Budesonide and Formoterol

Pronunciation

(byoo DES oh nide & for MOH te rol)

Index Terms

• Budesonide and Eformoterol
• Eformoterol and Budesonide
• Formoterol and Budesonide
• Formoterol Fumarate Dihydrate and Budesonide

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Aerosol, Inhalation:

Symbicort: Budesonide 80 mcg and formoterol fumarate dihydrate 4.5 mcg per actuation (6.9 g, 10.2 g); Budesonide 160 mcg and formoterol fumarate dihydrate 4.5 mcg per actuation (6 g, 10.2 g)

Generic: Budesonide 160 mcg and formoterol fumarate dihydrate 4.5 mcg per actuation (10.2 g); Budesonide 80 mcg and formoterol fumarate dihydrate 4.5 mcg per actuation (10.2 g)

Brand Names: U.S.

• Symbicort

Pharmacologic Category

• Beta2 Agonist
• Beta2-Adrenergic Agonist, Long-Acting
• Corticosteroid, Inhalant (Oral)

Pharmacology

Formoterol: Relaxes bronchial smooth muscle by selective action on beta2 receptors with little effect on heart rate; formoterol has a long-acting effect.

Budesonide: A corticosteroid which controls the rate of protein synthesis, depresses the migration of polymorphonuclear leukocytes/fibroblasts, and reverses capillary permeability and lysosomal stabilization at the cellular level to prevent or control inflammation.

Use: Labeled Indications

Asthma (controller/maintenance): Treatment of asthma in patients ≥6 years of age.

Chronic obstructive pulmonary disease: Maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema; to reduce COPD exacerbations.

Off Label Uses

Asthma (reliever for acute exacerbations)

Data from 2 randomized, double-blind, parallel group trials support the use of budesonide/formoterol (single combination inhaler) as quick relief on an as-needed basis for acute asthma exacerbations in outpatients with mild to mild to moderate asthma, and reduced overall corticosteroid exposure [Bateman 2018], [O’Byrne 2018]. In addition, data from 2 studies showed a reduction in the rate of severe asthma exacerbations when compared to use of an as-needed short-acting beta agonist [Beasley 2019], [O’Byrne 2018]. Data from 2 randomized, parallel group trials support the use of budesonide/formoterol single combination inhaler for use as maintenance and reliever therapy (SMART) and was shown to reduce the risk of severe asthma exacerbations and oral systemic corticoid exposure [Patel 2013], [Rabe 2006]. Data from a meta-analysis (15 clinical trials) also support the use of budesonide/formoterol as single maintenance and reliever therapy compared to standard therapy in patients with persistent asthma and was associated with a lower risk of asthma exacerbations [Sobieraj 2018].

Based on the Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention guidelines, use of combination low dose budesonide/formoterol single inhaler in patients with asthma exacerbations may be used as both maintenance and reliever treatment and was shown to reduce exacerbations, including exacerbations requiring oral corticosteroids and hospitalizations [GINA 2020].

Contraindications

Hypersensitivity to budesonide, formoterol, or any component of the formulation; primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

Documentation of allergenic cross-reactivity for corticosteroids and/or sympathomimetics are limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to inhaled lactose.

Dosing: Adult

Note: If chronic obstructive pulmonary disease symptoms occur in the period between doses, an inhaled, short-acting beta-2 agonist (SABA) should be taken for immediate relief. For acute asthma exacerbations, budesonide/formoterol is preferred as a reliever; however, SABAs may be used. In patients presenting to primary care or acute care facility, SABAs are recommended for the acute management of exacerbations. For both Step 1 and Step 2 mild asthma, budesonide/formoterol may be used on an as-needed basis for control of asthma symptoms. Alternatively, a SABA as needed and daily use of low-dose inhaled glucocorticoid for Step 2 mild asthma may be used. Both options appear equally effective in reducing the frequency and severity of exacerbations in Step 2 mild asthma, but symptom control is somewhat better with daily inhaled glucocorticoids (Busse 2008; GINA 2020). The maximum dose is based on the formoterol component; to increase the dose of the inhaled glucocorticoid component, a separate inhaler with a higher budesonide dose per inhalation must be prescribed.

