(byoo DES oh nide & for MOH te rol)
Treatment of asthma in patients ≥12 years of age where combination therapy is indicated; maintenance treatment of airflow obstruction associated with chronic obstructive pulmonary disease (COPD; including chronic bronchitis and emphysema)
Hypersensitivity to budesonide, formoterol, or any component of the formulation; need for acute bronchodilation in COPD or asthma (including status asthmaticus)
Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to inhaled lactose
Long-acting beta-2 adrenergic agonists (LABAs) such as formoterol, one of the active ingredients in budesonide/formoterol, increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of the LABAs, 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 LABAs. Available data from controlled clinical trials suggest that LABAs increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, only use budesonide/formoterol for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid, or for patients whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (eg, discontinue budesonide/formoterol) 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 budesonide/formoterol for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.
Asthma: Oral inhalation:
U.S. labeling: Symbicort 80/4.5, Symbicort 160/4.5: Two inhalations twice daily (maximum: 4 inhalations/day). Recommended starting dose combination is determined according to asthma severity. In patients not adequately controlled on the lower combination dose following 1 to 2 weeks of therapy, consider the higher dose combination.
Canadian labeling:
Symbicort 100 Turbuhaler [CAN; not available in U.S.], Symbicort 200 Turbuhaler [CAN; not available in U.S.]:
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 (maximum: 8 inhalations/day as temporary treatment in periods of worsening asthma)
Symbicort Maintenance and Reliever Therapy (Symbicort SMART): Note: Not approved in the U.S.:
Maintenance: Symbicort 100 Turbuhaler [CAN] or Symbicort 200 Turbuhaler [CAN]: 1 to 2 inhalations twice daily or 2 inhalations once daily
Reliever therapy: Symbicort 100 Turbuhaler [CAN] or Symbicort 200 Turbuhaler [CAN]: 1 additional inhalation as needed, may repeat if no relief for up to 6 inhalations total (maximum: 8 inhalations/day)
COPD: Oral inhalation:
U.S. labeling: Symbicort 160/4.5: Two inhalations twice daily (maximum: 4 inhalations/day)
Canadian labeling: Symbicort 200 Turbuhaler [CAN; not available in U.S.]: Two inhalations twice daily (maximum: 4 inhalations/day)
Refer to adult dosing.
Asthma: Oral inhalation:
Children 5 to 11 years (off-label): Symbicort 80/4.5: Two inhalations twice daily. Do not exceed 4 inhalations per day (Morice, 2008; NAEPP, 2007).
Children ≥12 years: Refer to adult dosing.
No dosage adjustment provided in the manufacturer 's labeling (has not been studied).
No dosage adjustment provided in manufacturer 's labeling (has not been studied). However, close monitoring of patients with hepatic disease may be warranted due to hepatic metabolism of both agents.
Symbicort 80/4.5, Symbicort 160/4.5: 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 (do not use the "float test " � to determine amount remaining in canister).
Symbicort Turbuhaler [CAN; not available in U.S.]:
To "load " � inhaler: Turn 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 held for 5 to 10 seconds. The amount of drug delivered is small, and the individual will not sense the medication as it is inhaled. Remove mouthpiece prior to exhalation. Patient should not breathe out through the mouthpiece. After use of the inhaler, patient should rinse mouth/oropharynx with water and spit out rinse solution.
Symbicort 80/4.5, Symbicort 160/4.5: Store at room temperature of 20 � �C to 25 � �C (68 � �F to 77 � �F) with mouthpiece down. Do not puncture, incinerate, or store near heat or open flame. Discard inhaler after the labeled number of inhalations have been used or within 3 months after removal from foil pouch.
Symbicort Turbuhaler: Store at room temperature of 15 � �C to 30 � �C. Protect from heat and moisture.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Aerosol for oral inhalation:
Symbicort 80/4.5: Budesonide 80 mcg and formoterol fumarate dihydrate 4.5 mcg per actuation (6.9 g); budesonide 80 mcg and formoterol fumarate dihydrate 4.5 mcg per actuation (10.2 g)
Symbicort 160/4.5: Budesonide 160 mcg and formoterol fumarate dihydrate 4.5 mcg per actuation (6 g); budesonide 160 mcg and formoterol fumarate dihydrate 4.5 mcg per actuation (10.2 g)
Aldesleukin: Corticosteroids may diminish the antineoplastic effect of Aldesleukin. Avoid combination
Amphotericin B: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Amphotericin B. Monitor therapy
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
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. Exceptions: Cannabidiol. Monitor therapy
Ceritinib: Corticosteroids may enhance the hyperglycemic effect of Ceritinib. Monitor therapy
Corticorelin: Corticosteroids may diminish the therapeutic effect of Corticorelin. Specifically, the plasma ACTH response to corticorelin may be blunted by recent or current corticosteroid therapy. Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Budesonide (Oral Inhalation). Monitor therapy
Deferasirox: Corticosteroids may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy
Doxofylline: Sympathomimetics may enhance the adverse/toxic effect of Doxofylline. Monitor therapy
Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification
Hyaluronidase: Corticosteroids may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving corticosteroids (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification
Inhalational Anesthetics: May enhance the arrhythmogenic effect of Formoterol. Monitor therapy
Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Avoid combination
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
Long-Acting Beta2-Agonists: May enhance the adverse/toxic effect of other Long-Acting Beta2-Agonists. Avoid combination
Loop Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Loop Diuretics. Monitor therapy
Loop Diuretics: Corticosteroids (Orally Inhaled) 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
MAO Inhibitors: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy
MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification
Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. 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
Telaprevir: May increase the serum concentration of Budesonide (Oral Inhalation). Management: Concomitant use of these agents is not recommended, unless the risk for excessive systemic corticosteroid effects is outweighed by the potential benefits. If combined, monitor patients closely for signs and symptoms of corticosteroid excess/toxicity. Consider therapy modification
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
Thiazide and Thiazide-Like Diuretics: Corticosteroids (Orally Inhaled) may enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy
Tricyclic Antidepressants: May enhance the adverse/toxic effect of Beta2-Agonists. Monitor therapy
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)
Note: Percentage of adverse events may be dose related; causation not established. Also see individual agents.
