Dosage Form: aerosol
FULL PRESCRIBING INFORMATION
Long-acting beta2-adrenergic agonists (LABA), such as formoterol one of the active ingredients in Symbicort, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. study that compared the safety of another long-acting beta2-adrenergic agonist (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 LABA, 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 LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, Symbicort should only be used for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Symbicort) 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 Symbicort for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids [see Warnings and Precautions (5.1)].
Indications and Usage for Symbicort
Treatment of Asthma
Symbicort is indicated for the treatment of asthma in patients 12 years of age and older.
Long-acting beta2-adrenergic agonists, such as formoterol one of the active ingredients in Symbicort, increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see Warnings and Precautions (5.1)]. Therefore, when treating patients with asthma, Symbicort should only be used for patients not adequately controlled on a long-term asthma-control medication such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g. discontinue Symbicort) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as inhaled corticosteroid. Do not use Symbicort for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.
Important Limitations of Use:
• Symbicort is NOT indicated for the relief of acute bronchospasm.
Maintenance Treatment of Chronic Obstructive Pulmonary Disease (COPD)
Symbicort 160/4.5 is indicated for the twice daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and emphysema. Symbicort 160/4.5 is the only approved dosage for the treatment of airflow obstruction in COPD.
Important Limitations of Use: Symbicort is not indicated for the relief of acute bronchospasm.
Symbicort Dosage and Administration
Symbicort should be administered twice daily every day by the orally inhaled route only. After inhalation, the patient should rinse the mouth with water without swallowing. [see Patient Counseling Information (17.4)]
Prime Symbicort before using for the first time by releasing two test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well before each spray and releasing two test sprays into the air away from the face.
More frequent administration or a higher number of inhalations (more than 2 inhalations twice daily) of the prescribed strength of Symbicort is not recommended as some patients are more likely to experience adverse effects with higher doses of formoterol. Patients using Symbicort should not use additional long-acting beta2-agonists for any reason. [See Warnings and Precautions (5.3, 5.12)]
Asthma
If asthma symptoms arise in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.
Adult and Adolescent Patients 12 Years of Age and Older: For patients 12 years of age and older, the dosage is 2 inhalations twice daily (morning and evening, approximately 12 hours apart).
The recommended starting dosages for Symbicort for patients 12 years of age and older are based upon patients' asthma severity.
The maximum recommended dosage is Symbicort 160/4.5 mcg twice daily.
Improvement in asthma control following inhaled administration of Symbicort can occur within 15 minutes of beginning treatment, although maximum benefit may not be achieved for 2 weeks or longer after beginning treatment. Individual patients will experience a variable time to onset and degree of symptom relief.
For patients who do not respond adequately to the starting dose after 1-2 weeks of therapy with Symbicort 80/4.5, replacement with Symbicort 160/4.5 may provide additional asthma control.
If a previously effective dosage regimen of Symbicort fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, (e.g., replacing the lower strength of Symbicort with the higher strength, adding additional inhaled corticosteroid, or initiating oral corticosteroids) should be considered.
Chronic Obstructive Pulmonary Disease (COPD)
For patients with COPD the recommended dose is Symbicort 160/4.5, two inhalations twice daily.
If shortness of breath occurs in the period between doses, an inhaled, short-acting beta2-agonist should be taken for immediate relief.
Dosage Forms and Strengths
Symbicort is available as a metered-dose inhaler containing a combination of budesonide (80 or 160 mcg) and formoterol (4.5 mcg) as an inhalation aerosol in the following two strengths: 80/4.5 and 160/4.5. Each dosage strength contains 60 or 120 actuations per/canister. Each strength of Symbicort is supplied with a red plastic actuator with a gray dust cap.
Contraindications
The use of Symbicort is contraindicated in the following conditions:
• Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.
• Hypersensitivity to any of the ingredients in Symbicort.
Warnings and Precautions
Asthma-Related Death
Long-acting beta2-adrenergic agonists, such as formoterol, one of the active ingredients in Symbicort, increase the risk of asthma-related death. 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 LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, Symbicort should only be used for patients not adequately controlled on a long-term asthma-control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g. discontinue Symbicort) 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 Symbicort for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.
