Formoterol Fumarate Inhalation Solution formoterol fumarate dihydrate 20 ug/2mL Solution — NDC 76204-030-02 (Billing 76204-0030-02)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Formoterol fumarate is a long-acting, beta 2 -adrenergic receptor agonist (beta 2 -agonist). 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.

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, 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. In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol 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 with COPD is unknown.

12.2Pharmacodynamics Systemic Safety and Pharmacokinetic / Pharmacodynamic Relationships The major adverse effects of inhaled beta 2 -agonists occur as a result of excessive activation of the systemic beta-adrenergic receptors. The most common adverse effects in adults include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose. Changes in serum potassium and serum glucose were evaluated in 12 COPD patients following inhalation of single doses of Formoterol Fumarate Inhalation Solution containing 10, 20 and 244 mcg of formoterol fumarate (calculated on an anhydrous basis) in a crossover study.

At 1 hour after treatment with formoterol fumarate inhalation solution, mean (± standard deviation) serum glucose rose 26 ± 30, 29 ± 28, and 38 ± 44 mg/dL, respectively, and was not significantly different from baseline or trough level at 24 hours post-dose. At 1 hour after dosing with formoterol fumarate inhalation solution 244 mcg, serum potassium fell by 0.68 ± 0.4 mEq/L, and was not different from baseline or trough level at 24 hours post-dose. Linear pharmacokinetic/pharmacodynamic (PK/PD) relationships between urinary formoterol excretion and decreases in serum potassium, increases in plasma glucose, and increases in heart rate were generally observed with another inhalation formulation of formoterol fumarate and hence would be expected with Formoterol Fumarate Inhalation Solution also.

Following single dose administration of 10-fold the recommended clinical dose of the other formoterol fumarate inhalation formulation having comparable exposure to single dose of 244 mcg of Formoterol Fumarate Inhalation Solution (approximately 12-fold the recommended clinical dose) in healthy subjects, the formoterol plasma concentration was found to be highly correlated with the reduction in plasma potassium concentration. Data from this study showed that maximum reductions from baseline in plasma potassium ranged from 0.55 to 1.52 mmol/L with a median maximum reduction of 1.01 mmol/L.

Generally, the maximum effect on plasma potassium was noted 1 to 3 hours after peak formoterol plasma concentrations were achieved. Electrophysiology In the dose-ranging study of Formoterol Fumarate Inhalation Solution, ECG-determi… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Formoterol fumarate is a long-acting, beta 2 -adrenergic receptor agonist (beta 2 -agonist). 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.

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, 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. In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol 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 with COPD is unknown.

12.3Pharmacokinetics Information on the pharmacokinetics of formoterol (dry powder and/or inhalation solution) in plasma and/or urine is available in healthy subjects as well as patients with chronic obstructive pulmonary disease after oral inhalation of doses at and above the therapeutic dose. Urinary excretion of unchanged formoterol was used as an indirect measure of systemic exposure. Plasma drug disposition data parallel urinary excretion, and the elimination half-lives calculated for urine and plasma are similar.

Absorption Pharmacokinetic properties of formoterol fumarate were evaluated in 12 COPD patients following inhalation of single doses of Formoterol Fumarate Inhalation Solution containing 10, 20 and 244 mcg of formoterol fumarate (calculated on an anhydrous basis) and 12 mcg formoterol fumarate dry powder, through 36 hours after single-dose administration. Formoterol fumarate concentrations in plasma following the 10 and 20 mcg doses of Formoterol Fumarate Inhalation Solution and the 12 mcg dose of formoterol fumarate dry powder were undetectable or only detected sporadically at very low concentrations.

Following a single 244 mcg dose of Formoterol Fumarate Inhalation Solution (approximately 12 times the recommended clinical dose), formoterol fumarate concentrations were readily measurable in plasma, exhibiting rapid absorption into plasma, and reaching a maximum drug concentration of 72 pg/mL within approximately 12 minutes of dosing. The mean amount of formoterol excreted unchanged in 24-hour urine following single oral inhalation doses of 10, 20, and 244 mcg Formoterol Fumarate Inhalation Solution were found to be 109.7 ng, 349.6 ng, and 3317.5 ng, respectively.

These findings indicate a near dose proportional increase in systemic exposure within the dose range tested. When 12 mcg of a dry powder formulation of formoterol fumarate was given twice daily to COPD patients by oral inhalation for 12 weeks, the accumulation index, based on the urinary excretion of unchanged formoterol was 1.19 to 1.38. This suggests some accumulation of formoterol in plasma with multiple dosing.

