ProAir RespiClick (Albuterol Sulfate): First Breath-Actuated Inhaler Approved for the Treatment or Prevention of Bronchospasm

March 2016, Vol 9, Seventh Annual Payers' Guide - Drug Updates, FDA News & Updates, Online First
Lisa A. Raedler, PhD, RPh
Medical Writer

Bronchospasm is defined as sudden and involuntary contraction of smooth muscle in the bronchioles. It occurs in patients with allergic diseases, including asthma, and results in airway constriction and shortness of breath.

Allergic diseases, including asthma, represent the fifth most common chronic diseases in individuals of all ages, and the third most common chronic diseases in children.1 Asthma is a reversible obstructive lung disease in which the airways overreact to various stimuli or triggers, such as smoke, allergens, stress, and exercise.2 Asthma is a chronic condition that is marked by inflammation, bronchospasm, and acute exacerbations. Asthma can be life-threatening if it is not properly managed.2

Although asthma can occur at any age, it most often begins during childhood.3 Approximately 25 million Americans have asthma, including 7.1 million children aged <18 years.2,3 More than half of individuals with asthma experience at least 1 asthma exacerbation yearly, leading to more than 1.7 million visits to emergency departments and approximately 450,000 hospitalizations annually.3

The exact cause of the inflammatory process leading to asthma is unknown; however, evidence shows that asthma may be inherited.4,5 Other contributing factors include allergies, viral respiratory infections during infancy and early childhood, and environmental factors, including allergens, certain irritants, and air pollution.4

Asthma is classified into 4 categories––intermittent, mild persistent, moderate persistent, and severe persistent.5 The National Heart, Lung, and Blood Institute (NHLBI) treatment guidelines recommend specific treatment approaches based on the severity of asthma symptoms (Figure).5

Figure

Exercise-induced bronchospasm (also often called exercise-induced asthma) can occur in patients with asthma and should be suspected when symptoms of cough, shortness of breath, chest pain or tightness, wheezing, or endurance problems occur during exercise.5 Exercise can also induce bronchospasm in individuals who do not have asthma, including elite athletes.6

The diagnosis of exercise-induced bronchospasm is established when a ≥15% decrease in lung function (measured by peak expiratory flow or forced expiratory volume in 1 second [FEV1]) is observed after an exercise challenge.5

The primary goals of therapy for patients with asthma focus on reduction of impairment associated with asthma symptoms, prevention of exacerbations, and maintenance of normal lung function and activity levels.5 The NHLBI recommends a comprehensive asthma management approach that includes assessment and monitoring, patient and family education, control of environmental factors and comorbid conditions that affect asthma, and medications.5

Medications for the treatment of patients with asthma include long-term control agents and quick-relief therapies (Table 1).5 Specific agents are selected based on disease severity, the general mechanisms of action of the medications, delivery devices, and safety.5

Table

Several types of delivery devices are available for inhaled asthma medications, including nebulizers, metered-dose inhalers, and dry powder inhalers. The medication doses may vary considerably among devices and for different age-groups.5 In addition, patients with asthma often encounter situations that require adjustment of their medication regimen.5

Dry powder inhalers require a rapid deep inhalation, and the dose may be lost if patients exhale through the device after actuating.5 Breath-actuated dry powder inhalers may be particularly useful for patients who are unable to coordinate inhalation and inhaler actuation; some patients with asthma incorrectly stop inhalation right after actuation of the device.5

Inhaled beta2-agonists are used to prevent exercise­induced bronchospasm. The use of a short-acting beta2-agonist before exercise is often helpful for 2 to 3 hours, whereas the use of a long-acting beta2-agonist can be protective for up to 12 hours.5
Asthma is a serious chronic condition that, over time, can result in persistent changes in the airway structure, including fibrosis, mucus hypersecretion, epithelial cell injury, smooth muscle hypertrophy, and angiogenesis.5 Recent studies have identified different phenotypes of asthma with varying patterns of inflammation, such as cellular mediator patterns and variable therapeutic responses to medications. Efforts are under way to determine if specific treatment approaches can benefit patients with these different patterns of inflammation.5

