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Each puff contains Budesonide 200 mcg.
Pharmacotherapeutic Group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: RO3B A02.
Pharmacology: Pharmacodynamics: Mechanism of Action: Budesonide is a glucocorticosteroid which possesses a high local anti-inflammatory action, with a lower incidence and severity of adverse effects than those seen with oral corticosteroids.
Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has an approximately 200-fold higher affinity for the glucocorticoid receptor and a 1,000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay. The precise mechanism of corticosteroid actions on inflammation in asthma is not well known. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (eg, histamine, eicosanoids, leukotrienes, cytokines) involved in allergic and nonallergic-mediated inflammation.
The anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide dose range of inhaled budesonide in a variety of formulations and delivery systems including budesonide inhalation-driven, multi-dose dry powder inhaler and the inhalation suspension for nebulization. This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first-pass hepatic degradation of orally absorbed drug (85% to 95%), and the low potency of metabolites.
The therapeutic effects of conventional doses of orally inhaled budesonide are largely explained by its direct local action on the respiratory tract. To confirm that systemic absorption is not a significant factor in the clinical efficacy of inhaled budesonide, a clinical study in adult patients with asthma was performed comparing 400 mcg budesonide administered via a pressurized metered dose inhaler with a tube spacer to 1,400 mcg of oral budesonide and placebo. The study demonstrated the efficacy of inhaled budesonide but not orally ingested budesonide despite comparable systemic levels. Improvement in the control of asthma symptoms following inhalation of budesonide inhalation suspension can occur within 2 to 8 days of beginning treatment, although maximum benefit may not be achieved for 4 to 6 weeks. The effects of budesonide inhalation suspension on the hypothalamic-pituitary-adrenal (HPA) axis were studied in three, 12-week, double-blind, placebo-controlled studies in 293 children, 6 months to 8 years of age, with persistent asthma. For most patients, the ability to increase cortisol production in response to stress, as assessed by the short cosyntropin (ACTH) stimulation test, remained intact with budesonide inhalation suspension treatment at recommended doses. In the subgroup of children age 6 months to 2 years (n = 21) receiving a total daily dose of budesonide inhalation suspension equivalent to 0.25 mg (n = 5), 0.5 mg (n = 5), 1 mg (n = 8), or placebo (n = 3), the mean change from baseline in ACTH-stimulated cortisol levels showed a decline in peak stimulated cortisol at 12 weeks compared to an increase in the placebo group. These mean differences were not statistically significant compared to placebo. Another 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. A total of 28, 17, and 31 patients in the budesonide inhalation suspension 0.5 mg, 1 mg, and placebo arms respectively, had an evaluation of serum cortisol levels post-ACTH stimulation both at baseline and at the end of the study. The mean change from baseline to week 12 ACTH-stimulated minus basal plasma cortisol levels did not indicate adrenal suppression in patients treated with budesonide inhalation suspension versus placebo. However, 7 patients in this study (4 of whom received budesonide inhalation suspension 0.5 mg, 2 of whom received budesonide inhalation suspension 1 mg and 1 of whom received placebo) showed a shift from normal baseline stimulated cortisol level (greater than or equal to 500 nmol/L) to a subnormal level (less than 500 nmol/L) at week 12. In 4 of these patients receiving budesonide inhalation suspension, the cortisol values were near the cutoff value of 500 nmol/L.
The effects of budesonide inhalation suspension at doses of 0.5 mg twice daily, and 1 mg and 2 mg twice daily (2 times and 4 times the highest recommended total daily dose, respectively) on 24-hour urinary cortisol excretion were studied in 18 patients between 6 to 15 years of age with persistent asthma in a cross-over study design (4 weeks of treatment per dose level). There was a dose-related decrease in urinary cortisol excretion at 2 and 4 times the recommended daily dose. The 2 higher doses of budesonide inhalation suspension (1 and 2 mg twice daily) showed statistically significantly reduced (43% to 52%) urinary cortisol excretion compared to the run-in period. The highest recommended dose of budesonide inhalation suspension, 1 mg total daily dose, did not show statistically significantly reduced urinary cortisol excretion compared to the run-in period.
Budesonide inhalation suspension, like other inhaled corticosteroid products, may impact the HPA axis, especially in susceptible individuals, in younger children, and in patients given high doses for prolonged periods.
