Albuterol

Albuterol Sulfate

Levalbuterol Hydrochloride

Levalbuterol Tartrate

AHFS Class: Selective beta-2-Adrenergic Agonists (12:12.08.12)

VA Class: RE102

Salbutamol

(R)-Salbutamol Hydrochloride

View the associated Essentials monograph.

Introduction

Albuterol (a racemic mixture) and levalbuterol (the R-enantiomer) are synthetic sympathomimetic amines that stimulate β-adrenergic receptors. The drugs are relatively selective, short-acting β₂-agonists.

Uses

Bronchospasm

Albuterol is used by oral inhalation for the symptomatic management of bronchospasm in patients with reversible, obstructive airway disease^{114 115 132 139 154 249 255} and for the prevention of exercise-induced bronchospasm.^{132 181 249} 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.^{132 181 241 249 282} Levalbuterol hydrochloride is used by oral inhalation for the symptomatic management or prevention of bronchospasm in patients with reversible, obstructive airway disease.^{216 219 254 276} 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.^{233 250 251 252}

Albuterol

Oral or orally inhaled albuterol has a longer duration of action than isoproterenol and only occasionally causes cardiac stimulation. Bronchodilation produced by oral inhalation of usual doses of albuterol is equal to or greater than that produced by oral inhalation of usual doses of isoproterenol. Oral inhalation of usual doses of albuterol appears to be as effective as usual doses of metaproterenol in producing bronchodilation, with similar adverse effects. Although it has not been clearly established, the duration of action of albuterol may be slightly longer than that of metaproterenol. In one study, albuterol also appeared to have a longer duration of action than isoetharine following oral inhalation of doses of either drug that produced equivalent bronchodilation. Clinical studies in adults and children 4 years of age or older indicate that albuterol sulfate inhalation aerosol without chlorofluorocarbon propellants (e.g., Proventil^® HFA, Ventolin^® HFA) has bronchodilator efficacy similar to that of albuterol inhalation aerosol with chlorofluorocarbons.^{181 237 238 239} Data from comparative clinical studies in adults and children 12 years of age or older with asthma indicate that albuterol sulfate inhalation aerosol without chlorofluorocarbon propellants (i.e., Proair^® HFA) has bronchodilator efficacy (as measured by forced expiratory volume in 1 second [FEV₁]) similar to that of another (unspecified) commercially available albuterol sulfate HFA inhalation aerosol.²⁸²

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^{102 103 105 107 109 110 121 122} and for patients (e.g., children) who find it difficult or are unable to optimally inhale the drug orally via an inhaler.^{102 103 104 106 107 108 109 120 121 122} 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-week), 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.²⁵⁵ 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.²⁵⁵

Levalbuterol

Levalbuterol hydrochloride solution for nebulization is used as a bronchodilator for the symptomatic management and prevention of bronchospasm in patients with reversible obstructive airway disease.^{216 219 221 276} 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.^{216 221 222 223 224 225 229 230} (See Pharmacology.)

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.²¹⁶ Adverse systemic β-adrenergic adverse 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.²¹⁶

In a short-term (4-week), 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).²¹⁹ 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.²¹⁹ 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.^{216 219} All active treatments were associated with improvement in FEV₁ compared with placebo, and adverse effects of levalbuterol and albuterol were similar.^{216 219}

In a short-term (3-week), 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^{216 254} in addition to existing therapy (e.g., inhaled corticosteroids),²⁵⁴ the mean peak change in FEV₁ with levalbuterol (R-albuterol) was similar to that produced by albuterol.^{216 254} All active treatments were associated with improvement in FEV₁ compared with placebo, and adverse effects of levalbuterol were less than that associated with albuterol.²⁵⁴ 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.²¹⁶

The mean time to achieve a 15% increase in FEV₁ from baseline with levalbuterol doses of 0.63 and 1.25 mg was about 17 and 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.²¹⁶ 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.²¹⁶

Asthma

In the stepped-care approach to antiasthmatic drug therapy, use of a selective short-acting inhaled β₂-adrenergic agonist (e.g., albuterol, levalbuterol, pirbuterol) on an intermittent, as-needed basis to control acute symptoms (e.g., cough, wheezing, dyspnea) is recommended for all patients with asthma; such use of an inhaled short-acting β₂-agonist alone generally is sufficient as initial treatment for newly diagnosed patients with mild intermittent asthma (e.g., patients with daytime symptoms of asthma not more than twice weekly and nocturnal symptoms not more than twice a month).^{188 189 190 191 249 259} 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.^{175 249} Use of short-acting inhaled β₂-agonists in asymptomatic asthma should be limited to pretreatment prior to exercise and, in mild intermittent asthma, should be limited to providing relief as symptoms develop; some clinicians suggest that patients requiring symptomatic relief more than once weekly but less than once daily during a period of 3 months may require long-term control.²⁴⁹ In patients whose mild asthma progresses, the frequency of dosing of short-acting inhaled β₂-agonists may be increased up to 3 or 4 times daily.^{175 188 191 249 259}

