Brovana

— THERAPEUTIC CATEGORIES —
  • Asthma/COPD
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Brovana Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Arformoterol tartrate 15mcg/2mL; inhalation soln.

    Pharmacological Class

    Long-acting beta-2 agonist (LABA).

    How Supplied

    Vials (2mL)—30, 60

    How Supplied

    Brovana Inhalation Solution is supplied in a single strength (15mcg of arformoterol, equivalent to 22mcg of arformoterol tartrate) as 2mL of a sterile solution in unit-dose vials.

    Brovana Inhalation Solution is available in a shelf-carton containing 30 individually pouched unit-dose vials or 60 unit-dose vials (15 x 4 unit-dose vial pouches). 

    Storage

    Brovana Inhalation Solution should be stored in the protective foil pouch under refrigeration at 36°-46°F (2°-8°C). 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. The product should be protected 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.

    Manufacturer

    Sunovion

    Generic Availability

    YES

    Mechanism of Action

    Arformoterol, the (R,R)-enantiomer of formoterol, is a selective long-acting beta2-adrenergic receptor agonist that has two-fold greater potency than racemic formoterol (which contains both the (S,S) and (R,R)-enantiomers). The 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 (cAMP). Increased intracellular cAMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

    Brovana Indications

    Indications

    Long-term maintenance treatment of bronchoconstriction in COPD, including chronic bronchitis and emphysema.

    Limitations of Use

    Not indicated to treat acute deteriorations of COPD or for treatment of asthma.

    Brovana Dosage and Administration

    Adult

    By nebulizer: 15mcg by inhalation twice daily (AM & PM); max 30mcg/day. Use standard jet (eg, PARI LC Plus) nebulizer with air compressor (eg, PARI DURA-NEB 3000). Reevaluate periodically.

    Children

    Not established.

    Elderly

    No dose adjustment required.

    Administration

    Brovana Inhalation Solution should be administered by the orally inhaled route via a standard jet nebulizer connected to an air compressor. The safety and efficacy of Brovana Inhalation Solution were established in clinical trials when administered using the PARI LC® Plus nebulizer (with a face mask or mouthpiece) and the PARI DURA NEBTM 3000 compressor. The safety and efficacy of Brovana Inhalation Solution delivered from non-compressor based nebulizer systems have not been established.

    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.

    Nursing Considerations

    Brovana Inhalation Solution is for use by nebulization only. It should not be swallowed. An opened unit-dose vial should be used right away.

    Brovana Contraindications

    Contraindications

    Use of LABA without inhaled corticosteroid (ICS) in asthma.

    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. Immediate hypersensitivity reactions may occur after administration.

    Use of a long-acting beta2-adrenergic agonist without an inhaled corticosteroid is contraindicated in patients with asthma. Brovana Inhalation Solution is not indicated for the treatment of asthma.

    Brovana Boxed Warnings

    Not Applicable

    Brovana Warnings/Precautions

    Warnings/Precautions

    LABA as monotherapy (without ICS) for asthma can increase risk of asthma-related events. Do not initiate in acute deteriorating COPD. Not for relief of acute symptoms. Prescribe a short-acting β2-agonist for acute symptoms; monitor for increased need. Do not exceed recommended dose. Discontinue if paradoxical bronchospasm or cardiovascular effects occur. Cardiovascular disease (esp. coronary insufficiency, arrhythmias, hypertension). Convulsive disorders. Thyrotoxicosis. Hyperresponsiveness to sympathomimetics. Diabetes. Ketoacidosis. Hypokalemia. Monitor potassium and blood glucose levels. Hepatic impairment. Pregnancy. Labor & delivery. Nursing mothers.

    Warnings/Precautions

    Long-acting beta2-adrenergic agonists (LABA) as monotherapy (without inhaled corticosteroids) for asthma can increase risk of asthma-related events. The increased risk of asthma-related death is considered a class effect of the LABA. There is no adequate study to determine whether the rate of asthma-related death is increased in patients treated with Brovana Inhalation Solution. Available data do not suggest an increased risk of death with use of LABA in COPD patients. Brovana Inhalation Solution is not indicated for asthma.

    Do not initiate Brovana Inhalation Solution in patients with acutely deteriorating COPD; use in this setting is inappropriate.

