1.1 Maintenance Treatment of COPD

Arformoterol Tartrate Inhalation Solution is indicated for the long-term, twice daily (morning and evening) maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Arformoterol Tartrate Inhalation Solution is for use by nebulization only.

1.2 Important Limitations of Use

Arformoterol Tartrate Inhalation Solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease [ see Warnings and Precautions ( 5.2) ].

Arformoterol Tartrate Inhalation Solution is not indicated to treat asthma. The safety and effectiveness of Arformoterol Tartrate Inhalation Solution in asthma have not been established.

5.1 Serious Asthma-Related Events - Hospitalizations, Intubations, Deaths

• The safety and efficacy of Arformoterol Tartrate Inhalation Solution in patients with asthma have not been established. Arformoterol Tartrate Inhalation Solution is not indicated for the treatment of asthma [ see Contraindications ( 4) ].
• Use of long-acting beta 2-adrenergic agonists (LABA) as monotherapy [without inhaled corticosteroids (ICS)] for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, and death) compared with ICS alone.
• A 28-week, placebo-controlled US study comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the LABA, including Arformoterol Tartrate Inhalation Solution.
• No study adequate to determine whether the rate of asthma-related death is increased in patients treated with Arformoterol Tartrate Inhalation Solution has been conducted. Clinical studies with racemic formoterol suggested a higher incidence of serious asthma exacerbations in patients who received racemic formoterol than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups.
• Available data do not suggest an increased risk of death with use of LABA in patients with COPD.

5.2 Deterioration of Disease and Acute Episodes

Arformoterol Tartrate Inhalation Solution should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. The use of Arformoterol Tartrate Inhalation Solution in this setting is inappropriate.

Arformoterol Tartrate Inhalation Solution is not indicated for the treatment of acute episodes of bronchospasm, i.e., as rescue therapy and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta 2-agonist.

When beginning Arformoterol Tartrate Inhalation Solution, patients who have been taking inhaled short-acting beta 2-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing Arformoterol Tartrate Inhalation Solution, the healthcare provider should also prescribe an inhaled, short-acting beta 2-agonist and instruct the patient how it should be used. Increasing inhaled beta 2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If Arformoterol Tartrate Inhalation Solution no longer controls the symptoms of bronchoconstriction, or the patient's inhaled, short-acting beta 2-agonist becomes less effective or the patient needs more inhalation of short-acting beta 2-agonist than usual, these may be markers of deterioration of disease. In this setting, a reevaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of Arformoterol Tartrate Inhalation Solution beyond the recommended 15 mcg twice daily dose is not appropriate in this situation.

5.3 Excessive Use of Arformoterol Tartrate Inhalation Solution and Use with Other Long-Acting Beta 2-Agonists

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. As with other inhaled beta 2-adrenergic drugs, Arformoterol Tartrate Inhalation Solution should not be used more often, at higher doses than recommended, or in conjunction with other medications containing long-acting beta 2-agonists.

5.4 Paradoxical Bronchospasm

As with other inhaled beta 2-agonists, Arformoterol Tartrate Inhalation Solution can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, Arformoterol Tartrate Inhalation Solution should be discontinued immediately and alternative therapy instituted.

5.5 Cardiovascular Effects

Arformoterol Tartrate Inhalation Solution, like other beta 2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic and/or diastolic blood pressure, and/or symptoms. If such effects occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T-wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Arformoterol Tartrate Inhalation Solution, as with other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.6 Coexisting Conditions

Arformoterol Tartrate Inhalation Solution, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to sympathomimetic amines. In two pooled, 12-week, placebo-controlled trials investigating Arformoterol Tartrate Inhalation Solution doses of 15 μg BID, 25 μg BID, and 50 μg QD, changes in mean predose and 2-hour post dose systolic and/or diastolic blood pressure were seen as a general fall of 2-4 mm/Hg; for pulse rate the mean of maximal increases were 8.8-12.0 beats/min. Over the course of a one-year study measuring serial electrocardiograms while receiving a dose of 50 mcg daily of Arformoterol Tartrate Inhalation Solution resulted in an approximately 3.0 ms increase in QT C-Fcompared to the active comparator, salmeterol. Doses of the related beta 2-agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.7 Hypokalemia and Hyperglycemia

Beta-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [ see Clinical Pharmacology ( 12.2) ]. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients.