When control of symptoms deteriorates in mild 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 more than twice per month), current asthma management guidelines and most clinicians recommend anti-inflammatory therapy with orally inhaled corticosteroids as first-line therapy for long-term control of persistent asthma, supplemented by intermittent, as-needed use of a short-acting, inhaled β₂-agonist.^{158 171 175 188 191 249 259} Recommended alternatives to low-dose inhaled corticosteroids for mild persistent asthma in adults and children older than 5 years of age include extended-release theophylline, mast-cell stabilizers (e.g., cromolyn, nedocromil), or leukotriene modifiers (e.g., montelukast, zafirlukast, zileuton), but these therapies are less effective and generally not preferred as initial therapy.^{249 259} Some experts recommend that long-term control therapy be considered in infants and young children who have identifiable risk factors for asthma and who in the previous year have had more than 3 episodes of wheezing that lasted more than 1 day and symptoms that affected sleep.²⁵⁹ While controlled studies comparing inhaled corticosteroids with other long-term control therapies are lacking in children younger than 5 years of age, low-dose inhaled corticosteroids also are recommended as the preferred initial therapy in such children based on extrapolation of data from studies in older children.²⁵⁹ Cromolyn sodium or a leukotriene modifier (e.g., montelukast) are recommended by some experts as alternative, but not preferred, therapy in children younger than 5 years of age with mild persistent asthma.²⁵⁹

When daily asthmatic symptoms (moderate persistent asthma) develop, most experts recommend that a long-acting bronchodilator (e.g., preferably an inhaled β₂-agonist such as salmeterol or formoterol)^{188 190 191 249} be added to inhaled corticosteroid therapy.^{249 259} Alternatively, if control of moderate persistent asthma is not sufficient with a low dosage of inhaled corticosteroid (e.g., 200–600 mcg of budesonide or equivalent daily in adults),²⁵⁹ the maintenance dosage of the inhaled corticosteroid can be increased to a medium dosage (e.g., 600–1200 mcg of budesonide or equivalent daily in adults).^{249 259} Most experts state that combination therapy with another class of controller drug is preferable to increasing the dosage of corticosteroid monotherapy.^{249 259} However, FDA has issued a public health advisory requesting labeling changes for all long-acting bronchodilators, including salmeterol xinafoate (Serevent^® Diskus^®), formoterol fumarate (Foradil^® Aerolizer^®), and salmeterol xinafoate in combination with fluticasone propionate (Advair^® Diskus^®), to provide additional information about an increased risk of severe asthma exacerbations and asthma-related death with these drugs.²⁷⁴ Included in FDA's advisory was the recommendation that long-acting bronchodilators be added to asthma therapy only if other asthma controller drugs, such as low- to medium-dose corticosteroids, proved inadequate in controlling asthma symptoms.²⁷⁴ For additional information, see Respiratory Effects: Asthma-related Life-threatening Events, in Cautions in Salmeterol 12:12.08.12. There is a lack of data on the use of long-acting inhaled β₂-agonists in children younger than 4 years of age, and use of these drugs in this age group is based on extrapolation of data from studies in older children.²⁵⁹

While addition of a long-acting β₂-agonist to inhaled corticosteroid therapy is the preferred initial combination therapy option for control of moderate persistent asthma, alternative less effective therapies that may be added to a low or medium dosage of inhaled corticosteroid include an oral extended-release theophylline, a long-acting oral β₂-agonist, or a leukotriene modifier.^{249 259} An evening dose of a long-acting inhaled bronchodilator such as salmeterol or formoterol may provide control of nocturnal symptoms, and a short-acting inhaled β₂-agonist (or alternatively, an inhaled anticholinergic agent, short-acting oral β₂-agonist, or short-acting theophylline [in the absence of concomitant extended-release theophylline therapy])²⁴⁹ can be used as supplemental therapy for the treatment of acute symptoms that may occur despite maintenance therapy.^{188 189 190 191 249}

If daytime asthma symptoms are continuous and nighttime symptoms frequent (severe persistent asthma) and not controlled with high maintenance dosages of the inhaled corticosteroid (e.g., exceeding 1200 mcg of budesonide or equivalent daily in adults) and a long-acting inhaled β₂-agonist bronchodilator,^{188 249 259} an oral corticosteroid (at the lowest possible daily or alternate-day dose) can be added.^{249 259} Other add-on therapy recommended by some clinicians includes an extended-release theophylline, leukotriene modifier, omalizumab, and/or long-acting oral β₂-agonist.^{249 259}

