levalbuterol 1.25 mg/3 ml sol generic xopenex

Uses

Bronchospasm

Albuterol sulfate is used orally or by oral inhalation for the symptomatic management of bronchospasm in patients with reversible, obstructive airway disease and by oral inhalation for the prevention of exercise-induced bronchospasm. Levalbuterol hydrochloride or levalbuterol tartrate is used by oral inhalation for the symptomatic management or prevention of bronchospasm in patients with reversible, obstructive airway disease. Albuterol sulfate in fixed combination with ipratropium bromide is used by oral inhalation for the symptomatic management of bronchospasm associated with chronic obstructive pulmonary disease (COPD) in patients who continue to have evidence of bronchospasm despite the regular use of an orally inhaled bronchodilator and who require a second bronchodilator.

Clinical studies in adults and children 4 years of age or older indicate that albuterol sulfate inhalation aerosol with a hydrofluoroalkane (HFA) propellant (e.g., Proventil HFA, Ventolin HFA) has bronchodilator efficacy similar to that of albuterol inhalation aerosol with chlorofluorocarbons (no longer commercially available in the US). In one short-term (3 weeks' duration), randomized, double-blind, placebo-controlled study in children 4 to 11 years of age with asthma, patients receiving albuterol sulfate HFA inhalation aerosol (i.e., ProAir HFA) at dosages of 180 mcg 4 times daily showed greater improvement in FEV₁ compared with baseline than did patients receiving placebo. In this study, 42% of children receiving albuterol sulfate HFA inhalation aerosol achieved a 15% increase in FEV₁ within 30 minutes postdose on the first day of the trial.

Albuterol solution for nebulization is used for the symptomatic treatment and control of acute, potentially recurrent bronchospasm in patients with reversible obstructive airway disease, including those with bronchial asthma, chronic bronchitis, pulmonary emphysema, and cystic fibrosis. Administration of β-adrenergic agonist bronchodilators via nebulization generally is reserved for patients with severe disease who do not respond adequately to more conventional therapy and for patients (e.g., children) who find it difficult or are unable to optimally inhale the drug orally via an inhaler. In clinical studies of orally inhaled albuterol sulfate via nebulization in asthmatic children aged 3 years or older, improvement in indices of pulmonary function (FEV₁ or PEFR) occurred within 2-20 minutes following single doses of nebulized drug. Following oral inhalation of nebulized albuterol sulfate (0.1 mg/kg or higher), clinically important increases in FEV₁ (as measured by a 15% increase compared with baseline) have been observed for up to 6 hours in children 5-11 years of age. In a short-term (4-weeks' duration), randomized, double-blind, placebo-controlled study in children 6-12 years of age with mild to moderate asthma (mean baseline FEV₁ 60-70% of predicted values) who received albuterol 0.63 or 1.25 mg 3 times daily via nebulization with or without corticosteroids, the mean percent change in the area under the FEV₁-time curve over 6 hours with albuterol exceeded that produced by placebo. The mean time to peak effect (as determined by increase in FEV₁) with both doses was approximately 30-60 minutes postdose; no diminution of effect was noted during the 4-week period of observation.

Levalbuterol hydrochloride solution for nebulization and levalbuterol tartrate inhalation aerosol are used as bronchodilators for the symptomatic management and prevention of bronchospasm in patients with reversible obstructive airway disease. Current evidence suggests that most, if not all, of the bronchodilatory activity of albuterol is attributable to levalbuterol (R-albuterol) and that the S-enantiomer may potentially detract from the efficacy of racemic albuterol.(See Pharmacology.)

Safety and efficacy of levalbuterol tartrate with an HFA propellant via a metered-dose inhaler for the treatment of asthma have been established in 3 randomized, double-blind, placebo- and active-controlled studies of 4-8 weeks' duration in adults and children 4 years of age or older. Levalbuterol (90 mcg) and racemic albuterol with an HFA propellant (180 mcg) were more effective than placebo in improving lung function (defined as mean peak percent change from baseline in FEV₁).

In a small, placebo-controlled, dose-ranging study in adults with mild to moderate asthma receiving single doses of orally inhaled levalbuterol (0.31, 0.63, or 1.25 mg) or racemic albuterol (2.5 mg) via nebulization, the bronchodilator response to the highest dosage of levalbuterol (1.25 mg) was clinically comparable to that with albuterol 2.5 mg over the 6-hour evaluation period, although the period during which the increase in FEV₁ exceeded 15% compared with baseline was slightly more prolonged with levalbuterol. Adverse systemic β-adrenergic effects were observed with both treatments and generally were dose-related for R-albuterol, although the 1.25-mg dosage of levalbuterol was associated with a slightly greater incidence of such adverse effects than the 2.5-mg dosage of albuterol.

In a short-term (4-weeks' duration), placebo-controlled study in adults and adolescents with moderate to severe asthma (mean baseline FEV₁ 60% of predicted) who received levalbuterol 0.63 or 1.25 mg 3 times daily or albuterol 1.25 or 2.5 mg 3 times daily via nebulization, the mean peak change in FEV₁ with levalbuterol (R-albuterol) exceeded that produced by equivalent dosages of the drug given as racemic albuterol (50:50 mixture of R- and S-albuterol). This improvement in FEV₁ in all patients receiving levalbuterol exceeded that for the combined albuterol group after the first dose (day 1) but not at the end (day 29) of the study. Improvement in FEV₁ was greatest and of longest duration with the levalbuterol 1.25-mg dosage regimen on days 1 and 29, while efficacy of the levalbuterol 0.63-mg and albuterol 2.5-mg regimens was similar at all time points measured. All active treatments were associated with improvement in FEV₁ compared with placebo, and adverse effects of levalbuterol and albuterol were similar.

In a short-term (3-weeks' duration), randomized, double-blind, placebo-controlled study in children (6-11 years of age) with mild to moderate asthma (mean baseline FEV₁ 73% of predicted) who received levalbuterol (0.31 or 0.63 mg 3 times daily) or racemic albuterol (1.25 or 2.5 mg 3 times daily) via nebulization in addition to existing therapy (e.g., inhaled corticosteroids), the mean peak change in FEV₁ with levalbuterol (R-albuterol) was similar to that produced by albuterol. All active treatments were associated with improvement in FEV₁ compared with placebo, and adverse effects of levalbuterol were less than that associated with albuterol.

Asthma

Considerations in Initiating Antiasthma Therapy

In the current stepped-care approach to antiasthmatic drug therapy, asthma is classified according to severity upon initial presentation (intermittent asthma or mild, moderate, or severe persistent asthma) and also by response to treatment (i.e., asthma control). While classification of asthma severity is useful for determining initial treatment, disease severity may vary over time and with treatment; therefore, after therapy is initiated, periodic assessment of asthma control is emphasized for guiding treatment decisions. Current asthma management guidelines state that initial therapy for asthma should correspond to disease severity, with subsequent monitoring and adjustments in therapy to achieve and maintain control of asthma according to the goals of treatment. Asthma therapy is aimed at achieving and maintaining control of asthma by reducing ongoing impairment (e.g., prevention of chronic and troublesome symptoms, reducing use of reliever drugs, maintaining normal or near-normal lung function and activity levels) and risk of future events (e.g., exacerbations requiring systemic corticosteroids, treatment-related adverse effects). These 2 components of asthma control (i.e., current impairment and future risk) may respond differently to treatment.

The National Asthma Education and Prevention Program (NAEPP) classifies the levels of asthma control as well controlled, not well controlled, or very poorly controlled. In the stepped-care approach, the treatment step selected for asthma control in patients already receiving asthma therapy is based on the patient's current treatment and level of asthma control. Stepwise therapy is meant to assist, not replace, the clinical decision-making process in selecting therapy for individual patients. Once initiated, treatment is adjusted continuously according to changes in asthma control. Patients should be monitored every 2-6 weeks following initiation of therapy to ensure that asthma control is achieved. If asthma symptoms are not controlled with the current treatment regimen, treatment is stepped up until control is achieved. If an alternative treatment was used and produced an inadequate response, the preferred treatment should be used before stepping up to the next level of therapy. Regular monitoring at 1- to 6-month intervals, depending on the level of control, is recommended to ensure that control of asthma is maintained and that appropriate adjustments in therapy are made. When control has been maintained for at least 3 months, treatment intensity may be stepped down to find the lowest dosage and/or number of drugs required to maintain asthma control, with continued follow-up at 3-month intervals.

Drugs for asthma may be categorized as relievers (e.g., bronchodilators taken as needed for acute symptoms) or controllers (principally inhaled corticosteroids or other anti-inflammatory agents taken regularly to achieve long-term control of asthma).

Intermittent Asthma

A reliever drug such as a selective short-acting inhaled β₂-adrenergic agonist (e.g., albuterol, levalbuterol, pirbuterol), is recommended on an as-needed basis to control occasional acute symptoms (e.g., cough, wheezing, dyspnea) of short duration; such use of an inhaled short-acting β₂-agonist alone generally is sufficient as initial treatment for newly diagnosed patients whose asthma severity is initially classified as intermittent (e.g., patients with daytime symptoms of asthma not more than twice weekly and nocturnal symptoms not more than twice a month). Most experts consider short-acting inhaled β₂-adrenergic agonists to be drugs of choice for treating acute asthma symptoms and exacerbations and for preventing exercise-induced bronchospasm. Alternatives to short-acting inhaled β₂-agonists recommended by some clinicians for relief of acute asthma symptoms include an inhaled anticholinergic agent (e.g., ipratropium), a short-acting oral β₂-agonist, or a short-acting theophylline (provided extended-release theophylline is not already used), but these alternatives have a slower onset of action and/or a greater risk of adverse effects. Oral β₂-adrenergic agonist therapy is suggested for use principally in patients unable to use inhaled bronchodilators (e.g., young children). Other experts do not recommend oral β₂-agonists for relief of acute asthma symptoms. Use of short-acting inhaled β₂-agonists in asymptomatic asthma should be limited to pretreatment prior to exercise and, in intermittent asthma, should be limited to providing relief as symptoms develop; some clinicians state that patients requiring symptomatic relief more than twice weekly or repeatedly over 1 or 2 days should be evaluated for possible initiation of long-term controller therapy.

Mild Persistent Asthma

When control of symptoms deteriorates in patients with intermittent asthma and symptoms become persistent (e.g., daytime symptoms of asthma more than twice weekly but less than once daily, and nocturnal symptoms of asthma 3-4 times per month), current asthma management guidelines and most clinicians recommend initiation of a controller drug such as an anti-inflammatory agent, preferably a low-dose orally inhaled corticosteroid, (e.g., 88-264, 88-176, or 176 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adolescents and adults, children 5-11 years of age, or children 4 years of age or younger, respectively) as first-line therapy for persistent asthma, supplemented by as-needed use of a short-acting, inhaled β₂-agonist. Alternatives to low-dose inhaled corticosteroids for mild persistent asthma include certain leukotriene modifiers (i.e., montelukast, zafirlukast), extended-release theophylline, or mast-cell stabilizers (i.e., cromolyn, nedocromil [preparations for oral inhalation no longer commercially available in the US]), but these therapies are less effective and generally not preferred as initial therapy. Some experts recommend that long-term control therapy be considered in infants and children 4 years of age or younger who have identifiable risk factors for asthma (e.g., parental history of asthma, clinician-diagnosed atopic dermatitis, sensitization to aeroallergens, or 2 of the following conditions: sensitization to foods, peripheral blood eosinophilia exceeding 4%, or wheezing unrelated to colds) and who in the previous year have had 4 or more episodes of wheezing that lasted more than 1 day and symptoms that affected sleep. Low-dose inhaled corticosteroids also are recommended as the preferred initial therapy in such children. Cromolyn sodium is suggested (based on extrapolation of data from studies in older children) or montelukast is recommended by some experts as an alternative, but not preferred, therapy in children 4 years of age or younger with mild persistent asthma. Other experts do not consider mast-cell stabilizers or extended-release theophylline to be acceptable alternatives to inhaled corticosteroids for routine use as initial long-term therapy in such patients.

Moderate Persistent Asthma

According to current asthma management guidelines, therapy with a long-acting inhaled β₂-agonist such as salmeterol or formoterol generally is recommended in adults and adolescents who have moderate persistent asthma and daily asthmatic symptoms that are inadequately controlled following addition of low-dose inhaled corticosteroids to as-needed inhaled β₂-agonist treatment. However, the NAEPP recommends that the beneficial effects of long-acting inhaled β₂-agonists should be weighed carefully against the increased risk (although uncommon) of severe asthma exacerbations and asthma-related deaths associated with daily use of such agents. Current asthma management guidelines also state that an alternative, but equally preferred option for management of moderate persistent asthma that is not adequately controlled with a low dosage of inhaled corticosteroid is to increase the maintenance dosage to a medium dosage (e.g., exceeding 264 but not more than 440 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler in adults and adolescents). Alternative less-effective therapies that may be added to a low dosage of an inhaled corticosteroid include oral extended-release theophylline or certain leukotriene modifiers (i.e., montelukast, zafirlukast).

Limited data are available in infants and children 11 years of age or younger with moderate persistent asthma, and recommendations of care are based on expert opinion and extrapolation from studies in adults. According to current asthma management guidelines, a long-acting inhaled β₂-agonist (e.g., salmeterol, formoterol), a leukotriene modifier (i.e., montelukast, zafirlukast), or extended-release theophylline (with appropriate monitoring) may be added to low-dose inhaled corticosteroid therapy in children 5-11 years of age. Because comparative data establishing relative efficacy of these agents in this age group are lacking, there is no clearly preferred agent for use as adjunctive therapy with a low-dose inhaled corticosteroid for treatment of asthma in these children. In children 5-11 years of age with moderate persistent asthma that is not controlled with a low dosage of an inhaled corticosteroid, another preferred option according to current asthma management guidelines is to increase the maintenance dosage of the inhaled corticosteroid to a medium dosage (e.g., exceeding 176 but not more than 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler). In infants and children 4 years of age or younger with moderate persistent asthma that is not controlled by a low dosage of an inhaled corticosteroid, the only preferred option is to increase the maintenance dosage of the inhaled corticosteroid to a medium dosage (e.g., exceeding 176 but not more than 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler).

Severe Persistent Asthma

Maintenance therapy with an inhaled corticosteroid at medium dosages or high dosages (e.g., exceeding 440 mcg of fluticasone propionate in adults and adolescents or 352 mcg of the drug in children 5-11 years of age [or its equivalent] daily via a metered-dose inhaler) and adjunctive therapy with a long-acting inhaled β₂-agonist is the preferred treatment according to current asthma management guidelines in adults and children 5 years of age or older with severe persistent asthma (i.e., continuous daytime asthma symptoms, nighttime symptoms 7 times per week). Such recommendations in children 5-11 years of age are based on expert opinion and extrapolation from studies in older children and adults. Alternatives to a long-acting inhaled β₂-agonist for severe persistent asthma in adults and children 5 years of age or older receiving medium-dose inhaled corticosteroids include extended-release theophylline or certain leukotriene modifiers (i.e., montelukast, zafirlukast), but these therapies are generally not preferred. Omalizumab may be considered in adults and adolescents with severe asthma with an allergic component who are inadequately controlled with high-dose inhaled corticosteroids and a long-acting β₂-agonist. In infants and children 4 years of age or younger with severe asthma, maintenance therapy with an inhaled corticosteroid at medium or high dosages (e.g., exceeding 352 mcg of fluticasone propionate [or its equivalent] daily via a metered-dose inhaler) and adjunctive therapy with either a long-acting inhaled β₂-agonist or montelukast is the only preferred treatment according to current asthma management guidelines. Recommendations for care of infants and children with severe asthma are based on expert opinion and extrapolation from studies in adolescents and adults.

Poorly Controlled Asthma

If asthma symptoms in adults and children 5 years of age or older with moderate to severe asthma are very poorly controlled (i.e., at least 2 exacerbations per year requiring oral corticosteroids) with low-to-high maintenance dosages of an inhaled corticosteroid and a long-acting inhaled β₂-agonist bronchodilator, a short course (3-10 days) of an oral corticosteroid may be added to gain prompt control of asthma. In infants and children 4 years of age or younger with moderate to severe asthma who are very poorly controlled (more than 3 exacerbations per year requiring oral corticosteroids) with medium to high maintenance dosages of an inhaled corticosteroid with or without adjunctive therapy (i.e., a long-acting inhaled β₂-agonist, montelukast), a short course (3-10 days) of an oral corticosteroid may be added to gain prompt control of asthma.

While clinical efficacy of oral corticosteroids as add-on therapy in adults and children 5 years of age or older with severe asthma who are inadequately controlled with a high-dose inhaled corticosteroid, intermittent oral corticosteroid therapy, and a long-acting inhaled β₂-agonist bronchodilator has not been established in randomized controlled studies, some experts suggest regular use of oral corticosteroids in such patients, based on consensus and clinical experience. Similarly, some experts, based on consensus and clinical experience, suggest regular use of oral corticosteroid therapy in infants and children 4 years of age or younger with severe asthma who are not controlled with a high-dose inhaled corticosteroid and either a long-acting inhaled β₂-agonist or montelukast and intermittent oral corticosteroid therapy. However, other experts do not consider regular use of oral corticosteroid therapy to be appropriate therapy in children with severely uncontrolled asthma.