Asthma (controller/maintenance): Oral inhalation:

Starting dose is based on asthma severity.

Metered-dose inhaler:

Budesonide 80 mcg/formoterol 4.5 mcg: 2 inhalations once or twice daily (GINA 2020; Rabe 2006); if response is inadequate, may increase to higher dose combination after 1 to 2 weeks; maximum dose: Budesonide 160 mcg/formoterol 4.5 mcg: 2 inhalations twice daily.

Budesonide 160 mcg/formoterol 4.5 mcg: 2 inhalations twice daily (Patel 2013)

Dry powder inhaler [Canadian product]:

Moderate to severe asthma, inhaler used as maintenance therapy only:

Symbicort 100 Turbuhaler, Symbicort 200 Turbuhaler: 1 to 2 inhalations once or twice daily until symptom control, then titrate to lowest effective dosage to maintain control. Maximum recommended maintenance dose: 4 inhalations/day. During periods of worsening asthma, the dose may temporarily be increased up to a maximum of 8 inhalations/day.

Symbicort Forte Turbuhaler: 1 inhalation once or twice daily until symptom control, then titrate to lowest effective dosage to maintain control. Maximum dose: 4 inhalations/day.

Moderate to severe asthma, maintenance therapy (as part of a combined maintenance/reliever protocol using the same inhaler): Symbicort 100 Turbuhaler or Symbicort 200 Turbuhaler: 1 to 2 inhalations twice daily or 2 inhalations once daily.

Asthma (reliever for acute exacerbations): Oral inhalation: Note: Based on asthma severity, this regimen can be reliever only or maintenance PLUS reliever.

Metered-dose inhaler (off-label use):

Budesonide 80 mcg/formoterol 4.5 mcg or budesonide 160 mcg/formoterol 4.5 mcg: 1 inhalation as needed; may repeat if no relief (Bateman 2018; Beasley 2019; GINA 2020; O’Byrne 2018; Patel 2013; Rabe 2006). Maximum: Up to 12 inhalations/day (GINA 2020; Rabe 2006).

Dry powder inhaler [Canadian products]:

Mild persistent asthma, inhaler used as reliever therapy only: Symbicort 200 Turbuhaler: 1 inhalation as needed; may repeat if no relief after a few minutes, up to 6 inhalations per single occasion. Maximum daily dose: 8 inhalations/day.

Moderate to severe asthma, reliever therapy (as part of a combined maintenance/reliever protocol using the same inhaler): Symbicort 100 Turbuhaler or Symbicort 200 Turbuhaler: 1 inhalation as needed, may repeat if no relief for up to 6 inhalations per single occasion (maximum: 8 inhalations/day including maintenance therapy).

Chronic obstructive pulmonary disease: Oral inhalation:

Budesonide 160 mcg/formoterol 4.5 mcg: Metered-dose inhaler: 2 inhalations twice daily (maximum: 2 inhalations twice daily).

Symbicort 200 Turbuhaler [Canadian product]: Dry powder inhaler: 2 inhalations twice daily (maximum: 2 inhalations twice daily).

Symbicort Forte Turbuhaler: [Canadian product]: Dry powder inhaler: 1 inhalation twice daily (maximum: 1 inhalation twice daily).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Asthma; maintenance treatment:

Symbicort: Metered-dose inhaler: Note: Do not administer more than 2 inhalations twice daily for maintenance treatment. The maximum maintenance dose is based on the formoterol component; to increase the dose of the inhaled glucocorticoid component, a separate inhaler with a higher budesonide dose per inhalation must be prescribed. If asthma symptoms occur in the period between doses, consider an inhaled, short-acting beta-2 agonist for immediate relief.

