Brovana Information
Brovana () Indications And Usage
Brovana () Inhalation Solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease [see ]
Brovana () Inhalation Solution is not indicated to treat asthma. The safety and effectiveness of Brovana () Inhalation Solution in asthma have not been established.
Brovana () Dosage And Administration
The recommended dose of Brovana () (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 (see the accompanying ). 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 facemask or mouth piece) 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.
Brovana () Dosage Forms And Strengths
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.
Brovana () 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 [see ].
Brovana () Warnings And Precautions
[see ]
Data from a large placebo-controlled study in asthma patients showed that long-acting beta-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 ]. Data are not available to determine whether the rate of deaths in patients with COPD is increased by long-acting beta-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 beta-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.
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 beta-agonist.
When beginning Brovana () Inhalation Solution, patients who have been taking inhaled short-acting beta-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 beta-agonist and instruct the patient how it should be used. Increasing inhaled beta-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 beta-agonist becomes less effective or the patient needs more inhalation of short-acting beta-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.
Beta-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see ]. 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.
Brovana () Adverse Reactions
Brovana () Drug Interactions
Concomitant treatment with methylxanthine (aminophylline, theophylline), steroids, or diuretics may potentiate any hypokalemic effect of adrenergic agonists including Brovana () Inhalation Solution [see ].
The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving Brovana () Inhalation Solution has not been completely evaluated. In two combined 12-week placebo controlled trials that included Brovana () Inhalation Solution doses of 15 mcg twice daily, 25 mcg twice daily, and 50 mcg 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 50 mcg 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.
Brovana () Use In Specific Populations
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.
Brovana () Drug Abuse And Dependence
There were no reported cases of abuse or evidence of drug dependence with the use of Brovana () Inhalation Solution in the clinical trials.
Brovana () Overdosage
The expected signs and symptoms associated with overdosage of Brovana () (arformoterol tartrate) Inhalation Solution are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms listed under . Signs and symptoms may include angina, hypertension or hypotension, tachycardia, with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of Brovana () Inhalation Solution.
Treatment of overdosage consists of discontinuation of Brovana () Inhalation Solution together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Brovana () Inhalation Solution. Cardiac monitoring is recommended in cases of overdosage.
Clinical signs in dogs included flushing of the body surface and facial area, reddening of the ears and gums, tremor, and increased heart rate. A death was reported in dogs after a single oral dose of 5 mg/kg (approximately 4500 times the maximum recommended daily inhalation dose in adults on a mg/m basis). Death occurred for a rat that received arformoterol at a single inhalation dose of 1600 mcg/kg (approximately 430 times the maximum recommended daily inhalation dose in adults on a mg/m basis).
Brovana () Description
Brovana () (arformoterol tartrate) Inhalation Solution is a sterile, clear, colorless, aqueous solution of the tartrate salt of arformoterol, the (R,R)-enantiomer of formoterol.
Arformoterol is a selective beta-adrenergic bronchodilator. The chemical name for arformoterol tartrate is formamide, N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]-, (2R,3R)-2,3-dihydroxybutanedioate (1:1 salt), and its established structural formula is as follows:
The molecular weight of is 494.5 g/mol, and its empirical formula is CHNO۰CHO (1:1 salt). It is a white to off-white solid that is slightly soluble in water.
Arformoterol tartrate is the United States Adopted Name (USAN) for (R,R)-formoterol L-tartrate.
Brovana () (arformoterol tartrate) Inhalation Solution is supplied as 2 mL of arformoterol tartrate solution packaged in 2.1 mL unit-dose, low-density polyethylene (LDPE) unit-dose vials. Each unit-dose vial contains 15 mcg of arformoterol (equivalent to 22 mcg of arformoterol tartrate) in a sterile, isotonic saline solution, pH-adjusted to 5.0 with citric acid and sodium citrate.
Brovana () Inhalation Solution requires no dilution before administration by nebulization. Like all other nebulized treatments, the amount delivered to the lungs will depend upon patient factors, the nebulizer used, and compressor performance. Using the PARI LC PLUS nebulizer (with mouthpiece) connected to a PARI DURA NEB3000 compressor under conditions, the mean delivered dose from the mouthpiece (% nominal) was approximately 4.1 mcg (27.6%) at a mean flow rate of 3.3 L/min. The mean nebulization time was 6 minutes or less. Brovana () Inhalation Solution should be administered from a standard jet nebulizer at adequate flow rates via face mask or mouthpiece.
Patients should be carefully instructed on the correct use of this drug product (please refer to the accompanying ).
