Arformoterol Tartrate Inhalation 15 ug/2mL Solution — NDC 73043-052-60 (Billing 73043-0052-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Arformoterol, the (R, R)-enantiomer of formoterol, is a selective long-acting beta 2 -adrenergic receptor agonist (beta 2 -agonist) that has two-fold greater potency than racemic formoterol (which contains both the (S,S) and (R,R)-enantiomers). The (S,S)-enantiomer is about 1,000-fold less potent as a beta 2 -agonist than the (R, R)-enantiomer. While it is recognized that beta 2 receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 receptors are the predominant receptors in the heart, data indicate that 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 arformoterol, 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 intracellular cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that arformoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Arformoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

12.2Pharmacodynamics Systemic Safety and Pharmacokinetic/Pharmacodynamic Relationships The predominant adverse effects of inhaled beta 2 -agonists occur as a result of excessive activation of systemic beta-adrenergic receptors. The most common adverse effects may include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose. Effects on Serum Potassium and Serum Glucose Levels Changes in serum potassium and serum glucose were evaluated in a dose-ranging study of twice daily (5 mcg, 15 mcg, or 25 mcg; 215 patients with COPD) and once daily (15 mcg, 25 mcg, or 50 mcg; 191 patients with COPD) Arformoterol Tartrate Inhalation Solution in COPD patients.

At 2 and 6 hours post dose at week 0 (after the first dose), mean changes in serum potassium ranging from 0 to -0.3 mEq/L were observed in the Arformoterol Tartrate Inhalation Solution groups with similar changes observed after 2 weeks of treatment. Changes in mean serum glucose levels, ranging from a decrease of 1.2 mg/dL to an increase of 32.8 mg/dL were observed for Arformoterol Tartrate Inhalation Solution dose groups at both 2 and 6 hours post dose, both after the first dose and 14 days of daily treatment. Electrophysiology The effect of Arformoterol Tartrate Inhalation Solution on QT interval was evaluated in a dose-ranging study following multiple doses of Arformoterol Tartrate Inhalation Solution 5 mcg, 15 mcg, or 25 mcg twice daily or 15 mcg, 25 mcg, or 50 mcg once daily for 2 weeks in patients with COPD.

ECG assessments were performed at baseline, time of peak plasma concentration and throughout the dosing interval. Different methods of correcting for heart rate were employed, including a subject-specific method and the Fridericia method. Relative to placebo, the mean change in subject-specific QTc averaged over the dosing interval ranged from -1.8 to 2.7 msec, indicating little effect of Arformoterol Tartrate Inhalation Solution on cardiac repolarization after 2 weeks of treatment.

The maximum mean change in subjectspecific QTc for the Arformoterol Tartrate Inhalation Solution 15 mcg twice daily dose was 17.3 msec, compared with 15.4 msec in the placebo grou… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Arformoterol, the (R, R)-enantiomer of formoterol, is a selective long-acting beta 2 -adrenergic receptor agonist (beta 2 -agonist) that has two-fold greater potency than racemic formoterol (which contains both the (S,S) and (R,R)-enantiomers). The (S,S)-enantiomer is about 1,000-fold less potent as a beta 2 -agonist than the (R, R)-enantiomer. While it is recognized that beta 2 receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 receptors are the predominant receptors in the heart, data indicate that 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 arformoterol, 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 intracellular cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that arformoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Arformoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

12.3Pharmacokinetics The pharmacokinetics (PK) of arformoterol have been investigated in healthy subjects, elderly subjects, renally and hepatically impaired subjects, and COPD patients following the nebulization of the recommended therapeutic dose and doses up to 96 mcg. Absorption In COPD patients administered 15 mcg arformoterol every 12 hours for 14 days, the mean steady-state peak (R,R)-formoterol plasma concentration (C max ) and systemic exposure (AUC 0-12h ) were 4.3 pg/mL and 34.5 pg•hr/mL, respectively. The median steady-state peak (R, R) - formoterol plasma concentration time (t max ) was observed approximately one-half hour after drug administration.

