These highlights do not include all the information needed to use SYMBICORT safely and effectively. See full prescribing information for SYMBICORT. ,(budesonide 80 mcg and formoterol fumarate dihydrate 4.5 mcg) Inhalation Aerosol,(budesonide 160 mcg and f
SYMBICORT Information
Company Name AstraZeneca LP
Symbicort (Budesonide and formoterol fumarate dihydrate) Warning: Asthma-related Death
Long-acting beta-adrenergic agonists (LABA), such as formoterol one of the active ingredients in Symbicort (Budesonide and formoterol fumarate dihydrate) , increase the risk of asthma-related death. Data from a large placebo-controlled U.S. study that compared the safety of another long-acting beta-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 (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) ) 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 (Budesonide and formoterol fumarate dihydrate) for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids [see Warnings and Precautions (5.1)].
Symbicort (Budesonide and formoterol fumarate dihydrate) Indications And Usage
Symbicort (Budesonide and formoterol fumarate dihydrate) is indicated for the treatment of asthma in patients 12 years of age and older.
Long-acting beta-adrenergic agonists, such as formoterol one of the active ingredients in Symbicort (Budesonide and formoterol fumarate dihydrate) , 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 [)]. Therefore, when treating patients with asthma, Symbicort (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) ) 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 (Budesonide and formoterol fumarate dihydrate) for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.
Important Limitations of Use:
• Symbicort (Budesonide and formoterol fumarate dihydrate) is NOT indicated for the relief of acute bronchospasm.
Symbicort (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) 160/4.5 is the only approved dosage for the treatment of airflow obstruction in COPD.
Important Limitations of Use:
Symbicort (Budesonide and formoterol fumarate dihydrate) Dosage And Administration
Symbicort (Budesonide and formoterol fumarate dihydrate) 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.
Prime Symbicort (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) is not recommended as some patients are more likely to experience adverse effects with higher doses of formoterol. Patients using Symbicort (Budesonide and formoterol fumarate dihydrate) should not use additional long-acting beta-agonists for any reason.
Symbicort (Budesonide and formoterol fumarate dihydrate) Dosage Forms And Strengths
Symbicort (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) is supplied with a red plastic actuator with a gray dust cap.
Symbicort (Budesonide and formoterol fumarate dihydrate) Contraindications
The use of Symbicort (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) .
Symbicort (Budesonide and formoterol fumarate dihydrate) Warnings And Precautions
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 (Budesonide and formoterol fumarate dihydrate) . No study adequate to determine whether the rate of asthma-related death is increased with Symbicort (Budesonide and formoterol fumarate dihydrate) 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.
Symbicort (Budesonide and formoterol fumarate dihydrate) should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. Symbicort (Budesonide and formoterol fumarate dihydrate) has not been studied in patients with acutely deteriorating asthma or COPD. The initiation of Symbicort (Budesonide and formoterol fumarate dihydrate) in this setting is not appropriate.
Increasing use of inhaled, short-acting beta-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 (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) .
Symbicort (Budesonide and formoterol fumarate dihydrate) 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 beta-agonist, not Symbicort (Budesonide and formoterol fumarate dihydrate) , should be used to relieve acute symptoms such as shortness of breath. When prescribing Symbicort (Budesonide and formoterol fumarate dihydrate) , the physician must also provide the patient with an inhaled, short-acting beta-agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of Symbicort (Budesonide and formoterol fumarate dihydrate) .
When beginning treatment with Symbicort (Budesonide and formoterol fumarate dihydrate) , patients who have been taking oral or inhaled, short-acting beta-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.
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 (Budesonide and formoterol fumarate dihydrate) 160/4.5 (7.6%) than in those receiving Symbicort (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) 160/4.5 (8.1%) than in those receiving Symbicort (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) 160/4.5 group (4.0%) compared with placebo (5.0%).
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., beta-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.
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 (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) . Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with Symbicort (Budesonide and formoterol fumarate dihydrate) . Lung function (mean forced expiratory volume in 1 second [FEV] 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 (Budesonide and formoterol fumarate dihydrate) 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.
Budesonide, a component of Symbicort (Budesonide and formoterol fumarate dihydrate) , 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 (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.
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 . Therefore, Symbicort (Budesonide and formoterol fumarate dihydrate) , 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 (Budesonide and formoterol fumarate dihydrate) , 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.
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 (Budesonide and formoterol fumarate dihydrate) and periodically thereafter. If significant reductions in BMD are seen and Symbicort (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) 160/4.5, Symbicort (Budesonide and formoterol fumarate dihydrate) 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/cm). 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.
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 (Budesonide and formoterol fumarate dihydrate) . 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 (Budesonide and formoterol fumarate dihydrate) 160/4.5, Symbicort (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) 160/4.5 group, 4 patients (3.8%) in the Symbicort (Budesonide and formoterol fumarate dihydrate) 80/4.5 group, 5 patients (4.2%) in the formoterol group, and 6 patients (5.2%) in the placebo group.
Symbicort (Budesonide and formoterol fumarate dihydrate) Adverse Reactions
Systemic and inhaled corticosteroid use may result in the following:
- Candida albicans infection
- Pneumonia or lower respiratory tract infections in patients with COPD
- Immunosuppression
- Hypercorticism and adrenal suppression
- Growth effects in pediatric patients
- Glaucoma and cataracts
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.
Symbicort (Budesonide and formoterol fumarate dihydrate) Drug Interactions
In clinical studies, concurrent administration of Symbicort (Budesonide and formoterol fumarate dihydrate) and other drugs, such as short-acting beta-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 (Budesonide and formoterol fumarate dihydrate) .
Symbicort (Budesonide and formoterol fumarate dihydrate) Use In Specific Populations
Teratogenic Effects: Pregnancy Category C.
There are no adequate and well-controlled studies of Symbicort (Budesonide and formoterol fumarate dihydrate) in pregnant women. Symbicort (Budesonide and formoterol fumarate dihydrate) 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 (Budesonide and formoterol fumarate dihydrate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Symbicort (Budesonide and formoterol fumarate dihydrate)
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/m 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/m basis.
Budesonide
Studies of pregnant women have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (ie, Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared to the general population rate (3.8% vs 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs 3.3, respectively).
These same data were utilized in a second study bringing the total to 2534 infants whose mothers were exposed to inhaled budesonide. In this study, the rate of' congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%).
Budesonide produced fetal loss, decreased pup weight, and skeletal abnormalities at subcutaneous doses in rabbits less than the maximum recommended human daily inhalation dose on a mcg/m basis and in rats at doses approximately 6 times the maximum recommended human daily inhalation dose on a mcg/m basis. In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up to 3 times the maximum recommended human daily inhalation dose on a mcg/m basis.
Experience with oral corticosteroids since their introduction in pharmacologic as opposed to physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.
Formoterol
Formoterol fumarate has been shown to be teratogenic, embryocidal, to increase pup loss at birth and during lactation, and to decrease pup weights in rats when given at oral doses 1400 times and greater the maximum recommended human daily inhalation dose on a mcg/m basis. Umbilical hernia was observed in rat fetuses at oral doses 1400 times and greater the maximum recommended human daily inhalation dose on a mcg/m basis. Brachygnathia was observed in rat fetuses at an oral dose 7000 times the maximum recommended human daily inhalation dose on a mcg/m basis. Pregnancy was prolonged at an oral dose 7000 times the maximum recommended human daily inhalation dose on a mcg/m basis. In another study in rats, no teratogenic effects were seen at inhalation doses up to 500 times the maximum recommended human daily inhalation dose on a mcg/m basis.
Subcapsular cysts on the liver were observed in rabbit fetuses at an oral dose 54,000 times the maximum recommended human daily inhalation dose on a mcg/m basis. No teratogenic effects were observed at oral doses up to 3200 times the maximum recommended human daily inhalation dose on a mcg/m basis.
Nonteratogenic Effects
Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.
Since there are no data from controlled trials on the use of Symbicort (Budesonide and formoterol fumarate dihydrate) by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue Symbicort (Budesonide and formoterol fumarate dihydrate) , taking into account the importance of Symbicort (Budesonide and formoterol fumarate dihydrate) to the mother.
Budesonide, like other corticosteroids, is secreted in human milk. Data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother []. For Symbicort (Budesonide and formoterol fumarate dihydrate) , the dose of budesonide available to the infant in breast milk, as a percentage of the maternal dose, would be expected to be similar.
In reproductive studies in rats, formoterol was excreted in the milk. It is not known whether formoterol is excreted in human milk.
Safety and effectiveness of Symbicort (Budesonide and formoterol fumarate dihydrate) in asthma patients 12 years of age and older have been established in studies up to 12 months. In the two 12-week, double-blind, placebo-controlled US pivotal studies 25 patients 12 to 17 years of age were treated with Symbicort (Budesonide and formoterol fumarate dihydrate) twice daily []. Efficacy results in this age group were similar to those observed in patients 18 years and older. There were no obvious differences in the type or frequency of adverse events reported in this age group compared with patients 18 years of age and older.
The safety and effectiveness of Symbicort (Budesonide and formoterol fumarate dihydrate) in asthma patients 6 to
Overall 1447 asthma patients 6 to
Controlled clinical studies have shown that orally inhaled corticosteroids including budesonide, a component of Symbicort (Budesonide and formoterol fumarate dihydrate) , may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of HPA-axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effect of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final height are unknown. The potential for “catch-up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.
In a study of asthmatic children 5-12 years of age, those treated with budesonide DPI 200 mcg twice daily (n=311) had a 1.1 centimeter reduction in growth compared with those receiving placebo (n=418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment. By the end of 4 years, children treated with budesonide DPI and children treated with placebo had similar growth velocities. Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study.
The growth of pediatric patients receiving orally inhaled corticosteroids, including Symbicort (Budesonide and formoterol fumarate dihydrate) , should be monitored. If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained. To minimize the systemic effects of orally inhaled corticosteroids, including Symbicort (Budesonide and formoterol fumarate dihydrate) , each patient should be titrated to the lowest strength that effectively controls his/her asthma [].
Of the total number of patients in asthma clinical studies treated with Symbicort (Budesonide and formoterol fumarate dihydrate) twice daily, 149 were 65 years of age or older, of whom 25 were 75 years of age or older.
In the COPD studies of 6 to 12 months duration, 349 patients treated with Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 twice daily were 65 years old and above and of those, 73 patients were 75 years of age and older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.
As with other products containing beta-agonists, special caution should be observed when using Symbicort (Budesonide and formoterol fumarate dihydrate) in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta-agonists.
Based on available data for Symbicort (Budesonide and formoterol fumarate dihydrate) or its active components, no adjustment of dosage of Symbicort (Budesonide and formoterol fumarate dihydrate) in geriatric patients is warranted.
Symbicort (Budesonide and formoterol fumarate dihydrate) Overdosage
Symbicort (Budesonide and formoterol fumarate dihydrate) contains both budesonide and formoterol; therefore, the risks associated with overdosage for the individual components described below apply to Symbicort (Budesonide and formoterol fumarate dihydrate) . In pharmacokinetic studies, single doses of 960/54 mcg (12 actuations of Symbicort (Budesonide and formoterol fumarate dihydrate) 80/4.5) and 1280/36 mcg (8 actuations of 160/4.5), were administered to patients with COPD. A total of 1920/54 mcg (12 actuations of Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5) was administered as a single dose to both healthy subjects and patients with astma. In a long-term active-controlled safety study in asthma patients, Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 was administered for up to 12 months at doses up to twice the highest recommended daily dose. There were no clinically significant adverse reactions observed in any of these studies.
Clinical signs in dogs that received a single inhalation dose of Symbicort (Budesonide and formoterol fumarate dihydrate) (a combination of budesonide and formoterol) in a dry powder included tremor, mucosal redness, nasal catarrh, redness of intact skin, abdominal respiration, vomiting, and salivation; in the rat, the only clinical sign observed was increased respiratory rate in the first hour after dosing. No deaths occurred in rats given a combination of budesonide and formoterol at acute inhalation doses of 97 and 3 mg/kg, respectively (approximately 1200 and 1350 times the maximum recommended human daily inhalation dose on a mcg/m basis). No deaths occurred in dogs given a combination of budesonide and formoterol at the acute inhalation doses of 732 and 22 mcg/kg, respectively (approximately 30 times the maximum recommended human daily inhalation dose of budesonide and formoterol on a mcg/m basis).
The potential for acute toxic effects following overdose of budesonide is low. If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur []. Budesonide at five times the highest recommended dose (3200 mcg daily) administered to humans for 6 weeks caused a significant reduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%). The corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma cortisol response to ACTH.
In mice, the minimal inhalation lethal dose was 100 mg/kg (approximately 600 times the maximum recommended human daily inhalation dose on a mcg/m basis). In rats, there were no deaths following the administration of an inhalation dose of 68 mg/kg (approximately 900 times the maximum recommended human daily inhalation dose on a mcg/m basis). The minimal oral lethal dose in mice was 200 mg/kg (approximately 1300 times the maximum recommended human daily inhalation dose on a mcg/m basis) and less than 100 mg/kg in rats (approximately 1300 times the maximum recommended human daily inhalation dose on a mcg/m basis).
An overdose of formoterol would likely lead to an exaggeration of effects that are typical for beta-agonists: seizures, angina, hypertension, hypotension, tachycardia, atrial and ventricular tachyarrhythmias, nervousness, headache, tremor, palpitations, muscle cramps, nausea, dizziness, sleep disturbances, metabolic acidosis, hyperglycemia, hypokalemia. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of formoterol. No clinically significant adverse reactions were seen when formoterol was delivered to adult patients with acute bronchoconstriction at a dose of 90 mcg/day over 3 hours or to stable asthmatics 3 times a day at a total dose of 54 mcg/day for 3 days.
