Budesonide and Formoterol (SYMBICORT): A Review

The lung diseases asthma and chronic obstructive pulmonary disease (COPD) together afflict 40 million Americans[1],[2] and result in disability and life-threatening complications for many affected individuals. Although there is no cure for either condition, several drugs have been approved over the years to help improve patients’ symptoms and prevent acute exacerbations (sudden attacks or worsening of shortness of breath, cough or other symptoms).

One of these drugs is Symbicort, a combination of the long-acting beta agonist (LABA) formoterol and the inhaled corticosteroid (ICS) budesonide. The Food and Drug Administration (FDA) has approved Symbicort to treat both asthma and COPD.[3] Because of concerns with its effectiveness and its safety, we have designated this drug as Limited Use for certain patients with asthma and COPD.

Effectiveness

In patients with moderate or severe COPD, Symbicort is effective in improving lung function, symptoms and quality of life.[4] and in preventing acute exacerbations.[5],[6] However, in patients with milder forms of COPD, it is unknown whether Symbicort is any more effective than formoterol (or another LABA) alone.

In patients with asthma, Symbicort and other LABA/ICS combination medications are effective, but whether they are more effective than an ICS alone has long been unclear. A recent review of the best evidence on this question revealed that the addition of a LABA to an ICS did not reduce the rate of serious asthma attacks in children.[7]

In adults, the evidence seems to indicate that, for asthmatic patients whose symptoms are not well-controlled by an ICS alone, the addition of a LABA may help reduce asthma attacks and improve lung function.[8]

Safety

Like all inhaled drugs containing a corticosteroid, Symbicort can cause pneumonia, potentially at a greater rate than other inhaled therapies for COPD.[9] Other side effects of Symbicort include oral thrush (a fungal infection in the mouth), immune system suppression, sudden constriction of the airways, chest pain, high blood pressure, high heart rate or heart rhythm disturbances, decreased bone density, reduced growth in children, glaucoma, cataracts, low blood potassium and high blood sugar levels.[10]

In 2010, the FDA issued a warning against the use of LABAs without an anti-inflammatory medication (such as an ICS) because taking LABAs alone was associated with an increased risk of asthma-related death.[11] It was unclear, however, whether taking an ICS in combination with a LABA or regularly scheduled short-acting beta agonist inhaler would eliminate this risk entirely and, if so, what dose of ICS would be necessary to do so. For this reason, five very large clinical trials testing the safety of LABAs added to ICSs were mandated by the FDA in 2011.[12]

Three of these trials have now been completed and were published in 2016 in the New England Journal of Medicine.[13],[14],[15] One of these trials assessed the effects of adding formoterol to budesonide in more than 11,500 adults and adolescents with moderate to severe asthma.[16] The trial found that the addition of formoterol to budesonide did not increase the risk of serious asthma-related side effects or death and reduced the risk of asthma attacks. Importantly, the FDA has not yet released its independent assessment of this or the other two completed, agency-mandated trials. Therefore, it is premature to draw definitive conclusions from the published results. In addition, the trials excluded subjects with a history of life-threatening asthma attacks, making it impossible to determine whether LABA-containing medications are safe in these very high-risk patients.[17]

What You Can Do

For current smokers, the single most important step one can take to improve COPD or asthma symptoms (and to prevent the diseases from getting worse) is to quit smoking. Adults with either asthma or COPD should get the pneumococcal vaccine known as PPSV23 to prevent pneumonia.[18] All children with asthma should get the routine childhood pneumonia vaccines (PCV13), and children aged two or older with asthma who must take high-dose oral steroids should then get the PPSV23 vaccine.[19] If you have COPD and a very low blood oxygen level at rest, you also should be on oxygen therapy.[20]

COPD patients

Because of the risk of pneumonia and other side effects from the ICS component of Symbicort, we recommend using Symbicort or another LABA/ICS combination inhaler only if you have moderate or severe symptoms and are at high risk of a future exacerbation. You should use a combination inhaler that has the lowest ICS dose necessary to achieve some relief from your symptoms.

Asthma patients

We recommend against the use of Symbicort in children or adolescents with asthma because LABA-containing medicines may carry increased risks of asthma-related side effects[21] and provide no added benefit over an ICS alone in terms of preventing asthma attacks[22] in these age groups. In adults, because of similar safety concerns,[23] we recommend that Symbicort be used cautiously for asthma and only when symptoms or lung dysfunction are severe and do not respond adequately to an ICS alone.