    Not for relief of acute symptoms; acute symptoms should be treated with inhaled short-acting beta2-agonist. Prescribe a short-acting β2-agonist for acute symptoms; monitor for increased need.

    Do not exceed the recommended dose. Fatalities have been reported with excessive use of inhaled sympathomimetic drugs.

    Discontinue if paradoxical bronchospasm or cardiovascular effects occur. 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. ECG changes have also been reported. Use with caution in patients with cardiovascular disorders (esp. coronary insufficiency, arrhythmias, hypertension). Consider discontinuing treatment if significant cardiovascular effects occur.

    Use with caution in patients with convulsive disorders.

    Use with caution in patients with thyrotoxicosis.

    Use with caution in patients who are unusually responsive to sympathomimetic amines.

    Beta-agonists may produce transient hyperglycemia in some patients. Clinically significant and dose-related changes in blood glucose were infrequent during clinical trials with long-term administration of Brovana Inhalation Solution at the recommended dose.

    Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate ketoacidosis.

    Beta-agonists may produce significant hypokalemia in some patients. This is usually transient and does not require supplementation. Clinically significant and dose-related changes in serum potassium were infrequent during clinical trials with long-term administration of Brovana Inhalation Solution at the recommended dose.

    Pregnancy Considerations

    No adequate and well-controlled studies in pregnant women. Brovana should only be used during pregnancy if the expected benefit to the patient outweighs the potential risk to the fetus. Because of the potential for beta-agonist interference with uterine contractility, use of Brovana during labor should be restricted to whom the benefits clearly outweigh the risk.

    Nursing Mother Considerations

    There are no data on the presence of arformoterol or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Brovana and any potential adverse effects on the breastfed infant from Brovana or from the underlying maternal condition.

    Pediatric Considerations

    Safety and effectiveness have not been established in pediatric patients.

    Geriatric Considerations

    No overall differences in safety or effectiveness were observed between geriatric patients (65 years and older) and younger patients. Greater sensitivity of some older individuals cannot be ruled out.

    Renal Impairment Considerations

    Systemic exposure to arformoterol was similar to renally impaired patients compared with demographically matched healthy individuals.

    Hepatic Impairment Considerations

    Should be used cautiously in patients with hepatic impairment due to increased systemic exposure in these patients.

    Brovana Pharmacokinetics

    Absorption

    Median steady-state peak (R,R)-formoterol plasma concentration time (tmax) was observed approximately one-half hour after drug administration.

    Distribution

    Binding of arformoterol to human plasma proteins in vitro was 52-65%.

    Metabolism

    Primarily metabolized by direct conjugation (glucuronidation) and secondarily by O-demethylation.

    Elimination

    Mean terminal half-life of arformoterol was 26 hours.

    Brovana Interactions

    Interactions

    See Contraindications. Avoid other sympathomimetics (except short-acting bronchodilators). Caution with MAOIs, tricyclics, or drugs known to prolong the QTc interval; may increase risk of arrhythmias. Antagonized by β-blockers. K+-depleting diuretics, theophylline, aminophylline, steroids may potentiate hypokalemia.

    Interactions

    Caution with:

    • Other sympathomimetics (except short-acting bronchodilators); sympathetic effects of arformoterol may be potentiated.
    • Βeta-blockers: block therapeutic effect of beta-agonists and may produce severe bronchospasm in COPD patients. Use beta-blockers only when medically necessary.
    • Monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants: effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents.
    • Drugs known to prolong the QTc interval: may increase risk of arrhythmias.
    • K+-depleting diuretics: hypokalemia may be potentiated with concomitant use of beta-agonists.
    • Xanthine derivatives (eg, theophylline, aminophylline): may potentiate hypokalemia and may also affect heart rate and systolic blood pressure.
    • Steroids: may potentiate hypokalemia.

    Brovana Adverse Reactions

    Adverse Reactions

    Pain, chest pain, back pain, diarrhea, sinusitis, leg cramps, dyspnea, rash, flu syndrome, peripheral edema, lung disorder; cardiovascular effects (eg, increased pulse rate or BP, ECG changes); rarely: paradoxical bronchospasm, hypersensitivity reactions.

