BEVESPI AEROSPHERE Glycopyrrolate and formoterol fumarate 9 ug; 4.8 ug Aerosol, Metered, 120-count — NDC 0310-4600-12 (Billing 00310-4600-12)

12 CLINICAL PHARMACOLOGY

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

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, especially from mast cells.

12.2Pharmacodynamics Cardiac Electrophysiology The potential for QTc interval prolongation 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 BEVESPI AEROSPHERE 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 BEVESPI AEROSPHERE and glycopyrrolate/formoterol fumarate 72/19.2 mcg, respectively. Chronic Obstructive Pulmonary Disease The effect of glycopyrrolate/formoterol fumarate on cardiac rhythm in subjects with COPD was assessed using 24-hour Holter monitoring in 2-week and 24-week trials. All treatments were administered as two inhalations twice daily.

In the 2-week trial, the Holter monitoring population included 58 subjects on glycopyrrolate/formoterol fumar… [Excerpted — this section continues on DailyMed.]

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

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, especially from mast cells.

12.3Pharmacokinetics Linear pharmacokinetics were observed for glycopyrrolate (dose range: 18 to 144 mcg) and formoterol fumarate (dose range: 2.4 to 19.2 mcg) after oral inhalation. Absorption Glycopyrrolate: Following inhaled administration of BEVESPI AEROSPHERE in subjects with COPD, C max occurred at 5 minutes. Steady state is expected to be achieved within 2-3 days of repeated dosing of BEVESPI AEROSPHERE and the extent of exposure is approximately 2.3 times higher than after the first dose.

Formoterol Fumarate: Following inhaled administration of BEVESPI AEROSPHERE in subjects with COPD, C max occurred within 20 to 60 minutes. Steady state is expected to be achieved within 2-3 days of repeated dosing with BEVESPI AEROSPHERE and the extent of exposure is approximately 1.5 times higher than after the first dose. Distribution Glycopyrrolate: Population pharmacokinetic analysis showed that estimated Vc/F (volume of the central compartment), and V2/F (volume of the peripheral compartment) are 951 L, and 2019 L, respectively.

Formoterol Fumarate: Population pharmacokinetic analysis showed that estimated Vc/F (volume of the central compartment), and V2/F (volume of the peripheral compartment) are 948 L, and 434 L, respectively. Over the concentration range of 10-500 nmol/L, plasma protein binding of formoterol ranged from 46% to 58%. Elimination Glycopyrrolate: After IV administration of a 0.2 mg dose of radiolabeled glycopyrrolate, 85% of the dose recovered was recovered in urine 48 hours post dose and some of radioactivity was also recovered in bile.

The terminal elimination half-life derived via population pharmacokinetics analysis was 11.8 hours. Formoterol Fumarate: The excretion of formoterol was studied in four healthy subjects following simultaneous administration of radiolabeled formoterol via the oral and IV routes. In that study, 62% of the radiolabeled formoterol was excreted in the urine while 24% was eliminated in the feces.

The terminal elimination half-life derived via population pharmacokinetics analysis was 11.8 hours. Metabolism Glycopyrrolate : Based on literature, and an in-vitro human hepatocyte study, metabolism plays a minor role in the overall elimination of glycopyrronium. CYP2D6 was found to be the predominant enzyme involved in the metabolism of glycopyrronium.

In-vitro studies indicate the glycopyrrolate does not inhibit any subtype of cytochrome P450 and that there is no induction of CYP1A2, 2B6, or 3A4 at therapeutically relevant concentrations. Formoterol Fumarate : The primary metabolism of formoterol is by direct glucuronidation and by O-demethylation followed by conjugation to inactive metabolites. Secondary metabolic pathways include deformylation and sulfate conjugation.

CYP2D6 and CYP2C have been identified as being primarily responsible for O-demethylation. Specific Populations Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age, sex, race/ethnicity, or body weight on the pharmacokinetics of glycopyrrolate and formoterol. Patients with Hepatic Impairment: Dedicated studies evaluating effect of hepatic impairment on the pharmacokinetics of glycopyrrolate and formoterol were not conducted.

Patients with Renal Impairment: Dedicated studies evaluating effect of renal impairment on the pharmacokinetics of glycopyrrolate and formoterol were not conducted. When glycopyrrolate was administered IV in uremic patients undergoing renal transplantation, mean elimination half-life was significantly longer (46.8 minutes) than in healthy patients (18.6 minutes). The mean AUC (10.6 hr-mcg/L), mean plasma clearance (0.43 L/hr/kg), and mean 3-hour urine excretion (0.7%) for glycopyrrolate were also significantly different than those of controls (3.73 hr-mcg/L,

1.14L/hr/kg, and 50%, respectively). A population pharmacokinetic analysis using BEVESPI AEROSPHERE showed that formoterol systemic exposure (AUC 0-12 ) in subjects with COPD with moderate renal impairment… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology The potential for QTc interval prolongation 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 BEVESPI AEROSPHERE 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 BEVESPI AEROSPHERE and glycopyrrolate/formoterol fumarate 72/19.2 mcg, respectively. Chronic Obstructive Pulmonary Disease The effect of glycopyrrolate/formoterol fumarate on cardiac rhythm in subjects with COPD was assessed using 24-hour Holter monitoring in 2-week and 24-week trials. All treatments were administered as two inhalations twice daily.

In the 2-week trial, the Holter monitoring population included 58 subjects on glycopyrrolate/formoterol fumarate 18/4.8 mcg, 58 subjects on glycopyrrolate 18 mcg, and 60 subjects on formoterol fumarate 4.8 mcg. In the 24-week trial, the Holter monitoring population included 171 subjects on BEVESPI AEROSPHERE, 160 subjects on glycopyrrolate 9 mcg, 174 subjects on formoterol fumarate 4.8 mcg, and 80 subjects on placebo. No clinically meaningful effects on cardiac rhythm were observed.