FDA Approves Albuterol Sulfate Inhalation Powder for Bronchospasm

On March 31, 2015, the US Food and Drug Administration (FDA) approved albuterol sulfate (ProAir RespiClick; Teva Respiratory) inhalation powder for oral inhalation use for the treatment or the prevention of bronchospasm in patients with a reversible obstructive airway disease, and for the prevention of exercise-induced bronchospasm in patients aged ≥12 years.7 Albuterol sulfate is the first breath-­actuated inhaler approved for use in the United States.7

“ProAir RespiClick is the first and only breath-actuated, dry-powder rescue inhaler to be approved by the FDA for the treatment of acute asthma symptoms,” said David I. Bernstein, MD, University of Cincinnati College of Medicine, Division of Immunology, Allergy, and Rheumatology, in a press release from the drug manufacturer. “The approval of ProAir RespiClick is significant as it eliminates the need for hand-breath coordination during inhalation.”8

Mechanism of Action

Albuterol sulfate is a breath-actuated, multidose, short-acting beta2-adrenergic agonist drug powder inhaler.9 By activating beta2-adrenergic receptors on airway smooth muscle, albuterol sulfate activates adenylcyclase and increases intracellular concentrations of 3´, 5´-cyclic­adenosine monophosphate (AMP).9 These increases in cyclic AMP levels are associated with a series of events that lower intracellular ionic calcium concentrations and allow bronchial smooth muscles to relax. Higher levels of cyclic AMP also inhibit the mediator release from mast cells in the lungs.9 Because albuterol relaxes airways regardless of the spasmogen involved, it protects against all bronchoconstrictor challenges.9

Similar to other beta-adrenergic agonist drugs, inhaled albuterol can result in significant cardiovascular effects in some patients, including cardiovascular symptoms and changes in pulse rate, blood pressure, and electrocardiograph results.9

Dosing and Administration

During each actuation, 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) is delivered from the mouthpiece.9
For the treatment of acute episodes of bronchospasm or for the prevention of bronchospasm-associated symptoms, albuterol sulfate should be administered as 2 inhalations and repeated every 4 to 6 hours; for some patients, only 1 inhalation administered every 4 hours may be enough. More inhalations or more frequent use of this inhaler is advised.9

The recommended dosage of albuterol sulfate for the prevention of exercise-induced bronchospasm is 2 inhalations administered 15 to 30 minutes before beginning exercise.9

The albuterol sulfate inhaler should only be used orally, and does not require priming. It should not be used with a spacer or with a volume-holding chamber.9

Clinical Trials

The clinical development program for albuterol sulfate comprised 8 clinical trials that evaluated its safety and efficacy in adults and adolescents (aged ≥12 years) with bronchospasm associated with asthma or with exercise­induced bronchospasm.8,9

Bronchospasm Associated with Asthma

The efficacy and safety of albuterol sulfate inhalation powder in patients with bronchospasm associated with asthma were evaluated in 2 randomized, double-blind, placebo-controlled, 12-week studies of identical design (Study 1 and Study 2).8 In the first study, 153 patients with asthma were randomized to receive albuterol sulfate, and 163 patients with asthma received a placebo dry powder inhaler.8 All patients were aged 12 to 76 years and received inhaled corticosteroid as maintenance therapy. Albuterol sulfate was administered at a dose of 180 mcg 4 times daily.9

Serial FEV1 measurements performed through day 85 demonstrated that 2 inhalations of albuterol sulfate significantly improved FEV1 area under the curve from time 0 to 6 hours over the pretreatment value versus placebo.9

In this study, 56% (44 of 78) of patients who received albuterol sulfate achieved a 15% increase in FEV1 within 30 minutes of dosing on day 1. The median time to onset of this benefit was 5.7 minutes, and the median duration of effect (15% increase in FEV1) was approximately 2 hours. Consistent FEV1 results were observed in the second placebo-controlled study.9

