Brovana

Brovana is a prescription medication used to used to control wheezing, shortness of breath, coughing, and chest tightness caused by chronic obstructive pulmonary disease, or COPD. Brovana belongs to a group of drugs called long-acting beta agonists (LABAs). These work by relaxing and opening air passages in the lungs, making it easier to breathe.

This medication comes in oral inhalational form and is taken twice a day, 12 hours apart, with a nebulizer machine.

Common side effects of Brovana include chest or back pain, diarrhea, and sinus congestion.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.
 

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Brovana crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using Brovana.

Bronchodilator; relatively selective long-acting β2-agonist.1 2 3 12 13

COPD

Long-term treatment of bronchoconstriction associated with COPD, including chronic bronchitis and emphysema.1 3 6

Long-acting β2-adrenergic agonists recommended as maintenance therapy in patients with moderate (e.g., forced expiratory volume in 1 second [FEV1] ≥50 but <80% of predicted) to very severe COPD (e.g., FEV1 <30% of predicted or <50% of predicted plus chronic respiratory failure) who have persistent symptoms not relieved by as-needed therapy with short-acting bronchodilators (e.g., ipratropium, β2-adrenergic agonist).5 9

Regular treatment with long-acting bronchodilators more effective and convenient than treatment with short-acting bronchodilators.5 Superiority of one long-acting bronchodilator over another currently not established.11 If inadequate response, may use a combination of long-acting bronchodilators, such as a long-acting inhaled anticholinergic agent (tiotropium) and a long-acting β2-adrenergic agonist.5 9

In patients with severe (e.g., FEV1 <50% of predicted, history of repeated exacerbations) to very severe COPD, add regular treatment with an inhaled corticosteroid to long-acting bronchodilator therapy.5 9 11 If inadequate response or limiting adverse effects occur, add or substitute extended-release oral theophylline.9 11

Not to be used for immediate relief of acute exacerbations of COPD.1 6 Use short-acting inhaled β2-agonist intermittently (as needed) for acute symptoms of COPD.1 5 (See Acute Exacerbations of COPD under Cautions.) Efficacy and safety of long-acting bronchodilators, with or without inhaled corticosteroids, during acute exacerbations of COPD not established.1 5

Contraindications

Known hypersensitivity to arformoterol, formoterol, or any ingredient in formulation.1

All long-acting β2-adrenergic agonists, including arformoterol, contraindicated in patients with asthma without concomitant use of long-term asthma controller therapy; safety and efficacy of arformoterol in patients with asthma† not established.1 (See Asthma-related Death under Cautions.)

Warnings/Precautions

Warnings

Increased risk of asthma-related death reported with long-acting β2-adrenergic agonists.1 (See REMS and also see Boxed Warning.)

All long-acting β2-adrenergic agonists, including arformoterol, contraindicated in patients with asthma without concomitant use of long-term asthma controller therapy.1 Safety and efficacy of arformoterol in patients with asthma† not established.1

Data from large placebo-controlled safety study (Salmeterol Multicenter Asthma Research Trial [SMART]) showed an increase in asthma-related deaths in patients receiving salmeterol in addition to usual asthma therapy,1 14 15 16 17 which is considered class effect of long-acting β2-adrenergic agonists, including arformoterol.1 However, no adequate studies conducted to determine whether rate of asthma-related death is increased in patients receiving arformoterol.1 (See Advice to Patients.)

While data from currently available studies do not show increased risk of asthma-related death with racemic formoterol, data from small clinical studies suggest higher incidence of serious asthma exacerbations with formoterol compared with placebo.1 7

Not known whether rate of death is increased in patients with COPD receiving arformoterol.1 2 7 Data from large placebo-controlled study (TOwards a Revolution in COPD Health [TORCH]) evaluating survival in patients with COPD receiving salmeterol, fluticasone propionate, or both drugs over a 3-year period did not reveal an increased incidence of COPD-related or overall deaths in patients receiving salmeterol in addition to usual COPD therapy.22 23

Do not initiate therapy in patients with acutely deteriorating COPD, which may be life threatening;1 not indicated for treatment of acute episodes of bronchospasm (i.e., rescue therapy).1 6 Safety and efficacy of arformoterol for relief of acute symptoms of COPD not established.1 6

Failure to respond to a previously effective dosage of arformoterol or supplemental short-acting β2-agonist (e.g., increased need for additional short-acting β2-agonist) may indicate substantially worsening COPD.1 6 Promptly reevaluate COPD therapy.1 6 Do not use extra doses of arformoterol alone or with other long-acting, inhaled β2-adrenergic agonists (e.g., formoterol) for maintenance therapy of COPD or any other reason.1 2 6 7

Possible clinically important changes in systolic and/or diastolic BP, heart rate, ECG (e.g., flattening of T wave, prolongation of QTc interval, ST-segment depression) changes, and/or cardiovascular symptoms.1 3 6 13 Such effects uncommon with recommended dosage; may require discontinuance of drug.1 6

Use with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, or hypertension.1 6