Treatment of formoterol overdosage consists of discontinuation of the medication together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of formoterol. Cardiac monitoring is recommended in cases of overdosage.
No deaths were seen in mice given formoterol at an inhalation dose of 276 mg/kg (more than 62,200 times the maximum recommended human daily inhalation dose on a mcg/m basis). In rats, the minimum lethal inhalation dose was 40 mg/kg (approximately 18,000 times the maximum recommended human daily inhalation dose on a mcg/m basis). No deaths were seen in mice that received an oral dose of 2000 mg/kg (more than 450,000 times the maximum recommended human daily inhalation dose on a mcg/m basis). Maximum nonlethal oral doses were 252 mg/kg in young rats and 1500 mg/kg in adult rats (approximately 114,000 times and 675,000 times the maximum recommended human inhalation dose on a mcg/m basis).
Symbicort (Budesonide and formoterol fumarate dihydrate) Description
Symbicort (Budesonide and formoterol fumarate dihydrate) 80/4.5 and Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 each contain micronized budesonide and micronized formoterol fumarate dihydrate for oral inhalation only.
Each Symbicort (Budesonide and formoterol fumarate dihydrate) 80/4.5 and Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 canister is formulated as a hydrofluoroalkane (HFA 227; 1,1,1,2,3,3,3-heptafluoropropane)-propelled pressurized metered dose inhaler containing either 60 or 120 actuations []. After priming, each actuation meters either 91/5.1 mcg or 181/5.1 mcg from the valve and delivers either 80/4.5 mcg, or 160/4.5 mcg (budesonide micronized/formoterol fumarate dihydrate micronized) from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between actuation of the device and inspiration through the delivery system. Symbicort (Budesonide and formoterol fumarate dihydrate) also contains povidone K25 USP as a suspending agent and polyethylene glycol 1000 NF as a lubricant.
Symbicort (Budesonide and formoterol fumarate dihydrate) should be primed 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 for 5 seconds before each spray and releasing two test sprays into the air away from the face.
One active component of Symbicort (Budesonide and formoterol fumarate dihydrate) is budesonide, a corticosteroid designated chemically as (RS)-11β, 16α, 17,21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is CHO and its molecular weight is 430.5. Its structural formula is:
Budesonide is a white to off-white, tasteless, odorless powder which is practically insoluble in water and in heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 7.4 is 1.6 x 10.
The other active component of Symbicort (Budesonide and formoterol fumarate dihydrate) is formoterol fumarate dihydrate, a selective beta-agonist designated chemically as (R*,R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide, (E)-2-butendioate(2:1), dihydrate. The empirical formula of formoterol is CHNO and its molecular weight is 840.9. Its structural formula is:
Formoterol fumarate dihydrate is a powder which is slightly soluble in water. Its octanol-water partition coefficient at pH 7.4 is 2.6. The pKa of formoterol fumarate dihydrate at 25°C is 7.9 for the phenolic group and 9.2 for the amino group.
Symbicort (Budesonide and formoterol fumarate dihydrate) Clinical Pharmacology
Symbicort (Budesonide and formoterol fumarate dihydrate)
Symbicort (Budesonide and formoterol fumarate dihydrate) contains both budesonide and formoterol; therefore, the mechanisms of action described below for the individual components apply to Symbicort (Budesonide and formoterol fumarate dihydrate) . These drugs represent two classes of medications (a synthetic corticosteroid and a long-acting selective beta-adrenoceptor agonist) that have different effects on clinical, physiological, and inflammatory indices of Chronic Obstructive Pulmonary Disease (COPD) and asthma.
Budesonide
Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay.
In glucocorticoid receptor affinity studies, the 22R form of budesonide was two times as active as the 22S epimer. studies indicated that the two forms of budesonide do not interconvert.
Inflammation is an important component in the pathogenesis of COPD and asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (eg, histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non–allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in COPD and asthma.
Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide range of doses of budesonide. This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85%-95%), and the low potency of formed metabolites.
Formoterol
Formoterol fumarate is a long-acting selective beta-adrenergic agonist (beta-agonist) with a rapid onset of action. Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. studies have shown that formoterol has more than 200-fold greater agonist activity at beta-receptors than at beta-receptors. The binding selectivity to beta- over beta-adrenoceptors is higher for formoterol than for albuterol (5 times), whereas salmeterol has a higher (3 times) beta -selectivity ratio than formoterol.
Although beta-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta-receptors are the predominant receptors in the heart, there are also beta-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta-agonists may have cardiac effects.
The pharmacologic effects of beta-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
Asthma
1
In the United States, five 12-week, active- and placebo-controlled studies evaluated 2152 patients aged 12 years and older with asthma. Systemic pharmacodynamic effects of formoterol (heart/pulse rate, blood pressure, QTc interval, potassium, and glucose) were similar in patients treated with Symbicort (Budesonide and formoterol fumarate dihydrate) , compared with patients treated with formoterol dry inhalation powder 4.5 mcg, two inhalations twice daily. No patient had a QT or QTc value ≥500 msec during treatment.
In three placebo-controlled studies in adolescents and adults with asthma, aged 12 years and older, a total of 1232 patients (553 patients in the Symbicort (Budesonide and formoterol fumarate dihydrate) group) had evaluable continuous 24-hour electrocardiographic monitoring. Overall, there were no important differences in the occurrence of ventricular or supraventricular ectopy and no evidence of increased risk for clinically significant dysrhythmia in the Symbicort (Budesonide and formoterol fumarate dihydrate) group compared to placebo.
ECGs recorded at multiple clinic visits on treatment in both studies showed no clinically important differences for heart rate, PR interval, QRS duration, heart rate, signs of cardiac ischemia or arrhythmias between Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 the monoproducts and placebo, all administered as two inhalations twice daily. Based on ECGs, 6 patients treated with Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5, 6 patients treated with formoterol 4.5, and 6 patients in the placebo group experienced atrial fibrillation or flutter that was not present at baseline. There were no cases of nonsustained ventricular tachycardia in the Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5, formoterol 4.5, or placebo groups.
In the 12-month study, 520 patients had evaluable continuous 24-hour ECG (Holter) monitoring prior to the first dose and after approximately 1 and 4 months on treatment. No clinically important differences in ventricular or supraventricular arrhythmias, ventricular or supraventricular ectopic beats, or heart rate were observed among the groups treated with Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5, formoterol or placebo taken as two inhalations twice daily. Based on ECG (Holter) monitoring, one patient on Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5, no patients on formoterol 4.5, and three patients in the placebo group experienced atrial fibrillation or flutter that was not present at baseline.
Other Budesonide Products
To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled budesonide, a clinical study in patients with asthma was performed comparing 400 mcg budesonide administered via a pressurized metered dose inhaler with a tube spacer to 1400 mcg of oral budesonide and placebo. The study demonstrated the efficacy of inhaled budesonide but not orally ingested budesonide, despite comparable systemic levels. Thus, the therapeutic effect of conventional doses of orally inhaled budesonide are largely explained by its direct action on the respiratory tract.
