Long-acting beta2-adrenergic agonists may increase the risk of asthma-related death. Therefore, when treating patients with asthma, SYMBICORT 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 two 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 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 Should Not Be Initiated In Patients During Rapidly Deteriorating Or Potentially Life-Threatening Episodes Of Asthma.
Do Not Use SYMBICORT to Treat Acute Symptoms. SYMBICORT should not be used to treat acute symptoms of asthma. An inhaled, short-acting beta2-agonist (e.g., albuterol), should be used to relieve acute asthma symptoms. Therefore, when prescribing SYMBICORT, the physician must also provide the patient with an inhaled, short-acting beta2-agonist for treatment of symptoms that occur acutely, despite regular twice-daily (morning and evening) use of SYMBICORT.
When beginning treatment with SYMBICORT, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs. For patients on SYMBICORT, short-acting, inhaled beta2-agonists should only be used for symptomatic relief of acute asthma symptoms (see PRECAUTIONS, Information for Patients).
Watch for Increasing Use of Inhaled, Short-Acting Beta2-Agonists, Which Is a Marker of Deteriorating Asthma. Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient's inhaled, short-acting beta2-agonist becomes less effective, the patient needs more inhalations than usual, or the patient develops a significant decrease in lung function, these may be markers of destabilization of asthma. In this setting, the patient requires immediate re-evaluation and reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of SYMBICORT with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than two actuations twice daily (morning and evening) of SYMBICORT.
SYMBICORT Should Not be Used For Transferring Patients from Systemic Corticosteroid Therapy. Particular care is needed for patients who are transferred from systemically active corticosteroids to inhaled corticosteroids. Deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months may be required for recovery of 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 inhaled corticosteroid therapy 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 medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or a severe asthma attack.
Do Not Use an Inhaled, Long-Acting Beta2-Agonist in Conjunction With SYMBICORT. Patients who are receiving SYMBICORT twice daily should not use additional formoterol or other long-acting inhaled beta2-agonists (e.g., salmeterol) for prevention of exercise-induced bronchospasm (EIB) or the maintenance treatment of asthma. Additional benefit would not be gained from using supplemental formoterol or salmeterol for prevention of EIB since SYMBICORT already contains an inhaled, long-acting beta2-agonist.
Do Not Exceed Recommended Dosage. SYMBICORT should not be used more often or at higher doses than recommended. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected. In addition, data from clinical studies with formoterol dry powder inhaler suggest that the use of doses higher than recommended (24 mcg twice daily) is associated with an increased risk of serious asthma exacerbations. In a 52-week active-controlled safety study evaluating SYMBICORT 160/4.5, patients treated with twice the highest recommended dose of SYMBICORT demonstrated a similar safety profile to that of patients treated with the highest recommended dose.
Paradoxical Bronchospasm. As with other inhaled asthma medications, SYMBICORT may produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with SYMBICORT, treatment with SYMBICORT should be discontinued immediately and alternate therapy should be instituted.
Immediate Hypersensitivity Reactions. Immediate hypersensitivity reactions, such as urticaria, angioedema, rash, and bronchospasm may occur after administration of SYMBICORT.
Cardiovascular Disorders. SYMBICORT, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Formoterol, a component of SYMBICORT, may 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 SYMBICORT at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (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.
Discontinuation of Systemic Corticosteroids. Transfer of patients from systemic corticosteroid therapy to inhaled corticosteroids may unmask conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, and arthritis.
Immunosuppression. Persons who are using drugs that suppress the immune system are more susceptible to infections 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. It is unknown how the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient on immunosuppressant doses of corticosteroids is exposed to chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intramuscular immunoglobulin (IG), 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 (see PRECAUTIONS, Drug Interactions).
Sympathomimetic Effects. The cardiovascular and central nervous system effects seen with all sympathomimetic drugs (e.g., increased blood pressure, heart rate, excitement) can occur after use of formoterol, a component of SYMBICORT, and may require discontinuation of SYMBICORT. SYMBICORT, like all medications containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, untreated hypokalemia, or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines.
As has been described with other beta-adrenergic agonist bronchodilators, clinically important changes in electrocardiograms, systolic and/or diastolic blood pressure, and pulse rate were seen infrequently in individual patients during controlled clinical studies with SYMBICORT at recommended doses.
Metabolic and Other Effects. Long-term use of orally inhaled corticosteroids, such as budesonide, a component of SYMBICORT, may affect normal bone metabolism resulting in a loss of bone mineral density. In patients with major risk factors for decreased bone mineral content, such as tobacco use, advanced age, sedentary lifestyle, poor nutrition, family history or osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids), orally inhaled corticosteroids may pose an additional risk.
Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis. High doses of beta-adrenergic agonist medications may produce significant hypokalemia in some patients, through intracellular shunting, which may have the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation.
Clinically important changes in blood glucose and/or serum potassium were seen rarely during clinical studies with SYMBICORT at recommended doses.
During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function.
Budesonide, a component of SYMBICORT, will often permit control of 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, patients should not exceed the recommended dosage of SYMBICORT. Individual patients should be titrated to the lowest effective dose in order to minimize HPA dysfunction. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing SYMBICORT.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with SYMBICORT should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.
