Albuterol Sulfate Inhalation 90 ug Inhalant — NDC 69238-1291-1 (Billing 69238-1291-01) · Product 69238-1291

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Albuterol sulfate is a beta 2 -adrenergic agonist. The pharmacologic effects of albuterol sulfate are attributable to activation of beta 2 -adrenergic receptors on airway smooth muscle. Activation of beta 2 -adrenergic receptors leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3', 5’-adenosine monophosphate (cyclic AMP).

This increase of 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. Albuterol relaxes the smooth muscle of all airways, from the trachea to the terminal bronchioles. Albuterol 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 beta 2 -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 cardiac beta 2 -adrenergic receptors. The precise function of these receptors has not been established [see Warnings and Precautions ( 5.4 )] .

Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. However, inhaled albuterol, like other 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 [see Warnings and Precautions ( 5.4 )] .

12.2Pharmacokinetics The systemic levels of albuterol are low after inhalation of recommended doses. In a crossover study conducted in healthy male and female volunteers, high cumulative doses of Albuterol Sulfate Inhalation Aerosol (1,080 mcg of albuterol base administered over one hour) yielded mean peak plasma concentrations (C max ) and systemic exposure (AUC inf ) of approximately 4,100 pg/mL and 28,426 pg/mL*hr, respectively compared to approximately 3,900 pg/mL and 28,395 pg/mL*hr, respectively following the same dose of an active HFA-134a albuterol inhaler comparator.

The terminal plasma half-life of albuterol delivered by Albuterol Sulfate Inhalation Aerosol was approximately 6 hours. Comparison of the pharmacokinetic parameters demonstrated no differences between the products. The pharmacokinetic profile of Albuterol Sulfate Inhalation Aerosol was evaluated in a two-way cross-over study in 11 healthy pediatric volunteers, 4 to 11 years of age.

A single dose administration of Albuterol Sulfate Inhalation Aerosol (180 mcg albuterol base) yielded a least square mean (SE) C max and AUC 0- ∞ of 1,100 (1.18) pg/mL and 5,120 (1.15) pg/mL*hr, respectively. The least square mean (SE) terminal plasma half-life of albuterol delivered by Albuterol Sulfate Inhalation Aerosol was 166 (7.8) minutes. Metabolism and Elimination: Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (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 the (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULTIA3.

The primary route of elimination of albut… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Albuterol sulfate is a beta 2 -adrenergic agonist. The pharmacologic effects of albuterol sulfate are attributable to activation of beta 2 -adrenergic receptors on airway smooth muscle. Activation of beta 2 -adrenergic receptors leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3', 5’-adenosine monophosphate (cyclic AMP).

This increase of 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. Albuterol relaxes the smooth muscle of all airways, from the trachea to the terminal bronchioles. Albuterol 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 beta 2 -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 cardiac beta 2 -adrenergic receptors. The precise function of these receptors has not been established [see Warnings and Precautions ( 5.4 )] .

Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. However, inhaled albuterol, like other 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 [see Warnings and Precautions ( 5.4 )] .

12.2Pharmacokinetics The systemic levels of albuterol are low after inhalation of recommended doses. In a crossover study conducted in healthy male and female volunteers, high cumulative doses of Albuterol Sulfate Inhalation Aerosol (1,080 mcg of albuterol base administered over one hour) yielded mean peak plasma concentrations (C max ) and systemic exposure (AUC inf ) of approximately 4,100 pg/mL and 28,426 pg/mL*hr, respectively compared to approximately 3,900 pg/mL and 28,395 pg/mL*hr, respectively following the same dose of an active HFA-134a albuterol inhaler comparator.

The terminal plasma half-life of albuterol delivered by Albuterol Sulfate Inhalation Aerosol was approximately 6 hours. Comparison of the pharmacokinetic parameters demonstrated no differences between the products. The pharmacokinetic profile of Albuterol Sulfate Inhalation Aerosol was evaluated in a two-way cross-over study in 11 healthy pediatric volunteers, 4 to 11 years of age.

A single dose administration of Albuterol Sulfate Inhalation Aerosol (180 mcg albuterol base) yielded a least square mean (SE) C max and AUC 0- ∞ of 1,100 (1.18) pg/mL and 5,120 (1.15) pg/mL*hr, respectively. The least square mean (SE) terminal plasma half-life of albuterol delivered by Albuterol Sulfate Inhalation Aerosol was 166 (7.8) minutes. Metabolism and Elimination: Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (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 the (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULTIA3.

The primary route of elimination of albuterol is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected 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.

Geriatric, Pediatric, Hepatic/Renal Impairment: No pharmacokinetic studies for Albuterol Sulfate Inhalation Aerosol have been conducted in neonates or elderly subjects. The effect of hepatic impairment on the pharmacokinetics of Albuterol Sulfate Inhalation Aerosol has not been evaluated. The effect of renal impairment on the pharmacokinetics of 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 albuterol clearance. Caution should be used when administering high doses of Albuterol Sulfate Inhalation Aerosol to patients with renal impairment [see Use in Specific Populations ( 8.5 )] .