When asthma symptoms at any stage are not controlled with maintenance therapy (e.g., inhaled corticosteroids) plus supplemental short-acting inhaled β₂-agonist bronchodilator therapy as needed (e.g., if there is a need to increase the dose or frequency of administration of the short-acting sympathomimetic agent), prompt reevaluation is required to adjust dosage of the maintenance regimen or institute an alternative maintenance regimen.

Home Management of Acute Asthma Exacerbations

For acute exacerbations of asthma, initial home treatment consists of use of an inhaled short-acting β₂-agonist (no more than 2 doses via a metered-dose inhaler with 2-6 inhalations per dose or via nebulization every 20 minutes). Patients who have exacerbations of less severity may require a reduced dosage of a short-acting β₂-agonist. If response is good (peak expiratory flow [PEF] returns to at least 80% of predicted value or personal best and response is maintained for 3-4 hours), therapy with a short-acting β₂-agonist should be continued every 3-4 hours for 24-48 hours, and a short course of an oral corticosteroid may be considered. If response is incomplete (PEF 50-79% of predicted value or personal best), therapy with an inhaled short-acting β₂-agonist should be continued, and an oral corticosteroid should be added. If patients have a poor response to bronchodilator therapy (PEF less than 50% of predicted value or personal best), administration of an inhaled short-acting β₂-agonist should be repeated immediately, and an oral corticosteroid should be added.

For management of exacerbations due to viral respiratory infections, a short-acting inhaled β₂-agonist every 4-6 hours for 24 hours (longer therapy requires consultation with a clinician) in patients with mild symptoms may be sufficient to control symptoms and improve lung function. If viral infection-associated exacerbations occur more frequently than every 6 weeks, use of long-term control therapy should be considered. If a viral respiratory infection provokes moderate to severe exacerbations, a short course of an oral corticosteroid should be considered. For those with a history of severe exacerbations associated with viral infections, initiation of oral corticosteroids should be considered at the first sign of infection.

Prehospital Management of Acute Asthma Exacerbations

Should the response to home-initiated drug therapy be incomplete (PEF 50-79% of predicted value or personal best) or poor (PEF less than 50% of predicted value or personal best) after short-acting β₂-agonist therapy, the patient should seek medical attention urgently (same day if response is incomplete) or proceed immediately to the emergency department of a hospital (if response is poor). Orally inhaled, selective short-acting β₂-adrenergic agonists (i.e., albuterol, levalbuterol, pirbuterol) currently are recommended by an expert panel of NAEPP for prehospital management of asthma exacerbations (e.g., in emergency medicine facilities and/or ambulances). A short-acting β₂-agonist should be administered via metered-dose inhaler or nebulization at a frequency not exceeding 3 doses every 20 minutes during the first hour, followed by 1 dose hourly thereafter; supplemental oxygen is also currently recommended. If a β₂-adrenergic agonist and appropriate administration devices are not available for prehospital management, subcutaneous epinephrine or terbutaline should be given for severe exacerbations. During prolonged emergency transport, NAEPP recommends that other asthma therapies such as ipratropium bromide and oral corticosteroids should also be available for use. In patients with acute exacerbations of asthma, ipratropium generally has been reserved for use as an adjunct to other therapy, usually in combination with a β₂-adrenergic agonist bronchodilator. Because of its delayed onset, ipratropium generally should not be used alone for the management of acute bronchospasm, particularly if a prompt response is required.

Management of Acute Asthma Exacerbations in Acute Care Setting

In the emergency department, orally inhaled, selective β₂-adrenergic agonists via metered-dose inhaler or nebulization (not exceeding 3 doses every 20 minutes during the first hour) and supplemental oxygen currently also are recommended for asthma management in patients with mild to moderate acute exacerbations (FEV₁ or PEF at least 40% of predicted or personal best). If response to a β₂-adrenergic agonist in patients with mild to moderate asthma exacerbations is not immediate or if patients used oral corticosteroids as self-medication prior to hospitalization, systemic oral corticosteroids should be added to the regimen in the emergency department. Some clinicians suggest that adjunctive therapy with an inhaled anticholinergic bronchodilator (i.e., ipratropium) be considered in the emergency department in patients with moderate or severe exacerbations (PEF 60-80% or less than 60%, respectively, of predicted or personal best) of asthma who fail to respond adequately to β₂-adrenergic agonists and corticosteroids. NAEPP recommends adjunctive therapy with ipratropium (via nebulization or a metered-dose inhaler) and oral corticosteroids in patients with severe asthma exacerbations (FEV₁ or PEF less than 40% of predicted or personal best) in the emergency department who fail to respond adequately to short-acting, inhaled β₂-agonists. If the episode is severe, 1 dose of a short-acting β₂-agonist should be given and the patient should be assessed for potential hospitalization. Adjunctive therapy such as IV magnesium sulfate or a nebulization gas mixture of helium and oxygen (heliox) may be considered to decrease the likelihood of intubation, but intubation should not be delayed if the procedure is deemed necessary. In patients with impending respiratory failure, intubation and mechanical ventilation with 100% oxygen, a short-acting β₂-adrenergic agonist in combination with ipratropium via nebulization given hourly or continuously, and an IV corticosteroid should be administered in the emergency department. In certain children with acute exacerbations of asthma, some evidence suggests that an orally inhaled β₂-adrenergic agonist in conjunction with orally inhaled ipratropium (via nebulization) may be more effective than therapy with a β₂-agonist alone. In one study in children with severe acute asthma, children with the most severe bronchospasm (defined as baseline FEV₁ not exceeding 30% of predicted) who received repeated does of ipratropium in conjunction with albuterol were less likely to require hospitalization or additional bronchodilator therapy than children receiving albuterol alone. However, ipratropium does not appear to confer additional benefit in children once they have been hospitalized and treated with an intensive regimen including a nebulized β₂-agonist and systemic corticosteroids. Based on such data in children, NAEPP recommends discontinuance of ipratropium upon hospitalization for severe asthma exacerbations for patients of all age groups.

A repeat assessment of response should be made in all patients after the initial hour of intensive conventional treatment in the emergency department. In patients who have a moderate asthma exacerbation (FEV₁ or PEF of 40-69% of predicted or personal best) after the initial hour of intensive conventional treatment, an oral corticosteroid and an inhaled short-acting β₂-agonist (once every hour) should be continued for 1-3 hours provided there is improvement; assessment of response and decision to hospitalize the patient should be made in less than 4 hours after admittance to the emergency department. For severe asthma exacerbations not responding to 1 hour of intensive conventional therapy, oxygen and oral corticosteroids should be continued and an inhaled short-acting β₂-agonist and ipratropium should be administered via nebulization either continuously or hourly in the emergency department. Assessment of response in patients with severe asthma exacerbations should be repeated at 2 hours and discharge is appropriate in patients with a good response (FEV₁ or PEF at least 70% of predicted value or personal best that is sustained for 60 minutes after last treatment, normal physical examination). If response is incomplete (FEV₁ or PEF 40-69% of predicted or personal best and continuing mild to moderate symptoms), the decision to hospitalize the patient should be individualized.

Upon hospitalization, therapy with oxygen and an inhaled short-acting β₂-agonist should be continued, and therapy with oral corticosteroids should be continued or intensified (switched from oral to IV). Adjunctive therapies (e.g., magnesium sulfate, heliox) could be considered in patients with an incomplete response to several hours of intensive therapy. Patients admitted to the hospital should be reassessed at regular intervals. Patients with a poor response to such hospitalization and interventions (FEV₁ or PEF less than 40% of predicted or personal best) and those with an incomplete response after 6-12 hours of hospitalization should be admitted to an intensive care unit (ICU). Patients with a poor response to several hours of intensive therapy and patients with impending respiratory failure also should be admitted to an ICU. Upon ICU admission, therapy with ipratropium should be discontinued, but therapy with a short-acting β₂-agonist, an IV corticosteroid, and possible adjunctive therapy should be continued. Discharge is appropriate in hospitalized patients with a good response. Upon discharge, treatment with a short-acting β₂-agonist and an oral corticosteroid (3-10 days) should be continued and initiation of an inhaled corticosteroid should be considered.

Regular Use of Short-acting β2-Agonists

Concerns about the safety of regular use of short-acting inhaled β₂-agonist bronchodilators for maintenance therapy of asthma have been raised by evidence from some studies suggesting increased morbidity and mortality in patients receiving long-term therapy with short-acting, inhaled β-agonists, particularly fenoterol (currently not commercially available in the US). Other studies in patients with mild or moderate asthma suggest that while regularly scheduled use of short-acting, inhaled β₂-agonists may not cause harm, such use does not appear to have demonstrable advantages compared with intermittent use and does not adequately control asthmatic symptoms, peak flow variability, or airway hyperresponsiveness. Suggested mechanisms for detrimental effects of regularly scheduled, inhaled β-agonist therapy include down-regulation of β-adrenergic receptors (tolerance)(see Cautions: Precautions and Contraindications), increased responsiveness of airways to allergens and exercise, genetic changes in β₂-agonist receptor gene, or increased airway accessibility to inhaled allergens, which may lead to increased airway inflammation and reactivity and worsening of asthma symptoms. The validity of the evidence from these studies has been criticized in terms of study design and/or interpretation of study findings and a causal relationship between inhaled β₂-agonist therapy and asthma mortality has not been proven. Current asthma management guidelines and many clinicians recommend anti-inflammatory therapy with an inhaled corticosteroid as first-line therapy for long-term control in patients with persistent asthma, supplemented by as-needed use of a short-acting, inhaled β₂-agonist. Regular, daily use of a short-acting, inhaled β₂-agonist generally is not recommended, and increased chronic use of such β₂-agonists more than twice weekly (excluding use for exercise-induced bronchospasm) or acute use (e.g., repeated use over more than 1-2 days) for asthma deterioration may indicate the need to initiate or increase long-term control therapy for asthma.

Exercise-Induced Bronchospasm

Orally inhaled albuterol sulfate administered via a metered-dose aerosol is used as a bronchodilator in the prevention of exercise-induced bronchospasm. Most experts consider short-acting inhaled β₂-adrenergic agonists to be drugs of choice for prevention of exercise-induced bronchospasm. Treatment with a short-acting, inhaled β₂-agonist immediately before vigorous activity or exercise may be helpful for 2-3 hours. If symptoms occur during usual exercise or play activities, a step up in long-term control therapy is warranted.

In clinical studies of orally inhaled albuterol aerosol for the prevention of exercise-induced bronchospasm in adults and children, administration of the drug 15 minutes prior to exercise prevented bronchospasm as evidenced by maintenance of FEV₁ within 80% of baseline in most patients. In one placebo-controlled clinical study of orally inhaled albuterol sulfate aerosol (ProAir HFA) for the prevention of exercise-induced bronchospasm in adults and adolescents 12 years of age or older, administration of the drug 30 minutes prior to exercise prevented bronchospasm as evidenced by maintenance of FEV₁ within 80% of baseline in most patients. In another study in adults, a similar prophylactic effect was observed despite repeated exercise challenge for up to 4 hours in the majority of patients and for 6 hours in approximately one third of such treated patients. In one study in asthmatic children, oral albuterol was as effective as orally inhaled albuterol, both in ability to produce bronchodilation and to prevent exercise-induced bronchospasm; however, oral albuterol's bronchodilating effect was delayed and its effect on some measures of pulmonary function (i.e., forced expiratory flow during the middle half of forced vital capacity [FEF_25-75%], maximum expiratory flow after 75% forced vital capacity [V₂₅]) following exercise was slightly less than that of orally inhaled albuterol.

Chronic Obstructive Pulmonary Disease

Regular use of selective, short-acting inhaled β₂-adrenergic agonists in the management of chronic obstructive pulmonary disease (COPD), in contrast to that in asthma, does not appear to be detrimental. However, as long-acting β₂-adrenergic agonists have become available for maintenance treatment of COPD, short-acting β₂-adrenergic agonists are used by some clinicians mainly to relieve acute symptoms of COPD. Albuterol is used in combination with other bronchodilators or alone on an as-needed or regular (e.g., 4 times daily) basis for the management of mild to very severe COPD. Albuterol sulfate in fixed combination with ipratropium bromide is used as maintenance therapy of reversible bronchospasm associated with COPD in patients who continue to have evidence of bronchospasm despite regular use of an orally inhaled bronchodilator and who require a second bronchodilator. Therapy with anticholinergic and/or β-adrenergic agonist bronchodilators increases airflow and exercise tolerance and reduces dyspnea in patients with COPD.

In the stepped-care approach to drug therapy in patients with COPD, mild intermittent symptoms and minimal lung impairment (e.g., FEV₁ at least 80% of predicted) can be treated with a short-acting, selective inhaled β₂-agonist such as albuterol as needed for acute symptoms. Inhaled β₂-adrenergic agonists are preferred over oral β₂-agonist therapy for treatment of COPD. Oral β₂-adrenergic agonists have a slower onset of action and an increased incidence of adverse effects compared with inhaled therapy; the role of oral β₂-adrenergic agonists in treatment of COPD is limited.

In patients with moderate (e.g., FEV₁ 50-80% of predicted) COPD who have persistent symptoms despite as-needed therapy with ipratropium or a selective inhaled β₂-agonist, maintenance treatment with a long-acting bronchodilator (e.g., formoterol, salmeterol, tiotropium) can be added and a short-acting, selective inhaled β₂-agonist be used as needed for immediate symptom relief. Maintenance treatment with long-acting bronchodilators is recommended in such patients as this therapy is more effective and convenient than regular use of short-acting bronchodilators. For patients not responding adequately to treatment following addition of a long-acting bronchodilator, a combination of several long-acting bronchodilators such as tiotropium and a long-acting β-adrenergic agonist may be used.

Maintenance therapy (e.g., 4 times daily) with a short-acting, selective inhaled β₂-agonist is not preferred but may be used in patients with persistent symptoms of COPD; such therapy should not exceed 6-12 inhalations daily. Current guidelines for the management of COPD state that low- to high-dose ipratropium (6-16 inhalations daily) can be added to therapy with a short-acting, selective inhaled β₂-agonist in patients with mild to moderate persistent symptoms of COPD, with the frequency of inhalation therapy with either agent not to exceed 4 times daily; the high dosage of ipratropium included in some guidelines for COPD exceeds the manufacturer's maximum recommended dosage (12 inhalations). Combining bronchodilators from different classes and with differing durations of action may increase the degree of bronchodilation with a similar or lower frequency of adverse effects. In several randomized, double-blind clinical trials, albuterol sulfate and ipratropium bromide in fixed combination for oral inhalation produced greater improvement in pulmonary function (i.e., mean FEV₁ compared with baseline) than either drug alone; the median duration of effect (as measured by FEV₁) was 4-5 hours for the fixed combination compared with 4 hours for ipratropium bromide and 3 hours for albuterol sulfate. For additional information on the use of albuterol and ipratropium in fixed combination for patients with COPD,

For treatment of severe to very severe COPD (e.g., FEV₁ 30-50% of predicted or less, history of exacerbations), the addition of an inhaled corticosteroid to one or more long-acting bronchodilators given separately or in fixed combination may be needed. If symptoms are not adequately controlled with inhaled corticosteroids and a long-acting bronchodilator, or if limiting adverse effects occur, oral extended-release theophylline may be added or substituted.

Management of acute exacerbations of COPD at home is based initially on the same drugs used for management of the stable patient. A short-acting β₂-adrenergic agonist is the preferred bronchodilator for treatment of acute exacerbations of COPD. If response to a short-acting β₂-adrenergic agonist alone is inadequate, some clinicians recommend the addition of ipratropium. In a severe exacerbation (FEV₁ less than 50% of predicted) treated at home, administration of these agents by nebulization or metered-dose inhalation with a spacer device may be used as needed for short-term therapy. For more severe exacerbations of COPD (e.g., FEV₁ less than 50% of predicted), a short (e.g., 7-10 days) course of oral corticosteroids (e.g., equivalent to 30-40 mg of prednisone daily) can be added to bronchodilator therapy. If symptoms of COPD continue to deteriorate several hours after administration of oral corticosteroids (e.g., sudden development of resting dyspnea, cyanosis, peripheral edema, changes in mental status, inability to eat or sleep because of symptoms), the patient should be hospitalized. Following initiation of oxygen therapy in hospitalized patients, therapy with short-acting β₂-adrenergic agonist and/or ipratropium (administered separately or in fixed combination) should be used for acute exacerbations of COPD, although the effectiveness of such combination therapy remains controversial. Oral corticosteroids are especially helpful within the first 72 hours of an acute exacerbation and should be initiated early in the management of the hospitalized patient. If patients cannot tolerate oral corticosteroids, IV corticosteroids should be initiated. If necessary for severe exacerbations, appropriate anti-infective therapy can be initiated if indicated (purulent exacerbations).