Although multiple-dose pharmacokinetic data is unavailable fromFormoterol Fumarate Inhalation Solution, assumption of linear pharmacokinetics allows a reasonable prediction of minimal accumulation based on single-dose pharmacokinetics. As with many drug products for oral inhalation, it is likely that the majority of the inhaled formoterol fumarate delivered is swallowed and then absorbed from the gastrointestinal tract. Distribution The binding of formoterol to human plasma proteins in vitro was 61% to 64% at concentrations from 0.1 to 100 ng/mL.

Binding to human serum albumin in vitro was 31% to 38% over a range of 5 to 500 ng/mL. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 244 mcg dose of Formoterol Fumarate Inhalation Solution. Metabolism Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups.

Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group.

In vitro studies showed that multiple drug-metabolizing enzymes catalyze glucuronidation (UGT1A1, 1A8, 1A9, 2B7 and 2B15 were the most predominant enzymes) and O-demethylation (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) of formoterol. Formoterol did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both.

Whether a deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Systemic Safety and Pharmacokinetic / Pharmacodynamic Relationships The major adverse effects of inhaled beta 2 -agonists occur as a result of excessive activation of the systemic beta-adrenergic receptors. The most common adverse effects in adults include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose. Changes in serum potassium and serum glucose were evaluated in 12 COPD patients following inhalation of single doses of Formoterol Fumarate Inhalation Solution containing 10, 20 and 244 mcg of formoterol fumarate (calculated on an anhydrous basis) in a crossover study.

At 1 hour after treatment with formoterol fumarate inhalation solution, mean (± standard deviation) serum glucose rose 26 ± 30, 29 ± 28, and 38 ± 44 mg/dL, respectively, and was not significantly different from baseline or trough level at 24 hours post-dose. At 1 hour after dosing with formoterol fumarate inhalation solution 244 mcg, serum potassium fell by 0.68 ± 0.4 mEq/L, and was not different from baseline or trough level at 24 hours post-dose. Linear pharmacokinetic/pharmacodynamic (PK/PD) relationships between urinary formoterol excretion and decreases in serum potassium, increases in plasma glucose, and increases in heart rate were generally observed with another inhalation formulation of formoterol fumarate and hence would be expected with Formoterol Fumarate Inhalation Solution also.

Following single dose administration of 10-fold the recommended clinical dose of the other formoterol fumarate inhalation formulation having comparable exposure to single dose of 244 mcg of Formoterol Fumarate Inhalation Solution (approximately 12-fold the recommended clinical dose) in healthy subjects, the formoterol plasma concentration was found to be highly correlated with the reduction in plasma potassium concentration. Data from this study showed that maximum reductions from baseline in plasma potassium ranged from 0.55 to 1.52 mmol/L with a median maximum reduction of 1.01 mmol/L.

Generally, the maximum effect on plasma potassium was noted 1 to 3 hours after peak formoterol plasma concentrations were achieved. Electrophysiology In the dose-ranging study of Formoterol Fumarate Inhalation Solution, ECG-determined heart rate increased by a mean of 6 ±3 beats per minute at 6 hours after a single dose of 244 mcg, but was back to predose level at 16-24 hours. The effect of Formoterol Fumarate Inhalation Solution on heart rate and cardiac rhythm was studied in a 12-week clinical trial comparing Formoterol Fumarate Inhalation Solution to placebo and an active control treatment.

COPD patients, including 105 patients exposed to Formoterol Fumarate Inhalation Solution, underwent continuous electrocardiographic (Holter) monitoring during two 24-hour periods (study baseline and after 8-12 weeks of treatment). ECGs were performed pre-dose and at 2 to 3 hours post-dose at study baseline (prior to dosing) and after 4, 8 and 12 weeks of treatment. Bazett’s and Fridericia’s methods were used to correct the QT interval for heart rate (QTcB and QTcF, respectively).

The mean increase from baseline in QTcB interval over the 12-week treatment period was ≤ 4.8 msec for Formoterol Fumarate Inhalation Solution and ≤ 4.6 msec for placebo. The percent of patients who experienced a maximum change in QTc greater than 60 msec at any time during the 12-week treatment period was 0% and 1.8% for Formoterol Fumarate Inhalation Solution and placebo, respectively, based on Bazett’s correction, and 1.6% and 0.9%, respectively, based on Fridericia’s correction. Prolonged QT was reported as an adverse event in 1 (0.8%) patient treated with Formoterol Fumarate Inhalation Solution and 2 (1.8%) placebo patients.

No occurrences of atrial fibrillation or ventricular tachycardia were observed during 24-hour Holter monitoring or reported as adverse events in patients treated with Formoterol Fumarate Inhalation Solution… [Excerpted — this section continues on DailyMed.]