A 28-week, placebo controlled US study comparing the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). This finding with salmeterol is considered a class effect of the LABA, including formoterol, one of the active ingredients in Symbicort. No study adequate to determine whether the rate of asthma-related death is increased with Symbicort has been conducted.
Clinical studies with formoterol suggested a higher incidence of serious asthma exacerbations in patients who received formoterol than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups.
Deterioration of Disease and Acute Episodes
Symbicort should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. Symbicort has not been studied in patients with acutely deteriorating asthma or COPD. The initiation of Symbicort in this setting is not appropriate.
Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate re-evaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of Symbicort with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 2 inhalations twice daily (morning and evening) of Symbicort.
Symbicort should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not Symbicort, should be used to relieve acute symptoms such as shortness of breath. When prescribing Symbicort, the physician must also provide the patient with an inhaled, short-acting beta2-agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of Symbicort.
When beginning treatment with Symbicort, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.
Excessive Use of Symbicort and Use with Other Long-Acting Beta2-Agonists
As with other inhaled drugs containing beta2-adrenergic agents, Symbicort should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing long-acting beta2-agonists, 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 should not use an additional long-acting beta2-agonist (e.g., salmeterol, formoterol fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced bronchospasm (EIB) or the treatment of asthma or COPD.
Local Effects
In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with Symbicort. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while treatment with Symbicort continues, but at times therapy with Symbicort may need to be interrupted. Patients should rinse the mouth after inhalation of Symbicort.
Pneumonia and Other Lower Respiratory Tract infections
Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of pneumonia and exacerbations frequently overlap. Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids.
In a 6 month study of 1,704 patients with COPD, there was a higher incidence of lung infections other than pneumonia (e.g., bronchitis, viral lower respiratory tract infections, etc.) in patients receiving Symbicort 160/4.5 (7.6%) than in those receiving Symbicort 80/4.5 (3.2%), formotero1 4.5 mcg (4.6%) or placebo (3.3%). Pneumonia did not occur with greater incidence in the Symbicort 160/4.5 group (1.1 %) compared with placebo (1.3%). In a 12-month study of 1,964 patients with COPD, there was also a higher incidence of lung infections other than pneumonia in patients receiving Symbicort 160/4.5 (8.1%) than in those receiving Symbicort 80/4.5 (6.9%), formoterol 4.5 mcg (7.1%) or placebo (6.2%). Similar to the 6 month study, pneumonia did not occur with greater incidence in the Symbicort 160/4.5 group (4.0%) compared with placebo (5.0%).
Immunosuppression
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. The immune responsiveness to varicella vaccine was evaluated in pediatric patients with asthma ages 12 months to 8 years with budesonide inhalation suspension.
An open-label, nonrandomized clinical study examined the immune responsiveness to varicella vaccine in 243 asthma patients 12 months to 8 years of age who were treated with budesonide inhalation suspension 0.25 mg to 1 mg daily (n=151) or noncorticosteroid asthma therapy (n=92) (i.e., beta2-agonists, leukotriene receptor antagonists, cromones). The percentage of patients developing a seroprotective antibody titer of >5.0 (gpELISA value) in response to the vaccination was similar in patients treated with budesonide inhalation suspension (85%), compared to patients treated with noncorticosteroid asthma therapy (90%). No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination.
Inhaled corticosteroids 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.
Transferring Patients From Systemic Corticosteroid Therapy
Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. 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 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 may provide control of asthma 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 asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians 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 asthma attack.
Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to Symbicort. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with Symbicort. Lung function (mean forced expiratory volume in 1 second [FEV1] or morning peak expiratory flow [PEF], beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.
Transfer of patients from systemic corticosteroid therapy to inhaled corticosteroids or Symbicort may unmask conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). 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.
Hypercorticism and Adrenal Suppression
Budesonide, a component of Symbicort, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since budesonide is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of Symbicort in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with Symbicort 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, particularly when budesonide is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of Symbicort should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.
Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors
Caution should be exercised when considering the coadministration of Symbicort with 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), Clinical Pharmacology (12.3)]
Paradoxical Bronchospasm and Upper Airway Symptoms
As with other inhaled medications, Symbicort can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Symbicort, it should be treated immediately with an inhaled, short-acting bronchodilator, Symbicort should be discontinued immediately, and alternative therapy should be instituted.
Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions may occur after administration of Symbicort, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm.
