AIRSUPRA Albuterol sulfate and budesonide 90 ug; 80 ug Aerosol, Metered — NDC 0310-9080-12 (Billing 00310-9080-12)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action AIRSUPRA contains both albuterol and budesonide; therefore, the mechanisms of action described below for the individual components apply to AIRSUPRA. These drugs represent two classes of medications (a short-acting selective beta 2 -adrenergic agonist and a synthetic corticosteroid) that have different effects on clinical, physiological, and inflammatory indices of asthma. Albuterol In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol.

Although beta 2 -adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -adrenoceptors are the predominant receptors in the heart, there are also beta 2 -adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta 2 -agonists may have cardiac effects. Activation of beta 2 -adrenergic receptors on airway smooth muscle leads to the activation of adenyl cyclase and to an increase in the intracellular concentration of cyclic-3′,5′-adenosine monophosphate (cyclic AMP).

This increase of 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. Albuterol relaxes the smooth muscles 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. 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. Controlled clinical studies and other clinical experience have shown that 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 (5.3) ] .

Budesonide Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay.

The clinical significance of this is unknown. In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert.

The precise mechanism of corticosteroid actions on inflammation in asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation.

These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and both genomic and non-genomic systemic corticosteroid effects over a wide range of doses of inhaled bu… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action AIRSUPRA contains both albuterol and budesonide; therefore, the mechanisms of action described below for the individual components apply to AIRSUPRA. These drugs represent two classes of medications (a short-acting selective beta 2 -adrenergic agonist and a synthetic corticosteroid) that have different effects on clinical, physiological, and inflammatory indices of asthma. Albuterol In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol.

Although beta 2 -adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -adrenoceptors are the predominant receptors in the heart, there are also beta 2 -adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta 2 -agonists may have cardiac effects. Activation of beta 2 -adrenergic receptors on airway smooth muscle leads to the activation of adenyl cyclase and to an increase in the intracellular concentration of cyclic-3′,5′-adenosine monophosphate (cyclic AMP).

This increase of 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. Albuterol relaxes the smooth muscles 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. 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. Controlled clinical studies and other clinical experience have shown that 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 (5.3) ] .

Budesonide Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay.

The clinical significance of this is unknown. In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert.

The precise mechanism of corticosteroid actions on inflammation in asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation.

These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and both genomic and non-genomic systemic corticosteroid effects over a wide range of doses of inhaled budesonide. This is explain… [Excerpted — this section continues on DailyMed.]

12.3Pharmacokinetics The pharmacokinetics of AIRSUPRA and its individual components were evaluated in 3 studies in subjects 18 years of age and older (2 studies in healthy subjects and 1 study in patients with asthma). The pharmacokinetics of albuterol and budesonide from AIRSUPRA are comparable to the pharmacokinetics of albuterol and budesonide when administered as single dose of the individual components in studies of healthy subjects. The pharmacokinetics presented below are primarily from studies conducted on AIRSUPRA and on its individual components, albuterol (AS MDI) and budesonide (BD MDI), also administered by the inhaled route.

Absorption Albuterol Healthy Subjects : Following inhaled administration of AIRSUPRA 180 mcg/160 mcg (administered as 2 inhalations of 90 mcg/80 mcg), the median t max of albuterol was 1.00 hour (individual values ranged from 0.08 to 6.05 hours). Geometric mean C max was 472.2 pg/mL (individual values ranged from 38.4 to 971 pg/mL). Asthma Patients : Following increasing cumulative doses (a total dose of 1440 mcg) of albuterol (AS MDI) and an active albuterol aerosol inhaler comparator in patients with asthma, mean albuterol plasma concentrations (at 15 minutes after dose) increased from predose levels (44.2 and 51.4 pg/mL) to 3278.0 pg/mL and 5241.7 pg/mL with AS MDI and the comparator, respectively.

Results from this study indicate the total systemic exposure of albuterol was 21% (for AUC) and 27% (for C max ) lower for AS MDI than for the comparator. Budesonide Healthy Subjects : Following inhaled administration in healthy subjects of AIRSUPRA 180 mcg/160 mcg (administered as 2 inhalations of 90 mcg/80 mcg), the median t max of budesonide was 0.33 hours (individual values ranged from 0.08 to 4.00 hours). Geometric mean C max was 272.8 pg/mL (individual values ranged from 51.7 to 819 pg/mL).