    Adverse Reactions

    Most common adverse reactions (≥2% incidence and more common than placebo): pain, chest pain, back pain, diarrhea, sinusitis, leg cramps, dyspnea, rash, flu syndrome, peripheral edema and lung disorder.

    Long-acting beta2-adrenergic agonists, such as Brovana, as monotherapy (without inhaled corticosteroids) for asthma increase the risk of asthma-related events. Brovana Inhalation Solution is not indicated for the treatment of asthma.

    Beta2-agonist adverse reactions can include: angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia.

    Results from a double-blind, randomized, placebo-controlled.52-week safety trial in adults with moderate to severe COPD:

    • Total of 841 patients: 420 to Brovana Inhalation Solution 15mg twice daily and 421 to placebo.
    • 225 patients in the Brovana group and 211 patients in the placebo group completed 1 year of treatment.
    • Primary endpoint was time to either respiratory death or first COPD exacerbation-related hospitalization, whichever occurred first.
    • Findings showed Brovana did not increase the risk of respiratory death or COPD exacerbation-related hospitalization compared with placebo.

    Brovana Clinical Trials

    Clinical Trials

    Brovana Inhalation Solution was studied in 2 identical, 12-week, double-blind, placebo- and active-controlled, randomized, multicenter, parallel group trials.

    Patient demographics: (N=1456)

    • Age range: 34-89 years; mean age 63 years
    • 860 males, 596 females
    • 1383 Caucasions, 49 Blacks, 10 Asians, 10 Hispanics, and 4 patients classified as Other
    • Mean FEV1: 1.3L (42% of predicted)
    • 80% of patients had bronchodilator reversibility, defined as a 10% or greater increase in FEV1 after inhalation of 2 actuations (180mcg racemic albuterol from a metered dose inhaler)

    Patients were randomly assigned to Brovana 15mcg twice daily (n=288), 25mcg twice daily (n=292), 50mcg twice daily (n=293), or placebo (n=293). Both trials included salmeterol inhalation aerosol, 42mcg twice daily as an active comparator (290 patients).

    In both 12-week trials, treatment with Brovana 15mcg 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 with placebo.

    Higher doses of Brovana did not provide sufficient additional benefit on a variety of endpoints, including FEV1, to support use.

    Brovana 15mcg twice daily significantly improved bronchodilation compared with placebo over the 12 hours after dosing; improvement was maintained over the 12-week study period.

    The median time to onset of bronchodilation (defined by an FEV1 increase of 15%) following the first dose of Brovana 15mcg was 6.7 minutes. Time to onset of bronchodilation was 20 minutes when defined as an increase in FEV1 of 12% and 200mL. Peak bronchodilator effect was generally seen within 1-3 hours of dosing.

    Compared with placebo, patients treated with Brovana demonstrated improvements in peak expiratory flow rates, supplemental ipratropium and rescue albuterol use.

    Brovana Note

    Not Applicable

    Brovana Patient Counseling

    Patient Counseling

    Long-acting beta2-adrenergic agonists, such as Brovana, when used as monotherapy [without an inhaled corticosteroid], increase the risk of serious asthma-related events. Brovana is not indicated to treat asthma.

    Regular use of inhaled, short-acting beta2 agonists while on Brovana should be discontinued. Acute symptoms can be treated with an inhaled, short-acting beta2-agonist. Seek medical attention if symptoms worsen despite recommended doses of Brovana or if more than usual inhalations of a short-acting beta2-agonist are needed.

    Do not stop taking Brovana until instructed to do so. No more than 1 dose should be inhaled at any 1 time. Excessive use may cause significant cardiovascular effects and may even be fatal.

    Do not use Brovana with other medications containing long-acting beta2-agonists. Treatment with beta2-agonists can cause the following effects: palpitations, chest pain, rapid heart rate, increased or decreased blood pressure, headache, tremor, nervousness, dry mouth, muscle cramps, nausea, dizziness, fatigue, malaise, low blood potassium, high blood sugar, high blood acid, or trouble sleeping.

    Use a nebulizer to administer Brovana. Do not mix other medications into the nebulizer with Brovana. Do not inject or swallow Brovana.

    Brovana is supplied in small vials that may pose a choking risk to young children.

    Pregnant and lactating women: contact health care provider.

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