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Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3', 5'-adenosine monophosphate (cyclic AMP). This increase in cyclic AMP leads to the activation of protein kinase A, which inhibits thephosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Levalbuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Levalbuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved,thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.

While it is recognized that beta₂-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there is a population of beta₂-receptors in the human heart that comprise between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors has not been established (see WARNINGS). However, all beta-adrenergic agonist drugs can produce a significant cardiovascular effect in somepatients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.

Preclinical Studies

Results from an in vitro study of binding to human beta-adrenergic receptors demonstrated that levalbuterol has approximately 2-fold greater bindingaffinity than racemic albuterol and approximately 100-fold greater binding affinity than (S)-albuterol. In guinea pig airways, levalbuterol HCl and racemicalbuterol decreased the response to spasmogens (e.g., acetylcholine and histamine), whereas (S)-albuterol was ineffective. These results suggest thatthe bronchodilatory effects of racemic albuterol are attributable to the (R)-enantiomer.

Intravenous studies in rats with racemic albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5.0% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands),albuterol concentrations were found to be 100 times those in the whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologicevidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings isunknown.

Pharmacokinetics (Adults and Adolescents ≥ 12 years old)

The inhalation pharmacokinetics of Xopenex (levalbuterol) Inhalation Solution were investigated in a randomized cross-over study in 30 healthy adults followingadministration of a single dose of 1.25 mg and a cumulative dose of 5 mg of Xopenex (levalbuterol) Inhalation Solution and a single dose of 2.5 mg and a cumulative dose of 10 mg of racemic albuterol sulfate inhalation solution by nebulization using a PARI LC Jet™ nebulizer with a Dura-Neb® 2000 compressor.

Following administration of a single 1.25 mg dose of Xopenex (levalbuterol) Inhalation Solution, exposure to (R)-albuterol (AUC of 3.3 ng•hr/mL) was approximately 2-fold higher than following administration of a single 2.5 mg dose of racemic albuterol inhalation solution (AUC of 1.7 ng•hr/mL) (see Table 1).Following administration of a cumulative 5 mg dose of Xopenex (levalbuterol) Inhalation Solution (1.25 mg given every 30 minutes for a total of four doses) or a cumu-lative 10 mg dose of racemic albuterol inhalation solution (2.5 mg given every 30 minutes for a total of four doses), Cmax and AUC of (R)-albuterol werecomparable (see Table 1).

Table 1: Mean (SD) Values for Pharmacokinetic Parameters in Healthy Adults

Pharmacokinetics (Children 6-11 years old)

The pharmacokinetic parameters of (R)-and (S)-albuterol in children with asthma were obtained using population pharmacokinetic analysis. These data arepresented in Table 2. For comparison, adult data obtained by conventional pharmacokinetic analysis from a different study also are presented in Table 2. In children, AUC and Cmax of (R)-albuterol following administration of 0.63 mg Xopenex (levalbuterol) Inhalation Solution were comparable to those following admin-istration of 1.25 mg racemic albuterol sulfate inhalation solution.

When the same dose of 0.63 mg of Xopenex (levalbuterol) was given to children and adults, the predicted Cmax of (R)-albuterol in children was similar to that in adults(0.52 vs. 0.56 ng/mL), while predicted AUC in children (2.55 ng•hr/mL) was about 1.5-fold higher than that in adults (1.65 ng•hr/mL). These data sup-port lower doses for children 6-11 years old compared with the adult doses (see DOSAGE AND ADMINISTRATION).

Table 2: (R)-Albuterol Exposure in Adults and Pediatric Subjects (6-11 years)

Metabolism and Elimination

Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol enantiomers in humans isSULT1A3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there wasa 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold,suggesting that (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULT1A3.

The primary route of elimination of albuterol enantiomers is through renal excretion (80% to 100%) of either the parent compound or the primarymetabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% ofthe (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine.

Special Populations

Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of Xopenex (levalbuterol) Inhalation Solution has not been evaluated.

Renal Impairment: The effect of renal impairment on the pharmacokinetics of racemic albuterol was evaluated in 5 subjects with creatinine clearanceof 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67%decline in racemic albuterol clearance. Caution should be used when administering high doses of Xopenex (levalbuterol) Inhalation Solution to patients with renalimpairment.

Pharmacodynamics (Adults and Adolescents ≥ 12 years old)

In a randomized, double-blind, placebo-controlled, cross-over study, 20 adults with mild-to-moderate asthma received single doses of Xopenex (levalbuterol) Inhalation Solution (0.31, 0.63, and 1.25 mg) and racemic albuterol sulfate inhalation solution (2.5 mg). All doses of active treatment produced a significantly greater degree of bronchodilation (as measured by percent change from pre-dose mean FEV₁) than placebo, and there were no significant differences between any of the active treatment arms. The bronchodilator responses to 1.25 mg of Xopenex (levalbuterol) Inhalation Solution and 2.5 mg of racemicalbuterol sulfate inhalation solution were clinically comparable over the 6-hour evaluation period, except for a slightly longer duration of action ( > 15%increase in FEV₁ from baseline) after administration of 1.25 mg of Xopenex (levalbuterol) Inhalation Solution. Systemic beta-adrenergic adverse effects were observedwith all active doses and were generally dose-related for (R)-albuterol. Xopenex (levalbuterol) Inhalation Solution at a dose of 1.25 mg produced a slightly higher rateof systemic beta-adrenergic adverse effects than the 2.5 mg dose of racemic albuterol sulfate inhalation solution.