Children 5 to <12 years (limited data available for <6 years): Budesonide 80 mcg/formoterol 4.5 mcg: Oral inhalation: 2 inhalations twice daily (NAEPP 2007).

Children ≥12 years and Adolescents: Note: Initial dose prescribed should be based upon asthma severity and risk of exacerbation:

Budesonide 80 mcg/formoterol 4.5 mcg: 2 inhalations twice daily. If adequate response is not seen after 1 to 2 weeks, consider the higher dose combination.

Budesonide 160 mcg/formoterol 4.5 mcg: 2 inhalations twice daily.

Symbicort 100 Turbuhaler, Symbicort 200 Turbuhaler [Canadian products]: Children ≥12 years and Adolescents: Dry powder inhaler: Oral inhalation:

Maintenance therapy:

Initial: 1 to 2 inhalations twice daily until symptom control, then titrate to lowest effective dosage to maintain control.

Maintenance: 1 to 2 inhalations once or twice daily; may increase to 4 inhalations twice daily as temporary treatment in periods of worsening asthma; maximum daily dose: 8 inhalations/day.

Symbicort Maintenance and Reliever Therapy (Symbicort SMART) [Canadian product]:

Maintenance: 1 to 2 inhalations twice daily or 2 inhalations once daily.

Reliever therapy: 1 additional inhalation as needed, may repeat if no relief for up to 6 inhalations total; maximum daily dose: 8 inhalations/day.

Asthma, acute exacerbation: Note: Based on asthma severity, this regimen is for use when patient is on budesonide/formoterol as maintenance to allow for a single inhaler for both maintenance PLUS reliever; the benefit seems to be greatest with very early signs of exacerbation (GINA 2018). GINA guideline and study dosing is based on the dry powder inhaler product (Turbuhaler); dry powder inhaler not available in US. Limited data available:

Children 4 to 11 years: Budesonide 80 mcg/formoterol 4.5 mcg: Dry powder inhaler: Oral inhalation:

Maintenance: 1 inhalation once daily at bedtime (Bisgaard 2006; O'Byrne 2005).

Reliever therapy: 1 inhalation as needed; may repeat if no relief; maximum daily dose: 8 inhalations/day (including maintenance dose) (Bisgaard 2006; O'Byrne 2005).

Children ≥12 years and Adolescents: Budesonide 80 mcg/formoterol 4.5 mcg: Dry powder inhaler: Oral inhalation:

Maintenance: 1 inhalation twice daily or 2 inhalations once daily at bedtime (O'Byrne 2005; Rabe 2006).

Reliever therapy: 1 inhalation as needed; may repeat if no relief; maximum daily dose: 11 inhalations/day (including maintenance dose) (O'Byrne 2018; Rabe 2006).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Administration

Metered-dose inhaler: For oral inhalation only administered every morning and evening, approximately 12 hours apart. Prior to first use, inhaler must be primed by releasing 2 test sprays into the air; shake well for 5 seconds before each spray. Inhaler must be reprimed if not used for >7 days or if it has been dropped. Shake well for 5 seconds before each use. Discard inhaler after the labeled number of inhalations have been used or within 3 months after removal from foil pouch. Rinse mouth with water (spit out without swallowing) after each use. Do not wash inhaler with water; clean mouthpiece using a dry wipe every 7 days.

Delivery of dose: Instruct patient to place mouthpiece gently between teeth, closing lips around inhaler. Instruct patient to inhale deeply, press the top counter, and hold breath for up to 10 seconds or as long as they comfortably can. Remove mouthpiece from mouth prior to exhalation. Patient should not breathe out through the mouthpiece. Wait ≥30 seconds prior to the second inhalation dose.

Dry powder inhaler: Symbicort Turbuhaler [Canadian product]:

To “load” inhaler: Turn red grip on inhaler as far as it will move in one direction, then turn in opposite direction as far as it will go (inhaler is “loaded” with a dose, indicated by a “click”). Prior to first use, this procedure should be done twice, it does not need to be repeated with subsequent uses even when not used regularly.

