Information About the Risk in Asthma
Due to an increased risk of asthma-related death, FDA has mandated that all long-acting beta agonists (LABAs) including BROVANA Inhalation Solution carry a boxed warning. The boxed warning for BROVANA Inhalation Solution reads as follows:
WARNING: ASTHMA RELATED DEATH
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 (see WARNINGS). 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).
Information About the Risk in COPD
See the full Prescribing Information for a more complete description of both the safety and efficacy associated with the use of BROVANA Inhalation Solution in the treatment of COPD
Key Data Regarding the Risk in Patients With Asthma (e.g. SMART, SNS)
The FDA's decision to require a Risk Evaluation and Mitigation Strategy (REMS) and class labeling changes to the drug labels for LABAs is based on analyses from the Salmeterol Multicenter Asthma Research Trial (SMART), the Salmeterol Nationwide Surveillance study (SNS), and a meta-analysis conducted by FDA in 2008 and discussed at the joint Pulmonary Allergy Drugs, Drug Safety and Risk Management, and Pediatric Advisory Committees, held on December 10-11, 2008.
SMART was a large, randomized, 28-week, placebo-controlled trial that evaluated a total of 26,355 patients 12 years of age and older receiving standard asthma therapy and the addition of either salmeterol or placebo. Results showed that patients receiving salmeterol were at an increased risk for asthma-related death compared to patients receiving placebo (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). Subgroup analyses were also performed and found that asthma-related death in Caucasians and African Americans occurred at a higher rate in patients using salmeterol compared to placebo. The SNS was a 16-week, double-blind study that compared the addition of salmeterol or albuterol to standard asthma therapy in 25,180 asthma patients who were 12 years of age and older. In this study, there was an increase in the number of respiratory and asthma-related deaths in the salmeterol group compared to the albuterol group (0.07% [12 out of 16,787 patients]) compared to the albuterol group (0.02% [2 out of 8393 patients] relative risk of 3.0, p=0.105]).
In preparation for the December 2008 Advisory Committee, FDA conducted a meta-analysis of 110 studies evaluating the use of LABAs in 60,954 patients with asthma. The meta-analysis used a composite endpoint to measure severe exacerbation of asthma symptoms (asthma-related death, intubation, and hospitalization). The results of the meta-analysis suggested an increased risk for severe exacerbation of asthma symptoms in patients using LABAs compared to those not using LABAs. Other meta-analyses evaluating the safety of LABAs in the treatment of asthma have not shown a significant increase in the risk for severe asthma exacerbations.
For full details regarding each of these studies and additional detailed educational materials regarding serious risks associated with the use of LABAs in the treatment of asthma including asthma-related death, please see the information provided by the FDA at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200776.htm.
Based on the available information from these studies in asthma, the FDA concludes there is an increased risk for severe exacerbation of asthma symptoms, leading to hospitalizations in pediatric and adult asthma patients as well as death in some patients using LABAs for the treatment of asthma. However, the FDA is requiring the implementation of a REMS and class-labeling changes to improve the safe use of these products.
New Prescribing Guidelines
In February 2010, the FDA announced it was requiring manufacturers to revise their drug labels because of an increased risk of severe exacerbation of asthma symptoms, leading to hospitalizations, in pediatric and adult patients, as well as death in some patients using LABAs for the treatment of asthma (see http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200776.htm).
The new recommendations in the updated label state:
- All LABA are contraindicated in patients with asthma without use of a long-term asthma control medication.
BROVANA (arformoterol tartrate) Inhalation Solution is indicated for the long term, twice daily (morning and evening) maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Sunovion Pharamceuticals Inc. does not promote or recommend the use of BROVANA Inhalation Solution for the treatment of asthma. BROVANA Inhalation Solution is not indicated for the treatment of asthma.
See the full Prescribing Information for a more complete description of both the safety and efficacy associated with the use of BROVANA Inhalation Solution in the treatment of COPD.
Currently Available LABAs and Their Approved Uses
For reference the following table summarizes the currently available LABAs and their approved uses:
| Brand Name | LABA Active Ingredient |
Corticosteroid Active Ingredient |
FDA Approved Uses |
|---|---|---|---|
| BROVANA Inhalation Solution | arformoterol | none | COPD |
| Perforomist | formoterol | none | COPD |
| Foradil Aerolizer | formoterol | none | Asthma, COPD, EIB |
| Foradil Certihaler* | formoterol | none | Asthma |
| Serevent Diskus | salmeterol | none | Asthma, COPD, EIB |
| Advair Diskus | salmeterol | fluticasone | Asthma, COPD |
| Advair HFA | salmeterol | fluticasone | Asthma |
| Dulera Inhalation Aerosol | formoterol | mometasone | Asthma |
| Symbicort | formoterol | budesonide | Asthma, COPD |
COPD: chronic obstructive pulmonary disease; EIB: exercise-induced bronchospasm
* not currently marketed in the U.S.
Prescribing Information for BROVANA Inhalation Solution
See the full Prescribing Information for BROVANA Inhalation Solution at http://www.BROVANA.com.
Patient Counseling Information for BROVANA Inhalation Solution
See full Prescribing Information for BROVANA Inhalation Solution and Medication Guide.
Patients should be instructed to read the accompanying Medication Guide with each new prescription and refill. Patients should be counseled on the following information
Asthma-Related Death
Patients should be informed that long-acting beta2-adrenergic agonists (LABA), such as BROVANA Inhalation Solution, increase the risk of asthma-related death. All LABA, including BROVANA Inhalation Solution, should not be used in patients with asthma without use of a long-term asthma control medication.
It is not known if LABA medicines, such as BROVANA Inhalation Solution, increase the risk of death in people with chronic obstructive pulmonary disease.
BROVANA Inhalation Solution is not indicated for use in asthma. The efficacy and safety of BROVANA Inhalation Solution has not been established in patients with asthma. BROVANA Inhalation Solution is used long term, 2 times each day (morning and evening), in controlling symptoms of chronic obstructive pulmonary disease (COPD) in adults with COPD.
Other Serious Risks Associated with the use of BROVANA Inhalation Solution.
There are other serious risks associated with the use of BROVANA Inhalation Solution. Information regarding these risks is available in both the BROVANA Inhalation Solution Prescribing Information and the accompanying Medication Guide. The physician and patient must appropriately weigh both the risks and benefits of using BROVANA Inhalation Solution for the treatment of COPD.
Not for Acute Symptoms
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, beta2-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, if BROVANA Inhalation Solution treatment becomes less effective, or if they need more inhalations of a short-acting beta2-agonist than usual. 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). See Warnings Section of the full Prescribing Information.
Do Not Use Additional Long-Acting beta2-Agonists
When patients are prescribed BROVANA Inhalation Solution, other long-acting beta2- agonists should not be used. See Warnings Section of the full Prescribing Information.
Dosing and Administration
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).
Patients should be advised not to increase the dose or frequency of BROVANA Inhalation Solution. If they miss a dose, they should be instructed to take their next dose at the same time they normally do.
Patients should be instructed to use BROVANA Inhalation Solution by nebulizer only and not to inject or swallow this inhalation solution.
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.
Women should be advised to contact their physician if they become pregnant or if they are nursing.
It is important that patients understand how to use BROVANA Inhalation Solution appropriately and how it should be used in relation to other medications to treat COPD they are taking (see the accompanying Medication Guide and the Instructions for Using BROVANA Inhalation Solution).
Risks Associated With Beta-Agonist Therapy
Patients should be informed that treatment with beta2-agonists may lead to adverse events which include palpitations, chest pain, rapid heart rate, tremor, or nervousness.
Medication Guide for BROVANA Inhalation Solution
See BROVANA Inhalation Solution Medication Guide at http://www.BROVANA.com.
Questions and Answers
Questions about LABA safety
- Q1. Why is FDA requiring LABA manufacturers to have a risk management program for these medicines?
- A. Despite the benefits of long-acting beta2-agonists (LABAs) in helping people with asthma, FDA's analyses indicate there is an increase in the risk of severe exacerbation of asthma symptoms leading to hospitalizations in pediatric and adult patients as well as death in some patients with asthma that use a LABA compared to patients with asthma that do not use a LABA. Because of this risk, FDA wants to make sure LABAs are used appropriately in patients with asthma. In order to ensure the safe use of these medicines, FDA is requiring the manufacturers of LABAs to develop this risk management program for healthcare professionals and patients, regardless of whether or not the individual LABA is indicated for use in asthma. BROVANA Inhalation Solution is indicated for the treatment of COPD and not for the treatment of asthma.
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- Q2. What information did FDA review to help the Agency decide to require a risk management program?