It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear in a small number of patients, particularly at higher doses. If such changes occur, the total daily dose of SYMBICORT should be reduced slowly, consistent with accepted procedures for management of asthma symptoms and for tapering of systemic steroids.
Budesonide, a component of SYMBICORT, may cause a reduction in growth velocity when administered to pediatric patients. Patients should be maintained on the lowest dose of SYMBICORT that effectively controls their asthma (see PRECAUTIONS, Pediatric Use).
The long-term effects resulting from chronic use of budesonide on developmental or immunological processes in the mouth, pharynx, trachea, and lung are unknown. The local and systemic effects of SYMBICORT in humans have been studied for up to one year (see ADVERSE REACTIONS, Long Term Safety).
Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported following the inhaled administration of corticosteroids, including budesonide, a component of SYMBICORT.
Lower respiratory tract infections, including pneumonia, have been reported following the inhaled administration of corticosteroids, including budesonide, a component of SYMBICORT. In the 3 placebo-controlled US clinical studies, the incidence of lower respiratory tract infections, including pneumonia, was low, with no consistent evidence of increased risk for SYMBICORT compared to placebo.
In clinical studies with SYMBICORT, localized infections with Candida albicans have occurred in the mouth and pharynx. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (ie, oral) antifungal therapy while still continuing with SYMBICORT therapy, but at times the dose of SYMBICORT may need to be temporarily decreased or interrupted under close medical supervision.
Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral or parasitic infections, or ocular herpes simplex.
Information for Patients
Patients should be instructed to read the accompanying Medication Guide with each new prescription and refill.
Patients being treated with SYMBICORT should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of the medication. It is not a disclosure of all possible adverse or intended effects.
It is important that patients understand how to use the SYMBICORT inhaler device appropriately and how SYMBICORT should be used in relation to other asthma medications they are taking.
Patients should be informed that long-acting beta2-adrenergic agonists may increase the risk of asthma-related death. Patients should also be informed that data are not adequate to determine whether the concurrent use of inhaled corticosteroids, such as budesonide, the other component of SYMBICORT, or other asthma-controller therapy modifies this risk.
Patients should be instructed that the correct dose of SYMBICORT is 2 puffs inhaled twice daily of the appropriate dosage strength, 80/4.5 or 160/4.5. They should take 2 puffs of SYMBICORT in the morning and 2 puffs in the evening every day. The maximum daily recommended dose is 640/18 mcg budesonide/formoterol (given as two inhalations of SYMBICORT 160/4.5 twice daily). Do not use more than twice daily or use a higher number of inhalations (more than 2 inhalations twice daily) of the prescribed strength of SYMBICORT as this will result in a daily dose of formoterol in excess of the dose determined to be safe. Patients should also be instructed not to take SYMBICORT more often or use more puffs than you have prescribed. If they miss a dose, they should be instructed to take their next dose at the same time they normally do.
SYMBICORT is not meant to relieve acute asthma symptoms 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 on how it should be used).
The physician should be notified immediately if any of the following situations occur, which may be a sign of seriously worsening asthma:
Need for more inhalations than usual of inhaled, short-acting beta2-agonists
Significant decrease in lung function as outlined by the physician
Marked change in symptoms
When patients are prescribed SYMBICORT, other inhaled drugs and asthma medications should be used only as directed by a physician.
Patients who are receiving SYMBICORT should not use formoterol or another long-acting inhaled beta2-agonist for prevention of exercise-induced bronchospasm or maintenance treatment of asthma.
Patients should not stop therapy with SYMBICORT without physician/provider guidance since symptoms may recur after discontinuation.
Patients should be cautioned regarding common adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
Patients should be warned to avoid exposure to chicken pox or measles and if they are exposed, to consult their physician without delay.
Long-term use of inhaled corticosteroids, including budesonide, a component of SYMBICORT, may increase the risk of some eye problems (cataracts or glaucoma). Regular eye examinations should be considered.
If the patient is pregnant or nursing, they should contact their physician about the use of SYMBICORT.
Results of clinical trials indicate that in most patients, clinically significant improvement occurred within 15 minutes of beginning treatment with SYMBICORT. The maximum benefit may not be achieved for 2 weeks or longer after starting treatment. Individual patients may experience a variable time to onset and degree of symptom relief.
The bronchodilation from a dose (2 inhalations) of SYMBICORT has been shown to last up to 12 hours or longer. The recommended dosage should not be exceeded.
The following measures should be observed when using SYMBICORT:
SYMBICORT should be primed before using the first time and also when the inhaler has not been used for more than 7 days or when it has been dropped, by releasing 2 test sprays into the air away from the face, shaking well for 5 seconds before each spray.
Patients should replace the mouthpiece cover after each use.
To remove any excess medication, patients should rinse their mouth with water after each dose (do not swallow) to decrease the risk of the development of oral candidiasis.
Patients should clean the inhaler every 7 days by wiping the mouthpiece with a dry cloth.
Use SYMBICORT only with the actuator supplied with the product. Discard the inhaler after the labeled number of sprays have been used by the patient.