Cardiovascular and Central Nervous System Effects
Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see Overdosage (10)]. Therefore, Symbicort, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
Formoterol, a component of Symbicort, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of formoterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
Reduction in Bone Mineral Density
Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. 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, post menopausal 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 and periodically thereafter. If significant reductions in BMD are seen and Symbicort is still considered medically important for that patient's COPD therapy, use of medication to treat or prevent osteoporosis should be strongly considered.
Effects of treatment with Symbicort 160/4.5, Symbicort 80/4.5, formoterol 4.5, or placebo on BMD was evaluated in a subset of 326 patients (females and males 41 to 88 years of age) with COPD in the 12-month study. BMD evaluations of the hip and lumbar spine regions were conducted at baseline and 52 weeks using dual energy x-ray absorptiometry (DEXA) scans. Mean changes in BMD from baseline to end of treatment were small (mean changes ranged from -0.01 - 0.01 g/cm2). ANCOVA results for total spine and total hip BMD based on the end of treatment time point showed that all geometric LS Mean ratios for the pairwise treatment group comparisons were close to 1, indicating that overall, bone mineral density for total hip and total spine regions for the 12 month time point were stable over the entire treatment period.
Effect on Growth
Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving Symbicort routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including Symbicort, titrate each patient's dose to the lowest dosage that effectively controls his/her symptoms. [See Dosage and Administration (2.1), Use in Specific Populations (8.4).]
Glaucoma and Cataracts
Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with asthma and COPD following the long-term administration of inhaled corticosteroids, including budesonide, a component of Symbicort. Therefore, close monitoring is warranted in patients with a change in vision or with history of increased intraocular pressure, glaucoma, and/or cataracts.
Effects of treatment with Symbicort 160/4.5, Symbicort 80/4.5, formoterol 4.5, or placebo on development of cataracts or glaucoma were evaluated in a subset of 461 patients with COPD in the 12-month study. Ophthalmic examinations were conducted at baseline, 24 weeks, and 52 weeks. There were 26 subjects (6%) with an increase in posterior subcapsular score from baseline to maximum value (>0.7) during the randomized treatment period. Changes in posterior subcapsular scores of >0.7 from baseline to treatment maximum occurred in 11 patients (9.0%) in the Symbicort 160/4.5 group, 4 patients (3.8%) in the Symbicort 80/4.5 group, 5 patients (4.2%) in the formoterol group, and 6 patients (5.2%) in the placebo group.
Eosinophilic Conditions and Churg-Strauss Syndrome
In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions. Some of these patients have clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal relationship between budesonide and these underlying conditions has not been established.
Coexisting Conditions
Symbicort, like all medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
Hypokalemia and Hyperglycemia
Beta-adrenergic agonist medications 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. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with Symbicort at recommended doses.
Adverse Reactions
Long-acting beta2-adrenergic agonists, such as formoterol one of the active ingredients in Symbicort, increase the risk of asthma-related death. 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 LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Data from a large placebo-controlled US study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. [see Warnings and Precautions (5.1)].
Systemic and inhaled corticosteroid use may result in the following:
- Candida albicans infection [see Warnings and Precautions (5.4)]
- Pneumonia or lower respiratory tract infections in patients with COPD [see Warnings and Precautions (5.5)]
- Immunosuppression [see Warnings and Precautions (5.6)]
- Hypercorticism and adrenal suppression [see Warnings and Precautions (5.8)]
- Growth effects in pediatric patients [see Warnings and Precautions (5.14)]
- Glaucoma and cataracts [see Warnings and Precautions (5.15)]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clinical Trials Experience in Asthma Patients 12 years and older
The overall safety data in adults and adolescents are based upon 10 active- and placebo-controlled clinical trials in which 3393 patients ages 12 years and older (2052 females and 1341 males) with asthma of varying severity were treated with Symbicort 80/4.5 or 160/4.5 mcg taken two inhalations once or twice daily for 12 to 52 weeks. In these trials, the patients on Symbicort had a mean age of 38 years and were predominantly Caucasian (82%).