When asthma symptoms at any stage are not controlled with maintenance therapy 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.^{188 192 193 194 195 196 241 249 259 276} For acute exacerbations of asthma, initial home treatment consists of use of an inhaled short-acting β₂-agonist (2–4 inhalations every 20 minutes for the first hour).^{249 259} After the first hour, the dosage of β₂-agonist depends on the severity of the exacerbation.^{249 259} For home treatment of mild exacerbations of asthma (peak expiratory flow [PEF] exceeding 80% of predicted or personal best), 2–4 inhalations of a short-acting β₂-agonist every 3–4 hours for 24–48 hours is recommended.²⁴⁹ Moderate exacerbations of asthma (PEF 60–80% of predicted or personal best) may require 6–10 inhalations of a short-acting β₂-agonist every 1–2 hours for 24–48 hours.²⁴⁹ For severe asthma exacerbations, up to 10 inhalations of a short-acting β₂-agonist via metered-dose inhaler (preferably with a spacer) or full dosage given via nebulization may be required at less than hourly intervals; the improvement in lung function is equivalent with either route of administration with the same dose.²⁴⁹ Additional medication generally is not needed if response to the short-acting, inhaled β₂-agonist is complete.²⁴⁹ However, oral corticosteroids should be added to short-acting β₂-agonists to improve lung function in all but the mildest asthma exacerbations (e.g., if PEF does not exceed 80% of predicted or personal best within 1 hour and is not maintained for at least 3–4 hours).²⁴⁹ (See Asthma under Uses: Respiratory Diseases, in the Corticosteroids General Statement 68:04.)

Should the response to drug therapy be incomplete (PEF 60–80% of predicted or personal best) or poor (PEF less than 60% of predicted or personal best) after short-acting β₂-agonist therapy, the patient should seek medical attention urgently (if response is incomplete) or proceed immediately to the emergency department of a hospital (if response is poor).²⁴⁹ Initial hospital management includes oxygen and inhaled short-acting β₂-agonist therapy via metered-dose inhaler aerosol or nebulization.²⁴⁹ If response to the asthma exacerbation is not immediate, if patients used oral corticosteroids as self-medication prior to hospitalization, or if the episode is severe, systemic corticosteroids should be added to the regimen.²⁴⁹ An inhaled anticholinergic bronchodilator also may be added for continuing moderate or severe asthma exacerbations (PEF 80% or less of predicted or personal best).²⁴⁹ For severe asthma exacerbations not responding to the above regimen, administration of IV theophylline derivatives (e.g., aminophylline) may be used but should be considered as alternative therapy to inhaled short-acting β₂-agonist therapy because of an increased risk of adverse effects.²⁴⁹

Concerns about the safety of regular use of inhaled β-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).^{159 161 169 175 176 178 249} 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, ^{170 173 188 233 234 235 249} such use does not appear to have demonstrable advantages compared with intermittent use¹⁸⁸ and does not adequately control asthmatic symptoms, peak flow variability, or airway hyperresponsiveness.²⁴⁹ Suggested mechanisms for detrimental effects of regularly scheduled, inhaled β-agonist therapy include down-regulation of β-adrenergic receptors (tolerance)^{166 170} (see Precautions and Contraindications), increased responsiveness of airways to allergens,^{167 171} or increased airway accessibility to inhaled allergens, which may lead to increased airway inflammation and reactivity and worsening of asthma symptoms.^{155 157 168} While the validity of the evidence from these studies has been criticized in terms of study design and/or interpretation of study findings^{162 163 164 165} and a causal relationship between inhaled β₂-agonist therapy and asthma mortality has not been proven,^{160 166 169 172 176 177 178} current asthma management guidelines and many clinicians recommend concomitant anti-inflammatory therapy with an inhaled corticosteroid in patients receiving maintenance therapy with inhaled β-agonist bronchodilators.^{156 157 158 164 166 167 173 174 249} Regular, daily use of a short-acting, inhaled β₂-agonist generally is not recommended, and use of such β₂-agonists more than once weekly during a period of 3 months may indicate the need to initiate or increase long-term control therapy for asthma.²⁴⁹ (See Uses: Asthma and see Cautions: Respiratory Effects, in Salmeterol 12:12.08.12.)

