A 4-week, randomized, double-blind, parallel-group study evaluated 362 patients aged 12 years and older with moderate to severe asthma (forced expiratory volume in 1 second [FEV
1] between 45% and 70% of predicted).
18 In this study, subjects were randomly assigned to receive nebulized levalbuterol (0.63 mg or 1.25 mg), equivalent amounts of (R)-albuterol administered as racemic albuterol (1.25 mg or 2.5 mg), or placebo three times daily for 4 weeks. The mean percent change in FEV
1 after the first dose was significantly greater in the combined levalbuterol group than in the combined racemic albuterol group. There were similar, though statistically nonsignificant, improvements in FEV
1 measured at week 4 in the groups receiving levalbuterol compared with those receiving racemic albuterol. The greatest mean percent change in FEV
1 and the longest duration of improvement were seen in patients treated with levalbuterol 1.25 mg, whereas the smallest mean percent change in FEV
1 and the shortest duration of improvement were seen in patients treated with racemic albuterol 1.25 mg (
Figure 2). Patients receiving levalbuterol 0.63 mg had improvements in FEV
1 comparable to those receiving racemic albuterol 2.5 mg, but had significantly lower increases in ventricular heart rates. A post hoc analysis of serial pulmonary function data pooled from 4 randomized, double-blinded levalbuterol studies using racemic albuterol as an active comparator has shown that, after the first dose, levalbuterol 1.25 mg produced significantly greater bronchodilation than racemic albuterol 2.5 mg, as measured by area under the curve for the normalized mean percent change in FEV
1 versus time curve (
P < .05).
28,29
Additionally, compared with patients receiving placebo, those receiving levalbuterol 1.25 mg had a reduced need for rescue medication (racemic albuterol metered dose inhaler) between regularly scheduled treatments by an average of 2.2 puffs per day. Corticosteroid-naive patients who received levalbuterol or placebo had a mean 300-mL improvement in baseline pulmonary function during the 4-week study. In contrast, corticosteroid-naive patients receiving racemic albuterol demonstrated slightly reduced baseline pulmonary function after 4 weeks of treatment.
18 This phenomenon of reduced pulmonary function has been observed in other, but not all, studies of prolonged use of racemic albuterol.
9,10
Another multicenter, double-blind study evaluated 338 pediatric subjects aged 4 to 11 years (FEV
1 40% to 85% of predicted) who were randomized to receive nebulized levalbuterol (0.31 mg or 0.63 mg), racemic albuterol (1.25 mg or 2.50 mg), or placebo three times daily for 21 days.
19 Patients in all active treatment groups, including levalbuterol 0.31 mg and 0.63 mg, showed significant improvement in FEV
1 compared with those administered placebo (overall
P < .001), producing mean peak percent changes for placebo, levalbuterol 0.31 mg and 0.63 mg, and racemic albuterol 1.25 mg and 2.50 mg of 2.0%, 19.0%, 18.1%, 12.4%, and 15.6%, respectively. The 0.31-mg dose of levalbuterol was the only active treatment that did not differ from placebo with respect to changes in heart rate (
P > .05). Although this study was prospectively designed to compare racemic albuterol and levalbuterol to placebo and not to each other, the data show that levalbuterol (0.31 mg and 0.63 mg) provided bronchodilation comparable to that seen with racemic albuterol 2.5 mg with fewer β-mediated side effects.
18,19
Levalbuterol is currently available as an inhalation solution, with a labeled indication for the treatment and prevention of bronchospasm in adults, adolescents, and children 6 years of age and older with reversible obstructive airways disease. The recommended dose is levalbuterol 0.31 mg three times daily for children 6 to 11 years and 0.63 mg three times daily for adults and children 12 years and older. A higher dosage (1.25 mg three times daily) can be administered to patients 12 years of age and older who have more severe asthma or do not respond adequately to a dose of 0.63 mg. A levalbuterol hydrofluoroalkane metered dose inhaler formulation is currently under development.
Because levalbuterol costs more than racemic albuterol, which is available in generic formulations, health care professionals have questioned whether the clinical benefits outweigh the higher acquisition cost, and some have suggested that they may not.
30 However, it is important to not only consider the drug acquisition costs, but also the impact a drug may have on the total cost of care. For example, in a double-blind, randomized clinical trial among children aged 1 to 18 years treated for asthma exacerbations in an emergency department, there was a 9.4% absolute reduction in the hospital admission rate (20% relative reduction) among children treated with levalbuterol 1.25 mg (36%, 101 of 278 children), compared with those treated with racemic albuterol 2.5 mg (45%, 122 of 269 children) that was statistically significant (
P < .02).
31 Similarly, a retrospective chart review of more than 700 patients presenting to the emergency department with asthma exacerbations found that levalbuterol (1.25 mg) used in place of racemic albuterol (2.5 mg) resulted in statistically significant reductions in hospital admissions (15.1% admissions with racemic albuterol versus 4.7% admissions with levalbuterol;
P = .0016).
32
Another retrospective study among patients hospitalized with asthma or COPD showed that levalbuterol administered 1.25 mg every 8 hours and as needed, used in place of racemic albuterol administered 2.5 mg every 4 hours and as needed, shortened lengths of hospital stay by 16%, or 0.91 days (
P = .058).
33 On average, patients receiving levalbuterol were administered 38% fewer nebulized treatments (ipatropium bromide and β-agonist treatments) per hospital stay (19 ± 12.7 treatments for levalbuterol, and 30.8 ± 24 treatments for racemic albuterol), as well as 60% fewer ipatropium bromide treatments. Furthermore, despite less frequent dosing of levalbuterol than racemic albuterol, fewer levalbuterol patients required rescue medications of any kind between regularly scheduled doses. Total hospital costs for patients receiving levalbuterol compared to racemic albuterol were lower (
P = .1); on average, levalbuterol therapy reduced the cost of care for both asthma and COPD patients by approximately $600.
33 Thus, these study results suggest a possibility for reduced hospital admissions, less frequent bronchodilator treatments, and an overall cost savings with the use of levalbuterol in place of racemic albuterol in acute care settings. When considered in the context of data taken from large outpatient studies in adults and children with asthma, the use of levalbuterol in place of racemic albuterol may also provide greater clinical benefits in ambulatory patients.
Racemic albuterol has been an important bronchodilatory agent for obstructive airway diseases in both emergent and ambulatory treatment settings for many years. However, large, well-controlled clinical studies performed in adults with asthma have shown that nebulized levalbuterol 1.25 mg produces greater bronchodilation than the standard 2.5-mg dose of racemic albuterol, while levalbuterol 0.63 mg results in bronchodilation that is similar to that provided by racemic albuterol 2.5 mg but with fewer β-mediated side effects.
18 Additionally, studies in children with asthma have shown that 0.63- and 0.31-mg doses of levalbuterol produce bronchodilation that is comparable to that experienced by patients treated with racemic albuterol 2.5 mg and 1.25 mg.
19 Lower dosing of the (R)-albuterol isomer to patients with the use of levalbuterol provides comparable or superior bronchodilation as racemic albuterol, with the potential for fewer β-mediated side effects. Both clinical trials and preclinical experiments have suggested that the inclusion of (S)-albuterol in racemic albuterol provides no clinical benefit and may oppose some of the therapeutic benefits of the (R)-isomer (levalbuterol).