Store in a dry place at controlled room temperature 20°C to 25°C (68°F to 77°F) [see USP] and out of the reach of children.
In clinical studies, concurrent administration of SYMBICORT and other drugs, such as short-acting beta2-agonists, intranasal corticosteroids, and antihistamines/decongestants has not resulted in an increased frequency of adverse events. No formal drug interaction studies have been performed with SYMBICORT.
Short-Acting Beta2-Agonists: In three 12-week, placebo-controlled US clinical studies, the mean daily need for albuterol rescue use in 401 adult and adolescent patients using SYMBICORT twice daily was approximately 0.8 inhalations/day, and ranged from 0 to 14 inhalations/day. Approximately 2% (N= 8) of the SYMBICORT patients in these studies averaged 6 or more inhalations per day. No cardiac adverse events were reported in these patients.
Methylxanthines and leukotriene modifying agents: The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving SYMBICORT has not been completely evaluated. In clinical trials with SYMBICORT, a limited number of patients received concurrent methylxanthines or leukotriene modifying agents, and therefore no clinically meaningful conclusions on adverse events can be made.
Intranasal and systemic corticosteroids: Among adult and adolescent patients participating in active- and placebo-controlled US clinical trials, twice daily SYMBICORT was used concurrently with intranasal budesonide in 105 patients and with any intranasal corticosteroid in 585 patients. Two hundred seventeen patients used courses of systemic corticosteroids while taking SYMBICORT. There were no important differences noted in the adverse event profiles between these groups.
Monoamine Oxidase Inhibitors and Tricyclic Antidepressants: SYMBICORT should be administered with caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of formoterol, a component of SYMBICORT, on the vascular system may be potentiated by these agents. In clinical trials with SYMBICORT, a limited number of patients received tricyclic antidepressants and therefore no clinically meaningful conclusions on adverse events can be made.
Beta-Adrenergic Receptor Blocking Agents: Beta-blockers (including eye drops) may not only block the pulmonary effect of beta-agonists, such as formoterol, a component of SYMBICORT, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.
Diuretics: The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of SYMBICORT with nonpotassium-sparing diuretics.
Ketoconazole and Other Inhibitors of Cytochrome P450: The main route of metabolism of corticosteroids, including budesonide, a component of SYMBICORT, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a potent inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of other known inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, erythromycin, etc.) may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the coadministration of SYMBICORT with long-term ketoconazole and other known potent CYP3A4 inhibitors.
Varicella Vaccine: An open-label non-randomized 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 non-corticosteroid asthma therapy (N=92) (ie, 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 non-corticosteroid asthma therapy (90%). No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies were conducted in rats and mice using oral administration to evaluate the carcinogenic potential of budesonide.
In a two-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 two-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).
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).
Teratogenic Effects: Pregnancy Category C
SYMBICORT 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/m2 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/m2 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/m2 basis). There are no adequate and well-controlled studies in pregnant women. SYMBICORT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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/m2 basis) and 500 mcg/kg/day in rats (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 250 mcg/kg/day (approximately 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.
Studies of pregnant women, however, 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%).
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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 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/m2 basis).
There are no adequate and well-controlled studies with formoterol in pregnant women.
Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.
Use in Labor and Delivery
There are no well-controlled human studies that have investigated the effects of SYMBICORT on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of SYMBICORT for management of asthma during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.
Since there are no data from controlled trials on the use of SYMBICORT by nursing mothers, a decision should be made whether to discontinue nursing or to discontinue SYMBICORT, taking into account the importance of SYMBICORT to the mother.
It is not known whether budesonide, one of the main components of SYMBICORT, is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be exercised if budesonide is administered to nursing women.
In reproductive studies in rats, formoterol was excreted in the milk. It is not known whether formoterol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if formoterol is administered to nursing women.
Safety and effectiveness of SYMBICORT in 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. 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 effectiveness of SYMBICORT in patients 6 to <12 years of age has not been established.
Overall 1447 patients 6 to <12 years of age participated in placebo- and active-controlled SYMBICORT studies. Of these 1447 patients, 539 received SYMBICORT twice daily. The overall safety profile of these patients was similar to that observed in patients ≥12 years of age who also received SYMBICORT twice daily in studies of similar design.
Controlled clinical studies have shown that orally inhaled corticosteroids including budesonide, a component of SYMBICORT, 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 four 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, 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, each patient should be titrated to the lowest strength that effectively controls his/her asthma (see DOSAGE AND ADMINISTRATION).
In three 12-week, double-blind, placebo-controlled US clinical studies, 17 patients treated with SYMBICORT twice daily were 65 years of age or older, of whom 2 were 75 years of age or older. Of the total number of patients in clinical studies treated with SYMBICORT twice daily, 149 were 65 years of age or older, of whom, 25 were 75 years of age or older. No overall differences in safety were observed between these patients and younger patients. As with other products containing beta2-agonists, special caution should be observed when using SYMBICORT in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta2-agonists. Based on available data for SYMBICORT or its active components, no adjustment of dosage of SYMBICORT in geriatric patients is warranted.