Inhaled budesonide has been shown to decrease airway reactivity to various challenge models, including histamine, methacholine, sodium metabisulfite, and adenosine monophosphate in patients with hyperreactive airways. The clinical relevance of these models is not certain.
Pretreatment with inhaled budesonide, 1600 mcg daily (800 mcg twice daily) for 2 weeks reduced the acute (early-phase reaction) and delayed (late-phase reaction) decrease in FEV following inhaled allergen challenge.
The systemic effects of inhaled corticosteroids are related to the systemic exposure to such drugs. Pharmacokinetic studies have demonstrated that in both adults and children with asthma the systemic exposure to budesonide is lower with Symbicort (Budesonide and formoterol fumarate dihydrate) compared with inhaled budesonide administered at the same delivered dose via a dry powder inhaler []. Therefore, the systemic effects (HPA axis and growth) of budesonide delivered from Symbicort (Budesonide and formoterol fumarate dihydrate) would be expected to be no greater than what is reported for inhaled budesonide when administered at comparable doses via the dry powder inhaler [].
Other Formoterol Products
While the pharmacodynamic effect is via stimulation of beta-adrenergic receptors, excessive activation of these receptors commonly leads to skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose. Inhaled formoterol, like other beta-adrenergic agonist drugs, can produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium []. For Symbicort (Budesonide and formoterol fumarate dihydrate) , these effects are detailed in the section.
Use of long-acting beta-adrenergic agonist drugs can result in tolerance to bronchoprotective and bronchodilatory effects.
Rebound bronchial hyperresponsiveness after cessation of chronic long-acting beta-agonist therapy has not been observed.
Symbicort (Budesonide and formoterol fumarate dihydrate)
Absorption: Orally inhaled budesonide is rapidly absorbed in the lungs and peak concentration is typically reached within 20 minutes. After oral administration of budesonide peak plasma concentration was achieved in about 1 to 2 hours and the absolute systemic availability was 6%-13% due to extensive first pass metabolism. In contrast, most of the budesonide delivered to the lungs was systemically absorbed. In healthy subjects, 34% of the metered dose was deposited in the lung (as assessed by plasma concentration method and using a budesonide-containing dry powder inhaler) with an absolute systemic availability of 39% of the metered dose.
Following administration of Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, two or four inhalations twice daily) for 5 days in healthy subjects, plasma concentration of budesonide generally increased in proportion to dose. The accumulation index for the group that received two inhalations twice daily was 1.32 for budesonide.
Asthma Patients:
In a repeat dose study, the highest recommended dose of Symbicort (Budesonide and formoterol fumarate dihydrate) (160/4.5 mcg, two inhalations twice daily) was administered to patients with moderate asthma and healthy subjects for 1 week. Peak budesonide plasma concentration of 1.2 nmol/L occurred at 21 minutes in asthma patients. Peak budesonide plasma concentration was 27% lower in asthma patients compared to that in healthy subjects. However, the total systemic exposure of budesonide was comparable to that in asthma patients.
Peak steady-state plasma concentrations of budesonide administered by DPI in adults with asthma averaged 0.6 and 1.6 nmol/L at doses of 180 mcg and 360 mcg twice daily, respectively. In asthmatic patients, budesonide showed a linear increase in AUC and C with increasing dose after both single and repeated dosing of inhaled budesonide.
COPD Patients:
max
In the 6 month pivotal clinical study, steady-state pharmacokinetic data of budesonide was obtained in a subset of COPD patients with treatment arms of Symbicort (Budesonide and formoterol fumarate dihydrate) pMDI 160/4.5 mcg, Symbicort (Budesonide and formoterol fumarate dihydrate) pMDI 80/4.5 mcg, budesonide 160 mcg, budesonide 160 mcg and formoterol 4.5 mcg given together, all administered as two inhalations twice daily. Budesonide systemic exposure (AUC and C) increased proportionally with doses from 80 mcg to 160 mcg and was generally similar between the 3 treatment groups receiving the same dose of budesonide (Symbicort (Budesonide and formoterol fumarate dihydrate) pMDI 160/4.5 mcg, budesonide 160 mcg, budesonide 160 mcg and formoterol 4.5 mcg administered together).
Formoterol:
Inhaled formoterol is rapidly absorbed; peak plasma concentrations are typically reached at the first plasma sampling time, within 5-10 minutes after dosing. As with many drug products for oral inhalation, it is likely that the majority of the inhaled formoterol delivered is swallowed and then absorbed from the gastrointestinal tract.
Healthy Subjects:
Asthma patients:
In a repeat dose study, the highest recommended dose of Symbicort (Budesonide and formoterol fumarate dihydrate) (160/4.5 mcg, two inhalations twice daily) was administered to patients with moderate asthma and healthy subjects for 1 week. Peak formoterol plasma concentration of 28 pmol/L occurred at 10 minutes in asthma patients. Peak formoterol plasma concentration was about 42% lower in asthma patients compared to that in healthy subjects. However, the total systemic exposure of formoterol was comparable to that in asthma patients.
COPD patients:
max
In the 6 month pivotal clinical study, steady-state pharmacokinetic data of formoterol was obtained in a subset of COPD patients with treatment arms of Symbicort (Budesonide and formoterol fumarate dihydrate) pMDI 160/4.5 mcg, Symbicort (Budesonide and formoterol fumarate dihydrate) pMDI 80/4.5. mcg, formoterol 4.5 mcg, budesonide 160 mcg and formoterol 4.5 mcg given together, all administered as two inhalations twice daily. The systemic exposure of formoterol as evidenced by AUC, was about 30% and 16% higher from Symbicort (Budesonide and formoterol fumarate dihydrate) pMDI compared to formoterol alone treatment arm and coadministration of individual components of budesonide and formoterol treatment arm, respectively.
Formoterol:
Formoterol:
No unchanged budesonide was detected in the urine. The 22R form of budesonide was preferentially cleared by the liver with systemic clearance of 1.4 L/min vs 1.0 L/min for the 22S form. The terminal half-life, 2 to 3 hours, was the same for both epimers and was independent of dose.
Formoterol:
Special Populations
Geriatric
The pharmacokinetics of Symbicort (Budesonide and formoterol fumarate dihydrate) in geriatric patients have not been specifically studied.
Pediatric
Plasma concentrations of budesonide were measured following administration of four inhalations of Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 mcg in a single-dose study in pediatric patients with asthma, 6-11 years of age. Urine was collected for determination of formoterol excretion. Peak budesonide concentrations of 1.4 nmol/L occurred at 20 minutes post-dose. Approximately 3.5% of the delivered formoterol dose was recovered in the urine as unchanged formoterol. This study also demonstrated that the total systemic exposure to budesonide from Symbicort (Budesonide and formoterol fumarate dihydrate) was approximately 30% lower than from inhaled budesonide via a dry powder inhaler that was also evaluated at the same delivered dose.