Other Uses

Orally inhaled albuterol has been used effectively to prevent or alleviate episodes of muscle paralysis in the treatment of some patients with hyperkalemic familial periodic paralysis.

Dosage and Administration

Administration

Albuterol sulfate is administered orally or by oral inhalation via a metered-dose inhaler or nebulization. Albuterol sulfate is administered in fixed combination with ipratropium bromide via a metered-dose aerosol inhaler or via nebulization. Levalbuterol hydrochloride is administered by oral inhalation via nebulization. Levalbuterol tartrate with hydrofluoroalkane (HFA) propellant is administered by oral inhalation via a metered-dose inhaler. To avoid microbial contamination, proper aseptic technique should be used when albuterol or levalbuterol is administered via nebulization. Albuterol sulfate extended-release tablets should not be chewed or crushed.

Oral Inhalation via Metered-Dose Aerosol

Albuterol Sulfate

It is important that the patient receive careful instruction in the use of the metered-dose inhaler to obtain optimum results. Albuterol sulfate inhalation aerosol should only be used with the actuator supplied with the product. Before using, the inhaler must be shaken well. The aerosol inhaler should be test sprayed (3 times for ProAir HFA, 4 times for Ventolin HFA or Proventil HFA) into the air (away from the face) before initial use or whenever it has not been used for a prolonged period of time (i.e., exceeding 2 weeks). The manufacturer of Ventolin HFA states that the aerosol inhaler also should be test sprayed whenever it has been dropped.

After exhaling as completely as possible, the patient should place the mouthpiece of the inhaler well into the mouth and close the lips firmly around it. Then the patient should inhale deeply through the mouth while actuating the inhaler. After holding the breath for as long as possible, the patient should remove the mouthpiece from the mouth and exhale slowly. It is recommended that 1 minute elapse between inhalations of albuterol sulfate when a 2-inhalation dose is administered. Some clinicians recommend an interval of 10-20 minutes between the first and second inhalation of an orally inhaled sympathomimetic agent in order to increase bronchial penetration of the agent and bronchodilation.

The technique employed for administration of albuterol sulfate by oral inhalation via a metered-dose inhaler is similar in children to that in adults, since the smaller ventilatory capacity of children provides a proportionally smaller dose of the inhaled drug.

To clean the albuterol sulfate inhalation aerosol (Proventil HFA, Ventolin HFA, Proair HFA) inhaler, the metal canister should be removed and the plastic mouthpiece of the actuator cleansed by running warm water through the top and bottom for 30 seconds at least once a week. The mouthpiece of albuterol sulfate inhalation aerosol should be shaken to remove excess water, then air dried thoroughly (e.g., overnight) before replacing the metal canister and mouthpiece cap. If the inhaler is to be used before it is completely dry, excess water should be shaken off, the canister replaced, the inhaler test sprayed once (Ventolin HFA) or twice (Proventil HFA, Proair HFA) away from the face, and the prescribed dose taken. After such use, the mouthpiece should be rewashed and allowed to air dry. Proper cleaning of the albuterol sulfate inhaler (Proventil HFA, Ventolin HFA, Proair HFA) mouthpiece will prevent medication build-up and blockage.

The 3.7- or 6.7-g canister of albuterol sulfate inhalation aerosol (Proventil HFA) should be discarded after 100 or 200 sprays, respectively. The 18-g canister of albuterol sulfate inhalation aerosol (Ventolin HFA) should be discarded after 200 sprays or 2 months after removal from the foil pouch, whichever occurs first. The 8.5-g canister of albuterol sulfate inhalation aerosol (Proair HFA) should be discarded after 200 sprays. Patients should avoid spraying oral aerosols or oral inhalation solutions containing albuterol into the eyes.(See Cautions: Precautions and Contraindications.)

Levalbuterol Tartrate

Levalbuterol tartrate inhalation aerosol should be used only with the actuator provided by the manufacturer. Before using, the inhaler should be shaken well. The aerosol inhaler should be test sprayed (4 times, away from the face) before first use and whenever the inhaler has not been used for more than 3 days. Patients should avoid spraying levalbuterol inhalation aerosol into the eyes.

After exhaling slowly and completely, the mouthpiece of the inhaler should be placed well into the mouth with the lips closed around it. The patient should inhale slowly and deeply through the mouth and actuate the aerosol inhaler. The patient should withdraw the mouthpiece, hold the breath for 10 seconds, if possible, and exhale; 1 minute should elapse between inhalations from the aerosol inhaler.

To clean the metered-dose inhaler, the metal canister and blue mouthpiece (actuator) cap should be removed and cleansed by running warm water through the mouthpiece for 30 seconds at least once a week. The mouthpiece should be shaken to remove excess water and allowed to air dry thoroughly (e.g., overnight). After drying, the metal canister should be inserted into the mouthpiece and the mouthpiece cap replaced. Patients should not attempt to clean the metal canister or allow the canister to become wet. If the inhaler is to be used before it is completely dry, excess water should be shaken off, the canister replaced, and the inhaler tested by spraying twice (away from the face) before administering the dose. After such use, the mouthpiece should be rewashed and allowed to air dry. Proper cleaning of the mouthpiece will prevent medication build-up and blockage. If the actuator becomes blocked, medication should be removed by washing. The metal canister of levalbuterol should be discarded after 200 sprays have been delivered from the 15-g canister, as delivery of the correct dose of the drug cannot be ensured after the labeled number of actuations have been used.

Albuterol Sulfate and Ipratropium Bromide

Patients should insert the metal canister into the clear end of the mouthpiece. The aerosol inhaler should be shaken well for at least 10 seconds immediately prior to use and should be actuated 3 times prior to the initial use or if it has not been used for more than 24 hours. The mouthpiece provided for the inhalation aerosol of albuterol sulfate and ipratropium bromide should not be used for other aerosol drugs. Prior to use, the orange dust cap should be removed and the mouthpiece should be checked for foreign objects. Patients should avoid spraying albuterol sulfate and ipratropium bromide inhalation aerosol into their eyes. To avoid inadvertent contact of the drug with the eyes and subsequent adverse effects (e.g., temporary blurred vision, precipitation or worsening of angle-closure glaucoma, ocular pain), patients should be advised to close their eyes during inhalation of albuterol sulfate and ipratropium bromide aerosol.

The patient should exhale deeply within 30 seconds of shaking the aerosol inhaler and the mouthpiece of the inhaler should be placed into the mouth with the canister held upright. The patient should then inhale slowly and deeply through the mouth while actuating the inhaler. After holding the breath for 10 seconds, the patient should remove the mouthpiece and exhale slowly. If additional inhalations are required, the patient should wait approximately 2 minutes and repeat the procedure. The manufacturer recommends that the albuterol sulfate and ipratropium bromide oral inhaler mouthpiece be cleaned as needed by rinsing the mouthpiece in hot water. If soap is used, the mouthpiece should be rinsed thoroughly with plain water. When dry, the cap on the mouthpiece should be replaced when the inhaler is not in use.

Oral Inhalation via Nebulization

Albuterol Sulfate Concentrate

For administration of albuterol sulfate via a nebulizer using the concentrate solution, an appropriate volume of concentrate solution should be drawn into the specially marked dropper supplied with each bottle and then emptied into the nebulizer reservoir, taking care not to touch the dropper to any surface, including the reservoir or associated ventilatory equipment. The appropriate amount of 0.9% sodium chloride solution is then added to the reservoir to provide a total diluted volume of 3 mL. If the albuterol sulfate concentrate solution changes color or becomes cloudy, it should not be used. For administration of single-use units of albuterol sulfate 0.5% concentrate solution for nebulization, the entire contents of the plastic vial should be emptied into the nebulizer reservoir and 2.5 mL of 0.9% sodium chloride solution should be added to provide a final volume of 3 mL.

Albuterol Sulfate or Levalbuterol Hydrochloride Single-Use Solutions

For administration of albuterol sulfate or levalbuterol hydrochloride solution for nebulization in single-use polyethylene units via a nebulizer, the entire contents of the single-use unit of solution should be emptied into the nebulizer reservoir and used immediately to avoid microbial contamination. If albuterol sulfate solution for nebulization (in single-use units) becomes discolored, it should not be used. Vials of levalbuterol hydrochloride solution for nebulization should be discarded if the solution is not colorless.

Following addition of the drug to the nebulizer reservoir, the reservoir is attached to the mouthpiece or face mask and to the compressor according to the manufacturer's instructions. The patient should place the mouthpiece of the nebulizer in his or her mouth or put on the nebulizer face mask. The patient should then breathe through the mouthpiece as calmly, deeply, and evenly as possible until the nebulizer stops producing mist. The duration of treatment for oral inhalation of a full dose of albuterol sulfate or levalbuterol hydrochloride usually is about 5-15 minutes. The nebulizer should be cleaned after use according to the manufacturer's instructions in order to avoid microbial contamination.

Albuterol Sulfate and Ipratropium Bromide

Prior to administration of albuterol sulfate and ipratropium bromide inhalation solution for nebulization, the nebulizer manufacturer's information should be reviewed to assess any changes in administration. For administration of albuterol sulfate in fixed combination with ipratropium bromide (DuoNeb) via a nebulizer, the entire contents of the single-use vial of solution should be emptied into the nebulizer reservoir and the reservoir attached to the mouthpiece or face mask and to the compressor according to the manufacturer's instructions.

The patient should place the mouthpiece of the nebulizer into the mouth. Alternatively, patients may put the face mask over the mouth and nose. The patient should then breathe through the mouth as calmly, deeply, and evenly as possible until the nebulizer stops producing mist. The duration of treatment for oral inhalation of a full dose of albuterol sulfate and ipratropium in fixed combination usually is about 5-15 minutes. The nebulizer should be cleaned after use according to the manufacturer's instructions.

Dosage

Dosage of albuterol sulfate is expressed in terms of albuterol. Dosage of levalbuterol hydrochloride or tartrate is expressed in terms of levalbuterol. Dosage of albuterol sulfate and levalbuterol must be carefully adjusted according to individual requirements and response. The albuterol oral aerosol inhalers deliver 90 mcg of albuterol from the mouthpiece per metered spray. The levalbuterol tartrate oral aerosol inhaler delivers 45 mcg of levalbuterol from the mouthpiece per metered spray. The oral aerosol inhaler containing albuterol sulfate and ipratropium bromide delivers 18 mcg of ipratropium bromide and 103 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol) from the mouthpiece per metered spray. Using in vitro testing at an average flow rate of 3.6 L/minute for an average of 15 minutes, the Pari-LC Plus nebulizer delivered at the mouthpiece approximately 46 or 42% of the original dosage of albuterol or ipratropium bromide, respectively. Using in vitro testing at an average flow rate of 3.6 L/minute for an average of 15 minutes or less, the Pari-LC Plus nebulizer delivered at the mouthpiece approximately 43 or 39% of the original dosage of albuterol at the 1.25- or 0. 63-mg strength, respectively.

Commercially available albuterol sulfate aerosol with a hydrofluoroalkane (HFA) propellant delivers at least 200 metered sprays per 18-g (Ventolin HFA), 6.7-g (Proventil HFA), or 8.5-g (ProAir HFA) canister, respectively. The commercially available aerosol inhaler containing albuterol sulfate in fixed combination with ipratropium bromide delivers 200 metered sprays per 14.7-g canister. The commercially available levalbuterol aerosol inhaler delivers 200 metered sprays per 15-g canister. The canister should be discarded after the labeled number of actuations have been used.

Oral Inhalation via Metered-Dose Aerosol

Albuterol Sulfate

For the symptomatic relief of acute episodes of bronchospasm or prevention of asthmatic symptoms, the usual dosage of orally inhaled albuterol administered via a metered-dose aerosol for adults and children 4 years of age or older (Ventolin HFA, Proventil HFA, ProAir HFA) is 180 mcg (2 inhalations) every 4-6 hours. Some experts suggest 180 mcg of albuterol every 4-6 hours for the treatment of acute episodes of bronchospasm in infants and children younger than 4 years of age. In some patients, 90 mcg (1 inhalation) every 4 hours may be sufficient. Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, the manufacturers of Ventolin HFA or ProAir HFA inhalation aerosol suggest that patients in this age group receive initial dosages of the drug at the lower end of the usual range.

The manufacturers of albuterol sulfate inhalation aerosol state that more frequent administration or a larger number of inhalations of albuterol should not be used. However, for acute asthma exacerbations that are managed initially in the patient's home, some experts state that up to 2 doses (2-6 inhalations per dose) of a short-acting inhaled β₂-agonist may be administered via metered-dose inhaler 20 minutes apart. A lower dosage may be sufficient in patients who have less severe exacerbations. If response is good (peak expiratory flow [PEF] returns to at least 80% of predicted value or personal best and response is maintained for 3-4 hours), therapy with a short-acting β₂-agonist should be continued every 3-4 hours for 24-48 hours. If response is incomplete (PEF 50-79% of predicted or personal best), therapy with an inhaled short-acting β₂-agonist should be continued, and the patient should seek medical attention urgently (same day). If response is poor (PEF less than 50% of predicted value or personal best), treatment with the short-acting inhaled β₂-agonist should be repeated immediately (i.e., up to 2 additional doses [2-6 inhalations per dose] of the short-acting β₂-agonist should be administered via metered-dose inhaler 20 minutes apart). If respiratory distress is severe and not responsive to bronchodilator therapy, the patient should proceed immediately to the hospital emergency department for further management. For information on concurrent therapy in the treatment of acute exacerbations, see Asthma under Uses: Bronchospasm.

For treatment of acute mild to moderate asthma exacerbations (forced expiratory volume in 1 second [FEV₁] or PEF at least 40% of predicted value or personal best) in the emergency department in children 12 years of age or younger, some experts suggest 360-720 mcg (4-8 inhalations) of albuterol every 20 minutes for the first hour, followed by 360-720 mcg hourly for 1-4 hours. In adults and adolescents older than 12 years of age, some experts suggest 720 mcg of albuterol every 20 minutes for the first hour, followed by 720 mcg hourly for 1-4 hours. (For treatment of severe exacerbations, see Albuterol Sulfate under Dosage: Oral Inhalation via Nebulization, in Dosage and Administration and also see Albuterol Sulfate and Ipratropium Bromide under Dosage: Oral Inhalation via Nebulization, in Dosage and Administration.)

Current guidelines for the management of asthma do not recommend regular (e.g., 4 times daily) use of short-acting β₂-agonist oral inhalations as maintenance therapy for the control of asthma. Instead, use of short-acting inhaled β₂-agonists is recommended for acute relief of bronchospasm or to prevent exercise-induced bronchospasm. If control of mild asthma deteriorates and results in regular use of a short-acting β₂-agonist (i.e., 4 times daily), patients should be instructed to contact a clinician for reevaluation and possible institution of maintenance therapy.(See Asthma under Uses: Bronchospasm.) The safety of concomitant use of more than 8 inhalations per day of a short-acting β₂-adrenergic agonist with a long-acting orally inhaled β₂-agonist (i.e., salmeterol) has not been established. If the patient uses 4 or more inhalations per day of a short-acting β₂-agonist for 2 or more consecutive days or if more than 1 canister (200 inhalations per canister) of a short-acting β₂-agonist is required during an 8-week period, a clinician should be consulted for reevaluation of maintenance therapy.

For the prevention of exercise-induced bronchospasm, the usual dosage of albuterol inhalation aerosol with HFA propellant (Ventolin HFA, Proventil HFA, Proair HFA) is 180 mcg (2 inhalations) given 15-30 minutes before exercise.

Levalbuterol Tartrate

For the treatment of acute episodes of bronchospasm or prevention of asthmatic symptoms, the usual initial dosage of orally inhaled levalbuterol tartrate via a metered-dose inhaler for adults and children 4 years of age or older is 90 mcg (2 inhalations) every 4-6 hours. A dosage of 45 mcg (1 inhalation) every 4 hours may be sufficient in some patients. More frequent administration or a larger number of inhalations of levalbuterol is not routinely recommended. Levalbuterol inhalation aerosol should be used with caution in patients with renal impairment receiving high dosages of the drug.

Albuterol Sulfate and Ipratropium Bromide

For the management of bronchospasm associated with chronic obstructive pulmonary disease (COPD), the usual initial dosage of albuterol sulfate (90 mcg of albuterol base per inhalation) in fixed combination with ipratropium bromide (18 mcg per inhalation) via a metered-dose inhaler (Combivent) is 180 mcg (2 inhalations) 4 times daily. If necessary, additional inhalations may be used. Since fatalities have been reported in association with excessive use of inhaled β-adrenergic agonists in patients with asthma, the manufacturer recommends notexceeding 12 inhalations in 24 hours with the fixed combination of albuterol sulfate and ipratropium bromide.(See Cautions: Precautions and Contraindications.)

For initial management of severe asthma exacerbations (FEV₁ or PEF of less than 40% of predicted or personal best) in the emergency department in adolescents 12 years of age or older and adults receiving the fixed combination of albuterol sulfate (90 mcg of albuterol base per inhalation) and ipratropium bromide (18 mcg per inhalation) as the metered-dose aerosol, the National Asthma Education and Prevention Program (NAEPP) recommends an albuterol dosage of 720 mcg (8 inhalations) every 20 minutes as needed for up to 3 hours. For initial management of severe asthma exacerbations in children younger than 12 years of age receiving the fixed combination of albuterol sulfate and ipratropium bromide, NAEPP recommends an albuterol dosage of 360-720 mcg (4-8 inhalations) every 20 minutes as needed for up to 3 hours. If the patient is admitted to the hospital, treatment with ipratropium bromide should be discontinued, since the addition of ipratropium to albuterol has not been shown to provide additional benefit once the patient is hospitalized.

Oral Inhalation via Nebulization

Albuterol Sulfate

For administration via a nebulizer, the initial dosage of albuterol for adults and for children 2-12 years of age who weigh at least 15 kg is 2.5 mg 3 or 4 times daily. Alternatively, children 2-12 years of age may receive a lower initial albuterol dosage of 0.63 or 1.25 mg 3 or 4 times daily. More frequent administration or a higher dosage is not recommended by the manufacturers. Some experts suggest that infants and children 4 years of age or younger or children 5-11 years of age may receive 0.63-2.5 mg 4-6 times daily or 1.25-5 mg 3-6 times daily, respectively, based on clinical trial data. In children 2-12 years of age weighing less than 15 kg who require less than 2.5 mg of albuterol per dose, albuterol 0.5% inhalation solution should be used to prepare the appropriate dose. Alternatively, in children 2-12 years of age in whom an albuterol dose of less than 2.5 mg per dose is desired, a single-use pediatric formulation containing 0.63 or 1.25 mg of albuterol per 3 mL may be used. Children 6-12 years of age with more severe asthma (baseline FEV₁ less than 60% predicted) or weight more than 40 kg, or children 11-12 years of age may achieve a better initial response with an albuterol dosage of 1.25 mg. The manufacturer states that the single-use pediatric formulation containing 0.63 or 1.25 mg of albuterol per 3 mL (Accuneb) has not been studied in patients with acute exacerbations of asthma; use of a 2. 5-mg dose of albuterol administered using a more concentrated inhalation solution (0.083% solution containing 2.5 mg of albuterol per 3 mL) may be more appropriate for treating acute exacerbations, particularly in children 6 years of age or older.

The usual initial dosage of single-use albuterol inhalation solution via nebulization for the symptomatic relief of acute episodes of bronchospasm in adults and adolescents 12 years of age or older is 2.5 mg 3 or 4 times daily. In patients receiving nebulized albuterol, the flow rate of the nebulizer should be adjusted so that the albuterol is delivered over a period of approximately 5-15 minutes.

The manufacturers of albuterol inhalation solutions state that use of doses exceeding 2.5 mg or administering the drug more frequently than 4 times daily is not recommended and that medical assistance should be sought immediately if a previously effective dosage regimen fails to provide the usual relief. However, dosages (e.g., 5 mg 3-6 times daily) of albuterol inhalation solution that exceed the manufacturer-recommended dosage have been used in adolescents and adults for treatment of acute asthma.

For acute asthma exacerbations in adults and adolescents 12 years of age or older that are managed initially in the patient's home, some experts state that up to 2 doses (2.5-5 mg per dose) may be administered via nebulization 20 minutes apart. A reduced dosage of a short-acting β₂-agonist may be sufficient in patients who have less severe exacerbations. If response is good (PEF returns to at least 80% of predicted value or personal best), therapy with a short-acting β₂-agonist should be continued every 3-4 hours for 24-48 hours. If response is incomplete (PEF 50-79% of predicted value or personal best), therapy with an inhaled short-acting β₂-agonist should be continued, and the patient should seek medical attention urgently (same day). If response is poor (PEF less than 50% of predicted value or personal best), treatment with the short-acting inhaled β₂-agonist should be repeated immediately (i.e., up to 2 additional treatments may be administered via nebulization 20 minutes apart). If respiratory distress is severe and not responsive to bronchodilator therapy, the patient should proceed immediately to the hospital emergency department for further management. For information on concurrent therapy in the treatment of acute exacerbations, see Asthma under Uses: Bronchospasm.

For treatment of acute mild to moderate asthma exacerbations in the emergency department in children younger than 12 years of age, some experts suggest 0.15 mg/kg of albuterol inhalation solution every 20 minutes for the first hour, followed by 0.15-0.3 mg/kg (not exceeding 10 mg) every 1-4 hours as needed. In adults and adolescents 12 years of age and older, some experts suggest 2.5-5 mg of albuterol every 20 minutes for the first hour, followed by 2.5-10 mg every 1-4 hours as needed.

For treatment of acute severe asthma exacerbations in the emergency department in children younger than 12 years of age, albuterol inhalation solution may be given continuously at a rate of 0.5 mg/kg per hour or intermittently at 0.15 mg/kg every 20 minutes for the first hour. If the exacerbation continues to be severe after the first hour, albuterol inhalation solution is given intermittently at 0.15-0.3 mg/kg (not exceeding 10 mg) every hour or continuously at a rate 0.5 mg/kg per hour. In adults or adolescents 12 years of age or older, albuterol inhalation solution may be given continuously at a rate of 10-15 mg per hour for the first hour or intermittently at 2.5-5 mg of albuterol every 20 minutes for the first hour. If the exacerbation continues to be severe after the first hour, albuterol inhalation solution is given intermittently at 2.5-10 mg every hour or continuously at 10-15 mg per hour.

Levalbuterol Hydrochloride

For administration via a nebulizer, the manufacturer states that the initial dosage of levalbuterol for the management of acute bronchospasm in children 6-11 years of age is 0.31 mg 3 times daily. For adults or adolescents 12 years of age or older, the initial dosage of levalbuterol is 0.63 mg 3 times daily (every 6-8 hours). Children 6-11 years of age with more severe asthma or those not responding adequately to the 0. 31-mg dose may benefit from a higher dosage; however, routine dosage should not exceed 0.63 mg 3 times daily. Some experts suggest use of levalbuterol 0.31-0.63 mg 3 times daily as needed in children as young as 5 years of age with asthma. Patients 12 years of age or older with more severe asthma or those not responding adequately to the 0. 63-mg dose may benefit from a dosage of 1.25 mg 3 times daily as needed. Patients, including geriatric patients, receiving the higher dosage should be monitored closely for possible adverse systemic effects, and the risk versus benefit should be assessed carefully. The flow rate of the nebulizer should be adjusted so that the dose of levalbuterol is delivered over a period of approximately 5-15 minutes. Levalbuterol nebulization therapy should be continued as necessary to control recurrent bronchospasm. During acute exacerbations of asthma, most patients obtain optimum benefit when the solution for nebulization is used regularly rather than on-demand, at least initially.

Albuterol Sulfate and Ipratropium Bromide

For administration via a nebulizer, the dosage of albuterol sulfate (as albuterol base) in fixed combination with ipratropium bromide (0.5 mg) (DuoNeb) in adults is 2.5 mg 4 times daily, with up to 2 additional inhalations allowed daily. The flow rate of the nebulizer should be adjusted so that the dose is delivered over a period of approximately 5-15 minutes. The manufacturer of DuoNeb recommends not exceeding 6 inhalations daily since these dosages have not been studied for the treatment of COPD.

For initial management of severe asthma exacerbations using the fixed combination of albuterol sulfate and ipratropium bromide in the emergency department, the NAEPP recommends 2.5 mg of albuterol sulfate (as albuterol base) in combination with 0.5 mg of ipratropium bromide every 20 minutes for 3 doses initially in adolescents 12 years of age or older and adults. For initial management of severe asthma exacerbations using the fixed combination of albuterol sulfate and ipratropium bromide in children younger than 12 years of age, NAEPP recommends 1.25-2.5 mg of albuterol in fixed combination with ipratropium bromide (250-500 mcg) every 20 minutes for 3 doses initially. Alternatively, albuterol sulfate in fixed combination with ipratropium bromide may be used continuously via nebulization for the first 1 hour after admittance to the emergency department in patients with severe asthma exacerbations. If there is no improvement after the first hour of treatment, albuterol sulfate in fixed combination with ipratropium bromide may be continued for no more than 2 additional hours for a total duration of 3 hours of treatment. Similarly, if a severe exacerbation develops after the first hour of treatment with a short-acting β₂-agonist and an oral corticosteroid, albuterol sulfate in fixed combination with ipratropium bromide may be initiated and continued for no more than 2 additional hours. If the patient is admitted to the hospital, ipratropium bromide should be discontinued since benefit of the drug in addition to short-acting inhaled β₂-adrenergic agonist therapy (e.g., albuterol) has not been established once patients with severe asthma exacerbations are hospitalized.

Oral Dosage

Albuterol Sulfate

The usual initial oral dosage of albuterol for adults and children 12 years of age or older is 2 or 4 mg 3 or 4 times daily as conventional tablets. Alternatively, adults and children 12 years of age or older may receive an initial oral dosage of 8 mg every 12 hours as extended-release tablets; in some patients (e.g., those with low body weight), 4 mg every 12 hours may be sufficient. Dosages exceeding 4 mg 4 times daily as conventional tablets or 8 mg twice daily as extended-release tablets should be used only when the patient fails to respond to the usual initial dosage. If necessary, dosage may be cautiously and gradually increased to a maximum of 8 mg 4 times daily as conventional tablets or 16 mg twice daily as extended-release tablets in adults and adolescents 12 years of age or older. When patients stabilized on conventional albuterol sulfate tablets are transferred to extended-release tablets, each 2 mg administered every 6 hours as conventional tablets is approximately equivalent to 4 mg every 12 hours as extended-release tablets.

The usual initial oral dosage of albuterol for children 6 to younger than 12 years of age is 2 mg 3 or 4 times daily as conventional tablets. Dosages exceeding 2 mg 4 times daily as conventional tablets should be used only when the patient fails to respond to the usual initial dosage. If necessary, dosage may be cautiously and gradually increased to a maximum of 24 mg daily (in divided doses) as conventional tablets. In children 6-12 years of age, the usual initial dosage of albuterol extended-release tablets (VoSpire ER) is 4 mg every 12 hours. Dosage of albuterol given as extended-release tablets may be increased cautiously stepwise as tolerated to a maximum of 12 mg twice daily.

The usual initial oral dosage of albuterol as the oral solution (syrup) for children 6-14 years of age is 2 mg 3 or 4 times daily. In patients older than 14 years of age receiving the oral solution who fail to respond to the usual initial dosage, dosage may be cautiously and gradually increased to a maximum of 24 mg daily given in 4 divided doses. For children 2 to 6 years of age, the usual initial oral dosage is 0.1 mg/kg 3 times daily (not to exceed 2 mg 3 times daily) as the oral solution; in patients who fail to respond to the usual initial dosage, dosage may be gradually increased to 0.2 mg/kg 3 times daily (not to exceed 4 mg 3 times daily). The usual initial oral dosage of albuterol for adults or children older than 14 years of age is 2 or 4 mg 3 or 4 times daily as the oral solution. Subsequent dosage is adjusted according to the patient's tolerance and response. Dosages exceeding 4 mg 4 times daily as the oral solution should be used only when the patient fails to respond to the usual initial dosage. If necessary, dosage of albuterol oral solution may be cautiously and gradually increased to a maximum of 8 mg 4 times daily in adults and children older than 14 years of age.

In geriatric patients and those sensitive to sympathomimetic amines, the initial oral albuterol dosage is 2 mg 3 or 4 times daily as conventional tablets or oral solution; if necessary, dosage may be gradually increased to as much as 8 mg 3 or 4 times daily.

Cautions

Information on the adverse effects of orally inhaled albuterol and albuterol sulfate and conventional albuterol sulfate oral tablets has been obtained principally from clinical studies in adults and children 4 years of age or older with asthma who received the drug in short-term (e.g., 1-13-week) clinical trials. Information on the adverse effects of albuterol sulfate extended-release tablets has been obtained from clinical trials in adults and children 6 years of age or older. Adverse effects associated with oral dosage forms (i.e., conventional or extended-release tablets, oral solution) of albuterol generally are transient in nature and usually do not require discontinuance of therapy; in selected cases, oral dosage of albuterol may be reduced temporarily until the adverse effect has subsided, then increased in small increments until the optimum dosage is reached. Evidence principally from a short-term (4-week), comparative clinical trial in adults and adolescents with mild to moderate asthma suggest that levalbuterol hydrochloride, the R-enantiomer of albuterol, may be associated with somewhat fewer adverse β-adrenergic effects than racemic albuterol at dosages (0.63 mg of levalbuterol and 2.5 mg of albuterol) that provide equivalent bronchodilation.

The most common adverse effects of albuterol or levalbuterol are dose related and characteristic of sympathomimetic agents, although certain cardiovascular effects may occur less frequently with these drugs than with less receptor-selective agents. Tremor appears to be the most frequently reported adverse effect of albuterol, occurring in up to 20% of patients in clinical trials with various dosage forms of the drug. Other frequently reported adverse effects of albuterol include nervousness, nausea, tachycardia, palpitations, chest pain, shakiness, and dizziness. Limited data suggest that the incidence and nature of adverse effects in patients receiving albuterol sulfate oral inhalation aerosol containing the hydrofluoroalkane (HFA) propellant, a non-chlorofluorocarbon (CFC) propellant, (Proventil HFA, Ventolin HFA, ProAir HFA), are similar to those in patients receiving albuterol oral inhalation aerosol containing CFC propellants (e.g., Ventolin, no longer commercially available in the US).

Data from a short-term (4-week), comparative clinical trial in adults and adolescents with mild to moderate asthma suggest that nervousness and tremor are the most common, potentially drug-related adverse effects associated with levalbuterol hydrochloride oral inhalation for nebulization therapy. Discontinuance of therapy because of adverse effects in this trial was slightly more common in patients receiving levalbuterol 1.25 mg 3 times daily than with levalbuterol 0.63 mg 3 times daily, albuterol 2.5 mg 3 times daily, or placebo.

Nervous System Effects

Tremor was reported in 20% of patients receiving albuterol sulfate conventional oral tablets or oral inhalation via nebulization in clinical trials, and in less than 15% of patients 12 years of age or older receiving either albuterol or isoproterenol oral inhalation aerosol in a comparative clinical trial. Tremor was reported in 10% of children 6-12 years of age receiving escalating dosages of albuterol (4-12 mg twice daily) as albuterol sulfate extended-release tablets in a dose-ranging trial and also in 10% of adults and older children receiving albuterol sulfate oral solution in other clinical trials. In controlled clinical trials, tremor was reported in 24.2% of adults receiving albuterol sulfate extended-release tablets. In these trials, the frequency of tremor appeared to increase with increasing patient age, with tremor occurring in 1.2, 2.6, 6.9, and 6.9% of patients 12-20, 21-30, 31-40, and 41-50 years of age, respectively. The overall incidence of tremor in patients receiving conventional or extended-release albuterol sulfate tablets in clinical trials reportedly has been similar. Tremor was reported in 8 or 7% of patients receiving albuterol inhalation aerosol or albuterol sulfate inhalation aerosol, respectively; in 1% of patients receiving albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US), and in less than 1% of children 4-11 years of age receiving albuterol inhalation aerosol in clinical trials. In a comparative clinical trial in adults and adolescents with mild to moderate asthma, tremor was reported in 6.8 or 0% of patients receiving orally inhaled levalbuterol 1.25 or 0.63 mg, respectively, 3 times daily via nebulization and in 2.7% of those receiving nebulized albuterol 2.5 mg 3 times daily. Hypertonia occurred in 2.7% of patients receiving the 2.5 mg dose of orally inhaled albuterol via nebulization and in 0% of those receiving either 1.25 or 0.63 mg of levalbuterol oral inhalation via nebulization. Tremor was reported in less than 2% of patients receiving levalbuterol inhalation solution via nebulization in overall clinical trials.

Nervousness was reported in 20% of patients receiving albuterol sulfate oral tablets in clinical trials. Nervousness was reported in 15% of children 2-6 years of age receiving the oral solution in clinical trials, while nervousness/shakiness was reported in 9% of adults and older children (6-14 years of age) receiving the oral solution. Nervousness was reported in 13% of children 6-12 years of age receiving escalating dosages of albuterol (4-12 mg twice daily) as albuterol sulfate extended-release tablets in a dose-ranging trial. Nervousness was reported in 8.5% of adults receiving albuterol sulfate extended-release tablets in controlled clinical trials. In a comparative trial, nervousness was reported in 2 or 6% of patients receiving extended-release or conventional albuterol sulfate tablets, respectively. Nervousness occurred in less than 10% of patients 12 years of age or older receiving albuterol and in less than 15% of those receiving isoproterenol oral inhalation aerosol in a comparative clinical trial. Nervousness was reported in 9 or 7% of patients receiving albuterol (no longer commercially available in the US) or albuterol sulfate aerosol, respectively, and in 4% of patients receiving nebulized albuterol sulfate in clinical trials. Nervousness was reported in 1% of adults and children 12 years of age or older receiving albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US) and 1% of children 4-11 years of age receiving albuterol oral inhalation aerosol in clinical trials. Nervousness was reported during postmarketing experience in patients receiving levalbuterol HFA oral inhalation aerosol.

