arformoterol 0.0075 MG/ML Inhalation Solution [Brovana]

INDICATIONS AND USAGE Arformoterol tartrate inhalation solution is a long-acting beta 2 -adrenergic agonist (beta 2 -agonist) indicated for: Long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. ( 1.1 ) Important limitations of use: Arformoterol tartrate inhalation solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease. ( 1.2 , 5.2 ) Arformoterol tartrate inhalation solution is not indicated to treat asthma. ( 1.2 ) 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.

DOSAGE AND ADMINISTRATION The recommended dose of arformoterol tartrate inhalation solution is one 15 mcg unit-dose vial administered twice daily (morning and evening) by nebulization. A total daily dose of greater than 30 mcg (15 mcg twice daily) is not recommended. Arformoterol tartrate inhalation solution should be administered by the orally inhaled route via a standard jet nebulizer connected to an air compressor (see the accompanying Patient Information ). Arformoterol tartrate inhalation solution should not be swallowed. Arformoterol tartrate inhalation solution should be stored refrigerated in foil pouches. 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. If the recommended maintenance treatment regimen fails to provide the usual response, medical advice should be sought immediately, as this is often a sign of destabilization of COPD. Under these circumstances, the therapeutic regimen should be reevaluated and additional therapeutic options should be considered. No dose adjustment is required for patients with renal or hepatic impairment. However, since the clearance of arformoterol tartrate inhalation solution is prolonged in patients with hepatic impairment, they should be monitored closely. The drug compatibility (physical and chemical), efficacy, and safety of arformoterol tartrate inhalation solution when mixed with other drugs in a nebulizer have not been established. The safety and efficacy of arformoterol tartrate inhalation solution have been established in clinical trials when administered using the PARI LC ® Plus nebulizer (with a face mask or mouthpiece) and the PARI DURA NEB ™ 3000 compressor. The safety and efficacy of arformoterol tartrate inhalation solution delivered from non-compressor based nebulizer systems have not been established. For oral inhalation only. •A total daily dose of greater than 30 mcg is not recommended. ( 2 ) •One 15 mcg/2 mL vial every 12 hours. ( 2 ) •For use with a standard jet nebulizer (with a face mask or mouthpiece) connected to an air compressor. ( 2 )

WARNINGS AND PRECAUTIONS LABA as monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events. ( 5.1 ) Do not initiate Arformoterol Tartrate Inhalation Solution in acutely deteriorating patients. ( 5.2 ) Do not use for relief of acute symptoms. Concomitant short-acting beta2-agonists can be used as needed for acute relief. ( 5.2 ) Do not exceed the recommended dose. Excessive use of Arformoterol Tartrate Inhalation Solution, or use in conjunction with other medications containing long-acting beta2-agonists, can result in clinically significant cardiovascular effects, and may be fatal. ( 5.3 , 5.5 ) Life-threatening paradoxical bronchospasm can occur. Discontinue Arformoterol Tartrate Inhalation Solution immediately. ( 5.4 ) Use with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis, or with sensitivity to sympathomimetic drugs. ( 5.6 , 5.7 ) 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 beta2-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 beta2-agonist. When beginning Arformoterol Tartrate Inhalation Solution, patients who have been taking inhaled short-acting beta2-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 beta2-agonist and instruct the patient how it should be used. Increasing inhaled beta2-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 beta2-agonist becomes less effective or the patient needs more inhalation of short-acting beta2-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 beta2-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 beta2-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 beta2-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 QTC-F compared to the active comparator, salmeterol. Doses of the related beta2-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

CONTRAINDICATIONS Arformoterol tartrate inhalation solution is contraindicated in patients with a history of hypersensitivity to arformoterol, racemic formoterol or to any other components of this product. Use of a LABA, including arformoterol tartrate inhalation solution, without an inhaled cortisteroid is contraindicated in patients with asthma [ see Warnings and Precautions ( 5 ) ]. Arformoterol tartrate inhalation solution is not indicated for the treatment of asthma. Arformoterol tartrate inhalation solution is contraindicated in patients with a history of hypersensitivity to arformoterol, racemic formoterol or to any other components of this product. ( 4 ) Use of a LABA, including arformoterol tartrate inhalation solution without an inhaled corticosteroid is, contraindicated in patients with asthma. ( 4 )

CLINICAL PHARMACOLOGY 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 beta1-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 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 subject-specific 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), with two of these events leading to discontinuation of treatment (2 in placebo). There were no baseline occurrences of atrial fibrillation/flutter observed on 24-hour Holter monitoring in patients treated with Arformoterol Tartrate Inhalation Solution 15 mcg twice daily or placebo. New, treatment-emergent atrial fibrillation/flutter occurred in 0.4% of patients who received Arformoterol Tartrate Inhalation Solution 15 mcg twice daily and 0.3% of patients who received placebo. There was a dose-related increase in the frequency of atrial fibrillation/flutter reported in the Arformoterol Tartrate Inhalation Solution 25 mcg twice daily and 50 mcg once daily dose groups of 0.7% and 1.4%, respectively. Two cases of atrial fibrillation/flutter were reported as adverse events (1 in Arformoterol Tartrate Inhalation Solution 15 mcg twice daily and 1 in placebo). Dose-related increases in mean maximum change in heart rate in the 12 hours after dosing were also observed following 12 weeks of dosing with Arformoterol Tartrate Inhalation Solution 15 mcg twice daily (8.8 bpm), 25 mcg twice daily (9.9 bpm) and 50 mcg once daily (12 bpm) versus placebo (8.5 bpm). Tachyphylaxis/Tolerance Tolerance to the effects of inhaled beta-agonists can occur with regularly-scheduled, chronic use. In two placebo-controlled clinical trials in patients with COPD involving approximately 725 patients in each, the overall efficacy of Arformoterol Tartrate Inhalation Solution was maintained throughout the 12-week trial duration. However, tolerance to the bronchodilator effect of Arformoterol Tartrate Inhalation Solution was observed after 6 weeks of dosing, as measured by a decrease in trough FEV1. FEV1 improvement at the end of the 12-hour dosing interval decreased by approximately one-third (22.1% mean improvement after the first dose compared to 14.6% at week 12). Tolerance to the trough FEV1 bronchodilator effect of Arformoterol Tartrate Inhalation Solution was not accompanied by other clinical manifestations of tolerance in these trials. 12.3 Pharmacokinetics The pharmacokinetics (PK) of arformoterol have been investigated in healthy subjects, elderly subjects, renally and hepatically impaired subjects, and COPD pat