Systemic exposure to (R, R)-formoterol increased linearly with dose in COPD patients following arformoterol doses of 5 mcg, 15 mcg, or 25 mcg twice daily for 2 weeks or 15 mcg, 25 mcg, or 50 mcg once daily for 2 weeks. In a crossover study in patients with COPD, when arformoterol 15 mcg inhalation solution and 12 and 24 mcg formoterol fumarate inhalation powder (Foradil® Aerolizer®) was administered twice daily for 2 weeks, the accumulation index was approximately 2.5 based on the plasma (R,R)-formoterol concentrations in all three treatments.

At steady- state, geometric means of systemic exposure (AUC 0-12h ) to (R, R)-formoterol following 15 mcg of arformoterol inhalation solution and 12 mcg of formoterol fumarate inhalation powder were 39.33 pg•hr/mL and 33.93 pg•hr/mL, respectively (ratio 1.16; 90% CI 1.00, 1.35), while the geometric means of the C max were 4.30 pg/mL and 4.75 pg/mL, respectively (ratio 0.91; 90% CI 0.76, 1.09). In a study in patients with asthma, treatment with arformoterol 50 mcg with pre- and posttreatment with activated charcoal resulted in a geometric mean decrease in (R,R)-formoterol AUC 0-6h by 27% and C max by 23% as compared to treatment with arformoterol 50 mcg alone.

This suggests that a substantial portion of systemic drug exposure is due to pulmonary absorption . Distribution The binding of arformoterol to human plasma proteins in vitro was 52-65% at concentrations of 0.25, 0.5 and 1.0 ng/mL of radiolabeled arformoterol. The concentrations of arformoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of multiple doses of 50 mcg arformoterol.

Metabolism In vitro profiling studies in hepatocytes and liver microsomes have shown that arformoterol is primarily metabolized by direct conjugation (glucuronidation) and secondarily by O-demethylation. At least five human uridine diphosphoglucuronosyltransferase (UGT) isozymes catalyze arformoterol glucuronidation in vitro . Two cytochrome P450 isozymes (CYP2D6 and secondarily CYP2C19) catalyze the O-demethylation of arformoterol.

Arformoterol was almost entirely metabolized following oral administration of 35 mcg of radiolabeled arformoterol in eight healthy subjects. Direct conjugation of arformoterol with glucuronic acid was the major metabolic pathway. Most of the drug-related material in plasma and urine was in the form of glucuronide or sulfate conjugates of arformoterol.

O-Desmethylation and conjugates of the O-desmethyl metabolite were relatively minor metabolites accounting for less than 17% of the dose recovered in urine and feces. Elimination After administration of a single oral dose of radiolabeled arformoterol to eight healthy male subjects, 63% of the total radioactive dose was recovered in urine and 11% in feces within 48 hours. A total of 89% of the total radioactive dose was recovered within 14 days, with 67% in urine and 22% in feces.

Approximately 1% of the dose was recovered as unchanged arformoterol in urine over 14 days. Renal clearance was

8.9L/hr for unchanged arformoterol in these subjects. In COPD patients given 15 mcg inhaled arformoterol twice a day for 14 days, the mean terminal half-life of arformoterol was 26 hours. Special Populations: Gender A population PK analysis indicated that there was no effect of… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Systemic Safety and Pharmacokinetic/Pharmacodynamic Relationships The predominant adverse effects of inhaled beta 2 -agonists occur as a result of excessive activation of systemic beta-adrenergic receptors. The most common adverse effects may include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose. Effects on Serum Potassium and Serum Glucose Levels Changes in serum potassium and serum glucose were evaluated in a dose-ranging study of twice daily (5 mcg, 15 mcg, or 25 mcg; 215 patients with COPD) and once daily (15 mcg, 25 mcg, or 50 mcg; 191 patients with COPD) Arformoterol Tartrate Inhalation Solution in COPD patients.

