warnings and cautions
5 WARNINGS AND PRECAUTIONS • LABA as monotherapy (without an inhaled-corticosteroid) is associated with an increased risk of serious asthma-related events. ( 5.1 ) • Do not initiate in acutely deteriorating COPD. Do not use to relieve acute symptoms. ( 5.2 ) • Do not use in combination with an additional therapy containing a LABA because of the risk of overdosage. ( 5.3 ) • Oropharyngeal candidiasis may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 ) • Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. ( 5.5 ) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. ( 5.6 ) • Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to SYMBICORT AEROSPHERE. ( 5.7 ) • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, consider appropriate therapy. ( 5.8 ) • If paradoxical bronchospasm occurs, discontinue SYMBICORT AEROSPHERE and institute alternative therapy. ( 5.10 ) • Cardiovascular effects may occur. Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.12 ) • Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.13 ) • Glaucoma and cataracts may occur with long-term use of ICS. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use SYMBICORT AEROSPHERE long term. ( 5.14 ) • Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.15 ) • Be alert to hypokalemia and hyperglycemia. ( 5.16 ) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations and Death The safety and effectiveness of SYMBICORT AEROSPHERE in patients with asthma have not been established. SYMBICORT AEROSPHERE is not indicated for the treatment of asthma. Use of long-acting beta 2 -adrenergic agonists (LABA) as monotherapy [without inhaled corticosteroid (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 patients. These findings are considered a class effect of LABA monotherapy. When a LABA is 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 with ICS alone. Available data do not suggest an increased risk of death with use of LABA in patients with COPD. 5.2 Deterioration of Disease and Acute Episodes SYMBICORT AEROSPHERE should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. SYMBICORT AEROSPHERE has not been studied in patients with acutely deteriorating COPD. The initiation of SYMBICORT AEROSPHERE in this setting is not appropriate. SYMBICORT AEROSPHERE should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. SYMBICORT AEROSPHERE has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta 2 -agonist. When beginning treatment with SYMBICORT AEROSPHERE, patients who have been taking oral or inhaled, short-acting beta 2 -agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing SYMBICORT AEROSPHERE, the healthcare provider should also prescribe an inhaled, short acting beta 2 -agonist and instruct the patient on how it should be used. Increasing inhaled beta 2 -agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD symptoms may deteriorate acutely over a period of hours or chronically over several days or longer. If SYMBICORT AEROSPHERE no longer controls symptoms, or the patient’s inhaled, short-acting beta 2 -agonist becomes less effective or the patient needs more inhalations of short-acting beta 2 -agonist than usual, these may be markers of deterioration of disease. In this setting, re-evaluate the patient and the COPD treatment regimen at once. The daily dosage of SYMBICORT AEROSPHERE should not be increased beyond the recommended dose. 5.3 Risk Associated with Excessive Use of Long-Acting Beta 2 -Agonists, Including SYMBICORT AEROSPHERE As with other inhaled drugs containing beta 2 -adrenergic agents, SYMBICORT AEROSPHERE should not be used more often than recommended [see Dosage and Administration (2.1) ] , at higher doses than recommended, or in conjunction with other medications containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using SYMBICORT AEROSPHERE should not use another drug containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. 5.4 Oropharyngeal Candidiasis SYMBICORT AEROSPHERE contains budesonide, an ICS. Localized infections of the mouth and pharynx with Candida albicans have occurred in patients treated with orally inhaled drug products containing budesonide. Monitor patients periodically. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with SYMBICORT AEROSPHERE continues. In some cases, therapy with SYMBICORT AEROSPHERE may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following administration of SYMBICORT AEROSPHERE to help reduce the risk of oropharyngeal candidiasis. 5.5 Risk of Pneumonia Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap. 5.6 Immunosuppression and Risk of Infections Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see the respective package inserts for complete VZIG and IG prescribing information). If chicken pox develops, treatment with antiviral agents may be considered. ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.7 Transferring Patients From Systemic Corticosteroid Therapy HPA Suppression/Adrenal Insufficiency Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients during and after transfer from systemic corticosteroids to less systemically available ICS. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on dose of 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although SYMBICORT AEROSPHERE may provide control of COPD symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does not provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress, or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their healthcare practitioner for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, or a severe COPD exacerbation. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to SYMBICORT AEROSPHERE. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with SYMBICORT AEROSPHERE. Lung function (mean forced expiratory volume in 1 second [FEV 1 ]), beta-agonist use, and COPD symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Unmasking of Allergic Conditions Previously Suppressed by Systemic Corticosteroids Transfer of patients from systemic corticosteroid therapy to SYMBICORT AEROSPHERE may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). Corticosteroid Withdrawal Symptoms During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function. 5.8 Hypercorticism and Adrenal Suppression Inhaled budesonide is absorbed into the circulation and can be systemically active at higher doses. Effects of budesonide on the HPA axis are not observed with the therapeutic doses of budesonide in SYMBICORT AEROSPHERE. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA axis dysfunction [see Warnings and Precautions (5.9) and Drug Interactions (7.1) ] . Because of the possibility of systemic absorption of ICS, patients treated with SYMBICORT AEROSPHERE should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, appropriate therapy should be initiated as needed. 5.9 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of SYMBICORT AEROSPHERE with long-term ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . 5.10 Paradoxical Bronchospasm As with other inhaled therapies, SYMBICORT AEROSPHERE can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with SYMBICORT AEROSPHERE, it should be treated immediately with an inhaled, short-acting bronchodilator, SYMBICORT AEROSPHERE should be discontinued immediately, and alternative therapy should be instituted. 5.11 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions have been reported after administration of budesonide or formoterol fumarate, the components of SYMBICORT AEROSPHERE. If signs suggesting allergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing, swelling of tongue, lips, and face), urticaria, or skin rash, SYMBICORT AEROSPHERE should be stopped at once and alternative treatment should be considered [see Contraindications (4) ] . 5.12 Cardiovascular Effects SYMBICORT AEROSPHERE, like other drugs containing beta 2 ‑agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles [see Clinical Pharmacology (12.2) ] . If such effects occur, SYMBICORT AEROSPHERE may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Therefore, SYMBICORT AEROSPHERE should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, 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 (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating SYMBICORT AEROSPHERE and periodically thereafter. If significant reductions in BMD are seen and SYMBICORT AEROSPHERE is still considered medically important for that patient's COPD therapy, use of medication to treat or prevent osteoporosis should be strongly considered. 5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of ICS, including budesonide, a component of SYMBICORT AEROSPHERE. Therefore, close monitoring is warranted in patients with a change in vision or with history of increased intraocular pressure, glaucoma, and/or cataracts. Consider referral to an ophthalmologist in patients who develop ocular symptoms. 5.15 Risks of Using Sympathomimetic Amines in Certain Coexisting Conditions SYMBICORT AEROSPHERE, like all therapies containing sympathomimetic amines, should be used with caution in patients with convulsive disorders, thyrotoxicosis, or diabetes mellitus and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta 2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.16 Hypokalemia and Hyperglycemia Beta-adrenergic agonist drugs may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology (12.2) ] . The decrease in serum potassium is usually transient, not requiring supplementation. Beta 2 -agonist therapies may produce transient hyperglycemia in some patients.