Gender/Race
Specific studies to examine the effects of gender and race on the pharmacokinetics of Symbicort (Budesonide and formoterol fumarate dihydrate) have not been conducted. Population PK analysis of the Symbicort (Budesonide and formoterol fumarate dihydrate) data indicates that gender does not affect the pharmacokinetics of budesonide and formoterol. No conclusions can be drawn on the effect of race due to the low number of non-Caucasians evaluated for PK.
Nursing Mothers
The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum concentration of budesonide for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after dosing. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide levels in plasma samples obtained from five infants at about 90 minutes after breastfeeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (
Renal or Hepatic Insufficiency
There are no data regarding the specific use of Symbicort (Budesonide and formoterol fumarate dihydrate) in patients with hepatic or renal impairment. Reduced liver function may affect the elimination of corticosteroids. Budesonide pharmacokinetics was affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The intravenous budesonide pharmacokinetics was, however, similar in cirrhotic patients and in healthy subjects. Specific data with formoterol is not available, but because formoterol is primarily eliminated via hepatic metabolism, an increased exposure can be expected in patients with severe liver impairment.
Drug-Drug Interactions
A single-dose crossover study was conducted to compare the pharmacokinetics of eight inhalations of the following: budesonide, formoterol, and budesonide plus formoterol administered concurrently. The results of the study indicated that there was no evidence of a pharmacokinetic interaction between the two components of Symbicort (Budesonide and formoterol fumarate dihydrate) .
Inhibitors of cytochrome P450 enzymes
Ketoconazole:
Cimetidine: At recommended doses, cimetidine, a non-specific inhibitor of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics of oral budesonide.
Specific drug-drug interaction studies with formoterol have not been performed.
Symbicort (Budesonide and formoterol fumarate dihydrate) Nonclinical Toxicology
Budesonide
Long-term studies were conducted in rats and mice using oral administration to evaluate the carcinogenic potential of budesonide.
In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (less than the maximum recommended human daily inhalation dose on a mcg/m basis). No tumorigenicity was seen in male and female rats at respective oral doses up to 25 and 50 mcg/kg (less than the maximum recommended human daily inhalation dose on a mcg/m basis). In two additional 2-year studies in male Fischer and Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (less than the maximum recommended human daily inhalation dose on a mcg/m basis). However, in the male Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (less than the maximum recommended human daily inhalation dose on a mcg/m basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) in these two studies showed similar findings.
In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately equal to the maximum recommended human daily inhalation dose on a mcg/m basis).
Budesonide was not mutagenic or clastogenic in six different test systems: Ames /microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in , and DNA repair analysis in rat hepatocyte culture.
In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately equal to the maximum recommended human daily inhalation dose on a mcg/m basis). However, it caused a decrease in prenatal viability and viability in the pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg and above (less than the maximum recommended human daily inhalation dose on a mcg/m basis). No such effects were noted at 5 mcg/kg (less than the maximum recommended human daily inhalation dose on a mcg/m basis).
Formoterol
Long-term studies were conducted in mice using oral administration and rats using inhalation administration to evaluate the carcinogenic potential of formoterol fumarate.
In a 24-month carcinogenicity study in CD-1 mice, formoterol at oral doses of 0.1 mg/kg and above (approximately 20 times the maximum recommended human daily inhalation dose on a mcg/m basis) caused a dose-related increase in the incidence of uterine leiomyomas.
In a 24-month carcinogenicity study in Sprague-Dawley rats, an increased incidence of mesovarian leiomyoma and uterine leiomyosarcoma were observed at the inhaled dose of 130 mcg/kg (approximately 60 times the maximum recommended human daily inhalation dose on a mcg/m basis). No tumors were seen at 22 mcg/kg (approximately 10 times the maximum recommended human daily inhalation dose on a mcg/m basis).
Other beta-agonist drugs have similarly demonstrated increases in leiomyomas of the genital tract in female rodents. The relevance of these findings to human use is unknown.
Formoterol was not mutagenic or clastogenic in Ames /microsome plate test, mouse lymphoma test, chromosome aberration test in human lymphocytes, and rat micronucleus test.
A reduction in fertility and/or reproductive performance was identified in male rats treated with formoterol at an oral dose of 15 mg/kg (approximately 7000 times the maximum recommended human daily inhalation dose on a mcg/m basis). In a separate study with male rats treated with an oral dose of 15 mg/kg (approximately 7000 times the maximum recommended human daily inhalation dose on a mcg/m basis), there were findings of testicular tubular atrophy and spermatic debris in the testes and oligospermia in the epididymides. No such effect was seen at 3 mg/kg (approximately 1400 times the maximum recommended human daily inhalation dose on a mcg/m basis). No effect on fertility was detected in female rats at doses up to 15 mg/kg (approximately 7000 times the maximum recommended human daily inhalation dose on a mcg/m basis).
Preclinical:
Reproductive Toxicology Studies:
Symbicort (Budesonide and formoterol fumarate dihydrate)
Symbicort (Budesonide and formoterol fumarate dihydrate) has been shown to be teratogenic and embryocidal in rats when given at inhalation doses of 12/0.66 mcg/kg (budesonide/formoterol) and above (less than the maximum recommended human daily inhalation dose on a mcg/m basis). Umbilical hernia, a malformation, was observed for fetuses at doses of 12/0.66 mcg/kg and above (less than the maximum recommended human daily inhalation dose on a mcg/m basis). No teratogenic or embryocidal effects were detected at 2.5/0.14 mcg/kg (less than the maximum recommended human daily inhalation dose on a mcg/m basis).
Budesonide
As with other corticosteroids, budesonide has been shown to be teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weight, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg/day in rabbits (less than the maximum recommended human daily inhalation dose on a mcg/m basis) and 500 mcg/kg/day in rats (approximately 6 times the maximum recommended human daily inhalation dose on a mcg/m basis). In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up to 250 mcg/kg/day (approximately 3 times the maximum recommended human daily inhalation dose on a mcg/m basis).
Formoterol
Formoterol fumarate has been shown to be teratogenic, embryocidal, to increase pup loss at birth and during lactation, and to decrease pup weights in rats when given at oral doses of 3 mg/kg/day and above (approximately 1400 times the maximum recommended human daily inhalation dose on a mcg/m basis). Umbilical hernia, a malformation, was observed in rat fetuses at oral doses of 3 mg/kg/day and above (approximately 1400 times the maximum recommended human daily inhalation dose on a mcg/m basis). Brachygnathia, a skeletal malformation, was observed in rat fetuses at an oral dose of 15 mg/kg/day (approximately 7000 times the maximum recommended human daily inhalation dose on a mcg/m basis). Pregnancy was prolonged at an oral dose of 15 mg/kg/day (approximately 7000 times the maximum recommended human daily inhalation dose on a mcg/m basis). In another study in rats, no teratogenic effects were seen at inhalation doses up to 1.2 mg/kg/day (approximately 500 times the maximum recommended human daily inhalation dose on a mcg/m basis).
