer, are being used instead.

(Med Lett Drugs Ther 2010; 52:83) The second clinical trial described under the paragraph heading “Clinical Studies” compared the 2 different strengths of the combination with mometasone alone, 400 mcg twice daily, and not with placebo.

A combination of the corticosteroid mometasone furoate (Asmanex) and the long-acting beta₂-agonist (LABA) formoterol (Foradil) has become available in a single metered-dose inhaler (Dulera – Schering) for treatment of asthma in patients ≥12 years old. It is the third corticosteroid/LABA combination inhaler to become available for this indication in the US. None of these combinations should be used for initial treatment of asthma or for acute treatment of asthma symptoms.

The FDA has approved the marketing of the Alair Bronchial Thermoplasty System (Asthmatx) for treatment of severe persistent asthma in patients ≥18 years old whose asthma is not well controlled with inhaled corticosteroids and long-acting beta₂-agonists.

A little more than a year ago, The Medical Letter reported the results of an FDA meta-analysis which found that use of a long-acting beta-2 agonist (LABA) such as salmeterol (Severent) or formoterol (Foradil) in patients with asthma was associated with an increased risk of a composite endpoint of asthma-related death, intubation or hospitalization; the highest risk was in children 4-11 years old.There was no significant increase in risk when a long-acting beta-2 agonist was used with an inhaled corticosteroid.The Medical Letter recommended that long-acting beta-2 agonists should not be used as monotherapy for asthma, especially in children, and that long-acting beta-2 agonists should be used for asthma only in combination with an inhaled corticosteroid, preferably in a fixed-dose combination in the same inhaler.1

Now the FDA has issued new Safe Use Requirements2 and labeling requirements for long-acting beta-2 agonists that include the following: “Stop use of the LABA, if possible, once asthma control is achieved and maintain the use of an asthma-controller medication such as an inhaled corticosteroid.”3

It has not been determined that patients taking a longacting beta-2 agonist in a fixed-dose combination with an inhaled corticosteroid have an increased risk of death or that stopping long-acting beta-2 agonists in such patients will improve long-term outcomes. A controlled clinical trial of these new requirements would be welcome.

1. Long-acting beta-2 agonists in asthma. Med Lett Drugs Ther 2009; 51:1.
2. www.fda.gov/safety/medwatch/default.htm
3. BA Chowdhury and G Dal Pan. The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N Engl J Med 2010; Feb 24 (epub).

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Allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, anaphylaxis and asthma (not included here; reviewed in Treatment Guidelines 2008; 6:83) are prevalent worldwide, especially in industrialized countries. Pharmacologic treatment of these disorders continues to improve in efficacy and safety. In addition to using drugs to prevent and control these allergic diseases, patients should be instructed to avoid, if possible, specific allergens and/or environmental conditions that trigger or worsen their symptoms. Allergen-specific immunotherapy may be useful for treatment of allergic rhinitis and allergic conjunctivitis, and in preventing severe insect venom-triggered reactions.

Continued use of a long-acting beta-2 agonist for treatment of asthma may cause down-regulation of the beta-2 receptor with loss of the bronchoprotective effect from rescue therapy with a short-acting beta-2 agonist. After a large study (SMART) found an increased risk of asthma-related deaths in patients receiving the long-acting beta-2 agonist salmeterol, a boxed warning was added to the labeling of all medications containing a long-acting beta-2 agonist. Now the FDA has completed a meta-analysis of 110 asthma treatment studies in 60,954 patients taking any of the long-acting beta-2 agonist formulations listed in the table.

No truly new drugs have been approved for treatment of asthma since omalizumab (Xolair) in 2003, but some randomized controlled trials of older drugs have been published, and new guidelines have become available.

Inhaled drugs for asthma are available in the US mainly in pressurized metered-dose inhalers (MDIs), which require a propellant, and dry powder inhalers, which do not. The chlorofluorocarbon (CFC) propellants in MDIs are being replaced by hydrofluoroalkane (HFA) propellants for environmental reasons: CFCs contribute to the depletion of the ozone layer. December 31, 2008 will be the last day that albuterol MDIs using CFC propellants can be sold in the US. The FDA is expected to announce a termination date for other CFC-containing products in the near future.

Three HFA albuterol inhalers and one HFA levalbuterol inhaler have been approved by the FDA. None is available generically. HFA inhalers require priming — firing 4 puffs into the air (3 with ProAir) — the first time they are used, and after 2 weeks of non-use (3 days with Xopenex HFA).