Exercise-Induced Bronchospasm

Orally inhaled albuterol or albuterol sulfate administered via a metered-dose aerosol is used as a bronchodilator in the prevention of exercise-induced bronchospasm. 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 another 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.²⁸² In a study in adults, this 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 a 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.^{206 247 250 251} 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.^{181 206 251 265 266 267 268 269} 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.^{233 243} Therapy with anticholinergic and/or β-adrenergic agonist bronchodilators increases airflow and exercise tolerance and reduces dyspnea in patients with COPD.^{181 206 250 251 260 264 265 266 267 268 269}

In the stepped-care approach to drug therapy in patients with COPD, mild 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 during acute exacerbations, but use should not exceed 8–12 inhalations daily.^{181 206 251 266 267} Current guidelines for the management of COPD state that low- to high-dose ipratropium (6–16 inhalations daily)²⁶⁷ can be added to therapy with a short-acting, selective inhaled β₂-agonist in patients with mild to moderate persistent symptoms of COPD,^{267 268 269} 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).^{206 207 251 267 268} 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.^{266 269} 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.²³³ For additional information on the use of albuterol and ipratropium in fixed combination for patients with COPD, see the discussion on chronic obstructive pulmonary disease in Uses in Ipratropium Bromide 12:08.08.

In patients with moderate (e.g., FEV₁ 50–80% of predicted) COPD who have persistent symptoms despite regular therapy with ipratropium and a selective inhaled β₂-agonist, maintenance treatment with a long-acting bronchodilator (e.g., formoterol, salmeterol, tiotropium) can be substituted for regular use of short-acting bronchodilators and ^{266 267 268 269} a short-acting, selective inhaled β₂-agonist used as needed for immediate symptom relief.^{266 268} Maintenance treatment with long-acting bronchodilators in such patients is more effective and convenient than regular use of short-acting bronchodilators.²⁶⁶ 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.^{266 268 269} For treatment of severe to very severe COPD (e.g., FEV₁ less than 30–50% of predicted, 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.^{266 268 269} 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.^{267 268 269}

Management of acute exacerbations of COPD at home is based initially on the same drugs used for management of the stable patient.^{266 267 269} A short-acting β₂-adrenergic agonist is the preferred bronchodilator for treatment of acute exacerbations of COPD.²⁶⁶ If response to a short-acting β₂-adrenergic agonist alone is inadequate, some clinicians recommend the addition of ipratropium.^{266 267 268 269} 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.^{266 267 268 269} For more severe exacerbations of COPD (e.g., FEV₁ less than 50% of predicted), a short (e.g., 10–14 days) course of oral corticosteroids (e.g., equivalent to 30–40 mg of prednisone daily) can be added to bronchodilator therapy.^{266 267 269} 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.²⁶⁶ 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.^{266 267 268 269} 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.²⁶⁷ If patients cannot tolerate oral corticosteroids, IV corticosteroids should be initiated.²⁶⁷ If necessary for severe exacerbations, appropriate anti-infective therapy can be initiated if indicated (purulent exacerbations).^{266 267 268 269}

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 is administered by oral inhalation via a metered-dose inhaler.¹⁴⁶ Albuterol sulfate is administered orally^{100 139 208 271 280} or by oral inhalation via a metered-dose inhaler^{181 237 282} or nebulization. ^{241 242 244} Albuterol sulfate is administered in fixed combination with ipratropium bromide via a metered-dose aerosol inhaler²³³ or via nebulization.²⁴³ Levalbuterol hydrochloride is administered by oral inhalation via nebulization.^{216 226} Levalbuterol tartrate with hydrofluoroalkane (HFA) propellant is administered by oral inhalation via metered-dose inhaler.²⁷⁶ To avoid microbial contamination, proper aseptic technique should be used when albuterol or levalbuterol is administered via nebulization.^{114 241 242 244} Albuterol sulfate extended-release tablets should not be chewed or crushed.²⁷¹

Oral Inhalation via Metered-Dose Aerosol

Albuterol or Albuterol Sulfate. It is important that the patient receive careful instruction in the use of the metered-dose inhaler to obtain optimum results.^{146 181 282} Albuterol sulfate inhalation aerosol should only be used with the actuator supplied with the product.^{146 181 210 215 282} Before using, the inhaler must be shaken well.^{146 181 210 215 282} 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., more than 2 weeks).^{146 181 210 215 237 282} The manufacturer of Ventolin^® HFA states that the aerosol inhaler also should be test sprayed whenever it has been dropped.²³⁷

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.^{210 215} Then the patient should inhale deeply through the mouth while actuating the inhaler.^{210 215} After holding the breath for as long as possible, the patient should remove the mouthpiece from the mouth and exhale slowly.^{210 215} It is recommended that 1 minute elapse between inhalations of albuterol when a 2-inhalation dose is administered.²⁴⁸ 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.^{210 261}

