WARNINGS AND PRECAUTIONS
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 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.
5.3 Excessive Use of BROVANA Inhalation Solution and Use with Other Long-Acting Beta-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-agonist albuterol, 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 [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.
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.
USE IN SPECIFIC POPULATIONS
Pregnancy
Teratogenic Effects:
Pregnancy Category C
There are no adequate and well-controlled studies of BROVANA Inhalation Solution in pregnant women. Arformoterol has been shown to be teratogenic in rats and rabbits. Arformoterol also caused neonatal mortality and developmental delays in rats. Because animal reproduction studies are not always predictive of human response, BROVANA Inhalation Solution should be used during pregnancy, only if the potential benefit justifies the potential risk to the fetus.
Arformoterol has been shown to be teratogenic in rats based upon findings of omphalocele (umbilical hernia), a malformation, at oral doses equal to and greater than approximately 370 times adult exposure at the maximum recommended daily inhalation dose. Increased pup loss at birth and during lactation and decreased pup weights were observed in rats at oral doses equal to and greater than approximately 1100 times adult exposure at the maximum recommended daily inhalation dose. Delays in development were evident with an oral dose approximately 2400 times adult exposure at the maximum recommended daily inhalation dose.
Arformoterol has been shown to be teratogenic in rabbits based upon findings of malpositioned right kidney, a malformation, at oral doses equal to and greater than approximately 8400 times adult exposure at the maximum recommended daily inhalation dose. Malformations including brachydactyly, bulbous aorta, and liver cysts were observed at oral doses equal to and greater than approximately 22,000 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis. Malformations including adactyly, lobular dysgenesis of the lung, and interventricular septal defect were observed at an oral dose approximately 43,000 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis. Embryolethality was observed at an oral dose approximately 43,000 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis. Decreased pup body weights were observed at oral doses equal to and greater than approximately 22,000 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis. There were no teratogenic findings in rabbits with oral doses equal to or less than approximately 4900 times adult exposure at the maximum recommended daily inhalation dose.
Labor and Delivery
There are no human studies that have investigated the effects of BROVANA Inhalation Solution on preterm labor or labor at term.
Because beta-agonists may potentially interfere with uterine contractility, BROVANA Inhalation Solution should be used during labor and delivery only if the potential benefit justifies the potential risk.
Nursing Mothers
In reproductive studies in rats, arformoterol was excreted in the milk. It is not known whether arformoterol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BROVANA Inhalation Solution is administered to a nursing woman.
Pediatric Use
BROVANA 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 BROVANA Inhalation Solution in pediatric patients have not been established.
Geriatric Use
Of the 873 patients who received BROVANA 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 BROVANA 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 BROVANA 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.
Hepatic Impairment
BROVANA Inhalation Solution should be used cautiously in patients with hepatic impairment due to increased systemic exposure in these patients [see CLINICAL PHARMACOLOGY (12.3)].
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)].
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