Pharmacokinetics: Absorption: After a single dose of 1 mg budesonide, a peak plasma concentration of 2.6 nmol/L was obtained approximately 20 minutes after nebulization in asthmatic children 4 to 6 years of age. The exposure (AUC) of budesonide following administration of a single 1 mg dose of budesonide by nebulization to asthmatic children 4 to 6 years of age is comparable to healthy adults given a single 2 mg dose by nebulization. In asthmatic children 4 to 6 years of age, the total absolute bioavailability (ie, lung + oral) following administration of budesonide inhalation suspension via jet nebulizer was approximately 6% of the labeled dose. The peak plasma concentration of budesonide occurred 10 to 30 minutes after start of nebulization.
Distribution: In asthmatic children 4 to 6 years of age, the volume of distribution at steady-state of budesonide was 3 L/kg, approximately the same as in healthy adults. Budesonide is 85% to 90% bound to plasma proteins, the degree of binding being constant over the concentration range (1 to 100 nmol/L) achieved with, and exceeding, recommended doses. Budesonide showed little or no binding to corticosteroid-binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of approximately 0.8.
Metabolism: In vitro studies with human liver homogenates have shown that budesonide is rapidly and extensively metabolized. Two major metabolites formed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzed biotransformation have been isolated and identified as 16-hydroxyprednisolone and 6ß-hydroxybudesonide. The corticosteroid activity of each of these 2 metabolites is less than 1% of that of the parent compound. No qualitative difference between the in vitro and in vivo metabolic patterns have been detected. Negligible metabolic inactivation was observed in human lung and serum preparations. The activity of budesonide is due to the parent drug, budesonide. In glucocorticoid receptor affinity studies, the 22R form was 2 times as active as the 22S epimer. In vitro studies indicated that the 2 forms of budesonide do not interconvert.
Budesonide is primarily cleared by the liver. In asthmatic children 4 to 6 years of age, the terminal half-life of budesonide after nebulization is 2.3 hours, and the systemic clearance is 0.5 L/min, which is approximately 50% greater than in healthy adults after adjustment for differences in weight.
Excretion: Budesonide is excreted in urine and feces in the form of metabolites. In adults, approximately 60% of an intravenous radiolabeled dose was recovered in the urine. No unchanged budesonide was detected in the urine.
Special Populations: Hepatic Function Impairment: Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The IV pharmacokinetics of budesonide were, however, similar in cirrhotic patients and in healthy adults.
Children: Following IV dosing in children age 10 to 14 years, plasma half-life was shorter than in adults (1.5 hours vs 2 hours in adults). In the same population following inhalation of budesonide via a pressurized metered-dose inhaler, absolute systemic availability was similar to that in adults.
No pharmacokinetic differences have been identified due to race, gender, or age.
Toxicology: Preclinical Safety Data: The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticosteroids studied (beclomethasone dipropionate, fluocinolone acetonide).
Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than, or similar to, those observed after administration of the other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.
For the maintenance treatment of bronchial asthma as prophylactic therapy.
Aeronide 200 mcg is for oral inhalation use only.
General dosing considerations: In all patients, it is desirable to downward-titrate to the lowest effective dose once asthma stability is achieved. The improvement in asthma control following inhaled administration can occur within 2 to 8 days of initiation of treatment, although maximum benefit may not be achieved for 1 to 2 weeks.
The maximum dose in children is 1 mg/day.
Budesonide can be administered once daily either in the morning or in the evening. Gently shake the inhalation suspension using a circular motion before use.
The safety and efficacy of budesonide inhalation suspension when administered in excess of recommended doses have not been established. In children 6 months to 8 years of age should not be administered the excess of the recommended dose.
If deterioration in asthma occurs, the frequency of daily dosing and / or the total dose of budesonide may need to be increased.
Improvement in asthma control following inhaled administration can occur within 24 hours of initiation of treatment, although maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.