The technique employed for administration of albuterol 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.^{146 214}

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.^{181 215 237 282} 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.^{181 215 237 282} 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.^{215 237 282} After such use, the mouthpiece should be rewashed and allowed to air dry.^{215 282} Proper cleaning of the albuterol sulfate inhaler (Proventil^® HFA, Ventolin^® HFA, Proair^® HFA) mouthpiece will prevent medication build-up and blockage.^{181 215 237 282}

The 3.7- or 6.7-g canister of albuterol sulfate inhalation aerosol (Proventil^® HFA) should be discarded after 100 or 200 sprays, respectively.^{181 215} 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.²³⁷ The 8.5-g canister of albuterol sulfate inhalation aerosol (Proair^® HFA) should be discarded after 200 sprays.²⁸² Patients should avoid spraying oral aerosols or oral inhalation solutions containing albuterol into the eyes.^{181 210 215 237 243 282} (See Cautions: Precautions and Contraindications)

Levalbuterol Tartrate. Levalbuterol tartrate inhalation aerosol should be used only with the actuator provided by the manufacturer.²⁷⁷ Before using, the inhaler should be shaken well.^{276 277} 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.^{276 277} Patients should avoid spraying levalbuterol inhalation aerosol into the eyes.^{276 277}

After exhaling slowly and completely, the mouthpiece of the inhaler should be placed well into the mouth with the lips closed around it.²⁷⁷ The patient should inhale slowly and deeply through the mouth and actuate the aerosol inhaler.²⁷⁷ The patient should withdraw the mouthpiece, hold the breath for 10 seconds, if possible, and exhale;²⁷⁷ 1 minute should elapse between subsequent inhalations from the aerosol inhaler.²⁷⁷

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.^{276 277} The mouthpiece should be shaken to remove excess water and allowed to air dry thoroughly (e.g., overnight).^{276 277} After drying, the metal canister should be inserted into the mouthpiece and the mouthpiece cap replaced.²⁷⁷ Patients should not attempt to clean the metal canister or allow the canister to become wet.^{276 277} 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.^{276 277} After such use, the mouthpiece should be rewashed and allowed to air dry.^{276 277} Proper cleaning of the mouthpiece will prevent medication build-up and blockage.^{276 277} If the actuator becomes blocked, medication should be removed by washing.^{276 277} 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.²⁷⁶

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.^{114 244 257} 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.^{114 244 257} 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.^{272 273}

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.^{226 241 242 243 255 256 272 283} If albuterol sulfate solution for nebulization (in single-use units) becomes discolored, it should not be used.^{242 255} Vials of levalbuterol hydrochloride solution for nebulization should be discarded if the solution is not colorless.^{216 226}

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.^{226 256 257 283} The patient should place the mouthpiece of the nebulizer in his or her mouth or put on the nebulizer face mask.^{226 256 257 283} The patient should then breathe through the mouthpiece as calmly, deeply, and evenly as possible until the nebulizer stops producing mist.^{226 256 257 283} The duration of treatment for oral inhalation of a full dose of albuterol or levalbuterol usually is about 5–15 minutes.^{226 256 257 283} The nebulizer should be cleaned after use according to the manufacturer’s instructions in order to avoid microbial contamination.^{226 241 244 245 246 256 257 283}

Dosage

Dosage of albuterol sulfate is expressed in terms of albuterol.^{114 139 154 181 241 242 243 244 255 256 272} Dosage of levalbuterol hydrochloride or tartrate is expressed in terms of levalbuterol.^{216 276} Dosage of albuterol, 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.¹⁴⁵ The levalbuterol tartrate oral aerosol inhaler delivers 45 mcg of levalbuterol from the mouthpiece per metered spray.²⁷⁶ 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.²³³ 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.²⁴³ 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.²⁵⁵

Commercially available albuterol sulfate aerosol without chlorofluorocarbon propellants delivers at least 200 metered sprays per 18-g (Ventolin^® HFA), 6.7-g (Proventil^® HFA), or 8.5-g (Proair^® HFA) canister, respectively.^{181 237 282} The commercially available aerosol inhaler containing albuterol sulfate in fixed combination with ipratropium bromide delivers 200 metered sprays per 14.7-g canister.²³³ The commercially available levalbuterol aerosol inhaler delivers 200 metered sprays per 15-g canister.²⁷⁶ The canister should be discarded after the labeled number of actuations have been used.^{181 233 276 282}