The incidence of common adverse events in Table 1 below is based upon pooled data from three 12-week, double-blind, placebo-controlled clinical studies in which 401 adult and adolescent patients (148 males and 253 females) age 12 years and older were treated with two inhalations of Symbicort 80/4.5 or Symbicort 160/4.5 twice daily. The Symbicort group was composed of mostly Caucasian (84%) patients with a mean age of 38 years, and a mean percent predicted FEV1 at baseline of 76 and 68 for the 80/4.5 mcg and 160/4.5 mcg treatment groups, respectively. Control arms for comparison included two inhalations of budesonide HFA metered dose inhaler (MDI) 80 or 160 mcg, formoterol dry powder inhaler (DPI) 4.5 mcg, or placebo (MDI and DPI) twice daily. Table 1 includes all adverse events that occurred at an incidence of > 3% in any one Symbicort group and more commonly than in the placebo group with twice-daily dosing. In considering these data, the increased average duration of patient exposure for Symbicort patients should be taken into account, as incidences are not adjusted for an imbalance of treatment duration.
| Treatment* | Symbicort | Budesonide | Formoterol | Placebo | ||
|---|---|---|---|---|---|---|
| Adverse Event | 80/4.5 mcg N = 277 % | 160/4.5 mcg N =124 % | 80 mcg N =121 % | 160 mcg N = 109 % | 4.5 mcg N = 237 % | N = 400 % |
| ||||||
Nasopharyngitis | 10.5 | 9.7 | 14.0 | 11.0 | 10.1 | 9.0 |
Headache | 6.5 | 11.3 | 11.6 | 12.8 | 8.9 | 6.5 |
Upper respiratory tract infection | 7.6 | 10.5 | 8.3 | 9.2 | 7.6 | 7.8 |
Pharyngolaryngeal pain | 6.1 | 8.9 | 5.0 | 7.3 | 3.0 | 4.8 |
Sinusitis | 5.8 | 4.8 | 5.8 | 2.8 | 6.3 | 4.8 |
Influenza | 3.2 | 2.4 | 6.6 | 0.9 | 3.0 | 1.3 |
Back pain | 3.2 | 1.6 | 2.5 | 5.5 | 2.1 | 0.8 |
Nasal congestion | 2.5 | 3.2 | 2.5 | 3.7 | 1.3 | 1.0 |
Stomach discomfort | 1.1 | 6.5 | 2.5 | 4.6 | 1.3 | 1.8 |
Vomiting | 1.4 | 3.2 | 0.8 | 2.8 | 1.7 | 1.0 |
Oral Candidiasis | 1.4 | 3.2 | 0 | 0 | 0 | 0.8 |
Average Duration of Exposure (days) | 77.7 | 73.8 | 77.0 | 71.4 | 62.4 | 55.9 |
Long-term safety - asthma clinical trials in patients 12 years and older
Long-term safety studies in adolescent and adult patients 12 years of age and older, treated for up to 1 year at doses up to 1280/36 mcg/day (640/18 mcg twice daily), revealed neither clinically important changes in the incidence nor new types of adverse events emerging after longer periods of treatment. Similarly, no significant or unexpected patterns of abnormalities were observed for up to 1 year in safety measures including chemistry, hematology, ECG, Holter monitor, and HPA-axis assessments.
Clinical Trials Experience in Chronic Obstructive Pulmonary Disease
The incidence of common adverse events in Table 2 below is based upon pooled data from two double-blind, placebo-controlled clinical studies (6 and 12 months in duration) in which 771 adult COPD patients (496 males and 275 females) 40 years of age and older were treated with Symbicort 160/4.5, two inhalations twice daily. Of these patients 651 were treated for 6 months and 366 were treated for 12 months. The Symbicort group was composed of mostly Caucasian (93%) patients with a mean age of 63 years, and a mean percent predicted FEV1 at baseline of 33%. Control arms for comparison included two inhalations of budesonide HFA (MDI) 160 mcg, formoterol (DPI) 4.5 mcg or placebo (MDI and DPI) twice daily. Table 2 includes all adverse events that occurred at an incidence of ≥ 3% in the Symbicort group and more commonly than in the placebo group. In considering these data, the increased average duration of patient exposure to Symbicort should be taken into account, as incidences are not adjusted for an imbalance of treatment duration.