Fatalities associated with excessive use of inhaled sympathomimetic drugs.1 6 Do not use higher than recommended dosage of arformoterol.1 6

Patients receiving arformoterol should not use additional arformoterol or other long-acting β2-adrenergic agonists for maintenance treatment of COPD.1 2 6

Sensitivity Reactions

Immediate hypersensitivity reactions (e.g., anaphylactic reactions, urticaria, angioedema, rash, bronchospasm) reported.1 6

Major Toxicities

Possible acute, life-threatening, paradoxical bronchospasm may occur.1 6

Discontinue therapy immediately if bronchospasm occurs and institute alternative therapy.1 6

General Precautions

Possible hypokalemia; may increase risk of adverse cardiovascular effects.1 3 6 9 11 Hypokalemia usually transient, not requiring supplementation.1

Clinically important changes in blood glucose concentrations possible during long-term therapy at recommended dosage.1 3 6

Use with caution in patients with thyrotoxicosis.1 6

Use with caution in patients with seizure disorders and those unusually responsive to sympathomimetic amines.1 6

Specific Populations

Category C.1

Distributed into milk in rats.1 Not known whether distributed into human milk.1 Use caution.1

Safety and efficacy not established.1 COPD does not occur in children.1

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 Incidence of ventricular ectopy in geriatric patients 65–75 years of age with arformoterol comparable to that with placebo.1

Because plasma concentrations of arformoterol may be increased in patients with hepatic impairment, use with caution and monitor patients closely.1 (See Absorption under Pharmacokinetics.)

Common Adverse Effects

Pain (unspecified),1 chest pain,1 back pain,1 diarrhea,1 sinusitis,1 leg cramps,1 dyspnea,1 rash,1 flu syndrome,1 peripheral edema,1 lung disorder.1

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• If you have high blood sugar (diabetes), Brovana may sometimes raise blood sugar. Talk with your doctor about how to keep your blood sugar under control.
• Call your doctor right away if your breathing problems get worse, if your rescue inhaler does not work as well, or if you need to use your rescue inhaler more often.
• Do not take more of this medicine or use it more often than you have been told. Deaths have happened when too much of this type of drug has been taken. Talk with your doctor.
• If you are 65 or older, use Brovana with care. You could have more side effects.
• Do not give to a child. Talk with your doctor.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Brovana (arformoterol tartrate) Inhalation Solution is supplied as a sterile solution for nebulization in low-density polyethylene unit-dose vials. Each 2 mL vial contains 15 mcg of arformoterol equivalent to 22 mcg of arformoterol tartrate.

Mechanism of Action

Arformoterol, the (R,R)-enantiomer of formoterol, is a selective long-acting beta2-adrenergic receptor agonist (beta2-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 beta2-agonist than the (R,R)-enantiomer. While it is recognized that beta2-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 beta2-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 beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-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.

Pharmacodynamics

Systemic Safety and Pharmacokinetic/Pharmacodynamic Relationships

The predominant adverse effects of inhaled beta2-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) Brovana 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 Brovana 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 Brovana 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 Brovana Inhalation Solution on QT interval was evaluated in a dose-ranging study following multiple doses of Brovana 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 Brovana Inhalation Solution on cardiac repolarization after 2 weeks of treatment. The maximum mean change in subject-specific QTc for the Brovana 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 Brovana 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 Brovana 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 Brovana 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 Brovana 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 Brovana Inhalation Solution 15 mcg twice daily and 6.9% and 1.0% in placebo. In patients who received Brovana 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 Brovana 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 Brovana Inhalation Solution 15 mcg twice daily or placebo. New, treatment-emergent atrial fibrillation/flutter occurred in 0.4% of patients who received Brovana 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 Brovana 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 Brovana 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 Brovana 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 Brovana Inhalation Solution was maintained throughout the 12-week trial duration. However, tolerance to the bronchodilator effect of Brovana 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 Brovana Inhalation Solution was not accompanied by other clinical manifestations of tolerance in these trials.

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.

Absorption

In COPD patients administered 15 mcg arformoterol every 12 hours for 14 days, the mean steady-state peak (R,R)-formoterol plasma concentration (Cmax) and systemic exposure (AUC0-12h) were 4.3 pg/mL and 34.5 pg•hr/mL, respectively. The median steady-state peak (R,R)-formoterol plasma concentration time (tmax) 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 (AUC0-12h) 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 Cmax 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 post-treatment with activated charcoal resulted in a geometric mean decrease in (R,R)-formoterol AUC0-6h by 27% and Cmax 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 8.9 L/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 gender upon the pharmacokinetics of arformoterol.

Race

The influence of race on arformoterol pharmacokinetics was assessed using a population PK analysis and data from healthy subjects. There was no clinically significant impact of race upon the pharmacokinetic profile of arformoterol.

Geriatric

The pharmacokinetic profile of arformoterol in 24 elderly subjects (aged 65 years or older) was compared to a younger cohort of 24 subjects (18-45 years) that were matched for body weight and gender. No significant differences in systemic exposure (AUC and Cmax) were observed when the two groups were compared.

