Levalbuterol tartrate HFA inhalation 45 ug Aerosol, Metered — NDC 63187-876-15 (Billing 63187-0876-15)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Activation of beta 2 -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 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 beta 2 -adrenergic receptors.

The precise function of these receptors has not been established [see Warnings and Precautions (5) ]. 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.

12.2Pharmacokinetics 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 Levalbuterol tartrate HFA inhalation aerosol, yielded mean peak plasma concentrations (C max ) and systemic exposure (AUC 0-6 ) 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 Levalbuterol tartrate HFA inhalation aerosol, yielded C max and AUC 0-6 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 Levalbuterol tartrate HFA inhalation aerosol 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 (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 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. Special Populations Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of Levalb… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Activation of beta 2 -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 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 beta 2 -adrenergic receptors.

The precise function of these receptors has not been established [see Warnings and Precautions (5) ]. 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.

12.2Pharmacokinetics 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 Levalbuterol tartrate HFA inhalation aerosol, yielded mean peak plasma concentrations (C max ) and systemic exposure (AUC 0-6 ) 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 Levalbuterol tartrate HFA inhalation aerosol, yielded C max and AUC 0-6 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 Levalbuterol tartrate HFA inhalation aerosol 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 (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 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. Special Populations Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of Levalbuterol tartrate HFA inhalation aerosol has not been evaluated. Renal Impairment 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 Levalbuterol tartrate HFA inhalation aerosol to patients with renal impairment [see Use in Specific Populations (8.6)] .

6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults and Adolescents 12 Years of Age and Older Adverse reaction information concerning Levalbuterol tartrate HFA inhalation aerosol in adults and adolescents is derived from two 8-week, multicenter, randomized, double-blind, active- and placebo-controlled trials in 748 adult and adolescent patients with asthma that compared Levalbuterol tartrate HFA inhalation aerosol, a marketed albuterol HFA inhaler, and an HFA-134a placebo inhaler.

Table 1 lists the incidence of all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from these trials that occurred at a rate of 2% or greater in the group treated with Levalbuterol tartrate HFA inhalation aerosol and more frequently than in the HFA-134a placebo inhaler group. Table 1: Adverse Reaction Incidence (% of Patients) in Two 8-Week Clinical Trials in Adults and Adolescents ≥ 12 Years of Age* Body System Preferred Term Levalbuterol tartrate HFA inhalation aerosol 90 mcg (n=403) Racemic Albuterol HFA 180 mcg (n=179) Placebo (n=166) Body as a Whole Pain 4% 3% 4% Central Nervous System Dizziness 3% 1% 2% Respiratory System Asthma 9% 7% 6% Pharyngitis 8% 2% 2% Rhinitis 7% 2% 3% * This table includes all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from these trials that occurred at a rate of 2% or greater in the group treated with Levalbuterol tartrate HFA inhalation aerosol and more frequently than in the HFA-134a placebo inhaler group.

Adverse reactions reported by less than 2% and at least 2 or more of the adolescent and adult patients receiving Levalbuterol tartrate HFA inhalation aerosol and by a greater proportion than receiving HFA-134a placebo inhaler include cyst, flu syndrome, viral infection, constipation, gastroenteritis, myalgia, hypertension, epistaxis, lung disorder, acne, herpes simplex, conjunctivitis, ear pain, dysmenorrhea, hematuria, and vaginal moniliasis. There were no significant laboratory abnormalities observed in these studies.

Pediatric Patients 4 to 11 Years of Age Adverse reaction information concerning Levalbuterol tartrate HFA inhalation aerosol in children is derived from a 4-week, randomized, double-blind trial of Levalbuterol tartrate HFA inhalation aerosol, a marketed albuterol HFA inhaler, and an HFA-134a placebo inhaler in 150 children aged 4 to 11 years with asthma. Table 2 lists the adverse reactions reported for Levalbuterol tartrate HFA inhalation aerosol in children at a rate of 2% or greater and more frequently than for placebo.

Table 2: Adverse Reaction Incidence (% of Patients) in a 4-Week Clinical Trial in Children 4-11 Years of Age* Body System Preferred Term Levalbuterol tartrate HFA inhalation aerosol 90 mcg (n=76) Racemic Albuterol HFA 180 mcg (n=39) Placebo (n=35) Body as a Whole Accidental injury 9% 10% 6% Digestive System Vomiting 11% 8% 6% Respiratory System Bronchitis 3% 0% 0% Pharyngitis 7% 13% 6% * This table includes all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from the trial that occurred at a rate of 2% or greater in the group treated with Levalbuterol tartrate HFA inhalation aerosol and more frequently than in the HFA-134a placebo inhaler group.

The incidence of systemic beta-adrenergic adverse reactions (e.g., tremor, nervousness) was low and comparable across all treatment groups, including placebo.

14 CLINICAL STUDIES

14.1Bronchospasm Associated with Asthma Adults and Adolescent Patients 12 Years of Age and Older The efficacy and safety of Levalbuterol tartrate HFA inhalation aerosol were established in two 8-week, multicenter, randomized, double-blind, active- and placebo-controlled trial… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Although there have been no carcinogenesis studies with levalbuterol tartrate, racemic albuterol sulfate has been evaluated for its carcinogenic potential. In a 2-year study in Sprague-Dawley rats, dietary administration of racemic albuterol sulfate resulted in a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at doses of 2 mg/kg/day and greater (approximately 30 times the MRDI) dose of levalbuterol tartrate for adults and approximately 15 times the MRDI dose of levalbuterol tartrate for children on a mg/m 2 basis).

In an 18-month study in CD-1 mice and a 22-month study in the golden hamster, dietary administration of racemic albuterol sulfate showed no evidence of tumorigenicity. Dietary doses in CD-1 mice were up to 500 mg/kg/day (approximately 3800 times the MRDI dose of levalbuterol tartrate for adults and approximately 1800 times the MRDI dose of levalbuterol tartrate for children on a mg/m 2 basis) and doses in the golden hamster study were up to 50 mg/kg/day (approximately 500 times the MRDI dose of levalbuterol tartrate for adults on a mg/m 2 basis and approximately 240 times the MRDI dose of levalbuterol tartrate for children on a mg/m 2 basis).

Levalbuterol HCl was not mutagenic in the Ames test or the CHO/HPRT Mammalian Forward Gene Mutation Assay. Levalbuterol HCl was not clastogenic in the in vivo micronucleus test in mouse bone marrow. Racemic albuterol sulfate was not clastogenic in an in vitro chromosomal aberration assay in CHO cell cultures.

No fertility studies have been conducted with levalbuterol tartrate. Reproduction studies in rats using racemic albuterol sulfate demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg/day (approximately 750 times the maximum recommended daily inhalation dose of levalbuterol tartrate for adults on a mg/m 2 basis).

13.2Animal Toxicology and/or Pharmacology Propellant HFA-134a 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. 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.