Oral Inhalation via Metered-Dose Aerosol

Albuterol or 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) ^{181 237} or children 12 years of age or older (Proventil^®, Proair^® HFA)^{145 282} is 180 mcg (2 inhalations) every 4–6 hours. In some patients, 90 mcg (1 inhalation) every 4 hours may be sufficient.^{145 146 181 237 282} For maintenance therapy or prevention of exacerbation of bronchospasm, 180 mcg (2 inhalations) 4 times daily via metered-dose inhaler should be sufficient.^{145 146 181 237} 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.^{237 282} More frequent administration or a larger number of inhalations of albuterol should not be used.^{145 146 181 237 282}

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.^{188 189 190 191 192 249} Instead, use of short-acting inhaled β₂-agonists is recommended for acute relief of bronchospasm or to prevent exercise-induced bronchospasm.^{188 189 190 191 192 249} 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.^{188 189 190 191 192 194 197 249} (See 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.¹⁹² 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 one 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.^{192 193 196}

For the prevention of exercise-induced bronchospasm, the usual dosage of orally inhaled albuterol with chlorofluorocarbons (Proventil^®) for adults and children 4 years of age or older is 180 mcg (2 inhalations) administered via the metered-dose inhaler 15 minutes before exercise;¹⁴⁵ up to 12 inhalations may be administered within 24 hours.¹⁴⁵ The usual dosage of albuterol inhalation aerosol without chlorofluorocarbons (Ventolin^® HFA, Proventil^® HFA) is 180 mcg (2 inhalations) given 15–30 minutes before exercise; up to 12 inhalations may be administered within 24 hours. ^{181 237}

Levalbuterol Tartrate. For the treatment of acute episodes of bronchospasm or prevention of asthmatic symptoms, the usual initial dosage of orally inhaled levalbuterol via a metered-dose inhaler for adults and children 4 years of age or older is 90 mcg (2 inhalations) every 4–6 hours.²⁷⁶ A dosage of 45 mcg (1 inhalation) every 4 hours may be sufficient in some patients.²⁷⁶ More frequent administration or a larger number of inhalations of levalbuterol is not routinely recommended.²⁷⁶ Levalbuterol inhalation aerosol should be used with caution in patients with renal impairment receiving high dosages of the drug.²⁷⁶

Albuterol Sulfate and Ipratropium. For the management of bronchospasm associated with chronic obstructive pulmonary disease (COPD), the usual initial dosage of albuterol (as albuterol sulfate) in fixed combination with ipratropium bromide (18 mcg per inhalation) is 180 mcg (2 inhalations) 4 times daily.²³³ If necessary, additional inhalations may be used.²³³ However, since fatalities have been reported in association with excessive use of inhaled β-adrenergic agonists in patients with asthma, the manufacturer recommends not exceeding 12 inhalations in 24 hours with the fixed combination of albuterol sulfate and ipratropium bromide.²³³ (See Cautions: Precautions and Contraindications.)

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.^{242 258} 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.²⁵⁵ More frequent administration or a higher dosage is not recommended.^{241 255 258} 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.^{242 258} 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.²⁵⁵ 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.²⁵⁵ 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;²⁵⁵ 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.^{255 258}

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.^{241 272} 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.^{241 244 246 255 258 272}

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.^{114 241 258 272} However, for acute asthma exacerbations that are managed initially in the patient’s home, some experts state that full dosages (up to 10 inhalations of a metered-dose inhalation aerosol, preferably using a spacer, or full doses using a nebulizer) of a β₂-adrenergic agonist may be used at less than hourly intervals in patients who have not responded to initial β₂-agonist therapy (2–4 inhalations every 20 minutes for the first hour).²⁴⁹ Should the response to initial drug therapy at home be incomplete (peak expiratory flow 60–80% of predicted or personal best) or poor (peak expiratory flow less than 60% of predicted or personal best), the patient should seek medical attention urgently (if incomplete response) or immediately proceed to the hospital emergency department (if poor response) for further management.²⁴⁹ (See Asthma under Uses: Bronchospasm.)

Albuterol and Ipratropium. For administration via a nebulizer, the dosage of albuterol (as albuterol sulfate) in fixed combination with ipratropium bromide (0.5 mg) (DuoNeb ^®) in for adults is 2.5 mg 4 times.²⁴³ The flow rate of the nebulizer should be adjusted so that the dose is delivered over a period of approximately 5–15 minutes. ²⁴⁵ The manufacturer of DuoNeb^® recommends not exceeding 6 inhalations daily since these dosages have not been studied.²⁴³

Levalbuterol Hydrochloride. For administration via a nebulizer, 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.²¹⁶ 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).^{216 219 221} 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;^{216 254} however, routine dosage should not exceed 0.63 mg 3 times daily.²¹⁶ 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.^{216 219} 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.²¹⁶ 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.²²⁶ Levalbuterol nebulization therapy should be continued as necessary to control recurrent bronchospasm.²¹⁶ 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.^{216 249}

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.^{100 139 280} 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.²⁷¹ 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.^{100 139 271 280} 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.^{100 139 271 280} 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.²⁷¹

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.^{100 139 280} 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.²⁸⁰ If necessary, dosage may be cautiously and gradually increased to a maximum of 24 mg daily (in divided doses) as conventional tablets.²⁸⁰ In children 6–12 years of age, the usual initial dosage of albuterol extended-release tablets (VoSpire ER^®) is 4 mg every 12 hours.²⁷¹ Dosage of albuterol given as extended-release tablets may be increased cautiously stepwise as tolerated to a maximum of 12 mg twice daily.²⁷¹

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.²⁸¹ 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.²⁸¹ 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).²⁸¹ 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.²⁸¹ Subsequent dosage is adjusted according to the patient’s tolerance and response.²⁸¹ 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.²⁸¹ 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.²⁸¹

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;^{100 139 280 281} if necessary, dosage may be gradually increased to as much as 8 mg 3 or 4 times daily.^{100 139 280}

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.^{100 146 181} 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.²⁷¹ 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;^{100 139 208 271} 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.^{100 139 208} Evidence principally from a short-term (4-week), comparative clinical trial in adults and adolescents with mild-to-moderate asthma suggest that levalbuterol, 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.^{216 219 221 222}

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.^{100 114 139 146 181 208 241 242 244 282} Other frequently reported adverse effects of albuterol include nervousness, nausea, tachycardia, palpitations, chest pain, shakiness, and dizziness.^{100 114 146 181 208 241 242 244 255 281 282} 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^®).^{181 237 282}

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 oral inhalation for nebulization therapy.^{216 219} 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.^{216 219}

Nervous System Effects

Tremor was reported in 20% of patients receiving albuterol sulfate conventional oral tablets^{100 139} or oral inhalation via nebulization²⁴¹ 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.¹⁴⁶ 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 trial¹⁰⁰ 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.²⁷¹ 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.²⁷¹ The overall incidence of tremor in patients receiving conventional or extended-release albuterol sulfate tablets in clinical trials reportedly has been similar.¹⁰⁰ Tremor was reported in 8 or 7% of patients receiving albuterol inhalation aerosol or albuterol sulfate inhalation aerosol, respectively;¹⁸¹ in 1% of patients receiving albuterol sulfate oral inhalation powder (Rotacaps^®; no longer commercially available in the US),¹³² and in less than 1% of children 4–11 years of age receiving albuterol inhalation aerosol in clinical trials.¹⁴⁶ 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.²¹⁶ 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.²¹⁶ Tremor was reported in less than 2% of patients receiving levalbuterol inhalation solution via nebulization in overall clinical trials.²¹⁶

Nervousness was reported in 20% of patients receiving albuterol sulfate oral tablets in clinical trials.^{100 139} Nervousness was reported in 15% of children 2–6 years of age receiving the oral solution in clinical trials,²⁸¹ while nervousness/shakiness was reported in 9% of adults and older children (6–14 years of age) receiving the oral solution.^{208 281} 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.¹⁰⁰ Nervousness was reported in 8.5% of adults receiving albuterol sulfate extended-release tablets in controlled clinical trials.²⁷¹ In a comparative trial, nervousness was reported in 2 or 6% of patients receiving extended-release or conventional albuterol sulfate tablets, respectively.¹⁰⁰ 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.¹⁴⁶ Nervousness was reported in 9 or 7% of patients receiving albuterol or albuterol sulfate aerosol,¹⁸¹ respectively, and in 4% of patients receiving nebulized albuterol sulfate in clinical trials.^{114 241} 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)¹³² and 1% of children 4–11 years of age receiving albuterol oral inhalation aerosol¹⁴⁶ in clinical trials. Nervousness was reported during postmarketing experience in patients receiving levalbuterol HFA oral inhalation aerosol.²⁷⁶

Dizziness was reported in 7% of patients receiving albuterol sulfate inhalation solution via nebulization,^{114 241 242 244} 3% of patients (adults and children 6–14 years of age) receiving albuterol sulfate oral solution, 2% of patients receiving albuterol sulfate tablets,^{100 139 281} and in less than 1% of patients receiving albuterol sulfate inhalation powder (Rotacaps^®; no longer commercially available in the US) in overall clinical trials.¹³² 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.¹⁴⁶ Dizziness also has been reported in patients receiving albuterol sulfate inhalation aerosol,¹⁸¹ occurring in 3% of patients receiving albuterol sulfate HFA inhalation aerosol (Proair^® HFA) in a clinical trial.²⁸² 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.²¹⁶ 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% if patients receiving albuterol HFA inhalation aerosol.²⁷⁶