Dizziness was reported in 7% of patients receiving albuterol sulfate inhalation solution via nebulization, 3% of patients (adults and children 6-14 years of age) receiving albuterol sulfate oral solution, 2% of patients receiving albuterol sulfate tablets, and in less than 1% of patients receiving albuterol sulfate inhalation powder (Rotacaps; no longer commercially available in the US) in overall clinical trials. In another comparative trial in patients 12 years of age or older, dizziness occurred in less than 5% of patients receiving either albuterol (Ventolin, no longer commercially available in the US) or isoproterenol oral inhalation aerosol. Dizziness also has been reported in patients receiving albuterol sulfate inhalation aerosol, occurring in 3% of patients receiving albuterol sulfate HFA inhalation aerosol (Proair HFA) in a clinical trial. In one short-term (3-week) clinical trial in children 4-11 years of age receiving albuterol sulfate HFA inhalation aerosol (Proair HFA), adverse nervous system effects occurred at a low incidence (less than 2% in patients receiving albuterol) and were comparable to those effects observed with adults and adolescents. In a short-term, comparative clinical trial in adults and adolescents with mild to moderate asthma, dizziness was reported in 1.4 or 2.7% of patients receiving 0.63 or 1.25 mg doses, respectively, of orally inhaled levalbuterol and in 0% of patients receiving albuterol sulfate inhalation solution via nebulization. In short-term comparative trials in adults and adolescents with asthma, dizziness was reported in 2.7% of patients receiving levalbuterol HFA inhalation aerosol and in 0.6% of patients receiving albuterol HFA inhalation aerosol.

Headache was reported in 7% of patients receiving albuterol sulfate tablets and in 4% of patients (adults and children 6-14 years of age) receiving albuterol sulfate oral solution in clinical trials. In a dose-ranging trial, headache was reported in 22% of children 6-12 years of age receiving escalating dosages of albuterol (4-12 mg twice daily) as albuterol sulfate extended-release tablets. Headache occurred in 18.8% of adults receiving albuterol extended-release tablets in controlled clinical trials. Headache occurred in 5% of children 4-12 years of age and in 2% of adults and older children receiving albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US) in clinical trials. Headache occurred in 7% of adults and adolescents 12 year of age or older receiving albuterol sulfate oral inhalation aerosol (Proair HFA) in a clinical trial. Headache was reported in 3% of patients receiving nebulized albuterol sulfate inhalation solution and in 3% of children 4-11 years of age receiving albuterol oral inhalation aerosol in clinical trials.

Headache was reported in 7.6, 11.9, 9.4, or 3.3% of patients receiving orally inhaled levalbuterol 0.31 mg, levalbuterol 0.63 mg, albuterol 1.25 mg, or albuterol 2.5 mg 3 times daily via nebulization, respectively. In a short-term, comparative clinical trial in adults and adolescents with mild to moderate asthma, migraine was reported in 2.7 or 0% of patients receiving orally inhaled levalbuterol 1.25 or 0.63 mg 3 times daily, respectively, and in 0% of patients receiving orally inhaled albuterol 2.5 mg 3 times daily via nebulization. Headache has been reported with levalbuterol HFA inhalation aerosol during postmarketing experience. Migraine was reported in 1.7 or 0.9% of children receiving orally inhaled levalbuterol 0.63 or 1.25 mg 3 times daily, respectively, via nebulization.

Insomnia occurred in 11% of children 6-12 years of age receiving escalating dosages of albuterol (4-12 mg twice daily) as albuterol sulfate extended-release tablets in a dose-ranging trial. Insomnia was reported in 2.4% of adults receiving albuterol sulfate extended-release tablets in controlled clinical trials. Insomnia was reported in 2% of children 2-6 years of age receiving albuterol sulfate oral solution in clinical trials. Sleeplessness was reported in 1% of patients receiving nebulized albuterol and in less than 1% of patients receiving albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US) in clinical trials. Insomnia or sleeplessness was reported in 2% of patients receiving albuterol sulfate tablets; sleeplessness was reported in 1% and disturbed sleep was reported in less than 1% of adults and older children receiving albuterol sulfate oral solution in clinical trials. In a comparative trial, somnolence was reported in 2% of patients receiving either extended-release or conventional albuterol sulfate tablets.

Insomnia was reported in less than 2% of patients receiving orally inhaled levalbuterol via nebulization in clinical trials. Sleeplessness or CNS stimulation has been reported during postmarketing experience with levalbuterol HFA inhalation aerosol.

Inhalation site sensation was reported in 9 or 6%, and inhalation taste sensation in 3 or 4% of patients receiving albuterol (no longer commercially available in the US) or albuterol sulfate inhalation aerosol, respectively. Tinnitus, anxiety, ataxia, depression, somnolence, or hyperkinesia has been reported in less than 3% of patients receiving albuterol sulfate oral inhalation aerosol in clinical trials.

In overall clinical trials in patients receiving levalbuterol inhalation solution via nebulization, hypesthesia of the hand, anxiety, or paresthesia occurred in less than 2% of patients. In a short-term, comparative trial in adults and adolescents with mild to moderate asthma, anxiety was reported in 2.7 or 0% of patients receiving orally inhaled levalbuterol 1.25 or 0.63 mg 3 times daily, respectively, and in 0% of those receiving orally inhaled albuterol 2.5 mg 3 times daily via nebulization.

Hyperactivity was reported in 2% of adults and older children receiving albuterol sulfate oral solution, in 1% of children 4-11 years of age receiving albuterol oral inhalation aerosol, and in less than 1% of children 4-12 years of age receiving albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US) in clinical trials. In clinical trials with albuterol sulfate oral solution, excitement was noted more frequently in young children than in older children and adults, occurring in 20% of children 2-6 years of age and in 2% of adults and older children (6-14 years of age). Other adverse nervous system effects reported with albuterol sulfate oral solution in adults and older children (6-14 years of age) include irritable behavior and weakness in less than 1% of patients. Hyperkinesia was reported in 4%, and emotional lability or fatigue in 1% of children 2-6 years of age receiving the oral solution in clinical trials. Weakness was reported in 2%, and drowsiness, restlessness, or irritability were reported in less than 1% of patients receiving albuterol sulfate tablets in clinical trials. Agitation, nightmares, or aggressive behavior have been reported in 1% of children 4-11 years of age receiving albuterol oral inhalation aerosol in clinical trials. Lightheadedness was reported in less than 1% of patients receiving albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US) and in less than 1% of children 4-11 years of age receiving albuterol oral inhalation aerosol in clinical trials. Tinnitus has been reported in patients receiving albuterol sulfate oral tablets. Like other sympathomimetic agents, albuterol has been associated with vertigo or CNS stimulation.

GI Effects

The most frequently reported adverse GI effect of albuterol is nausea. In a comparative, placebo-controlled trial, nausea was reported in 9 or 10% of patients receiving albuterol (no longer commercially available in the US) or albuterol sulfate oral inhalation aerosol, respectively; vomiting was reported in 2 or 7%, respectively, of these patients. Nausea was reported in 2% of patients receiving albuterol sulfate conventional oral tablets in clinical trials. Nausea or vomiting was reported in 4 or 2%, respectively, of adults receiving extended-release or albuterol sulfate conventional tablets in a clinical trial. Nausea or vomiting was reported in 4.2% of adults receiving albuterol sulfate extended-release tablets in placebo-controlled or comparative clinical trials. In a comparative trial, nausea was reported in less than 15% of patients 12 years of age or older receiving either albuterol or isoproterenol oral inhalation aerosol. Nausea and/or vomiting was reported in 6% of children 4-11 years of age receiving albuterol oral inhalation aerosol. Nausea and/or vomiting was reported in 4% of children 4-12 years of age receiving albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US) in clinical trials. Nausea was reported in 4% or less than 2% of patients receiving albuterol oral inhalation solution or levalbuterol inhalation solution via nebulization in clinical trials. Vomiting was reported in less than 2% of patients receiving levalbuterol inhalation solution via nebulization in clinical trials (and less frequently than with placebo). Vomiting was reported in 10.5 or 7.7% of children 4-11 years of age receiving levalbuterol HFA or albuterol HFA inhalation aerosol, respectively, in a controlled clinical trial.

Increased appetite has been reported in 3% of adults and older children (6-14 years of age) receiving albuterol sulfate oral solution in clinical trials. Anorexia occurred in 1% of children 2-6 years of age in clinical trials. Epigastric pain or stomachache was reported in less than 1% of patients receiving albuterol sulfate oral solution in clinical trials. GI symptoms, which appeared to occur more frequently in young children than in older children and adults, were reported in 2% of children 2-6 years of age receiving albuterol sulfate oral solution. Dyspepsia was reported in 1% of patients receiving orally inhaled albuterol via nebulization in clinical trials; dyspepsia also has been reported in 2% of patients receiving albuterol sulfate tablets. In a comparative trial, heartburn occurred in less than 5% of patients 12 years of age or older receiving either albuterol or isoproterenol oral inhalation aerosol. Stomachache occurred in 3%, and diarrhea or discoloration of teeth in 1% of children 4-11 years of age receiving albuterol oral inhalation aerosol. Diarrhea occurred in less than 3% of adults and adolescents 12 years of age or older receiving albuterol sulfate HFA (ProAir HFA) inhalation aerosol in a clinical trial. Constipation or gastroenteritis occurred in less than 2% of adults and adolescents receiving albuterol sulfate HFA (ProAir HFA) inhalation aerosol but more frequently than with placebo in a few controlled clinical trials. Diarrhea, dyspepsia, constipation, or nausea occurred in 1.8, 1.3, more than 1, or 1.4%, respectively, of patients receiving the fixed combination of albuterol sulfate and ipratropium bromide inhalation solution via nebulization in a controlled clinical trial. Overall, in clinical trials in patients receiving levalbuterol inhalation solution via nebulization, diarrhea, dry mouth, dry throat, dyspepsia, or gastroenteritis was reported in less than 2% of patients. Diarrhea occurred in 1.5, 6, 1.6, and 0% of children receiving orally inhaled levalbuterol 0.31 mg, levalbuterol 0.63 mg, albuterol 1.25 mg, or albuterol 2.5 mg 3 times daily via nebulization, respectively. Dry mouth, eructation, or flatulence has been reported in less than 3% of patients receiving albuterol sulfate oral inhalation aerosol in clinical trials. Stomachache or unusual taste each was reported in 2% and diarrhea was reported in less than 1% of children 4-12 years of age receiving albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US) in clinical trials; burning in the stomach, dry mouth, or bad taste each was reported in less than 1% of patients 12 years of age or older receiving albuterol sulfate inhalation powder. Glossitis was reported in less than 3% of adults and adolescents 12 years of age or older receiving albuterol sulfate HFA (ProAir HFA) inhalation aerosol in a clinical trial. In one short-term (3-week) clinical trial in children 4-11 years of age receiving albuterol sulfate HFA inhalation aerosol (ProAir HFA), adverse GI effects occurred at a low incidence (less than 2% of children receiving albuterol) and were comparable to those effects observed in adults and adolescents. Throat irritation, altered taste, tongue ulceration, and gagging have been reported during postmarketing experience with albuterol sulfate HFA (ProAir HFA) inhalation aerosol.

Cardiovascular Effects

Albuterol sulfate may be associated with clinically important cardiovascular effects, including tachycardia, increased or decreased blood pressure, and related symptoms.

Clinically important changes in systolic and diastolic blood pressure have occurred in individual patients and could be expected to occur in some patients after use of any β-adrenergic bronchodilator. Although such effects are uncommon after recommended dosages of albuterol or levalbuterol therapy, cardiovascular effects may require discontinuance of the drug. Data from a study in a limited number of patients with mild asthma and experimentally induced hypoxia suggest that administration of orally inhaled albuterol may be associated with potentially detrimental cardiovascular effects (e.g., peripheral vasodilation, possible pulmonary shunting) in hypoxic patients, reinforcing the importance of concomitantly administering oxygen in patients with acute severe asthma receiving β-agonist bronchodilators.

ECG changes, including flattening of the T wave, prolongation of the QT_c interval, and ST-segment depression, have been reported infrequently with β-agonist therapy; the clinical importance of these findings is unknown. Cardiac arrhythmias (including atrial fibrillation, supraventricular tachycardia, and extrasystoles) also have been reported with albuterol or levalbuterol therapy. ECG changes or abnormal ECG has been reported in less than 2% of patients receiving levalbuterol inhalation solution via nebulization in overall clinical trials.

Tachycardia or palpitations were reported in 5% of patients receiving albuterol sulfate oral tablets and 1% of patients receiving albuterol oral inhalation solution via nebulization in clinical trials. In children 6-12 years of age receiving escalating dosages of albuterol (4-12 mg twice daily) as albuterol sulfate extended-release tablets, tachycardia or palpitations each occurred in 8% of patients. Tachycardia occurred in 2.7% of adults receiving albuterol sulfate extended-release tablets in controlled clinical trials. Tachycardia or pallor was reported in 2 or 1%, respectively, of children 2-6 years of age in clinical trials; tachycardia occurred in 1% of children 6-14 years of age and adults receiving albuterol sulfate oral solution. In a short-term, comparative clinical trial in adults and adolescents with mild to moderate asthma, tachycardia was reported in 2.7, 2.8, or 2.7% of patients receiving orally inhaled levalbuterol 1.25 mg, levalbuterol 0.63 mg, or albuterol 2.5 mg 3 times daily, respectively, via nebulization. In one short-term (3-week) clinical trial in children 4-11 years of age receiving albuterol sulfate HFA inhalation aerosol (Proair HFA), adverse cardiovascular effects occurred at a low incidence (less than 2% of children receiving albuterol) and were comparable to those effects observed in adults and adolescents. Palpitations have been reported with albuterol sulfate oral inhalation aerosol. In a comparative trial in patients 12 years of age or older, tachycardia was reported in 10% of patients receiving either albuterol or isoproterenol aerosol; palpitations were reported in less than 10% of patients receiving albuterol oral inhalation aerosol and in less than 15% of those receiving isoproterenol oral inhalation aerosol. Palpitations also were reported in less than 1% of patients receiving albuterol oral solution in clinical trials. Palpitations, tachycardia, arrhythmias, and hypertension have also been reported with the fixed combination of albuterol sulfate and ipratropium bromide inhalation aerosol or solution for nebulization. In one large, case-control study in patients with recently diagnosed COPD that evaluated the risk of cardiovascular, respiratory, and all-cause mortality and exposure to drugs used to treat COPD, use of ipratropium therapy alone within the previous 6 months was associated with an 11 and 34% increased risk of all-cause and cardiovascular mortality, respectively. Although use of ipratropium alone may have the potential for increasing the risk of mortality in patients with COPD, the possibility exists that some of this risk may be reduced by the concomitant use of other drugs for the treatment of COPD.

As with other sympathomimetic agents, angina has been reported in patients receiving albuterol or levalbuterol therapy. Chest pain or edema was reported in less than 3% of patients receiving albuterol sulfate oral inhalation aerosol in clinical trials, and flushing or chest discomfort was reported in less than 1% of patients receiving albuterol sulfate conventional oral tablets. Chest pain also was reported in less than 1% of patients receiving albuterol oral solution in clinical trials. In a short-term, placebo-controlled trial in children with mild to moderate asthma, chest pain was reported in 1.7 or 0.9% of children receiving orally inhaled albuterol pediatric inhalation solution 0.63 or 1.25 mg 3 times daily via nebulization, respectively. Chest pain was reported in less than 2% of patients receiving orally inhaled levalbuterol via nebulization in clinical trials. Chest pain was reported in less than 3% of adults and adolescents 12 years of age or older receiving albuterol sulfate HFA (ProAir HFA) inhalation aerosol in a clinical trial. Chest pain was reported in 2.6% of patients receiving the fixed combination of albuterol sulfate and ipratropium bromide inhalation solution via nebulization in a controlled clinical trial.

Hypertension has been reported in 1% or less than 2% of patients receiving albuterol sulfate or levalbuterol hydrochloride inhalation solution via nebulization, respectively, in clinical trials. Hypertension has been reported in less than 2% of adults and adolescents receiving levalbuterol HFA inhalation aerosol but more frequently than with placebo in a few controlled clinical trials. In a comparative trial, increased blood pressure was reported in less than 5% of patients 12 years of age or older receiving either albuterol or isoproterenol oral inhalation aerosol. In overall clinical trials with levalbuterol inhalation solution via nebulization, hypertension, hypotension, or syncope has been reported in less than 2% of patients.