Clinically significant and dose-related changes in serum potassium and blood glucose were infrequent during clinical trials with long-term administration of Arformoterol Tartrate Inhalation Solution at the recommended dose.

5.8 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of Arformoterol Tartrate Inhalation Solution as demonstrated by cases of anaphylactic reaction, urticaria, angioedema, rash and bronchospasm.

6.1 Beta 2-Agonist Adverse Reaction Profile

Adverse reactions to Arformoterol Tartrate Inhalation Solution are expected to be similar in nature to other beta 2-adrenergic receptor agonists including: angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia.

6.2 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

7.1 Adrenergic Drugs

If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of arformoterol may be potentiated [ see Warnings and Precautions ( 5.3, 5.5, 5.6, 5.7) ].

7.2 Xanthine Derivatives, Steroids, or Diuretics

Concomitant treatment with methylxanthine (aminophylline, theophylline), steroids, or diuretics may potentiate any hypokalemic effect of adrenergic agonists including Arformoterol Tartrate Inhalation Solution [ see Warnings and Precautions ( 5.7) ].

The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving Arformoterol Tartrate Inhalation Solution has not been completely evaluated. In two combined 12-week, placebo-controlled trials that included Arformoterol Tartrate Inhalation Solution doses of 15 mcg twice daily, 25 mcg twice daily, and 50 mcg once daily, 54 of 873 Arformoterol Tartrate Inhalation Solution-treated subjects received concomitant theophylline at study entry. In a 12-month controlled trial that included a 50 mcg once daily Arformoterol Tartrate Inhalation Solution dose, 30 of the 528 Arformoterol Tartrate Inhalation Solution-treated subjects received concomitant theophylline at study entry. In these trials, heart rate and systolic blood pressure were approximately 2-3 bpm and 6-8 mm Hg higher, respectively, in subjects on concomitant theophylline compared with the overall population.

7.3 Non-potassium Sparing Diuretics

The ECG changes and/or hypokalemia that may result from the administration of non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of beta-agonists, including Arformoterol Tartrate Inhalation Solution, with non-potassium sparing diuretics.

7.4 MAO Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs

Arformoterol Tartrate Inhalation Solution, as with other beta-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval because of the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.

7.5 Beta-Blockers

Beta-adrenergic receptor antagonists (beta-blockers) and Arformoterol Tartrate Inhalation Solution may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Arformoterol Tartrate Inhalation Solution is approved for use in the long-term maintenance treatment of bronchoconstriction associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. This disease does not occur in children. The safety and efficacy of Arformoterol Tartrate Inhalation Solution in pediatric patients have not been established.

8.5 Geriatric Use

Of the 873 patients who received Arformoterol Tartrate Inhalation Solution in two placebo-controlled clinical studies in adults with COPD, 391 (45%) were 65 years of age or older while 96 (11%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Among subjects age 65 years and older, 129 (33%) received Arformoterol Tartrate Inhalation Solution at the recommended dose of 15 mcg twice daily, while the remainder received higher doses. ECG alerts for ventricular ectopy in patients 65 to ≤75 years of age were comparable among patients receiving 15 mcg twice daily, 25 mcg twice daily, and placebo (3.9%, 5.2%, and 7.1%, respectively). A higher frequency (12.4%) was observed when Arformoterol Tartrate Inhalation Solution was dosed at 50 mcg once daily. The clinical significance of this finding is not known. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment

Arformoterol Tartrate Inhalation Solution should be used cautiously in patients with hepatic impairment due to increased systemic exposure in these patients [ see Clinical Pharmacology ( 12.3) ].

8.7 Renal Impairment

The systemic exposure to arformoterol was similar to renally impaired patients compared with demographically matched healthy control subjects [ see Clinical Pharmacology ( 12.3) ].

12.1 Mechanism 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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

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.

12.5 Pharmacogenomics

Arformoterol is eliminated through the action of multiple drug metabolizing enzymes. Direct glucuronidation of arformoterol is mediated by several UGT enzymes and is the primary elimination route. O-Desmethylation is a secondary route catalyzed by the CYP enzymes CYP2D6 and CYP2C19. In otherwise healthy subjects with reduced CYP2D6 and/or UGT1A1 enzyme activity, there was no impact on systemic exposure to arformoterol compared to subjects with normal CYP2D6 and/or UGT1A1 enzyme activities.