Headache was reported in 7% of patients receiving albuterol sulfate tablets^{100 139} and in 4% of patients (adults and children 6–14 years of age) receiving albuterol sulfate oral solution in clinical trials.²⁸¹ 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.¹⁰⁰ Headache occurred in 18.8% of adults receiving albuterol extended-release tablets in controlled clinical trials.²⁷¹ 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.¹³² 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.²⁸² Headache was reported in 3% of patients receiving nebulized albuterol sulfate inhalation solution^{114 241} and in 3% of children 4–11 years of age receiving albuterol oral inhalation aerosol in clinical trials.¹⁴⁶

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.²¹⁶ 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.²¹⁶ Headache has been reported with levalbuterol HFA inhalation aerosol during postmarketing experience.²⁷⁶ 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.²⁵⁵

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.¹⁰⁰ Insomnia was reported in 2.4% of adults receiving albuterol sulfate extended-release tablets in controlled clinical trials.²⁷¹ Insomnia was reported in 2% of children 2–6 years of age receiving albuterol sulfate oral solution in clinical trials.²⁰⁸ Sleeplessness was reported in 1% of patients receiving nebulized albuterol^{114 241} and in less than 1% of patients receiving albuterol sulfate oral inhalation powder (Rotacaps^®; no longer commercially available in the US) in clinical trials.¹³² Insomnia¹⁰⁰ or sleeplessness¹³⁹ was reported in 2% of patients receiving albuterol sulfate tablets; sleeplessness²⁰⁸ was reported in 1%^{100 139 281} and disturbed sleep²⁸¹ 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.¹⁰⁰

Insomnia was reported in less than 2% of patients receiving orally inhaled levalbuterol via nebulization in clinical trials.²¹⁶ Sleeplessness or central nervous system stimulation has been reported during postmarketing experience with levalbuterol HFA inhalation aerosol.²⁷⁶

Inhalation site sensation¹⁸¹ was reported in 9 or 6%, and inhalation taste sensation¹⁸¹ in 3 or 4% of patients receiving albuterol or albuterol sulfate inhalation aerosol, respectively.¹⁸¹ Tinnitus,¹⁸¹ anxiety,^{181 282} ataxia,¹⁸¹ depression,¹⁸¹ somnolence,¹⁸¹ or hyperkinesia¹⁸¹ 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.²¹⁶ 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.²¹⁶

Hyperactivity was reported in 2% of adults and older children receiving albuterol sulfate oral solution,²⁰⁸ in 1% of children 4–11 years of age receiving albuterol oral inhalation aerosol,¹⁴⁶ 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.¹³² 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).^{208 281} 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.²⁸¹ 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.²⁸¹ Weakness^{100 139} was reported in 2%, and drowsiness, restlessness, or irritability were reported in less than 1% of patients receiving albuterol sulfate tablets in clinical trials.^{100 139} 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.¹⁴⁶ Lightheadedness was reported in less than 1% of patients receiving albuterol sulfate oral inhalation powder (Rotacaps^®; no longer commercially available in the US)¹³² and in less than 1% of children 4–11 years of age receiving albuterol oral inhalation aerosol in clinical trials.¹⁴⁶ Tinnitus¹⁰⁰ has been reported in patients receiving albuterol sulfate oral tablets.¹⁰⁰ Like other sympathomimetic agents, albuterol has been associated with vertigo or CNS stimulation.^{100 139 181 282}

GI Effects

The most frequently reported adverse GI effect of albuterol is nausea.^{100 139 146 181} In a comparative, placebo-controlled trial, nausea was reported in 9 or 10% of patients receiving albuterol or albuterol sulfate oral inhalation aerosol, respectively; vomiting was reported in 2 or 7%, respectively, of these patients.¹⁸¹ Nausea was reported in 2% of patients receiving albuterol sulfate conventional oral tablets in clinical trials.^{100 139} Nausea or vomiting was reported in 4 or 2%, respectively, of adults receiving extended-release or albuterol sulfate conventional tablets in a clinical trial.¹⁰⁰ Nausea or vomiting was reported in 4.2% of adults receiving albuterol sulfate extended-release tablets in placebo-controlled or comparative clinical trials.²⁷¹ 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.¹⁴⁶ Nausea and/or vomiting was reported in 6% of children 4–11 years of age receiving albuterol oral inhalation aerosol.¹⁴⁶ 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.¹³² 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.^{114 216 241} Vom