At 2 and 6 hours post dose at week 0 (after the first dose), mean changes in serum potassium ranging from 0 to -0.3 mEq/L were observed in the Arformoterol Tartrate Inhalation Solution groups with similar changes observed after 2 weeks of treatment. Changes in mean serum glucose levels, ranging from a decrease of 1.2 mg/dL to an increase of 32.8 mg/dL were observed for Arformoterol Tartrate Inhalation Solution dose groups at both 2 and 6 hours post dose, both after the first dose and 14 days of daily treatment. Electrophysiology The effect of Arformoterol Tartrate Inhalation Solution on QT interval was evaluated in a dose-ranging study following multiple doses of Arformoterol Tartrate Inhalation Solution 5 mcg, 15 mcg, or 25 mcg twice daily or 15 mcg, 25 mcg, or 50 mcg once daily for 2 weeks in patients with COPD.

ECG assessments were performed at baseline, time of peak plasma concentration and throughout the dosing interval. Different methods of correcting for heart rate were employed, including a subject-specific method and the Fridericia method. Relative to placebo, the mean change in subject-specific QTc averaged over the dosing interval ranged from -1.8 to 2.7 msec, indicating little effect of Arformoterol Tartrate Inhalation Solution on cardiac repolarization after 2 weeks of treatment.

The maximum mean change in subjectspecific QTc for the Arformoterol Tartrate Inhalation Solution 15 mcg twice daily dose was 17.3 msec, compared with 15.4 msec in the placebo group. No apparent correlation of QTc with arformoterol plasma concentration was observed. Electrocardiographic Monitoring in Patients with COPD The effect of different doses of Arformoterol Tartrate Inhalation Solution on cardiac rhythm was assessed using 24-hour Holter monitoring in two 12-week, double-blind, placebo-controlled studies of 1,456 patients with COPD (873 received Arformoterol Tartrate Inhalation Solution at 15 or 25 mcg twice daily or 50 mcg once daily doses; 293 received placebo; 290 received salmeterol).

The 24-hour Holter monitoring occurred once at baseline, and up to 3 times during the 12-week treatment period. The rates of new-onset cardiac arrhythmias not present at baseline over the double-blind 12-week treatment period were similar (approximately 33-34%) for patients who received Arformoterol Tartrate Inhalation Solution 15 mcg twice daily to those who received placebo. There was a dose-related increase in new, treatment-emergent arrhythmias seen in patients who received Arformoterol Tartrate Inhalation Solution 25 mcg twice daily and 50 mcg once daily, 37.6% and 40.1%, respectively.

The frequencies of new treatment-emergent events of non-sustained (3-10 beat run) and sustained (>10 beat run) ventricular tachycardia were 7.4% and 1.1% in Arformoterol Tartrate Inhalation Solution 15 mcg twice daily and 6.9% and 1.0% in placebo. In patients who received Arformoterol Tartrate Inhalation Solution 25 mcg twice daily and 50 mcg once daily, the frequencies of non-sustained (6.2% and 8.2%, respectively) and sustained ventricular tachycardia (1.0% and 1.0%, respectively) were similar. Five cases of ventricular tachycardia were reported as adverse events (1 in Arformoterol Tartrate Inhalation Solution 15 mcg twice daily and 4 in placebo), and… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Adult COPD Trials Arformoterol Tartrate Inhalation Solution was studied in two identical, 12-week, double-blind, placebo- and active-controlled, randomized, multi-center, parallel group trials conducted in the United States (Clinical Trial A and Clinical Trial B). A total of 1,456 adult patients (age range: 34 to 89 years; mean age: 63 years; gender: 860 males and 596 females) with COPD who had a mean FEV 1 of

1.3L (42% of predicted) were enrolled in the two clinical trials. The racial/ethnic distribution in these two trials included 1383 Caucasians, 49 Blacks, 10 Asians, and 10 Hispanics, and 4 patients classified as Other. The diagnosis of COPD was based on a prior clinical diagnosis of COPD, a smoking history (greater than 15 pack-years), age (at least 35 years), spirometry results (baseline FEV 1 ≤65% of predicted value and >0.70 L, and a FEV 1 /forced vital capacity (FVC) ratio ≤70%).

