For Oral Inhalation Only
PRESCRIBING INFORMATION

DESCRIPTION

The active component of XOPENEX HFA (leva lbuterol tartrate) Inhalation Aerosol is leva lbuterol tartrate, the (R)-enantiomer of albuterol. Leva lbuterol tartrate is a relatively selective beta2-adrenergic receptor agonist (see CLINICAL PHARMACOLOGY). Leva lbuterol tartrate has the chemical name (R)-α1-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol L-tartrate (2:1 salt), and it has the following chemical structure:

The molecular weight of leva lbuterol tartrate is 628.71, and its empirical formula is (C13H21NO3)2 · C4H6O6. It is a white to light-yellow solid, freely soluble in water and very slightly soluble in ethanol.

Leva lbuterol tartrate is the generic name for (R)-albuterol tartrate in the United States. XOPENEX HFA Inhalation Aerosol is a pressurized metered-dose aerosol inhaler (MDI), which produces an aerosol for oral inhalation. It contains a suspension of micronized leva lbuterol tartrate, propellant HFA-134a (1,1,1,2-tetrafluoroethane), Dehydrated Alcohol USP, and Oleic Acid NF.

The inhaler should be primed by releasing 4 sprays into the air, away from the face, before using it for the first time and when the inhaler has not been used for more than 3 days. After priming with 4 actuations, each actuation delivers 59 mcg of leva lbuterol tartrate (equivalent to 45 mcg of leva lbuterol free base) from the actuator (or mouthpiece). Each 15 g canister provides 200 actuations (or inhalations) and each 8.4 g canister provides 80 actuations (or inhalations).

This product does not contain chlorofluorocarbons (CFCs).

CLINICAL PHARMACOLOGY

Mechanism of Action: Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenylate cyclase and to an increase in the intracellular concentration of cyclic-3', 5'-adenosine monophosphate (cyclic AMP). The increase in cyclic AMP is associated with the activation of protein kinase A, which in turn, inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Leva lbuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Increased cyclic AMP concentrations are also associated with the inhibition of the release of mediators from mast cells in the airways. Leva lbuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are beta2-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 some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.

Preclinical

Results from in vitro studies of binding to human beta-adrenergic receptors demonstrated that leva lbuterol has approximately 2-fold greater binding affinity than racemic albuterol and approximately 100-fold greater binding affinity than (S)-albuterol. In guinea pig airways, leva lbuterol HCl and racemic albuterol decreased the response to spasmogens (e.g., acetylcholine and histamine), whereas (S)-albuterol was ineffective. These results suggest that the 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), racemic 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 histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.

Propellant HFA-134a is devoid of pharmacological activity except at very high doses in animals (380 to 1300 times the maximum human exposure based on comparisons of AUC values), primarily producing ataxia, tremors, dyspnea, or salivation. These are similar to effects produced by the structurally related chlorofluorocarbons (CFCs), which have been used extensively in metered-dose inhalers.

In animals and humans, propellant HFA-134a was found to be rapidly absorbed and rapidly eliminated, with an elimination half-life of 3 to 27 minutes in animals and 5 to 7 minutes in humans. Time to maximum plasma concentration (tmax) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation.

Pharmacokinetics

A population pharmacokinetic (PPK) model was developed using plasma concentrations of (R)-albuterol obtained from 632 asthmatic patients aged 4 to 81 years in three large trials. The PPK model-derived pharmacokinetic parameters for (R)-albuterol in pediatric and adolescent/adult patients receiving a 90 mcg dose of XOPENEX HFA (leva lbuterol tartrate) Inhalation Aerosol or a 180 mcg dose of r