14 CLINICAL STUDIES

14.1Bronchospasm Associated with Asthma Adult and Adolescent Patients 12 Years of Age and Older: In a 6-week, randomized, double-blind, placebo-controlled trial, Albuterol Sulfate Inhalation Aerosol (58 patients) was compared to a matched placebo HFA inhalation aerosol (58 patients) in asthmatic patients 12 to 76 years of age at a dose of 180 mcg albuterol four times daily. An evaluator-blind marketed active comparator HFA-134a albuterol inhaler arm (56 patients) was included. Serial FEV 1 measurements, shown below as percent change from test-day baseline at Day 1 and at Day 43, demonstrated that two inhalations of Albuterol Sulfate Inhalation Aerosol produced significantly greater improvement in FEV 1 over the pre-treatment value than the matched placebo, as well as a comparable bronchodilator effect to the marketed active comparator HFA-134a albuterol inhaler.

FEV 1 as Mean Percent Change from Test-Day Pre-Dose in a 6-Week Clinical Trial Day 1 Day 43 In this study, 31 of 58 patients treated with Albuterol Sulfate Inhalation Aerosol achieved a 15% increase in FEV 1 within 30 minutes post-dose on Day 1. In these patients, the median time to onset, median time to peak effect, and median duration of effect were 8.2 minutes, 47 minutes, and approximately 3 hours, respectively. In some patients, the duration of effect was as long as 6 hours.

In a placebo-controlled, single-dose, crossover study, Albuterol Sulfate Inhalation Aerosol, administered at albuterol doses of 90, 180 and 270 mcg, produced bronchodilator responses significantly greater than those observed with a matched placebo HFA inhalation aerosol and comparable to a marketed active comparator HFA-134a albuterol inhaler. Pediatric Patients 4 to 11 Years of Age: In a 3-week, randomized, double-blind, placebo-controlled trial, the same formulation of albuterol as in Albuterol Sulfate Inhalation Aerosol (50 patients) was compared to a matched placebo HFA inhalation aerosol (45 patients) in asthmatic children 4 to 11 years of age at a dose of 180 mcg albuterol four times daily.

Serial FEV 1 measurements, expressed as the maximum percent change from test-day baseline in percent predicted FEV 1 at Day 1 and at Day 22 observed within two hours post-dose, demonstrated that two inhalations of HFA albuterol sulfate produced significantly greater improvement in FEV 1 over the pre-treatment value than the matched placebo. In this study, 21 of 50 pediatric patients treated with the same formulation of albuterol as in Albuterol Sulfate Inhalation Aerosol achieved a 15% increase in FEV 1 within 30 minutes post-dose on Day 1.

In these patients, the median time to onset, median time to peak effect and median duration of effect were 10 minutes, 31 minutes, and approximately 4 hours, respectively. In some pediatric patients, the duration of effect was as long as 6 hours. In a placebo-controlled, single-dose, crossover study in 55 pediatric patients 4 to 11 years of age, Albuterol Sulfate Inhalation Aerosol, administered at albuterol doses of 90 and 180 mcg, was compared with a matched placebo HFA inhalation aerosol.

Serial FEV 1 measurements, expressed as the baseline-adjusted percent predicted FEV 1 observed over 6 hours post-dose, demonstrated that one and two inhalations of Albuterol Sulfate Inhalation Aerosol produced significantly greater bronchodilator responses than the matched placebo. day 1 figure day 43 figure

14.2Exercise-Induced Bronchospasm In a randomized, single-dose, crossover study in 24 adults and adolescents with exercise-induced bronchospasm (EIB), two inhalations of Albuterol Sulfate HFA taken 30 minutes before exercise prevented EIB for the hour following exercise (defined as maintenance of FEV 1 within 80% of post-dose, pre-exercise baseline values) in 83% (20 of 24) of patients as compared to 25% (6 of 24) of patients when they received placebo. Some patients who participated in these clinical trials were using concomitant steroid therapy.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a dose-related increase in the incidence of benign leiomyomas of the mesovarium at and above dietary doses of 2 mg/kg (approximately 15 times and 6 times the maximum recommended human daily inhalation dose (MRHDID) for adults and children, respectively, on a mg/m 2 basis). In another study this effect was blocked by the co-administration of propranolol, a non-selective beta-adrenergic antagonist.

In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 500 mg/kg (approximately 1,900 times and 740 times the MRHDID for adults and children, respectively, on a mg/m 2 basis). In a 22-month study in Golden Hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 50 mg/kg (approximately 250 times and 100 times the MRHDID for adults and children, respectively, on a mg/m 2 basis). Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast.

Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay. Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately 380 times the MRHDID for adults on a mg/m 2 basis).

13.2Animal Toxicology and/or Pharmacology Preclinical: Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% 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 β-agonists and methylxanthines were 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 (T max ) and mean residence time are both extremely short leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation.