AstraZeneca (AZN) Announces Statistical, non-Inferiority SYMBICORT Safety Study Data in Asthma Exacerbations
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AstraZeneca (NYSE: AZN) announced results from the SYMBICORT® (budesonide/formoterol fumarate dihydrate) Inhalation Aerosol LABA (long-acting beta2-adrenergic agonist) safety study showing patients with controlled and uncontrolled asthma had a comparable risk of serious asthma-related events and a lower risk of asthma exacerbations when formoterol was combined with budesonide versus budesonide alone.
The study compared the safety of formoterol, a LABA, used in combination with budesonide, an inhaled corticosteroid (ICS)–the two active therapies in SYMBICORT pressurized metered dose inhaler (pMDI)–against budesonide (pMDI) to evaluate the risk of serious asthma-related events. These events are defined as a composite endpoint of asthma related events including asthma-related deaths, intubations, and hospitalizations, with time to first serious asthma-related event as the primary endpoint.
The results showed a comparable risk of serious asthma-related events when formoterol was combined with budesonide versus budesonide alone. Based on a predefined non-inferiority margin, the upper limit of the 95% confidence interval (CI) for the hazard ratio (HR) of the primary safety endpoint needed to be less than two. As a result, the findings demonstrated statistical non-inferiority of SYMBICORT to budesonide for time to first serious asthma-related event (HR [1.073], 95% CI, [0.698-1.650]). Furthermore, SYMBICORT therapy resulted in a 16.5% lower risk of asthma exacerbations than budesonide (HR, 0.835; 95% CI, 0.745 to 0.937; P = 0.002).
Full study results are now available in The New England Journal of Medicine. The study began in 2011 as a post-marketing requirement by the U.S. Food and Drug Administration (FDA) and all manufacturers of LABA-containing products indicated for the treatment of asthma in the U.S. were required to conduct similar studies evaluating the safety of LABAs when used in combination with an ICS.
Gregory Keenan, Vice President and Head Medical Officer, US Medical Affairs, said: “These findings reconfirm the well-established safety profile of SYMBICORT as demonstrated in our robust clinical program and extensive post-marketing surveillance from around the world. We are pleased to see the importance of ICS/LABA combination therapy in the management of asthma further validated through this study’s findings and its publication in The New England Journal of Medicine.”
The study was conducted at 534 centers in 25 countries and included patients 12 years of age or older with a documented clinical diagnosis of asthma for at least 1 year who were either currently being treated with an inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) combination, or who had asthma that was not adequately controlled on a long-term asthma control medication, or whose disease severity warranted initiation of treatment with ICS/LABA. Patients had at least one asthma exacerbation in the previous year. In total, 11,693 patients were randomized to either SYMBICORT pMDI (two inhalations of 80/4.5 micrograms or 160/4.5 micrograms) or budesonide pMDI (two inhalations of 80 micrograms or 160 micrograms) twice daily for 26 weeks. Forty-three patients receiving SYMBICORT experienced 49 serious asthma-related events and 40 patients receiving budesonide experienced 45 serious asthma-related events. Two asthma-related deaths occurred, both in the SYMBICORT arm; one of these patients also experienced an asthma-related intubation. The remaining events were asthma-related hospitalizations.
AstraZeneca has shared these results with the FDA and will soon be discussing next steps in line with post-marketing requirements.
SYMBICORT is indicated for the treatment of asthma in patients 12 years and older (also see Boxed WARNING).
SYMBICORT 160/4.5 is indicated for the maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
SYMBICORT is NOT indicated for the relief of acute bronchospasm.
IMPORTANT SAFETY INFORMATION, INCLUDING BOXED WARNING
- WARNING: Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in SYMBICORT, increase the risk of asthma-related death. A placebo-controlled study with another LABA (salmeterol) showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including formoterol. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients
- When treating patients with asthma, prescribe SYMBICORT only for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (eg, discontinue SYMBICORT) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use SYMBICORT for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids
- SYMBICORT is NOT a rescue medication and does NOT replace fast-acting inhalers to treat acute symptoms
- SYMBICORT should not be initiated in patients during rapidly deteriorating episodes of asthma or COPD
- Patients who are receiving SYMBICORT should not use additional formoterol or other LABA for any reason
- Localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with SYMBICORT. Patients should rinse the mouth after inhalation of SYMBICORT
- Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids
- Due to possible immunosuppression, potential worsening of infections could occur. A more serious or even fatal course of chickenpox or measles can occur in susceptible patients
- It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression may occur, particularly at higher doses. Particular care is needed for patients who are transferred from systemically active corticosteroids to inhaled corticosteroids. Deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids
- Caution should be exercised when considering administration of SYMBICORT in patients on long-term ketoconazole and other known potent CYP3A4 inhibitors
- As with other inhaled medications, paradoxical bronchospasm may occur with SYMBICORT
- Immediate hypersensitivity reactions may occur, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm
- Excessive beta-adrenergic stimulation has been associated with central nervous system and cardiovascular effects. SYMBICORT should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension
- Long-term use of orally inhaled corticosteroids may result in a decrease in bone mineral density (BMD). Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating SYMBICORT and periodically thereafter
- Orally inhaled corticosteroids may result in a reduction in growth velocity when administered to pediatric patients
- Glaucoma, increased intraocular pressure, and cataracts have been reported following the inhaled administration of corticosteroids, including budesonide, a component of SYMBICORT. Close monitoring is warranted in patients with a change in vision or history of increased intraocular pressure, glaucoma, or cataracts
- In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions
- SYMBICORT should be used with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines
- Beta-adrenergic agonist medications may produce hypokalemia and hyperglycemia in some patients
- The most common adverse reactions ≥3% reported in asthma clinical trials included nasopharyngitis, headache, upper respiratory tract infection, pharyngolaryngeal pain, sinusitis, influenza, back pain, nasal congestion, stomach discomfort, vomiting, and oral candidiasis
- The most common adverse reactions ≥3% reported in COPD clinical trials included nasopharyngitis, oral candidiasis, bronchitis, sinusitis, and upper respiratory tract infection
- SYMBICORT should be administered with caution to patients being treated with MAO inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents
- Beta-blockers may not only block the pulmonary effect of beta-agonists, such as formoterol, but may produce severe bronchospasm in patients with asthma
- ECG changes and/or hypokalemia associated with nonpotassium-sparing diuretics may worsen with concomitant beta-agonists. Use caution with the coadministration of SYMBICORT
Please see full Prescribing Information, including Boxed WARNING and Medication Guide.
NOTES TO EDITORS
About the Study
The global, multi-center study was a 26-week, randomized, double-blind, active-controlled clinical trial comparing SYMBICORT® (budesonide/formoterol fumarate dihydrate) Inhalation Aerosol with budesonide HFA pressurized metered dose inhaler (pMDI). The study evaluated the risk of serious asthma outcomes, defined as asthma-related hospitalizations, intubation or death, in 11,693 adult and adolescent patients 12 years of age and older with controlled and uncontrolled asthma.
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas – Respiratory and Autoimmunity, Cardiovascular and Metabolic Diseases, and Oncology. The company is also active in inflammation, infection and neuroscience through numerous collaborations. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca-us.com
Michele Meixell, +1 302 885 2677
Abigail Bozarth, +1 302 885 2677
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