Systemic exposure to budesonide with AIRSUPRA did not exceed that from inhaled budesonide via a dry powder inhaler comparator in healthy subjects. Distribution Albuterol Healthy Subjects : Following inhaled administration of AIRSUPRA 180 mcg/160 mcg (administered as 2 inhalations of 90 mcg/80 mcg), the mean apparent volume of distribution (Vz/F) of albuterol was 565.7 L. Budesonide Healthy Subjects : Following inhaled administration of AIRSUPRA 180 mcg/160 mcg (administered as 2 inhalations of 90 mcg/80 mcg), the mean apparent volume of distribution (Vz/F) of budesonide administered in AIRSUPRA was 1002 L.

Budesonide was 85-90% bound to plasma proteins. Protein binding was constant over the concentration range of 1‑100 nmol/L. Budesonide showed little or no binding to corticosteroid binding globulin.

Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8. Elimination Following inhaled single-dose administration with AIRSUPRA in healthy subjects, the mean terminal half-life of albuterol was estimated to be 7.1 hours (individual values ranged from 4.62 to 10.0 hours) and the mean terminal half-life of budesonide was estimated to be 4.1 hours (individual values ranges from 2.46 to 6.15 hours). Metabolism Albuterol Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (sulfotransferase).

Budesonide In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16α-hydroxyprednisolone and 6β-hydroxybudesonide. The corticosteroid activity of each of these two metabolites is less than 1% of that of the parent compound.

No qualitative differences between the in vitro and in vivo metabolic patterns have been detected. Negligible metabolic inactivation was observed in human lung and serum preparations. Excretion Albuterol The primary route of elimination of… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Albuterol 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. Controlled clinical studies and other clinical experience have shown that 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 (5.3) ] .

Budesonide The therapeutic effects of conventional doses of orally inhaled budesonide are largely explained by its direct local action on the respiratory tract. Inhaled budesonide has been shown to decrease airway reactivity in various challenge models, including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate in patients with hyperreactive airways. The clinical relevance of these models is not certain.

HPA Axis Effects AIRSUPRA, like other inhaled corticosteroid products, may impact the HPA axis, especially in susceptible individuals, in younger children, and in patients given high doses for prolonged periods [see Warnings and Precautions (5.10) ] . The effects of AIRSUPRA on hypothalamic-pituitary-adrenal (HPA) axis were not studied in dedicated clinical trials. The effects of inhaled AIRSUPRA 180 mcg/160 mcg and AS-BD MDI 180 mcg/80 mcg administered as 2 inhalations of 90 mcg/80 mcg or 90 mcg/40 mcg as needed in response to symptoms were studied on morning serum cortisol in 1254 patients with asthma between the ages of 4 and 84 years in MANDALA.

Morning serum cortisol was collected at baseline, Week 24, end of study, or time of discontinuation. Morning cortisol concentration changes over time varied across treatment groups with mean changes from baseline to the Week 24 visit of ‑1.52 nmol/L, +5.43 nmol/L, and +15.42 nmol/L in the AIRSUPRA 180 mcg/160 mcg, AS-BD MDI 180 mcg/80 mcg, and AS MDI 180 mcg treatment groups, respectively.

14 CLINICAL STUDIES The efficacy of AIRSUPRA was evaluated in MANDALA, DENALI and BATURA as described below. While patients 12 to 17 years of age were included in these trials, AIRSUPRA is not approved in this age group; therefore, efficacy results are presented for adults only. MANDALA The efficacy of AIRSUPRA 180 mcg/160 mcg was evaluated in patients 12 years of age and older with asthma in MANDALA (NCT03769090), a randomized, double-blind, multicenter study.

MANDALA was a variable length exacerbation study with at least 24 weeks duration. Patients 12 years of age and older were randomized (1:1:1) and received at least one dose of AIRSUPRA (AS-BD MDI 180 mcg/160 mcg), albuterol/budesonide (AS-BD MDI 180 mcg/80 mcg) or albuterol (AS MDI 180 mcg) as needed. Patients were required to be receiving medium to high dose ICS (inhaled corticosteroid) or low to high dose ICS/long-acting beta 2 -adrenergic agonists (LABA), with or without another controller medicine as maintenance therapy.

All patients continued their own maintenance therapy throughout the trial. MANDALA was conducted in symptomatic patients with a history of at least 1 severe asthma exacerbation in the year prior to screening, pre-bronchodilator FEV 1 40 to < 90% of predicted normal (for patients aged 12 to < 18 years old, ≥ 60%) and a confirmed reversibility to albuterol. The adult efficacy population (n=2940) in MANDALA had a mean age of 52 years (range: 18-84 years), with 66% female and 82% White, and 25% of Hispanic or Latino ethnicity.