Formoterol fumarate has been shown to be teratogenic in rabbits when given at an oral dose of 60 mg/kg (approximately 54,000 times the maximum recommended human daily inhalation dose on a mcg/m basis). Subcapsular cysts on the liver were observed in rabbit fetuses at an oral dose of 60 mg/kg (approximately 54,000 times the maximum recommended human daily inhalation dose on a mcg/m basis). No teratogenic effects were observed at oral doses up to 3.5 mg/kg (approximately 3200 times the maximum recommended human daily inhalation dose on a mcg/m basis).
Symbicort (Budesonide and formoterol fumarate dihydrate) Clinical Studies
Symbicort (Budesonide and formoterol fumarate dihydrate) has been studied in patients with asthma 12 years of age and older. In two clinical studies comparing Symbicort (Budesonide and formoterol fumarate dihydrate) with the individual components, improvements in most efficacy end points were greater with Symbicort (Budesonide and formoterol fumarate dihydrate) than with the use of either budesonide or formoterol alone. In addition, one clinical study showed similar results between Symbicort (Budesonide and formoterol fumarate dihydrate) and the concurrent use of budesonide and formoterol at corresponding doses from separate inhalers.
The safety and efficacy of Symbicort (Budesonide and formoterol fumarate dihydrate) were demonstrated in two randomized, double-blind, placebo-controlled US clinical studies involving 1076 patients 12 years of age and older. Fixed Symbicort (Budesonide and formoterol fumarate dihydrate) dosages of 160/9 mcg, and 320/9 mcg twice daily (each dose administered as two inhalations of the 80/4.5 and 160/4.5 mcg strengths, respectively) were compared with the monocomponents (budesonide and formoterol) and placebo to provide information about appropriate dosing to cover a range of asthma severity.
Study 1: Clinical Study with Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5
This 12-week study evaluated 596 patients 12 years of age and older by comparing Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, the free combination of budesonide 160 mcg plus formoterol 4.5 mcg in separate inhalers, budesonide 160 mcg, formoterol 4.5 mcg, and placebo; each administered as two inhalations twice daily. The study included a 2-week run-in period with budesonide 80 mcg, two inhalations twice daily. Most patients had moderate to severe asthma and were using moderate to high doses of inhaled corticosteroids prior to study entry. Randomization was stratified by previous inhaled corticosteroid treatment (71.6% on moderate- and 28.4% on high-dose inhaled corticosteroid). Mean percent predicted FEV at baseline was 68.1% and was similar across treatment groups. The coprimary efficacy end points were 12-hour-average postdose FEV at week 2, and predose FEV averaged over the course of the study. The study also required that patients who satisfied a predefined asthma-worsening criterion be withdrawn. The predefined asthma-worsening criteria were a clinically important decrease in FEV or peak expiratory flow (PEF), increase in rescue albuterol use, nighttime awakening due to asthma, emergency intervention or hospitalization due to asthma, or requirement for asthma medication not allowed by the protocol. For the criterion of nighttime awakening due to asthma, patients were allowed to remain in the study at the discretion of the investigator if none of the other asthma-worsening criteria were met. The percentage of patients withdrawing due to or meeting predefined criteria for worsening asthma is shown in Table 3.
Mean percent change from baseline in FEV measured immediately prior to dosing (predose) over 12 weeks is displayed in Figure 1. Because this study used predefined withdrawal criteria for worsening asthma, which caused a differential withdrawal rate in the treatment groups, predose FEV results at the last available study visit (end of treatment, EOT) are also provided. Patients receiving Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 mcg had significantly greater mean improvements from baseline in predose FEV at the end of treatment (0.19 L, 9.4%), compared with budesonide 160 mcg (0.10 L, 4.9%), formoterol 4.5 mcg (-0.12 L, -4.8%), and placebo (-0.17 L, -6.9%).
Figure 1 - Mean Percent Change From Baseline in Predose FEV Over 12 Weeks (Study 1)
The effect of Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 mcg two inhalations twice daily on selected secondary efficacy variables, including morning and evening PEF, albuterol rescue use, and asthma symptoms over 24 hours on a 0-3 scale is shown in Table 4.
The subjective impact of asthma on patients’ health-related quality of life was evaluated through the use of the standardized Asthma Quality of Life Questionnaire (AQLQ(S)) (based on a 7-point scale where 1 = maximum impairment and 7 = no impairment). Patients receiving Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 had clinically meaningful improvement in overall asthma-specific quality of life, as defined by a mean difference between treatment groups of >0.5 points in change from baseline in overall AQLQ score (difference in AQLQ score of 0.70 [95% CI 0.47, 0.93], compared to placebo).
Study 2: Clinical Study with Symbicort (Budesonide and formoterol fumarate dihydrate) 80/4.5
This 12-week study was similar in design to Study 1, and included 480 patients 12 years of age and older. This study compared Symbicort (Budesonide and formoterol fumarate dihydrate) 80/4.5 mcg, budesonide 80 mcg, formoterol 4.5 mcg, and placebo; each administered as two inhalations twice daily. The study included a 2-week placebo run-in period. Most patients had mild to moderate asthma and were using low to moderate doses of inhaled corticosteroids prior to study entry. Mean percent predicted FEV at baseline was 71.3% and was similar across treatment groups. Efficacy variables and end points were identical to those in Study 1.
The percentage of patients withdrawing due to or meeting predefined criteria for worsening asthma is shown in Table 5. The method of assessment and criteria used were identical to that in Study 1.
Mean percent change from baseline in predose FEV over 12 weeks is displayed in Figure 2.
Figure 2 - Mean Percent Change From Baseline in Predose FEV Over 12 Weeks (Study 2)
Efficacy results for other secondary end points, including quality of life, were similar to those observed in Study 1.
Onset and Duration of Action and Progression of Improvement in Asthma Control
The onset of action and progression of improvement in asthma control were evaluated in the two pivotal clinical studies. The median time to onset of clinically significant bronchodilation (>15% improvement in FEV) was seen within 15 minutes. Maximum improvement in FEV occurred within 3 hours, and clinically significant improvement was maintained over 12 hours. Figures 3 and 4 show the percent change from baseline in postdose FEV over 12 hours on the day of randomization and on the last day of treatment for Study 1.
Reduction in asthma symptoms and in albuterol rescue use, as well as improvement in morning and evening PEF, occurred within 1 day of the first dose of Symbicort (Budesonide and formoterol fumarate dihydrate) ; improvement in these variables was maintained over the 12 weeks of therapy.
Following the initial dose of Symbicort (Budesonide and formoterol fumarate dihydrate) , FEV improved markedly during the first 2 weeks of treatment, continued to show improvement at the Week 6 assessment, and was maintained through Week 12 for both studies.
No diminution in the 12-hour bronchodilator effect was observed with either Symbicort (Budesonide and formoterol fumarate dihydrate) 80/4.5 mcg or Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, as assessed by FEV, following 12 weeks of therapy or at the last available visit.
FEV data from Study 1 evaluating Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 mcg is displayed in Figures 3 and 4.
