Breztri budesonide, glycopyrrolate, and formoterol fumarate 160 ug; 18 ug; 4.8 ug Aerosol, Metered, 120-count — NDC 0310-6616-01 (Billing 00310-6616-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action BREZTRI AEROSPHERE BREZTRI AEROSPHERE contains budesonide, glycopyrrolate, and formoterol fumarate. The mechanism of action described below for the individual components applies to BREZTRI AEROSPHERE. These drugs represent three different classes of medications (a synthetic corticosteroid, an anticholinergic, and a long-acting selective beta 2 -adrenoceptor agonist) that have different effects on clinical physiology and inflammatory indices of COPD and asthma.

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.

In glucocorticoid receptor affinity studies, the 22R epimer of budesonide was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert. Inflammation is an important component in the pathogenesis of COPD and 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. Glycopyrrolate Glycopyrrolate is a long-acting antimuscarinic agent which is often referred to as an anticholinergic.

It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of the M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations.

In preclinical in vitro as well as in vivo studies, prevention of methylcholine and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted more than 12 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of glycopyrrolate is predominantly a site-specific effect.

Formoterol Fumarate Formoterol fumarate is a long-acting selective beta 2 -adrenergic agonist (beta 2 -agonist) with a rapid onset of action. Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta 2 -receptors than at beta 1 -receptors.

The in vitro binding selectivity to beta 2 - over beta 1 -adrenoceptors is higher for formoterol than for albuterol (5 times), whereas salmeterol has a higher (3 times) beta 2 -selectivity ratio than formoterol. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta 2 -agonists may have cardiac effects.

The pharmacologic effects of beta 2 -adrenoceptor agonist drugs, including formoterol fumarate, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypers… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action BREZTRI AEROSPHERE BREZTRI AEROSPHERE contains budesonide, glycopyrrolate, and formoterol fumarate. The mechanism of action described below for the individual components applies to BREZTRI AEROSPHERE. These drugs represent three different classes of medications (a synthetic corticosteroid, an anticholinergic, and a long-acting selective beta 2 -adrenoceptor agonist) that have different effects on clinical physiology and inflammatory indices of COPD and asthma.

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.

In glucocorticoid receptor affinity studies, the 22R epimer of budesonide was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert. Inflammation is an important component in the pathogenesis of COPD and 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. Glycopyrrolate Glycopyrrolate is a long-acting antimuscarinic agent which is often referred to as an anticholinergic.

It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of the M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations.

In preclinical in vitro as well as in vivo studies, prevention of methylcholine and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted more than 12 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of glycopyrrolate is predominantly a site-specific effect.

Formoterol Fumarate Formoterol fumarate is a long-acting selective beta 2 -adrenergic agonist (beta 2 -agonist) with a rapid onset of action. Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta 2 -receptors than at beta 1 -receptors.

The in vitro binding selectivity to beta 2 - over beta 1 -adrenoceptors is higher for formoterol than for albuterol (5 times), whereas salmeterol has a higher (3 times) beta 2 -selectivity ratio than formoterol. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta 2 -agonists may have cardiac effects.

The pharmacologic effects of beta 2 -adrenoceptor agonist drugs, including formoterol fumarate, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, es… [Excerpted — this section continues on DailyMed.]

12.3Pharmacokinetics Linear pharmacokinetics were demonstrated for budesonide (80 to 320 mcg), glycopyrrolate (18 to 144 mcg), and formoterol fumarate (2.4 to 38.4 mcg). Pharmacokinetic information for glycopyrrolate and formoterol fumarate is for the active moieties, glycopyrronium and formoterol, respectively. The pharmacokinetics of budesonide, glycopyrronium, and formoterol from BREZTRI AEROSPHERE are comparable to the pharmacokinetics of budesonide, glycopyrronium, and formoterol when administered as budesonide/formoterol or glycopyrrolate/formoterol in studies of healthy subjects (single dose) and subjects with COPD (repeated dose).

The pharmacokinetics of the individual components of BREZTRI AEROSPHERE are presented below. Absorption Budesonide: Following inhaled administration of BREZTRI AEROSPHERE in subjects with COPD or asthma, C max occurred within 20 to 40 minutes. Steady state is estimated to be achieved after approximately 1 day of repeated dosing of BREZTRI AEROSPHERE via population pharmacokinetic analysis in subjects with COPD and the AUC 0-12 is approximately 1.3 times higher than after the first dose.

