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Black Box Warning
WARNING: ASTHMA RELATED DEATH
See full prescribing information for complete Boxed Warning.
* Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol 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.
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
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.
BROVANA Inhalation Solution should be administered by the orally inhaled route via a standard jet nebulizer connected to an air compressor.BROVANA Inhalation Solution should not be swallowed. BROVANA 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 BROVANA Inhalation Solution is prolonged in patients with hepatic impairment, they should be monitored closely.
The drug compatibility (physical and chemical), efficacy, and safety of BROVANA Inhalation Solution when mixed with other drugs in a nebulizer have not been established.
The safety and efficacy of BROVANA 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 BROVANA Inhalation Solution delivered from non-compressor based nebulizer systems have not been established.
DOSAGE FORMS AND STRENGTHS
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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Arformoterol tartrate in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Arformoterol tartrate in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Arformoterol tartrate in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Arformoterol tartrate in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Arformoterol tartrate in pediatric patients.
Contraindications
BROVANA Inhalation Solution is contraindicated in patients with a history of hypersensitivity to arformoterol, racemic formoterol or to any other components of this product.
All LABA, including BROVANA Inhalation Solution, are contraindicated in patients with asthma without use of a long-term asthma control medication.
Warnings
WARNING: ASTHMA RELATED DEATH
See full prescribing information for complete Boxed Warning.
* Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol 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.
Asthma-Related Deaths
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. 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 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 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.
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 reevaluation 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.
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.
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.
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.
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 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 BROVANA Inhalation Solution resulted in an approximately 3.0 ms increase in QTC-F compared to the active comparator, salmeterol. Doses of the related beta2-agonistalbuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
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. 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.
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.
Adults with COPD in Short-Term Trials (12 weeks)
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. Among the 1,456 COPD patients in two 12-week, placebo-controlled trials, 288 were treated with BROVANA Inhalation Solution 15 mcg twice daily and 293 were treated with placebo. Doses of 25 mcg twice daily and 50 mcg once daily were also evaluated.
TABLE 1 shows adverse reaction rates among patients from these two trials where the frequency was greater than or equal to 2% in the BROVANA Inhalation Solution 15 mcg twice daily group and where the rate in the BROVANA Inhalation Solution 15 mcg twice daily group exceeded the rate in the placebo group. The total number and percent of patients who reported adverse events were 202 (70%) in the 15 mcg twice daily and 219 (75%) in the placebo groups. Ten adverse events demonstrated a dose relationship: asthenia, fever, bronchitis, COPD, headache, vomiting, hyperkalemia, leukocytosis, nervousness, and tremor.
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Adverse events occurring in patients treated with BROVANA Inhalation Solution 15 mcg twice daily with a frequency of <2%, but greater than placebo, were as follows:
In these trials, the overall frequency of all cardiovascular adverse events was 6.9% in BROVANA Inhalation Solution 15 mcg twice daily and 13.3% in the placebo group. There were no frequently occurring specific cardiovascular adverse events for BROVANA Inhalation Solution (frequency ≥1% and greater than placebo). The rate of COPD exacerbations was also comparable between the BROVANA Inhalation Solution 15 mcg twice daily and placebo groups, 12.2% and 15.1%, respectively.
Postmarketing Experience
There is limited information regarding Arformoterol tartrate Postmarketing Experience in the drug label.