The median duration of asthma was 21 years (range: 1 to 80 years) since the first diagnosis of asthma. The mean pre-bronchodilator percent predicted FEV 1 was 63% (range: 33% - 101%). The overall patterns of use of AIRSUPRA and AS MDI 180 mcg were similar during the randomized treatment period.

The primary efficacy endpoint was the time to first severe asthma exacerbation (defined as worsening or onset of asthma symptoms that required systemic corticosteroids for at least 3 days or an emergency room visit that led to the use of systemic corticosteroids for at least 3 days or a hospitalization for at least 24 hours due to asthma). Efficacy results are shown for only the approved adult population. Treatment with AIRSUPRA, compared with AS MDI 180 mcg, demonstrated statistically significant reductions in the risk of severe asthma exacerbations among adult patients, as assessed by the time to first severe asthma exacerbation as described in Figure 1.

Compared with AS MDI 180 mcg, patients receiving AIRSUPRA experienced a statistically significant 28% reduction (Hazard Ratio [HR]: 0.72; 95% CI: 0.60, 0.86) in the risk of a severe asthma exacerbation (p<0.001). Figure 1. Kaplan-Meier Cumulative Incidence Curve for Time to First Exacerbation (MANDALA) 1 There were reductions in severe asthma exacerbation risk regardless of exacerbation history (1 or > 1 in the past year), baseline lung function, and asthma severity (defined by background maintenance therapy) compared with AS MDI 180 mcg.

Treatment with AIRSUPRA 180 mcg/160 mcg statistically significantly reduced the annual rate of severe asthma exacerbations by 24% compared with AS MDI 180 mcg as shown in Table 2. Table 2 Annualized Rate of Severe Asthma Exacerbations (MANDALA) Analysis Group N n Number of Severe Exacerbations Annualized Rate Rate Ratio vs AS MDI (95% CI) P-value AIRSUPRA 180 mcg/160 mcg ≥ 18 years 979 198 (20%) 324 0.46 0.76 (0.62, 0.93) 0.008 AS MDI 180 mcg ≥ 18 years 980 259 (26%) 403

0.60N = number of adults in the efficacy population; n = number of adults who experienced at least one severe exacerbation The annualized total systemic corticosteroid (SCS) dose due to asthma was calculated for each patient during the study period. For patients treated with AIRSUPRA 180 mcg/160 mcg the annualized total SCS dose when compared with AS MDI 180 mcg was statistically significantly different, with a reduction in mean annualized dose of 40 mg per patient [AIRSUPRA (87 mg) vs A… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with AIRSUPRA; however, available studies for the individual components, albuterol and budesonide, are described below. Findings are reported based on the MRHDID for albuterol and budesonide contained in AIRSUPRA. Albuterol 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/day (approximately 15 times the MRHDID for adults on a mg/m 2 basis).

In another study this effect was blocked by the coadministration of propranolol, a nonselective 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/day (approximately 1,900 times the MRHDID for adults 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/day (approximately 250 times the MRHDID for adults 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/day (approximately 380 times the MRHDID for adults on a mg/m 2 basis).

Budesonide In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats receiving an oral dose of 50 mcg/kg/day (approximately 0.5 times the MRHDID in adults on a mcg/m 2 basis). No tumorigenicity was seen in male rats at oral doses up to 25 mcg/kg/day (approximately 0.5 times the MRHDID in adults on a mcg/m 2 basis) and in female rats at oral doses up to 50 mcg/kg/day (approximately 0.5 times the MRHDID doses in adults on a mcg/m 2 basis).

In two additional 2-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg/day (approximately 0.5 times the MRHDID in adults on a mcg/m 2 basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg/day (approximately 0.5 times the MRHDID in adults on a mcg/m 2 basis). The concurrent reference corticosteroids (prednisone and triamcinolone acetonide) in these two studies showed similar findings.

There was no evidence of a carcinogenic effect when budesonide was administered orally for 91 weeks to mice at doses up to 200 mcg/kg/day (equal to the MRHDID in adults on a mcg/m 2 basis). Budesonide was not mutagenic or clastogenic in six different test systems: Ames Salmonella /microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster , and DNA repair analysis in rat hepatocyte culture. Fertility and reproductive performance were unaffected in rats at subcutaneous doses up to 80 mcg/kg/day (approximately 0.8 times the MRHDID in adults on a mcg/m 2 basis).

At a subcutaneous dose of 20 mcg/kg/day (approximately 0.2 times the MRHDID in adults on a mcg/m 2 basis), decreases in maternal body weight gain, prenatal viability, and viability of the young at birth and during lactation were observed. No such effects were noted at 5 mcg/kg/day (approximately 0.05 times the MRHDID in adults on a mcg/m 2 basis).