Respiratory Effects

Bronchospasm has been reported in 8%, and wheezing in 1%, of patients receiving albuterol sulfate inhalation solution via nebulization. Bronchospasm has been reported in 1% of patients 12 years of age or older receiving albuterol sulfate inhalation powder (Rotacaps; no longer commercially available in the US) in clinical trials. Paradoxical bronchospasm, a potentially life-threatening event, has been reported with orally inhaled sympathomimetic amines, including orally inhaled albuterol or levalbuterol, albuterol sulfate oral solution, and extended-release albuterol tablets. When associated with inhaled formulations, paradoxical bronchospasm frequently occurs with the first use of a new canister or vial.(See Cautions: Precautions and Contraindications.) In overall clinical trials in patients receiving levalbuterol inhalation solution via nebulization, asthma exacerbation occurred in less than 2% of patients receiving the drug (and less frequently than with placebo). Asthma exacerbation occurred in 11.1 or 13% of children receiving orally inhaled albuterol 0.63 mg or 1.25 mg 3 times daily via nebulization, respectively. Asthma exacerbation occurred in 9.1, 9, 6.3, or 10% of patients receiving orally inhaled levalbuterol 0.31 mg, levalbuterol 0.63 mg, albuterol 1.25, or albuterol 2.5 mg 3 times daily via nebulization, respectively. Asthma exacerbation occurred in 9.4 or 7.3% of adults and adolescents receiving levalbuterol HFA or albuterol sulfate HFA inhalation aerosol, respectively, in controlled clinical trials. Asthma exacerbation, aggravated bronchospasm, or lack of efficacy has been reported during postmarketing experience in patients receiving albuterol sulfate HFA (ProAir HFA) inhalation aerosol. Lung disorder has been reported in less than 2% of adults and adolescents receiving levalbuterol HFA inhalation aerosol but more frequently than with placebo in a few controlled clinical trials. Wheezing has been reported in less than 2% of patients receiving levalbuterol inhalation solution via nebulization (and less frequently than with placebo). Dyspnea was reported during postmarketing experience in patients receiving levalbuterol via nebulization. Dyspnea was reported in less than 3% of adults and adolescents 12 years of age or older receiving albuterol sulfate HFA (ProAir HFA) inhalation aerosol in a clinical trial. In one short-term (3-week) clinical trial in children 4-11 years of age receiving albuterol sulfate HFA inhalation aerosol (Proair HFA), adverse respiratory effects occurred at a low incidence (less than 2% of children receiving albuterol) and were comparable to those effects observed in adults and adolescents.

Cough occurred in 5% of patients 12 years of age or older receiving albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US) and in 4% of patients receiving albuterol oral inhalation solution via nebulization in clinical trials. Cough was reported in 2% of children 4-12 years of age receiving albuterol oral inhalation aerosol (no longer commercially available in the US) or albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US) and in less than 1% of patients receiving albuterol sulfate oral solution in clinical trials. In a short-term, comparative clinical trial in adults and adolescents with mild to moderate asthma, increased coughing occurred in 4.1 or 1.4% of patients receiving orally inhaled levalbuterol 1.25 or 0.63 mg 3 times daily, respectively, and in 2.7% of those receiving albuterol 2.5 mg 3 times daily via nebulization. However, in overall clinical trials with levalbuterol inhalation solution via nebulization, increased cough was reported in less than 2% of patients (and less frequently than with placebo). Increased cough was reported during postmarketing experience in patients receiving levalbuterol via nebulization.

Bronchitis was reported in 4 or 1.7% of patients receiving albuterol oral inhalation solution via nebulization or the fixed combination of albuterol sulfate and ipratropium bromide inhalation solution via nebulization, respectively, in clinical trials. In a short-term, placebo-controlled trial, bronchitis was reported in 1.7 or 0.9% of children receiving the pediatric albuterol inhalation solution 0.63 or 1.25 mg 3 times daily, respectively, via nebulization. In another short-term comparative trial in children 4-11 years of age, bronchitis was reported in 2.6% of children receiving levalbuterol HFA inhalation aerosol and in none of the children receiving albuterol HFA or placebo. Nasal congestion was reported in 2% of children 4-12 years of age receiving albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US) in clinical trials. Nasal congestion was reported in 1% of patients receiving nebulized albuterol inhalation solution, and pharyngitis was reported in less than 1% of such patients. Pharyngitis, lung disease, or pneumonia was reported in 4.4, 6.4, or 1.3% of patients receiving fixed combination of albuterol sulfate and ipratropium bromide inhalation solution via nebulization in a controlled clinical trial. Pharyngitis was reported in 3, 10.4, 0, or 6.7% of children receiving orally inhaled levalbuterol 0.31 mg, levalbuterol 0.63 mg, albuterol 1.25 mg, or albuterol 2.5 mg 3 times daily via nebulization, respectively. Pharyngitis was reported in 7.9 or 2.2% of adults and adolescents receiving levalbuterol HFA or albuterol HFA inhalation aerosol, respectively, in controlled clinical trials. In a short-term comparative trial in children 4-11 years of age, pharyngitis was reported in 6.6 or 12.8% of children receiving levalbuterol HFA or albuterol HFA inhalation aerosol, respectively. Pharyngitis was reported in 14% of adults and adolescents 12 years of age or older receiving albuterol sulfate HFA inhalation aerosol (Proair HFA) in a clinical trial. Drying or irritation of the oropharynx has been reported during postmarketing experience in patients receiving levalbuterol inhalation aerosol.

Epistaxis occurred in 3% of children 4-11 years of age receiving albuterol oral inhalation aerosol, 2% of children 4-12 years of age receiving albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US), and 1% of patients receiving albuterol sulfate oral solution in clinical trials. Epistaxis occurred in less than 2% of adults and adolescents receiving levalbuterol HFA inhalation aerosol in a few controlled clinical trials. Turbinate edema was reported in 1.4 or 2.8% of patients receiving orally inhaled levalbuterol 1.25 or 0.63 mg 3 times daily via nebulization and in 0% of patients receiving albuterol sulfate inhalation solution via nebulization 3 times daily in a short-term, comparative trial. In a comparative trial, rhinitis was reported in 22 or 16% of patients receiving albuterol (no longer commercially available in the US) or albuterol sulfate inhalation aerosol (Proventil HFA), respectively; upper respiratory tract infection was reported in 20 or 21%, and unspecified respiratory disorder in 4 or 6% of these respective patients. Rhinitis was reported in 5% of adults and adolescents 12 years of age or older receiving albuterol sulfate inhalation aerosol (Proair HFA) in a clinical trial. Rhinitis was reported in 6.1, 10.4, 3.1, or 5% of children receiving orally inhaled levalbuterol 0.31 mg, levalbuterol 0.63 mg, albuterol 1.25 mg, or albuterol 2.5 mg 3 times daily via nebulization, respectively. Rhinitis was reported in 2.7, 11.1%, or 6.8% of patients receiving orally inhaled levalbuterol 1.25 mg, 0.63 mg, or albuterol 2.5 mg 3 times daily, respectively, via nebulization in a short-term, comparative trial. Rhinitis was reported in 7.4 or 2.2% of adults and adolescents receiving orally inhaled levalbuterol HFA or albuterol HFA inhalation aerosol, respectively, in a few short-term, comparative trials. Sinusitis occurred in 1.4, 4.2, or 2.7% of patients receiving levalbuterol 1.25 mg, 0.63 mg, or albuterol 2.5 mg 3 times daily, respectively, via nebulization, in this comparative trial.

Viral infection was reported in 6.9, 12.3, or 12.2% of patients receiving orally inhaled levalbuterol 1.25 or 0.63 mg or albuterol 2.5 mg 3 times daily, respectively, via nebulization, in this clinical trial. Viral infection was reported in less than 2% of adults and adolescents receiving levalbuterol HFA inhalation aerosol but more frequently than with placebo in a few controlled clinical trials.

Dysphonia or voice alterations have been reported in less than 3 or more than 1%, respectively, of patients receiving albuterol sulfate inhalation aerosol or the fixed combination of albuterol sulfate and ipratropium bromide inhalation solution via nebulization, respectively, in clinical trials. Throat irritation was reported in 6% of children 4-11 years of age receiving albuterol oral inhalation aerosol and in 2% of patients 12 years of age or older receiving albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US) in clinical trials. Increased hemoptysis in a patient with preexisting hemoptysis also has been reported with nebulized albuterol sulfate inhalation. Throat irritation or hoarseness each was reported in 2% of children 4-12 years of age receiving albuterol sulfate oral inhalation powder (Rotacaps; no longer commercially available in the US) in clinical trials. Hoarseness also has been reported in patients receiving albuterol sulfate inhalation solution via nebulization or oral solution.

Dermatologic and Sensitivity Reactions

Increased sweating has been reported in less than 3% of patients receiving albuterol sulfate oral inhalation aerosol, and sweating has been reported in less than 2% of patients receiving levalbuterol inhalation solution via nebulization and less than 1% of patients receiving albuterol sulfate oral solution in clinical trials. Erythema multiforme or Stevens-Johnson syndrome has been reported rarely with administration of oral albuterol sulfate in children. Acne or herpes simplex infection occurred in less than 2% of adults and adolescents receiving levalbuterol HFA inhalation aerosol and more frequently than with placebo in a few controlled clinical trials.

Allergic reactions were reported in 6 or 4% of patients receiving albuterol sulfate or albuterol inhalation aerosol, respectively, in a comparative, placebo-controlled trial. In a short-term, comparative trial in adults and adolescents with mild to moderate asthma, allergic reactions were reported in 2.7% of the patients receiving orally inhaled albuterol 2.5 mg 3 times daily and in 0 or 0% of patients receiving levalbuterol 1.25 or 0.63 mg 3 times daily, respectively, via nebulization. Allergic reactions were reported in 3.4 or 0.9% of children receiving orally inhaled pediatric formulation of albuterol 0.63 or 1.25 mg 3 times daily, respectively, via nebulization. Immediate hypersensitivity reactions, consisting of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and/or oropharyngeal edema, have been reported rarely in patients receiving orally inhaled or oral albuterol therapy alone or in fixed combination with ipratropium bromide. Angioedema, anaphylaxis, rash, or urticaria has been reported during postmarketing experience with levalbuterol via nebulization. Urticaria has been reported in 0.9 or 1.7% of children receiving orally inhaled albuterol pediatric inhalation solution 0.63 or 1.25 mg 3 times daily, respectively, in a controlled clinical trial. Skin/appendage infections occurred in 1.7% of children receiving orally inhaled albuterol sulfate inhalation solution pediatric formulation 1.25 mg 3 times daily and in none of the children receiving 0.63 mg 3 times daily via nebulization. The potential for hypersensitivity should be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions (urticaria, angioedema, rash, bronchospasm, anaphylaxis, oropharyngeal edema).

Endocrine and Metabolic Effects

Diabetes mellitus has been reported in less than 3% of patients receiving albuterol sulfate inhalation aerosol in clinical trials. Increased blood glucose has occurred following inhalation via nebulization of higher than recommended (i.e., 5-10 mg) doses of the drug. Large IV doses of albuterol (an IV dosage form of albuterol currently is not commercially available in the US) also have aggravated preexisting diabetes mellitus and ketoacidosis. In a short-term, comparative trial in adults and adolescents with mild to moderate asthma, levalbuterol hydrochloride or albuterol sulfate inhalation solution via nebulization produced comparable increases in plasma glucose concentration (mean change from baseline: 4.6-10.3 mg/dL) within 1 hour after administration of either agent; this effect diminished during continued therapy. In a short-term, placebo-controlled, comparative trial in children with mild to moderate asthma, a single dose of levalbuterol inhalation solution (0.31 mg) or placebo produced comparable increases in serum glucose concentration within 1 hour after administration, and these changes were less than those observed with racemic albuterol inhalation solution; this effect decreased during continued active therapy.

Albuterol and other β-adrenergic agonists may produce decreases in serum potassium concentration possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects.(See Cautions: Precautions and Contraindications.) Decreased serum potassium concentrations have occurred following inhalation of albuterol sulfate via nebulization in higher than recommended (i.e., 5-10 mg) doses or following repeated doses of 0.15 mg/kg in children aged 5-17 years; asymptomatic decline of 20-25% in serum potassium has been noted in these children. In a comparative clinical trial in adults and adolescents with mild to moderate asthma, small decreases in plasma potassium (0.2-0.3 mEq/L) were noted within 1 hour after administration of orally inhaled levalbuterol hydrochloride, albuterol sulfate, or placebo via nebulization; this effect diminished during continued therapy.

Musculoskeletal Effects

Muscle cramp was reported in 3% of patients receiving albuterol sulfate oral tablets and in 1% of children 4-11 years of age receiving albuterol oral inhalation aerosol in clinical trials. Muscle cramps were reported during postmarketing experience with albuterol sulfate HFA (ProAir HFA) inhalation aerosol. Muscle spasm was reported in less than 1% of patients receiving albuterol sulfate oral solution in clinical trials.

Flu-like syndrome was reported in 1.4, 4.2, or 2.7% of adults and adolescents receiving levalbuterol 1.25 mg or 0.63 mg or albuterol 2.5 mg 3 times daily, respectively, in a short-term, comparative trial. Rigors occurred in less than 3% of patients receiving albuterol sulfate oral inhalation aerosol in clinical trials. Leg cramps have been reported in less than 2% of patients receiving levalbuterol inhalation solution via nebulization in overall clinical trials and in 1.4, 2.7, or 0% of patients receiving orally inhaled albuterol sulfate 2.5 mg, levalbuterol 1.25 mg, or levalbuterol 0.63 mg, respectively, 3 times daily via nebulization in a short-term, comparative clinical trial. In a short-term comparative trial, back pain occurred in 2.7, 0, or 0% of patients receiving orally inhaled albuterol 2.5 mg 3 times daily or levalbuterol 1.25 or 0.63 mg 3 times daily, respectively, via nebulization. Back pain occurred in 2 or 4% of patients receiving albuterol (no longer commercially available in the US) or albuterol sulfate inhalation aerosol.

Pain was reported in 1.4-2.8 or 2.7% of patients receiving levalbuterol hydrochloride inhalation solution or albuterol sulfate inhalation solution via nebulization, respectively, in a comparative trial. Pain has been reported in 1.3% of patients receiving the fixed combination of albuterol sulfate and ipratropium bromide inhalation solution via nebulization. Pain was reported in 3, 1.5, 4.7, or 6.7% of children receiving orally inhaled levalbuterol 0.31 mg, levalbuterol 0.63 mg, albuterol 1.25 mg, or albuterol 2.5 mg 3 times daily via nebulization, respectively. Pain was reported in 4 or 3% of adults and adolescents (12 years of age or older) receiving levalbuterol tartrate HFA inhalation aerosol or albuterol sulfate HFA (ProAir HFA) inhalation aerosol, respectively, in a few clinical trials. In one short-term (3-week) clinical trial in children 4-11 years of age receiving albuterol sulfate HFA inhalation aerosol (Proair HFA), adverse musculoskeletal effects occurred at a low incidence (less than 2% of children receiving albuterol) and were comparable to those effects observed in adults and adolescents. Pooled data from clinical trials indicate that pain, leg cramps, or myalgia was reported in less than 2% of patients receiving levalbuterol inhalation solution via nebulization. Myalgia was reported in less than 2% of adults and adolescents receiving levalbuterol HFA inhalation aerosol and more frequently than with placebo in a few controlled clinical trials. Leg cramps also have been reported in 1.4% of patients receiving the fixed combination of albuterol sulfate and ipratropium bromide inhalation solution via nebulization.

Ocular and Otic Effects

Conjunctivitis was reported in 1% of children 2-6 years of age receiving albuterol sulfate oral solution in clinical trials. Conjunctivitis was reported in less than 2% of adults and adolescents receiving levalbuterol HFA aerosol and more frequently than with placebo in a few controlled clinical trials. Dilated pupils were reported in less than 1% of patients receiving albuterol sulfate oral solution in clinical trials. Ocular pruritus occurred in less than 2% of patients receiving levalbuterol hydrochloride inhalation solution via nebulization in overall clinical trials. Temporary pupillary dilation, blurred vision, ocular pain, or precipitation or aggravation of angle-closure glaucoma may occur following inadvertent exposure of the eyes to nebulized albuterol sulfate in fixed combination with ipratropium bromide.

