LEVALBUTEROL HYDROCHLORIDE- levalbuterol hydrochloride solution
Watson Laboratories, Inc.
Levalbuterol HCl Inhalation Solution is a sterile, clear, colorless, preservative-free solution of the hydrochloride salt of levalbuterol, the (R)-enantiomer of the drug substance racemic albuterol. Levalbuterol HCl is a relatively selective beta2 -adrenergic receptor agonist (see CLINICAL PHARMACOLOGY). The chemical name for levalbuterol HCl is (R)-α1 -[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol hydrochloride, and its established chemical structure is as follows:
The molecular weight of levalbuterol HCl is 275.8, and its empirical formula is C13 H21 NO3 •HCl. It is a white to off-white, crystalline solid, with a melting point of approximately 187°C and solubility of approximately 180 mg/mL in water.
Levalbuterol HCl is the USAN modified name for (R)-albuterol HCl in the United States.
Levalbuterol HCl Inhalation Solution is supplied in unit-dose vials and requires no dilution before administration by nebulization. Each 3 mL unit-dose vial contains 0.31 mg of levalbuterol (as 0.36 mg of levalbuterol HCl) or 0.63 mg of levalbuterol (as 0.73 mg of levalbuterol HCl) or 1.25 mg of levalbuterol (as 1.44 mg of levalbuterol HCl), sodium chloride to adjust tonicity, and sulfuric acid to adjust the pH to 4.0 (3.3 to 4.5).
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 the phosphorylation 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 some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.
Results from an in vitro study of binding to human beta-adrenergic receptors demonstrated that levalbuterol has approximately 2-fold greater binding affinity than racemic albuterol and approximately 100-fold greater binding affinity than (S)-albuterol. In guinea pig airways, levalbuterol 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), 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.
The inhalation pharmacokinetics of Levalbuterol HCl Inhalation Solution were investigated in a randomized cross-over study in 30 healthy adults following administration of a single dose of 1.25 mg and a cumulative dose of 5 mg of Levalbuterol HCl 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 Levalbuterol HCl 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 Levalbuterol HCl Inhalation Solution (1.25 mg given every 30 minutes for a total of four doses) or a cumulative 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 were comparable (see Table 1).
γ Median (Min, Max) reported for Tmax .* A negative Tmax indicates Cmax occurred between first and last nebulizations.** Values reflect only (R)-albuterol and do not include (S)-albuterol.
|Single Dose||Cumulative Dose|
|Levalbuterol HCl 1.25 mg||Racemic albuterolsulfate 2.5 mg||Levalbuterol HCl 5 mg||Racemic albuterolsulfate 10 mg|
|(R)-albuterol||1.1 (0.45)||0.8 (0.41)**||4.5 (2.20)||4.2 (1.51)**|
|(R)-albuterol||0.2 (0.17, 0.37)||0.2 (0.17, 1.50)||0.2 (–0.18*, 1.25)||0.2 (–0.28*, 1.00)|
|(R)-albuterol||3.3 (1.58)||1.7 (0.99)**||17.4 (8.56)||16.0 (7.12)**|
|(R)-albuterol||3.3 (2.48)||1.5 (0.61)||4.0 (1.05)||4.1 (0.97)|
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.