Delivery of dose: Instruct patient to place mouthpiece gently between teeth, closing lips around inhaler. Instruct patient to inhale deeply and hold breath for as long as they comfortably can. Remove mouthpiece prior to exhalation. Patient should not breathe out through the mouthpiece. Dose is lost if patient drops, shakes, or exhales into inhaler after a dose has been loaded. After use of the inhaler, patient should rinse mouth/oropharynx with water and spit out rinse solution. Do not wash inhaler with water; clean mouthpiece using a dry wipe every 7 days.

Storage

Symbicort 80/4.5, Symbicort 160/4.5: Store at 20°C to 25°C (68°F to 77°F) with mouthpiece down; temperatures above 49°C (120°F) may cause bursting. Contents under pressure; do not puncture, incinerate, or store near heat or open flame. Discard inhaler after the labeled number of inhalations have been used (the dose counter will read “0”) or within 3 months after removal from foil pouch.

Symbicort Turbuhaler [Canadian product]: Store at room temperature of 15°C to 30°C (59°F to 77°F).

Drug Interactions

Aldesleukin: Corticosteroids may diminish the antineoplastic effect of Aldesleukin. Avoid combination

AtoMOXetine: May enhance the tachycardic effect of Beta2-Agonists. Monitor therapy

AtoMOXetine: May enhance the hypertensive effect of Sympathomimetics. AtoMOXetine may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Atosiban: Beta2-Agonists may enhance the adverse/toxic effect of Atosiban. Specifically, there may be an increased risk for pulmonary edema and/or dyspnea. Monitor therapy

Beta2-Agonists (Long-Acting): May enhance the adverse/toxic effect of other Beta2-Agonists (Long-Acting). Avoid combination

Beta-Blockers (Beta1 Selective): May diminish the bronchodilatory effect of Beta2-Agonists. Of particular concern with nonselective beta-blockers or higher doses of the beta1 selective beta-blockers. Monitor therapy

Beta-Blockers (Nonselective): May diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination

Betahistine: May diminish the therapeutic effect of Beta2-Agonists. Monitor therapy

Caffeine and Caffeine Containing Products: May enhance the adverse/toxic effect of Formoterol. Caffeine and Caffeine Containing Products may enhance the hypokalemic effect of Formoterol. Monitor therapy

Cannabinoid-Containing Products: May enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Cocaine (Topical): May enhance the hypertensive effect of Sympathomimetics. Management: Consider alternatives to use of this combination when possible. Monitor closely for substantially increased blood pressure or heart rate and for any evidence of myocardial ischemia with concurrent use. Consider therapy modification

Cosyntropin: Corticosteroids (Orally Inhaled) may diminish the diagnostic effect of Cosyntropin. Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Budesonide (Oral Inhalation). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Budesonide (Oral Inhalation). Monitor therapy

Desmopressin: Corticosteroids (Orally Inhaled) may enhance the hyponatremic effect of Desmopressin. Avoid combination

Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Monitor therapy

Guanethidine: May enhance the arrhythmogenic effect of Sympathomimetics. Guanethidine may enhance the hypertensive effect of Sympathomimetics. Monitor therapy

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Inhalational Anesthetics: May enhance the arrhythmogenic effect of Formoterol. Monitor therapy

Linezolid: May enhance the hypertensive effect of Sympathomimetics. Management: Reduce initial doses of sympathomimetic agents, and closely monitor for enhanced pressor response, in patients receiving linezolid. Specific dose adjustment recommendations are not presently available. Consider therapy modification

Loop Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Loop Diuretics. Monitor therapy

Loxapine: Agents to Treat Airway Disease may enhance the adverse/toxic effect of Loxapine. More specifically, the use of Agents to Treat Airway Disease is likely a marker of patients who are likely at a greater risk for experiencing significant bronchospasm from use of inhaled loxapine. Management: This is specific to the Adasuve brand of loxapine, which is an inhaled formulation. This does not apply to non-inhaled formulations of loxapine. Avoid combination