In addition, a double-blind, randomized, placebo­controlled, single-dose, crossover study of albuterol sulfate inhalation powder and albuterol sulfate inhalation aerosol (ProAir HFA; Teva Respiratory) was conducted in 71 adults and adolescents (aged ≥12 years) with persistent asthma. At doses of 90 mcg and 180 mcg, albuterol sulfate inhalation powder demonstrated significantly greater bronchodilator efficacy compared with placebo.9

Exercise-Induced Bronchospasm

The efficacy and safety of albuterol sulfate inhalation powder in exercise-induced bronchospasm were assessed in a randomized, single-dose, crossover study (Study 2) in 38 adults and adolescents with exercise-induced bronchospasm. Overall, 2 inhalations of albuterol sulfate were administered 30 minutes before exercise. Patients who participated in these clinical trials were allowed to use concomitant steroid therapy.9

The prevention of exercise-induced bronchospasm was defined as the maintenance of FEV1 within 80% of the postdose, preexercise baseline values. This study demonstrated that albuterol sulfate prevented exercise-induced bronchospasm for 1 hour after exercise in 97% (37 of 38) of patients compared with the 42% (16 of 38) of patients who received placebo.9

Adverse Events

Overall, 1120 patients with asthma received albuterol sulfate during the medication’s clinical development program. Adverse reactions that occurred in at least 1% of patients who received albuterol sulfate inhalation powder and at a rate higher than placebo included back pain, pain, viral gastroenteritis, sinus headache, and urinary tract infection.9

Table 2 summarizes the most common adverse events that were reported during the 12-week blinded treatment period of 3 studies that compared albuterol sulfate 180 mcg 4 times daily with a double-blind matched placebo in 653 patients with asthma aged 12 to 76 years.9

Table 2

The most common adverse events (≥5%) in a long-term study of 168 patients who received albuterol sulfate for up to 52 weeks (including a 12-week double-blind period) included upper respiratory infection, nasopharyngitis, sinusitis, bronchitis, cough, oropharyngeal pain, headache, and pyrexia.9

Drug Interactions

Albuterol sulfate should not be used concomitantly with other short-acting sympathomimetic bronchodilators.9

Contraindications

The use of albuterol sulfate is contraindicated in patients with a history of hypersensitivity to albuterol and/or severe hypersensitivity to milk proteins. Hypersensitivity reactions, including urticaria, angioedema, and rash, have been reported after the use of albuterol sulfate. In addition, anaphylactic reactions have been reported in patients using inhalation therapies that contain lactose.9

Warnings and Precautions

Paradoxical bronchospasm. Albuterol sulfate can produce paradoxical bronchospasm, which may be life­threatening. Albuterol sulfate should be discontinued immediately and alternative therapy should be instituted if bronchospasm occurs.9

Deterioration of asthma. Asthma can deteriorate over a period of hours or over several days or longer. Patients who require more albuterol sulfate should be reevaluated, because this may be a marker of destabilization of asthma; anti-inflammatory treatment with corticosteroids may be required.9

Use of anti-inflammatory agents. The use of albuterol sulfate and other beta-adrenergic agonist bronchodilators may not adequately control asthma. The addition of anti-inflammatory agents, such as corticosteroids, should be considered.9

Cardiovascular effects. Albuterol sulfate can produce clinically significant cardiovascular effects, including changes in pulse rate and blood pressure, and/or symptoms. Albuterol sulfate may need to be discontinued if cardiovascular effects occur after administration.9

Beta-agonists can also produce electrocardiogram changes, including the flattening of the T-wave, prolongation of the corrected QT interval, and ST-segment depression. Albuterol sulfate should be used with caution in patients with cardiovascular disorders, including coronary insufficiency, cardiac arrhythmias, and hypertension.9

Do not exceed the recommended dose. The excessive use of inhaled sympathomimetic drugs in patients with asthma has been associated with fatalities. Although the exact cause of death is unknown, cardiac arrest after a severe acute asthmatic crisis and subsequent hypoxia are suspected.9