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. The clinical program for BEVESPI AEROSPHERE included 4,911 subjects with COPD in two 24-week lung function trials, one long-term safety extension study of 28 weeks, and 10 other trials of shorter duration. A total of 1,302 subjects have received at least 1 dose of BEVESPI AEROSPHERE.

The safety data described below are based on the two 24-week trials and the one 28-week long-term safety extension trial. Adverse reactions observed in the other trials were similar to those observed in these confirmatory trials. 24-Week Trials The incidence of adverse reactions with BEVESPI AEROSPHERE in Table 1 is based on reports in two 24-week, placebo-controlled trials (Trials 1 and 2; n=2,100 and n=1,610, respectively).

Of the 3,710 subjects, 56% were male and 91% were Caucasian. They had a mean age of 63 years and an average smoking history of 51 pack-years, with 54% identified as current smokers. At screening, the mean post-bronchodilator percent predicted forced expiratory volume in 1 second (FEV 1 ) was 51% (range: 19% to 82%) and the mean percent reversibility was 20% (range: -32% to 135%).

Subjects received one of the following treatments: BEVESPI AEROSPHERE, glycopyrrolate 18 mcg, formoterol fumarate 9.6 mcg, or placebo twice daily or active control. Table 1 - Adverse Reactions with BEVESPI AEROSPHERE ≥2% Incidence and More Common than with Placebo in Subjects with Chronic Obstructive Pulmonary Disease Adverse Reaction BEVESPI AEROSPHERE (n=1036) % Glycopyrrolate 18 mcg BID (n=890) % Formoterol Fumarate 9.6 mcg BID (n=890) % Placebo (n=443) % Respiratory, thoracic, and mediastinal disorders Cough 4.0 3.0 2.7

2.7Infections and infestation Urinary tract infection 2.6 1.8 1.5

2.3Other adverse reactions defined as events with an incidence of >1% but less than 2% with BEVESPI AEROSPHERE but more common than with placebo included the following: arthralgia, chest pain, tooth abscess, muscle spasms, headache, oropharyngeal pain, vomiting, pain in extremity, dizziness, anxiety, dry mouth, fall, influenza, fatigue, acute sinusitis, and contusion. Long-Term Safety Extension Trial In a 28-week long-term safety extension trial, 893 subjects who successfully completed Trial 1 or Trial 2 were treated for up to an additional 28 weeks for a total treatment period of up to 52 weeks with BEVESPI AEROSPHERE, glycopyrrolate 18 mcg, formoterol fumarate 9.6 mcg administered twice daily or active control.

Because the subjects continued from Trial 1 or Trial 2 into the safety extension trial, the demographic and baseline characteristics of the long-term safety extension trial were similar to those of the placebo-controlled efficacy trials described above. The adverse reactions reported in the long-term safety trial were consistent with those observed in the 24-week placebo-controlled trials. Additional Adverse Reactions : Other adverse reactions that have been associated with the component formoterol fumarate include: hypersensitivity reactions, hyperglycemia, sleep disturbance, agitation, restlessness, tremor, nausea, tachycardia, palpitations, cardiac arrhythmias (atrial fibrillation, supraventricular tachycardia, and extrasystoles).

14 CLINICAL STUDIES The safety and efficacy of BEVESPI AEROSPHERE was evaluated in a clinical development program that included 8 dose-ranging trials and two placebo-controlled lung function trials of 24-weeks duration that included a 28-week extension study to evaluate safety over 1 year. The efficacy of BEVESPI AEROSPHERE is based on the dose ranging trials in 822 subjects with COPD and the 2 placebo-controlled confirmatory trials in 3,705 subjects with COPD.

14.1Dose-Ranging Trials Dose selection for BEVESPI AEROSPHERE for COPD w… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility BEVESPI AEROSPHERE : No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with BEVESPI AEROSPHERE; however, separate studies of glycopyrrolate and formoterol fumarate are described below. 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 95 and 45 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 11,000 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 the 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 mcg/kg/day (approximately 2700 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 the MRHDID on a mcg/m 2 basis) caused a dose-related increase in the incidence of uterine leiomyomas. In a 24-month carcinogenicity study in Sprague-Dawley rats, an increased incidence of mesovarian leiomyoma and uterine leiomyosarcoma were observed at the inhaled dose of 130 mcg/kg (approximately 65 times the MRHDID on a mcg/m 2 basis).

No tumors were seen at 22 mcg/kg (approximately 10 times the MRHDID on a mcg/m 2 basis). Other beta-agonist drugs have similarly demonstrated increases in leiomyomas of the genital tract in female rodents. The relevance of these findings to human use is unknown.

Formoterol fumarate was not mutagenic or clastogenic in the Ames Salmonella/ microsome plate test, mouse lymphoma test, chromosome aberration test in human lymphocytes, and rat micronucleus test. A reduction in fertility and/or reproductive performance was identified in male rats treated with formoterol at an oral dose of 15,000 mcg/kg, (approximately 1900 times the MRHDID on an AUC basis). No such effect was seen at 3,000 mcg/kg (approximately 1500 times the MRHDID on a mcg/m 2 basis).

In a separate study with male rats treated with an oral dose of 15,000 mcg/kg (approximately 8000 times the MRHDID on a mcg/m 2 basis), there were findings of testicular tubular atrophy and spermatic debris in the testes and oligospermia in the epididymides. No effect on fertility was detected in female rats at doses up to 15,000 mcg/kg (approximately 1000 times the MRHDID on an AUC basis).