1.1 Maintenance Treatment of COPD

BROVANA (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. BROVANA Inhalation Solution is for use by nebulization only.

1.2 Important Limitations of Use

BROVANA Inhalation Solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease [see WARNINGS AND PRECAUTIONS (5.2)]

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

5.1 Asthma-Related Deaths [see BOXED WARNING]

Data from a large placebo-controlled study in asthma patients showed that long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. This finding is considered a class effect of LABA, including arformoterol, the active ingredient in BROVANA Inhalation Solution. The safety and efficacy of BROVANA Inhalation Solution in patients with asthma have not been established. All LABA, including BROVANA Inhalation Solution, are contraindicated in patients with asthma without use of a long-term asthma control medication [see CONTRAINDICATIONS (4)]. Data are not available to determine whether the rate of deaths in patients with COPD is increased by long-acting beta2-adrenergic agonists.

A 28-week, placebo-controlled US study comparing the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increases 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 long-acting beta2-adrenergic agonists, including BROVANA Inhalation Solution. No study adequate to determine whether the rate of asthma related death is increased in patients treated with BROVANA 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.

5.2 Deterioration of Disease and Acute Episodes

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

BROVANA 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 BROVANA 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 BROVANA 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 BROVANA 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 reeva luation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of BROVANA Inhalation Solution beyond the recommended 15 mcg twice daily dose is not appropriate in this situation.

5.3 Excessive Use of BROVANA Inhalation Solution and Use with Other Long-Acting Beta2-Agonists

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. As with other inhaled beta2-adrenergic drugs, BROVANA Inhalation Solution should not be used more often, at higher doses than recommended, or in conjunction with other medications containing long-acting beta2-agonists.

5.4 Paradoxical Bronchospasm

As with other inhaled beta2-agonists, BROVANA Inhalation Solution can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, BROVANA Inhalation Solution should be discontinued immediately and alternative therapy instituted.

5.5 Cardiovascular Effects

BROVANA 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. BROVANA 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

BROVANA 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 BROVANA Inhalation Solution doses of 15μg BID, 25μg 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 BROVANA Inhalation Solution resulted in an approximately 3.0 ms increase in QTC C-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 potassium and blood glucose were infrequent during clinical trials with long-term administration of BROVANA Inhalation Solution at the recommended dose.

5.8 Immediate Hypersensitivity Reactions

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

6.1 Beta2-Agonist Adverse Reaction Profile

Adverse reactions to BROVANA Inhalation Solution are expected to be similar in nature to other beta2-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.

The safety data described below for adults ≥35 years of age are based on 2 clinical trials of 12 weeks. In the 2 trials of 12 weeks duration, 1456 patients (860 males and 596 females, ages 34 to 89 years old) with COPD were treated with BROVANA Inhalation Solution 15 mcg twice daily, 25 mcg twice daily, 50 mcg once daily, Salmeterol 42 mcg twice daily, or placebo. The racial/ethnic distribution in these two trials included 1383 Caucasians, 49 Blacks, 10 Asians, and 10 Hispanics, and 4 patients classified as Other.

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 BROVANA Inhalation Solution [see WARNINGS AND PRECAUTIONS (5.7)].

The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving BROVANA Inhalation Solution has not been completely eva luated. In two combined 12-week placebo controlled trials that included BROVANA Inhalation Solution doses of 15 mcg twice daily, 25 mcg twice daily, and 50mcg once daily, 54 of 873 BROVANA Inhalation Solution treated subjects received concomitant theophylline at study entry. In a 12 month controlled trial that included a 50mcg once daily BROVANA Inhalation Solution dose, 30 of the 528 BROVANA 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 BROVANA Inhalation Solution with non-potassium sparing diuretics.

7.4 MAO Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs

BROVANA 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 BROVANA 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.