Ear pain was reported in less than 2% of adults and adolescents receiving levalbuterol HFA aerosol and more frequently than with placebo in a few controlled clinical trials. Ear disorder or ear pain was reported in less than 3% of adults and adolescents receiving albuterol sulfate HFA (ProAir HFA) inhalation aerosol in a clinical trial. In one short-term (3-week) clinical trial in children 4-11 years of age receiving albuterol sulfate HFA inhalation aerosol (ProAir HFA), adverse otic effects occurred at a low incidence (less than 2% of patients receiving albuterol) and were comparable to those effects observed in adults and adolescents. Otitis media occurred in 3.3% of children 6-11 years of age receiving orally inhaled albuterol inhalation solution 2.5 mg 3 times daily via nebulization and was not reported in children receiving orally inhaled levalbuterol inhalation solution in a controlled clinical trial.

Genitourinary Effects

Urinary tract infection was reported in 4 or 3% of patients receiving albuterol (no longer commercially available in the US) or albuterol sulfate inhalation aerosol (Proventil HFA), respectively, in a comparative trial; and fever in 2 or 6% of patients. Urinary tract infection was reported in less than 3% of adults and adolescents receiving another formulation of albuterol sulfate inhalation aerosol (ProAir HFA) in a clinical trial. In one short-term (3-week) clinical trial in children 4-11 years of age receiving albuterol sulfate HFA inhalation aerosol (ProAir HFA), adverse genitourinary effects occurred at a low incidence (less than 2% of children receiving albuterol) and were comparable to those effects observed in adults and adolescents. Urinary tract infection was reported in 1.6% of patients receiving the fixed combination of albuterol sulfate and ipratropium bromide inhalation solution via nebulization in a controlled clinical trial. Difficulty in micturition was reported in less than 1% of patients in clinical trials with albuterol sulfate tablets. Dysmenorrhea or vaginal moniliasis was reported in less than 2% of adults and adolescents receiving levalbuterol HFA inhalation aerosol and more frequently than with placebo in a few controlled clinical trials.

Other Adverse Effects

Accidental injury was reported in 2.7, 0, or 0% of patients receiving orally inhaled levalbuterol 1.25 mg or 0.63 mg or albuterol 2.5 mg 3 times daily, respectively, via nebulization in a short-term, comparative clinical trial. Accidental injury was reported in 6.1, 4.5, 3.1, or 5% of children receiving orally inhaled levalbuterol 0.31 mg, levalbuterol 0.63 mg, albuterol 1.25 mg, or albuterol 2.5 mg 3 times daily via nebulization, respectively. Accidental injury was reported in 9.2 or 10.3% of children 4-11 years of age receiving orally inhaled levalbuterol HFA or albuterol HFA inhalation aerosol, respectively, in a controlled clinical trial. Accidental injury was reported in less than 3% of adults and adolescents 12 years of age or older receiving albuterol sulfate inhalation aerosol (ProAir HFA) in a clinical trial. In one short-term (3-week) clinical trial in children 4-11 years of age receiving albuterol sulfate HFA inhalation aerosol (ProAir HFA), adverse effects occurred at a low incidence (less than 2% of children receiving albuterol) and were comparable to those effects observed in adults and adolescents.

Fever was reported in 9.1, 3, 1.6, or 6.7% of children receiving orally inhaled levalbuterol 0.31 mg, levalbuterol 0.63 mg, albuterol 1.25 mg, or albuterol 2.5 mg 3 times daily via nebulization, respectively. Viral infection was reported in 7.6, 9, 4.7, or 8.3% of children receiving orally inhaled levalbuterol 0.31 mg, levalbuterol 0.63 mg, albuterol 1.25 mg, or albuterol 2.5 mg 3 times daily via nebulization, respectively. Infection was reported in less than 3% of adults and adolescents 12 years of age or older receiving albuterol sulfate inhalation aerosol in a clinical trial. Lymphadenopathy was reported in 3, 0, 1.6, or 0% of children receiving orally inhaled levalbuterol 0.31 mg, levalbuterol 0.63 mg, albuterol 1.25 mg, or albuterol 2.5 mg 3 times daily via nebulization, respectively. Otitis media occurred in 0.9 or 4.3% of children receiving orally inhaled albuterol inhalation solution pediatric formulation 0.63 or 1.25 mg 3 times daily via nebulization, respectively.

Flu syndrome occurred in 2.6% of children receiving orally inhaled albuterol sulfate inhalation solution pediatric formulation (0.63 or 1.25 mg 3 times daily) via nebulization. Flu syndrome occurred in less than 2% of adults and adolescents receiving orally inhaled levalbuterol HFA aerosol and more frequently than with placebo. Lymphadenopathy occurred in 0.9 or 2.6% of children receiving orally inhaled albuterol inhalation solution pediatric formulation 0.63 or 1.25 mg 3 times daily via nebulization, respectively. Cold symptoms occurred in 3.4% of children receiving orally inhaled albuterol sulfate inhalation solution pediatric formulation 0.63 mg 3 times daily and in none of the children receiving 1.25 mg 3 times daily via nebulization. Chills or lymphadenopathy has been reported in less than 2% of patients receiving levalbuterol inhalation solution via nebulization in overall clinical trials. Sweating has been reported in less than 2% of patients receiving orally inhaled levalbuterol via nebulization in clinical trials (and less frequently than with placebo).

Cyst or hematuria occurred in less than 2% of adults and adolescents receiving orally inhaled levalbuterol HFA inhalation aerosol in clinical trials but more frequently than with placebo in a few controlled clinical trials.

Precautions and Contraindications

Oral inhalation therapy with short-acting β2-agonists is intended for the acute symptomatic relief of bronchospasm in reversible, obstructive airway disease, and should not be used regularly (e.g., 4 times daily) in asthmatic patients formaintenancetherapy. If control of mild asthma deteriorates and requires regular use of a short-acting β₂-agonist (i.e., 4 times daily), long-term maintenance therapy (e.g., inhaled corticosteroids) should be instituted; patients should be instructed to discontinue regular use of short-acting β₂-agonists and use them only for relief of acute asthma symptoms.(See Uses: Bronchospasm.) The safety of concomitant use of more than 8 inhalations per day of a short-acting β₂-adrenergic agonist with long-acting β₂-agonist (e.g., salmeterol) oral inhalation therapy has not been established. If the patient uses 4 or more inhalations per day of a short-acting β₂-agonist for 2 or more consecutive days or if more than 1 canister (200 inhalations per canister) of a short-acting β₂-agonist is required during an 8-week period, a clinician should be consulted for reevaluation of maintenance therapy.

When albuterol is used in fixed combination with ipratropium, the usual cautions, precautions, and contraindications associated with ipratropium must be considered in addition to those associated with albuterol. Adverse cardiovascular effects (e.g., alterations in heart rate, blood pressure, or other manifestations) have been reported with albuterol in fixed combination with ipratropium as an inhalation aerosol; the combination aerosol should be discontinued if such effects occur. The safety of more than 12 inhalations daily of albuterol sulfate and ipratropium bromide in fixed combination as an oral inhalation aerosol (Combivent) or more than 6 inhalations daily as an oral inhalation solution for nebulization (DuoNeb) has not been studied, nor has the safety of extra doses of albuterol sulfate or ipratropium bromide given in addition to the recommended dosage.

Excessive or prolonged use of some sympathomimetic amine aerosols can lead to tolerance. Failure to respond to a previously effective dosage of albuterol alone or in combination with ipratropium may indicate seriously worsening asthma that requires reevaluation and possible institution of alternative regimens or therapy. Patients should be instructed to contact their clinician if decreased effectiveness of albuterol or levalbuterol occurs rather than to increase the dose or frequency of administration. Fatalities have occurred following excessive use of sympathomimetic amine oral inhalations. The exact cause of death is not known; however, it has been suggested that severe, acute asthmatic crisis and hypoxia may have occurred in some patients, followed by cardiac arrest. Some evidence indicates that administration of β-adrenergic agonists in hypoxemic patients with asthma may be associated with detrimental cardiovascular effects such as peripheral vasodilation and possible pulmonary shunting.(See Cautions: Cardiovascular Effects.)

Paradoxical bronchospasm that is potentially life-threatening may occur with the use of orally inhaled albuterol or levalbuterol. When associated with inhaled formulations, paradoxical bronchospasm frequently occurs with the first use of a new canister or vial. Paradoxical bronchospasm also may occur with orally administered conventional or extended-release albuterol sulfate tablets or albuterol sulfate oral solution. Although the mechanism(s) has not been fully elucidated, paradoxical bronchospasm has occurred occasionally with repeated or excessive use of orally inhaled sympathomimetic amines, especially isoproterenol. Rarely, a patient may develop acute bronchospasm immediately upon inhalation of a sympathomimetic drug preparation. Acute bronchospasm probably represents a hypersensitivity reaction to the active drug or an ingredient in the commercial product. Although it may not be possible to distinguish paradoxical bronchoconstriction or that associated with hypersensitivity to the drug or an ingredient in the formulation from worsening of the asthma, albuterol or levalbuterol should be discontinued immediately if bronchoconstriction occurs and alternative therapy instituted.

Therapy with albuterol may produce clinically important hypokalemia in some patients, possibly via intracellular shunting, which has the potential to produce adverse cardiovascular effects; the decrease usually is transient and usually does not require supplementation.

Albuterol or levalbuterol should be used with caution in patients with sensitivity to sympathomimetic amines, hyperthyroidism, diabetes mellitus, seizure disorders, or cardiovascular disorders including coronary insufficiency, cardiac arrhythmias, or hypertension. Albuterol preparations are contraindicated in patients with a known hypersensitivity to the drug, and specific dosage forms are contraindicated in patients with known hypersensitivity to any ingredient in the specific formulation. Albuterol sulfate in fixed combination with ipratropium bromide is contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soybeans or peanuts; atropine and its derivatives; or any other ingredient in the specific formulation. Levalbuterol is contraindicated in patients with a known hypersensitivity to the drug, racemic albuterol, or any other ingredient in the specific formulation.

Pediatric Precautions

The safety and efficacy of orally inhaled albuterol sulfate aerosol with hydrofluoroalkane propellant have not been established in children younger than 4 years of age (Proair HFA, Proventil HFA, Ventolin HFA). The safety and efficacy of orally inhaled albuterol sulfate via nebulization have not been established in children younger than 12 years of age, although albuterol has been used in these patients with no unusual risk. The manufacturers of some albuterol inhalation solutions for nebulization (AccuNeb, albuterol inhalation solutions 0.083% from Dey and Roxane) state that the safety and efficacy have been established in pediatric patients aged 2-12 years and are based on studies in children 5-17 years of age and from published reports of trials of albuterol in pediatric patients 3 years of age or older. The safety and efficacy of these inhalation solutions for nebulization have not been established in children younger than 2 years of age; although such inhalation solutions have been used in these patients with no unusual risk. The safety and efficacy of orally inhaled levalbuterol hydrochloride via nebulization have not been established in children younger than 6 years of age, although the drug has been used in these patients with no unusual risk. The safety and efficacy of orally inhaled levalbuterol tartrate via a metered-dose inhaler have not been established in children younger than 4 years of age. The safety and efficacy of albuterol sulfate in fixed combination with ipratropium bromide for oral inhalation via nebulization have not been established in patients younger than 18 years of age, although the fixed combination has been used in these patients for management of asthma exacerbations with no unusual risk. The manufacturer states that safety and efficacy of albuterol sulfate in fixed combination with ipratropium bromide for oral inhalation via a metered-dose inhaler have not been established in children, although the fixed combination has been used in these patients with no unusual risk.

Safety and efficacy of albuterol conventional and extended-release tablets have not been established in children younger than 6 years of age. Use of extended-release albuterol sulfate tablets in children 6 years of age or older for the treatment of asthma is supported by safety and efficacy studies with extended-release tablets in adults, safety studies with extended-release tablets in this pediatric age group, and established use of conventional tablets in these children. The recommended dosage of extended-release tablets in pediatric patients is based on the recommended pediatric dosage for conventional tablets and on comparative pharmacokinetic studies in adults showing comparative bioavailability at steady state and reduced bioavailability after single-dose administration with extended-release albuterol tablets.(See Pharmacokinetics: Absorption.)

Careful titration of oral albuterol dosage is necessary in children younger than 6 years of age and may be achieved by use of the commercially available oral solution. Safety and efficacy of albuterol oral solution have not been established in children younger than 2 years of age. Some adverse reactions have occurred more frequently in children 2-6 years of age receiving albuterol sulfate oral solution than in adults and older children. (See Cautions.) However, in a clinical trial in children comparing albuterol oral inhalation aerosol with a tetrafluoroethane propellant (Proventil HFA) and albuterol inhalation aerosol with a chlorofluorocarbon propellant (no longer commercially available in the US), the incidence of adverse effects was low and similar to that observed in adult trials.

Geriatric Precautions

Data on the use of levalbuterol or albuterol inhalation aerosol in geriatric patients 65 years of age or older are limited and are insufficient to determine whether the efficacy and safety of levalbuterol are different in geriatric patients versus younger patients. Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, the manufacturers of albuterol sulfate and levalbuterol inhalation aerosol suggests that patients in this age group receive initial dosages of the drugs in the lower end of the usual range.(See Oral Inhalation via Metered-Dose Aerosol under Dosage and Administration: Dosage.)

Safety and efficacy of albuterol sulfate in fixed combination with ipratropium bromide inhalation solution in geriatric patients have not been specifically studied to date; however, in clinical studies of the combination for the treatment of bronchospasm, approximately 62% of the patients were 65 years of age or older and 19% were 75 years of age or older. Although no overall differences were observed between geriatric and younger patients in the safety and efficacy of the combination in clinical studies, the possibility that some elderly patients may exhibit increased sensitivity to the drug cannot be ruled out.

As albuterol and levalbuterol are substantially eliminated by the kidneys, the risk of toxic reactions may be greater in patients with renal impairment. Renal function should be assessed periodically in geriatric patients, as such patients are more likely to have decreased renal function.

Mutagenicity and Carcinogenicity

There was no evidence of mutagenicity when albuterol sulfate was tested in the Ames test (with or without metabolic activation), in a mutation test with yeast, or in fluctuation assays (with metabolic activation) in strains of Salmonella typhimurium or Escherichia coli. Levalbuterol was not mutagenic when tested in the Ames test or the HRT forward gene mutation assay in Chinese hamster ovary cells. The clastogenic potential of levalbuterol has not been evaluated. Albuterol did not exhibit mutagenic potential in vitro in a forward mutation assay or in a gene conversion assay in Saccharomyces cerevisiae with or without metabolic activation. Albuterol was not clastogenic in a human peripheral blood lymphocyte assay or in the AH1 mouse micronucleus assay at intraperitoneal doses of up to 200 mg/kg.

The carcinogenic potential of levalbuterol alone has not been evaluated; however, the carcinogenic potential of racemic albuterol sulfate has been investigated. There is no evidence to date that albuterol is tumorigenic in humans; however, in one study in rats receiving 2, 10, and 50 mg/kg of albuterol (as albuterol sulfate) (e.g., approximately 0.5, 3, and 15 times, respectively, the maximum recommended daily oral dosage of albuterol in adults; 0.5, 2, and 10 times, respectively, the maximum daily oral dosage of albuterol in children; at least equivalent to the maximum recommended daily inhalation dosage of albuterol alone or in fixed combination with ipratropium bromide via nebulization on a mg/m basis; at least twice the maximum recommended daily adult inhalation dosage of albuterol sulfate via nebulization on a mg/m basis; 0.6, 3 and 15 times the maximum recommended daily pediatric inhalation dosage via nebulization on a mg/m basis; 10, 50, and 250 times the maximum adult inhalation dosage of albuterol sulfate via nebulization for a 50 kg human; at least 14-15 times the maximum daily adult inhalation aerosol dosage; at least 6 times the maximum daily inhalation aerosol dosage in children on a mg/m basis; or at least twice the maximum recommended daily adult inhalation dosage of levalbuterol on a mg/m basis), the drug caused a dose-related increase in the incidence of benign leiomyomas of the mesovarium. In another study, this tumorigenic effect was blocked by concurrent administration of propranolol.

