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Symbicort

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Symbicort

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk of Asthma-related Death with Long-Acting Beta2-Adrenergic Agonists

Long-acting beta2-adrenergic agonists may increase the risk of asthma-related death [see WARNINGS AND PRECAUTIONS]. One of the active ingredients of SYMBICORT (budesonide and formoterol fumarate dihydrate) is formoterol, a long-acting beta2-agonist, therefore, when treating patients with asthma, SYMBICORT (budesonide and formoterol fumarate dihydrate) should only be used for patients not adequately controlled on other asthma-controller medications (e.g., low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies.

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). The increased risk of asthma-related death may represent a class effect of the long-acting beta2-adrenergic agonists, including formoterol. 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.

Deterioration of Disease and Acute Episodes

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 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 (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 beta2-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 beta2-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 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 (budesonide and formoterol fumarate dihydrate) and Use with Other Long-Acting Beta2-Agonists

As with other inhaled drugs containing beta2-adrenergic agents, SYMBICORT (budesonide and formoterol fumarate dihydrate) 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 (budesonide and formoterol fumarate dihydrate) 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 maintenance 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 (budesonide and formoterol fumarate dihydrate) . When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral antifungal) therapy while treatment with SYMBICORT (budesonide and formoterol fumarate dihydrate) continues, but at times therapy with SYMBICORT (budesonide and formoterol fumarate dihydrate) may need to be interrupted. Patients should rinse the mouth after inhalation of SYMBICORT (budesonide and formoterol fumarate dihydrate) .

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 (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%).

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 (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 [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 (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.

Hypercorticism and Adrenal Suppression

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.

Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors

Caution should be exercised when considering the coadministration of SYMBICORT (budesonide and formoterol fumarate dihydrate) 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, CLINICAL PHARMACOLOGY]

Paradoxical Bronchospasm and Upper Airway Symptoms

As with other inhaled medications, SYMBICORT (budesonide and formoterol fumarate dihydrate) can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with SYMBICORT (budesonide and formoterol fumarate dihydrate) , it should be treated immediately with an inhaled, short-acting bronchodilator, SYMBICORT (budesonide and formoterol fumarate dihydrate) should be discontinued immediately, and alternative therapy should be instituted.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of SYMBICORT (budesonide and formoterol fumarate dihydrate) , 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]. 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.

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 (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/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 dose 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 (budesonide and formoterol fumarate dihydrate) routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including SYMBICORT (budesonide and formoterol fumarate dihydrate) , titrate each patient's dose to the lowest dosage that effectively controls his/her symptoms. [See DOSAGE AND ADMINISTRATION, Use in Specific Populations.]

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 (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. Opthalmic 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.

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 (budesonide and formoterol fumarate dihydrate) , 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]. 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 (budesonide and formoterol fumarate dihydrate) at recommended doses.

Patient Counseling Information

See Medication Guide

Risk of Asthma-Related Death

Patients with asthma should be informed that formoterol fumarate dihydrate, one of the active ingredients in SYMBICORT (budesonide and formoterol fumarate dihydrate) , may increase the risk of asthma-related death.

They should also be informed that data are not adequate to determine whether the concurrent use of inhaled corticosteroids, the other component of SYMBICORT (budesonide and formoterol fumarate dihydrate) , or other asthma-controller therapy modifies this risk.

Not for Acute Symptoms

SYMBICORT (budesonide and formoterol fumarate dihydrate) is not meant to relieve acute asthma symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. (The physician should provide the patient with such medication and instruct the patient in how it should be used.)

Patients should be instructed to notify their physician immediately if they experience any of the following:

  • Decreasing effectiveness of inhaled, short-acting beta2-agonists
  • Need for more inhalations than usual of inhaled, short-acting beta2-agonists
  • Significant decrease in lung function as outlined by the physician

Patients should not stop therapy with SYMBICORT (budesonide and formoterol fumarate dihydrate) without physician/provider guidance since symptoms may recur after discontinuation.

Do Not Use Additional Long-Acting Beta2-Agonists

When patients are prescribed SYMBICORT (budesonide and formoterol fumarate dihydrate) , other long-acting beta2-agonists for asthma and COPD should not be used.