Immediate hypersensitivity reactions. Immediate hypersensitivity reactions can occur after the administration of albuterol sulfate; rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema have been reported.9

Albuterol sulfate contains small amounts of lactose, which may contain trace levels of milk proteins. Anaphylaxis, angioedema, pruritus, and rash have been reported with the use of medications containing lactose. Hypersensitivity must be considered for patients who experience immediate hypersensitivity reactions to albuterol sulfate.9

Coexisting conditions. Albuterol sulfate, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines.9

Hypokalemia. Albuterol sulfate can cause significant hypokalemia, potentially resulting in adverse cardiovascular effects. Decreases in potassium levels are typically transient and do not require supplementation.9

Use in Specific Populations

Pregnancy. There are no adequate and well-controlled studies of albuterol sulfate in pregnant women. Albuterol sulfate should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus.9

Labor and delivery. Because beta-agonists can interfere with uterine contractility, the use of albuterol sulfate for the relief of bronchospasm during labor should only be considered if the benefits clearly outweigh the risks.9

Nursing mothers. It is not known whether the components of albuterol sulfate are present in human breast milk. Nursing or albuterol sulfate should be discontinued based on the importance of the drug to the mother.9

Pediatric use. Albuterol sulfate inhalation powder is indicated for the treatmzent or the prevention of bronchospasm in patients with reversible obstructive airway disease and for the prevention of exercise-induced bronchospasm in patients aged ≥12 years. The safety and efficacy of albuterol sulfate in patients aged <12 years have not been established.9

Geriatric use. Clinical studies of albuterol sulfate did not include sufficient numbers of patients aged ≥65 years to determine whether they respond differently to albuterol sulfate inhalation powder compared with younger patients.9

Conclusion
Albuterol sulfate inhalation powder is the first breath-actuated, dry powder rescue inhaler approved for the treatment or prevention of bronchospasm in patients with a reversible obstructive airway disease, and for the prevention of exercise-induced bronchospasm. This dry powder oral inhaler offers a safe, effective, and convenient dosage form, especially for patients who experience difficulty coordinating inhalation and actuation.

References
1. American College of Allergy, Asthma, and Immunology. Allergy facts. http://acaai.org/news/facts-statistics/allergies. Accessed July 7, 2015.
2. American Lung Association. Asthma & children fact sheet. Updated September 2014. www.lung.org/lung-disease/asthma/resources/facts-and-figures/asthma-children-fact-sheet.html. Accessed July 7, 2015.
3. National Heart, Lung, and Blood Institute. Asthma info. Updated September 2011. www.nhlbi.nih.gov/health-pro/resources/lung/naci/asthma-info/. Accessed July 7, 2015.
4. American Lung Association. Learning more about asthma. www.lung.org/lung-disease/asthma/learning-more-about-asthma/. Accessed July 20, 2015.
5. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3 2007). NIH Publication No. 07-4051. Bethesda, MD: US Department of Health & Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program; 2007. www.nhlbi.nih.gov/health-pro/guidelines/current/asthma-guidelines/­summary-report-2007. Accessed July 20, 2015.
6. Dimov V; for Allergycases.org. Exercise-induced bronchospasm (EIB). Updated April 20, 2012. http://allergycases.blogspot.com/2006/10/exercise-induced-­asthma-and.html. Accessed July 7, 2015.
7. US Food and Drug Administration. Label and approval history: ProAir Respi­Click. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory. Accessed July 7, 2015.
8. Teva Pharmaceutical Industries Ltd. Teva Announces FDA Approval of ProAir RespiClick. Press release. April 1, 2015. www.tevapharm.com/news/­?itemid=%7BE269EFA8-CDA9-461E-95B0-5F5DE13A6B7F%7D.
9. ProAir RespiClick (albuterol) inhalation powder [prescribing information]. Horsham, PA: Teva Respiratory, LLC; March 2015.

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