Pediatric

The pharmacokinetics of arformoterol have not been studied in pediatric subjects.

Hepatic Impairment

The pharmacokinetic profile of arformoterol was assessed in 24 subjects with mild, moderate, and severe hepatic impairment. The systemic exposure (Cmax and AUC) to arformoterol increased 1.3 to 2.4-fold in subjects with hepatic impairment compared to 16 demographically matched healthy control subjects. No clear relationship between drug exposure and the severity of hepatic impairment was observed. Brovana Inhalation Solution should be used cautiously in patients with hepatic impairment.

Renal Impairment

The impact of renal disease upon the pharmacokinetics of arformoterol was studied in 24 subjects with mild, moderate, or severe renal impairment. Systemic exposure (AUC and Cmax) to arformoterol was similar in renally impaired patients compared with demographically matched healthy control subjects.

Drug-Drug Interaction

When paroxetine, a potent inhibitor of CYP2D6, was co-administered with Brovana Inhalation Solution at steady-state, exposure to either drug was not altered. Dosage adjustments of Brovana Inhalation Solution are not necessary when the drug is given concomitantly with potent CYP2D6 inhibitors.

Arformoterol did not inhibit CYP1A2, CYP2A6, CYP2C9/10, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11 enzymes at >1,000-fold higher concentrations than the expected peak plasma concentrations following a therapeutic dose.

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.

Adult COPD Trials

Brovana (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 FEV1 of 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 FEV1 ≤65% of predicted value and >0.70 L, and a FEV1/forced vital capacity (FVC) ratio ≤70%). About 80% of patients in these studies had bronchodilator reversibility, defined as a 10% or greater increase in FEV1 after inhalation of 2 actuations (180 mcg racemic albuterol from a metered dose inhaler). Both trials compared Brovana 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, Brovana Inhalation Solution 15 mcg twice daily resulted in a statistically significant change of approximately 11% in mean FEV1 (as measured by percent change from study baseline FEV1 at the end of the dosing interval over the 12 weeks of treatment, the primary efficacy endpoint) compared to placebo. Compared to Brovana Inhalation Solution 15 mcg twice daily, Brovana Inhalation Solution 25 mcg twice daily and 50 mcg once daily did not provide sufficient additional benefit on a variety of endpoints, including FEV1, to support the use of higher doses. Plots of the mean change in FEV1 values obtained over the 12 hours after dosing for the Brovana 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 FEV1 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 FEV1 Over Time for Clinical Trial A at Week 0 (Day 1)

Figure 2 Mean Change in FEV1 Over Time for Clinical Trial A at Week 12

Brovana Inhalation Solution 15 mcg twice daily significantly improved bronchodilation compared to placebo over the 12 hours after dosing (FEV1 AUC0-12h). This improvement was maintained over the 12-week study period.

Following the first dose of Brovana 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 1-3 hours of dosing.

In both clinical trials, compared to placebo, patients treated with Brovana Inhalation Solution demonstrated improvements in peak expiratory flow rates, supplemental ipratropium and rescue albuterol use.

Brovana (arformoterol tartrate) Inhalation Solution is supplied in a single strength (15 mcg of arformoterol, equivalent to 22 mcg of arformoterol tartrate) as 2 mL of a sterile solution in low-density polyethylene (LDPE) unit-dose vials overwrapped in foil. Brovana Inhalation Solution is available in a shelf-carton containing 30 or 60 unit-dose vials.

NDC 63402-911-30: carton of 30 individually pouched unit-dose vials.

NDC 63402-911-64: carton of 60 unit-dose vials (15×4 unit-dose vial pouches).

Storage and Handling

Store Brovana 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 Brovana 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.

You should not use Brovana if you are allergic to arformoterol.

Salmeterol, a medicine similar to arformoterol, has been shown to increase the risk of asthma-related death. It is not known whether Brovana could cause this same effect in people with chronic obstructive pulmonary disease. Use only the prescribed dose of this medication, and do not use it for longer than your doctor recommends. Follow all patient instructions for safe use. Talk with your doctor about your individual risks and benefits of using Brovana inhalation.

To make sure Brovana inhalation is safe for you, tell your doctor if you have:

• heart disease, a heart rhythm disorder, or high blood pressure;

• epilepsy or other seizure disorder;

• diabetes;

• glaucoma;

• a thyroid disorder;

• liver disease; or

• a personal or family history of Long QT syndrome.

It is not known whether Brovana will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether arformoterol inhalation passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Do not give Brovana to anyone under 18 years old without your doctor's advice.

Usual Adult Dose for Chronic Obstructive Pulmonary Disease -- Maintenance:

15 micrograms by nebulization twice a day (morning and evening). A total daily dose greater than 30 micrograms is not recommended.

Skip the missed dose and wait until your next regularly scheduled dose. Do not use two doses at the same time. It is important to use Brovana inhalation regularly to get the most benefit. Get your prescription refilled before you run out of medicine completely.