>10%:
Central nervous system: Headache (7% to 11%)
Respiratory: Nasopharyngitis (7% to 11%), upper respiratory tract infection (4% to 11%)
1% to 10%:
Central nervous system: Dizziness (<3%)
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%), lower respiratory tract infection (3% to 8%), sinusitis (4% to 6%), bronchitis (5%), nasal congestion (3%)
<1% (Limited to important or life-threatening): Agitation, anaphylaxis, angina pectoris, angioedema, anxiety, atrial arrhythmia, behavioral changes, bronchospasm, bruise, cataract, cough, decreased linear skeletal growth rate (pediatric patients), depression, dermatitis, 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
Concerns related to adverse effects:
- Adrenal suppression: May cause hypercorticism 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. 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: [U.S. Boxed Warning]: Long-acting beta2-agonists (LABAs), such as formoterol, increase the risk of asthma-related deaths; budesonide and formoterol should only be used in patients not adequately controlled on other a long-term asthma control medication (ie, inhaled corticosteroid) or whose disease severity requires initiation of two maintenance therapies. In a large, randomized, placebo-controlled U.S. clinical trial (SMART, 2006), salmeterol was associated with an increase in asthma-related deaths (when added to usual asthma therapy); risk is considered a class effect among all LABAs. Data are not available to determine if the addition of an inhaled corticosteroid lessens this increased risk of death associated with LABA use. Assess patients at regular intervals once asthma control is maintained on combination therapy to determine if step-down therapy is appropriate (without loss of asthma control), and the patient can be maintained on an inhaled corticosteroid only. LABAs are not appropriate in patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids
- Bone density: Long-term use may decrease bone mineral density in adults.
- 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. Exposure to chickenpox should be avoided; corticosteroids should not be used to treat ocular herpes simplex. Corticosteroids should not be used for cerebral malaria. Close observation is required in patients with latent tuberculosis and/or TB reactivity. Restrict use in active TB (only in conjunction with antituberculosis treatment).
- 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: Infections with Candida albicans in the mouth and throat (thrush) have been reported with use.
- 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 (Churg-Strauss syndrome) have been reported with use of inhaled corticosteroid
Disease-related concerns:
- Asthma: Appropriate use: Do not use for acute bronchospasm. Short-acting beta2-agonist (eg, albuterol) should be used for acute symptoms and symptoms occurring between treatments. Do not initiate in patients with significantly worsening or acutely deteriorating asthma.
- Cardiovascular disease: Use with caution in patients with cardiovascular disease (arrhythmia or hypertension or HF); beta agonists may cause elevation in blood pressure, heart rate and result in CNS stimulation/excitation. Beta2-agonists may also increase risk of arrhythmias.
- 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; beta2-agonists may increase serum glucose.
- Hepatic impairment: Use caution; budesonide and formoterol are hepatically cleared.
- Hypokalemia: Use with caution in patients with hypokalemia; beta2-agonists may decrease serum potassium.
- 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. Consider routine eye exams in chronic users.
- Osteoporosis: Use with caution in patients with osteoporosis; high doses and/or long-term use of corticosteroids have been associated with increased bone loss and osteoporotic fractures.
- 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 hypothyroid ones.
Concurrent drug therapy issues:
- High potential for interactions: Use with caution in patients taking strong CYP3A4 inhibitors (see Drug Interactions); consider alternative agents that avoid or lessen the potential for CYP-mediated interactions.
Special populations:
- Pediatric: [U.S. Boxed Warning]: LABAs may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Orally-inhaled and intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients (~1 centimeter per year [range 0.3-1.8 cm per year] and related to dose and duration of exposure). To minimize the systemic effects of orally-inhaled and intranasal corticosteroids, each patient should be titrated to the lowest effective dose. Growth should be routinely monitored in pediatric patients.
Dosage form specific issues:
- Lactose: Some products (available in Canada) contain lactose; very rare anaphylactic reactions have been reported in patients with severe milk protein allergy.
Other warnings/precautions:
- Discontinuation of therapy: Withdraw systemic therapy with gradual tapering of dose. There have been reports of systemic corticosteroid withdrawal symptoms (eg, joint/muscle pain, lassitude, depression) when withdrawing oral inhalation therapy.
- Patient information: Patients must be instructed to seek medical attention in cases where acute symptoms are not relieved by short-acting beta-agonist (not formoterol) or a previous level of response is diminished. Medical evaluation must not be delayed. Patients using inhaled, short acting beta2-agonists should be instructed to discontinue routine use of these medications prior to beginning treatment with Symbicort � �; short acting agents should be reserved for symptomatic relief of acute symptoms. Patients should not use additional long-acting beta2-adrenergic agonists.
C
Adverse events were observed in animal reproduction studies using this combination. Refer to individual agents.
Formoterol relaxes bronchial smooth muscle by selective action on beta2 receptors with little effect on heart rate. Formoterol has a long-acting effect. Budesonide is 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.
Asthma: 15 minutes; maximum benefit: May take ≥2 weeks
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience pharyngitis, abdominal pain, or rhinitis. Have patient report immediately to prescriber signs of infection, signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), angina, tachycardia, anxiety, mouth sores, bone pain, severe dizziness, passing out, severe headache, severe nausea, vomiting, burning or numbness feeling, difficulty speaking, vision changes, redness or white patches in mouth or throat, or signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse) (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.