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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. Levalbuterol 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. Levalbuterol 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.
A population pharmacokinetic model was developed using plasma concentrations of (R)- albuterol obtained from 632 asthmatic patients aged 4 to 81 years in three large trials. For adolescent and adult patients 12 years and older, following 90 mcg dose of XOPENEX HFA, yielded mean peak plasma concentrations (Cmax) and systemic exposure (AUC0-6) of approximately 199 pg/mL and 695 pg·h/mL, respectively compared to approximately 238 pg/mL and 798 pg·h/mL, respectively following 180 mcg dose of Racemic Albuterol HFA metered- dose inhaler. For pediatric patients from 4 to 11 years of age, following 90 mcg dose of XOPENEX HFA, yielded Cmax and AUC0-6 of approximately 163 pg/mL and 579 pg·h/mL, respectively compared to approximately 238 pg/mL and 828 pg·h/mL, respectively following 180 mcg dose of Racemic Albuterol HFA metered-dose inhaler.
These pharmacokinetic data indicate that mean exposure to (R)-albuterol was 13% to 16% less in adult and 30% to 32% less in pediatric patients given XOPENEX HFA as compared to those given a comparable dose of racemic albuterol. When compared to adult patients, pediatric patients given 90 mcg of levalbuterol have a 17% lower mean exposure to (R)-albuterol.
Metabolism and Elimination
Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol enantiomers in humans is SULT1A3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 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 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 primary metabolite. Less than 20% of the drug isdetected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine.
The effect of hepatic impairment on the pharmacokinetics of XOPENEX HFA has not been evaluated.
The effect of renal impairment on the pharmacokinetics of racemic albuterol was evaluated in 5 subjects with creatinine clearance of 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 HFA to patients with renal impairment. [see Use in Specific Populations]
Animal Toxicology and/or Pharmacology
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. Based on studies in animals, the propellant HFA-134a had no detectable toxicological activity at amounts less than 380 times the maximum human exposure based on comparisons of AUC values). The toxicological effects observed at these very high doses included ataxia, tremors, dyspnea, or salivation, similar to effects produced by the structurally related chlorofluorocarbons (CFCs) used in metered-dose inhalers, that were extensively used in the past.
Pregnant mice administered racemic albuterol sulfate subcutaneously resulted in a dose-related increased incidence of cleft palate in their fetuses (4.5% of fetuses at 0.25 mg/kg/day or greater, corresponding to approximately 2 times MRDI dose, 9.3% of fetuses at 2.5 mg/kg/day approximately 20 times MRDI dose of levalbuterol tartrate for adults on a mg/m² basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg/day (approximately 0.2 times MRDI dose of levalbuterol tartrate for adults on a mg/m² basis).
Bronchospasm Associated with Asthma
Adults and Adolescent Patients 12 Years of Age and Older
The efficacy and safety of XOPENEX HFA were established in two 8-week, multicenter, randomized, double-blind, active- and placebo-controlled trials in 748 adults and adolescents with asthma between the ages of 12 and 81 years. In these two trials, XOPENEX HFA (403 patients) was compared to an HFA-134a placebo MDI (166 patients), and the trials included a marketed albuterol HFA-134a MDI (179 patients) as an active control. Serial forced expiratory volume in 1 second (FEV1) measurements demonstrated that 90 mcg (2 inhalations) of XOPENEX HFA produced significantly greater improvement in FEV1 over the pretreatment value than placebo. The results from one of the trials are shown in Figure 1 as the mean percent change in FEV1 from test-day baseline at Day 1 (n=445) and Day 56 (n=387). The results from the second trial were similar.
Figure 1: Percent Change in FEV1 from Test-Day Baseline
in Adults and Adolescents Aged 12 to 81 Years at Day 1 and Day 56
For XOPENEX HFA on Day 1, the median time to onset of a 15% increase in FEV1 ranged from 5.5 to 10.2 minutes and the median time to peak effect ranged from 76 to 78 minutes. In the responder population, on Day 1 the median duration of effect as measured by a 15% increase in FEV1 was 3 to 4 hours, with duration of effect in some patients of up to 6 hours.
Pediatric Patients 4 to 11 Years of Age
The efficacy and safety of XOPENEX HFA in children were established in a 4-week, multicenter, randomized, double-blind, active- and placebo-controlled trial in 150 pediatric patients with asthma between the ages of 4 and 11 years.In this trial, XOPENEX HFA (76 patients) was compared to a placebo HFA-134a MDI (35 patients), and the trial included a marketed albuterol HFA-134a MDI (39 patients) as an active control. Serial FEV1 measurements demonstrated that 90 mcg (2 inhalations) of XOPENEX HFA produced significantly greater improvement in FEV1 over the pretreatment value than placebo and were consistent with the efficacy findings in the adult studies.
For XOPENEX HFA, on Day 1 the median time to onset of a 15% increase in FEV1 was 4.5 minutes and the median time to peak effect was 77 minutes. In the responder population, the median duration of effect as measured by a 15% increase in FEV1 was 3 hours, with a duration of effect in some pediatric patients of up to 6 hours.
Last reviewed on RxList: 8/8/2012
This monograph has been modified to include the generic and brand name in many instances.
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