Figure 3 - Mean Percent Change From Baseline in FEV on Day of Randomization (Study 1)
Figure 4 - Mean Percent Change From Baseline in FEV At End of Treatment (Study 1)
The efficacy of Symbicort (Budesonide and formoterol fumarate dihydrate) 80/4.5 and Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 in the maintenance treatment of airflow obstruction in COPD patients was evaluated in two randomized, double-blind, placebo-controlled multinational studies, conducted over 6 months (Study 1) and 12 months (Study 2), in a total of 3668 patients (2416 males and 1252 females). The majority of patients (93%) were Caucasian. All patients were required to be at least 40 years of age, with a FEV of less than or equal to 50% predicted, a clinical diagnosis of COPD with symptoms for at least 2 years, and a smoking history of at least 10 pack years, prior to entering the trial. The mean prebronchodilator FEV at baseline of the patients enrolled in the study was 34% predicted. Forty-eight percent of the patients enrolled were on inhaled corticosteroids and 52.7% of patients were on short-acting anticholinergic bronchodilators during run-in. On randomization, inhaled corticosteroids were discontinued, and ipratropium bromide was allowed at a stable dose for those patients previously treated with short-acting anticholinergic bronchodilators. The co-primary efficacy variables in both studies were the change from baseline in average pre-dose and 1-hour post-dose FEV over the treatment period. The results of both studies 1 and 2 are described below.
Study 1
This was a 6-month, placebo-controlled study of 1704 COPD patients (mean % predicted FEV at baseline ranging from 33.5% -34.7%) conducted to demonstrate the efficacy and safety of Symbicort (Budesonide and formoterol fumarate dihydrate) in the treatment of airflow obstruction in COPD. The patients were randomized to one of the following treatment groups: Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 (n=277), Symbicort (Budesonide and formoterol fumarate dihydrate) 80/4.5 (n=281), budesonide 160 mcg + formoterol 4.5 mcg (n=287), budesonide 160 mcg (n=275), formoterol 4.5 mcg (n=284), or placebo (n=300). Patients receiving Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, two inhalations twice daily, had significantly greater mean improvements from baseline in pre-dose FEV averaged over the treatment period [0.08 L, 10.7%] compared with formoterol 4.5 mcg [0.04 L, 6.9%] and placebo [0.01 L, 2.2%] (See Figure 5). Patients receiving Symbicort (Budesonide and formoterol fumarate dihydrate) 80/4.5 mcg, two inhalations twice daily, did not have significantly greater improvement from baseline in the pre-dose FEV averaged over the treatment period compared with formoterol 4.5 mcg.
Figure 5 Mean Percent Change From Baseline in Pre-dose FEV Over 6 months (Study 1)
Patients receiving Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, two inhalations twice daily, had significantly greater mean improvements from baseline in 1-hour post-dose FEV averaged over the treatment period [0.20 L, 22.6%], compared with budesonide 160 mcg [0.03 L, 4.9%] and placebo [0.03 L, 4.1%] (See Figure 6).
Figure 6 Mean Percent Change From Baseline in 1-hour Post-dose FEV Over 6 months (Study 1)
Study 2
This was a 12-month, placebo-controlled study of 1964 COPD patients (mean % predicted FEV at baseline ranging from 33.7% -35.5%) conducted to demonstrate the efficacy and safety of Symbicort (Budesonide and formoterol fumarate dihydrate) in the treatment of airflow obstruction in COPD. The patients were randomized to one of the following treatment groups: Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 (n=494), Symbicort (Budesonide and formoterol fumarate dihydrate) 80/4.5 (n=494), formoterol 4.5 mcg (n=495), or placebo (n=481). Patients receiving Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, two inhalations twice daily, had significantly greater improvements from baseline in mean pre-dose FEV averaged over the treatment period [0.10 L, 10.8%] compared with formoterol 4.5 mcg [0.06 L, 7.2%] and placebo [0.01 L, 2.8%]. Patients receiving Symbicort (Budesonide and formoterol fumarate dihydrate) 80/4.5 mcg, two inhalations twice daily, did not have significantly greater improvements from baseline in the mean pre-dose FEV averaged over the treatment period compared to formoterol. Patients receiving Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 mcg, two inhalations twice daily, also had significantly greater mean improvements from baseline in 1-hour post-dose FEV averaged over the treatment period [0.21 L, 24.0%] compared with placebo [0.02 L, 5.2%].
Serial FEV measures over 12 hours were obtained in a subset of patients in Study 1 (n=99) and Study 2 (n=121). The median time to onset of bronchodilation, defined as an FEV increase of 15% or greater from baseline, occurred at 5 minutes post-dose. Maximum improvement (calculated as the average change from baseline at each timepoint) in FEV occurred at approximately 2 hours post-dose.
In both Studies 1 and 2, improvements in secondary endpoints of morning and evening peak expiratory flow and reduction in rescue medication use were supportive of the efficacy of Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5.
Symbicort (Budesonide and formoterol fumarate dihydrate) How Supplied/storage And Handling
Symbicort (Budesonide and formoterol fumarate dihydrate) is available in two strengths and is supplied in the following package sizes:
Each strength is supplied as a pressurized aluminium canister with an attached counting device, a red plastic actuator body with a white mouthpiece, and attached gray dust cap. Each 120 inhalation canister has a net fill weight of 10.2 grams and each 60 inhalation canister has a net fill weight of 6.9 grams (Symbicort (Budesonide and formoterol fumarate dihydrate) 80/4.5) or 6 grams (Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5). Each canister is packaged in a foil overwrap pouch with desiccant sachet and placed into a carton. Each carton contains one canister and a Medication Guide.
The Symbicort (Budesonide and formoterol fumarate dihydrate) canister should only be used with the Symbicort (Budesonide and formoterol fumarate dihydrate) actuator, and the Symbicort (Budesonide and formoterol fumarate dihydrate) actuator should not be used with any other inhalation drug product.
The correct amount of medication in each inhalation cannot be ensured after the labeled number of inhalations from the canister have been used, even though the inhaler may not feel completely empty and may continue to operate. The inhaler should be discarded when the labeled number of inhalations have been used or within 3 months after removal from the foil pouch. Never immerse the canister into water to determine the amount remaining in the canister (“float test”).
Store at controlled room temperature 20°C to 25°C (68°F to 77°F) [see USP]. Store the inhaler with the mouthpiece down.
For best results, the canister should be at room temperature before use. Shake well for 5 seconds before using.
Keep out of the reach of children.
Do not puncture or incinerate. Do not store near heat or open flame. Exposure to temperatures over 120ºF may cause bursting. Never throw container into fire or incinerator.
Symbicort (Budesonide and formoterol fumarate dihydrate) . Medication Guide
Read the Medication Guide that comes with Symbicort (Budesonide and formoterol fumarate dihydrate) before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.
3. When your asthma is well controlled, your healthcare provider may tell you to stop taking Symbicort (Budesonide and formoterol fumarate dihydrate) . Your healthcare provider will decide if you can stop Symbicort (Budesonide and formoterol fumarate dihydrate) without loss of asthma control. Your healthcare provider may prescribe a different long-term asthma-control medicine for you, such as an inhaled corticosteroid.