Methacholine: Beta2-Agonists (Long-Acting) may diminish the therapeutic effect of Methacholine. Management: Hold long-acting beta2 agonists for 36 hours before methacholine use. Consider therapy modification

Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Ozanimod: May enhance the hypertensive effect of Sympathomimetics. Management: Concomitant use of ozanimod with sympathomimetic agents is not recommended. If combined, monitor patients closely for the development of hypertension, including hypertensive crises. Consider therapy modification

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Solriamfetol: Sympathomimetics may enhance the hypertensive effect of Solriamfetol. Sympathomimetics may enhance the tachycardic effect of Solriamfetol. Monitor therapy

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Monitor therapy

Tedizolid: May enhance the hypertensive effect of Sympathomimetics. Tedizolid may enhance the tachycardic effect of Sympathomimetics. Monitor therapy

Theophylline Derivatives: May enhance the adverse/toxic effect of Formoterol. Theophylline Derivatives may enhance the hypokalemic effect of Formoterol. Monitor therapy

Thiazide and Thiazide-Like Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Tobacco (Smoked): May diminish the therapeutic effect of Corticosteroids (Orally Inhaled). Monitor therapy

Tricyclic Antidepressants: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported incidences are for adolescents and adults unless specified otherwise. Also see individual agents.

>10%:

Central nervous system: Headache (7% to 11%; children: ≥3%)

Respiratory: Nasopharyngitis (7% to 11%), upper respiratory tract infection (4% to 11%; children: ≥3%)

1% to 10%:

Gastrointestinal: Abdominal distress (1% to 7%), oral candidiasis (1% to 6%), vomiting (1% to 3%)

Infection: Influenza (2% to 3%)

Neuromuscular & skeletal: Back pain (2% to 3%)

Respiratory: Pharyngolaryngeal pain (6% to 9%), pulmonary infection (7% to 8%), lower respiratory tract infection (3% to 8%), sinusitis (4% to 6%), bronchitis (5%), nasal congestion (3%), pharyngitis (children: ≥3%), rhinitis (children: ≥3%)

<1%, postmarketing, and/or case reports: Agitation, anaphylaxis, angina pectoris, angioedema, atrial arrhythmia, behavioral changes, bronchospasm, bruise, cataract, cough, decreased linear skeletal growth rate (pediatric patients), depression, dermatitis, dizziness, extrasystoles, glaucoma, hypercorticoidism signs and symptoms, hyperglycemia, hypersensitivity reaction, hypertension, hypokalemia, hypotension, immunosuppression, increased intraocular pressure, insomnia, muscle cramps, nausea, nervousness, palpitations, pruritus, restlessness, skin rash, tachycardia, throat irritation, tremor, urticaria, ventricular arrhythmia, voice disorder

Warnings/Precautions

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

Pregnancy Considerations

Adverse events were observed in animal reproduction studies using this combination. Refer to individual agents.

Patient Education

What is this drug used for?

• It is used to treat COPD (chronic obstructive pulmonary disease).

• It is used to treat asthma.

• This drug is not to be used to treat intense flare-ups of shortness of breath. Use a rescue inhaler. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Throat irritation

• Nose irritation

• Back pain

• Common cold symptoms

• Abdominal pain

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Infection

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit.

• Low potassium like muscle pain or weakness, muscle cramps, or an abnormal heartbeat.

• Adrenal gland problems like severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss.

• Chest pain

• Fast heartbeat

• Abnormal heartbeat

• Anxiety

• Mouth irritation

• Mouth sores

• Bone pain

• Dizziness

• Passing out

• Seizures

• Severe headache

• Tremors

• Severe nausea

• Vomiting

• Severe loss of strength and energy

• Trouble sleeping

• Burning or numbness feeling

• Flu-like symptoms

• Sinusitis

• Vision changes

• Eye pain

• Severe eye irritation

• Thrush

• Trouble breathing

• Wheezing

• Cough

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.