13.1 Carcinogenesis, 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 2basis).

13.2 Animal Toxicology and/or Pharmacology

14.1 Adult 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 1of 1.3 L (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 1after 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 1at 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 1values 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 Figure 1and 2 for Clinical Trial A, below. The plots include mean FEV 1change observed after the first dose and after 12 weeks of treatment. The results from Clinical Trial B were similar.

Arformoterol tartrate inhalation solution 15 mcg twice daily significantly improved bronchodilation compared to placebo over the 12 hours after dosing (FEV1 AUC0 to 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 FEV1 increase of 15%, occurred at 6.7 min. When defined as an increase in FEV1 of 12% and 200 mL, the time to onset of bronchodilation was 20 min after dosing. Peak bronchodilator effect was generally seen within 1 to 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.

Storage and Handling

Store Arformoterol Tartrate Inhalation Solution in the protective foil pouch under refrigeration at 36°-46°F (2°-8°C). Protect from light and excessive heat. After opening the pouch, unused unit-dose vials should be returned to, and stored in, the pouch. An opened unit-dose vial should be used right away. Discard any unit-dose vial if the solution is not colorless. Unopened foil pouches of Arformoterol Tartrate Inhalation Solution can also be stored at room temperature 68°-77°F (20°-25°C) for up to 6 weeks. If stored at room temperature, discard if not used after 6 weeks or if past the expiration date, whichever is sooner.

Serious Asthma-Related Events, Acute Exacerbations or Deteriorations

Patients should be informed that long-acting beta 2-adrenergic agonists, such as Arformoterol Tartrate Inhalation Solution, when used as monotherapy [without an inhaled corticosteroid], increase risk of serious asthma-related events, including asthma-related death. Arformoterol Tartrate Inhalation Solution is not indicated for the treatment of asthma.

Arformoterol Tartrate Inhalation Solution is not indicated to relieve acute respiratory symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta 2-agonist (the healthcare provider should prescribe the patient with such medication and instruct the patient in how it should be used). Patients should be instructed to seek medical attention if their symptoms worsen despite recommended doses of Arformoterol Tartrate Inhalation Solution, if Arformoterol Tartrate Inhalation Solution treatment becomes less effective, or if they need more inhalations of a short-acting beta 2-agonist than usual.

Appropriate Dosing

Patients should not stop using Arformoterol Tartrate Inhalation Solution unless told to do so by a healthcare provider because symptoms may get worse. Patients should not inhale more than one dose at any one time. The daily dosage of Arformoterol Tartrate Inhalation Solution should not exceed one unit-dose vial (15 mcg) by inhalation twice daily (30 mcg total daily dose). Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.

Concomitant Therapy

Patients who have been taking inhaled, short-acting beta 2-agonists (e.g., levalbuterol) on a regular basis should be instructed to discontinue the regular use of these products and use them only for the symptomatic relief of acute symptoms.

Arformoterol Tartrate Inhalation Solution should not be used in conjunction with other inhaled medications containing long-acting beta 2-agonists. Patients should be warned not to stop or change the dose of other concomitant COPD therapy without medical advice, even if symptoms improve after initiating treatment with Arformoterol Tartrate Inhalation Solution.

Common Adverse Reactions with Beta2-agonists

Patients should be informed that treatment with beta 2-agonists may lead to adverse reactions that include palpitations, chest pain, rapid heart rate, increased or decreased blood pressure, headache, tremor, nervousness, dry mouth, muscle cramps, nausea, dizziness, fatigue, malaise, low blood potassium, high blood sugar, high blood acid, or trouble sleeping [ see Adverse Reactions ( 6.1) ].

Instructions for Administration

It is important that patients understand how to use Arformoterol Tartrate Inhalation Solution with a nebulizer appropriately and how it should be used in relation to other medications to treat COPD they are taking [see the accompanying Patient Information]. Patients should be instructed not to mix other medications with Arformoterol Tartrate Inhalation Solution and not to inject or swallow Arformoterol Tartrate Inhalation Solution. Patients should throw the plastic dispensing vials away immediately after use. Due to their small size, the vials pose a danger of choking to young children.

Women should be advised to contact their physician if they become pregnant or if they are nursing.

FDA-Approved Patient Information

See the accompanying Patient Information.

Manufactured for:
Aucta Pharmaceuticals, Inc.
Piscataway, NJ 08854 USA

To report adverse events, call 1-800-655-9902

LB5033-00