Concomitant therapy with oral corticosteroids: For patients who are maintained on chronic oral corticosteroids, the usual maintenance dose should be used concurrently with the initial budesonide therapy. After approximately 1 week, gradual withdrawal of the systemic corticosteroid is started by reducing the daily or alternate daily dose. The next reduction is made after 1 or 2 weeks, depending on the response of the patient. Generally, these decrements should not exceed 25% of the prednisone dose or its equivalent. A slow rate of withdrawal is strongly recommended. During reduction of oral corticosteroids, patients should be carefully monitored for asthma instability, including objective measures of airway function, and for adrenal insufficiency. During withdrawal, some patients may experience symptoms of systemic corticosteroid withdrawal (eg, joint or muscular pain, lassitude, depression) despite maintenance or even improvement in pulmonary function. Such patients should be encouraged to continue with budesonide but should be monitored for objective signs of adrenal insufficiency. If evidence of adrenal insufficiency occurs, the systemic corticosteroid doses should be increased temporarily, and thereafter withdrawal should continue more slowly. During periods of stress or a severe asthma attack, transfer patients may require supplementary treatment with systemic corticosteroids.
Admixture compatibility: The effects of mixing Aeronide 200 mcg with other nebulizable medications have not been adequately assessed. Administer separately in the nebulizer.
Elderly: No dosage adjustment is necessary for elderly patients.
Hepatic function impairment: Exercise caution when administering to patients with hepatic impairment.
Patients not receiving systemic (oral) corticosteroids: Patients who require maintenance therapy of asthma may benefit from treatment with Aeronide 200 mcg at the doses recommended. For patients who do not respond adequately to the starting dose, consideration should be given to administering the total daily dose as a divided dose if a once-daily dosing schedule was followed. If necessary, higher doses, up to the maximum recommended doses, may provide additional asthma control.
Asthma: Children 1-8 years of age: Recommended Dosages in Children 1-8 years of age: See Table 1.
Click on icon to see table/diagram/image
Dosage adjustment: If once-daily treatment does not provide adequate control of asthma symptoms, the total daily dose should be increased or administered as a divided dose.
Symptomatic children not responding to nonsteroidal therapy (e.g., bronchodilator, mast-cell stabilizer): A starting dose of 200 mcg once daily may also be considered.
Children 7 years of age and above: Recommended dose is 200 to 800 mcg daily in divided into 2 to 4 administrations.
In children with mild to moderate asthma who have not previously received inhaled glucocorticosteroids, or who are already controlled on inhaled steroids (e.g. budesonide or beclomethasone dipropionate): 200 to 400 mcg daily may be used in divided into 2 administrations.
During periods of severe asthma, the daily dose can be increased up to 800 mcg.
Adults and children over 12 years of age: Recommended dose is 200 to 1600 mcg daily divided into 2 to 4 administrations.
In less severe cases 200 to 800 mcg daily (200 to 400 mcg may be used in patients with mild to moderate asthma who have not previously received inhaled glucocorticosteroids and up to 800 mcg may be used by patients with mild to moderate asthma already controlled on inhaled steroids e.g. budesonide or beclomethasone dipropionate, administered twice daily.)
In more severe cases 800 to 1600 mcg daily. Administration twice daily (morning and evening) is usually sufficient. In severe asthma and during exacerbations some patients may benefit from dividing the daily dose into 3 to 4 administrations per day. In mild asthmatics requiring up to 400 mcg daily for symptom control, the dose could be given once daily in the morning or in the evening.
The maintenance dose should be individualised and should be the lowest dose which leaves the patient symptom-free. Recommended doses are 100 to 400 mcg/daily. This may be given as a twice daily dose, or as a once daily dose given in the morning or the evening.
The potential for acute toxic effects following overdose of budesonide inhalation is low. If inhaled corticosteroids are used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism or growth suppression may occur.
In mice the minimal lethal inhalation dose was 100 mg/kg (approximately 410 or 120 times, respectively, the maximum recommended daily inhalation dose in adults or children on a mg/m2 basis). In rats there were no deaths at an inhalation dose of 68 mg/kg (approximately 550 or 160 times, respectively, the maximum recommended daily inhalation dose in adults or children on a mg/m2 basis). In mice the minimal oral lethal dose was 200 mg/kg (approximately 810 or 240 times, respectively, the maximum recommended daily inhalation dose in adults or children on a mg/m2 basis). In rats, the minimal oral lethal dose was less than 100 mg/kg (approximately 810 or 240 times, respectively, the maximum recommended daily inhalation dose in adults or children on a mg/m2 basis).
