Steroid withdrawal: Particular care is needed for patients who are transferred from systemically active corticosteroids to inhaled corticosteroids (eg, budesonide) because 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 are required for recovery of HPA-axis function. Patients who have been previously maintained on greater than or equal to 20 mg/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its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.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-axis 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 budesonide may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does not provide the mineralocorticoid activity that is necessary for coping with these emergencies.
Acute stress/severe asthma attack: During periods of stress or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further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.
Transfer from systemic steroids: Transfer of patients from systemic corticosteroid therapy to budesonide may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (eg, rhinitis, conjunctivitis, eczema).
Compromised immune system: Patients who are on drugs which suppress the immune system are more susceptible to infection than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults on immunosuppressant doses of corticosteroids. In children or adult patients who have not had these diseases, or who have not been properly vaccinated, 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 unknown. The contribution of the underlying disease or prior corticosteroid treatment to the risk is also not known. If exposed, therapy with varicella-zoster immune globulin (VZIG) or pooled IV immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled IM immunoglobulin (IG) may be indicated. If chickenpox develops, treatment with antiviral agents may be considered.
Acute asthma: Budesonide is not a bronchodilator and is not indicated for rapid relief of bronchospasm or other acute episodes of asthma.
Bronchospasm: As with other inhaled asthma medications, bronchospasm, with an immediate increase in wheezing, may occur after dosing. If bronchospasm occurs following dosing with budesonide, it should be treated immediately with a fast-acting inhaled bronchodilator. Treatment with budesonide should be discontinued and alternate therapy instituted. Patients should be instructed to contact their physicians immediately when episodes of asthma not responsive to their usual doses of bronchodilators occur during treatment with budesonide. During such episodes, patients may require therapy with oral corticosteroids.
Inhalation suspension: For inhalation use via compressed air driven jet nebulizers only (not for use with ultrasonic devices). Not for injection. Read patient instructions before using. During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (eg, joint or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.
Systemic corticosteroid effects: Because budesonide is absorbed into the circulation and may be systemically active, particularly at higher doses, suppression of HPA function may be associated when budesonide is administered at doses exceeding those recommended, or when the dose is not titrated to the lowest effected dose. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing budesonide.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with these drugs 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, budesonide should be reduced slowly, consistent with accepted procedures for management of asthma symptoms and for tapering of systemic corticosteroids.
Although patients in clinical trials have received budesonide powder for inhalation on a continuous basis for periods of 1 to 2 years and budesonide inhalation suspension on a continuous basis for up to 1 year, the long-term local and systemic effects of budesonide in human subjects are not completely known. In particular, the effects resulting from chronic use of budesonide on developmental or immunological processes in the mouth, pharynx, trachea, and lung are unknown.
Vision: Rare instances of glaucoma, increased intraocular pressure, and cataracts have been reported following the inhaled administration of corticosteroids.
Special risk patients: 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.
Carcinogenesis: Long-term studies were conducted in mice and rats 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 daily inhalation dose in adults and children 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 daily inhalation dose in adults and children on a mcg/m2 basis). In 2 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 daily inhalation dose in adults and children 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 daily inhalation dose in adults and children on a mcg/m2 basis). The concurrent reference corticosteroids (prednisolone and triamcinolone acetonide) in these 2 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 (less than the maximum recommended daily inhalation dose in adults and children on a mcg/m2 basis).
Mutagenesis: Budesonide was not mutagenic or clastogenic in 6 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.
Fertility impairment: In rats, budesonide had no effect on fertility at SC doses up to 80 mcg/kg (less than the maximum recommended daily inhalation dose in adults 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 SC doses of 20 mcg/kg and above (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis). No such effects were noted at 5 mcg/kg (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis).
Monitoring: A reduction of growth velocity in children or teenagers may occur as a result of inadequate control of chronic diseases such as asthma or from use of corticosteroids for treatment. Physicians should closely follow the growth of all children taking corticosteroids by any route and weigh the benefits of corticosteroid therapy and asthma control against the possibility of growth suppression.
Effects on the Ability to Drive and Use Machines: It does not affect the ability to drive or to use machines.
Use in Children: Safety in children 6 months to 12 months of age has been evaluated. Safety and effectiveness in children 12 months to 8 years of age have been established.
A 12-week study in 141 pediatric patients 6 to 12 months of age with mild to moderate asthma or recurrent/persistent wheezing was conducted. All patients were randomized to receive either 0.5 mg or 1 mg of budesonide inhalation suspension or placebo once daily. Adrenal axis function was assessed with an ACTH stimulation test at the beginning and end of the study, and mean changes from baseline in this variable did not indicate adrenal suppression in patients who received budesonide inhalation suspension vs placebo. However, on an individual basis, 7 patients in this study (6 in the budesonide inhalation suspension treatment arms and 1 in the placebo arm) experienced a shift from having a normal baseline stimulated cortisol level to having a subnormal level at week 12. Pneumonia was observed more frequently in patients treated with budesonide inhalation suspension than in patients treated with placebo, (n = 2, 1, and 0) in the budesonide inhalation suspension 0.5 mg, 1 mg, and placebo groups, respectively.
A dose-dependent effect on growth was also noted in this 12-week trial. Infants in the placebo arm experienced an average growth of 3.7 cm over 12 weeks compared with 3.5 cm and 3.1 cm in the budesonide inhalation suspension 0.5 mg and 1 mg arms respectively. This corresponds to estimated mean (95% CI) reductions in 12-week growth velocity between placebo and budesonide inhalation suspension 0.5 mg of 0.2 cm (–0.6 to 1) and between placebo and budesonide inhalation suspension 1 mg of 0.6 cm (–0.2 to 1.4). These findings support that the use of budesonide inhalation suspension in infants 6 to 12 months of age may result in systemic effects and are consistent with findings of growth suppression in other studies with inhaled corticosteroids.
Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm per year (range 0.3 to 1.8 cm per year) and appears to be related to dose and duration of exposure. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (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 effects of this reduction in growth velocity associated with inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for "catch-up" growth following discontinuation of treatment with inhaled corticosteroids has not been adequately studied. The growth of pediatric patients receiving inhaled corticosteroids, including budesonide inhalation suspension, should be monitored routinely (eg, via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of inhaled corticosteroids, including budesonide inhalation suspension, each patient should be titrated to his or her lowest effective dose.
Use in Elderly: Of the 215 patients in 3 clinical trials of budesonide inhalation suspension in adult patients, 65 (30%) were greater than or equal to 65 years of age, while 22 (10%) were greater than or equal to 75 years of age. No overall differences in safety were observed between these patients and younger patients, and other reported clinical or medical surveillance experience has not identified differences in responses between the elderly and younger patients.