In general, HFA sprays taste different, are less forceful, and are warmer and mistier than CFC sprays. Some patients may have to be reassured that they are getting enough of their medication, but actually the smaller particles of the HFA sprays may reach the lungs more readily than CFC sprays.

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The FDA has approved the marketing of the corticosteroid ciclesonide (Alvesco - Sepracor) in a hydrofluoroalkane (HFA) metered-dose inhaler formulation for maintenance treatment of asthma in patients >12 years old. Ciclesonide is also available in the US as a nasal spray for allergic rhinitis (Omnaris), and has been available for asthma in Europe since 2003.

Peptic ulcers caused by treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) are mainly gastric ulcers. The greater the number of office visits and the longer the counseling time, the higher the smoking cessation rates have been.

A combination of the corticosteroid budesonide and the long-acting beta₂-agonist formoterol (Symbicort - AstraZeneca) has become available in a metered dose inhaler for long-term maintenance treatment of asthma in patients ≥ 12 years old. A combination product that contains fluticasone propionate and salmeterol (Advair) is already available for this indication in the US. Neither one of these combinations is approved for acute treatment of asthma symptoms. A dry powder inhaler formulation of Symbicort has been available in Europe and Canada for several years.

The FDA has received new reports of serious and life-threatening hypersensitivity reactions to omalizumab (Xolair – Genentech), a monoclonal anti-IgE antibody injected subcutaneously for treatment of asthma (Med Lett Drugs Ther 2003; 45:67), and has added a black-box warning to the package insert.

Postmarketing reports submitted to the FDA included 124 reports of anaphylaxis among an estimated 57,300 patients (0.2%) who might have been treated with the drug between June 2003 and December 2006. Anaphylaxis occurred after the first dose of Xolair in 39% of cases, after a 2nd dose in 19%, after a 3rd dose in 10% and after subsequent doses in the rest; one case occurred after 39 doses (19 months of continuous therapy) when treatment was restarted after a 3-month gap. Most cases (59%) occurred within 2 hours of the injection, but 32% occurred later, up to 4 days after the injection. No deaths have been reported (www.fda.gov/cder/drug/infopage/omalizumab).

Use of omalizumab should be limited to patients with severe asthma that is not adequately controlled by other drugs and has a clear allergic component. Patients should be observed for 2 hours after injection in a setting where anaphylaxis can be diagnosed and treated promptly and should carry an epinephrine autoinjector (EpiPen; Twinject) for a few days following an injection.

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Levalbuterol, the R-isomer of the beta-2 adrenergic agonist albuterol, is now available in the US as a metered-dose inhaler (Xopenex HFA - Sepracor) for treatment of asthma in patients ≥ 4 years old. Levalbuterol has been available since 1999 in a nebulizer solution for treatment of bronchospasm in patients ≥ 6 years old.1 Outside the US, albuterol is called salbutamol, and levalbuterol is levosalbutamol.

The FDA has approved marketing of the corticosteroid mometasone furoate in an orally inhaled dry powder formulation (Asmanex Twisthaler - Schering-Plough) for maintenance treatment of asthma in patients at least 12 years old. Mometasone is also available as a mid-potency topical corticosteroid cream (Elocon) and as an intranasal spray (Nasonex) for treatment of allergic rhinitis.

Montelukast (Singulair - Merck) is an oral cysteinyl leukotriene D₄ receptor antagonist originally marketed for treatment of asthma. It was approved by the FDA in 2003 for treatment of seasonal allergic rhinitis and recently for use in perennial allergic rhinitis in adults and children ≥ 6 months old. Intranasal corticosteroids have generally been considered the most effective drugs available for prevention and treatment of allergic rhinitis.

Patients with mild, infrequent asthma symptoms may require only intermittent, asneeded use of an inhaled short-acting beta2-adrenergic agonist. Use of a short-acting beta2-agonist more than twice weekly, other than for exercise-induced bronchospasm, indicates a need for anti-inflammatory treatment. Inhaled corticosteroids are the most effective anti-inflammatory medication; leukotriene modifiers are less effective alternatives. If regular use of an inhaled corticosteroid in a low dose does not prevent symptoms, a long-acting beta2-agonist should be added; addition of a second drug is more effective than raising the dose of the inhaled steroid. A leukotriene modifier can also be used as the second drug. Omalizumab may be considered as adjunctive therapy for patients more than 12 years old who have allergic asthma not controlled by other drugs. A short course of oral corticosteroids may be useful for acute exacerbations. Treatment of acute severe asthma as a medical emergency is not included here; it has been reviewed elsewhere (ER McFadden Jr, Am J Respir Crit Care Med 2003; 168:740).