References


[1]Centers for Disease Control and Prevention. Most recent asthma data. https://www.cdc.gov/asthma/most_recent_data.htm. Accessed March 8, 2017.
[2]Centers for Disease Control and Prevention. Chronic obstructive pulmonary disease (COPD). https://www.cdc.gov/copd/index.htm. Accessed February 15, 2017.
[3]AstraZeneca. Label: budesonide and formoterol (SYMBICORT). January 2017. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=fafa4cf1-99c2-43d5-73ad-51f256de3be0&type=pdf&name=fafa4cf1-99c2-43d5-73ad- 51f256de3be0. Accessed March 8, 2017.
[4]Kew KM, Dias S, Cates CJ. Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: a network meta-analysis. Cochrane Database Syst Rev. 2014;(3):CD010844.
[5]Tricco AC, Strifler L, Veroniki AA, et al. Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta-analysis. BMJ Open. 2015;5(10):e009183.
[6]Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;9:CD006829.
[7]Chauhan BF, Chartrand C, Ni Chroinin M, et al. Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children. Cochrane Database Syst Rev. 2015;(11):CD007949.
[8]Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children. Cochrane Database Syst Rev. 2010;(5):CD005535.
[9]Tricco AC, Strifler L, Veroniki AA, et al. Comparative safety and effectiveness of long-acting inhaled agents for treating chronic obstructive pulmonary disease: a systematic review and network meta-analysis. BMJ Open. 2015;5(10):e009183.
[10]AstraZeneca. Label: budesonide and formoterol (SYMBICORT). January 2017. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=fafa4cf1-99c2-43d5-73ad-51f256de3be0&type=pdf&name=fafa4cf1-99c2-43d5-73ad-51f256de3be0. Accessed February 16, 2017.
[11]Food and Drug Administration. Questions and answers: New safety requirements for long-acting asthma medications called long-acting beta agonists (LABAs). February 18, 2010. http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm200719.htm. Accessed March 8, 2017.
[12]Food and Drug Administration. FDA Drug Safety Communication: FDA requires post-market safety trials for Long- Acting Beta-Agonists (LABAs). April 15, 2011. http://www.fda.gov/Drugs/DrugSafety/ucm251512.htm. Accessed March 8, 2017.
[13]Peters SP, Bleecker ER, Canonica GW, et al. Serious asthma events with budesonide plus formoterol vs. budesonide alone. N Engl J Med. 2016;375(9):850-860.
[14]Stempel DA, Raphiou IH, Kral KM, et al. Serious asthma events with fluticasone plus salmeterol versus fluticasone alone. N Engl J Med. 2016;374(19):1822-1830.
[15]Stempel DA, Szefler SJ, Pedersen S, et al. Safety of adding salmeterol to fluticasone propionate in children with asthma. N Engl J Med. 2016;375(9):840-849.
[16]Peters SP, Bleecker ER, Canonica GW, et al. Serious asthma events with budesonide plus formoterol vs. budesonide alone. N Engl J Med. 2016;375(9):850-860.
[17]Martinez FD. Safety of Fluticasone plus Salmeterol in Asthma--Reassuring Data, but No Final Answer. N Engl J Med. 2016;374(19):1887-1888.
[18]Centers for Disease Control and Prevention. Recommended Immunization Schedule for Adults Aged 19 Years or Older, United States, 2017. https://www.cdc.gov/vaccines/schedules/hcp/imz/adult-conditions.html. Accessed February 16, 2017.
[19]Centers for Disease Control and Prevention. Recommended Immunization Schedule for Children and Adolescents Aged 18 Years or Younger, United States, 2017. https://www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-child-combined-schedule.pdf. Accessed March 10, 2017.
[20]Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (2017 Report). http://www.citizen.org/documents/wms-GOLD-2017-FINAL.pdf. Accessed March 14, 2017.
[21]Cates CJ, Oleszczuk M, Stovold E, Wieland LS. Safety of regular formoterol or salmeterol in children with asthma: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2012;;(10):CD010005.
[22]Chauhan BF, Chartrand C, Ni Chroinin M, Milan SJ, Ducharme FM. Addition of long-acting beta2-agonists to inhaled corticosteroids for chronic asthma in children. Cochrane Database Syst Rev. 2015;(11):CD007949.
[23]Cates CJ, Wieland LS, Oleszczuk M, Kew KM. Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2014;(2):CD010314.