Sign and Symptoms: The only harmful effect that follows inhalation of large amounts of the drug over a short period is suppression of hypothalamic-pituitary-adrenal (HPA) function. No special emergency action needs to be taken.
Treatment: Treatment should be continued at the recommended dose to control the asthma.
Hypersensitivity to budesonide or any of the ingredients in its preparations.
Budesonide is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.
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.
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.
Special caution is necessary in patients with active or quiescent pulmonary tuberculosis, and in patients with fungal or viral infections in the airways.
Non steroid-dependent patients: A therapeutic effect is usually reached within 10 days. In patients with excessive mucus secretion in the bronchi, a short (about 2 weeks) additional oral corticosteroid regimen can be given initially.
Steroid-dependent patients: When transferral from oral steroids to Aeronide 200 mcg is started, the patient should be in a relatively stable phase. A high dose of Aeronide 200 mcg is then given in combination with the previously used oral steroid dose for about 10 days. After that, the oral steroid dose should be gradually reduced (by for example 2.5 milligrams prednisolone or the equivalent each month) to the lowest possible level. In many cases, it is possible to completely substitute Aeronide 200 mcg for the oral steroid.
During transfer from oral therapy to Aeronide 200 mcg, a generally lower systemic steroid action will be experienced which may result in the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiated for these conditions. During the withdrawal of oral steroids, patients may feel unwell in a non-specific way, even though respiratory function is maintained or improved. Patients should be encouraged to continue with Aeronide 200 mcg therapy whilst withdrawing the oral steroid, unless there are clinical signs to indicate the contrary. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of oral glucocorticosteroids is sometimes necessary.
As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. If a severe reaction occurs, treatment should be reassessed and an alternative therapy instituted if necessary.
Patients who have previously been dependent on oral steroids may, as a result of prolonged systemic steroid therapy, experience the effects of impaired adrenal function. Recovery may take a considerable amount of time after cessation of oral steroid therapy, hence oral steroid-dependent patients transferred to budesonide may remain at risk from impaired adrenal function for some considerable time. In such circumstances, HPA axis functions should be monitored regularly.
Acute exacerbations of asthma may need an increase in the dose of Aeronide 200 mcg or additional treatment with a short course of oral corticosteroid and/or an antibiotic, if there is an infection. The patient should be advised to use a short-acting inhaled bronchodilator as rescue medication to relieve acute asthma symptoms.
If patients find short-acting bronchodilator treatment ineffective or they need more inhalations than usual, medical attention must be sought. In this situation consideration should be given to the need for or an increase in their regular therapy, e.g., higher doses of inhaled budesonide or the addition of a long-acting beta agonist, or for a course of oral glucocorticosteroid.
Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than the recommended doses, may result in clinically significant adrenal suppression. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery. These patients should be instructed to carry a steroid warning card indicating their needs. Treatment with supplementary systemic steroids or Aeronide 200 mcg should not be stopped abruptly.
Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids. Possible systemic effects include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma. It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.
It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.
Reduced liver function may affect the elimination of glucocorticosteroids. The plasma clearance following an intravenous dose of budesonide however was similar in cirrhotic patients and in healthy subjects. After oral ingestion systemic availability of budesonide was increased by compromised liver function due to decreased first pass metabolism. The clinical relevance of this to treatment with the drug is unknown as no data exist for inhaled budesonide, but increases in plasma levels and hence an increased risk of systemic adverse effects could be expected.
In vivo studies have shown that oral administration of ketoconazole and itraconazole (known inhibitors of CYP3A4 activity in the liver and in the intestinal mucosa) causes an increase in the systemic exposure to budesonide. Concomitant treatment with ketoconazole and itraconazole or other potent CYP3A4 inhibitors should be avoided. If this is not possible, the time interval between administration of the interacting drugs should be as long as possible. A reduction in the dose of budesonide should also be considered.
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.
Pregnancy: Pregnancy Category B: Teratogenic Effects: As with other corticosteroids, budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at SC doses of 25 mcg/kg/day in rabbits (less than the maximum recommended daily inhalation dose in adults on a mcg/m2 basis) and 500 mcg/kg/day in rats (approximately 4 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis). In another study in rats, no teratogenic or embryocidal effects were seen at inhalation doses up 250 mcg/kg/day (approximately 2 times the maximum recommended daily inhalation dose in adults on a mcg/m2 basis).