Tiotropium bromide inhalation powder (Spiriva HandiHaler - Boehringer Ingelheim), a long-acting anticholinergic agent, has been approved by the FDA for once-daily maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD). Available in Europe since 2002, it is the first long-acting inhaled anticholinergic drug for treatment of COPD. Ipratropium bromide (Atrovent), an anticholinergic used four times daily, has been available in the US for many years.

The FDA has approved release of omalizumab (oh mah lye zoo mab; Xolair - Genentech, Novartis), a humanized monoclonal antibody given subcutaneously that binds to immunoglobulin E (IgE). The drug is labeled for patients at least 12 years old with moderate to severe persistent asthma who have shown reactivity to an allergen and whose symptoms are inadequately controlled by an inhaled corticosteroid. The manufacturer claims the drug can help stop allergic reactions before they begin.

New drug formulations continue to be introduced for the treatment of asthma, and new studies on older drugs continue to change our perspectives on the management of this chronic inflammatory disease. Treatment of asthma in the emergency department or hospital is not addressed here. More information on the diagnosis and treatment of asthma is available from Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma (Bethesda:NIH, 1997 and 2002 update; www.nhlbi.nih.gov).

Asthma is a chronic inflammatory disorder of the airways; inflammation caused by allergens, viral respiratory infections or other stimuli leads to bronchial hyperresponsiveness and obstruction of airflow. Anti-inflammatory drugs, particularly inhaled corticosteroids, are central to its management.

Levalbuterol, the R-isomer of racemic albuterol, has been approved by the FDA for prevention and treatment of bronchospasm in patients at least 12 years old.

Asthma is a chronic inflammatory disorder, with inflammation caused by allergens or other stimuli leading to bronchial hyperresponsiveness and obstruction of airflow.

Zileuton (zye loo' ton; Zyflo - Abbott), an inhibitor of leukotriene synthesis, has been approved by the US Food and Drug Administration (FDA) for prophylaxis and maintenance treatment of chronic asthma in adults and children more than 12 years old. A related drug—zafirlukast (Accolate), a leukotriene receptor antagonist—was recently reviewed in the Medical Letter (vol. 38, page 111, December 20, 1996). Neither of these drugs is recommended for treatment of acute asthma.

Zafirlukast (za fir loo kast; Accolate - Zeneca), the first leukotriene receptor anta-gonist approved by the US Food and Drug Administration, is now being heavily promoted for oral maintenance treatment of chronic asthma in patients more than 12 years old. It is not recommended for treatment of acute asthma.

An inhalation aerosol formulation of the corticosteroid fluticasone propionate (Flovent -Glaxo Wellcome) has been approved by the US Food and Drug Administration for maintenance treatment of asthma.

Asthma is now considered a chronic inflammatory disorder of the airways, with inflammation caused by allergens or other stimuli leading to bronchial hyper-responsiveness and obstruction of airflow. The recent therapeutic emphasis, therefore, has been on use of ati-inflammatory drugs (RA Goldstein et al, Ann Intern Med, 121:698, Nov 1, 1994). The treatment of asthma in the hospital or emergency room is not included here.

Salmeterol xinafoate (Serevent - Allen & Hanburys), a long-acting β 2 -selective adrenergic agonist for inhalation, has been approved by the US Food and Drug Administration for maintenance treatment of asthma, with or without concurrent use of inhaled corticosteroids. Salmeterol is not recommended for acute treatment of bronchospasm.

Interferon β-1b (Betaseron - Berlex), an analog of human interferon β pro-duced in E. coli, may soon be approved by the US Food and Drug Administration for treatment of relapsing-remitting multiple sclerosis (MS), the most common form of the disease (G Mitchell, Med Clin North Am, 77:231, 1993).

Most experts now consider asthma an inflammatory disorder of the airways, with inflammation caused by allergy or other stimuli leading to bronchial hyperresponsiveness and obstruction of airflow. The new therapeutic emphasis, therefore, is on use of anti-inflammatory drugs (Guidelines for Diagnosis and Management of Asthma, Publication No. 91-3042, Bethesda:National Institute of Health, 1991). Asthma is a chronic inflammatory disorder of the airways; inflammation caused by allergens, viral respiratory infections or other stimuli leads to bronchial hyperrespon-siveness and obstruction of airflow (WW Busse and RF Lemanske Jr, N Engl J Med 2001; 344:350). Anti-inflammatory drugs, particularly inhaled corticosteroids, are central to its management. Treatment of asthma in the hospital or emergency department is not addressed here.