Glycopyrrolate : Following inhaled administration of BREZTRI AEROSPHERE in subjects with COPD or asthma, C max occurred within 2 to 6 minutes. Steady state is estimated to be achieved after approximately 3 days of repeated dosing of BREZTRI AEROSPHERE via population pharmacokinetic analysis in subjects with COPD and the AUC 0-12 is approximately 1.8 times higher than after the first dose. Formoterol Fumarate: Following inhaled administration of BREZTRI AEROSPHERE in subjects with COPD or asthma, C max occurred within 20 to 90 minutes.

Steady state is estimated to be achieved after approximately 2 days of repeated dosing with BREZTRI AEROSPHERE via population pharmacokinetic analysis in subjects with COPD and the AUC 0-12 is approximately 1.4 times higher than after the first dose. Distribution Budesonide : The estimated budesonide apparent volume of distribution at steady-state in subjects with COPD is approximately 1200 L, via population pharmacokinetic analysis. Over the concentration range of 1-100 nmol/L, mean plasma protein binding of budesonide ranged from 86% to 87%.

Glycopyrrolate: The estimated glycopyrronium apparent volume of distribution at steady-state in subjects with COPD is approximately 5500 L, via population pharmacokinetic analysis. Over the concentration range of 2-500 nmol/L, plasma protein binding of glycopyrronium ranged from 43% to 54%. Formoterol Fumarate: The estimated formoterol apparent volume of distribution at steady-state in subjects with COPD is approximately 2400 L, via population pharmacokinetic analysis.

Over the concentration range of 10-500 nmol/L, plasma protein binding of formoterol ranged from 46% to 58%. Elimination Budesonide: Budesonide was excreted in urine and feces in the form of metabolites. Only negligible amounts of unchanged budesonide have been detected in the urine.

The effective half-life of budesonide in subjects with COPD derived via population pharmacokinetic analysis was approximately 5 hours. Glycopyrrolate: After IV administration of a 0.2 mg radiolabeled glycopyrronium, 85% of dose recovered was recovered in urine 48 hours post-dose and some of radioactivity was also recovered in bile. The effective half-life of glycopyrronium in subjects with COPD derived via population pharmacokinetics analysis was approximately 15 hours.

Formoterol Fumarate: The excretion of formoterol was studied in six healthy subjects following simultaneous administration of radiolabeled formoterol via the oral and IV routes. In that study, 62% of the drug related radioactivity of formoterol was excreted in the urine while 24% was eliminated in the feces. The effective half-life of formoterol in subjects with COPD derived via population pharmacokinetics analysis was approximately 10 hours.

Metabolism Budesonide : In vitro studies with human liver homogenates have shown that bud… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology A TQT study was not performed with BREZTRI AEROSPHERE as budesonide is not known to affect the QT interval. However, the potential for QTc interval prolongation with glycopyrrolate/formoterol fumarate was assessed in a double-blind, single-dose, placebo- and positive-controlled crossover trial in 69 healthy subjects. The largest mean (90% upper confidence bound) differences from placebo in baseline-corrected QTcI for 2 inhalations of glycopyrrolate/formoterol fumarate 9/4.8 mcg and glycopyrrolate/formoterol fumarate 72/19.2 mcg, were 3.1 (4.7) ms and 7.6 (9.2) ms, respectively, and excluded the clinically relevant threshold of 10 ms.

A dose-dependent increase in heart rate was also observed. The largest mean (90% upper confidence bound) differences from placebo in baseline-corrected heart rate were 3.3 (4.9) beats/min and 7.6 (9.5) beats/min seen within 10 minutes of dosing with 2 inhalations of glycopyrrolate/formoterol fumarate 9/4.8 mcg and glycopyrrolate/formoterol fumarate 72/19.2 mcg, respectively. Chronic Obstructive Pulmonary Disease The effects of BREZTRI AEROSPHERE on cardiac rhythm in subjects with COPD was assessed using 24-hour Holter monitoring at Week 16 in ETHOS.

