US FDA Updates SYMBICORT Label With LABA Safety Class Revisions And Removes Boxed WARNING For Serious Asthma-Related Outcomes

AstraZeneca today announced the U.S. Food and Drug Administration (FDA) has approved updates to the SYMBICORT ® (budesonide/formoterol fumarate dihydrate) Inhalation Aerosol labeling, including removal of the Boxed WARNING for serious asthma-related outcomes. SYMBICORT is a combination formulation containing budesonide, an inhaled corticosteroid (ICS), and formoterol, a long-acting beta 2-adrenergic agonist (LABA) bronchodilator in a single inhaler.

In 2011, to further evaluate the safety of LABAs when used in combination with ICS for the treatment of asthma, the FDA required the manufacturers of LABAs to conduct similar randomized, double-blind, controlled clinical trials comparing the addition of LABAs to ICS versus ICS alone. The required SYMBICORT study began in late 2011.

The FDA analyzed a total of four clinical trials involving 41,297 patients. Three of the four trials included adults and adolescents 12 years and older. One of the trials compared fluticasone/salmeterol to fluticasone, one compared mometasone/formoterol to mometasone, and one compared budesonide/formoterol (SYMBICORT) to budesonide. The fourth trial included pediatric patients 4-11 years and compared fluticasone/salmeterol to fluticasone.

The results did not show a significant increase in risk of a serious asthma-related event (hospitalization, intubations and death) with ICS/LABA fixed-dose combination compared with ICS alone. The trials did show that ICS/LABA combination medicines were more effective in decreasing asthma attacks (e.g., the need to use oral corticosteroids) compared to ICS alone. This additional information has been added to the ICS/LABA labels.

The four studies supported the decision to remove the Boxed WARNING for the ICS/LABA class. The labels of medicines that contain both an ICS and LABA retain a Warning and Precaution related to the increased risk of asthma-related death when LABAs are used without an ICS to treat asthma.

The full FDA Safety Communication is available here.

The most common adverse reactions =3% reported in asthma pivotal trials of SYMBICORT included nasopharyngitis, headache, upper respiratory tract infection, pharyngolaryngeal pain, sinusitis, pharyngitis, rhinitis, influenza, back pain, nasal congestion, stomach discomfort, vomiting, and oral candidiasis.

Chris Blango, VP of US Medical Affairs, Respiratory, at AstraZeneca, said: "This new labeling provides clinically relevant information on the safety profile of ICS/LABAs including SYMBICORT as a treatment option for people living with asthma, one of the most common chronic respiratory diseases. This year, SYMBICORT received two other label updates, in addition to this latest safety data update, which underscores AstraZeneca's commitment to continually validate the well-established safety profile of SYMBICORT and the importance of ICS/LABA combination therapy."

In 2017, the FDA also approved the following label updates for SYMBICORT:
  • In January 2017, SYMBICORT 80/4.5 was approved for the treatment of asthma in patients aged six up to 12 years. SYMBICORT 80/4.5 and 160/4.5 were already approved in the US to treat asthma in patients 12 years and older.
  • In September 2017, SYMBICORT160/4.5 was approved for reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD). This adds to the previously approved indication of maintenance treatment of airflow obstruction in patients with COPD including chronic bronchitis and/or emphysema.

SYMBICORT is NOT indicated for the relief of acute bronchospasm.

Full study results from the SYMBICORT Inhalation Aerosol LABA safety study were published in The New England Journal of Medicine in September 2016.

IMPORTANT SAFETY INFORMATION
  • Use of long-acting beta 2-adrenergic agonists (LABA) as monotherapy (without inhaled corticosteroids [ICS]) for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA. When LABA are used in fixed dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to ICS alone
  • 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 administration of ICS
  • 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 ICS. Deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available ICS
  • 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 ICS 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
  • ICS may result in a reduction in growth velocity when administered to pediatric patients
  • Glaucoma, increased intraocular pressure, and cataracts have been reported following the administration of ICS, 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 ICS 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, pharyngitis, rhinitis, 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

INDICATIONS

SYMBICORT is indicated for the treatment of asthma in patients 6 years and older not adequately controlled on a long-term asthma-control medication such as an ICS or whose disease warrants initiation of treatment with both an ICS and LABA. (also see DOSAGE AND ADMINISTRATION).

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/or emphysema, and to reduce COPD exacerbations.

SYMBICORT is NOT indicated for the relief of acute bronchospasm.

Please see full Prescribing Information , including Patient Information .

NOTES TO EDITORS

About Asthma

Asthma is one of the most common chronic respiratory diseases and it affects the health and day-to-day lives of approximately 25 million individuals in the United States 1. It is characterized by recurrent breathlessness and wheezing, which vary in severity and frequency from person to person. 2,3

About SYMBICORT

SYMBICORT is a combination formulation containing budesonide, an inhaled corticosteroid (ICS), and formoterol, a long-acting beta 2-adrenergic agonist bronchodilator (LABA), in a single inhaler.

About AstraZeneca in Respiratory Disease

Respiratory disease is one of AstraZeneca's main therapy areas, and the Company has a growing portfolio of medicines that reached more than 18 million patients in 2016. AstraZeneca's aim is to transform asthma and COPD treatment through inhaled combinations at the core of care, biologics for the unmet needs of specific patient populations, and scientific advancements in disease modification.

The Company is building on a 40-year heritage in respiratory disease and AstraZeneca's capability in inhalation technology spans both pMDIs and dry powder inhalers. AstraZeneca's research is focused on addressing underlying disease drivers focusing on the lung epithelium, lung immunity and lung regeneration.

About AstraZeneca

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 - Oncology, Cardiovascular & Metabolic Diseases and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. 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 and follow us on Twitter @AstraZenecaUS.

References:

1. Centers for Disease Control and Prevention. Asthma. Available at: https://www.cdc.gov/nchs/fastats/asthma.htm. Last accessed December 2017.2. NHS Choices. Asthma: Overview. Available at:  http://www.nhs.uk/conditions/asthma/Pages/Introduction.aspx. Last accessed December 2017.3. NHS Choices. Symptoms of asthma. Available at:  http://www.nhs.uk/Conditions/Asthma/Pages/Symptoms.aspx. Last accessed December 2017.

US-17086 Last Updated 12/17

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