- A. FDA used a variety of studies and research in patients with asthma using a LABA. Two specific asthma studies that provided valuable information were 1) the Salmeterol Multicenter Asthma Research Trial (SMART) and 2), the Serevent Nationwide Surveillance study (SNS). Salmeterol is the LABA in Serevent. Each of these studies showed a higher risk of death for patients with asthma that used a LABA (salmeterol) compared to patients with asthma that did not use a LABA. In addition, FDA used a research method called a meta-analysis to further understand the risks associated with the use of LABAs in patients with asthma. A meta-analysis uses data from multiple studies on a particular topic to enable scientists to combine information from those studies to make scientific conclusions or recommendations in that area. For more information on these specific asthma studies, please see http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm200776.htm for more information. BROVANA Inhalation Solution in not indicated for patients with asthma.
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- Q3. What is the goal of the new risk management program for LABAs?
- A. The risk management program for BROVANA Inhalation Solution intends to inform healthcare professionals and patients about the risk of LABAs for patients with asthma without encouraging its use in asthma. It is also a goal of this program to support the appropriate use of BROVANA Inhalation Solution to treat COPD when it is medically needed. In addition the prescribing information being provided to healthcare professionals has been updated to include the latest recommendations for the safe use of this important medicine.
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- Q4. What are the key points people should know about the safe use of LABAs in patients with asthma?
- A. The key points are:
- Use of a LABA alone without use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated in the treatment of asthma.
- LABAs should not be used in patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.
- LABAs should only be used as additional therapy for patients with asthma who are currently taking but are not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid.
- Once asthma control is achieved and maintained, patients should be assessed at regular intervals and step down therapy should begin (e.g., discontinue LABA), if possible without loss of asthma control, and the patient should continue to be treated with a long-term asthma control medication, such as an inhaled corticosteroid.
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- Q5. What are the names of LABA-containing medicines used to treat asthma?
- A. Below are the names of the LABA-containing medicines approved by FDA to treat asthma:
-
Brand Name(s) Generic Name(s) Description DULERA Inhalation Aerosol formoterol and mometasone formoterol is a LABA and mometasone is a corticosteroid long-term asthma control medication Advair Diskus, Advair HFA salmeterol and fluticasone salmeterol is a LABA and fluticasone is a corticosteroid long-term asthma control medication Symbicort Inhalation Solution formoterol and budesonide salmeterol is a LABA and budesonide is a corticosteroid long-term asthma control medication Serevent Diskus salmeterol single agent LABA with no corticosteroid long-term asthma control medication Foradil Aerolizer formoterol single agent LABA with no corticosteroid long-term asthma control medication - Back to Questions & Answers
Questions about BROVANA Inhalation Solution
- Q1. Why does BROVANA Inhalation Solution have a boxed warning?
- A. BROVANA Inhalation Solution belongs to a class of drugs known as long-acting beta agonists (LABA). As a safety measure, the U.S. FDA has requested that the Boxed Warning and other labeling sections, as well as the Medication Guide, be revised for all LABA, including BROVANA Inhalation Solution, to strengthen the language indicating that LABA increase the risk of asthma-related death. Please note that BROVANA Inhalation Solution is not indicated for asthma.
- The boxed warning for BROVANA Inhalation Solution reads as follows:
-
WARNING: ASTHMA-RELATED DEATH
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 (see WARNINGS). The safety and efficacy of BROVANA in patients with asthma have not been established. All LABA, including BROVANA, are contraindicated in patients with asthma without use of a long-term asthma control medication (see CONTRAINDICATIONS).
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- Q2. What should I tell patients about the risk of asthma-related death?
- A. The efficacy and safety of BROVANA Inhalation Solution has not been established in patients with asthma.Patients should be informed that arformoterol, the active ingredient in BROVANA Inhalation Solution, increases the risk of asthma-related death in patients with asthma. See Warnings Section of the full Prescribing Information.
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- Q3. Can BROVANA Inhalation Solution be used for acute COPD symptoms?
- A. No. 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, beta2-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, if BROVANA Inhalation Solution treatment becomes less effective, or if they need more inhalations of a short-acting beta2-agonist than usual. 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). See Warnings Section of the full Prescribing Information.
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- Q4. Can additional LABAs be used with BROVANA Inhalation Solution?
- A. No. When patients are prescribed BROVANA Inhalation Solution, other long-acting beta2- agonists should not be used. See Warnings Section of the full Prescribing Information.
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- Q5. What are the risks of Beta-Agonist Therapy?
- A. Patients should be informed that treatment with beta2-agonists may lead to adverse events which include palpitations, chest pain, rapid heart rate, tremor or nervousness. See Warnings Section of the full Prescribing Information for more information.
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