The Holter monitoring population in ETHOS included 180 subjects on BREZTRI AEROSPHERE 320 mcg/18 mcg/9.6 mcg, 160 subjects on glycopyrrolate and formoterol fumarate (GFF MDI 18 mcg/9.6 mcg), and 183 subjects on budesonide/formoterol fumarate (BFF MDI 320 mcg/9.6 mcg). No clinically meaningful effects on cardiac rhythm were observed. Asthma The effects of BREZTRI AEROSPHERE on cardiac rhythm in subjects with asthma was assessed using 24-hour Holter monitoring at Week 4 or Week 24 in KALOS.

The Holter monitoring population in KALOS included 44 subjects on BREZTRI AEROSPHERE 320 mcg/36 mcg/9.6 mcg, 56 subjects on budesonide and formoterol fumarate (BFF MDI) 320 mcg/9.6 mcg, and 36 subjects on budesonide/formoterol fumarate (BUD/FORM MDI) 320 mcg/9 mcg. No clinically meaningful effects on cardiac rhythm were observed. HPA Axis Effects Effects of BREZTRI AEROSPHERE on the HPA axis were assessed by measurement of 24-hour serum cortisol at Baseline and Week 24 in subjects with COPD.

The geometric mean ratio (Week 24/Baseline) was 0.86 (Co-efficient of variation (CV) =39%) and 0.94 (CV=36.6%) for BREZTRI AEROSPHERE 320 mcg/18mcg/9.6mcg and GFF MDI 18 mcg/9.6 mcg, respectively.

14 CLINICAL STUDIES

14.1Chronic Obstructive Pulmonary Disease The clinical efficacy of BREZTRI AEROSPHERE has been evaluated in two (ETHOS and KRONOS) randomized, double-blind, multicenter, parallel-group trials in subjects with moderate to very severe COPD who remained symptomatic while receiving 2 or more inhaled maintenance treatments for COPD for at least 6 weeks prior to screening. ETHOS (NCT02465567) was conducted over 52 weeks in a total of 8,588 subjects randomized (1:1:1:1) to receive BREZTRI AEROSPHERE (budesonide/glycopyrrolate/formoterol fumarate 320 mcg/18 mcg/9.6 mcg), budesonide, glycopyrrolate and formoterol fumarate (BGF MDI 160 mcg/18 mcg/9.6 mcg) (the BGF MDI 160 mcg/18 mcg/9.6 mcg dosing regimen is not approved), glycopyrrolate and formoterol fumarate (GFF MDI 18 mcg/9.6 mcg), or budesonide and formoterol fumarate (BFF MDI 320 mcg/9.6 mcg), all administered twice daily.

GFF MDI and BFF MDI used the same inhaler and excipients as BREZTRI AEROSPHERE. ETHOS was conducted in subjects with a history of 1 or more moderate or severe exacerbations in the year prior to screening, post-bronchodilator FEV 1 /FVC ratio less than 0.7 and the post-bronchodilator FEV 1 less than 65% predicted normal value. The population demographics across all treatments in ETHOS were: mean age of 65 years, 60% male, 85% Caucasian, and an average smoking history of 48 pack-years, with 41% identified as current smokers.

The mean post-bronchodilator percent predicted FEV 1 was 43% (range 16% to 73%). At study entry, the most common COPD medications were ICS + long-acting muscarinic antagonist (LAMA) + LABA (39%), ICS + LABA (31%), and LAMA + LABA (14%). In ETHOS, the primary endpoint was the rate of moderate or severe COPD exacerbations for BREZTRI AEROSPHERE compared with GFF MDI and BFF MDI.

KRONOS (NCT02497001) was conducted over 24 weeks, in a total of 1,896 subjects randomized (2:2:1:1) to receive BREZTRI AEROSPHERE (budesonide/glycopyrrolate/formoterol fumarate 320 mcg/18 mcg/9.6 mcg), glycopyrrolate and formoterol fumarate (GFF MDI 18 mcg/9.6 mcg), budesonide and formoterol fumarate (BFF MDI 320 mcg/9.6 mcg), or open-label active comparator, all administered twice daily. GFF MDI and BFF MDI used the same inhaler and excipients as BREZTRI AEROSPHERE. KRONOS was conducted in subjects with a screening post-bronchodilator FEV 1 /FVC ratio less than 0.7 and post-bronchodilator FEV 1 less than 80% predicted normal value.

Subjects in KRONOS were not required to have a history of moderate or severe exacerbations in the year prior to screening. The population demographics across all treatments in KRONOS were: mean age of 65 years, 71% male, 50% Caucasian, 45% Asian, and an average smoking history of 52 pack-years, with 40% identified as current smokers. The mean post-bronchodilator percent predicted FEV 1 was 50% (range 22% to 84%).