An 18-month study in mice revealed no evidence of tumorigenicity with albuterol at dietary dosages of up to 500 mg/kg daily (e.g., approximately 65 or 50 times the maximum recommended daily oral dosage for adults or children, respectively, on a mg/m basis; 140 times the maximum recommended daily adult inhalation dosage of albuterol sulfate in fixed combination with ipratropium bromide via nebulization on a mg/m basis; 140 or 200 times the maximum recommended daily adult inhalation dosage of albuterol sulfate via nebulization on a mg/m basis; 75 times the maximum recommended daily pediatric inhalation dosage of albuterol sulfate via nebulization on a mg/m basis; 1600-1700 times the maximum daily recommended adult inhalation aerosol dosage on a mg/m basis; 800 times the maximum recommended daily pediatric inhalation aerosol dosage on a mg/m basis; or approximately 260 times the maximum daily adult and pediatric inhalation dosage of levalbuterol on a mg/m basis). In a 22-month study in hamst

Drug Interactions

Sympathomimetic Agents

The manufacturers state that albuterol sulfate or levalbuterol tartrate should not be administered by oral inhalation concurrently with other short-acting, orally inhaled sympathomimetic agents or epinephrine. Current guidelines for the management of asthma state that orally inhaled short-acting β₂-adrenergic agonists can be used in patients with moderate to severe asthma for short-term relief of acute bronchospasm that occurs despite maintenance therapy that includes adjunctive therapy with a long-acting, orally inhaled β₂-adrenergic agonist, (e.g., formoterol, salmeterol); successful clinical experience with concomitant use of orally inhaled short-acting (for intermittent acute relief) and long-acting (for additional control) β₂-adrenergic agonists is extensive. Salmeterol is a highly selective β₂-agonist, and certain cardiovascular effects (e.g., ventricular or nodal arrhythmias, severe tachycardia, anginal-type pain, myocardial ischemia) reported with less receptor-selective β-adrenergic agonists such as isoproterenol theoretically may occur less frequently, or not at all, with salmeterol. In addition, if other sympathomimetic agents are to be administered by any route in patients receiving orally inhaled albuterol or levalbuterol, the additional agents should be used with caution to avoid deleterious cardiovascular effects. The manufacturers also state that oral albuterol sulfate should not be administered concurrently with other oral sympathomimetic agents, since serious adverse cardiovascular effects may occur; however, this does not preclude the cautious use of an orally inhaled sympathomimetic agent in patients receiving oral albuterol sulfate. Such concomitant use must be individualized and should not be employed on a routine basis; if such concomitant use is regularly required, alternative therapy should be considered.

Digoxin

Following single-dose IV or oral administration of albuterol to healthy individuals who had received digoxin for 10 days, a 16-22% decrease in serum digoxin concentration was observed. Although the clinical importance of these findings for patients receiving chronic albuterol or levalbuterol and digoxin therapy is unclear, patients receiving such concomitant therapy should have their serum digoxin concentration carefully evaluated.

Other Drugs

Since albuterol may lower serum potassium concentration, care should be taken in patients also receiving other drugs that can lower serum potassium concentration, as the effects may be additive. The electrocardiographic changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) may be aggravated by concomitant β-agonists, especially when the recommended dosage of the β-agonist is exceeded. Although the clinical importance of these effects is not known, caution is advised when administering β-agonists with nonpotassium-sparing diuretics.

The manufacturers state that the effects of albuterol or levalbuterol on the vascular system may be potentiated in patients receiving monoamine oxidase inhibitors or tricyclic antidepressants; therefore, albuterol or levalbuterol should be administered with extreme caution to patients receiving these drugs or within 2 weeks of discontinuation of such agents.

The action of albuterol or levalbuterol is antagonized by β-adrenergic blocking agents (e.g., propranolol). β-Adrenergic blocking agents not only block the pulmonary effects of β-agonists, but may produce severe bronchospasm in asthmatic patients; therefore, asthmatic patients should not normally be treated with β-adrenergic blocking agents. However, under certain circumstances (e.g., prophylaxis after myocardial infarction), there may be no acceptable alternatives to the use of β-adrenergic blocking agents in patients with asthma; cardioselective β-adrenergic blocking agents should be used with caution in these patients.

There is some evidence from animal studies that concomitant administration of a β-adrenergic agonist (e.g., isoproterenol) and a methylxanthine (aminophylline) may produce increased cardiotoxic effects (e.g., cardiac arrhythmias, sudden death, myocardial necrosis). Although such an interaction has not been established in humans, a few reports have suggested that such a combination may have the potential for producing cardiac arrhythmias. Further accumulation of clinical data is needed to determine whether this potential interaction exists in humans.

Pharmacokinetics

The pharmacokinetic disposition of racemic albuterol is enantioselective, with the R-enantiomer (levalbuterol) generally having a more rapid clearance, a lower bioavailability, and a shorter half-life than S-albuterol.

Absorption

Although albuterol appears to be absorbed from the respiratory tract over several hours following oral inhalation, this process has not been clearly characterized. Pharmacokinetic studies in asthmatic patients receiving albuterol sulfate inhalation solution indicate that less than 20% of a single dose of the drug is absorbed when administered by intermittent positive-pressure breathing (IPPB) or nebulization; the remainder of the dose was recovered from the nebulizer and apparatus and expired air. The amount delivered to the lungs depends on patient factors, the jet nebulizer used, and the compressor performance. It has been suggested that most of an orally inhaled dose of the drug is swallowed and absorbed from the GI tract; studies with isoproterenol indicate that less than 10% of an orally inhaled dose reaches the bronchial tree. In one study in a limited number of patients in whom a solution of radiolabeled albuterol was instilled directly into the bronchial tree via a bronchoscope, peak plasma radioactivity occurred within 10 minutes; however, following oral inhalation of albuterol in other studies, peak plasma albuterol concentrations occurred in 2-5 hours.

Bioavailability of levalbuterol is less than that of S-albuterol following administration of the enantiomers or racemic albuterol; in healthy individuals, the area under the blood concentration-time curve (AUC) for levalbuterol was about 5-7-fold less than that for the S-enantiomer. Population pharmacokinetic analysis of data from a clinical trial in children (6-11 years of age) receiving levalbuterol inhalation solution at a dosage of 0.63 mg or albuterol inhalation solution at a dosage of 1.25 mg indicates that peak plasma concentrations and AUC values of R-albuterol were similar. In a cross-study comparison of adults and adolescents 12 years of age or older and children (6-11 years of age) receiving a single dose of levalbuterol of 0.63 mg, peak plasma concentrations were similar. However, AUC values were 1.5-fold higher in children compared with values in adolescents and adults; these data support a lower dosage in children compared with adults.(See Levalbuterol under Dosage: Oral Inhalation Dosage, in Dosage and Administration.)

Population pharmacokinetic analysis of data from patients with asthma indicates that the mean exposure to levalbuterol (90 mcg) via aerosol inhalation of a formulation containing an HFA propellant was 13-16% less in adults and adolescents 12 years of age or older, or 30-32% less in children 4-11 years of age, than a comparable dose of albuterol (180 mcg) via aerosol inhalation of a formulation containing an HFA propellant. When compared with adults receiving a 90-mcg dose of levalbuterol via aerosol inhalation, the mean exposure (AUC) in pediatric patients was 17% lower.

Following administration of a 3-mg dose of albuterol via nebulization in adults, peak plasma albuterol concentrations of 2.1 ng/mL were reached within 0.5 hours. In a limited number of healthy adults receiving a single dose of albuterol (2.5 mg) or levalbuterol (1.25 mg) via nebulization, peak plasma concentrations of the R-enantiomer of albuterol were 1.1 or 0.8 ng/mL, respectively, at 0.2 hours. Peak plasma concentrations of S-albuterol following a single 2.5-mg dose of racemic albuterol via oral inhalation in healthy individuals reportedly are twice as high as those of the R-enantiomer (levalbuterol).

The propellant tetrafluoroethane is rapidly absorbed with time-to-peak plasma concentrations being extremely short. In a single-dose bioavailability study in healthy individuals receiving either metered-dose albuterol (no longer commercially available in the US) or albuterol sulfate inhalation aerosol, similar low blood concentrations of albuterol were observed with either formulation.

Following administration of a single 4-mg dose of albuterol as an oral solution in healthy individuals, peak plasma drug concentrations of 18 ng/mL are attained. In a limited number of healthy individuals, median peak plasma concentrations of S-albuterol and R-albuterol (levalbuterol) were 11.4 and 3.6 ng/mL, respectively, at 30-130 minutes following administration of racemic albuterol sulfate as an oral elixir. In healthy adults, steady-state plasma albuterol concentrations were reached within 2 days with either conventional albuterol tablets or extended-release tablets. In a dose-ranging study in adults, increases in plasma drug concentrations were dose-proportional with single 4- or 8-mg doses of albuterol extended-release tablets in the fasted state.

Albuterol sulfate is rapidly and well absorbed following oral administration. Oral bioavailability of extended-release albuterol sulfate tablets is about 80% that of conventional tablets when administered in single doses. Food reduces the rate of absorption of extended-release albuterol sulfate tablets. While studies with the extended-release tablets have not been conducted in pediatric patients, extrapolation of data from studies in adults also indicates similar bioavailability of conventional and extended-release tablets at steady state and reduced bioavailability with single-dose administration. Peak plasma albuterol concentrations occur within about 2.5 and 2 hours following administration of the conventional tablets and oral solution, respectively. Peak plasma albuterol concentrations occur within 6 hours following administration of albuterol extended-release tablets.

Bronchodilation begins within 5-15 minutes after oral inhalation of albuterol (no longer commercially available in the US) or albuterol sulfate via the metered-dose aerosol or via the special oral inhaler (Rotahaler; no longer commercially available in the US) that delivers powdered drug from capsules, with peak effect in 0.5-3 hours, and generally persists 2-5 hours; in some patients, bronchodilation may persist up to 6 hours. Following oral inhalation of albuterol sulfate via the metered-dose inhaler (Proventil HFA), the onset of appreciable bronchodilation (i.e., a 15% increase in forced expiratory volume in 1 second [FEV₁]) occurs within 6 minutes; mean time-to-peak bronchodilation occurs within 50-55 minutes. Bronchodilation persists for 3-6 hours. With administration of another albuterol sulfate metered-dose inhalation aerosol preparation (ProAirHFA) in adults and adolescents (12-16 years of age), the median time to onset, time to peak effect, and duration of effect are 8.2 minutes, 47 minutes, and approximately 3 hours, respectively. Bronchodilation usually begins within 5 minutes following nebulization with albuterol; the peak effect occurs in approximately 1-2 hours and bronchodilation generally persists 3-4 hours, but occasionally up to 6 hours or longer. Bronchodilation persists for up to 8 hours in some patients receiving levalbuterol hydrochloride inhalation solution via nebulization. Because of the prompt onset of action and a lack of correlation between plasma albuterol concentrations and bronchodilation, it has been suggested that the bronchodilating effect of orally inhaled albuterol results from a local action.

Bronchodilation begins within 30 minutes after oral administration of conventional tablets, with peak effect in 2-3 hours, and may persist up to 4-6 hours. Following a single oral dose of albuterol as conventional tablets, bronchodilation has persisted for up to 8 hours in some patients. Extended-release tablets of albuterol sulfate have a duration of action of up to 12 hours. Albuterol sulfate oral solution has a duration of action of up to 6 hours.

Following administration of a single dose (90 mcg) of levalbuterol via aerosol inhalation in adolescents and adults (12-81 years of age) with asthma, the median time to achieve a 15% increase in FEV₁ compared with baseline with levalbuterol was about 5.5-10.2 minutes, and the median time to reach peak effects was about 76-78 minutes. The median duration of bronchodilation (as determined by an increase in FEV₁ of 15% or greater from baseline) after levalbuterol administration was approximately 3-4 hours; some patients exhibited bronchodilatory effects for up to 6 hours.

Following administration of a single dose (90 mcg) of levalbuterol via aerosol inhalation in children (4-11 years of age) with asthma, the median time to achieve a 15% increase in FEV₁ compared with baseline, time to peak effect, and duration of effect (maintenance of an increase in FEV₁ of at least 15% compared with baseline) were 4.5 minutes, 77 minutes, and 3 hours, respectively. Some pediatric patients may experience bronchodilatory effects up to 6 hours following levalbuterol inhalation aerosol administration.

The onset (time to a 15% increase in FEV₁ compared with baseline) and duration (maintenance of a more than 15% increase in FEV₁ compared with test day baseline) of bronchodilation obtained with levalbuterol also were similar to those obtained with racemic albuterol.

In a 4-week study in adults and adolescents 12 years of age or older with asthma, the mean time to achieve a 15% increase in FEV₁ from baseline with levalbuterol doses of 0.63 or 1.25 mg via nebulization was about 17 or 10 minutes, respectively, while the mean time to reach peak effects for both of these doses was about 1.5 hours after 4 weeks of treatment. The mean duration of bronchodilation (as determined by the period during which the increase in FEV₁ from baseline exceeded 15%) was approximately 5 or 6 hours after levalbuterol doses of 0.63 or 1.25 mg, respectively; some patients exhibited bronchodilator effects for up to 8 hours.

Distribution

Results of animal studies indicate that albuterol crosses the blood-brain barrier, reaching the brain at concentrations that are approximately 5% of plasma concentrations. In glands outside the blood-brain barrier (pineal and pituitary glands), the drug achieves concentrations that are 100 times the concentrations achieved in whole brain. Albuterol apparently crosses the placenta, but it is not known whether albuterol is distributed into milk. Studies in pregnant rats given radiolabeled albuterol indicate that approximately 10% of the maternal dose is transferred to the fetus. Disposition in fetal lungs is comparable to that in maternal lungs, but fetal liver disposition is 1% that of the maternal liver concentrations.

Elimination

Following oral inhalation of radiolabeled albuterol in patients with asthma in one study, total plasma radioactivity declined with a half-life of 1.7-7.1 hours. In another study in healthy individuals receiving albuterol sulfate inhalation aerosol (Proair HFA) or another comparator albuterol sulfate HFA inhalation aerosol, the terminal plasma half-life of albuterol sulfate given as Proair HFA inhalation aerosol was approximately 6 hours; no differences in pharmacokinetics were noted between the formulations. In healthy individuals, the plasma clearance of R-albuterol (levalbuterol) exceeded that of S-albuterol following IV or oral dosing of racemic albuterol. After oral inhalation of albuterol in healthy adults in another study, the elimination half-life of unchanged drug was determined indirectly to be 3.8 hours based on urinary excretion data. Following nebulization of albuterol sulfate in fixed combination with ipratropium bromide in healthy individuals at twice the recommended dosage (i.e., 5 mg of albuterol and 1 mg of ipratropium bromide), the half-life of albuterol averaged 6.7 hours. In a small pharmacokinetic study in healthy adults, the half-life of levalbuterol, the R-enantiomer of albuterol, was 3.3 hours after a single 1.25-mg nebulized dose and 4 hours following multiple dosing (1.25 mg given every 30 minutes for 4 doses) via nebulization. In another cumulative-dose study in patients with mild to moderate asthma receiving orally inhaled R-albuterol as either the single enantiomer (levalbuterol) or racemic albuterol, the half-life of R-albuterol or S-albuterol averaged about 3.5 or 5 hours, respectively. After oral administration of albuterol sulfate conventional or extended-release tablets, the plasma half-life of albuterol reportedly is 5-7.2 or 9.3 hours, respectively. Following oral administration of albuterol oral solution in healthy individuals, the half-life of albuterol is about 5 hours. The propellant tetrafluoroethane in albuterol sulfate aerosol (Proventil HFA, Ventolin HFA) is eliminated rapidly, as reflected by a short residence time; accumulation of the propellant does not occur.

Albuterol enantiomers are extensively metabolized in the intestinal wall and liver by sulfotransferase 1A3 (dopamine phenolsulfotransferase), mainly to albuterol 4'-O-sulfate which has little or no β-adrenergic stimulating effect and no β-adrenergic blocking effect. Following administration of racemic albuterol either IV or by oral inhalation following oral charcoal administration, the AUCs for the S-enantiomer were 3-4 fold higher than for the R-enantiomer. However, following administration of racemic albuterol orally or via inhalation without oral charcoal pretreatment, the AUCs for the S-enantiomer were 8-24 fold higher than the R-enantiomer. These data suggest that the R-enantiomer of albuterol is preferentially metabolized in the GI tract, presumably by sulfotransferase 1A3. in vitro studies in human liver cytosol preparations, the rate of sulfate conjugation of R-albuterol (levalbuterol) exceeded that of the S-enantiomer by a factor of 10-15. Unlike isoproterenol, albuterol is not metabolized by the enzyme catechol-O-methyltransferase and is not a substrate for catecholamine cellular uptake processes. Albuterol and its metabolites are rapidly excreted in urine and feces. After oral inhalation of albuterol in patients with asthma, approximately 70% of a dose is excreted in urine as unchanged drug and metabolites within 24 hours and 80-100% within 72 hours; about 30% of the dose is excreted in urine unchanged in 24 hours. Following nebulization of a 5-mg dose of albuterol in fixed combination with a 1-mg dose of ipratropium bromide, a mean of 8.4% of the administered dose of albuterol is excreted unchanged in urine. Following administration of albuterol sulfate (180 mcg as albuterol base) and ipratropium bromide (36 mcg) inhalation aerosol, 27.1% of the estimated mouthpiece dose of albuterol is excreted unchanged in urine within 24 hours. About 10% of an inhaled dose of albuterol may be excreted in feces. Following oral administration of albuterol sulfate to healthy individuals, about 76% of a single dose is excreted in urine within 72 hours, mainly as the major metabolite; about 4% of the dose is excreted in feces.

Pharmacokinetics of levalbuterol or albuterol sulfate (Proair HFA) inhalation aerosol when administered as formulations containing an HFA propellant in patients with hepatic impairment have not been studied. In a small number of patients with renal impairment (creatinine clearance of 7-53 mL/minute), a 67% decline in albuterol clearance was reported, but half-life of the drug was not affected.