About 80% of patients in these studies had bronchodilator reversibility, defined as a 10% or greater increase in FEV 1 after inhalation of 2 actuations (180 mcg racemic albuterol from a metered dose inhaler). Both trials compared Arformoterol Tartrate Inhalation Solution 15 mcg twice daily (288 patients), 25 mcg twice daily (292 patients), 50 mcg once daily (293 patients) with placebo (293 subjects). Both trials included salmeterol inhalation aerosol, 42 mcg twice daily as an active comparator (290 patients).

In both 12-week trials, Arformoterol Tartrate Inhalation Solution 15 mcg twice daily resulted in a statistically significant change of approximately 11% in mean FEV 1 (as measured by percent change from study baseline FEV 1 at the end of the dosing interval over the 12 weeks of treatment, the primary efficacy endpoint) compared to placebo. Compared to Arformoterol Tartrate Inhalation Solution 15 mcg twice daily, Arformoterol Tartrate Inhalation Solution 25 mcg twice daily and 50 mcg once daily did not provide sufficient additional benefit on a variety of endpoints, including FEV 1 , to support the use of higher doses.

Plots of the mean change in FEV 1 values obtained over the 12 hours after dosing for the Arformoterol Tartrate Inhalation Solution 15 mcg twice daily dose group and for the placebo group are provided in Figures 1 and 2 for Clinical Trial A, below. The plots include mean FEV 1 change observed after the first dose and after 12 weeks of treatment. The results from Clinical Trial B were similar.

Figure 1 Mean Change in FEV 1 Over Time for Clinical Trial A at Week 0 (Day 1) Figure 2 Mean Change in FEV 1 Over Time for Clinical Trial A at Week 12 Arformoterol Tartrate Inhalation Solution 15 mcg twice daily significantly improved bronchodilation compared to placebo over the 12 hours after dosing (FEV 1 AUC 0-12h ). This improvement was maintained over the 12-week study period. Following the first dose of Arformoterol Tartrate Inhalation Solution 15 mcg, the median time to onset of bronchodilation, defined by an FEV 1 increase of 15%, occurred at 6.7 min.

When defined as an increase in FEV 1 of 12% and 200 mL, the time to onset of bronchodilation was 20 min after dosing. Peak bronchodilator effect was generally seen within 1-3 hours of dosing. In both clinical trials, compared to placebo, patients treated with Arformoterol Tartrate Inhalation Solution demonstrated improvements in peak expiratory flow rates, supplemental ipratropium and rescue albuterol use.

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13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies were conducted in mice using oral administration and rats using inhalation administration to evaluate the carcinogenic potential of arformoterol. In a 24-month carcinogenicity study in CD-1 mice, arformoterol caused a dose-related increase in the incidence of uterine and cervical endometrial stromal polyps and stromal cell sarcoma in female mice at oral doses of 1,000 mcg/kg and above (AUC exposure approximately 70 times adult exposure at the MRHDID).

In a 24-month carcinogenicity study in Sprague-Dawley rats, arformoterol caused a statistically significant increase in the incidence of thyroid gland c-cell adenoma and carcinoma in female rats at an inhalation dose of 200 mcg/kg (AUC exposure approximately 130 times adult exposure at the MRHDID). There were no tumor findings with an inhalation dose of 40 mcg/kg (AUC exposure approximately 55 times adult exposure at the MRHDID). Arformoterol was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacteria, chromosome aberration analyses in mammalian cells, and micronucleus test in mice.

Arformoterol had no effects on fertility and reproductive performance in rats at oral doses up to 10,000 mcg/kg (approximately 3,200 times the MRHDID in adults on a mcg/m 2 basis.

13.2Animal Toxicology and/or Pharmacology Animal Pharmacology In animal studies investigating its cardiovascular effects, arformoterol induced dose-dependent increases in heart rate and decreases in blood pressure consistent with its pharmacology as a beta-adrenergic agonist. In dogs, at systemic exposures higher than anticipated clinically, arformoterol also induced exaggerated pharmacologic effects of a betaadrenergic agonist on cardiac function as measured by electrocardiogram (sinus tachycardia, atrial premature beats, ventricular escape beats, PVCs).

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.