Brovana () Clinical Pharmacology
Arformoterol, the (R,R)-enantiomer of formoterol, is a selective long-acting beta-adrenergic receptor agonist (beta-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 beta-agonist than the (R,R)-enantiomer. While it is recognized that beta-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta-receptors are the predominant receptors in the heart, data indicate that there are also beta-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 beta-agonists may have cardiac effects.
The pharmacologic effects of beta-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.
Brovana () Nonclinical Toxicology
Long-term studies were conducted in mice using oral administration and rats using inhalation administration to evaluate the carcinogenic potential of arformoterol.
In a 24-month carcinogenicity study in CD-1 mice, arformoterol caused a dose-related increase in the incidence of uterine and cervical endometrial stromal polyps and stromal cell sarcoma in female mice at oral doses of 1 mg/kg and above (AUC exposure approximately 70 times adult exposure at the maximum recommended daily inhalation dose).
In a 24-month carcinogenicity study in Sprague-Dawley rats, arformoterol caused a statistically significant increase in the incidence of thyroid gland c-cell adenoma and carcinoma in female rats at an inhalation dose of 200 mcg/kg (AUC exposure approximately 130 times adult exposure at the maximum recommended daily inhalation dose). There were no tumor findings with an inhalation dose of 40 mcg/kg (AUC exposure approximately 55 times adult exposure at the maximum recommended daily inhalation dose).
Arformoterol was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacteria, chromosome aberration analyses in mammalian cells, and micronucleus test in mice.
Arformoterol had no effects on fertility and reproductive performance in rats at oral doses up to 10 mg/kg (approximately 2700 times the maximum recommended daily inhalation dose in adults on a mg/m basis).
Brovana () Clinical Studies
Brovana () How Supplied/storage And Handling
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).
Brovana () Patient Counseling Information
Patients should be instructed to read the accompanying Medication Guide with each new prescription and refill. The complete text of the Medication Guide is reprinted at the end of this document.
Asthma-Related Deaths, Acute Exacerbations or Deteriorations
Patients should be informed that long-acting beta-adrenergic agonists, such as Brovana () Inhalation Solution, increase risk of asthma-related death in patients with asthma.
Brovana () Inhalation Solution is not indicated to relieve acute respiratory symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting, beta-agonist (the health-care provider should prescribe the patient with such medication and instruct the patient in how it should be used). Patients should be instructed to seek medical attention if their symptoms worsen despite recommended doses of Brovana () Inhalation Solution, if Brovana () Inhalation Solution treatment becomes less effective, or if they need more inhalations of a short-acting beta-agonist than usual.
Appropriate Dosing
Patients should not stop using Brovana () Inhalation Solution unless told to do so by a healthcare provider because symptoms may get worse. Patients should not inhale more than one dose at any one time. The daily dosage of Brovana () Inhalation Solution should not exceed one unit-dose vial (15 mcg) by inhalation twice daily (30 mcg total daily dose). Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.
Concomitant Therapy
Patients who have been taking inhaled, short-acting beta-agonists (e.g., levalbuterol) on a regular basis should be instructed to discontinue the regular use of these products and use them only for the symptomatic relief of acute symptoms.
Brovana () Inhalation Solution should not be used in conjunction with other inhaled medications containing long-acting beta-agonists. Patients should be warned not to stop or change the dose of other concomitant COPD therapy without medical advice, even if symptoms improve after initiating treatment with Brovana () Inhalation Solution.
Common Adverse Reactions with Beta-agonists
Patients should be informed that treatment with beta-agonists may lead to adverse reactions that include 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 [see ].
Instructions for Administration
It is important that patients understand how to use Brovana () Inhalation Solution with a nebulizer appropriately and how it should be used in relation to other medications to treat COPD they are taking Patients should be instructed not to mix other medications with Brovana () Inhalation Solution and not to inject or swallow Brovana () Inhalation Solution. Patients should throw the plastic dispensing vials away immediately after use. Due to their small size, the vials pose a danger of choking to young children.
Women should be advised to contact their physician if they become pregnant or if they are nursing.
FDA-Approved Medication Guide
See the accompanying .
SUNOVION
Manufactured for: Marlborough, MA 01752 USABrovana () is a registered trademark of Sunovion Pharmaceuticals Inc.For customer service, call 1-888-394-7377.To report adverse events, call 1-877-737-7226.For medical information, call 1-800-739-0565.
July 2011901552R00
Brovana ()
Brovana ()
Brovana ()