In a randomized, double-blind, placebo-controlled, cross-over study, 12 adults with mild-to-moderate asthma were challenged with inhaled methacholine chloride 20 and 180 minutes following administration of a single dose of 2.5 mg of racemic albuterol sulfate, 1.25 mg of Xopenex (levalbuterol) , 1.25 mg of(S)-albuterol, or placebo using a PARI LC Jet™ nebulizer. Racemic albuterol sulfate, Xopenex (levalbuterol) , and (S)-albuterol had a protective effect against methacholine-induced bronchoconstriction 20 minutes after administration, although the effect of (S)-albuterol was minimal. At 180 minutes after administration, the bronchoprotective effect of 1.25 mg of Xopenex (levalbuterol) was comparable to that of 2.5 mg of racemic albuterol sulfate. At 180 minutes after administration, 1.25 mg of (S)-albuterol had no bronchoprotective effect.

In a clinical study in adults with mild-to-moderate asthma, comparable efficacy (as measured by change from baseline FEV₁) and safety (as measuredby heart rate, blood pressure, ECG, serum potassium, and tremor) were demonstrated after a cumulative dose of 5 mg of Xopenex (levalbuterol) Inhalation Solution(four consecutive doses of 1.25 mg administered every 30 minutes) and 10 mg of racemic albuterol sulfate inhalation solution (four consecutive dosesof 2.5 mg administered every 30 minutes).

Clinical Trials (Adults and Adolescents ≥ 12 years old)

The safety and efficacy of Xopenex (levalbuterol) Inhalation Solution were evaluated in a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 362 adult and adolescent patients 12 years of age and older, with mild-to-moderate asthma (mean baseline FEV₁ 60% of predicted).Approximately half of the patients were also receiving inhaled corticosteroids. Patients were randomized to receive Xopenex (levalbuterol) 0.63 mg, Xopenex (levalbuterol) 1.25 mg,racemic albuterol sulfate 1.25 mg, racemic albuterol sulfate 2.5 mg, or placebo three times a day administered via a PARI LC Plus™ nebulizer and aDura-Neb® portable compressor. Racemic albuterol delivered by a chlorofluorocarbon (CFC) metered dose inhaler (MDI) was used on an as-neededbasis as the rescue medication.

Efficacy, as measured by the mean percent change from baseline FEV₁, was demonstrated for all active treatment regimens compared with placebo onday 1 and day 29. On both day 1 (see Figure 1) and day 29 (see Figure 2), 1.25 mg of Xopenex (levalbuterol) demonstrated the largest mean percent change frombaseline FEV₁ compared with the other active treatments. A dose of 0.63 mg of Xopenex (levalbuterol) and 2.5 mg of racemic albuterol sulfate produced a clinicallycomparable mean percent change from baseline FEV₁ on both day 1 and day 29.

Figure 1: Mean Percent Change from Baseline FEV₁ on Day 1, Adults and Adolescents ≥ 12 years old

Figure 2: Mean Percent Change from Baseline FEV₁ on Day 29, Adults and Adolescents ≥ 12 years old

The mean time to onset of a 15% increase in FEV₁ over baseline for levalbuterol at doses of 0.63 mg and 1.25 mg was approximately 17 minutes and10 minutes, respectively, and the mean time to peak effect for both doses was approximately 1.5 hours after 4 weeks of treatment. The mean duration ofeffect, as measured by a > 15% increase from baseline FEV₁, was approximately 5 hours after administration of 0.63 mg of levalbuterol and approximately6 hours after administration of 1.25 mg of levalbuterol after 4 weeks of treatment. In some patients, the duration of effect was as long as 8 hours.

Clinical Trials (Children 6-11 years old)

A multi-center, randomized, double-blind, placebo- and active-controlled study was conducted in children with mild-to-moderate asthma (mean baseline FEV₁ 73% of predicted) (n=316). Following a 1-week placebo run-in, subjects were randomized to Xopenex (levalbuterol) (0.31 or 0.63 mg), racemic albuterol(1.25 or 2.5 mg), or placebo, which were delivered three times a day for 3-weeks using a PARI LC Plus™ nebulizer and a Dura-Neb® 3000 compressor.

Efficacy, as measured by mean peak percent change from baseline FEV₁, was demonstrated for all active treatment regimens compared with placebo onday 1 and day 21. Time profile FEV₁ curves for day 1 and day 21 are shown in Figure 3 and Figure 4, respectively. The onset of effect (time to a 15%increase in FEV₁ over test-day baseline) and duration of effect (maintenance of a > 15% increase in FEV₁ over test-day baseline) of levalbuterol were clinically comparable to those of racemic albuterol.

Figure 3: Mean Percent Change from Baseline FEV₁ on Day 1, Children 6-11 Years of Age

Figure 4: Mean Percent Change from Baseline FEV₁ on Day 21, Children 6-11 Years of Age

Last reviewed on RxList: 6/4/2008
This monograph has been modified to include the generic and brand name in many instances.