Concerns related to adverse effects:
• Adrenal suppression: May cause hypercortisolism or suppression of hypothalamic-pituitary-adrenal (HPA) axis, particularly in younger children or in patients receiving high doses for prolonged periods. HPA axis suppression may lead to adrenal crisis. Withdrawal and discontinuation of a corticosteroid should be done slowly and carefully. Particular care is required when patients are transferred from systemic corticosteroids to inhaled products due to possible adrenal insufficiency or withdrawal from steroids, including an increase in allergic symptoms. Adult patients receiving >20 mg per day of prednisone (or equivalent) may be most susceptible. Fatalities have occurred due to adrenal insufficiency in asthmatic patients during and after transfer from systemic corticosteroids to aerosol steroids; aerosol steroids do not provide the systemic steroid needed to treat patients having trauma, surgery, or infections. Do not use this product to transfer patients from oral corticosteroid therapy.
• Asthma-related deaths: The use of long-acting beta-2 agonists (LABAs) as monotherapy has been associated with an increased risk of severe exacerbations and asthma-related deaths (SMART 2006; Walters 2007); additional data from other clinical trials suggests risk of asthma-related hospitalization may also be increased with LABA monotherapy in pediatric and adolescent patients. However, data from large randomized, double-blind controlled trials do not show a significant increase in risk of serious asthma-related events (including hospitalizations, intubations, and death) in adults, adolescents, and pediatric patients (aged 4 to 11 years) when fixed-dose LABAs are used with inhaled corticosteroids combined in a single inhaler compared with inhaled corticosteroid monotherapy (FDA 2017). Current guidelines recommend the use of an as-needed low-dose inhaled corticosteroid with formoterol for patients with infrequent symptoms (GINA 2020). No data exist associating LABA use with an increased risk of death in patients with COPD.
• Bone density: Long-term use of inhaled corticosteroids have been associated with decreases in bone mineral density. Use with caution in patients with major risk factors for decreased bone mineral count such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (eg, anticonvulsants or oral corticosteroids); high doses and/or long-term use of inhaled corticosteroids have been associated with decreases in bone mineral density.
• Bronchospasm: Rarely, paradoxical bronchospasm may occur with use of inhaled bronchodilating agents; this should be distinguished from inadequate response.
• Hypersensitivity reactions: Immediate hypersensitivity reactions (urticaria, angioedema, rash, bronchospasm) have been reported.
• Immunosuppression: Prolonged use of corticosteroids may increase the incidence of secondary infection, mask acute infection (including fungal infections), prolong or exacerbate viral infections, or limit response to vaccines. Avoid use if possible in patients with ocular herpes; active or quiescent tuberculosis infections of the respiratory tract; or untreated viral, fungal, or bacterial or parasitic systemic infections. Exposure to chickenpox or measles should be avoided; if the patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin or pooled intravenous immunoglobulin may be indicated; if chickenpox develops, treatment with antiviral agents may be considered. If exposure to measles, prophylaxis with pooled intramuscular immunoglobulin may be indicated.
• Lower respiratory infections: Pneumonia and other lower respiratory tract infections have been reported in patients with COPD following the use of inhaled corticosteroids; monitor COPD patients closely since pneumonia symptoms may overlap symptoms of exacerbations.
• Oral candidiasis: Local oropharyngeal Candida infections have been reported; if this occurs, treat appropriately while either continuing or interrupting (if necessary) budesonide/formoterol therapy.
• Serious effects/fatalities: Do not exceed recommended dose; serious adverse events, including fatalities, have been associated with excessive use of inhaled sympathomimetics.
• Vasculitis: Rare cases of vasculitis (eosinophilic granulomatosis with polyangiitis [formerly known as Churg-Strauss]) or other systemic eosinophilic conditions can occur; often associated with decrease and/or withdrawal of oral corticosteroid therapy following initiation of inhaled corticosteroid.
Disease-related concerns:
• Asthma: Appropriate use: For acute asthma exacerbations, budesonide/formoterol is preferred as a reliever; however, short-acting beta-2 agonists (SABAs) may be used. In patients presenting to primary care or acute care facility, SABAs are recommended for the acute management of exacerbations (GINA 2020).
• Cardiovascular disease: Use with caution in patients with cardiovascular disease (arrhythmia, coronary insufficiency, or hypertension); beta agonists may cause elevation in blood pressure, heart rate and result in CNS stimulation/excitation. Beta-2 agonists may also increase risk of arrhythmias and ECG changes, such as flattening of the T-wave, prolongation of the QTc interval, and ST segment depression. Use with caution following acute MI; corticosteroids have been associated with myocardial rupture.
• COPD: Appropriate use: Do not use for acute episodes of COPD. Do not initiate in patients with significantly worsening or acutely deteriorating COPD. Data are not available to determine if LABA use increases the risk of death in patients with COPD.
• Diabetes: Use with caution in patients with diabetes mellitus; beta-2 agonists may increase serum glucose and aggravate preexisting diabetes mellitus and ketoacidosis.
• Hepatic impairment: Use with caution in patients with hepatic impairment; may lead to accumulation of budesonide and formoterol; monitor closely.
• Hypokalemia: Use with caution in patients with hypokalemia; beta-2 agonists may decrease serum potassium (transient).
• Ocular disease: Use with caution in patients with cataracts and/or glaucoma; increased intraocular pressure, open-angle glaucoma, and cataracts have occurred with prolonged use of inhaled corticosteroids. Consider routine eye exams in chronic users.
• Seizure disorders: Use with caution in patients with seizure disorders; beta agonists may result in CNS stimulation/excitation.
• Thyroid disease: Changes in thyroid status may necessitate dosage adjustments; metabolic clearance of corticosteroids increases in hyperthyroid patients and decreases in hypothyroidism.
Special populations:
• Pediatric: LABAs when used as monotherapy, may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. When LABAs are used in a fixed-dose combination with inhaled corticosteroids, data from large clinical trials in adolescents do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to inhaled corticosteroids alone. Orally inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients (~1 centimeter per year [range 0.3 to 1.8 cm per year] and related to dose and duration of exposure). To minimize the systemic effects of orally inhaled corticosteroids, each patient should be titrated to the lowest effective dose. Growth should be routinely monitored in pediatric patients.
Other warnings/precautions:
• Discontinuation of systemic corticosteroids: Withdraw systemic corticosteroid therapy with gradual tapering of dose; consider reducing the daily prednisone dose by 2.5 mg on a weekly basis beginning after at least 1 week of inhalation therapy. Monitor lung function, beta agonist use, asthma symptoms, and for signs and symptoms of adrenal insufficiency (fatigue, lassitude, weakness, nausea and vomiting, hypotension) during withdrawal.
Monitoring Parameters
FEV1, peak flow meter and/or other pulmonary function tests; monitor growth in pediatric patients, symptom relief, monitor for increased use if short-acting beta2-adrenergic agonists (may be a sign of asthma or COPD deterioration); HPA axis suppression; bone mineral density; blood pressure, heart rate; CNS stimulation; serum glucose, serum potassium