Risks Associated With Corticosteroid Therapy

Local Effects: Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with SYMBICORT (budesonide and formoterol fumarate dihydrate) , but at times therapy with SYMBICORT (budesonide and formoterol fumarate dihydrate) may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised.

Pneumonia: Patients with COPD have a higher risk of pneumonia and should be instructed to contact their healthcare provider if they develop symptoms of pneumonia.

Immunosuppression: Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chicken pox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.

Hypercorticism and Adrenal Suppression: Patients should be advised that SYMBICORT (budesonide and formoterol fumarate dihydrate) may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to SYMBICORT (budesonide and formoterol fumarate dihydrate) .

Reduction in Bone Mineral Density: Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk.

Reduced Growth Velocity: Patients should be informed that orally inhaled corticosteroids, component of SYMBICORT (budesonide and formoterol fumarate dihydrate) , may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route.

Ocular Effects: Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered.

Risks Associated With Beta-Agonist Therapy

Patients should be informed of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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/m2 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/m2 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/m2 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/m2 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/m2 basis).

Budesonide was not mutagenic or clastogenic in six different test systems: Ames Salmonella/microsome plate test, mouse micronucleus test, mouse lymphoma test, chromosome aberration test in human lymphocytes, sex-linked recessive lethal test in Drosophila melanogaster, 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/m2 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/m2 basis). No such effects were noted at 5 mcg/kg (less than the maximum recommended human daily inhalation dose on a mcg/m2 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/m2 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/m2 basis). No tumors were seen at 22 mcg/kg (approximately 10 times the maximum recommended human daily inhalation dose on a mcg/m2 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 Salmonella/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/m2 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/m2 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/m2 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/m2 basis).

Use In Specific Populations

Pregnancy

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/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

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/m2 basis and in rats at doses approximately 6 times the maximum recommended human daily inhalation dose on a mcg/m2 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/m2 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/m2 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/m2 basis. Brachygnathia was observed in rat fetuses at an oral dose 7000 times the maximum recommended human daily inhalation dose on a mcg/m2 basis. Pregnancy was prolonged at an oral dose 7000 times the maximum recommended human daily inhalation dose on a mcg/m2 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/m2 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/m2 basis. No teratogenic effects were observed at oral doses up to 3200 times the maximum recommended human daily inhalation dose on a mcg/m2 basis.

Nonteratogenic Effects

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.

Labor and Delivery

There are no well-controlled human studies that have investigated the effects of SYMBICORT (budesonide and formoterol fumarate dihydrate) on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of SYMBICORT (budesonide and formoterol fumarate dihydrate) for management of asthma during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

Nursing Mothers

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 [see CLINICAL PHARMACOLOGY, Pharmacokinetics]. 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.

Pediatric Use

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 twice daily [see Clinical Studies]. 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 < 12 years of age has not been established.

Overall 1447 asthma patients 6 to < 12 years of age participated in placebo- and active-controlled SYMBICORT (budesonide and formoterol fumarate dihydrate) studies. Of these 1447 patients, 539 received SYMBICORT (budesonide and formoterol fumarate dihydrate) twice daily. The overall safety profile of these patients was similar to that observed in patients ≥ 12 years of age who also received SYMBICORT (budesonide and formoterol fumarate dihydrate) twice daily in studies of similar design.

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 [see DOSAGE AND ADMINISTRATION].

Geriatric Use

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 beta2-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 beta2-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.

Hepatic Impairment

Formal pharmacokinetic studies using SYMBICORT (budesonide and formoterol fumarate dihydrate) have not been conducted in patients with hepatic impairment, However, since both budesonide and formoterol fumarate are predominantly cleared by hepatic metabolism, impairment of liver function may lead to accumulation of budesonide and formoterol fumarate in plasma. Therefore, patients with hepatic disease should be closely monitored.

Renal Impairment

Formal pharmacokinetic studies using SYMBICORT (budesonide and formoterol fumarate dihydrate) have not been conducted in patients with renal impairment.

Last reviewed on RxList: 6/2/2009
This monograph has been modified to include the generic and brand name in many instances.

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