Experience with oral corticosteroids in pharmacologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans. In addition, because there is a natural increase in corticosteroid production during pregnancy, most women will require a lower exogenous corticosteroid dose and many will not need corticosteroid treatment during pregnancy.
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 3 Swedish registries covering approximately 99% of the pregnancies from 1995 to 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 2,014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10 to 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 2,534 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%).
Despite the animal findings, it would appear that the possibility of fetal harm is remote if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, budesonide inhalation should be used during pregnancy only if clearly needed.
Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully observed.
Lactation: It is not known whether budesonide is excreted in human milk. Because other corticosteroids are excreted in human milk, caution should be exercised if budesonide is administered to nursing women.
The following adverse reactions were reported in children treated with budesonide inhalation suspension. The incidence of common adverse reactions is based on 3 double-blind, placebo-controlled, US clinical trials in which 945 patients, 12 months to 8 years of age, (98 patients greater than or equal to 12 months and less than 2 years of age; 225 patients greater than or equal to 2 and less than 4 years of age; and 622 patients greater than or equal to 4 and less than or equal to 8 years of age) were treated with budesonide inhalation suspension (0.25 to 1 mg total daily dose for 12 weeks) or vehicle placebo. The incidence and nature of adverse reactions reported for budesonide inhalation suspension was comparable to that reported for placebo. The following table shows the incidence of adverse reactions in US controlled clinical trials, regardless of relationship to treatment, in patients previously receiving bronchodilators or inhaled corticosteroids. This population included a total of 605 male and 340 female patients. (See Table 2.)
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The table shows all adverse reactions with an incidence of greater than or equal to 3% in at least 1 active treatment group where the incidence was higher with budesonide inhalation suspension than with placebo.
The following adverse reactions occurred with an incidence of greater than or equal to 3% in at least 1 budesonide inhalation suspension group where the incidence was equal to or less than that of the placebo group: Fever, sinusitis, pain, pharyngitis, bronchospasm, bronchitis, and headache.
Adverse reaction incidence of 1% to less than or equal to 3% (by body system) for inhalation suspension: The information below includes all adverse reactions with an incidence of 1 to less than or equal to 3%, in at least 1 budesonide inhalation suspension treatment group where the incidence was higher with budesonide inhalation suspension than with placebo, regardless of relationship to treatment.
CNS: Dysphonia; hyperkinesias.
Dermatologic: Eczema; pustular rash; pruritus; contact dermatitis.
Hematologic: Purpura; cervical lymphadenopathy.
Musculoskeletal: Fracture; myalgia.
Ophthalmic: Eye infection.
Psychiatric: Anorexia; emotional lability.
Respiratory: Stridor.
Special senses: Earache.
Miscellaneous: Allergic reaction; chest pain; fatigue; flu-like disorder; herpes simplex; external ear infection; infection.
In clinical studies, concurrent administration of budesonide and other drugs commonly used in the treatment of asthma has not resulted in an increased frequency of adverse reactions. The main route of metabolism of budesonide, as well as other corticosteroids, 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 (eg, itraconazole, clarithromycin, erythromycin) may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Care should be exercised when budesonide is coadministered with long-term ketoconazole and other known CYP3A4 inhibitors.
Omeprazole did not have effects on the pharmacokinetics of oral budesonide, while cimetidine, primarily an inhibitor of CYP1A2, caused a slight decrease in budesonide clearance and a corresponding increase in its oral bioavailability.
Handling Precaution: Avoid spraying in eyes.
Contents under pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 50°C may cause bursting. never throw container into fire or incinerator.
Store the inhaler with mouthpiece down. For best results, the inhaler should be at room temperature before use. SHAKE WELL BEFORE EACH SPRAY.
It does not contain chlorofluorocarbons (CFCs) as the propellant.
Store below 30°C. Keep in tight containers, protected from light.
R03BA02 - budesonide ; Belongs to the class of other inhalants used in the treatment of obstructive airway diseases, glucocorticoids.
Aeronide 200 MDI 200 mcg/dose
(CFC-free) 200 dose x 1's
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