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 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 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 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 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)

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