4. Children and adolescents who take LABA medicines may have an increased risk of being hospitalized for asthma problems.
Symbicort (Budesonide and formoterol fumarate dihydrate) combines an inhaled corticosteroid medicine, budesonide (the same medicine found in PULMICORT FLEXHALER), and a long-acting beta-agonist medicine (LABA), formoterol (the same medicine found in FORADIL AEROLIZER).
Symbicort (Budesonide and formoterol fumarate dihydrate) is used for asthma and chronic obstructive pulmonary disease (COPD) as follows:
Symbicort (Budesonide and formoterol fumarate dihydrate) is used to control symptoms of asthma, and prevent symptoms such as wheezing in adults and children ages 12 and older.
o are well controlled with an asthma-control medicine such as a low to medium dose of an inhaled corticosteroid medicine
o have sudden asthma symptoms
It is not known if Symbicort (Budesonide and formoterol fumarate dihydrate) is safe and effective in children ages 6 to less than 12 years of age with asthma.
COPD is a chronic lung disease that includes chronic bronchitis, emphysema, or both. Symbicort (Budesonide and formoterol fumarate dihydrate) 160/4.5 mcg is used long term, 2 times each day to help improve lung function for better breathing in adults with COPD.
Do not use Symbicort (Budesonide and formoterol fumarate dihydrate) :
• to treat sudden severe symptoms of asthma or COPD.
• if you are allergic to any of the ingredients in Symbicort (Budesonide and formoterol fumarate dihydrate) . See the end of the Medication Guide for a list of ingredients in Symbicort (Budesonide and formoterol fumarate dihydrate) .
Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Symbicort (Budesonide and formoterol fumarate dihydrate) and certain other medicines may interact with each other. This may cause serious side effects. Especially tell your healthcare provider if you take antifungal and anti-HIV medicines.
Know all the medicines you take. Keep a list and show it to your healthcare provider and pharmacist each time you get a new medicine.
Tell your healthcare provider about any side effect that bothers you or that does not go away.
These are not all the side effects of Symbicort (Budesonide and formoterol fumarate dihydrate) . Ask your healthcare provider or pharmacist for more information.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
You may also report side effects to AstraZeneca at 1-800-236-9933.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Symbicort (Budesonide and formoterol fumarate dihydrate) for a condition for which it was not prescribed. Do not give your Symbicort (Budesonide and formoterol fumarate dihydrate) to other people, even if they have the same condition. It may harm them.
This Medication Guide summarizes the most important information about Symbicort (Budesonide and formoterol fumarate dihydrate) . If you would like more information, talk with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for information about Symbicort (Budesonide and formoterol fumarate dihydrate) that was written for healthcare professionals. For more information, call 1-800-236-9933 or go to www.MySymbicort (Budesonide and formoterol fumarate dihydrate) .com.
Active ingredients: micronized budesonide and micronized formoterol fumarate dihydrate Inactive ingredients: hydrofluroalkane (HFA 227), povidone K25 USP, and polyethylene glycol 1000 NF
Follow the instructions below for using Symbicort (Budesonide and formoterol fumarate dihydrate) . You will breathe-in (inhale) the medicine. If you have any questions, ask your doctor or pharmacist.
- Take your Symbicort (Budesonide and formoterol fumarate dihydrate) out of the moisture-protective foil pouch before you use it for the first time and throw the foil away. Write the date that you open the foil pouch on the box.
- A counter is attached to the top of the metal canister. The counter will count down each time you release a puff of Symbicort (Budesonide and formoterol fumarate dihydrate) . The arrow points to the number of inhalations (puffs) left in the canister. The counter will stop counting at zero (“0”).
- Use the Symbicort (Budesonide and formoterol fumarate dihydrate) canister only with the red Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler supplied with the product. Parts of the Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler should not be used with parts from any other inhalation product.
- Shake your Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler well for 5 seconds right before each use. Remove the mouthpiece cover. Check the mouthpiece for foreign objects before use.
- Before you use Symbicort (Budesonide and formoterol fumarate dihydrate) for the first time, you will need to prime it. To prime Symbicort (Budesonide and formoterol fumarate dihydrate) , hold it in the upright position. See figure 1 above. Shake the Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler well for 5 seconds. Hold your Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler facing away from you and then release a test spray. Then shake it again for 5 seconds and release a second test spray. Your Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler is now primed and ready for use. After you have primed the Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler for the first time, the counter will read either 120 or 60, depending on which size was provided to you.
- Shake your Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler well for 5 seconds. Remove the mouthpiece cover. Check the mouthpiece for foreign objects
- Breathe out fully (exhale). Hold the Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler up to your mouth. Place the white mouthpiece fully into your mouth and close your lips around it. Make sure that the Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler is upright and that the opening of the mouthpiece is pointing towards the back of your throat (see Figure 4).
- Breathe in (inhale) deeply and slowly through your mouth. Press down firmly and fully on the top of the counter on the Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler to release the medicine (see Figures 2 and 3).
- Continue to breathe in (inhale) and hold your breath for about 10 seconds, or for as long as is comfortable. Before you breathe out (exhale), release your finger from the top of the counter. Keep the Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler upright and remove from your mouth.
- Shake the Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler again for 5 seconds and repeat steps 7 to 9.
- Replace the mouthpiece cover after use.
- After you finish taking Symbicort (Budesonide and formoterol fumarate dihydrate) (two puffs), rinse your mouth with water. Spit out the water. Do not swallow it.
- The arrow on the counter on the top of the Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler points to the number of inhalations (puffs) left in your inhaler.
- The counter will count down each time you release a puff of medicine (either when preparing your Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler for use or when taking the medicine).
- When the arrow on the counter approaches 20, you will notice the beginning of a yellow area letting you know that it is time to call your healthcare provider for a refill.
- It is important that you pay attention to the number of inhalations (puffs) left in your Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler by reading the counter. Throw away Symbicort (Budesonide and formoterol fumarate dihydrate) when the counter shows zero (“0”). Your Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler may not feel empty and it may continue to operate, but you will not get the right amount of medicine if you keep using it. Use a new Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler and follow the instructions for priming (instruction 5 above).
Clean the white mouthpiece of your Symbicort (Budesonide and formoterol fumarate dihydrate) inhaler every 7 days. To clean the mouthpiece:
Rev. 06/10
Manufactured for: AstraZeneca LP, Wilmington, DE 19850
By: AstraZeneca Dunkerque Production, Dunkerque, France
Product of France
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Symbicort (Budesonide and formoterol fumarate dihydrate) and PULMICORT FLEXHALER are trademarks of the AstraZeneca group of companies. ADVAIR DISKUS, ADVAIR HFA, SEREVENT and DISKUS are trademarks of GlaxoSmithKline. FORADIL AEROLIZER is a trademark of Novartis Pharmaceuticals Corporation.
©AstraZeneca 2006, 2007, 2009, 2010