14 CLINICAL STUDIES

14.1Adult COPD Trial Formoterol Fumarate Inhalation Solution was evaluated in a 12-week, double-blind, placebo- and active-controlled, randomized, parallel-group, multicenter trial conducted in the United States. Of a total enrollment of 351 adults (age range: 40 to 86 years; mean age: 63 years) with COPD who had a mean pre-bronchodilator FEV 1 of 1.34 liters (44% of predicted), 237 patients were randomized to Formoterol Fumarate Inhalation Solution 20 mcg or placebo, administered twice daily via a PARI-LC Plus ® nebulizer with a PRONEB ® Ultra compressor.

The diagnosis of COPD was based upon a prior clinical diagnosis of COPD, a smoking history (at least 10 pack-years), age (at least 40 years), and spirometry results (pre-bronchodilator baseline FEV 1 at least 30% and less than 70% of the predicted value, and the FEV 1 /FVC less than 70%). About 58% of patients had bronchodilator reversibility, defined as a 10% or greater increase in FEV 1 after inhalation of 2 actuations (180 mcg) of albuterol from a metered dose inhaler. About 86% (106) of patients treated with Formoterol Fumarate Inhalation Solution and 74% (84) of placebo patients completed the trial.

Formoterol Fumarate Inhalation Solution 20 mcg twice daily resulted in significantly greater post-dose bronchodilation (as measured by serial FEV 1 for 12 hours post-dose; the primary efficacy analysis) compared to placebo when evaluated at endpoint (week 12 for completers and last observation for dropouts). Similar results were seen on Day 1 and at subsequent timepoints during the trial. Mean FEV 1 measurements at Day 1 (Figure 1) and at endpoint (Figure 2) are shown below. *Figures show least-squares means adjusted for baseline FEV 1 Patients treated with Formoterol Fumarate Inhalation Solution used less rescue albuterol during the trial compared to patients treated with placebo.

Examination of age (≥ 65 or younger) and gender subgroups did not identify differences in response to Formoterol Fumarate Inhalation Solution. There were too few non-Caucasian subjects to assess differences in populations defined by race adequately. In the 12-week study, 78% of subjects achieved a 15% increase from baseline FEV 1 following the first dose of Formoterol Fumarate Inhalation Solution 20 mcg.

In these subjects, the median time to onset of bronchodilation, defined as 15% increase in FEV 1 , was 11.7 minutes. When defined as an increase in FEV 1 of 12% and 200 mL, the time to onset of bronchodilation was 13.1 minutes after dosing. The median time to peak bronchodilator effect was 2 hours after dosing. mean-fev1-day1 mean-fev1-12weeks

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of formoterol fumarate has been evaluated in 2-year drinking water and dietary studies in both rats and mice. In rats, the incidence of ovarian leiomyomas was increased at doses of 15,000 mcg/kg and above in the drinking water study and at 20,000 mcg/kg in the dietary study (AUC exposure approximately 2,300 times human exposure at the maximum recommended daily inhalation dose), but not at dietary doses up to 5,000 mcg/kg (AUC exposure approximately 570 times human exposure at the maximum recommended daily inhalation dose).

In the dietary study, the incidence of benign ovarian theca-cell tumors was increased at doses of 500 mcg/kg (AUC exposure was approximately 57 times human exposure at the maximum recommended daily inhalation dose) and above. This finding was not observed in the drinking water study, nor was it seen in mice (see below). In mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at doses of 69,000 mcg/kg (AUC exposure approximately 1000 times human exposure at the maximum recommended daily inhalation dose) and above in the drinking water study, but not at doses up to 50,000 mcg/kg (AUC exposure approximately 750 times human exposure at the maximum recommended daily inhalation dose) in the dietary study.

The incidence of hepatocarcinomas was increased in the dietary study at doses of 20,000 and 50,000 mcg/kg in females (AUC exposures approximately 300 and 750 times human exposure at the maximum recommended daily inhalation dose, respectively) and 50,000 mcg/kg in males, but not at doses up to 5,000 mcg/kg (AUC exposure approximately 75 times human exposure at the maximum recommended daily inhalation dose). Also in the dietary study, the incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of 2,000 mcg/kg (AUC exposure was approximately 30 times human exposure at the maximum recommended daily inhalation dose) and above.

Increases in leiomyomas of the rodent female genital tract have been similarly demonstrated with other beta-agonist drugs. Formoterol fumarate was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacterial and mammalian cells, chromosomal analyses in mammalian cells, unscheduled DNA synthesis repair tests in rat hepatocytes and human fibroblasts, transformation assay in mammalian fibroblasts and micronucleus tests in mice and rats. Reproduction studies in rats revealed no impairment of fertility at oral doses up to 3,000 mcg/kg (approximately 730 times the maximum recommended daily inhalation powder dose in humans on a mcg/m 2 basis).

13.2Animal Pharmacology Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac 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 [see DRUG INTERACTIONS, Xanthine Derivatives, Steroids, or Diuretics (7.2) ].