| ||||
Treatment* | Symbicort | Budesonide | Formoterol | Placebo |
Adverse Event | 160/4.5 mcg N=771 % | 160 mcg N=275 % | 4.5 mcg N=779 % | N=781 % |
Nasopharyngitis | 7.3 | 3.3 | 5.8 | 4.9 |
Oral candidiasis | 6.0 | 4.4 | 1.2 | 1.8 |
Bronchitis | 5.4 | 4.7 | 4.5 | 3.5 |
Sinusitis | 3.5 | 1.5 | 3.1 | 1.8 |
Upper respiratory tract infection viral | 3.5 | 1.8 | 3.6 | 2.7 |
Average Duration of Exposure (days) | 255.2 | 157.1 | 240.3 | 223.7 |
Lung infections other than pneumonia (mostly bronchitis) occurred in a greater percentage of subjects treated with Symbicort 160/4.5 compared with placebo (7.9% vs. 5.1%, respectively). There were no clinically important or unexpected patterns of abnormalities observed for up to 1 year in chemistry, haematology, ECG, ECG (Holter) monitoring, HPA-axis, bone mineral density and ophthalmology assessments.
Postmarketing Experience
The following adverse reactions have been reported during post-approval use of Symbicort. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Some of these adverse reactions may also have been observed in clinical studies with Symbicort.
Cardiac disorders: angina pectoris, tachycardia, atrial and ventricular tachyarrhythmias, atrial fibrillation, extrasystoles, palpitations
Endocrine disorders: hypercorticism, growth velocity reduction in pediatric patients
Eye disorders: cataract, glaucoma, increased intraocular pressure
Gastrointestinal disorders: oropharyngeal candidiasis, nausea
Immune system disorders: immediate and delayed hypersensitivity reactions, such as anaphylactic reaction, angioedema, bronchospasm, urticaria, exanthema, dermatitis, pruritus
Metabolic and nutrition disorders: hyperglycemia, hypokalemia
Musculoskeletal, connective tissue, and bone disorders: muscle cramps
Nervous system disorders: tremor, dizziness
Psychiatric disorders: behavior disturbances, sleep disturbances, nervousness, agitation, depression, restlessness
Respiratory, thoracic, and mediastinal disorders: dysphonia, cough, throat irritation
Skin and subcutaneous tissue disorders: skin bruising
Vascular disorders: hypotension, hypertension
Drug Interactions
In clinical studies, concurrent administration of Symbicort and other drugs, such as short-acting beta2-agonists, intranasal corticosteroids, and antihistamines/decongestants has not resulted in an increased frequency of adverse reactions. No formal drug interaction studies have been performed with Symbicort.
Inhibitors of Cytochrome P4503A4
The main route of metabolism of corticosteroids, including budesonide, a component of Symbicort, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the coadministration of Symbicort with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.9)].
Monoamine Oxidase Inhibitors and Tricyclic Antidepressants
Symbicort should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of formoterol, a component of Symbicort, on the vascular system may be potentiated by these agents. In clinical trials with Symbicort, a limited number of COPD and asthma patients received tricyclic antidepressants, and, therefore, no clinically meaningful conclusions on adverse events can be made.
Beta-Adrenergic Receptor Blocking Agents
Beta-blockers (including eye drops) may not only block the pulmonary effect of beta-agonists, such as formoterol, a component of Symbicort, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
Diuretics
The ECG changes and/or hypokalemia that may result from the administration of non−potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of Symbicort with non-potassium-sparing diuretics.
USE IN SPECIFIC POPULATIONS
Pregnancy
Teratogenic Effects: Pregnancy Category C.
There are no adequate and well-controlled studies of Symbicort in pregnant women. Symbicort was teratogenic and embryocidal in rats. Budesonide alone was teratogenic and embryocidal in rats and rabbits, but not in humans at therapeutic doses. Formoterol fumarate alone was teratogenic in rats and rabbits. Formoterol fumarate was also embryocidal, increased pup loss at birth and during lactation, and decreased pup weight in rats. Symbicort should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Symbicort
In a reproduction study in rats, budesonide combined with formoterol fumarate by the inhalation route at doses approximately 1/7 and 1/3, respectively, the maximum recommended human daily inhalation dose on a mg/m2 basis produced umbilical hernia. No teratogenic or embryocidal effects were detected with budesonide combined with formoterol fumarate by the inhalation route at doses approximately 1/32 and 1/16, respectively, the maximum recommended human daily inhalation dose on a mg/m2 basis.
Budesonide
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