At study entry, the most common COPD medications were ICS + LAMA + LABA (27%), ICS + LABA (38%), and LAMA + LABA (20%). In KRONOS, the primary endpoints were FEV 1 area under the curve from 0-4 hours (FEV 1 AUC 0-4 ) at Week 24 for BREZTRI AEROSPHERE compared to BFF MDI and change from baseline in morning pre-dose trough FEV 1 at Week 24 for BREZTRI AEROSPHERE compared to GFF MDI. Lung Function In ETHOS, a subset of subjects were included in a spirometric sub-study with primary endpoints of FEV 1 AUC 0-4 at Week 24 (mL) and change from baseline in morning pre-dose trough FEV 1 at Week 24 (mL).

BREZTRI AEROSPHERE demonstrated an increase in on-treatment FEV 1 AUC 0-4 and trough FEV 1 at Week 24 relative to BFF MDI and GFF MDI (Table 2). The effects on lung function (mean change from baseline in on-treatment morning pre-dose trough FEV 1 ) of BREZTRI AEROSPHERE compared with GFF MDI and BFF MDI were observed at all timepoints over the course of the study (Figure 1). In KRONOS, BREZTRI AEROSPHERE demonstrated an increase in on-treatment FEV 1 AUC 0-4 at Week 24 relative to BFF MDI and an increase in mean change fro… [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 BREZTRI AEROSPHERE; however, separate studies of budesonide, glycopyrrolate, and formoterol fumarate are described below. Budesonide Long-term studies were conducted in rats and mice using oral administration to evaluate the carcinogenic potential of budesonide. In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately equivalent to the MRHDID on a mcg/m 2 basis).

No tumorigenicity was seen in male and female rats at respective oral doses up to 25 and 50 mcg/kg (approximately equivalent to the MRHDID 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 (approximately equivalent to the MRHDID 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 (approximately equivalent to the MRHDID on a mcg/m 2 basis).

The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) in these two studies showed similar findings. In a 91-week carcinogenicity study in mice, budesonide produced no treatment-related increases in the incidence of tumors at oral doses up to 200 mcg/kg (approximately 2 times the MRHDID on a mcg/m 2 basis). Budesonide was not mutagenic or clastogenic in the 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 (approximately equal to the MRHDID on a mcg/m 2 basis). However, it caused a decrease in prenatal viability and viability in the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg and above (0.3 times the MRHDID on a mcg/m 2 basis). No such effects were noted at 5 mcg/kg (0.08 times the MRHDID on a mcg/m 2 basis).

Glycopyrrolate Long-term studies were conducted in mice using inhalation administration and rats using oral administration to evaluate the carcinogenic potential of glycopyrrolate. In a 24-month inhalation carcinogenicity study in B6C3F1 mice, glycopyrrolate produced no evidence of tumorigenicity when administered to males or females at doses up to 705 and 335 mcg/kg/day, respectively (approximately 48 and 23 times the MRHDID of glycopyrrolate on a mcg/m 2 basis, respectively). In a 24-month carcinogenicity study in rats, glycopyrrolate produced no evidence of tumorigenicity when administered to males or females by oral gavage at dosages up to 40,000 mcg/kg/day (approximately 5400 times the MRHDID of glycopyrrolate on a mcg/m 2 basis).

Glycopyrrolate was not mutagenic or clastogenic in the Ames Salmonella /microsome plate test, in vitro mammalian cell micronucleus assay in TK6 cells, or in vivo micronucleus assay in rats. Fertility and reproductive performance indices were unaffected in male and female rats that received glycopyrrolate by the subcutaneous route at doses up to 10,000 μg/kg/day (approximately 1350 times the MRHDID on a mcg/m 2 basis). Formoterol Fumarate Long-term studies were conducted in mice using oral administration and rats using inhalation administration to evaluate the carcinogenic potential of formoterol fumarate.

In a 24-month carcinogenicity study in CD-1 mice, formoterol fumarate at oral doses of 100 mcg/kg and above (approximately 25 times MRHDID on a mcg/m 2 basis) caused a dose-related increase in the incidence of uterine leiomyomas. In a 24-month carcinogenicity study… [Excerpted — this section continues on DailyMed.]